Tofogliflozin Salt Cocrystals with Sodium Acetate and Potassium Acetate.

We investigated the salt cocrystals formed by tofogliflozin with sodium acetate and potassium acetate by determining the crystal structures of the salt cocrystals and characterizing the solid states. The salt cocrystal screening using the slurry method and the liquid-assisted grinding method resulted in the formation of tofogliflozin-sodium acetate 1 : 1 and tofogliflozin-potassium acetate 1 : 1 salt cocrystals. Single-crystal X-ray diffraction revealed that, although each salt cocrystal belongs to a different space group, both of the salt cocrystals have almost similar structural features, including the conformation of tofogliflozin molecules, the coordination to Na+/K+ ions, and hydrogen bonds. The salt cocrystals exhibited extreme hygroscopicity with deliquescence, which is also a property of sodium acetate and potassium acetate. In addition, tofogliflozin-potassium acetate salt cocrystal had two polymorphs, which were enantiotropically related.

Effects of wet-granulation process parameters on the dissolution and physical stability of a solid dispersion.

This study investigated how the process parameters of wet-granulation affect the properties of solid dispersions (SDs), such as dissolution and physical stability. SDs of nilvadipine (NIL) and hypromellose prepared by spray-drying were wet-granulated and dried under various conditions. The NIL concentration at 4h and area under the curve from dissolution tests were taken to indicate dissolution. Then, the NIL crystallinity calculated from powder X-ray diffraction patterns of SD granules stored at 60°C for 3 months was evaluated to indicate physical stability. A statistical analysis revealed that the amount of granulation liquid (w/w%) and the ratio of water to ethanol in the liquid (v/v%) significantly affected the dissolution property, and that the drying temperature had a significant effect on the physical stability. Although exposure to water makes the wet-granulation process seem less suitable for granulating a SD, the results indicated that the process can be used to develop SD granules by selecting appropriate conditions, such as a lower proportion of granulation liquid, a higher water to ethanol ratio in the liquid, and a higher drying temperature.

Characterizing the dissolution profiles of supersaturable salts, cocrystals, and solvates to enhance in vivo oral absorption.

The purposes of this study were to elucidate the type-specific characteristics of salt, cocrystal, and solvate formulations upon dissolution and precipitation, and to clarify their effect on enhancing oral absorption. Several types of solid formulations (dantrolene sodium salt [DAN-NA], pioglitazone hydrochloride salt [PIO-HCL], megestrol acetate saccharin cocrystal [MEG-SA], and an in-house compound ZR ethanolate [ZR-ETH]) that induce supersaturation of BCS class II drugs were compared to their crystalline free forms. An in vitro miniscale dissolution test in biorelevant media was used to characterize their dissolution profiles and residue forms. Both salts (DAN-NA and PIO-HCL) rapidly reached the maximum concentration within 5min, whereas the cocrystal (MEG-SA) did so slowly. After the maximum concentration had been reached, the dissolved concentrations of DAN-NA, PIO-HCL, and MEG-SA decreased, but that of ZR-ETH did not. Time-dependent XRPD analysis revealed that the initial solid state of each salt dissolved within 5min, whereas the cocrystal remained for more than 10min, and the solvate remained for 4h. It also revealed that PIO-HCL and MEG-SA precipitated to the stable free form, while DAN-NA precipitated to the metastable form, which maintains a higher concentration than the stable free form continuously. In vivo absorption in beagle dogs was also examined. The plasma AUC of DAN-NA, MEG-SA, and ZR-ETH was respectively 1.5-, 2.1-, and 11-fold more than each free form. On the other hand, the absorption of PIO-HCL was not enhanced compared with its free form. The results in the present study clarified that not only the precipitation rate and the form of precipitation but also the retention of the initial solid state in the absorption process contribute to enhancing the in vivo absorption of Class II drugs from solid formulations such as salts, solvates, and cocrystals.

Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning.

Substituting a carbon atom with a nitrogen atom (nitrogen substitution) on an aromatic ring in our leads 11a and 13g by applying nitrogen scanning afforded a set of compounds that improved not only the solubility but also the metabolic stability. The impact after nitrogen substitution on interactions between a derivative and its on- and off-target proteins (Raf/MEK, CYPs, and hERG channel) was also detected, most of them contributing to weaker interactions. After identifying the positions that kept inhibitory activity on HCT116 cell growth and Raf/MEK, compound 1 (CH5126766/RO5126766) was selected as a clinical compound. A phase I clinical trial is ongoing for solid cancers.

A theoretical-empirical analysis on the initial dissolution rate of drugs from polydispersed particles.

The purpose of this work is to clarify the relationship of mean particle size to the dissolution rate of polydispersed particles for Biopharmaceutical Classification System (BCS) Class II drugs. An equation for the initial dissolution rate of polydispersed particles relative to mean particle diameter was theoretically derived from the Noyes-Whitney equation assuming spherical particles and sink conditions. To verify the relationship of dissolution to the mean particle diameters, the dissolution rates of 6 types of hypothetically-generated log-normal polydispersed particles and 3 different sized particles of aprepitant, a designated BCS class II drug, were compared with known mean diameters calculated according to surface area-weighted mean diameter (D(3,2), commonly referred to as the Sauter mean diameter), length-weighted mean diameter (D(3,1)) and number-weighted mean diameter (D(3,0)). The results confirmed that the initial dissolution rates of polydispersed particles reflect the mean diameter and correlated best with the reciprocal of D(3,2) at the start of dissolution, in accord with our theoretical conclusions. The particle size required for sufficient dissolution of aprepitant was also investigated by examining the relationship between D(3,2) and oral absorption predicted using a physiological-based model.

Dissolution improvement and the mechanism of the improvement from cocrystallization of poorly water-soluble compounds.

PURPOSE: To demonstrate improvement in the dissolution of exemestane and megestrol acetate from cocrystallization using various particle sizes and to investigate the mechanism of the improved dissolution. METHODS: Cocrystal screening was performed by slurry crystallization. The cocrystals were identified and characterized by powder X-ray diffraction, thermal analysis, and single crystal X-ray diffraction. Different particle sizes of each cocrystal were prepared from organic solutions. Solubility and dissolution rates were evaluated using dissolution tests. Transformation behavior of the cocrystals in suspension was analyzed by PXRD and polarization microscopy. RESULTS: Two novel cocrystals were obtained: exemestane (EX)/maleic acid (MAL) (cocrystal 1) and megestrol acetate (MA)/saccharin (SA) (cocrystal 2). Cocrystal 1 showed a high dissolution rate even with large particles. Cocrystal 2 showed supersaturation with fine particles. The transformation from cocrystal 1 to EX was observed within 1 min in suspension. Cocrystal 2 was transformed to MA within 2-4 h. CONCLUSIONS: 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.

Rate-limiting steps of oral absorption for poorly water-soluble drugs in dogs; prediction from a miniscale dissolution test and a physiologically-based computer simulation.

PURPOSE: Nonlinear oral absorption due to poor solubility often impedes drug development. The purpose of this study was to elucidate the rate-limiting process in oral absorption of Biopharmaceutical Classification System (BCS) class II (low solubility-high permeability) drugs in order to predict nonlinear absorption of dose caused by solubility-limited absorption. METHODS: Oral absorption of danazol, griseofulvin, and aprepitant was predicted from a miniscale dissolution test and a physiologically-based model. The effect of particle size reduction and dose increase on absorption was investigated in vitro and in vivo to clarify the rate-limiting steps of dissolution-rate-limited and solubility-limited absorption. RESULTS: The rate-limiting steps of oral absorption were simulated and increase in the dissolution rate and administration dose showed a shift from dissolution rate-limited to solubility-limited absorption. In the study in dogs, particle size reduction improved the oral absorption of large particle drugs but had little effect on small particle drugs. Dose nonlinearity was observed with small particles at a high dose. Our model quantitatively predicted results observed in vivo, including but not exclusively, dissolution-rate-limited and solubility-limited absorption. CONCLUSION: The present study provides a powerful tool to predict dose nonlinearity and will aid in the success of BCS class II drug development.