Abstract
The intrinsic dissolution rate (IDR) of active pharmaceutical ingredients (API) is a key property that aids in early drug development, especially selecting formulation strategies to improve dissolution and thereby drug absorption in the intestine. Here, we developed a robust method for rapid, medium throughput screening of IDR and established the largest IDR dataset in open literature to date that can be used for pharmaceutical computational modeling. Eighteen compounds with diverse physicochemical properties were studied in both fasted and fed state simulated intestinal fluids. Dissolution profiles were measured in small-scale experimental assays using compound suspensions or discs. IDR measurements were not solely linked to API solubility in either dissolution media. Multivariate data analysis revealed that IDR strongly depends on compound partitioning into bile salt and phospholipid micelles in the simulated intestinal fluids, a process that in turn is governed by API lipophilicity, hydrophobicity, and ionization.
Highlights
Pharmaceutical profiling of candidate drugs has primarily focused on properties, such as permeability and thermodynamic equilibrium solubility, as these are used to categorize them according to the biopharmaceutics classification system (BCS) [1]
The controlled suspensions were prepared by ball milling active pharmaceutical ingredients (API) for 20 min in an aqueous medium containing a low concentration (1.0% w/w) of a surfactant for particle stabilization, and these suspensions were used for small-scale dissolution measurements in the μDiss Profiler
We explore the fed state, since it is well-known that the additional amount of lipids and bile salts in the dissolution medium may significantly increase solubilization and the total amount of API dissolved
Summary
Pharmaceutical profiling of candidate drugs has primarily focused on properties, such as permeability and thermodynamic equilibrium solubility, as these are used to categorize them according to the biopharmaceutics classification system (BCS) [1]. The main approaches and equipment available are (i) miniaturized dissolution vessels, flow-through cells, or microtiter plate-based methods with off-line determination of API concentration changes [8], (ii) imaging-based methods [9], and (iii) small-scale (sometimes) automated dissolution instruments with in situ API concentration determination by UV fiber optic probes [10,11,12,13]. When used in situ such probes can monitor drug concentration over time during dissolution by UV absorbance spectroscopy This method is well suited to study the early stages of dissolution, as absorbance spectra can be collected very frequently (every second). Traditional determination of IDR (e.g., USP 1087) is carried out in six-vessel US Pharmacopeia (USP)-specified dissolution baths containing 900 mL of dissolution media and 150–700 mg of pure API compressed into discs, and relies on sampling and off-line API concentration determination by, e.g., high-performance liquid chromatography (HPLC)
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