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COMMENTARY

Biowaiver Monographs for Immediate Release Solid OralDosage 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 fur Pharmazeutische Technologie, Johann Wolfgang Goethe-Universitat, 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 waiverofin vivo bioequivalence testing for the approval of immediate release (IR) solid oral

dosage forms containing ranitidine hydrochloride are reviewed. According to the currentBiopharmaceutics 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, abiowaiver can be recommended for IR solid oral dosage forms that are rapidly dissolvingand 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 Classification System (BCS); ranitidine;

permeability; solubility

INTRODUCTION

A monograph based on literature data is pre-sented on ranitidine hydrochloride with respect toits biopharmaceutical properties and the risk ofwaiving in vivo bioequivalence testing for theapproval of new and reformulated IR solid oral

dosage forms. The purpose and scope of thesemonographs were discussed previously.1 Briefly,

the aims of the present study were to evaluate allpertinent data available from literature sources toassess the appropriateness of such a biowaiverfrom the biopharmaceutical point of view and alsofrom the perspective of public health risks.

EXPERIMENTAL

The databases Caplus, Ipa, and Medline wereutilized to search using the keyword permeability

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 8, AUGUST 2005 1617

This study reflects the scientific opinion of the authors andnot the policies of regulating agencies.

Correspondence to: Dirk M. Barends (Telephone: 31 302744209; Fax: 31 30 2744462; E-mail: [email protected])

Journal of Pharmaceutical Sciences, Vol. 94, 1617 1625 (2005) 2005 Wiley-Liss, Inc. and the American Pharmacists Association


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and Caplus and Ipa using the keywords dissolu-tion, solubility, and degradation. The pharmaco-kinetic data search was initiated from theMartindale and the Drug Information Fulltext,followed by reviewing the references cited.Information with regard to the double-peakphenomenon, site-dependent absorption, first-pass metabolism, enterohepatic recycling, andbioequivalence studies were reviewed from thecited literature obtained from Medline, using thekeyword pharmacokinetics. Only literature writ-ten in English and German was included and thesearches were not limited to a certain time period.

As the solubility data from literature did not coverthe entire physiological pH range, these wereobtained experimentally at Orion Pharma. Tri-plicate determinations were carried out in whichthe solute was shaken with buffers pH 1, 3, 5, and

7.4 at room temperature for 3 h and the obtain-ed solutions analyzed by high performance liquidchromatography.

RESULTS

General Characteristics

The INN and World Health Organization (WHO)name for ranitidine, isN-[2-[[[-5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N0-methyl-2-

nitro-1,1-ethenediamine.

Structure

See Figure 1.

Salt, Esters, Polymorphs

Most preparation contain the hydrochloride 2 andthis monograph covers only that salt of ranitidine.Ranitidine hydrochloride exhibits polymorphism.2

Immediate-release (IR) tablets containing raniti-

dine hydrochloride with different polymorphicforms were reported to be bioequivalent.3

Partition Coefficient

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 tobe 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, res-pectively, calculated with a structure-fragment-based approach.5

Indication

Ranitidine is a histamine H2-antagonist used inthe treatment of gastric and duodenal ulcerationwith or without Helicobacter pylori infection andfor gastro-oesophageal reflux disease.2 Ranitidineinhibits gastric acid secretion, which is stimu-lated by pentagastrin, histamine, and normalmeals.6 The incidence of adverse drug reactionswith H2-receptor antagonists are low (


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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 absorbedwhen administered via the oral route1418 andabsorption after oral administration is linear.19

A first peak in plasma concentrations is reachedwithin 0.51.5 h and a second peak is observedwithin 34 h after single doses.20,21 The reasonsfor this double-peak phenomenon are unclear.This is likely not due to biliary excretion, asbiliary excretion is only 0.4% after oral adminis-tration.22Variations in gastric emptying may also

not be a satisfactory explanation, since whenranitidine was administered as a solution directlyto the jejunum, double-peaks were observed evenmore often than after administration to thestomach.23 In any case, this double-peak pheno-menon is not relevant for biowaiver decisions, asthere is no indication that it is formulation-dependent.

The BA of ranitidine is significantly lower whenadministered as a solution directly to the coloninstead of stomach, jejunum, or ileum.23,24 Sincethe tight junctions in the colon are considerablyless permeable than those in the small intestine, it

can be hypothesized that ranitidine is absorbed bya paracellular mechanism, with the main absorp-tion site in the small intestine. Food in general hasno effect on the rate and extent of absorption.25

Permeability

Results of permeability measurements are shownin Table 1.

Theresults of theCaco-2 studies and the humanintestinal permeability technique show large dif-ferences. These differences have been reported

and discussed earlier as these observations can beexplained on the basis that tight junctions in theintestinal cell tissues are more permeable thanthe tight junctions in the Caco-2 monolayers.1

Despite these differences, both permeability tech-niques demonstrate that the permeability is low.Indeed, ranitidine is recommended as a low per-meability internal standard in the FDA guidelinefor Caco-2 permeability studies.12 The Caco-2 per-meability increases when calcium concentration isdecreased in the test medium,26 which can be ex-plained on the basis that low calcium concentra-tions cause opening of the tight junctions of theparacellular route or change the membrane integ-rity by disturbing the phospholipid bilayers. Thus,the main absorption mechanism of ranitidine isparacellular passive diffusion. In vitro and non-clinical studies have suggested that ranitidine is a

substrate for P-gp.28,30,32 But it is likely that highdoses of this highly soluble drug, formulated inrapidly dissolving tablets, will cause saturation ofthe P-gp efflux protein.

Distribution

The apparent volume of the distribution for ter-minal phase is about 1.161.87 L/kg.14,15,21,25,33

Ranitidine has a low protein binding of about15%.15

Metabolism and Excretion

The urinary excretion of unchanged ranitidinefollowing intravenous (i.v.) administration is 70%80%,4,17,18,21,25 whereas the renal excretion ofunchanged drug after oral dosing is 25%30%.4,15,17,21 Less than 10% of the dose is metabo-lized and excreted via the urinary route aftereither i.v. or oral dosing.15,17 Of orally adminis-tered 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 ranitidinefollows non-linear pharmacokinetics.

Table 1. Permeability of Ranitidine

Concentration Used (mM) Method Papp/Peff (107 cm/s) Reference

0.00014214.25 Caco-2 1.03 26

0.15 Caco-2 187.5 270.0055 Caco-2 2012 282.56 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.

BIOWAIVER MONOGRAPH FOR RANITIDINE HYDROCHLORIDE 1619

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Dosage Form Performance

Excipients

The excipients used in the formulations of IRproducts having a MA in DE, FI, and NL areshown in Table 2. In previous monographs, MAswere taken as indicators that these formulationshad passedin vivobioequivalence requirements.1

However, for ranitidine formulations with a MAin DE, this cannot always be assumed, because in1998 the bioavailability committee of the regula-tory authorities of DE classified ranitidine as an

API for whichin vivobioequivalence testing is notalways necessary, in view of its wide therapeuticindex and non critical therapeutic use.34 The DElist was recently withdrawn, but not the MAgranted under that provision.35 FI and NL mightalso have granted MAs without requiringin vivo

bioequivalence studies.Studies with specific excipients on the in vitro

permeability of BCS class III drugs have beenreported, some of which include ranitidinestudies.36,37 Excipients such as lactose, hydroxy-propylmethyl-cellulose, docusate sodium, EDTA,propylene glycol, and PEG 400 did not affect theCaco-2 permeability. However, other excipientssuch as sodium lauryl sulfate, sodium caprate,deoxycholate, glycocholate, taurodyhydrofusidate,and palmitoylcarnitine increased the Caco-2 per-meability. These latter excipients may open the

tight junctions and thus may affect absorption viathe paracellular route.Excipients which are osmotically active such as

sodium acid pyrophosphate and polyethyleneglycol 400 have been reported to reduce the BA ofranitidine when present in high concentrations(110 g), likely because these excipients shortenthe small intestinal transit time.3840

Dissolution

The USP 27 dissolution specification for raniti-

dine hydrochloride tablets is not less than 80% (Q)dissolved in 45 min in 900 mL water, using thepaddle at 50 rpm.41 Relevant dissolution studiesare presented in Table 3. In the reported study of

Ali et al.,42 about 80% of the studied formula-tions had trade names that also appear in Table 2.Most formulations showed rapid dissolution inthe reported medium, however, in most casesthe dissolution curves of these ranitidine pro-ducts did not meet the similarity factor (f2)requirement.12,13 Other studies, using water in-

stead of the 0.1N HCl as a medium arrived atanalogous results.4345

Polli45 investigated the association between thedissolution rate of three ranitidine hydrochlorideIR tablets and their bioequivalence relative toZantac1. The dissolution profiles were recordedusing the USP27 method. There were difference indissolution rate, but all four formulations werefound to be bioequivalent in a four-way, single dosebioequivalence study. The author concluded thatdifferences in dissolution rates observed earlierthan 30 min had negligible consequencesin vivo.

The effect of dissolution rate and gastro-intest-inal (GI) transit time on the bioequivalence ofranitidine has also been studied by computersimulations.46 These simulations also includedatenolol (low permeability) and metoprolol (highpermeability). It was concluded that peak plasma

concentrations (Cmax) appeared to be more sensi-tive to changes in dissolution and GI transit timesthan area under the curve (AUC). The higherthe permeability of the drug substance, the moresensitive Cmax was to the dissolution and gas-tric emptying rates. IR ranitidine hydrochloridetablets were predicted to be bioequivalent with anoral solution when dissolution was as slow as 85%in 1.5 h. This observation has alsobeennoted for IRtablets of metformin, which is also a BCS class IIIdrug with a paracellular transport mechanism.The IR tablets of metformin had similar in vivo

absorption as modified release tablets if theirdissolution rate was as slow as 85% dissolved in2 h.47,48

DISCUSSION

Solubility

Ranitidine hydrochloride can be expected to behighly soluble at 378C over the entire pH-range17.4.12,13

Permeability

The low BA of ranitidine is in line with its lowpermeability.

Risks with Respect to Compositionand/or Manufacturing Variations

For the excipients listed in Table 2, it can be con-cluded that there are little risks to cause clinical

1620 KORTEJA RVI ET AL.

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Table 2. Excipientsa Present in Ranitidine Hydrochloride IR Solid oral Drug Productsb with an MarketingAuthorization (MA) in Germany (DE), Finland (FI), and The Netherlands (NL)

Basic butylated methacrylate copolymer DE(13) NL (4) FI (5,6)Calcium hydrogen phosphate DE(713)NL (14)Carmellose sodium NL(15, 16)Carnauba wax DE (1720) NL (21, 22)Castor oil DE (2326) NL (27, 28)

Cellulose DE(13, 713, 1719, 2326, 2952) NL (4, 1416, 21, 22, 27, 28,5366)FI (5, 6, 6774)

Copovidone DE(13)Croscarmellose sodium 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)

Dextran DE(17, 19)Ethylcellulose FI(70)Glucose DE(39, 40, 43)Hydroxypropylcellulose FI(71)

Hypromellose DE(13, 713, 1720, 2326, 2952) NL (4, 1416, 21, 22, 27, 28,5366)FI (5, 6, 6774)

Lactose DE(713)NL (14)

Macrogol DE(1, 3, 713, 1720, 29, 3141, 4347) NL (4, 14, 16, 21, 22, 5662,64, 65)FI (5, 6, 67, 69, 70, 73)

Magnesium stearate DE(13, 713, 1720, 2326, 2952) NL (4, 1416, 21, 22, 27, 28,

5366)FI (5, 6, 6774)Maize starch DE(713)NL (14)Polydextrose DE(18, 20, 31, 32, 3538, 41, 4446) NL (16,21,22,57-61,65)FI (69,73)Polymethacrylate DE(29, 47) NL (56, 62, 64) FI (67)

Polymethacrylic acid DE(33)Polymethacrylic acid Copolymer DE(34)Polysorbate FI(70)Povidone DE(33, 34) FI (70)Shellac DE(25)Silica DE(1, 713, 18, 19, 2326, 30, 46)NL (14, 21, 22, 27, 28)FI (73)

Silica, hydrophobic DE(17, 41)Simethicone DE(25)Sodium starch glycolate DE(713)NL (14)FI (70)Soya-bean oil FI(70)

Talc DE(1, 2326, 29, 33, 34, 47) NL(4, 27, 28, 56, 62, 64)FI (5, 6, 67, 70, 73)Triacetin DE(30, 41, 4852) NL (15, 5355) FI (68, 72, 74)Triethyl citrate DE(31, 32, 3541, 43 46)NL (16, 5761, 65) FI (69, 73)

Sources of data: DE: www.rote-liste.de; FI: www.nam.fi; NL: www.cbg-meb.nlaPrinting inkt, colorants, and flavors are not included.bExcluded aredosageforms thatare swallowed by thepatientin liquid form,such as effervescentand 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.

5. Ranitidin Alpharma 150 mg/300 mg kalvopaallysteinen tabletti.6. Ranitidine Biochemie 150 mg/300 mg kalvopaallysteiset tabletti.7. Ranibeta1 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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issues as the drug products, in which these ex-cipients are formulated, are in therapeutic use.This observation is supported by Yu et al.,49

reporting that commonly used excipients used toformulate BSC Class III APIs had no significanteffect on their absorption. This risk to cause cli-nical issues can be estimated to be even smaller ifan excipient is present in a large number of regis-trated drug products. However, this conclusion

only holds when these excipients are present inamounts typically used in IR solid oral dosageforms. For instance, macrogol, i.e., PEG, is listedin Table 2, but is an osmotically active excipientand, as discussed above, reduces the BA of rani-tidine when administrated in gram amounts.However, when present in milligram amounts,as typically used in the coating of tablets, no effecton the BA is to be expected.

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, filmomhulde tabletten.66. Ranitidine 75 mg/150 mg/300 mg Katwijk, omhulde tabletten.67. Ranitidin Pliva 150 mg tabletti, kalvopaallysteinen.68. ESOFEX1 150 mg-tabletti, kalvopaallysteinen.69. Ranicur 150 mg/300 mg tabletti, kalvopaallysteinen.70. Ranil1 150 mg/300 mg kalvopaallysteinen tabletti.71. Ranimex 150 mg tabletti.72. Ranimex 75 mg tabletti, kalvopaallysteinen.73. Ranixal 150 mg/300 mg tabletti, kalvopaallysteinen.74. Zantac 150 mg/300 mg tabletti.




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Surrogate Techniques forIn VivoBioequivalence Testing

The rate-limiting step in the absorption process ofranitidine is its permeability. So, if there issufficient evidence that the excipients in the test

product have no effect on the permeability or GItransit time, comparative dissolution testing canprovide reasonable assurance for bioequivalencyof the product. According to the guidances, thetest product should be rapidly dissolving andalso meet the requirement of f2-dissolution curvesimilarity with the reference product to concludeto bioequivalence.12,13 Applying the f2criterion tothe studies reported in Table 3, most formulationsthat are bioequivalent to each other, or could beassumed to be therapeutically equivalent, wouldnot pass. In the most cases f2calculation showed a

greater than 10% difference between formula-tions. However, as long as the two preparationsreleased drug within 30 min, no differences in vivocould be demonstrated. Thus, it appears thatapplying both criteria, i.e., rapid dissolution andf2 >50 may be unnecessary restrictive for raniti-dine products. The too strict nature of the f2criterion for ranitidine is further supported bycomputer simulations, predictingin vivo bioequi-valence with an oral solution of IR tablets havingdissolution rates as slow as 85% in 1.5 h.46

Patients Risks Associated with Bioinequivalence

The unproblematic use of doses six times higherthan the recommended dose indicates that rani-tidine has a wide therapeutic range. Its IR oraldosage forms are not used for life-threateningindications. These two considerations open thepossibility for a biowaiver.

CONCLUSION

Ranitidine hydrochloride can be classified as aBCS Class III API. Present regulations describethe possibility of a biowaiver for BCS Class I APIcontaining drug products only.12,13 However,extensions of the present requirements to BCSClass III APIs have received increasing atten-tion.4951 The data evaluated and discussed inthis study show that it would be reasonably safe togrant biowaivers for IR solid oral dosage forms,provided that the test product is formulated withexcipients shown in Table 2, in amounts typicallyT

able

3.

DissolutionofRanitidineHydrochlorideIRFormulations

Formulations

DissolutionMe

thod

RapidlyDissolving

(>85%in30min)yes/no

SimilarityofDissolution

Profiles(f

2)yes/no

Reference

GenericIRproductsinDE

0.1NHCl,paddle

50rpm

47:yes;2:no

Mostprofiles:no

42

Zantac1150and300mgversus

BIPI(USP)

150and300mg

Water,paddle50rpm

b

150mg:no;300mg:

yes

150mg:no;300mg:yes

43

GenericIRtablet

Water,paddle50rpm

b

Yes

44

RanitidineHClZantac1,fast,m

ediumand

slowdissolvingIRtabletsa

Water,paddle50rpm

b

Yes

Fastversusslow:no

45

aThefourranitidineformulation

swerebioequivalenttooneanother.

bConformtoUSP27.




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

ACKNOWLEDGMENTS

Timo Oksanen, Orion Pharma is acknowledgedfor carrying out the solubility experiments andGert Ensing, RIVM, for aggregating excipientinformation into tabular format.

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