Poorly Soluble Marketed Drugs Display Solvation Limited Solubility

Abstract

We determined the intrinsic aqueous solubility of 15 poorly soluble drugs with solubilities ranging from 2.9 nM to 1.1 microM. We then analyzed the data from a physicochemical perspective, using experimentally determined solid-state properties and easily interpretable two-dimensional molecular descriptors, to better understand the factors underlying poor solubility. The analysis shows that poorly soluble drugs that have reached the market are solubility limited by solvation rather than by their solid state.

Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

“…Figure 19 is a plot of the above comparison. Notably, the logS 0 values from [118] are 1-3 (or more) log units lower than the average values reported from other published studies, with the exception of that of itraconazole. Although there may be a number of plausible explanations for the differences, it might be useful to consider the possibility that the double-centrifugation step led to under-estimated solubility, due to adsorption to the glass surfaces of the transfer vials.…”

“…Although there may be a number of plausible explanations for the differences, it might be useful to consider the possibility that the double-centrifugation step led to under-estimated solubility, due to adsorption to the glass surfaces of the transfer vials. In the case of itraconazole, the value reported by Glomme et al [117] may have had more adsorption than even in [118]. The former group used plastic UniPrep filter vials: "Even with the UniPrep filters, a loss of drug can sometimes occur through adsorption on the filter membrane.…”

“…However, centrifugation as a method for separating solid from saturated solution is not free from similar adsorption effects. Consider the Bergström et al [118] Table 2 lists the intrinsic solubility values of twelve practically-insoluble drugs taken from the above study, and compares them to corresponding averaged intrinsic solubilities taken from other published studies (with all values normalized to 25 °C [26]). Figure 19 is a plot of the above comparison.…”

Effect of particle size on solubility, dissolution rate, and oral bioavailability: evaluation using coenzyme Q10 as naked nanocrystals

“…In this paper, dissolution conditions were selected based on the following considerations: the barrier effect for diffusion caused by dialysis bags, which is a common method for dissolution testing, should be avoided; 28 the centrifugation method is used extensively for solid-liquid separation, but is not able to separate out small coenzyme Q 10 nanocrystals (a suspension of 139 nm nanocrystals was centrifuged at 30,000 rpm for one hour, and the size distributions of the top, middle, and bottom layers were all the same). There are also reports of using ultracentrifugation or centrifuging twice, 29,30 but this takes a considerably longer time and is conducted at a low temperature, which changes the drug dissolution conditions; submicron particles, eg, 80 nm, can easily pass through common filters ($0.1 µm), 4,31 and the three-layer filters described in the previous section are not appropriate for timely sampling. Although in vitro dissolution is often used to predict the in vivo behavior of drugs and experiments are usually carried out at 37°C, the temperature was set at 25°C considering the change in temperature during filtration with a 0.05 µm filter and the conditions being consistent with solubility measurement.…”

pH-triggered drug release from biodegradable microwells for oral drug delivery

“…However, an increasing number of new drug compounds exhibit poor aqueous solubility, a slow rate of dissolution and/or poor intestinal permeability, making effective oral drug delivery increasingly challenging (Bergstrom et al 2007;Newman et al 2008). Innovative drug delivery systems have the potential to facilitate an improvement in oral bioavailability compared to current drug formulations.…”