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.

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Pharmaceutical cocrystals of nonsteroidal anti-inflammatory drugs diflunisal (DIF) and diclofenac (DIC) with theophylline (THP) were obtained, and their crystal structures were determined. In both of the crystal structures, molecules form a hydrogen bonded supramolecular unit consisting of a centrosymmetric dimer of THP and two molecules of active pharmaceutical ingredient (API). Crystal lattice energy calculations showed that the packing energy gain of the [DIC + THP] cocrystal is derived mainly from the dispersion energy, which dominates the structures of the cocrystals. The enthalpies of cocrystal formation were estimated by solution calorimetry, and their thermal stability was studied by differential scanning calorimetry. The cocrystals showed an enhancement of apparent solubility compared to the corresponding pure APIs, while the intrinsic dissolution rates are comparable. Both cocrystals demonstrated physical stability upon storing at different relative humidity.

Crystal lattice characteristics from the literature for different polymorphic forms of some nonsteroidal anti-inflammatory drugs (diclofenac, niflumic, flufenamic, tolfenamic, mefenamic acid) and structural relative compounds (N-phenylanthranilic acid and diphenylamine) were summarized and compared. Molecular conformational states in the crystal lattices and hydrogen bond networks were described and analyzed. Temperature dependencies of vapor pressure of the molecular crystals were measured and sublimation thermodynamic parameters calculated. Thermodynamic characteristics of fusion and vaporization processes were derived. Relationships between the sublimation thermodynamic functions and the torsion angles between the benzene motives of the compounds and the polymorphic forms were revealed. Dependence between the sublimation enthalpies and the melting points was observed. Correlation of the fusion entropies with the free volume per molecule in the crystal lattices was found. The absolute values of the crystal lattices energies of the polymorphic forms I and II of mefenamic acid and forms I and III of flufenamic acid were evaluated on basis of the sublimation and solution calorimetric experiments.