The risk of recrystallization: changes to the toxicity and morphology of pyrimethamine.

PURPOSE: Pyrimethamine, an anti-malarial agent known to exhibit solid state polymorphism, may be purified by means of recrystallization. Recrystallization may alter the solid state chemistry of pharmaceuticals, which may impact the toxicity and/or manufacturability thereof. We evaluated the risks associated with the recrystallization of pyrimethamine. METHODS: Pyrimethamine was recrystallized using several organic solvents. X-ray diffraction, thermal analysis, infra-red spectroscopy, microscopy, flowability -, solubility and dissolution testing as well as computational work were employed to evaluate the recrystallized products. RESULTS: A toxic solvatomorph of pyrimethamine (Pyr-MeOH) was found to be the product from methanol recrystallization. The elucidation of - and the elaboration on the unique characteristics of Pyr-MeOH provides the pharmaceutical industry with several means to identify Pyr-MeOH and to distinguish it from the pharmaceutically preferred anhydrous form (Pyr). Thermal methods of analysis found that the toxicity of Pyr-MeOH may be reversed by overcoming a desolvation activation energy of 148 kJ/mol. In addition it was found that recrystallization altered the morphology of Pyr. Angle of repose and tapped density determinations identified that the different morphologies of Pyr displayed differences in powder flow and compressibility behaviour and In Silico calculations were successful in rendering morphologies resembling that found experimentally. CONCLUSION: We present a solvatomorph of pyrimethamine and provide several characteristic means to identify this unwanted toxic form and quantified the energy required to overcome its toxicity. In addition we describe that Pyr may present in different morphologies and show how it may impact the manufacturability thereof.

Comparison of the aqueous solubilization of practically insoluble niclosamide by polyamidoamine (PAMAM) dendrimers and cyclodextrins.

This study is the first report of the solubilization of niclosamide by cyclodextrin complexation or the interaction between the drug and polyamidoamine (PAMAM) dendrimers. Half generation dendrimers with more polar carboxylate surface functional groups did not increase the solubility of niclosamide. From the phase solubility studies, when the fold enhancement in solubility of niclosamide combined with full generation amine terminated PAMAM dendrimers was compared with that obtained when the drug was combined with beta- or hydroxypropyl-beta-cyclodextrin, the results showed that, except for G-0 dendrimer at pH 7, the solubility of niclosamide was significantly higher in the presence of the dendrimers. In addition, higher equilibrium stability constants and complexation efficiency showed that the dendrimers formed stronger more stable complexes than the CDs. However, the strong interaction between the amine surface functional groups and the niclosamide molecule complexes caused a decrease in dissolution rate compared to the CDs because the interaction retarded the release of the drug from the dendrimers. In addition to increasing the solubility, PAMAM dendrimers therefore also offer the possible for the controlled release of the drug from solid dosage forms.

Characterization of polymorph transformations that decrease the stability of tablets containing the WHO essential drug mebendazole.

This study investigated the influence of moisture and heat on the stability of mebendazole polymorph C in tablets. The polymorphic forms of mebendazole display significant differences in solubility and therapeutic efficacy and form C is preferred clinically due to its optimal bioavailability and reduced toxicity. An accelerated stability study of the polymorphs revealed that the Johnson-Mehl-Avrami-Erofeyev-Kolmogorov (JMAEK) model best described the kinetics of the solid-state transformation of form C to A. Rate constants obtained using this model was used to calculated half-lives and shelf lives of products stored under ICH conditions of 30 degrees C + 65% RH and 40 degrees C + 75% RH. Results showed that form C was converted to the thermodynamic stable, least soluble form A with increased temperatures and moisture, and at constant temperature and relative humidity this transformation was significantly increased when trace amounts of form A was present in the tablets. Four out of the seven products tested contained trace amounts of form A. In some tablets, the transformation to form A was so quick that it reduced the shelf life to less than 1 month. The tablet dissolution of these products was reduced to such an extent that it did not comply with USP and FDA specifications.