COMMENTARY Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms Based on Biopharmaceutics Classification System (BCS) Literature Data: Verapamil Hydrochloride, Propranolol Hydrochloride, and Atenolol H. VOGELPOEL,1* J. WELINK,2* G.L. AMIDON,3 H.E. JUNGINGER,4 K.K. MIDHA,5 H. MO¨ LLER,6 M. OLLING,2* V.P. SHAH,7* D.M. BARENDS1* 1RIVM—National Institute for Public Health and the Environment, Center for Quality of Chemical-Pharmaceutical Products, P.O. Box 1, 3720 BA Bilthoven, The Netherlands 2Medicines Evaluation Board in the Netherlands, P.O. Box 16229, 2500 BE The Hague, The Netherlands 3College of Pharmacy, University of Michigan, Ann Arbor, Michigan 4Leiden/Amsterdam Center for Drug Research, Leiden University, Division of Pharmaceutical Technology, P.O. Box 9502, 2300 RA Leiden, The Netherlands 5University of Saskatchewan, Saskatoon, Saskatchewan, Canada, S7N 5C9 6Zentrallaboratorium Deutscher Apotheker, Carl-Manich-Strasse 20, 65760 Eschborn, Germany 7Center of Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland Received 11 June 2003; revised 23 October 2003; accepted 1 January 2004 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20131 ABSTRACT: Literature data related to the Biopharmaceutics Classification System (BCS) are presented on verapamil hydrochloride, propranolol hydrochloride, and atenolol in the form of BCS-monographs. Data on the qualitative composition of immediate release (IR) tablets containing these active substances with a Marketing Authorization (MA) in the Netherlands (NL) are also provided; in view of these MA’s the assumption was made that these tablets were bioequivalent to the innovator product. The development of a database with BCS-related data is announced by the International Pharmaceutical Federation (FIP). ß 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1945–1956, 2004 Keywords: BCS; biowaiver; verapamil; propranolol; atenolol INTRODUCTION met considerable interest. A biowaiver implies that bioequivalence (BE) assessment studies are In recent years the necessity to provide a scientific waived for marketing authorizations (MA) by basis for biowaivers for individual substances has Health Authorities for a new tablet or capsule, or a new formulation of an existing immediate *This article reflects the scientific opinion of the authors release (IR) dosage form, and hence the product is and not the policies of regulating agencies. considered bioequivalent to its reference product, Correspondence to: Dirk M. Barends (Tel: þ31 30 2744209; without carrying out a BE study. In this case the Fax: þ31 30 2744462; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 93, 1945–1956 (2004) comparative in vitro study assures BE of the test ß 2004 Wiley-Liss, Inc. and the American Pharmacists Association product. The scientific basis for this work was JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 8, AUGUST 2004 1945 1946 VOGELPOEL ET AL. developed by Amidon et al.1 and is known as the The present article summarizes and discusses Biopharmaceutics Classification System (BCS). the main features obtained from the literature The BCS states that three major factors govern search. the rate and extent of drug absorption of IR solid oral dosage forms: dissolution rate, solubility, and intestinal permeability. For IR dosage forms RESULTS AND DISCUSSION containing active pharmaceutical ingredients (APIs) showing high solubility, high intestinal A literature search was performed in electroni- permeability, and rapid dissolution a waiver from cally available databases. The search performed performing BE studies (biowaiver) can be scien- included information from the Merck Index, the tifically justified. Dictionary of Substances and their Effects, the In the regulatory domain this is adopted by both Hazardous Substances Data Bank, Medline, Tox- the FDA and the European CPMP in their line and Embase. Only literature published in the Guidance for Industry: Waiver of In Vivo Bioavail- last 10 years and written in English or German ability (BA) and BE Studies for Immediate-Release was included. When searching for dissolution and Solid Oral Dosage Forms Based on a BCS,2 and the solubility data, two problems occurred. The Note for Guidance on the Investigation of BA and search resulted in a large number of hits so that BE,3 respectively, together referred to as the a detailed study of all references on relevant data Guidances. In particular the FDA document was considered to be too time consuming, and describes in detail the data that are necessary for secondly almost all literature was related to a successful application for a biowaiver. modified release dosage forms. Therefore, the When a set of BCS-data for an API is established decision was made to use, in general, only data and could be made publicly available in the form obtained form standard reference books like the of a monograph, this monograph could be referred United States Pharmacopeia (USP) and European to by subsequent applicants for biowaivers of Pharmacopoeia (EP). other IR oral dosage forms with the same API For data on permeability the literature search without the need for reestablishing the data. Such was performed in the same way as described above, a publicly available BCS-monograph is also of limiting the keywords to permeability and related interest for Official Medicines Control Labora- to permeability, and the drug substance name. The tories (OMCL’s), which want to translate their outcome of the search was satisfactory and dissolution test data into terms of the BA of the sufficient. Relevant literature on all three sub- tested IR solid oral dosage forms. stances was obtained in this way. To explore the scope and the possibilities of It is known that dissolution and permeability of gathering BCS related data from scientific litera- an API can be influenced by excipients in the solid ture, and in order to set up such BCS-monographs, oral dosage forms. In order to gather insight of a literature search was carried out on verapamil possible excipient interactions tablet compositions hydrochloride, propranolol hydrochloride, and of generic formulations registered in NL were atenolol. examined. The qualitative composition of the IR tablets containing one of the three active sub- stances was obtained from the publicly available EXPERIMENTAL Summary of Product Characteristics (SmPC). The SmPC’s can be obtained from the website of Both chemical–pharmaceutical and pharmacoki- the Medicines Evaluation Board in NL at www. netic BCS-related information on three sub- cbg-meb.nl. Only the excipients used in the tablet stances, verapamil hydrochloride, propranolol cores were considered since we made the assump- hydrochloride, and atenolol, was obtained by tion that the tablet coating for an IR tablet will be means of a literature search. The following data- of very limited influence on the dissolution proper- fields were defined in order to standardize the ties of the tablet. dataset: indication, solubility, dissolution, poly- The International Pharmaceutical Federation morphism, partition coefficient, pKa, available (FIP) will post these monographs on its website at dose, permeability, stereospecificity, pharmacoki- www.fip.org. Additional information will be pub- netic properties. In addition, the qualitative lished and discussed in the form of Addenda to composition of IR tablets having an MA in the these monographs. The corresponding author of Netherlands (NL) was included. this article can be contacted for any contribution. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 8, AUGUST 2004 BIOWAIVER MONOGRAPHS FOR VERAPAMIL, PROPRANOLOL, AND ATENOLOL 1947 The authors thank Dr. A.J.A.M. Sips and pKa Dr. C.A.M. Versantvoort on their comments on ApK of 8.6,8 and a range 8.6–8.9, respectively, the various documents. a were reported.9 The BCS-monographs of each of the three sub- stances are presented and discussed separately. Available Dose/Tablet Strengths currently having an MA in NL: 40, 80, VERAPAMIL HYDROCHLORIDE and 120 mg. Indication Permeability Verapamil hydrochloride is a well-known calcium antagonist. It is used in the treatment of angina The permeability data found for verapamil are pectoris, supraventricular arrhythmia’s, and summarized in Table 2. hypertension.4 Stereospecificy Solubility After oral administration of a mixture of R- and S- Soluble (1 g dissolves in 10–30 mL).5 verapamil, plasma concentrations of the R-isomer Water 7 g/100 g (218C, pH ¼ 4.24).6 were substantially higher than those of the S- The Analytical profiles of drug substances, isomer, suggesting stereospecific first-pass meta- (Volume 17)7 contain a profile for verapamil bolism.4,15 hydrochloride. The solubility of verapamil hydro- chloride as a function of the pH is shown in Table 1. Pharmacokinetic Properties Absorption Polymorphism Oral absorption of labeled 14C-verapamil in man No reference to polymorphic forms was found. averaged over 90%. The absolute BA is 10–20%, indicating extensive first-pass metabolism.4,16 Partition Coefficient Peak plasma concentrations are reached within 1–2 h after administration of a single dose.17,18 Kasim et al.8 calculated n-octanol/water partition Pharmacokinetics shows a large inter-individual coefficients using different fragmentation meth- variability.19 ods that were based on atomic contributions to Food intake prolonged the time to peak concen- lipophilicity; for uncharged verapamil, log p tration, but no effect was observed on C