Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1999-11-16
2000-09-26
O'Sullivan, Peter
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514821, 564 82, A61K 3118, C07C30344, C07C31111
Patent
active
061243639
DESCRIPTION:
BRIEF SUMMARY
This application was filed under 35 U.S.C. .sctn.371 based on PCT/EP98/06641 which was filed Oct. 9, 1998 which claims priority from British application 9722662.5 filed on Oct. 27, 1997.
The present invention relates to polymorphs of the compound known as dofetilide. More particularly, the invention relates to the novel dofetilide polymorphs known as P162, P162a and P143, and to processes for the preparation of, compositions containing and to the uses of, such polymorphs. Dofetilide, N-[4-(2-[2-[4-(methanesulphonamido)phenoxy]-N'-methylethylamino]ethyl)phen yl]methanesulphonamide, has the following structure: ##STR1##
Dofetilide is disclosed in EP-A-0245997 as an antiarrhythmic agent that prolongs the duration of the action potential in cardiac muscle and conducting tissue, thereby increasing refractoriness to premature stimuli. It is therefore a Class III antiarrhythmic agent according to the classification of Vaughan Williams ("Anti-Arrhythmic Action", E. M. Vaughan Williams, Academic Press, 1980). It is effective in atria, ventricles and conducting tissue both in vitro and in vivo and could therefore be useful for the prevention and treatment of a wide variety of ventricular and supraventricular arrhythmias including atrial and ventricular fibrillation. Since it does not alter the speed at which impulses are conducted, it has less propensity than other antiarrhythmic drugs (mostly Class I) to precipitate or aggravate arrhythmias and it also produces less neurological side effects. It also lacks negative inotropic activity and therefore offers advantages over other antiarrhythmic agents in patients with impaired cardiac pump function.
The use of dofetilide in treating heart failure, particularly congestive heart failure, is described in European Patent Application no. 98306188.8, the teaching of which is incorporated herein by reference.
A capsule formulation of dofetilide is currently preferred. Dofetilide is a very potent drug and is therefore to be used in very low dosage. Since a very low drug loading will be required for the capsule formulation, it is essential that the active ingredient has a small particle size to ensure that a homogeneous blend is achieved.
The previously known methods of preparing dofetilide that are described in EP-A-0245997 are difficult to reproduce and have either produced a mixture of dofetilide polymorphs P162/P162a, P162b/P136 or P162b/P136/P143 or, essentially, dofetilide polymorph P136 or P162b, all of which tend to crystallise in an agglomerated form that would have to be deagglomerated (e.g. by milling or micronisation) to achieve the required small particle size. Hence, none of these products would be directly suitable for use in a capsule formulation.
It is an object of this invention to provide a suitable, substantially pure, crystalline, polymorphic form of dofetilide that can be easily, economically and reproducibly prepared with the required small particle size for use in a capsule formulation, preferably without any milling of the drug being necessary in the production process.
It has now been surprisingly found that this object has been achieved by the present invention which provides a substantially pure, crystalline, polymorphic form of dofetilide known as P162 and an inventive process for the preparation thereof. Dofetilide polymorph P162 crystallises from aqueous acetonitrile as flakes/plates with a consistently small particle size distribution, 90% of the particles being less than 45 .mu.m in size. This form therefore does not require milling before use in a capsule formulation. It is also non-hygroscopic over a broad range of relative humidities, is chemically and physically stable, is rapidly absorbed in vivo and it can be routinely and reproducibly prepared in commercial quantities by the crystallisation process described herein.
Accordingly, the present invention provides substantially pure, crystalline, dofetilide polymorph P162 which is characterised by differential scanning calorimetry (DSC) in which it exhibits an endothermic thermal event at abou
REFERENCES:
E. M. Vaughan Williams, "Antiarrhythmic Action and the puzzle of perhexiline-5. Class 3 antiarrhythmic action" Academic Press, l980, p. 26-31.
Appleby Ian Colin
Newbury Trevor Jack
Nichols Gary
Benson Gregg C.
O'Sullivan Peter
Olson A. Dean
Pfizer Inc.
Richardson Peter C.
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