Accepted Manuscript

Biowaiver monographs for Immediate Release solid oral dosage forms: Enalapril

Roger K. Verbeeck, Isadore Kanfer, Raimar Lbenberg, Bertil Abrahamsson, Rodrigo

Cristofoletti, D.W. Groot, Peter Langguth, James E. Polli, Alan Parr, Vinod P. Shah,
Mehul Mehta, Jennifer B. Dressman
PII: S0022-3549(17)30253-8
DOI: 10.1016/j.xphs.2017.04.019
Reference: XPHS 742

To appear in: Journal of Pharmaceutical Sciences

Received Date: 27 March 2017

Revised Date: 10 April 2017
Accepted Date: 12 April 2017

Please cite this article as: Verbeeck RK, Kanfer I, Lbenberg R, Abrahamsson B, Cristofoletti R,
Groot DW, Langguth P, Polli JE, Parr A, Shah VP, Mehta M, Dressman JB, Biowaiver monographs for
Immediate Release solid oral dosage forms: Enalapril, Journal of Pharmaceutical Sciences (2017), doi:
10.1016/j.xphs.2017.04.019.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
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 ACCEPTED MANUSCRIPT

BIOWAIVER MONOGRAPHS FOR IMMEDIATE

RELEASE SOLID ORAL DOSAGE FORMS:
ENALAPRIL

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Roger K. Verbeeck1,2, Isadore Kanfer2,3, Raimar Lbenberg4*, Bertil
Abrahamsson5, Rodrigo Cristofoletti 6, D.W. Groot7, Peter Langguth8,

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James E. Polli9, Alan Parr10, Vinod P. Shah11 Mehul Mehta12, and
Jennifer B. Dressman13*

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1
School of Pharmacy, University of Namibia, Windhoek, Namibia
2
Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa
3 Lesley Dan Faculty of Pharmacy, University of Toronto, Canada

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4
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta,
Canada
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5
AstraZeneca, Mlndal, Sweden
6
Division of Bioequivalence, Brazilian Health Surveillance Agency (ANVISA),
Braslia, Brazil
7
RIVM National Institute for Public Health and the Environment, Bilthoven,
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The Netherlands
8
Institut fr Pharmazie und Biochemie, Johannes Gutenberg-Universitt
Mainz, Mainz, Germany
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School of Pharmacy, University of Maryland, Baltimore, MD, USA
10
GlaxoSmithKline, USA
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11
International Pharmaceutical Federation FIP, The Hague, The Netherlands
12
Division of Clinical Pharmacology 1, Food and Drug Administration, United
States Department of Health and Human Services
13
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Institute of Pharmaceutical Technology, Goethe University, Frankfurt am

Main, Germany
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Correspondence:
Prof. Dr. Jennifer Dressman, Goethe University, Frankfurt am Main (Tel. : +49 69
7982 9680, Fax : +49 69 7982 9724, email : dressman@em.uni-frankfurt.de)
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ABSTRACT

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence

testing for the marketing authorization of immediate release, solid oral dosage
forms containing enalapril maleate are reviewed. Enalapril, a prodrug, is

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hydrolyzed by carboxylesterases to the active angiotensin-converting enzyme
inhibitor enalaprilat. Enalapril as the maleate salt is shown to be highly soluble,
but only 60 to 70% of an orally administered dose of enalapril is absorbed from

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the gastrointestinal tract into the enterocytes. Consequently, enalapril maleate is
a BCS class III substance. Since in situ conversion of the maleate salt to the
sodium salt is sometimes used in production of the finished drug product, not

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every enalapril maleate labeled finished product actually contains the maleate
salt. Enalapril is not considered to have a narrow therapeutic index. With this
background, a biowaiver-based approval procedure for new generic products or
after major revisions to existing products is deemed acceptable, provided the in

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vitro dissolution of both test and reference preparation is very rapid (at least 85%
within 15 min at pH 1.2, 4.5 and 6.8). Additionally, the test and reference product
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must contain the identical active drug ingredient.

KEYWORDS:
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enalapril maleate; enalaprilat; absorption; Biopharmaceutics Classification

System (BCS); permeability; regulatory science; solubility, in-situ conversion
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INTRODUCTION

A biowaiver monograph based on literature data is presented on enalapril

concerning its properties related to the Biopharmaceutics Classification System
(BCS) and the risk of waiving in vivo bioequivalence (BE) testing in the approval
of new immediate release (IR) solid oral dosage forms containing enalapril,
including both reformulated products and new multisource drug products. The

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purpose and scope of these monographs have previously been described.1 In
short, the objective is to gather, summarize and evaluate all pertinent literature
data for the Active Pharmaceutical Ingredient (API) under consideration, in order

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to assess the risks associated with a BCS-biowaiver based approval. For the
purpose of the biowaiver monographs, risk is defined as the probability of an
incorrect biowaiver decision, as well as the consequences of such a decision in

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terms of both public health and the associated risks for the individual patient. This
approach to weigh up the pros and cons of a biowaiver decision was first
described in a guideline published by the World Health Organization (WHO).2
However, the biowaiver monographs are not intended to merely apply the criteria

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recommended by either the WHO, the US Food and Drug Administration (FDA)3,
the European Medicine Agency (EMA)4, or Health Canada,5 but rather to use
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these guidances as a basis to arrive at a scientifically and clinically reasonable
decision for granting of a biowaiver for products containing the given API.
Biowaiver monographs have already been published for over 40 APIs and are
available online through links to J. Pharm. Sci. and www.fip.org/bcs.6
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EXPERIMENTAL
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Literature data were obtained from the Pubmed database up to 11/2011. The
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keywords used for searching were: enalapril, oral, absorption, permeability,

pharmacokinetics, bioequivalence, solubility, dissolution, lipophilicity. In February
2016 the search was repeated using Scopus. Information was also obtained from
regulatory documents published by WHO2, FDA3,7 and EMA4 and Health
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Canada.5

To clarify the solubility characteristics of enalapril maleate, additional

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experiments were conducted at the Goethe University, Frankfurt. Downscaling

the shake-flask method using Uniprep systems (Whatman Inc., Piscataway,
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New Jersey), tests were conducted to determine whether a concentration of at

least 5 mg/ml could be achieved across the pH range of interest, including pH
1.2, 4.5, 6.8 and at the isoelectric point value of enalapril (~4.2).

Dissolution testing was undertaken by the University of Alberta, using Vasotec

20 mg tablets Merck Frosst (DIN 00670928 batch # NF61690 Exp: 04 2009)
purchased at a local pharmacy and enalapril maleate reference standard, which
was provided by the United States Pharmacopoeial Convention (Rockville, MD,
USA). Simulated Gastric Fluid USP without enzyme, USP acetate buffer pH 4.5

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and Simulated Intestinal Fluid USP without enzyme were used as the dissolution
media. A VK 7020 (Varian Inc.) with VK 8000 auto sampler was used for the
dissolution tests. Nine hundred mL degassed and pre-warmed relevant
dissolution medium was used per individual vessel and 1 mL samples were
removed at 10, 15, 20, 30, 45 and 60 minutes and placed into 2.5 mL HPLC
vials.

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A HPLC assay using a Lichrosphere RP 60 Select B column 5 m particle size
and column dimensions of 125 x 4 mm, a mobile phase consisting of phosphate
buffer (pH 2.2) and a flow rate of 1 mL/min was used to analyze the dissolution

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samples (10 L ) and the eluate was monitored at a wavelength of 206 nm.

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GENERAL CHARACTERISTICS

Name and chemical structure

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The structural formula of enalapril maleate (INN: C02EA02) is the (Z)-2-
butanedioate (1:1) salt of (S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-
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L-proline (C20H28N2O5.C4H4O4 = 492.5 Daltons) is shown in Figure 1.8 The
compound has three asymmetric centers. Enalapril is a prodrug: following oral
administration it is bioactivated by hydrolysis of the ethyl ester to enalaprilat
(synonym: enalaprilate, enalaprilic acid; C18H24N2O5 = 384.4 Daltons) which is
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the active angiotensin converting enzyme inhibitor.

Figure 1 here
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Therapeutic indication, dosing, therapeutic index and toxicity

Enalapril is a weak angiotensin-converting enzyme (ACE) inhibitor. After

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captopril, it was the second orally active ACE inhibitor to become commercially
available for the treatment of hypertension.9,10
It is also used in the management of symptomatic heart failure or asymptomatic
left ventricular dysfunction.11 Enalapril is a prodrug and its metabolic conversion
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by hydrolysis leads to enalaprilat, which is a more potent ACE inhibitor than the
parent compound.12 When enalapril is given in titrated dosages of 2.5 to 40
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mg/day (single or multiple doses based on the maleate salt) as monotherapy it

reduces systolic and diastolic blood pressure by about 15 to 25%, with diastolic
pressure normalization occurring in 50 to 75% of patients with essential or
renovascular hypertension.9 In general, enalapril is well tolerated.11 The most
frequent adverse events during enalapril treatment occur in less than 10% of
patients and are usually mild, transient and do not limit therapy. They include
dizziness, cough, blurred vision, orthostatic effects, weakness, somnolence,
abdominal pain and palpitations.9

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CHEMICAL PROPERTIES

Solubility

According to the literature, enalapril maleate is considered to be sparingly soluble

in water: 25 mg per ml at ambient temperature. 8,12 The solubility increases from

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approximately 25 mg/ml (sparingly soluble) at pH 3.5 to approximately 200 mg/ml
(freely soluble) at pH 7.0. Solubility studies performed at the Goethe University at
37C confirmed that the solubility is at least 5mg/ ml over the pH range of interest

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(pH 1.2 to 6.8) as well as at the isoelectric point (4.2). Enalaprilat, the diacid
hydrolysis product of enalapril, is less soluble in water (5 mg/ml) than the parent
compound enalapril maleate.8

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Polymorphism

Enalapril maleate is known to exist in two polymorphic modifications (Forms I and

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II) with Form II being the more thermodynamically stable form.12,13 Both forms
exhibit similar solubilities, IR and Raman spectra and Differential Scanning
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Calorimetry (DSC) thermograms. 12,14 Although recent work has suggested that
Form II of enalapril maleate may be more prone to degradation than Form I,
resulting in the formation of the diketopiperazine derivative, such potential
differences in degradation rate between the two polymorphs can be minimized by
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the simple addition of sodium bicarbonate or some other suitable stabilizer to the
tablet formulation (see also the description of in situ conversion below).15,16
Consequently, numerous abbreviated new drug applications (ANDAs) for
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enalapril maleate tablets which do not incorporate a specification for the

polymorphic form have been approved by the FDA.17 18
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Partition coefficient
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The log P (octanol/water) of enalapril has been reported to be 2.45.8 Kasim et

al.19 used calculated partition coefficients of the uncharged molecule to
provisionally classify the active substances on the WHO essential drugs list
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according to the BCS: Log P and ClogP of enalapril were thus calculated as 1.77
and 0.67, respectively.19 For comparison, metoprolol, which is often used as a
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permeability reference compound, the log P and ClogP values calculated by the
same method are 1.72 and 1.49, respectively. Enalaprilat has been reported to
have a log P of 0.16120 whereas the log P and ClogP, calculated as explained
above, are 1.17 and 0.88, respectively.19 The octanol-water distribution
coefficient at pH 2, 3, 4 and 5 were 0.36, 0.52, 0.85 and 0.76 for enalapril and
0.24, 0.28, 0.033 and 0.0024 for enalaprilat respectively.21

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pKa

Enalapril has two ionizable functions with pKa values of 2.97 (carboxylic acid
group) and 5.35 (amine group) at 25 C as determine d by aqueous acidic/basic
potentiometric titration.22 Enalaprilat has two carboxylic groups (calculated pKa of
1.60 and 3.10). The pKa value of the amine group in enalaprilat is calculated to
be 8.02, which is highly ionized at pH 6.5.23

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Stability/degradation and in-situ conversion

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The stability of enalapril maleate in aqueous buffer solutions has been studied
the pH range of 2 to 7. The rate and mode of enalapril maleate degradation are
dependent upon the pH of the solution.12 At room temperature and at a

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concentration of 0.5 mg/ml, t90 (i.e. the time required for 10% loss) was 262 days
and 114 days at pH 2 and 5, respectively. Maximum stability of enalapril maleate
in solution occurred at pH 3. At relatively low pH values (pH 3 or less), the
diketopiperazine cyclization product was the major degradation product and at

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pH 5 or above, hydrolysis to enalaprilat accounted for most of the degradation. 12
However, crystalline enalapril maleate is a very stable solid and after the
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compound was stored at room temperature (amber glass) for four years no
evidence of degradation was found by HPLC analysis.12 Early studies of
enalapril maleate tablets claimed a stable formulation when protected from
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elevated temperatures and high humidity.24 However later studies on dosage

forms showed a more complex situation due to instability caused by
excipient/drug interactions. 25-27
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Al-Omari et al. reported that the API itself was stable but formulations showed
instabilities. It was noted that the pathway of degradation of enalapril maleate is
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pH dependent. The authors then investigated the extent of degradation of two

different enalapril maleate tablet formulations (product A of a basic drug-matrix
and product B of an acidic drug-matrix). They found that the degradation of the
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product with the acidic matrix occurred to a significantly lower extent than the
basic matrix under same temperature and humidity conditions. Interestingly, the
main degradation product varied with the matrix used: diketopiperazine for the
product with the acidic matrix, but enalaprilat with the basic matrix. 25
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Similarly, Kello et al.27 manufactured four enalapril maleate formulations using

three different lubricants (glyceryl monostearate, sodium stearyl fumarate and
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zinc stearate) and a product containing citric acid anhydrous as a stabilizer. The
four formulations were subjected to stability studies as per International
Committee on Harmonization (ICH) guidelines at a temperature and humidity of
40 C / 75% RH for six months. Dissolution testing revealed that formulation IV
(containing citric acid anhydrous) was equivalent to Renitec 20 mg tablets (as
reference product), demonstrating the critical role of citric acid in stabilizing
enalapril maleate. It was also shown that glyceryl monostearate was not suitable
as a lubricant.

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A process patent showed that the addition of sodium carbonate to the API
transforms the maleate salt into the more stable sodium salt.28
Other authors29 reported that the addition of stearic acid stabilized the maleate
salt. They evaluated the effect of stearic acid on enalapril stability in
microcrystalline cellulose pellets containing enalapril maleate or enalapril sodium
according to the stability of enalapril and dissolution of the product. Both
diketopiperazine and enalaprilat formation were reduced by the addition of stearic

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acid.

In 1985 the FDA approved NDA 01899817 which, to our knowledge, used a

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process which converts the maleate salt into the sodium salt. Because of this, the
finished dosage form does not contain the maleate salt despite the fact that the
label states that the maleate is the Active Pharmaceutical Ingredient (API). This

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is due to the definitions used by the FDA of an API and its label requirements for
the finished product, whereby any substance or mixture of substances intended
to be used in the manufacture of a drug (medicinal) product, when used in the
production of a drug, becomes an active ingredient of the drug product.30 In most

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cases the substance used in the manufacturing process is the same as in the
finished product. However, in rare cases the API is converted in situ to another
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salt and the API used for the manufacturing and the active ingredient in the
finished product are not the same.18 The Canadian Vasotec product monograph
addresses this with the following statement: Each tablet is made with 2.5, 5, 10 or
20 mg of enalapril maleate that appears as 2, 4, 8 or 16 mg of enalapril sodium in
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the tablets.31
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PHARMACOKINETIC PROPERTIES
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Absorption

Enalapril is rapidly absorbed after oral administration of enalapril maleate,

reaching peak plasma concentrations at about 1 hour.9,32,33 After absorption
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enalapril is rapidly hydrolyzed by carboxylesterases, believed to take place

primarily in the liver and to a minor degree in other tissues, to form the active
metabolite enalaprilat,34,35 whereas Borde et al. reported that enalapril is stable in
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in human proximal small intestinal fluid and dog proximal small intestinal fluids.36
The exact location of the conversion of enalapril to the active moiety enalaprilat
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following oral administration, i.e. prior to or after intestinal membrane permeation,

has important consequences for the consideration and application of the BCS
approach to justify a biowaiver for formulations containing enalapril maleate and
these issues will be addressed in the Discussion.3

The Cmax of enalaprilat is approximately 3 to 4 hours following administration of

enalapril maleate and shows a dose-proportional relationship following
administration of single enalapril maleate doses between 2.5 mg to 40 mg.37

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The mean absolute oral bioavailability of enalapril maleate following

administration of single doses of 5, 10, 20 and 40 mg to healthy volunteers,
based on urinary recovery of enalapril plus enalaprilat was 63%, 73%, 62% and
59%, respectively.38 Urinary recovery of enalapril and enalaprilat following oral
administration of enalapril maleate was approximately 53 to 74%.37,39 After oral
administration of enalapril maleate approximately 33% of the dose is recovered in
faeces (6% as enalapril and 27% as enalaprilat) and 61% in urine (18% as

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enalapril and 43% as enalaprilat).34 For comparison, Till et al.40 reported that
between 92% and 96% of an intravenously administered enalaprilat dose was
recovered in urine as enalaprilat. Only about 3% of enalaprilat was absorbed

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when administered orally.32 This means that intraluminal intestinal conversion of
enalapril to enalaprilat by bacterial carboxylesterases, if it occurs, may explain
why approximately 27% of the administered enalapril dose is recovered in faeces

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as enalaprilat, but will not significantly contribute to the systemic absorption of
enalaprilat.41

The absorption of enalapril following administration of a single oral dose of 40 mg

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enalapril maleate, is not altered when it is taken with a standard breakfast. The
peak concentration (Cmax), time to peak (Tmax), area under the plasma
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concentration-time profile (AUC) for enalaprilat and urinary recoveries of
enalaprilat and total drug did not differ significantly between the fed and fasted
conditions.42,43
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Intestinal permeability

The human intestinal permeability (Peff) of enalapril and enalaprilat as measured

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by the in vivo intestinal perfusion technique are 1.57 x 10-4 cm/sec and 0.20 x 10-
4
cm/sec, respectively.43
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Enalapril has a Peff very similar to that of metoprolol (1.5-2.0 x 10-4 cm/sec), a
substance with a fraction dose absorbed of at least 0.90 and which is often used
as the reference high permeability molecule.44,45 Enalapril resembles the
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tripeptide Phe-Ala-Pro and is a substrate for the human intestinal PepT1

transporter.46,47 However, results of in vitro (Caco-2 cells, rat intestinal rings) and
in vivo studies (rats) indicate that enalapril is primarily absorbed by a non-
saturable, passive diffusion process, which is supported by recent observations
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that enalapril shows only very weak affinity for the human PepT1 transporter.48,49
It seems therefore likely that active transport does not substantially contribute to
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the overall intestinal absorption of enalapril in humans.

Distribution

Enalaprilat is approximately 50% bound to plasma proteins.9 There are two

binding sites: one is a low affinity, high capacity binding site and the other is a
high affinity, low capacity site which is presumably plasma angiotensin-converting
enzyme.50 Enalaprilat appears to penetrate into most body tissues - in particular

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the lungs, kidneys and vascular tissue but there is no direct evidence that it
crosses the blood-brain-barrier in humans at therapeutic doses.

Elimination

The elimination of enalapril is mainly by metabolic hydrolysis to enalaprilat which

is subsequently excreted in urine and to a lesser extent in faeces.38,39,50 Enalapril

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is reported to be hydrolyzed by human carboxylesterase-1 (CES1) but not by
human carboxylesterase-2 (CES2) 51 The human small intestine contains mainly
CES2 whereas CES1 is prominent in the liver.52 Consequently, following oral

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absorption the conversion of enalapril to enalaprilat has been suggested to take
place mostly in the liver.
No metabolites other than enalaprilat have been detected in humans.33 Enalapril

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is also partly excreted in the unchanged form in the urine. After oral dosing, some
enalaprilat is excreted in the faeces, of which the majority likely represents
conversion of enalapril to enalaprilat in the gastrointestinal tract.

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Renal clearance values for enalapril and enalaprilat are approximately 300
ml/min and 150 ml/min, respectively. The elimination of enalaprilat is polyphasic
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with a prolonged terminal phase.34,39 The elimination half-life of enalapril from
plasma is quite short ( 2 h). The plasma half-life of enalaprilat is around 5 hours
and this is followed by a prolonged terminal phase (30 to 35 hours) which reflects
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high affinity binding to plasma ACE. The area under the plasma concentration-
time curve (AUC) for enalaprilat is not linearly related to the administered
enalapril maleate dose. However, if the contribution of the prolonged terminal
phase is subtracted from the total AUC, it does appear that AUC increases in a
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dose-proportional manner over the usual therapeutic range.50 By contrast, the

terminal phase of the enalaprilat plasma concentration-time profile, while also
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reflecting high affinity binding to plasma ACE, involves a fixed amount of drug,
regardless of the dose administered. This is apparently the cause of the
nonlinear kinetics of enalaprilat.50 In vitro studies have shown that enalapril is a
substrate for OATP1B1.53 Human organic anion transporting polypeptide 1B1
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(OATP1B1) is mainly expressed at the basolateral membrane of hepatocytes and

may play an important role in transporting enalapril into the hepatocytes where it
is metabolized by carboxyesterases.54 Consistent with this hypothesis, genetic
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polymorphisms of the OATP1B1 gene have been shown to significantly affect the
systemic exposure of healthy Chinese men to enalapril and enalaprilat following
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single dose and multiple dose enalapril administration.55

DOSAGE FORMS

Dosage strengths and dosing recommendations

Enalapril maleate tablets are available as 2.5 mg, 5 mg, 10 mg and 20 mg dose
strengths. The highest available dose strength for enalapril maleate is thus 20
mg, but according to Goodman & Gilmans The Pharmacological Basis of

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Therapeutics the highest single dose administered is 40 mg.11 The WHO only
lists strengths of 2.5 and 5.0 mg in their list of essential drugs. 2
In Canada the product monograph for Vasotec states: Each tablet is made with
2.5, 5, 10 or 20 mg of enalapril maleate that appears as 2, 4, 8 or 16 mg of enalapril
sodium in the tablets.31
The FDA orange book lists enalapril maleate as the API and the 20 mg strength as
the reference listed drug, with lower strengths of 10, 5 and 2,5 mg.17

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Excipients

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The excipients present in enalapril maleate IR solid dosage forms registered in
20 countries are listed in Table 1. Almost 300 products have been registered and

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it can be assumed that most, if not all, of these have passed an in vivo BE study.
Although over 30 different excipients have been used to formulate enalapril
maleate products, there seem to be a few key excipients that are repeatedly
used.

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Table 1 here
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In vitro dissolution characteristics

According to the USP 38 not less than 80% (Q) of the labeled amount of enalapril
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maleate in enalapril maleate tablets are required to dissolve in USP apparatus 2

(paddle apparatus) at 50 rpm in 30 minutes in 900 ml pH 6.8 phosphate buffer.
Dissolution testing showed that over 85% of the labeled amount of enalapril in
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the Vasotec tablets dissolved in all three media in 15 minutes (see Figure 2).
These results are in accordance with those published in a recent article where
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the in vitro dissolution of enalapril maleate at pH 6.8 from a reference product

was found to be about 85% whereas several generic enalapril products failed to
release more than 85% within 15 min.56
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Figure 2 here
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Bioequivalence studies
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Several bioequivalence studies have been published in scientific journals

comparing the bioavailability of enalapril/enalaprilat following oral administration
of two different brands (generic vs. innovator) of enalapril maleate tablets.57-61
The referenced studies were all carried out in 18 to 24 healthy subjects. Plasma
concentrations of enalapril and/or enalaprilat were measured by RIA57, LC-
MS58,59 or GC-MS60. Bioequivalence between the test and reference enalapril
maleate preparations was concluded if the 90% confidence intervals around the
geometric mean ratios for AUC and Cmax of enalapril, enalaprilat and/or total

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enalapril (i.e. enalapril plus enalaprilat) fell within the 80-125% acceptance
range.57-59

In all reported studies the 90% confidence intervals around the geometric mean
ratios of AUC0-t and AUC0-inf for enalapril and/or enalaprilat or total enalapril were
within the 80-125% acceptance limits (Table 2). In two of the studies, the 90%
confidence interval for Cmax of enalapril or enalaprilat was outside the 80-125%

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acceptance range.57,59

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One of these two studies (Ribeiro et al.) was carried out in only 18 volunteers and
was likely underpowered.57 The other (Portoles et al.) 58 reported the Ln-
transformed parameters for enalapril for Cmax were between 77.35%-102.16%;

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while the one for enalaprilat were between 83.56%-103.46%. The reason for this
discrepancy is not known. Indeed, in one of the other studies the CVanova values
were reported to be 30.2, 29.9 and 31.4% for AUC0-t, AUC0-inf and Cmax of
enalaprilat, respectively, indicating that the pharmacokinetics of the active

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metabolite of enalapril tend to show a high intrasubject variability.60
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In the bioequivalence study of Lo et al., the oral bioavailability of a freeze-dried,
rapidly dissolving wafer formulation of enalapril maleate was compared to the
oral bioavailability of the conventional enalapril maleate tablet.61 Bioequivalence
was based on the cumulative urinary recovery of enalaprilat and total enalapril
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(i.e. enalapril plus enalaprilat), and the serum Cmax of enalaprilat. The results
showed that the rapidly dissolving wafer formulation is bioequivalent to the
conventional tablet.
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None of these papers reported the results of comparative in vitro dissolution

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testing on the test and reference products used in the in vivo bioequivalence
studies.
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DISCUSSION
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Solubility
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According to the current regulatory guidelines, an API is highly soluble if its

dose/solubility ratio (D/S) is 250 mL or less in the pH range of 1.0 6.82-5
or 1.0 7.53 at 37 C, in which dose is to be understood as t he highest dose
strength2,3 or the highest single dose administered. 4,5 The highest available dose
strength for enalapril maleate is 20 mg, but according to Goodman & Gilmans
The Pharmacological Basis of Therapeutics the highest single dose administered
is 40 mg.11 Assuming the worst case of highest single dose (40 mg)
recommended in the Prescribers Information as the Dose, and 5mg/ml as the

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minimum solubility throughout the pH range studied, the D/S would be 8 ml or

less.

This very low D/S ratio leads to the conclusion that enalapril maleate is a highly
soluble drug substance according to the BCS. This relatively high water solubility,
in addition to the body of data suggesting similar pharmaceutical properties
between the two polymorphic forms, indicates little or no value in controlling a

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particular crystalline form in the dosage form.

Permeability and oral absorption

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Enalapril is approximately 1000 times less potent than enalaprilat as an ACE
inhibitor and, therefore, it can be considered an inactive prodrug of enalaprilat.

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Enalapril was designed to improve the systemic availability of the active ACE
inhibitor enalaprilat which has poor oral absorption. FDA Guidances contain
specific sections on prodrugs. 3, 62 In view of the limited oral bioavailability of
enalaprilat, it is reasonable to assume that the prodrug-to-drug conversion occurs

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predominantly (60-70%) after intestinal membrane permeation of enalapril.
However, the fact that 27% of a 10 mg oral dose of enalapril maleate is
AN
recovered in faeces as enalaprilat suggests, as pointed out above, that some of
the hydrolysis of enalapril may occur in the intestinal tract before absorption of
enalapril takes place. According to the FDA Biowaiver Guidance: When the
prodrug-to-drug conversion is shown to occur predominantly after intestinal
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membrane permeation, the permeability of the prodrug should be measured. 3

Therefore, in the case of enalapril/enalaprilat, the permeability of the prodrug
should be taken into account for BCS classification.
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The effective permeability of enalapril as determined by the in vivo intestinal

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perfusion technique, which is 1.57 x 10-4 cm/sec, should be considered high as it

is similar to the effective permeability of metoprolol (1.34 x 10-4 cm/sec), a high
permeability reference substance.19,45 As a consequence, the Therapeutic
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System Research Laboratories website lists enalapril as a BCS class I

substance.63 However, according to the BCS based biowaiver guidelines, high
permeability can only be assumed for substances having a fraction absorbed
exceeding 85% (EMA, WHO, Health Canada) or 90% / 85% (FDA). 2-5,7
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Absolute bioavailability studies with urinary recovery of enalapril and enalaprilat

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in urine following oral administration of enalapril maleate show that absorption

(fa) is approximately 60 to 70%.37 However, 33% of an orally administered dose
is recovered in faeces, mainly as enalaprilat (27%) and to a minor extent as
unchanged enalapril (7%).32 It has been suggested that this faecal recovery
represents biliary excretion of enalaprilat and unabsorbed drug.9 Based on the
observation by Till et al. (1982) that between 92% and 96% of an intravenously
administered enalaprilat dose was recovered unchanged in urine, it is unlikely
that enalaprilat undergoes significant biliary excretion.40 It is therefore more likely
that (most of) the enalaprilat recovered in faeces (approximately 27%) following

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oral administration of enalapril maleate is the result of hydrolysis of enalapril to

enalaprilat in the intestinal tract before absorption of enalapril takes place.
Because of the poor absorption of enalaprilat from the gastrointestinal tract, the
enalaprilat thus formed in the gastrointestinal tract would mostly be excreted in
the faeces. Based on these considerations, it is likely that the reason behind the
oral bioavailability of enalapril maleate of 70% or less (based on urinary recovery
of enalapril plus enalaprilat), is the intestinal conversion of enalapril into

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enalaprilat rather than poor permeability of the parent.

However, without direct evidence of the extent of this conversion, for the

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purposes of applying the BCS based biowaiver it must be assumed that enalapril
is not highly permeable. This is supported by a negative Log D estimation, which
shows that the molecule partitions better into water than octanol at pH 6.8.64

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BCS Classification

Enalapril maleate is highly soluble as defined by the EMA, FDA and WHO BCS

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guidelines. Pharmacokinetic data show that only 60-70% of an oral dose of
enalapril maleate is absorbed from the intestinal tract into the enterocytes.
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Although estimates of enalaprils effective intestinal permeability are high and the
lack of complete absorption may be due to hydrolysis of enalapril to enalaprilat
within the gut lumen, it cannot be unequivocally ruled out that fa is less than the
cutoff value, especially in light of the low log D value.64 Thus enalapril cannot
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conclusively be considered a highly absorbable drug substance.65

Based on these results, enalapril maleate should be classified as BCS class III,
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which corresponds to its classification by the WHO.2

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Dissolution

Previously, according to the FDA, only APIs with high solubility and high
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permeability and which are formulated in solid, immediate release (IR) oral
dosage forms can be approved on the basis of the biowaiver procedure.3
However, the scientific community has given consideration to extending
biowaivers to other BCS classes66-69 and the FDA is moving into this direction
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too. 7 Consequently, the EMA, the WHO and Health Canada 2,4,5 now accept
BCS class III compounds as potential candidates for biowaivers and FDA has
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signaled its intention to move into this direction.7,70

Dissolution criteria for granting a biowaiver in the case of a BCS class III
compound are more stringent than those applied in the case of a BCS class I
compound. According to Health Canada5 and the revised EMA Guideline on the
Investigation of Bioequivalence, both test and reference product should show
very rapid (> 85 % within 15 min) in vitro dissolution at pH 1.2, 4.5 and 6.8.4 In
addition, special attention should be given to the excipients used in the test
product.57 Indeed, the EU Biowaiver Guidance requires essentially similar

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products which is defined as A medicinal product is essentially similar to an

original product where it satisfies the criteria of having the same qualitative and
quantitative composition in terms of active substances, of having the same
pharmaceutical form, and of being bioequivalent unless it is apparent in the light
of scientific knowledge that it differs from the original product as regards safety
and efficacy.4 A similar requirement is set out by Health Canada. 5 Davit et al.
compared the current similarities and differences between the different

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jurisdictions. 71

Since Enalapril maleate is classified as a BCS Class III API, the enalapril

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products studied by Ribeiro et al.57 which failed to meet the 85% or more in 15
minutes release criteria would not be eligible for a biowaiver according to the
revised EMEA BE guidelines4 or Health Canada..5Additionally, a meta-analysis

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published by ANVISA showed that half of the generic products on the Brazilian
market are not interchangeable.72

This is in contrast to studies of Lima et al. 56 who showed that approved products

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had different dissolution profiles. Some of the differences were due to chemical
degradation. However, Lo et al. 61 compared a fast dissolving tablet with a
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conventional tablet and showed that both were bioequivalent. This disparity
between in vitro and in vivo results demonstrates that the BCS-biowaiver concept
is conservative. For BCS class I/III drugs, where absorption is slower compared
to dissolution, in vitro studies tend to be over-discriminating.73 If products fail an
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over-discriminating in vitro test they can still be bioequivalent in vivo.

Nevertheless, for enalapril formulations which are unable to meet the BCS-
biowaiver criteria, in vivo studies which adhere to the recommendations of the
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appropriate regulatory authority should be used to assess their bioequivalence

with the comparator product.
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Risks for bioinequivalence caused by excipients and/or manufacturing

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Most of the 297 products covered in the excipient table (Table 1) contain
standard ingredients such as starch, pregelatinized starch, stearates or talc as
glidants, and lactose or microcrystalline cellulose as bulking agents. None of
these excipients are expected to influence motility or API permeability.
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One product contains mannitol and three of the 297 products summarized in the
table contain sodium lauryl sulfate. Although mannitol in large amounts can
accelerate motility and sodium lauryl sulfate can enhance permeability, and
noting that these effects cannot be studied with the biowaiver procedure, the fact
that these products can be assumed to have passed in vivo BE testing would
indicate that enalapril absorption is not greatly influenced by these excipients in
the amounts used.

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Lactose may be an issue used in large amounts if the subject is lactose-

intolerant, but all the products containing lactose were subjected to in vivo BE
testing and passed. As with all other foods and pharmaceutical products, patients
with lactose intolerance should be informed by the labeling about the presence of
this ingredient.

Many of the products contain (bi)carbonates to ensure adequate stability over the

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shelf life (Table 1). Its effect on the in situ conversion of enalapril maleate to an
alkali salt of enalapril e.g. sodium is described above. However, the addition of
stearic acid seems also to stabilize the API without the need of an in-situ

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conversion to the sodium salt. 29

From a regulatory point of view, the in situ conversion may give rise to a

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formulation not being pharmaceutically equivalent to the reference product, in
which case it would need to be considered as a pharmaceutical alternative,
which in turn raises additional questions, particularly the implications for declaring
therapeutic equivalence and hence interchangeability.74 According to the FDA

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biowaiver guideline a biowaiver can only be granted for pharmaceutically
equivalent dosage forms. That means for drug products with identical dosage
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forms that contain the same amounts of the active ingredient,74 which is different
from the API in the case of the finished enalapril maleate tablet which underwent
in situ conversion of the API.31 However, not all regulatory agencies have, to our
knowledge, requested Sponsors/manufacturers to alter their labeling to indicate
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that the dosage form contains either the sodium or potassium salt rather than the
maleate.31
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In vivo bioequivalence studies

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Several bioequivalence studies for generic oral formulations containing enalapril

maleate have been published in the scientific literature. In most cases,
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bioequivalence was established between the generic and the reference

preparation. However, there seems to be disagreement whether the parent
compound enalapril, the active metabolite enalaprilat, or both substances should
be measured in plasma to establish bioequivalence between two enalapril
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maleate oral preparations (see Table 2). In most cases BE metrics based on both
enalapril and enalaprilat plasma concentrations were used to calculate the 90%
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confidence intervals. In some cases enalapril plasma concentrations were not

measured but rather the combined plasma concentration of enalapril and
enalaprilat. Pooling of the plasma concentrations of parent drug and its
metabolite(s) to establish bioequivalence between two formulations is, however,
not acceptable for regulatory purposes.75 The FDA generally recommends
measurement of only the parent drug released from the dosage form, rather than
the metabolite.3 The reason for this is that generally metabolites are formed after
the absorption of the parent drug takes place and therefore, their
pharmacokinetics are much less sensitive to differences in formulation

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performance than that of the parent compound and are not reliable/appropriate
markers to determine bioequivalence.76 However, the FDA Guidance for Industry
also states the following: A metabolite may be formed as a result of gut wall or
other pre-systemic metabolism. If the metabolite contributes meaningfully to
safety and/or efficacy, we also recommend that the metabolite and the parent
drug be measured We recommend that the parent drug measured in these BE
studies be analyzed using a confidence interval approach. The metabolite data

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can be used to provide supportive evidence of comparable therapeutic outcome.
3, 62
Consequently, enalapril should be considered the primary analyte on which
bioequivalence should be based. Measurement of enalaprilat plasma

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concentrations may be used to provide supportive evidence according to the FDA
Draft Guidance on Enalapril Maleate.18 This approach is somewhat different than
that of the EMA. According to the revised EMA Guideline on the Investigation of

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Bioequivalence, however, even for inactive prodrugs, such as enalapril,
demonstration of bioequivalence for the parent compound is recommended and
the active metabolite, i.e. enalaprilat, does not need to be measured.4

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Patients Risks Associated with Bioinequivalence

When considering a biowaiver of in vivo BA/BE studies, the therapeutic index and
indications of the active drug substance must be taken into account. Enalapril
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maleate is an antihypertensive agent, also used in the management of

symptomatic heart failure or asymptomatic left ventricular dysfunction, with a
favorable efficacy and tolerability profile. There is a wide range of dosage
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strengths available, and the recommended dose ranges from 2.5 to 40 mg/day. It
is not considered to be a narrow therapeutic index drug. Consequently, relatively
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minor fluctuations in plasma concentrations of enalapril and enalaprilat between

different oral enalapril maleate preparations should not lead either to serious
concentration-related adverse events or therapeutic failure. In addition, the earlier
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or later appearance of the antihypertensive effect, i.e. differences in Tmax and

therefore also in Cmax, does not make any clinically significant difference in the
long term treatment of arterial hypertension with ACE inhibitors.77
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CONCLUSION
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Enalapril maleate is conservatively classified as belonging to BCS class III, which

corresponds to the classification by the WHO. Whereas excipients can affect the
rate and extent of drug absorption, using excipients that are currently in IR solid
oral dosage forms approved in ICH countries (such as those listed in Table 1)
should not affect the rate or extent of absorption of a highly soluble and highly
permeable drug substance that is formulated in a rapidly dissolving IR product.
For APIs belonging to BCS Class III, however, it is wiser to adhere to the tenet
that the risk of an incorrect BE decision can be reduced by using a composition

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for the test product that is close or essentially similar to that of the comparator
product. It is therefore recommended that a biowaiver is acceptable only if (i) the
actual active ingredient, rather than the labeled API is the same, (ii) the
composition of the test product (generic version or variation of an existing
product) is similar to that of the comparator product and (iii) the in vitro
dissolution of both test and comparator products is very rapid (at least 85%
within 15 min at pH 1.2, 4.5 and 6.8 under testing conditions adhering to the

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specifications set out in BCS based Biowaiver regulations).

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ACKNOWLEDGMENTS

A project of the International Pharmaceutical Federation FIP, Special Interest

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Group BCS & Biowaivers, www.fip.org/bcs.

This article reflects the scientific opinion of the authors and not necessarily the
policies of regulating agencies, or of the International Pharmaceutical Federation

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(FIP).
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The authors wish to acknowledge the contribution of Martin Hofs in performing
the equilibrium solubility studies.
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List of FIGURES AND LEGENDS

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Figure 1. Structural formula of enalapril maleate

Figure 2. Dissolution of enalapril from Vasotec 20 mg tablets in three media.
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Figures

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Figure 1. Structural formula of enalapril maleate.

U SC
120
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100

80 SIF
Release (%)

60 pH 4.5
Vasotec 20 mg
40 SGF
D

20
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0
0 10 20 30 40 50 60
Time min
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Figure 2. Dissolution of enalapril from Vasotec 20 mg tablets in three media.
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Table 1: See separate file (ENALAPRIL BCS manuscript ms - excipients TABLE 1)

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Table 2: Summary of five bioequivalence studies on oral formulations of enalapril maleate: 90%
confidence intervals are given for Cmax, AUC0-t, and AUC0-inf and/or U0-t (cumulative urinary
excretion from 0 to t). For details consult references.

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Reference analyte Cmax AUC0-t AUC0-inf U0-t
Ribeiro et al., 1996 (42) enalaprilat 96.2 131.0 99.6 123.6
total enalaprila 81.1 108.4 84.1 111.7

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Lo et al., 2000 (46) enalaprilat 100 122 93 115
total enalapril 88 - 117

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Najib et al., 2003 (43) enalapril 91.8 110.5 94.4 107.6 94.5 107.5
enalaprilat 93.3 110.7 94.3 109.6 93.7 108.6

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Niopas et al., 2003 (45) enalaprilat 91.0 123.4 88.7 118.9 88.0 117.6
Portols et al., 2004 (44) enalapril 77.4 102.2 87.1 101.6 87.4 101.5
enalaprilat 83.6 103.5 88.6 103.7 89.2 103.9

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a
total enalapril refers to enalapril plus enalaprilat plasma concentrations; data outside of the 80-125 range are indicated in bold italics

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53. Liu L, Cui Y, Chung AY, Shitara Y, Sugiyama Y, Keppler D, Pang KS 2006. Vectorial transport of enalapril by
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Oatp1a1/Mrp2 and OATP1B1 and OATP1B3/MRP2 in rat and human livers. Journal of Pharmacology and
Experimental Therapeutics 318(1):395-402.

26
 ACCEPTED MANUSCRIPT

54. Knig J, Cui Y, Nies AT, Keppler D 2000. A novel human organic anion transporting polypeptide localized to the
basolateral hepatocyte membrane. American Journal of Physiology - Gastrointestinal and Liver Physiology 278(1
41-1):G156-G164.

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55. Tian L, Liu H, Xie S, Jiang J, Han L, Huang Y, Li Y 2011. Effect of organic anion-transporting polypeptide 1B1

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(OATP1B1) polymorphism on the single- and multiple-dose pharmacokinetics of enalapril in healthy Chinese adult
men. Clinical Therapeutics 33(5):655-663.

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56. Lima DM, dos Santos LD, Lima EM 2008. Stability and in vitro release profile of enalapril maleate from different
commercially available tablets: Possible therapeutic implications. Journal of Pharmaceutical and Biomedical Analysis
47(4-5):934-937.

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57. Ribeiro W, Muscar MN, Martins AR, Moreno Jr H, Mendes GB, De Nucci G 1996. Bioequivalence study of two
enalapril maleate tablet formulations in healthy male volunteers: Pharmacokinetic versus pharmacodynamic
approach. European Journal of Clinical Pharmacology 50(5):399-405.

M
58. Najib NM, Idkaidek N, Adel A, Admour I, Astigarraga REB, De Nucci G, Mahmood Alam S, Dham R, Qumaruzaman

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A 2003. Bioequivalence evaluation of two brands of enalapril 20 mg tablets (Narapril and Renitec) in healthy human
volunteers. Biopharmaceutics and Drug Disposition 24(7):315-320.

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59. Portols A, Terleira A, Almeida S, Garca-Arenillas M, Caturla MC, Filipe A, Vargas E 2004. Bioequivalence study of
two formulations of enalapril, at a single oral dose of 20 mg (tablets): A randomized, two-way, open-label, crossover
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study in healthy volunteers. Current Therapeutic Research - Clinical and Experimental 65(1):34-46.

60. Niopas I, Daftsios AC, Nikolaidis N 2003. Bioequivalence study of two brands of enalapril tablets after single oral
C

administration to healthy volunteers. International Journal of Clinical Pharmacology and Therapeutics 41(5):226-
AC

230.

61. Lo MW, McCrea JB, Shadle CR, Hesney M, Chiou R, Cylc D, Yuan AS, Goldberg MR 2000. Enalapril in RAPIDISC
(wafer formulation): Pharmacokinetic evaluation of a novel, convenient formulation. International Journal of Clinical
Pharmacology and Therapeutics 38(7):327-332.

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 ACCEPTED MANUSCRIPT

62. U.S. Department of Health and Human Services, Food and Drug Administration (FDA) Center for Drug Evaluation
and Research (CDER). 2003. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally

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Administered Drug Products General Considerations.

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63. Biopharmaeutics Classification System (BCS). Therapeutic System Research Laboratories (TSRL inc.). Accessed
November 14, 2011, at: http://www.tsrlinc.com/services/bcs/search.cfm.

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64. ChemAxon, Enalaprilat maleate physicocemical descriptors and estimates. Accessed online February 28, 2016, at:
Chemicalizeit.org

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65. Lobenberg R, Amidon GL 2000. Modern bioavailability, bioequivalence and biopharmaceutics classification system.
New scientific approaches to international regulatory standards. European Journal of Pharmaceutics &
Biopharmaceutics 50(1):3-12.

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66. Yu LX, Amidon GL, Polli JE, Zhao H, Mehta MU, Conner DP, Shah VP, Lesko LJ, Chen ML, Lee VHL, Hussain AS

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2002. Biopharmaceutics classification system: The scientific basis for biowaiver extensions. Pharmaceutical
Research 19(7):921-925.

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67. Blume HH, Schug BS 1999. The biopharmaceutics classification system (BCS): Class III drugs - Better candidates
for BA/BE waiver? European Journal of Pharmaceutical Sciences 9(2):117-121.
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68. Cheng CL, Yu LX, Lee HL, Yang CY, Lue CS, Chou CH 2004. Biowaiver extension potential to BCS Class III high
solubility-low permeability drugs: Bridging evidence for metformin immediate-release tablet. European Journal of
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Pharmaceutical Sciences 22(4):297-304.

AC

69. Jantratid E, Prakongpan S, Amidon GL, Dressman JB 2006. Feasibility of biowaiver extension to Biopharmaceutics
Classification System Class III drug products: Cimetidine. Clinical Pharmacokinetics 45(4):385-399.

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70. U.S. Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and
Research (CDER). 2015. Dissolution Testing and Specification Criteria for Immediate-Release Solid Oral Dosage
Forms Containing Biopharmaceutics Classification System Class 1 and 3 Drugs. Accessed Feb 28 2016 at:

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http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM456594.pdf

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71. Davit BM, Kanfer I, Tsang YC, Cardot JM 2016. BCS Biowaivers: Similarities and Differences Among EMA, FDA,
and WHO Requirements. AAPS Journal:1-7.

SC
72. Lopes RA, Neves FA 2010. Meta-analysis for bioequivalence studies: interchangeability of generic drugs and similar
containing Hydrochlorothiazide is possible but not with Enalapril Maleate. Jornal brasileiro de nefrologia : orgo
oficial de Sociedades Brasileira e Latino-Americana de Nefrologia 32(2):173-181.

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AN
73. Azarmi S, Roa W, Lbenberg R 2007. Current perspectives in dissolution testing of conventional and novel dosage
forms. International Journal of Pharmaceutics 328(1 SPEC. ISS.):12-21.

M
74. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and
Research (CDER). 2016. Orange book preface.

D
75. Jackson AJ, Robbie G, Marroum P 2004. Metabolites and bioequivalence: Past and present. Clinical

TE
Pharmacokinetics 43(10):655-672.

76. Jackson AJ 2008. Role of metabolites in bioequivalence assessment. In Kanfer I and Shargel L, eds. Generic Drug
EP
Product Development: Bioequivalence Issues, New York: Informa Healthcare. p 171-183.

77. Leonetti G, Cuspidi C 1995. Choosing the Right ACE Inhibitor: A Guide to Selection. Drugs 49(4):516-535.
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Excipientsa present in Enalapril maleate IR solid oral drug productsb with a Marketing
Authorization (MA) in Canada (CA), Czech Republic (CZ), Germany (DE), Denmark
(DK), Spain (ES), Finland (FI), France (FR), Hungary (HU), Ireland (IE), Iceland (IS),
The Netherlands (NL), Norway (NO), Portugal (PT), Sweden (SE), United Kingdom
(UK) and the United States (US)c, and the minimal and maximal amount of that
excipient present pro dosage unit in solid oral drug products with a MA in the USd.

PT
Excipient Drug products containing that excipient with a MA granted by Range present
the named country in solid oral
dosage forms

RI
with a MA in
the US (mg)

SC
1 2,3 4 5 6
calcium hydrogen phosphate CZ( ) DK( ) FI( ) HU( ) SE( ) 104 - 850
carmellose sodium NL(7) 2.2 - 160
8
castor oil US( ) 0.03 3.1

U
castor oil, hydrogenated ES(9-11) PT(12) 0.93 - 38e
CA(13) CZ(1,14) DE(15-17) DK(2,3,18-21) ES(22-30) FI(4,31) HU(5,32,33) 4.6 - 1385e
AN
cellulose, microcrystalline
IS(34,35) NL(36,37) NO(38) PT(39-42) SE(6,43) US(44-47)
copovidone CA(48) 357 - 854
M

croscarmellose sodium CA(49) CZ(50) DE(51) DK(52,53) ES(25,26,54-56) FI(57) FR(58-63) HU(33) 2 - 180
64 65 66 67
IS( ) NL( ) SE( ) UK( )
crospovidone CZ(14) DE(15-17,68) DK(18-21) ES(23,29,30,69) FI(31) FR(70-72) HU(32,73) 4.4 - 792e
D

NL(36,37) NO(38) SE(43) UK(74) US(45)

TE

gelatin CZ(75) DE(76) HU(77) 1 756e

glycerol dibehenate ES(24) 2.5 - 14
78
glycerol distearate UK( ) 1.5
EP

glyceryl palmitostearate ES(24,79) UK(80) 18

81-83 17,84-93 94-96 9-11,97-99 100-102 103-107
hydroxypropylcellulose CZ( ) DE( ) DK( ) ES( ) FI( ) FR( ) 4 - 132
HU(108-112) IE(113,114) NL(115-117) NO(118,119) PT(12,120-124) SE(125-128)
C

hypromellose US(129-133) 0.8 - 537

AC

lactose CA(13,48,49,134-143) CZ(14,50,75,81-83,144-147) DE(15-17,51,68,76,84-93,148-161) 23 1020e

magnesium carbonate
magnesium stearate
DK(18-21,52,53,94-96,162-165) ES(9-11,23-26,29,30,54-56,69,79,97-99,166-205) FI(31,57,100-
102,206-211
) FR(58-63,70-72,103-107,212-218) HU(32,33,73,77,108-112,219-225)
IE(113,114,226-230) IS(34,35,64) NL(36,37,65,115-117,231-239) NO(38,118,119,240-244)
PT(12,39,120-124,245-257) SE(43,66,125-128,258-264) UK(67,74,78,80,265) US(8,44-
47,129-133,266-270
)
CZ(75) DE(76) ES(9,10,24) HU(77) PT(12) 1.1 - 250
13,49,135-137,139-143 1,14,50,75,81-83,144-147 15-17,51,68,76,84-93,148-161
CA( ) CZ( ) DE( ) 0.15 - 401e
DK(2,3,18-21,52,53,94-96,162-165) ES(9-11,22-24,27-30,54-56,69,97-99,166-168,170-189,191-

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193,195-205
) FI(4,31,57,100-102,206-211) FR(58-63,70-72,103-107,212-218)
HU(5,32,73,77,108-112,219-225) IE(113,114,226-230) IS(34,35,64) NL(7,36,37,65,115-
117,231-239
) NO(38,118,119,240-244) PT(12,39-42,120-124,245-257) SE(6,43,66,125-128,258-
264
) UK(67,74,265) US(8,44-47,267-270)
maleic acid DE(68) ES(25,26,69) FR(70-72) HU(33,73) UK(74) US(44,46,47) 2-4
79
mannitol ES( ) 33 - 484
79
methylhydroxyethylcellulose ES( ) 24

PT
45
potassium hydrogen carbonate US( ) 12
137 1,14 15-17 2,3,18-21 23,29,30,167 4,31 5,32
povidone CA( ) CZ( ) DE( ) DK( ) ES( ) FI( ) HU( ) 0.17 - 240
34,35 36,37 38 6,43
IS( ) NL( ) NO( ) SE( )

RI
silica CA(137) CZ(1,14,75) DE(16,76) DK(2,3,18,21) ES(22-30,167,169,200) FI(4) 0.50 - 100
5,32,33,77 34,35 36 39-42 6 44,46,47
HU( ) IS( ) NL( ) PT( ) SE( ) US( )

SC
sodium carbonate IS(35) 4.9 - 92
13,48,49,135-137,139-143 1,50,81-83,144-147 51,84-93,148-161
sodium hydrogen carbonate CA( ) CZ( ) DE( ) 2 - 125
2,3,52,53,94-96,162-165 22,27,28,54-56,97-99,166,168,170-189,191-193,195-199,201-
DK( ) ES(

U
205 4,57,100-102,206-211
) FI( ) FR(58-63,103-107,212-218) HU(5,108-112,219-225)
IE(113,114,226-230) IS(34,64) NL(7,65,115-117,231-239) NO(118,119,240-244) PT(39-
AN
42,120-124,245-257
) SE(6,66,125-128,258-264) UK(67,265) US(267-270)
sodium hydroxide CZ(14) DE(15-17) DK(18-21) ES(23,29,30) FI(31) HU(32) NL(36,37) NO(38) 0.74 6.7
M

43
SE( )
sodium laurilsulfate US(44,46,47) 0.65 - 52
75 76 24 77 34
sodium starch glycolate CZ( ) DE( ) ES( ) HU( ) IS( ) 2 - 876e
D

sorbitol ES(9-11) PT(12) 5 - 337

TE

13,49,135-137,139-141,143 81-83,144-147 68,84-93,148-161 3,94-96,162-

starch CA( ) CZ( ) DE( ) DK( 0.44 - 1135e
165
) ES(24,56,69,79,97-99,166-168,170-184,186-189,191-193,195-205) FI(100-102,206-211)
FR(70-72,103-107,212-218) HU(73,108-112,219-225) IE(113,114,226-230) IS(35) NL(115-
EP

117,231-239
) NO(118,119,240-244) PT(39,120-124,245-257) SE(125-128,258-264)
UK(74,78,80,265) US(47,129-133,268-270)
starch, pregelatinised CA(13,48,49,135-137,139-143) CZ(1,50,147) DE(51,68,150,160,161) DK(2,52,53,163) 5.0 - 600
C

9,11,22,27,28,54-56,69,170,173-177,179-187,193,196-199,202,204 4,57,206,208,211
ES( ) FI( )
AC

58-63,70-72,213,218 5,73,219 228-230 64 7,65,231,234,236,238,239

FR( ) HU( ) IE( ) IS( ) NL( )
241,244 12,40-42,245,246,254,256,257 6,66,258,260,264 67,74,265
NO( ) PT( ) SE( ) UK( )
44,46,267
US( )
stearic acid US(129-133) 0.9 - 72e
talc CA(137) CZ(14,81-83,144-146) DE(16,84-88,90-93,148,149,151-154,156-159) DK(18,21,94- 0.10 220e
96,162,164,165
) ES(23,24,29,30,79,97-99,167,169,178,189,191) FI(100-102,207,209,210)
FR(103-107,212,214-217) HU(32,108-112,220-224) IE(113,114,226,227) IS(34,35)
NL(36,115-117,232,233,235,237) NO(118,119,240,242,243) PT(39,120-124,248,251-253)
SE(125-128,259,261-263) US(129-133)

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zinc stearate CA(48,134,138) ES(25,26,169,190,194) HU(33) US(266) 2 - 10

a
Colourants, water and ethanol are not included.
b
Excluded are: soluble tablets and dispersible tablets.
c
Sources of data: CA, www.hc-sc.gc.ca (accessed 17-11-2010); CZ, www.sukl.cz/ (accessed 09-11-2010); DE,
www.rote-liste.de (assessed 09-11-2010); DK, www.dkma.dk (accessed 10-11-2010); ES, www.aemps.es
(accessed 10-11-2010); FI, http://www.fimea.fi (accessed 11-11-2010); FR, www.vidal.fr/ (accessed 11-11-
2010); HU, www.ogyi.hu (accessed 15-11-2010); IE, www.imb.ie/ (accessed 15-11-2010); IS, www.imca.is

PT
(accessed 15-11-2010); NL, http://www.cbg-meb.nl (accessed 08-11-2010); NO, www.legemiddelverket.no/
(accessed 15-11-2010); PT, http://www.infarmed.pt/infomed (accessed 17-11-2010); SE,

RI
www.lakemedelsverket.se (accessed 16-11-2010); UK, www.medicines.org.uk/emc/ (accessed 16-11-2010); US,
www.dailymed.nlm.nih.gov. (accessed 16-11-2010)
d
USA: FDA's Inactive Ingredient Database, http://www.fda.gov/Drugs/InformationOnDrugs/ucm113978.htm

SC
(version date 16-09-2013)
e
The upper range value reported is unusually high for solid oral dosage forms and the authors doubt its
correctness.

U
1. Enalapril Vitabalans 5/-10/-20 mg tablety. 2. Enalapril Vitabalans, tabletter 5/-10/-20 mg. 3. Enamaxin,
AN
tabletter 5/-10/-20 mg. 4. Enalapril Vitabalans 5/-10/-20 mg tabletit. 5. ENALATIDIN 5/-10/-20 mg tabletta. 6.
Enalapril Vitabalans 5/-10/-20 mg tabletter. 7. Enalaprilmaleaat Apotex 2,5/-5/-10/-20 mg, tabletten. 8.
ENALAPRIL MALEATE tablet 2.5/-5/-10/-20 mg [Sandoz Inc.]. 9. enalapril cinfa 5/-20 mg comprimidos EFG.
10. ENALAPRIL EDIGEN 5/-20 mg comprimidos EFG. 11. ENALAPRIL KERN PHARMA 5/-20 mg
M

comprimidos EFG. 12. Enalapril Cinfa 5/-20 mg Comprimidos. 13. RAN-ENALAPRIL tablets 2.5/-5/-10/-20
mg. 14. EDNYT 2,5/-5/-10/-20 mg tablety. 15. EnaHEXAL 2,5 mg Tabletten. 16. Enalagamma 2,5/-5/-10/-20
mg Tabletten. 17. Enalapril 2,5 1 A Pharma Tabletten. 18. Enalapril Teva, tabletter 2,5/-5/-10/-20 mg. 19.
Corodil, tabletter 2,5/-5/-10/-20 mg. 20. Enalapril 1A Farma, tabletter 5/-10/-20 mg. 21. Ednyt, tabletter 5/-20
D

mg. 22. ACETENSIL 5/-20 mg comprimidos. 23. Ednyt 5 mg comprimidos. 24. Enalapril aphar 5/-20 mg
comprimidos EFG. 25. ENALAPRIL COMBINO PHARM 5/-20 mg comprimidos EFG. 26. Enalapril Ranbaxy
5/-20 mg comprimidos EFG. 27. Enalapril ratiopharm 5/-10/-20 mg comprimidos. 28. ENALAPRIL TARBIS 5/-
TE

20 mg comprimidos EFG. 29. ENALAPRIL TEVA 5/-20 mg comprimidos EFG. 30. Enalapril UXA 20 mg
comprimidos EFG. 31. Linatil 2,5/-5/-10/-20 mg tabletit. 32. Ednyt 2,5/-5/-10/-20 mg tabletta. 33. Invoril 2,5/-5/-
10/-20 mg tabletta. 34. Enalaprl Portfarma tflur 5 mg. 35. Enalaprl Portfarma tflur 10/-20 mg. 36.
Enalaprilmaleaat 5/-10/-20/-40 PCH, tabletten. 37. Enalaprilmaleaat Sandoz tablet 5/-10/-20 mg, tabletten. 38.
EP

Linatil 2,5/-5/-10/-20 mg. 39. ENALAPRIL BALPRIL 5/-20 mg comprimidos. 40. ENALAPRIL Bluepharma
5/-20 mg comprimidos. 41. Enalapril Ciclum 5/-10/-20 mg comprimidos. 42. Enalapril Generis 5/-20 mg
comprimidos. 43. Linatil 2,5/-5/-10/-20 mg tabletter. 44. Enalapril maleate tablet 2.5/-5/-10/-20 mg [Mylan
Pharmaceuticals Inc.]. 45. Enalapril maleate tablet 2.5/-5/-10/-20 mg [Watson Laboratories Inc.]. 46.
C

ENALAPRIL MALEATE tablet 5/-10/-20 mg (I)[Contract Pharmacy Services-PA]. 47. ENALAPRIL

MALEATE tablet 2.5/-5/-10/-20 mg [UDL Laboratories, Inc.]. 48. Prpms-ENALAPRIL tablets 2.5/-5/-10/-20
AC

mg. 49. PrSANDOZ ENALAPRIL tablets 2.5/-5/-10/-20 mg. 50. APO-ENALAPRIL 5/-10/-20 mg tablety. 51.
Enadigal 5/-10/-20 mg Tabletten. 52. Enalapril Actavis, tabletter 5/-10/-20 mg. 53. Enalapril Alchemia,
tabletter 2,5/-5/-10/-20 mg. 54. Enalapril Belmac 2,5/-5/-10/-20 mg comprimidos. 55. Enalapril Davur 2,5/-5/-
10/-20 mg comprimidos. 56. Enalapril Rimafar 5/-20 mg comprimidos EFG. 57. Enalapril Actavis 5/-10/-20 mg
tabletti. 58. ENALAPRIL EVOLUGEN 5/-20 mg cp sc. 59. ENALAPRIL MYLAN 5/-20 mg cp sc. 60.
ENALAPRIL QUALIMED 5/-20 mg cp sc. 61. ENALAPRIL SANDOZ 5/-20mg cp sc. 62. ENALAPRIL
TEVA 5/-20mg cp sc. 63. ENALAPRIL ZYDUS 20mg cp sc. 64. Daren, 2,5/-5/-10/-20 mg, tflur. 65.
Enalaprilmaleaat Actavis 2,5/-5/-10/-20 mg, tabletten. 66. Enalapril Actavis 5/-10/-20 mg, tabletter. 67. Enalapril
Maleate 2.5/-5/-10/-20mg Tablets [Goldshield Pharmaceuticals Ltd]. 68. EnaLich 5/-10/-20 mg Tabletten. 69.
ENALAPRIL WINTHROP 5/-20 mg comprimidos EFG. 70. ENALAPRIL ALMUS 20mg cp sc. 71.
ENALAPRIL BIOGARAN 5/-20 mg cp sc. 72. ENALAPRIL WINTHROP 5/-20mg cp sc. 73. Enalapril-
Chinoin 2,5/-5/-10/-20 mg tabletta. 74. Enalapril Maleate 2.5/-5/-10/-20 mg Tablets [Winthrop Pharmaceuticals
UK Ltd]. 75. Berlipril 5/-10/-20 tablety (enalaprili maleas 5/10/20 mg). 76. Benalapril 5/-10/-20 mg Tabletten.
77. Berlipril 5/-10/-20 mg tabletta. 78. Enalapril 5/-10/-20mg Tablets [Pharmadreams Ltd]. 79. BITENSIL 5/-20
mg comprimidos. 80. Enalapril Maleate 2.5/-5/-10/-20mg tablets [Milpharm Limited]. 81. Enalapril-ratiopharm

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 ACCEPTED MANUSCRIPT
5 mg tablety. 82. ENAP 2,5/-5 mg tablety. 83. ENAPRIL 5, tablety. 84. Corvo 5 mg Tabletten. 85. Enabeta
2,5/-5 Tabletten. 86. EnaHEXAL 5 mg Tabletten. 87. Enalapril 5 1 A Pharma Tabletten. 88. Enalapril AbZ
2,5/-5 mg Tabletten. 89. Enalapril AL 2,5/-5 Tabletten. 90. Enalapril axcount 5 mg Tabletten. 91. Enalapril-CT 5
mg Tabletten. 92. Enalapril-ratiopharm 2,5/-5 mg Tabletten. 93. Enalapril STADA 2,5/-5 mg Tabletten. 94.
Enalapril Sandoz, tabletter 2,5/-5 mg. 95. Enalapril Krka, tabletter 5 mg. 96. Enacodan, tabletter 2,5/-5 mg. 97.
Enalapril farma ratio 5 mg comprimidos EFG. 98. Enalapril ratio 5 mg comprimidos EFG. 99. Enalapril Sandoz
5 mg comprimidos EFG. 100. Enalapril KRKA 5 mg tabletit. 101. Enalapril-ratiopharm 5 mg tabletti. 102.
Enalapril Sandoz 5 mg tabletti. 103. ENALAPRIL ACTAVIS 5 mg cp sc. 104. ENALAPRIL CRISTERS 5 mg
cp sc. 105. ENALAPRIL EG 5 mg cp sc. 106. ENALAPRIL RATIO 5mg cp sc. 107. ENALAPRIL RPG
5mg cp sc. 108. Enalapril 1a Pharma 5 mg tabletta. 109. Enalapril-ratiopharm 5 mg tabletta. 110. Enap 5 mg
tabletta. 111. Enapril 5 mg tabletta. 112. Renapril 5 mg tabletta. 113. ENAP 5mg Tablets. 114. Enapril Stada

PT
2.5/-5/-10mg tablets. 115. Enalaprilmaleaat Sandoz 5 mg, tabletten. 116. Enalaprilmaleaat CF 5 mg, tabletten.
117. Enalaprilmaleaat ratiopharm 5 mg, tabletten. 118. Enalapril Krka 5 mg tabletter. 119. Enalapril Sandoz 2,5/-
5 mg tabletter. 120. Enalapril Azevedos 5 mg Comprimido. 121. Enalapril Mepha 5 mg Comprimidos. 122.
ENALAPRIL SANDOZ 5 mg COMPRIMIDOS. 123. Enalapril-Ratiopharm 5 mg Comprimidos. 124. Enapress

RI
(tablet enalapril 2.5/-5/-10/-20 mg). 125. Enalapril Krka 2,5/-5 mg tabletter. 126. Enalapril ratiopharm 2,5/-5 mg
tabletter. 127. Enalapril Sandoz 2,5/-5 mg tabletter. 128. Enalapril Stada 2,5/-5 mg tabletter. 129. ENALAPRIL
MALEATE tablet 5/-10/-20 mg (II)[Contract Pharmacy Services-PA]. 130. ENALAPRIL MALEATE tablet

SC
2.5/-5/-10/-20 mg [NCS HealthCare of KY, Inc dba Vangard Labs]. 131. ENALAPRIL MALEATE tablet 2.5/-
5/-10/-20 mg [Physicians Total Care, Inc.]. 132. ENALAPRIL MALEATE tablet 2.5/-5/-10/-20 mg (I)[State of
Florida DOH Central Pharmacy]. 133. ENALAPRIL MALEATE tablet 2.5/-5/-10/-20 mg [WOCKHARDT USA
LLC]. 134. APO-ENALAPRIL 2.5/-5/-10/-20mg tablet. 135. PrCO ENALAPRIL tablets 2.5/-5/-10/-20 mg. 136.
Pr
MYLAN-ENALAPRIL tablets 2.5/-5/-10/-20 mg. 137. PrNOVO-ENALAPRIL tablets 2.5/-5/-10/-20/-40 mg.

U
138. PrPRO-ENALAPRIL 2.5/-5/-10/-20 mg tablets. 139. Prratio-ENALAPRIL tablets 2.5/-5/-10/-20 mg. 140.
Pr
RIVA-ENALAPRIL tablets 2.5/-5/-10/-20 mg. 141. PrSig-ENALAPRIL tablets 2.5/-5/-10/-20 mg. 142.
AN
Pr
TARO-ENALAPRIL tablets 2.5/-5/-10/-20 mg. 143. PrVASOTEC tablets 2.5/-5/-10/-20 mg. 144. Enalapril-
ratiopharm 10/-20 mg tablety. 145. ENAP 10/-20 mg tablety. 146. ENAPRIL 10/-20, tablety. 147. RENITEC 5/-
10/-20 mg tablety. 148. Corvo 10/-20 mg Tabletten. 149. Enabeta 10/-20 Tabletten. 150. Ena-Hennig 2,5/-5/-
10/-20 mg Tabletten. 151. EnaHEXAL 10/-20/-30/-40 mg Tabletten. 152. Enalapril 10/-20 1 A Pharma
M

Tabletten. 153. Enalapril 1 A Pharma 30/-40 mg Tabletten. 154. Enalapril AbZ 10/-20 mg Tabletten. 155.
Enalapril AL 10/-20 Tabletten. 156. Enalapril axcount 10/-20 mg Tabletten. 157. Enalapril-CT 10/-20 mg
Tabletten. 158. Enalapril-ratiopharm 10/-20 mg Tabletten. 159. Enalapril STADA 10/-20 mg Tabletten. 160.
XANEF 5/-10/-20 mg Tabletten. 161. XANEF Cor 2,5 mg Tabletten. 162. Enalapril Sandoz, tabletter 10/-20
D

mg. 163. Enalapril Mylan, tabletter 2,5/-5/-10/-20 mg. 164. Enalapril Krka, tabletter 10/-20 mg. 165. Enacodan,
tabletter 10/-20 mg. 166. BARIPRIL 5/-10 mg comprimidos. 167. Clipto 5/-20 mg comprimidos. 168.
TE

CONTROLVAS 5/-20 mg comprimidos. 169. CORPRILOR 5/-20 mg comprimidos. 170. CRINOREN 5/-20 mg
comprimidos. 171. DABONAL 5/-20 mg comprimidos. 172. DITENSOR 20 mg Comprimidos. 173. Enalapril
ALTER 5/-20 mg comprimidos EFG. 174. Enalapril Bexal 5/-20 mg comprimidos EFG. 175. ENALAPRIL
CUVE 20 mg comprimidos EFG. 176. Enalapril Durbn 5/-20 mg comprimidos EFG. 177. ENALAPRIL
FARMANEU 5/-20 mg comprimidos EFG. 178. Enalapril farma ratio 20 mg comprimidos EFG. 179.
EP

ENALAPRIL GENERICOS JUVENTUS 5/-20 mg comprimidos. 180. Enalapril KORHISPANA 5/-20 mg

comprimidos EFG. 181. Enalapril LAREQ 5/-20 mg comprimidos EFG. 182. Enalapril Lasa 20 mg comprimidos
EFG. 183. ENALAPRIL MABO 20 mg Comprimidos EFG. 184. Enalapril MYLAN 5/-20 mg comprimidos
EFG. 185. ENALAPRIL NORMON 5/-20 mg Comprimidos EFG. 186. Enalapril PENSA 5/-20 mg
C

comprimidos EFG. 187. ENALAPRIL PHARMAGENUS 20 mg comprimidos EFG. 188. ENALAPRIL

QUALIGEN 5/-20 mg comprimidos EFG. 189. Enalapril ratio 20 mg comprimidos EFG. 190. ENALAPRIL
AC

RUBI 5/-20 mg comprimidos. 191. Enalapril Sandoz 20 mg comprimidos EFG. 192. Enalapril STADA 5/-20
mg comprimidos EFG. 193. ENALAPRIL SUMOL 20 mg COMPRIMIDOS EFG. 194. ENALAPRIL
TAMARANG 5/-20 mg comprimidos EFG. 195. Enalapril Tecnigen 20 mg comprimidos EFG. 196. Enalapril
VIR 5/-20 mg comprimidos EFG. 197. HERTEN 5/-20 mg comprimidos. 198. Hipoartel 20 mg comprimidos.
199. IECATEC 5/-20 mg. 200. INSUP 20 mg comprimidos. 201. NAPRILENE 5/-20 mg comprimidos. 202.
NEOTENSIN 5/-20 mg Comprimidos. 203. PRESSITAN 5/-20 mg Comprimidos. 204. RECA 20 mg
comprimidos. 205. RENITEC 5/-20 mg comprimidos. 206. Enalapril Astimex 2,5/-5/-10/-20 mg tabletit. 207.
Enalapril KRKA 10/-20 mg tabletit. 208. Enalapril Mylan 2,5/-5/-10/-20 mg tabletti. 209. Enalapril-ratiopharm
10/-20 mg tabletti. 210. Enalapril Sandoz 10/-20 mg tabletti. 211. Renitec 5/-10/-20 mg tabletti. 212.
ENALAPRIL ACTAVIS 20 mg cp sc. 213. ENALAPRIL ARROW 5/-20 mg cp sc. 214. ENALAPRIL
CRISTERS 20 mg cp sc. 215. ENALAPRIL EG 20 mg cp sc. 216. ENALAPRIL RATIO 20mg cp sc. 217.
ENALAPRIL RPG 20mg cp sc. 218. RENITEC 5/-20 mg cp sc. 219. Acepril 2,5/-5/-10/-20 mg tabletta. 220.
Enalapril 1a Pharma 10/-20 mg tabletta. 221. Enalapril-ratiopharm 10/-20 mg tabletta. 222. Enap 10/-20 mg
tabletta. 223. Enapril 10/-20 mg tabletta. 224. Renapril 10/-20 mg tabletta. 225. Renitec 2,5/-5/-10/-20 mg

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tabletta. 226. ENAP 10/-20mg Tablets. 227. Enapril Stada 20 mg tablets. 228. Innopril 2.5/-5/-10/-20mg Tablets.
229. Innovace 2.5/-5/-10/-20 mg Tablets [Merck Sharp and Dohme Limited]. 230. Innovace 5/-20mg Tablets
[Imbat Limited]. 231. RENITEC 5/-10/-20 mg, tabletten. 232. Enalaprilmaleaat Sandoz 10/-20/-30/-40 mg,
tabletten. 233. Enalaprilmaleaat CF 10/-20 mg, tabletten. 234. Enalapril Maleaat Mylan 5/-10/-20 mg, tabletten.
235. Enalaprilmaleaat ratiopharm 10/-20 mg, tabletten. 236. Enalaprilmaleaat 5/-20 mg, tabletten. 237.
Enalaprilmaleaat 30/-40 mg, tabletten. 238. Enalaprilmaleaat 5/-20 mg Focus, tabletten. 239. Enalaprilmaleaat 5
A/-20 A tabletten 5/-20 mg. 240. Enalapril Krka 10/-20 mg tabletter. 241. Enalapril Mylan 5/-10/-20 mg
tabletter. 242. Enalapril ratiopharm 2,5/-5/-10/-20 mg tablett. 243. Enalapril Sandoz 10/-20 mg tabletter. 244.
RENITEC 2,5/-5/-10/-20 mg tabletter. 245. Cetampril 5/-20 mg comprimidos. 246. Denapril 5/-20 mg
comprimidos. 247. DIASISTOL, 20 mg, Comprimidos. 248. Enalapril Azevedos 20 mg Comprimido. 249.
Enalapril Farmoz 20 mg comprimidos. 250. Enalapril Inventis 5/-20 mg Comprimidos. 251. Enalapril Mepha 20

PT
mg Comprimidos. 252. ENALAPRIL SANDOZ 20 mg COMPRIMIDOS. 253. Enalapril-Ratiopharm 20 mg
Comprimidos. 254. Maleato de Enalapril Mylan - Tablet Enalapril 5/-20 mg. 255. PRILAN 5/-20 mg
Comprimidos. 256. RENITEC /-5, comprimidos 5/-20 mg. 257. Tensazol 5/-20 mg comprimidos. 258. Enalapril
Astimex 2,5/-5/-10/-20 mg tabletter. 259. Enalapril Krka 10/-20 mg tabletter. 260. ENALAPRIL Mylan 2,5/-5/-

RI
10/-20 mg tabletter. 261. Enalapril ratiopharm 10/-20 mg tabletter. 262. Enalapril Sandoz 10/-20 mg tabletter.
263. Enalapril Stada 10/-20 mg tabletter. 264. Renitec 2,5/-5/-10/-20 mg tabletter. 265. INNOVACE 2.5/-5/-
10/-20 mg Tablets. 266. Enalapril maleate tablet 2.5/-5/-10/-20 mg [Apotex Corp.]. 267. Enalapril maleate tablet

SC
2.5/-5/-10/-20 mg [Taro Pharmaceuticals U.S.A., Inc.]. 268. ENALAPRIL MALEATE tablet 2.5/-5/-10/-20 mg
(II)[State of Florida DOH Central Pharmacy]. 269. ENALAPRIL MALEATE tablet 2.5/-5/-10/-20 mg [TEVA
Pharmaceuticals USA Inc]. 270. VASOTEC (enalapril maleate) tablet 2.5/-5/-10/-20 mg [BTA Pharmaceuticals
Inc.].

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