Pharmaceutical composition containing crystalline macitentan

Abstract

The present invention relates to an oral solid dosage form, in particular a tablet, comprising macitentan free base polymorphic form I.

1 . A pharmaceutical composition comprising:
 crystalline macitentan free base having X-ray powder diffraction pattern showing peak maxima at 2 theta/° values of 11.4±0.2, 13.0±0.2, 16.1±0.2, and 25.4±0.2 when a radiation wavelength of 1.5419 Å is used; and   at least one excipient.   
     
     
         2 . The pharmaceutical composition according to  claim 1 , which is an oral solid dosage form. 
     
     
         3 - 13  (canceled). 
     
     
         14 . The pharmaceutical composition according to  claim 1 , comprising at most 5% by weight of amorphous Macitentan free base. 
     
     
         15 . The pharmaceutical composition according to  claim 1 , comprising at most 1% by weight of amorphous Macitentan free base. 
     
     
         16 . The oral solid dosage form according to  claim 2 , being a compressed dosage form. 
     
     
         17 . The oral solid dosage form according to  claim 2  being a tablet. 
     
     
         18 . The oral solid dosage form according to  claim 2  being an immediate release tablet. 
     
     
         19 . The oral solid dosage form according to  claim 2 , comprising at least one filler, at least one desintegrant, at least one binder, at least one lubricant, and at least one surfactant. 
     
     
         20 . The oral solid dosage form according to  claim 2 , wherein the crystalline Macitentan free base has a particle size distribution having a D98% of at most 680 μm and a D5% of at least 0.5 μm. 
     
     
         21 . The oral solid dosage form according to  claim 2 , wherein the crystalline Macitentan free base has a particle size distribution having a D50% of from 3 μm to 250 μm. 
     
     
         22 . The oral solid dosage form according to  claim 2 , wherein the crystalline Macitentan free base has a particle size distribution having a D50% of from 15 μm to 150 μm. 
     
     
         23 . The oral solid dosage form according to  claim 2 , wherein the oral solid dosage form is to be administered to patients in a country having an area with an Af or an Am climate according to the Köppen-Geiger climate classification. 
     
     
         24 . The oral solid dosage form according to  claim 2 , wherein said pharmaceutical composition is packaged in a packaging material having a moisture vapour transmission rate of at least 0.4 g M −2  d −1  as measured according to standard DIN 53122-1. 
     
     
         25 . The oral solid dosage form according to  claim 2 , wherein said pharmaceutical composition is packaged in a packaging material comprising polypropylene, polyvinylidenchloride and/orpolyvinylchloride. 
     
     
         26 . The oral solid dosage form according to  claim 2 , for use in the treatment of pulmonary arterial hypertension in patients in a country having an area with an Af or an Am climate according to the Köppen-Geiger climate classification. 
     
     
         27 . A method for the preparation of a pharmaceutical composition comprising:
 a) providing crystalline Macitentan free base according to  claim 1 ;   b) mixing the crystalline Macitentan free base provided in a) with at least one excipient;   c) preparing the pharmaceutical composition from the mixture obtained in b).   
     
     
         28 . The method according to  claim 27 , further comprising forming the pharmaceutical composition into an oral dosage form. 
     
     
         29 . The method according to  claim 27 , wherein the crystalline Macitentan free base of step a) is a composition of crystals of crystalline Macitentan free base according to  claim 1  which has a particle size distribution having a D98% of at most 680 μm and a D5% of at least 0.5 μm. 
     
     
         30 . The method according to  claim 27 , wherein the crystalline Macitentan free base of step a) is a composition of Macitentan free base form I crystals which have a particle size distribution having a D50% of from 3 μm to 250 μm. 
     
     
         31 . The method according to  claim 27 , wherein the crystalline Macitentan free base of step a) is a composition of Macitentan free base form I crystals which have a particle size distribution having a D50% of from 15 μm to 150 μm. 
     
     
         32 . A method of making a packaged oral solid dosage form comprising:
 forming the oral solid dosage from the crystalline Macitentan free base according to  claim 1 ; and   packaging the oral solid dosage form, wherein when the oral solid dosage form is packaged in a polypropylene film and stored in dark at 40° C. at a relative humidity of 75% for a period of at least 14 days, the packaged oral solid dosage form exhibits increased chemical stability compared to an identically packaged and stored oral solid dosage form comprising amorphous Macitentan free base.