US20070287194A1 - Screening For Solid Forms By Ultrasound Crystallization And Cocrystallization Using Ultrasound - Google Patents

Abstract

The present disclosure relates to crystallizing a chemical substance(s) using ultrasound. Methods are provided for screening a chemical substance according to its solid forms by using ultrasound to generate new or unusual solid forms. Methods are also provided for crystallizing a chemical substance by novel techniques that include sonication. The present disclosure also relates to cocrystallization using ultrasound. Methods are provided for preparing cocrystals of an active agent and a guest by sonicating and crystallizing. Methods are also provided for screening a sample according to solid state phases (such as cocrystals and salts) and include generating a cocrystal from the sample using ultrasound.

Description

FIELD OF THE INVENTION
• The present disclosure relates to crystallizing a chemical substance using ultrasound. Methods are provided for screening a chemical substance according to its solid forms by using ultrasound to generate new or unusual solid forms. Methods are also provided for crystallizing a chemical substance by novel techniques that include sonication. The present disclosure also relates to cocrystallization using ultrasound. Methods are provided for preparing cocrystals of an active agent and a guest by sonicating and crystallizing. Methods are also provided for screening a sample according to solid state phases (such as cocrystals and salts) and include generating a cocrystal from the sample using ultrasound.
BACKGROUND OF THE INVENTION
• Chemical substances (compounds, elements, and mixtures) have properties which tend to be unpredictable and variable. Certain chemical substances may have utility for numerous different applications, including vital biological applications, yet a slight change may reduce or eliminate the utility or beneficial purpose. Similarly, certain chemical processes may have better or worse performance based upon minor differences.
• An active agent may be provided in a variety of solid state phases. For example, it may be provided as a crystal of the pure compound. Alternatively, the active agent may be provided as a salt. Alternatively, the active agent may be provided as a cocrystal with another compound.
• Cocrystals are crystals that contain two or more non-identical components (for example, two non-identical molecules). The properties of cocrystals may be the same or different than the properties of the individual components or mixtures of crystals of the individual components. Examples of cocrystals may be found in the Cambridge Structural Database. Examples of cocrystals may also be found at Etter et al., “The use of cocrystallization as a method of studying hydrogen bond preferences of 2-aminopyridine”J. Chem. Soc., Chem. Commun.589-591 (1990); Etter, et al., “Graph-set analysis of hydrogen-bond patterns in organic crystals”Acta Crystallogr., Sect. B, Struct. Sci. B46 256-262 (1990); Etter, et al., “Hydrogen bond directed cocrystallization and molecular recognition properties of diarylureas”J. Am. Chem. Soc112 8415-8426 (1990); which are incorporated herein by reference in their entireties. The following articles are also incorporated herein by reference in their entireties: Görbotz, et al., “On the inclusion of solvent molecules in the crystal structures of organic compounds” Acta Cryst. B56 625-534 (2000); and Kumar, et al., “Molecular Complexes of Some Mono- and Dicarboxylic Acids with trans-1,4,-Dithiane-1,4-dioxide” American Chemical Society, Crystal Growth & Design, Vol. 2, No. 4 (2002). Additional information and details regarding cocrystallization may be found in U.S. application Ser. No. 10/763,987, “Novel Cocrystallization,” filed Jan. 21, 2004, which is incorporated by reference herein.
• A salt is a compound formed when the hydrogen of an acid is replaced by a metal or its equivalent (e.g., an NH₄⁺ radical). Hawley's Condensed Chemical Dictionary, p. 977 (14^thEd. 2001). In a salt one or more ionic bonds are formed. In a cocrystal, two or more compounds retain their own chemical identities, and no new ionic or covalent bonds are formed, although hydrogen bonds or other interactions may hold different compounds to each other.
• The identification of a desirable solid state phase for an active agent is important in the pharmaceutical field, as well as in other fields including nutraceuticals, agricultural chemicals, dyes, explosives, polymer additives, lubricant additives, photographic chemicals, and structural and electronic materials.
• In particular, the pharmaceutical industry spends a great deal of time, effort and expense on the identification of particular compounds, mixtures and formulations that will have beneficial effect. Research is done as to whether such compounds, mixtures and formulations will be safe and effective. Slight differences in chemical composition or structure may yield significant differences in biological activity. Thus, researchers frequently test many different compounds, mixtures and formulations for biological activity and other effects as well as testing different processes and conditions for the preparation of such chemical compounds and mixtures.
• The process of thorough analysis of different chemical compounds, mixtures, formulations, processes, or structures is commonly referred to as screening. Screening is partially a function of time and effort, with the quality or results of screening being related to the number of samples prepared and/or analyzed as well as the quality of preparation and/or analysis underlying those samples. To that end, it is frequently an objective with screening processes to increase the number of samples and decrease the amount of each sample used for analysis. Screening plays a vital role in the pharmaceutical field, as the most advantageous compound, mixture or formulation is frequently found through successful screening processes.
• In some screening processes, variations are introduced in order to see the result(s), if any, of such variations, or to confirm that variations do not lead to substantially different results. Generally, at least two samples of a screened chemical substance (in other words, a compound, element, or mixture that is the subject of the screening process) are subjected to differing parameters, and one or more properties of the samples are determined to see whether the differing parameters caused different results.
• Processes have been used for screening chemical compounds according to their solid form. When a compound has different solid forms, the different forms are frequently referred to as polymorphs of that compound. A polymorphic compound as used herein means a compound having more than one solid form. For example, a polymorphic compound may have different forms of its crystalline structure, or it may exist as different hydrates or solvates.
• The solid form of a chemical substance may have an impact on biological activity. The same chemical compound may exhibit different properties depending upon whether it is in an amorphous, crystalline or semisolid state. A semisolid as used herein indicates materials like waxes, gels, creams, and ointments. Furthermore, a chemical compound may exist in different solid forms within the different states, and those different solid forms may also exhibit different properties. For example, there may be several different crystalline solid forms of a substance, the different crystalline solid forms having different properties. As another example, a substance may have different amorphous forms, the amorphous forms having different properties. As a result, different solid forms, including different crystalline forms, of a chemical compound may have greater or lesser efficacy for a particular application. The identification of an optimal solid form, or other possible solid forms, is important in the pharmaceutical field, as well as in other fields including nutraceuticals, agricultural chemicals, dyes, explosives, polymer additives, lubricant additives, photographic chemicals, and structural and electronic materials.
• It is desirable in the pharmaceutical field as well as other fields to find the solid form of a chemical substance that exhibits desired physical and chemical properties. One form may be more stable or have other properties that make it preferable over other forms. One form of a chemical composition may have better bioavailabilty, solubility, or absorption characteristics or in other ways be more suitable for delivery of therapeutic doses than other forms. It is frequently desirable within a screening process to generate, or at least search for, all or most of the possible solid forms of a compound. Past attempts to generate a variety of solid forms included flash evaporations, cooling under different conditions and/or the addition of seeds of solid material. However, some materials strongly resist the generation of some of their possible solid forms.
• It is desirable in many fields to find a solid state phase of an active agent that exhibits desired physical and chemical properties. One solid state phase may be more stable or have other properties that make it preferable over other solid state phases. One solid state phase may have better bioavailabilty, solubility, or absorption characteristics or in other ways be more suitable for delivery of therapeutic doses than other forms. It is frequently desirable within a screening process to generate, or at least search for, all or most of the possible solid state phases of a compound.
• One or more solid forms may be generated by crystallization of a sample. One or more solid state phases may be generated by cocrystallization of a chemical substance with different guest molecule(s).
• Among the phenomena in crystallization are nucleation and growth. Crystal nucleation is the formation of an ordered solid phase from liquids, supersaturated solutions, saturated vapors, or amorphous phases. Growth is the enlargement of crystals caused by deposition of molecules on an existing surface.
• Nucleation may be induced by the presence of “seed” crystals. Some solid particle is present to provide a catalytic effect and reduce the energy barrier to formation of a new phase. Crystals may originate on a minute trace of a foreign substance (either impurities or container walls) acting as a nucleation site. Nucleation may also be promoted by external or nonchemical means, such as stirring the crystallization environment, or by applying ultrasound to the crystallization environment.
• As mentioned above, ultrasound has been applied to promote nucleation. For example, U.S. Pat. No. 6,630,185 discusses a process for the crystallization of a solid phase from a liquid, characterized in that the liquid during crystallization is subjected to ultrasound in the absence of transient cavitation. According to this patent, it has been known since 1927 that exposing supercooled melts or supersaturated solutions of various substances to ultrasound has an influence on the nucleation and/or the growth of crystals. The effect is referred to as sonocrystallisation. A particular aspect of sonocrystallisation is sononucleation. It deals with the initiation of crystal formation, has been studied extensively with sugar and is applied since the late 1950's. Sonocrystallisation of supercooled water, supercooled metal melts and supersaturated solutions of various inorganic materials are said to have received a lot of attention.
• U.S. Patent Application Publication No. 20030051659 A1 discusses a process for crystallizing small particles with a narrow particle size distribution. The crystals are obtained by introducing ultrasound into a solution or suspension of the substance to be crystallized while simultaneously adjusting a specific stirring power. U.S. Patent Application Publication No. 20030166726 A1 discusses a method for reducing the particle size of amino acid crystals using ultrasound.
• U.S. Patent Application Publication No. 20020054892 A1 discusses a method of inducing solidification in a fluid composition comprising a cosmetic active, a crystalline organic structurant and a carrier. The method comprises exposing the fluid composition to ultrasound or converting the composition to a soft solid.
• U.S. Pat. No. 5,830,418 discusses a method of using ultrasound to promote crystallization of solid substances contained in a flowable material. A flowable material, such as a supercooled melt or supersaturated solution, is dispensed onto a take-up member such as a belt or drum. Either prior to, or after being dispensed onto the take-up member, the material is exposed to ultrasound to promote the crystallization of solid substances in the material.
• None of the foregoing references discloses the use of ultrasound as a variable parameter in a screening method to identify the various solid forms of a chemical substance.
• There is a continued need to improve screening methods that identify all or a high percentage of possible forms of a chemical substance. There is also a need for improved methods of selectively generating the desired form of a chemical substance.
• There is a continued need to improve screening methods that identify all or a high percentage of possible solid state phases of a chemical substance. There is also a need for improved methods of selectively generating solid state phases, including cocrystals, of a chemical substance.
SUMMARY OF THE INVENTION
• As one aspect, a method is provided for screening a chemical substance for possible solid forms. The method comprises the steps of providing a chemical substance in a plurality of samples, sonicating at least one of the samples, and solidifying the chemical substance from the samples. The samples will usually be provided as a solution, suspension, melt, or other mixture of the chemical substance in one or more solvents. The screening method may comprise providing a first sample of the chemical substance in a first solvent, and a second sample of the chemical substance in a second solvent. The method may also comprise determining whether one or more solid forms of the chemical substance were generated.
• As another aspect, a method is provided for crystallizing a chemical substance. This method is beneficial for searching for and/or generating new or unusual solid forms of a chemical substance. The method comprises forming an emulsion comprising two or more substantially immiscible solvents and the chemical substance by applying ultrasound to a mixture of said solvents and the chemical substance. The chemical substance is in solution in one or both of the solvents. The method also comprises crystallizing the chemical substance from the emulsion.
• As yet another aspect, a method of crystallizing a chemical substance is provided. The method comprising the steps of providing a sample of the chemical substance in a solvent, sonicating the solution or suspension at a predetermined supersaturation level, and crystallizing the chemical substance from the sample.
• As another aspect, a method is provided for generating the most stable form of a chemical substance. The method comprises the steps of providing a sample of the chemical substance in a solvent, sonicating the sample at a predetermined supersaturation level, and crystallizing the chemical substance from the sample, and the crystallized chemical substance is the most stable solid form of the chemical substance relative to known solid forms of the chemical substance.
• As a further aspect, a method is provided for generating a solid form of a chemical substance from a metastable solution (a solution in which the chemical substance remains in solution indefinitely or for relatively long periods). The method comprises forming a metastable solution of the chemical substance in a solvent, sonicating the metastable solution, and crystallizing the chemical substance from the solution.
• As yet another aspect, a method is provided for obtaining a substantially pure solid form of a chemical substance. A substantially pure solid form of a chemical substance is a solid that is exclusively or almost exclusively of one solid form or has little or no other solid forms present. The method comprises the steps of providing a sample of the chemical substance in a solvent, sonicating the sample at a predetermined supersaturation level, and crystallizing the chemical substance from the sample, wherein a substantially pure solid form of the chemical substance is crystallized.
• As another aspect, a method is provided for preparing a solvate of a chemical substance. The method comprises the steps of providing a sample comprising the chemical substance and a solvent, sonicating the sample, and generating a solid from the sample, wherein the solid comprises a solvate of the chemical substance and the solvent.
• In the present methods, the solidifying step and the sonicating step may at least partially overlap. In some embodiments, the solidifying step and the sonicating step may overlap completely or almost completely. For example, where the solidifying step comprises evaporating a solvent from the samples, the method can comprise sonicating at least one of the samples until the solvent is substantially completely evaporated. Alternatively, the solidifying step can comprise at least partially evaporating the solvent from at least one of the samples before sonicating the sample.
• In the present methods, a solvent can be evaporated (to a greater or lesser extent) from at least one of the samples before, during, or after the sonicating step. The present methods may comprise the step of cooling at least one of the samples before, during or after the sonicating step. The present methods may comprise the step of crash-cooling at least one of the samples before, during or after the sonicating step. The present methods may comprise a mixture of those actions, for example, the samples may be cooled followed by sonication and evaporation of the solvent.
• The sample(s) can be sonicated by sonicating at least once or more than once. In some embodiments, the samples will be sonicated by ultrasound pulses. For example, one or more samples can be sonicated by at least one ultrasound pulse, or by at least 5 ultrasound pulses, or by any number of periodic ultrasound pulses. In some embodiments, the samples will be sonicated for a period of time. For example, one or more samples may be sonicated for about 5 to about 40 seconds, for at least about 5 minutes, or for another suitable time period.
• In the present methods, one or more samples may be sonicated at least once during the solidification step. In some embodiments, sonication will be substantially continuous during the solidification step; in other embodiments, sonication will be periodic during the solidification step.
• The present methods may also be employed to generate solid solvates and solid hydrates of the chemical substance.
• In the present methods, a predetermined supersaturation level of the chemical substance in a solvent may be selected at which to begin sonication. For example, the predetermined supersaturation level may be selected to generate a relatively stable form of the chemical substance, or the most stable form of the chemical substance, as determined by comparison of the known solid forms of the chemical substance. The predetermined supersaturation level can be selected to generate a solvate of the chemical substance.
• The present methods may comprise adding an antisolvent to a solution, suspension, emulsion, slurry or other composition of matter.
• The present methods increase the likelihood of generating all or a high percentage of possible solid forms of a chemical substance.
• As another aspect of the present invention, a method is provided for screening for possible cocrystals comprising an active agent. The method comprises the steps of providing a plurality of samples that contain the active agent. Each sample also contains at least one guest. It is contemplated that the samples may contain the same guest or a different guest. In a screening method, the samples will usually contain several different guests being used to evaluate different cocrystals (different solid state phases). The samples are sonicated, and the active agent and the guest are crystallized from the samples. The method comprises determining whether a cocrystal was generated in one or more of the samples. The method can also comprise analyzing the crystallized samples to determine one or more properties.
• As another aspect, a method is provided for preparing a cocrystal comprising an active agent and a guest. The method comprises providing a sample of an active agent and a guest. The sample is sonicated, and a cocrystal of the active agent and the guest is crystallized from the sample.
• As yet another aspect, a method is provided for screening for possible solid state phases, including salts, of an ionizable active agent and a counterion and optionally a guest. The method comprises providing an ionizable active agent and a counterion in a plurality of samples. An ionizable agent is an agent that can be ionized or has already been ionized; an ionizable agent is one that can be used to forming an ionic bond with a counterion. The samples are sonicated, and the ionizable active agent and the counterion form a salt and crystallize from the samples. The method further comprises determining whether a salt was generated in one or more of the samples.
• As yet another aspect, a method is provided for screening for possible salts comprising an ionizable active agent. The method comprises providing a plurality of samples comprising an ionizable active agent and one or more counterions. The samples are sonicated, and one or more crystallized salt compounds are formed from the samples. The crystallized salt compounds comprise the ionizable active agent and the counterions. The plurality of samples may contain the same or different counterions. For example, at least one sample may contain a different counterion than at least one other sample. As another example, the plurality of samples can comprise a plurality of sets, where the sets differ in having different counterions, and the samples within each set have the same counterion.
• The present techniques may be utilized in methods for screening an ionizable active agent according to its possible solid state phases, including cocrystals and/or salts. Such methods can comprise providing an ionizable active agent and one or more counterions in a plurality of samples, sonicating the sample(s), and forming a crystallized salt compound comprising the active agent and counterion. Suitable counterions include but are not limited to the cations or anions set forth in the present disclosure. Using the present techniques provides a greater likelihood of generating possible salts of the ionizable active agent. Moreover, a salt developed by such a method may be employed in connection with the methods described herein which relate to cocrystals comprising a salt and a guest.
• As yet another aspect, a method is provided for cocrystallizing two or more components, such as an active agent and a guest. The method comprises determining a concentration for two or more components in a sample effective for cocrystallization of the components. A sample is prepared which comprise the components, in an effective volume and an effective concentration. The sample is sonicated and a cocrystal is generated from the sample. The cocrystal comprises the components.
• The present methods may be used to form at least one new solid state phase of an active agent, including new solid state phases of active pharmaceutical ingredients. This can provide substantial benefits to the pharmaceutical industry and the public at large.
• In the foregoing methods, the sonicating step and the crystallizing step will usually overlap at least partially. The samples may become supersaturated with respect to at least one of the active agent and the guest before, during or after the sonicating step. In the present methods, each of the samples may comprise more than one solvent, more than one active agent, and/or more than one guest.
BRIEF DESCRIPTION OF THE FIGURES
• FIG. 1 is an x-ray powder diffraction (XRPD) pattern of sulfathiazole solidified from an acetonitrile solution which was sonicated.
• FIG. 2 is an XRPD pattern of sulfathiazole solidified from an acetonitrile solution which was not sonicated.
• FIG. 3 is an XRPD pattern of sulfathiazole solidified from an acetone solution which was sonicated.
• FIG. 4 is an XRPD pattern of sulfathiazole solidified from an acetone solution which was not sonicated.
• FIG. 5 is an XRPD pattern of carbamazepine solidified from a DMSO solution which was sonicated.
• FIG. 6 is an XRPD pattern of sulfathiazole solidified from a methylethylketone solution which was sonicated.
• FIG. 7 is an XRPD pattern of sulfathiazole solidified from an ethanol/p-cymene emulsion.
• FIGS.8(a) and (b) illustrate a crystal structure of an active agent and a cocrystal structure containing the same active agent with a guest.
• FIGS.9 (a) and (b) are drawings of two-dimensional and three-dimensional models of a cocrystal of fluoxetine HCl and benzoic acid (1:1).
• FIG. 10 shows examples of general classes of guests.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
• Ultrasound generally refers to sound vibrations beyond the limit of audible frequencies. Ultrasound is often used to refer to sound vibrations having a frequency of about 20 kHz or more. In many applications where ultrasound is used, the frequencies are in the range of 20 kHz to 5 MHz. However, the definition of ultrasound as having a frequency greater than 20 kHz is related to the average perception limit of the human ear rather than to industrial applications. The benefits of the present methods may be obtained with frequencies below 20 kHz. In the context of the present specification, ultrasound refers to sound vibrations having a frequency in the range of from about 10 kHz to about 10 MHz. However, for certain applications, ultrasound having frequencies in narrower ranges (such as, for example, from about 20 kHz to about 5 MHz or from about 40 kHz to about 2.5 MHz) may be desired.
• The terms sonicate and sonication are frequently used to refer to the application of ultrasound. A sample (for example, a solution or suspension) may be sonicated in a variety of ways, and may be sonicated continuously or by one or more pulses. For example, a sample may be sonicated by a series of ultrasound pulses, each pulse having a duration of from about 0.1 second to about 10 seconds. As another example, the sample may be sonicated at least once for at least about 5 minutes. In the present methods, where a method requires sonication or sonicating, it requires at least one pulse of ultrasonic energy which is generally on the order of seconds (for example, applying ultrasonic energy for 1 second or less, 5 seconds, 10 seconds or more). When a solution, suspension, solvent or other composition is sonicated “while” or “during” some other step or time period, it means at least one pulse is applied—it does not necessarily mean there is sonication over the entire step or period, although in some circumstances, it can be desirable to sonicate periodically or continuously throughout substantially an entire step or over substantially all of a time period, or for some portion of the step or period. For example, in some of the present techniques, it is stated that a solution is sonicated while a solvent is evaporated. Sonication in this situation may be a single pulse (for example, 5 seconds) to a solution, as well as multiple pulses or continuous sonication of a solution over substantially the entire time period of evaporation, or any application of ultrasound in between.
• Ultrasound can be applied to a chemical substance or a sample by conventional techniques such as by immersing a receptacle containing the chemical substance or the sample in an ultrasonic bath, or by placing the tip of an ultrasonic probe directly into the sample. Sonication may be performed using commercially available equipment. For example, a quarter-inch diameter (6 mm) ultrasonic probe operating at 20 kHz and a power input of 130 watts has been found convenient, but there will be many other commercially available devices which are suitable. Lower power ultrasound apparatus may also be suitable for crystallization. Suitable ultrasound devices are advertised by Cole-Palmer Instrument Co., of Vernon Hills, Ill., or Misonix Corporation, of Farmingdale, N.Y. For larger scale operations, a sonoreactor is advertised by AEA Technologies of the United Kingdom. Techniques and equipment include the use of ultrasonic probes or transducers, which techniques will be familiar to those skilled in the art.
• Where the samples are provided in a well plate, a well-plate sonicator may be used to sonicate the samples. Sonication of the sample may be performed using commercially available equipment. For example, a quarter-inch diameter (6 mm) ultrasonic probe operating at 20 kHz and a power input of 130 watts has been found convenient, but there will be many other commercially available devices which are suitable. As another example, a probe sonicator may be used for 2-5 seconds at 40 mW of power using a ⅛-inch probe. Lower power ultrasound apparatus may also be suitable for crystallization. The amount of time and power of the sonication are variable. In the example described below, sonication times of about 10 to 15 seconds applied every 5 minutes or so were used with a Misonix well-plate sonicator at medium power.
• The application of ultrasound to a sample containing a chemical substance to be crystallized can reduce the Metastable Zone Width for the sample (for example, a solution containing the chemical substance and solvent). For example, the sample may have a metastable zone, and the metastable zone has a width of at least about 1° C., alternatively at least about 2° C., alternatively at least about 5° C., alternatively at least about 10° C. The application of ultrasound to the sample may narrow the metastable zone, for example from a width of greater than about 10° C. to a width of at most about 5° C., or by reducing it by at least about 1° C. A reduction of the Metastable Zone Width offers a way to limit the level of supersaturation at which nucleation occurs. For a chemical substance that has two unsolvated polymorphic forms, where one is stable and one is metastable at a given temperature, the polymorph of higher free energy (that is, lower stability) has a higher solubility in any solvent compared to the polymorph of lower energy. If there is sufficient reduction of the Metastable Zone Width by application of ultrasound, such that the system becomes supersaturated with respect to the most stable form while being undersaturated with respect to the other form, then polymorphic selection favoring the most stable form will occur. This “zone of action” may be used in order to increase the chances to generate the most stable form of a chemical substance. In practice, as ultrasound does not typically reduce the Metastable Zone Width to zero, cases may occur where two polymorphs of similar of energy can be formed. Ultrasound can therefore be used as a tool to increase the probability of generating the most stable form, when working under low levels of supersaturation, or selectively crystallizing the more stable of two solid forms.
• Sometimes the most stable solid form is more difficult to generate than a less stable form. For example, with the compound WAY, the yellow form is frequently the first and most common form generated in screening method using small-scale crystallization and a variety of solvent mixtures. This may be explained by a faster nucleation and/or growth rate of the less stable form, compared to the more stable form.
• The application of ultrasound to a chemical substance to be crystallized from a solution can induce nucleation of supersaturated solutions in cases where the substance otherwise remains indefinitely or for relatively long periods in solution (in other words, in metastable solution). In this respect, the application of ultrasound is of considerable interest to find new solid forms difficult to find due to difficult conditions of crystallization. For example, the present techniques are beneficial for crystallization and finding new solid forms from viscous solutions, or from systems having a large Metastable Zone Width.
• Sonication generally increases the rate of nucleation in samples that are sufficiently supersaturated relative to the desired multi-component phase (the active agent(s) and the guest(s)). For example, sonication may increase the rate of cocrystallization by at least about 25%, alternatively at least about 100%, alternatively at least about 200%. Sonication generally reduces the activation barrier to nucleation and increases the number of successfully nucleated samples. The precise nature of the physical perturbations that cause nucleation when a sample is sonicated are not known with certainty. While the inventor does not intend to be bound by theory, it is presently theorized that entropic contributions may be more significant in multi-component samples because the independent components must be organized not only on a molecular level via aggregation through hydrogen bonding, but also in terms of mass transport. The growth of a cocrystal requires a consistent addition of a 1:1 mixture (or other fixed ratio) of the components to the cocrystal structure. Accordingly, local concentration gradients within the sample are undesirable. Sonication has a homogenizing effect and may assist in generating a more homogeneous distribution of the components in the sample. Thus, sonication is especially well-suited for methods of screening cocrystals where multiple compounds are to be brought together in a crystal. Sonication is also well-suited for methods of screening salts where an ionizable active agent and a counterion are to be brought together in a crystal.
• Ultrasound may be particularly beneficial where multi-component crystal growth is nucleation-limited. A system is nucleation-limited where crystals are generally not observed if nucleation does not occur during evaporation, and an amorphous solid results instead. In a nucleation-limited system, if nucleation occurs, then subsequent growth occurs efficiently and substantially completely. For example, a combination of fluoxetine HCl and benzoic acid in a 1:1 molar ratio is nucleation-limited in solutions of acetonitrile. This is a difficult system to nucleate and a minimum desired supersaturation level has been identified for cocrystallization. The minimum desired supersaturation level for fluoxetine HCl and benzoic acid in a 1:1 ratio in acetonitrite is about 35 mg/ml. Using the technique disclosed herein, minimum desired supersaturation levels for other systems can also be found.
• It has also been discovered that, even with ultrasound, it is desirable to maintain certain levels of supersaturation in the sample. In experiments using fluoxetine hydrochloride and benzoic acid in samples that included acetonitrile as a solvent, it was observed that sonication had a positive effect on cocrystallization. When concentrations of above 200 mg/ml of the mixture of active agent and guest in acetonitrile were used, sonication consistently nucleated the cocrystal. Between 35 and 100 mg/ml, nucleation could be caused by sonication, but nucleation was not observed spontaneously in unsonicated samples with concentrations below 100 mg/ml. Sonication provides a clear advantage in this case with respect to intermediate concentrations.
• Experiments at a concentration of about 200 mg/ml nucleated with sonication using either a probe or a well-plate sonicator. About 50% of wells nucleated and about 98% of the solids were cocrystals. In a control experiment without sonication, only about 15% of the wells nucleated, and the solid was benzoic acid rather than a cocrystal of fluoxetine HCl and benzoic acid.
• The application of ultrasound to the solution or suspension may narrow the metastable zone, for example, reducing it to less than 1° C. or from a width of greater than about 10° C. to a width of at most about 5° C. It appears that sonication reduces the metastable zone width, causing nucleation at lower supersaturation levels compared to slow evaporation (SE) results.
• Sonication can increase the rate of nucleation in systems where nucleation is slow. Among the advantages of sonication are that nucleation can occur faster, more completely, and can be initiated at lower concentrations. In addition, the rapid nature of the growth is more likely to produce a consistent form (the first form that nucleates) because of the massive secondary nucleation that occurs during sonication—one seed becomes many very quickly due to sonication. Ultrasound can therefore be used as a tool to increase the probability of generating a cocrystal, to generate cocrystals more rapidly, and/or to generate cocrystals at relatively low levels of supersaturation.
• Ultrasound may also be useful as a tool to increase the probability of generating a crystallized salt, to generate salts more rapidly, and/or to generate crystallized salts at relatively low levels of supersaturation.
• The present methods are useful for the generation of new solid forms as well as for screening a chemical substance according to its solid forms. The chemical substance may be a compound, element, or mixture. Chemical substances include organic and inorganic substances. Examples of chemical substances for use in the present techniques include, but are not limited to, pharmaceuticals, dietary supplements, alternative medicines, nutraceuticals, agricultural chemicals, dyes, explosives, polymer additives, lubricant additives, photographic chemicals, and structural and electronic materials. Preferably, the chemical substance is a pharmaceutical agent. Pharmaceutical agents suitable for use in the present technique include known pharmaceutical agents as well as those which may be developed. A pharmaceutical agent can be a large molecule (in other words, a molecule having a molecular weight of greater than about 1000 g/mol), such as oligonucleotides, polynucleotides, oligonucleotide conjugates, polynucleotide conjugates, proteins, peptides, peptidomimetics, or polysaccharides. A pharmaceutical agent can be a small molecule (in other words, a molecule having a molecular weight of about 1000 g/mol or less), such as hormones, steroids, nucleotides, nucleosides, or aminoacids. Examples of suitable small molecule pharmaceuticals include, but are not limited to, cardiovascular pharmaceuticals; anti-infective components; psychotherapeutic components; gastrointestinal products; respiratory therapies; cholesterol reducers; cancer and cancer-related therapies; blood modifiers; antiarthritic components; AIDS and AIDS-related pharmaceuticals; diabetes and diabetes-related therapies; biologicals; hormones; analgesics; dermatological products; anesthetics; migraine therapies; sedatives and hypnotics; imaging components; and diagnostic and contrast components.
• The chemical substances can have any utility, including utility as a pharmaceutical agent or other active agent. The present methods increase the likelihood of determining whether a chemical substance is polymorphic. A polymorphic chemical substance is a compound, element, or mixture having more than one solid form. The form of a compound, element, or mixture refers to the arrangement of molecules in the solid. The term solid form herein includes semisolids. Semisolids are materials like waxes, suspensions, gels, creams, and ointments. The forms which may be sought or generated may include amorphous forms, mixtures of amorphous forms, eutectic mixtures, mixed crystal forms, solid solutions, co-crystals, and other forms.
• A chemical compound, element, or mixture may be amorphous, meaning that it is not characterized by a long-range order of the molecules. Alternatively (or even to a limited extent within a mostly amorphous form), a compound, element, or mixture may be arranged in a crystalline state, where the molecules exist in fixed conformations and are arranged in a regular way. The same compound, element, or mixture may exhibit different properties depending upon which solid form that compound, element or mixture is in.
• Examples of compounds having more than one solid form include 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile and 4-methyl-2-nitroacetanilide, each of which has different colors in connection with different forms. Carbon, novobiocin, and furosemide are also examples of substances having more than one solid form.
• The present disclosure provides techniques for preparing cocrystals and for screening a chemical substance according to its possible solid state phases, in which one or more active agents are cocrystallized with one or more guests. It has been found that ultrasound may be used to facilitate cocrystallization and screening.
• Cocrystals are crystals that contain two or more non-identical molecules (two or more components) such as an active agent and a guest. FIGS.8(a) and (b) illustrate a crystal structure of an active agent (a one-component crystal) and a cocrystal structure containing the same active agent with a guest (a two-component crystal), respectively.
• Generating a variety of solid forms is an object of screening. A sufficient number of diverse processes and parameters should be employed to maximize the likelihood that a high percentage of possible solid forms of a chemical substance is generated. Samples should be generated under various thermodynamic and kinetic conditions. In the present methods, sonication is another parameter that is varied as part of the screening process.
• A compound is a substance composed of atoms or ions in chemical combination. A compound usually is composed of two or more elements, though as used in accordance with the present methods, a compound may be composed of one element.
• A mixture is a heterogeneous association of compounds or elements. The components of a mixture may or may not be uniformly dispersed.
• The present methods include providing samples comprising the chemical substance(s). In some embodiments, the samples may contain the chemical substance(s) alone, for example, in a melt or a physical mixture. More commonly, the sample will also contain a solvent(s) in which the active agent(s) and the guest(s) are dissolved, dispersed or otherwise disposed. The active agent(s) and the guest(s) may be completely or partially soluble in the solvent(s) or one or more of them may be substantially insoluble in the solvents. Accordingly, the sample may be in a solution, suspension, dispersion, mixture, slurry or emulsion, or other physical state. The sample's physical state going into the present methods is not critical to the broader applicability of the present methods, though in some embodiments, use of particular physical states for samples can be beneficial, as described in more detail herein. For example, the present methods may have additional benefits when the samples are metastable solutions, viscous solutions, emulsions or slurries.
• In the present methods, the chemical substance is solidified from the sample using a suitable solidification technique. As used herein, solidification includes any suitable technique for preparing a solid from the sample including but not limited to crystallization.
• The solidification technique(s) employed will depend in part on the sample(s). The samples may be provided as solutions, suspensions, melts, slurries, emulsions, or any other composition of matter which includes the chemical substance.
• Suitable crystallization (solidification) techniques include cooling, heating, evaporation, addition of an antisolvent, reactive crystallization, and using supercritical fluids as solvents. A fluid is an antisolvent with respect to a given solution of a chemical substance when the chemical substance is less soluble in that fluid than in the solvent used to form the solution; preferably, an antisolvent is a fluid in which the chemical substance is essentially insoluble or has a low solubility. Reactive crystallization refers to processes where means a chemical substance is formed from reactants and crystallized substantially simultaneously, for example, where the reaction is a driving force toward crystallization. A supercritical fluid is a fluid above its critical temperature and critical pressure which combines properties of gases and liquids. Examples of compounds employed as supercritical fluids include xenon, ethane and carbon dioxide.
• Alternatively, the mechanism by which crystallization is accomplished may include gel diffusion methods, thin-layer deposition methods, or other suitable methods. Other thermodynamic and kinetic conditions may be employed to solidify the compound or mixture. Slow cooling of a saturated solution is a typical thermodynamic condition. An addition of a solution of the compound or mixture to an excess of cold anti-solvent is a typical kinetic condition.
• Additionally, melt crystallization techniques may be used to generate a solid form. Through such techniques, the use of a solvent can be avoided. In such techniques, formation of crystalline material is from a melt of the crystallizing species rather than a solution. Additionally, the crystallization process may be done through sublimation techniques.
• In many embodiments, the samples will comprise the chemical substance in a solvent. Any suitable solvent can be used. Suitable solvents include acetone, acetonitrile, chloroform, dioxane, ethanol, ethyl acetate, heptane, butanone, methanol, nitromethane, tetrahydrofuran, toluene, water, dichloromethane, diethyl ether, isopropyl ether, cyclohexane, methylcyclohexane, isopropyl alcohol, isopropyl acetate, trimethylpentane, n-octane, trichloroethane, trifluoroethanol, pyridine, propanol, butanol, tetrachloroethylene, chlorobenzene, xylene, dibutyl ether, methyl-tert-butyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide, formamide, and dimethylformamide. It is also contemplated that the samples may be provided as the chemical substance in two or more solvents, either as a homogeneous solution or as an emulsion.
• In the solidifying step, the chemical substance is generally separated from the solvent though solids such as hydrates or solvates may be formed which include some solvent molecules. For example, the solvent may be evaporated either slowly (for example, evaporating to dryness over a time period of four days, alternatively two days or more) or quickly (for example, evaporating to dryness over a time period of 24 hours, alternatively under two days). By varying the rate of evaporation, one can introduce desired variability into a screening method. For example, in a screening method, a first portion of samples can be subjected to relatively slow evaporation, and a second portion of the samples can be subjected to relatively fast evaporation.
• In the present methods, ultrasound may be applied at different stages of a screening process or a crystallization process (or other solidification process). For example, a solution which comprises a solute to be crystallized can be sonicated at some point during the screening process. One may sonicate such a solution before, during, or after the initiation of cooling of the solution from an undersaturated, saturated, or supersaturated state. As other examples, one may sonicate a solution before, during, or after the beginning of evaporation of solvent, or before, during, or after the addition of an immiscible antisolvent to the solution.
• In the present methods, the solidifying step and the sonicating step can overlap. For example, where the samples are provided as a solution of the chemical substance in a solvent, the solidifying step may be performed by evaporating the solvent, and the sample may be sonicated during that evaporation. Furthermore, the sonication can be periodic during the evaporation. For example, the sample can be periodically sonicated for about 20 seconds, and the periods can be about 30 minutes (in other words, the sample is sonicated for about 20 seconds every 30 minutes). Furthermore, the sonication can be a single pulse. For example, the sonication could be carried out one time for 5 to 40 seconds or multiple times for a like period, or for other suitable period(s).
• In the present methods, the samples can comprise a solution, suspension, or melt of the chemical substance. Such a solution, suspension, or melt will typically be prepared by heating above room temperature to achieve supersaturation. It may be desirable to begin cooling the samples (for example, to room temperature) before the sonicating step. Alternatively, the samples may be cooled and sonicated at the same time. Alternatively, the method can include crash-cooling the samples (rapidly lowering the temperature, for example, by immersing in an ice bath) before the sonicating step. Alternatively, the samples may be crash-cooled and sonicated at the same time.
• The present methods can include the step of adding a second solvent to a solution containing the chemical substance. For example, the second solvent may be added to facilitate solidification.
• The solidification step can be initiated by sonication, and/or it may be initiated by seed materials or other techniques. In the various embodiments of the present methods, solidification may start before, during, or after the application of ultrasound. Frequently solidification will start during sonication and continue after sonication ceases. In many cases, the solidification and sonication steps will overlap. For example, sonication may begin before solidification but continue even after solidification begins. As another example, solidification may begin before sonication. As yet another example, the chemical substance may be sonicated in a pulsing manner throughout the solidification process. Alternatively, sonication may be employed to initiate solidification and be discontinued when solidification (such as nucleation) begins.
• As a broad example, solidification may be performed as follows: A solution containing a solvent and a chemical substance (such as a compound, element, or mixture) to be solidified is disposed in a receptacle, such as a vial, well-plate (such a 96 well plate) or capillary tube. The solution may be formed in the receptacle or formed outside the receptacle and then placed in it. The chemical substance can be present in a solution below, at or above its saturation point at a given temperature at the time it is placed in the receptacle. Through evaporation, the use of an antisolvent, temperature variation, and/or other suitable means, the solution reaches a point of supersaturation. The solution is sonicated, and further evaporation, the use of an antisolvent, temperature variation, and/or other suitable solidification technique may be employed. After a suitable amount of time, solidification progresses until a sufficient amount of solid or semisolid appears, and is ready for analysis to determine the solid form.
• The most preferred solidification techniques foster crystallization of the chemical substance. Suitable crystallization techniques may be employed with and without ultrasound in the present methods. Indeed, in a screening method, it may be desirable that some samples are sonicated and other samples are unsonicated.
• Crystallization may be performed as a seeded operation or an unseeded operation. In a seeded operation, a selected quantity of seed crystals is included in the system. The characteristics of the seed crystals typically influence the characteristics of the crystals generated from the system. Crystallization may be performed by heterogeneous or homogeneous mechanisms. However, it is noted that ultrasound may be applied as a way of omitting the presence of seed crystals.
• In other embodiments of the present methods, solids are generated other than by crystallization. The sample may be provided as a melt that is then added to the receptacle or may be provided within the receptacle and melted therein and allowed to solidify in an amorphous form.
• Another technique for crystallizing a chemical substance employs an emulsion. An emulsion is a mixture of two or more immiscible liquids where one liquid is in a discontinuous phase within the other liquid. Emulsions are frequently formed and/or stabilized by the use of agents called emulsifiers. However, sonication of an immiscible mixture of solvents also allows the generation of emulsions.
• The present methods may also include the step of forming an emulsion comprising two or more substantially immiscible solvents and the chemical substance. The emulsion can be formed during the sonicating step, wherein an immiscible mixture of said solvents is sonicated to form the emulsion. Alternatively, the emulsion can be formed before the sonicating step. Where an emulsion is employed, the chemical substance can be substantially soluble in one of the immiscible solvents and substantially insoluble in another of the immiscible solvents. The chemical substance is in solution in one or both of the solvents.
• Emulsions can be employed as part of a screening method and/or solidification method to generate additional solid forms of a chemical substance. Emulsions can allow interface between the two solvents over a high surface area. At such interfaces, nucleation and/or growth of some polymorphs may be favored, based on the influence of each solvent on the growth of each polymorph.
• An emulsion may be prepared by combining a solution of a chemical substance in a first solvent with a second solvent, wherein the first solvent and the second solvent are substantially immiscible with each other. The combined solvents may then be sonicated while evaporating, cooling, adding antisolvent, or using other solidification techniques until a precipitate containing the chemical substance appears.
• Another technique for crystallizing a chemical substance employs a slurry. A slurry is a dispersion of solid particles in a liquid phase. The liquid phase comprises one or more solvents in which the chemical substance is not completely soluble. The process of slurrying a metastable form of a chemical substance, aiming at finding a form of lower solubility in the solvent used, in other words, a form of lower energy (in the case of the transition between two unsolvated polymorphs) or a solvated form (in the case of a transition between an unsolvated form or solvated form from a different solvent to a solvated form), is foreseen to be accelerated by the use of ultrasound during the slurrying process.
• The present methods may also include the step of forming a slurry comprising a solvent and the chemical substance. The slurry can be formed during the sonicating step, wherein a mixture of the chemical substance and the solvent are sonicated to form the slurry. Alternatively, the slurry can be formed before the sonicating step.
• It is preferable in a screening method that the generation of solid forms is carried out under a wide variety of conditions. For example, solids should be generated in the presence and absence of various solvents, as the solvent may play a role in the formation of certain forms, and with and without sonication. As another example it is also preferable to prepare solid forms under different conditions of temperature and pressure, as different solid forms may be favored by different conditions. In some embodiments of the screening method, at least one sample is unsonicated so that the effect of ultrasound on solid form for that chemical substance can be determined.
• It is also contemplated that the present methods are advantageous for generating solid forms from viscous solutions. For example, the present methods may be used with samples that are solutions having a viscosity greater than about 5 cPoise, alternatively greater than 10 cPoise, alternatively greater than 20 cPoise, before the solution is sonicated.
• It is also contemplated that the present methods are advantageous for generating solid forms from amorphous forms of the chemical substance. Samples can be formed or provided by preparing a solution from an amorphous solid comprising the chemical substance and a solvent. The solvent may be sonicated while the amorphous solid is added to the solvent.
• It is contemplated that, in the context of a comprehensive screening method, the samples can be divided into subsamples or sets of subsamples. A multiplicity of subsamples and sets are useful so that more than one parameter may be varied and the cumulative effect of multiple varied parameters may be assessed. For example, a first sample (and/or a second sample) may be divided into subsamples, such as a first set of subsamples, a second set, a third set, and a fourth set. The first set and the second set can comprise a solution of the chemical substance in a first solvent, such as acetone, while the third set and the fourth set comprise a solution of the chemical substance in a second solvent, such as tetrahydrofuran. The first set and the third set can be sonicated, and the second set and the fourth set can be unsonicated. The benefit of this method is that the effects of ultrasonic crystallization on acetone and tetrahydrofuran solutions can be analyzed and compared.
• Solid forms generated after the solidification and sonication steps may be identified by any suitable method, including but not limited to visual analysis (such as when different forms exhibit different colors), microscopic analysis including electron microscopy (such as when different forms happen to have different morphologies), thermal analysis (such as determining the melting points), conducting diffraction analysis (such as x-ray diffraction analysis, electron diffraction analysis, neutron diffraction analysis, as well as others), conducting Raman or infrared spectroscopic analysis, or conducting other spectroscopic analysis. Any appropriate analytical technique that is used to differentiate structural, energetic, or performance characteristics may be used in connection with the present methods.
• In a preferred embodiment, the samples are placed in a well plate and then sonicated. The chemical substances solidify in the wells of the well plate. The solidified chemical substances are then analyzed in the well plate or a portion of the well plate. The solidified chemical substances can be analyzed by any one of the foregoing analysis techniques, preferably by x-ray diffraction (such as transmission x-ray diffraction or reflection x-ray diffraction) and/or by Raman spectroscopy. Well plates may be used which have a detachable portion, such as a detachable bottom portion. For example, well plates may be used which have polymer films, glass plates, or other substrates that are detachable from another portion of the well plates. Solidified chemical substances can be analyzed in the well plate or the detachable portion of the well plate. In particular, x-ray diffraction techniques such as transmission or reflection x-ray diffraction may be used to analyze the solidified chemical substances in well plates or the detachable portion of well plates (for example, the polymer film, glass plate, or other substrate).
• A synchrotron may be used as the source of radiation for conducting diffraction analyses. A synchrotron is a type of particle accelerator, which emits high energy, focused radiation. Synchrotron radiation is the byproduct of circulating electrons or positrons at speeds very close to the speed of light. Synchrotron radiation contains all the wavelengths of the electromagnetic spectrum and comprises the most intense source of wavelengths available in the x-ray and ultraviolet region. Synchrotron radiation allows analysis of smaller quantities of sample that would be difficult to analyze using other sources of x-ray radiation.
• One location for research using synchrotron radiation is the Stanford Synchrotron Radiation Laboratory (SSRL), which is funded by the Department of Energy as a national user facility. Another location is Argonne National Laboratory, which is available to outside users on a fee basis.
• Synchrotron radiation may be used to study structural details of solid samples with a resolution not practically attainable using traditional x-ray instrumentation. This may enable differentiation between different polymorphic forms or compounds that is not attainable with other x-ray radiation sources.
• The present methods can significantly assist in the identification of the solid form of a chemical substance that is most stable or has other properties that make it preferable over other forms. For example, the present methods can be used as part of a screening method and can improve the likelihood of identifying a form having biological activity such as better stability, bioavailability, solubility, or absorption characteristics. In some cases, an identified form may have better activity as an active agent.
• After a chemical substance (including a solution, melt, emulsion, slurry, suspension, or mixture containing the chemical substance) is placed in a receptacle, the receptacle may be centrifuged. Centrifugation may be employed for a variety of reasons. First, use of a centrifugal evaporator may assist evaporation while concentrating solid or semisolid material at one end of a capillary space. This has advantages in connection with in-situ analysis, in that the generated form will be located at a consistent place in the receptacle. Also or alternatively, centrifuging may be used to provide additional environmental variation, which is desirable in a screening method.
• The application of ultrasound to solutions containing multiple components to be crystallized can induce nucleation in cases where the components otherwise remain indefinitely or for relatively long periods in solution (in other words, in metastable solution). In this respect, the application of ultrasound is of considerable interest to find new cocrystals and salts which are otherwise difficult to find. For example, the present techniques are beneficial for cocrystallization from viscous solutions, or from systems having a large Metastable Zone Width.
• The present techniques are applicable to cocrystallize two or more active agents. (It is contemplated that more than one active agent may be employed in a cocrystal.) An active agent is a molecule whose activity is desirable or the object of interest. For example, where the active agent is an active pharmaceutical ingredient, the pharmaceutical activity of the active agent is desired or the object of interest. Active agents include organic and inorganic substances. Examples of active agents for use in the present techniques include, but are not limited to, pharmaceuticals, dietary supplements, alternative medicines, nutraceuticals, agricultural chemicals, dyes, explosives, polymer additives, lubricant additives, photographic chemicals, and structural and electronic materials. Preferably, the active agent is an active pharmaceutical ingredient (API). Pharmaceutical agents suitable for use in the present technique include known pharmaceutical agents as well as those which may be developed. A pharmaceutical agent can be a large molecule (in other words, a molecule having a molecular weight of greater than about 1000 g/mol), such as oligonucleotides, polynucleotides, oligonucleotide conjugates, polynucleotide conjugates, proteins, peptides, peptidomimetics, or polysaccharides. A pharmaceutical agent can be a small molecule (in other words, a molecule having a molecular weight of about 1000 g/mol or less), such as hormones, steroids, nucleotides, nucleosides, aminoacids, acetaminophen, nonsteroidal anti-inflammatory drugs, and others. Examples of suitable small molecule pharmaceuticals include, but are not limited to, cardiovascular pharmaceuticals; anti-infective components; psychotherapeutic components; gastrointestinal products; respiratory therapies; cholesterol reducers; cancer and cancer-related therapies; blood modifiers; antiarthritic components; AIDS and AIDS-related pharmaceuticals; diabetes and diabetes-related therapies; biologicals; hormones; analgesics; dermatological products; anesthetics; migraine therapies; sedatives and hypnotics; imaging components; and diagnostic and contrast components.
• The active agent may be provided as a salt. It is contemplated that one or more salts may be employed in a cocrystal, according to any of the present techniques. The salt may be prepared from an ionizable active agent or obtained from a commercial source. Hydrochloride salts of active pharmaceutical ingredients, especially of amine APIs, are especially preferred in the pharmaceutical industry.
• In general, it is contemplated that the present techniques will have particularly good results as applied to amine HCl salts as well as other ammonium salts as described in more detail herein. In ammonium acid salts, the active agent has at least one amine moiety which is relatively basic (at least one relatively basic nitrogen), and a salt is formed with an acid that reacts with the amine moiety. Cocrystals may be then formed between the ammonium salts and guests which act as hydrogen-bond donors to the salts. Cocrystals may be formed of chloride salts of APIs, for example buspirone hydrochloride and fluoxetine hydrochloride.
• While the inventors do not wish to be bound to theory, it is believed that excellent cocrystals may be formed using hydrochloride salts and similar salts which are strong hydrogen bond acceptors yet contain relatively undercoordinated ions. “Undercoordinated” in this case refers to ions, for example a chloride ion, that are able to form a number of strong hydrogen bonds. An undercoordinated counterion may have hydrogen bonds within a crystal of that salt, but it could form additional hydrogen bonds in a cocrystal and/or form relatively stronger hydrogen bonds in a cocrystal with a guest. An ion is “undercoordinated” when the system is limited in the number of hydrogen bond donors that are available and bonded to the ion. In these cases, the extra hydrogen bond acceptor sites are typically filled by weakly interacting donors such as C—H groups Chloride ions are strong hydrogen bond acceptors in a crystal structure. In a crystal structure such as fluoxetine hydrochloride, the chloride ion coordinates to the two strong hydrogen bond donors available in the system, and the chloride ion also has three weaker CH—Cl interactions resulting in a pseudo-octahedral coordination environment. There is an opportunity for bonding with these coordination sites, by displacing the weak CH donors that the chloride has recruited to fill its coordination sphere with somewhat stronger hydrogen bond donors from a guest such as benzoic acid, succinic acid, fumaric acid, or another carboxylic acid.
• It is useful in forming cocrystals to recognize that relatively weak interactions may be replaced by stronger interactions, even though those stronger interactions may be relatively weak themselves, compared to other interactions. For example, an undercoordinated chloride may have one strong hydrogen bond donor and several weak hydrogen bond donors or two strong hydrogen bond donors and several weak hydrogen bond donors. In a cocrystal, weaker interactions may be replaced by stronger interactions, although those stronger interactions may still be weaker than the strong interactions (charge-assisted hydrogen bonds) present in fluoxetine HCl crystals. The strongest interactions involving chloride ions in crystal structures of organic salts are the charge assisted hydrogen bonds that invariably form between the protonated nitrogen base and the chloride ion. The strongest interactions between neutral molecular groups and the chloride ion involve acids and the chloride ion. Carboxylic acids, for instance, have strong interactions with chloride ions. It can be seen that a combination of carboxylic acids and hydrochloride salts of nitrogen containing bases are especially well suited to cocrystal formation (as demonstrated by the examples included). Furthermore, it can be anticipated that different combinations of these elements could lead to other cocrystals. For example, the active molecule of interest may contain either the neutral carboxylic acid moiety or the protonated nitrogen. The potential exists to cocrystallize an API having a neutral carboxylic acid moiety with a guest that is a hydrochloride salt of a nitrogen-containing organic base.
• It is further contemplated that the nature of the protonated nitrogen base will affect the potential for cocrystallization. Numerous strong hydrogen bond donor groups will compete with the carboxylic acid guest for the open acceptor sites on the chloride ion. In order to favor cocrystal formation, the nitrogen base is preferably a tertiary amine because this presents a situation where only one strong charged hydrogen bond donor exists and thus will only occupy one site on the chloride acceptor. Additionally, systems that have only this one tertiary amine and no other strong donors present an especially favorable system for potential cocrystallization. Protonated secondary amines with two N—H donor groups are also favored, although protonated primary amines may also be used. Special consideration must be taken for systems with additional strong hydrogen bond donor and acceptor sites in order to determine the potential for cocrystallization and the optimal guest molecule type for cocrystallization. The potential for cocrystallization involving a carboxylic acid and a hydrochloride salt may be reduced as the number of available strong donors in the system is increased. Additional guidance as to evaluating undercoordination particularly in its discussion of nonbonded motifs may be found in: Scott L. Childs, “Nonbonded Interactions In Molecular Crystal Structures”, Emory Univ., USA, available from UMI, Order No. DA3009424 (288 pp.), Dissertation Abstract Int. Ref. B2001, 62(3), 1394 (which is incorporated by reference herein). In some circumstances, the undercoordination can be determined by measuring distances, comparing profiles in the Cambridge Structural Database, measuring the pKa of the donors and acceptors, or evaluating the ratio of strong hydrogen bond donors to available acceptors. Other crystal engineering theories may also be used.
• By cocrystallizing an active agent with a guest, one can create new solid state phases which may have improved properties over existing solid state phases of that active agent. For example, new drug formulations comprising salt of active pharmaceutical ingredients may have superior properties over existing drug formulations. The active agent and guest will vary depending on the industry. For example, in the pharmaceutical field, the active agent or guest may be an API, and the other component of the salt must be a pharmaceutically acceptable compound. The present techniques are also applicable to active agents from other fields including nutraceuticals, agricultural chemicals, pigments, dyes, explosives, polymer additives, lubricant additives, photographic chemicals, and structural and electronic materials.
• The present techniques may be employed to generate a wide variety of cocrystals of active agents and guests. For example, the present techniques may be used to generate cocrystals of a salt of an active agent, such as a salt of an active pharmaceutical ingredient, with a neutral guest. Alternatively, a cocrystal of a neutral or zwitterionic active agent (or a salt of an active agent) may be generated with a guest salt, which includes a positive ion and a negative ion of its own. Where the active agent is provided in a salt, it may be positively or negatively charged and have a negative or positive counterion. As an example, for fluoxetine HCl, the active agent fluoxetine is positively charged by virtue of accepting a proton from HCl to form a protonated amine, and chloride is present as a negative counterion. Furthermore, some of the present methods may be employed with a neutral or zwitterionic active agent to form a cocrystal with a neutral guest or ionic guest.
• The present techniques provide an opportunity to create a stable solid state phase of a hydrochloride salt of an API (or other active agents) that was previously found to have properties that were unsuitable for development. Opportunities for continued development in such a situation have often relied on the fortuitous formation of a stable hydrate or solvate, but the present techniques present the ability to systematically examine alternative formulations of the hydrochloride salt by cocrystallizing the hydrochloride salt of the API with appropriate guest molecules.
• Cocrystallization may be an attractive technique for salts of APIs that have been rejected due to problems relating to physical properties. Since cocrystals may have different physical properties than the individual components, APIs with unfavorable physical properties can be cocrystallized with suitable guest molecules and the physical properties of the resulting crystalline solids can be evaluated.
• Cocrystals of fluoxetine HCl provide examples of the modification of a physical property (solubility) of an API salt. Cocrystals of fluoxetine HCl:benzoic acid are less soluble and have a lower dissolution rate than crystals of fluoxetine HCl, while cocrystals of fluoxetine HCl:succinic acid are more soluble and have a faster dissolution rate than crystals of fluoxetine HCl.
• Other physical properties of APIs or their salts that may be modified by forming a cocrystal include: melting point, density, hygroscopicity, crystal morphology, loading volume, compressibility, and shelf life. Furthermore, other properties such as bioavailability, toxicity, taste, phy sical stability, chemical stability, production costs, and manufacturing method may be modified by the use of the present cocrystallization techniques.
• An active agent can be screened for possible cocrystals where polymorphic forms, hydrates or solvates are especially problematic. A ne-utral compound that can only be isolated as amorphous material could be cocrystallized. Forming a cocrystal may improve the performance of a drug formulation of an active pharmaceutical ingredient by changing physical properties. Some APIs are problematic during wet granulation and compression stages. A bioequivalent cocrystal could rectify this problem.
• An active agent can also be screened for possible salts. Forming a salt may improve the performance of a drug formulation by changing physical properties. A salt screen refers to a screening method in which one attempts to make one or more salts comprising an active agent under a variety of conditions and/or parameters, preferably including a variety of different counterions.
• A cocrystal or salt can be used to isolate or purify an active agent during manufacturing. If it is desirable to identify the solid state phases of an active pharmaceutical ingredient, then cocrystallization and/or salt formation may be particularly desirable.
• The present techniques provide new methods of developing and screening active pharmaceutical ingredients or other active agents. Non-toxic cocrystalline forms of neutral active pharmaceutical ingredients may be prepared, screened, tested, and commercialized. Furthermore, new types of HCl salt structures may be prepared. The properties of hydrochloride salts can be tuned and perfected. New, unique, stable, and marketable phases of hydrochloride salts may be prepared. One can choose whether to make the formulation more soluble or less soluble.
• As another aspect, the present techniques may also be used to remove or reduce the water of hydration, and/or to prepare a cocrystal substantially free of water of hydration. Water and guest acids perform a similar role in the stabilization of the crystal structure. In fact, about 28% of the hydrochloride salts of API in the Cambridge Structure Database are hydrates, compared to about 8% of all other organic structures. This indicates an affinity for hydration. The present techniques both capitalize and rectify this affinity, in that an affinity for cocrystallization (as evidence by hydration) is likely indicated, and this affinity for cocrystallization may be employed for the formation of cocrystals with a suitable guest, such as an acid, for example a carboxylic acid. Indeed, in many cocrystals, an acid may have stronger interactions than water molecules and may displace the water of hydration during the formation of the cocrystal. Accordingly, the present techniques provide a method of preparing a cocrystal from a hydrate. A hydrate of a salt is provided, and the hydrate comprises water of hydration. A guest is selected to coordinate with the counterion. Preferably, the guest coordinates more strongly with the counterion than the water of hydration does. A solution, melt or physical mixture is prepared which comprises the hydrate and the guest. The solution or melt is subjected to a crystallization process, or the physical mixture is subjected to grinding, and a cocrystal comprising the salt of the active agent and the guest is formed, and the salt comprises the active agent and a counterion. Similarly, the present techniques provide a method of preparing a cocrystal from a solvate. A solvate of a salt is provided, and the solvate comprises solvent molecules coordinated with the salt. A guest is selected to coordinate with the counterion. Preferably, the guest coordinates more strongly with the counterion than the solvent does. A solution, melt or physical mixture is prepared comprising the solvate and the guest. The solution or melt is subjected to a crystallization process, or the physical mixture is subjected to grinding, and a cocrystal comprising the salt of the active agent and the guest is formed. The salt comprises the active agent and a counterion.
• FIGS.9(a) and (b) are drawings of two-dimensional and three-dimensional models of a cocrystal of fluoxetine HCl and benzoic acid (1:1).FIG. 9(a) shows a two-dimensional model in which the chloride ion interacts with the hydrogens of the amine group of fluoxetine and of the hydroxyl group of benzoic acid. Through these interactions, which may be characterized as hydrogen bonding, fluoxetine hydrochloride and benzoic acid form a supramolecular structure that may be the basis of a cocrystal.FIG. 9(b) shows a three-dimensional model of the supramolecular organization of fluoxetine hydrochloride and benzoic acid.
• The present cocrystals may comprise salts other than chloride salts—the hydrochloride API salts that are listed above are only a sampling of the relevant compounds because the starting material need not be a known hydrochloride. Indeed, many relevant APIs are salts that are not HCl salts because the HCl salt was not believed to be an appropriate material and a different salt was commercialized instead. The present techniques may enable one to employ an HCl salt of an API that is marketed as another type of salt. Alternatively, it may be desirable to employ a salt other than an HCl salt, by replacing the HCl or by forming a salt comprising an active agent that acts as a base with an acid other than HCl. The following acids provide anionic counterions that would be used to replace chlorine. These are relatively strong acids, and include but are not limited to mineral acids, and the carboxylic acid guest is expected to form one or more hydrogen bonds with a hydrogen bond acceptor on the anionic counterion. The list is the conjugate acid that would react with a basic active agent to form a salt:
• sulfuric acid
• phosphoric acid
• hydrobromic acid
• nitric acid
• pyrophosphoric acid
• methanesulfonic acid
• thiocyanic acid
• naphthalene-2-sulfonic acid
• 1,5-naphthalenedisulfonic acid
• cyclamic acid
• p-toluenesulfonic acid
• maleic acid
• L-aspartic acid
• 2-hydroxy-ethanesulfonic acid
• glycerophosphoric acid
• ethanesulfonic acid
• hydroiodic acid
• The present techniques also extend beyond salts as starting materials and also include many weak bases that may have been marketed as neutral forms because the known salts did not have appropriate properties. These salts could be revisited and attempts could be made to cocrystallize the HCl salt. For example, a drug formulation marketed as a tartrate salt of an API could be reformulated by cocrystallizing the HCl salt of the active molecule with an appropriate guest molecule. Thus, cocrystallization could make a useful HCl cocrystal out of the API that is currently marketed as a tartrate, sulfate, or other salt formulation. For this reason the present disclosure includes APIs that are not HCl salts as starting materials.
• Furthermore, the present techniques relate to salts other than chloride salts. It is contemplated that hydrobromide salts and sodium salts of APIs may especially benefit from the present techniques, since they form relatively strong nonbonded interactions. For example, the hydrobromide salts citalopram hydrobromide and galantamine hydrobromide are contemplated for cocrystallization with benzoic acid, succinic acid, and other guests compatible with hydrochloride salts.
• The present techniques may be employed to form cocrystals of sodium salts of APIs such as, for example, naproxen sodium, tolmetin sodium, and warfarin sodium. When a sodium salt (or other salt of an API having a positive counterion) is employed, different guests are expected to be suitable for cocrystallization than when a hydrochloride salt (or other anionic salt) of an API is employed.
• Anions and Cations
• As one aspect, the active agent is provided as a salt. The salt of the active agent may be formed as part of sample preparation or separately. Alternatively or additionally, the guest is provided as a salt or a salt of the guest is formed. The salt may comprise the active agent and a counterion that is either a cation or an anion. Among the preferred cations (including cations as well as compounds that can form cations) are aluminum, ammonium, benzathine, calcium, diethanolamine, diethylamine, dimeglumine, disodium, lithium, lysine, magnesium, meglumine, potassium, sodium, and zinc. Among the preferred anions are acetate, L-aspartate, besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate, edisylate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, D-lactate, L-lactate, DL-lactate, D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate, sulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hybenzate, isethionate, malonate, methylsufate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, acefyllinate, aceturate, aminosalicylate, ascorbate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, glutamate, glutamate, glutarate, glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, and undecylenate.
• When a metal cation is employed as a counterion of the active agent, the interaction between guest and cation is not a hydrogen bond but rather is an intermolecular interaction between an electron rich group such as a carbonyl and the metal cation. This interaction is often not as strong as a hydrogen bond, but is still a favorable interaction and thus can contribute to the stabilization of a cocrystal.
• The HCl salt of an active pharmaceutical ingredient is especially preferred to create a new type of cocrystal. In this type of solid state phase, one can cocrystallize the HCl salt with a neutral guest molecule. By doing this one can create solid state phases with specific properties. For instance one can make a solid comprising an active pharmaceutical ingredient having greater or lesser intrinsic solubility and/or a faster or slower dissolution rate, depending on the guest compound that is chosen.
• The present techniques may be utilized in methods for screening an ionizable active agent according to its possible salts or for preparing a salt comprising an ionizable active agent and a guest. Such methods can comprise providing a plurality of samples comprising the active agent and one or more counterions; sonicating the sample(s); and forming crystallized salt compounds comprising the active agent and counterions. The counterions may be any of the cations or anions set forth above or elsewhere in the present disclosure. Using the present techniques provides a greater likelihood of generating possible salts of the ionizable active agent. Moreover, a salt developed by such a method may be employed in connection with the methods described herein which relating to cocrystals comprising a salt and a guest.
• Guests
• The guest is present in order to form the cocrystal with the active agent. It is contemplated that one or more guests may be employed in a cocrystal, according to any of the present techniques. Accordingly, the guest is not required to have an activity of its own, although it may have some activity that does not overly derogate from the desired activity of the active agent. In some situations, the guest may have the same activity as or an activity complementary to that of the active agent. The guest may be another API. For example, some guests may facilitate the therapeutic effect of an active pharmaceutical ingredient. For pharmaceutical formulations, the guest may be any pharmaceutically acceptable molecule(s) that forms a cocrystal with the API or its salt. The RTECS database is a useful source for toxicology information, and the GRAS list contains about 2500 relevant compounds.
• The guest may be neutral (such as benzoic acid and succinic acid in the examples below) or ionic (such as sodium benzoate or sodium succinate). Neutral guests are nonionic guests. Ionic guests are compounds or complexes having ionic bonds.FIG. 10 shows several general classes of guests (organic bases, organic salts, alcohols & aldehydes, amino acids, sugars, ionic inorganics, aliphatic esters & ketones, organic acids, and aromatic esters & ketones).
• The guest may be an acid that forms hydrogen bonds with the chloride (or other anion). For example, suitable guests which are acids include (but not are not limited to):
• ascorbic acid
• glucoheptonic acid
• sebacic acid
• alginic acid
• cyclamic acid
• ethane-1,2-disulfonic acid
• 2-hydroxyethanesulfonic acid
• 2-oxo-glutaric acid
• naphthalene-1,5-disulfonic acid
• nicotinic acid
• pyroglutamic acid
• 4-acetamidobenzoic acid
• Table 8 sets forth a group of presently preferred guests. It is contemplated that the guests set forth in the Table may be arranged in subgroups based upon molecular structure and/or physiological effect. Furthermore, the foregoing list is intended to provide a written description of any sublist that omits one or more guests.
• Table 9 sets forth another group of preferred guests. It is contemplated that the guests set forth in the Table may be arranged in subgroups based upon molecular structure and/or physiological effect. Furthermore, the foregoing list is intended to provide a written description of any sublist that omits one or more guests.
• Table 10 sets forth the group comprising molecules believed at present to be suitable guests. It is contemplated that the guests set forth in the Table may be arranged in subgroups based upon molecular structure and/or physiological effect. Furthermore, the foregoing list is intended to provide a written description of any sublist that omits one or more guests.
• Ionic guests are salts themselves, and may be formed from bases and acids prior to being used to form cocrystals. For example, the following bases and acids may be reacted to form ionic guests:
• Bases
• Ammonia
• L-Arginine
• Benethamine
• Benzathine
• Betaine
• Calcium Hydroxide
• Choline
• Deanol
• Diethanolamine
• Diethylamine
• 2-(Diethylamino) ethanol
• 2-Aminoethanol
• Ethylenediamine
• N-Methylglucamine
• Hydrabamine
• 1H-Imidazole
• Lysine
• Magnesium Hydroxide
• Morpholine
• 4-(2-Hydroxyethyl)Morpholine
• Piperazine
• Potassium Hydroxide
• Pyrrolidine
• 1-(2-Hydroxyethyl)Pyrrolidine
• Sodium Hydroxide
• Triethanolamine
• Tromethamine
• Zinc Hydroxide
• Acids
• (+)-L-Tartaric Acid
• 1,2, 2-Trimethyl-1,3-cyclopentanedicarboxylic Acid
• 10-Undecylenic Acid
• 1-Hydroxy-2-naphthoic Acid
• (+)-Camphor-10-sulfonic Acid
• 2,5-Dihydroxybenzoic Acid
• 2-Furancarboxylic Acid
• 2-Mercaptobenzoic Acid
• 3-Cyclopentylpropionic Acid
• 3-Phenylpropionic Acid
• 4-Aminosalicylic Acid
• 4-Hydroxybenzoic Acid
• Acetic Acid
• Adipic Acid
• alpha-Hydroxypropionic Acid
• Benzenesulfanic Acid
• Benzoic Acid
• Carbonic Acid
• Cholic Acid
• Citric Acid
• (−)-D-Tartaric Acid
• (+)-D-Camphoric Acid
• (+)-D-Malic Acid
• (+)-L-Malic Acid
• 2,2-Dichloroacetic Acid
• DL-10-Camphorsulfonic Acid
• DL-Glutamic Acid
• DL-Malic Acid
• DL-Tartaric Acid
• Dodecylsulfuric Acid
• Ethanesulfonic Acid
• Ethylenediaminetetraacetic Acid
• Ethylsulfonic Acid
• Fumaric Acid
• Galactaric Acid
• Gallic Acid
• Gluconic Acid
• Glutaric Acid
• Glycolic Acid
• Hippuric Acid
• Hydriodic Acid
• Hydrobromic Acid
• Hydrochloric Acid
• (−)-L-Apple Acid
• (+)-L-Lactic Acid
• (+)-L-Tartaric Acid
• D,L-Lactic Acid
• Lactobionic Acid
• L-Aspartic Acid
• Lauric Acid
• L-Glutamic Acid
• Maleic Acid
• (−)-L-Malic Acid
• Malonic Acid
• D,L-Mandelic Acid
• Methanesulfonic Acid
• Naphthalene-2-sulfonic acid
• n-Butyric Acid
• n-Decanoic Acid
• n-Hexanoic Acid
• Nitric acid
• n-Tetradecanoic Acid
• Octanoic Acid
• Oleic Acid
• Orotic Acid
• Orthoboric Acid
• Oxalic Acid
• 4-Acetamidobenzoic Acid
• Palmitic Acid
• Pamoic Acid
• Phosphoric Acid
• Picric Acid
• Pivalic Acid
• Propionic Acid
• p-Toluenesulfonic Acid
• Pyrophosphoric Acid
• Salicylic Acid
• Stearic Acid
• Succinic Acid
• Sulfosalicylic Acid
• Sulfuric Acid
• Terephthalic Acid
• Thiocyanic Acid
• Valeric Acid
• Valproic Acid
• Typically, suitable guests will have complementary ability to noncovalently bond to the active agent or its salt, for example the ability to form hydrogen bonds with the active agent or its salt. Suitable guests for active agents having negative counterions include, but are not limited to, compounds having alcohol, ketone, ester, and/or carboxylic acid functionalities. Suitable guests may include organic acids, organic bases, organic salts, alcohols, aldehydes, amino acids, sugars, ionic inorganic compounds, aliphatic esters and ketones, and aromatic esters and ketones.
• Among the presently preferred neutral guests are those which are not liquids at room temperature. Also among the presently preferred neutral guests are carboxylic acids having at least three carbon atoms, alternatively at least four carbon atoms, and which do not form solvates. For example, if the following acids were combined with active agents, the combination would more properly be considered a solvate than a cocrystal: acetic acid, propionic acid, and butyric acid. However, in certain embodiments of the present invention (for example, in certain cocrystals, cocrystallization methods, and screening methods), the use of solvents and solvates may still be desirable, and the use of solvents and solvates is not excluded from the scope of any cocrystal or method except where explicitly stated.
• In the present methods, the active agent(s) and guest(s) to be cocrystallized are provided as one or more samples to be used within the present techniques. The samples may be provided by being formed, created or prepared as an initial step in the present methods, or they may be obtained ready-to-use from another source.
• In some embodiments, the samples may contain the active agent(s) and the guest(s) alone, for example, in a melt or a physical mixture. Alternatively, the sample will also contain a solvent(s) in which the active agent(s) and the guest(s) are dissolved, dispersed or otherwise disposed. The active agent(s) and the guest(s) may be completely or partially soluble in the solvent(s) or one or more of them may be substantially insoluble in the solvents. Accordingly, the sample may be in a solution, dispersion, suspension, mixture, slurry or emulsion, or other physical state. The sample's physical state going into the present methods is not critical to the broader applicability of the present methods, though in some embodiments, use of particular physical states for samples can be beneficial, as described in more detail herein. For example, the present methods may have additional benefits when the samples are metastable solutions, viscous solutions, emulsions or slurries.
• Cocrystallization
• In the present methods, the active agent and the guest are cocrystallized from the sample using a suitable crystallization technique. As used herein, crystallization includes any suitable technique for preparing a crystal from the sample.
• The crystallization technique(s) employed will depend in part on the sample(s). Suitable crystallization techniques include cooling, heating, evaporation, addition of an antisolvent, reactive crystallization, and using supercritical fluids as solvents. A fluid is an antisolvent with respect to a given solution of components to be cocrystallized when at least one component is less soluble in that fluid than in the solvent used to form the solution; preferably, an antisolvent is a fluid in which both components are essentially insoluble or have a low solubility. Reactive crystallization refers to processes where a chemical compound is formed from reactants and crystallized substantially simultaneously, for example, where the reaction is a driving force toward crystallization. A supercritical fluid is a fluid above its critical temperature and critical pressure which combines properties of gases and liquids. Examples of compounds employed as supercritical fluids include xenon, ethane and carbon dioxide.
• Alternatively, the mechanism by which crystallization is accomplished may include gel diffusion methods, thin-layer deposition methods, or other suitable methods. Other thermodynamic and kinetic conditions may be employed for cocrystallization. Slow cooling of a saturated solution is a typical thermodynamic condition. An addition of a solution of the components to be cocrystallized to an excess of cold anti-solvent is a typical kinetic condition.
• Additionally, melt crystallization techniques may be used to generate a cocrystal. Through such techniques, the use of a solvent can be avoided. In such techniques, formation of crystalline material is from a melt of the crystallizing components rather than a solution. Additionally, the crystallization process may be done through sublimation techniques.
• In many embodiments, the samples will comprise a solvent. Any suitable solvent can be used. Suitable solvents include acetone, acetonitrile, chloroform, 1,4-dioxane, ethanol, ethyl acetate, heptane, 2-butanone, methanol, nitromethane, tetrahydrofuran, toluene, water, dichloromethane, diethyl ether, isopropyl ether, cyclohexane, methylcyclohexane, isopropyl alcohol, trimethylpentane, n-octane, trichloroethane, trifluoroethanol, pyridine, 1-butanol, tetrachloroethylene, chlorobenzene, xylene, dibutyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide, formamide, and dimethylformamide. It is also contemplated that the samples may comprise the components to be cocrystallized in two or more solvents, either as a homogeneous solution, as an emulsion, or in another physical state.
• The crystallization may be accomplished in a variety of ways, and preferably includes evaporation of the solvent(s). For example, the solvent may be evaporated either slowly (for example, evaporating to dryness over a time period of four days, alternatively two days or more) or quickly (for example, evaporating to dryness over a time period of 24 hours, alternatively under two days). By varying the rate of evaporation among separate samples, one can introduce desired variability into a screening method. For example, in a screening method, a first portion of samples can be subjected to relatively slow evaporation, and a second portion of the samples can be subjected to relatively fast evaporation.
• In the present methods, ultrasound may be applied at different stages of a screening process or a crystallization process. For example, a solution which comprises the components to be cocrystallized can be sonicated at some point during the screening process. One may sonicate such a solution before, during, or after the initiation of cooling of the solution from an undersaturated, saturated, or supersaturated state. As other examples, one may sonicate a solution before, during, or after the beginning of evaporation of solvent, or before, during, or after the addition of an immiscible antisolvent to the solution.
• In the present methods, the crystallizing step and the sonicating step can overlap. For example, where the samples are provided as a solution of the components to be cocrystallized in a solvent, the crystallizing step may be performed by evaporating the solvent, and the sample may be sonicated during that evaporation. Furthermore, the sonication can be periodic during the evaporation. For example, the sample can be periodically sonicated for about 20 seconds, and the periods can be about 30 minutes (in other words, the sample is sonicated for about 20 seconds every 30 minutes). Furthermore, the sonication can be a single pulse. For example, the sonication could be carried out one time for 5 to 40 seconds or multiple times for a liked period, or for other suitable period(s).
• In the present methods, the samples can comprise a solution, suspension (such as a melt), or other mixture of the components to be cocrystallized. The sample will typically be prepared by heating above room temperature to achieve supersaturation of the components. It may be desirable to begin cooling the samples (for example, to room temperature) before the sonicating step. Alternatively, the samples may be cooled and sonicated at the same time. Alternatively, the method can include crash-cooling the samples (rapidly lowering the temperature, for example, by immersing in an ice bath) before the sonicating step. Alternatively, the samples may be crash-cooled and sonicated at the same time.
• The present methods can include the step of adding a second solvent to a solution containing the components to be cocrystallized. For example, the second solvent may be added to facilitate crystallization.
• The crystallization step can be initiated by sonication, and it may additionally be initiated by seed materials or other techniques. In the various embodiments of the present methods, crystallization may start before, during, or after the application of ultrasound. In many cases, the crystallization and sonication steps will overlap. For example, sonication may begin before crystallization but continue even after crystallization begins. As another example, crystallization may begin before sonication. As yet another example, the samples may be sonicated in a pulsing manner throughout the crystallization process. Alternatively, sonication may be employed to initiate crystallization and be discontinued when crystallization (such as nucleation) begins.
• The sample containing two or more components to be cocrystallized is provided in a receptacle suitable for crystallization, such as a vial, well-plate or capillary tube. The sample may be formed in the receptacle or formed outside the receptacle and then placed in it. The components can initially be present in the sample below, at or above the point of saturation at a given temperature at the time of placement in the receptacle. Through evaporation, the use of an antisolvent, temperature variation, and/or other suitable means, the sample will reach a point where crystallization begins. After a suitable amount of time, when a solid or semisolid appears, the resulting sample (more particularly, the solid formed from the sample) is ready for analysis.
• Crystallization may be performed as a seeded operation or an unseeded operation. In a seeded operation, a selected quantity of seed crystals is included in the system. The characteristics of the seed crystals typically influence the characteristics of the crystals generated from the system. Crystallization may be performed by heterogeneous or homogeneous mechanisms. However, it is noted that ultrasound may be applied as a way of omitting the presence of seed crystals.
• Another technique for cocrystallizing chemical substances employs an emulsion. An emulsion is a mixture of two or more immiscible liquids where one liquid is in a discontinuous phase within the other liquid. Emulsions are frequently formed and/or stabilized by the use of agents called emulsifiers. However, sonication of an immiscible mixture of solvents also allows the generation of emulsions.
• The present methods may also include the step of forming an emulsion comprising two or more substantially immiscible solvents and the components to be cocrystallized. The emulsion can be formed during the sonicating step, wherein an immiscible mixture of said solvents is sonicated to form the emulsion. Alternatively, the emulsion can be formed before the sonicating step.
• Emulsions can be employed as part of a screening method and/or solidification method to generate additional solid state phases of an active agent. Emulsions can allow interface between the two solvents over a high surface area. At such interfaces, nucleation and/or growth of some solid state phases may be favored, based on the influence of each solvent on the growth of each solid state phase.
• An emulsion may be prepared by combining a solution of an active agent and a guest in a first solvent with a second solvent, wherein the first solvent and the second solvent are substantially immiscible with each other. The combined solvents may then be sonicated while evaporating cooling, adding and antisolvent, or using other solidification techniques until a precipitate containing the active agent and the guest appears.
• Another technique for cocrystallizing employs a slurry. A slurry is a dispersion of solid particles in a liquid phase. The liquid phase comprises one or more solvents in which at least one of the active agent and a guest is not completely soluble. The process of slurrying a metastable form of an active agent and/or guest, aiming at finding a cocrystal or a solvated form, is foreseen to be accelerated by the use of ultrasound during the slurrying process.
• The present methods may also include the step of forming a slurry comprising a solvent and the active agent and the guest. The slurry can be formed during the sonicating step, wherein a mixture of the active agent and the guest and the solvent are sonicated to form the slurry. Alternatively, the slurry can be formed before the sonicating step.
• Generating a variety of solid state phases is an important object of screening. A sufficient number of diverse processes and parameters should be employed to maximize the likelihood that a high percentage of possible solid state phases is generated. Samples should be generated under various thermodynamic and kinetic conditions.
• It is preferable that the generation of solid state phases is carried out under a wide variety of conditions. For example, solids should be generated in the presence and absence of various solvents, as the solvent may play a role in the formation of certain forms, and with and without sonication. As another example it is also preferable to prepare solid forms under different conditions of temperature and pressure, as different solid forms may be favored by different conditions.
• It is also contemplated that the present methods are advantageous for generating solid state phases from viscous solutions. For example, the present methods may be used with samples that are solutions having a viscosity greater than about 0.9 poise before the solution is sonicated.
• It is also contemplated that the present methods are advantageous for generating solid state phases from amorphous forms of the active agent. Samples can be formed or provided by preparing a solution from a solvent and an amorphous solid comprising the active agent. The solvent may be sonicated while the amorphous solid is added to the solvent.
• It is contemplated that, in the context of a comprehensive screening method, a plurality of samples can be divided into a large number of sets and subsets. A multiplicity of sets and subsets are useful so that more than one parameter may be varied and the cumulative effect of multiple varied parameters may be assessed. For example, a plurality of samples may be divided into a first set, a second set, a third set, and a fourth set. The first set and the second set can comprise a solution of the active agent in a first solvent or with a first guest, while the third set and the fourth set comprise a solution of the active agent in a second solvent or with a second guest. The first set and the third set can be sonicated, and the second set and the fourth set can be unsonicated. The benefit of this method is that the effects of ultrasonic crystallization with different solvents and/or different guests can be analyzed and compared.
• Detection of Cocrystals and Crystals
• Cocrystals (as well as other crystals) may be detected by x-ray diffraction analysis, Raman analysis, or other suitable techniques. The observation of physical properties of a solid (particularly its melting point) which differ from the physical properties of the starting materials and the polymorphs and/or solvates and/or hydrates of the starting materials, is an indicator that a cocrystal has been formed.
• Cocrystals and other crystals generated after crystallization and sonication steps may be identified by any suitable method, including but not limited to visual analysis (such as when different forms exhibit different colors), microscopic analysis including electron microscopy (such as when different forms happen to have different morphologies), thermal analysis (such as determining the melting points), conducting diffraction analysis (such as x-ray diffraction analysis, electron diffraction analysis, neutron diffraction analysis, as well as others), conducting Raman or infrared spectroscopic analysis, or conducting other spectroscopic analysis. Any appropriate analytical technique that is used to differentiate structural, energetic, or performance characteristics may be used in connection with the present methods.
• In a preferred embodiment, the samples are placed in a well plate and then sonicated. The chemical substances solidify in the wells of the well plate (for example, a 96-well plate or 384-well plate). The solidified chemical substances are then analyzed in the well plate by one of the foregoing analysis techniques, preferably by x-ray diffraction (such as transmission x-ray diffraction) and/or by Raman spectroscopy. A synchrotron may be used as the source of radiation for conducting diffraction analyses.
• Synchrotron radiation may be used to study structural details of solid samples with a resolution not practically attainable using traditional x-ray instrumentation. This may enable differentiation between different solid state phases that is not attainable with other x-ray radiation sources.
• The present methods can significantly assist in the identification of the possible cocrystals of a chemical substance(s). For example, the present methods can be used as part of a screening method and can improve the likelihood of identifying a solid state phase having properties such as better stability, bioavailability, solubility, or absorption characteristics. In some cases, an identified cocrystal of an active agent and a guest may have better biological activity than a crystal of the active agent.
• After samples (including a solution, emulsion, slurry, or mixture containing the active agent and guest) are placed in a receptacle, the receptacle may be centrifuged. Centrifugation may be employed for a variety of reasons. First, use of a centrifugal evaporator may assist evaporation while concentrating solid or semisolid material at one end of a capillary space. This has advantages in connection with in-situ analysis, in that the generated form will be located at a consistent place in the receptacle. Also or alternatively, centrifuging may be used to provide additional environmental variation, which is desirable in a screening method.
EXAMPLE 1
• In this Example, a new solid form of sulfathiazole was prepared from solution in acetonitrile using sonication. This form was not seen without sonication under the same conditions. Form II of sulfathiazole was generated without sonication.
• A saturated solution of sulfathiazole in acetonitrile at 45° C. was prepared, filtered hot and split between two pre-heated 1-dram vials (about 1 ml each). The samples were left to slowly cool to room temperature. One sample was then nucleated by ultrasound treatment using 5 pulses of one second each at 20 kHz, amplitude control set at 40, using a Cole Palmer ultrasonic processor CP130 fitted with a 6 mm tip stainless steel probe, while the other sample was left undisturbed (unsonicated). Both samples were then left to evaporate slowly to dryness. XRPD patterns of the sonicated and unsonicated samples showed that the sonicated sample gave an unknown pattern (FIG. 1) whereas the unsonicated sample yielded the known Form II of sulfathiazole (FIG. 2). The sonicated sample is believed to be a novel solid form of sulfathiazole.
EXAMPLE 2
• In this Example, an unusual solid form of an acetone solvate of sulfathiazole was prepared. Without sonication, this form was only seen in a mixture with the known form of an acetone solvate of sulfathiazole.
• A saturated solution of sulfathiazole in acetone at 45° C. was prepared, filtered hot and split between two pre-heated 1-dram vials (about 1 ml each). The samples were left to slowly cool to room temperature. One sample was then nucleated by ultrasound treatment using 5 pulses of one second each at 20 kHz, amplitude control set at 40, using a Cole Palmer ultrasonic processor CP130 fitted with a 6 mm tip stainless steel probe, while the other sample was left undisturbed (unsonicated). Both samples were then left to evaporate slowly to dryness. XRPD patterns of the sonicated and unsonicated patterns showed that the sonicated sample gave an unknown pattern (FIG. 3) whereas the unsonicated sample yielded a mixture of this same form with the known acetone solvate of sulfathiazole (FIG. 4). The sonicated sample is believed to contain an unusual solid form which is novel in its purity.
EXAMPLE 3
• In this Example, a new DMSO solvate of carbamazepine was prepared.
• Three 100 μl samples of a saturated solution of carbamazepine in DMSO at 50° C. were placed in 3 pre-heated HPLC vials. The samples were allowed to cool to ambient temperature. One sample was nucleated by ultrasound treatment (5 one-second pulses, 20 kHz, amplitude control set at 40, using the Cole Palmer ultrasonic processor with a 3 mm tip stainless steel probe), while another was stirred using a stir bar and the other was left undisturbed (unsonicated). While the sonicated sample yielded a new DMSO solvate, the other samples remained as solutions indefinitely. The XRPD pattern of the new DMSO solvate is shown inFIG. 5.
EXAMPLE 4
• In this Example, a new form of sulfathiazole was made from a sonicated supersaturated solution in methylethylketone.
• A saturated solution of sulfathiazole in methylethylketone at 55° C. was split in 3 pre-heated vials (about 0.5-1 ml each). The samples were crash-cooled by placing them in an ice/water bath. One sample was then sonicated for five minutes (amplitude 20 kHz, amplitude control set at 40, using the Cole Palmer ultrasonic processor with a 6 mm probe), while another was stirred using a magnetic stir bar. The last sample was left undisturbed. The three samples were then placed in the refrigerator (5-6° C.). While the sonicated sample was found to have crystallized, the unsonicated samples remained indefinitely as solutions (still solutions after three weeks). The solids in the sonicated sample were filtered and an XRPD pattern taken (FIG. 6), indicative of an unknown form, and it was determined that this solid was unsolvated according to TGA and DSC scans.
EXAMPLE 5
• In this Example, crystallization of the most stable form of 4-methyl-2-nitroacetanilide was performed on a small scale. The compound 4-methyl-2-nitroacetanilide is known to crystallize in three polymorphic forms, White, Amber, or Yellow. The compound is known as “WAY” due to the colors of its forms. The relative stability of the three forms has been studied and it was demonstrated that the white form was the most stable form, and the yellow form was more stable than the amber form. (See, for example, Yeadon, PhD thesis, Burnel University, West Yorkshire, UK (1985), and Xiaorong He, “Thermodynamic and kinetic control of the crystallization of polymorphs”, PhD thesis, Purdue University, West Lafayette, Ind. USA (2000)). The least stable amber form has rarely been seen. All three crystal structures have been solved and published. (See, for example, Moore et al., “Yellow and white forms”, J. Cryst. Spect. Res., 13, 279 (1983), and Moore et al., “Amber form”, J. Cryst. Spect. Res., 14, 283 (1984).
• Sixty-four evaporative experiments in various solvents and combinations of solvents (32 sonicated samples and 32 unsonicated samples) were carried out on the compound WAY.
• A weighed amount of the compound WAY was placed in a vial and a measured volume (V) of solvent added (solvent 1), so as to dissolve the solids. In some samples, an additional volume of a second solvent (solvent 2) was added to the solution. All solutions were filtered using a 0.2 μm nylon filter and split 4-ways into 4 1-dram vials. The vials were then covered individually with aluminum foil. The aluminum foil was pierced with one hole for slow evaporations (SE) and 5 holes for fast evaporations (FE). Half of the vials were then sonicated twice a day, every day, until complete evaporation of the solvents. The other half of the vials were left to evaporate undisturbed. Table 1 summarizes the solvent conditions used for these evaporations, each set of solvent conditions being used for four vials (two for samples to be sonicated while evaporating (SE and FE), two for control experiments without sonication (SE and FE)).

  TABLE 1
  Solutions used for crystallization of
  4-methyl-2-nitroacetanilide

  WAY (mg)	Solvent 1	V (S1)	Solvent 2	V (S2)
  146.3	1,4-dioxane	3 ml	—	—
  149.8	acetone	3 ml	—	—
  155.2	tetrahydrofuran	3 ml	—	—
  149.9	ethanol	10 ml	—	—
  147.7	2-butanone	3 ml	—	—
  155.6	dichoromethane	1 ml	—	—
  146.2	chloroform	1 ml	—	—
  155.0	trifluroethanol	1 ml	—	—
  151.0	ethyl acetate	3 ml	—	—
  148.9	dichloroethane	1 ml	—	—
  149.1	pyridine	1 ml	—	—
  156.5	methanol	5 ml	—	—
  150.2	acetonitrile	2 ml	—	—
  144.9	dichloromethane	2 ml	nitromethane	2 ml
  155.5	dichloromethane	2 ml	heptane	2 ml
  146.7	trifluoroethanol	2 ml	water	2 ml
  154.3	acetone	3 ml	toluene	1 ml
  146.4	acetone	3 ml	water	1 ml

• The results are presented in Table 2, showing the occurrences of mixtures of the white and yellow solid forms and of the most stable solid form of the compound, the white form of WAY. All other solids were the faster growing, less stable yellow form. These results show that using ultrasound as part of a screening process can increase the likelihood of obtaining the possible solid forms of a chemical substance. These results also show that using ultrasound in a crystallization process can facilitate the generation of the most stable form of the chemical substance.

  TABLE 2
  	Sonicated	Sonicated	Unsonicated	Unsonicated
  Evaporative	SE	FE	SE	FE
  conditions
  # of	16	16	16	16
  samples
  Solids	16	16	14	16
  White +	5	3	1	1
  yellow
  mixture
  Pure White	4	2	0	1
  Form

EXAMPLE 6
• In this Example, a micro-scale crystallization study was performed to yield the most stable form of 4-methyl-2-nitroacetanilide (WAY).
• Solutions of WAY were prepared in various solvents by dissolution of a weighed amount of the solid compound in a measured volume of solvent (solvent 1). These solutions were then filtered using a 0.2 μm nylon filter. The weights and volumes used to prepare each solutions are summarized in Table 3.

  TABLE 3
  Summary Table Of Experimental Conditions For
  The Preparation Of Solutions Of Way

  WAY (mg)	Solvent	V (ml)

  103.2	chloroform	5.16
  107.7	1,4-dioxane	5.37
  101.9	acetone	5.1
  100.8	tetrahydrofuran	5.04
  112.7	ethanol	11.3
  105.7	2-butanone	5.27
  108.6	acetonitrile	5.43
  94.0	methanol	4.7

• Each solution was then used directly or was diluted with a second solvent in a 3:1 ratio of the first solvent to the second solvent. Aliquots of 200 μl of the solutions were placed in wells of a flat bottom polypropylene 96-well plate and covered by a polypropylene mat. The mat was pierced to provide one hole per well. Two identical plates were prepared. The solvent(s) used in each of the wells are shown in Table 4. One plate was sonicated for 20 seconds every 30 minutes until evaporation to dryness of all or the majority of the samples in each well. Sonication was performed using aMisonix 3000 sonicator with microplate horn. The second plate was kept undisturbed (unsonicated) during the time of the evaporation.

  TABLE 4
  Solvent Conditions Used For Individual Wells
  Of The 96-Well Plate Evaporation Experiment

  	1	2	3	4	5	6	7	8	9	10	11	12

  A

  CH

  CH

  CH:WA

  CH:WA

  CH:NM

  CH:NM

  CH:TO

  CH:TO

  CH:EA

  CH:EA

  CH:HE

  CH:HE

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:

  B

  DX

  DX

  DX:WA

  DX:WA

  DX:NM

  DX:NM

  DX:TO

  DX:TO

  DX:EA

  DX:EA

  DX:HE

  DX:HE

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:

  C

  AC

  AC

  AC:WA

  AC:WA

  AC:NM

  AC:NM

  AC:TO

  AC:TO

  AC:EA

  AC:EA

  AC:HE

  AC:HE

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  D

  TH

  TH

  TH:WA

  TH:WA

  TH:NM

  TH:NM

  TH:TO

  TH:TO

  TH:EA

  TH:EA

  TH:HE

  TH:HE

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  E

  EO

  EO

  EO:WA

  EO:WA

  EO:NM

  EO:NM

  EO:TO

  EO:TO

  EO:EA

  EO:EA

  EO:HE

  EO:HE

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  F

  MK

  MK

  MK:WA

  MK:WA

  MK:NM

  MK:NM

  MK:TO

  MK:TO

  MK:EA

  MK:EA

  MK:HE

  MK:HE

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  G

  AN

  AN

  AN:WA

  AN:WA

  AN:NM

  AN:NM

  AN:TO

  AN:TO

  AN:EA

  AN:EA

  AN:HE

  AN:HE

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  H

  MO

  MO

  MO:WA

  MO:WA

  MO:NM

  MO:NM

  MO:TO

  MO:TO

  MO:EA

  MO:EA

  MO:HE

  MO:HE

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

  3:1

• In Table 4, the solvent mixtures are described as X:Y volume:volume ratio of solvents. In Table 4, the following abbreviations are used: AC=acetone; AN=acetonitrile; CH=chloroform; DX=1,4-dioxane; EO=ethanol; EA=ethyl acetate; HE=heptane; MK=2-butanone; MO=methanol, NI=nitromethane; TH=tetrahydrofuran; TO=toluene; WA=water.

  TABLE 5
  Summary Table Of Results Obtained For The Sonicated
  Plate

  	1	2	3	4	5	6	7	8	9	10	11	12

  A

  Y

  W

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  B

  NC

  NC

  N

  N

  NC

  NC

  NC

  NC

  NC

  NC

  NC

  NC

  C

  W

  W

  Y

  Y

  NC

  W

  W

  W

  Y

  Y

  W

  W

  D

  W

  W

  W

  W

  Y

  Y

  W

  W

  W

  W

  W

  Y

  E

  NC

  NC

  NC

  NC

  NC

  Y

  NC

  Y

  NC

  NC

  NC

  NC

  F

  W

  NC

  W

  NC

  NC

  W

  W

  Y

  W

  Y

  W

  W

  G

  Y

  W

  W

  NC

  NC

  W

  W

  NC

  W

  NC

  Y

  Y

  H

  W

  W

  W

  W

  W

  Y

  W

  W

  NC

  W

  Y

  Y

  In Table 5, the following abbreviations are used:

  Y = Yellow form;

  W = White form;

  N = Nucleated = mostly liquid with a small fraction of indeterminate solids;

  NC = Not Crystallized).

• Table 5 shows which solid form of WAY was generated in each of the wells of the 96-well plate that was sonicated.

  TABLE 6
  Summary Table Of Results Obtained For The Unsonicated
  Plate

  	1	2	3	4	5	6	7	8	9	10	11	12

  A

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  W

  Y

  B

  NC

  NC

  N

  N

  NC

  NC

  NC

  NC

  NC

  NC

  NC

  NC

  C

  Y

  Y

  Y

  Y

  Y

  NC

  Y

  Y

  Y

  Y

  Y

  Y

  D

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  E

  NC

  NC

  NC

  NC

  NC

  NC

  Y

  Y

  NC

  Y

  NC

  NC

  F

  Y

  Y

  Y

  Y

  NC

  NC

  NC

  NC

  Y

  Y

  Y

  NC

  G

  Y

  Y

  Y

  Y

  NC

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  H

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  Y

  NC

  Y

  Y

  In Table 6, the following abbreviations are used:

  Y = Yellow form;

  W = White form;

  N = Nucleated = mostly liquid with a small fraction of indeterminate solids;

  NC = Not Crystallized).

• Table 6 shows which solid form of WAY was generated in each of the wells of the 96-well plate that was not sonicated.
• This shows that a screening process in which samples are sonicated yielded more occurrences of the most stable (but less-frequently generated) white form.
EXAMPLE 7
• In this Example, a micro-scale crystallization study of sulfamerazine was performed. The study showed that sonication facilitated the generation of a difficult-to-make more stable form.
• Sulfamerazine is known to crystallize in two polymorphic forms, Form I and Form II, with Form I being the most commonly encountered form. Despite the elusive character of Form II, it has been demonstrated that Form II was the most stable form at room temperature. Zhang et al., J. Pharm. Sci., 91(4), 1089-1100 (2002).
• Solutions of sulfamerazine at a concentration of 10 mg/ml were prepared in acetone and in tetrahydrofuran by dissolution of a weighed amount of sulfamerazine in a measured volume of solvent. The solutions were then filtered using a 0.2 μm nylon filter. Aliquots of 150 μl of solution (acetone or tetrahydrofuran) were added to 50 μl of a second solvent in the wells of a flat bottom polypropylene 96-well plate. The plate was covered by a polypropylene mat, and the mat was pierced with one hole per well. Two identical plates were prepared. One of the plates was sonicated for 20 seconds every 30 minutes until evaporation to dryness of all samples in each well. Sonication was performed using aMisonix 3000 sonicator with microplate horn. The second plate was kept undisturbed (unsonicated), during the time of the evaporation. Table 7 summarizes the results obtained for the sonicated and unsonicated plates for each condition of evaporation. The difficult-to-make but more stable Form II was found in the sonicated plate but not in the unsonicated plate.

  TABLE 7
  Conditions Of Evaporations From Mixture Of Solvents

  				Non-
  			Sonicated	sonicated
  	Solvent 1	Solvent 2	Form	Form
  	acetone	Acetonitrile	IIa	Ia
  	acetone	Chloroform	I	I
  	acetone	1,4-dioxane	I	Ac
  	acetone	Ethanol	I	I
  	acetone	ethyl acetate	I	I
  	acetone	Heptane	I	I
  	acetone	2-butanone	I	I
  	acetone	Methanol	I	I
  	acetone	Nitromethane	IIb	Ia
  	acetone	Tetrahydrofuran	I	I
  	acetone	Toluene	I	I
  	acetone	Water	I	I
  	tetrahydrofuran	Acetone	I	I
  	tetrahydrofuran	Acetonitrile	I	I
  	tetrahydrofuran	Chloroform	I	I
  	tetrahydrofuran	1,4-dioxane	I	Ac
  	tetrahydrofuran	Ethanol	I	I
  	tetrahydrofuran	ethyl acetate	I	I
  	tetrahydrofuran	heptane	I	I
  	tetrahydrofuran	2-butanone	I	I
  	tetrahydrofuran	methanol	I	I
  	tetrahydrofuran	nitromethane	I	I
  	tetrahydrofuran	toluene	I	I
  	tetrahydrofuran	Water	I	I
  	aduplicate experiment gave the same result
  	bduplicate experiment gave form I
  	cnew form

• In this example, the elusive, more stable Form II of sulfamerazine was generated by a crystallization process that included ultrasound application, but was not generated without ultrasound application. This example shows that a screening process that includes sonication is more likely to generate the more stable solid forms of the chemical substance. This example also demonstrates that it may be desirable to include some unsonicated samples in a screening process, as this can increase the likelihood of obtaining the possible solid forms of the chemical substance.
EXAMPLE 8
• In this Example, the difficult-to-make Form I of sulfathiazole was generated by crystallization from a solvent mixture with sonication used to form an emulsion.
• Sulfathiazole Form I is a disappearing polymorph, today rarely seen crystallized directly from solution. This result is of interest for polymorph screening purposes. Blagden et al., “Crystal structure and solvent effects in polymorphic systems: sulfathiazole,” J. Chem. Soc. Faraday, 94, 1035-1045 (1998)
• A 500 μl aliquot of a saturated solution of sulfathiazole in ethanol at 50° C. was filtered hot and added to 500 μl of warm p-cymene in a pre-heated 1-dram vial on a hotplate at 55° C. The biphasic sample was then sonicated while evaporating until a precipitate appeared (40 minutes sonication, using a Cole-Palmer ultrasonic processor fitted with a 6 mm tip stainless steel probe, amplitude control set at 60). The solids obtained were filtered and analyzed by XRPD. The XRPD pattern was characteristic of sulfathiazole Form I (FIG. 7)
EXAMPLE 9
• In this example a polymorph screen is carried out. Solutions of chemical substance A in the following solvents or solvent mixtures (with volume:volume ratio indicated) are prepared by robotic weighing of chemical substance and solvent delivery and mixing: acetone, acetonitrile, chloroform, 1,4-dioxane, ethanol, ethyl acetate, heptane, 2-butanone, methanol, nitromethane, tetrahydrofuran, toluene, water, dichloromethane, diethyl ether, isopropyl ether, cyclohexane, methylcyclohexane, isopropyl alcohol, trimethylpentane, n-octane, tri-chloroethane, trifluoroethanol, pyridine, 1-butanol, tetrachloroethylene, chlorobenzene, xylene, dibutyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide, formamide, dimethylformamide, 2:1 methanol:acetonitrile, 2:1 methanol:dichloromethane, 3:1 methanol:ethyl acetate, 4:1 methanol:methyl-tert-butyl ether, 1:1 methanol:2-butanone, 3:1 trifluoroethanol:isopropyl acetate, 2:1 trifluoroethanol:isopropyl ether, 1:1 trifluoroethanol:nitromethane, 1:5 water:acetone, 1:4 water:acetonitrile, 1:5 water:dioxane, 1:9 water:2-propanol, and 1:5 water:tetrahydrofuran.
• Aliquots of 200 μL of each solution are delivered in duplicate using a liquid handler to the wells of a 96 well plate. Concentrations of the solutions are selected such that the final amount of chemical substance in each well is between 0.1 mg and 1.0 mg. The well plate body is made of polypropylene. The well plate is a thin bottom well plate suitable for x-ray diffraction analysis of crystals in the well plate. Two wells contain samples of an x-ray powder diffraction standard. The well plate solutions are left uncovered and are allowed to evaporate to dryness while being sonicated for 20 seconds every hour using aMisonix 3000 sonicator with microplate horn. Nitrogen flow into wells is used when evaporation needs to be facilitated. The well plate is mounted on edge on the stage of a Bruker D8 microdiffractometer with the well openings facing the x-ray source. The solids at the bottom of each well are analyzed by automated stage movement. It is expected that a useful variety of different solid forms of the chemical substance will be produced in the wells.
EXAMPLE 10
• Cocrystals of fluoxetine HCl:benzoic acid were formed using the following procedures. A solution of fluoxetine HCl and benzoic acid in acetonitrile was prepared. A physical mixture of fluoxetine HCl and benzoic acid in a 1:1 molar ratio was used to make a solution having a concentration of about 200 mg/mL. The solution was placed in four 96-well plates. The only difference among well plates was the amount of solution put into each well. Two well plates were charged with 15 μL per well, and two plates were charged with 50 μL per well. One of the well plates containing 15 μL samples and one of the well plates containing 50 μL samples were sealed and left standing at room temp. The other well plate containing 15 μL samples and the other well plate containing 50 μL samples were sealed and sonicated with a Misonix 96-well plate sonicator.
• None of the wells in the 15 μL plates (either standing or sonicated) nucleated (even after very strong sonication with the Misonix plate sonicator or the probe). The plate left standing at room temp with 50 μL volumes nucleated in about 15% of the wells nucleated on standing (but the majority of the wells had benzoic acid growth, not cocrystal nucleation). For the 50 μL plate that was sonicated, almost half of the wells nucleated (with only one well of benzoic acid and the rest as cocrystal).
• In a system comprising a 1:1 molar ratio of fluoxetine HCl and benzoic acid in acetonitrile, concentrations of about 200 mg/ml of the API:guest mixture in CH₃CN (acetonitrile) were used. Nucleation could be caused by sonication in a concentration range of from about 35 to about 100 mg/ml. Sonication indicates a clear advantage in this case of intermediate concentrations. Almost all of the samples having a concentration of 200 mg/ml nucleated with sonication using either a probe or the well-plate sonicator. In contrast, about 15% of the wells in a plate at 200 mg/ml nucleated the cocrystal without sonication.
EXAMPLE 11
• Cocrystal screening of chlorzoxazone is carried out using the following procedures. Solutions of chlorzoxazone and various guests are prepared in acetonitrile, methanol, aqueous ethanol, and acetone in 1:1 molar ratios having a concentrations of about 10 mg/mL. The guests used include benzoic acid, gallic acid, and 2,5-dihydroxybenzoic acid. Aliquots of 20 microliters of the solutions are placed in different capillary tubes. The samples are sonicated for 1 minute by placement of the capillary tubes in a sonication bath after the volume of the solutions are reduced to the point where both components are supersaturated. This concentration is calculated based on the solubility of the individual components. The sonication is repeated every hour for 24 hours as the solutions evaporate. A duplicate set of capillary tubes is allowed to evaporate at room temperature without sonication.
• Solids are present in most of the capillary tubes and are analyzed by Raman spectroscopy and by x-ray powder diffraction. It is expected that a number of cocrystals are present in the sonicated capillary tubes and that different polymorphs, hydrates, or solvates of the cocrystals may also be present. It is expected that solids in the unsonicated capillary tubes will have a different variety of solid forms present compared to the sonicated samples and that there will not be as many cocrystals formed.
• This example demonstrates the use of capillary tubes for cocrystallization. This example also demonstrations that samples having low concentrations and/or low volumes may be employed in a cocrystallization process.
EXAMPLE 12
• Cocrystal and salt screening of imipramine hydrochloride is carried out using the following procedures. Solutions of imiprimine hydrochloride and various guests are prepared in acetonitrile, methanol, aqueous ethanol, and acetone in 1:1 molar ratios having a concentrations of about 10 mg/mL. The guests include benzoic acid, gallic acid, and 2,5-dihydroxybenzoic acid. Aliquots of 100 microliters of the solutions are placed in different wells of 96-well polypropylene plates that have thin walls. The plates are sonicated for 1 minute in a sonication bath after the volume of the solutions are reduced to the point where both components are supersaturated. This concentration is calculated based on the solubility of the individual components. The sonication is repeated every hour for 24 hours as the solutions continue to evaporate. A duplicate set of well plates is allowed to evaporate at room temperature without sonication.
• Solids are present in most of the wells and are analyzed in situ, automatically by transmission x-ray powder diffraction through the well plates. It is expected that a number of cocrystals and/or salts are present in the sonicated plates and that different polymorphs, hydrates, solvates, desolvates, and dehydrates of the cocrystals and/or salts may also be present. It is expected that solids in the unsonicated plates will have a different variety of solid forms present compared to the sonicated samples and that there will not be as many cocrystals and/or salts formed.
• All patents, test procedures, and other documents cited herein, including priority documents, are fully incorporated by reference to the extent such disclosure is not inconsistent with this invention and for all jurisdictions in which such incorporation is permitted.
• While the present invention has been described and illustrated by reference to particular-embodiments, it will be appreciated by those off ordinary skill in the art that the invention lends itself to many different variations not illustrated herein. For these reasons, then, reference should be made solely to the appended claims for purposes of determining the true scope of the present invention.
• Although the appendant claims have single appendencies in accordance with U.S. patent practice, each of the features in any of the appendant claim can be combined with each of the features of other appendant claims or the main claim.

  	TABLE 8
  	10-camphorsulfonic acid
  	10-undecylenic acid
  	1-hydroxy-2-naphthoic acid
  	2,4-dihydroxybenzoic acid
  	2,5-dihydroxybenzoic acid
  	2-aminopropionic acid
  	2-ethylbutyrinc acid
  	2-furancarboxylic acid
  	2-mercaptobenzoic acid
  	3-methylbutanoic acid
  	3-phenylpropionic acid
  	4-aminobenzoic acid
  	4-aminosalicylic acid
  	4-hydroxybenzoic acid
  	adipic acid
  	alginic acid
  	anisic acid
  	arginine
  	ascorbic acid
  	asparagine
  	aspartic acid
  	aspirin
  	benzenesulfonic acid
  	benzoic acid
  	4-acetamidobenzoic acid
  	beta-alanine
  	camphoric acid
  	camphorsulfonic acid
  	carbonic acid
  	cholic acid
  	cinnamic acid
  	citric acid
  	cyclamic acid
  	cyclohexanecarboxylic acid
  	cyclohexylacetic acid
  	cysteine
  	diphenylacetic acid
  	dodecylsulfonic acid
  	ethane-1,2-disulfonic acid
  	ethanesulfonic acid
  	ethanesulfonic acid, 2-hydroxy
  	ethylenediaminetetraacetic acid
  	ethylsulfuric acid
  	fumaric acid
  	galactaric acid
  	gallic acid
  	gentisic acid
  	glucoheptonic acid
  	gluconic acid
  	glutamic Acid
  	glutamine
  	glutaric acid
  	glutaric acid, 2-oxo-
  	glycine
  	glycolic acid
  	hippuric acid
  	histidine
  	hydroxyproline
  	isoleucine
  	lactobionic acid
  	lauric acid
  	leucine
  	levulinic acid
  	lysine
  	maleic acid
  	malic acid
  	malonic acid
  	mandelic acid
  	m-methoxybenzoic acid
  	naphthalene-1,5-disulfonic acid
  	naphthalene-2-sulfonic acid
  	n-decanoic acid
  	niacin
  	nicotinic acid
  	n-tetradecanoic acid
  	oleic acid
  	o-methylbenzoic acid
  	orotic acid
  	orthoboric acid
  	o-toluic acid
  	p-acetamidobenzoic acid
  	palmitic acid
  	pamoic acid
  	phenoxyacetic acid
  	phenylacetic acid
  	phenylalanine
  	picric acid
  	pivalic acid
  	proline
  	p-toluenesulfonic acid
  	pyroglutamic acid
  	pyruvic acid
  	salicylic acid
  	sebacic acid
  	serine
  	sorbic acid
  	stearic acid
  	succinic acid
  	sulfosalicylic acid
  	tartaric acid
  	terephthalic acid
  	thiocyanic acid
  	threonine
  	tiglic acid
  	tryptophan
  	tyrosine
  	valeric acid
  	valine

• 	TABLE 9
  	Name	CAS #
  	Potassium bicarbonate	298-14-6
  	Potassium carbonate	584-08-7
  	Potassium chloride	7447-40-7
  	Potassium hydroxide	1310-58-3
  	Potassium metabisulfite	16731-55-8
  	Potassium nitrate	7757-79-1
  	Potassium nitrite	7758-09-0
  	Potassium permanganate	7722-64-7
  	Potassium persulfate	7727-21-1
  	Potassium phosphate, dibasic	2139900
  	Potassium Phosphate Monobasic	7778-77-0
  	potassium phosphate, tribasic,	7778-53-2
  	n-hydrate
  	Potassium sulfate	7778-80-5
  	Sodium bicarbonate	144-55-8
  	Sodium bisulfite	7631-90-5
  	Sodium borohydride	16940-66-2
  	Sodium carbonate	497-19-8
  	Sodium Carbonate Monohydrate	1486118
  	Sodium chloride	7647-14-5
  	Sodium dithionite	7775-14-6
  	Sodium fluoride	7681-49-4
  	Sodium hexametaphosphate	10124-56-8
  	Sodium hydroxide	1310-73-2
  	Sodium hypochlorite	7681-52-9
  	Sodium Metabisulfite	7681-57-4
  	Disodium metasilicate	6834-92-0
  	sodium monophosphate	7681-53-0
  	Sodium nitrate	7631-99-4
  	Sodium nitrite	7632-00-0
  	sodium hydrogen phosphate	7558-79-4
  	Sodium phosphate Monobasic	7558-80-7
  	Sodium Pyrophosphate	7722-88-5
  	Sodium silicate	1344-09-8
  	Sodium Sulfate Decahydrate	7727-73-3
  	Sodium sulfite	7757-83-7
  	Sodium Thiosulfate	10102-17-7
  	Pentahydrate
  	Calcium acetate	5743-26-0
  	Calcium Carbonate	471-34-1
  	Calcium Chloride Dihydrate	10035-04-8
  	Calcium gluconate	299-28-5
  	Calcium hydroxide	1305-62-0
  	Calcium oxide	1305-78-8
  	Calcium phosphate, dibasic	7757-93-9
  	Calcium Phosphate Monobasic	7758-23-8
  	Calcium sulfate	7778-18-9
  	Magnesium hydroxide	1309-42-8
  	Magnesium Sulfate Heptahydrate	10034-99-8
  	Aluminum	7429-90-5
  	Aluminum ammonium sulfate	7784-26-1
  	Aluminum chloride	7446-70-0
  	Aluminum hydroxide	21645-51-2
  	Aluminum potassium sulfate,	7784-24-9
  	dodecahydrate
  	Orthoboric acid	10043-35-3
  	formaldehyde	50-00-0
  	DL-Isoleucine	443-79-8
  	(2S,7S)-(−)-Cystine	56-89-3
  	DL-Alanine	302-72-7
  	beta-Alanine	107-95-9
  	(S)-(+)-Arginine	74-79-3
  	(S)-(−)-Cysteine	52-90-4
  	DL-Glutamic acid	617-65-2
  	Glycine	56-40-6
  	(S)-(−)-Histidine	71-00-1
  	(S)-(+)-Lysine	56-87-1
  	DL-Methionine	59-51-8
  	DL-Phenylalanine	150-30-1
  	(S)-(−)-Phenylalanine	63-91-2
  	D-(+)-Proline	344-25-2
  	(S)-(−)-Tryptophan	73-22-3
  	(S)-(−)-Tyrosine	60-18-4
  	Carvone	99-49-0
  	Citral	5392-40-5
  	Ethyl butyrate	105-54-4
  	Isobutyl propionate	540-42-1
  	Methyl butyrate	623-42-7
  	n-Propyl acetate	109-60-4
  	Isobutyl formate	542-55-2
  	Benzyl acetate	140-11-4
  	6-Methyl-5-hepten-2-one	110-93-0
  	Butyl acetate	123-86-4
  	Ethyl acetoacetate	141-97-9
  	Isopentyl Acetate	123-92-2
  	Cinnamaldehyde	104-55-2
  	Methyl benzoate	93-58-3
  	Butyl sulfide	544-40-1
  	Ethyl benzoate	93-89-0
  	2,4-Hexadienoic acid,	24634-61-5
  	potassium salt, (E,E)-
  	Potassium bitartrate	868-14-4
  	Lauric acid	143-07-7
  	Benzyl benzoate	120-51-4
  	Picric acid	88-89-1
  	Benzoyl peroxide	94-36-0
  	Palmitic acid	57-10-3
  	Dibutyl phthalate	84-74-2
  	Stearic acid	57-11-4
  	Succinic anhydride	108-30-5
  	Diethylenetriamine	111-40-0
  	Diethanolamine	111-42-2
  	Benzaldehyde	100-52-7
  	Phenethylamine	64-04-0
  	Salicylylaldehyde	90-02-8
  	Sodium benzoate	532-32-1
  	Cinnamic acid	621-82-9
  	Triethanolamine	102-71-6
  	L-(+)-Tartaric Acid	87-69-4
  	Eugenol	97-53-0
  	D-mannitol	69-65-8
  	Butyl paraben	94-26-8
  	Benzoin	119-53-9
  	Diethyl phthalate	84-66-2
  	Oleic acid	112-80-1
  	Sodium lactate	72-17-3
  	Indole	120-72-9
  	ethyl lactate	97-64-3
  	quinoline	91-22-5
  	Thymol	89-83-8
  	Methyl anthranilate	134-20-3
  	Methyl salicylate	119-36-8
  	Diethyl malonate	105-53-3
  	Citric acid	77-92-9
  	Sodium dodecyl sulfate	151-21-3
  	Morpholine	110-91-8
  	Furfural	98-01-1
  	Niacin	59-67-6
  	Choline chloride	67-48-1
  	L-Menthol	2216-51-5
  	Meso-inositol	87-89-8
  	ethylenediaminetetraacetic	60-00-4
  	acid
  	EDTA, calcium derivative,	62-33-9
  	disodium salt
  	Calcium pantothenate	137-08-6
  	Riboflavin	83-88-5
  	Zinc carbonate	3486-35-9
  	Amyl alcohol	71-41-0
  	Mineral oil	8012-95-1
  	Triton(R) X-100	9002-93-1
  	Acetaldehyde	75-07-0
  	Acetic Acid	64-19-7
  	Acetone	67-64-1
  	Acetophenone	98-86-2
  	4-Aminobenzoic acid	150-13-0
  	Anisole	100-66-3
  	Vitamin C	50-81-7
  	Benzoic Acid	65-85-0
  	Biphenyl	92-52-4
  	2-Methyl-1-propanol	78-83-1
  	n-Butanol	71-36-3
  	n-Butylamine	109-73-9
  	ethyl acetate	141-78-6
  	Caffeine	58-08-2
  	Chloroacetic Acid	79-11-8
  	Dichloroacetic Acid	79-43-6
  	Diethylamine	109-89-7
  	Ethanol Amine	141-43-5
  	n-Butyric Acid	107-92-6
  	Ethylenediamine	107-15-3
  	Formic acid	64-18-6
  	n-Hexanol	111-27-3
  	Methanol	67-56-1
  	Methyl Acetate	79-20-9
  	Methyl 4-hydroxybenzoate	99-76-3
  	m-Cresol	108-39-4
  	p-Cresol	106-44-5
  	Phenol	108-95-2
  	n-Propanol	71-23-8
  	Propionic Acid	79-09-4
  	Salicylic acid	69-72-7
  	Sucrose	57-50-1
  	Vanillin	121-33-5
  	Vitamin E	59-02-9
  	Potassium citrate, monohydrate	1534146
  	p-toluenesulfonic acid	6192-52-5
  	monohydrate
  	D-(+)-Maltose	69-79-4
  	Tetrasodium	64-02-8
  	ethylenediaminetetraacetate
  	Saccharin sodium	128-44-9
  	Sodium Acetate Trihydrate	6131-90-4
  	Quinine sulfate, dihydrate	6119-70-6
  	Sulfosalicylic acid, dihydrate	5965-83-3
  	L-(+)-Arginine	1119-34-2
  	monohydrochloride
  	Procaine hydrochloride	51-05-8
  	Pyridoxine Hydrochloride	58-56-0
  	Thiamine hydrochloride	67-03-8
  	Propionaldehyde	123-38-6
  	Urea	57-13-6
  	2-Propanol	67-63-0
  	Pyrrole	109-97-7
  	Sodium formate	141-53-7
  	Pyrrolidine	123-75-1
  	Methyl ethyl ketone	78-93-3
  	Ethyl formate	109-94-4
  	Propylene glycol	57-55-6
  	Thiourea	62-56-6
  	Ammonium acetate	631-61-8
  	Benzene	71-43-2
  	Sodium acetate	127-09-3
  	Cyclopentanone	120-92-3
  	Cyclohexane	110-82-7
  	piperidine	110-89-4
  	2-Pentanone	107-87-9
  	hexane	110-54-3
  	Isoamyl Alcohol	123-51-3
  	Lactic acid	50-21-5
  	2-Ethoxyethanol	110-80-5
  	Propionic acid, sodium salt	137-40-6
  	Potassium acetate	127-08-2
  	cyclohexyl amine	108-91-8
  	methyl methacrylate	80-62-6
  	methyl isobutyl ketone	108-10-1
  	Acetic anhydride	108-24-7
  	Isopropyl Acetate	108-21-4
  	2,2′-Oxybisethanol	111-46-6
  	Benzyl alcohol	100-51-6
  	Resorcinol	108-46-3
  	2-Butoxy ethanol	111-76-2
  	Cumene	98-82-8
  	2-Amino-2-(hydroxymethyl)-1,3-	77-86-1
  	propanediol
  	Phenethyl alcohol	60-12-8
  	2-Ethyl-1-hexanol	104-76-7
  	2-Octanol	123-96-6
  	2-(2-Ethoxyethoxy)ethanol	111-90-0
  	2,6-Dimethyl-4-heptanone	108-83-8
  	Benzophenone	119-61-9
  	D-(−)-Fructose	57-48-7
  	D-Glucose	50-99-7
  	D-Ribose	50-69-1
  	D-(+)-Xylose	58-86-6
  	Pectin sugar	5328-37-0
  	D-(+)-Lactose	63-42-3
  	Camphene	79-92-5
  	Isoquinoline	119-65-3
  	2,4-Dimethylphenol	105-67-9
  	2,5-Dimethylphenol	95-87-4
  	2,6-Dimethylphenol	576-26-1
  	Methanesulfonic Acid	75-75-2
  	o-Methoxybenzoic Acid	579-75-9
  	Saccharin	81-07-2
  	Thiazole	288-47-1
  	Trifluoromethanesulfonic Acid	1493-13-6
  	Trimethylamine	75-50-3
  	Coumarin	91-64-5
  	Dimethylamine	124-40-3
  	Ethyl Alcohol	64-17-5
  	Butyl benzyl phthalate	85-68-7
  	2,6-dimethylpyrazine	108-50-9
  	taurocholic acid	81-24-3
  	geraniol	106-24-1
  	linalool	78-70-6
  	ethyl isovalerate	108-64-5
  	ethyl 2-methylbutyrate	7452-79-1
  	1-octen-3-ol	3391-86-4
  	ethyl 2-trans-4-cis-	3025-30-7
  	decadienoate
  	Dihydromyrcenol	18479-58-8
  	citronellal	106-23-0
  	linalyl acetate	115-95-7
  	8-mercapto-p-menthan-3-one	38462-22-5
  	Ammonium citrate	3012-65-5
  	Ammonium bicarbonate	1066-33-7
  	Ammonium chloride	12125-02-9
  	Ammonium hydroxide	1336-21-6
  	Ammonium persulfate	7727-54-0
  	Ammonium phosphate, dibasic	7783-28-0
  	Ammonium Phosphate Monobasic	7722-76-1
  	Ammonium sulfate	7783-20-2
  	Ammonium sulfide	12135-76-1
  	Hydrazine	302-01-2
  	Nitric acid	7697-37-2
  	phosphoric acid	7664-38-2
  	Phosphorus oxychloride	10025-87-3
  	Hydriodic acid	10034-85-2
  	Hydrobromic acid	10035-10-6
  	Hydrochloric acid	7647-01-0
  	hydrogen peroxide	7722-84-1
  	Periodic Acid	10450-60-9
  	Sulfamic acid	5329-14-6
  	Sulfuric acid	7664-93-9
  	Sulfurous acid	7782-99-2
  	Dexpanthenol	81-13-0
  	4-oxoisophorone	1125-21-9
  	Copper(II) sulfate	7758-98-7
  	ferric chloride	7705-08-0
  	Ferric oxide	1309-37-1
  	ferric sulfate	10028-22-5
  	Iron(II)Sulfate Heptahydrate	7782-63-0
  	Iron	7439-89-6
  	Manganese (II) Sulfate	10034-96-5
  	Monohydrate
  	Nickel	7440-02-0
  	Titanium dioxide	13463-67-7
  	Zinc chloride	7646-85-7
  	Zinc oxide	1314-13-2
  	1,1′-Azobisformamide	123-77-3
  	1,3-Butanediol	107-88-0
  	1-Methylnaphthalene	90-12-0
  	2,6-Di-tert-Butyl-p-Cresol	128-37-0
  	2,6-Dimethylpyridine	108-48-5
  	Disodium	138-93-2
  	cyanodithioimidocarbonate
  	3-Methyl-2-Cyclopentene-2-ol-	80-71-7
  	one
  	6-Methylcoumarin	92-48-8
  	acetoin	513-86-0
  	alpha-Phellandrene	99-83-2
  	alpha-Terpinene	99-86-5
  	Benzenesulfonic Acid	98-11-3
  	Benzothiazole	95-16-9
  	borates, tetrasodium salts	1330-43-4
  	Butyl butyrate	109-21-7
  	Butyl Mercaptan	109-79-5
  	Butyraldehyde	123-72-8
  	Capsaicin	404-86-4
  	Chloromethyl Methyl Ether	107-30-2
  	Cymene	99-87-6
  	Diallyl Disulfide	2179-57-9
  	Diethylaminoethanol	100-37-8
  	dimethyldisulfide	624-92-0
  	Dimethyl Succinate	106-65-0
  	Dimethyl Sulfate	77-78-1
  	Dimethyl Sulfide	75-18-3
  	Dipropyl Disulfide	629-19-6
  	Dipropyl Ketone	123-19-3
  	Ethyl Acrylate	140-88-5
  	Ethyl Butyl Ketone	106-35-4
  	Ethyl Propionate	105-37-3
  	Furfuryl Alcohol	98-00-0
  	gamma-Butyrolactone	96-48-0
  	Glutaraldehyde	111-30-8
  	glycerin	56-81-5
  	Glycolic Acid	79-14-1
  	Isobutyl Acetate	110-19-0
  	Isobutyl Isobutyrate	97-85-8
  	Isobutyraldehyde	78-84-2
  	Isoheptanol	543-49-7
  	Isophorone	78-59-1
  	Isopropyl Mercaptan	75-33-2
  	Methyl isobutenyl ketone	141-79-7
  	Methyl n-amyl ketone	110-43-0
  	methyl acrylate	96-33-3
  	Methyl Isobutyrate	547-63-7
  	Methyl Mercaptan	74-93-1
  	N,N-Dimethylethanolamine	108-01-0
  	n-Butyl Lactate	138-22-7
  	n-Hexyl Acetate	142-92-7
  	n-Valeraldehyde	110-62-3
  	Nitrous Oxide	10024-97-2
  	p-Anisaldehyde	123-11-5
  	2-Methylcyclohexanone	583-60-8
  	Octanoic Acid	124-07-2
  	Oxalic Acid	144-62-7
  	Phenyl ether	101-84-8
  	Phenylmercaptan	108-98-5
  	Propargyl Alcohol	107-19-7
  	Propyl paraben	94-13-3
  	sec-Butyl Alcohol	78-92-2
  	Sodium Gluconate	527-07-1
  	Sodium Tripolyphosphate	7758-29-4
  	Tetrahydro-2-furanmethanol	97-99-4
  	Valeric Acid	109-52-4
  	3,4-xylenol	95-65-8
  	3-hexanol	623-37-0
  	3-methyl-1-pentanol	589-35-5
  	1,1-diethoxyethane	105-57-7
  	Aluminum Sulfate	10043-01-3
  	ammonium sulfite	10196-04-0
  	amyl butyrate	540-18-1
  	borneol	507-70-0
  	butyl formate	592-84-7
  	calcium peroxide	1305-79-9
  	n-Hexanoic Acid	142-62-1
  	cyclohexyl acetate	622-45-7
  	diacetyl	431-03-8
  	dimethyl carbonate	616-38-6
  	ethyl butyraldehyde	97-96-1
  	Ethyl crotonate	623-70-1
  	ethyl isobutyrate	97-62-1
  	ethyl nitrite	109-95-5
  	fumaric acid	110-17-8
  	hexaldehyde	66-25-1
  	isobutyric acid	79-31-2
  	methyl isovalerate	556-24-1
  	methyl propionate	554-12-1
  	methyl valeraldehyde	123-15-9
  	nitrosyl chloride	2696-92-6
  	octafluorocyclobutane	115-25-3
  	peroxyacetic acid	79-21-0
  	propyl formate	110-74-7
  	propyl mercaptan	107-03-9
  	Sodium aluminate	1302-42-7
  	sodium chlorite	7758-19-2
  	Terephthalic Acid	100-21-0
  	allyl isothiocyanate	57-06-7
  	Vitamin B1	59-43-8
  	Valproic acid	99-66-1
  	Ethoxyquin	91-53-2
  	n-Amyl Ethyl Ketone	106-68-3
  	Nabam	142-59-6
  	Sodium sulfide	1313-82-2
  	Thiocyanic acid	463-56-9
  	2-Methyl-5-(1-methylethenyl)-	2244-16-8
  	2-cyclohexene-1-one
  	4-(2,6,6-Trimethyl-2-	127-41-3
  	cyclohexen-1-yl)-3-buten-2-one
  	4-(2,6,6-trimethyl-1-	14901-07-6
  	cyclohexen-1-yl)-3-buten-2-one
  	Isoamyl propionate	105-68-0
  	3-Methylbutanoic acid	503-74-2
  	L-Menthone	14073-97-3
  	4-Ethylphenol	123-07-9
  	o-cresol	95-48-7
  	dimethyl-Carbamodithioic acid,	128-04-1
  	sodium salt
  	Anethole	104-46-1
  	Dimethyl terephthalate	120-61-6
  	propyl gallate	121-79-9
  	L-Ascorbic Acid Sodium Salt	134-03-2
  	4-Hexylresorcinol	136-77-6
  	Estragole	140-67-0
  	L-monosodium glutamate	142-47-2
  	Malonaldehyde, sodium salt	24382-04-5
  	Butylated hydroxyanisole	25013-16-5
  	allyl 3-methylbutyrate	2835-39-4
  	DL-monosodium glutamate	32221-81-1
  	3-Acetyl-6-methyl-2,4-	520-45-6
  	pyrandione
  	L-Glutamic Acid	56-86-0
  	DL-alpha-tocopheryl acetate	58-95-7
  	D-limonene	5989-27-5
  	Calcium Acetate	62-54-4
  	Erythorbic Acid Monosodium	6381-77-7
  	Salt
  	Ethyl methylphenylglycidate	77-83-8
  	2,4,6-Trinitro-1,3-dimethyl-5-	81-15-2
  	tert-butylbenzene
  	Dimethoxane	828-00-2
  	3,5-Di-tert-butyl-4-	88-26-6
  	hydroxybenzyl alcohol
  	6-Methylquinoline	91-62-3
  	alpha-Methylbenzyl alcohol	98-85-1
  	Nicotinamide	98-92-0
  	3,4-Dihydrocoumarin	119-84-6
  	Geranyl Acetate	105-87-3
  	Sodium (2-Ethylhexyl)Alcohol	126-92-1
  	Sulfate
  	Cyclohexanol, 5-methyl-2-(1-	89-78-1
  	methylethyl)-,
  	(1alpha,2beta,5alpha)-
  	(+)-Camphor	464-49-3
  	(1S)-(−)-alpha-Pinene	7785-26-4
  	1,3-Dihydroxy-5-methylbenzene	504-15-4
  	1,5-Naphthalenedisulfonic Acid	1655-29-4
  	Disodium Salt
  	1-Hydroxy-2-naphthoic Acid	86-48-6
  	1-Penten-3-ol	616-25-1
  	1-Phenyl-1-propanol	93-54-9
  	10-Undecylenic Acid	112-38-9
  	2′-Hydroxyacetophenone	118-93-4
  	2,4-Dihydroxybenzoic Acid	89-86-1
  	2-Acetylfuran	1192-62-7
  	2-Furancarboxylic Acid	88-14-2
  	2-Isopropylphenol	88-69-7
  	2-Ketoglutaric Acid	328-50-7
  	2-Ketovaline	759-05-7
  	2-n-Propylphenol	644-35-9
  	2-Naphthalenethiol	91-60-1
  	2-Phenyl-1-propanol	1123-85-9
  	3,3′-Thiodipropionic Acid	111-17-1
  	3,5,5-Trimethylhexanal	5435-64-3
  	3-Phenyl-1-propanol	122-97-4
  	3-Phenylpropionic Acid	501-52-0
  	4-Aminosalicylic Acid	65-49-6
  	4-Ethoxyphenol	622-62-8
  	4-Hydroxybenzoic Acid	99-96-7
  	4-Phenyl-2-butanol	2344-70-9
  	4-tert-Octylphenol	140-66-9
  	Allyl Cinnamate	1866-31-5
  	Allyl Mercaptan	870-23-5
  	alpha-L-Rhamnose	3615-41-6
  	Alpha-Terpineol	98-55-5
  	Anisic Acid	100-09-4
  	Benzalacetone	122-57-6
  	Benzaldehyde Dimethylacetal	1125-88-8
  	Benzyl Ether	103-50-4
  	Benzyl Formate	104-57-4
  	Benzyl Mercaptan	100-53-8
  	Benzyl Salicylate	118-58-1
  	Calcium Citrate	813-94-5
  	Calcium Glycerophosphate	27214-00-2
  	Calcium Hypophosphite	7789-79-9
  	Calcium Iodate	7789-80-2
  	Propanoic acid, 2-hydroxy-,	814-80-2
  	calcium salt (2:1)
  	Calcium Phosphate Tribasic	7758-87-4
  	Calcium Propionate	4075-81-4
  	Calcium Pyrophosphate	7790-76-3
  	Cholic Acid	81-25-4
  	Choline	123-41-1
  	Choline Bitartrate	87-67-2
  	trans-Cinnamic Aldehyde	14371-10-9
  	Cinnamyl Alcohol	104-54-1
  	Citronellol	106-22-9
  	Copper(I)Iodide	7681-65-4
  	D-(+)-Glucono-1,5-lactone	90-80-2
  	D-(−)-Tartaric Acid	147-71-7
  	D-Isoascorbic Acid	89-65-6
  	D-Tyrosine	556-02-5
  	Sodium dehydroacetate	4418-26-2
  	Deoxycholic Acid	83-44-3
  	Dibenzyl Ketone	102-04-5
  	Diethyl L-(+)-Tartrate	87-91-2
  	Diethyl Succinate	123-25-1
  	Dimethylacetal	534-15-6
  	DL-Cystine	923-32-0
  	DL-Proline	609-36-9
  	DL-Tartaric Acid	133-37-9
  	DL-Tyrosine	556-03-6
  	DL-Valine	516-06-3
  	Enanthoic Acid	111-14-8
  	Erythorbic Acid Sodium Salt	7378-23-6
  	Ethyl 2-Aminobenzoate	87-25-2
  	Ethyl Cinnamate	103-36-6
  	Ethyl n-Valerate	539-82-2
  	Ethyl Phenylacetate	101-97-3
  	Ethyl Salicylate	118-61-6
  	Ethyl Sulfide	352-93-2
  	Ethyl Vanillin	121-32-4
  	Ethylene Mercaptan	540-63-6
  	Farnesene	502-61-4
  	Folic acid	59-30-3
  	gamma-Nonanolactone	104-61-0
  	gamma-Valerolactone	108-29-2
  	Gluconic Acid	526-95-4
  	Gluconic Acid Potassium Salt	299-27-4
  	Glutaric Acid	110-94-1
  	Guanosine-5′-monophosphate,	1333479
  	disodium salt
  	Heliotropine	120-57-0
  	Hippuric Acid	495-69-2
  	Hydroquinone Dimethyl Ether	150-78-7
  	Inosine-5′-monophosphate	4691-65-0
  	Sodium Salt
  	iso-Amyl Mercaptan	541-31-1
  	Isoamyl Salicylate	87-20-7
  	iso-Butyl n-Hexanoate	105-79-3
  	isovaleraldehyde	590-86-3
  	Isoamyl Benzoate	94-46-2
  	Isoamyl Formate	110-45-2
  	Isoamyl n-Butyrate	106-27-4
  	Isoamylamine	107-85-7
  	Isobutyl n-Butyrate	539-90-2
  	Isocaproic Acid	646-07-1
  	Isoeugenol	97-54-1
  	Isopropyl Benzoate	939-48-0
  	Isopropyl Formate	625-55-8
  	Isopropyl N-Butyrate	638-11-9
  	Isopropyl Propionate	637-78-5
  	isobutyl Mercaptan	513-44-0
  	L-(+)-Isoleucine	73-32-5
  	L-(−)-Apple Acid	97-67-6
  	L-2-Aminopropionic Acid	56-41-7
  	L-Aspartic acid	56-84-8
  	L-Carnitine	541-15-1
  	L-Cysteine Hydrochloride	52-89-1
  	L-Glutamic Acid Hydrochloride	138-15-8
  	L-Glutamine	56-85-9
  	L-Hydroxyproline	51-35-4
  	L-Proline	147-85-3
  	L-Serine	56-45-1
  	L-Threonine	72-19-5
  	L-Valine	72-18-4
  	N-Acetylglycine	543-24-8
  	n-Amyl Formate	638-49-3
  	n-Amyl n-Caproate	540-07-8
  	n-Butyl n-Caproate	626-82-4
  	n-Butyl Propionate	590-01-2
  	n-Butyl Salicylate	2052-14-4
  	n-Decanoic Acid	334-48-5
  	n-Hexyl Mercaptan	111-31-9
  	n-Propyl Benzoate	2315-68-6
  	n-Propyl Isobutyrate	644-49-5
  	n-Tetradecanoic Acid	544-63-8
  	Nitrilotriacetic Acid	5064-31-3
  	Trisodium Salt
  	o-Toluenethiol	137-06-4
  	Orotic Acid	65-86-1
  	p-Acetamidobenzoic Acid	556-08-1
  	p-Anise Alcohol	105-13-5
  	Phenoxyacetic Acid	122-59-8
  	Phenyl Acetate	122-79-2
  	Piperine	94-62-2
  	Pivalic Acid	75-98-9
  	Potassium Benzoate	582-25-2
  	Potassium Diphosphate	7320-34-5
  	Potassium Hypophosphite	7782-87-8
  	Potassium Metaphosphate	7790-53-6
  	Potassium Sulfite	10117-38-1
  	Quinine Hydrochloride	130-89-2
  	sec-Amyl Alcohol	6032-29-7
  	Sodium D-Pantothenate	867-81-2
  	Di(2-ethylhexyl) sulfosuccinic	577-11-7
  	acid, sodium salt
  	Sodium Sorbate	7757-81-5
  	Succinic acid, disodium salt	150-90-3
  	Sodium Taurocholate	145-42-6
  	Taurine	107-35-7
  	Thiamine Nitrate	532-43-4
  	Thioanisole	100-68-5
  	Tiglic Acid	80-59-1
  	Tri-n-butyrin	60-01-5
  	Triacetin	102-76-1
  	Trisodium Citrate	68-04-2
  	Veratraldehyde	120-14-9
  	Veratrole	91-16-7
  	Vitamin P	520-26-3
  	Vitamin U Chloride	582174
  	L-methionine	63-68-3
  	2-Chloro-1-propanol	78-89-7
  	2-Ethylbutyric acid	88-09-5
  	2-Methylbutyraldehyde	96-17-3
  	2-Methyl-5-ethylpyridine	104-90-5
  	n-propyl butyrate	105-66-8
  	Ethyl caprylate	106-32-1
  	Propyl propionate	106-36-5
  	2-Methylpyrazine	109-08-0
  	3,3,5-Trimethyl-1-cyclohexanol	116-02-9
  	Ethyl caproate	123-66-0
  	o-methoxybenzaldehyde	135-02-4
  	2,4-Hexadienal	142-83-6
  	3-Hexanone	589-38-8
  	3-Methyl-2-butanol	598-75-4
  	Methyl isopropenyl ketone	814-78-8
  	3-Methyl-2-butanethiol	2084-18-6
  	3,5,5-Trimethylhexanol	3452-97-9
  	Methylglyoxal	78-98-8
  	Malonaldehyde	542-78-9
  	1,4-Dithiane	505-29-3
  	Amylcinnamaldehyde	122-40-7
  	Benzyl cinnamate	103-41-3
  	tert-Butylhydroquinone	1948-33-0
  	Fusidic Acid Sodium Salt	751-94-0
  	Hydroxycitronellal	107-75-5
  	Musk ketone	81-14-1
  	L-Asparagine	70-47-3
  	phenethyl acetate	103-45-7
  	Riboflavin-5-Phosphate	146-17-8
  	Potassium Sodium Tartrate	304-59-6
  	Galactaric acid	526-99-8
  	Sodium Tartrate	868-18-8
  	trisodium phosphate	7601-54-9
  	Disodium Pytophosphate	7758-16-9
  	Magnesium chloride	7786-30-3
  	Sodium Polymethacrylate	54193-36-1
  	propiophenone	93-55-0
  	2-ethylhexanoic acid	149-57-5
  	3,7,7-trimethyl bicyclohep-3-	13466-78-9
  	ene
  	2,6-dimethyl-4-heptanol	108-82-7
  	5-isopropyl-2-methyl-phenol	499-75-2
  	L-Bornyl acetate	5655-61-8
  	caryophyllene	87-44-5
  	hydroxymethylpyrone	118-71-8
  	neosperidin dihydrochalcone	20702-77-6
  	2,2-Dibromo-3-	10222-01-2
  	nitrilopropionamide
  	Xylitol	87-99-0
  	Sulfosalicylic acid	97-05-2
  	Riboflavin 5′-(dihydrogen	130-40-5
  	phosphate), monosodium salt
  	Ethylenediaminetetraacetic	139-33-3
  	acid, disodium salt
  	Gallic acid	149-91-7
  	Carbonic acid	463-79-6
  	Potassium carbonate,	6381-79-9
  	sesquihydrate
  	Magnesium phosphate tribasic	7757-87-1
  	diallyl sulfide	592-88-1
  	ethyl 4-oxopentanoate	539-88-8
  	methyl caproate	106-70-7
  	isopropyl isobutyrate	617-50-5
  	diethyl hydroxybutanedioate	2065419
  	propyl isopentanoate	557-00-6
  	benzyl ethyl ether	539-30-0
  	isobutyl isopentanoate	589-59-3
  	propyl hexanoate	626-77-7
  	4-methylquinoline	491-35-0
  	methyl cinnamate	103-26-4
  	cumic alcohol	536-60-7
  	thujone	471-15-8
  	dihydrocarveol	619-01-2
  	fenchyl alcohol	1632-73-1
  	Nerol	106-25-2
  	isopentyl isopentanoate	659-70-1
  	methyleugenol	93-15-2
  	methyl 2-naphthyl ketone	93-08-3
  	diphenyldisulfide	882-33-7
  	citronellyl acetate	150-84-5
  	menthyl acetate	89-48-5
  	menthyl isovalerate	16409-46-4
  	5-Ethyl-3-hydroxy-4-methyl-	698-10-2
  	2(5H)-furanone
  	malic acid	6915-15-7
  	3-methylbutanoic acid butyl	109-19-3
  	ester
  	3-phenyloxiranecarboxylic acid	121-39-1
  	ethyl ester
  	1,2-Benzisothiazol-3(2H)-one	6381-61-9
  	1,1-dioxide, ammonium salt
  	1-methyl-4-(1-methylethyl)-	99-85-4
  	1,4-Cyclohexadiene
  	3-mercapto-2-Butanol	54812-86-1
  	(1R)-2,6,6-	7785-70-8
  	trimethylbicyclo[3.1.1]hept-2-
  	ene
  	(1S)-6,6-dimethyl-2-	18172-67-3
  	methylenebicyclo[3.1.1]heptane
  	1-methyl-4-(1-	586-62-9
  	methylethylidene)cyclohexene
  	1-(3-pyridinyl)ethanone	350-03-8
  	1-pyrazinylethanone	22047-25-2
  	1-(2-furyl)-2-propanone	6975-60-6
  	1-Penten-3-one	1629-58-9
  	2,3-pentanedione	600-14-6
  	2,5-dimethylpyrazine	123-32-0
  	2-isobutyl-3-methoxypyrazine	24683-00-9
  	4-methyl-2,3-pentanedione	7493-58-5
  	5-methylfurfural	620-02-0
  	Dimethyltrisulfide	3658-80-8
  	furfuryl acetate	623-17-6
  	furfurylmethylether	13679-46-4
  	terpinen-4-ol	562-74-3
  	Calcium sorbate	7492-55-9
  	Potassium lactate	996-31-6
  	1-Hydroxyethylidene-1,1-	2809-21-4
  	diphosphonic acid
  	L-glutamic acid monopotassium	19473-49-5
  	salt
  	3-methyl-2-buten-1-ol	556-82-1
  	phenylethanal	122-78-1
  	4′-Methoxyacetophenone	100-06-1
  	L-borneol	464-45-9
  	2,4-Hexadien-1-ol	111-28-4
  	D-Fenchone	4695-62-9
  	3-Phenylpropyl formate	104-64-3
  	Cinnamyl formate	104-65-4
  	D-galacturonate	685-73-4
  	D-glucuronate	1700908
  	5′ IMP	131-99-7
  	1-Methoxy-4-methylbenzene	104-93-8
  	2-Methylbutanoic acid	116-53-0
  	2,4,6-Tribromophenol	118-79-6
  	3-Ethyl pyridine	536-78-7
  	Zinc acetate	557-34-6
  	Methyl pentanoate	624-24-8
  	Methylthioethane	624-89-5
  	3-Penten-2-one	625-33-2
  	Glycocholic acid	475-31-0
  	m-Methoxybenzoic acid	586-38-9
  	alpha-Hydroxypropionic acid	598-82-3
  	Methyl 2-furoate	611-13-2
  	2-Furancarboxylic acid, propyl	615-10-1
  	ester
  	Benzylacetoacetic acid, ethyl	620-79-1
  	ester
  	2,5-Dimethyl pyrrole	625-84-3
  	4-methyl-1,1′-biphenyl	644-08-6
  	p-Isopropylacetophenone	645-13-6
  	4-methyl-thiazole	693-95-8
  	gamma-Decalactone	706-14-9
  	2-acetylpyrrole	1072-83-9
  	2-acetylpyridine	1122-62-9
  	tetramethyl-pyrazine	1124-11-4
  	Methyl 4-phenylbutyrate	2046-17-5
  	2,3,6-trimethyl-phenol	2416-94-6
  	2-Methoxypyrazine	3149-28-8
  	2-Ethylfuran	3208-16-0
  	2,3-dimethyl-pyrazine	5910-89-4
  	Thiophenethiol	7774-74-5
  	o-Tolyl isobutyrate	36438-54-7
  	cis-3-Hexenyl pyruvate	68133-76-6
  	cis-3-Hexenyl cis-3-hexenoate	61444-38-0
  	trans-2-Hexenyl isovalerate	68698-59-9
  	trans-2-Hexenyl formate	53398-78-0
  	trans-2-Hexenyl valerate	56922-74-8
  	1-Octen-3-yl butyrate	16491-54-6
  	Methyl 4-(methylthio)butyrate	53053-51-3
  	2,4-Octadien-1-ol	18409-20-6
  	2,4-Nonadien-1-ol	62488-56-6
  	2,4-Decadien-1-ol	18409-21-7
  	(e,z)-2,6-Nonadienyl acetate	68555-65-7
  	3-Hexenal	4440-65-7
  	Tetrahydro-2-furanmethanol	637-64-9
  	acetate
  	Methyl benzaldehyde	1334-78-7
  	Dodecylsulfonic acid	1510-16-3
  	Methylethyl disulfide	4253-89-8
  	Farnesol	4602-84-0
  	Thiobenzoic acid, S-methyl	5925-68-8
  	ester
  	Hexyl benzoate	6789-88-4
  	2,5-Diethyltetrahydrofuran	41239-48-9
  	Zinc hydrosulfite	7779-86-4
  	(2R,3S)-Tartaric Acid	147-73-9
  	Ethylsulfuric acid	540-82-9
  	1,2,2-Trimethyl-1,3-	5394-83-2
  	cyclopentanedicarboxylic acid
  	2-Methyl-3-buten-2-ol	115-18-4
  	trans-2-Hexenal	6728-26-3
  	4-Hexen-3-one	2497-21-4
  	1-Hexen-3-ol	4798-44-1
  	2-Methyl-1-butanethiol	1878-18-8
  	4-Methylcyclohexanone	589-92-4
  	3-Heptanol	589-82-2
  	o-methylanisole	578-58-5
  	trans-2-octenal	2363-89-5
  	2,3,4-Trimethyl-3-pentanol	3054-92-0
  	Acetylacetaldehyde dimethyl	5436-21-5
  	acetal
  	p-methylacetophenone	122-00-9
  	o-aminoacetophenone	551-93-9
  	4-Propylphenol	645-56-7
  	2,4-Dimethylanisole	6738-23-4
  	Benzyl methyl sulfide	766-92-7
  	Methyl phenylacetate	101-41-7
  	4-Ethoxybenzaldehyde	10031-82-0
  	p-tolyl acetate	140-39-6
  	2,6-Dimethoxyphenol	91-10-1
  	Isoborneol	124-76-5
  	Methyl 2-methoxybenzoate	606-45-1
  	Phenylacetaldehyde dimethyl	101-48-4
  	acetal
  	3-Phenylpropyl acetate	122-72-5
  	Ethyl 3-phenylpropionate	2021-28-5
  	Benzyl butyrate	103-37-7
  	Anisyl acetate	104-21-2
  	Isobutyl phenylacetate	102-13-6
  	p-vinylphenol	2628-17-3
  	o-tolyl acetate	533-18-6
  	2,5-Dihydroxybenzoic acid	490-79-9
  	o-methoxyphenyl acetate	613-70-7
  	Lactobionic acid	96-82-2
  	Magnesium hydrogen phosphate	7782-75-4
  	trihydrate
  	Iberverin	505-79-3
  	alpha-methylcinnamaldehyde	101-39-3
  	benzyl phenylacetate	102-16-9
  	1,3-dimercaptopropane	109-80-8
  	p-cymen-8-ol	1197-01-9
  	phenethyl anthranilate	133-18-6
  	trihydroxybutyrophenone	1421-63-2
  	o-methoxycinnamaldehyde	1504-74-1
  	3-propylidene phthalide	17369-59-4
  	trans,trans-2,4-decadienal	25152-84-5
  	piperonyl acetate	326-61-4
  	2,3-hexanedione	3848-24-6
  	isopropyl phenylacetate	4861-85-2
  	ethyl 3-hydroxybutyrate	5405-41-4
  	furfural acetone	623-15-4
  	beta-(2-furyl)acrolein	623-30-3
  	linalyl anthranilate	7149-26-0
  	citral diethyl acetal	7492-66-2
  	allyl anthranilate	7493-63-2
  	acetyl tributyl citrate	77-90-7
  	butyl anthranilate	7756-96-9
  	cyclohexyl anthranilate	7779-16-0
  	isoamyl cinnamate	7779-65-9
  	isobutyl anthranilate	7779-77-3
  	carvyl acetate	97-42-7
  	carveol	99-48-9
  	3-(Methylthio)propionaldehyde	3268-49-3
  	Alpha-damascone	43052-87-5
  	Dimethyldicarbonate	4525-33-1
  	Procaine	59-46-1
  	5-hydroxy-6-methyl-3,4-	65-23-6
  	pyridinedimethanol
  	2-methoxy-Naphthalene	93-04-9
  	Methyl nicotinate	93-60-7
  	Ethyl benzoylacetate	94-02-0
  	Phenethyl benzoate	94-47-3
  	2-methyl-pentanoic acid	97-61-0
  	Cyclohexanecarboxylic acid	98-89-5
  	Methyl b-phenylpropionate	103-25-3
  	Benzyl 3-methyl butanoate	103-38-8
  	Naphthalene-2-sulfonic acid	120-18-3
  	Methyl 4-methoxybenzoate	121-98-2
  	3-Phenylprop-2-enyl cinnamate	122-69-0
  	7-methyl-3-methylene-1,6-	123-35-3
  	Octadiene
  	Levulinic acid	123-76-2
  	2-Mercaptobenzoic acid	147-93-3
  	m-Dimethoxybenzene	151-10-0
  	3-butyl-1(3H)-isobenzofuranone	6066-49-5
  	5-Methylquinoxaline	13708-12-8
  	2-Ethyl Pyrazine	13925-00-3
  	trimethyl-pyrazine	14667-55-1
  	2-ethyl-3-methyl-pyrazine	15707-23-0
  	2,3-diethyl-pyrazine	15707-24-1
  	2,3-diethyl-5-methyl-pyrazine	18138-04-0
  	2-Methylthiopyrazine	21948-70-9
  	5-Methyl-3H-furan-2-one	591-12-8
  	cis-3-Hexen-1-ol	928-96-1
  	3,7-Dimethyl-1,3,6-octatriene	13877-91-3
  	calcium cyclamate	139-06-0
  	aconitic acid	499-12-7
  	2-Dehydrolinalool	29171-20-8
  	2-Mercaptopropionic acid	79-42-5
  	3-Methyl-2-butenal	107-86-8
  	Allylacetic acid	591-80-0
  	Allyl cyclohexylacetate	4728-82-9
  	Allyl cyclohexylpropionate	2705-87-5
  	Allyl phenoxyacetate	7493-74-5
  	Allyl phenylacetate	1797-74-6
  	Allyl alpha-ionone	79-78-7
  	Butyl butyrolactate	7492-70-8
  	Cinnamyl isobutyrate	103-59-3
  	Cinnamyl propionate	103-56-0
  	Dibenzyl disulfide	150-60-7
  	Isobornyl acetate	125-12-2
  	Methyl heptyne carbonate	111-12-6
  	Triethyl citrate	77-93-0
  	gamma-Undecalactone	104-67-6
  	alpha-Amylcinnamyl alcohol	101-85-9
  	1,3,4,6,7,8-Hexahydro-	1222-05-5
  	4,6,6,7,8,8-hexamethyl
  	cyclopenta[g][2]benzopyran
  	2-Ethylbutyl acetate	10031-87-5
  	Triphosphoric acid,	13845-36-8
  	pentapotassium salt
  	L-(+)-Lactic acid	79-33-4
  	Mannitol	87-78-5
  	2-Methoxy-4-methylphenol	93-51-6
  	1,2,3-Propanetricarboxylic	144-33-2
  	acid, 2-hydroxy-, disodium
  	salt
  	Ethanesulfonic acid, 2-	1562-00-1
  	hydroxy-, monosodium salt
  	2-Methoxy-4-propylphenol	2785-87-7
  	3,7-Dimethyl-3-octanol	78-69-3
  	2-Pentyl-furan	3777-69-3
  	Butanoic acid, 3-oxo-, butyl	591-60-6
  	ester
  	4-(4-Hydroxy-4-methyl pentyl)-	31906-04-4
  	3-cyclohexene-1-carboxaldehyde
  	Methyl 3-oxo-2-	24851-98-7
  	pentylcyclopentaneacetate
  	Naphthalene, 2-(2-	2173-57-1
  	methylpropoxy)-
  	Perillol	536-59-4
  	2-Acetyl-1-methylpyrrole	932-16-1
  	4-Allyl-2,6-dimethoxyphenol	6627-88-9
  	Butyl levulinate	2052-15-5
  	D-(+)-Camphoric acid	124-83-4
  	D(+)-10-Camphorsulfonic acid	3144-16-9
  	L-(−)-Carvone	6485-40-1
  	(−)-Carvyl propionate	97-45-0
  	(−)-Caryophyllene oxide	1139-30-6
  	Cyclohexylacetic acid	5292-21-7
  	3-Cyclopentylpropionic acid	140-77-2
  	(−)-Dihydrocarvyl acetate	20777-49-5
  	3,3-Dimethylacrylic acid	541-47-9
  	2,4-Dimethylbenzaldehyde	15764-16-6
  	1,4-Dithiane-2,5-diol	40018-26-6
  	Ethanesulfonic acid	594-45-6
  	Ethyl butyrylacetate	3249-68-1
  	Ethyl (methylthio)acetate	4455-13-4
  	Ethyl pyruvate	617-35-6
  	Ethyl sorbate	2396-84-1
  	5-Formyl-2-furansulfonic acid,	31795-44-5
  	sodium salt
  	Furfuryl mercaptan	98-02-2
  	1,6-Hexanedithiol	1191-43-1
  	trans-2-Hexenoic acid	13419-69-7
  	trans-2-Hexen-1-ol	928-95-0
  	4-(4-Hydroxyphenyl)-2-butanone	5471-51-2
  	Isopulegol	89-79-2
  	Isopulegyl acetate	89-49-6
  	2-Ketobutyric acid	600-18-0
  	(−)-Limonene	5989-54-8
  	4-Methoxyphenylacetone	122-84-9
  	Methyl cyclohexanecarboxylate	4630-82-4
  	3-Methylcyclohexanone	591-24-2
  	3-Methyl-2-cyclohexen-1-one	1193-18-6
  	3-Methyl-1,2-cyclopentanedione	765-70-8
  	3-Methyl-2-cyclopenten-1-one	2758-18-1
  	N-Methyl-D-glucamine	6284-40-8
  	Methyl 3-	13532-18-8
  	(methylthio)propionate
  	4-Methyl-5-thiazoleethanol	137-00-8
  	5-Methyl-2-	13679-70-4
  	thiophenecarboxaldehyde
  	DL-3-Methylvaleric acid	105-43-1
  	(−)-Myrtenal	564-94-3
  	Nopol	128-50-7
  	gamma-Octanoic lactone	104-50-7
  	3-Octanol	589-98-0
  	E-2-Octenoic acid	1871-67-6
  	Pamoic acid	130-85-8
  	4-Phenyl-2-butyl acetate	10415-88-0
  	1-Phenyl-1,2-propanedione	579-07-7
  	2-Phenylpropyl butyrate	80866-83-7
  	2-Phenylpropyl isobutyrate	65813-53-8
  	cis-2-Hexen-1-ol	928-94-9
  	Bis(methylthio)methane	1618-26-4
  	Magnesium carbonate hydroxide,	39409-82-0
  	Light
  	N-Acetyl-L-methionine	65-82-7
  	4-Methyl-5-vinylthiazole	1759-28-0
  	2-Methyl-1-phenyl-2-propanol	100-86-7
  	3-Phenylpropionaldehyde	104-53-0
  	N-Benzyl-2-phenylethylamine	3647-71-0
  	1-Phenylethyl propionate	120-45-6
  	3-Phenylpropyl isobutyrate	103-58-2
  	Allyl hexanoate	123-68-2
  	alpha, 4-Dimethylbenzylalcohol	536-50-5
  	(−)-Menthyl lactate	59259-38-0
  	2,6-Dimethylthiophenol	118-72-9
  	2,4,5-Trimethylthiazole	13623-11-5
  	Ethyl 3-(methylthio)propionate	13327-56-5
  	Phenylethyl isovalerate	140-26-1
  	2-Propylpyrazine	18138-03-9
  	2-Methyltetrahydrofuran-3-one	3188-00-9
  	Ethyl 2-	23747-43-5
  	(methyldithio)propionate
  	3,4-Dimethyl-1,2-	13494-06-9
  	cyclopentanedione
  	Difurfurylsulfide	13678-67-6
  	Difurfuryldisulfide	4437-20-1
  	3-(Methylthio)propanol	505-10-2
  	Methyl phenyl disulfide	14173-25-2
  	2-(Methyldithio)-	67952-60-7
  	isobutyraldehyde
  	Methyl 2-thiofuroate	13679-61-3
  	2-Isobutylthiazole	18640-74-9
  	4-Methyl-5-thiazolylethyl	656-53-1
  	acetate
  	2-Acetylthiazole	24295-03-2
  	2-Ethyl-3,5(6)-	27043-05-6
  	dimethylpyrazine
  	5-Methyl-6,7-dihydro-5H-	23747-48-0
  	cyclopenta(b)pyrazine
  	Cinnamyl acetate	103-54-8
  	2,5-Dihydroxy-2,5-dimethyl-	55704-78-4
  	1,4-dithiane
  	5,6,7,8-Tetrahydroquinoxaline	34413-35-9
  	2-Methyl-3-furanethiol	28588-74-1
  	Styrallyl acetate	93-92-5
  	2-Methylhexanoic acid	4536-23-6
  	2-Methylheptanoic acid	1188-02-9
  	2,2,6-Trimethylcyclohexanone	2408-37-9
  	L-Tyrosine ethyl ester	4089-07-0
  	hydrochloride
  	Ethyl 4-methoxybenzoate	94-30-4
  	4-Ethylbenzaldehyde	4748-78-1
  	N-Ethyl-p-menthane-3-	39711-79-0
  	carboxamide
  	1-(2-Furyl)-1,3-butanedione	25790-35-6
  	Menthofuran	494-90-6
  	Methylsulfuric acid sodium	512-42-5
  	salt
  	Sucrose diacetate	126-13-6
  	hexaisobutyrate
  	N,2,3-Trimethyl-2-	51115-67-4
  	isopropylbutamide
  	Tripropionin	139-45-7
  	(+/−)-Citronellic acid	502-47-6
  	5-Acetyl-2,4-dimethylthiazole	38205-60-6
  	Neryl acetate	141-12-8
  	Benzyl propionate	122-63-4
  	1R-(−)-Camphorsulfonic acid	35963-20-3
  	3,4-Hexanedione	4437-51-8
  	cis-3-Hexenoic acid	4219-24-3
  	cis-4-Heptenal	6728-31-0
  	(E,Z)-2,6-nonadienal	557-48-2
  	trans-2,trans-6-Nonadienal	17587-33-6
  	4-Methyl-2-pentenal	5362-56-1
  	cis-6-Nonenal	2277-19-2
  	Methyl propyl disulfide	2179-60-4
  	8-p-Menthen-1-ol	138-87-4
  	p-Menthan-2-one	499-70-7
  	Bisabolene	495-62-5
  	Ethyl cyclohexanecarboxylate	3289-28-9
  	Phenylpyruvate	156-06-9
  	Hydroxypyruvate	1113-60-6
  	4-Methyl-2-oxopentanoate	816-66-0
  	(+)-Neomenthol	2216-52-6
  	trans-Citral	141-27-5
  	Piperitenone	491-09-8
  	Sabinene hydrate	546-79-2
  	Perillyl aldehyde	2111-75-3
  	2-Hydroxyethanesulfonate	107-36-8
  	Acetyl isovaleryl	13706-86-0
  	Acetyl valeryl	96-04-8
  	Butylidene phthalide	551-08-6
  	Carvacryl ethyl ether	4732-13-2
  	Ethyl vanillin propylene	68527-76-4
  	glycol acetal
  	Hexyl hexanoate	6378-65-0
  	2-Methyl-5-(methylthio)-furan	13678-59-6
  	2-Methyl-4-pentenoic acid	1575-74-2
  	2-Methyl-4-propyl-1,3-	67715-80-4
  	oxathiane
  	3-Methylthio-1-hexanol	51755-66-9
  	cis-6-Nonenol	35854-86-5
  	Rose oxide	16409-43-1
  	L-Linalool	126-91-0
  	5,6-Dimethyl-8-	4674-50-4
  	isopropenylbicyclo[4.4.0]dec-
  	1-en-3-one
  	2-Ethyl-3,5-dimethylpyrazine	13925-07-0
  	2-Isopropylpyrazine	29460-90-0
  	2-Isobutyl-3-methyl-pyrazine	13925-06-9
  	2-Methoxy-3-sec-butyl-pyrazine	24168-70-5
  	2-Methylthio-3(6)-methyl-	67952-65-2
  	pyrazine
  	Benzylcarbinyl propionate	122-70-3
  	Bornyl acetate	76-49-3
  	furaneol	3658-77-3
  	Methoxycinnamaldehyde	1963-36-6
  	Methylphenol, hydrogen sulfate	68127-34-4
  	Lactitol monohydrate	81025-04-9
  	2H-Pyrrole, 3,4-dihydro-	5724-81-2
  	2-Butenal, 2-methyl-, (E)-	497-03-0
  	2-Pentenal	764-39-6
  	Ethanethioic acid, S-methyl	1534-08-3
  	ester
  	2-Hexenal	505-57-7
  	2-Methyl-2-pentenal	623-36-9
  	Cyclopentanethiol	1679-07-8
  	Butane, 2-ethoxy-	2679-87-0
  	S-Ethyl thioacetate	625-60-5
  	ethyl methyl carbonate	623-53-0
  	3(2H)-Furanone, 2,5-dimethyl-	14400-67-0
  	Allyl propionate	2408-20-0
  	methyl 2-methylbutanoate	868-57-5
  	2-Butanone, 1-(methylthio)-	13678-58-5
  	Ethanethioic acid, S-propyl	2307-10-0
  	ester
  	1,2-Butanedithiol	16128-68-0
  	6-Methyl-3,5-heptadiene-2-one	1604-28-0
  	2-Octen-4-one	4643-27-0
  	2,5-dimethyl-3-furanthiol	55764-23-3
  	2-Heptenoic acid	18999-28-5
  	Butanoic acid, 2-propenyl	2051-78-7
  	ester
  	6-Methyl-5-hepten-2-ol	1569-60-4
  	trans-2-Octen-4-ol	20125-81-9
  	cis-3-Octen-1-ol	20125-84-2
  	1-Butanol, 2-methyl-, acetate	624-41-9
  	4-methyl-alpha-methylstyrene	1195-32-0
  	trans-3-phenyl-2-propen-1-ol	4407-36-7
  	Benzeneacetaldehyde, alpha-	93-53-8
  	methyl-
  	Benzene, (2-methoxyethyl)-	3558-60-9
  	Cyclohexene, 1-methyl-4-(1-	7705-14-8
  	methylethenyl)-, (+−)-
  	Phenol, 2-(methylthio)-	1073-29-6
  	2-Hexen-1-yl acetate	2497-18-9
  	3-Hexen-1-ol, acetate, (Z)-	3681-71-8
  	5-Hydroxy-4-octanone	496-77-5
  	butyl 2-methylpropanoate	97-87-0
  	Benzofuran-2-carboxaldehyde	4265-16-1
  	DL-Lysine	70-54-2
  	1-Hexanethiol, 2-ethyl-	7341-17-5
  	2′,4′-Dimethylacetophenone	89-74-7
  	2-Pentylpyridine	2294-76-0
  	1-Methoxy-4-propyl benzene	104-45-0
  	1-Hydroxy-2-methoxy-4-ethyl	2785-89-9
  	benzene
  	Nonalactone	6008-27-1
  	Cyclohexyl propionate	6222-35-1
  	Allyl 2-ethylbutyrate	7493-69-8
  	Butanoic acid, 3-oxo-, 2-	7779-75-1
  	methylpropyl ester
  	n-Butyl pentanoate	591-68-4
  	3,7-Dimethyl-1-octanol	106-21-8
  	3-Buten-2-one, 3-methyl-4-	1901-26-4
  	phenyl-
  	2-Propenoic acid, 3-phenyl-,	1754-62-7
  	methyl ester, (E)-
  	Benzene, 4-ethenyl-1,2-	6380-23-0
  	dimethoxy-
  	Benzenepropanol, alpha,alpha-	103-05-9
  	dimethyl-
  	Benzene, (butoxymethyl)-	588-67-0
  	Dimethyl anthranilate	85-91-6
  	2-Hexanoylfuran	14360-50-0
  	Cyclohexyl butyrate	1551-44-6
  	Naphthalene, 2-ethoxy-	93-18-5
  	Acetoacetic acid isoamyl ester	2308-18-1
  	Propanoic acid, 2-methyl-, 4-	103-93-5
  	methylphenyl ester
  	4-(4-Methoxyphenyl)-2-butanone	104-20-1
  	Isobutyl benzoate	120-50-3
  	Benzene, 1,2-dimethoxy-4-(1-	93-16-3
  	propenyl)-
  	beta-	10415-87-9
  	Phenylethylmethylethylcarbinol
  	1,1-Dimethoxy-2-phenylpropane	90-87-9
  	Geranyl formate	105-86-2
  	Bornyl formate	7492-41-3
  	6-Octen-1-ol, 3,7-dimethyl-,	105-85-1
  	formate
  	Benzeneacetic acid, butyl	122-43-0
  	ester
  	3,5,9-Undecatrien-2-one, 6,10-	141-10-6
  	dimethyl-
  	Anisyl propionate	7549-33-9
  	Butanoic acid, 3-phenyl-2-	103-61-7
  	propenyl ester
  	2-Propenoic acid, 3-phenyl-,	122-67-8
  	2-methylpropyl ester
  	Eugenyl acetate	93-28-7
  	3-Methylbutyl phenylacetate	102-19-2
  	Benzoic acid, 2-(methylamino)-,	65505-24-0
  	2-methylpropyl ester
  	Phenoxy ethyl isobutyrate	103-60-6
  	Anisyl butyrate	6963-56-0
  	2,6-Octadien-1-ol, 3,7-	105-91-9
  	dimethyl-, propanoate, (Z)-
  	Isobornyl propionate	2756-56-1
  	1,3,5-Trithiane, 2,2,4,4,6,6-	828-26-2
  	hexamethyl-
  	Geranyl N-butyrate	106-29-6
  	Geranyl isobutyrate	2345-26-8
  	Thiophene, 2,2′-dithiobis-	6911-51-9
  	2-Propenoic acid, 3-phenyl-,	7779-17-1
  	cyclohexyl ester
  	Benzeneacetic acid, 3-phenyl-	7492-65-1
  	2-propenyl ester
  	Anisyl phenylacetate	102-17-0
  	2-Propenoic acid, 3-phenyl-,	122-68-9
  	3-phenylpropyl ester
  	Geranyl phenylacetate	102-22-7
  	hexyl 2-methylbutyrate	10032-15-2
  	4-heptanolide	105-21-5
  	Neral	106-26-3
  	(E)-2-octenol	18409-17-1
  	Ethyl 3-hydroxyhexanoate	2305-25-1
  	isopropyl hexanoate	2311-46-8
  	hexyl butanoate	2639-63-6
  	bis(2-methyl-3-furyl)disulfide	28588-75-2
  	3-hydroxy-4,5-dimethyl-2(5H)-	28664-35-9
  	furanone
  	2-acetyl-2-thiazoline	29926-41-8
  	(E,E)-2,4-octadienal	30361-28-5
  	geranyl acetone	3796-70-1
  	1-octen-3-one	4312-99-6
  	3-mercapto-2-pentanone	67633-97-0
  	(Z)-3-hexenal	6789-80-6
  	4-hexanolide	695-06-7
  	5-octanolide	698-76-0
  	delta-decalactone	705-86-2
  	4-vinylguaiacol	7786-61-0
  	Amyl salicylate	2050-08-0
  	Cyclohexyl formate	4351-54-6
  	Dimethylbenzylcarbinyl acetate	151-05-3
  	Geranyl propionate	105-90-8
  	Terpinyl acetate	80-26-2
  	isopropyl 3-methylbutanoate	32665-23-9
  	isopropyl 2-methylbutanoate	66576-71-4
  	3-Hexenyl 3-methylbutanoate	10032-11-8
  	Isoamyl 2-methylbutyrate	27625-35-0
  	3-Octyl acetate	4864-61-3
  	Benzyl isobutyrate	103-28-6
  	Cis-3-hexenyl butyrate	16491-36-4
  	Cis-3-hexenyl lactate	61931-81-5
  	Citronellyl butyrate	141-16-2
  	Citronellyl propionate	141-14-0
  	Isoamyl hexanoate	2198-61-0
  	1,3,5-Undecatriene	16356-11-9
  	1-Benzyloxy-2-methoxy-4-	120-11-6
  	propenyl benzene
  	1-Octen-3-yl acetate	198242
  	2-Acetyl-3-ethyl pyrazine	32974-92-8
  	2-Isopropyl-4-methyl thiazole	15679-13-7
  	2-Methyl-2-pentenoic acid	3142-72-1
  	2-sec-butyl thiazole	18277-27-5
  	4,5-Dimethyl thiazole	3581-91-7
  	4-(2,6,6-Trimethyl-2-	31499-72-6
  	cyclohexen-1-yl)butan-2-one
  	4-(2,6,6-Trimethyl cyclohexa-	23696-85-7
  	1,3-dienyl)but-2-en-4-one
  	Acetaldehyde phenethyl propyl	7493-57-4
  	acetal
  	Acetaldehyde ethyl cis-3-	28069-74-1
  	hexenyl acetal
  	Acetone propylene glycol	1193-11-9
  	acetal
  	Acetyl isoeugenol	93-29-8
  	2-Acetyl-5-methyl furan	1193-79-9
  	Allyl cyclohexylbutyrate	7493-65-4
  	Alpha,alpha-dimethylphenethyl	10094-34-5
  	butyrate
  	Alpha,alpha-dimethyl phenethyl	10058-43-2
  	formate
  	Alpha,beta-santalol	11031-45-1
  	Alpha-amyl cinnamaldehyde	91-87-2
  	dimethyl acetal
  	Alpha-fenchyl acetate	13851-11-1
  	Alpha-furfuryl pentanoate	36701-01-6
  	Alpha-ionol	25312-34-9
  	6-Methyl-alpha-ionone	79-69-6
  	Alpha-methyl-p-	103-95-7
  	isopropylphenylpropanaldehyde
  	Alpha-n-amyl-beta-phenylacryl	7493-78-9
  	acetate
  	Alpha-piperitone	6091-50-5
  	Alpha-n-amyl-beta-phenyl acryl	7493-80-3
  	isovalerate
  	6-Amyl-alpha-pyrone	27593-23-3
  	Anisyl formate	122-91-8
  	Benzylcarbinyl 2-methyl	24817-51-4
  	butyrate
  	Benzylcarbinyl 3-phenyl	103-53-7
  	propenoate
  	Benzylcarbinyl alpha-toluate	102-20-5
  	Benzylcarbinyl butyrate	103-52-6
  	Benzylcarbinyl caproate	6290-37-5
  	Benzylcarbinyl formate	104-62-1
  	Benzylcarbinyl isobutyrate	103-48-0
  	Benzylcarbinyl salicylate	87-22-9
  	Benzylcarbinyl tiglate	55719-85-2
  	Benzyl dipropyl ketone	7492-37-7
  	Benzyl tiglate	37526-88-8
  	Beta-homocyclocitral	472-66-2
  	Beta-ionol	22029-76-1
  	3-Phenylpropyl propanoate	122-74-7
  	Bois de rose oxide	7392-19-0
  	Butyl 2-methyl butyrate	15706-73-7
  	Butyl cinnamate	538-65-8
  	ortho-sec-Butyl cyclohexanone	14765-30-1
  	isobutyl cis-2-methyl-2-	7779-81-9
  	butenoate
  	5-n-Butyl-delta-valerolactone	3301-94-8
  	Campholenic aldehyde	4501-58-0
  	Cedran-8-yl acetate	77-54-3
  	Cinnamyl isovalerate	140-27-2
  	Cis-3-hexenyl benzoate	25152-85-6
  	Cis-3-hexenyl caproate	31501-11-8
  	Cis-3-hexenyl formate	33467-73-1
  	Cis-3-hexenyl isobutyrate	41519-23-7
  	Cis-3-hexenyl phenylacetate	42436-07-7
  	Cis-3-hexenyl propionate	33467-74-2
  	Cis-3-hexenyl tiglate	67883-79-8
  	Cis-3-hexenyl valerate	35852-46-1
  	cis-4-Hepten-1-ol	6191-71-5
  	Cis-5-octen-1-ol	64275-73-6
  	Citral dimethyl acetal	7549-37-3
  	Citronellyl isobutyrate	97-89-2
  	Citronellyl isovalerate	68922-10-1
  	Citronellyl valerate	7540-53-6
  	Citroxide	7416-35-5
  	Cocal	21834-92-4
  	p-Cresyl alpha-toluate	101-94-0
  	p-Cresyl isovalerate	55066-56-3
  	Dehydro-beta-cyclocitral	116-26-7
  	8,8-Diethoxy-2,6-dimethyl-2-	7779-94-4
  	octanol
  	5,7-Dihydro-2-methyl	36267-71-7
  	thieno(3,4-d)pyrimidine
  	2,5-Dihydro-4,5-dimethyl-2-(2-	65894-83-9
  	methyl propyl)thiazole
  	Dihydrojasmone	1128-08-1
  	Dihydroxyacetophenone	28631-86-9
  	1,1-Dimethoxy-3,7-dimethyl-7-	141-92-4
  	octanol
  	3,7-Dimethyl-1,6-octadien-3-yl	126-64-7
  	benzoate
  	3,7-Dimethyl-1,6-octadien-3-yl	78-36-4
  	butyrate
  	3,7-Dimethyl-1,6-octadien-3-yl	78-35-3
  	isobutyrate
  	3,7-Dimethyl-1,6-octadien-3-yl	144-39-8
  	propanoate
  	cis-3,7-Dimethyl-2,6-octadien-	2345-24-6
  	1-yl 2-methyl propanoate
  	2,4-Dimethyl-3-cyclohexene-1-	68039-49-6
  	carboxaldehyde
  	2,6-Dimethyl-5-hepten-1-al	106-72-9
  	trans,cis-2,6-Dodecadien-1-al	21662-13-5
  	Eglantal	26643-91-4
  	Ethyl E-2-hexenoate	27829-72-7
  	Ethyl tiglate	5837-78-5
  	Ethyl trans-4-decenoate	76649-16-6
  	5-Ethyl-4-hydroxy-2-methyl-	27538-09-6
  	3[2H]furanone
  	2-Ethyl-4-methyl thiazole	15679-12-6
  	2,6,10-Trimethyl-2,6,10-	762-29-8
  	pentadecatrien-14-one
  	Guaiacyl phenyl acetate	4112-89-4
  	3-Hepten-2-one	1119-44-4
  	trans-2-Hexen-1-ol	2305-21-7
  	Trans-2-hexenyl butyrate	53398-83-7
  	Hexyl phenylacetate	5421-17-0
  	Hexyl propionate	2445-76-3
  	Hydroxycitronellol	107-74-4
  	Isobutyl 2-butenoate	589-66-2
  	Isobutyl salicylate	87-19-4
  	Isodihydro lavandulal	35158-25-9
  	Isoeugenyl phenyl acetate	120-24-1
  	Isopropyl alpha-	1733-25-1
  	methylcrotonate
  	p-Menth-1-en-8-yl propionate	80-27-3
  	Menthalactone	13341-72-5
  	3-Methoxy-p-cymene	1076-56-8
  	Methyl 4-methyl pentanoate	2412-80-8
  	alpha-Methyl benzyl formate	7775-38-4
  	2-Methylbutyl 2-	2445-78-5
  	methylbutanoate
  	Methyl e-2-octenoate	2396-85-2
  	p-Methyl hydratropaldehyde	99-72-9
  	3-(5-Methyl-2-furyl)butanal	31704-80-0
  	Nerol oxide	1786-08-9
  	trans,cis-2,6-Nonadien-1-ol	7786-44-9
  	trans-2-Octen-1-yl acetate	3913-80-2
  	3-Octen-2-one	1669-44-9
  	2-Phenyl-2-butenal	4411-89-6
  	2-Propionylthiazole	43039-98-1
  	1-Hydroxy-2-butanone	5077-67-8
  	2-Butanone, 3-hydroxy-, (+−)-	52217-02-4
  	Thiazole, 2,5-dimethyl-	4175-66-0
  	Butanethioic acid, S-methyl	2432-51-1
  	ester
  	2,4-Hexadienoic acid, methyl	689-89-4
  	ester, (E,E)-
  	Benzeneacetaldehyde, 4-methyl-	104-09-6
  	Bicyclo[4.1.0]hept-3-ene,	498-15-7
  	3,7,7-trimethyl-, (1S)-
  	Ethyl 3-hexenoate	2396-83-0
  	1H-Pyrrole, 1-(2-	1438-94-4
  	furanylmethyl)-
  	6-Octenal, 3,7-dimethyl-, (R)-	2385-77-5
  	Ethanethioic acid, S-(2-	13678-68-7
  	furanylmethyl) ester
  	6-Octen-1-ol, 3,7-dimethyl-,	1117-61-9
  	(R)-
  	6-Octen-1-ol, 3,7-dimethyl-,	7540-51-4
  	(S)-
  	DL-Tetrohydrofurfuryl	637-65-0
  	propionate
  	Benzenepentanol	10521-91-2
  	Cyclohexaneethanol, acetate	21722-83-8
  	Benzyl isobutyl ketone	5349-62-2
  	Butanoic acid, 3-oxo-,	5396-89-4
  	phenylmethyl ester
  	1,2-Ethanediamine, N,N′-	140-28-3
  	bis(phenylmethyl)-
  	2-Ethyl-3-hydroxy-4-pyrone	1110651
  	Dicyclohexyl disulfide	2550-40-5
  	Tetrahydrofurfuryl butyrate	2217-33-6
  	Thujone	546-80-5
  	Benzyl alcohol, alpha-methyl-,	3460-44-4
  	butyrate
  	Citronellyl tiglate	24717-85-9
  	Lactitol	585-86-4
  	Nonivamide	2444-46-4
  	2-Acetoxy-3-butanone	4906-24-5
  	3-Acetyl-2,5-dimethylthiophene	230378
  	3-Acetyl-2-5dimethylfuran	10599-70-9
  	4-Acetyl-6-t-butyl-1,1-	13171-00-1
  	dimethylindan
  	Allyl 2-furoate	4208-49-5
  	Allyl sorbate	7493-75-6
  	Allyl thiopropionate	41820-22-8
  	Allyl tiglate	7493-71-2
  	Amylcyclohexyl acetate	67874-72-0
  	Benzaldehyde glyceryl acetal	1319-88-6
  	Benzaldehyde propylene glycol	2568-25-4
  	acetal
  	Bornyl isovalerate	76-50-6
  	1,3-Butanedithiol	24330-52-7
  	2,3-Butanedithiol	4532-64-3
  	Butyl cinnamic aldehyde	7492-44-6
  	Cinnamyl benzoate	5320-75-2
  	Citral ethylene glycol acetal	66408-78-4
  	Citronellyloxyacetaldehyde	7492-67-3
  	Citronellyl phenylacetate	139-70-8
  	Cyclohexyl isovalerate	7774-44-9
  	Decalactone	5579-78-2
  	2,5-Dimethyl-4-methoxy-3(2H)-	4077-47-8
  	furanone
  	6,10-Dimethyl-9-undecen-2-one	4433-36-7
  	2-Ethoxythiazole	15679-19-3
  	Ethyl 2-mercaptopropionate	19788-49-9
  	Ethyl 2-methyl-4-pentenoate	53399-81-8
  	Ethyl 3-(2-furyl)propanoate	94278-27-0
  	Ethyl cyclohexanepropionate	10094-36-7
  	Ethyl (p-tolyloxy)acetate	67028-40-4
  	3-Ethyl-2-hydroxy-2-	21835-01-8
  	cyclopenten-1-one
  	Ethylene brassylate	105-95-3
  	2-Ethylfenchol	18368-91-7
  	Furfuryl 3-methylbutanoate	13678-60-9
  	Furfuryl butyrate	623-21-2
  	Furfuryl isopropyl sulfide	1883-78-9
  	Furfuryl methyl sulfide	1438-91-1
  	Furfuryl propionate	623-19-8
  	Furfuryl thiopropionate	59020-85-8
  	Geranyl acetoacetate	10032-00-5
  	Geranyl benzoate	94-48-4
  	Geranyl isovalerate	109-20-6
  	delta-Hexalactone	823-22-3
  	trans-3-Hexenal	69112-21-6
  	cis-3-Hexenyl anthranilate	65405-76-7
  	trans-2-Hexenyl propionate	53398-80-4
  	5-(cis-3-Hexenyl) dihydro-5-	70851-61-5
  	methyl-2(3H)furanone
  	Hexyl 2-formate	39251-86-0
  	Hexyl crotonate	19089-92-0
  	Hexyl formate	629-33-4
  	Isoamyl 3-(2-furyl)propionate	7779-67-1
  	Isoamyl pyruvate	7779-72-8
  	Isobutyl furylpropionate	105-01-1
  	Isohexenyl cyclohexenyl	37677-14-8
  	carboxaldehyde
  	p-Isopropyl phenylacetaldehyde	4395-92-0
  	Linalyl cinnamate	78-37-5
  	Linalyl formate	115-99-1
  	Linalyl isovalerate	1118-27-0
  	Linalyl phenylacetate	7143-69-3
  	Maltol isobutyrate	65416-14-0
  	Methyl 2-methylpentanoate	2177-77-7
  	Methyl 3-hydroxyhexanoate	21188-58-9
  	Methyl 3-nonenoate	13481-87-3
  	Methyl furfuryl disulfide	57500-00-2
  	Methyl p-tert-	3549-23-3
  	butylphenylacetate
  	3-Methyl-1,2-cyclohexanedione	3008-43-3
  	alpha-Methylanisalacetone	104-27-8
  	2-Methylbutyl isovalerate	2445-77-4
  	4-Methylnonanoic acid	45019-28-1
  	4-Methyloctanoic acid	54947-74-9
  	2-Methyltetrahydrothiophen-3-	13679-85-1
  	one
  	3-(Methylthio)butanal	16630-52-7
  	4-(Methylthio)butanol	20582-85-8
  	4-Methylthio-2-butanone	34047-39-7
  	4-Methylthio-4-methyl-2-	23550-40-5
  	pentanone
  	Neryl butyrate	999-40-6
  	Neryl formate	2142-94-1
  	Neryl isovalerate	3915-83-1
  	Octahydrocoumarin	4430-31-3
  	Phenethyl 2-furoate	7149-32-8
  	1-Phenyl-2-pentanol	705-73-7
  	Phenylacetaldehyde	68345-22-2
  	diisobutylacetal
  	Phenylacetaldehyde glyceryl	29895-73-6
  	acetal
  	2-(3-Phenylpropyl)pyridine	2110-18-1
  	Propyl phenylacetate	4606-15-9
  	Pyrazineethanethiol	35250-53-4
  	Ethyl 2-methyl pentanoate	39255-32-8
  	Methyl 2,4-decadienoate	4493-42-9
  	alpha-Isomethyl ionone	127-51-5
  	5-Methyl hexanoic acid	628-46-6
  	Ethyl 3-methyl pentanoate	5870-68-8
  	Ethyl 2-methyl-3,4-	60523-21-9
  	pentadienoate
  	3-Nonen-2-one	14309-57-0
  	5-Methyl-3-hexen-2-one	5166-53-0
  	Maltol propionate	68555-63-5
  	2-Methyl-3-(2-furyl) acrolein	874-66-8
  	Ethyl 3(2-furyl)propanoate	10031-90-0
  	2-Phenyl-3-(2-furyl)-propenal	57568-60-2
  	4-Methyl-2-pentyl-1,3-	1599-49-1
  	dioxolane
  	2-Ethyl-4,5-dimethyl oxazole	53833-30-0
  	Isobornyl isovalerate	7779-73-9
  	Theophylline-7-acetic acid	652-37-9
  	Ethyl trans-2-octenoate	7367-82-0
  	DL-Arginine	7200-25-1
  	Allyl Crotonate	20474-93-5
  	2-Methoxystyrene	612-15-7
  	Magnesium Fumarate	7704-71-4
  	2-Propionylpyrrole	1073-26-3
  	2-methyl-1,3-dithiolane	5616-51-3
  	2-ethyl-5-methyl pyrazine	13360-64-0
  	2-methyl-3-(dimercaptomethyl)-	65505-17-1
  	furan
  	Magnesium gluconate	3632-91-5
  	Manganese gluconate	6485-39-8
  	Erythritol	149-32-6
  	D-Arabinose	28697-53-2
  	D-Galactose	59-23-4
  	D-(+)-Mannose	3458-28-4
  	Sorbitol	50-70-4
  	Aspartame	22839-47-0
  	Cyclamic Acid	100-88-9
  	Dulcin	150-69-6
  	Glucose-1-phosphate	29732-59-0
  	Dipotassium Salt
  	L-(+)-Arabinose	87-72-9
  	Fructose-6-Phosphate	643-13-0
  	D-Maltose Monohydrate	6363-53-7
  	Ribose	24259-59-4
  	Fructose 1,6-Diphosphate	26177-85-5
  	Disodium Salt
  	Saccharin sodium, dihydrate	6155-57-3
  	1,2-Benzisothiazol-3(2H)-one	6485-34-3
  	1,1-dioxide, calcium salt
  	1,2-Benzisothiazolin-3-one	10332-51-1
  	1,1-dioxide, potassium salt
  	zeranol	26538-44-3
  	beta-D-fructopyranose	7660-25-5
  	D-fructose 1,6-bisphosphate	488-69-7
  	Ribose 5-phosphate	4300-28-1
  	Arabinose	147-81-9
  	Saccharin, sodium salt hydrate	82385-42-0
  	Maltitol	585-88-6
  	D-Fructose 1-phosphate	15978-08-2
  	D-Sorbitol 6-phosphate	108392-12-
  	alpha-D-Xylose	31178-70-8
  	Inositol 1-phosphate	573-35-3

• 	TABLE 10
  	Name	CAS #
  	Sodium Metabisulfite	7681-57-4
  	sodium hydrogen phosphate	7558-79-4
  	Sodium Phosphate Monobasic	7558-80-7
  	Sodium thiosulfate	7772-98-71
  	Orthoboric acid	10043-35-3
  	Diethanolamine	111-42-2
  	Benzaldehyde	100-52-7
  	Sorbic acid	110-44-1
  	L-(+)-Tartaric Acid	87-69-4
  	D-mannitol	69-65-8
  	Butyl paraben	94-26-8
  	Thymol	89-83-8
  	Methyl salicylate	119-36-8
  	Citric acid	77-92-9
  	Creatinine	60-27-5
  	Vitamin C	50-81-7
  	Benzoic Acid	65-85-0
  	Methyl 4-hydroxybenzoate	99-76-3
  	m-Cresol	108-39-4
  	p-Cresol	106-44-5
  	Aspirin	50-78-2
  	Phenol	108-95-2
  	Sucrose	57-50-1
  	Potassium citrate, monohydrate	1534146
  	Sodium acetate	127-09-3
  	Lactic acid	50-21-5
  	Propionic acid, sodium salt	65-85
  	Benzyl alcohol	100-51-6
  	Phenethyl alcohol	60-12-8
  	Cholesterol	57-88-5
  	D-Glucose	50-99-7
  	Sorbitol	50-70-4
  	Aspartame	22839-47-0
  	Saccharin	81-07-2
  	2,6-Di-tert-Butyl-p-Cresol	128-37-0
  	4-Chloro-3-methylphenol	59-50-7
  	glycerin	56-81-5
  	Propyl paraben	94-13-3
  	fumaric acid	110-17-8
  	dabco	280-57-9
  	p-Phenylenediamine	106-50-3
  	Anethole	4180-23-8
  	propyl gallate	121-79-9
  	L-monosodium glutamate	142-47-2
  	Butylated hydroxyanisole	25013-16-5
  	Cyclohexanol, 5-methyl-2-(1-	89-78-1
  	methylethyl)-,
  	(1alpha,2beta,5alpha)-
  	alpha-Thioglycerol	96-27-5
  	Sodium dehydroacetate	4418-26-2
  	Ethyl 4-hydroxybenzoate	120-47-8
  	Ethyl Vanillin	121-32-4
  	Triacetin	102-76-1
  	Potassium sorbate	590-00-1
  	Triethyl citrate	77-93-0
  	(S)-(+)-Arginine	74-79-3
  	Glycine	56-40-6
  	(S)-(−)-Histidine	71-00-1
  	(S)-(+)-Lysine	56-87-1
  	Quinone	106-51-4
  	Naphthalene, 2-ethoxy-	93-18-5
  	Methanesulfonic Acid	75-75-2
  	DL-Tartaric Acid	133-37-9
  	Cyclamic acid	100-88-9
  	(S)-(−)-Phenylalanine	63-91-2
  	(S)-(−)-Tyrosine	60-18-4
  	Carvone	99-49-0
  	Ethyl butyrate	105-54-4
  	6-Methyl-5-hepten-2-one	110-93-0
  	Ethyl acetoacetate	141-97-9
  	Methyl benzoate	93-58-3
  	Phenylacetic Acid	103-82-2
  	Adipic acid	124-04-9
  	Ethyl benzoate	93-89-0
  	Benzyl benzoate	120-51-4
  	Pyruvic acid	127-17-3
  	Succinic acid	110-15-6
  	Indole	120-72-9
  	Methyl anthranilate	134-20-3
  	Diethyl malonate	105-53-3
  	Niacin	59-67-6
  	Meso-inositol	87-89-8
  	4-Aminobenzoic acid	150-13-0
  	Anisole	100-66-3
  	Urea	57-13-6
  	Pyrrolidine	123-75-1
  	Cyclopentanone	120-92-3
  	Acetic anhydride	108-24-7
  	Benzophenone	119-61-9
  	D-(−)-Fructose	57-48-7
  	D-(+)-Xylose	58-86-6
  	o-Methoxybenzoic Acid	579-75-9
  	linalool	78-70-6
  	ethyl isovalerate	108-64-5
  	1,1′-Azobisformamide	123-77-3
  	6-Methylcoumarin	92-48-8
  	acetoin	513-86-0
  	alpha-Phellandrene	99-83-2
  	Cymene	99-87-6
  	Dimethyl Succinate	106-65-0
  	p-Anisaldehyde	123-11-5
  	Phenyl ether	101-84-8
  	Tetrahydro-2-furanmethanol	97-99-4
  	Valeric Acid	109-52-4
  	3,4-xylenol	95-65-8
  	1,1-diethoxyethane	105-57-7
  	ethyl butyraldehyde	97-96-1
  	Ethyl crotonate	623-70-1
  	ethyl isobutyrate	97-62-1
  	methyl isovalerate	556-24-1
  	methyl propionate	554-12-1
  	methyl valeraldehyde	123-15-9
  	4-(2,6,6-Trimethyl-2-	127-41-3
  	cyclohexen-1-yl)-3-buten-2-one
  	4-(2,6,6-trimethyl-1-	14901-07-6
  	cyclohexen-1-yl)-3-buten-2-one
  	Maleic acid	110-16-7
  	3-Methylbutanoic acid	503-74-2
  	L-Glutamic Acid	56-86-0
  	D-limonene	5989-27-5
  	1-Phenyl-1-propanol	93-54-9
  	2′-Hydroxyacetophenone	118-93-4
  	2,4-Dihydroxybenzoic Acid	89-86-1
  	2-Phenyl-1-propanol	1123-85-9
  	3-Phenylpropionic Acid	501-52-0
  	4-Ethoxyphenol	622-62-8
  	Alpha-Terpineol	98-55-5
  	Benzaldehyde Dimethylacetal	1125-88-8
  	Benzyl Ether	103-50-4
  	Benzyl Formate	104-57-4
  	Benzyl Salicylate	118-58-1
  	Cinnamyl Alcohol	104-54-1
  	D-(+)-Glucono-1,5-lactone	4253-68-3
  	D-Isoascorbic Acid	89-65-6
  	2,3-Naphthalenediol	92-44-4
  	Diethyl Succinate	123-25-1
  	Ethyl 2-Aminobenzoate	87-25-2
  	Ethyl Cinnamate	103-36-6
  	Ethyl Phenylacetate	101-97-3
  	Ethyl Salicylate	118-61-5
  	gamma-Valerolactone	108-29-2
  	Hydroquinone Dimethyl Ether	150-78-7
  	Isocaproic Acid	645-07-1
  	Isoeugenol	97-54-1
  	Isopropyl Benzoate	939-48-0
  	L-(+)-Isoleucine	73-32-5
  	L-Malic acid	97-67-6
  	L-2-Aminopropionic Acid	56-41-7
  	L-Carnitine	541-15-1
  	L-Glutamine	56-85-9
  	L-Hydroxyproline	51-35-4
  	L-Proline	147-85-3
  	L-Serine	56-45-1
  	L-Threonine	72-19-5
  	L-Valine	72-18-4
  	Phenoxyacetic Acid	122-59-8
  	Veratrole	91-16-7
  	2-Ethylbutyric acid	88-09-5
  	2-Methylpyrazine	109-08-0
  	o-methoxybenzaldehyde	135-02-4
  	L-Leucine	61-90-5
  	L-Asparagine	70-47-3
  	propiophenone	93-55-0
  	5-isopropyl-2-methyl-phenol	499-75-2
  	Xylitol	87-99-0
  	ethyl 4-oxopentanoate	539-88-8
  	methyl cinnamate	103-26-4
  	cumic alcohol	536-60-7
  	methyl 2-naphthyl ketone	93-08-3
  	1-methyl-4-(1-methylethyl)-	99-85-4
  	1,4-Cyclohexadiene
  	en-ethylene diamine
  	Caffeine	58-08-2
  	5-methylfurfural	620-02-0
  	furfuryl acetate	623-17-6
  	terpinen-4-ol	10482-56-1
  	phenylethanal	122-78-1
  	4′-Methoxyacetophenone	100-06-1
  	D-Fenchone	4695-62-9
  	1-Methoxy-4-methylbenzene	104-93-8
  	o-methylanisole	578-58-5
  	Acetylacetaldehyde dimethyl	5436-21-5
  	acetal
  	p-methylacetophenone	122-00-9
  	Methyl phenylacetate	101-41-7
  	4-Ethoxybenzaldehyde	10031-82-0
  	p-tolyl acetate	140-39-6
  	2,6-Dimethoxyphenol	91-10-1
  	Methyl 2-methoxybenzoate	606-45-1
  	alpha-methylcinnamaldehyde	101-39-3
  	2-methoxycinnamaldehyde	60125-24-8
  	Potassium bicarbonate	298-14-6
  	piperonyl acetate	326-61-4
  	2,3-hexanedione	3848-24-6
  	furfural acetone	623-15-4
  	trans beta-(2-furyl)acrolein	623-30-3
  	carveol	99-48-9
  	Methyl nicotinate	93-60-7
  	Ethyl benzoylacetate	94-02-0
  	Methyl 4-methoxybenzoate	121-98-2
  	Levulinic acid	123-76-2
  	m-Dimethoxybenzene	151-10-0
  	2-acetylpyridine	1122-62-9
  	tetramethyl-pyrazine	1124-11-4
  	2,3-dimethyl-pyrazine	5910-89-4
  	trimethyl-pyrazine	14667-55-1
  	2-ethyl-3-methyl-pyrazine	15707-23-0
  	5-Methyl-3H-furan-2-one	591-12-8
  	2-Methoxy-4-methylphenol	93-51-6
  	piperazine	110-85-0
  	2-Methoxy-4-propylphenol	2785-87-7
  	Naphthalene, 2-(2-	2173-57-1
  	methylpropoxy)-
  	2-Acetyl-1-methylpyrrole	932-16-1
  	3,3-Dimethylacrylic acid	541-47-9
  	Ethyl sorbate	2396-84-1
  	4-(4-Hydroxyphenyl)-2-butanone	5471-51-2
  	4-Methoxyphenylacetone	122-84-9
  	(−)-Myrtenal	564-94-3
  	3-Phenylpropionaldehyde	104-53-0
  	1-Phenylethyl propionate	120-45-6
  	2-Methyltetrahydrofuran-3-one	3188-00-9
  	Cinnamyl acetate	103-54-8
  	Styrallyl acetate	93-92-5
  	Ethyl 4-methoxybenzoate	94-30-4
  	Benzyl propionate	122-63-4
  	Phenylpyruvate	156-06-9
  	furaneol	3658-77-3
  	methyl 2-methylbutanoate	868-57-5
  	Benzeneacetaldehyde, alpha-	93-53-8
  	methyl-
  	Dimethyl anthranilate	85-91-6
  	1,1-Dimethoxy-2-phenylpropane	90-87-9
  	4-hexanolide	695-06-7
  	Dimethylbenzylcarbinyl acetate	151-05-3
  	Benzyl isobutyrate	103-28-6
  	Acetyl isoeugenol	93-29-8
  	2-Acetyl-5-methyl furan	1193-79-9
  	Alpha-methyl-p-	103-95-7
  	isopropylphenylpropanaldehyde
  	Benzylcarbinyl formate	104-62-1
  	p-Cresyl alpha-toluate	101-94-0
  	Potassium bisulfate	7646-93-7
  	Potassium carbonate	584-08-7
  	Potassium chloride	7447-40-7
  	Potassium hydroxide	1310-58-3
  	Ethyl tiglate	5837-78-5
  	Nerol oxide	1786-08-9
  	DL-Tetrohydrofurfuryl	637-65-0
  	propionate
  	Benzaldehyde propylene glycol	2568-25-4
  	acetal
  	2-Methyl-3-(2-furyl) acrolein	874-66-8
  	vanillin	121-33-5
  	Cholic acid	81-25-4
  	R-Carvone	6485-40-1
  	Potassium nitrate	7757-79-1
  	Potassium permanganate	7722-64-7
  	Potassium persulfate	7727-21-1
  	Potassium phosphate, dibasic	2139900
  	Potassium Phosphate Monobasic	7778-77-0
  	Potassium sulfate	7778-80-5
  	Sodium bicarbonate	144-55-8
  	Sodium bisulfite	7631-90-5
  	Sodium carbonate	497-19-8
  	Sodium chloride	7647-14-5
  	Sodium dithionite	7775-14-6
  	Sodium hydroxide	1310-73-2
  	Sodium nitrite	7632-00-0
  	Sodium Pyrophosphate	7722-88-5
  	Sodium sulfate	7757-82-6
  	Sodium sulfite	7757-83-7
  	Sodium thiocyanate	540-72-7
  	Calcium Carbonate	471-34-1
  	Calcium chloride	10043-52-4
  	Calcium gluconate	299-28-5
  	Calcium hydroxide	1305-62-0
  	Calcium phosphate, dibasic	7757-93-9
  	Calcium sulfate	7778-18-9
  	N-Methyl-D-glucamine	6284-40-8
  	Calcium oxide	1305-78-8
  	Calcium Phosphate Monobasic	7758-23-8
  	Magnesium chloride hexahydrate	7791-18-6
  	Magnesium sulfate	7487-88-9
  	Magnesium Sulfate Heptahydrate	10034-99-8
  	Aluminum chloride hexahydrate	7784-13-6
  	aluminum nitrate nonahydrate	7784-27-2
  	Aluminum potassium sulfate,	7784-24-9
  	dodecahydrate
  	Aluminum sulfate,	7784-31-8
  	octadecahydrate
  	(S)-(−)-Cysteine	52-90-4
  	p-Toluenesulfonic Acid	104-15-4
  	Potassium bitartrate	868-14-4
  	DL-aspartic acid	617-45-8
  	p-Dimethylaminobenzaldehyde	100-10-7
  	Sodium salicylate	54-21-7
  	Benzoin	119-53-9
  	Sodium dodecyl sulfate	151-21-3
  	L-Menthol	2216-51-5
  	Tiron	149-45-1
  	Riboflavin	83-88-5
  	Sodium Acetate Trihydrate	6131-90-4
  	Disodium Succinate Hexahydrate	6106-21-4
  	Disodium	6381-92-6
  	ethylenediaminetetraacetate
  	dihydrate
  	sodium citrate, dihydrate	1545801
  	Sodium potassium tartrate,	6381-59-5
  	tetrahydrate
  	L-(+)-Arginine	1119-34-2
  	monohydrochloride
  	Ethylenediamine	333-18-6
  	dihydrochloride
  	Sodium formate	141-53-7
  	Sodium acetate	127-09-3
  	Potassium acetate	127-08-2
  	Ammonium citrate	3012-65-5
  	Ammonium bicarbonate	1066-33-7
  	Ammonium chloride	12125-02-9
  	Ammonium nitrate	6484-52-2
  	Ammonium persulfate	7727-54-0
  	Ammonium sulfate	7783-20-2
  	Zinc chloride	7646-85-7
  	Sulfuric acid, zinc salt	7446-20-0
  	(1:1), heptahydrate
  	Sodium Tripolyphosphate	7758-29-4
  	ammonium benzoate	1863-63-4
  	ammonium bisulfite	10192-30-0
  	1,5-Naphthalenedisulfonic Acid	1655-29-4
  	Disodium Salt
  	4-Hydroxybenzoic Acid	99-96-7
  	Diphenylacetic Acid	117-34-0
  	Glutaric Acid	110-94-1
  	L-(−)-Fucose	2438-80-4
  	L-Cysteine Hydrochloride	52-89-1
  	L-Histidine Hydrochloride	1880304
  	Monohydrate
  	o-Toluic Acid	118-90-1
  	Pivalic Acid	75-98-9
  	Pyruvic Acid Sodium Salt	113-24-6
  	Potassium bromide	2139626
  	Sodium Dithionate Dihydrate	7631-94-9
  	Sodium Malonate	141-95-7
  	Trisodium Citrate	68-04-2
  	Potassium Sodium Tartrate	304-59-6
  	Potassium Citrate	866-84-2
  	D-Maltose Monohydrate	6363-53-7
  	Cyclohexaamylose	10016-20-3
  	Dodecyl sulfate, lithium salt	2044-56-6
  	Manganese chloride	2145076
  	methyl-urea	598-50-5
  	beta-Cyclodextrin	7585-39-9
  	Triphosphoric acid,	13845-36-8
  	pentapotassium salt
  	Glycine ethyl ester	623-33-6
  	hydrochloride
  	L-Histidine methyl ester	7389-87-9
  	dihydrochloride
  	L-Leucine methyl ester	7517-19-3
  	hydrochloride
  	D-Lysine hydrochloride	7274-88-6
  	2-Naphthalenesulfonic acid	532-02-5
  	sodium salt
  	calcium nitrate tetrahydrate	13477-34-4
  	Vitamin B1	59-43-8
  	Zinc Acetate Dihydrate	5970-45-6
  	Potassium fluoride	7789-23-3
  	Potassium iodate	2139718
  	Potassium iodide	7681-11-0
  	Potassium thiocyanate	333-20-0
  	Sodium bromide	7647-15-6
  	Sodium fluoride	7681-49-4
  	Sodium iodide	7681-82-5
  	Sodium nitrate	7631-99-4
  	Calcium acetate	5743-26-0
  	Trichloroacetic acid	76-03-9
  	Ammonium acetate	631-61-8
  	Ammonium fluoride	12125-01-8
  	DL-malic acid	617-48-1
  	t-Butyl Alcohol	75-65-0
  	beta-Alanine	107-95-9
  	(S)-(−)-Tryptophan	73-22-3
  	Malonic acid	141-82-2
  	Phenethylamine	64-04-0
  	Salicylylaldehyde	90-02-8
  	Sodium benzoate	532-32-1
  	Mandelic acid	90-64-2
  	Calcium pantothenate	137-08-6
  	Chloroacetic Acid	79-11-8
  	Ethanol Amine	141-43-5
  	Salicylic acid	69-72-7
  	Saccharin sodium	128-44-9
  	Thiamine hydrochloride	67-03-8
  	2,2′-Oxybisethanol	111-46-6
  	Resorcinol	108-46-3
  	2-Amino-2-(hydroxymethyl)-1,3-	77-86-1
  	propanediol
  	2,5-Dimethylphenol	95-87-4
  	Ammonium Phosphate Monobasic	7722-76-1
  	1,3-Butanediol	107-88-0
  	Glycolic Acid	79-14-1
  	Sodium Gluconate	527-07-1
  	Terephthalic Acid	100-21-0
  	L-Ascorbic Acid Sodium Salt	134-03-2
  	3-Acetyl-6-methyl-2,4-	520-45-6
  	pyrandione
  	Calcium Acetate	62-54-4
  	Nicotinamide	98-92-0
  	1-Hydroxy-2-naphthoic Acid	86-48-6
  	2-Isopropylphenol	88-69-7
  	4-Aminosalicylic Acid	65-49-6
  	Calcium Glycerophosphate	27214-00-2
  	Erythorbic Acid Sodium Salt	7378-23-6
  	Gluconic Acid Potassium Salt	299-27-4
  	Orotic Acid	65-86-1
  	p-Anise Alcohol	105-13-5
  	Potassium Benzoate	582-25-2
  	Taurine	107-35-7
  	Thiamine Nitrate	532-43-4
  	3,3,5-Trimethyl-1-cyclohexanol	116-02-9
  	tert-Butylhydroquinone	1948-33-0
  	Sulfosalicylic acid	97-05-2
  	Gallic acid	149-91-7
  	L-borneol	464-45-9
  	Isoborneol	124-76-5
  	2,5-Dihydroxybenzoic acid,	490-79-9
  	Gentisic acid
  	5-hydroxy-6-methyl-3,4-	65-23-6
  	pyridinedimethanol
  	Naphthalene-2-sulfonic acid	120-18-3
  	Ethanesulfonic acid, 2-	1562-00-1
  	hydroxy-, monosodium salt
  	Pamoic acid	130-85-8
  	2,4-Dimethylphenol	105-67-9
  	3,5-Dihydroxyacetophenone	51863-60-6
  	Eugenol	97-53-0
  	n-Butyric Acid	107-92-6
  	Hydroquinone	123-31-9
  	Propionic Acid	79-09-4
  	meta-Phenylenediamine	108-45-2
  	Oxalic Acid	144-62-7
  	n-Hexanoic Acid	142-62-1
  	2-Furancarboxylic Acid	88-14-2
  	4′-Nitroacetanilide	104-04-1
  	D-(−)-Tartaric Acid	147-71-7
  	p-Acetamidobenzoic Acid	556-08-1
  	Galactaric acid	526-99-8
  	D-glucuronate	1700908
  	Lactobionic acid	96-82-2
  	p-Formylacetanilide	122-85-0
  	2-Mercaptobenzoic acid	147-93-3
  	Propanoic acid, 2-hydroxy-,	28305-25-1
  	calcium salt (2:1), (S)-
  	D(+)-10-Camphorsulfonic acid	3144-16-9
  	3-Cyclopentylpropionic acid	140-77-2
  	1R-(−)-Camphorsulfonic acid	35963-20-3
  	DL-Lysine	70-54-2
  	Cinnamic acid	621-82-9
  	Triethanolamine	102-71-6
  	Acetic Acid	64-19-7
  	Dichloroacetic Acid	79-43-6
  	Diethylamine	109-89-7
  	Diethylaminoethanol	100-37-8
  	N-(2-Hydroxyethyl)Morpholine	622-40-2
  	Octanoic Acid	124-07-2
  	isobutyric acid	79-31-2
  	Anisic Acid	100-09-4
  	Betaine	107-43-7
  	Enanthoic Acid	111-14-8
  	Hippuric Acid	495-69-2
  	Tiglic Acid	80-59-1
  	Cyclohexanecarboxylic acid	98-89-5
  	m-Methoxybenzoic acid	586-38-9
  	D-(+)-Camphoric acid	124-83-4
  	N-(2-Hydroxyethyl)pyrrolidine	2955-88-6
  	Sodium Metabisulfite	7681-57-4
  	sodium hydrogen phosphate	7558-79-4
  	Sodium Phosphate Monobasic	7558-80-7
  	Sodium thiosulfate	7772-98-71
  	Orthoboric acid	10043-35-3
  	Diethanolamine	111-42-2
  	Benzaldehyde	100-52-7
  	Sorbic acid	110-44-1
  	L-(+)-Tartaric Acid	87-69-4
  	D-mannitol	69-65-8
  	Butyl paraben	94-26-8
  	Thymol	89-83-8
  	Methyl salicylate	119-36-8
  	Citric acid	77-92-9
  	Creatinine	60-27-5
  	Vitamin C	50-81-7
  	Benzoic Acid	65-85-0
  	Methyl 4-hydroxybenzoate	99-76-3
  	m-Cresol	108-39-4
  	p-Cresol	106-44-5
  	Aspirin	50-78-2
  	Phenol	108-95-2
  	Sucrose	57-50-1
  	Potassium citrate, monohydrate	1534146
  	Sodium acetate	127-09-3
  	Lactic acid	50-21-5
  	Propionic acid, sodium salt	65-85
  	Benzyl alcohol	100-51-6
  	Phenethyl alcohol	60-12-8
  	Cholesterol	57-88-5
  	D-Glucose	50-99-7
  	Sorbitol	50-70-4
  	Aspartame	22839-47-0
  	Saccharin	81-07-2
  	2,6-Di-tert-Butyl-p-Cresol	128-37-0
  	4-Chloro-3-methylphenol	59-50-7
  	glycerin	56-81-5
  	Propyl paraben	94-13-3
  	fumaric acid	110-17-8
  	dabco	280-57-9
  	p-Phenylenediamine	106-50-3
  	Anethole	4180-23-8
  	propyl gallate	121-79-9
  	L-monosodium glutamate	142-47-2
  	Butylated hydroxyanisole	25013-16-5
  	Cyclohexanol, 5-methyl-2-(1-	89-78-1
  	methylethyl)-,
  	(1alpha,2beta,5alpha)-
  	alpha-Thioglycerol	96-27-5
  	Sodium dehydroacetate	4418-26-2
  	Ethyl 4-hydroxybenzoate	120-47-8
  	Ethyl Vanillin	121-32-4
  	Triacetin	102-76-1
  	Potassium sorbate	590-00-1
  	Triethyl citrate	77-93-0
  	(S)-(+)-Arginine	74-79-3
  	Glycine	56-40-6
  	(S)-(−)-Histidine	71-00-1
  	(S)-(+)-Lysine	56-87-1
  	Quinone	106-51-4
  	Naphthalene, 2-ethoxy-	93-18-5
  	Methanesulfonic Acid	75-75-2
  	DL-Tartaric Acid	133-37-9
  	Cyclamic acid	100-88-9
  	(S)-(−)-Phenylalanine	63-91-2
  	(S)-(−)-Tyrosine	60-18-4
  	Carvone	99-49-0
  	Ethyl butyrate	105-54-4
  	6-Methyl-5-hepten-2-one	110-93-0
  	Ethyl acetoacetate	141-97-9
  	Methyl benzoate	93-58-3
  	Phenylacetic Acid	103-82-2
  	Adipic acid	124-04-9
  	Ethyl benzoate	93-89-0
  	Benzyl benzoate	120-51-4
  	Pyruvic acid	127-17-3
  	Succinic acid	110-15-6
  	Indole	120-72-9
  	Methyl anthranilate	134-20-3
  	Diethyl malonate	105-53-3
  	Niacin	59-67-6
  	Meso-inositol	87-89-8
  	4-Aminobenzoic acid	150-13-0
  	Anisole	100-66-3
  	Urea	57-13-6
  	Pyrrolidine	123-75-1
  	Cyclopentanone	120-92-3
  	Acetic anhydride	108-24-7
  	Benzophenone	119-61-9
  	D-(−)-Fructose	57-48-7
  	D-(+)-Xylose	58-86-6
  	o-Methoxybenzoic Acid	579-75-9
  	linalool	78-70-6
  	ethyl isovalerate	108-64-5
  	1,1′-Azobisformamide	123-77-3
  	6-Methylcoumarin	92-48-8
  	acetoin	513-86-0
  	alpha-Phellandrene	99-83-2
  	Cymene	99-87-6
  	Dimethyl Succinate	106-65-0
  	p-Anisaldehyde	123-11-5
  	Phenyl ether	101-84-8
  	Tetrahydro-2-furanmethanol	97-99-4
  	Valeric Acid	109-52-4
  	3,4-xylenol	95-65-8
  	1,1-diethoxyethane	105-57-7
  	ethyl butyraldehyde	97-96-1
  	Ethyl crotonate	623-70-1
  	ethyl isobutyrate	97-62-1
  	methyl isovalerate	556-24-1
  	methyl propionate	554-12-1
  	methyl valeraldehyde	123-15-9
  	4-(2,6,6-Trimethyl-2-	127-41-3
  	cyclohexen-1-yl)-3-buten-2-one
  	4-(2,6,6-trimethyl-1-	14901-07-6
  	cyclohexen-1-yl)-3-buten-2-one
  	Maleic acid	110-16-7
  	3-Methylbutanoic acid	503-74-2
  	L-Glutamic Acid	56-86-0
  	D-limonene	5989-27-5
  	1-Phenyl-1-propanol	93-54-9
  	2′-Hydroxyacetophenone	118-93-4
  	2,4-Dihydroxybenzoic Acid	89-86-1
  	2-Phenyl-1-propanol	1123-85-9
  	3-Phenylpropionic Acid	501-52-0
  	4-Ethoxyphenol	622-62-8
  	Alpha-Terpineol	98-55-5
  	Benzaldehyde Dimethylacetal	1125-88-8
  	Benzyl Ether	103-50-4
  	Benzyl Formate	104-57-4
  	Benzyl Salicylate	118-58-1
  	Cinnamyl Alcohol	104-54-1
  	D-(+)-Glucono-1,5-lactone	4253-68-3
  	D-Isoascorbic Acid	89-65-6
  	2,3-Naphthalenediol	92-44-4
  	Diethyl Succinate	123-25-1
  	Ethyl 2-Aminobenzoate	87-25-2
  	Ethyl Cinnamate	103-36-6
  	Ethyl Phenylacetate	101-97-3
  	Ethyl Salicylate	118-61-6
  	gamma-Valerolactone	108-29-2
  	Hydroquinone Dimethyl Ether	150-78-7
  	Isocaproic Acid	646-07-1
  	Isoeugenol	97-54-1
  	Isopropyl Benzoate	939-48-0
  	L-(+)-Isoleucine	73-32-5
  	L-Malic acid	97-67-6
  	L-2-Aminopropionic Acid	56-41-7
  	L-Carnitine	541-15-1
  	L-Glutamine	56-85-9
  	L-Hydroxyproline	51-35-4
  	L-Proline	147-85-3
  	L-Serine	56-45-1
  	L-Threonine	72-19-5
  	L-Valine	72-18-4
  	Phenoxyacetic Acid	122-59-8
  	Veratrole	91-16-7
  	2-Ethylbutyric acid	88-09-5
  	2-Methylpyrazine	109-08-0
  	o-methoxybenzaldehyde	135-02-4
  	L-Leucine	61-90-5
  	L-Asparagine	70-47-3
  	propiophenone	93-55-0
  	5-isopropyl-2-methyl-phenol	499-75-2
  	Xylitol	87-99-0
  	ethyl 4-oxopentanoate	539-88-8
  	methyl cinnamate	103-26-4
  	cumic alcohol	536-60-7
  	methyl 2-naphthyl ketone	93-08-3
  	1-methyl-4-(1-methylethyl)-	99-85-4
  	1,4-Cyclohexadiene
  	en-ethylene diamine
  	Caffeine	58-08-2
  	5-methylfurfural	620-02-0
  	furfuryl acetate	623-17-6
  	terpinen-4-ol	10482-56-1
  	phenylethanal	122-78-1
  	4′-Methoxyacetophenone	100-06-1
  	D-Fenchone	4695-62-9
  	1-Methoxy-4-methylbenzene	104-93-8
  	o-methylanisole	578-58-5
  	Acetylacetaldehyde dimethyl	5436-21-5
  	acetal
  	p-methylacetophenone	122-00-9
  	Methyl phenylacetate	101-41-7
  	4-Ethoxybenzaldehyde	10031-82-0
  	p-tolyl acetate	140-39-6
  	2,6-Dimethoxyphenol	91-10-1
  	Methyl 2-methoxybenzoate	606-45-1
  	alpha-methylcinnamaldehyde	101-39-3
  	2-methoxycinnamaldehyde	60125-24-8
  	Potassium bicarbonate	298-14-6
  	piperonyl acetate	326-61-4
  	2,3-hexanedione	3848-24-6
  	furfural acetone	623-15-4
  	trans beta-(2-furyl)acrolein	623-30-3
  	carveol	99-48-9
  	Methyl nicotinate	93-60-7
  	Ethyl benzoylacetate	94-02-0
  	Methyl 4-methoxybenzoate	121-98-2
  	Levulinic acid	123-76-2
  	m-Dimethoxybenzene	151-10-0
  	2-acetylpyridine	1122-62-9
  	tetramethyl-pyrazine	1124-11-4
  	2,3-dimethyl-pyrazine	5910-89-4
  	trimethyl-pyrazine	14667-55-1
  	2-ethyl-3-methyl-pyrazine	15707-23-0
  	5-Methyl-3H-furan-2-one	591-12-8
  	2-Methoxy-4-methylphenol	93-51-6
  	piperazine	110-85-0
  	2-Methoxy-4-propylphenol	2785-87-7
  	Naphthalene, 2-(2-	2173-57-1
  	methylpropoxy)-
  	2-Acetyl-1-methylpyrrole	932-16-1
  	3,3-Dimethylacrylic acid	541-47-9
  	Ethyl sorbate	2396-84-1
  	4-(4-Hydroxyphenyl)-2-butanone	5471-51-2
  	4-Methoxyphenylacetone	122-84-9
  	(−)-Myrtenal	564-94-3
  	3-Phenylpropionaldehyde	104-53-0
  	1-Phenylethyl propionate	120-45-6
  	2-Methyltetrahydrofuran-3-one	3188-00-9
  	Cinnamyl acetate	103-54-8
  	Styrallyl acetate	93-92-5
  	Ethyl 4-methoxybenzoate	94-30-4
  	Benzyl propionate	122-63-4
  	Phenylpyruvate	156-06-9
  	furaneol	3658-77-3
  	methyl 2-methylbutanoate	868-57-5
  	Benzeneacetaldehyde, alpha-	93-53-8
  	methyl-
  	Dimethyl anthranilate	85-91-6
  	1,1-Dimethoxy-2-phenylpropane	90-87-9
  	4-hexanolide	695-06-7
  	Dimethylbenzylcarbinyl acetate	151-05-3
  	Benzyl isobutyrate	103-28-6
  	Acetyl isoeugenol	93-29-8
  	2-Acetyl-5-methyl furan	1193-79-9
  	Alpha-methyl-p-	103-95-7
  	isopropylphenylpropanaldehyde
  	Benzylcarbinyl formate	104-62-1
  	p-Cresyl alpha-toluate	101-94-0
  	Potassium bisulfate	7646-93-7
  	Potassium carbonate	584-08-7
  	Potassium chloride	7447-40-7
  	Potassium hydroxide	1310-58-3
  	Ethyl tiglate	5837-78-5
  	Nerol oxide	1786-08-9
  	DL-Tetrohydrofurfuryl	637-65-0
  	propionate
  	Benzaldehyde propylene glycol	2568-25-4
  	acetal
  	2-Methyl-3-(2-furyl) acrolein	874-66-8
  	vanillin	121-33-5
  	Cholic acid	81-25-4
  	R-Carvone	6485-40-1
  	Potassium nitrate	7757-79-1
  	Potassium permanganate	7722-64-7
  	Potassium persulfate	7727-21-1
  	Potassium phosphate, dibasic	2139900
  	Potassium Phosphate Monobasic	7778-77-0
  	Potassium sulfate	7778-80-5
  	Sodium bicarbonate	144-55-8
  	Sodium bisulfite	7631-90-5
  	Sodium carbonate	497-19-8
  	Sodium chloride	7647-14-5
  	Sodium dithionite	7775-14-6
  	Sodium hydroxide	1310-73-2
  	Sodium nitrite	7632-00-0
  	Sodium Pyrophosphate	7722-88-5
  	Sodium sulfate	7757-82-6
  	Sodium sulfite	7757-83-7
  	Sodium thiocyanate	540-72-7
  	Calcium Carbonate	471-34-1
  	Calcium chloride	10043-52-4
  	Calcium gluconate	299-28-5
  	Calcium hydroxide	1305-62-0
  	Calcium phosphate, dibasic	7757-93-9
  	Calcium sulfate	7778-18-9
  	N-Methyl-D-glucamine	6284-40-8
  	Calcium oxide	1305-78-8
  	Calcium Phosphate Monobasic	7758-23-8
  	Magnesium chloride hexahydrate	7791-18-6
  	Magnesium sulfate	7487-88-9
  	Magnesium Sulfate Heptahydrate	10034-99-8
  	Aluminum chloride hexahydrate	7784-13-6
  	aluminum nitrate nonahydrate	7784-27-2
  	Aluminum potassium sulfate,	7784-24-9
  	dodecahydrate
  	Aluminum sulfate,	7784-31-8
  	octadecahydrate
  	(S)-(−)-Cysteine	52-90-4
  	p-Toluenesulfonic Acid	104-15-4
  	Potassium bitartrate	868-14-4
  	DL-aspartic acid	617-45-8
  	p-Dimethylaminobenzaldehyde	100-10-7
  	Sodium salicylate	54-21-7
  	Benzoin	119-53-9
  	Sodium dodecyl sulfate	151-21-3
  	L-Menthol	2216-51-5
  	Tiron	149-45-1
  	Riboflavin	83-88-5
  	Sodium Acetate Trihydrate	6131-90-4
  	Disodium Succinate Hexahydrate	6106-21-4
  	Disodium	6381-92-6
  	ethylenediaminetetraacetate
  	dihydrate
  	sodium citrate, dihydrate	1545801
  	Sodium potassium tartrate,	6381-59-5
  	tetrahydrate
  	L-(+)-Arginine	1119-34-2
  	monohydrochloride
  	Ethylenediamine	333-18-6
  	dihydrochloride
  	Sodium formate	141-53-7
  	Sodium acetate	127-09-3
  	Potassium acetate	127-08-2
  	Ammonium citrate	3012-65-5
  	Ammonium bicarbonate	1066-33-7
  	Ammonium chloride	12125-02-9
  	Ammonium nitrate	6484-52-2
  	Ammonium persulfate	7727-54-0
  	Ammonium sulfate	7783-20-2
  	Zinc chloride	7646-85-7
  	Sulfuric acid, zinc salt	7446-20-0
  	(1:1), heptahydrate
  	Sodium Tripolyphosphate	7758-29-4
  	ammonium benzoate	1863-63-4
  	ammonium bisulfite	10192-30-0
  	1,5-Naphthalenedisulfonic Acid	1655-29-4
  	Disodium Salt
  	4-Hydroxybenzoic Acid	99-96-7
  	Diphenylacetic Acid	117-34-0
  	Glutaric Acid	110-94-1
  	L-(−)-Fucose	2438-80-4
  	L-Cysteine Hydrochloride	52-89-1
  	L-Histidine Hydrochloride	1880304
  	Monohydrate
  	o-Toluic Acid	118-90-1
  	Pivalic Acid	75-98-9
  	Pyruvic Acid Sodium Salt	113-24-6
  	Potassium bromide	2139626
  	Sodium Dithionate Dihydrate	7631-94-9
  	Sodium Malonate	141-95-7
  	Trisodium Citrate	68-04-2
  	Potassium Sodium Tartrate	304-59-6
  	Potassium Citrate	866-84-2
  	D-Maltose Monohydrate	6363-53-7
  	Cyclohexaamylose	10016-20-3
  	Dodecyl sulfate, lithium salt	2044-56-6
  	Manganese chloride	2145076
  	methyl-urea	598-50-5
  	beta-Cyclodextrin	7585-39-9
  	Triphosphoric acid,	13845-36-8
  	pentapotassium salt
  	Glycine ethyl ester	623-33-6
  	hydrochloride
  	L-Histidine methyl ester	7389-87-9
  	dihydrochloride
  	L-Leucine methyl ester	7517-19-3
  	hydrochloride
  	D-Lysine hydrochloride	7274-88-6
  	2-Naphthalenesulfonic acid	532-02-5
  	sodium salt
  	calcium nitrate tetrahydrate	13477-34-4
  	Vitamin B1	59-43-8
  	Zinc Acetate Dihydrate	5970-45-6
  	Potassium fluoride	7789-23-3
  	Potassium iodate	2139718
  	Potassium iodide	7681-11-0
  	Potassium thiocyanate	333-20-0
  	Sodium bromide	7647-15-6
  	Sodium fluoride	7681-49-4
  	Sodium iodide	7681-82-5
  	Sodium nitrate	7631-99-4
  	Calcium acetate	5743-26-0
  	Trichloroacetic acid	76-03-9
  	Ammonium acetate	631-61-8
  	Ammonium fluoride	12125-01-8
  	DL-malic acid	617-48-1
  	t-Butyl Alcohol	75-65-0
  	beta-Alanine	107-95-9
  	(S)-(−)-Tryptophan	73-22-3
  	Malonic acid	141-82-2
  	Phenethylamine	64-04-0
  	Salicylylaldehyde	90-02-8
  	Sodium benzoate	532-32-1
  	Mandelic acid	90-64-2
  	Calcium pantothenate	137-08-6
  	Chloroacetic Acid	79-11-8
  	Ethanol Amine	141-43-5
  	Salicylic acid	69-72-7
  	Saccharin sodium	128-44-9
  	Thiamine hydrochloride	67-03-8
  	2,2′-Oxybisethanol	111-46-6
  	Resorcinol	108-46-3
  	2-Amino-2-(hydroxymethyl)-1,3-	77-86-1
  	propanediol
  	2,5-Dimethylphenol	95-87-4
  	Ammonium Phosphate Monobasic	7722-76-1
  	1,3-Butanediol	107-88-0
  	Glycolic Acid	79-14-1
  	Sodium Gluconate	527-07-1
  	Terephthalic Acid	100-21-0
  	L-Ascorbic Acid Sodium Salt	134-03-2
  	3-Acetyl-6-methyl-2,4-	520-45-6
  	pyrandione
  	Calcium Acetate	62-54-4
  	Nicotinamide	98-92-0
  	1-Hydroxy-2-naphthoic Acid	86-48-6
  	2-Isopropylphenol	88-69-7
  	4-Aminosalicylic Acid	65-49-6
  	Calcium Glycerophosphate	27214-00-2
  	Erythorbic Acid Sodium Salt	7378-23-6
  	Gluconic Acid Potassium Salt	299-27-4
  	Orotic Acid	65-86-1
  	p-Anise Alcohol	105-13-5
  	Potassium Benzoate	582-25-2
  	Taurine	107-35-7
  	Thiamine Nitrate	532-43-4
  	3,3,5-Trimethyl-1-cyclohexanol	116-02-9
  	tert-Butylhydroquinone	1948-33-0
  	Sulfosalicylic acid	97-05-2
  	Gallic acid	149-91-7
  	L-borneol	464-45-9
  	Isoborneol	124-76-5
  	2,5-Dihydroxybenzoic acid,	490-79-9
  	Gentisic acid
  	5-hydroxy-6-methyl-3,4-	65-23-6
  	pyridinedimethanol
  	Naphthalene-2-sulfonic acid	120-18-3
  	Ethanesulfonic acid, 2-	1562-00-1
  	hydroxy-, monosodium salt
  	Pamoic acid	130-85-8
  	2,4-Dimethylphenol	105-67-9
  	3,5-Dihydroxyacetophenone	51863-60-6
  	Eugenol	97-53-0
  	n-Butyric Acid	107-92-6
  	Hydroquinone	123-31-9
  	Propionic Acid	79-09-4
  	meta-Phenylenediamine	108-45-2
  	Oxalic Acid	144-62-7
  	n-Hexanoic Acid	142-62-1
  	2-Furancarboxylic Acid	88-14-2
  	4′-Nitroacetanilide	104-04-1
  	D-(−)-Tartaric Acid	147-71-7
  	p-Acetamidobenzoic Acid	556-08-1
  	Galactaric acid	526-99-8
  	D-glucuronate	1700908
  	Lactobionic acid	96-82-2
  	p-Formylacetanilide	122-85-0
  	2-Mercaptobenzoic acid	147-93-3
  	Propanoic acid, 2-hydroxy-,	28305-25-1
  	calcium salt (2:1), (S)-
  	D(+)-10-Camphorsulfonic acid	3144-16-9
  	3-Cyclopentylpropionic acid	140-77-2
  	1R-(−)-Camphorsulfonic acid	35963-20-3
  	DL-Lysine	70-54-2
  	Cinnamic acid	621-82-9
  	Triethanolamine	102-71-6
  	Acetic Acid	64-19-7
  	Dichloroacetic Acid	79-43-6
  	Diethylamine	109-89-7
  	Diethylaminoethanol	100-37-8
  	N-(2-Hydroxyethyl)Morpholine	622-40-2
  	Octanoic Acid	124-07-2
  	isobutyric acid	79-31-2
  	Anisic Acid	100-09-4
  	Betaine	107-43-7
  	Enanthoic Acid	111-14-8
  	Hippuric Acid	495-69-2
  	Tiglic Acid	80-59-1
  	Cyclohexanecarboxylic acid	98-89-5
  	m-Methoxybenzoic acid	586-38-9
  	D-(+)-Camphoric acid	124-83-4
  	N-(2-Hydroxyethyl)pyrrolidine	2955-88-6
  	Sodium Metabisulfite	7681-57-4
  	sodium hydrogen phosphate	7558-79-4
  	Sodium Phosphate Monobasic	7558-80-7
  	Sodium thiosulfate	7772-98-71
  	Orthoboric acid	10043-35-3
  	Diethanolamine	111-42-2
  	Benzaldehyde	100-52-7
  	Sorbic acid	110-44-1
  	L-(+)-Tartaric Acid	87-69-4
  	D-mannitol	69-65-8
  	Butyl paraben	94-26-8
  	Thymol	89-83-8
  	Methyl salicylate	119-36-8
  	Citric acid	77-92-9
  	Creatinine	60-27-5
  	Vitamin C	50-81-7
  	Benzoic Acid	65-85-0
  	Methyl 4-hydroxybenzoate	99-76-3
  	m-Cresol	108-39-4
  	p-Cresol	106-44-5
  	Aspirin	50-78-2
  	Phenol	108-95-2
  	Sucrose	57-50-1
  	Potassium citrate, monohydrate	1534146
  	Sodium acetate	127-09-3
  	Lactic acid	50-21-5
  	Propionic acid, sodium salt	65-85
  	Benzyl alcohol	100-51-6
  	Phenethyl alcohol	60-12-8
  	Cholesterol	57-88-5
  	D-Glucose	50-99-7
  	Sorbitol	50-70-4
  	Aspartame	22839-47-0
  	Saccharin	81-07-2
  	2,6-Di-tert-Butyl-p-Cresol	128-37-0
  	4-Chloro-3-methylphenol	59-50-7
  	glycerin	56-81-5
  	Propyl paraben	94-13-3
  	fumaric acid	110-17-8
  	dabco	280-57-9
  	p-Phenylenediamine	106-50-3
  	Anethole	4180-23-8
  	propyl gallate	121-79-9
  	L-monosodium glutamate	142-47-2
  	Butylated hydroxyanisole	25013-16-5
  	Cyclohexanol, 5-methyl-2-(1-	89-78-1
  	methylethyl)-,
  	(1alpha,2beta,5alpha)-
  	alpha-Thioglycerol	96-27-5
  	Sodium dehydroacetate	4418-26-2
  	Ethyl 4-hydroxybenzoate	120-47-8
  	Ethyl Vanillin	121-32-4
  	Triacetin	102-76-1
  	Potassium sorbate	590-00-1
  	Triethyl citrate	77-93-0
  	(S)-(+)-Arginine	74-79-3
  	Glycine	56-40-6
  	(S)-(−)-Histidine	71-00-1
  	(S)-(+)-Lysine	56-87-1
  	Quinone	106-51-4
  	Naphthalene, 2-ethoxy-	93-18-5
  	Methanesulfonic Acid	75-75-2
  	DL-Tartaric Acid	133-37-9
  	Cyclamic acid	100-88-9
  	(S)-(−)-Phenylalanine	63-91-2
  	(S)-(−)-Tyrosine	60-18-4
  	Carvone	99-49-0
  	Ethyl butyrate	105-54-4
  	6-Methyl-5-hepten-2-one	110-93-0
  	Ethyl acetoacetate	141-97-9
  	Methyl benzoate	93-58-3
  	Phenylacetic Acid	103-82-2
  	Adipic acid	124-04-9
  	Ethyl benzoate	93-89-0
  	Benzyl benzoate	120-51-4
  	Pyruvic acid	127-17-3
  	Succinic acid	110-15-6
  	Indole	120-72-9
  	Methyl anthranilate	134-20-3
  	Diethyl malonate	105-53-3
  	Niacin	59-67-6
  	Meso-inositol	87-89-8
  	4-Aminobenzoic acid	150-13-0
  	Anisole	100-66-3
  	Urea	57-13-6
  	Pyrrolidine	123-75-1
  	Cyclopentanone	120-92-3
  	Acetic anhydride	108-24-7
  	Benzophenone	119-61-9
  	D-(−)-Fructose	57-48-7
  	D-(+)-Xylose	58-86-6
  	o-Methoxybenzoic Acid	579-75-9
  	linalool	78-70-6
  	ethyl isovalerate	108-64-5
  	1,1′-Azobisformamide	123-77-3
  	6-Methylcoumarin	92-48-8
  	acetoin	513-86-0
  	alpha-Phellandrene	99-83-2
  	Cymene	99-87-6
  	Dimethyl Succinate	106-65-0
  	p-Anisaldehyde	123-11-5
  	Phenyl ether	101-84-8
  	Tetrahydro-2-furanmethanol	97-99-4
  	Valeric Acid	109-52-4
  	3,4-xylenol	95-65-8
  	1,1-diethoxyethane	105-57-7
  	ethyl butyraldehyde	97-96-1
  	Ethyl crotonate	623-70-1
  	ethyl isobutyrate	97-62-1
  	methyl isovalerate	556-24-1
  	methyl propionate	554-12-1
  	methyl valeraldehyde	123-15-9
  	4-(2,6,6-Trimethyl-2-	127-41-3
  	cyclohexen-1-yl)-3-buten-2-one
  	4-(2,6,6-trimethyl-1-	14901-07-6
  	cyclohexen-1-yl)-3-buten-2-one
  	Maleic acid	110-16-7
  	3-Methylbutanoic acid	503-74-2
  	L-Glutamic Acid	56-86-0
  	D-limonene	5989-27-5
  	1-Phenyl-1-propanol	93-54-9
  	2′-Hydroxyacetophenone	118-93-4
  	2,4-Dihydroxybenzoic Acid	89-86-1
  	2-Phenyl-1-propanol	1123-85-9
  	3-Phenylpropionic Acid	501-52-0
  	4-Ethoxyphenol	622-62-8
  	Alpha-Terpineol	98-55-5
  	Benzaldehyde Dimethylacetal	1125-88-8
  	Benzyl Ether	103-50-4
  	Benzyl Formate	104-57-4
  	Benzyl Salicylate	118-58-1
  	Cinnamyl Alcohol	104-54-1
  	D-(+)-Glucono-1,5-lactone	4253-68-3
  	D-Isoascorbic Acid	89-65-6
  	2,3-Naphthalenediol	92-44-4
  	Diethyl Succinate	123-25-1
  	Ethyl 2-Aminobenzoate	87-25-2
  	Ethyl Cinnamate	103-36-6
  	Ethyl Phenylacetate	101-97-3
  	Ethyl Salicylate	118-61-6
  	gamma-Valerolactone	108-29-2
  	Hydroquinone Dimethyl Ether	150-78-7
  	Isocaproic Acid	646-07-1
  	Isoeugenol	97-54-1
  	Isopropyl Benzoate	939-48-0
  	L-(+)-Isoleucine	73-32-5
  	L-Malic acid	97-67-6
  	L-2-Aminopropionic Acid	56-41-7
  	L-Carnitine	541-15-1
  	L-Glutamine	56-85-9
  	L-Hydroxyproline	51-35-4
  	L-Proline	147-85-3
  	L-Serine	56-45-1
  	L-Threonine	72-19-5
  	L-Valine	72-18-4
  	Phenoxyacetic Acid	122-59-8
  	Veratrole	91-16-7
  	2-Ethylbutyric acid	88-09-5
  	2-Methylpyrazine	109-08-0
  	o-methoxybenzaldehyde	135-02-4
  	L-Leucine	61-90-5
  	L-Asparagine	70-47-3
  	propiophenone	93-55-0
  	5-isopropyl-2-methyl-phenol	499-75-2
  	Xylitol	87-99-0
  	ethyl 4-oxopentanoate	539-88-8
  	methyl cinnamate	103-26-4
  	cumic alcohol	536-60-7
  	methyl 2-naphthyl ketone	93-08-3
  	1-methyl-4-(1-methylethyl)-	99-85-4
  	1,4-Cyclohexadiene
  	en-ethylene diamine
  	Caffeine	58-08-2
  	5-methylfurfural	620-02-0
  	furfuryl acetate	623-17-6
  	terpinen-4-ol	10482-56-1
  	phenylethanal	122-78-1
  	4′-Methoxyacetophenone	100-06-1
  	D-Fenchone	4695-62-9
  	1-Methoxy-4-methylbenzene	104-93-8
  	o-methylanisole	578-58-5
  	Acetylacetaldehyde dimethyl	5436-21-5
  	acetal
  	p-methylacetophenone	122-00-9
  	Methyl phenylacetate	101-41-7
  	4-Ethoxybenzaldehyde	10031-82-0
  	p-tolyl acetate	140-39-6
  	2,6-Dimethoxyphenol	91-10-1
  	Methyl 2-methoxybenzoate	606-45-1
  	alpha-methylcinnamaldehyde	101-39-3
  	2-methoxycinnamaldehyde	60125-24-8
  	Potassium bicarbonate	298-14-6
  	piperonyl acetate	326-61-4
  	2,3-hexanedione	3848-24-6
  	furfural acetone	623-15-4
  	trans beta-(2-furyl)acrolein	623-30-3
  	carveol	99-48-9
  	Methyl nicotinate	93-60-7
  	Ethyl benzoylacetate	94-02-0
  	Methyl 4-methoxybenzoate	121-98-2
  	Levulinic acid	123-76-2
  	m-Dimethoxybenzene	151-10-0
  	2-acetylpyridine	1122-62-9
  	tetramethyl-pyrazine	1124-11-4
  	2,3-dimethyl-pyrazine	5910-89-4
  	trimethyl-pyrazine	14667-55-1
  	2-ethyl-3-methyl-pyrazine	15707-23-0
  	5-Methyl-3H-furan-2-one	591-12-8
  	2-Methoxy-4-methylphenol	93-51-6
  	piperazine	110-85-0
  	2-Methoxy-4-propylphenol	2785-87-7
  	Naphthalene, 2-(2-	2173-57-1
  	methylpropoxy)-
  	2-Acetyl-1-methylpyrrole	932-16-1
  	3,3-Dimethylacrylic acid	541-47-9
  	Ethyl sorbate	2396-84-1
  	4-(4-Hydroxyphenyl)-2-butanone	5471-51-2
  	4-Methoxyphenylacetone	122-84-9
  	(−)-Myrtenal	564-94-3
  	3-Phenylpropionaldehyde	104-53-0
  	1-Phenylethyl propionate	120-45-6
  	2-Methyltetrahydrofuran-3-one	3188-00-9
  	Cinnamyl acetate	103-54-8
  	Styrallyl acetate	93-92-5
  	Ethyl 4-methoxybenzoate	94-30-4
  	Benzyl propionate	122-63-4
  	Phenylpyruvate	156-06-9
  	furaneol	3658-77-3
  	methyl 2-methylbutanoate	868-57-5
  	Benzeneacetaldehyde, alpha-	93-53-8
  	methyl-
  	Dimethyl anthranilate	85-91-6
  	1,1-Dimethoxy-2-phenylpropane	90-87-9
  	4-hexanolide	695-06-7
  	Dimethylbenzylcarbinyl acetate	151-05-3
  	Benzyl isobutyrate	103-28-6
  	Acetyl isoeugenol	93-29-8
  	2-Acetyl-5-methyl furan	1193-79-9
  	Alpha-methyl-p-	103-95-7
  	isopropylphenylpropanaldehyde
  	Benzylcarbinyl formate	104-62-1
  	p-Cresyl alpha-toluate	101-94-0
  	Potassium bisulfate	7646-93-7
  	Potassium carbonate	584-08-7
  	Potassium chloride	7447-40-7
  	Potassium hydroxide	1310-58-3
  	Ethyl tiglate	5837-78-5
  	Nerol oxide	1786-08-9
  	DL-Tetrohydrofurfuryl	637-65-0
  	propionate
  	Benzaldehyde propylene glycol	2568-25-4
  	acetal
  	2-Methyl-3-(2-furyl) acrolein	874-66-8
  	vanillin	121-33-5
  	Cholic acid	81-25-4
  	R-Carvone	6485-40-1
  	Potassium nitrate	7757-79-1
  	Potassium permanganate	7722-64-7
  	Potassium persulfate	7727-21-1
  	Potassium phosphate, dibasic	2139900
  	Potassium Phosphate Monobasic	7778-77-0
  	Potassium sulfate	7778-80-5
  	Sodium bicarbonate	144-55-8
  	Sodium bisulfite	7631-90-5
  	Sodium carbonate	497-19-8
  	Sodium chloride	7647-14-5
  	Sodium dithionite	7775-14-6
  	Sodium hydroxide	1310-73-2
  	Sodium nitrite	7632-00-0
  	Sodium Pyrophosphate	7722-88-5
  	Sodium sulfate	7757-82-6
  	Sodium sulfite	7757-83-7
  	Sodium thiocyanate	540-72-7
  	Calcium Carbonate	471-34-1
  	Calcium chloride	10043-52-4
  	Calcium gluconate	299-28-5
  	Calcium hydroxide	1305-62-0
  	Calcium phosphate, dibasic	7757-93-9
  	Calcium sulfate	7778-18-9
  	N-Methyl-D-glucamine	6284-40-8
  	Calcium oxide	1305-78-8
  	Calcium Phosphate Monobasic	7758-23-8
  	Magnesium chloride hexahydrate	7791-18-6
  	Magnesium sulfate	7487-88-9
  	Magnesium Sulfate Heptahydrate	10034-99-8
  	Aluminum chloride hexahydrate	7784-13-6
  	aluminum nitrate nonahydrate	7784-27-2
  	Aluminum potassium sulfate,	7784-24-9
  	dodecahydrate
  	Aluminum sulfate,	7784-31-8
  	octadecahydrate
  	(S)-(−)-Cysteine	52-90-4
  	p-Toluenesulfonic Acid	104-15-4
  	Potassium bitartrate	868-14-4
  	DL-aspartic acid	617-45-8
  	p-Dimethylaminobenzaldehyde	100-10-7
  	Sodium salicylate	54-21-7
  	Benzoin	119-53-9
  	Sodium dodecyl sulfate	151-21-3
  	L-Menthol	2216-51-5
  	Tiron	149-45-1
  	Riboflavin	83-88-5
  	Sodium Acetate Trihydrate	6131-90-4
  	Disodium Succinate Hexahydrate	6106-21-4
  	Disodium	6381-92-6
  	ethylenediaminetetraacetate
  	dihydrate
  	sodium citrate, dihydrate	1545801
  	Sodium potassium tartrate,	6381-59-5
  	tetrahydrate
  	L-(+)-Arginine	1119-34-2
  	monohydrochloride
  	Ethylenediamine	333-18-6
  	dihydrochloride
  	Sodium formate	141-53-7
  	Sodium acetate	127-09-3
  	Potassium acetate	127-08-2
  	Ammonium citrate	3012-65-5
  	Ammonium bicarbonate	1066-33-7
  	Ammonium chloride	12125-02-9
  	Ammonium nitrate	6484-52-2
  	Ammonium persulfate	7727-54-0
  	Ammonium sulfate	7783-20-2
  	Zinc chloride	7646-85-7
  	Sulfuric acid, zinc salt	7446-20-0
  	(1:1), heptahydrate
  	Sodium Tripolyphosphate	7758-29-4
  	ammonium benzoate	1863-63-4
  	ammonium bisulfite	10192-30-0
  	1,5-Naphthalenedisulfonic Acid	1655-29-4
  	Disodium Salt
  	4-Hydroxybenzoic Acid	99-96-7
  	Diphenylacetic Acid	117-34-0
  	Glutaric Acid	110-94-1
  	L-(−)-Fucose	2438-80-4
  	L-Cysteine Hydrochloride	52-89-1
  	L-Histidine Hydrochloride	1880304
  	Monohydrate
  	o-Toluic Acid	118-90-1
  	Pivalic Acid	75-98-9
  	Pyruvic Acid Sodium Salt	113-24-6
  	Potassium bromide	2139626
  	Sodium Dithionate Dihydrate	7631-94-9
  	Sodium Malonate	141-95-7
  	Trisodium Citrate	68-04-2
  	Potassium Sodium Tartrate	304-59-6
  	Potassium Citrate	866-84-2
  	D-Maltose Monohydrate	6363-53-7
  	Cyclohexaamylose	10016-20-3
  	Dodecyl sulfate, lithium salt	2044-56-6
  	Manganese chloride	2145076
  	methyl-urea	598-50-5
  	beta-Cyclodextrin	7585-39-9
  	Triphosphoric acid,	13845-36-8
  	pentapotassium salt
  	Glycine ethyl ester	623-33-6
  	hydrochloride
  	L-Histidine methyl ester	7389-87-9
  	dihydrochloride
  	L-Leucine methyl ester	7517-19-3
  	hydrochloride
  	D-Lysine hydrochloride	7274-88-6
  	2-Naphthalenesulfonic acid	532-02-5
  	sodium salt
  	calcium nitrate tetrahydrate	13477-34-4
  	Vitamin B1	59-43-8
  	Zinc Acetate Dihydrate	5970-45-6
  	Potassium fluoride	7789-23-3
  	Potassium iodate	2139718
  	Potassium iodide	7681-11-0
  	Potassium thiocyanate	333-20-0
  	Sodium bromide	7647-15-6
  	Sodium fluoride	7681-49-4
  	Sodium iodide	7681-82-5
  	Sodium nitrate	7631-99-4
  	Calcium acetate	5743-26-0
  	Trichloroacetic acid	76-03-9
  	Ammonium acetate	631-61-8
  	Ammonium fluoride	12125-01-8
  	DL-malic acid	617-48-1
  	t-Butyl Alcohol	75-65-0
  	beta-Alanine	107-95-9
  	(S)-(−)-Tryptophan	73-22-3
  	Malonic acid	141-82-2
  	Phenethylamine	64-04-0
  	Salicylylaldehyde	90-02-8
  	Sodium benzoate	532-32-1
  	Mandelic acid	90-64-2
  	Calcium pantothenate	137-08-6
  	Chloroacetic Acid	79-11-8
  	Ethanol Amine	141-43-5
  	Salicylic acid	69-72-7
  	Saccharin sodium	128-44-9
  	Thiamine hydrochloride	67-03-8
  	2,2′-Oxybisethanol	111-46-6
  	Resorcinol	108-46-3
  	2-Amino-2-(hydroxymethyl)-1,3-	77-86-1
  	propanediol
  	2,5-Dimethylphenol	95-87-4
  	Ammonium Phosphate Monobasic	7722-76-1
  	1,3-Butanediol	107-88-0
  	Glycolic Acid	79-14-1
  	Sodium Gluconate	527-07-1
  	Terephthalic Acid	100-21-0
  	L-Ascorbic Acid Sodium Salt	134-03-2
  	3-Acetyl-6-methyl-2,4-	520-45-6
  	pyrandione
  	Calcium Acetate	62-54-4
  	Nicotinamide	98-92-0
  	1-Hydroxy-2-naphthoic Acid	86-48-6
  	2-Isopropylphenol	88-69-7
  	4-Aminosalicylic Acid	65-49-6
  	Calcium Glycerophosphate	27214-00-2
  	Erythorbic Acid Sodium Salt	7378-23-6
  	Gluconic Acid Potassium Salt	299-27-4
  	Orotic Acid	65-86-1
  	p-Anise Alcohol	105-13-5
  	Potassium Benzoate	582-25-2
  	Taurine	107-35-7
  	Thiamine Nitrate	532-43-4
  	3,3,5-Trimethyl-1-cyclohexanol	116-02-9
  	tert-Butylhydroquinone	1948-33-0
  	Sulfosalicylic acid	97-05-2
  	Gallic acid	149-91-7
  	L-borneol	464-45-9
  	Isoborneol	124-76-5
  	2,5-Dihydroxybenzoic acid,	490-79-9
  	Gentisic acid
  	5-hydroxy-6-methyl-3,4-	65-23-6
  	pyridinedimethanol
  	Naphthalene-2-sulfonic acid	120-18-3
  	Ethanesulfonic acid, 2-	1562-00-1
  	hydroxy-, monosodium salt
  	Pamoic acid	130-85-8
  	2,4-Dimethylphenol	105-67-9
  	3,5-Dihydroxyacetophenone	51863-60-6
  	Eugenol	97-53-0
  	n-Butyric Acid	107-92-6
  	Hydroquinone	123-31-9
  	Propionic Acid	79-09-4
  	meta-Phenylenediamine	108-45-2
  	Oxalic Acid	144-62-7
  	n-Hexanoic Acid	142-62-1
  	2-Furancarboxylic Acid	88-14-2
  	4′-Nitroacetanilide	104-04-1
  	D-(−)-Tartaric Acid	147-71-7
  	p-Acetamidobenzoic Acid	556-08-1
  	Galactaric acid	526-99-8
  	D-glucuronate	1700908
  	Lactobionic acid	96-82-2
  	p-Formylacetanilide	122-85-0
  	2-Mercaptobenzoic acid	147-93-3
  	Propanoic acid, 2-hydroxy-,	28305-25-1
  	calcium salt (2:1), (S)-
  	D(+)-10-Camphorsulfonic acid	3144-16-9
  	3-Cyclopentylpropionic acid	140-77-2
  	1R-(−)-Camphorsulfonic acid	35963-20-3
  	DL-Lysine	70-54-2
  	Cinnamic acid	621-82-9
  	Triethanolamine	102-71-6
  	Acetic Acid	64-19-7
  	Dichloroacetic Acid	79-43-6
  	Diethylamine	109-89-7
  	Diethylaminoethanol	100-37-8
  	N-(2-Hydroxyethyl)Morpholine	622-40-2
  	Octanoic Acid	124-07-2
  	isobutyric acid	79-31-2
  	Anisic Acid	100-09-4
  	Betaine	107-43-7
  	Enanthoic Acid	111-14-8
  	Hippuric Acid	495-69-2
  	Tiglic Acid	80-59-1
  	Cyclohexanecarboxylic acid	98-89-5
  	m-Methoxybenzoic acid	586-38-9
  	D-(+)-Camphoric acid	124-83-4
  	N-(2-Hydroxyethyl)pyrrolidine	2955-88-6

Claims (90)

1. A method of screening a chemical substance for possible solid forms, said method comprising the steps of:

preparing a first sample comprising a chemical substance in a first solvent;

preparing a second sample comprising the chemical substance in a second solvent;

sonicating the first and second samples; and

solidifying the chemical substance from the first and second samples.

2. The method ofclaim 1, wherein the solidifying step and the sonicating step at least partially overlap.

3. The method ofclaim 1, wherein at least one of said solvents is selected from the group consisting of acetone, acetonitrile, chloroform, dioxane, ethanol, ethyl acetate, heptane, butanone, methanol, nitromethane, tetrahydrofuran, toluene, water, dichloromethane, diethyl ether, isopropyl ether, cyclohexane, methylcyclohexane, isopropyl alcohol, isopropyl acetate, trimethylpentane, n-octane, trichloroethane, trifluoroethanol, pyridine, propanol, butanol, tetrachloroethylene, chlorobenzene, xylene, dibutyl ether, methyl-tert-butyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide, formamide, and dimethylformamide.

4. The method ofclaim 1, wherein the first solvent comprises a mixture of solvents.

5. The method ofclaim 4, wherein the second solvent comprises a mixture of solvents.

6. The method ofclaim 1, wherein at least one of the samples is a solution having a viscosity greater than about 10 cPoise before the solution is sonicated.

7. The method ofclaim 1, wherein the samples are provided by preparing a solution from an amorphous solid comprising the chemical substance.

8. The method ofclaim 7, wherein the solvent is sonicated while the amorphous solid is added to the solvent.

9. The method ofclaim 1, wherein at least one of the samples is an emulsion comprising two or more substantially immiscible solvents and the chemical substance.

10. The method ofclaim 1, wherein at least one of the samples is a slurry comprising a solvent and the chemical substance.

11. The method ofclaim 1, comprising providing a plurality of subsamples of said first sample, and wherein a first portion of the subsamples are subjected to relatively slow evaporation, and a second portion of the subsamples are subjected to relatively fast evaporation.

12. The method ofclaim 1, wherein the solidifying step comprises evaporating a solvent from the samples, and the method comprises sonicating at least one of the samples until the solvent is substantially completely evaporated.

13. The method ofclaim 1, comprising the step of evaporating a solvent from at least one of the samples during the sonicating step.

14. The method ofclaim 1, comprising the step of evaporating a solvent from at least one of the samples after the sonicating step.

15. The method ofclaim 1, comprising the step of cooling at least one of the samples before the sonicating step.

16. The method ofclaim 1, comprising the step of cooling at least one of the samples during the sonicating step.

17. The method ofclaim 1, comprising the step of cooling at least one of the samples after the sonicating step.

18. The method ofclaim 1, comprising the step of crash-cooling at least one of the samples before the sonicating step.

19. The method ofclaim 1, wherein at least one of the samples is sonicated by at least one ultrasound pulse.

20. The method ofclaim 1, wherein at least one of the samples is sonicated by a series of at least 5 ultrasound pulses.

21. The method ofclaim 1, wherein at least one of the samples is sonicated by sonicating at least once for about 5 minutes.

22. The method ofclaim 1, wherein the sonication is substantially continuous during the solidification step.

23. The method ofclaim 1, wherein the solidification comprises generating at least one solid solvate of the chemical substance.

24. The method ofclaim 1, wherein the solidification comprises generating at least one solid hydrate of the chemical substance.

25. The method ofclaim 1, wherein the first sample and the second sample are placed in a well plate.

26. The method ofclaim 25, wherein the solidified chemical substances are analyzed in the well plate by x-ray diffraction.

27. The method ofclaim 1, wherein the solidified chemical substances are analyzed by transmission x-ray diffraction.

28. The method ofclaim 1, wherein the solidified chemical substances are analyzed by Raman spectroscopy.

29. The method ofclaim 1, wherein the first sample and the second sample are sonicated in a well plate.

30. The method ofclaim 1, further comprising the step of determining whether one or more solid forms were generated using an analytical method selected from the group consisting of visual analysis, microscopic analysis, thermal analysis, diffraction analysis, and spectroscopic analysis.

31. The method ofclaim 1, further comprising the step of determining whether one or more solid forms were generated using x-ray diffraction analysis

32. The method ofclaim 1, further comprising the step of determining whether one or more solid forms were generated using Raman spectroscopic analysis.

33. A method of crystallizing a chemical substance, said method comprising the steps of:

forming an emulsion comprising two or more substantially immiscible solvents and the chemical substance by applying ultrasound to a mixture of said solvents and the chemical substance; and

crystallizing the chemical substance from the emulsion.

34. The method ofclaim 33, further comprising the steps of adding an antisolvent to the emulsion, and thereafter further sonicating the emulsion.

35. The method ofclaim 33, wherein the chemical substance is substantially soluble in one of said immiscible solvents and substantially insoluble in another of said immiscible solvents.

36. A method of crystallizing a chemical substance, said method comprising the steps of:

providing a sample of the chemical substance in a solvent;

sonicating the sample at a predetermined supersaturation level; and

crystallizing the chemical substance from the sample.

37. The method ofclaim 36, wherein the sonicating and crystallizing steps at least partially overlap.

38. The method ofclaim 36, wherein the sample is cooled before sonicating.

39. The method ofclaim 36, wherein the solvent is evaporated after sonicating.

40. The method ofclaim 36, wherein the predetermined supersaturation level is selected to generate a relatively stable form of the chemical substance.

41. The method ofclaim 36, wherein the predetermined supersaturation level is selected to generate a solvate of the chemical substance.

42. The method ofclaim 36, further comprising adding an additional solvent to the sample.

43. The method ofclaim 36, wherein the sample is a solution having a viscosity greater than about 10 cPoise before the solution is sonicated.

44. The method ofclaim 36, wherein the sample has a metastable zone, and the metastable zone has a width of at least about 1° C.

45. The method ofclaim 36, wherein the sample has a metastable zone, and the metastable zone has a width that is reduced by at least about 1° C. through sonicating the sample.

46. The method ofclaim 36, wherein the forming step comprises forming a solution or suspension from a solvent and an amorphous solid comprising the chemical substance.

47. A method of screening a chemical substance for possible solid forms, said method comprising the steps of:

providing a chemical substance in a plurality of samples;

sonicating at least one of the samples, wherein at least one other sample is unsonicated;

solidifying the samples of the chemical substance; and

determining whether one or more solid forms of the chemical substance were generated.

48. A method of generating the most stable form of a chemical substance, said method comprising the steps of:

providing a sample of the chemical substance in a solvent;

sonicating the sample at a predetermined supersaturation level; and

crystallizing the chemical substance from the sample;

wherein the crystallized chemical substance is the most stable solid form of the chemical substance relative to known solid forms of the chemical substance.

49. A method of generating a solid form of a chemical substance from a meta stable solution, said method comprising the steps of:

forming a metastable solution of the chemical substance in a solvent;

sonicating the metastable solution; and

crystallizing the chemical substance from the solution.

50. A method of obtaining a substantially pure solid form of a chemical substance, said method comprising the steps of:

providing a sample of the chemical substance in a solvent;

sonicating the sample at a predetermined supersaturation level; and

crystallizing the chemical substance from the sample;

wherein a substantially pure solid form of the chemical substance is crystallized.

51. A method of preparing a solvate of a chemical substance, said method comprising the steps of:

providing a sample comprising the chemical substance and a solvent;

sonicating the sample; and

generating a solid from the sample, wherein the solid comprises a solvate of the chemical substance and the solvent.

52. A method of screening for possible cocrystals comprising an active agent, said method comprising the steps of:

providing a plurality of samples, each sample comprising the active agent and one or more guests, wherein the plurality of samples contains the same or different guests;

sonicating the samples;

crystallizing the active agent and the guest from the samples; and

determining whether a cocrystal was generated in one or more of the samples.

53. The screening method ofclaim 52, wherein at least one sample contains a different guest than at least one other sample.

54. The screening method ofclaim 52, wherein each sample contains a different guest.

55. The screening method ofclaim 52, wherein the sonicating step and the crystallizing step at least partially overlap.

56. The screening method ofclaim 52, wherein the samples are placed in a well plate and sonicated in the well plate.

57. The screening method ofclaim 52, wherein the samples are supersaturated with respect to at least one of the active agent and the guest before the sonicating step.

58. The method ofclaim 52, wherein at least some of the samples comprise more than one solvent.

59. The method ofclaim 52, wherein the samples are sonicated by at least one ultrasound pulse.

60. The method ofclaim 52, wherein at least one of the samples is sonicated by a series of ultrasound pulses, each pulse having a duration of from about 0.1 second to about 10 seconds.

61. The method ofclaim 52, wherein at least one of the samples is sonicated at least once for at least about 1 minute.

62. The method ofclaim 52, wherein at least one of the samples is sonicated at least once for at least about 5 minutes.

63. The method ofclaim 52, further comprising the step of determining whether a cocrystal was generated using an analytical method selected from the group consisting of visual analysis, microscopic analysis, thermal analysis, diffraction analysis, and spectroscopic analysis.

64. The method ofclaim 52, further comprising the step of determining whether a cocrystal was generated using x-ray diffraction analysis.

65. The method ofclaim 52, further comprising the step of determining whether a cocrystal was generated using Raman spectroscopic analysis.

66. The method ofclaim 52, wherein at Least one new solid state phase is formed by the crystallizing step.

67. The method ofclaim 52, further comprising crystallizing at least one unsonicated sample that is substantially the same as at least one sonicated sample.

68. A method of preparing a cocrystal comprising an active agent and a guest, said method comprising the steps of:

providing a sample of an active agent and a guest;

sonicating the sample; and

crystallizing a cocrystal from the sample, the cocrystal comprising the active agent and the guest.

69. The method ofclaim 68 wherein the active agent is an active pharmaceutical ingredient.

70. The method ofclaim 68, wherein the active agent is provided as a salt in the sample.

71. The method ofclaim 70, wherein the salt comprises chloride.

72. The method ofclaim 68, wherein the guest is a salt.

73. The method ofclaim 68, wherein the guest is an organic acid.

74. The method ofclaim 68, wherein the active agent is not a salt.

75. The method ofclaim 68, wherein the active agent is neutral or zwitterionic.

76. The method ofclaim 68, wherein the sample comprises a solvent selected from the group consisting of acetone, acetonitrile, chloroform, 1,4-dioxane, ethanol, ethyl acetate, heptane, 2-butanone, methanol, nitromethane, tetrahydrofuran, toluene, water, dichloromethane, diethyl ether, isopropyl ether, cyclohexane, methylcyclohexane, isopropyl alcohol, trimethylpentane, n-octane, trichloroethane, trifluoroethanol, pyridine, 1-butanol, tetrachloroethylene, chlorobenzene, xylene, dibutyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide, formamide, and dimethylformamide.

77. The method ofclaim 68, wherein the sample comprises more than one solvent.

78. The method ofclaim 68, wherein the sample comprises more than one guest.

79. The method ofclaim 68, wherein at least one of the samples is sonicated by at least one ultrasound pulse.

80. The method ofclaim 68, wherein at least one of the samples is sonicated by a series of ultrasound pulses, each pulse having a duration of from about 0.1 second to about 10 seconds.

81. The method ofclaim 68, wherein at least one of the samples is sonicated at least once for at least about 1 minute.

82. The method ofclaim 68, wherein at least one of the samples is sonicated at least once for at least about 5 minutes.

83. The method ofclaim 68, wherein the sonication is substantially continuous during the crystallization step.

84. A method of cocrystallizing two or more components, said method comprising the steps of:

(a) determining a concentration for two or more components in a sample effective for cocrystallization of the components;

(b) preparing the sample comprising the components, said sample having an effective concentration of the components;

(c) sonicating the sample; and

(d) generating a cocrystal from the sample, the cocrystal comprising the components.

85. The method ofclaim 84, wherein the components comprise an active agent and a guest.

86. A method for speeding the cocrystallization of an active agent and a guest comprising:

providing a sample in an effective volume;

sonicating the sample;

cocrystallizing said active agent and said guest from the sample;

wherein the rate of cocrystallization is increased by at least 25%.

87. The method ofclaim 84, wherein the sample is a metastable solution.

88. A method for screening for possible salts comprising an ionizable active agent, said method comprises:

providing a plurality of samples comprising an ionizable active agent and one or more counterions, wherein the plurality of samples contains the same or different counterions;

sonicating the samples;

forming one or more crystallized salt compounds from the samples, said crystallized salt compounds comprising the ionizable active agent and the counterions.

89. The method ofclaim 88, wherein at least one sample contains a different counterion than at least one other sample.

90. The method ofclaim 88, wherein the plurality of samples comprises a plurality of sets, and the sets differ in having different counterions, and the samples within each set have the same counterion.

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