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To make rapidly disintegrating tablets with sufficient mechanical integrity as well as a pleasant taste, microcrystalline cellulose (MCC), Tablettose (TT), and crosslinked sodium carboxymethyl cellulose (Ac-di-sol) or erythritol (ET) were formulated. Tablets were made by a direct compression method (I). Tablet properties such as porosity, tensile strength, and disintegration time were determined. The tensile strength and disintegration time were selected as response variables, tablet porosity and parameters representing the characteristics of formulation were selected as controlling factors, and their relation was determined by the polynomial regression method. Response surface plots and contour plots of tablet tensile strength and disintegration time were also constructed. The optimum combination of tablet porosity and formulation was obtained by superimposing the contour diagrams of tablet tensile strength and disintegration time. Rapidly disintegrating tablets with durable structure and desirable taste could be prepared within the obtained optimum region.

Dissolution behavior of diclofenac sodium (DS) from wax matrix granules (WMGs) prepared using a twin-screw compounding extruder is closely related to swelling ability and solubility of the rate-controlling agent employed. A swellable and soluble (hydroxypropyl)-cellulose (HPC-SL) generates both an expansion of pores inside WMGs and a structural change observed as cracking on the surface of WMGs. These changes are confirmed by mercury porosimetry. Release of DS was increased with an increase in the amount of HPC-SL in WMGs, but only 35% of DS was released from WMGs containing 73% (w/w) NaCl at the 24 h point of the dissolution. Further, no cracking was observed on the surface of NaCl-containing WMGs. A linear relationship between mean dissolution time (MDT) of DS for WMGs containing different types of HPC (HPC-SL, -M, and -H) and swelling abilities suggests that release of DS could be directly controlled by swelling of HPCs. In addition to this result, an application of the exponential model (Mt/M infinity = kt(n)) introduced by Ritger and Peppas (J. Controlled Release 1987, 5, 23-36) to DS release indicates that case II release plays a critical role in HPC-SL-containing WMGs and Fickian release is predominant in NaCl-containing WMGs since the values of n of WMGs containing 73% (w/w) NaCl and 40% (w/w) HPC-SL are 0.41 and 0.71, respectively. These results suggest that proper selection of rate-controlling agents based on their physicochemical properties (such as swelling ability and solubility) is important in designing WMGs with desired dissolution profiles.

No abstract

Nicotinamide is a hydrotropic agent that has been demonstrated to solubilize a wide variety of drugs through complexation. Past investigations on the potential interaction of nicotinamide with a solubilized drug have inadequately focused on aliphatic hydrotropes. This study examined the mechanism for the hydrotropic solubilization of nifedipine, a poorly water-soluble drug, in the aqueous solution of nicotinamide using not only nicotinamide analogues but also urea analogues as aliphatic hydrotropes. The values of stability constants, K1:2, at different temperatures in nicotinamide solution were determined by the phase solubility technique, and were utilized to estimate the thermodynamic parameters of complex formation between nifedipine and nicotinamide. The enthalpy change values suggested the participation of intermolecular forces other than hydrogen bonding in complexion. The aqueous solubility of nifedipine was measured in the presence of nicotinamide, urea and their analogues: N-methylnicotinamide, N,N-diethylnicotinamide, nipecotamide, methylurea, ethylurea and butylurea. The drug solubility increased in proportion to the amount of alkyl substituent on the amide nitrogen, and the solubilizing effect of butylurea was as high as that of nicotinamide. Furthermore, the relationship between the logarithmic drug solubilities in 1.0 M aqueous solutions of nicotinamide or urea analogues versus the logarithmic octanol-water partition coefficient values of ligands as an indication of hydrophobicity was found to be linear. The significant contributor to the hydrotropic solubilization of nifedipine with nicotinamide was therefore the ligand hydrophobicity rather than the aromaticity of the pyridine ring.

No abstract

Solid dispersions (SD) of nitrendipine (NTD), a poorly water-soluble drug, were prepared using the meltmixing method with hydrophilic silica particles (Aerosil and Sylysia) with different particle size and specific surface areas as carriers. Powder X-ray diffraction and differential scanning calorimetry evaluation showed that NTD in the SDs treated with the melt-mixing method was dispersed in the amorphous state. FT-IR spectroscopy obtained with the SDs indicated the presence of hydrogen bonding between the secondary amine groups of NTD and silanol groups of silica particles. The dissolution property of NTD in the SDs was remarkably improved regardless of the grade of silica. At the end of the dissolution test (60 min) the concentrations of NTD for the SDs with Aerosil 200 and Sylysia 350 were 8.88 and 10.09 m mg/ml, corresponding to 28 and 31 times that of the original NTD crystals, respectively. The specific surface area and the adsorbed water amount of the SDs were also significantly improved. The rapid dissolution rate from the SDs was attributed to the amorphization of drug, improved specific surface area and wettability than the original drug crystals. In the stability test, powder X-ray diffraction pattern indicated that amorphous NTD in the SD with Aerosil 200 was stable for at least 1 month under the humid conditions (40°C/75% RH).

Examination was made of the release of indomethacin from hydroxypropylmethylcellulose (HPMC) matrices and the results were found to usually follow first order release kinetics. The release mechanism changed with formulation. HPMC content was the predominant controlling factor. As the HPMC content increased, drug release rate decreased, and the release mechanism gradually changed from Higuchi diffusion release to case II transport. Additives increased the release rate and enhanced Fickian diffusion. As drug content increased, release rate calculated from percent release data decreased while that calculated from mg release data increased. When indomethacin content was lower, drug release was diffusion controlled and when higher, non-Fickian transport or case II transport was apparent. Additive effects were also examined. Starch was found to most effectively maintain case II release. Complex additives containing starch were superior to any additive by itself. A multiple regression model was used to determine the relationship between response (release rate) and factors (content of HPMC and diluents), and on the basis of this model a formulation was established and found valid by agreement with data from the regression model.