Revealing the intergrowth phenomenon of aspirin polymorphs through a swift cooling crystallization process

Abstract

Nucleation control and isolation of polymorphic forms of the essential pharmaceutical medicine aspirin (ASP) was examined by a supersaturation-dependent swift cooling crystallization process using acetonitrile as solvent. In the present investigation, a saturated solution was prepared at 323 K and swiftly cooled down to various temperatures below the equilibrium temperature in steps of 1 K by conducting a series of 49 systematic cooling experiments which gave a very clear nucleation matrix, indicating the preferred nucleation region of all the three polymorphic forms of aspirin under different supersaturation conditions in the range 0.20 < σ < 1.65. Moreover, an observed solution-mediated polymorphic phase transformation (SMPT) under specific supersaturation conditions (σ = 0.97) indicates that the dissolution of characteristic faces { 0 2} and { 1 1} occurs in the grown metastable form-II, and the characteristic face {0 0 } of form-I simultaneously nucleates and grows over form-II in the −c and +c crystallographic directions on the surface of form-II. This discovery may provide a better understanding of the intergrowth phenomenon of aspirin polymorphs. The occurrence of this peculiar phenomenon was further ensured by attachment energy calculations, morphology assessment, and relative area analyses. Also, the nucleation kinetics of the grown ASP polymorphs were evaluated using the experimentally obtained induction time and calculated supersaturation values, by the classical nucleation theory (CNT) approach, and these results are well matched with the obtained experimental results. The structural and phase stability of the grown polymorphs were ascertained by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) analyses.