CN1446089A - Pharmaceutical composition containing citalopram - Google Patents
Pharmaceutical composition containing citalopramDownload PDFInfo
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- CN1446089A CN1446089ACN01813752ACN01813752ACN1446089ACN 1446089 ACN1446089 ACN 1446089ACN 01813752 ACN01813752 ACN 01813752ACN 01813752 ACN01813752 ACN 01813752ACN 1446089 ACN1446089 ACN 1446089A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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Abstract
Translated fromChineseDescription
The present invention relates to a kind of citalopram that contains, i.e. 1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-1, the new pharmaceutical composition of the different benzo of 3-dihydro-5--furan nitrile.
Background of invention
Citalopram is a kind of known antidepressants, and following structure is arranged:
It is a kind of optionally, maincenter active serum element (5-hydroxy tryptamine; 5-HT) reuptake inhibitor, thereby have antidepressant activity.
Citalopram at first is at DE2657013, is equivalent among the US4136193 disclosed.This patent documentation has been described the recapitulative method that is used to prepare citalopram.The citalopram of gained is respectively isolating with the crystal form of oxalates, hydrobromate and hydrochlorate.In addition, citalopram alkali obtains (boiling point 175C/0.03mmHg) with oil form.The document also general description contain the preparation of citalopram salt tablets.Citalopram is respectively commercially available with its hydrobromate and hydrochloride form.
The crystalline preparation of citalopram alkali discloses in the unsettled DK200000402 of co-applications.The crystalline preparation of citalopram alkali has been described in this patent application, and citalopram alkali becomes purposes in the pure product of citalopram hydrobromate as intermediate with citalopram hydrobromate purifying crude.The document also general description contain the preparation of the tablet of citalopram alkali.
Citalopram becomes tablet commercially available in many countries by citalopram hydrobromate, lactose and other excipient pelletizing press sheet.
As everyone knows, the preparation of tablet is to need all dried ingredients to have good mobility.If active component has good flowability, can prepare tablet by direct compression process.Yet in many cases, the grain diameter of active substance is too little, and active matter is bonded together, and is mobile very poor.
And in preparation tablet process, the active substance of small particle diameter is mixed with bigger excipient, mixed non-uniform phenomenon usually occurs.
The problem of the too little and mobile difference of granule can solve by the particle diameter that strengthens active substance routinely, normally adopt with active substance separately or with the mixed way of granulating of the material of filler and/or conventional film-making agent.
A kind of method of granulation is called as " wet method " and granulates.Making in this way, is that exsiccant solid matter (active substance, filler, binding agent etc.) is mixed, water or other moistening reagent (as alcohol) moistening, the solid-state agglomerate or the granule that can obtain wetting.Up to obtaining ideal homogeneous size particles, the gained granule carries out drying.
Another kind of " wet method " granulates is " fusion " granulation, also can be called " thermoplastic " and granulate, and be as granulation reagent with a kind of low-melting solid.At first, exsiccant solid is mixed, and heating is until adhesive melts.Adhesive melts also is distributed in particle surface, and these granules are mutually bonding just to obtain required granule.Adhesive cools solidify to form the dried granules product.
The mixed legal system grain that the picture fusion method is granulated needs comparatively complicated and expensive equipment, and operating technology requires also higher.
The citalopram hydrobromate particle diameter that obtains with conventional method is very little, greatly about 2-20 μ m, and its mobile non-constant.Therefore, in the preparation tablet, obtaining suitable citalopram dosage, be necessary to prepare the citalopram granule of greater particle size, to improve its flowability.
Commercially available citalopram tablet obtains by citalopram hydrobromate and mixed granulation of multiple excipient.
Consider that direct compression process with respect to the granulation pressed disc method not only simply but also cheap, therefore wishes the direct compression process of a kind of citalopram hydrobromate of invention.
By a large amount of laboratory researches, the difficulty that the obstruction direct compression process prepares the citalopram tablet is resolved.
Have been found that bulky grain, just particle diameter can be compared with the particle diameter of filler, can obtain by new, creative preparation process, and these can be used for the preparation of the direct compression process of tablet.The capsule of exact dose also can use described bulky grain.
Be astoundingly, also find, can obtain the very little citalopram tablet of content difference by citalopram hydrobromate direct compression that will be more much smaller than filler particle diameter.Although the particle diameter of citalopram is very little, the capsule of exact dose also can obtain.
Goal of the invention
The purpose of this invention is to provide a kind of drug unit dosage form of the citalopram that contains suitable particle diameter newly, described unit dosage form can obtain by direct compacting.
Second purpose of the present invention provides the capsule that contains citalopram.
The 3rd purpose of the present invention provides the megacryst of suitable directly compacting citalopram officinal salt.
The 4th purpose of the present invention provides the method for the megacryst of preparation citalopram officinal salt.
Summary of the invention
The present invention is particularly including following independent scheme or their combination:
A kind of solid unit dosage form comprises by with the direct citalopram that gets of compacting of citalopram alkali or its officinal salt and pharmaceutically acceptable excipient, or above-mentioned mixture is packed in the hard capsules.
Be suitable for the crystal of citalopram officinal salt of the mean diameter at least 40 μ m of solid unit dosage form.
Preparation has at least 40 μ m mean diameters, and can be used for the crystalline method of citalopram officinal salt of solid unit dosage form, this method is that the solution system that will be dissolved in the citalopram officinal salt of appropriate solvent at first is cooled to second temperature from first temperature, the crystal seed that adds described citalopram salt then, under second temperature, place a period of time, control is cooled to the 3rd temperature and separates out crystal, separates with conventional solid/liquid separation technique.
Citalopram, filler and other pharmaceutically acceptable excipient directly are pressed into tablet very big advantage, can save and granulate and exsiccant step.And, owing to saved granulation step, also no longer need to have added binding agent.
Here, " directly compacting " meaning be the preparation of solid unit dosage form by active component and excipient simply mixed back compacting are got, do not need active component is made intermediate particle with the formation bulky grain, improve its flowability.
Here, " binding agent " is meant in wet method or melt granulation and uses, make the reagent of adhesive effect in grain products.
Here, " particulate distribution " be meant with Sympatec Helos equipment and under 1 crust dispersive pressure, decide the distribution of suitable bulb diameter by laser diffraction." mean diameter " is meant the meansigma methods of said particulate distribution accordingly.
Here, " reflux temperature " is meant that solvent or solvent system reflux or the temperature when seething with excitement under normal pressure.
In a specific embodiments of the present invention, relate to tablet with the mixture direct compression gained of citalopram alkali or its officinal salt and pharmaceutically acceptable excipient.
In another embodiment, the present invention relates to mixture with citalopram alkali or its officinal salt and pharmaceutically acceptable excipient and be filled to capsule in the hard capsules.
In a specific embodiments, the present invention relates to comprise the solid unit dosage form of mean diameter less than the citalopram crystal form of 20 μ m.
In another embodiment, the present invention relates to comprise mean diameter at least 40 μ m, preferably at 40-200 μ m, be more preferably the m at 45-150 μ, most preferably is the solid unit dosage form at the crystal form of 50-100 μ m.
Flowability separate and layering, and the citalopram crystal except depending on size, also depends on particulate distribution to the suitability of straight pressing.
Preferably, solid unit dosage form of the present invention does not contain binding agent.
Solid unit dosage form of the present invention, can contain the 2-60% percentage by weight with citalopram alkali active ingredient calculated, preferably 10-40%w/w is more preferably 15-25%w/w.Suitable is, solid unit dosage form of the present invention comprise 20%w/w with citalopram alkali active ingredient calculated.
Especially, the present invention relates to the solid unit dosage form, wherein active component is citalopram hydrobromate or citalopram hydrochlorate.Preferably, the active component that is included in the solid unit dosage form of the present invention is the citalopram hydrobromate.
Solid unit dosage form of the present invention can contain filler, is selected from lactose, or other sugar, as Sorbitol, and mannitol, dextrose plus saccharose, calcium phosphate (binary, ternary, moisture and water-free), starch, modified starch, microcrystalline Cellulose, calcium sulfate, and/or calcium carbonate.In a preferred embodiment, solid unit dosage form of the present invention does not contain lactose.
Suitable is, filler is a microcrystalline Cellulose, the ProSolv SMCC90 that makes as Penwest Pharmaceuticals, or the Avicel PH200 of FMC Corporation.
Except active component and filler, the medicinal solid unit dosage form can contain various other conventional excipients, as disintegrating agent and optional a spot of lubricant, coloring agent and sweeting agent.
The used lubricant of the present invention can be one or more following Metallic stearates (magnesium, calcium, sodium), stearic acid, wax, hydrogenated vegetable oil, Pulvis Talci and colloidal silicon dioxide.
Examples of suitable lubricants is magnesium stearate or calcium stearate.
Disintegrating agent includes sodium starch glycolate, croscarmellose, cross-linked pvp, low-substituted hydroxypropyl cellulose, modified corn starch, pregelatinized Starch and native starch.
Medicinal solid unit dosage form of the present invention can use the tablet machine preparation with forced feed performance with conventional method.
Capsule of the present invention can use the capsule loader filling that is fit to powder packing with conventional method.
In a specific embodiments of the present invention, the crystal of medicinal citalopram officinal salt has mean diameter 40-200 μ m, preferably at 45-150 μ m, is more preferably 50-120 μ m.
In the preferred embodiments of the invention, crystal is citalopram hydrobromate or citalopram hydrochlorate, preferably citalopram hydrobromate.
In another specific embodiments of the present invention, mean diameter at least 40 μ m and be applicable to that the citalopram officinal salt crystal of solid unit dosage form separates out from the citalopram officinal salt solution the appropriate solvent system.Above-mentioned solvent system can comprise one or more alcohol and optional water, and preferred solvent systems is the mixture of first alcohol and water, and wherein the weight ratio of first alcohol and water is 5: 1 to 50: 1, is more preferably 10: 1 to 30: 1, most preferably is 15: 1 to 25: 1.Above-mentioned citalopram officinal salt preferably is dissolved in described solvent system at 50 ℃ to the solvent system reflux temperature, preferably 60 ℃ to reflux temperature, be more preferably at 64 ℃ to reflux temperature.The amount of citalopram officinal salt and solvent for use is preferably 0.5: 1 to 5: 1 according to solvent and solute weight ratio, is more preferably 0.7: 1 to 2: 1, most preferably is to determine in 0.9: 1 to 1.5: 1.The solution of citalopram officinal salt is cooled to separates out crystalline temperature, it is in 20-40 ℃ of scope, preferably in 25-35 ℃ of scope, the citalopram crystal is separated out under this temperature, and its growth of maintenance under this temperature, time is 30 minutes to 7 days, preferably 1 hour to 4 days, and more preferably 12-36 hour.After this standing time, control be cooled to gradually crystallization will be from mother solution isolating temperature, the above-mentioned cooling process of controlling gradually is progressively to lower the temperature in the time range at 5 minutes to 6 hours, preferably at 15 minutes to 4 hours, is more preferably 30 minutes to 2 hours.Citalopram officinal salt crystal isolated temperature from mother solution is more preferably in the 5-15 ℃ of scope preferably in 0-20 ℃ of scope, and separation is an isolation technics routinely, carries out as filtration.
The preparation of the citalopram officinal salt small crystals in a specific embodiments of the present invention is according to the described method preparation of US4136193.
The crystalline preparation of citalopram alkali in a specific embodiments of the present invention is to prepare according to the method described in the NL patent No.1016435.
Below will the present invention be described by embodiment.Yet these embodiment only are explanation the present invention, the present invention are not played any qualification effect.
Embodiment 1
The citalopram hydrobromate crystallizes into megacryst
Citalopram hydrobromate (200g) is dissolved under 69 ℃ in the mixed solvent of methanol (200g) and water (20g).This solution is cooled to 30 ℃, makes crystal seed with citalopram hydrobromate crystal, places 24 hours down at 30 ℃, then is cooled to 10 ℃ in 1 hour.Gained crystallization isolated by filtration is with cold methanol wash, drying.The crystalline particle size distribution situation of gained sees Table 1.
Embodiment 2
The citalopram hydrobromate crystallizes into megacryst
Citalopram hydrobromate (12.0kg) is dissolved under reflux state in the mixed solvent of methanol (12.5kg) and water (1.2kg).This solution is cooled to 30 ℃, makes crystal seed with citalopram hydrobromate crystal (27g), places 16 hours down at 30 ℃, then is cooled to 10 ℃ in 1 hour.Gained crystallization isolated by filtration is with cold (10 ℃) methanol (3.5kg) washing, drying.The crystalline particle size distribution situation of gained sees Table 1.
Embodiment 3
The citalopram hydrobromate crystallizes into small crystals
Citalopram hydrobromate (200kg) is dissolved under 56 ℃ in the mixed solvent of methanol (170L) and acetone (680L).This solution is cooled to 15 ℃, makes crystal seed with citalopram hydrobromate crystal (50g), gradually hexane (1600L) is added in 60 minutes, and the gained suspension keeps under middling speed stirs and put cold 8 hours.The crystallization isolated by filtration is at first used the mixed liquid washing of cold (10 ℃) acetone (50L) and hexane, uses cold (10 ℃) hexanes (220L) washing then, drying.The crystalline particle size distribution situation of gained sees Table 1.
Embodiment 4
The crystallization of citalopram free alkali
Citalopram hydrobromate (101g) is suspended in the mixed solvent of water (500ml) and toluene (500ml).Add NaOH (60ml, 5N (aq)), mixed liquid (PH＞10) stirred layering 15 minutes.The organic facies washing (2 * 100ml), filter with filter pad.The decompression volatilization desolventizes, and obtains buttery chemical compound.Add normal heptane (400ml), mixture is heated to 70 ℃.Cooling obtains crystallization.Filtration obtains the white crystals of citalopram alkali, and vacuum drying spends the night at ambient temperature.
Table 1: the particle size distribution situation of crystallization of citalopram hydrobromate and ProSolv SCMC90 (Sympatec Helos)
| Distributed number (%) | Embodiment 1 (μ m) | Embodiment 2 (μ m) | Embodiment 3 (μ m) | ?ProSolv?SCMC90 ????(μm) |
| ????95 | ????465.43 | ????549.42 | ????96.96 | ????279.94 |
| ????90 | ????342.89 | ????352.23 | ????72.27 | ????231.66 |
| ????50 | ????96.87 | ????52.70 | ????14.04 | ????114.17 |
| ????10 | ????16.54 | ????11.97 | ????1.19 | ????32.10 |
| ????5 | ????8.23 | ????6.67 | ????0.82 | ????20.56 |
Embodiment 5
The direct compression process of citalopram hydrobromate small crystals prepares tablet
Tablet is formed:
Citalopram, HBr5800g(20%w/w)
ProSolv?SMCC9023055g(79.5％w/w)
Magnesium stearate145g(0.5%w/w)
The citalopram hydrobromate crystal and the ProSolv SMCC90 that derive from embodiment 3 mix 10 minutes under the 7rpm rotating speed in 100 liters of Bohle PTM 200 blenders.Add magnesium stearate, continued mixed 3 minutes.
Gained 25kg mixture uses rectangle on 30 station Fette P 1200/IC tablet machine, convex 5,5 * 8mm drift carries out tabletting (125,000 slices/hour).Label weight is set 125mg.Design output is approximately 200,000.The tabletting process carries out having exceeded the forced feed device until the mixture level, that is to say, the tabletting process is long as much as possible, up to determining that mixture has reached the amount that produces separation trend.
The tablet properties parameter:
Comprcssive strength: 70N
Disintegration time: 30 seconds
Fragility: NA
Weight differential: 0.84% relative standard deviation (20 of measuring amount)
Sticking situation: do not observe
Compositions citalopram content in the tabletting process
Be to measure separation trend, pick test at any time in whole tabletting process.Owing to there is the significant difference of size between active component citalopram hydrobromate and the filler ProSolv SMCC90, as shown in table 1, so unequigranular component may have the separation case generation when material was deposited in feeder when material is transferred to the tabletting feeder from blender or the tabletting process, promptly separate mixed.
Carry out regularly 50 times in the check of tabletting sampling from process, be equivalent to per 4000 sampling inspection once.Sample survey is each time extracted two out.
What the assay of tablet was used is the UV absorption process of the aqueous solution of standard, adds up to 100 and analyzes.The relative standard deviation of citalopram content is 1.6%.
The Strength Changes of tablet is very little, and this is because for filler, the particle diameter of citalopram hydrobromate is less.
To the possible separation trend that is interpreted as the little citalopram crystallization of particle diameter and bigger filler of of wonderful like this favourable outcome by the relatively poor mobile institute balance of small crystals.
Embodiment 6
Big citalopram hydrobromate crystallization direct compression process prepares tablet
Tablet is formed:
Citalopram, HBr (20%w/w)
ProSolv?SMCC90(79.5％w/w)
Magnesium stearate (0.5%w/w)
The crystallization of citalopram hydrobromate and the ProSolv SMCC90 that derive from embodiment 2 are mixed.Adding magnesium stearate immediately continues mixed.
Preparation is designed to the heavy tablet of 125mg sheet.
Tablet has gratifying processing performance.
Embodiment 7
Citalopram crystallization direct compression process prepares tablet
Tablet is formed:
Citalopram alkali (16%w/w)
ProSolv?SMCC90(83.3％w/w)
Magnesium stearate (0.7%w/w)
The sieve of 0.3mm is crossed in the citalopram alkali crystallization that derives from embodiment 4, then mixes 3 minutes with ProSolvSMCC90 in the Turbula blender.Adding magnesium stearate immediately continued mixed 30 seconds again.
Use one-shot head Korsch EK0 tablet machine tabletting.
The tablet properties parameter:
Sheet intensity, mg:20
Theoretical sheet is heavy, mg:125
Diameter, mm:7
Shape: peplos, specific
Comprcssive strength: 61.6N
Disintegration time, min:＜1
Brittleness: 0.1%
Average sheet is heavy: 125.4
Weight differential: 0.22% relative standard deviation
The gained tablet has gratifying processing performance.
Claims (33)
1. the solid unit dosage form that contains citalopram, it is characterized in that be by with citalopram alkali or its officinal salt and pharmaceutically acceptable excipient directly compacting get, or above-mentioned mixture is packed in the hard capsules.
2. solid unit dosage form as claimed in claim 1 is characterized in that it is the tablet that forms by with citalopram alkali or its officinal salt and pharmaceutically acceptable excipient direct compression.
3. solid unit dosage form as claimed in claim 1 is characterized in that it is to be packed in the hard capsules by the mixture with citalopram alkali or its officinal salt and pharmaceutically acceptable excipient to form.
4. as the described solid unit dosage form of claim 1-3, it is characterized in that not comprising binding agent.
5. as the described solid unit dosage form of claim 1-4, it is characterized in that containing the 2-60% percentage by weight with citalopram alkali active ingredient calculated, preferably 10-40%w/w is more preferably 15-25%w/w.
6. as the described solid unit dosage form of claim 1-5, it is characterized in that containing filler, be selected from lactose, sugar, preferred Sorbitol, mannitol, glucose and/or sucrose, calcium phosphate, preferred binary, ternary, moisture and/or water-free, starch, modified starch, microcrystalline Cellulose, calcium sulfate, and/or calcium carbonate.
7. solid unit dosage form as claimed in claim 6 is characterized in that described filler is a microcrystalline Cellulose, as ProSolv SMCC90 or Avicel PH 200.
8. as the described solid unit dosage form of claim 1-7, it is characterized in that containing lubricant, be selected from stearate (magnesium, calcium, sodium), stearic acid, wax, hydrogenated vegetable oil, Pulvis Talci and colloidal silicon dioxide.
9. solid unit dosage form as claimed in claim 8 is characterized in that described lubricant is magnesium stearate or calcium stearate.
10. as the described solid unit dosage form of claim 1-9, it is characterized in that it is substantially free of lactose.
11., it is characterized in that active component is a citalopram alkali as the described solid unit dosage form of claim 1-10.
12., it is characterized in that active component is the hydrobromate or the hydrochlorate of citalopram as the described solid unit dosage form of claim 1-10.
13. solid unit dosage form as claimed in claim 12 is characterized in that active component is the hydrobromate of citalopram.
14. as the described solid unit dosage form of claim 12-13, it is characterized in that active component is a crystal form, its mean diameter is less than 20 μ m.
15. as the described solid unit dosage form of claim 12-13, it is characterized in that active component is a crystal form, its mean diameter at least 40 μ m preferably at 40-200 μ m, are more preferably the m at 45-150 μ, most preferably are at 50-100 μ m.
16. the crystal of the officinal salt of citalopram is characterized in that its crystalline mean diameter at least 40 μ m.
17. crystal as claimed in claim 16 is characterized in that described crystal is the hydrobromate or the hydrochlorate of citalopram.
18. crystal as claimed in claim 17 is characterized in that described crystal is the hydrobromate of citalopram.
19. as the described crystal of claim 16-18, it is characterized in that described crystal mean diameter,, be more preferably m at 50-120 μ preferably at 45-150 μ m at 40-200 μ m.
20. preparation has the crystalline method of citalopram officinal salt of at least 40 μ m mean diameters, the solution system that it is characterized in that being dissolved in the citalopram officinal salt of appropriate solvent at first is cooled to second temperature from first temperature, the crystal seed that adds described citalopram salt then, under second temperature, keep a period of time, control is cooled to the 3rd temperature and separates out crystal, separates with conventional solid/liquid separation technique.
21. as method as described in the claim 20, it is characterized in that described crystal mean diameter,, be more preferably m at 50-100 μ preferably at 45-150 μ m at 40-200 μ m.
22., it is characterized in that described dissolved substances is citalopram hydrobromate or hydrochlorate as method as described in the claim 20-21.
23., it is characterized in that described dissolved substances is the citalopram hydrobromate as method as described in the claim 22.
24., it is characterized in that described solvent system comprises one or more alcohol and optional water as method as described in the claim 20-23.
25., it is characterized in that solvent system is the mixed solvent of first alcohol and water as method as described in the claim 24.
26. as method as described in the claim 25, the weight ratio that it is characterized in that the first alcohol and water is 5: 1 to 50: 1, preferably 10: 1 to 30: 1, is more preferably 15: 1 to 25: 1.
27., it is characterized in that solvent and solute weight ratio are 0.5: 1 to 5: 1, preferably 0.7: 1 to 2: 1, are more preferably 0.9: 1 to 1.5: 1 as method as described in the claim 20-26.
28. as method as described in the claim 20-27, it is characterized in that described first temperature be 50 ℃ to the solvent system reflux temperature, preferably 60 ℃ to reflux temperature, be more preferably at 64 ℃ to reflux temperature.
29. as method as described in the claim 20-28, it is characterized in that described second temperature in 20-40 ℃ of scope, preferably in 25-35 ℃ of scope.
30. as method as described in the claim 20-29, it is characterized in that described standing time at 30 minutes to 7 days, preferably 1 hour to 4 days, more preferably 12-36 hour.
31. as method as described in the claim 20-30, it is characterized in that described the 3rd temperature in 0-20 ℃ of scope, preferably in 5-15 ℃ of scope.
32., it is characterized in that described control cooling is progressively cooling in 5 minutes to 6 hours time range, preferably at 15 minutes to 4 hours, is more preferably 30 minutes to 2 hours as method as described in the claim 20-31.
33., it is characterized in that described crystal isolating method from mother solution with the citalopram officinal salt is to filter as method as described in the claim 20-32.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200001202 | 2000-08-10 | ||
| DKPA200001202 | 2000-08-10 | ||
| DKPA200001614 | 2000-10-27 | ||
| DKPA200001614 | 2000-10-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1446089Atrue CN1446089A (en) | 2003-10-01 |
Family
ID=26068858
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN01813752APendingCN1446089A (en) | 2000-08-10 | 2001-07-30 | Pharmaceutical composition containing citalopram |
Country Status (34)
| Country | Link |
|---|---|
| EP (1) | EP1318805A2 (en) |
| JP (1) | JP2003531153A (en) |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100353939C (en)* | 2006-01-05 | 2007-12-12 | 昆明积大制药有限公司 | Antidepressant composition containing citalopram and cyclodextrin |
| CN106389374A (en)* | 2015-08-03 | 2017-02-15 | 深圳信立泰药业股份有限公司 | Pharmaceutical composition containing LCZ696 and preparation method of pharmaceutical composition |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2353693C (en)* | 2000-08-10 | 2003-07-22 | H. Lundbeck A/S | Pharmaceutical composition containing citalopram |
| AU2001100195B4 (en)* | 2001-01-05 | 2001-12-20 | H Lundbeck As | Pharmaceutical composition containing citalopram. |
| GB0206708D0 (en)* | 2002-03-21 | 2002-05-01 | Cipla Ltd | Pharmaceutical salts |
| US6812355B2 (en) | 2002-10-22 | 2004-11-02 | Sekhsaria Chemicals Limited | Process for the manufacture of citalopram hydrobromide from 5-bromophthalide |
| JP4658613B2 (en)* | 2002-12-23 | 2011-03-23 | ハー・ルンドベック・アクチエゼルスカベット | Escitalopram hydrobromide and process for producing the same |
| WO2004103361A2 (en)* | 2003-05-20 | 2004-12-02 | Ranbaxy Laboratories Limited | A pharmaceutical dosage form of citalopram |
| HU227491B1 (en)* | 2003-11-25 | 2011-07-28 | Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag | Tablet containing citalopram hydrogen bromide |
| WO2006038217A1 (en)* | 2004-10-05 | 2006-04-13 | Strides Acrolab Limited | An improved drug delivery system of citalopram hydrobromide and process for producing the same |
| US7834201B2 (en) | 2005-06-22 | 2010-11-16 | H. Lundbeck A/S | Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base |
| GB2480191A (en)* | 2007-02-02 | 2011-11-09 | Ubiquisys Ltd | Determining the location of a base station |
| WO2022153262A1 (en)* | 2021-01-18 | 2022-07-21 | Anton Frenkel | Pharmaceutical dosage form |
| CN120583942A (en) | 2023-02-07 | 2025-09-02 | 拉塞·凯那司特 | An immediate-release oral pharmaceutical dosage form of escitalopram or its racemate with increased API content |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US1358915A (en)* | 1919-04-14 | 1920-11-16 | Amici Domenico | Aeroplane |
| GB1358915A (en)* | 1971-09-13 | 1974-07-03 | Merck & Co Inc | Directly compressed tablet and composition therefor |
| GB1526331A (en) | 1976-01-14 | 1978-09-27 | Kefalas As | Phthalanes |
| GB8419963D0 (en) | 1984-08-06 | 1984-09-12 | Lundbeck & Co As H | Intermediate compound and method |
| GB8814057D0 (en)* | 1988-06-14 | 1988-07-20 | Lundbeck & Co As H | New enantiomers & their isolation |
| US5296507A (en)* | 1990-09-06 | 1994-03-22 | H.Lundbeck A/S | Treatment of cerbrovascular disorders |
| EP0714663A3 (en)* | 1994-11-28 | 1997-01-15 | Lilly Co Eli | Potentiation of a drug by a serotonin 1A receptor antagonist |
| GB9714841D0 (en)* | 1997-07-14 | 1997-09-17 | Smithkline Beecham Plc | Treatment method |
| GB2357762B (en)* | 2000-03-13 | 2002-01-30 | Lundbeck & Co As H | Crystalline base of citalopram |
| US6977306B2 (en) | 2000-05-02 | 2005-12-20 | Sumitomo Chemical Company, Limited | Citalopram hydrobromide crystal and method for crystallization thereof |
| CA2353693C (en)* | 2000-08-10 | 2003-07-22 | H. Lundbeck A/S | Pharmaceutical composition containing citalopram |
- 2001
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- 2001-07-30JPJP2001577732Apatent/JP2003531153A/ennot_activeWithdrawn
- 2001-07-30WOPCT/DK2001/000520patent/WO2001080619A2/ennot_activeApplication Discontinuation
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- 2001-07-30KRKR10-2003-7001683Apatent/KR20030024833A/ennot_activeCeased
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- 2001-07-31GBGB0118579Apatent/GB2368014B/ennot_activeExpired - Fee Related
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- 2001-08-07ATAT0062401Upatent/AT5744U1/ennot_activeIP Right Cessation
- 2001-08-08CHCH01469/01Apatent/CH694242A5/ennot_activeIP Right Cessation
- 2001-08-08CHCH01422/03Apatent/CH694241A5/ennot_activeIP Right Cessation
- 2001-08-08FRFR0110586Apatent/FR2812811B1/ennot_activeExpired - Fee Related
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- 2001-08-09NONO20013891Apatent/NO20013891L/ennot_activeApplication Discontinuation
- 2001-08-09ESES200101877Apatent/ES2172481B2/ennot_activeExpired - Fee Related
- 2001-08-09FIFI20010303Upatent/FI5176U1/enactive
- 2001-08-10BEBE2001/0537Apatent/BE1013559A6/ennot_activeIP Right Cessation
- 2001-08-10NLNL1018741Apatent/NL1018741C1/ennot_activeIP Right Cessation
- 2003
- 2003-02-21BGBG107578Apatent/BG107578A/enunknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100353939C (en)* | 2006-01-05 | 2007-12-12 | 昆明积大制药有限公司 | Antidepressant composition containing citalopram and cyclodextrin |
| CN106389374A (en)* | 2015-08-03 | 2017-02-15 | 深圳信立泰药业股份有限公司 | Pharmaceutical composition containing LCZ696 and preparation method of pharmaceutical composition |
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