In situ UV-monitoring was applied to the study of dissolution profiles and solubility behavior of practically insoluble compounds introduced as powders to small volumes of biorelevant dissolution media (BDM).

The objective of this study was to investigate the properties of several of the polymorphs of sulfathiazole using a novel powder intrinsic dissolution rate (IDR) approach1, and to relate the powder IDR values to results obtained with new miniaturized disk IDR apparatus2 and to solubility of sulfathiazole.

In the present study, we explored a new miniaturized disk intrinsic dissolution rate (IDR) method applied to 14 model drug compounds, using as little as 5 mg to make compacted disks of 0.071 cm2 exposed surface area, rotated in buffer media of as little as 10 mL volume. Drug concentration was measured by an in situ fiber optic UV method. All of the low-soluble and many of the high-soluble model drugs considered by Yu et al.1 along with some other compounds with available IDR data obtained by traditional means were included in the comparison. The main objective of the study was to demonstrate that the miniaturized disk IDR apparatus and method can produce results of comparable reliability as those obtained by traditional Wood’s apparatus methods, without the need for any scaling adjustments, and that the miniaturized apparatus can be potentially useful in BCS classification of solubility, applied at a much earlier time in the development cycle.

The purpose of this project was to measure the apparent solubility of a diverse series of poorly soluble compounds (fig. 1) in four different biorelevant dissolution media (BDM) simulating intestinal conditions to investigate potential consequences for an apparent BCS classification.

It has been shown1, that disk intrinsic dissolution rate (IDR) can be determined from powder dissolution experiments for BCS class II and IV (low soluble) compounds. This research investigated the applicability of a novel approach for estimating particle size from powder dissolution experiments of very small quantities of compounds. Five model compounds were selected for the study: hydrochlorothiazide, phenazopyridine, 2-naphthoic acid, indomethacin, and dipyridamole (span in solubility 5-911 μg/mL).2

The mechanism of drug release from complex dosage forms, such as multivesicular liposomes (MVLs), is complex and oftentimes sensitive to the release environment. This challenges the design and development of an appropriate in vitro release test (IVRT) method. In this study, a commercial bupivacaine MVL product was selected as a model product and an IVRT method was developed using a modified USP 2 apparatus in conjunction with reverse-dialysis membranes. This setup allowed the use of in situ UV–Vis probes to continuously monitor the drug concentration during release. In comparison to the traditional sample-and-separate methods, the new method allowed for better control of the release conditions allowing for study of the drug release mechanism. Bupivacaine (BPV) MVLs exhibited distinct tri-phasic release characteristics comprising of an initial burst release, lag phase and a secondary release. Temperature, pH, agitation speed and release media composition were observed to impact the mechanism and rate of BPV release from MVLs. The size and morphology of the MVLs as well as their inner vesicle compartments were analyzed using cryogenic-scanning electron microscopy (cryo- SEM), confocal laser scanning microscopy and laser diffraction, where the mean diameters of the MVLs and their inner “polyhedral” vesicles were found to be 23.6 ± 11.5 μm and 1.52 ± 0.44 μm, respectively. Cryo-SEM results further showed a decrease in particle size and loss of internal “polyhedral” structure of the MVLs over the duration of release, indicating erosion and rearrangement of the lipid layers. Based on these results a potential MVL drug release mechanism was proposed, which may assist with the future development of more biorelevant IVRT method for similar formulations.