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.