Microgravity Crystallization of Active Pharmaceutical Ingredients (APIs): Impact on Crystalline Forms

Controlling the nature of solid forms of active pharmaceutical ingredients (APIs) can enhance the chemical stability, increase or decrease the solubility, reduce the dose required, reduce waste production, increase manufacturing yield, and improve the route of therapeutic delivery. Mefenamic acid, theophylline, mebendazole, acetazolamide, and carbamazepine–saccharin cocrystals were crystallized in microgravity aboard the International Space Station and in matched ground controls, and were characterized by optical microscopy, Raman spectroscopy, and FTIR spectroscopy. The outcomes were system-dependent. Mebendazole and acetazolamide gave a single polymorph in flight, whereas the ground controls gave two-form mixtures. Mefenamic acid gave the anhydrous form in flight and the dimethylformamide solvate on the ground. The carbamazepine–saccharin cocrystal system gave cocrystal needles in the analyzed flight samples, whereas the ground control also contained free carbamazepine alongside the cocrystal, with no accompanying change in cocrystal form. Theophylline gave the same form in both environments, with the flight crystals more numerous, larger, and more uniform in size and appearance. This study demonstrates that microgravity can influence solid-form selectivity, phase purity, crystal habit, crystal size, and morphological uniformity to differing extents depending on the system.