Haste Makes Waste: The Interplay Between Dissolution and Precipitation of Supersaturating Formulations

Abstract

Contrary to the early philosophy of supersaturating formulation design for oral solid dosage forms, current evidence shows that an exceedingly high rate of supersaturation generation could result in a suboptimal in vitro dissolution profile and subsequently could reduce the in vivo oral bioavailability of amorphous solid dispersions. In this commentary, we outline recent research efforts on the specific effects of the rate and extent of supersaturation generation on the overall kinetic solubility profiles of supersaturating formulations. Additional insights into an appropriate definition of sink versus nonsink dissolution conditions and the solubility advantage of amorphous pharmaceuticals are also highlighted. The interplay between dissolution and precipitation kinetics should be carefully considered in designing a suitable supersaturating formulation to best improve the dissolution behavior and oral bioavailability of poorly water-soluble drugs.

Keywords: amorphous formulation; kinetic solubility; nonsink dissolution testing; poorly water-soluble drug; supersaturation rate.

Fig. 1

Indomethacin release from amorphous solid dispersions at a drug loading of 32.9% in soluble carriers (PVP and HPMCAS) via a dissolution-controlled mechanism and insoluble carrier (PHEMA) via a diffusion-controlled mechanism under nonsink dissolution conditions (SI = 0.1 from Eq. 2). The dashed line represents the equilibrium solubility of indomethacin in the dissolution medium. Figures adapted in part from Sun et al. (14) and Sun and Lee (15) (reproduced with permission from the European Journal of Pharmaceutics and Biopharmaceutics and Journal of Controlled Release, Copyright Elsevier, 2012/2015)

Fig. 2

In vitro dissolution profiles of amorphous fenofibrate from ordered mesoporous silica with varying pore sizes (2.7, 4.4, and 7.3 nm) under dissolution conditions with Sink Index (SI) values of a SI = 3.56 (in FaSSIF + 1% SLS), b SI = 0.538 (in FeSSIF), and c SI = 0.136 (in FaSSIF), calculated from Eq. 2. The dashed line represents the equilibrium solubility of fenofibrate in its respective dissolution medium. Figure adapted in part from Van Speybroeck et al. (18) (reproduced with permission from the European Journal of Pharmaceutical Sciences, Copyright Elsevier, 2010)

Fig. 3

In vivo PK profiles of fenofibric acid after oral administration of amorphous fenofibrate in ordered mesoporous silica with varying pore sizes (2.7, 4.4, and 7.3 nm) in rats under fasted conditions. Figure adapted in part from Van Speybroeck et al. (18) (reproduced with permission from the European Journal of Pharmaceutical Sciences, Copyright Elsevier, 2010)

Fig. 4

In vitro dissolution profiles of Sporanox and other itraconazole ASD systems based on HPMC, Eudragit E100, and Eudragit E100-PVPVA64 prepared by hot-melt extrusion under dissolution conditions with Sink Index (SI) value of 0.02. The dashed line represents the equilibrium solubility of itraconazole (approximately 4 μg/mL) at pH 1 as described in the original publication. Figure adapted in part from Six et al. (20) (reproduced with permission from the European Journal of Pharmaceutical Sciences, Copyright Elsevier, 2005)

Fig. 5

Average plasma concentration-time profiles of itraconzole after oral administration of Sporanox and other itraconazole ASD systems based on HPMC, Eudragit E100, and Eudragit E100-PVPVA64 in healthy human subjects (n = 8) with error bars omitted for clarity of trend. Figure adapted in part from Six et al. (20) (reproduced with permission from the European Journal of Pharmaceutical Sciences, Copyright Elsevier, 2005)

Fig. 6

Comparison of kinetic solubility profiles of indomethacin between experimental (symbols) and predicted (lines) data as functions of a supersaturation rate and b initial degree of supersaturation (S _initial) generated from infusion of indomethacin solution in ethanol under nonsink dissolution conditions. Inset: Effects of drug infusion rate and initial degree of supersaturation on the AUC of the resulting kinetic solubility profiles. Figures adapted in part from Sun and Lee (27,28) (reproduced with permission from Molecular Pharmaceutics, Copyright American Chemical Society 2013/2015)

Fig. 7

Indomethacin crystallization kinetics as functions of a supersaturation rate generated with various drug solution (indomethacin in ethanol) infusion rates and b initial degree of supersaturation (S _initial), converted from the kinetic solubility data described in Fig. 4. Figures adapted in part from Sun and Lee (27,28) (reproduced with permission from Molecular Pharmaceutics, Copyright American Chemical Society 2013/2015)

Fig. 8

Spectrum of molecular arrangements as a function of the order of length of molecular alignment