Thermal analysis, microcalorimetry and combined techniques for the study of the polymorphic behaviour of a purine derivative

The polymorphic behaviour of the purine derivative MKS 492 was studied with investigations of suspensions of selected samples in different solvents an d of samples obtained by crystallizations. The samples were analyzed by DSC , TG and X-ray diffraction. Six different crystalline modifications called A, B, B', C, D and E and an amorphous form were identified. Four pure cryst alline modifications, A, B, C and D have been manufactured and characterize d by DSC, X-ray, IR, solubilities, densities, hygroscopicity and dissolutio n measurements. The four forms A, C, D and E are monotrop to the form B. Th e form B is enantiotrop to the form B', which revealed the highest melting point of all known polymorphs. This form B' is only stable at high temperat ure. Temperature resolved X-ray diffraction was very helpful for proper int erpretation of the thermal events. The melting peaks of the forms A and C a nd the endothermic peak corresponding to the enantiotropic transition B int o B' occur in a narrow range of temperature. The form B which is the most s table one at room temperature has been chosen for further development. Quan titative methods to determine the content of the forms A, C and D in sample s of form B or to determine the content of form A, B and D in form C have b een developed by using X-ray diffraction. Limits of detection are 1 or 2%. For the quantitative determination of the amorphous fraction, X-ray diffrac tion and microcalorimetry are compared. For high amounts of the amorphous f raction, the X-ray diffraction method is preferred because it is faster. Mi crocalorimetry is very attractive for levels below 10% amorphous content. T he lowest limit of detection is obtained by microcalorimetry, about 1%.