Understanding the Mechanisms, Thermodynamics and Kinetics of Cocrystallization to Control Phase Transformations.

The solid-state form of a drug influences its physico-chemical and biopharmaceutical properties. Consequently, phase transformations induced during processing/storage affects drug performance. Understanding the transformation mechanisms is valuable for anticipating and controlling phase transformations. In this dissertation, the mechanisms of conversion of crystalline drugs to cocrystals and factors affecting cocrystal stability are reported. Specifically, the objectives are to: (i) identify the factors governing the formation of different stoichiometry cocrystals, (ii) examine coformer, excipients and cosolvents effects on cocrystal hydrate thermodynamic stability, (iii) investigate the propensity and mechanisms of cocrystallization in solid mixtures due to moisture sorption, and (iv) identify the mechanisms by which mechanical activation induces cocrystal formation in mixtures. Model compounds selected in this study include carbamazepine, theophylline and coformers that form cocrystals. Coformer solution concentration governs the formation and stability of different stoichiometry cocrystals. Studies with 1:1 and 2:1 carbamazepine-4-aminobenzoic acid cocrystals indicate that the cocrystal richer in coformer is more stable at higher coformer concentration. Phase diagrams showing cocrystal solubility and stability domains are generated using mathematical models based on cocrystal and solution chemistry. Coformer concentration also governs the formation and stability of cocrystal hydrates in aqueous solutions. Studies with theophylline-citric acid and carbamazepine-4-aminobenzoic acid cocrystal hydrates indicate that coformers that modulate the water activity (aw) of aqueous solutions can induce cocrystal hydrate to anhydrous cocrystal conversion. Addition of excipients or cosolvents to aqueous solutions similarly affects cocrystal hydrate stability by decreasing aw. Cocrystallization can also occur in solid mixtures of cocrystal reactants. Cocrystals of carbamazepine-nicotinamide, carbamazepine-saccharin, and caffeine or theophylline with various carboxylic acid coformers are formed due to moisture sorption and deliquescence in reactant mixtures. Transformation mechanism involves moisture uptake, reactant dissolution, cocrystal nucleation and growth. The rate and extent of cocrystal formation depends on RH, moisture uptake, deliquescent material, mixture composition, and reactant dissolution rates. In the solid-state, cogrinding carbamazepine with saccharin or nicotinamide forms cocrystals. Cocrystal formation is shown to be amorphous phase mediated, and depends on cogrinding temperature, presence of moisture, and reactant hydrated form. Higher cogrinding temperature and water present in crystal lattice or vapor phase enhance cocrystallization.Ph.D.Pharmaceutical SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/61651/1/ajayasan_1.pd

Transformation pathways of cocrystal hydrates when coformer modulates water activity

An important attribute of cocrystals is that their properties can be tailored to meet required solubility and stability specifications. But before such practical uses can be realized, a better understanding of the factors that dictate co-crystal behavior is needed. This study attempts to explain the phase behavior of anhydrous/hydrated cocrystals when the coformer modulates both water activity and co-crystal solubility. Stability dependence on solution composition and water activity was studied for theophylline–citric acid (THP–CTA) anhydrous and hydrated cocrystals by both suspension and vapor equilibration methods. Eutectic points and associated water activities were measured by suspension equilibration methods to determine stability regions and phase diagrams. The critical water activity for the anhydrous–hydrate co-crystal was found to be 0.8. It is shown that (a) both water and coformer activities determine phase stability, and (b) excipients that alter water activity can profoundly affect the hydrate/anhydrous eutectic points and phase stability. Vapor phase stability studies demonstrate that cocrystals of highly water soluble coformers, such as citric acid, are predisposed to conversions due to moisture uptake and deliquescence of the coformer. The presence of such coformers as trace level impurities with co-crystal will alter hygroscopic behavior and stability. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3977–3985, 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77537/1/22245_ftp.pd