Note: Descriptions are shown in the official language in which they were submitted.
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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 the R(-)-N-
(4,4-di(3-methylthien-2-yl)but-3-enyl)-nipecotic acid hydrochloride its prepar-
ation and use as therapeutic agent.
USP 5,010,090 discloses a class of novel compounds that exhibit gamma-
amino butyric acid uptake (referred to as GABA uptake) inhibitory properties
and therefore said compounds are valuable for therapeutic use in the treat-
ment of epilepsy and other diseases related to GABA uptake.
In the present invention the R(-)-N-(4,4-di(3-methylthien-2-yl)but-3-enyl)-
nipecotic acid is referred to by its generic name of Tiagabine (INN).
In USP 5,354,760 Tiagabine hydrochloride is disclosed in its monohydrate
form.
Method for transdermal delivery of N-(4,4-di(3-methylthien-2-yl)-but-3-enyl)-
nipecotic acid and pharmaceutically acceptable derivatives thereof is
disclosed
in WO 95/31976.
However, the monohydrate, which is stable at normal room temperature under
dry and dark conditions, has shown less stability at elevated temperatures.
The monohydrate will give off water at higher temperatures starting at about
50°C and resulting in a total loss of all water at the melting point at
80-85°C.
The features of the monohydrate is very inconvenient in the formulation work
with the compound. The alternative product, which is described in the US
Patent 5,010,090 (column 8, line 62) can only be prepared through a labour
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intensive process as described, using ethyl acetate.
Furthermore analysis has shown that products manufactured by this process
contain unwanted amounts of the crystallizing solvent.
Other organic solvents may be used in the isolation of the product, but
organic solvents will often form chlathrates, i.e. solvates of tiagabine
hydrochloride and the resp. organic solvent.
These solvents are unwanted because they are either toxic to humans or may
give rises to interaction-reactions with other ingredients in the
pharmaceutical
preparation, 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 found that an anhydrate form can be obtained from water
solutions under special conditions, which allow the anhydrate to be formed
selectively and in high purity and recovery.
The anhydrate form of Tiagabine hydrochloride is non-hygroscopic and
thermally stable under normal storage conditions.
The anhydrous form of the present invention is very applicable for the
pharmaceutical formulation and stable under the normal process conditions
used.
The Tiagabine hydrochloride anhydrate is characterized by a specific X-ray
powder diffractogram and a typical lR-spectrum of the crystals in KBr. The
_._. _.. T _ __. _...___._ ..
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Differential Scanning Calorimetry (DSC) profile of the anhydrite is typical of
showing only 1 peak indicating the melting of the compound at temperatures
from 190 to 200°C.
The present invention also provides a process for producing the crystalline
anhydrous Tiagabine hydrochloride, which comprises crystallizing Tiagabine
hydrochloride from an aqueous hydrochloric acid solution in not less than
0.55 M hydrochloric acid concentration, preferably in not less than 1 .3 M
hydrochloric acid concentration.
The solution of Tiagabine and hydrochloride is normally made up at a tempera-
ture above 50°C.
The crystallization may be initiated by seeding, but this can also be omitted
as
the crystallization can start spontaneously.
The crystals can be isolated by conventional procedures such as filtration or
centrifugation. The crystals may be rinsed by water or diluted hydrochloric
acid before drying, which can be performed either under reduced pressure or
at normal pressure at room temperature or higher temperatures.
It has now been found that the anhydrite form of N-(4,4-di(3-methylthien-2-
yl)-but-3-enyl)-nipecotic acid hydrochloride obtained as described in the
present invention will solve the problems related to the monohydrate-form
in the manufacture of the medicinal product. The present invention also
provides pharmaceutical compositions comprising the anhydrous crystalline
form of the R(-)-N-(4,4-di(3-methylthien-2-yl)but-3-enyl)-nipecotic acid
hydrochloride and a pharmaceutically acceptable carrier.
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The compositions of this invention are usually adapted for oral
administration,
but formulations for dissolution for parenteral administration, transdermal
delivery or sustained release delivery are also within the scope of this inven-
tion.
The composition is usually presented as a unit dose composition containing
0.1-3000 mg of a compound in accordance with the invention for oral dosing.
Typical dosage for the treatment of epilepsy would vary between 1.0-500 mg,
preferably between 1-1000 mg per day and more preferably between 1 to
~0 100 mg per day either once or divided in 2 or 3 doses when administered
orally.
Preferred unit dosage forms include in solid form, tablets or capsules, in
liquid
form, solutions, suspensions, emulsions, elixirs or capsules filled with the
i 5 same, in the form of patches for transdermal administration or in form of
sterile injectable solutions.
The composition of this invention may be formulated by conventional methods
of galenic pharmacy.
Conventional excipients are such pharmaceutically acceptable organic or
inorganic carrier substances suitable for parenteral or oral application which
do not deleteriously react with the active compound.
Examples of such carriers are water, salt solutions, alcohols, polyethylene
glycols, polyhydroxy ethoxylated castor oil, syrup, peanut oil, olive oil,
gelatin, lactose, terra alba, sucrose, agar, pectin, acacia, amylose,
magnesium
stearate, talc, silicic acid, stearic acid, tatty acid monoglycerides and
diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and
_...._ T
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polyvinylpyrrolidone.
The pharmaceutical preparations can be sterilized and mixed, if desired, with
auxiliary agents, such as binders, lubricants, preservatives, disintegrants,
5 stabilizers, wetting agents, emulsifiers, salt for influencing osmotic
pressure,
buffers and/or colouring substances and the like, which do not deleteriously
react with the active compound.
For parenteral application, particularly suitable are injectable solutions or
suspensions, preferably aqueous solutions with the active compound
dissolved in polyhydroxylated castor oil.
For oral administration, particularly suitable are tablets, dragees, or
capsules
having talc and/or a carbohydrate carrier or binder or the like, the carrier
preferably being lactose and/or corn starch and/or potato starch. A syrup,
elixir or like can be used when a sweetened vehicle can be employed.
A typical tablet, which may be prepared by conventional tabletting tech-
niques, contains:
Tablet Strenghts, mg 8
Tablet Gross Mass, mg 320
Tiagabine Hydrochloride Anhydrate8.35
Polyethylene Glycol 6000, NF 16.0
Lactose, anhydrous, NF 279
_ 8-Tocopherol, Ph.Eur. 0.800
Talc, Ph.Eur. 16.0
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The invention also provides methods of treatment of diseases related to GAGA
uptake in mammals including humans which methods comprises administering
an effective amount of an anhydrous crystalline form of the R(-)-N-(4,4-di(3-
methylthien-2-yl)but-3-enyl)-nipecotic acid hydrochloride.
The invention further provides a pharmaceutically acceptable anhydrous
crystalline form of the R(-)-N-(4,4-di(3-methylthien-2-yl)but-3-enyl)-
nipecotic
acid hydrochloride for therapeutic use in the treatment of epilepsy and other
diseases related to GABA uptake.
Example 1
Tiaaabine, hydrochloride (anhydrous)
7 5 100 g of Tiagabine, hydrochloride monohydrate was dissolved in 700 ml of
0.2 N hydrochloric acid at 55°C. The concentration of hydrochloric
acid, was
adjusted to 1.3 N by addition of conc. hydrochloric acid. The crystallization
of
the product started spontaneous during addition of the acid. Stirring is
continued at 50°C for 17 hrs. The product was filtered off and dried
under
vacuum giving 95% of tiagabine, hydrochloride.
Karl Fisher (K.F.): < 1 % water.
X-Ray: Complies with the anhydrous crystal form.
Example 2
Tiaaabine, hydrochloride (anhydrous)
Tiagabine hydrochloride was dissolved in 7 ml of 0.25 N HCI pr. gram of
T -..~.__...._.
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tiagabine at 55°C. The solution was adjusted to 0.8 N with conc.
hydrochloric
acid. Then 0.5 g/1 of seed crystals were charged to the solution, which was
stirred at 52°C for 18 hrs. The product was filtered off and dried at
room
temperature, giving 85 % in yield.
X-Ray complies with the anhydrous crystal form.
Example 3
TiaQabine, hydrochloride (anhydrous?
75 g Tiagabine hydrochloride monohydrate was dissolved in 613 mf of water
at 65°C. The solution was filtered and 37 g of conc. hydrochloric acid
diluted
in 1 15 g of water was added.
~ 5 The solution was cooled to 52°C and stirred overnight.
The suspension was cooled to 40°C before filtering off the product. The
filter
cake was rinsed with 2 times 55 g of water before drying in vacuum at
30°C.
K.F.: 0% water.
X-Ray: Complies with the anhydrous crystal form.
DSC: onset 193°C.
HPLC: 99.9% purity.
EXAMPLE 4
Tiaaabine, hydrochloride (anhydrous)
10 g of Tiagabine, hydrochloride monohydrate was stirred with 100 ml 1 N
hydrochloric acid at 70°C.
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The mixture was cooled to room temperature and stirred overnight giving a
suspension of fine crystals.
The product was filtered off and washed with water before drying in vacuum
at 40°C.
Yield: 9 g " 95
HPLC purity: 99.9
DSC (Onset): 197.8°C
1o Thermal Gravimetric Analysis (TGA): 0.15 % weightloss to 160°C
X-Ray: Complies with the anhydrous crystal form.
Example 5
Tiaqabine, hydrochloride (anhydrous)
To a 1 L flask, 50 g of tiagabine ethyl ester, 750 ml of water and 1 1 g of
conc. hydrochloric acid were charged. The mixture was heated to reflux for 2
hours and then ethanol/water, a total of 400 ml, was distilled off over a
2o period of 4 hours. The remaining solution was stirred under reflux
overnight. It
was cooled to 55 - 60 °C and then an additional 37.5 g of conc.
hydrochloric
acid was added over a period of 5 min. The solution was cooled to 50 -52
°C
and was stirred at this temperature for 18 hours. The resulting precipitate
was
collected by filtration and was washed with 20 ml of water. The product
v~:°as
dried under vacuum at room temperature to give 40.5 g of Tiagabine,
hydrochloride.
Yield: 86%.
K.F. : 0.4% water.
._.. . T. _... _.._.__..__
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X-Ray: Complies with the anhydrous crystal form.
Example 6
Tiagabine, hydrochloride_ fanhydrousl
To a 1 L flask, 50 g of tiagabine ethyl ester, 575 ml of water and 25 g of
conc. hydrochloric acid were charged. The mixture was heated to reflux for 1
hour and then ethanol/water, a total of 200 ml, was distilled off over a
period
~o of 4 hours. The reaction solution was cooled to 88 °C and then an
additional
23.5 g of conc. hydrochloric acid was added. The solution was gradually
cooled to room temperature i22°C) while the reaction was stirred for 18
hours. The resulting precipitate was collected by filtration and was washed
with 20 ml of water. The product was dried under vacuum at room
~ 5 temperature to give 42.0 g of Tiagabine, hydrochloride.
Yield: 90%.
K.F. : 0.1 % water.
X-Ray: Complies with the anhydrous crystal form.
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