Design of gastroretentive bilayer floating films of
propranolol hydrochloride and rosuvastatin calcium.
Presented by,
Mr. ...
CONTENTS
Introduction
Need of present investigation
Literature survey
Material and methods
Results and discussion
Conclusi...
INTRODUCTION
The goal of any drug delivery system is to provide a therapeutic
amount of drug to proper site in the body to...
-Physiological difficulties:
Inability to restrain and locate the controlled drug delivery system
within the desired regio...
The real challenge in development of oral controlled release drug
delivery system is to sustain the release as well as pro...
Advantages of GRDDS
Improved drug absorption
Controlled delivery of drugs
Treatment of gastrointestinal disorders
Site...
Limitations of GRDDS
 It is not a suitable system for drugs with stability or solubility
problem in stomach.
 FDDS requi...
STRATEGIES FOR GASTRORETENTION
Low density systems (<1.004 g/cm3)
High density systems (3 g/cm3)
Mucoadhesive systems
Supe...
Superporous hydrogels
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 loa...
Preparation:
Solvent evaporation method
Drug release profile can be modified by using different polymers.
Layer-by-layer...
Film forming polymers in floating films:
 Provide quick disintegration and mechanical strength to the films.
Examples- pu...
Plasticizers used in floating films:
It helps to improve the flexibility of the film and reduces the
brittleness of the fi...
NEED OF PRESENT INVESTIGATION
Cardiovascular diseases (CVDs) are the number one cause of death.
According to the WHO Repor...
A strong need was recognized for the design of a single dosage form
which will give therapeutic effects on two or more dis...
Objectives
To formulate gastroretentive bilayer floating films of propranolol
HCl and rosuvastatin calcium.
To investigate...
Kumar MP et al (2010) have studied the gastroretentive delivery of
mucoadhesive films containing pioglitazone using ethyl ...
Patel N et al (2011) have carried out formulation and evaluation of
floating tablets of metoprolol tartrate. They prepared...
Literature review
Bhosale UV et al (2012) have studied the effect of concentration and
viscosity grade of polymer on drug ...
Brahmaiah B et al (2013) have formulated and evaluated of
gastroretentive floating drug delivery system of metoprolol tart...
DRUG PROFILE
Propranolol Hydrochloride
Propranolol hydrochloride is non-selective beta-adrenergic receptor
blocking agent....
PKa: 9.4
Melting point: 162-165°C
Molecular formula: C16H21NO2.HCl
Molecular weight: 295.80
Pharmacokinetics-
Propranolol ...
Rosuvastatin Calcium
Rosuvastatin calcium is a synthetic lipid-lowering agent.
Rosuvastatin is an inhibitor of HMG-CoA red...
Treatment LDL reduction HDL increase
Atorvastatin (10-80 mg) 37-51 % 5.7-2 %
Simvastatin (10-80 mg) 28-46 % 5.3 -6.8 %
Ros...
MATERIALS AND METHODS
Propranolol hydrochloride and rosuvastatin calcium were supplied by
Watson Pharma, Mumbai and Okasa ...
Methods:
Selection of Drug:
Propranolol hydrochloride-
It was decided to formulate it in gastroretentive dosage forms beca...
Selection of Polymers and Excipients:
HPMC K4M polymer is hydrophilic in nature and has good gelling
properties hence suit...
Sr. No. Ingredients Category
1. Rosuvastatin calcium API
2. Propranolol hydrochloride API
2. HPMC K4M, HPMC E5LV Hydrophil...
Preformulation Study:
Characterization of drug:
 Solubility profile
 Melting point of drug
 λ max determination and cal...
Ingredients
Formulation codes
RP1 RP2 RP3 RP4 RP5 RP6 RP7 RP8 RP9
Immediate Release layer R1 R2 R3 R4 R5 R6 R7 R8 R9
Rosuv...
Preparation of films
 Films with single and double layer were prepared by solvent
casting method.
Preparation of solution...
Preparation of sustained release (SR) layer:
HPMC K4M and Eudragit RS 100 were individually dissolved in
distilled water a...
Preparation of bilayer film:
Firstly solution of sustained release (SR) layer was casted on
petriplate and allowed to dry ...
Evaluation of gastroretentive drug delivery system
Visual appearance, thickness and weight of film
Folding endurance of fi...
Quantitative estimation of propranolol hydrochloride and
rosuvastatin calcium by UV spectroscopy
If the sample contain two...
Where as,
ax1 and ax2 are absorptivities of PRO at λ1 and λ2 respectively.
ay1 and ay2 are absorptivities of ROS at λ1 and...
RESULTS AND DISCUSSION:
Preformulation Studies:
Solubility of drug:
 Rosuvastatin calcium:
Freely soluble in ethanol, met...
λ max determination:
Propranolol hydrochloride
(289 nm)
Rosuvastatin calcium
(240.5 nm)
Calibration curve of propranolol hydrochloride
Concentration
(µg/ml)
Absorbance
0 0.0000
4 0.1561
8 0.2946
12 0.4452
16 0....
Calibration curve of rosuvastatin calcium
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0 6 12 18 24 30 36
Absorbance
Concentration (µg/ml)
...
Drug and polymer compatibility:
Fourier transform infrared spectroscopy (FTIR):
Sr. No.
Wave number
(cm-1) for drug
Group ...
Differential Scanning Calorimetry (DSC):
UV spectrophotometric method:
UV spectrophotometric method was used for simultaneous
quantitative determination of propran...
Batch
code
Visual
appearance
Wt. of films
(mg)
Film thickness
(m)
Folding
Endurance
Tensile
strength (%)
Moisture
uptake ...
0 25 50 75 100 125 150
RP1
RP2
RP3
RP4
RP5
RP6
RP7
RP8
RP9
Film weight (mg)Formulationcode
14
16
18
20
22
24
26
RP1
RP2
RP...
R
P
1
R
P
2
R
P
3
R
P
4
R
P
5
R
P
6
R
P
7
R
P
8
R
P
9
50
55
60
65
70
Formulation code
Tensilestrength
Folding endurance
Te...
RP1
RP2
RP3
RP4
RP5
RP6
RP7
RP8
RP9
0
2
4
6
8
10
Formulation code
%Moistureabsorption
Percent moisture
absorption
0 2 4 6
...
Batch RP1 RP2 RP3 RP4 RP5 RP6 RP7 RP8 RP9
Immediate release (IR) layer: Rosuvastatin calcium
Batch R1 R2 R3 R4 R5 R6 R7 R8...
In-vitro drug release:
Immediate release (IR) layer (Rosuvastatin calcium)
Time R1 R2 R3 R4 R5 R6 R7 R8 R9
1min 4.4±0.56 1...
Sustained release (SR) layer (Propranolol hydrochloride)
P1 P2 P3 P4 P5 P6 P7 P8 P9
1h 47.9±0.66 39.2±0.42 35.4±0.64 44.6±...
Data Analysis of Formulations
Responses X1 X2 TS (%) Rel8h (%) SI5h
RP1 -1 -1 57.26 101.6 1.54
RP2 -1 0 59.23 93.7 1.51
RP...
ANOVA Study
Source
Sum of
Squares
Degree of
Freedom
Mean
Square
F Value P Value
Model
Significant/
Not
significant
Model 3...
Analysis of variance for tensile strength
Source
Sum of
Squares
Degree of
Freedom
Mean
Square
F Value P Value
Model
Signif...
Response Surface Plot:
Contour plot Response 3D surface plot
Contour plot Response 3D surface plot
Contour plot Response 3D surface plot
CONCLUSION
The gastroretentive floating bilayer films of rosuvastatin calcium and
propranolol hydrochloride were prepared ...
- Multilayer film DDS
- In-vitro buoyancy by string technique/endoscopy/gamma
scintigraphy
FUTURE PERSPECTIVES
REFERENCES
 AK Beckett, JB Stenlake. Practical Pharmaceutical Chemistry, 4th edition part II, CBS
Publisher and Distribut...
 Chawla G, Gupta P, Koradia V, Bansal AK. Gastroretention a means to address regional
variability in intestinal drug abso...
 Jasmine Chaudhari, Aakash Jain, Vipine Saini. Simultaneous estimation of multicomponent
formulations by UV visible spect...
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Design of gastroretentive bilayer floating films of propranolol hydrochloride and rosuvastatin calcium

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Design of gastroretentive bilayer floating films of propranolol hydrochloride and rosuvastatin calcium

  1. 1. Design of gastroretentive bilayer floating films of propranolol hydrochloride and rosuvastatin calcium. Presented by, Mr. Namdeo G. Shinde B. Pharm. Under the guidance of, Dr. N. H. Aloorkar M. Pharm. Ph. D Satara College of Pharmacy, Degaon-Satara. 2013-2014.
  2. 2. CONTENTS Introduction Need of present investigation Literature survey Material and methods Results and discussion Conclusion Future perspectives References
  3. 3. INTRODUCTION 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.
  4. 4. -Physiological difficulties: Inability to restrain and locate the controlled drug delivery system within the desired region of the GIT due to variable gastric emptying and motility. Phases of migrating myoelectric cycle (MMC) Phase I Phase lasts for 40-60 min. with rare contractions. Phase II (Pre-burst phase) Phase lasts for 40-60 min. Intensity and frequency increases gradually. Phase III (burst phase) 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 consecutive cycles
  5. 5. 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 formulation. 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).
  6. 6. 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
  7. 7. 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.
  8. 8. STRATEGIES FOR GASTRORETENTION Low density systems (<1.004 g/cm3) High density systems (3 g/cm3) Mucoadhesive systems Superporous hydrogels Expandable/swelling systems (12-18mm) Magnetic systems
  9. 9. Superporous hydrogels Swelling system Gastroretentive floating film Gas generating system
  10. 10. 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. Advantages- Preparation of film is simple Time saving Chances of cross contamination are very less Handling of film is easy
  11. 11. Preparation: 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. 1 • Polymeric dispersion of drug and polymer 2 • Poured in petriplate and dried 3 • Thin layered film
  12. 12. 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.
  13. 13. 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. Examples- Glycerol, propylene glycol, low molecular weight polyethylene glycols, citrate derivatives like triacetin, acetyl citrate, phthalate derivatives like dimethyl, diethyl, dibutyl derivatives, etc.
  14. 14. 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 cardiovascular system.
  15. 15. 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.
  16. 16. Objectives 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.
  17. 17. 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 mucoadhesive polymers. They found that the polymer concentration was a major factor affecting the drug release and mucoadhesive strength of film. Literature review
  18. 18. 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. Literature review
  19. 19. Literature review 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.
  20. 20. 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. Literature review
  21. 21. DRUG PROFILE Propranolol Hydrochloride Propranolol hydrochloride is non-selective beta-adrenergic receptor blocking agent. It is white crystalline solid readily soluble in water and ethanol. 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
  22. 22. PKa: 9.4 Melting point: 162-165°C Molecular formula: C16H21NO2.HCl Molecular weight: 295.80 Pharmacokinetics- 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 2-Propranol,1-[(1-methylethyl)amino]-3-(1-napthalenyloxy)-hydrochloride
  23. 23. Rosuvastatin Calcium 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. Brand names Dose (mg) Manufacturers Brand name Dose (mg) Manufacturers 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.
  24. 24. 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 PKa: 4.6 Melting point: 151-156°C Molecular formula: (C22H27FN3O6S)2.Ca Molecular weight: 1001.14°C N NN SO2Me O- OH OH O F Ca2+ Bis[(E)-7-[4-(flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl]-(3R,5S)-3-5-dihydroxyhept-6-enoic acid] calcium salt 2
  25. 25. 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. Sr. No. 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 5. USP tablet dissolution apparatus Electrolab, TDT- 08L, Mumbai, India 6. Fourier transform infrared spectrophotometer (FTIR) Alpha Bruker, Germany 7. Differential scanning calorimeter Mettler- Toledo, Switzerland
  26. 26. Methods: Selection of Drug: Propranolol hydrochloride- It was decided to formulate it in gastroretentive dosage forms because it has short half-life (1-4 h), has less oral bioavailability (25%). Rosuvastatin calcium- 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.
  27. 27. 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.
  28. 28. 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 FORMULATION INGREDIENTS
  29. 29. Preformulation Study: Characterization of drug:  Solubility profile  Melting point of drug  λ max determination and calibration curve of propranolol hydrochloride and rosuvastatin calcium Compatibility study between drug and excipients:  DSC Study  IR spectroscopy
  30. 30. Ingredients Formulation codes RP1 RP2 RP3 RP4 RP5 RP6 RP7 RP8 RP9 Immediate Release layer R1 R2 R3 R4 R5 R6 R7 R8 R9 Rosuvastatin calcium 5 5 5 5 5 5 5 5 5 HPMC E5LV 15 15 15 20 20 20 25 25 25 Dibutyl phthalate 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 Ethanol: Water 3:4 3:4 3:4 3:4 3:4 3:4 3:4 3:4 3:4 Sustained Release layer P1 P2 P3 P4 P5 P6 P7 P8 P9 Propranolol hydrochloride 40 40 40 40 40 40 40 40 40 HPMC K4M 20 20 20 25 25 25 30 30 30 Eudragit RS 100 04 06 08 04 06 08 04 06 08 Dibutyl phthalate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Ethanol: Water 3:7 3:7 3:7 3:7 3:7 3:7 3:7 3:7 3:7 FORMULATION TABLE
  31. 31. Preparation of films  Films with single and double layer were prepared by solvent casting method. 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 stirrer. 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.
  32. 32. 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).
  33. 33. 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 30-60 min. On removal, the films were checked for possible imperfections before being cut into 3×2 cm rectangles and stored.
  34. 34. 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 Swelling index 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
  35. 35. 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 Vierodt’s method. 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, 𝑪𝒑𝒓𝒐 = 𝑨 𝟐 𝒂𝒚 𝟏 − 𝑨 𝟏 𝒂𝒚 𝟐 𝒂𝒙 𝟐 𝒂𝒚 𝟏 − 𝒂𝒙 𝟏 𝒂𝒚 𝟐
  36. 36. Where as, 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. 𝑪𝒓𝒐𝒔 = 𝑨 𝟏 𝒂𝒙 𝟐 − 𝑨 𝟐 𝒂𝒙 𝟏 𝒂𝒙 𝟐 𝒂𝒚 𝟏 − 𝒂𝒙 𝟏 𝒂𝒚 𝟐
  37. 37. RESULTS AND DISCUSSION: Preformulation Studies: Solubility of drug:  Rosuvastatin calcium: Freely soluble in ethanol, methanol, slightly soluble in water  Propranolol hydrochloride: Freely soluble in water, ethanol, methanol etc. Melting Point of propranolol hydrochloride and rosuvastatin calcium: Name of drug Melting point in OC (Test compound) Melting point in OC (Literature value) Propranolol hydrochloride 159-161 162-165 Rosuvastatin calcium 152-154 151-156
  38. 38. λ max determination: Propranolol hydrochloride (289 nm) Rosuvastatin calcium (240.5 nm)
  39. 39. Calibration curve of propranolol hydrochloride Concentration (µg/ml) Absorbance 0 0.0000 4 0.1561 8 0.2946 12 0.4452 16 0.5874 20 0.7443 24 0.8389 28 0.9542 32 1.163 36 1.2895 40 1.3726 λmax 289 nm Slope 0.0347075 Intercept 0.019104545 Correlation coefficient 0.998617469 Beers range 4-40 µg/mi 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 0 4 8 12 16 20 24 28 32 36 40 Absorbance Concentration (µg/ml)
  40. 40. Calibration curve of rosuvastatin calcium 0 0.2 0.4 0.6 0.8 1 1.2 1.4 0 6 12 18 24 30 36 Absorbance Concentration (µg/ml) Concentration (µg/ml) Absorbance 0 0.000 6 0.223 12 0.4452 18 0.6129 24 0.7962 30 0.9876 36 1.2976 λmax 240.5 nm Slope 0.034363 Intercept 0.004679 Correlation coefficient 0.996826 Beers range 6-36 µg/ml
  41. 41. Drug and polymer compatibility: Fourier transform infrared spectroscopy (FTIR): Sr. No. Wave number (cm-1) for drug Group responsible Propranolol hydrochloride (E) 1. 798 Α-substituted naphthalene (790 cm-1) 2. 1264 Aryl O-CH2 asymmetric stretch 3. 1030 Aryl O-CH2 symmetric stretch (1035 cm-1) 4. 2962 C-H stretching (3000-2950 cm-1) Rosuvastatin calcium (D) 5. 2822 N-H stretching 6. 1732.13 C=O stretching 7. 1544 C=C stretching 8. 2922.25 C-H stretching (3000-2950 cm-1) 9. 1433 N-H bending 10. 1430 Asymmetric bending vibration of CH3 group 11. 1379 Symmetric bending vibration of CH3 group 12. 1328 Asymmetric vibration for S=O 13. 774 , 588, 488 C=C of benzene ring 14. 1227 Bending vibration for C-H 15. 1150 C-F stretching vibrations A) Eudragit RS100 B) HPMC K4M, C) HPMC E5LV D) Rosuvastatin calcium, E) Propranolol hydrochloride, F) Physical mixture of drug and polymer, G) Representative formulation
  42. 42. Differential Scanning Calorimetry (DSC):
  43. 43. 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 hydrochloride Absorptivity of rosuvastatin calcium 289 nm (ax1) 240.5 nm (ay1) 240.5 nm (ax2) 289 nm (ay2) Mean (n=3) 228.6 298.8 378.3 103.0 ± SD 1.000 0.5859 1.336 1.261
  44. 44. Batch code Visual appearance Wt. of films (mg) Film thickness (m) Folding Endurance Tensile strength (%) Moisture uptake study 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
  45. 45. 0 25 50 75 100 125 150 RP1 RP2 RP3 RP4 RP5 RP6 RP7 RP8 RP9 Film weight (mg)Formulationcode 14 16 18 20 22 24 26 RP1 RP2 RP3 RP4 RP5 RP6 RP7 RP8 RP9 Film thickness (µm) Formulationcode Weight of film Thickness of film
  46. 46. R P 1 R P 2 R P 3 R P 4 R P 5 R P 6 R P 7 R P 8 R P 9 50 55 60 65 70 Formulation code Tensilestrength Folding endurance Tensile strength 0 50 100 150 200 250 300 350 RP1 RP2 RP3 RP4 RP5 RP6 RP7 RP8 RP9 Foldingendurance Formulation code
  47. 47. RP1 RP2 RP3 RP4 RP5 RP6 RP7 RP8 RP9 0 2 4 6 8 10 Formulation code %Moistureabsorption Percent moisture absorption 0 2 4 6 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 RP1 RP2 RP3 RP4 RP5 RP6 RP7 RP8 RP9 Time (h) Swellingindex Swelling index
  48. 48. Batch RP1 RP2 RP3 RP4 RP5 RP6 RP7 RP8 RP9 Immediate release (IR) layer: Rosuvastatin calcium Batch R1 R2 R3 R4 R5 R6 R7 R8 R9 % content 97.5±0.74 101.6±0.25 103.1±0.57 100.26±0.92 104.34±0.81 102.3±0.66 100.12±0.11 102.33±0.53 104.27±0.34 Sustained release (SR) layer: Propranolol hydrochloride Batch P1 P2 P3 P4 P5 P6 P7 P8 P9 % content 102.7±0.59 99.40±0.61 101.5±0.83 104.40±0.57 99.60±0.29 97.5±0.67 99.70±0.73 97.00±0.26 98.80±0.57 Drug Content:
  49. 49. In-vitro drug release: Immediate release (IR) layer (Rosuvastatin calcium) Time R1 R2 R3 R4 R5 R6 R7 R8 R9 1min 4.4±0.56 10.8±0.6 10.0±0.57 4.2±0.66 30.0±0.42 10.4±0.2 12.6±0.5 16.4±0.5 10.4±0.5 2 min 28.8±0.44 26.4±0.5 38.6±0.66 30.0±0.6 42.0±0.57 31.4±0.6 43.4±0.6 46.8±0.3 33.2±0.8 3 min 44.0±0.66 58.8±0.2 51.2±0.54 37.6±0.7 71.0±0.66 52.2±0.4 76.8±0.2 59.6±0.7 78.2±0.6 4 min 48.6±0.58 66.0±0.4 75.41±0.5 55.2±0.6 76.8±0.24 75.4±0.6 79.6±0.5 74.6±0.6 93.6±0.4 5 min 77.4±0.66 97.6±0.66 97.6±0.42 90.4±0.84 97.0±0.23 94.6±0.57 93.8±0.45 87.2±0.82 100.8±0.4 6 min 94.0±0.57 99.4±.44 99.4±0.66 99.0±0.57 103.8±0.4 101.4±0.5 99.0±0.47 101.4±0.2 102.8±0.1 0.0 1.5 3.0 4.5 6.0 0 10 20 30 40 50 60 70 80 90 100 110 R1 R2 R3 R4 R5 R6 R7 R8 R9 Time (Min.) %Drugrelease
  50. 50. Sustained release (SR) layer (Propranolol hydrochloride) P1 P2 P3 P4 P5 P6 P7 P8 P9 1h 47.9±0.66 39.2±0.42 35.4±0.64 44.6±0.56 38.4±0.42 31.8±0.53 52.6±0.74 51.5±0.68 38.5±0.37 2h 51.40±0.2 49.2±0.92 42.1±0.57 51.5±0.37 51.7±0.57 46.5±0.14 62.7±0.42 60.6±0.94 45.4±0.66 3h 57.7±0.76 50.3±0.35 47.7±0.34 55.3±0.74 59.2±0.66 48.2±0.12 66.8±0.94 65.0±0.47 52.8±0.43 4h 61.8±0.38 61.1±0.57 59.6±0.84 66.0±0.42 62.5±0.24 52.2±0.46 73.8±0.35 74.3±0.57 60.2±0.34 5h 72.8±0.56 67.0±0.34 65.1±0.57 73.8±0.24 69.2±0.23 60.2±0.84 80.1±0.57 81.1±0.22 60.7±0.74 6h 82.8±0.27 71.2±0.64 73.1±0.66 86.6±0.77 76.08±0.4 51.0±0.35 89.8±0.66 81.3±0.66 73.9±0.33 7h 87.8±0.66 86.8±0.66 86.8±0.36 95.9±0.14 80.9±0.3 69.2±0.67 99.0±0.57 85.2±0.72 76.8±0.44 8h 101.6±0.5 95.7±0.72 88.7±0.57 101.8±0.5 93.5±0.4 87.2±0.57 99.65±0.35 89.2±0.66 85.5±0.37 0 2 4 6 8 0 10 20 30 40 50 60 70 80 90 100 110 P1 P2 P3 P4 P5 P6 P7 P8 P9 Time (Hours) %Drugrelease
  51. 51. Data Analysis of Formulations Responses X1 X2 TS (%) Rel8h (%) SI5h RP1 -1 -1 57.26 101.6 1.54 RP2 -1 0 59.23 93.7 1.51 RP3 -1 +1 59.93 87.7 1.53 RP4 0 -1 60.07 101.8 2.49 RP5 0 0 60.26 93.5 2.52 RP6 0 +1 60.81 87.2 2.51 RP7 +1 -1 61.12 99.60 3.54 RP8 +1 0 61.31 89.2 3.42 RP9 +1 +1 62.09 85.5 3.40 Rel8h= +92.98889 -1.45X1 – 7.100X2 – 0.05000X1 2 -1.28333X2 2 + 1.76664X1X2 (R2 = 0.9920) SI= +2.49444 + 0.96333X1 – 0.021667X2 (R2 = 0.9982) TS (%) =+60.42+1.35X1+0.73 X2 (R2 = 0.9534)
  52. 52. ANOVA Study Source Sum of Squares Degree of Freedom Mean Square F Value P Value Model Significant/ Not significant Model 324.62 5 64.92 74.12 0.0024 Significant 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 Source Sum of Squares Degree of Freedom Mean Square F Value P Value Model Significant/ Not significant Model 5.58 5 1.12 713.98 ˂0.0001 Significant 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
  53. 53. Analysis of variance for tensile strength Source Sum of Squares Degree of Freedom Mean Square F Value P Value Model Significant/ Not significant Model 14.13 2 7.07 27.19 0.0010 Significant 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 - - -
  54. 54. Response Surface Plot: Contour plot Response 3D surface plot
  55. 55. Contour plot Response 3D surface plot
  56. 56. Contour plot Response 3D surface plot
  57. 57. CONCLUSION 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 formulation.
  58. 58. - Multilayer film DDS - In-vitro buoyancy by string technique/endoscopy/gamma scintigraphy FUTURE PERSPECTIVES
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  62. 62. THANK YOU…

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