Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2000-11-21
2003-02-18
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C514S408000, C548S561000
Reexamination Certificate
active
06521787
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a crystalline polymorph of non-hydrated gabapentin and to the utility thereof as a starting product for the preparation of pharmaceutical grade gabapentin. Likewise, the invention relates to processes for the preparation of the new crystalline polymorph and for the preparation of pharmaceutical grade gabapentin.
PRIOR ART REFERENCE
Gabapentin is a synthetic amino acid related to &ggr;-aminobutyric acid (GABA) responding to the chemical name of 1-(aminomethyl) cyclohexane acetic acid (The Merck Index, Ed. XII) and the following formula
The said compound has a therapeutical activity for convulsive type cerebral disorders, such as epilepsy, hypokinesia, including fainting, and other brain trauma and, in general, it is deemed to produce an improvement of the cerebral functions.
Gabapentin and several processes for the preparation thereof are described in Spanish patent ES-A-443 723, corresponding to U.S. Pat. No. 4,024,175, Example 1 of which describes the preparation of the free amino acid from the hydrochloride thereof, by treatment of an aqueous solution thereof with a basic ion exchanger, evaporation of the solvent and subsequent crystallisation from ethanol/ether.
The thus obtained product corresponds to a non-hydrated crystalline form coinciding with the one shown by the commercial pharmaceutical Neurontin® which is the pharmaceutical standard for gabapentin.
On the other hand, EP-B-0 340 677 and the Spanish part thereof, ES-T3-2 061 774, disclose a new hydrated form of gabapentin characterised by its X-ray diffraction data and the process for the preparation thereof, as well as a process for preparing the non-hydrated crystalline form requiring the prior preparation of the said hydrated form. Said process consists of the following successive steps:
a) passing an aqueous gabapentin hydrochloride solution through a basic ion exchange column.
b) concentrating the eluate to form a suspension.
c) cooling and adding alcohol to the above suspension.
d) cooling and centrifuging the thus prepared suspension.
e) drying the product obtained, which is the hydrated form of gabapentin.
f) dissolving the above pure hydrated form in methanol.
g) diluting and cooling the thus prepared solution until a suspension is obtained.
h) centrifuging the suspension and drying the product, which is the non-hydrated form of gabapentin.
The above described process is obviously complicated from the industrial point of view, since it requires several steps and the isolation of an intermediate in pure form, the hydrated form, prior to a final crystallisation. All of this leads to an excessive occupation of the industrial plant and losses in the yield of the desired product.
There is, therefore, a need to develop alternative processes for the preparation of non-hydrated pharmaceutical grade gabapentin allowing the industrial preparation of the product to be simplified, with a consequent reduction of the production costs.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide an non-hydrated gabapentin polymorph allowing pharmaceutical grade gabapentin to be prepared in an industrially improved way over the prior art.
It is also an object of the invention to provide a process for the preparation of said polymorph and a process for the preparation of pharmaceutical grade gabapentin from said polymorph.
REFERENCES:
patent: 4024175 (1977-05-01), Satzinger et al.
patent: 4087544 (1978-05-01), Satzinger et al.
patent: 4960931 (1990-10-01), Butler et al.
patent: 5068413 (1991-11-01), Steiner et al.
patent: 0 340 677 (1994-02-01), None
patent: 443 723 (1974-12-01), None
Bosch Lladó Jordi
García Cruz Rafael
Molins Grau Elias
Onrubia Miguel Maria del Carmen
Medichem S.A.
Reyes Hector M
Rotman Alan L.
Scully Scott Murphy & Presser
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