CN1634869A - Novel pregabalin crystalline form and its preparing process - Google Patents
Novel pregabalin crystalline form and its preparing process Download PDFInfo
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- CN1634869A CN1634869A CN 200410096903 CN200410096903A CN1634869A CN 1634869 A CN1634869 A CN 1634869A CN 200410096903 CN200410096903 CN 200410096903 CN 200410096903 A CN200410096903 A CN 200410096903A CN 1634869 A CN1634869 A CN 1634869A
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- lyrica
- crystal formation
- pharmaceutical composition
- pregabalin
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- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 title claims abstract description 75
- 229960001233 pregabalin Drugs 0.000 title abstract description 23
- 238000000034 method Methods 0.000 title description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 6
- 229910002483 Cu Ka Inorganic materials 0.000 claims abstract description 4
- 230000005855 radiation Effects 0.000 claims abstract description 4
- 239000013078 crystal Substances 0.000 claims description 56
- 229940009697 lyrica Drugs 0.000 claims description 52
- 230000015572 biosynthetic process Effects 0.000 claims description 29
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 9
- 239000002775 capsule Substances 0.000 claims description 9
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 7
- 239000013543 active substance Substances 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000003826 tablet Substances 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 239000008187 granular material Substances 0.000 claims description 4
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 3
- 239000003814 drug Substances 0.000 abstract description 7
- 206010015037 epilepsy Diseases 0.000 abstract description 3
- 208000004296 neuralgia Diseases 0.000 abstract description 3
- 208000021722 neuropathic pain Diseases 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 7
- 239000000080 wetting agent Substances 0.000 description 7
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 6
- 239000000825 pharmaceutical preparation Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 229960002870 gabapentin Drugs 0.000 description 3
- -1 lyrica compound Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 206010013786 Dry skin Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000004567 concrete Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a novel crystalline form of pregabalin drug for treating epilepsy and neuropathic pain and its preparation method. Compared to others pregabalin with agraphitic form and other forms, pregabalin with the novel crystalline form has good stability and is suitable for mass production. Pregabalin with the novel crystalline form uses Cu-Ka radiation and its X-ray powder diffraction has characteristic peak at 9.5(9.3), 12.3(7.2), 16.7(5.3), 18.4(4.8), 19.9(4.5) and 23.3(3.8) with the coordinate of 2-theta and interplanar spacing (d).
Description
Technical field:
The present invention relates to a kind of new crystal for the treatment of the crystal habit, particularly lyrica of epilepsy, neuropathic pain medicine, contain its composition and method of making the same.
Background technology:
The chemical name of lyrica (pregabalin) is (+)-4-amino-3 (S)-isobutyl-butyric acid.Lyrica is a kind of γ-An Jidingsuan (GABA) receptor antagonist, and (gabapentin) is similar with gabapentin, also is 3 alkyl substituents of GABA, but compares with gabapentin that this product has advantages such as dosage is low, medicining times is few, side effect is little.Clinical study is used for the treatment of diseases such as epilepsy, neuropathic pain and other anxiety, depression.Relevant information discloses to be had: world patent WO9638405, and WO9640617, WO04054565, WO03066040, WO03061656, WO03020273; Drugs of the Future1999,24 (8): 826～870.The open report of no relevant lyrica crystal formation in the existing document.
Summary of the invention
The invention provides a kind of lyrica compound of crystal habit, the lyrica of this crystal habit is compared with the lyrica of noncrystalline form and other forms, has good stability, is fit to scale operation, help the operation in the preparation process, advantages such as controllable product quality.
Lyrica crystal formation with good stability of the present invention be with lyrica with a certain proportion of pure water mixed solvent heating for dissolving, filtered while hot is cooled to the certain temperature crystallization, filters the lyrica crystallization of a kind of new shape that forms after the vacuum-drying.The lyrica of this crystal formation uses the Cu-Ka radiation, X-ray powder diffraction with 2 θ angles and spacing (d value) expression has characteristic peak about 9.5 (9.3), 12.3 (7.2), 16.7 (5.3), 18.4 (4.8), 19.9 (4.5) and 23.3 (3.8), as shown in Figure 1.
Lyrica crystal formation of the present invention forms in preparation lyrica product process, and the ratio of lyrica crystal formation in product is can reach purpose of the present invention more than 50%, preferably more than 70%, more preferably more than 85%.
The present invention also provides a kind of method for preparing lyrica crystal formation of the present invention.This method may further comprise the steps:
(1) with lyrica with 1～100 times of pure water mixed solvent heating for dissolving;
(2) filtered while hot, the filtrate cooling crystallization;
(3) filter 35～45 ℃ of vacuum-dryings.
The volume ratio of alcohol to water of pure water mixed solvent is 0.1～20: 1 in step (1), and used alcohol is selected from one or more in the following alcohols: ethanol, propyl alcohol, Virahol, propylene glycol, butanols, isopropylcarbinol, butyleneglycol.
The purity of the lyrica crystal formation that use present method makes can reach more than 80%.
The present invention also provides the pharmaceutical composition made from lyrica crystal formation of the present invention.
The present invention also provides the pharmaceutically active substance that contains lyrica crystal formation of the present invention, this material is the raw material of pharmaceutical compositions, this material is made up of lyrica, wherein contain lyrica crystalline form of 5 of the present invention more than 0%, all the other are the lyrica of non-lyrica crystal formation of the present invention or amorphous kenel, this pharmaceutically active substance shows and the same or analogous physicochemical property of pure or pure substantially lyrica crystal formation of the present invention, this material is also as content of the present invention, particularly preferably be the pharmaceutically active substance that contains the lyrica crystal formation of the present invention more than 80% or 85%, be beneficial to control the quality standard of medicine material of the present invention and pharmaceutical preparation.
The pharmaceutical composition of lyrica crystal formation of the present invention contains the lyrica crystal formation of the present invention and the suitable pharmaceutical excipient of physiology significant quantity, and described composition is the medically acceptable pharmaceutical preparation that lyrica crystal formation and pharmaceutical excipient are mixed with.More particularly, relate to any pharmaceutical dosage forms of taking, as the solid pharmaceutical preparation of tablet, powder, granule and capsule dosage form commonly used.
The invention still further relates to the pharmaceutical composition that contains lyrica crystal formation of the present invention and one or more natural amino acids, described natural amino acid is selected from L-Xie Ansuan, L-L-Ala, D-L-Ala, DL-valine etc., and the existence of natural amino acid has increased the stability of composition.
Pharmaceutical composition of the present invention can contain vehicle commonly used, such as tackiness agent, weighting agent, thinner, tablet agent, lubricant, disintegrating agent, tinting material, seasonings and wetting agent, can carry out dressing to tablet in case of necessity.
In preparation pharmaceutical composition process of the present invention, the wetting agent that can add comprises ethylene glycol, propylene glycol, butyleneglycol, sorbyl alcohol and glycerine and fatty acid ester thereof, and these wetting agents can use separately or use with two or more any combination wherein.Total consumption of wetting agent can be 0.01～30% of a lyrica crystal formation weight of the present invention, or when adding other vehicle when producing pharmaceutical preparation, is 0.01～30% of lyrica crystal formation of the present invention and vehicle gross weight.It is definite that total consumption can add the kind and the consumption of vehicle according to the kind of used wetting agent, the concrete dosage form of solids composition that contains lyrica crystal formation of the present invention and institute.Under any circumstance, wetting agent all should use keeping the significant quantity of stablizing lyrica by the moisture of guaranteeing pharmaceutical preparation.In many cases, total consumption of wetting agent is preferably 0.02～15% of lyrica crystal formation weight of the present invention, or when adding other vehicle when producing pharmaceutical preparation, is 0.02～15% of lyrica crystal formation of the present invention and vehicle gross weight.
Solid composite medicament of the present invention can be by carrying out granulation step, encapsulation step or film-making step and coating steps (if necessary) obtains with the routine dose form successively, is generally tablet, powder, the granule of tablet or surface coatings, the granule or the capsule dosage form of surface coatings.
Pharmaceutical composition of the present invention can be by the preparation of pharmaceutics routine techniques.
Below by stability experiment data declaration excellent results of the present invention.
Test a novel pregabalin crystal form study on the stability
Get the novel pregabalin crystal form sample of same lot number, get and be loaded in right amount in three plates, place following condition (45001x ± 5001x illumination, 45 ℃ of high temperature, relative humidity 92.5% high humidity) to investigate its stable crystal form down respectively, crystal formation assay result as shown in Table 1.
Table one novel pregabalin crystal form study on the stability result
The novel pregabalin crystal form and the novel pregabalin crystal form composition of the present invention's preparation have good stable crystal form, are convenient to produce, transport and store.The results showed that the lyrica of new crystal can keep under normal temperature condition that crystal formation does not change substantially more than 2 years, medicament contg does not reduce, and meets the requirement of medicine fully.
Description of drawings
Fig. 1 is the X-ray powder diffraction of novel pregabalin crystal form.
Fig. 2 is the infrared absorption spectrum of novel pregabalin crystal form.
Embodiment:
The following examples will the present invention will be further explained, but the present invention is not limited only to these embodiment, the scope that these embodiment do not limit the present invention in any way.Some change that those skilled in the art has done within the scope of the claims and adjust also should be thought and belongs to scope of the present invention.
In the 250ml flask, add 5 gram lyricas, add 90ml Virahol and 30ml water, be heated to 70-75 ℃ and make it dissolving, filtered while hot, be cooled to 0 ℃ of crystallization, placement is spent the night, and filters, washed with isopropyl alcohol, 40 ℃ of vacuum-drying 12 hours promptly gets the novel pregabalin crystal form of purity 88%.
In the 250ml flask, add 5 gram lyricas, add 120ml ethanol and 30ml water, be heated to 70-75 ℃ and make it dissolving, filtered while hot, be cooled to 0 ℃ of crystallization, placement is spent the night, and filters, washing with alcohol, 40 ℃ of vacuum-drying 12 hours promptly gets the novel pregabalin crystal form of purity 84%.
Embodiment 3
In the 250ml flask, add 5 gram lyricas, add 80ml propyl alcohol and 30ml water, be heated to 70-75 ℃ and make it dissolving, filtered while hot, be cooled to 0 ℃ of crystallization, placement is spent the night, and filters, propyl alcohol washing, 40 ℃ of vacuum-drying 12 hours promptly gets the novel pregabalin crystal form of purity 85%.
Capsule (the specification: 75mg) of embodiment 4 preparation novel pregabalin crystal forms
Prepare every capsule that contains the 75mg lyrica as follows:
Prescription: lyrica 75g, butyleneglycol 0.75ml makes 1000.
Method: the 75g novel pregabalin crystal form is wetting with the 7.5ml10% butyleneglycol aqueous solution, with mortar said mixture is made granulated powders, 60 ℃ of dryings are sealed adding to depress with capsule filling machine.
Capsule (the specification: 150mg) of embodiment 5 preparation novel pregabalin crystal forms
Prepare every capsule that contains the 150mg lyrica as follows:
Prescription: lyrica 150g, butyleneglycol 1.5ml makes 1000.
Method: the 150g novel pregabalin crystal form is wetting with the 15ml10% butyleneglycol aqueous solution, with mortar said mixture is made granulated powders, 60 ℃ of dryings are sealed adding to depress with capsule filling machine.
The mensuration of embodiment 6 novel pregabalin crystal form physical propertys
Place on the powder diffractometer by the lyrica powder of X-ray powder diffraction method new crystal, with 4 degree/minute scanning speed scan between the 2 θ angles at 2.5～40 degree, use Cu-Ka 40Kv～100mAX x radiation x, X-ray powder diffraction with the lyrica of the new crystal of 2 θ angles and spacing (d value) expression should have characteristic peak about 9.5 (9.3), 12.3 (7.2), 16.7 (5.3), 18.4 (4.8), 19.9 (4.5), 23.3 (3.8) and 23.3 (3.8), as shown in Figure 1.
The infrared spectra of checking novel pregabalin crystal form with the FT-IR spectrophotometer shows that the lyrica of new crystal is at about 2955,2922,2897,1645,1551,1390,1335,1280 and 702 (cm
-1) located key band, as shown in Figure 2.
Below be the explanatory note of Fig. 1:
Claims (10)
1. lyrica crystal formation, it is characterized in that, use the Cu-Ka radiation, the X-ray powder diffraction of representing with 2 θ angles and spacing (d value) has characteristic peak about 9.5 (9.3), 12.3 (7.2), 16.7 (5.3), 18.4 (4.8), 19.9 (4.5) and 23.3 (3.8).
2. a pharmaceutically active substance for preparing the lyrica pharmaceutical composition is made up of lyrica, and the lyrica crystal formation that wherein contains claim 1 is more than 50%.
3. the pharmaceutically active substance of claim 2, the lyrica crystal formation that wherein contains claim 1 is more than 85%.
4. contain the pharmaceutical composition of the lyrica crystal formation of claim 1, it is characterized in that, it contains the described lyrica crystal formation of claim 1 and the appropriate drug vehicle of physiology significant quantity.
5. the pharmaceutical composition of claim 4 is characterized in that, it contains the described pharmaceutically active substance of claim 2 and the appropriate drug vehicle of physiology significant quantity.
6. the pharmaceutical composition of claim 4 is characterized in that, it contains the described pharmaceutically active substance of claim 3 and the appropriate drug vehicle of physiology significant quantity.
7. the pharmaceutical composition of claim 4, its pharmaceutical composition is selected from tablet, powder, granule or capsule.
8. the preparation method of the lyrica crystal formation of claim 1 comprises the steps:
(1) with lyrica with 1～100 times of pure water mixed solvent heating for dissolving;
(2) filtered while hot, the filtrate cooling crystallization;
(3) filter 35～45 ℃ of vacuum-dryings;
9. preparation method according to claim 8 is characterized in that, the described alcohol of step (1) is selected from one or more in the following alcohols: ethanol, propyl alcohol, Virahol, propylene glycol, butanols, isopropylcarbinol, butyleneglycol.
10. preparation method according to claim 8 is characterized in that, the volume ratio of pure water is 0.1～20: 1 in the described pure water mixed solvent of step (1).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410096903 CN1634869A (en) | 2004-12-06 | 2004-12-06 | Novel pregabalin crystalline form and its preparing process |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410096903 CN1634869A (en) | 2004-12-06 | 2004-12-06 | Novel pregabalin crystalline form and its preparing process |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006108151A1 (en) * | 2005-04-06 | 2006-10-12 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of pregabalin |
| CZ297970B6 (en) * | 2005-08-10 | 2007-05-09 | Zentiva, A. S | Process for preparing (S)-3-(aminomethyl)-5-methyl-hexanoic acid (pregabalin) |
| WO2008040935A1 (en) * | 2006-10-07 | 2008-04-10 | Pliva Hrvatska D.O.O. | New polymorphic forms of pregabalin |
| US7446220B2 (en) | 2005-09-19 | 2008-11-04 | Teva Pharmaceutical Industries Ltd. | Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid |
| US7462738B2 (en) | 2006-05-24 | 2008-12-09 | Teva Pharmaceutical Industries Ltd. | Processes for the preparation of R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid and salts thereof |
| US7462737B2 (en) | 2005-05-10 | 2008-12-09 | Teva Pharmaceutical Industries Ltd. | Pregabalin free of isobutylglutaric acid and a process for preparation thereof |
| US7488846B2 (en) | 2005-04-11 | 2009-02-10 | Teva Pharmaceuical Industries Ltd. | Pregabalin free of lactam and a process for preparation thereof |
| EP2067768A1 (en) | 2007-12-03 | 2009-06-10 | Dipharma Francis S.r.l. | A process for the preparation of (S)(+)-3-(aminomethyl)-5-methylhexanoic acid |
| US7619112B2 (en) | 2005-05-10 | 2009-11-17 | Teva Pharmaceutical Industries Ltd. | Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid |
| US7763749B2 (en) | 2005-05-10 | 2010-07-27 | Teva Pharmaceutical Industries Ltd. | Method for the preparation of Pregabalin and salts thereof |
| US8097754B2 (en) | 2007-03-22 | 2012-01-17 | Teva Pharmaceutical Industries Ltd. | Synthesis of (S)-(+)-3-(aminomethyl)-5-methyl hexanoic acid |
| CN103145571A (en) * | 2013-03-27 | 2013-06-12 | 李兴惠 | Crystal form of derivative of aminomethyl caproic acid |
-
2004
- 2004-12-06 CN CN 200410096903 patent/CN1634869A/en active Pending
Cited By (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7417165B2 (en) | 2005-04-06 | 2008-08-26 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of pregabalin |
| WO2006108151A1 (en) * | 2005-04-06 | 2006-10-12 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of pregabalin |
| US7488846B2 (en) | 2005-04-11 | 2009-02-10 | Teva Pharmaceuical Industries Ltd. | Pregabalin free of lactam and a process for preparation thereof |
| US7763749B2 (en) | 2005-05-10 | 2010-07-27 | Teva Pharmaceutical Industries Ltd. | Method for the preparation of Pregabalin and salts thereof |
| US7678938B2 (en) | 2005-05-10 | 2010-03-16 | Teva Pharmaceutical Industries Ltd. | Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid |
| US7619112B2 (en) | 2005-05-10 | 2009-11-17 | Teva Pharmaceutical Industries Ltd. | Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid |
| US7462737B2 (en) | 2005-05-10 | 2008-12-09 | Teva Pharmaceutical Industries Ltd. | Pregabalin free of isobutylglutaric acid and a process for preparation thereof |
| CZ297970B6 (en) * | 2005-08-10 | 2007-05-09 | Zentiva, A. S | Process for preparing (S)-3-(aminomethyl)-5-methyl-hexanoic acid (pregabalin) |
| US7586005B2 (en) | 2005-09-19 | 2009-09-08 | Teva Pharmaceutical Industries Ltd. | Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid |
| US7687656B2 (en) | 2005-09-19 | 2010-03-30 | Teva Pharmaceutical Industries Ltd. | Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid |
| US8212071B2 (en) | 2005-09-19 | 2012-07-03 | Teva Pharmaceutical Industries Ltd. | Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid |
| US7563923B2 (en) | 2005-09-19 | 2009-07-21 | Teva Pharmaceutical Industries Ltd. | Chiral 3-carbamoylmethyl-5-methyl hexanoic acids, key intermediates for the synthesis of (S)-Pregabalin |
| US7465826B2 (en) | 2005-09-19 | 2008-12-16 | Teva Pharmaceutical Industries Ltd. | Chiral 3-carbamoylmethyl-5-methyl hexanoic acids, key intermediates for the synthesis of (S)-pregabalin |
| US7973196B2 (en) | 2005-09-19 | 2011-07-05 | Teva Pharmaceutical Industries Ltd. | Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid |
| US7446220B2 (en) | 2005-09-19 | 2008-11-04 | Teva Pharmaceutical Industries Ltd. | Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid |
| US7470812B2 (en) | 2005-09-19 | 2008-12-30 | Teva Pharmaceutical Industries Ltd. | Chiral 3-carbamoylmethyl-5-methyl hexanoic acids, key intermediates for the synthesis of (S)-Pregabalin |
| US7960583B2 (en) | 2005-09-19 | 2011-06-14 | Teva Pharmaceutical Industries Ltd. | Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid |
| US7851651B2 (en) | 2005-09-19 | 2010-12-14 | Teva Pharmaceutical Industries Ltd. | Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid |
| US7923575B2 (en) | 2005-09-19 | 2011-04-12 | Teva Pharmaceutical Industries Limited | Asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid |
| US7462738B2 (en) | 2006-05-24 | 2008-12-09 | Teva Pharmaceutical Industries Ltd. | Processes for the preparation of R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid and salts thereof |
| WO2008040935A1 (en) * | 2006-10-07 | 2008-04-10 | Pliva Hrvatska D.O.O. | New polymorphic forms of pregabalin |
| US8097754B2 (en) | 2007-03-22 | 2012-01-17 | Teva Pharmaceutical Industries Ltd. | Synthesis of (S)-(+)-3-(aminomethyl)-5-methyl hexanoic acid |
| EP2067768A1 (en) | 2007-12-03 | 2009-06-10 | Dipharma Francis S.r.l. | A process for the preparation of (S)(+)-3-(aminomethyl)-5-methylhexanoic acid |
| CN103145571A (en) * | 2013-03-27 | 2013-06-12 | 李兴惠 | Crystal form of derivative of aminomethyl caproic acid |
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