Category: Formulation and Quality
Purpose: In the drug developments, about 70% of candidate compounds are poorly water-soluble. The amorphization of poorly water-soluble drugs is one of the useful technique to improve the water solubility by deforming the crystal structures of drugs. On the other hand, the amorphous state results in crystallization due to their low physical stability. The amorphous solid dispersion consisted of an amorphous drug and a water-soluble polymer has been investigated to inhibit physically the crystallization of drugs. Meloxicam (MLX), a representative NSAIDs classified into BCS class II, has been used as a model drug to improve the solubility by solid dispersion. Recently, the coamorhpous system which is the amorphous complex consisted of drugs and additives with the intermolecular interaction has attracted attention as new amorphous system. The coamorphous system has the improvement effect of not only the solubility of the poorly water-soluble drug but also the physical stability for the amorphous drugs. Therefore, the aim of this study was to characterize formation of the coamorphous system for MLX by grinding and to investigate the solubility and the storage stability. The effect of the coamorphous system on the membrane permeability through Caco-2 monolayer was evaluated.
Methods: MLX and meglumine (MGL) were weighed at equimolar and physically mixed (physical mixture (PM)). Then, ground mixture (GM) was obtained by grinding of PM for 60 min with a vibrating ball mill. To confirm the formation of coamorphous consisting of MLX and MGL, the powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and infrared spectroscopy (IR) were determined about the obtained GM. Solubility and stability of the formed coamorphous were examined under the accelerated condition (40°C and 75% relative humidity (RH)) Membrane permeability of MLX was evaluated using Caco-2 cell monolayer.
Results: In the PXRD pattern of GM, the hallo patterns derived from the amorphous state were observed. A single glass transition temperature at 50.7°C was observed in DSC curve of GM. These results indicated that each amorphous component was homogeneously mixed resulting in the formation of a single amorphous phase. Furthermore, IR spectra showed the shift of the peak derived from the amide carbonyl group of MLX and the disappearance of the peak derived from the amide group or hydroxyl group of MGL in GM as compared with that of amorphous MLX and PM. Therefore, it was suggested that the cogrinding of MLX and MGL could form the coamorphous system with intermolecular interaction. In the solubility test at pH 7.2, the supersaturated solubility of MLX in GM after 30 min was increased 2- and 3-fold compared to PM and the amorphous MLX, respectively. When the pH of test solution was measured, the increase of pH in the solution due to the addition of MGL was observed in PM, whereas the pH of the solution in GM did not change. These results showed that the solubility of MLX might be improved by maintaining the intermolecular interaction of the coamorphous in the test solution. As a result of the storage stability test, the crystallization of MLX in the coamorphous was suppressed for at least 1month whereas the crystallization of amorphous MLX occurred within 5 days. These results suggested that the formation of coamorphous could inhibit the crystallization of MLX under 40°C and 75%RH conditions and stabilize physically the MLX amorphous state. Finally, the permeated rate of MLX across Caco-2 monolayer was about 60% in GM containing coamorphous whereas that of amorphous MLX or PM were less than 30%. This increased permeated amount would be due to the MLX concentration gradient between both sides of the Caco-2 monolayer caused by the supersaturation of MLX on the apical side. This result suggested the mucosal permeability of MLX was enhanced by preparing of the coamophous containing of MLX.
Conclusion: In the present study, we characterized that the new coamorphous consisting from MLX and MGL. Comparing with the amorphous of MLX, this coamorphous could be expected to use as a pharmaceutical solid-form for improving the physicochemical properties.