Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2003-05-27
2004-09-14
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C514S561000
Reexamination Certificate
active
06790986
ABSTRACT:
The present invention relates to a process for the preparation of gabapentin (1-(aminomethyl)-cyclohexaneacetic acid) of formula
free from inorganic ions, in particular chlorides, and from the corresponding lactam.
TECHNOLOGICAL BACKGROUND
A number of processes for the preparation and/or purification of gabapentin are known: see, for instance, U.S. Pat. Nos. 4,024,175; 5,068,413; 5,091,567; 5,132,451; 5,319,135; 5,362,883; 6,054,482; 6,531,509. The latter two, in particular, respectively concern a process for the preparation gabapentin containing less than 0.5% by weight of lactam and less than 20 ppm of a mineral acid anion (in particular chlorides) and pharmaceutical compositions of gabapentin containing less than 0.5% by weight of lactam and more than 20 ppm of a mineral acid anion (in particular chlorides). According to U.S. Pat. No. 6,054,482, the presence of chlorides in amounts above 20 ppm promotes the conversion of gabapentin into lactam (having some toxicity), which conversion, according to the same Patent, is prevented or slowed down not only by the low content in chlorides, but also by the presence of a number of adjuvants in the corresponding pharmaceutical compositions. On the other hand, according to U.S. Pat. No. 6,531,509 the presence of adjuvants, which are partly the same as those claimed in U.S. Pat. No. 6,054,482, in the compositions would be sufficient for the purpose.
Numerous processes for reducing the chloride ions content in gabapentin exist. For example, aqueous solutions of gabapentin (which is known to be highly water-soluble) are passed through ion exchange columns; or solutions of the corresponding hydrochloride are treated with bases in solvents in which gabapentin is soluble, while the base hydrochloride of is not, or, vice versa, in a solvent wherein the base hydrochloride is soluble whereas gabapentin is not. In each case, according to U.S. Pat. No. 6,054,482 gabapentin completely free from chloride ions cannot be obtained. In this connection, the Patent reads: “The active materials of formula (I) must be prepared as highly purified, nonderivatized free amino acids, for example, from the corresponding hydrochloride by ion exchange. The proportion of remaining hydrochloride admixtures should thereby not exceed 20 ppm. The same also applies to other mineral acids.”
SUMMARY OF THE INVENTION
It has now been found that gabapentin completely free from chloride ions (or, more generally, from mineral acids ion) can be obtained from a gabapentin aqueous solution by treatment with a hydroxybenzoic acid (optionally substituted in the ring with lower alkyl or alkoxy groups), preferably with 4-hydroxybenzoic acid and most preferably with salicylic acid. It has in fact been found that the water-solubility of gabapentin 4-hydroxybenzoate, and that of the salicylate even more, is so poor as to obtain its precipitation in satisfactory yields, and that treatment of the solutions of said salts in solvents wherein gabapentin is insoluble or sparingly soluble with suitable organic bases provides precipitation of highly pure gabapentin, containing less 100 ppm of the hydroxybenzoic acid used, while the hydroxybenzoates of said organic bases remain in solution. Furthermore it has been found that the resulting gabapentin, if necessary after stirring with alcohols, substantially contains no lactam. Moreover, in the corresponding pharmaceutical formulations no substantial increases in said content are observed after one-year storage at 25° C. and 60% humidity.
REFERENCES:
patent: 6054482 (2000-04-01), Augart et al.
Assanelli Cinzia
Breviglieri Gabriele
Contrini Sergio
Farchemia S.r.l.
Oh Taylor V.
Schneider Walter H.
Trinh Ba K.
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