Indonesian Journal of Pharmacy

VOL 32 (1) 2021: 43–51 | RESEARCH ARTICLE

Optimization of Hydroxy Propyl Methyl Cellulose and Carbomer in

Diltiazem Hydrochloride Mucoadhesive Buccal Film
Lina Winarti, Bagus Tri Laksono, Lusia Oktora Ruma Kumala Sari

Department of Pharmaceutics, Faculty of Pharmacy, University of Jember East Java Indonesia

Info Article ABSTRACT

Submitted: 07-12-2020 Diltiazem hydrochloride (HCl) is a drug with low bioavailability due to
Revised: 03-02-2021 the high rate of the first-pass metabolism and a short half-life of the drug
Accepted: 13-02-2021 (3-5h); hence, mucoadhesive buccal films were made to overcome this
weakness. The bioavailability of Diltiazem HCl may increase if the buccal
*Corresponding author
Lina Winarti
preparations can make good contact with the mucosa for a sufficient amount
of time. Therefore, in this study, two polymers, Hydroxy Propyl Methyl
Email: Cellulose (HPMC) and Carbomer were combined to obtain good film
lina.winarti@unej.ac.id characteristics, especially in residence time and mucoadhesive strength. This
study aimed to optimize the amount of HPMC and Carbomer needed and
evaluate the release kinetics of Diltiazem HCl from the mucoadhesive buccal
film. The formula was prepared by the solvent casting method and optimized
with the design expert software, while the release kinetics and mechanism
were evaluated using the DDSolver program. The optimum amount of
polymer obtained from optimization was 40mg of HPMC and 10mg of
Carbomer. The FTIR spectra showed there was no interaction between
Diltiazem HCl and other excipients. The dissolution model of Diltiazem HCl
from buccal mucoadhesive film follows Korsmeyer-Peppas. The release
exponent (n) of 0.55 shows a non-fickian/anomalous diffusion release
mechanism. These mechanisms represent drug release controlled by a
combination of diffusion and erosion. This study concluded that the buccal
film was successfully formulated by using a combination of HPMC and
Carbomer with the potential to increase Diltiazem HCl bioavailability and
half-life by increasing its contact time and controlling the release.
Keywords: Diltiazem HCl, HPMC, Carbomer, Mucoadhesive Buccal Film

INTRODUCTION Buccal films are flexible, elastic, and soft but

Hypertension is one of the cardiovascular are still able to stay in the mouth. So the system can
diseases that have a high prevalence in several prolong the duration of the medicine residence
countries in the world (WHO, 2012). Diltiazem HCl time in the buccal absorption site, reduce the
is usually used as antihypertensive, antiarrhythmic, frequency of use (Hagerstrom, 2003), and
and anti-angina. Diltiazem HCl affects smooth modulate the permeability to epithelial tissue by
muscle relaxation from the blood vessels, causing loosening the intercellular junction (Lehr, 1999).
peripheral vascular resistance (Patel et al., 2015). The length of residence time depends on the
Diltiazem HCl has a half-life of 3-5h in the bioadhesive strength of the polymer used (Peh and
body (Sweetman, 2009). If given orally, Diltiazem Wong, 1999). The polymers used for mucoadhesive
HCl will experience the first-pass metabolism; buccal film preparations in this study were
therefore, its bioavailability is low (40%) (Wang et Carbomer and HPMC.
al., 2016). In order to avoid the first-pass Carbomer is an anionic polymer that can
metabolism, Diltiazem hydrochloride has been bind to the mucosa through hydrophobic
formulated into a mucoadhesive buccal film. The interactions, hydrogen bonds, and Van der Walls
buccal film has the advantage of bypass first-pass bonds. It is a polyacrylic acid class polymer which
metabolism; hence, the bioavailability of drugs is insoluble in water and will expand to form a gel
through this route will be better when compared when hydrated (Woodley, 2001). Carbomer has a
with a conventional oral formulation. flexible chain and has non-abrasive characteristics

Indonesian J Pharm 32(1), 2021, 43-51 | indonesianjpharm.farmasi.ugm.ac.id 43

Copyright © 2020 THE AUTHOR(S). This article is distributed under a Creative Commons Attribution-ShareAlike 4.0
International (CC BY-SA 4.0)
 Hydroxy Propyl Methyl Cellulose and Carbomer in Diltiazem Hydrochloride

when it is hydrated, thereby reducing the risk of glycerin. Diltiazem HCl was dissolved in a mixture
tissue damage when it comes into contact with of water:ethanol of 1:5 and NaOH 1N. Diltiazem HCl
friction (Carvalho et al., 2010). solution was then added to a mixture of polymer
HPMC is combined with carbomer because it and glycerin and stirred using a magnetic stirrer for
is a hydrophilic nonionic polymer with 20min at a speed of 100rpm. The film mixture was
mucoadhesive strength lower than anionic poured into the mold and left overnight to remove
polymers (Mortazavi and Moghimi, 2003) but air bubbles. The film in the mold was dried using an
capable to form a flexible film, biocompatible, and oven at 45ᵒC for 24h. The dry film is cut into a size
biodegradable (Byun et al., 2012). HPMC is also a of 2x2 cm (4cm2). The composition of the formula
bioadhesive with excellent water absorption for 16 films (Table I).
capacity and is not easily eroded by saliva (Garg
and Kumar, 2007). According to Roda et al. (2018), Mucoadhesive buccal films evaluation
the use of a combination of HPMC and carbomer Organoleptic property
was the best carrier in buccal patches for the The buccal film's organoleptic properties
delivery of Hydrochlorotiazid and Atenolol observed include color, odor, taste, texture, and
compared with the use of a combination surface conditions.
of Sodium Alginate - HPMC, Carbomer –
Carboxymethylcellulose (CMC Na), or HPMC - CMC Weight uniformity
Na. Three films of each formula were weighed
Based on the previous description, it is using digital scales (Semalty et al., 2008) the mean
essential to determine the effect of HPMC and and standard deviation of the measurements were
Carbomer combination on Diltiazem HCl buccal calculated.
film swelling index, mucoadhesive strength, and
residence time. FTIR analysis and drug release Thickness
study were also conducted to evaluate the release The thicknesses of the three films were
kinetics and mechanism. measured using a micrometer screw gauge at five
different points: in the middle and the four corners
MATERIAL AND METHODS of the film (Semalty et al., 2008). The average and
Diltiazem HCl was a gift sample from Kimia standard deviation (Table II).
Farma company (Indonesia), HPMC K4M,
Carbomer, Glycerin, Ethanol 96%, KH2PO4, NaOH, Folding endurance
HCl were purchased from PT. BrataChem Folding endurance was examined by
(Indonesia), and buccal mucosa of male goats aged repeatedly folding at the same place for up to 300
3-4 years obtained from a nearby slaughterhouse. folds (Alagusundaram et al., 2009).

Table I. The composition of the buccal film Surface pH

Diltiazem HCl formula For determination of surface pH, three films
of each formulation were allowed to swell in 5mL
Materials F1 FA FB FAB of distilled water for 2h on the agar plate/petri-
Diltiazem HCl 0.64g 0.64g 0.64g 0.64g dish. The surface pH was measured by using a pH
HPMC 0.32g 0.64g 0.32g 0.64g meter placed on the surface of the swollen buccal
Carbomer 0.16g 0.16g 0.32g 0.32 g film. The mean value of three readings was
Glycerin 0.3mL 0.3mL 0.3mL 0.3mL recorded (Salehi and Boddohi, 2017).
NaOH 1.6mL 1.6mL 1.6mL 1.6mL
Ethanol 95% 5mL 5mL 5mL 5mL % Drug Content
Distilled water 40mL 40mL 40mL 40mL The drug content determination was
done by dissolving 2x2cm film in 100mL
Preparation of Mucoadhesive Buccal Film of phosphate buffer (pH 6.6), and the absorbance
Diltiazem HCl was observed at a wavelength of 237nm.
The buccal film was prepared by the solvent The film's Diltiazem content was calculated
casting method. Carbomer and HPMC polymers using a calibration curve prepared from
were weighed and then dispersed in distilled water the Diltiazem HCl working standards at 4.1, 6.0,
until a clear gel formed. The mixture of the polymer 8.3, 10.3, and 12.0ppm obtained from
was mixed until homogeneous and added with diluting a 100ppm Diltiazem HCl stock solution.

44 Volume 32 Issue 1 (2021)

Lina Winarti

The percentage of drug content was calculated with Fourier Transform Infrared (FTIR) Analysis
equation 1, and the average of % Diltiazem HCl FTIR analysis aimed to determine whether
content from three films was recorded. there was an interaction shown by HPMC and
Carbomer with Diltiazem HCl. Scanning was done
Experiment Resul content at 4000-600cm-1. Each spectrum was compared
% Content = x100%
Theoretical content and observed for the presence or absence of
................................(1) interactions, as indicated by a fluctuating shift in
the absorption band in the optimum formula (El-
Swelling Index Maghraby and Abdelzaher, 2015).
One film was weighed (W0) and placed on a
petri dish containing 5mL phosphate buffer. The Diltiazem HCl Release Study
film was allowed to expand. The film was then The drug release was evaluated using
weighed (Wt) at intervals of 5, 15, 30, and 60min paddle-type equipment. The study was done using
(Puratchikody et al., 2011). The swelling index was 500mL of phosphate buffer (pH 6.6) as a
calculated using the following equation (2): dissolution medium, temperature of 37±0.5°C, and
stirring speed of 50 rpm. Films containing 40 mg of
Wt – W0 Diltiazem HCl were attached to the object-glass
% Swelling Index =
W0 using cyanoacrylate adhesive. Samples of 5 ml were
.................................(2) taken at certain time intervals (0, 15, 30, 45, 60, 90,
120, 150, 180, 210, 240, 300, 360, 420, 480min)
Mucoadhesive strength followed by replacement of the dissolution medium
Mucoadhesive strength was evaluated using by 5mL. The sample was filtered and analyzed with
the Texture Analyzer by attaching the film to the a UV spectrophotometer at a wavelength of 237 nm
probe's tip. The probe gives a force of 500 gF with (El-Maghraby and Abdelzaher, 2015).
a speed of 0.5mm/s for 60 s (Skulason et al., 2009).
The probe is then lifted at a rate of 1mm/s. The RESULT AND DISCUSSION
force required until the film detaches from the The Physicochemical Characteristics
buccal tissue was recorded in grams force (gF). The composition of the Diltiazem HCl
mucoadhesive buccal film (Table I). The prepared
Mucoadhesive Residence Time films were subjected to different physicochemical
The film was attached to the buccal goat tests such as weight variation, thickness, content
tissue and onto a glass object placed on the edge of uniformity, swelling index, surface pH, in-vitro
a 1000 mL glass beaker. One side of the film was residence time, and in vitro drug release studies.
moistened with phosphate buffer medium pH 6.6. The four-film formulas were transparent, odorless,
The beaker glass was filled with 500mL phosphate slightly sweet, supple, dry, and had a smooth
buffer medium of pH 6.6 at 37ᵒ±0.5ᵒC. The medium surface (Figure 1).
was stirred at 50 rpm and observed for 8h (Patel et The film formulas have uniform weights and
al., 2007; Roda et al., 2018). thicknesses indicated by the p-value > 0.05
(Table II). Film weight and thickness are influenced
Formula Optimization by the amount of polymer used. The more polymer
The swelling index, mucoadhesive strength, used, the higher the film's weight and thickness,
and residence time of Diltiazem HCl mucoadhesive and vice versa.
buccal film were analyzed using design expert Based on the folding endurance evaluation,
software version 11. The optimum formula was all the films had good flexibility indicated by the
obtained from the overlay of the three responses. film's ability to fold up to >300 folds
(Alagusundaram et al., 2009). The values revealed
Optimum Formula Verification excellent film properties.
Predicted responses from the factorial The pH of the film should meet the ideal pH
design to the observation results were compared for buccal application because the acidic or alkaline
statistically with the One-Sample T-test using a pH may irritate the buccal mucosa. The film's
confidence level of 95%. The p-value >0.05 shows surface pH meets the pH range that the buccal
no difference between the predicted responses and cavity can accept (5.5-7) (Patel et al., 2011); hence
the observed responses (Arwani, 2017). no mucosal.

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 Hydroxy Propyl Methyl Cellulose and Carbomer in Diltiazem Hydrochloride

Figure 1. Diltiazem HCl mucoadhesive Buccal Film

Figure 3. Overlay Plot of Three Responses (shown in Yellow)

Table II. Physical evaluation of Diltiazem HCl mucoadhesive buccal films

Film weight (mg) Film thickness (cm) Folding endurance Surface pH % Drug Content
F1 91.7±0.60 0.021±0.001 >300 5.91±0.061 99.16±0.47
FA 95.8±0.25 0.027±0.001 >300 6.00±0.031 97.78±1.08
FB 94.3±0.55 0.025±0.000 >300 5.75±0.059 95.55±1.04
FAB 107.1±1.14 0.029±0.001 >300 5.71±0.051 94.99±1.16

The Calibration Curve The linear regression equation was found to be Y =

The method for determining Diltiazem HCl is 0.0577x – 0.0246, R2 = 0.9995 which depicts the
deemed valid when the accuracy, precision, linearity (Figure 2).
linearity, and detection and quantification limits The content of diltiazem HCl in the film
are within the acceptable values. A serial preparations ranged from 94,99 - 99,16%;
concentration of Diltiazem HCl (4.1–12.0μg/mL) therefore, the four formulas had fulfilled the range
was observed by UV spectroscopy at the λmax of 237 of required levels in the film preparations, which
nm. The calibration curve was the result of are 85-115% (Dixit dan Puthli, 2009). The drug
observed absorbance values plotted to different content in each film will contribute to its
concentrations resulted from the serial dilution. therapeutic effect.

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Table III. The results of three buccal film response for optimization

Swelling index Mucoadhesive strength (gF) Mucoadhesive residence time (min)

F1 2.67±0.06 27.93±1.90 350.0±3.61
FA 4.29±0.17 53.63±2.11 531.3± 3.51
FB 2.79±0.05 29.47±0.81 482.1± 3.51
FAB 3.15±0.11 37.43±2.28 514.7± 4.51

Swelling index The formula optimization and verification

Swelling index measurement aims to The optimum formula was determined from
determine the level of hydration that occurs. The the highest predicting value of three responses
results of the sequential swelling index are as with a desirability index close to one.
follows FA>FAB>FB>F1 (Table III). The use of a Determination of the optimum area is selected
high amount of HPMC and a low amount of based on the overlay plot generated from three
carbomers (FA) gives good film hydration, responses. The optimum area is shown in yellow
providing the best swelling index. Carbomers have (Figure 3), which shows the amount of HPMC and
excellent hydration properties than HPMC, but Carbomer that gives the highest value for the
when used at a large amount, the film will be swelling index, mucoadhesive strength, and
hydrated excessively (overhydration), which residence time. Based on the optimization process,
results in the removal of the polymer chain in the six solutions were obtained, then one solution with
film. It results in eroded and dissolved films, which the highest desirability (HPMC of 40mg and
reduce the swelling index (Morales and McConville, Carbomer of 10mg) was selected as the optimum
2011). formula. The optimum formula verification aimed
to confirm the factorial design-predicted results
Mucoadhesive strength and residence time with the experimental results. Verification was
Mucoadhesive strength and residence done using a one-sample t-test with a confidence
time evaluation aims to determine the film's level of 95%. The predictive response shows no
attachment strength to the buccal mucosa; thus, the significant difference from the experimental result
film does not detach although it is exposed to with a p-value > 0.05.
mechanical forces in the oral cavity (Kumria et al.,
2014). The mucoadhesive strength and FTIR analysis
residence time results (Table III) as follows: FTIR spectra of the optimum formula,
FA>FAB>FB>F1. Diltiazem HCl, HPMC, and Carbomer (Figure 4).
Carbomers belong to an anionic polymer Diltiazem hydrochloride has O-CH3, amine, acetate,
group, thus, they have higher mucoadhesive and and lactam as functional groups at which the
swelling index strength than HPMC (Morales and chemical interaction may occur. FT-IR spectral
McConville, 2011); a better swelling index indicates analysis shows no interference to the functional
excellent hydration. On the contrary, carbomers at groups as Diltiazem HCl's principle peaks were
high concentrations will produce massive unaltered in the mucoadhesive buccal film,
hydration; there will be overhydration and reduced indicating no interaction between the drug and the
adhesive strength due to the polymer chain's excipients.
decomposition (Peh and Fun Wong, 1999). Thus, a
formula with a high amount of HPMC (FA) provides Release study
greater mucoadhesive strength than that with a The Diltiazem HCl buccal film using a
high amount of carbomers (FB). The mucoadhesive combination of HPMC and carbomer exhibited a
residence time is related to mucoadhesive strength. controlled release over more than eight
When the mucoadhesive strength increases, the hours and can release 95.43% of the drug
film will need a longer time to detach from the after 480min. The results are in accordance
buccal mucus membrane, and vice versa (Roda et with Patel et al. (2013), who formulated
al., 2018). The results show that all the buccal film chlorpheniramine maleate tablets using a matrix
formulas exhibited good mucoadhesive strength of HPMC K15M, HPMC K100M, and carbomer,
and residence time. which produced a controlled release over 6h.

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 Hydroxy Propyl Methyl Cellulose and Carbomer in Diltiazem Hydrochloride

Figure 4.The FTIR result of optimum formula, pure diltiazem HCl, HPMC, and carbomer

Table IV. The dissolution parameters obtained from DDSolver program

The dissolution model parameters

Dissolution model
R2 Adjusted MSE WSS AIC MSC
Zero-order 0.78 160.74 2250.37 117.76 1.36
First-order 0.95 33.58 470.08 94.19 2.93
Higuchi 0.99 8.24 115.36 73.2 4.33
Korsmeyer-Peppas 0.99 6.18 80.29 69.61 4.57
Hixson-Crowell 0.93 47.13 659.77 99.32 2.59
Hopfenberg 0.95 36.18 470.33 96.2 2.8
Baker-Lonsdale 0.95 34.39 481.51 94.64 2.9
Weibull 0.97 18.35 220.23 86.77 3.43

HPMC K100M produced slower release than the Peppas is more appropriate for describing the
other two polymers, which followed zero-order dissolution of Diltiazem HCl from the buccal film
release kinetics and the Fickian diffusion because the model has the highest adjusted R 2 and
mechanism. MSC (Model Selection Criterion) but has the
DDSolver program was used to analyze the smallest MSE (mean square error), WSS (weighted
release kinetics of Diltiazem HCl from the sum of squares), and AIC (Akaike Information
mucoadhesive buccal film. DDSolver is an add-in Criterion) compared to other models (Nugroho et
program for Microsoft Excel, which is easy to use. al., 2014). The highest adjusted R2 and MSC values
The analysis of statistical parameters (table 4) show the model's best suitability, while the lowest
using DDSolver shows that the dissolution model MSE, WSS, and AIC values show high precision of
followed the Korsmeyer-Peppas. The Korsmeyer- the model (Siswanto et al., 2015).

48 Volume 32 Issue 1 (2021)

Lina Winarti

Figure 5: Diltiazem HCl profile of predictive dissolution (Qp) and experimental results (Qo) versus time
(n = 6). A Zero order; B First order; C Higuchi; D Korsmeyer Peppas; E Hixson Crowell; F Hopfenberg; G
Baker-lonsdale; H Weibull model.

In the Korsmeyer-Peppas equation, the n- Siswanto et al. (2015) also used DDSolver to
value (the release exponent) was 0.55. Based on the analyze the release kinetics of Aspirin floating
n-value, the release of Diltiazem HCl from the tablet using Methocel K4M CR, NaHCO3, Ethocel,
buccal film follows the non-fickian/anomalous Aerosil, and dicalcium phosphate anhydrous as
diffusion release mechanism. This mechanism excipients. Their dissolution data were evaluated
describes controlled drug release through a using DDSolver conducted by Statistical
combination of diffusion and erosion. Erosion parameters (R2 adjusted, AIC, MSC) and Visual
during the release process happens when a large goodness of fit (GOF). The results showed the same
amount of carbomer is used. The film is release kinetics with the Diltiazem HCl buccal film.
overhydrated due to the high carbomer content, The Aspirin floating tablets release kinetics
which removes the polymer chain in the film. followed the Korsmeyer-Peppas model and
Hence, it results in drug release from the eroded occurred through anomalous transport, which
matrix. The diffusion happens when carbomer and combines Fickian diffusion and polymer relaxation.
HPMC are in contact with water. The matrix will not Therefore, Methocel K4M CR, NaHCO3, Ethocel,
dissolve but will expand in the water to form a gel- Aerosil, and dicalcium phosphate anhydrous as
layer so that the drug diffuses more slowly excipients in the Aspirin floating tablets resulted in
(Merchant et al., 2006). the same release mechanism as a combination
The results of curve fitting analysis of HPMC and Carbomer in Diltiazem HCl buccal
strengthen the release kinetics determination film.
based on statistical parameters. The curve fitting
(figure 5) shows that the Korsmeyer-Peppas model CONCLUSION
is the most appropriate model to explain the From the study, it can be concluded that the
dissolution of Diltiazem HCl from the buccal film combination of HPMC and carbomer could obtain
using HPMC and carbomer as the polymer. The good film characteristics with a controlled release
Korsmeyer-Peppas model provides observation over 8 hours. The combination also improved
dissolution data (Qo) around the predicted residence time and mucoadhesive strength for
dissolution data curve (Qp). Meanwhile, dissolution sufficient contact time to the mucosa. The overall
modeling with zero-order, first-order, Higuchi, results show the potential combination of HPMC
Hixson-Crowell, Hopfenberg, Baker-Londsdale, and and carbomer to increase bioavailability and half-
Weibull resulted in a more considerable difference life of Diltiazem HCl.
between Qo and Qp.

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 Hydroxy Propyl Methyl Cellulose and Carbomer in Diltiazem Hydrochloride

ACKNOWLEDGMENT Controlled Release, 65(2000), 19–29.

The authors acknowledge the Faculty of https://doi.org/10.1016/S0168-
Pharmacy University of Jember for supporting this 3659(99)00228-X
research. Merchant H A., Shoaib H M., Tazeen J., Yousuf RI.
2006. Once-daily tablet formulation and in
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