Abstract
Understanding polymorphism in chiral systems for drug manufacturing is essential to avoid undesired therapeutic effects. Generally, polymorphism is studied through changes in temperature and solution concentration. A less common approach is the application of pressure. The goal of this work is to investigate the effect of pressure on levetiracetam (pure enantiomer) and etiracetam (racemic compound). Anisotropic compressions of levetiracetam and etiracetam are observed to 5.26 and 6.29 GPa, respectively. The most compressible direction for both was identified to be perpendicular to the layers of the structure. Raman spectroscopy and an analysis of intermolecular interactions suggest subtle phase transitions in levetiracetam (∼2 GPa) and etiracetam (∼1.5 GPa). The stability of etiracetam increases with respect to levetiracetam on compression; hence, the chiral resolution of this system is unfavorable using pressure. This work contributes to the ongoing efforts in understanding the stability of chiral systems.
Highlights
Polymorphism is the ability of a chemical compound to exist in more than one crystalline form.[1]
This phenomenon plays an important role in the development of new drugs due to a possible modification of physicochemical properties in active pharmaceutical ingredients (APIs): e.g., solubility, processing behavior, and bioavailability.[2,3]
Polymorphism can be found in chiral compounds, which are more than 50% of the active pharmaceutical compounds currently in the market.[4]
Summary
Polymorphism is the ability of a chemical compound to exist in more than one crystalline form.[1] This phenomenon plays an important role in the development of new drugs due to a possible modification of physicochemical properties in active pharmaceutical ingredients (APIs): e.g., solubility, processing behavior, and bioavailability.[2,3] Polymorphism can be found in chiral compounds, which are more than 50% of the active pharmaceutical compounds currently in the market.[4] Chirality is identified when a chemical compound exhibits two nonsuperimposable mirror-image conformers (enantiomers). Racemic compounds are the main products of synthesis and extra separation techniques are necessary to obtain the pure enantiomer.[5] The physicochemical properties of the two enantiomers are identical; their optical activities are opposite and their different conformations can lead to different physiological responses, enantiopure API crystal forms are selected preferentially for manufacture.[4,6−8]
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