Drug Delivery

ISSN: 1071-7544 (Print) 1521-0464 (Online) Journal homepage: http://www.tandfonline.com/loi/idrd20

Formulation and Evaluation of Dextromethorphan

Hydrobromide Sustained Release Tablets

Subramania Nainar Meyyanathan, Sekar Rajan, Selvadurai Muralidaharan,

Mahesh Kumar Siddaiah, Kaliaperumal Krishnaraj & Bhojraj Suresh

To cite this article: Subramania Nainar Meyyanathan, Sekar Rajan, Selvadurai Muralidaharan,
Mahesh Kumar Siddaiah, Kaliaperumal Krishnaraj & Bhojraj Suresh (2008) Formulation and
Evaluation of Dextromethorphan Hydrobromide Sustained Release Tablets, Drug Delivery, 15:7,
429-435, DOI: 10.1080/10717540802035301

To link to this article: http://dx.doi.org/10.1080/10717540802035301

Published online: 16 Dec 2008.

Submit your article to this journal

Article views: 240

View related articles

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=idrd20

Download by: [125.167.187.86] Date: 12 April 2017, At: 06:31

Drug Delivery, 15:429435, 2008
Copyright

c Informa UK, Ltd
ISSN: 1071-7544 print / 1521-0464 online
DOI: 10.1080/10717540802035301

Formulation and Evaluation of Dextromethorphan

Hydrobromide Sustained Release Tablets

Subramania Nainar Meyyanathan, Sekar Rajan, and Selvadurai Muralidaharan

Department of Pharmaceutical Analysis, JSS College of Pharmacy, Rocklands,
Ootacamund-643 001, India

Mahesh Kumar Siddaiah and Kaliaperumal Krishnaraj

TIFAC CORE, JSS College of Pharmacy, Rocklands, Ootacamund-643 001, India

Bhojraj Suresh
Principal, JSS College of Pharmacy, Rocklands, Ootacamund-643-001, India

Sustained release (SR) matrix tablets of dextromethorphan
hydrobromide were prepared by wet granulation using hydrox-
ypropyl methyl cellulose (HPMC-K-100 CR) as the hydrophilic rate
controlling polymer. The effect of the concentration of the polymer
and different fillers on the in vitro drug release rate was studied.
The studies indicated that the drug release can be modulated by
varying the concentration of the polymer and the fillers. A com-
plete cross-over bioavailability study of the optimized formulation
of the developed sustained tablets and marketed immediate release
tablets was performed on six healthy male volunteers. The extent
of absorption of drug from the SR tablets was significantly higher
than that for the marketed dextromethorphan hydrobromide
tablet because of lower elimination rate and longer half-life.
Keywords Bioavailability, Sustained release, Hydrophilic matrices,
Dextromethorphan Hydrobromide
Dextromethorphan hydrobromide (DH), a well-known non
narcotic antitussive agent, is generally used as an ingredient in
cough and cold remedies. The dosage of the drug is usually
three to four times a day because of its short half-life (Silvati et
al. 1987). Therefore, sustained release dosage forms were de-
veloped to avoid repeated administrations and increase patient
compliance. Sustained release (SR) delivery systems for oral
dosing are effective in achieving optimal therapy with drugs that
have a narrow therapeutic range of blood concentration or elim-
inate rapidly. SR products are designed to bring the blood level
of a drug immediately to therapeutic concentrations by means
Received 25 December 2007; revised 25 January 2008: accepted
27 January 2008.
Address correspondence to S. Rajan, Dept. of Pharmaceutical
Analysis, J.S.S. College of Pharmacy, Rocklands, Ooty-643 001,
Tamilnadu, India. Tel: +91 423 2443393, Fax: +91 423 2442937. E-
mail: Rasan cadrat@rediffmail.com
of an initial dose portion and then sustain this level for a cer-
tain predetermined time with the maintenance portion (Hosny
et al. 1997; El-Sayed et al. 1995; El-Said and Hashem 1991). At
present there are no sustained release dextromethorphan matrix
tablets available in India. A sustained release dextromethorphan
tablet can lead to the reduction of the number of doses admin-
istered; less of a chance of an overdose, and it is a good dosage
form for asthma patients for night time cough.
Various types of oral sustained release (SR) formulations
have been developed to improve the clinical efficacy of drugs
having short half-lives as well as to increase patient compliance
(DeHaan and Lerk 1984). These formulations are designed
to deliver drugs at a predetermined rate over a wide range of
conditions and durations of therapeutic treatments. One of the
most commonly used methods of developing SR formulations
for therapeutic agents is to include it in matrix tablets, as they
are easy to manufacture (Cardinal 1984). Using a suitable rate
controlling polymer, the matrix can be tableted by direct com-
pression or conventional wet granulation method. Because of
their simplicity and cost effectiveness, hydrophilic gel forming
matrix polymers are used extensively for oral SR dosage forms.
The purpose of our present study was to investigate the in vitro
and in vivo performance of compressed matrix tablets prepared
by granulating hydrophilic polymeric substance, HPMC-K-100-
CR, with polyvinyl pyrolidine in isopropyl alcohol to produce a
sustained release dosage form containing the dextromethorphan
hydrobromide. The effect of the polymer concentration and the
various fillers on the in vitro release rate also was proposed to be
studied. The comparative bioavailability study of the optimized
formulation and the marketed immediate release (IR) formula-
tion also would be carried out in healthy male volunteers.
MATERIALS AND METHODS
Dextromethorphan hydrobromide (DM) was a gift sample
from Divis Laboratories (Hyderabad, India); HPMC (Methocel

429
430 S. N. MEYYANATHAN ET AL.

K100CR, apparent viscosity, 2% in water at 20 C is 80,000 Granule Properties

12000 cP) and starch 1500 were gift sample from Colorcon
(Goa, India). Polyvinyl pyrolidine (PVP-K-30) was a gift sample
from Anshul Agencies (Mumbai, India). Aerosil was purchased
from Degussa (Mumbai, India). Lactose was purchased from
Lactose Limited (Mumbai, India). All the other chemicals were
of analytical grade or HPLC grade.
Preparation of DM Tablets
DM matrix tablets were prepared by the wet granulation
method. All the composition, with the exception of magnesium
stearate and aerosil were thoroughly mixed in a tumbling mixer
for 5 min and wetted in a mortar with isopropyl alcohol. The
wet mass was sieved (16 mesh) and granules were dried at
60 C for 2 hr. The dried granules were sieved (22 mesh) and
these granules were lubricated with a mixture of magnesium
stearate and aerosil (2:1). The DM tablets were prepared using
an electrically operated punching machine. Compression was
performed after granulation process with a single punch press
applying a compression force of a 9 KN (preliminary work) or
12 KN (experimental design), equipped with an 8-mm concave
punch.
For the preliminary work, batches of 100 tablets were pre-
pared. Each batch of experimental design consisted of 100
tablets (drug content in the tablet was 200 mg). Three batches
were prepared for each formulation and the compositions of dif-
ferent batches of dextromethorphan hydrobromide SR tablets
are given in Table 1.
The granules were evaluated for angle of repose (Cooper
and Gunn 1986), loose bulk density (LBD), tapped bulk density
(TBD) using USP tapped density tester (Banker and Anderson
1987) and Carrs index (Aulton and Wells 1988).
Tablet Properties
The average weight, thickness (Digital slide calipers,
Mitutoyo, Japan), hardness (Monsanto hardness tester, Cadmach
machineries, Ahmedabad, India), Friability (friability testing ap-
paratus, Electrolab, Mumbai, India), drug content, and in vitro
drug release of the formulated tablets were evaluated.
Drug Content
Two tablets were weighed individually and crushed in mortar.
An accurately weighed quantity of powered tablets (60 mg) was
extracted with pH 7.5 buffer and the solution was filtered through
0.45 membrane. The drug content was estimated by HPLC
under suitable optimized condition after suitable dilution.
In Vitro Dissolution Studies
Dissolution was performed for the manufactured tablets ac-
cording to the USP 26 dissolution procedure over a 24-hour pe-
riod, using an Electro labTablet dissolution Tester, USP XXIII
Model. The media was 0.1N Hcl at pH 2.0 and a volume of
700 mL for the first 2 hr after which 200 mL of 0.2 M sodium
phosphate tribasic, was added to give a final pH of 7.5 and main-
tained at 37 C. Dissolution tests were performed on six tablets

TABLE 1
Formulations prepared by wet granulation method (F1 F18 )
Dextromethorphan Magnesium Total
Fa HBr HPMC Carbopol Avicel stearate Aerosil PVP-k-30 (mg/tab)
F1 60.00 15.00 102.00 2.00 1.00 20.00 200.00
F2 60.00 30.00 87.00 2.00 1.00 20.00 200.00
F3 60.00 45.00 72.00 2.00 1.00 20.00 200.00
F4 60.00 60.00 57.00 2.00 1.00 20.00 200.00
F5 60.00 90.00 27.00 2.00 1.00 20.00 200.00
F6 60.00 117.00 2.00 1.00 20.00 200.00
F7 60.00 15.00 102.00 2.00 1.00 20.00 200.00
F8 60.00 30.00 87.00 2.00 1.00 20.00 200.00
F9 60.00 45.00 72.00 2.00 1.00 20.00 200.00
F10 60.00 60.00 57.00 2.00 1.00 20.00 200.00
F11 60.00 90.00 27.00 2.00 1.00 20.00 200.00
F12 60.00 117.00 2.00 1.00 20.00 200.00
F13 60.00 7.5 7.5 102.00 2.00 1.00 20.00 200.00
F14 60.00 15.00 15.00 87.00 2.00 1.00 20.00 200.00
F15 60.00 22.5 22.5 72.00 2.00 1.00 20.00 200.00
F16 60.00 30.00 30.00 57.00 2.00 1.00 20.00 200.00
F17 60.00 45.00 45.00 27.00 2.00 1.00 20.00 200.00
F18 60.00 58.5 58.00 2.00 1.00 20.00 200.00
a
Code of formulations.
 DEXTROMETHORPHAN HYDROBROMIDE 431

TABLE 2 TABLE 3
Comparison of the physical properties of the matrix tablets Granule properties of the different formulations of
containing DM dextromethorphan hydrobromide
Physical characteristics Fb Angle of LBDb TBDc Carrs
F a
repose ( C) (gm/cm3 ) (gm/cm3 ) index (%)
Hardness Thickness Friability
Fa (N) (cm) Weight (g) (%) F1 25.11 0.283 0.339 1.94
F2 22.97 0.266 0.338 1.72
F1 5.00 0.04 3.56 0.03 0.1980 0.002 1.21 0.15 F3 24.28 0.256 0.366 1.67
F2 4.98 0.06 3.56 0.08 0.2070 0.004 0.13 0.02 F4 23.88 0.285 0.417 1.26
F3 5.02 0.05 3.65 0.06 0.2020 0.002 0.12 0.06 F5 23.96 0.267 0.365 1.06
F4 4.55 0.20 3.71 0.03 0.2019 0.003 0.06 0.01 F6 24.11 0.272 0.388 1.84
F5 5.17 0.28 3.74 0.03 0.2037 0.003 0.05 0.02 F7 24.15 0.300 0.426 1.28
F6 5.37 0.27 3.80 0.11 0.2090 0.002 0.11 0.06 F8 23.76 0.255 0.349 0.98
F7 4.51 0.41 3.73 0.04 0.2006 0.004 0.03 0.00 F9 27.72 0.313 0.402 1.72
F8 5.55 0.27 3.70 0.03 0.2021 0.005 0.49 0.07 F10 25.55 0.278 0.305 1.56
F9 6.00 0.20 3.84 0.06 0.2043 0.007 0.01 0.00 F11 24.30 0.333 0.458 1.64
F10 5.50 0.29 3.79 0.03 0.2014 0.008 0.06 0.03 F12 25.38 0.346 0.422 1.92
F11 6.00 0.17 3.88 0.02 0.2048 0.007 0.05 0.01 F13 22.30 0.251 0.320 1.45
F12 5.31 0.36 4.01 0.02 0.2074 0.002 0.06 0.01 F14 25.18 0.284 0.121 1.32
F13 5.13 0.12 3.78 0.04 0.2084 0.003 0.08 0.02 F15 24.23 0.321 0.457 1.80
F14 4.83 0.14 3.82 0.07 0.2110 0.005 0.24 0.05 F16 20.41 0.357 0.439 1.76
F15 4.62 0.24 3.69 0.06 0.2031 0.005 0.08 0.01 F17 27.72 0.320 0.441 1.37
F16 5.00 0.08 3.84 0.08 0.2019 0.007 0.09 0.01 F18 25.29 0.345 0.512 1.28
F17 4.75 0.21 3.85 0.17 0.2062 0.006 0.10 0.02
a
F18 5.09 0.39 4.00 0.05 0.2173 0.003 0.18 0.07 Code of formulations.
b
Loose bulk density.
a c
Formulas for the specified formulations are given in Table 1. Tapped bulk density.
b
Results represent the mean of replicate determination with the stan-
dard deviation given in parenthesis. veloped two sustained release tablets (test product) contain-
ing 60 mg of dextromethorphan and commercially available IR
and the amount of drug released was analyzed by HPLC at a tablets (reference product Romilar tablets) containing 15 mg
wavelength of 280 nm. The stationary phase was a Phenomenex of dextromethorphan hydrobromide which was carried at in 6
C18 (250 4.6 mm i.d., 5 ) column. The mobile phase was pre- healthy male volunteers of 2225 years of age, weighing be-
pared by mixing acetonitrile 0.5% triethylamine pH 7.5 (50:50, tween 5075 kg under fasting conditions. The functions of their
v/v) (adjusted with orthophosphoric acid). The injection volume livers and kidneys were assessed by clinical and biochemical
was 50 l and run time was 10 min. The mobile phase was fil- tests and were found to be normal. The subjects selected did not
tered using a 0.45 m membrane filter (Millipore, Milford, MA, use alcohol or tobacco and had not taken any medication for 1
USA) and sonicated with ultrasonicator. The mobile phase flow week prior to the study. All the volunteers gave written consent
rate was 1.0 mL/min. Dissolution samples were collected at the and the study protocol was approved by the ethical committee
following time 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12.0, of the institution (Approval no. CADRAT DEX 01/20062007).
18.0, and 24.0 hr. Percentage of drug release and cumulative The volunteers received either of the study formulations accord-
drug release were calculated. ing to their code number with 240 ml of water. Blood samples
(5 ml) were collected in heparinized centrifuge tubes after dos-
Kinetics and Mechanism of Drug Release ing for 24 hr. Plasma was separated by centrifugation, and the
The in vitro drug release profiles were plotted according drug levels in plasma were then estimated by a validated reverse
to zero-order, first-order, Higuchi (Higuchi 1963), and Peppas phase HPLC method.
(Peppas 1985) equations to understand the mechanism of drug
release and to compare the differences in the release profile of High-Performance Liquid Chromatography (HPLC)
different batches of matrix tablets. Analysis of Plasma Samples
Analysis was performed on a Shimadzu Scientific Instru-
Bioavailability Studies ments (Kyoto, Japan) liquid chromatographic system composed
A randomized, three-treatment, three-period, three-sequence, of a LC-10ADVP pump, a SPD-10ADVP variable wavelength
single-dose, cross over bioavailability study was for the de- detector, a CTO-10ADVP column oven and a SIL-10ADVP
432 S. N. MEYYANATHAN ET AL.

FIG. 1. Dissolution profiles of HPMC-containing formulations F1 F6 .

autosample injector. The analytical column employed was a Pharmacokinetic Analysis

VYDAC Monomeric C18 reversed-phase column 250 4.6 mm
i.d., 5 m particle size. The mobile phase consisted of
acetonitrile-0.5% trifluoroacetic acid (40:60, v/v). The analyses
were conducted at 40 C, flow rate 1.0 mL/min, and detection
wavelength at 280 nm.
All pharmacokinetic parameters of dextromethorphan hydro-
bromide were calculated by the noncompartment method us-
ing a Kinetica software version 4.4 Cmax (maximum plasma
concentration of dextromethorphan hydrobromide) and Tmax
(the time of reach Cmax ) were obtained directly from the

FIG. 2. Dissolution profiles of carbopol-containing formulations F7 F12 .

 DEXTROMETHORPHAN HYDROBROMIDE 433

FIG. 3. Dissolution profiles of HPMC- and carbopol-containing formulations F13 F18 .

concentration-time curve. AUC0t (area under the plasma
concentrationtime curve of dextromethorphan hydrobromide
from zero to the last measurable sample time) was calculated us-
ing the linear trapezoidal method. Kel was calculated by applying
a log-linear regression analysis to at least the last three concen-
trations of dextromethorphan hydrobromide. T1/2 (the terminal
half-life) was calculated as 0.693/Kel (Ritschel 1992).
RESULTS AND DISCUSSION
Granulation is the key process in the production of many
dosage forms. The sustained release tablets were prepared by
wet granulation technique. Physical properties of granules such
as specific surface area, shape, hardness, surface characteris-
tics and size can significantly affect the rate of dissolution of
drugs contained in a heterogenous formulation. The granules of

FIG. 4. Higuchi chart of optimized DM formulations F1 F4 .

434 S. N. MEYYANATHAN ET AL.

FIG. 5. Peppas chart of optimized DM formulations F1 F4 .

different formulations were evaluated for angle of repose, loose
bulk density (LBD), tapped bulk density (TBD), and Carrs in-
dex as shown in Table 2. The results of angle of repose indicate
good flow properties of the granules. However, the granules had
fair to poor Carrs index values. Aerosil therefore was added to
dried granules prior to compression to improve the flow.
The physical properties of different batches of developed
tablets are given in Table 3. All the batches showed uniform
thickness. The average percentage deviation of 20 tablets of
each formula was less than 5% and hence all formulations
passed the test for uniformity of weight as per official require-
ments (Pharmacopoeia of India 1996). Good uniformity content
was found among three different batches of tablets.
Another measure of tablets strength is friability. Conventional
compressed tablets with less than 1% w/w of their weight are
generally considered acceptable. In the present study, the per-
centage friability for all the formulations was below 1% w/w, in-
dicating that the friability is within the prescribed limits (Banker
and Anderson 1987). All the tablet formulations showed ac-
ceptable pharmacotechnical properties and complied with the
specifications for weight variation, drug content, hardness, and
friability.

FIG. 6. Plasma concentration-time profile of DM from developed SR tablets (test) and marketed IR tablet (reference).
 DEXTROMETHORPHAN HYDROBROMIDE
TABLE 4
Pharmacokinetic parameters of the developed sustained release (SR) tablets and marketed immediate release (IR) tablets of
dextromethorphan hydrobromide
Sample Pharmacokinetic Developed SR tablets
Number parameters slow release
1 AUC024 28686.50 1828.40
2 AUC0 36289.19 2364.84
3 Cmax 2086.81 152.93
4 Tmax 6.33 0.81
5 Keli 0.072 0.005
6 T1/2 9.62 0.72
Friability values of all the batches were less than 1%. There
was no accordance between hardness values and friability ob-
servations. Small values in friability imply much less friability
during transportation, which is important in terms of sustained
release of tablets. In all the batches, we observed that as the
polymer concentration increases, the drug release rate decreases
(Figures 13).
The in vitro drug release characteristics of the developed SR
and the marketed IR tablets were studied. Dissolution data for
all the experiments were highly reproducible and hence only the
average values were plotted. The dissolution of the marketed IR
tablets indicated that more than 80% of the drug was released
within 1 hr, which complies with the pharmacopoeial speci-
fications. In all the batches, we observed that as the polymer
concentration increases, the drug release rate decreases.
To know the mechanism of drug release from these formula-
tions, the data were treated according to zero-order (cumulative
amount of drug released versus time), first-order (log cumulative
percentage of drug released versus time), Higuchi (cumulative
percentage of drug released versus square root of time), and
Peppas (log cumulative percentage of drug released versus log
time) equations that are clearly revealed in Figures 4 and 5.
The release profiles the DM, when plotted according to
Higuchis equation and Peppas equation, confirm that drug re-
lease was diffusion control as evident by the values of correlation
(r2 ).
The relative bioavailability of the SR 60 mg tablets (slow,
fast) given daily was compared with one dose of the marketed
15 mg dextromethorphan hydrobromide tablet. The developed
SR tablet produced a plasma concentration-time profile typical
of the prolonged dissolution characteristic of a SR formulation,
as evident from Figure 6 and Table 4. The developed SR tablets
demonstrated a longer time to reach a peak concentration than
the marketed tablets and appeared to have more consistent over-
all performance.
This was no significant difference in extent of absorption as
assessed by measurement AUC0t . However, AUC0 values
for the SR tablets were higher than the marketed IR tablets indi-
cating more efficient and controlled drug delivery, which would
maintain plasma dextromethorphan levels better. This was also
435
Developed SR tablets
fast release Marketed IR tablets
31720.58 3681.88 5281.0611 518.57
38845.90 3894.99 6537.59 781.23
2191.66 108.58 1229.60 59.69
5.33 1.03 1.66 0.25
0.076 0.068 0.27 0.02
9.16 0.86 2.51 0.20
evident by the lower elimination rate constant and higher t1/2
values.
CONCLUSIONS
The sustained release tablets of dextromethorphan hydrobro-
mide were well absorbed and the extent of absorption was higher
than that of the marketed tablet. The sustained and efficient drug
delivery system developed in the present study will maintain
plasma dextromethorphan levels better, which will overcome
the drawbacks associated with the conventional therapy.
REFERENCES
Aulton, M. E., and Wells, T. I. 1988. Pharmaceutics: The Science of Dosage
Form Design, 247248. London: Churchill Livingstone.
Banker, G. S., and Anderson, N. R. 1987. In The Theory and Practice of Indus-
trial Pharmacy, ed. Lachman, L., Liberman, A. H., and Kanig, J. L., 297321.
Mumbai: Varghese Publishers.
Cardinal, J. R. 1984. Matrix systems. In Medical Applications of Controlled
Release: Classes of Systems, ed. Langer, R.S., and Wise, D.L., 4167. Boca
Raton, FL: CRC Press.
Cooper, J., and Gunn, C. 1986. Powder flow and compaction. In Tutorial Phar-
macy, ed. Carter, S. J., 211233. New Delhi: CBS Publishers and Distributors.
DeHaan, P., and Lerk, C. F., 1984. Oral controlled release dosge forms: a review.
Pharm. Weekbl. Sci. 6:5767.
El-Sayed, Y. M., Niazy, E. M., and Khidr, S. H. 1995. In-vivo evaluation of
sustained-release microspheres of metoclopramide hydrochloride in beagle
dogs. Int. J. Pharm. 123:113118.
Higuchi, T. 1963. Mechanism of sustained action medication: theoretical anal-
ysis of rate of release of solid drugs dispersed in sold matrices. J. Pharm. Sci.
52(12):11451149.
Hosny, E. A., Al-Helw, A. R. M., and Al-Dardiri, M. A. 1997. Compara-
tive study of in-vitro release diclofenac sodium from certain hydrophilic
polymers and commercial tablets in beagle dogs. Pharm. Acta Helv. 73:159
164.
Peppas, N. A. 1985. Analysis of Fickian and nonfickian drug release from
polmers. Pharm. Acta. Helv. 60:110111.
Pharmacopoeia of India. 1996. New Delhi: Controller of Publications, Ministry
of Health and Family Welfare.
Silvati, Y., Kartunen, P., Tukiainen, H., Kokkonen, P., Hanninen, U., and
Nykanen, S. 1987. Pharmacokinetics of Dextromethorphan and dextrorphan:
a single dose comparison of three preparations in human volunteers. Int. J.
Clin. Pharmacol. Ther. Toxicol. 25:493497.
Ritschel, W. A. 1992. Handbook of Basic Pharmacokinetics. Hamilton, Illinois,
USA: Drug Intelligence.