CRYSTALLINE TIAGABINE HYDROCHLORIDE MONOHYDRATE, ITS PREPARATION AND USE

Abstract: The invention provides crystalline R-isomer of N-(4,4-di(3-methylthien-2-yl)but-3-enyl-nipecotic acid hydrochloride with the generic name Tiagabine hydrochloride, process for its preparation, compositions containing the same and its therapeutic use as anti-epileptic agent.

Description: Crystalline Tiagabine hydrochloride monohydrate, its preparation and use This invention relates to crystalline Tiagabine and in particular to its monohydrate, its preparation and its use as a therapeutic agent. Danish Patent no. 156398 discloses a class of novel compounds that exhibit gamrna-aminobutyric acid-uptake (GABA-uptake) inhibitory properties and therefore said compounds are valuable for therapeutic use in the treat¬ ment of epilepsy and other CNS related diseases. In Example 2 of Danish Patent 156398 the preparation of N-(4,4-di(3-methylthien-2-yl)-but-3-enyl)nipecotic acid hydrochloride is described. In C. Braestrup et. al. , Int. Congr. Ser.-Exerpta Med., 1987, 750 (Pharmacology), 125-8(Ref. 1)), various ste- reo-isomers of said compound are mentioned. In Ref. (1) it is described that N- (4,4-di(3-methyl- thien-2-yl)-but-3-enyl)nipecotic acid hydrochloride is available in its R,S-, S- and R-form and that the R- isomer is the preferred form due to better inhibitory 3 effect of H-GABA-uptake into rat forebrain synaptoso- mes. In the present invention the R-isomer of N-(4,4-di(3- methylthien-2-yl)but-3-enyl-nipecotic acid is referred to by its generic name of Tiagabine (proposed INN). In Danish Patent 156398 the preferred salts of N-(4,4- di(3-methylthien-2-yl)-but-3-enyl)nipecotic acid are described. In example 2 of the same patent the most preferred salt of N-(4,4-di(3-methylthien-2-yl)-but-3-enyl)nipecotic acid is indicated to be the hydrochloride. Further, it is described that the final crystallization of the hydrochloride salt takes place with ethyl ace¬ tate as the crystallizing solvent. The method of preparation as described in the Danish Patent 156398 is applicable also for the crystalliza- tion of the preferred stereochemical form of the com¬ pound, the R-isomer. This method of preparation is ra¬ ther labourous because purification by column chromato- graphy has been be applied before a crystalline com¬ pound could be obtained. This kind of purification is rather expensive and unwanted in a commercial produc¬ tion process. Furthermore analysis has shown that products manufac¬ tured by this process contain unwanted amounts of the crystallizing solvent, ethyl acetate. Use of alternative organic solvents such as acetonitri- le, butyl acetate, toluene, acetone, dichloromethane etc. also gives products containing various amounts of the used crystallizing solvent. These solvents are unwanted because they are either toxic to humans or may give rise to interaction-reac¬ tions with other ingredients in the pharmaceuical pre- paration, resulting in low stability of the dosage form. Further it has been found that the compound is heavily soluble in the applied organic solvents, which is very inconvenient when working on larger scale. It has now been discovered that these disadvantages can be avoided by a new process giving crystals in a manner which is reproducible in a production scale. The present invention provides R(- )N-4,4-di(3-methyl- thien-2-yl)-but-3-enyl nipecotic acid hydrochloride monohydrate crystals as a novel material, in particular in pharmaceutically acceptable form. It has now been found that water can be used as a crys¬ tallizing solvent for this compound giving very repro- ducible results of a monohydrate crystal form. These products are stable under normal storage conditions and is very applicable for the pharmaceutical formula¬ tions as the only residural solvent in the product is water. Tiagabine hydrochloride as monohydrate crystals is stable and non- hygroscopic. It is characterized by an X-ray powder diffractogram as shown in fig. 1. A typi¬ cal H-NMR spectrum is shown in fig. 2 and a typical IR-spectrum of the crystals in KBr is shown in fig. 3. The DSC profile of the monohydrate is shown in fig. 4. Under dissication conditions the bound water may partly be removed, but on exposure to normal humi- dity the crystals very rapidly will take up water to reform the monohydrate. The present invention also provides a process for pro¬ ducing crystalline Tiagabine hydrochloride monohydrate, which comprises crystallizing Tiagabine hydrochloride monohydrate from an aqueous solution containing from one to several equivalents of hydrogenchloride. The so- lution may be obtained either by dissolving the com¬ pound as the amphoteric salt or by dissolving the hydro¬ chloride of the compound. Hydrochloric acid can be ad¬ ded either as a diluted or as a concentrated solution in the range of 1-10 equivalents to the aqueous solu¬ tion of Tiagabine. The aqueous solution of Tiagabine is usually made at temperatures ranging from 40 -75 C. Higher temperatures may be used, but is not necessary as yields are very high using the above mentioned range. The solution may be seeded in order to start the crystallization, but this can also be omitted. The aqueous solution of Tiagabine can further be obtained by acid catalyzed hydrolysis of R(-)-ethyl-N- (4,4-di(3-methylthien-2-yl)-but-3-enyl)nipecotate in aqueous solution. The acid catalyzed hydrolysis can be carried out by using e.g. phosphoric acid, sulfuric acid, hydrobromic acid, hydrochloric acid or hydroiodic acid, preferably hydrochloric acid. The crystals can be isolated from the solution by nor¬ mally used procedures, such as filtration, centrifuga- tion etc. The crystals can be rinsed by pure water or a diluted hydrochloric acid solution before drying. Drying can be performed either under vacuum or at nor¬ mal pressure. The present invention also provides a pharmaceutical composition comprising crystalline Tiagabine monohydra¬ te which comprises crystalline tiagabine monohydrate and a pharmaceutically acceptable carrier. The compositions of this invention are usually adapted for oral administration, but formulations for dissolu¬ tion for parenteral administration are also within the scope of this invention. The composition is usually presented as a unit dose composition containing from 1 to 200 mg, more usually from 2 to 100 mg, for example 2 to 50 mg such as 2, 4, 8, 10, 20, 25 or 30 mg. Such composition is normally taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 4 to 400 mg. Preferred unit dosage forms include tablets or capsu¬ les. The composition of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing. Suitable carriers for use in this invention include a diluent, a binder, a disintegrant, a colouring agent, a flavouring agent and/or a preservative. These agents may be utilized in conventional manner, for example in a manner similar to that already used for clinically used epileptic agents. The invention also provides a method of treatment of epilepsy in mammals including humans which method comprises administering an effective amount of pharma¬ ceutically acceptable crystalline Tiagabine monohydra¬ te. The invention further provides pharmaceutically accept¬ able crystalline Tiagabine hydrochloride monohydrate for use in the treatment of epilepsy. The following examples illustrate the invention: EXAMPLE 1 A. Crude R( - )-N-(4, 4-di(3-methylthien-2-yl)-but- 3-enyl)nipecotic acid, hydrochloride 1.200 g of R(-)-Ethyl-N-(4,4-di(3-methylthien-2-yl)- but-3-enyl)nipecotate was dissolved in 12 1 of 90% ethanol. 360 ml of 36% aqueous solution of sodium hydroxide was added at room temperature. 10 1 of wa¬ ter was added slowly under good stirring. When all starting materials had been hydrolized, pH was adjust¬ ed to 4.5 with dilute hydrochloric acid. The ethanol was stripped off. The product precipitated as an oil in the water. The oil was taken up in dichlorometha- ne and the water phase was discarded. The organic phase was dried and 0.9 equivalent of dry HC1 was added to the solution at 15 C. After stirring over¬ night the product was recovered by filtration and dried in vacuo at 40 C. Yield: 1170 g of crude crys¬ talline material. B. Crystallization of R(- )-N-(4,4-di(3-methylthien- 2-yl)-but-3-enyl)nipecotic acid, hydrochloride monohydrate 1.050 g of crude product was dissolved in 6000 ml of water at 60 C. The solution was filtered to remove any undissolved matter. 1400 g of IN aqueous hydro¬ chloric acid was added at 60 C. At 45 C the solution was seeded. After 2 h the temperature was lowered to 10 C. The crystalline product was recovered by fil¬ tration and dried in vacuo at 40 C. Yield: 960 g. DSC onsett: 82.6°C. H-NMR: comply HPLC purity: 99.4 X-Ray: comply H 2 0: 4.6% EXAMPLE 2 R( - )-N-(4, 4-di(3-methylthien-2-yl )-but-3-enyl )nipe- cotic acid, hydrochloride monohydrate 220 g of crude R( - )-N-(4, 4-di(3-methylthien-2-yl )- but-3-enyl )nipecotic acid, hydrochloride was dissolv¬ ed at 50°C in 1100 ml of water. At 40°C the solution was seeded and crystallisation started giving a sus- pension of fine crystals. The suspension was cooled to 0 C before filtration. The filtercake was washed with cold water before drying in vacuo at 60 C. Yield: 193 g. HPLC purity: 99.3% EXAMPLE 3 R( - )-N-( 4, 4-di(3-methylthien-2-yl )-but-3-enyl )nipe- cotic acid, hydrochloride monohydrate Dissolve 174 g of crude product in 5200 ml of water at 40-50°C. Add 145 ml of cone, hydrochloride acid (37%) to the solution under good stirring. At 40 C 0.5 g of seed crystals are added. The mixture is stirred for 4 h at 40°C before cooling to 20 C. The solid is filtered and vacuum dried at 40 C overnight. Yield: 140 g. HPLC purity: 99.7% The reproducibility is further illustrated by the fol¬ lowing results (Table 1) where batches (A-G) are crys¬ tallized using different concentrations of the compound and of HC1: TABLE 1 REPRODUCIBILITY OF FROM WATER OF [R(-)-N-(4,4-ά_L(3-met_hylthien-2-yl)-but-3-enyl)nipeootic acid, hydrochloride, mc ohydrate] EXAMPLE 4 R( - )-N-(4,4-di(3-methylthien-2-yl)-but-3-enyl)nipecotic acid, hydrochloride monohydrate 26 g of R(-)-ethyl-N-(4,4-di(3-methylthien-2-yl)-but- 3-enyl )nipecotate, hydrochloride is dissolved in 385 ml of water. Under good stirring is added 5 ml of cone, hydrochloric acid and the solution is heated to reflux for 5-10 hours until the reaction is completed. The solution is concentrated by destilling off 30-50% of the solvent. Extract with 40 ml of toluene. To the aqueous layer is added hydrocloric acid and the solution is cooled to 5 C before the product is filtered off and dried in vacuo at 40°C. Yield: 20 g of R( - )-N-(4,4-di(3- methylthien-2-yl)-but-3-enyl)nipecotic acid, hydro¬ chloride monohydrate. HPLC purity: 99.5% X-Ray: comply H 2 0: 4,6%

Claims: CLAIMS 1. Crystalline (R( - )-N-(4, 4-di(3-methylthien-2-yl)-but- 3-enyl )nipecotic acid, hydrochloride monohydrate (Tia- gabine hydrochloride monohydrate) . 2. Crystalline Tiagabine hydrochloride monohydrate in substantially pure form. 3^ Crystalline Tiagabine hydrochloride monohydrate, having substantially the same X-ray diffractogram as set out in Fig. 1, substantially the same IR spectrum, in a KBr, as set out in Fig. 3, and substantially the same DSC profile as set out in Fig. 4. 4. A process for the preparation of crystalline Tiaga¬ bine hydrochloride monohydrate, which process comprises forming an aqueous solution of Tiagabine hydrochloride and crystallizing Tiagabine hydrochloride monohydrate from the solution. 5. A process for the preparation of crystalline Tiagabine hydrochloride monohydrate comprising acid catalyzed hydrolysis of the ethyl ester of Tiagabine hydrochloride in an aqueous solution followed by cry¬ stallization of Tiagabine hydrochloride monohydrate from the aqueous solution. 6. A pharmaceutical composition comprising Tiagabine hydrochloride monohydrate together with a pharmaceutically acceptable carrier or diluent. 7. A pharmaceutical composition comprising an effec¬ tive anti-epileptic amount of crystalline Tiagabine hydrochloride monohydrate together with a pharmaceuti¬ cally acceptable carrier or diluent. 8. The pharmaceutical composition according to claim 6 or 7 in the form of an oral dosage unit containing from 1 to 200 mg of Tiagabine hydrochloride monohydrate. 9. A method of treating epilepsy in mammals comprising administering an effective amount of crystalline Tia¬ gabine hydrochloride monohydrate. 10. A method of treating epilepsy in mammals comprising administering a pharmaceutical composition according to claim 7. 11. The use of Tiagabine hydrochloride monohydrate for the preparation of a medicament useful in treating epilepsy.

Inventors: CAIN MICHAEL, NIELSEN PETER, PATEL R SUBHASH, PETERSEN HENNING, CAIN, MICHAEL, NIELSEN, PETER, PATEL, R., SUBHASH, PETERSEN, HENNING
Applicants: NOVONORDISK AS, NOVO NORDISK A/S
Application year: 1992
Main classification: C07D409
IPC codes: A61K31, A61P25, C07D409