Salts of an anti-migraine indole derivatives

Details Salts of an anti-migraine indole derivatives Salts of an anti-migraine indole derivatives

2000-06-15

2002-04-30

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S365000, C514S323000, C548S131000, C548S181000, C548S468000

Reexamination Certificate

active

06380226

ABSTRACT:

The present invention relates to hydrobromide salts of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenytsulphonylethyl)-1H-indole having the formula (I):
In a preferred aspect, the invention relates to a particular polymorphic form, hereinafter referred to as the &agr;-form, of the hydrobromide salt identified above. In addition it relates to an intermediate polymorphic form, hereinafter referred to as the &bgr;-form, of the said hydrobromide salt, to processes for the preparation of the &agr;- and &bgr;-forms, to pharmaceutical compositions containing the &agr;-form, and to uses of the &agr;-form in medicine.
WO-A-92/06973 relates to a series of 3,5disubstituted 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 hemisuocinate salt, the latter being characterised as a non-crystalline 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 &agr;-form of the hydrobromide salt of formula (I) which meets the above requirements; thus it is proeminently 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° 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-tanrate, 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/sticky solids, gums, glasses, froths, resins or oils. Moreover, of the four crystalline salts, the benzenesulphonate proved to have an insufficiently high melting point (m.p.) of 74-75° C. Thus only the hemisulphate, hydrochloride and hydrobromide salts were progressed to more detailed studies.
Hemisulphate Salt
The hemisulphate salt initially isolated (m.p. 145-147° C.), designated the &bgr;-form, does not show a clean single-melting endotherm when examined by differential scanning calorimetry (DSC) but rather a complex trace indicative of polymorphic transition. Indeed, this &bgr;-form is very hygroscopic at relative humidities (RH) higher than 50% and, under certain conditions, water uptake can cause polymorphic conversion to an alternative form, designated the &agr;-form, of m.p. 185° C., or even degradation. Furthermore, the &bgr;-form undergoes a colour change on compression and causes punch-filming during tabletting and thus, for a variety of reasons, its physicochemical properties render it unsuitable for the development of solid dosage forms.
Whilst the &agr;-form of the hemisulphate salt does not display solid state instability associated with water uptake, it is extremely hygroscopic nevertheless and therefore also unsuitable for development because of consequential difficulties with variable flow properties, and bulk and dosage form instability which precludes, inter alia, accurate assignment of drug activity.
Hydrochloride Salt
Depending on the solvent used as reaction medium and for crystallisation, either of two forms of the hydrochloride salt can be obtained. The first of these to be isolated and characterised, designated the &bgr;-form, of m.p. 125-129° C. (broad endotherm at 135° C. at a scan rate of 20° C./min. by DSC, but no dehydration endotherms apparent), was found to have a water content of 4.42% (1.08 mol) by Karl Fischer titrimetry (KFT). However, although hygroscopicity studies revealed that the &bgr;-form does not display solid state instability, it was excluded from further development by its behaviour during compression studies in which melting and sticking of the disk to the punches were observed, thus reinforcing the requirement for a higher melting solid.
The alternative hydrochloride salt, designated the &agr;-form, showed a major, sharp endotherm at 165° C. by DSC (scan rate 20° C./min.). Determination of its hygroscopicity profile revealed that after seven days at a temperature (T) of 40° C. and RH of 75%, unlike the &bgr;-form, a significant amount of water had been taken up. This water uptake was found to be associated with changes in the DSC trace which demonstrated that, at least under these humidity conditions, the anhydrous &agr;-form converts to the hydrated &bgr;-form. Thus pharmaceutical development of the &agr;-form is also precluded by inadequate physical stability.
Hydrobromide Salt
The hydrobromide salt is also isolable in one of two forms, depending on the preparative conditions employed. The lower melting form, designated the &bgr;-form, was found not to be a viable option for the development of a solid dosage form because, when attempts are made to improve its quality, it undergoes polymorphic conversion to a higher melting form, designated the &agr;-form.
However, by contrast, the novel &agr;-form of the hydrobromide salt of formula (I) was found to be unique in unexpectedly possessing the combination of properties required to enable the efficient development of solid dosage forms, namely those of crystallinity, sufficiently high m.p., lack of hygroscopicity, solid-state stability, compressibility and lack of polymorphic conversion, together with satisfactory solubility and dissolution rate profiles.
The present invention therefore provides a crystalline, polymorphic &agr;-form of a hydrobromide salt of formula (I), whose infra-red (IR) spectrum as a mull in nujol shows significant absorption bands at &ngr;=3371, 3293, 2713, 2524, 1419, 1343, 1307, 1264, 1151, 1086, 1020, 1008, 999, 922, 900, 805, 758, 740, 728, 689, 672, 652, 640, 598

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