Physicochemical Characterization of the Various Solid Forms of Carbovir, An Antiviral Nucleoside

Abstract

Carbovir, which exhibits promising in-vitro activity against HIV, is shown to exist in five forms: I, II, III, IV, and V. Forms I-III and V were characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM), Karl Fischer titrimetry (KFT), powder X-ray diffraction (PXD), intrinsic dissolution rate (IDR) studies, heat of solution measurements (SC), scanning electron microscopy (SEM), Fourier-transform infrared (FTIR) spectroscopy, and water uptake at various relative humidities (water activities). Form IV could not be characterized fully, as it is stable only over a narrow temperature range (267-275 °C) which is immediately followed by melting and decomposition. With increasing temperature in DSC, forms I and V transformed successively to form III (195 °C), then to form II (220 °C), and then to form IV (275 °C). The PXD patterns, FTIR spectroscopy, IDR, and SC showed significant differences between these polymorphs. For each of the forms I, II, and III, there exists a critical value of relative humidity above which absorption of water proceeds steeply, leading to the formation of form V, which is more heavily hydrated than any of the other forms. Forms I and V each showed a two-step weight loss in TGA (24-120 °C), suggesting the presence of water molecules with two different binding energies probably corresponding to two different locations in the crystal lattice; HSM confirmed the dehydration. Thus, while forms I and V are hydrates, containing ca. 0.9 and 1.2 mol of water/mol of carbovir, respectively, from KFT, forms II-IV are different unsolvated polymorphic forms. Form I is a (pseudopolymorphic) hydrate which may have variable water stoichiometry. The order of the IDR values of compacted disks into water at 25 °C is form II ≫ form III > form I ∼ form V, corresponding to the order of free energy with respect to the aqueous solution. While the dissolution of forms I, III, and V was linear, the IDR of form II decreased after 15 min to a constant value, corresponding to conversion to form V. In contact with water, forms I and III also convert to form V but more slowly, beyond the 1 h time span of the IDR measurements. The order of the endothermic heats of solution into pH 12.4 glycine buffer is form V ∼ form I ≫ form III ∼ form II, corresponding to the reverse order of the enthalpy of the solid phases. ESEM micrographs showed the platy habits of forms I-III and V and the fractured surfaces of the desolvated polymorph, form II.