Multistep Crystallization of Pharmaceutical Amorphous Nanoparticles via a Cognate Pathway of Oriented Attachment: Direct Evidence of Nonclassical Crystallization for Organic Molecules

Crystallization of organic molecules is important in a wide range of scientific disciplines. However, in contrast to maturely studied crystallization of inorganic materials, the crystallization mechanisms of organic molecules involving nucleation and crystal growth are still poorly understood. Here, we used time-resolved cryogenic transmission electron microscopy to directly map the morphological evolution of amorphous cyclosporin A (CyA) nanoparticles during CyA crystallization. We successfully observed its initial nucleation and found that the amorphous CyA nanoparticles crystallized via a pathway cognate with oriented attachment, which is the nonclassical crystallization mechanism usually reported for inorganic compounds. Crystalline mesostructured intermediates (mesocrystals) were formed during crystallization. This study revealed clear and direct evidence of mesocrystal formation and oriented attachment in organic pharmaceuticals, providing new insights into the crystallization of organic molecules and theories of nonclassical crystallization.