COMMENTARY

Biowaiver Monographs for Immediate Release Solid Oral

Dosage Forms: Ranitidine Hydrochloride
H. KORTEJARVI,1 M. YLIPERTTULA,1 J.B. DRESSMAN,2 H.E. JUNGINGER,3 K.K. MIDHA,4
V.P. SHAH,5 D.M. BARENDS6
1

Orion Pharma, Research and Development, Espoo, Finland

Institut fur Pharmazeutische Technologie, Johann Wolfgang Goethe-Universitat, Frankfurt am Main, Germany

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

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 Classification 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 Classification 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 reflects the scientific 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 Briefly,
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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RVI ET AL.
KORTEJA

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, firstpass 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.

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.

dine hydrochloride with different polymorphic

forms 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 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 reflux 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.

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.

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

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 defined 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

BIOWAIVER MONOGRAPH FOR RANITIDINE HYDROCHLORIDE

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 first 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 significantly 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.

1619

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 efflux 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.

Permeability of Ranitidine

Concentration Used (mM)

0.00014214.25
0.15
0.0055
2.56

0.5

Method

Papp/Peff (
107 cm/s)

Reference

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

1.03
187.5
2012
3.1a
12.4
270

26
27
28
29
30
31

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 classified 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 specific 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

Dissolution
The USP 27 dissolution specification 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

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 profiles 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 modified 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

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

BIOWAIVER MONOGRAPH FOR RANITIDINE HYDROCHLORIDE

1621

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.fi; NL: www.cbg-meb.nl

a
Printing inkt, colorants, and flavors 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.
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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RVI ET AL.
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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, 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.

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

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.

44
45

The rate-limiting step in the absorption process of

ranitidine is its permeability. So, if there is
sufficient 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

The four ranitidine formulations were bioequivalent to one another.

Conform to USP 27.

Patients Risks Associated with Bioinequivalence

Yes
Yes
Water, paddle 50 rpmb
Water, paddle 50 rpmb

1623

Surrogate Techniques for In Vivo

Bioequivalence Testing

Fast versus slow: no

42
43
Most profiles: 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

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

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

Table 3.

Dissolution of Ranitidine Hydrochloride IR Formulations

Similarity of Dissolution
Profiles (f2) yes/no

Reference

BIOWAIVER MONOGRAPH FOR RANITIDINE HYDROCHLORIDE

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.

CONCLUSION
Ranitidine hydrochloride can be classified 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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1624

RVI ET AL.
KORTEJA

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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Midha KK, Moller H, Olling M, Shah VP, Barends
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urine by reversed-phase ion-pair high-performance
liquid chromatography. J Chromatogr 225:161
168.
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Avery GS. 1982. Ranitidine: a review of its pharmacology and therapeutic use in peptic ulcer disease
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par/edl/expcom13/eml13_en.doc.
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Aulendorf, Germany. www.rote-liste.de.
10. www.nam.fi/laakeinformaatio/index.html.
11. www.cbg-meb.nl.
12. U.S. Department of Health and Human Services
Food and Drug Administration Center for Drug
Evaluation and Research (CDER). 2000. Guidance
for Industry: Waiver of In Vivo Bioavailability and
Bioequivalence Studies for Immediate-Release
Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System.

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