RESEARCH ARTICLE Abhijeet et.

al / IJIPSR / 8 (05), 2020, 1-13

Department of Pharmaceutics ISSN (online) 2347-2154
DOI: 10.21276/IJIPSR.2020.08.05.880

International Journal of Innovative

Pharmaceutical Sciences and Research
www.ijipsr.com

FORMULATION AND EVALUATION OF EXTENDED RELEASE

PELLETS OF DEXTROMETHORPHAN HYDROBROMIDE BY
THE USE OF COMPLEXATION TECHNIQUE
1
Abhijeet Kunwarpuriya*, 2Dr. Amitkumar Janardan Raval, 3Dr. Nilesh Mahadeo Khutle,
1
Vishakha Vishwanath Doke
1
Research Scholar (Ph.D.),Faculty of Pharmacy, Pacific Academy of Higher Education
and Research University,Udaipur, INDIA
2
Professor (Pharmaceutics), Faculty of Pharmacy, Pacific Academy of Higher Education and
Research University, Udaipur, INDIA
3
Professor (Pharmaceutics), Faculty of Pharmacy, Dr. L.H. Hiranandani College of Pharmacy
Mumbai, INDIA

Abstract
An ideal drug delivery system reduces the undue exposure of the drug to other tissues and thus is
responsible for accurately delivering the drug at a desired rate and thus minimize its side-effects.
Modified-release dosage form is a product that alters the timing and rate of release of drug substance
and it refers to both delayed and extended release systems for oral administration. The basic rational
for modified release drug delivery is to alter the Pharmacokinetics and pharmacodynamics of
pharmacologically active moieties by using release modifying polymers and novel techniques like
fluidization, pelletization and thus effectively optimize the bioavailability and resulting blood
concentration-time profiles of drugs .3Oral modified release dosage form can be broadly classified
into two categories: Single-unit and Multiple-unit dosage forms.
Keywords: Dextromethorphan Hydrobromide, fluidization, pelletization, Drug-Resin complex.

Corresponding Author:
Abhijeet Kunwarpuriya
Research Scholar (Ph.D.), Faculty of Pharmacy,
Pacific Academy of Higher Education and Research University,
Udaipur, INDIA
Email: abhijust111@gmail.com
Phone: +91- 9860579111 / 8983026666

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RESEARCH ARTICLE Abhijeet et.al / IJIPSR / 8 (05), 2020, 1-13
Department of Pharmaceutics ISSN (online) 2347-2154
DOI: 10.21276/IJIPSR.2020.08.05.880
INTRODUCTION
An ideal drug delivery system reduces the undue exposure of the drug to other tissues and thus is
responsible for accurately delivering the drug at a desired rate and thus minimize its side-effects.
Modified-release dosage form is a product that alters the timing and rate of release of drug
substance and it refers to both delayed and extended release systems for oral administration. The
basic rational for modified release drug delivery is to alter the Pharmacokinetics and
pharmacodynamics of pharmacologically active moieties by using release modifying polymers
and novel techniques like fluidization, pelletization and thus effectively optimize the
bioavailability and resulting blood concentration-time profiles of drug [1] .Oral modified release
dosage form can be broadly classified into two categories: Single-unit and Multiple-unit dosage
forms [2]. The single-unit dosage forms include matrix tablet or coated or uncoated tablet or
capsules [3]. The multiple-unit dosage forms consist of pellets, micropellets or microencapsulated
drug filled in a capsule or compressed into a tablet or suspended in suspension [4]. The individual
subunits like pellets release the dose of the active ingredient and the functionality of the entire
dose depends on the quality of the subunits [5]. Multiparticulate dosage forms provide increased
bioavailability, reduced risk of systemic toxicity, reduced risk of local irritation and predictable
gastric emptying [5] due to which they are preferred over single-unit dosage forms [6]
Dextromethorphan hydrobromide is widely used in relief of cough due to bronchial irritation or
minor throat irritation. The drug has a faint odour, bitter taste and is sparingly soluble in water,
freely soluble in alcohol and in chloroform. The pH of the drug lies between 5.2 and 6.5 implying
its basic nature. It has a short half-life and is rapidly absorbed from the gastrointestinal tract,
where it enters the bloodstream and crosses the blood-brain barrier [7]. Because of shorter half
life it requires frequent administration [8].
The objective of the current research is to formulate the robust, stable & extended release taste
masked micro pellets of drug Dextromethorphan Hydrobromide having bitter taste and shorter
half life of 2 to 4 hrs. Initially attempts were made to mask the bitter taste of drug by means of
complexation with ion exchange resin. Complexation with resin not only masks bitter taste of the
drug but also delay its release [9]. To modify further release of dextromethorphan its coating was
performed using release retarding polymer. These coated micro pellets can be used to formulate
extended release dosage forms such as capsule, suspension etc. [10]

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RESEARCH ARTICLE Abhijeet et.al / IJIPSR / 8 (05), 2020, 1-13
Department of Pharmaceutics ISSN (online) 2347-2154
DOI: 10.21276/IJIPSR.2020.08.05.880
MATERIALS & METHODS
Preformulation studies
Preformulation studies were carried out in order to maximise the chances in formulating an
acceptable, safe, efficient, stable dosage form. Physical characteristics of dextromethorphan
hydrobromide were studied.
Assay of the drug by HPLC analysis
An HPLC system ( pump, chemstn software) along with C18, column5µm, 150 × 4.6 mm (Water-
Symmetry) was used to carry out assay of drug dextromethorphan hydrobromide. 20ul injections
of standard and sample were prepared using the mobile phase consisting of Acetonitrile:
Ammonium phosphate- Octanesulfonic acid buffer in the ratio of 30:70 v/v. 5.75g of Ammonium
phosphate and 5.41g of Octanesulfonic acid was weighed in a suitable container and diluted to
1000ml with water. It was further adjusted to pH 2.5 with Phosphoric acid and filtered through
0.45 um milipore filter to give 50nM Ammonium phosphate 25mM 1- Octanesulfonic acid buffer
with pH 2.5. 300 ml of acetonitrile was mixed with 700 mL of ammonium phosphate-
Octanesulfonic acid buffer, stirred and sonicated for 10 minutes respectively and allowed to cool
at room temperature. Flow rate was1.7mL/min and the retention and run times were 15 minutes
and 25 minutes respectively. The detection was carried out at 280nm.
FORMULATION AND DEVELOPMENT OF MICROPELLETS
Preparation of Drug-Resin complex
Complexation with ion exchange was selected as a strategy for taste masking of drug
Dextromethorphan Hydrobromide. The detailed development with respect to manufacturing
formula and procedure is given below.
Selection of resin grade
4 trials were carried out for selection of appropriate resin grade. In these trials, drug-resin
complexes were formulated with different grades of Sodium polysterene Sulfonates such as Grade
“Z”, Grade “W”, Grade “Y” and Grade “V” and corresponding batches were analyzed for
impurities. 100g of Dextromethorphan Hydrobromide was dissolved in 2L of purified water at
room temperature under stirring which was continued for 45 minutes till clear solution was
obtained. Batch quantities of individual resin were added to the drug solution prepared slow speed
stirring. After stirring of drug resin complex slurry, it was filtered using #200 (ASTM, 75µ) sieve.
The insoluble drug resin complex was separated from the filtrate. The resultant wet mass of drug

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RESEARCH ARTICLE Abhijeet et.al / IJIPSR / 8 (05), 2020, 1-13
Department of Pharmaceutics ISSN (online) 2347-2154
DOI: 10.21276/IJIPSR.2020.08.05.880
resin complex was dried at not more than 50°C product bed temperature. The Drug-resin complex
obtained after processing above batches was characterized for impurities.
Optimization of ratio of drug to resin in Drug-Resin complex
Optimization of drug: resin ratio was carried out by evaluation of ratio ‘1:3’, ratio ‘1:1’ and ratio
‘2:1’, the composition of the batches to be evaluated for optimization is given in below table2.
The batch quantity of selected resin was added to drug solution under stirring.During stirring of
drug resin complex slurry, samples were withdrawn at 20, 40, 60, 80 ,100, 120 and 180 minute
time points. The samples were allowed to stand undisturbed and the insoluble drug resin complex
was separated from the medium by using 200 (ASTM, 75µ) sieve. The filtrate obtained was
analyzed for content of free/ uncomplexed drug. The Drug-Resin complex obtained after filtration
was dried at a product bed temperature of not more than50 ºC. The dried Drug-Resin complex
obtained in all batches was sifted through # 120(ASTM, 125µ) sieve. The sifted complex was
analyzed for drug release profile (dissolution) to evaluate the impact of different ratios of drug:
resin. The drying operation was continued till LOD below 8% was obtained. The drying
parameters are provided in below table 1.
Table 1: Drying parameters for Drug-Resin complex
Drying time Inlet air temperature Product bed temperature LOD achieved
(minutes) (°C) (°C) (% w/w)
240 minutes 40-55 25-60 6.33

Table 2: Composition of batches manufactured to optimize drug: resin ratio

Formulation Details
Ratio A (1:3) Ratio B (1:1) Ratio (2:1)
[Drug: Resin]
Ingredients mg/unit % w/w mg/unit % w/w mg/unit % w/w
Drug 30 25.00 30 50 60 66.66
Sodium polysterene
90 75.00 30 50 30 33.33
Sulfonate
Purified water q.s. q.s. q.s. q.s. q.s. q.s.
Theoretical weight of
drug-resin complex 120 100 60 100 90 100
(mg)

Physical characterization of Drug-Resin complex

Light brown coloured micro pellets of Drug-Resin were obtained. Physical characterization tests
of drug-Resin complex were performed and mentioned in result and discussion section.
Chemical characterization of Drug-Resin complex
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RESEARCH ARTICLE Abhijeet et.al / IJIPSR / 8 (05), 2020, 1-13
Department of Pharmaceutics ISSN (online) 2347-2154
DOI: 10.21276/IJIPSR.2020.08.05.880
The chemical characterization of Drug-Resin complex was performed with respect to tests like
assay and dissolution.LOD was performed by the oven method at 105°C for 1 hour.
Solvation coating on Drug-Resin complex
The main ingredients for solvation coating were PEG and purified water. Compositions of trials
performed to optimize the concentration of solvating solution are given in below table 3.Two
concentrations of solvating solution were evaluated for processability and their observations are
presented accordingly. Drug-Resin complex was loaded in to the coating bowl of fluidized bed
coater. The product bed was heated to achieve a temperature of 25-35 °C by setting appropriate
temperature (30-90° C) for inlet air. The machine parameters, process parameters and coating
parameters recorded during solvation coating are given in table 4
Table 3: Composition of coating solution for trials performed to optimize the solid content
of solvating solution
Ingredients Batch A Batch B

Polyethylene glycol 38.36 27.78

Purified water 61.64 72.22

Theoretical total 100.00 100.00

Ethyl cellulose coating on Drug-Resin complex

Ethyl cellulose is a commonly used release rate controlling polymer. The mechanism of
controlling the drug release by application of ethyl cellulose films is by diffusion. Ethyl cellulose
coating solution was prepared by dissolving Dibutylsebacate used as a plasticizer followed by
Ethyl Cellulose NF22 having viscosity between 18-22 cps in a mixture of IPA: DCM (90:10)
under stirring for 5 minutes. The stirring was continued for 30 – 40 minutes after which a clear
solution was obtained. This solution was sifted through # 80(ASTM, 180µ) sieve. The dried and
sifted Drug-Resin complex was considered as the product bed for EC coating. The Drug-Resin
complex was coated with Ethyl cellulose solution such that 4% weight gain was obtained on
product bed. The manufacturing formula for 4% w/w of coated drug-resin complex is given in
table 4.

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RESEARCH ARTICLE Abhijeet et.al / IJIPSR / 8 (05), 2020, 1-13
Department of Pharmaceutics ISSN (online) 2347-2154
DOI: 10.21276/IJIPSR.2020.08.05.880
Table 4: Machine parameter and process parameter
Machine Parameters Observations
Nozzle diameter (mm) 0.8
Internal diameter of silicon tubing (mm) 4
Wurster column height (mm) 20
Bottom sieve size ( # size) # 250
Peristaltic pump (rpm) 3-4
Coating attachment Bottom spray
Process parameters
Inlet air temperature (°C) 26 – 41
Product bed temperature (°C) 26-30
Spray atomization air pressure (bars) 1.00
Exhaust Temperature(°C) 26-28
Spray rate (g/ min) 1.4-2.05

Table 5: Batch compositions in terms of 4 %w/w of Coated Drug-Resin complex

Ingredients Quantities
Drug-Resin complex 96.15
Ethyl cellulose N 22 3.51
Dibutylsebacate 0.34
Isopropyl alcohol q.s.
Dichloromethane q.s.
Theoretical total 100.00

Optimization of % Ethyl Cellulose coat on drug-resin complex.

In order to achieve extended release formulation for 24 hours, the micropellets were coated with
different level (%) of Ethyl cellulose such as 4%, 18%, 20.5%, 23%, 25% and 28% and effect of
this on assay, LOD and dissolution profile was studied.
Table 6: Machine and process parameters
Machine Parameters Observations
Nozzle diameter (mm) 0.8
Internal diameter of silicon tubing (mm) 4
Wurster column height (mm) 20
Bottom sieve size ( # size) # 250
Peristaltic pump (rpm) 3-4
Coating attachment Bottom spray
Process parameters
Inlet air temperature (°C) 26 – 41
Product bed temperature (°C) 26-30
Spray atomization air pressure (bars) 1.00
Exhaust Temperature(°C) 26-28
Spray rate (g/ min) 1.4-2.05

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RESEARCH ARTICLE Abhijeet et.al / IJIPSR / 8 (05), 2020, 1-13
Department of Pharmaceutics ISSN (online) 2347-2154
DOI: 10.21276/IJIPSR.2020.08.05.880
RESULTS AND DISCUSSION
Table 7: Physical Characteristics of the drug
Test Results
Description White crystalline solid or powder
Taste Bitter in taste
Odour Faint odour
Bulk density 0.55 gm/mL
Tap density 0.8 g/cc
Compressibility index 10
Particle size distributions 99.0% on 80 mesh
Angle of repose (°) -
LOD at 105°C for 5 minutes (%) 4.98%
pH Between 4 to 5
Residue on ignition NMT 0.1%
Sparingly soluble in water, freely soluble in
Solubility
alcohol and in Chloroform
Hygroscopicity Non-hygroscopic

Table 8: Slope and Linearity of Dextromethorphan Hydrobromide:

Y-intercept at 100%
Slope (m) Intercept (b) Y=m*x + b
level (%)
201.89 31.04 11975.03 0.26

Table 9: Assay of the drug by HPLC analysis

Actual Conc. Mean Area
Correlation coefficient Coefficient Determination [R2]
(µg/ml) (mAU*min)
1.8 370.762
14.8 3047.197
29.6 5978.671 1.0000 0.9999
59.2 12025.872
71.0 14325.795

Fig. 1: Linearity of Dextromethorphan Hydrobromide

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RESEARCH ARTICLE Abhijeet et.al / IJIPSR / 8 (05), 2020, 1-13
Department of Pharmaceutics ISSN (online) 2347-2154
DOI: 10.21276/IJIPSR.2020.08.05.880
Table 10: Selection of resin grade
Formulation details % Total impurity
Drug: Resin (Grade “Z” ) 0.00
Drug: Resin (Grade “W” ) 0.35
Drug: Resin (Grade “Y” ) 0.06
Drug: Resin (Grade “V” ) 0.29
The total % Impurity levels for drug resin complex manufactured with Amberlite IRP 69” were
not detected. Resin with grade “IRP 69” was selected for complexation with the drug .

Table 11: Dissolution of drug resin complexes with different ratios of drug: resin
Time (hrs) Ratio A(1:0.5) Ratio B (1:1) Ratio C (1:3)
% of Drug released
0.5 88.0 48.9 43.1
1 99.3 57.9 48.2
3 105.5 61.3 50.1

Fig.2: Dissolution of drug resin complexes with different ratios of drug: resin
The drug: resin ratio was optimized as ratio ‘1:3’ for further development of Drug-Resin
complex based on dissolution profile.
Table 12: Optimization of contact time between drug and resin.
Time of sample withdrawal Concentration of Drug in filtrate
After 20 minute stirring 0.31
After 40 minute stirring 0.44
After 60 minute stirring 0.36
After 80 minute stirring 0.44
After 100 minute stirring 0.16
After 120 minute stirring 0.08
After 140 minute stirring 0.08

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RESEARCH ARTICLE Abhijeet et.al / IJIPSR / 8 (05), 2020, 1-13
Department of Pharmaceutics ISSN (online) 2347-2154
DOI: 10.21276/IJIPSR.2020.08.05.880
After completion of 120 minutes of stirring, it was seen that drug content of slurry remained
constant withrespect to content of free/uncomplexed Dextromethorphan Hydrobromide i.e no
further complexation occurs. The stirring time required for drug-resin complex formation was
optimized as 120 minute (2 hours) after addition of resin to drug solution.
Table 13: Physical characterization of Drug-Resin complex
Parameters Observations
Bulk Density (g/ml) 0.5360
Tapped Density (g/ml) 0.7216
Angle of repose (°) 25.17
Flow rate (g/sec) 7.62
Particle size distribution (Sieve analysis method)
Mesh size % Retained
On 60 # (> 250 µ) 0.00
On 80 # (> 180 µ) 1.02
On 100 # (> 150 µ) 2.17
Below 100 # (< 150 µ) 96.81
The physical characterization of Drug-Resin complex showed that majority of particles were
below # 120 (ASTM, 125 µ) sieve. The angle of repose value suggests good flow properties.
Table 14: Chemical characterization of Drug-Resin complex
Parameters Observations Acceptance criteria
Assay (on dried
15 % w/w Dried complex should contain 12 – 18 % w/w
basis)
LOD 7.00 % w/w NMT 8 % w/w

Table 15: Dissolution profile of Drug Resin Complex:

Time (hrs) % drug released
0.0 0.0
0.5 43.1
1.0 48.2
3.0 50.1

Fig. 3: Dissolution profile of drug-resin complex

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RESEARCH ARTICLE Abhijeet et.al / IJIPSR / 8 (05), 2020, 1-13
Department of Pharmaceutics ISSN (online) 2347-2154
DOI: 10.21276/IJIPSR.2020.08.05.880
The release kinetics/ dissolution behavior of Drug-Resin complex shows 42% drug release in first
0.5 hrs and approximately 50 % of drug release at the end of 3 hrs.
Comparative FTIR of Drug, Resin & Drug Resin complex

Fig. 4: FTIR Spectrum of the drug

Fig. 5 FTIR Spectrum of resin

Fig. 6: FTIR Spectrum of drug-resin complex

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RESEARCH ARTICLE Abhijeet et.al / IJIPSR / 8 (05), 2020, 1-13
Department of Pharmaceutics ISSN (online) 2347-2154
DOI: 10.21276/IJIPSR.2020.08.05.880
Table 16: Dissolution profiles of trials taken for optimizing percentage of PEG 4000 coat
% Release of Dextromethorphan Hydrobromide
Trial 8 Trial 9
Time in hours % Average release % Average release
0.5 39.6 35.5
1.0 44.8 42.4
3.0 47.1 47.0

Fig.7: Dissolution profiles of trials taken for optimizing percentage of PEG 4000 coat

Table 17: Data on optimization of % Ethyl Cellulose coat on drug-resin complex.

EC Coat % 4.0 18.00 20.5 23.00 25.5 28.00

LOD % 7.18 6.20 6.60 6.20 6.7 6.90
Assay% 15.04 16.10 15.79 15.35 15.52 14.55
Dissolution
% drug release at 80.1 67.18 65.9 62.4 61.5 54.8
12 hrs.

Fig. 9: Dissolution profile of EC Coated pellets

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RESEARCH ARTICLE Abhijeet et.al / IJIPSR / 8 (05), 2020, 1-13
Department of Pharmaceutics ISSN (online) 2347-2154
DOI: 10.21276/IJIPSR.2020.08.05.880

Fig. 10: Dissolution profile of EC Coated pellets

The dissolution profile of this 25.5% EC coated drug resin complex shows that 61.5 % of drug
was released within 12 hours. From above data it can be conclude that 28% EC coating can cause
more drug retardation as compare to 23.5% EC coating this is due to over coating. Based on
results of dissolution profile of all the above trials and conclusion, 23.5 % EC coated micro
pellets were selected as a final optimized formulation. Thus micropellets of dextromethorphan
hydrobromide were prepared.
CONCLUSION
The study was undertaken with an aim to formulate dextromethorphan hydrobromide as sustained
release micropellets. The Preformulation studies were carried out on drug. Micromeritics like
bulk density, tap density, particle size analysis of Dextromethorphane HBR were carried out and
it was shows that Drug has good flow property. Various ion exchange resins were screened for
complexation with the drug and ratio of drug: resin was optimized along with manufacturing
process for complexation. The Drug-Resin complex was further coated with suitable hydrophobic
release rate retarding polymeric coatings using fluid bed processor. Optimization of % Ethyl
Cellulose coat on drug-resin complex was carried out and 23.5% EC coat was selected for
preparing final batch of micropellets of the drug Dextromethorphan hydrobromide. Thus it can be
concluded that micropellets of dextromethorphan hydrobromide are successful in providing
extended drug release.
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RESEARCH ARTICLE Abhijeet et.al / IJIPSR / 8 (05), 2020, 1-13
Department of Pharmaceutics ISSN (online) 2347-2154
DOI: 10.21276/IJIPSR.2020.08.05.880
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