Didanosine and lopinavir : non–conventional solid–states

Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2012The physicochemical properties of several novel polymorphs and amorphous forms of the antiretroviral (ARV) agents, didanosine and lopinavir, are reported. The polymorphs were prepared from recrystallisation and the glasses from cooling of the melt. These products were then characterised by means of thermal, absorption and diffraction analyses and compared to the raw material for polymorphic differences. Didanosine yielded recrystallisation products from methanol, ethanol, 1- and 2-propanol, 1- butanol and acetonitrile. Of all these, only the product obtained from methanol exhibited a powder x-ray diffraction (PXRD) pattern different from that of didanosine raw material. To investigate methanol’s capacity to produce new polymorphs of didanosine, supersaturated solutions of didanosine in water were prepared and different amounts of methanol were added as antisolvent. The crystals hereby obtained, displayed macro- and microscopic morphologies similar to that of the crystals obtained from pure methanol, however, their infrared (IR) absorption spectra and PXRD diffractograms differed slightly from those of the raw material and the crystals obtained from methanol alone. All of didanosine’s recrystallisation products from alcohols exhibited non-stoichiometric weight loss from the start of a thermogravimetric analysis (TGA), long desolvation times on hot stage micrographs and broad desolvation endothermic peaks on differential scanning calorimeter (DSC) thermograms. This lead to the conclusion that the solvent was not incorporated into channels, as is usually the case with solvates, but rather that it formed a thin film around the crystals and was present in the capillary network between the fine, elongated crystals. Upon drying the didanosine crystals from alcohols lost their morphologies and reverted back to the same polymorphic form as the raw material. The presence of solvent around the crystals was necessary for them to maintain their morphologies. This same metastability was observed upon storing of the recrystallisation products, where they started to revert back to the raw material even while under the recrystallisation medium. At around two weeks small bundles of powder formed on top of the mesh network of crystals and after one month only powder remained, analysis of this powder proved it to be the same polymorphic form as the raw material, indicating that the raw material is the most stable form of didanosine. Comparison between the results from the solubility study and scanning electron microscope (SEM) micrographs, showed an increase in solubility corresponding to a decrease in crystal size. The different crystal morphologies had no influence on the wettability or the acid lability of didanosine, a direct result of the film of solvent coating the crystals. Any liquid that came into contact with the crystals was automatically dispersed across its surface. Lopinavir formed several recrystallisation products including large hexagonal plates from acetone, long hexagonal staffs from ethyl acetate, needles from diethyl ether and resins from chloroform and dichloromethane. Initial thermal analysis showed all the recrystallisation products, even the more crystalline ones, to be at least partially amorphous. For comparative purposes, two additional glasses were prepared from cooling of the melt. One was cooled at ambient temperature and the other was quench cooled using liquid nitrogen. Activation energies for β-relaxations (ΔEβ) and glass transitions were calculated from non-isothermal kinetics data obtained by DSC and from the activation energies for glass transition of each sample, the fragility (m) and strength (D) parameters of each sample were calculated. Comparisons between the ΔEβ and m were in excellent coherence to the macro- and microscopic characteristics of each sample and offered valuable insight into certain physical behaviour. The amorphous content of each sample was determined by means of DSC and Fourier transform infrared (FTIR) spectroscopy. Results from the solubility study exhibited little coherence with the crystalline/amorphous content of the samples analysed as well as with the m and D values. There was however, an inverse correlation between the solubility and the ΔEβ of each sample, suggesting that the increased local molecular motilities of the samples with low ΔEβ values (and the subsequent decrease of the contact angle), facilitated dissolution from these regions, leading to surface roughening and an increasing in effective surface area. The progression of this process, resulting from the ongoing coupling of the β- relaxations, eventually increased the solubility of the samples exhibiting the lowest ΔEβ values.Doctora