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.
Highlights
In the development of new oral drugs, poorly water-soluble compounds remain a challenge for the pharmaceutical industry even though substantial efforts have been made to tackle this problem
We explored the extent to which disc IDR (DIDR) is viable for poorly water-soluble compounds
The solid material of the suspensions formed by solvent shift and wet-milling was investigated by differential scanning calorimetry (DSC) measurements (Table I)
Summary
In the development of new oral drugs, poorly water-soluble compounds remain a challenge for the pharmaceutical industry even though substantial efforts have been made to tackle this problem. Previous investigations of marketed compounds estimate approximately 30% to be BCS class 2 compounds showing poor solubility but high permeability [2,3]. The trend towards selection of lipophilic compounds during the drug optimization process has increased the proportion of BCS class 2 compounds in the drug discovery pipeline from ~30% to ~50–60% [4], but numbers as high as 90% have been reported [3]. Physicochemical properties of BCS class 2 compounds allow them to quickly permeate biomembranes, and for these compounds the dissolution rate. Alvebratt and Bergström and/or the solubility become the limiting factors to drug absorption. Since the transit time through the main absorptive site in the intestine is short, a low dissolution rate often results in low bioavailability of the compound. Methods to estimate drug dissolution and formulation strategies to improve drug dissolution are of interest
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