The Risk of Recrystallization: Changes to the Toxicity and Morphology of Pyrimethamine

Abstract

-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 PyrMeOH 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.

The Pressure-Induced Polymorphic Transformations in Fluconazole

“…The occurrence of polymorphism in an API and its impact on physicochemical and pharmaceutical properties can result in changes in the solubility, stability, dissolution, bioavailability, and efficacy of a drugs. This problem is well documented in the pharmaceutical literature . However, during a pharmaceutical manufacturing, the initial compound purity can degrade as a result of stresses and other factors leading to the irreproducible transformations .…”

“…The two forms of fluconazole named as polymorphic forms I and II were explored well by means of an X‐ray diffraction, Raman spectroscopy, and differential scanning calorimetry . Prior to the melting of fluconazole form I, a transition into a glassy state was found, which is subsequently transformed to a stable polymorphic form II after cooling .…”