Research on film coating formulation of sustained release pellets of verapamil hydrochloride

Journal OF MILITARY PHARMACO - MEDICINE N04 - 2021 
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RESEARCH ON FILM COATING FORMULATION OF SUSTAINED 
RELEASE PELLETS OF VERAPAMIL HYDROCHLORIDE 
Truong Duc Manh1, Vo Xuan Minh2, Phan Thi Hoa1 
Nguyen Van Bach1, Dinh Dinh Chinh3 
SUMMARY 
Objectives: To determine the optimized parameters of the technical process and the 
adequate excipient ingredients of the pellet film coat which control release to develop the 
basic formula of the sustained release (SR) pellet of Verapamil hydrochloride (VER.HCl). 
Materials and method: Prepare SR VER.HCl pellet with film coating using Mini-Glatt 
fluidized bed; quantify VER.HCl with UV spectroscopy method; examine the effect of excipients 
(EC, HPMC, DBP, TEC and Talc) on the dissolution of SR VER.HCl pellet. Results: With 
excipients EC N20, HPMC E15, HPMC E5, TEC and Talc, the release rate of VER.HCl was 
9.02%, 26.55%, 48.90% and 83.73% at the time of 1, 2, 4 and 8 hours, respectively. 
Conclusion: EC N10, HPMC E15 and HPMC E5 controlled release excipients suitable for 
formula of SR VER.HCl pellet film 120 mg. 
* Keywords: Verapamil hydrochloride; Pellet; Sustained release; Preparation. 
INTRODUCTION 
Verapamil hydrochloride (VER.HCl) is 
a calcium channel blocker used to treat 
angina pectoris, hypertension and 
arrhythmia. VER.HCl is completely 
absorbed in the gastrointestinal tract 
(about 90%), but the bioavailability is only 
20 - 35% due to its rapid metabolism 
through liver. This pharmaceutical 
substances have a short half - life 
(2.8 - 7.4 hours) causing patients to 
administer many times a day [1, 2, 3]. 
Therefore, in order to improve 
bioavailability and reduce the dosing 
frequency for patients, the study of SR 
VER.HCl pellet preparation is essential 
[4, 5]. In the formulation of SR VER.HCl 
pellet, controlled release film coating 
ingredients play a critical role, greatly 
influencing the rate and degree of 
pharmaceutical substance release from 
the drug form and drug bioavailability. 
Through this study, we aimed: To produce 
the results of investigating the effects of 
certain parameters of the technical process 
and controlled release film coating excipient 
as the basis for developing the basic 
formulation of SR VER.HCl pellet film 
120 mg. 
1Vietnam Military Medical University 
2Hanoi University of Pharmacy 
3Military Central Hospital 108 
Corresponding author: Truong Duc Manh (manhxn150@yahoo.com) 
 Date received: 19/02/2021 
 Date accepted: 26/4/2021 
Journal OF MILITARY PHARMACO - MEDICINE N04 - 2021 
 144 
MATERIALS AND METHODS 
1. Materials and equipment 
*Materials and chemicals: VER.HCl 
Standard: Provided by Ho Chi Minh City 
Drug Quality Control Institute (QT242010914, 
concentration 100.52%), Pharmaceutical 
VER.HCl: USP 38 (China), HPMC E6, 
E15: USP 38 (China), Talc: USP 38 (China), 
EC N10, N20: USP 38 (China), DBP: 
USP 38 (India), TEC: USP 38 (China), 
Ethanol 96%: Vietnamese Pharmacopoeia IV. 
*Equipment and tools: Mini-Glatt film 
coating fluidized bed (Germany), Copley 
DIS 8000 dissolution tester (UK), Labomed 
UV-VIS spectrophotometer UVD-2960 
(USA), analytical balance Mettler Toledo 
with readability down to 0.1 mg 
(Switzerland), PHARMATEST PTF E 
abrasion tester (Germany), ERWEKA 
SVM powder and granule tapped volume 
tester (Germany), ERWEKA GWF granular 
tester (Germany), sieve analysis (China) 
and other tools meeting laboratory and 
analytical testing standards. 
2. Methods 
*Preparation of VER.HCl controlled 
release pellets by pan coating technique: 
SR VER.HCl pellet was prepared by 
coating a release control film onto the 
core pellet which is a composition 
including: EC (release control polymer), 
HPMC (creating diffusion channel), DBP, 
TEC (plasticizer), Talc (anti-sticking agent), 
96% ethanol (solvent). The process of 
coating release control film was carried 
out in steps as follows: 
- Prepare coating solution: Soak and 
dissolve completely EC in approximately 
2/3 of 96% ethanol, add HPMC to dissolve. 
Add plasticizer to the solution above, stir 
to homogenize. Crush talcum powder, sift 
through a 125 µm sieve. Add 96% ethanol 
and grind thoroughly, and pull gradually 
into the beaker containing coating solution. 
Stir the solution on a magnetic stirrer for 
about 30 minutes. Filter through a 125 µm 
sieve to obtain a homogeneous coating 
solution. Make up to the needed volume 
with 96% ethanol. The solution was 
stirred continuously on a magnetic stirrer 
throughout the coating process. 
- Put pellets in the coating equipment: 
Dry pellets for about 15 minutes to heat 
up before spraying on the coating. Spray 
the coating solution. Keep spraying until 
coating solution runs out, leave the 
equipment on for another 15 minutes. 
Table 1: Parameters of the coating 
process. 
Spray pressure to be determined 
Spray rate to be determined 
Fluidizing air volume to be determined 
Inlet air temperature 55 ± 5°C 
Outlet air temperature 42 ± 1°C 
Spray gun diameter 1.2 mm 
- The obtained pellets were dried at 
60°C for 6 hours and left overnight for the 
coating film to stabilize, then sifted to 
retain diameter of 0.8 - 1.5 mm. 
- Film coating performance: calculated 
by the formula: 
Film-coating efficiency (%) = 
3
21
m
mm −
 x 100% 
Of which: m1: Total weight of pellet 
after coating (g); 
m2: Weight of core pellet before 
coating (g); 
m3: Weight of solids in the formula of 
film coat (g). 
Journal OF MILITARY PHARMACO - MEDICINE N04 - 2021 
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* Drug content: 
- Test sample: Weigh approximately 2g 
of pellet, grind into fine powder. Precisely 
weigh the corresponding amount of fine 
powder to roughly 50 mg of VER.HCl. 
Transfer to a 50 mL beaker. Add 
approximately 30 mL of pH 7.5 phosphate 
buffer solution. Shake in ultrasonic shaker 
for 60 mins. Transfer to a 50 mL 
volumetric flask, add phosphate buffer of 
pH 7.5 to the mar ... ry out coating each batch of 20g core pellets of VER.HCl. 
Testing results of the film forming polymer concentration were shown in table 5 and figure 1. 
Journal OF MILITARY PHARMACO - MEDICINE N04 - 2021 
 148 
Table 5: Release rate of VER.HCl during EC proportion testing (n = 6; ± SD) 
Release rate of VER.HCl over time (hour) 
Formulations 
1 2 4 8 
CT1 42.08 ± 1.04 72.74 ± 1.66 86.84 ± 1.03 101.19 ± 1.53 
CT2 21.65 ± 1.13 47.43 ± 1.12 67.92 ± 1.98 95.21 ± 1.97 
CT3 17.42 ± 0.76 31.70 ± 0.90 61.20 ± 1.40 83.29 ± 3.35 
CT4 6.91 ± 0.12 8.95 ± 0.43 18.83 ± 0.82 29.76 ± 1.05 
CT5 6.11 ± 0.05 7.18 ± 0.10 11.07 ± 0.37 13.32 ± 0.75 
CT6 5.67 ± 0.02 5.68 ± 0.02 5.82 ± 0.05 6.15 ± 0.07 
USP 41 (%) 2 - 12 10 - 25 25 - 50 > 80 
0
20
40
60
80
100
120
0 1 2 3 4 5 6 7 8 9
Time (hour)
%
VE
R.
HC
l r
e
le
a
se
CT1 CT2 CT3
CT4 CT5 CT6
Figure 1: The release rate of VER.HCl over time during EC proportion testing. 
Increased proportion of both types of EC in the film ingredients reduced the release 
rate of VER.HCl as when the EC proportion increases, the pellet film thickness also 
increases, thereby increasing the diffusion distance leading to a decrease in the 
release rate of pharmaceutical substance to the dissolved medium. With EC N10 film 
forming polymer, all three formulations yielded higher rate of pharmaceutical substance 
release than criteria in USP41. Particularly, at 1 hour, all three formulations CT1, CT2 
and CT3 showed the release rate of pharmaceutical substance higher than 12%. 
4 hours later, it exceeded 50% and these formulations were almost completely 
released 8 hours later. The formulation using 5g of EC (CT3 and CT6), the coating had 
some difficulties due to the increased viscosity of the film-forming suspension resulting 
in pellet agglutination. Thus, EC N10 is not adequate to be used as an ingredient of 
release control VER.HCl pellet film. Replace EC N10 with EC N20, all three 
formulations adequately controlled rate of pharmaceutical substance release. CT5 and 
CT6 gave the lowest rate of drug release due to great film thickness which prevented 
VER.HCl from diffusing into the dissolved medium. After 8 hours, both CT5 and CT6 
yielded rate lower than 15%. CT4 using 3g of EC N20 was capable of controlling 
pharmaceutical substance release. As a result, CT4 was selected for the next studies. 
Journal OF MILITARY PHARMACO - MEDICINE N04 - 2021 
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- Effects of the proportion and type of polymer combination: 
As CT4 gave a relatively small rate of pharmaceutical substance release compared 
to what was required by USP 41, it was necessary to increase the rate of pharmaceutical 
substance release by combining some hydrophilic polymers to create diffusion 
channels on the pellet film to enhance the rate. Based on the formulations designed as 
in table 6, the dissolution is evaluated and presented as results in table 7 and figure 2. 
Table 6: Formulations designed to determine the optimized proportion of polymer 
combination. 
Formulations 
Ingredients 
CT4 CT7 CT8 CT9 CT10 CT11 CT12 
EC N20 (g) 3 3 3 3 3 3 3 
HPMC E6 (% w/w EC) 0 15.0 17.5 20.0 0 0 0 
HPMC E15 (% w/w EC) 0 0 0 0 15.0 17.5 20.0 
DBP (% w/w EC) 6 6 6 6 6 6 6 
Talc (% w/w EC) 50 50 50 50 50 50 50 
EtOH 96% (mL) 50 50 50 50 50 50 50 
Table 7: Released rate of VER.HCl during polymer combination proportion testing 
(n = 6; ± SD). 
Rate of VER. HCl released over time (hour) 
Formulations 
1 2 4 8 
CT4 6.91 ±0.12 8.95±0.43 18.83±0.82 29.76±1.05 
CT7 7.44±0.13 17.89±0.83 38.67±1.16 66.74±1.38 
CT8 16.95±0.85 35.93±0.97 83.77±2.16 93.54±2.16 
CT9 30.06±0.90 50.12±1.56 91.27±4.21 98.66±3.97 
CT10 7.21±0.36 8.73±0.13 16.68±0.79 27.24±1.06 
CT11 8.02±0.11 19.93±0.89 40.23±0.81 70.30±2.52 
CT12 18.02±0.58 28.88±1.15 55.03±1.49 84.34±2.61 
USP 41 (%) 2-12 10-25 25-50 > 80 
0
20
40
60
80
100
120
0 1 2 3 4 5 6 7 8 9
Time (hour)
%
VE
R.
HC
l r
e
le
a
s
e
CT4 CT7 CT8 CT9
CT10 CT11 CT12
Figure 2: The release rate of VER.HCl over time during polymer combination proportion testing. 
Journal OF MILITARY PHARMACO - MEDICINE N04 - 2021 
 150 
Increased amount of HPMC E6 and E15 
enhanced the release rate of pharmaceutical 
substance of the formulation due to an 
increase in the number of pharmaceutical 
substance diffusion channels. The results 
showed that all six formulations increased 
the release rate of pharmaceutical 
substance compared to F4. With both 
types of HPMC used at low levels (CT7 
and CT10), the rate after 8 hours of 
release was lower than 70% as compared 
to high levels (20%), the release rate of the 
formulation exceeded the requirement by 
USP 41. With two types of polymers, 
HPMC E15 controlled release better than 
E5 due to its higher viscosity. Based on 
the obtained results above, CT11 was 
selected (HPMC E15 = 17.5% compared 
to EC) to be used in the next studies. 
- Effects of HPMC E6 and HPMC E15 
proportion: 
Based on HPMC type testing, it was 
found that HPMC E5 with lower viscosity 
would give higher rate of pharmaceutical 
substance release in the first hours while 
HPMC E15 with higher viscosity would 
corrode and swell more slowly enabling it 
to control pharmaceutical substance release 
in hours that follow. Therefore, it is 
necessary to select the combination of 
these two polymers to be used in pellet 
film ingredients. However, since HPMC 
has poorer solubility in ethanol than water, 
an additional 5 mL of distilled water should 
be used to dissolve HPMC. Based on the 
formulations designed as in table 8, the 
dissolution was evaluated and presented 
as results in table 9 and figure 3. 
Table 8: Formulations designed to determine the optimized HPMC E6 and HPMC 
E15 combination proportion. 
Formulations Ingredients 
CT11 CT13 CT14 CT15 
EC N20 (g) 3 3 3 3 
HPMC E6 (% w/w EC) 0 2.5 5.0 7.5 
HPMC E15 (% w/w EC) 17.5 15.0 12.5 10.0 
DBP (% w/w EC) 6 6 6 6 
Talc (% w/w EC) 50 50 50 50 
Distilled water (mL) 5 5 5 5 
EtOH 96% (mL) 50 50 50 50 
Table 9: The release rate of VER.HCl during HPMC E6 and HPMC E15 combination 
proportion testing (n = 6; ± SD). 
Release rate of VER. HCl over time (hour) 
Formulations 
1 2 4 8 
CT11 8.02 ± 0.11 19.93 ± 0.89 40.23 ± 0.81 70.30 ± 2.52 
CT13 9.31 ± 0.45 26.62 ± 0.82 52.12 ± 1.19 83.21 ± 2.70 
CT14 13.65 ± 0.54 30.06 ± 2.21 56.81 ± 0.59 89.30 ± 3.50 
CT15 21.47 ± 0.98 42.33 ± 1.29 65.09 ± 1.44 96.84 ± 3.34 
USP 41 (%) 2 - 12 10 - 25 25 - 50 > 80 
Journal OF MILITARY PHARMACO - MEDICINE N04 - 2021 
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0
20
40
60
80
100
120
0 1 2 3 4 5 6 7 8 9
Time (hour)
%
VE
R.
HC
l r
el
ea
se
CT11 CT13
CT14 CT15
Figure 3: The release rate of VER. HCl over time during HPMC E6 and 
HPMC E15 combination proportion testing. 
Reduced HPMC E15/HPMC E6 increased the release rate of pharmaceutical 
substance of all formulations due to an increase in the weight of HPMC E5 in the 
polymer mixture. The results showed that all three formulations increased the rate 
compared to CT11 (without HPMC E5). CT14 and CT15 (using HPMC E5 at 5% and 
7.5%) which yielded higher release rate of pharmaceutical substance in the first hours 
due to low viscosity accounted for a large proportion in the combined polymer mixture. 
They absorbed water and dissolved quickly creating porous diffusion in pellet film, thus 
released more pharmaceutical substances than CT13 (HPMC E15 = 2.5% compared to 
EC). Based on the findings above, CT13 (HPMC E15 = 2.5% compared to EC) was 
selected to be used in the next study. 
- Effects of plasticizer: 
Testing with two plasticizers, DBP and TEC were conducted. Based on the 
formulations designed as in table 10, the dissolution was evaluated and presented as 
results in table 11 and figure 4. 
Table 10: Formulations designed to determine the optimized plasticizer. 
Formulations 
Ingredients 
CT13 CT16 CT17 CT18 CT19 CT20 
EC N20 (g) 3 3 3 3 3 3 
HPMC E6 (% w/w EC) 2.5 2.5 2.5 2.5 2.5 2.5 
HPMC E15 (% w/w EC) 15.0 15.0 15.0 15.0 15.0 15.0 
DBP (% w/w EC) 6 8 10 - - - 
TEC (% w/w EC) - - - 6 8 10 
Talc (% w/w EC) 50 50 50 50 50 50 
Distilled water (mL) 5 5 5 5 5 5 
EtOH 96% (mL) 50 50 50 50 50 50 
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Table 11: Release rate of VER.HCl during plasticizer testing (n = 6; ± SD). 
Release rate % of VER. HCl over time (hour) 
Formulations 
1 2 4 8 
CT13 9.31 ± 0.45 26.62 ± 0.82 52.12 ± 1.19 83.21 ± 2.70 
CT16 8.99 ± 0.14 19.31 ± 0.59 42.16 ± 1.34 76.11 ± 1.84 
CT17 8.58 ± 0.42 17.71 ± 0.88 39.56 ± 1.27 69.35 ± 2.97 
CT18 10.45 ± 0.36 30.51 ± 1.28 50.04 ± 1.70 86.56 ± 3.88 
CT19 12.71 ± 0.43 30.09 ± 1.23 55.04 ± 1.93 90.49 ± 3.60 
CT20 18.31 ± 0.85 39.29 ± 1.53 58.75 ± 1.68 97.09 ± 4.32 
USP 41 (%) 2 - 12 10 - 25 25 - 50 > 80 
0
20
40
60
80
100
120
0 1 2 3 4 5 6 7 8 9
Time (hour)
%
VE
R.
HC
l r
el
ea
se
CT13 CT16 CT17
CT18 CT19 CT20
Figure 4: Release rate (%) of VER. HCl over time during plasticizer testing. 
 Increased proportion of DEP in pellet film formulations would reduce film 
permeability as DEP, a known hydrophobic plasticizer, lower pharmaceutical 
substance release rate. Specifically: CT16 and CT17 with large DEP proportions 
reduced pharmaceutical substance release rate more clearly than CT13. These two 
formulations released less than 80% pharmaceutical substance after 8 hours. In the 
case of TEC plasticizer, a hydrophilic plasticizer, higher proportion of TEC would result 
in higher rate of pharmaceutical substance release. During the preparation process, 
DBP was also found to be difficult to dissolve in 96% ethanol, the coating solution 
easily formed a sheen on the surface. It was difficult for DBP to disperse to uniformly 
plasticize the film surface. Based on the findings above and to be in line with the USP 
41 standard on solubility, CT18 with TEC proportion of 6% of EC weight is selected to 
be used in the next study. 
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- Effect of anti-sticking agent: 
Testing out formulations with different talc proportions as shown in table 12 and 
coating on 20g pellets with 50 mL of coating solution containing approximately 10% 
solids with similar coating performance. Dissolution evaluation results are shown in 
table 13 and figure 5. 
Table 12: Formulations designed to determine the optimized anti-sticking agent. 
Formulations 
Ingredients 
CT18 CT21 CT22 CT23 
EC N20 (g) 3 3 3 3 
HPMC E6 (% w/w EC) 2.5 2.5 2.5 2.5 
HPMC E15 (% w/w EC) 15.0 15.0 15.0 15.0 
Talc (% w/w EC) 50 60 40 30 
TEC (% w/w EC) 6 6 6 6 
Distilled water (mL) 5 5 5 5 
96% EtOH (mL) 50 50 50 50 
Table 13: Release rate of VER.HCl during anti-sticking agent testing (n = 6; ± SD). 
Release rate % of VER. HCl over time (hour) 
Formulations 
1 2 4 8 
CT18 10.45 ± 0.36 30.51 ± 1.28 50.04 ± 1.70 86.56 ± 3.88 
CT21 22.90 ± 1.02 46.90 ± 2.03 79.54 ± 3.09 97.33 ± 3.69 
CT22 9.02 ± 0.14 26.55 ± 1.20 48.90 ± 1.42 83.73 ± 2.70 
CT23 32.65 ± 1.24 60.11 ± 1.65 90.59 ± 3.37 98.18 ± 4.09 
USP 41 (%) 2 - 12 10 - 25 25 - 50 > 80 
0
20
40
60
80
100
120
0 1 2 3 4 5 6 7 8 9
Time (hour)
%
VE
R.
HC
l r
el
ea
se
CT18 CT21
CT22 CT23
Figure 5: The rate of VER. HCl released over time during anti-sticking agent testing. 
Journal OF MILITARY PHARMACO - MEDICINE N04 - 2021 
 154 
With a small talc proportion (30%), the 
release rate of pharmaceutical substance 
obtained was more than 30%. The cause 
may be due to the insufficient amount of 
talc which failed to prevent agglutination 
during the coating process, ultimately 
causing agglutination and puncture in pellet 
films. As for the large talc proportion (60%), 
high rate of pharmaceutical substance 
release was also obtained (22.9% after 
1 hour) for which the reason was that an 
excessive amount of talc powder led to 
unstable and cracked films when 
measuring solubility. CT18 and CT22 
have similar solubility curves, the less the 
amount of talc, the slower pharmaceutical 
substance is to release. It was observed 
that CT22 released more slowly and gave 
the release rate of pharmaceutical 
substance at all hours closer to what is 
stipulated by USP 41. 
CONCLUSIONS 
- Having determined the effects of 
certain parameters of the technical film 
coating process to control the release of 
core pellet of VER.HCl. With parameters 
such as: Spray pressure: 1.2 bar, spray 
rate: 0.85 mL/min, fluidizing air volume: 
18 m3/hour, inlet air temperature: 55 ± 5°C, 
outlet air temperature: 42 ± 1°C, spray 
gun diameter: 1.2 mm, the coating process 
gave a high efficiency (73.21%) in which 
pellet fluidizing was stable, uniform and 
smooth surface finish was achieved. 
- Having selected release control 
excipients EC N20 as well as two 
hydrophilic polymers, HPMC E15/E6, 
to create diffusion channels, from which 
the pellet film formulation is formulated 
consisting of: EC N20, HPMC E6, HPMC E15, 
Talc, TEC, distilled water and EtOH 96%. 
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