(W1230-03-16) Evaluation of the Selectivity of In Vitro Dissolution Absorption System 2 (IDAS2) Through Immediate-Release and Immediate-Extended Bilayer Formulations of BCS Class I Drugs

Purpose: The In Vitro Dissolution Absorption System 2 (IDAS2) has been developed and qualified to simultaneously assess the dissolution and permeation profiles of oral products in biorelevant conditions [1-5]. The objective of this study was to demonstrate the IDAS2 selectivity by distinguishing between oral formulations of BCS Class I drugs, acetaminophen and guaifenesin, which were expected to perform differently in vivo due to their formulation properties. Commercially available immediate-release (IR) tablets and immediate-extended bilayer (ER) tablets were selected as model formulations. The ER tablets for both drugs consisted of equal amounts of the IR and ER layers, which are expected to exhibit distinct performance characteristics compared to the IR tablets. To assess the ability of IDAS2 to distinguish oral formulation performance, dissolution and permeation profiles of acetaminophen and guaifenesin formulations were monitored in IDAS2. The ability for IDAS2 to be selective to known formulation variations and differences supports further future evaluation of product similarity.

Methods: The IDAS2 comprised a dissolution vessel (500 mL, pH 6.5 FaSSIF) and two permeation chambers (2 × 8 mL, pH 7.4 4.5% BSA-HBSSg) mounted with Caco-2 cell monolayers as the biological barrier. The paddle rotation speed was set at 50 rpm, and the water bath was warmed at 37°C. In this system, the dose concentration is determined by two doses per 500 mL, which is equivalent to the Biopharmaceutics Classification System of standard, the dose per 250 mL. Four IR tablets (4 × 325 mg) or two ER tablets (2 × 650 mg) of acetaminophen, as well as three IR tablets (3 × 400 mg) or two ER tablets (2 × 600 mg) of guaifenesin, were added to the dissolution vessel. Dissolution and permeation samples were collected at multiple time points over 2 hours. The drug concentration in the dissolution and permeation samples were quantified using an HPLC-UV and an LC/MS/MS analytical method, respectively. For the selectivity assessment of the dissolution profiles, the similarity of the dissolution profiles between the IR and ER formulations was evaluated using the similarity factor (f2) value. For the selectivity assessment of the permeation profiles, the permeation rate and the area under the permeation curve (AUC_permeation) from 0 to 2 hours were calculated as indicators of in vitro rate and extent of absorption. The 90% confidential intervals (CIs) of the difference in the mean logarithmic values between the formulations were calculated to assess the selectivity of oral formulations for IDAS2. The acceptance range of the CI was defined as log 0.80-1.25.

Results: The acetaminophen IR tablet exhibited rapid dissolution, reaching complete dissolution (100%) by 10 min. In contrast, the acetaminophen ER tablet demonstrated a sustained release profile over time due to its specific formulation properties. The guaifenesin IR tablet also demonstrated a rapid dissolution profile, although its dissolution rate was slightly slower than that of acetaminophen. Conversely, the guaifenesin ER tablet showed a much slower release profile. The f2 values between the IR and the ER tablets were 17.7 for acetaminophen and 11.8 for guaifenesin, indicating that the dissolution profiles of the two formulations are not similar for either drug. For both model drugs, the permeation rates observed for IR tablets were significantly higher than those for ER tablets, due to the more rapid dissolution and availability of the drug from the IR tablets. The 90% CIs of the differences in both permeation rates and AUC_permeation values were outside the log 0.80-1.25, confirming to a significant difference between the IR and ER formulations for both drugs. The ratios of permeation rates (in vitro rate of absorption) for the ER tablet to the IR tablet were quantitatively consistent with those of C_max (in vivo rate of absorption) observed in human studies for both drugs. The ratios of AUC_permeation (in vitro extent of absorption) were lower than those of AUC_plasma (in vivo extent of absorption) for both drugs. These lower in vitro AUC_permeation ratios were likely attributable to differences in duration between IDAS2 (in vitro) and the clinical studies (in vivo), as the ER tablets had insufficient time to reach complete dissolution comparable to the IR tablets in vitro.

Conclusion: This study successfully demonstrated the selectivity of IDAS2 using commercially available formulations with modified excipient content and varying performance characteristics. Although the current dataset is limited, the findings suggest that IDAS2 can distinguish between different oral formulations and provide an in vitro approach for predicting in vivo outcomes which could facilitate bioequivalence extrapolation for oral generic products when assessed with the appropriate selectivity variant for the products.

References: [1] J Pharm Sci. 108, 2334-2340 (2019).
[2] Eur J Pharm Sci. 143, 105164 (2020).
[3] J Pharm Innov. 15, 591-602 (2020).
[4] Eur J Pharm Biopharm. 165, 1-12 (2021).
[5] Biol. Pharm. Bull. 47, 1123–1127 (2024).