Crystallization and Polymorphism of Felodipine

Two previously known polymorphs (forms I and II) and two new polymorphs (forms III and IV) of the calcium-channel blocker felodipine were obtained during attempts to cocrystallize the compound with a variety of potential cocrystal formers. A correlation was observed between the polymorphic outcome and the effective pH value in the presence of the cocrystal former, and it was possible subsequently to produce the four polymorphs by pH adjustment using H2SO4(aq) or NaOH(aq). This suggests that there is no distinct structure-directing role for the molecular additives present during the cocrystallization trials. The crystal structures of the new forms III and IV were determined using single-crystal X-ray diffraction. Forms I, II, and III were obtained in bulk form and characterized by a variety of analytical methods, including thermal analysis, solution calorimetry, intrinsic dissolution rate measurement, and solubility measurement. Form IV could be obtained only as a few isolated single crystals, and its crystallization could not be reproduced. On the basis of the measured thermochemical data and solubility studies, form I appears to be the thermodynamically most stable phase at ambient conditions, although the new form III is practically isoenergetic. Form II shows the highest solubility and intrinsic dissolution rate, consistent with the lowest thermodynamic stability. Forms I, II, and III are all monotropically related.