Crystal Forms of Anti-HIV Drugs: Role of Recrystallization

Abstract

Understanding and controlling the solid-state chemistry of active pharmaceutical ingredients (APIs) is an important aspect of drug development process. APIs can exist in a variety of distinct solid forms, including polymorphs, solvates, hydrates, salts, cocrystals and amorphous solids. Most APIs are purified and isolated by crystallization from an appropriate solvent during the final step in the synthetic process. A large number of factors can influence the crystal nucleation and growth during this process, including the composition of the crystallization medium and the processes used to generate supersaturation and promote crystallization. For development of a pharmaceutical product, it is generally accepted that the stable form should be identified and chosen for development. However, the stable crystal form of the parent compound may exhibit inadequate solubility or dissolution rate resulting in poor oral absorption, particularly for water insoluble compounds whereas a metastable form might have advantageous properties. Moreover, the metastable polymorphs constitute local minima in the energy landscape (Figure 1) with the thermodynamically stable form being the absolute minimum at a given temperature and pressure. Thus, the search for absolute minimum and energy differences between the local minima of the drug substances is the goal of material and formulation scientists in the pharmaceutical industry. While significant efforts are made by drug development groups to identify and characterize thermodynamically stable crystal forms early in development, there are many instances where new crystal forms have been discovered later in development process. The late emergence of thermodynamically stable crystal form is often explained by Ostwald’s law of stages which states that the least stable crystal form is likely to crystallize first. Metastable forms appear first during crystallization process as their crystallization kinetics is faster than those of stable forms but eventually transform into a stable form. It is important to study the transformations, because the sudden appearance or disappearance of a polymorphic form in pharmaceutical products can lead to serious consequences.