Effect of enantiomeric ratio and preparation method on proline crystal form

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Proline enantiomers were crystallized in a range of enantiomeric ratios and characterized by thermal methods, X-ray diffraction, and solid-state NMR spectroscopy to qualitatively and quantitatively characterize the resulting crystal forms. When crystallized by solvent evaporation or in the absence of enantiomeric excess, the observed racemic cocrystal consisted of only the previously published form, DL-proline (form I). However, lyophilization of solutions containing enantiomeric excess resulted in the presence of a new, thermodynamically stable polymorph of the racemic cocrystal, DL-proline form II. Both the enantiomeric ratio and crystallization method influenced the polymorphism of the racemic cocrystal. Due to the prevalence of chiral molecules and cocrystals among pharmaceuticals, this work has implications for current polymorphic screening methods.