Jung-Cook et al

Tropical Journal of Pharmaceutical Research September 2018; 17 (9): 1685-1691

ISSN: 1596-5996 (print); 1596-9827 (electronic)
© Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria.

Available online at http://www.tjpr.org

http://dx.doi.org/10.4314/tjpr.v17i9.1
Original Research Article

Comparative in vitro dissolution and in vivo bioavailability

of commercial amlodipine tablets
Helgi Jung-Cook1, Lourdes Mayet-Cruz1, María Elena Girard-Cuesy2
1
Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México. Ciudad de México,
2
Investigación, Ciencia y Tecnología (ICT) Internacional, México

*For correspondence: Email: helgi@unam.mx; Tel: +52 55 56 22 52 82; Fax: +52 55 56 22 53 29

Sent for review: 30 November 2017 Revised accepted: 24 August 2018

Abstract
Purpose: To evaluate the in vivo and in vitro behavior of amlodipine immediate release products.
Methods: Three Mexican amlodipine products and the innovator (Norvasc®) were evaluated. Three
bioequivalence studies were performed in 24 healthy male and female volunteers each. Plasma
concentrations were determined using a liquid chromatographic method coupled with tandem mass
spectrometry (LC/MS/MS). Dissolution profiles were evaluated using USP type apparatus 2 at 75 rpm
and 500 mL of HCl 0.1N, pH 4.5 and pH 6.8. Also, the dissolution behavior of different lots of the
innovator product was evaluated using apparatus 1 or 2 and 900 mL of buffer pH 6.8.
Results: All the generic products under study were bioequivalent to the innovator. In vitro data showed
that although at pH 1.2 and 4.5, the products met the specifications for very rapidly dissolving products
but at pH 6.8, neither the innovator nor the test products complied with the criteria for rapidly dissolving
products. When the study was performed at pH 6.8 in 900 mL of medium, the innovator showed a rapid
dissolution behavior.
Conclusion: The results show that the use of WHO conditions (900 mL of media, apparatus 2 at 75
rpm) are more adequate to predict the in vivo behavior of the amlodipine products.

Keywords: Biopharmaceutics Classification System (BCS), Dissolution, Bioequivalence, Solubility,

Permeability

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INTRODUCTION Bioequivalence, EMA [2] specifies the following

experimental conditions: apparatus 1 at 100 rpm
The Biopharmaceutics Classification System or apparatus 2 at 50 rpm, using 900 mL or less
(BCS) is used as a waiver of bioequivalence for and the following dissolution media: pH 1.0 – 1.2
immediate-release solid dosage forms [1]. (usually 0.1 N HCl or SGF without enzymes), pH
Although the different BCS guidelines agree that 4.5 and pH 6.8 (or SIF without enzymes at 37 ±
the biowaiver criteria can be applied to BCS 0.5 ºC). The same conditions are specified in the
class 1 or class 3 drug products, there is no Health Canada Biowaiver Guidance [3] however
international consensus on the test conditions. this guidance indicates that if coning is observed
Thus, the Guideline for the Investigation of for the test as well as for the reference products,
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© 2018 The authors. This work is licensed under the Creative Commons Attribution 4.0 International License
Trop J Pharm Res, September 2018; 17(9): 1685
 Jung-Cook et al

speed could be increased to 75 rpm, Drug products

nevertheless, the results obtained with the lower
speed should also be reported. WHO guidance Two different batches of the innovator product
indicates that the test should be performed in (Norvas® 5 mg) (Pfizer, Mexico) (R1 and R2)
900 mL or less of dissolution media at pH 1.2, and three generic products containing 5 mg of
4.5 and 6.8, using apparatus 2 at 75 rpm or amlodipine besylate (B, C and D) marketed in
apparatus 1 at 100 rpm [4], while FDA Guidance Mexico were evaluated.
[5] recommends the use of apparatus 2 at 75
rpm or apparatus 1 at 100 rpm, and 500 mL of In vivo studies
buffer media at pH 1.2, 4.5 and 6.8.
Three separate bioequivalence studies, in 24
Amlodipine besylate is a long acting calcium healthy male and female volunteers each group,
channel blocker dihydropyridine used for were performed using the innovator product
treatment of hypertension, coronary artery (Norvas® 5 mg) as the reference product. The
disease and chest pain (angina) [6,7]. studies were conducted in accordance to the
Amlodipine is indexed in the Essential Medicines Helsinki Declaration [14]. Protocols number
WHO Model List as an antihypertensive drug in BE0734, BE06026 and BE13021 were approved
dose of 5 mg [8]. In Mexico, it is also included in by the Ethics Committee (Comité de Ética e
the Basic Drug Catalog as 5 mg tablets [9]. The Investigación Biofarmacéutico de México). All the
recommended dose is 5 - 10 mg once daily. subjects gave their written informed consent prior
Amlodipine is a weak base with a pKa value of to study admission.
about 9.0 at 25 ºC. The reported aqueous
solubility is 0.774 mg/mL [10]. In relation to Each Bioequivalence study was performed using
amlodipine besylate, solubility values at pH 1.2, a randomized, cross-over design 2 x 2 with 2-
4.5 and 6.8 are 0.38 ± 0.017, 0.31 ± 0.005 and week washout.
0.110 ± 0.002 mg/mL respectively [11]. Since
the dose administered is up to 10mg, the dose- In the first two bioequivalence studies (using
to-solubility ratio is low, and therefore it is products B and C), each subject received a
considered a highly soluble compound. With single oral dose of 10 mg (two 5 mg tablets) of
regard to its permeability, Caron et al [12] found the reference (R1) or the test product. In the third
that neutral amlodipine shows high permeability study, a single 5-mg dose of the reference (R2)
while cationic amlodipine does not permeate. In or of test product (D) was administered.
vivo studies have shown that although
bioavailability is low (60 – 65 %), its permeability Products were orally administered after 10 h
could be considered high due to metabolite fasting with 250 mL of water. No food intake was
excretion in urine (90 – 95 %) [13]. Moreover, the permitted for 4 h after dosing. At this time, a
WHO guidance assigned amlodipine to BCS standard meal was provided. Blood samples
class 1 [4]; therefore, it has been considered as a were taken at pre-dose and at the following
candidate for a biowaiver through dissolution times: 1, 2, 3, 4, 6, 8, 10, 12, 14, 24, 48, 96, 120
testing. and 144 h. Samples were centrifuged at 3000
rpm for 10 min. Plasma was separated and kept
The main purposes of the present study were to at - 70 °C until assay.
assess the bioequivalence of three marketed
products of amlodipine and to evaluate the effect Plasma concentrations of amlodipine were
of different media in the dissolution profile of determined using a liquid chromatographic
these products. method with tandem mass spectrometry (LC-
MS/MS), which was developed and validated
EXPERIMENTAL before the studies were performed. The system
consisted of a Shimadzu SIL-HTA autosampler
Materials and reagents (Kyoto, Japan) coupled to a turbo ionspray
ionization-triple quadrupole mass spectrometer
Amlodipine besylate and dexamethasone API 4000 (AB MDS Sciex. Toronto, Canada),
(internal standard) were acquired from Sigma- with positive ion electrospray ionization using
Aldrich. HPLC organic solvents were obtained multiple reaction monitoring (MRM) mode. The
from J.T. Baker. Drug release media and buffers analytical column was a Gemini® (Phenomenex)
were prepared using hydrochloric acid, acetic C18 (5 μm, 150 mm x 4.6 i.d.). The mobile phase
acid, sodium acetate, potassium chloride and consisted of acetonitrile:methanol (70:30, v/v)
potassium dihydrogenphosphate (J.T. Baker). with 20 mM of ammonium acetate. Table 1
Water was obtained from a Milli-Q (Millipore, shows tandem mass spectrometric parameters.
Milford, MA, USA) system.

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 Jung-Cook et al

Table 1: Tandem mass spectrometric parameters of amlodipine and dexamethasone

Compound Mol Wt Protonated Fragment CE DP EP CXP

(g/mol) ion (eV) (V) (V) (V)
Amlodipine 408.879 409.224 237.939 13.49 41.48 10 4.99

Dexamethasone 392.464 393.214 373.200 14 35.54 6.8 6.7

(internal standard)
Note: CE = Collision energy, eV = Electron volt, DP = Declustering potential, V = Volt, EP = Entrance potential,
CXP = Collision cell exit potential

Sample preparation: A volume of 400 µL of %. For dissolution profile comparison, f2 similarity

plasma sample was transferred to an assay tube test was used.
and spiked with 100 µL of internal standard
(dexamethasone) at a concentration of 250 Additionally, the dissolution profiles of other three
ng/mL. Then 200 µL of 1M sodium hydroxide batches of the reference product: R3, R4 and R5
were added mixed in vortex during 1 min and 3 were evaluated using 900 mL of pH 6.8 buffer
mL of ether:hexane:dichloromethane (60:30:10) and apparatus 2 at 75 rpm or apparatus 1 at 100
were added. Samples were shaken in vortex and rpm.
centrifuged. The organic layer was evaporated
with nitrogen stream at 40 °C. The residue was Solubility study at pH 6.8
reconstituted using 300 µL of mobile phase and
20 µL were injected into the chromatographic Amlodipine besylate, equivalent to 5 mg of
system. The analytical assay was linear from 0.1 amlodipine, was placed in 250 mL of phosphate
– 12 ng/mL. Intra-day and inter-day coefficients buffer pH 6.8. Samples were stirred at 37 °C for
of variation were less than 15 %. The recovery 48 h. Afterwards, samples were filtered using a
from amlodipine ranged from 80 to 85%. 0.45 μm HV Durapore® membrane filters
(Millipore) and analyzed with the same analytical
Non compartmental analysis of pharmacokinetic method used for the dissolution study. The
parameters was performed using WinNonlin experiment was performed in triplicate.
Version 5.0.1 (Pharsight, Mountain View, CA,
USA). The following pharmacokinetic parameters RESULTS
were obtained: Cmax, tmax, area under the curve
from 0 to the time of the last measurable plasma In vivo data
concentration (AUC0 - tlast), AUC extrapolated to
time infinity (AUC0 - inf) and terminal elimination Bioequivalence studies were conducted in
half-life (t1/2). accordance with the current bioequivalence
guidelines [15,16]. In each bioequivalence trial,
Bioequivalence was established if the 90 % 24 subjects were enrolled and completed the
confidence intervals of the geometric mean ratios study and no severe adverse events occurred
of the plasma Cmax and AUC fell within the range during the different studies.
of 80 % to 125 %.
Figure 1 shows the mean plasma concentration
In vitro studies data of amlodipine obtained in the three
bioequivalence studies. It can be seen that
Dissolution profiles were evaluated using the amlodipine plasma profiles were similar between
same products as in the bioequivalence studies. the test and the reference products, with peak
Studies were carried out using USP apparatus 2 levels around 6 h after drug administration.
(Vankel 7000) at 75 rpm with twelve replicates at
37 ± 0.5 °C. The following media (500 mL) were Table 2 shows the mean values of the
used: pH 1.2 (hydrochloric acid solution), 0.05 M pharmacokinetic parameters, as well as the 90 %
acetate buffer pH 4.5, and 0.05 M phosphate confidence intervals for the different amlodipine
buffer pH 6.8. In all cases, 5 mL samples were products under study. Results showed that the
removed at 10, 15, 20, 30 and 45 min without mean half-life was approximately 49 hours for all
medium reposition. Samples were filtered treatments. In the three bioequivalence studies,
through 0.45 μm HV Durapore® membrane Cmax, AUC0 – 144 h and AUC0 – inf for each pair of
filters (Millipore) and assayed using a previously products (test vs reference) were not statistically
validated spectrophotometric method at 240 nm different (p > 0.05). The relative bioavailability (F)
(UV/VIS Shimadzu spectrophotometer). The was 0.99, 1.03 and 1.03 for the ratios B/R1, C/R1
method was linear from 1 - 12 µg/mL. Intra-day and D/R2, respectively. Moreover, the 90 %
and inter-day coefficients of variation were < 2 confidence intervals of the log transformed Cmax,

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 Jung-Cook et al

Figure 1: Plasma profiles of amlodipine besylate after the administration of the different products in
bioequivalence studies, (R1 VS B and R1 VS C single oral dose of 10 mg, R2 VS D single oral dose of 5 mg).
Keys: ● R1, ○ B,  C,  D, ■ R2

AUC0 – 144 h and AUC0 – inf in each set of studies dissolved within 15 min). Nevertheless when pH
were within the range of 80 – 125 %. On the 6.8 was used, neither the reference nor the test
basis of the above analysis, the test products products B and C met the criteria for rapidly
were considered bioequivalent with the innovator dissolving products (> 85 % dissolved within 30
product. In the different studies, the intra-subject min). Under these dissolution conditions, all the
coefficient of variation for Cmax was 11.4, 10.9 test products had a higher dissolution rate than
and 11.6 %, while the values for AUC0–144h were the reference product and therefore none of them
15.4, 12.7 and 10.9 % (R1 vs B, R1 vs C and R2 met the (f2) acceptance criteria with values of 37,
vs D), respectively. 41 and 39 for products B, C and D, respectively.

In vitro results Due to the low percentage of amlodipine

dissolved at pH 6.8 for most of the products, a
Figure 2 illustrates the release properties of the solubility study of the drug substance was
amlodipine besylate products in the different performed. The results showed that the dose of 5
dissolution media. It can be seen that at pH 1.2 mg of amlodipine is completely soluble at this
and 4.5, all the products fulfilled the criteria for pH.
very rapidly dissolving products (> 85 %

Table 2: Mean pharmacokinetic parameters and confidence Intervals using ln-transformed data in the three
bioequivalence studies after oral administration of amlodipine besylate

R1 vs B R1 Mean±SD) B Mean±SD Confidence Intervals Power

Single oral dose (10mg)
-1
Cmax (ngmL ) 8.4±2.3 8.3±2.0 93.24-104.37 0.99
-1
AUC0→tlast(nghmL ) 419.6±44.7 415.8±128.6 93.68-109.11 0.99

AUC0→inf(nghmL )
-1 499.1± 93.4 479.8±158.5 92.22-102.98 0.99
tmax (h) 7.3±2.4 7.1±1.6
t1/2 (h) 48.4±14.1 45.5±12.2
R1 vs C R1 C
Single oral dose (10mg)
-1
Cmax (ngmL ) 7.8±1.8 8.3±1.8 96.83-107.91 0.99
-1
AUC0→tlast (nghmL ) 398.8±86.8 409.2±101.1 99.30-112.63 0.99

AUC0→inf(nghmL )
-1 459.7±103.2 476.3±131.4 97.53-106.17 0.99
tmax (h) 7.4±2.8 7.4±3.1
t1/2 (h) 49.4±16.9 47.6±11.9
R2 vs D R2 D
Single oral dose (5mg)
-1
Cmax (ngmL ) 4.5 ±1.1 4.4±1.2 93.04-104.36 0.99
-1
AUC0→tlast (nghmL ) 198.6± 46.1 200.5±46.5 96.03-105.70 0.99

AUC0→inf(nghmL )
-1 234.6±66.5 232.2 ± 61.6 93.85-104.50 0.99
tmax (h) 5.6±0.8 5.5 ± 0.8
t1/2 (h) 51.0±16.7 48.7 ± 11.5

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 Jung-Cook et al

Table 3: Drug dissolved at pH 6.8 (mean ± RSD) in batches of reference product (R3, R4 and R5) at different
conditions of agitation, media volume and apparatus

Variable % Dissolved R3 R4 R5
at pH 6.8 (mean ± RSD) (mean ± RSD) (mean ± RSD)
Apparatus 2, 500 mL, 75 15 min 68±4 63±10 58±4
rpm 30 min 79±3 73±8 68±4

Apparatus 2, 900 mL, 75 15 min 79±7 76±3 78±3

rpm 30 min 87±6 86 ±3 86±3

Apparatus 1, 900 mL, 100 15 min 91±2 94±4 88±1

rpm 30 min 95±3 99±4 93±3
RSD: Relative Standard Deviation

Figure 2: Release profiles of amlodipine in HCl 0.1N, pH 4.5 and pH 6.8.

Keys: ● R1, ○ B,  C,  D, ■ R2

Taking into account the low dissolution of the performed to determine the release of amlodipine
reference product at pH 6.8, we decided to Besylate tablets using various dissolution
compare the performance of three additional conditions, and results are discordant. Thus,
batches (R3, R4 and R5) in this medium, using Shohin et al [13] evaluated the dissolution
apparatus 2 at 75 rpm and 500 or 900 mL of characteristics of the reference product and one
dissolution media or apparatus 1 at 100 rpm and product marketed in Russia, using 500 mL of
900 mL of media. Table 3 shows the results USP buffer solutions at pH 1.2, 4.5 and 6.8 and
obtained. It can be see that when 500 mL of apparatus 2 at 75 rpm. They found that the
media were used, the dissolution behavior was products dissolved very rapidly at pH 1.2 and
consistent with those previously obtained with 4.5, while at pH 6.8 they behaved as rapidly
batches R1 and R2, with low percentage dissolving products and dissolution profiles were
dissolved at 30 min. Nevertheless when 900 mL comparable.
of media and apparatus 2 was used, batches
complied with the rapidly dissolution criteria. In Akinleye et al [19] evaluated the dissolution
the case of apparatus 1, the products dissolved profiles of two generic products of amlodipine
more than 85 % in 10 minutes, and therefore available in Nigeria, and the reference product
complied with the acceptance criteria for very (Norvasc®) using apparatus 2 at 50 rpm and 900
rapidly dissolving products. mL of buffers at pH 1.2, 4.5 and 6.8. They found
that in all media, dissolution was low, and hence
DISCUSSION none of the products complied the biowaiver
criteria for very rapidly or rapidly dissolving
The Biopharmaceutical Classification System tablets. The f2 test showed that the release of
(BCS) provides a scientific framework to one of the generic products (B) was similar to the
determine either the requirement of innovator product in all media (f2 ≥ 50), while the
bioequivalence studies for generic products or if similarity factor f2 of the other generic product (A)
in vitro data can be applied to support a waiver at pH 4.5 was lower than 50 due to the rapid
for an in vivo study [17,18]. With regard to dissolution of the generic product. On the other
amlodipine, different studies have been hand, Feroz et al [20] evaluated the dissolution

Trop J Pharm Res, September 2018; 17(9): 1689

 Jung-Cook et al

characteristics of six different brands of Posgrado (PAIP 50009137), Facultad de

amlodipine besylate 5 mg tablets in 900 mL of Química, UNAM.
different dissolution media (water, pH 1.2, 4.5
and 6.8) using apparatus 2 at 75 rpm. They Conflict of interest
found that under biowaiver conditions, all
products tested behaved as very rapidly No conflict of interest is associated with this
dissolving products, and therefore they were work.
considered equivalent.
Contribution of authors
To our knowledge, this is the first report in which
the in vivo as well as the in vitro characteristics of
We declare that this work was done by the
amlodipine besylate under biowaiver conditions
author(s) named in this article and all liabilities
were evaluated. In vivo studies showed that after
the oral administration of amlodipine, Cmax and pertaining to claims relating to the content of this
tmax values were similar to those reported [21,22]. article will be borne by the authors. All authors
The results also revealed that the three generic read and approved the manuscript for
products were bioequivalent to the innovator publication.
product; however, the in vitro dissolution profiles
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