Quantitative Analysis of the Effect of Supersaturation on in Vivo Drug Absorption

Abstract

The purpose of this study is to clarify the effects of intestinal drug supersaturation on solubility-limited nonlinear absorption. Oral absorption of a novel farnesyltransferase inhibitor (FTI-2600) from its crystalline free base and its HCl salt was determined in dogs. To clarify the contribution of supersaturation on improving drug absorption, in vivo intraluminal concentration of FTI-2600 after oral administration was estimated from the pharmacokinetics data using a physiologically based model. Dissolution and precipitation characteristics of FTI-2600 in a biorelevant media were investigated in vitro using a miniscale dissolution test and powder X-ray diffraction analysis. In the in vitro study, the HCl salt immediately dissolved but precipitated rapidly. The metastable amorphous free base precipitant, which did not convert into the stable crystalline free base in the simulated intestinal fluids for several hours, generated a 5-fold increase in dissolved concentration compared to the equilibrium solubility of the crystalline free base. By computer simulation, the intraluminal drug concentration after administration of the free base was estimated to reach the saturated solubility, indicating solubility-limited absorption. On the other hand, administration of the HCl salt resulted in an increased intraluminal concentration and the plasma concentration was 400% greater than that after administration of the free base. This in vivo/in vitro correlation of the increased drug concentrations in the small intestine provide clear evidence that not only the increase in the dissolution rate, but also the supersaturation phenomenon, improved the solubility-limited absorption of FTI-2600. These results indicate that formulation technologies that can induce supersaturation may be of great assistance to the successful development of poorly water-soluble drugs.

Characterization and Quality Control of Pharmaceutical Cocrystals

“…64) Small-scale dissolution assays have appropriately provided the dissolution properties and precipitation behavior of pharmaceutical cocrystals. 84) Solids precipitated at the bottom of vessels exhibit changes in crystal form and composition that insolubilize APIs in test solutions (e.g., API hydrate crystal), as characterized by PXRD and Raman spectroscopy. Further studies on the dissolution and solution stability of cocrystals in physiological conditions are expected to ensure API safety and efficacy in large patient Fig.…”

“…87) Understanding the complex effect of the excipients on the solubility of the cocrystals and the stability of the supersaturated solutions are critical for the rational development of pharmaceutical cocrystal formulations. 84) 6.3 API-Coformer Interactions in Solution Many API-coformer combinations in orally administrated pharmaceutical cocrystals are considered to dissociate upon dissolution and dilution in the gastrointestinal tract, as suggested by studies on the relation between cocrystal in vitro dissolution and in vivo pharmacokinetics. 5) Cocrystal regulation pathways mainly target these APIs.…”

Supersaturated polymeric micelles for oral cyclosporine A delivery

“…When developing supersaturated oral delivery systems for highly hydrophobic drugs, such as CsA, it is important to adequately control the degree of supersaturation in order to avoid precipitation upon dilution [43,44], because sink conditions do not always prevail in gastrointestinal tract due to limited drug solubility [45]. In vitro supersaturation tests for Super-PMs with different drug/polymer ratios were conducted in PBS (pH6.8) at 37°C for 24 h. The concentrations of CsA within CsA Super-PMs over time are presented in Fig.…”

Biopharmaceutic Profiling of Salts to Improve Absorption of Poorly Soluble Basic Drugs

“…[9][10][11] The aim is to improve the absorption by increasing the amount dissolved in the GI tract. Supersaturation may be achieved using a number of different formulation approaches such as an amorphous form of the compound, 12-16 a less stable crystalline form, 17,18 crystalline salts, 11,19,20 formulating with cosolvents, 21 adsorption-based formulations, 22 cocrystals, 23,24 and lipid-based formulations. [25][26][27][28] However, in generating supersaturation, the drug in solution is thermodynamically unstable, generating a driving force for precipitation in the GI tract.…”