Assessing Supersaturation and Its Impact on In Vivo Bioavailability of a Low-Solubility Compound ABT-072 With a Dual pH, Two-Phase Dissolution Method.

ABT-072 is a candidate drug evaluated for treatment of hepatitis C virus. It is an acidic compound with extremely low intrinsic aqueous solubility. An in vitro dissolution-partition system, referred as biphasic test method, was used to characterize ABT-072 prototype formulations. This test used 2 aqueous dissolution media of pH 2 and 6.5 in a sequential manner to simulate the transition of drug in gastrointestinal tract. The biphasic test used in this work effectively differentiated various ABT-072 formulations derived from conventional and enabling technologies. In vitro profiles of these formulations indicate a complex interplay among the 3 competitive kinetic processes including dissolution, precipitation, and partition in the aqueous media. The relative amount of drug partitioned into the organic phase (i.e., octanol) from different formulations was found to be directly related to their in vivo exposures observed in both dogs and human subjects, respectively. An in vitro-in vivo relationship was obtained between ABT-072 concentrations in octanol at t = 2 h from these formulations and the relative bioavailabilities in dogs and human subjects. This work revealed the significance of polymeric precipitation inhibition by sustaining a supersaturated state of ABT-072 and its impact on in vivo exposure in human subjects.

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.

Mechanisms by which moisture generates cocrystals.

The purpose of this study is to determine the mechanisms by which moisture can generate cocrystals when solid particles of cocrystal reactants are exposed to deliquescent conditions (when moisture sorption forms an aqueous solution). It is based on the hypothesis that cocrystallization behavior during water uptake can be derived from solution chemistry using models that describe cocrystal solubility and reaction crystallization of molecular complexes. Cocrystal systems were selected with active pharmaceutical ingredients (APIs) that form hydrates and include carbamazepine, caffeine, and theophylline. Moisture uptake and crystallization behavior were studied by gravimetric vapor sorption, X-ray powder diffraction, and on-line Raman spectroscopy. Results indicate that moisture uptake generates cocrystals of carbamazepine-nicotinamide, carbamazepine-saccharin, and caffeine or theophylline with dicarboxylic acid ligands (oxalic acid, maleic acid, glutaric acid, and malonic acid) when solid mixtures with cocrystal reactants deliquesce. Microscopy studies revealed that the transformation mechanism to cocrystal involves (1) moisture uptake, (2) dissolution of reactants, and (3) cocrystal nucleation and growth. Studies of solid blends of reactants in a macro scale show that the rate and extent of cocrystal formation are a function of relative humidity, moisture uptake, deliquescent material, and dissolution rates of reactants. It is shown that the interplay between moisture uptake and dissolution determines the liquid phase composition, supersaturation, and cocrystal formation rates. Differences in the behavior of deliquescent additives (sucrose and fructose) are associated with moisture uptake and composition of the deliquesced solution. Our results show that deliquescence can transform API to cocrystal or reverse the reaction given the right conditions. Key indicators of cocrystal formation and stability are (1) moisture uptake, (2) cocrystal aqueous solubility, (3) solubility and dissolution of cocrystal reactants, and (4) transition concentration.

Cocrystal formation during cogrinding and storage is mediated by amorphous phase.

PURPOSE: The purpose of this work was to investigate the mechanisms of cocrystal formation during cogrinding and storage of solid reactants, and to establish the effects of water by cogrinding with hydrated form of reactants and varying RH conditions during storage. METHODS: The hydrogen bonded 1:1 carbamazepine-saccharin cocrystal (CBZ-SAC) was used as a model compound. Cogrinding of solid reactants was studied under ambient and cryogenic conditions. The anhydrous, CBZ (III), and dihydrate forms of CBZ were studied. Coground samples were stored at room temperature at 0% and 75% RH. Samples were analyzed by XRPD, FTIR and DSC. RESULTS: Cocrystals prepared by cogrinding and during storage were similar to those prepared by solvent methods. The rate of cocrystallization was increased by cogrinding the hydrated form of CBZ and by increasing RH during storage. Cryogenic cogrinding led to higher levels of amorphization than room temperature cogrinding. The amorphous phase exhibited a T (g) around 41 degrees C and transformed to cocrystal during storage. CONCLUSIONS: Amorphous phases generated by pharmaceutical processes lead to cocrystal formation under conditions where there is increased molecular mobility and complementarity. Water, a potent plasticizer, enhances the rate of cocrystallization. This has powerful implications to control process induced transformations.

General principles of pharmaceutical solid polymorphism: a supramolecular perspective.

The diversity of solid-state forms that an active pharmaceutical ingredient (API) may attain relies on the repertoire of non-covalent interactions and molecular assemblies, the range of order, and the balance between entropy and enthalpy that defines the free energy landscape. It is recognized that crystallization is associated with molecular recognition events that lead to self-assembly, and that pharmaceutical function and thermodynamic stability can be altered with a slight change in the interacting molecules or their molecular network motifs. Our current understanding of pharmaceutical solids in terms of molecular recognition and complementarity provides new insights into the design and function of single and fully miscible, multiple-component solids with varying degrees of order, from amorphous to crystalline states, and in this way is leading the path to supramolecular pharmaceutics. This review describes pharmaceutical solids in terms of supramolecular chemistry and crystal engineering concepts, and discusses the events that control crystallization and solid phase transformations.