Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-19
2002-04-09
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S468000
Reexamination Certificate
active
06369094
ABSTRACT:
The application claims the benefit of U.K. patent application No. 9922963.5, filed Sep. 28, 1999.
The present invention relates to the hemisulphate salt of the anti-migraine drug 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole having formula (I):
Specifically, the invention relates to a particular polymorphic form of said hemisulphate salt, to processes for the preparation of said form, to pharmaceutical compositions containing same and to its use in medicine, particularly the treatment of conditions for which an agonist of 5-HT
1
receptors is indicated, for example, migraine.
International Patent Application PCT/US91/07194 describes a series of 3,5-disubstituted indoles and pharmaceutically acceptable salts thereof. The hemisuccinate salt of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole is specifically described therein as a non-crystalline foam unsuitable for the preparation of pharmaceutical compositions, but subsequent studies indicated that the hemisulphate, hydrochloride and hydrobromide salts were all sufficiently crystalline and high-melting to be considered for this purpose.
Thus European Patent 0776323 is concerned with specific polymorphic forms of the corresponding hydrobromide salt and describes for the purposes of comparison two polymorphs of the hemisulphate salt which are referred to therein as the &agr;- and &bgr;-forms. In contrast to the polymorphs of the hydrobromide salt, the &agr;- and &bgr;-polymorphs of the hemisulphate salt are variously described as hygroscopic, polymorphically unstable and giving rise to colour change and punch filming during tabletting. In short, the hemisulphate polymorphs described in '323 were considered unsuitable for the preparation of solid dosage forms.
International Patent Application PCTI/EP98/04176 is concerned with aqueous pharmaceutical compositions comprising the preferred hydrobromide polymorph identified in '323 and describes for the purposes of comparison the preparation of a corresponding hemisulphate composition. The hemisulphate salt used for the preparation of said composition is the &bgr;-polymorph described in '323.
We have now unexpectedly found that there exists a third polymorph of the hemisulphate salt of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole which overcomes the disadvantages associated with the &agr;- and &bgr;-forms described in European Patent 0776323. Furthermore, it has advantages over the preferred polymorph of the corresponding hydrobromide salt in terms of liquid dosage preparation.
Thus the problem addressed by the present invention is to provide a pharmaceutically acceptable hemisulphate salt of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole which may be efficiently processed to provide stable and effective pharmaceutical compositions, particularly those in solid or liquid dosage form. Important criteria to be satisfied are, inter alia, that the selected salt should be crystalline, non-hygroscopic and compressible, possess solid-state stability, be of suitable melting point and have acceptable solubility characteristics.
As indicated, this problem has been solved by the surprising finding of a novel polymorphic form of the hemisulphate salt of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole which meets the foregoing requirements, overcomes the disadvantages associated with the &agr;- and &bgr;-polymorphs described in European Patent 0776323 and has advantages with regard to solubility and the ability to prepare liquid dosage forms over the preferred polymorph of the corresponding hydrobromide salt.
Thus according to the present invention, there is provided a crystalline, polymorphic form of a compound of formula (I) characterised by a powder X-ray diffraction (PXRD) pattern having main peaks at 9.28, 10.38, 11.37, 12.40, 16.84, 17.46, 17.53, 17.78, 17.98, 19.48, 20.70, 21.29, 21.45, 22.21, 22.64, 23.08, 25.20 and 25.79.
The polymorph of the invention is further characterised by its infrared (IR) spectrum which shows significant absorption bands at &ugr;=3385.3, 3172.0, 3143.8, 3058.0, 3022.6, 2954.8, 2928.3, 2893.5, 2650.7, 2436.4, 1622.6, 1584.1, 1480.8, 1445.6, 1362.4, 1354.4, 1304.8, 1246.0, 1229.9, 1164.3, 1149.6, 1137.5, 1087.1, 1071.7, 1019.5, 958.9, 929.8, 899.1, 878.9, 842.6, 793.8, 759.3, 751.4, 731.3, 690.4, 619.9, 606.3, 564.9, 533.7, 512.2, 503.6, 485.3, 457.5 and 428.9 cm
−1
.
The polymorph of the invention is yet further characterised by its Differential Scanning Calorimetry (DSC) trace which shows a sharp endotherm at 226° C. corresponding to its melting point.
In marked contrast to the &agr;- and &bgr;-polymorphs, the hemisulphate polymorph of the present invention shows negligible hygroscopicity, no change in its polymorphic form after seven months as demonstrated by Powder X-Ray Diffraction (PXRD) and Differential Scanning Calorimetry (DSC) and no significant colour change or punch filming upon compression. At pH 4.0, the polymorph of the invention has a solubility very similar to that of the preferred hydrobromide of '323, but at the more biologically significant pH 6.0 its solubility increases to 478 mg/ml compared to 2.90 mg/ml for the hydrobromide.
The foregoing properties render the polymorph of the invention eminently suitable for the preparation of pharmaceutical compositions, particularly those in solid or liquid dosage form. Thus, according to a further aspect of the present invention, the polymorph of the invention and pharmaceutical compositions thereof are provided for use as medicaments.
The present invention also provides processes for the preparation of said polymorph, either in a single solvent or by reprocessing the initially-formed product in a different solvent. Reprocessing typically takes the form of refluxing the initially-formed product in a different solvent followed by isolation of the desired polymorph.
The polymorph of the invention may, for example, be obtained by
(i) treatment of a solution of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole in a first suitable solvent, for example, acetone or tetrahydrofuran, with concentrated sulphuric acid, typically at a temperature of from −2 to 2° C., followed by heating under reflux in the same solvent; or by
(ii) treatment of a solution of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole in a first suitable solvent, typically acetone, with concentrated sulphuric acid, typically at a temperature of from −2 to 2° C., followed by isolation of the resulting slurry and reprocessing in a second suitable solvent, for example, tetrahydrofuran.
In both cases, the resulting solution is cooled and the desired polymorph isolated. Seeding may be employed to induce crystallisation, but this is usually unnecessary.
According to a further aspect of the present invention, there are provided pharmaceutical compositions comprising the hemisulphate polymorph of the invention together with a pharmaceutically acceptable excipient, diluent, or carrier.
Thus the compound of the invention may be administered alone, but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent, or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
For example, the compound of the invention may be administered orally, buccally, or sublingually in the form of optionally flavoured and/or coloured tablets, capsules, ovules, elixirs, solutions, or suspensions suitable for immediate, delayed, or controlled release applications. The compound may also be administered by intracavernosal injection.
Such tablets may contain excipients, such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, or glycine, disintegrants, such as starch (preferably corn, potato, or tapioca starch), sodium starch glycollate, croscarmellose sodium or certain complex silicates, and granulation binders such as p
Bentley Arthur
Howard-Field Simon Arnold
Ogilvie Ronald James
Gerstl Robert
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Waldron Roy F.
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