PHYSICOCHEMICAL CHARACTERIZATION OF THE VARIOUS SOLID FORMS OF CARBOVIR, AN ANTIVIRAL NUCLEOSIDE

Carbovir, which exhibits promising in-vitro activity against HIV, is s hown to exist in five forms: I, II, III, IV, and V. Forms I-III and V were characterized by differential scanning calorimetry (DSC), thermog ravimetric analysis (TGA), hot-stage microscopy (HSM), Karl Fischer ti trimetry (KFT), powder X-ray diffraction (PXD), intrinsic dissolution rate (IDR) studies, heat of solution measurements (SC), scanning elect ron microscopy (SEM), Fourier-transform infrared (FTIR) spectroscopy, and water uptake at various relative humidities (water activities). Fo rm IV could not be characterized fully, as it is stable only over a na rrow temperature range (267-275 degrees C) which is immediately follow ed by melting and decomposition. With increasing temperature in DSC, f orms I and V transformed successively to form III (195 degrees C), the n to form II (220 degrees C), and then to form IV (275 degrees C). The PXD patterns, FTIR spectroscopy, IDR, and SC showed significant diffe rences between these polymorphs. For each of the forms I, II, and III, there, exists a critical value of relative humidity above which absor ption of water proceeds steeply, leading to the formation of form V, w hich 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 degrees C), sugge sting the presence of water molecules with two different binding energ ies probably corresponding to two different locations in the crystal l attice; HSM confirmed the dehydration. Thus, while forms I and V are h ydrates, containing ca. 0.9 and 1.2 mol of water/mol of carbovir, resp ectively, hom KFT, forms II-IV are different unsolvated polymorphic fo rms. Form I is a (pseudopolymorphic) hydrate which may have variable w ater stoichiometry. The order of the IDR values of compacted disks int o water at 25 degrees C is form II much greater than form III > form I similar to form V, corresponding to the order of free energy with res pect to the aqueous solution. While the dissolution of forms I, III, a nd V was linear, this IDR of form II decreased after 15 min to a const ant value, corresponding to conversion to form V. In contact with wate r, 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 he ats of solution into pH 12.4 glycine buffer is form V similar to form I much greater than form III similar to form II, corresponding to the reverse order of the enthalpy of the solid phases. ESEM micrographs sh owed the platy habits of forms I-III; and V and the fractured surfaces of the desolvated polymorph, form II.