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ISSN: 0975 -8542
Journal of Global Pharma Technology
Available Online at: www.jgpt.co.in
REVIEW ARTICLE
©2009-2020, JGPT. All Rights Reserved 574
Development of Extemporaneously Prepared Captopril Oral
Dosage Forms - A Comprehensive Chronological Study
Ayman M. Al-Qaaneh1,2* , Ebtesam A. Al-Suhaimi3,4 , Ali A. Rabaan5 , Zagit Z.
Gaymalov6
1Department of Genetic Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin
Faisal University, Dammam 31441, Saudi Arabia.
2Pharmacy Services Department, Johns Hopkins Aramco Healthcare (JHAH), Dhahran 31311, Saudi Arabia.
3Biology Department, Science College, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia.
4Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam
31441, Saudi Arabia.
5Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare (JHAH), Dhahran 31311, Saudi Arabia.
6 Earlystage OÜ, Lasnamäe linnaosa, Sepapaja tn 6, Harju maakond, Tallinn, Estonia 15551
*Corresponding Author: Ayman M. Al-Qaaneh
Abstract
Captopril is an Angiotensin-converting enzyme inhibitor, its effectiveness as an antihypertensive agent
and in the treatment of several cardiovascular conditions in neonates and children has been proved
clinically. Unfortunately, in many countries, it is available as a solid dosage form only. As this does not
satisfy the needs of these patients in terms of dosage and pharmaceutical formulations,
extemporaneously prepared formulations represent the only available solution for this situation. Many
attempts have been made to study the different factors that may affect the stability of captopril in oral
liquid formulations, aiming to design a formula with maximum stability profile. Although there is still
debate about the effect of some factors on captopril stability, other factors have a clear role. Low storage
temperature, acidic media (up to pH 4), use captopril powder, absence of heavy metals, increase drug
concentration, sugar-free vehicle, decrease oxygen contents in the formulation, and excipients such as
chelating agents and antioxidants are well known to increase captopril stability. Varies type of
extemporaneously prepared dosage forms (liquid, powder, or tablet) with different formulations have
been prepared and studied. Unfortunately, the stability of captopril in these preparations has been
highly variable and sometimes conflicting results obtained, reflecting the sensitivity of captopril to a
variety of factors that have not yet been completely identified. This review discusses these factors and
extemporaneously prepared formulations in a comprehensive chronological way.
Keywords: Captopril, extemporaneous preparation, Drug stability, Pharmaceutical formulation, Drug
compounding.
Introduction
Captopril is the first Angiotensin-Converting
Enzyme (ACE) inhibitor available as an oral
dosage form. As a result of this inhibitory
activity, it prevents the conversion of
angiotensin-I to angiotensin-II, making it an
effective antihypertensive drug and can be
used in the treatment of several
cardiovascular conditions that affect adults
and children [1, 2].
Since captopril is not commercially available
in a liquid dosage form and the conventional
tablets available in the market (12.5 mg, 25
mg, and 50 mg) do not satisfy the needs of
infants and small children in term of low
doses required by these group of patients and
as a suitable pharmaceutical formulation, the
extemporaneously prepared captopril oral
powder or liquid dosage forms represent the
only solution for this problem.
Ayman M. Al-Qaaneh et. al.| Journal of Global Pharma Technology | 2020| Vol. 12| Issue 06 |574-586
©2009-2020, JGPT. All Rights Reserved 575
However, although extemporaneously
prepared captopril oral preparations provide
dose consistency, which warrants a proper
adherent to the therapy plan, it also
possesses some limitations such as;
physicochemical stability of the prepared
dosage forms as well as microbial
contaminations, especially when it is
prepared in a liquid dosage form. This review
discusses the development of
extemporaneously prepared captopril oral
dosage forms and the limitations
accompanied with each formula and
preparation in a comprehensive systematic-
chronological way.
Captopril as a Powder and Aqueous
Dosage Forms
Although the use of extemporaneously
prepared captopril oral solution appeared in
the literature since 1983, in a letter sent to
clinical pharmacy journal (discontinued in
1993) from Iafrate et al. [3], it is believed that
its use was started before that time [4-6]. The
first attempt to study the stability of
captopril in the aqueous system was made by
Timmins et al., by assessing the stability of
captopril powder in acidic (pH 2) and alkaline
(pH 8.5) aqueous solutions, its mode of
degradation, the oxidative and hydrolytic
degradation products under these conditions,
and the effect of different buffers (pH range
2.1-5.6) on the rate of captopril oxidation.
Revealing that oxidation is the most
predominant route of captopril degradation
over a wide range of pH values, with
maximum stability occurs at pH below 4.
Also, they found that while antioxidants (e.g.,
Propyl gallate) and chelating agents (e.g.,
Sodium edetate) provide protection against
captopril oxidation and are necessary in
developing stable formulations, contaminant
trace metal ions (e.g., copper and iron) in
solution formulation increase oxidative
degradation rate [7].
These results are confirmed after five years
in a study done by Lee & Notari by studying
the kinetics and the mechanism of captopril
oxidation in aqueous solution under
controlled oxygen partial pressure at a pH
range of 6.6 to 8.0 at 32°C, with and without
the addition of cupric ions [8]. Similar to
what reported by Timmins et al. 1982 [7],
this study pointed out that oxidation is the
main pathway of captopril degradation with
captopril disulfide is the only degradation
product under all study conditions.
Furthermore, by studying the rate of
captopril oxidative-degradation, it indicated
that in addition to being pH-dependent, it
also depends on the initial captopril
concentration, presence of other trace metals,
and oxygen partial pressure. Kinetically, this
study proved that Captopril degradation shift
from first-order kinetic to zero-order kinetic
with the decrease in captopril concentration
(The exact concentration at which this kinetic
transition occurs is a function of different
studied factors, such as; pH, oxygen partial
pressure, and cupric ion concentration),
increase oxygen contents in the prescription
bottle, and presence of contaminant copper
ions while the first-order degradation profile
predominates as pH value increases.
Adding different chelating agents (EDTA and
8-hydroxyquinoline) to the captopril solution
inhibits the oxidation process to 50 hours in
comparison to the control that oxidized
entirely in 10 hours [8]. The first clinical
study conducted by using extemporaneously
prepared oral captopril solution for treating
hypertension in neonates was done by O'Dea
et al. In which the treated patients
administered captopril solution via
nasogastric tube after dissolving the 25mg
tablets in water. Because the prepared
solution has a short half-life, he prepared a
new solution just immediately before each
dose [9].
As its use in clinical practice continues to
present a promising result, especially in
neonates and children [10-16], this created
an increased need of individualized doses
with more extended stability profile.
Taketpmo et al. studied the stability of
triturated Captopril 12.5 mg tablets in
lactose powder papers to a final
concentration of 0.02% (w/w) in three
different storage containers stored at room
temperature (25±2 °C), protected from light
and analyzed at different time intervals for
up to 24 weeks.
By using stability-indicating high-
performance liquid chromatography method,
all captopril powder papers stored in class
"A" prescription vial and Moisture
Proof Barrier bags were stable for the entire
period of the study (24 weeks).
Ayman M. Al-Qaaneh et. al.| Journal of Global Pharma Technology | 2020| Vol. 12| Issue 06 |574-586
©2009-2020, JGPT. All Rights Reserved 576
In comparison, captopril powder papers
stored in plastic zip-lock bags showed a
degradation product (captopril disulfide) in
one sample at 24 weeks. However, none of
the samples at all storage conditions lost
more than 10% of its initial captopril
contents during the first 12 weeks of the
study [17].
Furthermore, after two years, Pereira and
Tam used the Arrhenius plot to calculate the
time required for captopril 1 mg/mL oral
solutions to reach 90% of its original
captopril concentrations. Solutions were
prepared from tablets in tap water, stored at
various temperatures (5, 25, 50, and 75°C),
and analyzed for captopril concentration for
up to 28 days using stability-indicating
HPLC method.
Calculated shelf lives were 27, 11.8, 3.6, and
2.1 days, respectively. Although formulation
was prepared using tap water, the authors
did not study their microbial burden, and the
used assay method was unable to detect
captopril disulfide dimer, which represents
the only degradation product of captopril
under the conditions of the assay [18]. It's
worth mentioning here that the results of
this study cannot be universalized as the
contents of tap water can vary significantly
from one source to another, e.g., the
concentration of heavy metals such as copper
and iron, which are known to affect the
stability of captopril in solution.
Also, in the same year, Pramar et al. during
his search to determine the shelf life of
Captopril 5 mg/mL in some aqueous systems
stored for up to 27 days at 5°C and 25°C in
amber-colored glass bottle analyzed using
stability-Indicating HPLC method,
discovered that captopril oral liquid prepared
in water did not follow any known order of
reaction kinetic and was more stable at both
temperatures than captopril oral liquid
prepared in syrup (follow first-order kinetic),
with maximum stability occurred at 5°C.
Additionally, captopril oral liquid prepared
using the powder in water was more stable
than the one prepared using tablets with
shelf lives of 27 days and 20 days,
respectively, at 5°C. The author attributed
this decrease in shelf life to the tablet's
excipients that may adversely affect the
stability of captopril in the solution [19]. In
contrast to what was mentioned by Pereira
and Tam [18], the developed assay method
was sensitive and able to differentiate
captopril disulfide.
Also, although captopril concentration was
less than 90% of its initial concentrations,
solutions prepared from the water had a foul
odor and signs of fungal infection after 18
days of storage. These results vary from the
results of Anaizi & Swenson who conducted
an experiment to compare the stability
profile of captopril 1 mg/mL solution
prepared from Captopril 25 mg tablets in
sterile water for irrigation and in the tap
water for up to 28 days at 5°C protected from
light, using a stability-indicating (HPLC).
In this experiment, they found that captopril
degrades to captopril disulfide at a markedly
faster rate in tap water than in sterile water
for irrigation, and by using graphical
analysis of the stability data, he calculated
three days shelf life for captopril solution
prepared in sterile water for irrigation at 5°C
protected from light. Also, he found that
adding citric acid at a concentration of 40
mg/mL to the captopril 1 mg/mL solution
prepared in sterile water for irrigation stored
at 5°C protected from light does not influence
on the captopril stability [20].
As Lee & Notari reported that the stability of
captopril powder in aqueous solution
increases with increasing concentration [8],
Chan et al. conducted an experiment to
figure if this applies to captopril solution
prepared from the tablet as well. In this
experiment, they studied the stability profile
of two captopril aqueous solutions prepared
from Captopril 25 mg tablets at two different
concentrations ( 0.1% and 1%) and once
captopril aqueous solution (1%) prepared
from captopril powder. All three samples
were prepared in sterile water for irrigation,
stored in sterile glass containers, and
protected from light at (20-26°C). samples
were analyzed for captopril and captopril
disulfide for up to 28 days using stability-
indicating HPLC method.
This experiment presents the first attempt
where microbiological assay tests have been
done for extemporaneously prepared oral
liquid dosage forms in which the author
tested the sample against two cultures (Acid-
fast bacilli and fungal cultures) [21]. The
results of this experiments varied from Lee &
Notari's results, in which captopril solution
prepared from the tablet at a concentration of
1% was less stable (< 90% of its initial
Ayman M. Al-Qaaneh et. al.| Journal of Global Pharma Technology | 2020| Vol. 12| Issue 06 |574-586
©2009-2020, JGPT. All Rights Reserved 577
concentration at 14 days with crystal
formation) than the solution prepared from
the tablet at a concentration of 0.1% (≈98% of
its initial concentration at 28 days) [8], the
author referred this instability accompanied
with a higher concentration of captopril
prepared from the tablets to the presence of
metal ions in the table excipients which were
absent in captopril solution prepared from
captopril powder. Captopril prepared from
powder at a concentration of 1% maintains
its stability all over the study period (≈ 100%
of its initial concentration at 28 days).
Regarding microbiological burden assay, all
cultures were negative for bacterial and
fungal growth [21].
Captopril in Simple Vehicles
Nahata et al. conducted two experiments to
study the stability of captopril in four
different liquid dosage forms; I. mixture of
(Syrup: Methylcellulose, 1:1), II. Distilled
water, III. Distilled water contains sodium
ascorbate injection (as an antioxidant at a
concentration of 5 mg/mL), and IV. And
distilled water contains an ascorbic acid
tablet (as an antioxidant at a concentration of
5 mg/mL). All formulas were prepared from
50 mg tablets at a concentration of 1 mg/mL
and stored in glass bottles at 4°C and 21-
23°C protected from light for up 91 days
(formula IV stored for up to 56 days at the
same conditions) and analyzed using
stability-indicating HPLC.
The results revealed that captopril liquid
preparations stored at 4°C have shelf lives of
7, 14, 56, and 56 days for formulations I-IV,
respectively. In comparison, preparations
stored at 21-23°C had a shelf life of 7, 7, 14,
and 28 days, respectively [13, 22]. Also,
Sornchaithawatwong et al. evaluated the
stability of two extemporaneously prepared
captopril formulations; i. Captopril
suspension (1 mg/mL) prepared from
captopril tablets with ascorbic acid 10% (from
tablet) in suspension consisting of
carboxymethylcellulose mucilage 14 mL, 70%
sorbitol 20 mL, purified water 5mL, 10%
methylparaben & 2% propylparaben in
propylene glycol 0.8mL, and syrup qs to 100
mL and II.
Captopril powder for reconstitution (1
mg/mL) prepared from captopril tablets with
ascorbic acid 10% (from the tablet) and stored
as powder form in light-resistant bag, to be
reconstituted upon opening with the same
vehicle mentioned for captopril suspension.
Both formulations (along with the vehicle for
captopril powder for reconstitution) stored in
an amber bottle at 2-8°C and 25-28°C for 28
days, and analyzed for captopril
concentration using HPLC method. Results
showed that at 2-8°C, both formulations are
stable for 28 days. While at 25-28°C, the
suspension was stable for 28 days, while
reconstituted powder for suspension was
stable for seven days only.
The authors postulated the instability of
captopril powder for reconstitution at higher
temperatures to the higher surface area of
powder particles, which make them highly
exposed to moisture in the air, as well as
powder for reconstitution stored in light-
resistant polyethylene bags have some extent
of oxygen permeability, which allows some
oxygen to defuse inside these bags, which
recommend storing dry powder in amber
glass bottles as moisture and air can't pass
through these glass containers.
As a side note, the authors did not specify the
time between captopril powder for
reconstitution preparation and the actual
reconstitution time [2].After the invention of
ready to use sweetening and suspending
agents, Allen and Erickson studied the
stability of captopril tablets 100 mg in three
different liquid dosage forms; I. Mixture of
Ora-Sweet and Ora-Plus (1:1), II. Mixture of
Ora-Sweet SF and Ora-Plus (1:1), and III.
Mixture of Cherry syrup concentrate and
simple syrup (1:4).All liquids prepared at a
concentration of 0.75 mg/mL and stored in
amber plastic polyethylene terephthalate
prescription bottles with a low-density
polyethylene foam cap lining at 5°C and
25°C. Samples were analyzed for captopril
concentration by stability-indicating HPLC
method for up to 60 days.
The results revealed less stability profile of
captopril tablets in sweetened vehicles
compared to the aqueous solutions (data from
previous studies). In which prepared
formulations retained ≥ 90% of its initial
captopril concentration after 14, 10, and 2
days when stored at 5°C, and 7, 2, and 2 days
when stored at 25°C for I, II, and III liquid
dosage forms, respectively [23].
Ayman M. Al-Qaaneh et. al.| Journal of Global Pharma Technology | 2020| Vol. 12| Issue 06 |574-586
©2009-2020, JGPT. All Rights Reserved 578
Later and after one year, Lye et al. studied
the stability of fourteen different Captopril 1
mg/mL liquid formulations prepared from
either powder or 12.5 mg tablets in I & II.
Sterile water for irrigation (powder and
tablets), III & IV. Highly purified water
(Milli Q reagent water) (powder and tablets),
V & VI.
Syrup (sucrose 85 % with preservative)
(powder and tablets), VII & VIII. Sterile
water for irrigation: syrup (50:50) (powder
and tablets), IX & X. 2% Methylcellulose in
sterile water for irrigation (powder and
tablets), XI & XII.4% Methylcellulose in
sterile water for irrigation (powder and
tablets), XIII. Sterile water for irrigation:
syrup (50:50) plus 0.1% (w/v) edetate
disodium (from powder only), XIV.
2% Methylcellulose in sterile water for
irrigation plus 0.1% (w/v) edetate disodium
(from powder only).The liquids were stored at
5°C in amber glass containers. Since trace
metals contaminants available in the vehicles
(syrup and methylcellulose), e.g., iron and
copper, are well known to affect the stability
of captopril in liquid dosage forms, edetate
disodium was added as a chelating agent in
two of the formulation. Samples were
assayed for captopril concentration by
stability-indicating HPLC method for up to
30 days.
Also, they studied the influence of the degree
of methoxy substitution in the
methylcellulose on the stability profile of the
captopril liquid (1 mg/mL) prepared from
powder [24]. Strangely and vary from what
was reported by Pramar et al. and Chan et
al. [19, 21], formulas prepared from captopril
tablets were more stable than formulas
prepared from captopril powder. There was
no significant difference in stability profile
between formulas prepared in highly purified
water (Milli Q reagent water) and formulas
prepared in sterile water for irrigation.
Furthermore, the authors noticed that the
formulation prepared in undiluted syrup was
more stable than formulations, where water
was part of its vehicle or formulas contained
methylcellulose. The author referred the
higher stability of captopril in undiluted
syrup, comparing to the diluted one to the
antioxidant effect of sucrose at higher
concentrations, while low stability profile of
captopril in methylcellulose formula referred
to the direct chemical reaction between them
or due to its metal contaminants.
Regarding methylcellulose type and
concentration, after seven days analysis
results revealed that liquids containing a
higher concentration of methylcellulose or
methylcellulose with higher methoxy
substitution have less stability profile, this is
due to the increased electron density around
the oxygen of the methylcellulose's methoxy
group which make captopril's sulfhydryl
group more susceptible to nucleophilic attack.
Additionally, it's markedly noticed that
edetate disodium increases the stability of
captopril, which explains the vital role of
trace metals in captopril degradations.
The maximum stability of the formulas was
7, 10, 10, 15, 15, 15, 3, 3, unstable, 3,
unstable, 1, 30, 30 days for formulations i-xiv
[24]. In order to assess the hypothesis
proposed by Lye et al. that captopril is more
stable in undiluted syrup due to the
antioxidant effect of its invert sugar contents
(D-(+)-glucose and D-(-)-fructose) [24], Sam
and HO conducted an experiment comparing
the stability profile of captopril 1mg/mL
prepared from powder in five different
concentrations of invert sugar solution (0%
(Milli-Q water), 1%, 10%, 30%, and 85% w/v)
stored at 5°C.
Samples were analyzed for captopril
concentration for up to 30 days using
stability-indicating HPLC method. Results
indicated that Captopril in Milli-Q water (0%
of inverts sugar) was more stable compared
to that in invert sugar solutions (1%, 10%,
30% w/v). In comparison, captopril in 85%
invert sugar solution was more stable than
Captopril in Milli-Q water (0% of inverts
sugar). Although higher stability noticed
with higher invert sugar concentration, the
findings in this study did not support the
hypothesis proposed by Lye et al.
As in general, antioxidants exert their effects
at low concentrations, which not seen here
with low concentrations of invert sugar. The
authors attributed the differences in
Captopril 1 mg/mL stability in solutions
containing different concentrations of invert
sugar to the dissolved oxygen contents in the
formulation, which decreases (oxygen
contents) as the water content of the formula
decrease resulting in a more stable
formulation.
Ayman M. Al-Qaaneh et. al.| Journal of Global Pharma Technology | 2020| Vol. 12| Issue 06 |574-586
©2009-2020, JGPT. All Rights Reserved 579
Using initial rate constant to calculate the
rate of Captopril 1 mg/mL degradation in
invert sugar at 5°C resulted in (5, 3, 3, 4, 20
days) as a shelf life for formulas containing
(0%, 1%, 10%, 30%, and 85% w/v) inverted
sugar [25].
Consequently, as formulations containing a
high concentration of sucrose have a harmful
effect to the teeth of children and the
possibility of its crystallization under
refrigeration, and based on the findings by
Chen et al. as that low concentration of citric
buffer (0.03M) enhances the stability of
captopril in liquid formulations, Liu et al.
studied the stability of Captopril 1 mg/mL
(prepared from powder) in twelve liquid
formulations containing different
concentrations of sucrose with/without citric
buffer adjusted to pH=3 (i-viii) in the
presence of glucose oxidase (antioxidant)
adjusted to pH=4.5 (ix-xii), stored in an
amber glass bottle at 5°C (i-x) and 32°C (xi
and xii).
Formulations were analyzed for captopril
concentration for up to 30 days (i-viii) and
two days (ix-xii) using stability-indicating
HPLC method. Results obtained indicate that
citric buffer at low concentration (0.03M) has
No apparent stabilizing effect on captopril's
formulations do not contain sucrose or
containing 30 % sucrose.
In comparison, the stabilizing effect was
significant on captopril's formulation
containing sucrose at a concentration of 10%
and 85%. By using the degradation rate
constant of captopril in formulation i-viii, the
shelf lives have been calculated to be; 11, 13,
18, 29, 7, 10, 26, and 22 days, respectively.
With maximum stability obtained for
Captopril 1 mg/mL in 10% w/v sucrose in
Milli Q reagent water with 0·03 M citric
buffer. Captopril in formulations containing
glucose oxidase (antioxidant) degraded very
rapidly within the first day of preparation,
signifying its destabilizing effect on captopril
stability, although the results showed its
strong capabilities to remove dissolved
oxygen from formulations [26, 27].
Markoulina et al., used the stability-
indicating HPLC method to assess the
stability of ten Captopril 1 mg/mL
formulations, stored in amber glass bottles at
2-8°C and 20-24°C for 30 days. Formulations
were prepared from either captopril powder
or tablets based on formulas mentioned in
the literature and known to have a
reasonable stability profile (sometimes with
some modification) and were as following; I &
II. Purified water containing 1 mg/mL
disodium edetate (powder/tablet), III & IV.
Purified water containing 5 mg/mL sodium
ascorbate (powder/tablet), V & VI. Purified
water containing 1 mg/mL disodium edetate
and 5 mg/mL sodium ascorbate
(powder/tablet), VII & VIII. Mixture of Ora-
Sweet and Ora-Plus (1:1) (powder/tablet), IX
& X. Purified water only (powder/tablet) [13,
22-24, 26, 28-29]. All formulations were
stable for all study period (3o days) at both
storage conditions except formulations
prepared in a mixture of Ora-Sweet and Ora-
Plus (VII & VIII) were unstable at both
storage conditions and formulation prepared
from powder in Purified water containing 5
mg/mL sodium ascorbate (iii) stored at 20-
24°C.
A formulation consisting of Captopril 1
mg/mL solution prepared from powder in
purified water containing 1 mg/mL disodium
edetate (i) showed the maximum stability
after 30 days of storage and has been selected
for long-term stability study conducted for
two years at 2-8°C and 20-24°C, and one year
at 38-42°C using the same analysis method.
Furthermore, the microbiological assay of
these formulations has been conducted
initially, after six months, and at the end of
the study period. Results revealed that a
modified formula (based on formula
mentioned by Lye et al.) [24] consisting of
Captopril 1 mg/mL solution prepared from
powder in purified water containing 1 mg/mL
disodium edetate (preservative and chelating
agent) is chemically and microbiologically
stable for up to two years in amber glass
bottle stored at 2-8°C and 20-24°C, and 12
months at 38-42°C [30].
Additionally, Imre et al. in their attempts to
study the stability of different captopril 1
mg/mL oral liquid formulations stored at 8
and 19-25°C for 38 days, they found that
formulations containing ascorbic acid are
physically, chemically, and microbiologically
stable for seven days at both storage
temperatures (No further information
available) [31]. Furthermore, Geiger et al.
studied the stability of captopril 0.8mg/mL
prepared from powder in ready to use Syr
Ayman M. Al-Qaaneh et. al.| Journal of Global Pharma Technology | 2020| Vol. 12| Issue 06 |574-586
©2009-2020, JGPT. All Rights Reserved 580
Spend SF suspending vehicle (Sorbitol-,
sugar- and alcohol-free suspending agent)
stored in low-actinic, protect from light
plastic prescription bottle at 2-8°C for up to
32 days, using stability-indicating HPLC
method. The results revealed that the
captopril formulation remained stable for up
to 14 days with captopril concentration
around 95% of its initial concentration, while
it decreased to 86% after 32 days of storage
[32].
Captopril in Advanced Vehicles
Mulla et al. during their survey to determine
the inter hospital consistency of
extemporaneously prepared captopril oral
solutions used to treat children with cardiac
problems in 26 healthcare facilities based on
United Kingdome, they reported the use of
nine different captopril liquid formulations;
Three of the liquid formulations were
procured from "special" manufacturer, where
concentrations vary, and the vehicle
consisting of (i) fractionated coconut oil and
Cab-o-sil (90 days expiry), (ii) Xanthan gum
1% and ascorbic acid (28 days expiry), (iii-a)
suspension diluent containing (xanthan gum
1%, methyl hydroxybenzoate, and
propylhydroxy benzoate) diluted in 1:1 ratio
with water (8 days expiry), and (iii-b)
suspension diluent containing (xanthan gum
1%, methyl hydroxybenzoate, and
propylhydroxy benzoate) diluted in 1:1 ratio
with water and favored with ascorbic acid (28
days expiry).
One formulation obtained from an NHS
manufacturing unit with a concentration of 1,
5, and 12.5 mg/mL in a vehicle consisting of
(iv) Xanthan gum 0.4%, methyl
hydroxylbenzoate, and propylhydroxy
benzoate (35 days expiry). One formulation
was imported from outside the country with a
concentration of 5 mg/mL in a vehicle
consisting of (v) Citric acid, sodium citrate,
disodium edetate, and sodium benzoate (28
days expiry). As well as four formulations
were extemporaneously prepared where
concentrations vary and the vehicle
consisting of (vi) Ascorbic acid and water,
(vii) suspension diluent containing (xanthan
gum 1%, methyl hydroxybenzoate and
propylhydroxy benzoate), (viii)
OraPlus/OraSweet (1:1 ratio), and (ix)
suspension diluent containing (xanthan gum
1%, methyl hydroxybenzoate and
propylhydroxy benzoate) diluted in 1:1 ratio
with water.
All these four formulations were stable for 14
days. Based on the author's investigation,
none of the nine formulas suppliers (either
manufacturer or hospital), except for the
formulation imported from outside the
country, had conducted stability study for
their final product to support claimed shelf
life [33]. For this review, Unfortunately, all
nine mentioned formulas could not be traced
to any valid stability study except for
formulas used to prepare formulation
vi&Viii. In order to come with a new formula
with extended stability, Kristensen et al.
studied the effect of different formulation
properties on the chemical stability of
captopril powder in acidic aqueous solutions
at pH 3.
The studied factors were; (i) captopril
concentration; the effect of captopril
concentration on the stability profile of
captopril in buffer-free water for injection at
low pH stored at 25°C has been studied.
Results showed that an increase in drug
concentration from 1 to 5 mg/mL improves
the chemical stability of captopril. Also,
kinetically, the degradation reaction of
captopril on pure aqueous solution follows
zero-order kinetics at low captopril
concentration, and will change at higher
concentration (≥ 2.5 mg/mL) to a different
model, apparently, does not fit well first-
order kinetic model.
The shelf lives of the prepared solutions
were; 7, 33, and 54 days for concentrations 1,
2.5, and 5 mg/mL stored at 25°C at pH 3. It is
worth mentioning here that a black
precipitate has been noticed after 57 days of
storage for Captopril 5 mg/mL solution, and
73 days for captopril 1 and 2.5 mg/mL
solutions stored at 25°C which expected to be
captopril disulfide degradation product.
(ii) Storage temperature; the decrease in the
storage temperature improved the chemical
stability of the drug. As captopril 1 mg/mL
prepared in aqueous solution found to be
stable up to 26, 7, and 4 days at 2, 25, and
36°C storage temperatures, respectively. (iii)
Mechanism of drug degradation; it has been
postulated that the intramolecular proton
transfer from the captopril thiol group to the
carboxylic group represents the first step in
the captopril oxidative degradation process.
(iv) different solvents; by studying the effect
of different solvents on captopril stability,
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©2009-2020, JGPT. All Rights Reserved 581
Kristensen and colleagues found that
captopril stability depends on the
amphiprotic properties of the solvent used, in
which solvents with proton donor properties
destabilize captopril. In contrast, solvents
with proton acceptors properties stabilize it.
Long-term stability (one year stored at 36°C)
indicated that sugar alcohol solvents such as
glycerol and Sorbitol have a destabilizing
effect on captopril 1mg/mL aqueous solution
adjusted to pH 3 (v) Solvent polarity; the
results of the role of solvent polarity on the
stability profile of captopril are not
consistent, with no clears consensus about
this factor. (vi) solvent viscosity; The authors
studied the stability profile of captopril in
different glycerol concentrations (0-80%)
which represent different solvent viscosities
and found that captopril degradation
increase as the solvent viscosity increase up
to glycerol concentration 50%, then decrease
at higher concentration of glycerol which
indicates that there are many factors more
important than solvent viscosity able to affect
captopril stability at glycerol concentration ≤
50% before viscosity becomes an issue (≥
50%) and reduce drug degradation rate. (vii)
Chelating agents; Long-term stability (one-
year study at 36°C) of captopril 1mg/mL
aqueous solution adjusted to pH 3 indicated
that Na-EDTA at a concentration of 0.1
mg/mL significantly stabilizes the
formulation, which is a tenth of the
concentration mentioned by Markoulina et al.
[34]. (viii) Salt contents; increase salt
contents in the prepared formulations will
promote captopril degradation and
formulation destabilization. (ix) Buffer effect;
citrate buffer and phosphate buffer found to
have a destabilizing effect on captopril
solution at acidic media (pH 3). This
destabilizing effect of citrate buffer is
contradictory to what was mentioned by
previous studies [20, 26-27].
Authors studied the effect of different
concentrations of citrate buffer. They found
that the stability effect of citrate buffer (as a
chelating agent) is dose-dependent, in which
at higher citrate concentration, it forms a
complex formation with drug molecules
rendering them unstable. (x) Oxygen
contents; although oxygen content in water
decrease as the temperature increase, it was
found here that the degradation is
independent on the oxygen level as
temperature increase (xi) combined effect; In
order to study the influence of combined
factors on captopril 1 mg/mL aqueous
solution stability in acidic media (pH 3),
stored at 36°C for one year, an experiment
has been conducted in the presence of Na
EDTA (0.1 or 1 mg/mL), sorbitol (30-35
mg/mL), with/without purged with N2-gas.
The results revealed that Sorbitol
destabilizes the captopril solution, while Na-
EDTA 0.1 mg/mL in the presence of Sorbitol
(35%) is sufficient to stabilize the
formulation. Furthermore, purging prepared
formulation with N2-gas to remove dissolved
oxygen before storage is not crucial as long as
Na-EDTA is present. This step (purging with
N2-gas) becomes significant at a low level of
Na-EDTA (0.1 mg/mL) combined with a
higher level of Sorbitol (35%).
All Captopril 1 mg/mL formulations stored at
36°C in aqueous acidic solution (pH 3)
containing Sorbitol (at a concentration of 0,
20 or 35%) and Na-EDTA (at a concentration
of 0, 0.1 or 1 mg/mL) purged or not purged
with nitrogen gas were stable for 365 days
except for captopril 1 mg/mL aqueous acidic
formulation pH 3 with sorbitol 35% and Na-
EDTA 0.1 mg/mL and Not purged with
nitrogen gas was stable for 188 days [35].
Based on these formulation properties and
After one year, the same team designed a
new extemporaneously prepared captopril 1
& 5 mg/mL oral liquid formulations, using
captopril powder in sterile water for
irrigation with Sorbitol (70%) 287 mg/mL,
disodium edetate 0.1 mg/mL, and sodium
benzoate 1 mg/mL. formulations were
adjusted to pH<4 and stored in amber glass
bottles with headspace air at 21.5-22.5°C for
12 months. captopril concentration was
measured using stability-indicating HPLC
method.
Furthermore, microbiological burden for
bacteria, fungi, and the presence of
Escherichia coli has been studied at 0, 6, and
12 months for 1mg/mL formulation, and at 0
and 12 months for 5 mg/mL formulations.
Also, they studied the stability of Captopril 1
mg/mL (prepared using same constituents)
after one month of simulated daily use, at the
start and the end of the 12 months study
period (from the start of the study to 1 month
of storage and from the 11th to the 12th
month of storage) stored at 2-8°C, as well as
its microbiological quality.
Ayman M. Al-Qaaneh et. al.| Journal of Global Pharma Technology | 2020| Vol. 12| Issue 06 |574-586
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Although the results revealed that all
prepared captopril formulations were
chemically (≥ 98.5% of initial captopril
concentration) and physically stable without
any evidence of microbial contamination
during study periods at all mentioned storage
conditions, captopril 5 mg/mL formulation
showed a slightly sulfurous taste and smell.
Also, results indicate that oxygen content in
captopril formulation is not a factor in its
stability, as air could access the solution
during simulated one-month usage without
any apparent effect [36].
Pabari et al. surveyed the extemporaneously
prepared captopril liquid formulations in
Irland. Then, The stability of the most
commonly used formulation was evaluated
and compared with a newly
extemporaneously prepared fast-dispersing
tablet using stability-indicating HPLC
method.
i. xanthan gum, ii. Water, ascorbic acid, and
xanthan gum, or iii. Ora-sweet: ora-plus,
represent the most commonly used captopril
formulations prepared from tablets. These
formulations could be traced to a valid
formula mentioned in the literature.
Accordingly, The stability of captopril 1, 2.5,
and 10 mg/mL liquid formulations prepared
from the tablet in 0.4% xanthan gum
suspension stored in an amber glass bottle at
2-6°C have been validated using Stability-
indicating HPLC for 56 days. The results
revealed that all captopril formulations were
stable for up to 7 days, irrespective of the
captopril concentration.
Where the concentration of captopril in all
formulation was <90 at 14 days analysis,
where the decrease in captopril concentration
was inversely related to the starting
concentration, it is worth mentioning here
that prepared formulations had a slightly
sulfurous to acidic odor, which starts to
increase after seven days of storage and with
an increase in drug concentration, and
become a pungent smell after 14 days and
last over the study period (56 days) making
the formulation unpalatable.
Captopril fast-dispersing 2.5 and 10 mg
tablet have been prepared using captopril
tablet with mannitol 200 (171.4 mg and 123.4
mg, for 2.5 and 10 mg captopril fast-
dispersing tablets, respectively), Crosslinked
Polyvinylpyrrolidone 5% w/w (10 mg),
Magnesium stearate 0.5% w/w (1 mg), and
Raspberry flavor 0.8 w/w (1.6 mg). the total
weight of each prepared tablet was 200 mg.
Then tablets were compressed at 7 rpm and a
compression force of 10 KN and stored at
room temperature till the time of analysis.
Fast-Dispersing tablets found to
disintegrates in less than 32 seconds, with no
sign of sticking or capping and no change in
color or appearance with a consistent weight.
Surprisingly, although Captopril 10 mg Fast
dispersing tablets were stable all over the
study period (56 days), Captopril 2.5 mg
captopril fast-dispersion tablet showed less
than 90% of captopril concentration after 28
days which indicate that the degradation of
captopril in the solid dosage form is, also,
dose-dependent.
Although the authors mentioned Fast-
dispersing tablets as a doable technique to
prepare captopril in the most stable
formulation extemporaneously, this kind of
formulations still needs the availability of
some excipients and compressing machines
that are not available in all hospitals [37].
Casas et al. Surveyed 20 hospitals in Spain
for captopril formulations. Then, formulation
with the maximum stability profile was
selected to validate its physiochemical
stability using stability-indicating HPLC
method.
Accordingly, captopril 1 mg/mL liquid
solution was prepared from powder in
purified water with edetate disodium
0.1mg/mL, stored in amber glass bottles at 2-
8, 23-27, and 38-42°C for up to 90 days.
Results showed that captopril 1 mg/mL oral
solution is more stable at 2-8°C than at the
upper temperature. Also, Although all
captopril formulations were stable for 30
days at all storage temperatures (Retained
100, 98, and 97% of its initial captopril
concentration at 2-8, 23-27, and 38-42°C
storage temperature, respectively), only
formulation stored at 2-8°C retained its
stability profile till 50 days of study (97, 86,
and 82% of its initial captopril concentration
at 2-8, 23-27, and 38-42°C storage
temperature, respectively).
It worth mentioning here that after 50 days,
captopril stored at 25 and 40 C showed signs
of microbiological contamination. At the end
of the study period (90 days), none of the
prepared formulation maintained more than
Ayman M. Al-Qaaneh et. al.| Journal of Global Pharma Technology | 2020| Vol. 12| Issue 06 |574-586
©2009-2020, JGPT. All Rights Reserved 583
40 % of its initial captopril concentration
[38]. Sathapanapitagkit et al. studied the
stability of four Captopril 1 mg/mL
suspension prepared from the tablet in I. 80%
simple syrup (preserved with sodium
benzoate 1 mg/mL), II. 80% simple syrup
(preserved with sodium benzoate 1 mg/mL)
and citric acid (chelating agent and pH
reducer agent) at a concentration of 20
mg/mL, III. 80% simple syrup (preserved
with sodium benzoate 1 mg/mL) and ascorbic
acid tablets (from 100 mg tablet as
antioxidant) at a concentration of 4 mg/mL,
and IV.
80% simple syrup (preserved with sodium
benzoate 1 mg/mL) and ascorbic acid tablets
(from 100 mg tablet as antioxidant) at a
concentration of 5 mg/mL, stored in a. amber
polyethylene terephthalate bottle and b. clear
glass bottle protected from light by
aluminum foil, at 2-8°C for 90 days, and at
30°C for 60 days, formulations were analyzed
using the HPLC method.
The results revealed that adding citric acid
reduced the pH of the suspension to 2.66.
While ascorbic acid reduced the pH to 4.4 and
4.42 for 4 and 5 mg/ml, indicating that the
increase in ascorbic acid concentration has no
apparent effect on the pH of prepared
formulations. Also, an increase in storage
temperature has a destabilizing effect on all
captopril formulations. At 2-8°C, the addition
of citric acid or ascorbic acid (4 or 5 mg/mL)
rendered captopril formulations stable for all
study period (90 days), whereas formulation
without stabilizers remained stable for 74
days.
At 30°C, all formulations showed drug
stability up to 28 days except for the
formulation with citric acid, which found to
accelerate captopril degradation at this
temperature [39]. This destabilizing effect of
citric acid at this temperature varies from
what was discovered by Chen et al
[26].Which attributed to the differences in pH
values of the studied formulations (pH 2.66
and 6). Furthermore, the increase in ascorbic
acid concentration had no significant effect
on captopril stability.
Goes et al. in their attempt to suggest
favorable conditions for the development of
stable captopril formulation, they studied the
compatibility between captopril (powder) and
some pharmaceutical excipients; EDTA, citric
acid, dihydrate sodium citrate, and sucralose
in a solid phase using thermal analysis
methods; differential scanning calorimetry
(DSC), differential thermal analysis (DTA)
and thermogravimetry (TG) analysis. The
results of this thermal analysis revealed that
there is No interaction between captopril
powder and both EDTA and dehydrate
sodium citrate, while there is a possibility of
interaction between captopril and two
excipients; citric acid and sucralose (not
conclusive, need further confirmation by
other methods).
However, both excipients (sucralose and
citric acid) are not determining factors for
captopril stability in aqueous solutions, as
presented later by the results of the stress
test. Furthermore, they studied the influence
of interaction between pH, quality of water,
and chelating agent concentration (EDTA) in
the stability profile of extemporaneously
prepared captopril 5 mg/mL oral solution
prepared from powder.
To do so, they prepared 12 different captopril
5 mg/mL formulations in; Distilled water (I-
VI), or mineral water (VII-XII).Containing;
0.05 mg/mL EDTA (I-III & VII-IX), or 1
mg/mL EDTA (IV-VI & X-XII). At three pH
values; 2.5 (I, IV, VII, and X), 4 (II, V, VIII,
and XI), and 5.5 (Iii, VI, IX, XII). In addition,
Sucralose (sweetener) was added based on
the pH value of formulation (0.15, 0.17, and
0.2 %, for formulations have a pH value of
5.5, 4.0, 2.5, respectively).
All twelve formulations were stored at 58-
62°C (stress test) and analyzed for captopril
concentration using the HPLC method. The
results of this stress test indicate that the
decrease in the pH value (up to 4), increase
EDTA concentration, and use of mineral
water instead of distilled water render
captopril formulations more stable.
Where higher stability obtained for Captopril
5 mg/ml in mineral water containing 1 mg/ml
EDTA and kept at a pH value of 4. It is
postulated that higher pH values enhance
captopril degradation by promoting its
ionization. While at low pH values (< 4), the
degradation is independent of the ionization
process and defined as acid-catalyzed
degradation. Also, authors attributed the
higher stability of captopril in mineral water
to the presence of some ions in the water that
can interact with metals ions able to degrade
captopril through the oxidative degradation
process.
Ayman M. Al-Qaaneh et. al.| Journal of Global Pharma Technology | 2020| Vol. 12| Issue 06 |574-586
©2009-2020, JGPT. All Rights Reserved 584
It's worth mentioning here that by studying
all factors collectively, results showed that
increase in the concentration of EDTA (from
0.05 to 1 mg/mL) enhances the stability of
captopril on the solution only when other
factors are not supporting captopril stability,
e.g., High pH values or using distilled water.
Also, results showed that captopril
degradation follows zero-order kinetics,
which indicates that captopril degradation is
independent of the captopril concentration in
the solution [40].
Surprisingly, these results vary from what
was mentioned by other studies [34-36].
Furthermore, sucralose, as a sweetening
agent found to has no effect on captopril
stability in aqueous solution. The t90 has been
calculated to be around 6, 8, 2, 6, 14, 4, 13,
14, 5, 15, 16, and 4 days for formulations i-xii
stored at 58-62°C, respectively. In conclusion,
the authors assumed that captopril 5 mg/mL
with EDTA 0.8 mg/mL and a buffering
system consisting of anhydrous citric acid
and sodium citrate dihydrate added to bring
the pH to 3.85 possess the maximum stability
profile.
Bioequivalence of Extemporaneously
Prepared Captopril Formulations
Although there is No bioequivalence study
available for extemporaneously prepared
captopril oral formulations, one open-label
crossover study assessed the bioequivalence
of two ready to use captopril oral liquid
preparations against tablet form in a group of
18 healthy adult volunteers. Results showed
that both ready to use liquid formulations
failed to be bioequivalent to captopril tablets
or each other in terms of maximum plasma
concentration (Cmax) and area under the
curve (AUC), indicating that formulation
substitution should be done with care and
may require close monitoring to the patients
upon formulation substitution [33].
Conclusion
Although captopril is not available as ready
to use Oral liquid preparations for neonates
and children, it is still representing a corn
stone in hypertension and other cardiac
problems treatments in these groups of
patients. Many attempts have been made to
prepare it extemporaneously with a
reasonable stability profile in various types of
vehicles with different pharmaceutical
excipients. Although researchers were able to
do that, the inconsistency of stability results
of the same formulation prepared by different
teams represent the extent of sensitivity of
this drug to a variety of factors. Till it become
available as ready to use oral liquid
formulation, these attempts will continue by
researchers and pharmaceutical industries.
Acknowledgments
The author thanks Prof. Ebtesam Al-
Suhaimi, the Dean of the Institute for
Research and Medical Consultations (IRMC),
Imam Abdulrahman Bin Faisal University.
And Dr. Fuad Al-Ghamdi, Senior Director of
Pharmacy Services Department, Johns
Hopkins Aramco Healthcare (JHAH) for their
continuous support and encouragement. And
Mrs. Ahlam Al-Salih for her support and
critical review.
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