Development and Application of a Biorelevant Dissolution Method Using USP Apparatus 4 in Early Phase Formulation Development Jiang B. Fang,* Vivian K. Robertson, Archana Rawat, † Tawnya Flick, ‡ Zhe J. Tang, § Nina S. Cauchon, and James S. McElvain | Amgen Inc., One Amgen Center DriVe, Thousand Oaks, California 91320 Received April 19, 2010; Revised Manuscript Received August 6, 2010; Accepted August 11, 2010 Abstract: Dissolution testing is frequently used to determine the rate and extent at which a drug is released from a dosage form, and it plays many important roles throughout drug product development. However, the traditional dissolution approach often emphasizes its application in quality control testing and usually strives to obtain 100% drug release. As a result, dissolution methods are not necessarily biorelevant and meaningful application of traditional dissolution methods in the early phases of drug product development can be very limited. This article will describe the development of a biorelevant in vitro dissolution method using USP apparatus 4, biorelevant media, and real-time online UV analysis. Several case studies in the areas of formulation selection, lot-to-lot variability, and food effect will be presented to demonstrate the application of this method in early phase formulation development. This biorelevant dissolution method using USP apparatus 4 provides a valuable tool to predict certain aspects of the in vivo drug release. It can be used to facilitate the formulation development/selection for pharmaco- kinetic (PK) and clinical studies. It may also potentially be used to minimize the number of PK studies, and to aid in the design of more efficient PK and clinical studies. Keywords: Biorelevant; dissolution; USP apparatus 4; flow-through cell; formulation develop- ment; formulation rank order; food effect; in vivo drug release; rate profile Introduction Dissolution testing determines the rate and extent at which the drug is released from its pharmaceutical dosage form. It plays many important roles in new drug product develop- ment, especially for solid oral dosage forms. 1,2 For example, it is frequently used as a quality control (QC) tool to ensure consistent lot-to-lot quality for commercial small molecule drug products; it can serve as an in Vitro surrogate for in ViVo bioequivalence studies and in ViVo and in Vitro correlation (IVIVC) studies, 3-8 and it can also provide valuable information and guidance for formulation develop- ment. Throughout the drug development process, dissolution * Corresponding author: Analytical R&D, Amgen Inc., One Amgen Center Dr., Mailstop 8-1-C, Thousand Oaks, CA 91320-1799. E-mail: fang@amgen.com. Phone: (805) 313- 6514. Fax: (805) 376-8505. † Current address: School of Pharmacy, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, CT 06269-3092. E-mail: archana.rawat@uconn.edu. ‡ Current address: Department of Chemistry, Rm 419 Latimer Hall, University of California, Berkeley, CA 94720-1460. E-mail: tflick@berkeley.com. § Current address: US FDA; White Oak CDER Office Building 21, 10903 New Hampshire Avenue, Silver Spring, MD 20993. E-mail: zhe.tang@fda.hhs.gov. | Current address: Kythera Biopharmaceuticals Inc., 27200 Agoura Road, Agoura Hills, CA 91301. (1) Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Drug Dosage Forms; U.S. Food and Drug Administra- tion, Center of Drug Evaluation and research (CDER): Rockville, 1997. (2) Zhang, H.; Yu, L. X. Dissolution Testing for Solid Oral Drug Products: Theoretical Considerations. Am. Pharm. ReV. 2004, 7 (5), 26–31. (3) Haidar, S. H.; Davit, B.; Chen, M. L.; Conner, D.; Lee, L. M.; Li, Q. H.; Lionberger, R.; Makhlouf, F.; Patel, D.; Schuirmann, D.; Xu, J.; Lawrence, X. Bioequivalence Approaches for Highly Variable Drugs and Drug Products. Pharm. Res. 2008, 25 (1), 237–241. articles 1466 MOLECULAR PHARMACEUTICS VOL. 7, NO. 5, 1466–1477 10.1021/mp100125b  2010 American Chemical Society Published on Web 08/11/2010