Design of gastroretentive bilayer floating films of propranolol hydrochloride and rosuvastatin calcium
Design of gastroretentive bilayer floating films of
propranolol hydrochloride and rosuvastatin calcium.
Mr. Namdeo G. Shinde
Under the guidance of,
Dr. N. H. Aloorkar
M. Pharm. Ph. D
Satara College of Pharmacy, Degaon-Satara.
Need of present investigation
Material and methods
Results and discussion
The goal of any drug delivery system is to provide a therapeutic
amount of drug to proper site in the body to achieve and maintain
therapeutic concentration within range and to show pharmacological
action with minimum incidence of adverse effects.
To achieve this goal one should maintain dosing frequency and suitable
route of administration.
-Oral, parenteral, topical, nasal, rectal, vaginal, ocular etc.
Out of these routes, oral route of drug delivery is considered as the
most favored route of drug delivery, because of ease of
administration, more flexibility in designing, ease of production
and low cost.
Inability to restrain and locate the controlled drug delivery system
within the desired region of the GIT due to variable gastric emptying
Phases of migrating myoelectric cycle (MMC)
Phase I Phase lasts for 40-60 min. with rare contractions.
Phase lasts for 40-60 min.
Intensity and frequency increases gradually.
Phase lasts for 4-6 min. It includes intense and regular contractions for
short period. It is also known as the housekeeper wave.
Phase IV Phase lasts for 0-5 min and occurs between phases III and I of two
The real challenge in development of oral controlled release drug
delivery system is to sustain the release as well as prolong the
presence of dosage form in stomach or upper small intestine until
drug is completely released in desired period of time from suitable
Gastroretentive system can remain in the gastric region for several
hours and hence significantly prolongs gastric residence time of drug
which improves bioavailability.
To provide good floating behavior in the stomach the density of
system should be less than density of gastric contents
(~ 1.004 g/cm3).
Advantages of GRDDS
Improved drug absorption
Controlled delivery of drugs
Treatment of gastrointestinal disorders
Site-specific drug delivery
Ease of administration and better patient compliance
Simple and conventional equipments are required for manufacturing
Limitations of GRDDS
It is not a suitable system for drugs with stability or solubility
problem in stomach.
FDDS require sufficiently high level of fluid in the stomach.
Drugs having irritant effect on gastric mucosa are not suitable.
Retention of high-density systems in the antrum part under the
migrating waves of the stomach is questionable.
STRATEGIES FOR GASTRORETENTION
Low density systems (<1.004 g/cm3)
High density systems (3 g/cm3)
Expandable/swelling systems (12-18mm)
Swelling system Gastroretentive floating film
Gas generating system
Floating film delivery system
Emerged as an advanced alternative to traditional dosage forms
Floating film is drug loaded polymeric film consisting of an active
pharmaceutical ingredient, polymers, film forming agent, plasticizer
and suitable solvent.
Preparation of film is simple
Chances of cross contamination are very less
Handling of film is easy
Solvent evaporation method
Drug release profile can be modified by using different polymers.
Layer-by-layer film formulation technique in which one layer is
of controlled release polymer and another layer is of sustained release
polymer can be prepared.
• Polymeric dispersion of drug and
• Poured in petriplate and dried
• Thin layered film
Film forming polymers in floating films:
Provide quick disintegration and mechanical strength to the films.
Examples- pullulan, gelatin, guar gum, xanthan gum, hydroxyl propyl
methylcellulose, modified starches.
Ideal properties of the polymers used in the film drug delivery:
Non-toxic, non- irritant
Low density and readily available
Sufficient shear and tensile strength and shelf life.
Plasticizers used in floating films:
It helps to improve the flexibility of the film and reduces the
brittleness of the film.
Plasticizer significantly improves the film properties by reducing the
glass transition temperature of the polymer.
Glycerol, propylene glycol, low molecular weight polyethylene
glycols, citrate derivatives like triacetin, acetyl citrate, phthalate
derivatives like dimethyl, diethyl, dibutyl derivatives, etc.
NEED OF PRESENT INVESTIGATION
Cardiovascular diseases (CVDs) are the number one cause of death.
According to the WHO Report 2012, CVDs will be the largest cause of
death and disability in India by 2020.
Hypertension and hyperlipidemia are the major disorders of the
A strong need was recognized for the design of a single dosage form
which will give therapeutic effects on two or more diseases like
hypertension and hyperlipidemia simultaneously.
Hence to deliver propranolol HCl and rosuvastatin calcium
in the stomach, bilayer floating film was prepared.
To formulate gastroretentive bilayer floating films of propranolol
HCl and rosuvastatin calcium.
To investigate the effect of polymer and plasticizer on the film.
UV-Spectroscopic simultaneous estimation of propranolol HCl and
rosuvastatin calcium in pure drug and in bilayer film.
To evaluate gastroretentive bilayer floating films of propranolol
HCl and rosuvastatin calcium.
Kumar MP et al (2010) have studied the gastroretentive delivery of
mucoadhesive films containing pioglitazone using ethyl cellulose as a
rate controlling polymer, HPMC and carbopol-934 were used as
They found that the polymer concentration was a major factor
affecting the drug release and mucoadhesive strength of film.
Patel N et al (2011) have carried out formulation and evaluation of
floating tablets of metoprolol tartrate. They prepared tablets by using
MCC, HPMC K100M and HPMC K4M as polymers and sodium
bicarbonate as a gas-generating agent.
From this, they concluded that the floating tablets of metoprolol
tartrate could retard the release of drug upto a period of 8 hours.
Bhosale UV et al (2012) have studied the effect of concentration and
viscosity grade of polymer on drug release. They used hydroxypropyl
methylcellulose of different viscosity grades (HPMC K4M, HPMC
E5LV, HPMC K100M) as polymer and sodium bicarbonate as a gas-
generating agent to reduce floating lag time.
They concluded that as the viscosity and concentration of the
polymer was increased, drug release was decreased.
Brahmaiah B et al (2013) have formulated and evaluated of
gastroretentive floating drug delivery system of metoprolol tartarate.
They prepared floating tablets using HPMC K4M and HPMC K100M
as the release retardant polymers.
From this, they concluded that the floating tablets could control the
fluctuations in the plasma drug concentration, increased the
gastric residence time and eventually improved the bioavailability
of the drug.
Propranolol hydrochloride is non-selective beta-adrenergic receptor
blocking agent. It is white crystalline solid readily soluble in water and
Brandname Manufacturer Brandname Manufacturer
Beptazine MM Labs Inderal ® LA Wyeth pharmaceuticals
Betaprp- DZ Concern pharma. Pr Inderal ® LA Pfizer
Ciplar H Cipla Ltd. Propranolol hcl oral solution Roxane labs.
Corbetazine Nicholas piramal Inderal ® Akrimax pharmaceuticals
Dizepax Unimark pharma Tensyn plus Synokem pharmaceuticals
Syziral Psyco remedies Innopran XL Reliant pharmaceuticals
Melting point: 162-165°C
Molecular formula: C16H21NO2.HCl
Molecular weight: 295.80
Propranolol is completely absorbed after oral administration.
Due to first pass metabolism bioavailability is less (25%).
Peak plasma concentration occur about 1 to 4 h after an oral dose.
About 90 % of circulating propranolol is bound to plasma proteins.
Propranolol is extensively metabolized in kidney.
OCH2CHOHCH2NHCH(CH3)2 . HCl
Rosuvastatin calcium is a synthetic lipid-lowering agent.
Rosuvastatin is an inhibitor of HMG-CoA reductase. This enzyme
catalyzes the conversion of HMG-CoA to mevalonate, an early and
rate-limiting step in cholesterol biosynthesis.
Bestor 5,10 Biocon Ltd. Rozavel 5,10 Sun pharmaceuticals
Fortius 5,10,20 Nicholas piramal Rozucor 5,10 Torrent pharmaceuticals
Ldnil FC 10,20 Saremed Ltd. Rostar 5,10 Vencare formulations Ltd.
Novastat 5,20 Lupin Turbovas 5,10 Microlabs Ltd.
Razel 5,10,20 Glenmark Zyrova 5,10 Zydus Cadila healthcare
Suvalip 5,10 Orchid chemicals Rovalip 10 Cadila pharmaceuticals
Rosuvas 5,10,20 Ranbaxy Rosuvastat 10 Dr. Reddys Lab.
Treatment LDL reduction HDL increase
Atorvastatin (10-80 mg) 37-51 % 5.7-2 %
Simvastatin (10-80 mg) 28-46 % 5.3 -6.8 %
Rosuvastatin (5-40 mg) 46-55 % 7.6-9.6 %
Pravastatin (10-40 mg) 20-30 % 3.2-5.5 %
Effect of drugs on LDL and HDL levels
Melting point: 151-156°C
Molecular formula: (C22H27FN3O6S)2.Ca
Molecular weight: 1001.14°C
pyrimidin-5-yl]-(3R,5S)-3-5-dihydroxyhept-6-enoic acid] calcium salt
MATERIALS AND METHODS
Propranolol hydrochloride and rosuvastatin calcium were supplied by
Watson Pharma, Mumbai and Okasa Pharma, Satara respectively. HPMC
K4M, HPMC E5LV, Eudragit RS 100, dibutyl phthalate were procured
from Research-Lab Fine Chemicals, Mumbai.
Name of Equipments Manufacturer
1. Electronic balance AW 220, Shimadzu, Japan
2. UV Spectrophotometer Pharmaspec 1700, Shimadzu , Japan
3. Hot air oven Singhla Scientific, Ambala Cantt
4. Magnetic stirrer Remi Equipments, Mumbai
USP tablet dissolution
Electrolab, TDT- 08L, Mumbai, India
Fourier transform infrared
Alpha Bruker, Germany
Mettler- Toledo, Switzerland
Selection of Drug:
It was decided to formulate it in gastroretentive dosage forms because
it has short half-life (1-4 h), has less oral bioavailability (25%).
From literature survey it was found that rosuvastatin calcium causes
more decrease in cholesterol than any other statins. Its absolute
bioavailability is 20 %. The half-life is 19 h.
Selection of Polymers and Excipients:
HPMC K4M polymer is hydrophilic in nature and has good gelling
properties hence suitable for use in sustained release layer.
HPMC E5LV mainly cause rapid release of drug because of its low
viscosity hence suitable for incorporation in immediate release layer.
Eudragit RS-100, a polymethacrylate, was used as water insoluble film
former in sustained release layer and drug release retardant.
Dibutyl phthalate was used as a plasticizer. Water and ethyl alcohol
were used as solvents.
Sr. No. Ingredients Category
1. Rosuvastatin calcium API
2. Propranolol hydrochloride API
2. HPMC K4M, HPMC E5LV Hydrophilic polymers
3. Eudragit RL-100 Film former and drug release retardant
4. Dibutyl phthalate Plasticizer
5. Ethanol Solvent for Eudragit RS-100
6 Water Solvent for HPMC K4M and HPMC E5LV
Characterization of drug:
Melting point of drug
λ max determination and calibration curve of propranolol
hydrochloride and rosuvastatin calcium
Compatibility study between drug and excipients:
Preparation of films
Films with single and double layer were prepared by solvent
Preparation of solution for immediate release (IR) layer:
Polymeric dispersion were prepared by dissolving HPMC E5LV in
distilled water with constant stirring (300-350 rpm) on magnetic
Rosuvastatin calcium was separately dissolved in ethanol: water
(3:1) and added in polymeric solution followed by addition of
dibutyl phthalate as plasticizer.
Final solution was stirred vigorously on magnetic stirrer
(600-650 rpm) for 5 min.
Preparation of sustained release (SR) layer:
HPMC K4M and Eudragit RS 100 were individually dissolved in
distilled water and ethanol respectively.
Propranolol hydrochloride was dissolved in little quantity of water
and slowly added in polymeric dispersion followed by addition of
dibutyl phthalate as plasticizer with vigorous stirring on magnetic
stirrer (300-350 rpm).
Preparation of bilayer film:
Firstly solution of sustained release (SR) layer was casted on
petriplate and allowed to dry naturally (35-40 0C) at least for
40 min. then solution of immediate release layer (IR) was casted on
the dried film of CR layer and allowed to dry for at least 50 min.
naturally followed by drying in hot air oven at 45-50 0C for
On removal, the films were checked for possible imperfections
before being cut into 3×2 cm rectangles and stored.
Evaluation of gastroretentive drug delivery system
Visual appearance, thickness and weight of film
Folding endurance of film
Tensile strength of film
Percent moisture absorption study
Drug content and dissolution:
1 Apparatus USP Type II
2 Volume of medium 900 ml
3 Temperature 37±0.50C
4 Paddle Speed 50 rpm
5 Dissolution medium used 0.1 M HCl
Quantitative estimation of propranolol hydrochloride and
rosuvastatin calcium by UV spectroscopy
If the sample contain two absorbing drugs each of which absorb at
λmax of the other, it may be possible to determine both drugs by
Simultaneous estimation of two drugs can be possible only when
λmax of both drug components are reasonably dissimilar and two
components do not interact chemically.
It is calculated by formula,
𝑨 𝟐 𝒂𝒚 𝟏 − 𝑨 𝟏 𝒂𝒚 𝟐
𝒂𝒙 𝟐 𝒂𝒚 𝟏 − 𝒂𝒙 𝟏 𝒂𝒚 𝟐
ax1 and ax2 are absorptivities of PRO at λ1 and λ2 respectively.
ay1 and ay2 are absorptivities of ROS at λ1 and λ2 respectively.
A1 an A2 are absorbance of sample at λ1 and λ2 respectively.
𝑨 𝟏 𝒂𝒙 𝟐 − 𝑨 𝟐 𝒂𝒙 𝟏
𝒂𝒙 𝟐 𝒂𝒚 𝟏 − 𝒂𝒙 𝟏 𝒂𝒚 𝟐
RESULTS AND DISCUSSION:
Solubility of drug:
Freely soluble in ethanol, methanol, slightly soluble in water
Freely soluble in water, ethanol, methanol etc.
Melting Point of propranolol hydrochloride and rosuvastatin
calcium: Name of drug Melting point in OC
Melting point in OC
Propranolol hydrochloride 159-161 162-165
Rosuvastatin calcium 152-154 151-156
UV spectrophotometric method:
UV spectrophotometric method was used for simultaneous
quantitative determination of propranolol hydrochloride and
rosuvastatin calcium in bulk and pharmaceutical dosage form.
Absorptivity of propranolol
Absorptivity of rosuvastatin
Mean (n=3) 228.6 298.8 378.3 103.0
± SD 1.000 0.5859 1.336 1.261
Wt. of films
RP1 Opaque 91.74±0.23 16.66±0.57 308±2.00 57.26 1.15±1.02
RP 2 Opaque 92.69±0.23 17.50±0.50 291±3.60 59.23 1.60±0.60
RP 3 Opaque 92.85±0.17 17.33±0.57 271±2.52 59.93 2.41±0.69
RP 4 Opaque 117.07±0.23 20.56±0.51 265±2.08 60.07 2.08±0.96
RP 5 Opaque 117.17±0.96 20.66±0.57 259±2.65 60.26 2.77±0.57
RP 6 Opaque 118.23±0.32 20.33±0.15 249±1.53 60.81 2.41±0.66
RP 7 Opaque 124.20±0.40 22.86±0.87 232±3.51 61.12 5.05±0.46
RP 8 Opaque 127.13±0.59 22.00±1.00 217±3.06 61.31 6.98±0.42
RP 9 Opaque 127.21±0.50 23.29±0.61 205±3.00 62.09 7.86±0.80
Evaluation of gastroretentive floating bilayer films
0 25 50 75 100 125 150
Film weight (mg)Formulationcode
Film thickness (µm)
Weight of film
RP1 RP2 RP3 RP4 RP5 RP6 RP7 RP8 RP9
F Value P Value
Model 324.62 5 64.92 74.12 0.0024
X1 12.61 1 12.61 14.40 0.0321
X2 302.46 1 302.46 345.30 0.0003
X1X2 1.00 1 1.00 0.011 0.9217
(X1)2 3.29 1 3.29 3.76 0.1478
(X2)2 6.24 1 6.24 7.13 0.0757
Residual 2.63 3 0.88 - -
Core Total 327.254 8 - - -
Analysis of variance drug release
F Value P Value
Model 5.58 5 1.12 713.98 ˂0.0001
X1 5.57 1 5.57 3564.62 ˂0.0001
X2 2.81 1 2.81 1.80 0.2719
Residual 4.68 3 1.56 - -
Core Total 5.58 8 - - -
Analysis of variance for swelling index at 5h
Analysis of variance for tensile strength
F Value P Value
Model 14.13 2 7.07 27.19 0.0010
X1 10.94 1 10.94 42.07 0.0006
X2 3.20 1 3.20 12.30 0.0127
Residual 1.56 6 0.26 - -
Core Total 15.69 8 - - -
Response Surface Plot:
Contour plot Response 3D surface plot
The gastroretentive floating bilayer films of rosuvastatin calcium and
propranolol hydrochloride were prepared using immediate and
controlled release polymers by solvent casting method.
Based on the % drug release, swelling index, folding endurance and
floating time formulation RP5 was selected as an optimized
- Multilayer film DDS
- In-vitro buoyancy by string technique/endoscopy/gamma
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