WO2005092886A1 - Process for the preparation of amorphous form of tiagabine - Google Patents

Process for the preparation of amorphous form of tiagabine Download PDF

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Publication number
WO2005092886A1
WO2005092886A1 PCT/IB2005/000809 IB2005000809W WO2005092886A1 WO 2005092886 A1 WO2005092886 A1 WO 2005092886A1 IB 2005000809 W IB2005000809 W IB 2005000809W WO 2005092886 A1 WO2005092886 A1 WO 2005092886A1
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Prior art keywords
tiagabine hydrochloride
tiagabine
hydrochloride
amoφhous form
solution
Prior art date
Application number
PCT/IB2005/000809
Other languages
French (fr)
Inventor
Prosenjit Bose
Pramod Kumar
Yoginder Pal Sachdeva
Shilpi Mittal
Yatendra Kumar
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Ranbaxy Laboratories Limited
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Filing date
Publication date
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Publication of WO2005092886A1 publication Critical patent/WO2005092886A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the field of the invention relates to processes for the preparation of amorphous form of tiagabine hydrochloride.
  • the invention also relates to pharmaceutical compositions that include the amorphous form of tiagabine hydrochloride, and use of said compositions for the treatment of epilepsy and other diseases related to gamma-amino butyric acid uptake (GABA uptake).
  • GABA uptake gamma-amino butyric acid uptake
  • tiagabine is R(-)-N-(4,4-di(3-methylthien-2-yl)but-3-enyl)-nipecotic acid having the structural Formula I. and is l ⁇ iown from U.S.
  • Patent No. 5,010,090 It is an amino acid derivative exhibiting GABA (gamma-amino butyric acid, a neurotransmitter in the central nervous system)-uptake inhibitory properties and exerts useful pharmacological effects on the central nervous system by selectively enhancing the GABA activity.
  • GABA gamma-amino butyric acid, a neurotransmitter in the central nervous system
  • U.S. Patent No. 5,354,760 discloses tiagabine hydrochloride as a monohydrate.
  • U.S. Patent No. 5,958,951 discloses that tiagabine hydrochloride can be isolated as anhydrous. The two forms may interconvert under certain temperature or humidity conditions (McGra et al., Derwent abstr. 1994, 95-05633).
  • amorphous form of tiagabine hydrochloride may have, for example, the X-ray diffraction pattern of Figure 1, infrared spectrum of Figure 2, and differential scanning calorimetry curve of Figure 3.
  • a pharmaceutical composition that includes a therapeutically effective amount of the amorphous form of tiagabine hydrochloride; and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • a process for the preparation of amorphous form of tiagabine hydrochloride may be any suitable pharmaceutically acceptable carriers, excipients or diluents.
  • the process includes obtaining a solution of tiagabine hydrochloride in one or more solvents; and recovering the tiagabine hydrochloride in the amorphous form from the solution thereof by the removal of the solvent.
  • the solvent may be, for example, one or more of lower alkanols, aromatic hydrocarbons, ketones, ethers, water, or mixtures thereof.
  • the lower alkanol may include one or more of primary, secondary and tertiary alcohol having from one to six carbon atoms.
  • the lower alkanol may include one or more of methanol, ethanol, n-propanol, isopropanol and butanol.
  • the aromatic hydrocarbon may include one or more of benzene, toluene, and n- hexane.
  • the ketone may include one or more of acetone, ethyl methyl ketone, methyl isobutyl ketone, and diisobutyl ketone.
  • the tiagabine hydrochloride in an amorphous form may be recovered from the solution by spray drying.
  • the tiagabine hydrochloride in an amo ⁇ hous form may be recovered from the solution by freeze-drying.
  • the process may include further forming of the product so obtained into a finished dosage form.
  • the process may include further drying of the product obtained.
  • the process may produce the amorphous form of the tiagabine hydrochloricTe having the X-ray diffraction pattern of Figure 1, infrared spectrum of Figure 2, and differential scanning calorimetry curve of Figure 3.
  • a method of inhibiting uptake of .gamma- amino butyric acid in a warm-blooded animal comprising administering a therapeutically effective amount of the amorphous form of tiagabine hydrochloride.
  • Figure 1 is an X-ray powder diffraction pattern of amo ⁇ hous form of tiagat>ine hydrochloride.
  • Figure 2 is an infrared spectrum in potassium bromide of amo ⁇ hous form o-f tiagabine hydrochloride.
  • Figure 3 is a differential scanning calorimetry curve of amo ⁇ hous form o f tiagabine hydrochloride.
  • the inventors have developed processes for the preparation of the amoiphoms form of tiagabine hydrochloride.
  • the amo ⁇ hous form is characterized by its X-ray powder diffraction pattern, infrared spectrum and differential scanning calorimetry curve as shown in Figures 1, 2 and 3, respectively.
  • the inventors have developed a process for the preparation of the pure amo ⁇ hous form of tiagabine hydrochloride, by obtaining a solution of tiagabine hydrochloride in one or more of solvents; and recovering the amo ⁇ hous form of tia..gabme hydrochloride by the removal of the solvent.
  • the inventors also have developed pharmaceutical compositions that contain the amo ⁇ hous form of the tiagabine hydrochloride, in admixture with one or more solid or liquid pharmaceutical diluents, carriers, and or excipients.
  • the solution of tiagabine hydrochloride may be obtained by dissolving crystalline tiagabine hydrochloride in a suitable solvent.
  • a solirtion may be obtained directly from the last step of a reaction in which tiagabine hydrochloride is formed.
  • the solution of crystalline tiagabine hydrochloride may be obtained by heating the solvent containing crystalline tiagabine hydrochloride. It may be heated from about 40 °C to about 200 °C, for example from about 50 °C to about 150 °C. It may be heated from about 10 minutes to about 24 hours. The solution may be filtered to remove any undissolved foreign particulate matter.
  • the crystalline tiagabine hydrochloride can be prepared by methods l ⁇ iown in the art, for example processes reported in U.S. Patent Nos. 5,010,090; 5,354,760 and 5,958,951.
  • the term "crystalline tiagabine hydrochloride" includes all polymo ⁇ hic forms, anhydrous, solvates, hydrates, or mixtures thereof.
  • the solvent may be recovered from the solution by a technique which includes, for example, distillation, distillation under vacuum, evaporation, spray drying, freeze drying, filtration, filtration under vacuum, decantation, and centrifugation.
  • the solution may be concentrated to remove the solvent. The concentration can be carried out under vacuum of about 100 to 0.01 mm of Hg.
  • T he solvent may be removed by vacuum distillation of the solution with simultaneous heating the solution at a temperature of about 15 to 55 °C to effect faster removal of the solvent.
  • tiagabine hydrochloride in amo ⁇ hous form is recovered from the solution using a spray drying technique.
  • a Mini-Spray Dryer (Model: Buchi 190, Switzerland) can be used.
  • the Buchi 190 Mini-Spray Dryer operates on the principle of nozzle spraying in a parallel flow, i.e., the sprayed product and the drying gas flow in the same direction.
  • the drying gas can be air or inert gases such as nitrogen, argon and carbon dioxide. In particular, the drying gas can be nitrogen.
  • the gas inlet temperature to the spray drier may range from about 40°C to about 100°C and outlet temperature may range from about 20°C to about 80°C.
  • suitable solvent includes any solvent or solvent mixture in which tiagabine hydrochloride is soluble, including, for example, lower alkanol, aromatic hydrocarbons, ketones, ethers, water, and mixtures thereof.
  • alkanol include those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • Suitable lower alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol.
  • ketones include solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and diisobutyl ketone.
  • aromatic hydrocarbons include solvents such as benzene, toluene and n- hexane.
  • ethers include tetrahydrofuran and ter-butylmethyl ether. Mixtures of all of these solvents are also contemplated.
  • the product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Dryer.
  • the resulting pure amo ⁇ hous form of tiagabine hydrochloride may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. hi these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.
  • the compositions include dosage forms suitable for oral, buccal, rectal, and parenteral (including subcutaneous, intramuscular, and ophthalmic) administration.
  • the oral dosage forms may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions, emulsions, pastes and elixirs.
  • Parenteral dosage forms may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like.
  • the amo ⁇ hous form of tiagabine hydrochloride can be administered for the treatment of pain, anxiety, epilepsy, certain muscular and movement disorders, other neurological disorders; and as a sedative, hypnotic and in adjunctive therapy in the treatment of partial seizures, in a warm-blooded animal.
  • a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.
  • the present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
  • Crystalline tiagabine hydrochloride (50g) was dissolved in methanol (250 ml) at 25 to 30° C. The clear solution thus obtained was filtered through a hyflo bed to remove any suspended particles and subjected to spray drying in a mini spray dryer (Buchi Model 190).
  • the spray drier was set such as to have a nitrogen gas flow rate at 600 NL/hour. Inlet temperature was kept at 80° C and accordingly outlet temperature was 40° to 45° C.
  • Powder XRD, IR and DSC are similar to those shown in Figures 1, 2 and 3, respectively.

Abstract

The present invention relates to processes for the preparation of amorphous form of tiagabine hydrochloride. The invention also relates to pharmaceutical compositions that include the amorphous form of tiagabine hydrochloride, and use of said compositions for the treatment of epilepsy and other diseases related to gamma-amino butyric acid uptake (GABA uptake).

Description

PROCESS FOR THE PREPARATION OF AMORPHOUS FORM OF TIAGABINE Field of the Invention The field of the invention relates to processes for the preparation of amorphous form of tiagabine hydrochloride. The invention also relates to pharmaceutical compositions that include the amorphous form of tiagabine hydrochloride, and use of said compositions for the treatment of epilepsy and other diseases related to gamma-amino butyric acid uptake (GABA uptake). Background of the Invention Chemically, tiagabine is R(-)-N-(4,4-di(3-methylthien-2-yl)but-3-enyl)-nipecotic acid having the structural Formula I. and is lαiown from U.S. Patent No. 5,010,090. It is an amino acid derivative exhibiting GABA (gamma-amino butyric acid, a neurotransmitter in the central nervous system)-uptake inhibitory properties and exerts useful pharmacological effects on the central nervous system by selectively enhancing the GABA activity.
Figure imgf000003_0001
Formula I
Tiagabine has been reported to exist in two crystalline forms. U.S. Patent No. 5,354,760 discloses tiagabine hydrochloride as a monohydrate. U.S. Patent No. 5,958,951 discloses that tiagabine hydrochloride can be isolated as anhydrous. The two forms may interconvert under certain temperature or humidity conditions (McGra et al., Derwent abstr. 1994, 95-05633).
Summary of the Invention In one general aspect there is provided amorphous form of tiagabine hydrochloride. The amorphous form of tiagabine hydrochloride may have, for example, the X-ray diffraction pattern of Figure 1, infrared spectrum of Figure 2, and differential scanning calorimetry curve of Figure 3. In another general aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of the amorphous form of tiagabine hydrochloride; and one or more pharmaceutically acceptable carriers, excipients or diluents. In another general aspect there is provided a process for the preparation of amorphous form of tiagabine hydrochloride. The process includes obtaining a solution of tiagabine hydrochloride in one or more solvents; and recovering the tiagabine hydrochloride in the amorphous form from the solution thereof by the removal of the solvent. The solvent may be, for example, one or more of lower alkanols, aromatic hydrocarbons, ketones, ethers, water, or mixtures thereof. The lower alkanol may include one or more of primary, secondary and tertiary alcohol having from one to six carbon atoms. The lower alkanol may include one or more of methanol, ethanol, n-propanol, isopropanol and butanol. The aromatic hydrocarbon may include one or more of benzene, toluene, and n- hexane. The ketone may include one or more of acetone, ethyl methyl ketone, methyl isobutyl ketone, and diisobutyl ketone. The ether may include one or both of tetrahydrofuran and tert-butylmethyl ether. Removing the solvent may include, for example, one or more of distillation, distillation under vacuum, evaporation, spray drying, freeze-drying, filtration, filtration under vacuum, decantation and centrifugation. The tiagabine hydrochloride in an amorphous form may be recovered from the solution by spray drying. Alternatively, the tiagabine hydrochloride in an amoφhous form may be recovered from the solution by freeze-drying. The process may include further forming of the product so obtained into a finished dosage form. The process may include further drying of the product obtained. The process may produce the amorphous form of the tiagabine hydrochloricTe having the X-ray diffraction pattern of Figure 1, infrared spectrum of Figure 2, and differential scanning calorimetry curve of Figure 3. In another general aspect there is provided a method of inhibiting uptake of .gamma- amino butyric acid in a warm-blooded animal comprising administering a therapeutically effective amount of the amorphous form of tiagabine hydrochloride. The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims. Description of the Drawings Figure 1 is an X-ray powder diffraction pattern of amoφhous form of tiagat>ine hydrochloride. Figure 2 is an infrared spectrum in potassium bromide of amoφhous form o-f tiagabine hydrochloride. Figure 3 is a differential scanning calorimetry curve of amoφhous form o f tiagabine hydrochloride. Detailed Description of the Invention The inventors have developed processes for the preparation of the amoiphoms form of tiagabine hydrochloride. The amoφhous form is characterized by its X-ray powder diffraction pattern, infrared spectrum and differential scanning calorimetry curve as shown in Figures 1, 2 and 3, respectively. The inventors have developed a process for the preparation of the pure amoφhous form of tiagabine hydrochloride, by obtaining a solution of tiagabine hydrochloride in one or more of solvents; and recovering the amoφhous form of tia..gabme hydrochloride by the removal of the solvent. The inventors also have developed pharmaceutical compositions that contain the amoφhous form of the tiagabine hydrochloride, in admixture with one or more solid or liquid pharmaceutical diluents, carriers, and or excipients. In general, the solution of tiagabine hydrochloride may be obtained by dissolving crystalline tiagabine hydrochloride in a suitable solvent. Alternatively, such a solirtion may be obtained directly from the last step of a reaction in which tiagabine hydrochloride is formed. The solution of crystalline tiagabine hydrochloride may be obtained by heating the solvent containing crystalline tiagabine hydrochloride. It may be heated from about 40 °C to about 200 °C, for example from about 50 °C to about 150 °C. It may be heated from about 10 minutes to about 24 hours. The solution may be filtered to remove any undissolved foreign particulate matter. The crystalline tiagabine hydrochloride can be prepared by methods lαiown in the art, for example processes reported in U.S. Patent Nos. 5,010,090; 5,354,760 and 5,958,951. The term "crystalline tiagabine hydrochloride" includes all polymoφhic forms, anhydrous, solvates, hydrates, or mixtures thereof. The solvent may be recovered from the solution by a technique which includes, for example, distillation, distillation under vacuum, evaporation, spray drying, freeze drying, filtration, filtration under vacuum, decantation, and centrifugation. In one aspect, the solution may be concentrated to remove the solvent. The concentration can be carried out under vacuum of about 100 to 0.01 mm of Hg. T he solvent may be removed by vacuum distillation of the solution with simultaneous heating the solution at a temperature of about 15 to 55 °C to effect faster removal of the solvent. In another aspect, tiagabine hydrochloride in amoφhous form is recovered from the solution using a spray drying technique. A Mini-Spray Dryer (Model: Buchi 190, Switzerland) can be used. The Buchi 190 Mini-Spray Dryer operates on the principle of nozzle spraying in a parallel flow, i.e., the sprayed product and the drying gas flow in the same direction. The drying gas can be air or inert gases such as nitrogen, argon and carbon dioxide. In particular, the drying gas can be nitrogen. The gas inlet temperature to the spray drier may range from about 40°C to about 100°C and outlet temperature may range from about 20°C to about 80°C. The term "suitable solvent" includes any solvent or solvent mixture in which tiagabine hydrochloride is soluble, including, for example, lower alkanol, aromatic hydrocarbons, ketones, ethers, water, and mixtures thereof. Examples of alkanol include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable lower alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol. Examples of ketones include solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and diisobutyl ketone. Examples of aromatic hydrocarbons include solvents such as benzene, toluene and n- hexane. Examples of ethers include tetrahydrofuran and ter-butylmethyl ether. Mixtures of all of these solvents are also contemplated. The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Dryer. The resulting pure amoφhous form of tiagabine hydrochloride may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. hi these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients. The compositions include dosage forms suitable for oral, buccal, rectal, and parenteral (including subcutaneous, intramuscular, and ophthalmic) administration. The oral dosage forms may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions, emulsions, pastes and elixirs. Parenteral dosage forms may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like. The amoφhous form of tiagabine hydrochloride can be administered for the treatment of pain, anxiety, epilepsy, certain muscular and movement disorders, other neurological disorders; and as a sedative, hypnotic and in adjunctive therapy in the treatment of partial seizures, in a warm-blooded animal. For the puφose of this disclosure, a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds. The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Methods:
X-Ray Powder Diffraction
X-Ray Difractometer, Rigaku Cooφeration, RU-H3R
Goniometer CN2155A3
X-Ray tube with Cu target anode
Divergence slits 1°, Receiving slit 0.15mm, Scatter slit 1°
Power: 40 KV, 100 mA
Scanning speed: 2 deg/min step: 0.02 deg
Wave length: 1.5406 A
FT-Infrared
Instrument: Perkin Elmer, Spectrum 1
SCAN: 16scans, 4.0 cm"1 according to the USP 25, general test methods page 1920, infrared absoφtion spectrum by potassium bromide pellet method
Differential Scanning Calorimetry
DSC821 e, Mettler Toledo Sample weight: 2-5 mg Temperature range: 25-225° C Heating rate: 10° C/min
Nitrogen 50.0 mL/min
Example 1: Preparation of amoφhous tiagabine hydrochloride
Crystalline tiagabine hydrochloride (50g) was dissolved in methanol (250 ml) at 25 to 30° C. The clear solution thus obtained was filtered through a hyflo bed to remove any suspended particles and subjected to spray drying in a mini spray dryer (Buchi Model 190). The spray drier was set such as to have a nitrogen gas flow rate at 600 NL/hour. Inlet temperature was kept at 80° C and accordingly outlet temperature was 40° to 45° C. Tiagabine hydrochloride was charged in the spray drier at a feed rate of 3-4ml/min and 35 g of white fluffy powder was collected and dried under reduced pressure at 50 to 55° C for 12 hours. Moisture content: 1.5 % w/w (by F) HPLC purity ==98%
Powder XRD, IR and DSC are similar to those shown in Figures 1, 2 and 3, respectively.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

Claims

We Claim:
1. Amoφhous form of tiagabine hydrochloride of Formula I.
Figure imgf000010_0001
Formula I
2. The amoφhous form of tiagabine hydrochloride of claim 1 , wherein the tiagabine hydrochloride has the X-ray diffraction pattern of Figure 1.
3. The amoφhous form of tiagabine hydrochloride of claim 1, wherein the tiagabine hydrochloride has the infrared spectrum of Figure 2.
4. A pharmaceutical composition comprising: a therapeutically effective amount of an amoφhous form of tiagabine hydrochloride; and one or more pharmaceutically acceptable carriers, excipients or diluents.
5. The pharmaceutical composition of tiagabine hydrochloride of claim 1, wherein the tiagabine hydrochloride has the X-ray diffraction pattern of Figure 1.
6. The pharmaceutical composition of tiagabine hydrochloride of claim 1 , wherein the tiagabine hydrochloride has the infrared spectrum of Figure 2.
7. A method of treating epilepsy and other diseases related to gamma-amino butyric acid uptake in a warm-blooded animal comprising administering a pharmaceutical composition that includes the amoφhous form of tiagabine hydrochloride.
8. A process for the preparation of amoφhous form of tiagabine hydrochloride, the process comprising: obtaining a solution of tiagabine hydrochloride in one or more solvents; and recovering the tiagabine hydrochloride in the amoφhous form from the solution thereof by the removal of the solvent.
9. The process according to claim 8, wherein the solvent comprises one or more of lower alkanol, aromatic hydrocarbon, ketone, ether, water, or mixtures thereof.
10. The process of claim 9, wherein the lower alkanol comprises one or more of primary, secondary and tertiary alcohol having from one to six carbon atoms.
11. The process of claim 9, wherein the lower alkanol comprises one or more of methanol, ethanol, n-propanol, isopropanol and butanol.
12. The process of claim 9, wherein the aromatic hydrocarbon comprises one or more of benzene, toluene, and n-hexane.
13. The process of claim 9, wherein the ketone comprises one or more of acetone, ethyl methyl ketone, methyl isobutyl ketone, and diisobutyl ketone.
14. The process of claim 9, wherein the ether comprises one or both of tetrahydrofuran and tert-butylmethyl ether.
15. The process of claim 8, wherein removing the solvent comprises one or more of distillation, distillation under vacuum, evaporation, spray drying, freeze drying, filtration, filtration under vacuum, decantation, and centrifugation.
16. The process of claim 8, wherein the tiagabine hydrochloride in an amoφhous form is recovered from the solution by spray drying.
17. The process of claim 8, wherein the tiagabine hydrochloride in an amoφhous form is recovered from the solution by freeze-drying.
18. The process of claim 8, wherein the tiagabine hydrochloride in an amoφhous form is recovered from the solution by filtration.
19. The process of claim 8, further comprising additional drying of the product obtained.
20. The process of claim 8, further comprising forming the product obtained into a finished dosage form.
21. The process of claim 8, wherein the tiagabine hydrochloride has the X-ray diffraction pattern of Figure 1.
22. The process of claim 8, wherein the tiagabine hydrochloride has the infrared spectrum of Figure 2.
PCT/IB2005/000809 2004-03-29 2005-03-29 Process for the preparation of amorphous form of tiagabine WO2005092886A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006062980A2 (en) * 2004-12-07 2006-06-15 Nektar Therapeutics Stable non-crystalline formulation comprising tiagabine
WO2008021518A2 (en) * 2006-08-18 2008-02-21 Cephalon, Inc. Crystalline forms of tiagabine hydrochloride and processes for the preparation of amorphous tiagabine hydrochloride
WO2008021559A2 (en) * 2006-08-18 2008-02-21 Cephalon, Inc. Crystalline and amorphous forms of tiagabine

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US5010090A (en) * 1985-06-26 1991-04-23 Novo Nordisk A/S. N-(butenyl substituted) azaheterocyclic carboxylic acids
US5354760A (en) * 1991-04-02 1994-10-11 Novo Nordisk A/S Crystalline Tiagabine monohydrate, its preparation and use
WO1997047619A1 (en) * 1996-06-14 1997-12-18 Novo Nordisk A/S Modified form of the r(-)-n-(4,4-di(3-methylthien-2-yl)but-3-enyl)-nipecotic acid hydrochloride

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5010090A (en) * 1985-06-26 1991-04-23 Novo Nordisk A/S. N-(butenyl substituted) azaheterocyclic carboxylic acids
US5354760A (en) * 1991-04-02 1994-10-11 Novo Nordisk A/S Crystalline Tiagabine monohydrate, its preparation and use
WO1997047619A1 (en) * 1996-06-14 1997-12-18 Novo Nordisk A/S Modified form of the r(-)-n-(4,4-di(3-methylthien-2-yl)but-3-enyl)-nipecotic acid hydrochloride

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Title
MCGRAW, SCOTT E.; AMSLER, ROLF; RUSTUM, ABU; ALVAREZ, FRANCISCO J.; NIELSEN, PETER G.: "The identification and characterization of polymorphism in tiagabine HCl bulk drug", PHARMACEUTICAL RESEARCH, & NINTH ANNUAL MEETING OF THE AMERICAN ASSOCIATION OF PHARMACEUTICAL SCIENTISTS, SAN DIEGO, NOV. 6-10, 1994, vol. 11, no. 10, 1994, New York, pages S150, XP009050971 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006062980A2 (en) * 2004-12-07 2006-06-15 Nektar Therapeutics Stable non-crystalline formulation comprising tiagabine
WO2006062980A3 (en) * 2004-12-07 2007-02-08 Nektar Therapeutics Stable non-crystalline formulation comprising tiagabine
WO2008021518A2 (en) * 2006-08-18 2008-02-21 Cephalon, Inc. Crystalline forms of tiagabine hydrochloride and processes for the preparation of amorphous tiagabine hydrochloride
WO2008021559A2 (en) * 2006-08-18 2008-02-21 Cephalon, Inc. Crystalline and amorphous forms of tiagabine
WO2008021518A3 (en) * 2006-08-18 2008-04-24 Cephalon Inc Crystalline forms of tiagabine hydrochloride and processes for the preparation of amorphous tiagabine hydrochloride
WO2008021559A3 (en) * 2006-08-18 2009-04-30 Cephalon Inc Crystalline and amorphous forms of tiagabine

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