SOLID STATE FORMS, PHARMACEUTICAL COMPOSITIONS, PREPARATION METHODS AND USE THEREOFTechnical Fields of the Invention
The invention generally relates to therapeutic compositions and methods of use thereof. More particularly, the invention provides novel solid-state forms, pharmaceutical compositions, and methods of preparation and use thereof.
Background of the InventionDifferent solid-state forms (solid forms) of active ingredients may have different physical, mechanical, chemical, or physicochemical properties, such as stability, solubility, melting point, hardness, shelf-life, or compressibility, which may result in different bioavailability, dissolution profile, process reproducibility, ease of manufacturing, or formulation properties of one form over the other (s) .
The compound of Formula (I) , a potent and selective Janus kinase 1 (JAK1) inhibitor,
was disclosed in WO 2020/088659 A1 (PCT/CN2019/115069, filed November 1, 2019, priority date November 1, 2018) , the content of which is incorporated herein by reference in its entirety for all purposes. Preparation of the compound was disclosed therein as were certain beneficial biological activities of the compound.
Solid forms, in particular crystalline forms, are of particular interest in the development of suitable dosage forms of pharmaceuticals. Finding which solid form is the most stable under each condition of interest and the processes that lead to changes in a solid form is crucial to the design of a drug manufacturing process in order to ensure that the final product maintains its required efficacy and safety profiles.
There remains an ongoing need to identify suitable solid forms of the above compound that exhibit desirable physicochemical properties suitable for production and therapeutic use.
Summary of the InventionThe present invention provides novel solid forms (e.g., crystalline forms) of the compound of Formula (I) having one or more desirable properties, such as high stability, high crystallinity, high purity, low hygroscopicity, favorable dissolution and/or favorable mechanical properties. In particular, solid forms of the compound of Formula (I) disclosed herein exhibit improved physical stability and/or physicochemical properties suitable for clinical studies, product manufacture and therapeutic use. The solid forms disclosed herein can be utilized to treat various diseases or disorders (e.g., a JAK1-mediated disease or disorder) .
In one aspect, the invention generally relates to a solid form (e.g., a crystalline form) of a compound of Formula (I) , which is Form B, wherein X-ray powder diffraction (XRPD) pattern thereof comprises characteristic diffraction peaks at the following 2θangles: 10.815°±0.2°, 13.475°±0.2°, 17.225°±0.2°, 21.804°±0.2°, and 22.361°±0.2°, with a radiation source of Cu-Kα,
In another aspect, the invention generally relates to a process for preparing a solid form, which is Form B of the compound of Formula (I) , comprising adding water into a solution of the compound of Formula (I) followed by cooling the solution, wherein solvent of the solution is a mixture of acetone and H2O.
In yet another aspect, the invention generally relates to a solid form of a compound of Formula (I) , which is Form A, wherein the XRPD pattern thereof comprises characteristic diffraction peaks at the following 2θangles: 4.940°±0.2°, 9.954°±0.2°, 12.881°±0.2°, 17.094°±0.2°, and 22.969°±0.2°, with a radiation source of Cu-Kα,
In yet another aspect, the invention generally relates to a process for preparing a solid form, which is Form A of the compound of Formula (I) , comprising adding water into a solution of compound of Formula (I) , wherein solvent of the solution is dimethyl sulfoxide (DMSO) .
In yet another aspect, the invention generally relates to a crystalline form of a compound of Formula (I) , wherein crystallographic data and refinement parameters of single crystal of the crystalline form comprise those shown in Table 9.
In yet another aspect, the invention generally relates to a pharmaceutical composition comprising a solid form (e.g., crystalline form) disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent.
In yet another aspect, the invention generally relates to a unit dosage form comprising a solid form (e.g., crystalline form) disclosed herein and/or a pharmaceutical composition disclosed herein.
In yet another aspect, the invention generally relates to use of a solid (e.g., crystalline) form or the pharmaceutical composition in the manufacture of a medicament.
In yet another aspect, the invention generally relates to use of the solid (e.g., crystalline) form or a pharmaceutical composition disclosed herein in the manufacture of a medicament for treating a JAK1-mediated disease or disorder.
In yet another aspect, the invention generally relates to a method for treating a JAK1-mediated disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a solid (e.g., crystalline) form or a pharmaceutical composition disclosed herein.
Brief Description of the DrawingsFIG. 1 is an exemplary XRPD pattern of Form A.
FIG. 2 is an exemplary DSC curve of Form A.
FIG. 3 is an exemplary TGA curve of Form A.
FIG. 4 is an exemplary 1H NMR spectrum of Form A.
FIG. 5 is an exemplary PLM image of Form A.
FIG. 6 is an exemplary XRPD pattern of Form B.
FIG. 7 is an exemplary DSC curve of Form B.
FIG. 8 is an exemplary TGA curve of Form B.
FIG. 9 is an exemplary 1H NMR spectrum of Form B.
FIG. 10 is an exemplary PLM image of Form B.
FIG. 11 is an exemplary PLM image of the Form B single crystal sample at the end of a 50-day period.
FIG. 12 depicts an atomic thermal ellipsoid drawing of Form B single crystal sample in an asymmetric unit.
FIG. 13 is an exemplary DVS plot of Form B.
FIG. 14 is an exemplary XRPD pattern of an amorphous starting material.
Definitions
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.
As used in the present disclosure, the following words and phrases are generally intended to have the meanings as set forth below unless expressly indicated otherwise or the context in which they are used indicates otherwise.
In this specification and the appended claims, the singular forms "a, " "an, " and "the" include plural reference, unless the context clearly dictates otherwise.
The term “and/or” is used in this disclosure to mean either “and” or “or” unless the context clearly dictates otherwise.
As used herein, “at least” a specific value is understood to be that value and all values greater than that value.
The terms “comprises” , “comprising, ” “has, ” “having, ” “includes” and “including, ” when used to define compositions and methods, are intended to mean that the compositions and methods include the recited elements, but do not exclude other elements.
Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.
The term “consisting essentially of” , when used to define compositions and methods, shall mean that the compositions and methods include the recited elements and exclude other elements of any essential significance to the compositions and methods. For example, “consisting essentially of” refers to administration of the pharmacologically active agents expressly recited and excludes pharmacologically active agents not expressly recited. The term consisting essentially of does not exclude pharmacologically inactive or inert agents, e.g., pharmaceutically acceptable excipients, carriers or diluents. The term “consisting of” , when used to define compositions and methods, shall mean excluding trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01%of the stated value. Unless otherwise clear from context, all numerical values provided herein can be modified by the term about.
At various places in the present specification, variables or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, a range of 1 to 16 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
As used herein, “XRPD” refers to X-ray powder diffraction. An XRPD pattern is an x-y graph with 2θ (diffraction angle) plotted on the x-axis and intensity plotted on the y-axis. These are the diffraction peaks which may be used to characterize a crystalline material. The diffraction peaks are usually represented and referred to by their position on the x-axis rather than the intensity of the diffraction peaks on the y-axis because diffraction peak intensity can be particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee&Web, pp. 255-257 (2003) ) . Thus, intensity is not typically used by those of skill in the art to characterize a crystalline material.
As used herein, the term “2 theta value” or “2θ” refers to the peak position in degrees based on the experimental setup of the X-ray diffraction experiment and is a common abscissa unit in diffraction patterns. The experimental setup requires that if a reflection is diffracted when the incoming beam forms an angle theta (θ) with a certain lattice plane, the reflected beam is recorded at an angle 2 theta (2θ) . It should be understood that reference herein to specific 2θvalues for a specific solid form is intended to mean the 2θvalues (in degrees) as measured using the X-ray diffraction experimental conditions as described herein.
As with any data measurement, there may be variability in XRPD data. In addition to the variability in diffraction peak intensity, there may also be variability in the position of the diffraction peaks on the x-axis. This variability can, however, typically be accounted for when reporting the positions of diffraction peaks for purposes of characterization. Such variability in the position of diffraction peaks along the x-axis may be derived from several sources. One such source can be sample preparation. Samples of the same crystalline material prepared under different conditions may yield slightly different diffractograms. Factors such as particle size, moisture content, solvent content, temperature, and orientation may all affect how a sample diffracts X-rays. Another source of variability comes from instrument parameters. Different X-ray powder diffractometers operate using different parameters and may lead to slightly different diffraction patterns from the same crystalline material. Likewise, different software packages process XRPD data differently and this may also lead to variability. These and other sources of variability are known to those of ordinary skill in the art. Due to such sources of variability, the values of each X-ray diffraction peak may be preceded with the term “about” or proceeded with an appropriate range defining the experimental variability (e.g., ±0.1°, ±0.2°, ±0.3°, ±0.4°, ±0.5°, etc. ) .
Crystalline forms, such as crystalline forms of a compound of Formula (I) , are readily analyzed by XRPD. The data from X-ray powder diffraction may be used in multiple ways to characterize crystalline forms. For example, the entire x-ray powder diffraction pattern output from a diffractometer may be used to characterize a crystalline form (e.g., of a compound of Formula (I) ) . A smaller subset of such data, however, may also be suitable and used for characterizing such crystalline forms. Indeed, often even a single x-ray powder diffraction peak may be used to characterize such a crystalline form. With respect to crystalline forms of a compound of Formula (I) , any one or more of the peaks in the x-ray powder diffraction pattern may be used to characterize the crystalline form of a compound of Formula (I) disclosed herein.
The term “characteristic peaks” when referring to the peaks in an XRPD pattern of a crystalline form of a given chemical entity (e.g., a crystalline form of a compound of formula (I)) refers to a collection of specific diffraction peaks whose values span a range of 2θvalues (e.g., 0°-40°) that are, as a whole, unique to that specific crystalline form.
Differential scanning calorimetry (DSC) profiles can be particularly sensitive to sample preparation and parameters. Thus, there may be variability in DSC data (e.g., location of onset and peak maximum temperatures) . Due to such sources of variability, the values of each temperature based on DSC data may be preceded with the term “about” or proceeded with an appropriate range defining the experimental variability (e.g., ±0.5℃, ±1℃, ±3℃, ±4℃, ±5℃, etc. ) .
As used herein, the term “crystalline” refers to any solid substance exhibiting three-dimensional order, which in contrast to an amorphous solid substance, gives a distinctive X-ray powder diffraction (XRPD) pattern with sharply defined peaks.
As used herein, the term “amorphous” refers to any solid substance that lacks order in three dimensions. In some instances, amorphous solids may be characterized by known techniques, including XRPD crystallography, solid-state nuclear magnet resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques. Amorphous solids give diffuse XRPD patterns, typically comprised of one or two broad peaks (i.e., peaks having base widths of about 5° 2θ. or greater) .
As used herein, the term “polymorph” refers to different crystalline forms of the same compound and includes, but is not limited to, other solid state molecular forms including hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound.
As used herein, the term “essentially the same” with reference to X-ray powder diffraction peak positions and/or patterns means that typical peak position and intensity variability are taken into account. For example, one skilled in the art will appreciate that the peak positions (2θ) will show some variability, typically as much as 0.1 to 0.2 degrees, as well as on the apparatus being used to measure the diffraction. Further, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measures only. Similarly, as used herein, "essentially the same" with reference to DSC is intended to also encompass the variability associated with these analytical techniques, which are known to those of skill in the art.
As used herein, the term “stable” refers to a compound that is not substantially altered when subjected to conditions to allow for its production, detection, recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 ℃ or less, in the absence of moisture or other chemically reactive conditions, for at least a week, preferably for at least a month, more preferably for at least six months, even more preferably for at least one year.
As used herein, the term “solvate” refers to a crystalline solid adduct containing either stoichiometric or nonstoichiometric amounts of a solvent incorporated within the crystal structure. When the solvent is tightly bound to the drug the resulting complex will have a well-defined stoichiometry that is independent of humidity. When, however, the solvent is weakly bound, as in channel solvates and hygroscopic compounds, the solvent content will be dependent on humidity and drying conditions. In such cases, the complex will often be non-stoichiometric. If the incorporated solvent is water, such adduct is referred to as a "hydrate" . Thus, the term “hydrate” describes a solvate comprising the drug substance and a stoichiometric or non-stoichiometric amount of water.
As used herein, the term "anhydrous" or "anhydrate" when referring to a crystalline form (e.g., a crystalline form of the compound of Formula (I) ) means that no water molecules form a portion of the unit cell of the crystalline form. An anhydrous crystalline form may nonetheless contain water molecules that do not form part of the unit cell of the anhydrous crystalline form (e.g., as residual solvent molecule left behind from the production of the crystalline form) . In a preferred embodiment, water can make up about 0.5%by weight of the total composition of a sample of an anhydrous form. In a more preferred embodiment, water can make up about 0.2%by weight of the total composition of a sample of an anhydrous form. In some embodiments, a sample of an anhydrous crystalline form of the compound of formula (I) contains no water molecules, e.g., no detectable amount of water.
As used herein, “pharmaceutical composition” refers to the combination of a therapeutically active agent with one or more pharmaceutically acceptable excipients, carriers, or diluents, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
As used herein, the term “pharmaceutically acceptable excipient, carrier, or diluent” refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult) ) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys) , cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.
As used herein, “administering” means oral administration, administration as a pulmonary, suppository, intramuscular administration, intrathecal administration, intranasal administration or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or) . Parenteral administration includes, e.g., intramuscular and subcutaneous. Other modes of delivery include, but are not limited to, the use of liposomal formulations, etc. By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., therapeutic agent, chemotherapeutic, or treatment for a neurodegenerative disease) . The compound of formula (I) can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent) . Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation) .
The terms “disease, ” “disorder, ” and “condition” are used interchangeably herein.
As used herein, and unless otherwise specified, the terms “treat, ” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition ( “therapeutic treatment” ) , and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition ( “prophylactic treatment” ) . In one embodiment, the compounds provided herein are contemplated to be used in methods of therapeutic treatment wherein the action occurs while a subject is suffering from the specified disease, disorder or condition and results in a reduction in the severity of the disease, disorder or condition, or retardation or slowing of the progression of the disease, disorder or condition. In an alternate embodiment, the compounds provided herein are contemplated to be used in methods of prophylactic treatment wherein the action occurs before a subject begins to suffer from the specified disease, disorder or condition and results in preventing a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or preventing the recurrence of the disease, disorder or condition.
In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response e.g., to treat a disease or disorder described herein. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment (i.e., encompasses a “therapeutically effective amount” and a “prophylactically effective amount” ) .
Detailed Description of the InventionThe present invention is based in part on the unexpected discovery of novel solid forms (e.g., crystalline forms) of the compound of Formula (I) having one or more desirable properties, such as high stability, high crystallinity, high purity, low hygroscopicity, favorable dissolution and/or favorable mechanical properties. In particular, solid forms of the compound of Formula (I) disclosed herein provide improved physical stability and/or physicochemical properties suitable for clinical studies, product manufacture and therapeutic use.
While multiple solid forms of the compound of Formula (I) have been identified, each solid form can be uniquely identified by different analytical parameters, alone or in combination, such as, but not limited to: X-ray powder diffraction (XRPD) , thermogravimetric analysis (TGA) , differential scanning calorimetry (DSC) , dynamic vapor sorption (DVS) , polarized light microscope (PLM) , high-performance liquid chromatography (HPLC) , and nuclear magnetic resonance (NMR) .
Diseases and disorders that may be treated by the solid forms, pharmaceutical compositions and methods disclosed herein include one or more JAK1-mediated diseases or disorders selected from asthma, allergies, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) , juvenile arthritis, inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease) , endocrinopathies (e.g., type 1 diabetes and Graves’ disease) , neurodegenerative diseases (e.g., multiple sclerosis (MS) ) , autistic spectrum disorder, depression, Alzheimer's disease, Guillain-Barre syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome DES, Sjogren's syndrome, amyotrophic lateral sclerosis (ALS) , Parkinson's disease, Huntington's Disease, Guillain-Barre syndrome, myasthenia gravis, and chronic idiopathic demyelinating disease (CID) , vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis) , skin diseases (e.g., acne vulgaris dermatomyositis, pemphigus, systemic lupus erythematosus (SLE) , discoid lupus erthematosus, scleroderma, psoriasis, plaque psoriasis, vasculitics, vitiligo and alopecias) , Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS) , celiac disease, pemphigus, transplant rejection (allograft transplant rejection) , graft-versus-host disease (GVDH) , an inflammatory disease, an autoimmune disease, an immune-mediated disease, cancer, rheumatoid arthritis, ankylosing spondylitis, psoriasis, atopic dermatitis, inflammatory bowel disease, Crohn’s , ulcerative colitis, DES, vitiligo, alopecia areata, and alopecia totalis.
In one aspect, the invention generally relates to a solid form (e.g., a crystalline form) of a compound of Formula (I) , which is Form B, wherein X-ray powder diffraction (XRPD) pattern thereof comprises characteristic diffraction peaks at the following 2θangles: 10.815°±0.2°, 13.475°±0.2°, 17.225°±0.2°, 21.804°±0.2°, and 22.361°±0.2°, with a radiation source of Cu-Kα,
In some embodiments, the XRPD pattern of the solid form further comprises one or more than one of characteristic diffraction peaks at the following 2θangles: 9.959°±0.2°, 11.757°±0.2°, 14.974°±0.2°, 20.481°±0.2°, 21.033°±0.2°, 21.544°±0.2°, 23.462°±0.2°, 23.687°±0.2°, 25.155°±0.2°, 29.747°±0.2°, 30.292°±0.2°, and 38.075°±0.2°, with a radiation source of Cu-Kα.
In some embodiments, the XRPD pattern of the solid form comprises characteristic diffraction peaks at the following 2θangles: 9.959°±0.2°, 10.815°±0.2°, 11.757°±0.2°, 13.475°±0.2°, 14.974°±0.2°, 17.225°±0.2°, 20.481°±0.2°, 21.033°±0.2°, 21.544°±0.2°, 21.804°±0.2°, 22.361°±0.2°, 23.462°±0.2°, 23.687°±0.2°, 25.155°±0.2°, 29.747°±0.2°, 30.292°±0.2°, and 38.075°±0.2°, with a radiation source of Cu-Kα.
In some embodiments, the XRPD pattern of the solid form further comprises one or more than one of characteristic diffraction peaks at the following 2θangles: 10.092°±0.2°, 13.198°±0.2°, 16.360°±0.2°, 16.784°±0.2°, 17.918°±0.2°, 18.347°±0.2°, 19.243°±0.2°, 20.062°±0.2°, 22.774°±0.2°, 24.153°±0.2°, 24.906°±0.2°, 26.188°±0.2°, 26.697°±0.2°, 27.787°±0.2°, 28.192°±0.2°, 30.957°±0.2°, 31.486°±0.2°, 32.819°±0.2°, 32.973°±0.2°, 33.579°±0.2°, 34.573°±0.2°, 34.939°±0.2°, 35.947°±0.2°, 36.722°±0.2°, 36.954°±0.2°, 39.153°±0.2°, and 39.714°±0.2°, with a radiation source of Cu-Kα.
In some embodiments, the XRPD pattern of the solid form comprises characteristic diffraction peaks at the following 2θangles: 9.959°±0.2°, 10.092°±0.2°, 10.815°±0.2°, 11.757°±0.2°, 13.198°±0.2°, 13.475°±0.2°, 14.974°±0.2°, 16.360°±0.2°, 16.784°±0.2°, 17.225°±0.2°, 17.918°±0.2°, 18.347°±0.2°, 19.243°±0.2°, 20.062°±0.2°, 20.481°±0.2°, 21.033°±0.2°, 21.544°±0.2°, 21.804°±0.2°, 22.361°±0.2°, 22.774°±0.2°, 23.462°±0.2°, 23.687°±0.2°, 24.153°±0.2°, 24.906°±0.2°, 25.155°±0.2°, 26.188°±0.2°, 26.697°±0.2°, 27.787°±0.2°, 28.192°±0.2°, 29.747°±0.2°, 30.292°±0.2°, 30.957°±0.2°, 31.486°±0.2°, 32.819°±0.2°, 32.973°±0.2°, 33.579°±0.2°, 34.573°±0.2°, 34.939°±0.2°, 35.947°±0.2°, 36.722°±0.2°, 36.954°±0.2°, 38.075°±0.2°, 39.153°±0.2°, and 39.714°±0.2°, with a radiation source of Cu-Kα.
In some embodiments, the XRPD pattern of the solid form comprises characteristic diffraction peaks at the 2θangles shown in Table 1.
Table 1
In some embodiments, the XRPD pattern of the solid form is essentially the same as that shown in FIG. 6, with a radiation source of Cu-Kα.
In some embodiments, the XRPD pattern of the solid form is obtained with parameters shown in Table 2.
Table 2
In some embodiments, the DSC curve of the solid form comprises an endothermic peak with a peak value at 235.7℃±4℃ and an exothermic peak with a peak value at 241.6℃±4℃.
In some embodiments, the DSC spectrum of the solid form is essentially the same as that shown in FIG. 7.
In some embodiments, the DSC curve of the solid form is obtained with parameters shown in Table 3.
Table 3
In some embodiments, the TGA curve of the solid form has a weight loss of 0.22%at 233.4 ℃±4℃.
In some embodiments, the TGA curve of the solid form is essentially the same as that shown in FIG. 8.
In some embodiments, the TGA spectrum of the solid form is obtained with parameters shown in Table 4.
Table 4
In some embodiments, the solid form is anhydrate.
In some embodiments, the solid form is non-solvent.
In some embodiments, the solid form is composed of irregular crystals, with a size of less than about 20 microns.
The certain embodiments, a solid form referred to herein is a crystalline form of Form B.
In another aspect, the invention generally relates to a process for preparing a solid form, which is Form B of the compound of Formula (I) , comprising adding water into a solution of the compound of Formula (I) followed by cooling the solution, wherein solvent of the solution is a mixture of acetone and H2O.
In some embodiments of the process, the solution is prepared by dissolving compound of Formula (I) in the solvent, preferably at a temperature of about 50-60℃; the water is added into the solution of compound of Formula (I) by dripping, wherein preferably a mass ratio of added water to compound of Formula (I) is about 19: 1; a mass ratio of acetone to H2O in the solvent is about 3: 1; a mass ratio of acetone to compound of Formula (I) is about (8-9) : 1; and/or the cooling is performed at about 45-50℃for about 0.5-1 h, about 30-40℃for about 1-2 h, and about 15-25℃ for about 10-16 h.
In some embodiments, the solution is prepared by dissolving compound of Formula (I) in solvent.
In some embodiments, dissolving temperature is about 50-60℃.
In some embodiments, the water is added into the solution of compound of Formula (I) by dripping; preferably, mass ratio of added water to compound of Formula (I) is about 19: 1.
In some embodiments, mass ratio of acetone to H2O in the solvent is about 3: 1.
In some embodiments, mass ratio of acetone to compound of Formula (I) is about (8-9) : 1.
In some embodiments, the cooling is performed at about 45-50℃ for about 0.5-1 h, about 30-40℃ for about 1-2 h, about 15-25℃ for about 10-16 h.
In yet another aspect, the invention generally relates to a solid form of a compound of Formula (I) , which is Form A, wherein the XRPD pattern thereof comprises characteristic diffraction peaks at the following 2θangles: 4.940°±0.2°, 9.954°±0.2°, 12.881°±0.2°, 17.094°±0.2°, and 22.969°±0.2°, with a radiation source of Cu-Kα,
In some embodiments, the XRPD pattern of the solid form further comprises one or more than one of characteristic diffraction peaks at the following 2θangles: 11.327°±0.2°, 15.607°±0.2°, 19.619°±0.2°, 20.153°±0.2°, 21.133°±0.2°, 22.272°±0.2°, 22.765°±0.2°, 24.587°±0.2°, 25.058°±0.2°, 25.772°±0.2°, 25.996°±0.2°, 26.903°±0.2°, 29.314°±0.2°, 29.842°±0.2°, and 35.495°±0.2°, with a radiation source of Cu-Kα.
In some embodiments, the XRPD pattern of the solid form comprises characteristic diffraction peaks at the following 2θangles: 4.940°±0.2°, 9.954°±0.2°, 11.327°±0.2°, 12.881°±0.2°, 15.607°±0.2°, 17.094°±0.2°, 19.619°±0.2°, 20.153°±0.2°, 21.133°±0.2°, 22.272°±0.2°, 22.765°±0.2°, 22.969°±0.2°, 24.587°±0.2°, 25.058°±0.2°, 25.772°±0.2°, 25.996°±0.2°, 26.903°±0.2°, 29.314°±0.2°, 29.842°±0.2°, and 35.495°±0.2°, with a radiation source of Cu-Kα.
In some embodiments, the XRPD pattern of the solid form further comprises one or more than one of characteristic diffraction peaks at the following 2θangles: 11.042±0.2°, 15.833±0.2°, 16.137±0.2°, 17.880±0.2°, 18.654±0.2°, 21.975±0.2°, 24.367±0.2°, 28.844±0.2°, 30.483±0.2°, 31.245±0.2°, 32.729±0.2°, 33.589±0.2°, 34.152±0.2°, 37.458±0.2°, and 39.182±0.2°, with a radiation source of Cu-Kα.
In some embodiments, the XRPD pattern of the solid form comprises characteristic diffraction peaks at the following 2θangles: 4.940°±0.2°, 9.954°±0.2°, 11.042±0.2°, 11.327°±0.2°, 12.881°±0.2°, 15.607°±0.2°, 15.833±0.2°, 16.137±0.2°, 17.094°±0.2°, 17.880±0.2°, 18.654±0.2°, 19.619°±0.2°, 20.153°±0.2°, 21.133°±0.2°, 21.975±0.2°, 22.272°±0.2°, 22.765°±0.2°, 22.969°±0.2°, 24.367±0.2°, 24.587°±0.2°, 25.058°±0.2°, 25.772°±0.2°, 25.996°±0.2°, 26.903°±0.2°, 28.844±0.2°, 29.314°±0.2°, 29.842°±0.2°, 30.483±0.2°, 31.245±0.2°, 32.729±0.2°, 33.589±0.2°, 34.152±0.2°, 35.495°±0.2°, 37.458±0.2°, and 39.182±0.2°, with a radiation source of Cu-Kα.
In some embodiments, the XRPD pattern of the solid form comprises characteristic diffraction peaks at the 2θangles shown in Table 5.
Table 5
In some embodiments, the XRPD pattern of the solid form is essentially the same as that shown in FIG. 1, with a radiation source of Cu-Kα.
In some embodiments, the XRPD pattern of the solid form is obtained with following parameters shown in Table 6.
Table 6
In some embodiments, the DSC curve of the solid form comprises an endothermic peak with a peak value at 242.10℃±4℃ and an exothermic peak with a peak value at 246.75℃±4℃.
In some embodiments, the DSC curve of the solid form is essentially the same as that shown in FIG. 2.
In some embodiments, the DSC curve of the solid form is obtained with parameters shown in Table 7.
Table 7
In some embodiments, the TGA curve of the solid form has a weight loss of 0.01%at 200℃±4℃.
In some embodiments, the TGA curve of the solid form is essentially the same as that shown in FIG. 3.
In some embodiments, the TGA curve of the solid form is obtained with parameters shown in Table 8.
Table 8
In some embodiments, the solid form is anhydrate.
In some embodiments, the solid form is non-solvent.
In some embodiments, the solid form is composed of irregular crystals, with a size of less than about 20 microns.
The certain embodiments, a solid form referred to herein is a crystalline form of Form
A.
In yet another aspect, the invention generally relates to a process for preparing a solid form, which is Form A of the compound of Formula (I) , comprising adding water into a solution of compound of Formula (I) , wherein solvent of the solution is DMSO.
In some embodiments of the process, the solution is prepared by dissolving compound of Formula (I) in the solvent to obtain a suspension and filtering; a mass/volume ratio of compound of Formula (I) to solvent is about 272 g/L; and/or the water is added by dripping; preferably, mass/volume ratio of compound of Formula (I) to added water is about 60 g/L.
In some embodiments of the present disclosure, the solution is prepared by dissolving compound of Formula (I) in solvent to obtain a suspension and filtering (for example, at room temperature) .
In some embodiments of the present disclosure, mass/volume ratio of compound of Formula (I) to solvent is about 272 g/L.
In some embodiments of the present disclosure, the water is added by dripping (for example, at about 20-30℃) ; preferably, mass/volume ratio of compound of Formula (I) to added water is about 60 g/L.
In yet another aspect, the invention generally relates to a crystalline form of a compound of Formula (I) , wherein crystallographic data and refinement parameters of single crystal of the crystalline form comprise those shown in Table 9.
Table 9
In some embodiments, the crystallographic data and refinement parameters of the single crystal of the crystalline form further comprise those shown in Table 10.
Table 10
In yet another aspect, the invention generally relates to a pharmaceutical composition comprising a solid form (e.g., crystalline form) disclosed herein, and a pharmaceutically acceptable excipient, carrier or diluent.
In yet another aspect, the invention generally relates to a unit dosage form comprising a solid form (e.g., crystalline form) disclosed herein and/or a pharmaceutical composition disclosed herein.
In yet another aspect, the invention generally relates to use of a solid (e.g., crystalline) form or the pharmaceutical composition in the manufacture of JAK1 inhibitor.
In yet another aspect, the invention generally relates to use of the solid (e.g., crystalline) form or the pharmaceutical composition in the manufacture of a medicament for treating a JAK1-mediated disease or disorder.
In yet another aspect, the invention generally relates to a method for treating a JAK1-mediated disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of the solid (e.g., crystalline) form or the pharmaceutical composition.
In yet another aspect, the invention generally relates to a solid (e.g., crystalline) form or the pharmaceutical composition for use in treating a JAK1-mediated disease or disorder.
In yet another aspect, the invention generally relates to crystalline form or the pharmaceutical composition for use in inhibiting JAK-1.
In some embodiments, the JAK1-mediated disease or disorder is selected from asthma, allergies, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) , juvenile arthritis, inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease) , endocrinopathies (e.g., type 1 diabetes and Graves’ disease) , neurodegenerative diseases (e.g., multiple sclerosis (MS) ) , autistic spectrum disorder, depression, Alzheimer's disease, Guillain-Barre syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome DES, Sjogren's syndrome, amyotrophic lateral sclerosis (ALS) , Parkinson's disease, Huntington's Disease, Guillain-Barre syndrome, myasthenia gravis, and chronic idiopathic demyelinating disease (CID) , vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis) , skin diseases (e.g., acne vulgaris dermatomyositis, pemphigus, systemic lupus erythematosus (SLE) , discoid lupus erthematosus, scleroderma, psoriasis, plaque psoriasis, vasculitics, vitiligo and alopecias) , Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS) , celiac disease, pemphigus, transplant rejection (allograft transplant rejection) , graft-versus-host disease (GVDH) , and a related disease or disorder thereof.
In some embodiments, the JAK1-mediated disease or disorder is an inflammatory disease.
In some embodiments, the JAK1-mediated disease or disorder is an autoimmune disease.
In some embodiments, the JAK1-mediated disease or disorder is an immune-mediated disease.
In some embodiments, the JAK1-mediated disease or disorder is cancer.
In some embodiments, the JAK1-mediated disease or disorder is selected from one or more of rheumatoid arthritis, ankylosing spondylitis, psoriasis, atopic dermatitis, inflammatory bowel disease, Crohn’s, ulcerative colitis, DES, vitiligo, alopecia areata, and alopecia totalis.
In yet another aspect, the invention generally relates to use of the crystalline form or the pharmaceutical composition in the manufacture of a medicament for treating disease, the disease is asthma, allergies, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) , juvenile arthritis, inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease) , endocrinopathies (e.g., type 1 diabetes and Graves’ disease) , neurodegenerative diseases (e.g., multiple sclerosis (MS) ) , autistic spectrum disorder, depression, Alzheimer's disease, Guillain-Barre syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome DES, Sjogren's syndrome, amyotrophic lateral sclerosis (ALS) , Parkinson's disease, Huntington's Disease, Guillain-Barre syndrome, myasthenia gravis, and chronic idiopathic demyelinating disease (CID) , vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis) , skin diseases (e.g., acne vulgaris dermatomyositis, pemphigus, systemic lupus erythematosus (SLE) , discoid lupus erthematosus, scleroderma, psoriasis, plaque psoriasis, vasculitics, vitiligo and alopecias) , Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS) , celiac disease, pemphigus, transplant rejection (allograft transplant rejection) , graft-versus-host disease (GVDH) , inflammatory disease, autoimmune disease, immune-mediated disease, cancer, atopic dermatitis, alopecia areata or alopecia totalis.
In yet another aspect, the invention generally relates to a method for treating disease in a subject in need thereof, comprising administering to the subject an effective amount of the crystalline form or the pharmaceutical composition, the disease is asthma, allergies, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) , juvenile arthritis, inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease) , endocrinopathies (e.g., type 1 diabetes and Graves’ disease) , neurodegenerative diseases (e.g., multiple sclerosis (MS)) , autistic spectrum disorder, depression, Alzheimer's disease, Guillain-Barre syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome DES, Sjogren's syndrome, amyotrophic lateral sclerosis (ALS) , Parkinson's disease, Huntington's Disease, Guillain-Barre syndrome, myasthenia gravis, and chronic idiopathic demyelinating disease (CID) , vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis) , skin diseases (e.g., acne vulgaris dermatomyositis, pemphigus, systemic lupus erythematosus (SLE) , discoid lupus erthematosus, scleroderma, psoriasis, plaque psoriasis, vasculitics, vitiligo and alopecias) , Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS) , celiac disease, pemphigus, transplant rejection (allograft transplant rejection) , graft-versus-host disease (GVDH) , inflammatory disease, autoimmune disease, immune-mediated disease, cancer, atopic dermatitis, alopecia areata or alopecia totalis.
In yet another aspect, the invention generally relates to a solid (e.g., crystalline) form or the pharmaceutical composition for use in treating a disease; the disease is asthma, allergies, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) , juvenile arthritis, inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease) , endocrinopathies (e.g., type 1 diabetes and Graves’ disease) , neurodegenerative diseases (e.g., multiple sclerosis (MS) ) , autistic spectrum disorder, depression, Alzheimer's disease, Guillain-Barre syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome DES, Sjogren's syndrome, amyotrophic lateral sclerosis (ALS) , Parkinson's disease, Huntington's Disease, Guillain-Barre syndrome, myasthenia gravis, and chronic idiopathic demyelinating disease (CID) , vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis) , skin diseases (e.g., acne vulgaris dermatomyositis, pemphigus, systemic lupus erythematosus (SLE) , discoid lupus erthematosus, scleroderma, psoriasis, plaque psoriasis, vasculitics, vitiligo and alopecias) , Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS) , celiac disease, pemphigus, transplant rejection (allograft transplant rejection) , graft-versus-host disease (GVDH) , inflammatory disease, autoimmune disease, immune-mediated disease, cancer, atopic dermatitis, alopecia areata or alopecia totalis.
The following examples are meant to be illustrative of the practice of the invention and not limiting in any way.
Examples
Abbreviations and Definitions
Instrumentation
X-raypower diffraction (XRPD)
Bruker D8 Advance X-ray powder diffractometer was used to collect the XPRD data. The XRPD parameters are listed in Table 11.
Table 11. Parameters for XRPD
Test method: Fine powder sample: put a proper amount of sample in a single crystal silicon sample tray, spread it evenly, and flatten it with a platen.
Sample with larger particles: put the sample in a mortar and grind it into fine powder (if necessary, a 120-mesh sieve can be used) , put a proper amount of ground sample in a monocrystalline silicon sample tray, spread it evenly, and flatten it with a platen.
Determination: put the prepared sample into the corresponding card slot of the instrument, set the sample information and scan.
Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC)
TGA data were collected using TA Q5000/Discovery 5500. DSC was performed using TA Q2000/Discovery 2500. The TGA and DSC parameters are listed in Table 12.
Table 12. Parameters for TGA and DSC
Dynamic Vapor Sorption (DVS)
DVS was measured using SMS (Surface Measurement Systems) DVS Intrinsic. The relative humidity at 25℃ was calibrated against deliquescence point of LiCl, Mg (NO3) 2 and KCl. The DVS parameters are listed in Table 13.
Table 13. Parameters for DVS
1H Nuclear Magnetic Resonance (NMR)
1H NMR data were collected on Bruker 400M NMR Spectrometer using DMSO-d6. Polarized Light Microscopy (PLM)
PLM images were captured using Axio Lab. A1 upright microscope with CT3 camera at RT.
High Performance Liquid Chromatography (HPLC)
Agilent HPLC was used to evaluate sample purity and solubility. The HPLC conditions are listed in Tables 14-15.
Table 14. HPLC Parameters for Purity Tests
Table 15. HPLC Parameters for Solubility Tests
Single Crystal X-ray Diffraction (SCXRD)
A suitable single crystal with good diffraction quality was selected and wrapped with Paratone-N (an oil based cryoprotectant) . The crystal was mounted on a mylar loop in a random orientation and immersed in a stream of nitrogen at 120 K. Preliminary examination and data collection were performed on a Rigaku XtaLAB Synergy R (CuKαradiation, ) diffractometer and analyzed with the CrysAlisPro (Rigaku, V1.171.40.14e, 2018) software package. Cell parameters and an orientation matrix for data collection were retrieved and refined (T-vector Dirax algorithm) by CrysAlisPro (Rigaku, V1.171.40.14e, 2018) software using the setting angles of 31762 reflections in the range 4.9840°<θ<75.1670°. The data were collected to a minimum diffraction angle (θ) of 5.001°and a maximum diffraction angle (θ) of 68.080°at 120 K. The final completeness is 99.7%. The mean I/σ of the data is 94.4 and the maximum resolution was
Example: Crystalline Form A and B of the Compound of Formula (I)
1. Preparation of Form A and Form B
The compound of Formula (I) was prepared according to the method described in page sixty of Example 1 in WO2020/088695A1. It was used as the starting material in the preparation of Form A and Form B.
Representative preparation method of crystalline form A
In a 1L three-necked round-bottomed flask, 120g of starting material and 400ml of dimethyl sulfoxide were added in turn. The mixture was stirred at room temperature for 30min to 1h to ensure that most of the solids were dissolved. Then, the mixed solution was filtered through celite, and the filter cake was rinsed with 40 ml of dimethyl sulfoxide. The filtrates were combined and transferred to another 2L three-necked round-bottomed flask. Stirring was started and the internal temperature was adjusted to 20～30℃ followed by slowly adding of about 2L water through a dropping funnel for at least 1h. After the dropping, the reaction solution was kept warm and stirred for another 1h. The solution was filtered, and the filter cake was washed with 200～300ml of water. The filter cake was taken out and dried in vacuum until the weight was constant. Yield: 92%.
Representative preparation method of crystalline form B
16.2kg acetone, 5.2kg purified water and 2.05 kg starting material were added into reactor R1 in turn. After that, stirring was started and the reactor was heated to 50～60℃. After the material was completely dissolved, the reactor was kept warm and stirred for 0.5～1 hour. The material liquid in reactor R1 was filtered through a precision filter and transferred to reactor R2 until no liquid droplets came out. Subsequently, 1.6kg acetone and 0.6kg purified water were added to rinse reactor R1 and the resulting solution was filtered through the precision filter to reactor R2. The internal temperature of R2 was controlled at 45～50℃ and 39.6kg purified water was dropped into the reactor through a high-level tank. After the dropping, the temperature in the reactor was controlled at 45-50℃ and maintained for 0.5-1 hour. The reactor R2 was slowly cooled down to an internal temperature of 30-40℃ and the temperature was maintained for 1-2 hours. The reactor R2 was further cooled down until the internal temperature was around 15-25℃ and the temperature was maintained for 10-16 hours. The material in the reactor R2 is filtered through a filter. 10.4 Kg purified water was used to wash the reactor and the resulting solution was filtered to wash the filter cake until almost no liquid drops flowed out. The wet product was taken out, transferred to a vacuum oven and dried in vacuum for 12～36 hours to obtain crystal form B. HPLC purity: 99.55%, yield: 82.7%.
The above two crystalline forms were characterized by X-ray powder diffraction (XRPD) , thermogravimetric analysis (TGA) , differential scanning calorimetry (DSC) , proton nuclear magnetic resonance (1H NMR) , and polarized light microscopy (PLM) . The results indicated the two forms are anhydrates.
2. Characteristics of Form A and Form B
Form A
FIG. 1 shows the XRPD pattern of Form A. According to TGA and DSC experiments of Form A, there was a weight loss of 0.01%up to 200℃ (FIG. 3) and an endothermic peak at 242.10℃ (peak value) and an exothermic peak at 246.75℃ (peak value) (FIG. 2) . FIG. 4 shows the 1H NMR spectrum of Form A, indicating no residual solvent peak. An exemplary PLM image of Form A (FIG. 5) indicated that Form A was composed of irregular shaped crystals, which were less than about 200 microns in size.
Form B
FIG. 6 shows the XRPD of Form B. According to TGA and DSC experiments of Form B, there was a weight loss of 0.22%up to 233.4℃ (FIG. 8) and one endothermic peak at 235.7℃ (peak temperature) and one exothermic peak at 241.6℃ (peak temperature) (FIG. 7) . FIG. 9 shows the 1H NMR spectrum of Form B indicating no residual solvent peak. An exemplary PLM image of Form B (FIG. 10) indicated that Form B was composed of irregular crystals, which were less than about 20 microns in size.
SCXRD of Form B
The SCXRD characterization of Form B indicated that it crystalizes as a triclinic crystal system and in the space group. The unit cell parameters are α=83.7635 (5) °, β=89.7471 (4) °, γ=80.2878 (5) °, and The asymmetric unit of the single crystal structure is comprised of only one molecule of the compound of formula (I) , confirming that Form B is an anhydrate. Additional crystallographic data and refinement parameters are summarized in Table 16.
Table 16. Crystallographic data and refinement parameters of Form B single crystal
The single crystal sample was obtained by adding 31.8 mg of the starting material into a 3 mL glass vial with 1.0 mL ethanol/water (70/30, v/v) . After being shaken, the suspension was equilibrated at 50℃ for 2 hours, followed by filtration via a 0.45μm PTFE filter. The clear filtrate was placed in a new clean 3 mL vial (the filter membrane and 3 mL vial were pre-heated at 50℃) . The vial was sealed with a cap and placed in a 50℃ biochemical incubator for slow cooling (50℃ to 5℃ cooling at 0.1℃/min) . The vial was cooled to-20℃ for 4 hours. The solution was filtered to a new clean 3 mL vial then sealed withM Film with 8 pinholes on it for slow evaporation at RT. After 4 days of slow evaporation, a crystal sample was obtained in the mother liquid. XRPD characterization showed the obtained crystal was the Form A polymorph. The 3 mL vial was then sealed by cap and stored at RT for another 50 days, and the XRPD characterization showed the Form A had changed to the Form B. An exemplary PLM image of the sample at the end of the 50 days is shown in FIG. 11.
The atomic thermal ellipsoids drawing of Form B in the asymmetric unit is shown in FIG. 12. Adjacent molecules interact by intermolecular hydrogen bonds. See also Table 17.
Table 17. Classic H-bonds list in Form B single crystal structure
An XRPD pattern generated from the Form B single crystal XRD data is consistent with the experimental XRPD patterns of the Form B single crystal sample.
Effect Examples
Thermodynamic stability of Form A and Form B
The thermodynamic stability relationship between Form A and Form B was investigated via heating experiments and slurry competition experiments. In the slurry competition experiments (Table 18) , saturated solutions of the starting material were prepared in ethanol or 2-MeTHF at RT and at 50℃. Then, equal amounts of Form A and Form B were added to the saturated solutions to form suspensions. The suspensions were slurred for about 0.5 h and the resulting solids were isolated. XRPD patterns of the solids after slurry in ethanol or 2-MeTHF at RT and 50℃ were consistent with the XRPD pattern of Form B, indicating that Form B was thermodynamically more stable than Form A from RT to 50℃.
Table 18. Summary of slurry competition experiments of the compound of Formula (I)
Stability studies of Form A and Form B in water at RT
Stability studies of Form A and Form B were performed in water at RT. About 8 mg of each crystalline solids were suspended in 1.0 mL ultrapure water. The suspensions were stirred (1000 rpm) at RT for 24 hrs. prior to centrifugation and filtration through 0.45μm membrane to obtain supernatants for pH analysis, and the residual solids were analyzed by XRPD. The results are summarized in Table 19. No form change was observed.
Table 19. Summary of solubility and pH results of Form A and Form B in water at RT
Hygroscopicity
The hygroscopicity of Form B was evaluated via DVS at 25℃. The DVS plot (FIG. 13) showed Form B hardly absorbed water in the humidity range of 0-90%RH, and the weight change was 0.063% (the difference between the highest point and the lowest point in cycle 2) . The XRPD pattern of Form B after DVS indicated there was no form change.
Thermodynamic solubility in bio-relevant media
The thermodynamic solubility of Form B was evaluated in bio-relevant media (SGF, FaSSIF and FeSSIF) at 37℃ for 1, 4, or 24 hrs. About 35 mg of Form B was added to 3.5 mL biorelevant media to obtain a suspension. The suspensions were shaken (500 rpm) at 37℃ for 1, 4, or 24 hrs. prior to centrifugation and filtration through 0.45 μm membrane to obtain supernatants for HPLC solubility and pH analysis. The residual solids were analyzed by XRPD. Solubility results are summarized in Table 20. The solubility of Form B decreased as biorelevant media pH increased (maximum solubility was 3.2 mg/mL in SGF) , and XRPD results indicated that there was no form change.
Table 20. Summary of solubility and pH results of Form B in bio-relevant media at 37℃
*Initial pH of bio-relevant media was: SGF pH=1.8, FaSSIF pH=6.5, FeSSIF pH=5.1
The results show that the crystal form B has good solubility (far greater than 68 μg/mL) in the simulated gastrointestinal fluid, and the stable absorption of a preparation can be kept in the subsequent preparation development and production.
Stress test, accelerated stability and long-term stability studies of Form B
Form B was placed at conditions of high temperature of 60℃, high humidity of 92.5%RH for 30 days illumination condition of 1×ICH (total illumination not less than 1.2×106 Lux·hr, near ultraviolet energy not less than 200 w·hr/m2) , accelerated condition (40±2℃/75%±5%RH) for 6 months and long term condition (25±2℃/60%±5%RH) for 24 months. After these tests, the appearance, related substances, content (calculated as anhydrous and solvent-free) , water content, crystal form, assay and microbial limit all meet the corresponding quality standards. Details are summarized in the Table 21.
Table 21
Accelerated condition (40℃/75%RH) of Form B
Long term condition (25℃/60%RH) of Form B
Feasibility of preparation
As the basic properties of solid powder, such as the determination of bulk density and tap density are essential factors for preparation development. According to calculation, the Karl index of Form B is about 24%, and the Hasen ratio is about 1.31, which means that the fluidity of From B can meet the demand of preparation production.
Table 22. Bulk Density and Tap Density of Form B
Test procedure
(1) Instruments
Table 23
(2) Bulk density test
The compound to be tested (aperture 1 mm, No. 18) was sieved to remove the compound caked during storage. A proper amount of the sieved compound was weighed and put into a 10 ml graduated cylinder, the powder was carefully leveled without compaction, and its apparent volume (V0, mL) was read. The bulk density was calculated according to the following formula:
ρ (bulk) =m/V0 (Eq. 1)
(3) Tap density test
An appropriate amount of test compound was weighed and gently added into a 10 ml graduated cylinder. First, the cylinder was vibrated for 1 minute and 40 seconds, and the volume Va after vibration was read to the nearest scale unit. Then it was vibrated for 2 minutes and 30 seconds and 4 minutes and 10 seconds in turn, and the volume after vibration, Vb and Vc, were read. If the cubic volume deviation was less than 2%, Vc was the final vibration volume, which was recorded as Vf (milliliter) . The tap density (g/ml) was calculated according to the following formula:
ρ (tapped) =m/Vf (Eq. 2)
The bulk density and tap density were tested three times, and new sieved solid powder was added for testing each time.
Compressibility Index and Hausner Ratio were calculated according to the following formula:
Karl index (Compressibility Index) =100× (1-ρ (bulk) /ρ (tapped) ) (Eq. 3)
Hausner Ratio=ρ (tapped) /ρ (bulk) (Eq. 4)
ρ (bulk) is the bulk density of powder, and ρ (tapped) is the tap density of powder.
Table 24. Fluidity evaluation standard
Mill grinding
About 2kg of Form B was weighed and micronized by jet mill, and the crystal form transformation and the change of crystallinity were studied by XRPD characterization. The results show that the Form B remains stable before and after grinding conditions, which is beneficial to the subsequent preparation production, and controlling the particle size is also beneficial to the stable bioavailability.
Table 25
Applicant’s disclosure is described herein in preferred embodiments with reference to the Figures, in which like numbers represent the same or similar elements. Reference throughout this specification to “one embodiment, ” “an embodiment, ” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment, ” “in an embodiment, ” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.
The described features, structures, or characteristics of Applicant’s disclosure may be combined in any suitable manner in one or more embodiments. In the description, herein, numerous specific details are recited to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that Applicant’s composition and/or method may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the disclosure.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.
Incorporation by Reference
References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.
Equivalents
The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.