Amorphization Alone Does Not Account for the Enhancement of Solubility of Drug Co-ground with Silicate: The Case of Indomethacin

Abstract

Abstract. The solubility advantage of indomethacin amorphized by co-grinding with Neusilin US2 in various media was investigated. Physical mixtures of γ-indomethacin and Neusilin US2 (in the ratios 1:1, 1:4 and 1:5) were amorphized at room temperature employing 75% RH in a porcelain jar mill using zirconia balls. The crystallinity of the samples was determined using ATR-FTIR and PXRD. The solubility and dissolution profiles of co-ground powders and crystalline counterparts were evaluated in 0.1 N HCl, water and phosphate buffer (pH 6.8) in a USP type II dissolution apparatus at 250 rpm and 37°C. Very high concentrations of dissolved indomethacin as compared to the solubility of γ-indomethacin (~500 times in water and~3.7 times in phosphate buffer) were attained. However, the presence of other polymorphs detected by PXRD and a change in the pH of the medium made interpretation of the results difficult. In 0.1 N HCl the solubility (i.e., the peak in a concentration versus time plot) of the amorphized drug in a 1:5 ratio with Neusilin increased to 109 times the solubility of crystalline γ-indomethacin alone. An increase in amount of drug and Neusilin in the same ratio added to the dissolution medium also increased peak and plateau dissolution concentrations. The presence of silicic acid and ions (Mg 2+ and Al 3+ ) in the dissolution media were found to cause the increase in the plateau concentration of indomethacin. Amorphization alone does not account for all of the dissolution enhancement; acidity, ions, and silicic acid are major contributors to dissolution enhancement.

Topical ophthalmic lipid nanoparticle formulations (SLN, NLC) of indomethacin for delivery to the posterior segment ocular tissues

“…IN (pKa of 4.5) exhibits pH-dependent solubility, which increases as a function of higher pH (acidic to neutral/alkaline: 1.5 µg/mL at pH 1.2 and 105.2 µg/mL at pH 7.4). IN displayed a solubility of 0.64 ± 0.02 mg/mL in phosphate buffer at pH 7.0, which is consistent with previously reported data [32, 33]. Additionally, the solubility of IN was increased by ~5 and ~6-fold with 5% w/v HPβCD and RMβCD in phosphate buffer at pH 7.0.…”

Cogrinding as a Tool to Produce Sustained Release Behavior for Theophylline Particles Containing Magnesium Stearate

“…Yang et al (12) showed a slower dissolution rate of prednisone compared to its crystalline form. An improvement in the dissolution rate and bioavailability of indomethacine by interaction with silica was reported by Watanabe et al (13) Most of the previous studies on cogrinding reported a dramatic increase in the dissolution rate of drug amorphized by cogrinding technique with carrier (14,15). The product obtained from the cogrinding process can be packaged into sachets as powder form with pharmaceutically acceptable excipients.…”

“…Therefore, it is important to compare release rates of physical mixtures with coground samples to explore advantages of coground samples over simple physical mixtures. The physical mixtures of theophylline with various concentrations of magnesium stearate (1%, 3%, 5%, and 10%, w/w) were prepared at different mixing times (1,5,15, and 30 min), and the results of drug release from these formulations were presented in Fig. 2.…”

Manufacture and Performance Evaluation of a Stable Amorphous Complex of an Acidic Drug Molecule and Neusilin

“…Similar dissolution behavior has also been observed for indomethacin-Neusilin amorphous complexes. 25 Crystalline Sulindac did not show any appreciable improvement in dissolution or solubility when Neusilin was added to the dissolution media. Thus, the presence of Neusilin cannot explain the increased plateau concentration observed for the amorphous complexes.…”