(M1130-11-61) Development of Biorelevant Dissolution Methods for Potential Risk-Based Biowaivers of BCS Class IIa Compounds: Impact of pH, Buffer Capacity and Hydrodynamics of Dissolution Media

Purpose: Dissolution testing is an integral analytical methodology in product development and analysis, that attempt to bridge in-vitro and in-vivo performance. Over the years, BCS-based biowaivers have provided regulatory reprieve for products containing BCS I and III drugs. However, BCS-II drugs still face challenges in granting the BCS-based biowaivers as dissolution tests have failed to predict differences in absorption rates for such products, thus limiting the clinical relevance of in vitro dissolution methods (1). BCS-IIa small molecule weak acids, such as NSAIDs, are interesting candidates, because of their high permeability in GI tract and improved solubility at intestinal pH ( >6) (2). However, these drugs demonstrate low solubility in gastric pH which imposes significant barrier for considering these drug molecules for BCS-based biowaivers (3). Therefore, identifying suitable dissolution methods that can predict differences in absorption rates for such products can aid in potentially extending biowaivers to BCS-IIa products and offload regulatory hurdles for development of such drug products. The objective of this project is to identify and develop biorelevant dissolution methods and Biopharmaceutics risk-based strategies for Ibuprofen products, a model BCS Class IIa drug product, to evaluate potential biowaiver extension for immediate-release, solid oral, BCS-IIa drug products. In this preliminary study, dissolution differences of various Ibuprofen products were investigated at different pH conditions, buffer capacity, and agitation speeds to determine optimal dissolution parameters for further dissolution testing.

Methods: Briefly, suitable generic (G-Tablet/G-Caplet) and innovator Ibuprofen drug products (I-Caplet/I-2 Caplet/I-2-Tablet) were identified, and dissolution testing was conducted for these products based on compendial methods in multiple pH dissolution media using USP Apparatus 2 (paddle). The dissolution results were corroborated with the findings from physicochemical characterization and equilibrium solubilities at different pHs. Separately, hydrodynamic agitation was altered using different paddle speeds and the effect of buffer capacity on the dissolution of the drug products was evaluated. The impact of dissolution parameters on API alone, excluding excipients, was investigated for Intrinsic Dissolution Rate (IDR) using USP stationary disk method.

Results: The equilibrium solubility of the Ibuprofen at pH 4.5, 5.6 and 7.2, was observed to be 0.108 mg/mL, 0.317 mg/mL and >2.27 mg/mL respectively. Composition (qualitative and quantitative) and physico-chemical properties of G-Tablet/G-Caplet were similar to the I-products, whereas I-2-Caplet and I-2-Tablet were different from G and I-products. The dissolution profiles for the Ibuprofen products demonstrated distinct differences in the overall release with varying pH as shown in Figure 1. All products showed 100% drug release by the first 30 minutes at pH 7.2, whereas the drug release decreased in pH 5.6 and pH 4.5 media (closer to Ibuprofen pK_a of 4.4). The drug products demonstrated < 50% drug release within 60 minutes at pH 4.5, reflecting the possible saturation of dissolution media, whereas pH 5.6 showed wider dissolution trend from 50-100% at 60 minutes sampling time-point. Despite the ability of media to solvate the drug further (based on equilibrium solubility), the dissolution profile for most of the products couldn’t achieve 100% drug release by 60 minutes, due to the physiochemical and formulation differences. However, the pH window from 4.5-7.2 is critical, as it aligns with the upper intestinal pH range observed during fed condition, thus weak acidic drugs like Ibuprofen could show improved dissolution and permeation, like BCS-I drugs. Dissolution trend at pH 5.6 was further investigated using I-Caplet with change in agitation and buffer capacity. The change in the hydrodynamics by doubling the paddle speed from 50 rpm to 100 rpm, did not result in a significant increase in the dissolution profile as shown in Figure 2A. The change in the buffer capacity of the pH 5.6 dissolution media showed reduced drug release with decrease in the buffer capacity as shown in Figure 2B. The decrease in pH with dissolution time appears to have limited the pH dependent Ibuprofen release, as shown in Figure 2C. The intrinsic dissolution studies demonstrated exactly similar trend of dissolution rate differences with selected pH (data not shown), corelating with the dissolution testing, however the hydrodynamics change altered intrinsic dissolution rate of ibuprofen significantly, unlike dissolution profile of Ibuprofen products.

Conclusion: Based on our preliminary results with optimization of dissolution media pH, buffer capacity, and hydrodynamic parameters of dissolution media, significant differences in dissolution were observed for different ibuprofen products in different dissolution medium, pH 5.6 among the tested pH conditions, corroborating with the equilibrium solubility of ibuprofen at that specific pH. Change in buffer capacity of the dissolution media slowed down the release closer to drug pK_a. Hydrodynamic alteration impacted intrinsic dissolution of API, unlike ibuprofen products, where difference in dissolution profile due to increased agitation was nominal, due to potential decrease in the diffusion layer. This study established initial dissolution testing conditions for further dissolution testing of Ibuprofen products in biorelevant media and in silico studies.

References: (1) Álvarez, C., Núñez, I., Torrado, J. J., Gordon, J., Potthast, H., & García-Arieta, A. (2011). Investigation on the possibility of biowaivers for ibuprofen. Journal of pharmaceutical sciences, 100(6), 2343-2349.
(2) Tsume, Y., Langguth, P., Garcia-Arieta, A., & Amidon, G. L. (2012). In silico prediction of drug dissolution and absorption with variation in intestinal pH for BCS class II weak acid drugs: ibuprofen and ketoprofen. Biopharmaceutics & drug disposition, 33(7), 366-377.
(3) Yazdanian, M., Briggs, K., Jankovsky, C., & Hawi, A. (2004). The “high solubility” definition of the current FDA guidance on biopharmaceutical classification system may be too strict for acidic drugs. Pharmaceutical research, 21, 293-299.

Acknowledgements: Disclaimer
This work reflects the views of the authors and should not be construed to represent FDA’s views or policies.
Ishwor Poudel was supported in part by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy (DOE) and U.S. FDA (United States Food and Drug Administration).


Figure 1. The dissolution profiles of five different Ibuprofen products at pH 7.2, pH 5.6 and pH 4.5 under USP testing conditions. All the data is represented as mean ± SD (n=6), for respective time points.


Figure 2. (A) Impact of hydrodynamic agitation on dissolution profile at pH 5.6 (n=6), (B) Impact of buffer capacity of media on dissolution profile at pH 5.6 (n=6), (C) Monitoring change in bulk pH of dissolution media at different buffered conditions at pH 5.6 (n=3). All the data is represented as mean ± SD, for respective time points.