KR100491636B1 - Modified form of the r(-)-n-[4,4-di(3-methylthien-2-yl)but-3-enyl)-nipecotic acid hydrochloride - Google Patents

Abstract

The present invention provides a pure and stable anhydrous form of R (-)-N- [4,4-di (3-methylthien-2-yl) but-3-enyl) -nifecotic acid hydrochloride.

Description

Modified form of R (-)-N- [4,4-di (3-methylthien-2-yl) but-3-enyl) -nifecortic acid hydrochloride {MODIFIED FORM OF THE R (-)-N- [4,4-DI (3-METHYLTHIEN-2-YL) BUT-3-ENYL) -NIPECOTIC ACID HYDROCHLORIDE}

The present invention relates to the anhydrous crystalline form of R (-)-N- [4,4-di (3-methylthien-2-yl) but-3-enyl) -nifecotic acid hydrochloride, its preparation and use as a therapeutic agent. It is about.

USP 5,010,090 discloses a new class of compounds that exhibit gammaaminobutyric acid uptake (referred to as GABA uptake), and therefore these compounds are of value for therapeutic use in the treatment of epilepsy and other diseases associated with GABA uptake.

In the present invention, R (-)-N- [4,4-di (3-methylthien-2-yl) but-3-enyl) -nifecotic acid is referred to as tiagabine (INN) as a generic name. .

Thiagabine hydrochloride in USP 5,354,760 discloses its monohydrate form.

Methods for transdermal delivery of N- [4,4-di (3-methylthien-2-yl) but-3-enyl) -nifecotic acid and pharmaceutically acceptable derivatives thereof are disclosed in WO 95/31976. It is.

However, monohydrate is stable at normal room temperature under dry and dark conditions, but shows reduced stability at high temperatures. Monohydrate releases water at higher temperatures starting at about 50 ° C and results in a total loss of all water at the melting point of 80-85 ° C. The characteristic of monohydrate is very uncomfortable in the preparation of the compound. Alternative products are described in US Pat. No. 5,010,090 (column 8, line 62), which can be prepared only by labor-intensive methods, as described, using ethyl acetate.

Furthermore, the analysis showed that the product produced by this method contained an undesired amount of crystallization solvent.

Other organic solvents may be used to separate the product, but the organic solvent will often form clathrates, i.e., solvates of thiagabine hydrochloride with each organic solvent.

These solvents are undesirable because they are toxic to humans or may cause interaction-reaction with other components in the pharmaceutical formulation, resulting in low stability of the dosage form.

In addition, the compounds were found to be slowly soluble in the added organic solvent, which is very inconvenient when working on a large scale.

It has now been found that anhydride forms can be obtained from aqueous solutions under special conditions, which allow the anhydrides to be selectively formed with high purity and high recovery.

The anhydride form of tiagabine hydrochloride is non-hygroscopic and thermostable under normal storage conditions.

The anhydride forms of the invention are very applicable to pharmaceutical preparations and are stable under the usual process conditions used.

Thiagabin hydrochloride anhydride is characterized by the typical X-ray powder diffractogram and the typical IR-spectrum of the crystal at KBr. Differential scanning calorimetry (DSC) profiles of anhydrides typically show only one peak and indicate melting of the compound at temperatures between 190 and 200 ° C.

 The present invention also provides a process for the preparation of crystalline anhydrous thigabine hydrochloride, which consists of crystallizing thiagabin hydrochloride from an aqueous hydrochloric acid solution of at least 0.55 M hydrochloric acid, preferably at least 1.3 M hydrochloric acid.

Solutions of tiagabine and hydrochloride are usually made at temperatures above 50 ° C.

Crystallization may be initiated by seeding, but seeding may be omitted because crystallization may be initiated spontaneously.

Crystals can be separated by conventional procedures such as filtration or centrifugation. The crystals are washed with water or with dilute hydrochloric acid and then dried, and drying can be carried out under reduced pressure or under normal pressure at room temperature or at high temperature.

The anhydride form of N- [4,4-di (3-methylthien-2-yl) but-3-enyl) -nifecotic acid hydrochloride, now obtained as described herein, is in monohydrate form in the preparation of a pharmaceutical product. It has been found to solve problems related to. The invention also provides an anhydrous crystalline form of R (-)-N- [4,4-di (3-methylthien-2-yl) but-3-enyl) -nifecotic acid hydrochloride and a pharmaceutically acceptable carrier. It provides a pharmaceutical composition comprising.

Compositions of the present invention are usually made for oral administration, but dissolution aids for parenteral administration, transdermal or sustained release are also within the scope of the present invention.

The composition is usually provided as a unit dosage composition containing 0.1-3000 mg of the compound according to the invention for oral administration. Typical dosages for the treatment of epilepsy vary from 1.0-500 mg per day, preferably 1-1000 mg, more preferably 1-100 mg per day, upon oral or divided into two or three doses.

Preferred unit dosage forms include tablets or capsules in solid form, solutions, suspensions, emulsions, elixirs or capsules containing them, in the form of patches for transdermal administration or sterile injectable solutions.

The composition of the present invention may be prepared by conventional methods of biopharmaceuticals.

Conventional excipients are such pharmaceutically acceptable organic or inorganic carriers suitable for parenteral or oral use that do not adversely react with the active compound.

Examples of such carriers are water, saline solution, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, syrup, peanut oil, olive oil, gelatin, lactose, clay, sucrose, agar, pectin, acacia, amylose, stearic acid Magnesium, talc, silicic acid, stearic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.

Pharmaceutical preparations may be sterile and, if desired, with auxiliaries such as binders, lubricants, preservatives, disintegrants, stabilizers, hydrating agents, emulsifiers, salts affecting osmotic pressure, buffers and / or coloring substances, etc., which do not adversely react with the active compound. Can be mixed.

For parenteral use, injectable solutions or suspensions are particularly suitable and preferably aqueous solutions with active compounds dissolved in polyhydroxylated castor oil.

For oral administration, tablets, dragees or capsules with talc and / or carbohydrate carriers or binders and the like are particularly suitable and the carriers are preferably lactose and / or costach and / or potato starch. Syrups, elixirs and the like can be used when sweet excipients can be used.

Typical tablets that can be prepared by conventional tableting techniques include the following.

Tablet strength, mg 8

Tablet Mass, mg 320

Thiagabin Hydrochloride Anhydride 8.35

Polyethylene Glycol 6000, NF 16.0

Lactose, Anhydrous, NF 279

δ-tocopherol, Ph. Eur. 0.800

Talc, Ph.Eur. 16.0

The present invention also provides a method of treating a disease associated with GABA uptake in a mammal, including human, wherein the method comprises R (-)-N- [4,4-di (3-methylthien-2-yl) but An effective amount of the anhydrous crystalline form of -3-enyl) -nifecotic acid hydrochloride is administered.

The invention also relates to R (-)-N- [4,4-di (3-methylthien-2-yl) but-3-enyl) -nife for therapeutic use in the treatment of epilepsy and other diseases associated with GABA. Provided are pharmaceutically acceptable anhydrous crystalline forms of formic acid hydrochloride.

Example 1

Tiagabine, hydrochloride (anhydrous)

100 g of tiagabine and hydrochloride monohydrate were dissolved in 700 ml of 0.2 N hydrochloric acid at 55 deg. The concentration of hydrochloric acid was adjusted to 1.3 N by addition of concentrated hydrochloric acid. Crystallization of the product started spontaneously during the addition of the acid. Stirring was continued at 50 ° C. for 17 hours. The product was filtered and dried in vacuo to give 95% tiagabine, hydrochloride.

Karl Fisher (K.F.): <1% water

X-ray: consistent with anhydrous crystalline form.

Example 2

Tiagabine, hydrochloride (anhydrous)

Thigabine hydrochloride was dissolved in 7 ml of 0.25 N HCL per gram of thiagabin at 55 ° C. The solution was adjusted to 0.8 N with concentrated hydrochloric acid. Next, 0.5 g / L seed crystals were added to the solution, which was stirred at 52 ° C. for 18 hours. The product was filtered and dried at room temperature to give 85% yield. X-ray coincides with the anhydrous crystalline form.

Example 3

Tiagabine, hydrochloride (anhydrous)

75 g tiagabine, hydrochloride monohydrate was dissolved in 613 ml of water at 65 deg. The solution was filtered and 37 g of concentrated hydrochloric acid diluted in 115 g of water was added. The solution was cooled to 52 ° C. and stirred overnight. The suspension was cooled to 40 ° C. and the product was filtered off. The filter cake was washed twice with 55 g of water and dried in vacuo at 30 ° C.

K.F .: 0% water

X-ray: consistent with anhydrous crystalline form.

DSC: start 193 ° C.

HPLC: 99.9% Purity

Example 4

Tiagabine, hydrochloride (anhydrous)

10 g tiagabine and hydrochloride monohydrate were stirred with 100 mL 1N hydrochloric acid at 70 ° C.

The mixture was cooled to room temperature and stirred overnight to give a suspension of microcrystals.

The product was filtered off, washed with water and dried in vacuo at 40 ° C.

Yield: 9 g-95%

HPLC: 99.9% Purity

DSC (started): 197.8 ° C.

Thermal Gravimetric Analysis (TGA): 0.15% weight loss at 160 ° C

X-ray: consistent with anhydrous crystalline form.

Example 5

Tiagabine, hydrochloride (anhydrous)

In a 1 L flask was charged with 50 g of tiagabine ethyl ester, 750 ml of water and 11 g of concentrated hydrochloric acid. The mixture was heated to reflux for 2 hours and then 400 mL of ethanol / water in total was distilled over 4 hours. After cooling to 55-60 ° C., an additional 37.5 g of concentrated hydrochloric acid was added over a period of 5 minutes. The solution was cooled to 50-52 ° C. and stirred at this temperature for 18 hours. The resulting precipitate was collected by filtration and washed with 20 ml of water. The product was dried under vacuum at room temperature to give 40.5 g of thiagabin, hydrochloride.

Yield: 86%

K.F .: 0.4% water

X-ray: consistent with anhydrous crystalline form

Example 6

Tiagabine, hydrochloride (anhydrous)

In a 1 L flask, 50 g of tiagabine ethyl ester, 575 ml of water and 25 g of concentrated hydrochloric acid were added. The mixture was heated at reflux for 1 hour and then 200 mL of ethanol / water in total was distilled over a period of 4 hours. The reaction solution was cooled to 88 ° C. and then an additional 23.5 g of concentrated hydrochloric acid was added. The solution was gradually cooled to room temperature (22 ° C.) while the reaction was stirred for 18 hours. The resulting precipitate was collected by filtration and washed with 20 ml of water. The product was dried under vacuum at room temperature to afford 42.0 g of tiagabine, hydrochloride.

Yield: 90%

K.F .: 0.1% water

X-ray: consistent with anhydrous crystalline form.

Claims (5)

Anhydrous crystalline form of R (-)-N- [4,4-di (3-methylthien-2-yl) but-3-enyl) -nifecotic acid hydrochloride without bound organic solvents. a) dissolving tiagabine hydrochloride in an aqueous hydrochloric acid solution, b) R (-)-N- [4,4-di (3-methylthien-2-yl) but-3-enyl) -nife according to claim 1, comprising the step of precipitating thiagabine hydrochloride from an aqueous solution of hydrochloric acid. A method for producing anhydrous crystalline form of formic acid hydrochloride, wherein the aqueous hydrochloric acid solution is 1.3 M or more. A pharmaceutical composition for treating epilepsy, comprising a therapeutically effective amount of the crystallization according to claim 1 together with a pharmaceutically acceptable carrier or diluent. The pharmaceutical composition for treating epilepsy according to claim 3, which is in the form of a dosage unit containing about 1.0 to 1500 mg of the active ingredient. A method for preparing a pharmaceutical composition for treating epilepsy, comprising using the crystal salt according to claim 1.