Wetting Kinetics: an Alternative Approach Towards Understanding the Enhanced Dissolution Rate for Amorphous Solid Dispersion of a Poorly Soluble Drug.

Developing amorphous solid dispersions of water-insoluble molecules using polymeric materials is a well-defined approach to improve the dissolution rate and bioavailability. While the selected polymer plays a vital role in stabilizing the amorphous solid dispersion physically, it is equally important to improve the dissolution profile by inhibiting crystallization from the supersaturated solution generated by dissolution of the amorphous material. Furthermore, understanding the mechanism of dissolution rate enhancement is of vital importance. In this work, wetting kinetics was taken up as an alternative approach for understanding the enhanced dissolution rate for amorphous solid dispersion of a poorly soluble drug. While cilostazol (CIL) was selected as the model drug, povidone (PVP), copovidone, and hypromellose (HPMC) were the polymers of choice. The concentrations against time profiles were evaluated for the supersaturated solutions of CIL in the presence and absence of the selected polymers. The degree of supersaturation increased significantly with increase in polymer content within the solid dispersion. While povidone was found to maintain the highest level of supersaturation for the greatest length of time both in dissolution and solution crystallization experiments, copovidone and hypromellose were found to be the less effective as crystallization inhibitor. The ability of polymers to generate and maintain supersaturated drug solutions was assessed by dissolution studies. The wetting kinetics was compared against the solid dispersion composition to establish a correlation with enhanced dissolution rate.

Disintegration mediated controlled release supersaturating solid dispersion formulation of an insoluble drug: design, development, optimization, and in vitro evaluation.

The objective of this study was to develop a solid dispersion based controlled release system for drug substances that are poorly soluble in water. A wax-based disintegration mediated controlled release system was designed based on the fact that an amorphous drug can crystallize out from hydrophilic matrices. For this study, cilostazol (CIL) was selected as the model drug, as it exhibits poor aqueous solubility. An amorphous solid dispersion was prepared to assist the drug to attain a supersaturated state. Povidone was used as carrier for solid dispersion (spray drying technique), hydrogenated vegetable oil (HVO) as wax matrix former, and sodium carboxymethyl cellulose (NaCMC) as a disintegrant. The extreme vertices mixture design (EVMD) was applied to optimize the designed and developed composition. The optimized formulation provided a dissolution pattern which was equivalent to the predicted curve, ascertaining that the optimal formulation could be accomplished with EVMD. The release profile of CIL was described by the Higuchi's model better than zero-order, first-order, and Hixson-Crowell's model, which indicated that the supersaturation state of CIL dominated to allow drug release by diffusion rather than disintegration regulated release as is generally observed by Hixson-Crowell's model. The optimized composition was evaluated for disintegration, dissolution, XRD, and stability studies. It was found that the amorphous state as well as the dissolution profile of CIL was maintained under the accelerated conditions of 40°C/75% RH for 6 months.

A systematic approach to design and prepare solid dispersions of poorly water-soluble drug.

The objective of the present study was to define a systematic approach to design and prepare solid dispersions of poorly water-soluble drug. The systematic approach can be defined in four phases. In the first phase, glass forming ability is assessed, and in the second phase, probable excipients are screened. The screened excipients are evaluated (third phase) for glass transition temperatures (Tg) and miscibility studies according to Florey-Huggins interaction parameter. The predicted excipients are used to prepare the solid dispersion and evaluated for Tg and any interactions using Fourier transfer infrared studies (fourth phase), and the findings are correlated with phase three predictions. For this investigation, cilostazol (CIL) was selected as model drug, which was classified as a poor glass former. As per the physical chemical properties of CIL, ten excipients, both polymeric and non-polymeric, were selected and screened. Out of these, povidone, copovidone, hypromellose and Eudragit EPO were found theoretically miscible with CIL. After going through phase 2 to phase 4, only povidone, copovidone and hypromellose were confirmed as polymer of choice for preparing the solid dispersion of CIL with a prediction of better physical solid-state stability on the basis of good miscibility between drug and carrier.

Rheological characterization of Microcrystalline Cellulose/Sodiumcarboxymethyl cellulose hydrogels using a controlled stress rheometer: part I.

Rheological properties of two different commercial grades of Microcrystalline Cellulose/Sodiumcarboxymethyl Cellulose (MCC/NaCMC) hydrogels were investigated. A controlled stress rheometer fitted with parallel plate geometry was used. Application of the Cross Model relating the viscosity and shear rate data indicated the gels are extremely shear thinning. The two grades of Avicel (RC-591 and CL-611) made of varying MCC and NaCMC concentrations, exhibited distinguishable changes in yield stress and shear thinning behavior attributable to the individual composition. The hydrogels reached structural equilibrium in 1 week after manufacture. Lot to lot variability of Formula A hydrogels had minimal influence on the rheological properties of the resulting hydrogels. The yield stress and/or initial viscosity values observed were proportional to the concentration or phase volume of the MCC/NaCMC in water.

Rheology of Microcrystalline Cellulose and Sodiumcarboxymethyl Cellulose hydrogels using a controlled stress rheometer: part II.

Rheological properties of two different commercial grades of Microcrystalline Cellulose/Sodiumcarboxymethyl Cellulose (MCC/NaCMC) hydrogels were investigated. Viscoelastic characterization of the hydrogels using a controlled stress rheometer revealed that structure formation in the gels could be detected at a concentration as low as 1.0% w/w MCC/NaCMC in purified water. The elastic modulus (G') and the linear viscoelastic region (LVR) increased with increase in hydrogel concentration. The frequency sweep study of the hydrogels exhibited a flat G', indicating a stable structure at 1.5% w/w and 2.0% w/w concentrations. The oscillation time sweep study indicated that the rate of structure build up was dependent on the concentration of hydrogel. Structure buildup at various temperatures indicated that structure formation was rapid at higher temperature (40 degrees C), and the gel point was reached fairly quickly. Phase volume of the hydrogel significantly influenced structural recovery at different temperatures.