COMMENTARY Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Ranitidine Hydrochloride H. KORTEJA¨ RVI,1 M. YLIPERTTULA,1 J.B. DRESSMAN,2 H.E. JUNGINGER,3 K.K. MIDHA,4 V.P. SHAH,5 D.M. BARENDS6 1Orion Pharma, Research and Development, Espoo, Finland 2Institut fu¨r Pharmazeutische Technologie, Johann Wolfgang Goethe-Universita¨t, Frankfurt am Main, Germany 3Leiden/Amsterdam Center for Drug Research, Leiden University, Division of Pharmaceutical Technology, Leiden, The Netherlands 4University of Saskatchewan, Saskatoon, Canada 5U.S. Food and Drug Administration, Center of Drug Evaluation and Research, Rockville, Maryland 6RIVM, National Institute for Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven, The Netherlands Received 8 December 2004; revised 1 April 2005; accepted 7 April 2005 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20392 ABSTRACT: Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate release (IR) solid oral dosage forms containing ranitidine hydrochloride are reviewed. According to the current Biopharmaceutics Classification System (BCS), ranitidine hydrochloride should be as- signed to Class III. However, based on its therapeutic and therapeutic index, pharma- cokinetic properties and data related to the possibility of excipient interactions, a biowaiver can be recommended for IR solid oral dosage forms that are rapidly dissolving and contain only those excipients as reported in this study. ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:1617–1625, 2005 Keywords: absorption; Biopharmaceutics Classification System (BCS); ranitidine; permeability; solubility INTRODUCTION dosage forms. The purpose and scope of these monographs were discussed previously.1 Briefly, A monograph based on literature data is pre- the aims of the present study were to evaluate all sented on ranitidine hydrochloride with respect to pertinent data available from literature sources to its biopharmaceutical properties and the risk of assess the appropriateness of such a biowaiver waiving in vivo bioequivalence testing for the from the biopharmaceutical point of view and also approval of new and reformulated IR solid oral from the perspective of public health risks. This study reflects the scientific opinion of the authors and not the policies of regulating agencies. EXPERIMENTAL Correspondence to: Dirk M. Barends (Telephone: þ31 30 2744209; Fax: þ31 30 2744462; E-mail: [email protected]) The databases Caplus, Ipa, and Medline were Journal of Pharmaceutical Sciences, Vol. 94, 1617–1625 (2005) ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association utilized to search using the keyword permeability JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 8, AUGUST 2005 1617 1618 KORTEJA¨ RVI ET AL. and Caplus and Ipa using the keywords dissolu- dine hydrochloride with different polymorphic tion, solubility, and degradation. The pharmaco- forms were reported to be bioequivalent.3 kinetic data search was initiated from the Martindale and the Drug Information Fulltext, followed by reviewing the references cited. Partition Coefficient Information with regard to the double-peak LogP (water/n-octanol) was reported to be 0.2.4 phenomenon, site-dependent absorption, first- This value is likely for the ionized form, i.e., logD. pass metabolism, enterohepatic recycling, and LogP (for the neutral molecule) was calculated to bioequivalence studies were reviewed from the be 1.28.5 cited literature obtained from Medline, using the keyword pharmacokinetics. Only literature writ- ten in English and German was included and the pKa searches were not limited to a certain time period. The two pK values reported 8.2 and 2.7 4 are in As the solubility data from literature did not cover a agreement with the values of 8.4 and 3.5, res- the entire physiological pH range, these were pectively, calculated with a structure-fragment- obtained experimentally at Orion Pharma. Tri- based approach.5 plicate determinations were carried out in which the solute was shaken with buffers pH 1, 3, 5, and 7.4 at room temperature for 3 h and the obtain- Indication ed solutions analyzed by high performance liquid chromatography. Ranitidine is a histamine H2-antagonist used in the treatment of gastric and duodenal ulceration with or without Helicobacter pylori infection and for gastro-oesophageal reflux disease.2 Ranitidine RESULTS inhibits gastric acid secretion, which is stimu- lated by pentagastrin, histamine, and normal General Characteristics meals.6 The incidence of adverse drug reactions with H -receptor antagonists are low (<3%) and The INN and World Health Organization (WHO) 2 are usually minor in nature.7 For Zollinger– name for ranitidine, is N-[2-[[[-5-[(dimethylamino) Ellison syndrome doses up to 900 mg daily have methyl]-2-furanyl]methyl]thio]ethyl]-N0-methyl-2- been used without troublesome side effects.6 nitro-1,1-ethenediamine. The WHO recommended dose for ranitidine tablets is 150 mg ranitidine base, given as the hydrochloride salt.8 Strengths currently having a Structure marketing authorization (MA) in Germany (DE)9, See Figure 1. Finland (FI),10 and The Netherlands (NL)11 are the equivalents of 75, 150, and 300 mg ranitidine base. Salt, Esters, Polymorphs Most preparation contain the hydrochloride 2 and Solubility this monograph covers only that salt of ranitidine. The solubility of ranitidine hydrochloride in water Ranitidine hydrochloride exhibits polymorphism.2 is 660 mg/mL and it is reported to be freely soluble Immediate-release (IR) tablets containing raniti- in water.2 The solubility in the pH range 1–7.4 was experimentally found to be over 550 mg/mL. As the highest strength is 300 mg, the dose: solubility ratio is less than 0.55 mL, far below the critical value of 250 mL.12,13 However, these data were obtained at room temperature and the cri- teria of ‘‘highly soluble’’ according to FDA and EMEA Guidelines are defined at 378C.12,13 But, supposing that the solubility will be higher at 378C than at room temperature, it is reason- Figure 1. Structure of ranitidine. able safe to classify ranitidine hydrochloride as a JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 8, AUGUST 2005 BIOWAIVER MONOGRAPH FOR RANITIDINE HYDROCHLORIDE 1619 ‘‘highly soluble’’ active pharmaceutical ingredient and discussed earlier as these observations can be (API). explained on the basis that tight junctions in the intestinal cell tissues are more permeable than the tight junctions in the Caco-2 monolayers.1 Pharmacokinetics Despite these differences, both permeability tech- Absorption niques demonstrate that the permeability is low. Indeed, ranitidine is recommended as a low per- The oral bioavailability (BA) of ranitidine is 50%– meability internal standard in the FDA guideline 60%. The drug is reported to be rapidly absorbed for Caco-2 permeability studies.12 The Caco-2 per- when administered via the oral route14–18 and meability increases when calcium concentration is absorption after oral administration is linear.19 decreased in the test medium,26 which can be ex- A first peak in plasma concentrations is reached plained on the basis that low calcium concentra- within 0.5–1.5 h and a second peak is observed tions cause opening of the tight junctions of the within 3–4 h after single doses.20,21 The reasons paracellular route or change the membrane integ- for this double-peak phenomenon are unclear. rity by disturbing the phospholipid bilayers. Thus, This is likely not due to biliary excretion, as the main absorption mechanism of ranitidine is biliary excretion is only 0.4% after oral adminis- paracellular passive diffusion. In vitro and non- tration.22 Variations in gastric emptying may also clinical studies have suggested that ranitidine is a not be a satisfactory explanation, since when substrate for P-gp.28,30,32 But it is likely that high ranitidine was administered as a solution directly doses of this highly soluble drug, formulated in to the jejunum, double-peaks were observed even rapidly dissolving tablets, will cause saturation of more often than after administration to the the P-gp efflux protein. stomach.23 In any case, this double-peak pheno- menon is not relevant for biowaiver decisions, as Distribution there is no indication that it is formulation- dependent. The apparent volume of the distribution for ter- The BA of ranitidine is significantly lower when minal phase is about 1.16–1.87 L/kg.14,15,21,25,33 administered as a solution directly to the colon Ranitidine has a low protein binding of about instead of stomach, jejunum, or ileum.23,24 Since 15%.15 the tight junctions in the colon are considerably less permeable than those in the small intestine, it Metabolism and Excretion can be hypothesized that ranitidine is absorbed by The urinary excretion of unchanged ranitidine a paracellular mechanism, with the main absorp- following intravenous (i.v.) administration is 70%– tion site in the small intestine. Food in general has 80%,4,17,18,21,25 whereas the renal excretion of no effect on the rate and extent of absorption.25 unchanged drug after oral dosing is 25%– 30%.4,15,17,21 Less than 10% of the dose is metabo- Permeability lized and excreted via the urinary route after Results of permeability measurements are shown either i.v. or oral dosing.15,17 Of orally adminis- in Table 1. tered ranitidine, 26% is excreted with the feces.10 The results of the Caco-2 studies and the human Half-life of elimination phase is 1.7–2.1 h after i.v. intestinal permeability technique show large dif- dose.14,15,19,21 There are no reports that ranitidine ferences. These differences have been reported follows non-linear pharmacokinetics. Table 1. Permeability of Ranitidine Concentration Used (mM) Method Papp/Peff (Â10À7 cm/s) Reference 0.000142–14.25 Caco-2 1.03 26 0.1–5 Caco-2 18–7.5 27 0.005–5 Caco-2 20–12 28 2.56 Caco-2 3.1a 29 — Caco-2 12.4 30 0.5 Intestinal perfusion 270 31 aFurosemide, atenolol, and propranolol were used as reference compounds.