Effects of Polymers on Cocrystal Growth in a Drug-Drug Coamorphous System: Relations between Glass-to-Crystal Growth and Surface-Enhanced Crystal Growth.

Coamorphous and cocrystal drug delivery systems provide attractive crystal engineering strategies for improving the solubilities, dissolution rates, and oral bioavailabilities of poorly water-soluble drugs. Polymeric additives have often been used to inhibit the unwanted crystallization of amorphous drugs. However, the transformation of a coamorphous phase to a cocrystal phase in the presence of polymers has not been fully elucidated. Herein, we investigated the effects of low concentrations of the polymeric excipients poly(ethylene oxide) (PEO) and poly(vinylpyrrolidone) (PVP) on the growth of carbamazepine-celecoxib (CBZ-CEL) cocrystals from the corresponding coamorphous phase. PEO accelerated the growth rate of the cocrystals by increasing the molecular mobility of the coamorphous system, while PVP had the opposite effect. The coamorphous CBZ-CEL system exhibited two anomalously fast crystal growth modes: glass-to-crystal (GC) growth in the bulk and accelerated crystal growth at the free surface. These two fast growth modes both disappeared after doping with PEO (1-3% w/w) but were retained in the presence of PVP, indicating a potential correlation between the two fast crystal growth modes. We propose that the different effects of PEO and PVP on the crystal growth modes arose from weaker effects of the polymers on cocrystallization at the surface than in the bulk. This work provides a deep understanding of the mechanisms by which polymers influence the cocrystallization kinetics of a multicomponent amorphous phase and highlights the importance of polymer selection in stabilizing coamorphous systems or preparing cocrystals via solid-based methods.

Melt Crystallization of Celecoxib-Carbamazepine Cocrystals with the Synchronized Release of Drugs.

PURPOSE: The fixed-dose combination drug products have been increasingly used to treat some complex diseases. A cocrystal containing two therapeutic components, named as a drug-drug cocrystal, is an ideal solid form to formulate as a fixed-dose combination product. The aim of the study is to prepare celecoxib-carbamazepine (CEL-CBZ) cocrystals by melt crystallization to achieve the synchronized release of drugs. METHOD: The crystal structure of the CEL-CBZ cocrystal was determined from the cocrystals harvested from melt by single crystal X-ray diffraction. The binary phase diagram and crystal growth kinetics of the CEL-CBZ cocrystal from melt were studied to optimize the process parameters of hot-melt extrusion for manufacturing large-scale cocrystals. The intrinsic dissolution rate studies were conducted to compare the dissolution profiles of drugs in the cocrystal and their individual forms. RESULT: The CEL-CBZ cocrystal crystallized in the triclinic space group with one CEL and one CBZ molecule in the asymmetric unit. The crystallization of CEL-CBZ cocrystals were observed both in the supercooled liquid and glassy state. The formation of drug-drug cocrystals significantly alter the intrinsic dissolution rates of the parent drugs to favor the synchronized release. CONCLUSION: Melt crystallization is an alternative, efficient and eco-friendly approach for preparing drug-drug cocrystals on a large scale. The synchronized drug release by drug-drug cocrystals can be used to modulate the release profiles of parent drugs in the fixed-dose combination products.

Advances in the development of amorphous solid dispersions: The role of polymeric carriers.

Amorphous solid dispersion (ASD) is one of the most effective approaches for delivering poorly soluble drugs. In ASDs, polymeric materials serve as the carriers in which the drugs are dispersed at the molecular level. To prepare the solid dispersions, there are many polymers with various physicochemical and thermochemical characteristics available for use in ASD formulations. Polymer selection is of great importance because it influences the stability, solubility and dissolution rates, manufacturing process, and bioavailability of the ASD. This review article provides a comprehensive overview of ASDs from the perspectives of physicochemical characteristics of polymers, formulation designs and preparation methods. Furthermore, considerations of safety and regulatory requirements along with the studies recommended for characterizing and evaluating polymeric carriers are briefly discussed.

Mechanistic insights into the crystallization of coamorphous drug systems.

In our previous study, the coamorphous formulation of lurasidone hydrochloride (LH) with saccharin (SAC) showed significantly enhanced dissolution and physical stability compared to crystalline/amorphous LH. However, the coamorphous system is still in amorphous state, and has the tendency to recrystallization, which will in turn result in the loss of above advantages. In this study, the crystallization kinetics under isothermal and non-isothermal conditions was investigated. Compared to amorphous LH, coamorphous LH-SAC showed 68.3-361.2 and 2.6-6.1 times lower crystallization rates in glassy state and supercooled liquid state, respectively. After co-amorphization, the addition of SAC changed the crystallization mechanism of amorphous LH from nucleation-controlled to diffusion-controlled manner. Amorphous LH followed the site-saturated nucleation, whereas the coamorphous system exhibited a fixed number of nuclei. The non-isothermal crystallization indicated amorphous LH and coamorphous LH-SAC showed two-dimensional (JMAEK 2) and three-dimensional (JMAEK 3) growth of nuclei, respectively. Furthermore, coamorphous LH-SAC exhibited higher molecular mobility and dynamic fragility (mD) than amorphous LH, which is kinetically unfavorable for its physical stability. However, from thermodynamic perspective, coamorphous LH-SAC had a higher configurational entropy, i.e., a higher entropy barrier for crystallization, which is beneficial to hinder its crystallization. Therefore, it was concluded that the higher configurational entropy rather than the molecular mobility was proposed to be responsible for its improved stability. In addition, molecular dynamics simulations with miscibility, radial distribution function and binding energy calculations suggested coamorphous components exhibited good miscibility and strong intermolecular interactions, which was also conductive to the enhancement in its stability. This study offers an in-depth understanding about the effect of the coformer on the crystallization kinetics of coamorphous systems, and points out the important contribution of the configurational entropy in stabilizing the coamorphous systems.