Process for producing gabapentin or pharmaceutical grade

Details Process for producing gabapentin or pharmaceutical grade Process for producing gabapentin or pharmaceutical grade

2001-10-18

2003-03-04

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C514S561000

Reexamination Certificate

active

06528682

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of gabapentin suitable for pharmaceutical use by neutralization of alcoholic solutions of gabapentin hydrochloride with basic ion exchange resins.
PRIOR ART REFERENCE
Gabapentin is a synthetic amino acid related to &ggr;-aminobutyric acid (GABA), responding to the chemical name of 1-(aminomethyl)cyclohexaneacetic 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 crystallization from a mixture of ethanol/ether. This process, which is only outlined without details in the said patents, has drawbacks for the industrial application thereof derived from having to evaporate large amounts of water, with the high energy consumption required thereby, and involving the use of a solvent such as ether, which is extremely dangerous and hard to handle on an industrial scale.
The product obtained with the above process corresponds to a non-hydrated crystalline form coinciding with the one shown by the commercial pharmaceutical Neurontin®, which is the pharmaceutical standard for gabapentin.
Subsequently, EP-B-0 340 677 discloses a process for preparing said non-hydrated crystalline form requiring the prior preparation of a new hydrated form of gabapentin, characterized by the X-ray diffraction data thereof. 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, the evaporation of large amounts of water and the isolation of an intermediate in pure form, the hydrated form, prior to a final crystallization. All of this means that the process is complex, there is an excessive occupation of the industrial plant and losses in the yield of the desired product.
It is disclosed in U.S. Pat. No. 5,319,135, col. 13, lines 47 et seq. that the products to which it relates, among which there is gabapentin, may be prepared from the acid addition salts thereof, e.g., from the hydrochlorides, by their neutralization with a long list of bases, among which there are the free amines and basic ion exchange resins. However, the examples of said patent only describe the use of the said resins for neutralizing aqueous solutions, i.e., a method coinciding with the one already described in the aforementioned patents ES-A-443 723 and EP-A-0 340 677. Example 6 of U.S. Pat. No. 5,068,413 also describes a process coinciding essentially with the one described in the above patents.
Patent application WO-A-98/28255 discloses a method for preparing gabapentin base consisting of dissolving gabapentin hydrochloride in a solvent and neutralizing it by addition of an amine in solution, said solvent being chosen in such a way that the amine hydrochloride formed during the neutralization is more soluble therein than the anhydrous gabapentin. In accordance with the above patent application, a new form of anhydrous gabapentin, named form III, is prepared in the neutralization process. It is necessary to reprocess this form III by digestion or recrystallisation in another solvent, to be able to prepare the pharmaceutical grade anhydrous gabapentin base, which is named form II in the said patent application.
This process does not require the use of ion exchange resins, but has the drawback that, unless closely adjusted amounts of neutralizing amine are used, the product obtained may be contaminated with appreciable amounts of the amine used in the neutralization and which have to be removed subsequently from the end product, by additional purification steps. Therefore, it is proposed in Example 1 of the patent application, which lays down the guidelines for the rest of the preparative Examples described therein, to use an evident molar deficit of amine relative to the gabapentin hydrochloride, which has indubitable repercussions in the form of a reduction of the yield of the product obtained. Furthermore, this process also requires the preparation of an intermediate, the so-called form III, which has to be reprocessed, with the consequent complication of the operative process.
There is, therefore, a need for developing alternative processes for the preparation of pharmaceutical grade gabapentin, allowing the industrial preparation of this product to be simplified and, therewith, the production costs to be reduced.
OBJECT OF THE INVENTION
It is the object of the invention to provide a simplified process for the preparation of pharmaceutical grade gabapentin, not requiring the preparation of intermediates which have to be reprocessed.
DESCRIPTION OF THE INVENTION
The process according to the present invention consists, in the essential aspects thereof, of:
(i) dissolving gabapentin hydrochloride in a short chain alcohol,
(ii) treating the solution obtained with a basic ion exchange resin,
(iii) concentrating the resulting solution until a dense anhydrous gabapentin suspension is formed in the rest of the alcoholic solvent,
(iv) adding to the suspension formed in the previous step a mixture of a short chain alcohol and water and heating until the precipitate is completely redissolved, and
(v) precipitating the anhydrous gabapentin by cooling and recovering the product obtained by filtering and drying.
Both the gabapentin precipitated during the concentration step (iii) and that obtained as end product are anhydrous gabapentin base with the crystalline structure proper to the conventional pharmaceutical grade product, as is to be gathered from the substantial coincidence of the IR spectrum and the X-ray powder diffractogram thereof with those of the said conventional product.
The starting gabapentin hydrochloride may be prepared by the processes described in any of patents ES-A-443 723 and EP-B-0 340 677, although other additional descriptions may be cited, such as those contained in patents U.S. Pat. No. 5,132,451, U.S. Pat. No. 5,319,135, U.S. Pat. No. 5,362,883, U.S. Pat. No. 5,068,413, U.S. Pat. No. 5,091,567, U.S. Pat. No. 5,095,148, U.S. Pat. No. 5,130,455, U.S. Pat. No. 5,136,091 and U.S. Pat. No. 5,149,870. The said starting hydrochloride may be used in anhydrous form or be hydrated with variable proportions of water ranging from 2% to 12% by weight and does not require prior purification, whereby the crude gabapentin hydrochloride obtained from the previous synthesis steps may be advantageously used as starting product.
Both the short chain alcohol of step (i) and that of step (iv) of the process according to the invention are selected from among the straight or branched chain C
1
-C
4
aliphatic alcohols, such as methanol, ethanol, n-propanol, isopropanol, etc, although the use of methanol is preferred in both cases.
The basic ion exchange resins are selected from among those regularly available in commerce, well known to the man of the art, such as for example the commercial products BAYER MP-62 or AMBERLITE® IRA-67.
The alcoholic gabapentin hydrochloride solu

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