This new system quantitatively simulated human absorption and would be beneficial for the prediction of human F(a) values for BCS class II drugs.

Cocrystallizations of EX and MA improved initial dissolution rates compared to the respective original crystals. The mechanism of dissolution enhancement varied. With cocrystal 1, fine particle formation resulted in enhancement, whereas with cocrystal 2, enhancement was due to the maintenance of the cocrystal form and rapid dissolution before transformation to the original crystal.

The present study provides a powerful tool to predict dose nonlinearity and will aid in the success of BCS class II drug development.

A slurry crystallization technique was used in cocrystal screening of two nonionizable pharmaceutical host compounds, stanolone and mestanolone, with 11 pharmaceutically acceptable guest acids. Crystallization was performed simply by adding crystallization solvents to solid mixtures of a host and a guest, which had been prepared using lyophilization of their dimethyl sulfoxide solution. Powder X-ray diffraction and thermogravimetric/differential thermal analysis were used to identify new solid forms. Two resultant new forms, stanolone L-tartaric acid 1:1 cocrystal and mestanolone salicylic acid 1:1 cocrystal, were characterized using single-crystal X-ray diffraction. The hosts, despite having the same steroidal skeleton and the same functional groups that form strong hydrogen bonds, each formed a cocrystal with a different guest molecule. All functional groups of the host and guest molecules that form strong hydrogen bonds were engaged in hydrogen bonding, but, despite the highly analogous molecular structures of the hosts, the two cocrystals exhibited dissimilar crystal structures. The present study shows the slurry technique to be viable and practical for cocrystal screening and demonstrates the importance not only of hydrogen bonding but also of geometric fit in cocrystal formation.

Alectinib, a lipophilic, basic, anaplastic lymphoma kinase (ALK) inhibitor with very low aqueous solubility, has received Food and Drug Administration-accelerated approval for the treatment of patients with ALK+ non-small-cell lung cancer. This paper describes the application of physiologically based absorption modeling during clinical development to predict and understand the impact of food and gastric pH changes on alectinib absorption. The GastroPlus software was used to develop an absorption model integrating in vitro and in silico data on drug substance properties. Oral pharmacokinetics was simulated by linking the absorption model to a disposition model fit to pharmacokinetic data obtained after an intravenous infusion. Simulations were compared to clinical data from a food effect study and a drug-drug interaction study with esomeprazole, a gastric acid-reducing agent. Prospective predictions of a positive food effect and negligible impact of gastric pH elevation were confirmed with clinical data, although the exact magnitude of the food effect could not be predicted with confidence. After optimization of the absorption model with clinical food effect data, a refined model was further applied to derive recommendations on the timing of dose administration with respect to a meal. The application of biopharmaceutical absorption modeling is an area with great potential to further streamline late stage drug development and with impact on regulatory questions.

The purpose of this study is to clarify the effects of intestinal drug supersaturation on solubility-limited nonlinear absorption. Oral absorption of a novel farnesyltransferase inhibitor (FTI-2600) from its crystalline free base and its HCl salt was determined in dogs. To clarify the contribution of supersaturation on improving drug absorption, in vivo intraluminal concentration of FTI-2600 after oral administration was estimated from the pharmacokinetics data using a physiologically based model. Dissolution and precipitation characteristics of FTI-2600 in a biorelevant media were investigated in vitro using a miniscale dissolution test and powder X-ray diffraction analysis. In the in vitro study, the HCl salt immediately dissolved but precipitated rapidly. The metastable amorphous free base precipitant, which did not convert into the stable crystalline free base in the simulated intestinal fluids for several hours, generated a 5-fold increase in dissolved concentration compared to the equilibrium solubility of the crystalline free base. By computer simulation, the intraluminal drug concentration after administration of the free base was estimated to reach the saturated solubility, indicating solubility-limited absorption. On the other hand, administration of the HCl salt resulted in an increased intraluminal concentration and the plasma concentration was 400% greater than that after administration of the free base. This in vivo/in vitro correlation of the increased drug concentrations in the small intestine provide clear evidence that not only the increase in the dissolution rate, but also the supersaturation phenomenon, improved the solubility-limited absorption of FTI-2600. These results indicate that formulation technologies that can induce supersaturation may be of great assistance to the successful development of poorly water-soluble drugs.

We investigated the structures of the hydrated and dehydrated states and the in vitro dissolution of a spironolactone−saccharin 1:1 cocrystal hemihydrate, the cocrystal hydrate of a nonionizable, poorly water-soluble drug with a pharmaceutically acceptable coformer. The cocrystal hydrate has linear channels in its crystal structure where the water molecules locate and shows nonstoichiometric hydration, suggesting that the cocrystal hydrate and anhydrate are isostructural. Single-crystal X-ray diffraction using the cocrystal anhydrate prepared from single-crystal to single-crystal dehydration confirmed the isostructural relationship and showed retention of the linear channels and subtle shrinkage of the unit cell volume (∼0.3%) after dehydration. The dissolution of the cocrystal hydrate was evaluated in simulated intestinal fluid and fasted-state simulated intestinal fluid. The cocrystal hydrate improved solubility at about 2-fold the maximum supersaturated concentration with respect to the saturated solubility of spironolactone form II (the most stable form) in both media. However, the concentration decreased after reaching the maximum and the cocrystal hydrate converted to a previously unreported spironolactone 1/3 hydrate which was ∼0.8 times less soluble than spironolactone form II.

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