COMMENTARY Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Ranitidine Hydrochloride

RVI,1 M. YLIPERTTULA,1 J.B. DRESSMAN,2 H.E. JUNGINGER,3 K.K. MIDHA,4 H. KORTEJA V.P. SHAH,5 D.M. BARENDS6
1 2

Orion Pharma, Research and Development, Espoo, Finland t, Frankfurt am Main, Germany r Pharmazeutische Technologie, Johann Wolfgang Goethe-Universita Institut fu

3 Leiden/Amsterdam Center for Drug Research, Leiden University, Division of Pharmaceutical Technology, Leiden, The Netherlands 4 5 6

University of Saskatchewan, Saskatoon, Canada U.S. Food and Drug Administration, Center of Drug Evaluation and Research, Rockville, Maryland RIVM, 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 Classication System (BCS), ranitidine hydrochloride should be assigned to Class III. However, based on its therapeutic and therapeutic index, pharmacokinetic 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. 2005 Wiley-Liss, Inc. and the
American Pharmacists Association J Pharm Sci 94:16171625, 2005

Keywords: absorption; Biopharmaceutics Classication System (BCS); ranitidine; permeability; solubility

INTRODUCTION
A monograph based on literature data is presented on ranitidine hydrochloride with respect to its biopharmaceutical properties and the risk of waiving in vivo bioequivalence testing for the approval of new and reformulated IR solid oral
This study reects the scientic opinion of the authors and not the policies of regulating agencies. Correspondence to: Dirk M. Barends (Telephone: 31 30 2744209; Fax: 31 30 2744462; E-mail: dirk.barends@rivm.nl)
Journal of Pharmaceutical Sciences, Vol. 94, 16171625 (2005) 2005 Wiley-Liss, Inc. and the American Pharmacists Association

dosage forms. The purpose and scope of these monographs were discussed previously.1 Briey, the aims of the present study were to evaluate all pertinent data available from literature sources to assess the appropriateness of such a biowaiver from the biopharmaceutical point of view and also from the perspective of public health risks.

EXPERIMENTAL
The databases Caplus, Ipa, and Medline were utilized to search using the keyword permeability
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and Caplus and Ipa using the keywords dissolution, solubility, and degradation. The pharmacokinetic data search was initiated from the Martindale and the Drug Information Fulltext, followed by reviewing the references cited. Information with regard to the double-peak phenomenon, site-dependent absorption, rstpass metabolism, enterohepatic recycling, and bioequivalence studies were reviewed from the cited literature obtained from Medline, using the keyword pharmacokinetics. Only literature written in English and German was included and the searches were not limited to a certain time period. As the solubility data from literature did not cover the entire physiological pH range, these were obtained experimentally at Orion Pharma. Triplicate 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 obtained solutions analyzed by high performance liquid chromatography.

dine hydrochloride with different polymorphic forms were reported to be bioequivalent.3 Partition Coefcient LogP (water/n-octanol) was reported to be 0.2.4 This value is likely for the ionized form, i.e., logD. LogP (for the neutral molecule) was calculated to be 1.28.5 pKa The two pKa values reported 8.2 and 2.7 4 are in agreement with the values of 8.4 and 3.5, respectively, calculated with a structure-fragmentbased approach.5 Indication 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 reux disease.2 Ranitidine inhibits gastric acid secretion, which is stimulated by pentagastrin, histamine, and normal meals.6 The incidence of adverse drug reactions with H2-receptor antagonists are low (<3%) and are usually minor in nature.7 For Zollinger Ellison syndrome doses up to 900 mg daily have been used without troublesome side effects.6 The WHO recommended dose for ranitidine tablets is 150 mg ranitidine base, given as the hydrochloride salt.8 Strengths currently having a marketing authorization (MA) in Germany (DE)9, Finland (FI),10 and The Netherlands (NL)11 are the equivalents of 75, 150, and 300 mg ranitidine base. Solubility The solubility of ranitidine hydrochloride in water is 660 mg/mL and it is reported to be freely soluble in water.2 The solubility in the pH range 17.4 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 criteria of highly soluble according to FDA and EMEA Guidelines are dened at 378C.12,13 But, supposing that the solubility will be higher at 378C than at room temperature, it is reasonable safe to classify ranitidine hydrochloride as a

RESULTS
General Characteristics The INN and World Health Organization (WHO) name for ranitidine, is N-[2-[[[-5-[(dimethylamino) methyl]-2-furanyl]methyl]thio]ethyl]-N0 -methyl-2nitro-1,1-ethenediamine.

Structure See Figure 1.

Salt, Esters, Polymorphs Most preparation contain the hydrochloride 2 and this monograph covers only that salt of ranitidine. Ranitidine hydrochloride exhibits polymorphism.2 Immediate-release (IR) tablets containing raniti-

Figure 1. Structure of ranitidine.

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highly soluble active pharmaceutical ingredient (API). Pharmacokinetics Absorption The oral bioavailability (BA) of ranitidine is 50% 60%. The drug is reported to be rapidly absorbed when administered via the oral route1418 and absorption after oral administration is linear.19 A rst peak in plasma concentrations is reached within 0.51.5 h and a second peak is observed within 34 h after single doses.20,21 The reasons for this double-peak phenomenon are unclear. This is likely not due to biliary excretion, as biliary excretion is only 0.4% after oral administration.22 Variations in gastric emptying may also not be a satisfactory explanation, since when ranitidine was administered as a solution directly to the jejunum, double-peaks were observed even more often than after administration to the stomach.23 In any case, this double-peak phenomenon is not relevant for biowaiver decisions, as there is no indication that it is formulationdependent. The BA of ranitidine is signicantly lower when administered as a solution directly to the colon instead of stomach, jejunum, or ileum.23,24 Since the tight junctions in the colon are considerably less permeable than those in the small intestine, it can be hypothesized that ranitidine is absorbed by a paracellular mechanism, with the main absorption site in the small intestine. Food in general has no effect on the rate and extent of absorption.25 Permeability Results of permeability measurements are shown in Table 1. The results of the Caco-2 studies and the human intestinal permeability technique show large differences. These differences have been reported
Table 1. Permeability of Ranitidine Method

and discussed earlier as these observations can be 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 Despite these differences, both permeability techniques demonstrate that the permeability is low. Indeed, ranitidine is recommended as a low permeability internal standard in the FDA guideline for Caco-2 permeability studies.12 The Caco-2 permeability increases when calcium concentration is decreased in the test medium,26 which can be explained on the basis that low calcium concentrations cause opening of the tight junctions of the paracellular route or change the membrane integrity by disturbing the phospholipid bilayers. Thus, the main absorption mechanism of ranitidine is paracellular passive diffusion. In vitro and nonclinical studies have suggested that ranitidine is a substrate for P-gp.28,30,32 But it is likely that high doses of this highly soluble drug, formulated in rapidly dissolving tablets, will cause saturation of the P-gp efux protein. Distribution The apparent volume of the distribution for terminal phase is about 1.161.87 L/kg.14,15,21,25,33 Ranitidine has a low protein binding of about 15%.15 Metabolism and Excretion The urinary excretion of unchanged ranitidine following intravenous (i.v.) administration is 70% 80%,4,17,18,21,25 whereas the renal excretion of unchanged drug after oral dosing is 25% 30%.4,15,17,21 Less than 10% of the dose is metabolized and excreted via the urinary route after either i.v. or oral dosing.15,17 Of orally administered ranitidine, 26% is excreted with the feces.10 Half-life of elimination phase is 1.72.1 h after i.v. dose.14,15,19,21 There are no reports that ranitidine follows non-linear pharmacokinetics.

Concentration Used (mM) 0.00014214.25 0.15 0.0055 2.56 0.5

a

Papp/Peff (107 cm/s) 1.03 187.5 2012 3.1a 12.4 270

Reference 26 27 28 29 30 31

Caco-2 Caco-2 Caco-2 Caco-2 Caco-2 Intestinal perfusion

Furosemide, atenolol, and propranolol were used as reference compounds.

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Dosage Form Performance Excipients The excipients used in the formulations of IR products having a MA in DE, FI, and NL are shown in Table 2. In previous monographs, MAs were taken as indicators that these formulations had passed in vivo bioequivalence requirements.1 However, for ranitidine formulations with a MA in DE, this cannot always be assumed, because in 1998 the bioavailability committee of the regulatory authorities of DE classied ranitidine as an API for which in vivo bioequivalence testing is not always necessary, in view of its wide therapeutic index and non critical therapeutic use.34 The DE list was recently withdrawn, but not the MA granted under that provision.35 FI and NL might also have granted MAs without requiring in vivo bioequivalence studies. Studies with specic excipients on the in vitro permeability of BCS class III drugs have been reported, some of which include ranitidine studies.36,37 Excipients such as lactose, hydroxypropylmethyl-cellulose, docusate sodium, EDTA, propylene glycol, and PEG 400 did not affect the Caco-2 permeability. However, other excipients such as sodium lauryl sulfate, sodium caprate, deoxycholate, glycocholate, taurodyhydrofusidate, and palmitoylcarnitine increased the Caco-2 permeability. These latter excipients may open the tight junctions and thus may affect absorption via the paracellular route. Excipients which are osmotically active such as sodium acid pyrophosphate and polyethylene glycol 400 have been reported to reduce the BA of ranitidine when present in high concentrations (110 g), likely because these excipients shorten the small intestinal transit time.3840

stead of the 0.1N HCl as a medium arrived at analogous results.4345 Polli45 investigated the association between the dissolution rate of three ranitidine hydrochloride IR tablets and their bioequivalence relative to Zantac1. The dissolution proles were recorded using the USP27 method. There were difference in dissolution rate, but all four formulations were found to be bioequivalent in a four-way, single dose bioequivalence study. The author concluded that differences in dissolution rates observed earlier than 30 min had negligible consequences in vivo. The effect of dissolution rate and gastro-intestinal (GI) transit time on the bioequivalence of ranitidine has also been studied by computer simulations.46 These simulations also included atenolol (low permeability) and metoprolol (high permeability). It was concluded that peak plasma concentrations (Cmax) appeared to be more sensitive to changes in dissolution and GI transit times than area under the curve (AUC). The higher the permeability of the drug substance, the more sensitive Cmax was to the dissolution and gastric emptying rates. IR ranitidine hydrochloride tablets were predicted to be bioequivalent with an oral solution when dissolution was as slow as 85% in 1.5 h. This observation has also been noted for IR tablets of metformin, which is also a BCS class III drug with a paracellular transport mechanism. The IR tablets of metformin had similar in vivo absorption as modied release tablets if their dissolution rate was as slow as 85% dissolved in 2 h.47,48

DISCUSSION
Solubility Ranitidine hydrochloride can be expected to be highly soluble at 378C over the entire pH-range 17.4.12,13

Dissolution The USP 27 dissolution specication for ranitidine hydrochloride tablets is not less than 80% (Q) dissolved in 45 min in 900 mL water, using the paddle at 50 rpm.41 Relevant dissolution studies are presented in Table 3. In the reported study of Ali et al.,42 about 80% of the studied formulations had trade names that also appear in Table 2. Most formulations showed rapid dissolution in the reported medium, however, in most cases the dissolution curves of these ranitidine products did not meet the similarity factor (f2) requirement.12,13 Other studies, using water inJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 8, AUGUST 2005

Permeability The low BA of ranitidine is in line with its low permeability.

Risks with Respect to Composition and/or Manufacturing Variations For the excipients listed in Table 2, it can be concluded that there are little risks to cause clinical

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Table 2. Excipientsa Present in Ranitidine Hydrochloride IR Solid oral Drug Productsb with an Marketing Authorization (MA) in Germany (DE), Finland (FI), and The Netherlands (NL) Basic butylated methacrylate copolymer Calcium hydrogen phosphate Carmellose sodium Carnauba wax Castor oil Cellulose Copovidone Croscarmellose sodium Dextran Ethylcellulose Glucose Hydroxypropylcellulose Hypromellose Lactose Macrogol Magnesium stearate Maize starch Polydextrose Polymethacrylate Polymethacrylic acid Polymethacrylic acid Copolymer Polysorbate Povidone Shellac Silica Silica, hydrophobic Simethicone Sodium starch glycolate Soya-bean oil Talc Triacetin Triethyl citrate DE (13) NL (4) FI (5,6) DE (713) NL (14) NL (15, 16) DE (1720) NL (21, 22) DE (2326) NL (27, 28) DE (13, 713, 1719, 2326, 2952) NL (4, 1416, 21, 22, 27, 28, 5366) FI (5, 6, 6774) DE (13) DE (1721, 2326, 29, 30, 32, 36, 38, 40, 41, 43, 4547, 49, 52) NL (4, 22, 27, 28, 56, 59, 61, 62, 64) FI (5, 6, 67, 69, 73, 74) DE (17, 19) FI (70) DE (39, 40, 43) FI (71) DE (13, 713, 1720, 2326, 2952) NL (4, 1416, 21, 22, 27, 28, 5366) FI (5, 6, 6774) DE (713) NL (14) DE (1, 3, 713, 1720, 29, 3141, 4347) NL (4, 14, 16, 21, 22, 5662, 64, 65) FI (5, 6, 67, 69, 70, 73) DE (13, 713, 1720, 2326, 2952) NL (4, 1416, 21, 22, 27, 28, 5366) FI (5, 6, 6774) DE (713) NL (14) DE (18, 20, 31, 32, 3538, 41, 4446) NL (16,21,22,57-61,65) FI (69,73) DE (29, 47) NL (56, 62, 64) FI (67) DE (33) DE (34) FI (70) DE (33, 34) FI (70) DE (25) DE (1, 713, 18, 19, 2326, 30, 46) NL (14, 21, 22, 27, 28) FI (73) DE (17, 41) DE (25) DE (713) NL (14) FI (70) FI (70) DE (1, 2326, 29, 33, 34, 47) NL (4, 27, 28, 56, 62, 64) FI (5, 6, 67, 70, 73) DE (30, 41, 4852) NL (15, 5355) FI (68, 72, 74) DE (31, 32, 3541, 4346) NL (16, 5761, 65) FI (69, 73)

Sources of data: DE: www.rote-liste.de; FI: www.nam.; NL: www.cbg-meb.nl a Printing inkt, colorants, and avors are not included. b Excluded are dosage forms that are swallowed by the patient in liquid form, such as effervescent and dispersible tablets. Chewable tablets are also excluded. 1. Raniberl1 150 mg/-300 mg Filmtabletten. 2. Ranitidoc 300 mg Filmtabletten. 3. Rani-nerton1 150/-300 Filmtabletten. 4. Ranitidine Sandoz 150/300, tabletten 150 mg/300 mg. a llysteinen tabletti. 5. Ranitidin Alpharma 150 mg/300 mg kalvopa a llysteiset tabletti. 6. Ranitidine Biochemie 150 mg/300 mg kalvopa 1 7. Ranibeta 150/-300 Filmtabletten. 8. Raniprotect1 150/-300 Filmtabletten. 9. Ranitic1 75 akut bei Sodbrennen Filmtabletten. 10. Ranitic1 150/-300/-150 akut/-300 akut Filmtabletten. 11. Ranitidin 75-1 A Pharma Filmtabletten. 12. Ranitidin 150/-300-1 A Pharma Filmtabletten. 13. RANITIDIN BASICS 150 mg/-300 mg Filmtabletten. 14. Ranitidine 150 mg/300 mg, tabletten. 15. Zantac 300, tabletten 300 mg. 16. Ranitidine Merck 300 mg, tabletten. 17. Ranitidin PB 150 mg/-300 mg Filmtabletten. 18. Ranitidin Sandoz1 150 mg/-300 mg Filmtabletten.

(Continued )

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Table 2. (Continued )
19. Ranitidin STADA1 150 mg/-300 mg Filmtabletten. 20. Ran Lich1 150 mg/-300 mg Filmtabletten. 21. Ranitidine CF 150 mg/300 mg, omhulde tabletten. 22. Ranitidine 150/300 PCH, tabletten 150 mg/300 mg. 23. Ranitab1 75 mg Filmtabletten. 24. Ranitidin-ratiopharm1 75 mg Filmtabletten gegen Sodbrennen. 25. Ranitidin STADA1 75 mg Filmtabletten. 26. ranitidin von ct 75 mg Filmtabletten. 27. Ranitidine 150/300 Ranbaxy, omhulde tabletten 150 mg/300 mg. 28. Ranitidine 75 mg Hexal, tabletten. 29. Junizac1 150 mg/-300 mg Filmtabletten. 30. Rani 150 mg/-300 mg AbZ Filmtabletten. 31. Ranibloc1 150 Filmtabletten. 32. Ranibloc1 300 Filmtabletten. 33. Ranicux1 75 mg Filmtabletten. 34. Ranicux1 150 mg/-300 mg Filmtabletten. 35. Ranidura1 T 150 mg Filmtabletten. 36. Ranidura1 T 300 mg Filmtabletten. 37. Ranimerck1 150 mg Filmtabletten. 38. Ranimerck1 300 mg Filmtabletten. 39. RANI-PUREN1 150 Filmtabletten. 40. RANI-PUREN1 300 Filmtabletten. 41. ranitidin 150/-300 von ct Filmtabletten. 42. Ranitidin acis1 300 mg Filmtabletten. 43. Ranitidin AL 150/-300 Filmtabletten. 44. Ranitidin-ISIS1 150 Filmtabletten. 45. Ranitidin-ISIS1 300 Filmtabletten. 46. Ranitidin-ratiopharm1 150/-300/-150 akut/-300 akut Filmtabletten. 47. Ranitidin-saar1 150 mg/-300 mg Filmtabletten. 48. Sostril1 150 mg Filmtabletten. 49. Sostril1 300 mg Filmtabletten. 50. Zantic1 75 mg Magentabletten Filmtabletten. 51. Zantic1 150 mg Filmtabletten. 52. Zantic1 300 mg Filmtabletten. 53. Zantac 150, tabletten 150 mg. 54. Zantac 75, tabletten 75 mg. 55. Zantac 150, tabletten 150 mg. 56. Ranitidine Dumex 150 mg, tabletten. 57. Ranitidine Merck 150 mg, tabletten. 58. Ranitidine 150 mg Katwijk, tabletten. 59. Ranitidine 300 mg Katwijk, tabletten. 60. Ranitidine CF 150 mg, tabletten. 61. Ranitidine CF 300 mg, tabletten. 62. Ranitidine Gf 150 mg/300 mg, tabletten. 63. Ranitidine 75 mg/150 mg/300 mg, omhulde tabletten (Pharmacin Products). 64. Ranitidine 150 mg/300 mg, omhulde tabletten (Delphi). 65. Ranitidine FLX 75 mg/150 mg/300 mg, lmomhulde tabletten. 66. Ranitidine 75 mg/150 mg/300 mg Katwijk, omhulde tabletten. a llysteinen. 67. Ranitidin Pliva 150 mg tabletti, kalvopa a llysteinen. 68. ESOFEX1 150 mg-tabletti, kalvopa a llysteinen. 69. Ranicur 150 mg/300 mg tabletti, kalvopa a llysteinen tabletti. 70. Ranil1 150 mg/300 mg kalvopa 71. Ranimex 150 mg tabletti. a llysteinen. 72. Ranimex 75 mg tabletti, kalvopa a llysteinen. 73. Ranixal 150 mg/300 mg tabletti, kalvopa 74. Zantac 150 mg/300 mg tabletti.

issues as the drug products, in which these excipients are formulated, are in therapeutic use. This observation is supported by Yu et al.,49 reporting that commonly used excipients used to formulate BSC Class III APIs had no signicant effect on their absorption. This risk to cause clinical issues can be estimated to be even smaller if an excipient is present in a large number of registrated drug products. However, this conclusion
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only holds when these excipients are present in amounts typically used in IR solid oral dosage forms. For instance, macrogol, i.e., PEG, is listed in Table 2, but is an osmotically active excipient and, as discussed above, reduces the BA of ranitidine when administrated in gram amounts. However, when present in milligram amounts, as typically used in the coating of tablets, no effect on the BA is to be expected.

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Reference

42 43

44 45

Surrogate Techniques for In Vivo Bioequivalence Testing The rate-limiting step in the absorption process of ranitidine is its permeability. So, if there is sufcient evidence that the excipients in the test product have no effect on the permeability or GI transit time, comparative dissolution testing can provide reasonable assurance for bioequivalency of the product. According to the guidances, the test product should be rapidly dissolving and also meet the requirement of f2-dissolution curve similarity with the reference product to conclude to bioequivalence.12,13 Applying the f2 criterion to the studies reported in Table 3, most formulations that are bioequivalent to each other, or could be assumed to be therapeutically equivalent, would not pass. In the most cases f2 calculation showed a greater than 10% difference between formulations. However, as long as the two preparations released drug within 30 min, no differences in vivo could be demonstrated. Thus, it appears that applying both criteria, i.e., rapid dissolution and f2 >50 may be unnecessary restrictive for ranitidine products. The too strict nature of the f2 criterion for ranitidine is further supported by computer simulations, predicting in vivo bioequivalence with an oral solution of IR tablets having dissolution rates as slow as 85% in 1.5 h.46

Similarity of Dissolution Proles (f2) yes/no

Most proles: no 150 mg: no; 300 mg: yes 47: yes; 2: no 150 mg: no; 300 mg: yes 0.1N HCl, paddle 50 rpm Water, paddle 50 rpmb

Rapidly Dissolving (>85% in 30 min) yes/no

Dissolution of Ranitidine Hydrochloride IR Formulations

Water, paddle 50 rpmb Water, paddle 50 rpmb

Dissolution Method

Yes Yes

Fast versus slow: no

Patients Risks Associated with Bioinequivalence

The four ranitidine formulations were bioequivalent to one another. Conform to USP 27.

The unproblematic use of doses six times higher than the recommended dose indicates that ranitidine has a wide therapeutic range. Its IR oral dosage forms are not used for life-threatening indications. These two considerations open the possibility for a biowaiver.

Generic IR products in DE Zantac1 150 and 300 mg versus BIPI (USP) 150 and 300 mg Generic IR tablet Ranitidine HCl Zantac1, fast, medium and slow dissolving IR tabletsa

CONCLUSION
Ranitidine hydrochloride can be classied as a BCS Class III API. Present regulations describe the possibility of a biowaiver for BCS Class I API containing drug products only.12,13 However, extensions of the present requirements to BCS Class III APIs have received increasing attention.4951 The data evaluated and discussed in this study show that it would be reasonably safe to grant biowaivers for IR solid oral dosage forms, provided that the test product is formulated with excipients shown in Table 2, in amounts typically
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Formulations

Table 3.

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used in IR solid oral dosage forms, and the test product is also rapidly dissolving.12,13

ACKNOWLEDGMENTS
Timo Oksanen, Orion Pharma is acknowledged for carrying out the solubility experiments and Gert Ensing, RIVM, for aggregating excipient information into tabular format.

REFERENCES
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13. Committee for Proprietary Medicinal Products (CPMP). 2001. Note for Guidance on the Investigation of Bioavailability and Bioequivalence. 14. Bogues K, Dixon GT, Fowler P, Jenner WN, Maconochie JG, Martin LE, Willoughby BA. 1980. Pharmacokinetics and bioavailability of ranitidine in humans. Br J Clin Pharmacol 73:275P276P. 15. Garg DC, Weidler DJ, Baltodano N, Eshelman FN. 1981. Pharmacokinetics of ranitidine, a new histamine H2-receptor blocker. Br J Clin Pharmacol 29: 247248. 16. Chau NP, Zech PY, Pozet N, Hadj-Aissa A. 1982. Ranitidine kinetics in normal subjects. Clin Pharmacol Ther 31:770774. 17. Martin LE, Bell JA, Carey PF, Dallas FAA, Dixon GT, Jenner WN. 1982. A review of pharmacokinetics and metabolism of ranitidine in animals and man. Med Publ Found Symp Ser 5:2331. 18. Garg DC, Weidler DJ, Eshelman FN. 1983. Ranitidine bioavailability and kinetics in normal male subjects. Clin Pharmacol Ther 33:445452. 19. Mignon M, Chau NP, Nguyen-Phuoc BK, Sauvage M, Leguy F, Bonls S. 1982. Ranitidine upon mealinduced gastric secretion: oral pharmacokinetics and plasma concentration effect relationships. Br J Clin Pharmacol 14:187193. 20. Woodings EP, Dixon GT, Harrison C, Carey P, Richards DA. 1980. Ranitidinea new H2-receptor antagonist. Gut 21:187191. 21. Van Hecken AM, Tjandramaga TB, Mullie A, Verbesselt R, De Schepper PJ. 1982. Ranitidine: single dose pharmacokinetics and absolute bioavailability in man. Br J Clin Pharmacol 14:195 200. 22. Klotz U, Walker S. 1990. Biliary excretion of H2receptor antagonists. Eur J Clin Pharmacol 39: 9192. 23. Williams MF, Dukes GE, Heizer W, Han Y-H, Hermann DJ, Lampkin T, Hak LJ. 1992. Inuence of gastrointestinal site of drug delivery on the absorption characteristics of ranitidine. Pharm Res 9:11901194. 24. Pithavala YK, Heizer WD, Parr AF, OConnorSemmes RL, Brouwer KL. 1998. Use of the InteliSite capsule to study ranitidine absorption from various sites within the human intestinal tract. Pharm Res 15:18691875. 25. Mc Neil JJ, Mihaly GW, Anderson A, Marshall AW, Smallwood RA, Louis WJ. 1981. Pharmacokinetics of the H2-reeceptor antagonist ranitidine in man. Br J Clin Pharmacol 12:411415. 26. Gan LS, Hsyu PH, Pritchard JF, Thakker D. 1993. Mechanism of intestinal absorption of ranitidine and ondansetron: transport across Caco-2 cell monolayers. Pharm Res 10:17221725. 27. Lee K, Thakker DR. 1999. Saturable transport of H2-antagonists ranitidine and famotidine across Caco-2 cell monolayers. J Pharm Sci 88:680687.

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JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 8, AUGUST 2005