Controlled Suspensions Enable Rapid Determinations of Intrinsic Dissolution Rate and Apparent Solubility of Poorly Water-Soluble Compounds

Abstract

PurposeTo develop a small-scale set-up to rapidly and accurately determine the intrinsic dissolution rate (IDR) and apparent solubility of poorly water-soluble compounds.MethodsThe IDR and apparent solubility (Sapp) were measured in fasted state simulated intestinal fluid (FaSSIF) for six model compounds using wet-milled controlled suspensions (1.0% (w/w) PVP and 0.2% (w/w) SDS) and the μDISS Profiler. Particle size distribution was measured using a Zetasizer and the total surface area was calculated making use of the density of the compound. Powder and disc dissolution were performed and compared to the IDR of the controlled suspensions.ResultsThe IDR values obtained from the controlled suspensions were in excellent agreement with IDR from disc measurements. The method used low amount of compound (μg-scale) and the experiments were completed within a few minutes. The IDR values ranged from 0.2–70.6 μg/min/cm2 and the IDR/Sapp ratio ranged from 0.015 to 0.23. This ratio was used to indicate particle size sensitivity on intestinal concentrations reached for poorly water-soluble compounds.ConclusionsThe established method is a new, desirable tool that provides the means for rapid and highly accurate measurements of the IDR and apparent solubility in biorelevant dissolution media. The IDR/Sapp is proposed as a measure of particle size sensitivity when significant solubilization may occur.

Intrinsic Dissolution Rate Profiling of Poorly Water-Soluble Compounds in Biorelevant Dissolution Media

“…Active pharmaceutical ingredients (APIs), were selected from previous studies performed in our laboratories [7,15,19,20]. Most of the compounds have poor water solubility and belong to BCS Class II [1].…”

“…In the powder-based assay, coarse powder is added directly to the vials used for the dissolution experiment, and the apparent total surface area of the compound can then be back-calculated after dissolution rate has been determined [10,15]. In contrast, in suspension-based assays, the particle surface area is determined prior to the dissolution experiment, for example by dynamic light scattering (DLS), and the suspension method provides a more accurate measure of total surface area than the powder method [7,16]. Furthermore, suspensions can be (and typically are) stabilized by polymers or surfactants to hinder sedimentation, which is a phenomenon often observed in powder-based assays [10].…”

“…Such data sets are suitable to be established with small-scale dissolution studies using in situ UV probes, ideally from suspension-based assays to increase throughput and reduce material needed. However, previous such studies have only explored a small data set with a maximum of six compounds in FaSSIF and phosphate buffer [7,17].…”

“…The aim of this study was therefore to establish a standardized protocol for determining IDR from discs or suspensions (depending on compound solubility) in such simulated intestinal media. We based our study on Andersson et al [7], who used controlled suspensions to measure IDR, but we simplified the procedure to allow faster preparation of suspensions and thereby greater throughput. This allowed us to establish an IDR database of 18 compounds in four different, commercially available biorelevant media and to use those data for computational modeling to identify correlations between physicochemical properties and resulting IDRs.…”

A Modified In Situ Method to Determine Release from a Complex Drug Carrier in Particle-Rich Suspensions

“…The μDiss Profiler, a small-scale dissolution apparatus, enables in situ UV measurements of drug dissolution. This apparatus has been successfully used to determine dissolution rates and intrinsic dissolution rates (IDR) from powder, controlled suspensions, and compressed discs (14)(15)(16). It has also been used to study supersaturation obtained from SDDSs and release from drug-loaded MMC (11,17).…”