New Crystalline Form of Pemirolast

Abstract

There is provided a hemihydrate form of the sodium salt of pemirolast.

1 . A hemihydrate form of the sodium salt of pemirolast. 
     
     
         2 . A compound as claimed in  claim 1 , which contains between about 0.3 and about 0.7 moles of water per mole of pemirolast. 
     
     
         3 . A compound as claimed in  claim 1 , which is substantially crystalline. 
     
     
         4 . A compound as claimed in  claim 1  having a powder X-ray diffraction pattern comprising a characteristic crystalline peak with a 2-Theta value (in degrees) of around 26.6. 
     
     
         5 . A compound as claimed in  claim 4  having a powder X-ray diffraction pattern comprising a further strong crystalline peak with a 2-Theta value of around 25.3. 
     
     
         6 . A compound as claimed in  claim 4  having a powder X-ray diffraction pattern comprising further strong crystalline peaks with 2-Theta values of around 13.0, 15.3, 18.2 and/or 28.4. 
     
     
         7 . A process for the preparation of a hemihydrate form of the sodium salt of pemirolast, wherein the process comprises crystallisation from a solvent. 
     
     
         8 . A process as claimed in  claim 7  which further comprises reacting pemirolast with a sodium-containing base prior to the crystallisation. 
     
     
         9 . A process as claimed in  claim 8  wherein the base is sodium hydroxide or a sodium alkoxide. 
     
     
         10 . A process as claimed in  claim 7  wherein the solvent comprises a lower alkyl alcohol. 
     
     
         11 . A process as claimed in  claim 10 , wherein the solvent is methanol or ethanol. 
     
     
         12 . A process as claimed in  claim 7 , wherein the crystallisation comprises partial dissolution of pemirolast sodium in the solvent, in the presence of no more than about 10% (w/w, as a proportion of the solvent) of water. 
     
     
         13 . A process as claimed in  claim 12 , which is carried out at a temperature of less than about 70° C. 
     
     
         14 . A process as claimed in  claim 7 , wherein the crystallisation comprises partial dissolution of pemirolast sodium in an aqueous solvent at about 72° C. or above. 
     
     
         15 . A process as claimed in  claim 14 , which further comprises filtration at about 72° C. or above to isolate the compound. 
     
     
         16 . A process as claimed in  claim 7 , wherein the crystallisation comprises dissolution of pemirolast sodium in an aqueous solvent followed by addition of an excess of antisolvent. 
     
     
         17 . A process as claimed in  claim 16 , wherein the antisolvent comprises ethanol. 
     
     
         18 . A process as claimed in  claim 16  wherein the antisolvent is added at around the boiling point of the solvent until precipitation takes place, and the resultant is cooled to about room temperature. 
     
     
         19 . A process for the preparation of a compound as claimed in  claim 1 , which comprises dehydration of a higher hydrate of pemirolast sodium. 
     
     
         20 . A compound prepared by a process according to  claim 7 . 
     
     
         21 . (canceled) 
     
     
         22 . A pharmaceutical formulation comprising a compound as claimed in  claim 1  in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
         23 - 24 . (canceled) 
     
     
         25 . A method of treatment of an inflammatory disorder, which method comprises the administration of a compound as defined in  claim 1  to a patient in need of such treatment. 
     
     
         26 . A method as claimed in claim,  25 , wherein the disorder is atherosclerosis or an associated cardiovascular disorder. 
     
     
         27 . A method as claimed in  claim 26 , wherein the disorder is atherosclerosis. 
     
     
         28 . A method as claimed in  claim 26 , wherein the cardiovascular disorder associated with atherosclerosis is selected from an aortic aneurysm, arteriosclerosis, peripheral arterial occlusive disease, a coronary artery disease, a coronary disease, plaque rupture and/or instability, atheroma rupture and/or instability, a vascular disease, an arterial disease, an ischaemic disease, ischaemia and stroke. 
     
     
         29 . A method as claimed in  claim 28 , wherein the coronary artery disease is selected from angina pectoris, myocardial infarction and heart attack; the coronary disease is selected from a cardiac disease and a heart disease; the stroke is selected from cerebro-vascular accident and transient ischaemic attack; and/or the disorder is plaque rupture and/or instability, or atheroma rupture and/or instability. 
     
     
         30 . A method as claimed in  claim 28 , wherein the disorder is an aortic aneurysm. 
     
     
         31 . A method as claimed in  claim 26 , wherein the patient has an acute coronary syndrome. 
     
     
         32 . A method as claimed in  claim 25 , wherein the disorder is systemic low grade inflammation. 
     
     
         33 . A method as claimed in  claim 25 , wherein the disorder is selected from metabolic syndrome, obesity, diabetes mellitus and/or a diabetic vascular complication. 
     
     
         34 . A combination product comprising:
 (a) a compound as defined in  claim 1 ; and   (b) one or more active ingredient that is useful in the treatment of an inflammatory disorder, or a pharmaceutically-acceptable salt or solvate thereof.   
     
     
         35 . A combination product as claimed in  claim 34 , which comprises a pharmaceutical formulation including a compound as defined in  claim 1 ; an active ingredient that is useful in the treatment of an inflammatory disorder, or a pharmaceutically-acceptable salt or solvate thereof; and a pharmaceutically-acceptable adjuvant, diluent or carrier. 
     
     
         36 . A combination product as claimed in  claim 34 , which comprises a kit of parts comprising components:
 (A) a pharmaceutical formulation including a compound as defined in  claim 1 , in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and   (B) a pharmaceutical formulation including an active ingredient that is useful in the treatment of an inflammatory disorder, or a pharmaceutically-acceptable salt or solvate thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier,   
       which components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other. 
     
     
         37 . A combination product as claimed in  claim 34 , wherein the active ingredient that is useful in the treatment of an inflammatory disorder is a thromboxane A2 antagonist, a P2Y 12  antagonist, a PPARγ agonist, a compound that inhibits the formation and/or action of angiotensin II, a platelet aggregation inhibiting drug or a statin. 
     
     
         38 . A combination product as claimed in  claim 37 , wherein the active ingredient is a statin. 
     
     
         39 . A combination product as claimed in  claim 38 , wherein the active ingredient is atorvastatin or rosuvastatin. 
     
     
         40 . A combination product as claimed in  claim 37 , wherein the active ingredient is aspirin/acetylsalicylic acid, egualen, ozagrel, picotamide, terutroban, seratrodast, ramatroban, prasugrel, ticagrelor, clopidogrel, rivoglitazone, naveglitazar, balaglitazone, rosiglitazone, pioglitazone, captopril, perindopril, ramipril, candesartan, losartan, valsartan or aliskiren. 
     
     
         41 . A compound according to  claim 1  which is substantially crystallographically pure.