GENERAL COMMENTARY

Biowaiver Monographs for Immediate-Release Solid Oral Dosage

Forms: Nifedipine
JAYACHANDAR GAJENDRAN,1,2 JOHANNES KRÄMER,1 VINOD P. SHAH,3 PETER LANGGUTH,2 JAMES POLLI,4 MEHUL MEHTA,5
D.W. GROOT,6 RODRIGO CRISTOFOLETTI,7 BERTIL ABRAHAMSSON,8 JENNIFER B. DRESSMAN9
1
PHAST GmbH, Homburg, Germany
2
Department of Pharmaceutical Technology and Biopharmaceutics, Johannes Gutenberg University, Mainz, Germany
3
International Pharmaceutical Federation, The Hague, The Netherlands
4
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland
5
Center for Drug Evaluation and Research, Office of Clinical Pharmacology, US Food and Drug Administration, Maryland
6
RIVM-National Institute for Public Health and the Environment, Bilthoven, The Netherlands
7
Brazilian Health Surveillance Agency (Anvisa), Division of Bioequivalence, Brasilia, Brazil
8
AstraZeneca R&D, Mölndal, Sweden
9
Institute of Pharmaceutical Technology, J.W. Goethe University, Frankfurt am Main, Germany

Received 19 May 2015; revised 29 May 2015; accepted 1 June 2015

Published online 6 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24560

ABSTRACT: Literature data relevant to the biopharmaceutical properties of the active pharmaceutical ingredient (API) nifedipine are
reviewed to evaluate whether a waiver of in vivo bioequivalence (BE) testing of immediate-release (IR) dosage forms formulated as tablets
and soft gelatin capsules is warranted. Nifedipine’s solubility and permeability, its therapeutic use and index, pharmacokinetics, food drug
interactions, and any reported BE/bioavailability problems were all taken into consideration. Solubility and BA data indicate conclusively
that nifedipine is a class II substance of biopharmaceutics classification system (BCS) and that the formulation of drug product plays a key
role on the dissolution characteristics of the API. Therefore, a BCS biowaiver-based approval of nifedipine containing IR oral dosage forms
cannot be recommended for reformulated/new multisource drug products or for major scale-up and postapproval changes to the existing
drug products.  C 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3289–3298, 2015

Keywords: nifedipine; absorption; bioavailability; bioequivalence; soft gelatin capsules; tablets; solubility; permeability; dissolution

INTRODUCTION
A monograph based on the literature data is presented for
nifedipine with respect to its biopharmaceutical properties. The
purpose and scope of these monographs have been discussed
previously.1 To illustrate the various considerations that are
used to determine whether the biowaiver procedure can be
recommended or not, biowaiver monographs for active phar-
maceutical ingredients (APIs) belonging to all four biophar-
maceutics classification system (BCS) classes have been pub-
lished (www.fip.org/bcs). Nifedipine is predominantly used in
the management of hypertension and is listed in the WHO
Model List of Essential Medicines,2 which justifies its impor-
tance for biowaiver assessment. In this monograph, the risks of
waiving in vivo bioequivalence (BE) testing for the approval of
new multisource and/or reformulated immediate-release (IR)
oral dosage forms containing only nifedipine as an API are
evaluated. Nifedipine IR dosage forms having a marketing au-
thorization in the countries listed in Tables 1 and 2 include soft
gelatin capsules (SGCs) and film-coated tablets. The biowaiver
evaluation is directed to drug products containing nifedipine
as the single API, independent of its state in the dosage form,
namely, tablets or SGC, but does not consider combination drug
products.
Correspondence to: Jennifer B. Dressman (Telephone: +49-69-79829680;
Fax: +49-59-79829724; E-mail: dressman@em.uni-frankfurt.de)
Journal of Pharmaceutical Sciences, Vol. 104, 3289–3298 (2015)

C 2015 Wiley Periodicals, Inc. and the American Pharmacists Association
EXPERIMENTAL
A literature search was performed in the PubMed Central
database using the keyword nifedipine with the combination
of one or more of the following terms: solubility, permeabil-
ity, partition coefficient, polymorphism, pharmacokinetics, ab-
sorption, absolute and relative bioavailability (BA), BE, food
effects, and dissolution. Whenever possible, primary literature
was consulted and the data from secondary sources were in-
cluded for completeness of the information only when original
literature could not be located. The publicly available litera-
ture accessed until March 25, 2015 were considered for the
monograph.
GENERAL CHARACTERISTICS
The chemical description of nifedipine (The USP) is dimethyl
1, 4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicar-
boxylate and has the molecular formula C17 H18 N2 O6 . Its molec-
ular weight is 346.33 g/mol and the melting range is 171°C–
175°C.3,4 The structure of nifedipine is shown in Figure 1.
Therapeutic Indications, Therapeutic Index, and Toxicity
Nifedipine is a calcium channel blocking agent used widely
for the treatment of angina pectoris and in the management of
hypertension.5–10 Though inhibition of transmembrane calcium
flux is the predominant mechanism of action, its affinity for
vascular tissue with no myocardial depressant effect is useful

Gajendran et al., JOURNAL OF PHARMACEUTICAL SCIENCES 104:3289–3298, 2015 3289

3290 GENERAL COMMENTARY

Table 1. Excipients#;* Present in Nifedipine IR Solid Oral Drug Products (Capsules) with a Marketing Authorization in Germany (DE),
Denmark (DK), Finland (FI), France (FR), The Netherlands (NL), Norway (NO), Spain (ES), and Sweden (SE), and the Minimal and Maximal
Amount of That Excipient Present Pro-Dosage Unit in Solid Oral Drug Products with a MA in the United States

Drug Products Containing That Excipient Range Present in Solid Oral Dosage Forms
Excipient with a MA Granted by the Named Country with a MA in the United States (mg)

Ethanol DEa
Ethylparahydroxybenzoate NLb–d
Gelatin DEa,e–p , DKq,r , FRs,t , NLb–d,u–x , ESy 1–756
Glycerol DEa,e–o , DKq,r , FRs,t , NLb–d,u–x , ESy 0.14–224
Glycofurol DEa,i,k,l
Macrogol DEe–h,j,m–p , DKq,r , FRs,t , NLb–d,u–x , ESy 0.12–961
Mannitol DEh 10–454
Polysorbate 80 DEa,i,k,l 0.41–418
Povidone DEa,i,k,l,p 0.17–75
Propylparahydroxybenzoate NLb–d 0.002–0.2
Sorbitan DEh 0.11–154
Sorbitol DEh 5–337
Water DEa,e,i,m–o , DKq,r , FRs,t , NLc,d,u–x , ESy

Sources of data: DE: http://www.rote-liste.de (assessed February 2, 2007); DK: www.dkma.dk (assessed February 13, 2007); ES: www.agemed.es (assessed
February 13, 2007); FI: www.nam.fi (assessed February 13, 2007); FR: www.vidal.fr (assessed February 13, 2007); NL: www.cbg-meb.nl. (assessed February 5, 2007);
NO: www.legemiddelverket.no (assessed February 13, 2007); SE: www.lakemedelsverket.se (assessed February 13, 2007).
USA: http://www.fda.gov/cder/iig/iigfaqWEB.htm#purpose (version date January 9, 2007).
#
Colorants, flavors, and ingredients present in the coating and/or the printing ink are not included.
*
Excluded are: oromucosal preparations, oral lyophilisates, soluble tablets, effervescent tablets, dispersible tablets, chewable tablets, sublingual tablets, enteric
coated tablets, oral powders, oral granulates, oral suspension, oral solution, and powder for oral solution. Drug products containing more than one API are also
excluded.
a
Nifedipin-Ratiopharm R
20 Weichkapseln (Mono).
b
Nifedipine Ratiopharm 10 mg capsules.
c
Nifedipine Sandoz 5/10, capsules 5/10 mg.
d
Nifedipine 5/10 PCH, capsules 5/10 mg.
e
AdalatR
5/10 Kapseln (Mono).
f
NifeclairR
5/−10 mg Kapseln (Mono).
g
NifecorR
5/−10 Kapseln (Mono).
h
Nife-CT 10 mg Kapseln (Mono).
i
Nifedipin AbZ 5 mg Kapseln Weichkapseln (Mono).
j
Nifedipin AL 5/10 Weichkapseln (Mono).
k
Nifedipin-Ratiopharm R
5/10 Weichkapseln (Mono).
l
Nifedipin Sandoz R
5/−10 mg Weichkapseln (Mono).
m
Nifedipin STADA R
5/−10 mg Kapseln (Mono).
n
Nifedipin Verla R
Kaps 10 mg Kapseln (Mono).
o
NifeHEXAL R
5/10/20 Kapseln (Mono).
p
ApricalR
10 mg Kapseln (Mono).
q
Nifedipin 10 “Stada”, kapsler, hårde.
r
Hexadilat, kapsler, bløde 10 mg.
s
ADALATE 10 mg capsules.
t
NIFEDIPINE G GAM 10 mg capsules.
u
Nifedipine CF 5/−10 mg, capsules.
v
Nifedipine Albic 5/−10 mg, capsules.
w
Nifedipine FLX 10 mg, capsules.
x
Nifedipine Sandoz 5/−10 mg, capsules.
y
ADALAT 10 mg cápsulas, 50/500 cápsulas.

in treating conditions associated with vascular spasm, variant Liste R

angina, and Raynaud’s phenomenon.7
Nifedipine IR tablet and SGC formulations are usually dosed
at 5 or 10 mg, and administered thrice daily with a maximum
daily dose not exceeding 60 mg.6,11 The recommended starting
dose is 5 mg given every 8 h with subsequent titration of dose
according to pharmacological response permitting an increase
to a maximum of 20 mg every 8 h for capsule formulations. The
dosage is usually individualized based on the patient’s toler-
ance and response.
Pharmacodynamic studies of both the tablet and SCG for-
mulations show their effectiveness in lowering blood pressure;
however, differences in time to reach maximum concentration
and duration of action have been reported.10,12 Several years
ago, IR tablets containing nifedipine alone were discontinued
from the German market: they have not appeared on the Rote
website (http://www.rote-liste.de/) since 2008, and nowa-
days SGCs are the only solid oral IR release formulations in
this country. The selection of dose per intake is based on the
type of indication required for treatment. It has even been rec-
ommended to bite and swallow the SGC formulation when an
immediate onset of action is required. However, this method of
administration was found to be less advantageous and resulted
in peak plasma concentrations lower than that following usual
oral administration.13
The minimal effective plasma concentration (MEC) of
nifedipine was estimated to be 13.4 ng/mL.14 During chronic
treatment, a plasma concentration of 10 ng/mL14 was found
to be effective in lowering blood pressure. MECs ranging from
15 to 25 ng/mL have also been often reported by authors to
elicit a therapeutic effect9,15–17 and a therapeutic range of 25–
100 ng/mL was also reported.7,18

Gajendran et al., JOURNAL OF PHARMACEUTICAL SCIENCES 104:3289–3298, 2015 DOI 10.1002/jps.24560

 GENERAL COMMENTARY 3291

Table 2. Excipients#,* Present in Nifedipine IR Solid Oral Drug Products** (Tablets) with a Marketing Authorization in Germany (DE),
Denmark (DK), Finland (FI), France (FR), The Netherlands (NL), Norway (NO), Spain (ES), and Sweden (SE), and the Minimal and Maximal
Amount of That Excipient Present Pro-Dosage Unit in Solid Oral Drug Products with a MA in the United States

Drug Products Containing That Excipient Range Present in Solid Oral Dosage Forms
Excipient with a MA Granted by the Named Country with a MA in the United States (mg)

Calcium carbonate DEa 8.6–350

Carnauba wax DEa 0.16–58
Cellulose DKb–f , FIg , NOh , SEi 4.6–1385
Gelatin DEa , FIg 1–756j
Glucose, liquid DEa 10–14
Hypromellose DKb–f , NOh , SEi 0.8–86
Lactose DEa , DKb–d,f , FIg , NOh , SEi 23–1020
Macrogol DEa , DKb–f , NOh , SEi 0.12–500
Magnesium stearate DEa , DKb–f , FIg , NOh , SEi 0.15–401j
Mannitol DKe 10–454
Polysorbate SEi
Polysorbate 80 DKb–d,f , FIg , NOh 2.2–418j
Povidone DEa , DKe 0.17–75
Silica DKe 0.65–99
Sodium lauryl sulfate DKe 0.65–50
Sodium starch glycolate DKe , FIg 2–876j
Starch DEa , DKb–d,f , NOh , SEi 0.44–1135j
Starch, pregelatinized FIg 6.6–600
Sucrose DEa 12–900
Talc DEa , DKb,d,e 0.26–220j

Sources of data: DE: www.rote-liste.de (assessed February 12, 2007); DK: www.dkma.dk (assessed February 13, 2007); ES: www.agemed.es (assessed February
13, 2007); FI: www.nam.fi (assessed February 13, 2007); FR: www.vidal.fr (assessed February 13, 2007); NL: www.cbg-meb.nl. (assessed February 5, 2007); NO:
www.legemiddelverket.no (assessed February 13, 2007); SE: www. lakemedelsverket.se (assessed February 13, 2007).
USA: http://www.fda.gov/cder/iig/iigfaqWEB.htm#purpose (version date January 9, 2007).
#
Colorants, flavors, and ingredients present in the coating and/or the printing ink are not included.
*
Excluded are: oromucosal preparations, oral lyophilisates, soluble tablets, effervescent tablets, dispersible tablets, chewable tablets, sublingual tablets, enteric
coated tablets, oral powders, oral granulates, oral suspension, oral solution, and powder for oral solution. Drug products containing more than one API are also
excluded.
a
Nifedipin STADA R
10 mg Dragees (Mono).
b
Nifedipin 20 “Stada”, filmovertrukne tabletter.
c
Adalat, tabletter 10/20 mg.
d
Nifecodan, filmovertrukne tabletter.
e
Nifedipin “NM”, tabletter, filmovertrukne.
f
Hexadilat, filmovertrukne tabletter 20 mg.
g
Nifangin 10 mg tabletti, kalvopäällysteinen.
h
Adalat 10 mg tabletter, drasjerte.
i
Adalat 10/−20 mg tabletter.
j
The upper range value reported is unusually high for solid oral dosage forms and the authors doubt on its correctness.
**
The authors have doubt on the correctness of these data. Such amounts are normally present in a SGCs, but not in capsules, as indicated by FDA Inactive
Ingredients Database.

In a study reported by Lesko et al.,19 nifedipine was well PHYSICOCHEMICAL PROPERTIES

tolerated by subjects who received a maximum daily dose
of 60 mg/day from the SGC formulation. The doses were
continued for 5 days to achieve steady state. The Cmax at
steady state observed following the multiple doses was slightly
higher than the Cmax following a single dose of 10 mg. This
indicated a partial saturation of the first-pass metabolism
and minor accumulation of the drug in comparison to single
dose.
As the dosage regime is usually individually titrated, no
severe adverse drug reactions (ADR) have been reported in
the accessed literature within the prescribed dosage limits.
Nifedipine may produce side effects ranging from flushing and
tachycardia in some patients to hyperglycemia, metabolic aci-
dosis, hypoxia, cardiogenic shock associated with pulmonary
edema in case of severe drug poisoning. Most of these effects
are considered to be related to its high fluctuation index (ra-
tio of peak to trough plasma concentration) caused by rapid
absorption from SGCs, as observed from its pharmacokinetic
profile.6
Isomers and Polymorphs
No stereo isomers were found to exist for nifedipine. Keymolen
et al.20 reported evidence of four crystalline polymorphic forms
of nifedipine. The stable nifedipine polymorph was shown to
melt at approximately 172°C, with a metastable polymorph
melting at approximately 168°C. The remaining two polymor-
phic forms are short lived. Although the polymorphic form could
influence dissolution from tablets, nifedipine is in solution in
SGC formulations so a discussion of the polymorphic form is
irrelevant to product performance for this particular dosage
form.
Photostability
Nifedipine is a highly photosensitive drug substance that
decomposes in the presence of UV light to yield the 4-(2-
nitrophenyl) pyridine homolog, and in the presence of day light
to yield the 4-(2-nitrosophenyl)-pyridine homolog.21–25 As a re-
sult, practical precautions are needed to protect nifedipine from

DOI 10.1002/jps.24560 Gajendran et al., JOURNAL OF PHARMACEUTICAL SCIENCES 104:3289–3298, 2015

3292 GENERAL COMMENTARY
Figure 1. Chemical structure of nifedipine.
light when working in the laboratory (e.g., working under yel-
low light conditions and covering all experimental apparatus,
samples, and stock solutions containing nifedipine with alu-
minum foil), and the packaging of the dosage form also has to
ensure protection from light.
Solubility
The solubility data relevant for the BCS-based classification
were obtained from standard available references. According to
the European Pharmacopoeia (Ph. Eur.),26 nifedipine is practi-
cally insoluble in water. The solubility of nifedipine in aqueous
buffer solutions determined at 37°C and 25°C and reported in
the open literature is summarized in Table 3. A review of the
solubility data revealed that the method of solubility deter-
mination was often not clearly described and did not indicate
whether photoinstability of nifedipine was considered. How-
ever, the reported values are consistent among authors. For
these data, the dose–solubility (D/S) ratio was also calculated
and reported in Table 3.27–30
Partition Coefficient
The log P value of a compound is the logarithm of its parti-
tion coefficient between n-octanol and water log (cOct /cwater ), is
a well-established measure of a compound’s lipophilicity. The
following log P values for nifedipine have been reported by var-
ious authors as 2.5,31 2.2,4 or 4.5 In another study, Lichtlen
and Reale32 reported the partition coefficient determined using
cyclohexane aqueous buffers pH 0–13 as 1.28.
pKa
The following pKa values have been reported in the literature,
pKa1 = −0.9,33 pKa2 = 13.33 The pKa values indicate that
nifedipine is not ionized over the gastrointestinal (GI) pH range
so that the solubility is independent of the pH of the solution
in this range.
Dose and Dosage Form Strengths
The most common IR dosage forms are SGC filled with nifedip-
ine solution and film-coated tablets.34 Tables 1 and 2 contain
the dosage strengths of formulations having MA in 2007 in
the countries listed, which include: SGC: 5, 10, and 20 mg
film-coated tablets: 10 mg. Recently, the 20-mg SGC and tablet
Gajendran et al., JOURNAL OF PHARMACEUTICAL SCIENCES 104:3289–3298, 2015
formulations containing nifedipine as the only API have been
withdrawn from the market in most, if not all countries and
the highest dosage strength listed in the WHO Model List of
Essential Medicines List2 is 10 mg as an SGC. Nifedipine is of-
ten formulated in an extended-release (“retard”) dosage form,
but such formulations are outside the scope of this biowaiver
monograph.
PHARMACOKINETIC PROPERTIES
Absorption and BA
Absorption of nifedipine is rapid and complete from the GI
tract following oral administration, as evidenced in many
studies.6,7,9,35–38 The rate and extent of absorption of nifedipine
from tablets is slower than from SGC as indicated by the time
to peak plasma concentrations (tmax ) ranging from 1.6 (SGC) to
4.2 h (tablets).5,10,39 However, no significant difference in Cmax
or extent of absorption (AUC) was observed between the re-
ported formulations. tmax for the SGC ranged between 0.25 and
2.9 h.4,6,19,37,40,41 The average absolute BA for the oral to the
intravenous (i.v.) dose was about 43.8%.35 The oral BA of SGC
reported ranged from 31% to 81%,6,7,9,35–38 because of the exten-
sive and variable presystemic and first-pass metabolism. The
pharmacokinetics were found to be linear and quite predictable
in the dose range from 5 to 20 mg.10,37 These results were con-
firmed in a further study by Banzet et al.,42 who applied 20, 40,
and 60 mg tablet formulations as a single dose.
In a study reported by Pabst et al.,8 subjects received two
10 mg nifedipine SGCs as a single dose on day 1, followed by
the same dosage strength twice daily with an 8-h interval in be-
tween for 3 days until steady state was reached. The AUC(0–)
of single and multiple doses at steady state indicated no sig-
nificant difference in the extent of absorption. This suggests
that there is no accumulation of serum nifedipine within the
dosage strength investigated. The study results are in agree-
ment with the conclusions derived independently from another
study reported by Raemsch and Sommer37 However, the valid-
ity of results cannot be considered conclusive as the duration of
pharmacokinetic studies was limited to 5 days that may not ad-
equately reflect the conditions of chronic treatment. In a sepa-
rate study reported by Lesko et al.,19 accumulation of nifedipine
following the multiple dosing was observed particularly when
the dosage strength was increased from 10 to 20 mg per intake
in 8 h intervals.
Mass balance studies on nifedipine after administration as
an oral solution in the stomach, small intestine, or at one of
two sites in the colon indicate that only a negligible amount of
unchanged nifedipine is recovered in feces and that the extent
of absorption is similar from all sites.35 The absolute BA ranged
from 42% to 56% owing to first-pass metabolism. These results
also suggest that nifedipine is almost completely absorbed from
the GI tract.
Permeability
Bode et al.35 investigated the absorption of nifedipine from
four different sites of the GI tract using a high-frequency
(HF)-triggered capsule containing nifedipine dissolved in wa-
ter, polyethylene glycol, and polysorbate.35 The HF capsule was
triggered to open in different regions of the GI tract, based on
the expected GI passage times. In addition to studies with the
HF capsule containing nifedipine in solution, an i.v. infusion
DOI 10.1002/jps.24560

Table 3. Aqueous Solubility Data of Nifedipine (Literature Data)
pH °C Medium
SGF pH1.2 37 Buffer
pH 2.2–10 25 Buffer
pH 4 37 Buffer
SIF pH 6.8 37 Buffer
pH 7 37 Buffer
pH 9 37 Buffer
pH 13 37 Buffer
a
On the basis of the highest available single dose (10 mg) given in WHO model lists of essential medicines.
and an oral solution were administered to estimate the abso-
lute and relative BA. Plasma and feces samples were collected
and analyzed for unchanged nifedipine and its metabolites. It
was found that the absorption of nifedipine is rapid in all re-
gions except the colon. However, the BA was not affected by
the slower absorption in this region: no difference in extent of
absorption relative to the oral solution was observed. The dif-
ferences in absorption rates reflected as mean absolute BA in
the several studied regions were small and all in the range of
47%–56%, indicating the absence of a GI absorption window for
nifedipine. The fraction of the dose absorbed is not subject to
saturation within the therapeutic dose range.43
The permeability coefficient (Papp , ×10−6 cm/s) of 52.3 using
Caco-2 studies was reported by Lau et al.44 Nifedipine has also
been classified as “highly permeable” on the basis of its octanol–
water partition coefficient. This partition coefficient was esti-
mated by two different methods, and for nifedipine, the data
correlated reasonably well with human jejunal permeability
data.45 Inherent high permeability is also supported by the
negligible amount of unchanged nifedipine recovered (<0.3% of
dose) from the feces.35
Distribution
Nifedipine is very strongly bound by the proteins of human
serum, the percentage of bound substance being between 91%
and 98%.46 It undergoes significant tissue distribution with the
steady-state volume of distribution being 0.62–0.77 L/kg, more
than twice the volume of distribution of the central compart-
ment (0.25–0.29 L/kg).6
Metabolism and Excretion
Nifedipine is rapidly oxidized to its nitropyridine metabolites
and 70%–80% of the dose is excreted in the urine mainly as
inactive metabolites and only a negligible amount of unchanged
(<0.1%) form was detected in urine.47,48 The remaining dose
is excreted in the feces as metabolites resulting from biliary
excretion. The reported total body clearance ranges from 450 to
700 mL/min,7,19,37,48 which concurs with the mean elimination
rate constant of 0.173 h−1 .19
Food Effect and Interactions
The food effect on the BA following nifedipine SGC administra-
tion has been published.49 The reported Cmax and tmax values
following fasting, low-fat, and high-fat meals were 79, 42, and
59 ng/mL and 0.97, 1.89, and 1.07 h, respectively.49 Interest-
ingly, for nifedipine, the food effect is greater when a low fat
than a high fat meal is coadministered. This is not in line with
the usual assumption that a high-fat meal is the most stringent
DOI 10.1002/jps.24560
GENERAL COMMENTARY 3293
Solubility (mg/mL) D/S Ratio Calculated (mL)a References
0.011 892 27
0.005–0.006 1667–2000 28
0.0058 1724 29
0.0111 937 27
0.0056–0.006 1786–1667 29,30
0.0078 1282 27
0.006 1667 29
test of food effects on drug absorption.50 In another study with
SGC formulations, it was shown that the presence of food in
the GI tract does not alter the extent of nifedipine absorption.
However, the rate of absorption was slowed down, as observed
from the decrease in the peak plasma concentration.49,51
Food effects were also reported after concomitant admin-
istration of grape fruit juice (GJ) concentrate resulting in a
twofold increase in peak plasma concentration.52,53 It was re-
ported that nifedipine interacts with GJ,53,54 because it under-
goes cytochrome (CYP) P450 oxidative metabolism in the in-
testinal wall or liver. GJ contains various bioflavonoids that
have been demonstrated to affect the CYP P450 system (espe-
cially at CYP3A4) by binding to the isoenzyme and impairing
the first-pass metabolism by direct inactivation or inhibition of
the enzyme. The net effect on the CYP enzymes from this inhi-
bition seems to be a selective downregulation of CYP3A4 in the
small intestine.35 Similarly, an interaction of rifampicin with
nifedipine has been reported.55 Rifampicin selectively induces
CYP 3A4 in liver and gut wall that subsequently altered the
nifedipine clearance following oral administration and reduced
the nifedipine BA.55
DOSAGE FORM PERFORMANCE
Excipients
A wide range of excipients is used in the nifedipine IR SGC
and tablet formulations. Tables 1 and 2 list separately all
the excipients present in nifedipine capsules and tablets with
a MA in DE, DK, FI, FR, NL, NO, ES, SE, and USA.34
Coloring agents and coating substances are not included in
this table as coatings in an IR formulation are not antic-
ipated to have an influence on pharmacokinetic properties.
A marketing authorization3 in these countries indicates that
BE had been successfully established. In 1989, Blume and
Mutschler.56 published the re-evaluated pharmacokinetic data
of commercially available IR dosage forms on the German
market at that time. These data were obtained from the
MA sponsors and were taken from BE studies of generics
against the innovator, Adalat R
. No data pertaining to the
qualitative and quantitative composition of the excipients and
their specific excipient interactions were found in the accessed
literatures. However, a comparison of their qualitative compo-
sitions in 199257 with their qualitative compositions in 200258
revealed no differences. So, one can assume with a high proba-
bility that the excipients listed in Tables 1 and 2 for the products
having MA in Germany were also present in products reported
by Blume.56 The results in the Blume re-evaluation publication
Gajendran et al., JOURNAL OF PHARMACEUTICAL SCIENCES 104:3289–3298, 2015
3294 GENERAL COMMENTARY
would therefore suggest a lack of interactions of these excipi-
ents in terms of BA for tablets and SGC formulations.
In Vivo BE Studies
Bioequivalence studies are generally conducted by comparing
the in vivo rate and extent of systemic appearance of a drug
from a test and a reference drug product in healthy subjects.
A test product is currently considered to be bioequivalent to a
reference product if the 90% confidence interval of the geomet-
ric mean ratio of AUC and Cmax between the test and reference
fall within 80%–125%. Currently, the BE limits of 80%–125%
have been applied to almost all drug products by the US FDA
and the EMA. However, concerns have been raised regarding
the difficulty of meeting the standard BE criteria for highly
variable drugs and/or drug products exhibiting intrasubject
variability greater than 30% CV with respect to AUC and/or
Cmax .59 Nifedipine is an example of a drug that exhibits highly
variable pharmacokinetic properties.
A retrospective review of pharmacokinetic data published
by Blume et al.4,60 clearly shows that although all nifedipine
IR formulations marketed as SGCs were bioequivalent to the
innovator according to the criteria that were used at the time,
that is, acceptance limits of 80%–120% for AUC and 70%–130%
for Cmax values determined at the 90% confidence interval,4,56,60
some would not have been bioequivalent according to the cur-
rent guidelines,61–63 unless the wider range for Cmax applicable
for highly variable APIs was applied.
In other studies, BE of nifedipine 10 mg SGC formula-
tions with MA in various countries has been reported by many
authors.40,64–69 In a study reported by Dahmen et al.,64 10 mg
generic SGC were tested for BE with the marketed reference
product. No statistically significant differences in the pharma-
cokinetic parameters between the products were observed. The
plasma concentration curves were identical except that the re-
ported peak plasma concentration of the test and the reference
product differed slightly. The time to peak plasma concentra-
tion of 0.5 h remained unchanged for both the formulations.
Similar BE results were also reported by Kozjek et al.65 In an-
other study by Achtert et al.,66 BE of generic 5 mg SGCs to
the reference product was demonstrated. A small difference in
absolute peak plasma concentration between the test and ref-
erence product was observed. The findings are in line with the
results reported by Dahmen et al.64 The BE of Myograd R
10 mg
nifedipine capsule to the reference product Adalat R
was also
reported by Rawashdeh et al.67 The authors concluded that the
test product was bioequivalent (80%–125%) to the reference
product with respect to the rate and extent of absorption and
elimination. The oral absorption of nifedipine from 10 mg SGCs
was also studied by Menke et al.68 Minor differences in Cmax and
AUC were observed by the authors but it was concluded that
the differences are clinically unimportant and statistically in-
significant between the test and the reference product. Similar
findings were also indicated by Shaheen et al.69 The study was
conducted to test the BE of Nifecard R
10 mg SGC to the ref-
erence product Adalat R
10 mg SGC. No significant differences
in oral absorption, Cmax , tmax , t1/2 , and AUC between NifecardR
R
and Adalat were observed. According to the authors, the prod-
ucts are bioequivalent and produced similar pharmacological
effects.
The PK data for the nifedipine 10 mg film-coated tablet for-
mulations were also evaluated by Blume et al.60 The review
Gajendran et al., JOURNAL OF PHARMACEUTICAL SCIENCES 104:3289–3298, 2015
of the data shows that most of the investigated formulations
were BE to the innovator. Any failure to meet the current BE
criterion was usually observed for Cmax .
Dissolution
The specification of USP 37 for in vitro dissolution of nifedipine
capsule is not less than 80% (Q) of the labeled amount dissolved
in 20 min in 900 mL of simulated gastric fluid (SGF) TS with-
out pepsin using the paddle method operated at 507 rpm.70 The
WHO BCS guidelines recommend an in vitro dissolution utiliz-
ing the paddle apparatus at 757 rpm or the basket apparatus
at 1007 rpm in standard media at pH 1.2, 4.5, and 6.8.71 The
current acceptance criteria for a biowaiver application is disso-
lution 85% (Q) in 15 min for very rapidly dissolving products
or 85% (Q) in 30 min for rapidly dissolving products in all the
three media. Mehta et al.72 evaluated the in vitro performance
of 14 samples of nifedipine 5 and 10 mg capsules from eight dif-
ferent manufacturers. The in vitro dissolution was performed
in USP paddle apparatus 2 at 507 rpm using 900 mL SGF pH
1.2. More than 80% of the drug was released in 20 min for all
the tested products. In another study,73 performance of a total of
nine different generic SGCs containing 5 and 10 mg of nifedip-
ine was compared with the innovator according to the method
described in the USP. The results indicated that all the prod-
ucts conformed to USP release specification except one product
where the capsule shell failed to open even after testing for 2 h.
The literature found on the performance of nifedipine, formula-
tions were limited to methods described in the USP and to the
SGCs. No literature was found on the dissolution behavior of
nifedipine in other buffer solutions covering the physiological
range. As nifedipine has pH-independent solubility behavior,
it is reasonable to expect that its dissolution behavior would
be similar at pH 4.5 and 6.8 unless there are excipients with
pH-dependent characteristics in the formulation.
DISCUSSION
Solubility
Nifedipine clearly fails to meet the FDA74 criteria regarding sol-
ubility for BCS class I substance74 and also the criteria of the
EU75 and the WHO76 for “highly soluble” substance. Similarly,
Kasim et al.45 compiled the solubility data of nifedipine and
classified nifedipine as practically insoluble and calculated the
dose number (Do) as 8 for the highest dosage strength (20 mg)
approved at the time of classification (refer to Table 3). The
currently approved highest dosage strength is 10 mg.77 On the
basis of the new available dosage strength, the Do would be
4. Although not all BCS-relevant pH conditions have been re-
ported in the literature, the solubility data that do exist in the
literature4,77,78 indicate the pH-independent and poor solubil-
ity characteristics that preclude the possibility to character-
ize nifedipine under BCS class I. Lindenberg et al.79 classified
nifedipine as poorly soluble based on the BCS-relevant testing
conditions.
Permeability
According to the FDA guidelines,74 the permeability class of the
drug substance from intestinal absorption data determined by
mass balance studies or a direct comparison of i.v. dose as a ref-
erence is well accepted. In addition to the regional absorption
study results and BA of orally administered dosage forms, the
DOI 10.1002/jps.24560

urinary excretion of 70%–80% of dose47 (as inactive metabo-
lites) with very low amounts detected in the feces48 provides
strong evidence for high permeability. Supporting evidence for
the high permeability of nifedipine comes from the Caco-2 Papp
value of 52.3 × 10−6 cm/s.44 Indirect techniques employing ani-
mal or in vitro model to predict the human permeation are used
second only to the direct measurements. Log P and Clog P of
the uncharged form of the drug substance can also be used as a
guide to the permeability class of the drug substance, although
this is not accepted as proof of permeability class by any reg-
ulatory authority that considers BCS-based biowaivers. In the
case of nifedipine, the log P values of 2.2–4.0 reported by the
authors3,4,31 is well above the log P value of metoprolol (1.72),34
which is generally considered as a reference standard for the
low-/high-class boundary as 95% of the dose is well absorbed
in the GI tract. Taking all the above factors into consideration,
nifedipine can be regarded as a “highly permeable” substance.
BCS Classification
The literature data on solubility, permeability, and the oral
absorption clearly shows that nifedipine is a poorly soluble
substance with high permeability characteristics. According
to Kasim et al.,45 nifedipine would be classified as BCS class
II substance. This classification was also suggested by Lin-
denberg et al.79 Similarly, other studies on solubility78 and
permeability35 conclusively show the BCS class II character-
istic of nifedipine.
Surrogate Techniques for In Vivo BE Testing
The differences in purpose between the dissolution tests of the
guidances74–76 and the USP have been discussed previously.1,80
The USP methods on dissolution testing neither claim to re-
flect the in vivo physiology nor to predict the in vivo per-
formance. One of the main criteria for the application of
BCS-based biowaivers is that the dosage form dissolves rapidly
under conditions representative of pH in the GI tract, with the
pharmaceutical composition having no significant influence on
the absorption. Although the test specifications of the USP 37
are suitable to control the batch to batch product consistency
and performance, the USP dissolution test condition is limited
to SGF pH 1.2 that may not be reliable to predict the per-
formance of the capsules in the other buffers relevant to the
physiological range.
Bottom et al.81 investigated the performance of two different
nifedipine capsule formulations after storage at less than 25°C.
Both formulations failed to meet the USP acceptance criteria,
which according to the authors may be partly because of the
gelatin cross-linking on storage and exposure to high humid-
ity. Thelen et al.82 observed an incomplete dissolution from two
10 mg nifedipine (20 mg) capsules in 250 mL of fasted-state SGF
(FaSSGF), whereas the dissolution of 10 mg capsule formula-
tion in 250 or 500 mL of FaSSGF was complete. The authors
related the reduced Cmax observed from the simulation studies
of the 20-mg dosage strength to the incomplete dissolution. Al-
though nifedipine is in solution in the capsule formulation and
thus (at least theoretically) requires no dissolution step prior
to absorption, the authors postulated that the precipitation of
nifedipine could occur at higher doses resulting in incomplete
availability for absorption that may or may not be predicted by
existing in vitro techniques. No in vitro dissolution data relat-
ing to nifedipine tablets could be found by the literature search.
DOI 10.1002/jps.24560
GENERAL COMMENTARY 3295
In summary, although there seems to be some link between
dissolution in a biorelevant gastric medium to the in vivo per-
formance nifedipine SGC, this would require further validation
to be considered a reliable surrogate method.
Risk of Bioinequivalence Caused by Excipients and/or
Manufacturing
In view of its high permeability, an excipient interaction with
respect to the permeability of nifedipine seems very unlikely.
In the IR capsules having an MA in those countries listed in
Table 1, a wide range of excipients are used. As these dosage
forms have MA, it can be expected that BE to the innovator’s
product have been demonstrated. Even though the BE accep-
tance criteria for the MA approval was different from current
practice, this provides evidence that the usual pharmaceutical
excipients in IR capsules have little or no effect on the extent
and rate of absorption to be expected. This is in line with the
pharmacokinetic data of the generic capsules with MA in Ger-
many; all these capsules were bioequivalent to the innovator
(at least according to the criteria of the day) and the excipients
listed are qualitatively known. The risk of bioinequivalence
could be further reduced when the test product is formulated
using the excipients listed in products having MA in those coun-
tries listed in Table 1.
In case of tablets formulated as IR dosage forms, nifedipine
is still present in the solid state and contains a wide range
of excipients. In such conditions, manufacturing and formula-
tion play a key role in the solubility and dissolution rate en-
hancement. Several techniques have been reported to improve
the solubility83–88 of the API directly or through excipients. For
these formulations, application of in vitro dissolution to waive
the BE testing is not reliable enough to recommend a biowaiver.
Patient Risks Associated with Bioinequivalence
A false-positive BE decision to the nifedipine IR capsule dosage
forms that actually are not bioequivalent to the innovator could
result in subtherapeutic plasma concentrations that may lead
to a therapeutic failure or, on the contrary, concentrations above
the recommended upper therapeutic concentrations could re-
sult in ADR. This situation is further exacerbated by the rapid
onset of action of nifedipine. Nifedipine IR capsules have been
indicated for a range of coronary heart diseases. In general,
dosage is individualized depending on the severity of disease,
patient’s tolerance, and responsiveness to nifedipine. In such
situations, it is necessary to ensure BE of the product, so that
the therapeutic outcome from treatment with generic products
could be well predicted during the management of pharmaco-
logical indications.
Following oral administration, nifedipine appears in the
plasma at concentrations ranging from 25 to 100 ng/mL.18 As
far as the supraequivalent levels are concerned, patients have
reported mild to moderate side effects. However, in most situa-
tions, the doses are well tolerated within the therapeutic range
and also above the recommended dose.7,13,19,41 The patient risks
associated with the subequivalent levels from the capsule for-
mulations pose more serious consequences because of therapeu-
tic insufficiency. In case of tablet formulations marketed as IR
dosage forms, the solubility of nifedipine is enhanced by the ex-
cipients used or the manufacturing methods used. However, no
data pertaining to drug–excipient interactions for tablets and
SGCs during dissolution testing were found in the accessed
Gajendran et al., JOURNAL OF PHARMACEUTICAL SCIENCES 104:3289–3298, 2015
3296 GENERAL COMMENTARY
literature. In such situations, dissolution data may not be reli-
able to predict the performance of the product in vivo.
In summary, based on the analysis of the risks and benefits
associated, the biowaiver procedure cannot be recommended to
the IR SGC and tablet formulations containing nifedipine.
CONCLUSION
Nifedipine exhibits poor solubility characteristics that are inde-
pendent of pH within the physiological range. Nifedipine clearly
fails the eligibility criteria for solubility to be classified as a
highly soluble substance. The permeability of nifedipine across
the intestinal epithelium is high and the absorption is com-
plete following oral administration: the BA is not limited by its
permeability. On the basis of the review of the data presented,
nifedipine can be conclusively assigned as BCS class II sub-
stance according to the criteria of the WHO, FDA, and EMA.
As the data available for dissolution of nifedipine IR capsule
formulations was based only on quality control methods, waiv-
ing in vivo BE studies and substituting them with dissolution
testing cannot be scientifically justified. As far as the IR tablet
formulations are concerned, nifedipine is present as the only
API and the dissolution is limited by the solubility characteris-
tics of the drug substance. For such dosage forms, formulation
plays a key role in the solubility enhancement that needs to be
considered as a critical variable for assessing the dissolution
behavior. The patient risks associated with waiving in vivo BE
testing for both the capsule and tablet formulations outweigh
the benefits. In conclusion, the BCS-based biowaiver procedure
cannot be recommended for either the SGC or tablet IR formu-
lations, and BE should be established in vivo.
ACKNOWLEDGMENTS
This biowaiver monograph is part of a project of the FIP, Focus
Group BCS and Biowaiver, www.fip.org/bcs. This article reflects
the scientific opinion of the authors and not necessarily the
policies of the regulating agencies: the FIP, RIVM, ANVISA, or
the World Health Organization (WHO).
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DOI 10.1002/jps.24560