Nucleation Control and Isolation of Polymorphic Forms of Aspirin through an Efficient Template‐Assisted Swift Cooling Process

Abstract

Aspirin, a commonly used pharmaceutical therapeutic pharmacological substance, exhibits cross‐nucleation (intergrowth or overgrowth) of stable polymorphic Form‐I over the preferably required metastable polymorphic Form‐II, which creates a bottleneck issue in the solution crystallization of aspirin in most organic solvents and their mixtures. Controlling the overgrowth phenomenon is a key factor for designing the pharmaceutical drug material aspirin with desired properties. Hence, our present work chose a novel template‐assisted swift cooling crystallization with selected templates like copper‐wire and nylon 6/6 polymer, and also N‐N‐Dimethylformamide (DMF) as a solvent. The pure solution in the absence and the presence of a nylon 6/6 template in all the experimental supersaturation ranges achieves only thermodynamically stable polymorphic Form‐I of aspirin with slightly different morphologies. Contrarily, the presence of a copper‐wire template induces both stable and metastable polymorphs of aspirin depending on the level of supersaturation in the mother solution. The effect of templates on the nucleation kinetics of aspirin polymorphs is estimated using classical nucleation theory, and the determined values exactly match with experimental results. The polymorphic nature of the grown crystals is ascertained by powder X‐ray diffraction (PXRD), single crystal X‐ray diffraction (SCXRD), and differential scanning calorimetry (DSC) analyses.