Physicochemical characterization of the various solid forms of carbovir, an antiviral nucleoside.
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 degrees C) which is immediately followed by melting and decomposition. With increasing temperature in DSC, forms I and V transformed successively to form III (195 degrees C), then to form II (220 degrees C), and then to form IV (275 degrees 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 degrees 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Nguyen
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NA
Pharmaceutical Development, Glaxo Inc., Research Triangle Park, NC 27709.
Ghosh
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S
Gatlin
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Grant
D J
DJ
D000998:Antiviral Agents / Q000737:chemistry*; D002151:Calorimetry; D002152:Calorimetry, Differential Scanning; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015224:Dideoxynucleosides / Q000737:chemistry*; D006813:Humidity; D008855:Microscopy, Electron, Scanning; D012995:Solubility; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared; D013816:Thermodynamics; D013818:Thermogravimetry; D014961:X-Ray Diffraction
D000998:Antiviral Agents; D015224:Dideoxynucleosides; C057503:carbovir