Vol 10, Special Issue 1, 2018
ISSN - 0975-7058
Research Article
FORMULATION OF SUSPENDING VEHICLES FOR EXTEMPORANEOUS ORAL LIQUID
COMPOUNDING WITH DILTIAZEM HYDROCHLORIDE AS A DRUG MODEL
SUTRIYO*, ZAHRA MEILIA NISA
Department of Pharmacy, Universitas Indonesia, Depok, 16424, Indonesia. Email: sutriyo@farmasi.ui.ac.id
Received: 04 May 2018, Revised: 29 September 2018, Accepted: 15 November 2018
ABSTRACT
Objective: This study aimed to determine the optimum concentrations of a suspending vehicle and develop a physically and chemically stable
formulation containing diltiazem hydrochloride (DTZ).
Methods: Stability testing was performed for 30 days in selected suspending vehicle formulas (Formulas A and E). Physical stability tests were
performed at room temperature, and physical properties (odor and color) and pH values of suspensions were evaluated.
Results: The oral suspensions of DTZ were white and had a drug-like odor, and the pH had significantly decreased during storage. Chemical stability
tests of suspensions were performed at room temperature and 4°C±2°C using ultraviolet-visible spectrophotometry.
Conclusion: The concentrations of DTZ in oral suspensions fluctuated during the storage period, suggesting that the oral suspensions of DTZ are
physically stable but not chemically stable during storage.
Keywords: Diltiazem hydrochloride, Suspending vehicle, Extemporaneous oral liquid formulation, Stability.
© 2018 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.
org/licenses/by/4. 0/) DOI: http://dx.doi.org/10.22159/ijap.2018.v10s1.51
INTRODUCTION
Extemporaneous compounding in liquid vehicles facilitates the
regulation of drug dosing in patients with swallowing difficulties
and can provide greater ease for patients taking the drug [1].
Extemporaneous oral liquid compounding also has several advantages
including masking of the bitter taste and uniformity of drug doses. In
particular, extemporaneous oral liquid compounding will be of great
use in pediatric patients [2,3].
Liquid oral formulation is comparatively quick to prepare and allow
in the dosage form [4]. The lack of oral liquid drug formulations is
problematic for patients with swallowing difficulties such as pediatric
and geriatric patients. These patients require the production of
extemporaneous compounding in liquid vehicles that are compatible
with oral administration [5]. Accordingly, previous pharmaceutical
studies show that formulations of extemporaneous compounding in
liquid vehicles can assist patients with swallowing difficulty [6].
According to surveys conducted at several hospitals in Australia by
Stewart and Tucker, 116 types of prescribed drugs were made into
270 forms of extemporaneous compounding in liquid vehicles, and
these are particularly used for pediatric patients. The preparation of
extemporaneous compounding in liquid vehicles is relatively easy
and can be achieved by simply dispersing the active drug agent into a
suspending vehicle [2].
In Australia, Europe, and the United States, suspending vehicles for
extemporaneous oral liquid compounding have been circulated in the
market as Ora-Plus, which is a physically stable suspending vehicle with
an elegant appearance and a uniform dose [6].
Herein, since the Ora-Plus vehicle is not available in Indonesia, we
developed a suspending vehicle formulation for extemporaneous
compounding using diltiazem hydrochloride (DTZ) as a drug model.
This compound is a calcium channel blocker that is used for the
treatment of angina pectoris and hypertension, particularly in
pediatric and geriatric patients. It is highly protein bound 70–90%
and undergoes extensive first-pass metabolism with relatively poor
oral bioavailability of 40% [7]. We selected this drug as an active agent
because it is compatible with suspending vehicles, which are intended
for the treatment of pediatric and geriatric patients [8]. The present
suspending vehicles were then evaluated for appearance, physical
stability, and dose uniformity in combination with the active ingredient.
METHODS
Formulation of suspending vehicles
To produce suspending vehicles, suspending agents were dispersed in
water and then stirred using a homogenizer. Preservative agents were
then dissolved in solutions containing sufficient amounts of propylene
glycol and were then added to suspending solutions. Mixtures were then
homogenized using a homogenizer. Subsequently, buffer was dissolved
in aquadest and was added to mixtures of suspending and preservative
agents. After mixing using a homogenizer, dimethicone was added and
mixed with the suspending agent, buffer, and preservative. Calcium
sulfate was then dissolved in residual propylene glycol and was
incorporated into the mixture using the homogenizer. Finally, sufficient
volumes of aquadest were added quickly with stirring (Table 1).
Evaluations of suspending vehicles
Sedimentation volumes
Sedimentation volumes are ratios of the final volume of the sediment
formed to the initial volume of the suspension vehicle before settling
and are calculated using the following formula:
F (%)=100 Vu/Vo,
Where, F is the sedimentation volume, Vu is the final volume of sediment,
and Vo is the initial volume of the suspension vehicle before settling.
To determine sedimentation volumes, 50-mL aliquots of the suspending
vehicle were transferred to a measuring cup and sediment formation
was monitored during storage for 1, 5, 10, 15, 20, 25, and 30 days [9].
The 2nd Physics and Technologies in Medicine and Dentistry Symposium (PTMDS), Universitas Indonesia. Depok, Indonesia
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Int J App Pharm, Vol 10, Special Issue 1, 2018
Table 1: Suspending vehicle formulations
Material components
Microcrystalline cellulose
Sodium carboxymethylcellulose
Xanthan gum
Carrageenan
Calcium sulfate
Methylparaben
Potassium sorbate
Citric acid
Sodium dihydrogen phosphate
Dimethicone
Propylene glycol
Aquadest
Formula (%)
A
B
C
D
E
F
G
0.5
0.5
0.1
0.5
0.4
0.03
0.1
0.3
0.1
0.5
10
ad 100
3
0.5
0.4
0.03
0.1
0.3
0.1
0.5
10
ad 100
3
0.1
0.4
0.03
0.1
0.3
0.1
0.5
10
ad 100
3
0.75
0.4
0.03
0.1
0.3
0.1
0.5
10
ad 100
0.5
0.1
0.4
0.03
0.1
0.3
0.1
0.5
10
ad 100
0.5
0.75
0.4
0.03
0.1
0.3
0.1
0.5
10
ad 100
0.1
0.75
0.4
0.03
0.1
0.3
0.1
0.5
10
ad 100
Redispersion
50 mL aliquots of suspending vehicle were placed into glass bottles
and were stored at room temperature for 1 month. On days 1, 5, 10,
15, 20, 25, and 30, redispersion tests were performed by shaking and
observing redispersion of the sediments that formed during storage [9].
Comparisons were made in terms of numbers of shakes required to
disperse sediments.
Viscosity tests
Viscosity was tested using a Brookfield viscometer at 100 rpm with
spindles 1 or 2 depending on the viscosity of the suspending vehicle
formulas [10]. Experiments were performed in triplicate and viscosities
were expressed as means [9].
Particle size tests
Particle size testing was performed using a Mastersizer tool, which
calculates particle size distributions in solutions of micron-sized particles.
Experiments were performed 3 times and the data are expressed as mean
particle size distributions for each suspending vehicle.
pH tests
Suspending vehicles were placed in glass beakers and pH values were
measured using a pH meter that had been calibrated using buffer
solutions at pH 4 and 7 [11].
Selection of suspending vehicle formulas
Active substance in the form of diluted DTZ tablets was incorporated
into suspending vehicle formulas, and selected suspending vehicle
formulas A and E were produced. Physical and chemical stability tests
were conducted after 1 month, and DTZ levels in suspending vehicles
were determined using ultraviolet (UV)-visible spectrophotometry.
To produce oral suspensions of DTZ, 24 tablets containing 30 mg of
dilute DTZ were added to 60-mL aliquots of suspending vehicle to give a
concentration of 12 mg/mL (Table 2). Mixtures were then shaken until
DTZ powder was evenly dispersed in suspending vehicle. Sedimentation
volume tests, redispersion tests, viscosity tests, pH tests, and physical
and chemical stability tests were then performed at the indicated times.
Physical stability tests
Physical stability testing was performed at room temperature
(25°C±2°C) with samples of selected suspending vehicle mixtures
containing DTZ. Organoleptic observations (odor and color) were
observed and pH values of vehicles were tested after 0, 3, 5, 10, 15, 20,
25, and 30 days [1].
Determination of DTZ concentrations
Preparation of DTZ standard solution
Standard DTZ powder was weighed and 10-mg samples were added to
100-mL measuring flasks. Subsequently, 50-mL aliquots of aquadest
Table 2: DTZ contents in suspending vehicle
Material components
Total
Final concentration
DTZ tablet 30 mg
Selected suspending vehicle
24 tablet
Add 60 mL
12 mg/mL
DTZ: Diltiazem hydrochloride
were added to the measuring flasks and were sonicated for 15 min.
Flasks were then filled to volume with aquadest to achieve a standard
concentration of 100-μg/mL DTZ, and 10-mL aliquots were then placed
into 100 mL measuring flasks and were diluted 10-fold with aquadest
to a final concentration of 10 μg/mL [12].
Determination of wavelength maxima
Wavelength maxima of the standard 10-μg/mL DTZ solution were
determined using a UV-visible spectrophotometer at a wavelength
range of 200–400 nm. Aquadest was used as the blank solution and a
maximum wavelength of 236 nm was identified for the standard DTZ
solution [12].
DTZ calibration curve
Standard solutions containing 100-μg/mL DTZ were diluted into
6-, 8-, 10-, 12-, 14-, and 16-μg/mL solutions. Absorbance was then
determined using a UV-visible spectrophotometer at 236 nm. The
relationship between absorbance and concentration was expressed as a
linear regression equation and is presented as a calibration curve [12].
Determination of DTZ tablet concentrations
A total of 20 tablets containing 30 mg of DTZ each were weighed
and then powdered, and average weights were then calculated. An
equivalent powder containing 10 mg of DTZ was dissolved in 30 mL of
aquadest using sonication and was then diluted to volume in 100 mL of
aquadest. Subsequently, 5-mL aliquots of the first filtrates were removed
and diluted to 10 μg/mL, and DTZ concentrations were determined in
triplicate at 236 nm using a UV-visible spectrophotometer [12].
Determination of DTZ concentrations in suspensions
Suspensions of 5 mL containing 60 mg of DTZ were extracted in a
separating funnel using 50 mL of chloroform. Mixtures were shaken
for about 1 min and after separation from suspension phases, organic
phases were taken and filtered through Whatman filter paper No. 42.
Filtrates were then dried in a vaporizer plate in an acid cupboard until
the chloroform had evaporated entirely. The resulting residues were
then added to 50-mL measuring flasks and were diluted to volume
in aquadest. Further, dilutions were performed with 1-mL aliquots
of solution in 100-mL measuring flasks to achieve a concentration of
1 μg/mL. DTZ concentrations were then determined at a wavelength of
238.4 nm using a UV-visible spectrophotometer in triplicate [13].
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Chemical stability test
Selected suspending vehicles containing DTZ tablets were stored at
4°C±2°C and at room temperature 25°C±2°C for 1 month [1].
RESULTS AND DISCUSSION
Suspending vehicle formula
Microcrystalline cellulose, sodium carboxymethylcellulose, xanthan
gum, and carrageenan were selected as suspending agents because
the Ora-Plus vehicle contains these four suspending agents. For
comparisons, formulations were prepared using two variations of
suspending materials. Other ingredients that are used as additives
in the formulation of suspending vehicles include calcium sulfate
as a flocculating agent, methylparaben and potassium sorbate as
preservatives, citric acid and sodium dihydrogen phosphate as buffers,
dimethicone as an antifoaming agent, propylene glycol as stabilizing
agent, and aquadest as a solvent.
Evaluations of suspending vehicle
Sedimentation volumes
Observations of sedimentation volumes in the present seven suspending
vehicle formulations were performed after storage for 1, 5, 10, 15, 20,
25, and 30 days (Table 3).
The sedimentation volume of formula A indicated optimal vehicle
characteristics, with no sedimentation at any of the observation times.
These properties are in accordance with those of good suspensions,
particularly because the particles in the vehicle were homogenously
suspended and did not sediment quickly. Sedimentation rates are
inversely proportional to vehicle viscosities. Thus, greater viscosity
prevents the formations of sediments from suspension, as indicated
by the lower sedimentation volumes seen in experiments with
formula A.
The sedimentation volume in formula C was low at 14%, although this
value may in part reflect the density of the formed sediment. Likewise,
formula B had a low sedimentation volume at 22%, and similar to
formula C formed compact and hard caked sediments after prolonged
storage. Although these sedimentation volumes were small, they were
unfavorably difficult to disperse, indicating physical instability of the
suspensions.
Formula E had the second lowest sedimentation value after
formula C, and after addition of DTZ tablets, weak interactions with
suspending agents allowed rapid sedimentation. In contrast with the
aforementioned formulas that form hard cake sediments, sediments
from formula E tended to be stable for short times and were easier to
resuspend with shaking. Hence, given the sedimentation volume after
the addition of DTZ, the best formulation was formula E.
Redispersion
During storage, the suspending vehicle precipitates and the formed
sediment must be redispersed by shaking to ensure appropriate doses
at delivery. Thus, we compared redispersion of suspending vehicle
formulas to rectify the sedimented particle so that with shaking, the
particles in the vehicle can be evenly dispersed again [9].
In comparisons of the seven formulas, those for which formed sediments
could be dispersed by shaking were favored because they did not form
caked sediments after 30 days of storage. Formula A was the easiest
formula to regenerate because it formed less sediment than the other
formulas. Formula A also had favorable redispersion characteristics
of the vehicle. In contrast, formula B required the most agitation to
disperse the sediment evenly, and the sediment formed hard cakes
after longer storage periods. Redispersion of formulas was compared in
terms of numbers of shakes required (Table 4).
Viscosity tests
Viscosity tests were performed on the seven suspending vehicle formulas
with and without DTZ tablets. In these experiments, formula A had the
greatest viscosity, reflecting its four suspending agents. In formula C, high
viscosity was observed due to the combination of cellulose microcrystalline
and xanthan gum, and the latter is known to have a high viscosity degree
at low concentrations. Compared with formula E, which also comprises
a mixture of xanthan gum and sodium carboxymethylcellulose, the
viscosity of formula C was higher. These observations can be explained by
the presence of cellulose microcrystalline at 3% in formula C, compared
with carboxymethylcellulose sodium at only 0.5% in formula E.
Furthermore, the viscosity produced by sodium carboxymethylcellulose
in solutions was higher than that of carrageenan, reflecting the ease of
expansion of the former following dispersion in hot water. Therefore,
dispersion of sodium carboxymethylcellulose in hot water may be causal
of the high viscosity of formulas B and F. When compared with formula B,
however, formula F had lower viscosity than B formula, which contained
3% microcrystalline cellulose, whereas formula F only contained
carrageenan at 0.75%. Formula D had higher viscosity than formula G,
despite having equal carrageenan contents. This can be explained by
the presence of higher cellulosic microcrystalline contents in formula
D then gum xanthan concentrations in formula G. Thus, in decreasing
order of viscosity, the formulas are arranged as follows: C, E, B, F, D, and G
(Table 5).
Particle sizes
D values (4.3) were calculated to indicate average particle sizes of
formulations. Of the seven suspending vehicle formulas, formula E had the
largest particle size, with a D value (4.3) of 234 μm reflecting the mixture
of sodium carboxymethylcellulose and xanthan gum (Fig. 1). Both of these
suspending agents have high degrees of pseudoplasticity and form clear
colloidal solutions when dispersed in water. Furthermore, in the formula G,
which was a mixture of xanthan gum and carrageenan, the resulting
particle size was larger than that of formula C, which comprises a mixture
of xanthan gum and microcrystalline cellulose. Xanthan gum also has a
high degree of pseudoplasticity, but in comparisons of formulas G and C,
particle sizes were greater in G because the carrageenan was dispersed
in warm water to form hydrocolloids. In contrast, dispersion of cellulosic
microcrystalline in water results in comparatively dilute solutions. Formula
D comprised a mixture of cellulose microcrystalline and carrageenan and
had the smallest particle size, with a D value (4.3) of 41.9 μm.
pH tests
In pH tests of the vehicle, pH values decreased after addition of DTZ
tablets to all seven suspending vehicle formulas (Fig. 2). These
Table 3: Percentage sedimentation volumes of suspending vehicle formulas
Day of
observation
Sedimentation volume (%)
Formula A
Formula B
Formula C
Formula D
Formula E
Formula F
Formula G
1
5
10
15
20
25
30
0
0
0
0
0
0
0
22
22
22
22
22
22
22
10
14
14
14
14
14
14
70
66
64
64
64
64
64
22
22
20
20
20
20
20
0
0
0
96
96
94
92
0
96
94
92
86
80
76
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Table 4: Redispersion of suspending vehicle formulas
Days of
observation
Redispersion (Times)
Formula A
Formula B
Formula C
Formula D
Formula E
Formula F
Formula G
1
5
10
15
20
25
30
1
1
1
1
1
1
1
6
15
16
16
16
16
16
6
11
12
12
12
12
12
3
4
4
4
4
4
4
4
5
7
7
7
7
7
2
2
2
2
2
2
2
1
2
2
2
2
2
2
Table 5: Mean viscosities of formulas A–G
Viscosity
Formula
A
B
C
D
E
F
G
Mean value suspending vehicle (cPs)
Mean value DTZ suspension (cPs)
586.67
130.67
116.67
101.67
125
123
88
96
114.67
114.67
97.33
97.33
61.33
101.33
DTZ: Diltiazem hydrochloride
Fig. 1: Particle size distributions of formulas A–G
Fig. 2: Graph of pH ratios between suspending vehicle and suspension after addition of diltiazem hydrochloride tablets
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Int J App Pharm, Vol 10, Special Issue 1, 2018
Table 6: Physical stability tests of Formulas A and E
Days
DTZ tablets were analyzed after 0, 10, 20, and 30 days of storage at
room temperature (25°C±2°C) and in a refrigerator (4°C±2°C).
pH
0
3
5
10
15
20
25
30
Formula A
Formula E
3.83
3.78
3.70
3.62
3.61
3.58
3.56
3.50
3.86
3.68
3.61
3.60
3.59
3.57
3.46
3.47
Table 7: Determinations of DTZ concentrations in suspensions
Condition
Formula
Days
Concentration
(mean) (%)
Room temperature
Formula A
4±2°C
Formula A
Room temperature
Formula E
0
10
20
30
0
10
20
30
0
10
20
30
0
10
20
30
75.11±8.426
91.99±2.817
84.11±0.964
67.09±3.007
90.67±8.614
83.92±3.304
78.11±0.543
66.28±4.773
83.54±1.315
78.85±6.848
62.21±5.066
54.45±1.189
77.48±7.868
83.61±1.769
82.42±5.552
65.97±2.726
4±2°C
Formula E
Absorption spectra of DTZ differed between the 1st and past days
of storage, particularly in formulations formula A and E at room
temperature and in the refrigerator (Table 7). These data indicate that
determinations of drug contents are not quantitative and suggest that
the long extraction process using chloroform, which was performed
with 24 h evaporation, introduces other compounds that can absorb
at the same maximum wavelength, thus influencing determinations at
the time of analysis. In addition, differences in the assay results may
reflect a temporary diffusion process between the suspension and the
organic chloroform phase during shaking for 1 min. This may decrease
concentrations of active substance, with active ingredient remaining
in the chloroform fraction. Nonetheless, chloroform is required to
separate active ingredient from suspensions for the determinations of
concentrations of DTZ in suspensions.
CONCLUSION
The present physical stability test results show that our suspension
carrier is physically stable for 30 days storage at room temperature,
but that DTZ formulations were chemically unstable. In comparisons
of the present formulations, the best suspending oral vehicle for DTZ
was formula A.
CONFLICTS OF INTEREST
All authors declare that they have no conflicts of interest.
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DTZ: Diltiazem hydrochloride
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3.
Physical stability tests
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Determination of DTZ concentrations in suspensions
DTZ concentrations were determined in suspensions using UV-visible
spectrophotometry. Samples of suspending vehicle containing 30-mg
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