Study of solid-state transitions and its impact on solubility and stability of Repaglinide

The aim of this research was to study the impact of melting and quenching approach on solid-state characteristics of amorphous dispersion and its impact on dissolution and solubility of Repaglinide, a BCS Class II drug. Solid dispersions of Repaglinide were prepared separately by quench cooling technique using Syloid® 244FP (porous silicon dioxide) and Microcrystalline Cellulose (MCC) PH 101 (Vivapur® 101) as carriers in 1:3, 1:1 and 3:1 ratio. A Repaglinide control sample was prepared using melting followed by rapid cooling. The control and solid dispersions prepared using both carriers were placed on stability at 40oC/75% RH and 30oC/60% RH conditions for 4 weeks to observe their physical state and solubility.

Partial crystallinity in the samples was determined using differential scanning calorimetry (DSC). The DSC data showed that there was an increase of 31% crystallinity of drug in 4 weeks for amorphous samples that were stored at 40oC/75%RH. The crystallinity of Repaglinide in solid dispersions with Syloid® 244FP (all three ratios) and MCC PH101 (1:3, 1:1 ratios) was less than 3% suggesting substantial stabilization in amorphous state. The amorphous dispersions were further characterized by Scanning Electron Microscope and Fourier Transform Infrared (FT-IR) which suggested that there was a hydrogen bond formation between Repaglinide and both carriers and was more prominent at higher carrier ratios of 1:3 and 1:1. Solubility of the Repaglinide and its dispersion were measured in presence of citrate-phosphate buffer at pH 5.0 using UV spectrophotometer.

Repaglinide is a zwitter-ionic compound has less solubility at pH 5. The saturation solubility of Repaglinide original sample was 4.9 µg/ml in pH 5.0 citro-phosphate buffer, which was improved in the solid dispersions prepared with Syloid® 244FP and MCC PH 101 as a carrier in the ratio of 1:3 and 1:1 (Repaglinide: Carrier). Repaglinide: Syloid® 244FP dispersion showed significantly higher solubility than Repaglinide: MCC PH 101. The porous silicon dioxide (Syloid® 244FP) incorporated into solid dispersion acted as a carrier with high surface area to disperse the Repaglinide in dissolution media and prevented precipitation to keep the drug in solution and hence, enhance solubility of the drug. This research indicates that colloidal surface solid dispersion is a unique approach of adsorbing an amorphous drug onto a colloidal carrier, that could be useful to enhance solubility of a poorly soluble drug.

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Study of solid-state transitions and its impact on solubility and stability of Repaglinide
A Dissertation In Pharmaceutical SciencesPresented to the Graduate faculty of the University of the Sciences in Philadelphia in Partial Fulfillment of Requirements for the Degree of DOCTOR OF PHILOSOPHY
Submitted By Meet N. Desai, July 29, 2021