Development of a Biorelevant, Material-Sparing Membrane Flux Test for Rapid Screening of Bioavailability-Enhancing Drug Product Formulations

Abstract

Bioavailability-enhancing formulations are often used to overcome challenges of poor gastrointestinal solubility for drug substances developed for oral administration. Conventional in vitro dissolution tests often do not properly compare such formulations due to the many different drug species that may exist in solution. To overcome these limitations, we have designed a practical in vitro membrane flux test, that requires minimal active pharmaceutical ingredient (API) and is capable of rapidly screening many drug product intermediates. This test can be used to quickly compare performance of bioavailability-enhancing formulations with fundamental knowledge of the rate-limiting step(s) to membrane flux. Using this system, we demonstrate that the flux of amorphous itraconazole (logD = 5.7) is limited by aqueous boundary layer (ABL) diffusion and can be increased by adding drug-solubilizing micelles or drug-rich colloids. Conversely, the flux of crystalline ketoconazole at pH 5 (logD = 2.2) is membrane-limited, and adding solubilizing micelles does not increase flux. Under certain circumstances, the flux of ketoconazole may also be limited by dissolution rate. These cases highlight how a well-designed in vitro assay can provide critical insight for oral formulation development. Knowing whether flux is limited by membrane diffusion, ABL diffusion, or dissolution rate can help drive formulation development decisions. It may also be useful in predicting in vivo performance, dose linearity, food effects, and regional-dependent flux along the length of the gastrointestinal tract.

Physical stability and release properties of lumefantrine amorphous solid dispersion granules prepared by a simple solvent evaporation approach

“…The 40 wt% drug loading ASD leads to a total mass of 300 mg of ASD as the intermediate material to be used in the final formulation, which is reasonable. However, it is well known that dissolution performance can be impaired at higher drug loadings ( Mosquera-Giraldo et al, 2018 ; Purohit and Taylor, 2017 ), and that amorphous drug-rich colloids, thought to be beneficial for oral absorption, may not be formed ( Stewart et al, 2017 ; Wilson et al, 2018 ). First, we note that all of the dispersions lead to a significant degree of supersaturation.…”

Interplay of Supersaturation and Solubilization: Lack of Correlation between Concentration-Based Supersaturation Measurements and Membrane Transport Rates in Simulated and Aspirated Human Fluids

“…[15][16][17] Therefore, particle drifting into the unstirred water layer, has also been suggested as a mechanism by which absorption is enhanced by colloidal drug aggregates. 18,19 It should be noted that supersaturated solutions as well as phase separated systems containing colloidal drug-rich aggregates will only exist if crystallization is prevented or glycochenodeoxycholate (SGCDC). The molecular structure of bile salts is distinctive with a steroid ring system to which three (STC and SGC) or two hydroxyl groups (STDC, STCDC, SGDC and SGCDC) are attached.…”

Enhancement of ketoconazole dissolution rate by the liquisolid technique

“…The samples, all containing 100 mg of ketoconazole, were placed in a vessels containing 900 mL of simulated gastric fluid (pH = 1.2) under rotational agitation of 100 ± 2 rpm at 37 ± 0.1 °C. At specified intervals (5,10,15,20,30,45, 60 and 90 min), 5 mL of the prepared solutions was taken and filtered through a Millipore membrane with a pore diameter of 0.45 μm. After that, an equal amount of fresh dissolution fluid was added to the solution so as to retain a constant volume.…”

“…Ketoconazole (KCZ) is one of the poorly soluble drugs with high permeability in GI (class II) and its release rate in the GI tract controls its oral absorption rate (17,18). Consequently, in addition to permeability, the dissolution rate and solubility of the drug are crucial for its oral bioavailability (19)(20)(21). GI injuries may also increase due to this unfavorable characteristic that increases the duration of the drug's contact with the GI mucosa; therefore, enhancement of the dissolution rate of poorly soluble drugs by liquisolid compacts appears to be a good choice.…”