New Ideas about the Solubility of Drugs

Abstract

Methods are described for detecting precipitation of ionisable drugs under conditions of changing pH, estimating kinetic solubility from the onset of precipitation, and measuring solubility by chasing equilibrium. Definitions are presented for kinetic, equilibrium, and intrinsic solubility of ionisable drugs, supersaturation and subsaturation, and for chasers and non-chasers, which are two classes of ionisable drug with significantly different solubility properties. The use of Bjerrum Curves and Neutral-Species Concentration Profiles to depict solubility properties are described and illustrated with case studies showing super-dissolving behaviour, conversion between crystalline forms and enhancement of solubility through supersaturation, and the use of additives and simulated gastrointestinal fluids.

An In Vitro Methodology for Forecasting Luminal Concentrations and Precipitation of Highly Permeable Lipophilic Weak Bases in the Fasted Upper Small Intestine

“…Prediction of luminal supersaturation after administration of weak bases has been recently evaluated by applying in vitro solvent-shift methods (3,4). Although these approaches are very useful for initial evaluations, one issue is that estimation of degree of supersaturation of luminal contents is contingent on equilibrium solubility of the administered form, e.g.…”

The intrinsic aqueous solubility of indomethacin

“…NMR spectral data (500 MHz Solubility measurements were carried out using the CheqSol and Curve Fitting methods. These methods and the associated Bjerrum Curves are described in detail elsewhere [26][27][28]. Indomethacin samples of around 2 mg were weighed accurately into glass vials.…”

“…The concentration of neutral indomethacin in solution at the onset of precipitation is referred to as the kinetic solubility. After precipitation the experiments followed CheqSol or Curve Fitting protocols, which are described elsewhere [28]. Results of these solubility measurements are listed in Table 2.…”

Glossary of terms used in medicinal chemistry. Part II (IUPAC Recommendations 2013)

“…See also equilibrium solubility, kinetic solubility, solubility, supersaturated solution. [27][28][29] …”