An amorphous form of tiagabine hydrochloride, an N-(butenylsubstituted)-azaheterocyclic carboxylic acid, process for preparing the amorphous form, pharmaceutical compositions comprising the amorphous form, and its use as a selective GABA'ergic activity enhancer for the treatment of conditions such as epilepsy, are provided.
Chemically, tiagabine is R(-)-N-(4.4-di(3-methyithien-2-yl)but-3-enyl)-nipecotic acid and is known from U.S. Patent No. 5,010,090. It is an amino acid derivative exhibiting GABA (y-aminobutyric 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. Tiagabine hydrochloride has been reported to exist in two crystalline forms- monohydrate and anhydrous, as described in US 5,354,760 and US 5,958,951, respectively. The two forms may interconvert under certain temperature or humidity conditions as per McGraw et al. Derwent abst 95-05633, 1994.
In one aspect, a new form of tiagabine hydrochloride, the amorphous form, is provided.
In another aspect, process for preparing the amorphous form of tiagabine hydrochloride is provided comprising spray drying a solution of tiagabine hydrochloride. In a further aspect, a pharmaceutical composition comprising the amorphous form of tiagabine hydrochloride, along with pharmaceutically acceptable excipients is provided. In yet another aspect, a method of inhibiting uptake of gamma-amino butyric acid in a subject in need of such treatment comprising administering a therapeutically effective amount of amorphous form of tiagabine hydrochloride, is provided.
Figure 1, as shown in the accompanied drawings, is an X-ray diffraction spectrum of
amorphous form of tiagabine hydrochloride.
Figure 2, as shown in the accompanied drawings, is an IR spectrum of amorphous form of
tiagabine hydrochloride using potassium bromide pellets.
Figure 3, as shown in the accompanied drawings, is a DSC graph of amorphous form of
tiagabine hydrochloride.

The amorphous form of tiagabine hydrochloride is characterized by its non-crystalline nature. Additionally, it may be characterized by X-ray powder diffraction spectrum, IR spectrum or DSC graph as shown in Figures 1, 2 and 3 of the accompanied drawings.
A process for preparing the amorphous form of tiagabine hydrochloride is provided comprising recovering amorphous tiagabine hydrochloride from a solution thereof in a suitable solvent by spray drying.
The solution of tiagabine hydrochloride may be obtained by dissolving crystalline tiagabine hydrochloride in a suitable solvent or alternatively a solution of tiagabine hydrochloride may be obtained directly from the last step of a reaction in which tiagabine hydrochloride is formed. Crystalline tiagabine hydrochloride used as a starting material may be any of the forms known in the prior art i.e., monohydrate, anhydrous, solvates or mixtures thereof. Tiagabine hydrochloride can be obtained by methods known in the art, such as processes reported in US 5,010,090, US 5,354,760 and US 5,958,951.
Suitable solvent includes any solvent or solvent mixture in which tiagabine hydrochloride is soluble. Examples of suitable solvents include water, alcohols such as methanol, ethanol, isopropanol, and butanol; aromatic hydrocarbons such as toluene; ketones such as acetone; ethers such as tetrahydrofuran and tert-butymethyl ether; and mixtures thereof.
The spray drying may be accomplished using a spray dryer, which 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 or carbon dioxide.
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 amorphous form of tiagabine hydrochloride exhibits GABA uptake inhibitory properties and exerts useful pharmacological effects on the central nervous system, i.e., a selective enhancement of GABA activity. Thus, a method of inhibiting uptake of gamma-ammo butyric acid in a subject in need of such treatment comprising administering a

therapeutically effective amount of amorphous tiagabine hydrochloride. Amorphous tiagabine hydrochloride may be used for 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.
The amorphous form of tiagabine hydrochloride may be administered as part of a pharmaceutical composition. Accordingly, in a further aspect, pharmaceutical composition may be produced that comprise an effective amount of amorphous form of tiagabine hydrochloride and pharmaceutically acceptable carriers, diluents or excipients and optionally other therapeutic ingredients. The amorphous form of tiagabine hydrochloride may be conventionally formulated into tablets, capsules, suspensions, dispersions, injectables, creams, ointments, gels, solutions, transdermal patches, aerosols and other pharmaceutical forms. Any suitable route of administration may be employed for example topical, peroral or parental.
The pharmaceutical carrier employed may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, corn and/or potato starch, amylose, silicic acid, fatty acid monoglycerides and diglycendes, pentaerythritol fatty acid esters, magnesium stearate and stearic acid. Examples of liquid carriers are salt solutions, syrup, alcohols, polyethylene glycols, polyhydroxy ethoxylated castor oil, peanut oil, olive oil and water. Similarly, the carrier or diluent may include any time delay material well known to the art, such as glyceryl monostearate, glyceryl distearate, hydroxymethylcellulose and polyvinylpyrrolidone alone or mixed with a wax.
If a solid carrier for oral administration is used, the preparation can be tabletted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier will vary widely, but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may appear in the form of syrup, emulsion, soft gelatin capsule or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension.

The pharmaceutical compositions of this invention can be made following the conventional techniques of the pharmaceutical industry involving mixing, granulating and compressing or variously mixing and dissolving the ingredients as appropriate to give the desired end product
The composition is usually presented as a unit dose composition containing from 1 to 200 mg, for example 2, 4, 8, 12, or 16 mg of tiagabine hydrochloride. 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.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as diluents, binders, lubricants, preservatives, disintegrants, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers, coloring agents, flavoring agents and the like, which do not deleteriously react with the active compound.
In the following section embodiments are described by way of example to illustrate the process of invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of this example would be evident to persons ordinarily skilled in the art.
METHODS Powder XRD
X-Ray Difractometer, Rigaku Coorperation, 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
Wavelength: 1.5406 A
FT-IR
Instrument: Perkin EElmer, Spectrum 1 SCAN: 16scans, 4.0 cm-1

according to the USP 25, general test methods page 1920, infrared absorption spectrum by potassium bromide pellet method.
DSC
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:
Crystalline tiagabine hydrochloride (50g) was dissolved in methanol (250 ml) at 25 to 30° C. The clear solution thus obtained was filtered through hyflo bed to remove any suspended particles and subjected to spray drying in mini spray dryer (Buchi Model 190). Spray drier was set such as to have 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 3-4 ml/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 KF) HPLC purity = 98 %
Powder XRD. IR and DSC were similar to those shown in Figures 1, 2 and 3 respectively of the accompanied drawings.