Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-02-02
2000-08-29
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546201, 548468, A01N 4340, A61K 31445, C07D40100, C07D20902
Patent
active
061109401
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to hydrobromide salts of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole having the formula (I): ##STR2##
In a preferred aspect, the invention relates to a particular polymorphic form, hereinafter referred to as the .alpha.-form, of the hydrobromide salt identified above. In addition it relates to an intermediate polymorphic form, hereinafter referred to as the .beta.-form, of the said hydrobromide salt, to processes for the preparation of the .alpha.- and .beta.- forms, to pharmaceutical compositions containing the .alpha.-form, and to uses of the .alpha.-form in medicine.
WO-A-92106973 relates to a series of 3,5-disubstituted indoles and pharmaceutically acceptable salts thereof useful in the treatment of migraine and other disorders. Examples cited therein of such salts are the hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate or bisulphate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulphonate and pamoate. Specifically disclosed therein is 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole and its hemisuccinate salt, the latter being characterised as a noncrystalline foam. Further studies have confirmed that this salt is unsuitable for pharmaceutical formulation, as numerous attempts to obtain it in a form which has the properties required for formulation have been unsuccessful.
Thus the problem addressed by the present invention is the provision of a pharmaceutically acceptable salt of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole which can be efficiently processed to provide stable and effective formulations of the drug, in particular solid and compressible dosage forms. Such dosage forms include conventional-release oral tablets, controlled-release (matrix) tablets, fast-dissolving tablets (e.g. freeze-dried), sublingual tablets, buccal tablets, oral powder- and granule-filled capsules, powders for reconstituted suspensions, conventional and controlled-release multiparticulate systems filled into capsules or compressed into tablets, lozenges, dragees, suppositories, pessaries, solid implants, lyophile plugs, nanoparticles and microparticles and powder for suspension and nasal delivery, and dry inhalation systems.
Important criteria to be satisfied are, inter alia, that the selected salt should be crystalline, of suitable melting point, non-hygroscopic, compressible and possess solid-state stability, coupled with acceptable solubility and dissolution behaviour.
This problem has been solved by the surprising finding of a novel .alpha.-form of the hydrobromide salt of formula (I) which meets the above requirements; thus it is pre-eminently suitable for providing pharmaceutical formulations in solid dosage form, in particular for oral, buccal and sublingual administration.
The first step in approaching the solution to the problem was the generation of an acid addition salt of the monoacidic base, 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole, which is both crystalline and of high enough melting point (>ca. 130.degree. C.) to have the potential to undergo pharmaceutical processing during solid dosage form manufacture and compaction.
Attempts were made to obtain a suitable form of the following salts: hydrochloride, hydrobromide, hemisulphate, bisulphate, nitrate, acid phosphate, phosphate, methanesulphonate, benzenesulphonate, p-toluenesulphonate, (+)-camphorsulphonate, acetate, benzoate, citrate, hemifumarate, fumarate, hemimaleate, maleate, hemisuccinate, succinate, hemi-L-tartrate, L-tartrate, hemi-D-tartrate, D-tartrate, L-lactate, (R)-(-)-mandelate, hippurate, hemiphthalate, phthalate and hemiterephthalate.
Of these thirty possible salts, only four could be obtained as crystalline solids, namely the hemisulphate, hydrochloride, hydrobromide and benzenesulphonate; the remainder were obtained as non-crystalline/low or non-sharp melting
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Harding Valerie Denise
Macrae Ross James
Ogilvie Ronald James
Fuller Jr. Grover F.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Shah Mukund J.
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