Formulation and Evaluation of Fast Dissolving film of Labetalol Hydrochloride

 

Sanket Jain*, Sujit Pillai, Rampal Singh Mandloi, Nidhi Namdev, Nikhlesh Birla

GRY Institute of Pharmacy, Borawan (Distt. Khargone) 451228.

*Corresponding Author E-mail: sanketj0960@gmail.com

 

ABSTRACT:

The present study was aimed to formulate and evaluate oral fast dissolving oral films of Labetalol Hydrochloride using different grades of water soluble polymers HPMC (E5, E15, E50). The suitable plasticizer Propylene Glycol were selected for the preparation of the film. The films are prepared by solvent casting method. Nine formulations (F1-F9) of Labetalol Hydrochloride films were prepared and films were evaluated for appearance, weight variations, thickness, folding endurance, surface pH, drug content and In-vitro dissolution studies gave satisfactory result. F2 was found to be the best and acceptable formulation which contains HPMC E5 whose drug content was about 99.06±0.025% and percentage (%) drug release in 9 min. is about (99.2±0.152%) high as compared to other formulation and has surface pH of (6.6±0.126) obtained in simulated saliva (pH buffer 6.7).

 

KEYWORDS: Labetalol Hydrochloride, HPMC (E5, E15, E50), Propylene Glycol, Polyvinylpyrrolidone, Citric acid.

 

 


1.    INTRODUCTION:

Despite of tremendous advancement in drug delivery the oral route of drug administration is the most important method of administration of drug for systemic effect. Oral route is most preferred route by medical practitioners and manufacturer due to highest acceptability of patients.[1] Many pharmaceutical companies have directed their research activity in reformulating existing drugs into new dosage forms. One such relatively new dosage form is the oral strip, a thin film that is prepared using hydrophilic polymers that rapidly dissolves on the tongue or buccal cavity.[2] It is an ultrathin strip (50-150 microns thick) of postage stamp size with an active agent which is simply placed on the patient’s tongue or any oral mucosal tissue, instantly wet by saliva the film rapidly hydrates and adheres onto the site of application. It then rapidly disintegrates in a matter of seconds and dissolves to release medication for oromucosal absorption.[3]

 

Hypertension is the state of increase in blood pressure than normal tension of 120/80 mm Hg. It is not a disease in itself, but is an important risk factor for cardio-vascular mortality and morbidity.[4]

 

Anti-Hypertensive’s are the agents that tend to lower the Blood pressure. Different classes of drugs have received prominence with passage of time.[4]

 

Labetalol HCl competitively blocks adrenergic stimulation of β-receptors within the myocardium (β1-receptors) and within bronchial and vascular smooth muscle (β2-receptors), and α1-receptors within vascular smooth muscle.[5] Labetalol is a white or off-white crystalline powder, soluble in water. It is used to treat chronic and acute hypertension of pheochromocytoma and hypertension crisis. It has a half life of 6-8 hrs.[4]

 

2. MATERIAL AND METHOD:

Labetalol hydrochloride was purchased by Yarrow Pharm Pvt. Ltd, Mumbai. HPMC [E5, E15], vanillin was purchased by Yarrow Pharma Pvt. Ltd, Mumbai, Propylline Glycol, Citric acid, HPMC E50 was purchased by Loba chem Pvt. Ltd., Indore. Mannitol was purchased by Merck, Mumbai. Polyvenylpyrollidone was purchased by Sisco Research Lab, Mumbai.

 

2.1 METHODOLOGY:

Preparation of fast dissolving films:

The fast dissolving film of Labetalol Hydrochloride were prepared by solvent casting technique using different grades of HPMC (E5, E15, E50) as water soluble polymer. PG (Propylene glycol) were used as plasticizer. The required amount of polymer was dissolved in boiled distilled water with continous stirring using magnetic stirrer for 30 minutes. The calculated amount of Labetalol Hydrochloride was dissolved in distilled water along with other excipients in separate beaker for 30 minutes and drug solution were mixed to polymer solution and kept for stirring for 30 minutes. The solution were casted on petri dish (areas of 25 cm2) then kept in tray dryer at 42oc for 24 hours. Then film was further peeled and cut into 2×2 cm2 area and kept in dessicator till next use.[1]


 

Table no. 1 Composition of fast dissolving films of Labetalol Hydrochloride

Ingredients (mg)

F1

F2

F3

F4

F5

F6

F7

F8

F9

Labetalol Hydrochloride

280

280

280

280

280

280

280

280

280

HPMC E5

250

500

750

-

-

-

-

-

-

HPMC E15

-

-

-

250

500

750

-

-

-

HPMC E50

-

-

-

-

-

-

250

500

750

PVP

250

250

250

250

250

250

250

250

250

PG (ml)

0.5

0.5

0.5

0.5

0.5

0.5

0.5

0.5

0.5

Citric acid

10

10

10

10

10

10

10

10

10

Vannilin

10

10

10

10

10

10

10

10

10

Mannitol

10

10

10

10

10

10

10

10

10

 


 

 

Fig No. 1 Fast dissolving oral film of Fig no. 2 Desired dose of fast dissolving film of Labetalol Hydrochloride with HPMC E5 Labetalol Hydrochloride with HPMC E5.

 

3. Evaluation of film:

3.1 Physical appearance:[6]

This parameter was checked simply with a visual inspection of films.

 

3.2 Weight variation:[7]

The patches were subjected to mass variation study by individually weighing randomly selected patches. The average of five observations of each batch was calculated. Such determinations were carried out for each batch.

 

3.3 Thickness:[8]

The thickness of the Fast dissolving film was evaluated using vernier calipers (Mitutoyo, Japan)[9] at the different strategic locations. This is essential to ascertain uniformity in the thickness of the film as this is directly related to the accuracy of the dose in the strip[8]. The average of three readings was taken as mean thickness. The results are shown in table.[9]

 

3.4 Folding Endurance:[10]

The folding endurance is expressed as the number of folds (number of times of film is folded at the same plain) required breaking the specimen or developing visible cracks. This indicates the brittleness of the film. A small strip of 4 square cm was subjected to this test by folding the film at the same plane repeatedly several times until a visible crack was observed.

 

3.5 Surface pH test[1]

The film is slightly wet with the help of water. The pH is measured by bringing the electrode in contact with the surface of the oral film. This study is performed on three films of each formulation and means ± S.D calculated.

 

3.6 Drug Content[11]

Drug content can be determined by dissolving the film in 100ml of distill water to get 20μg/ml solutions. An aliquot of a 2ml sample can withdraw and diluted to 10 ml with a solution. Then the solution can be filtered through Whatman filter and solution analyzed spectrophotometrically at 302.00nm.

 

3.7 In vitro dissolution studies:[1]

In-vitro dissolution of fast dissolving film was studied in the USP paddle dissolution test apparatus using phosphate buffer pH 6.8 as the dissolution medium. The temperature was maintained at 37±0.5ºC throughout the experiment. 5ml sample was withdrawn at 1-minute intervals and the same quantity was replaced with phosphate buffer of pH 6.8. The aliquots are analyzed by estimating absorbance after suitable dilution at 304.30 nm by using a UV visible spectrophotometer.

 

 

Table no: 2 Dissolution Study Parameter

S.No.

Parameters

Specifications

1.

USP dissolution apparatus

Type II [Paddle method]

2.

Volume of dissolution medium

900 ml

3.

Speed of rotation

50 rpm

4.

Temperature

37º±0.5ºC

5.

Dissolution medium

Phosphate buffer pH 6.8

 

4.0 RESULT AND DISCUSSION:

4.1 Evaluations:

4.1.1 Physical appearance:[6]

The appearance of all formulations were found smooth and transparent.

 

4.1.2 Weight variation:[7]

The weight variation for all the formulation is tabulated in (Table No.1). It was found to be uniform 512±0.57 mg to 698.5±0.71 mg. The weight of all the oral fast-dissolving film (Table No. 11) was found to be uniform.

 

4.1.3 Thickness:[8]

All the films have uniform thickness throughout. The thickness of all the formulations ranged between 0.186±0.116 mm to 0.321±0.166. In all the cases the standard deviation values are very low which suggest the prepared films were uniform in thickness. The results are given in (Table No.1)

4.1.4 Folding Endurance:[11]

The folding endurance was measured manually. The results are shown in (Table No.1). The folding endurance of all the formulations ranged between 89±0.56 to 265±0.98. The folding endurance values of the FDF were found to be optimum and therefore, the fast dissolving film exhibited good physical and mechanical properties.

 

4.1.5 Surface pH test:[1]

The surface pH was found to be in the range of 6.3 ± 0.128 to 6.9 ± 0.165 which is close to salivary pH, which indicates that films may have less potential to irritate the oral mucosa, thereby they are comfortable. The results are given in (Table No.1).

 

4.1.6 Drug Content:[11]

The drug content was performed for all the nine formulations and results are shown in (Table No.1). Three trials for each formulation were analyzed spectrophotometrically. The drug content of the film was found-between (95.6±0.051 % to 99.06±0.025 %) of Labetalol Hydrochloride. The results indicated that all formulations of the drug content were uniform.

 


 

Table No: 3 Observation of Evaluation Parameters of Fast Dissolving films of Labetalol HCl

S. No.

Appearance

Weight variations(mg)

Thickness(mm)

Folding endurance

Surface Ph

Drug content (%)

F1

Transparent

512±0.57

0.285±0.013

247±0.57

6.4 ±0.065

98.49±0.151

F2

Transparent

603±0.15

0.321±0.166

265±0.98

6.6 ± 0.323

99.06 ±0.025

F3

Transparent

552.7±0.63

0.198±0.106

232±0.84

6.4 ± 0.133

96.6±0.148

F4

Transparent

563.3±0.25

0.207±0.189

198±0.65

6.3 ± 0.207

97.9±0.115

F5

Transparent

696.3±0.61

0.245±0.065

227±0.87

6.5 ± 0.126

98.06±0.091

F6

Transparent

618.3±0.812

0.309±0.024

109±0.9

6.9 ± 0.165

97.24±0.270

F7

Transparent

521.4±0.191

0.189±0.09

204±0.12

6.3 ± 0.128

95.74±0.138

F8

Transparent

698.5±0.71

0.186±0.116

191±0.25

6.5 ± 0.341

96.15±0.048

F9

Transparent

537.1±0.95

0.202±0.091

89±0.56

6.9 ± 0.243

95.6 ± 0.051

(Mean ± S.D., n=3)

 

Table no: 4 Cumulative in-vitro dissolution drug release data for fast dissolving film.

Time

(per Minute)

% Cumulative Drug release

F1

F2

F3

F4

F5

F6

F7

F8

F9

0

0

0

0

0

0

0

0

0

0

1.

21.7±0.125

25±0.226

19±0.055

16±0.121

19±0.024

13±0.171

17±0.266

15.6±0.142

11±0.145

2.

28.4±0.225

37.8±0.056

27±0.214

23±0.256

27.1±0.115

19.6±0.190

26±0.096

23.5±0.051

19.4±0.041

3.

34.4±0.126

49.7±0.135

36.76±0.154

34.1±0.056

35.5±0.054

27±0.231

35.4±0.010

34.1±0.042

26.1±0.112

4.

41.2±0.165

58.4±0.018

45.6±0.145

41.2±0.151

41.4±0.245

36.7±0.026

44.1±0.185

47.1±0.247

34.5±0.269

5.

47.1±0.054

69.29±0.114

52.1±0.262

51.4±0.056

55±0.159

48.5±0.064

51.4±0.078

51±0.256

41.3±0.052

6.

57.6±0.215

76.1±0.210

61±0.184

61.76±0.095

62±0.151

57.2±0.241

61.7±0.098

59.7±0.158

53.7±0.149

7.

65.4±0.012

83.5±0.021

69.11±0.091

70.5±0.045

75.2±0.058

63±0.116

72.4±255

67.1±0.081

61±0.351

8.

77.2±0.036

91.8±0.143

77.4±0.245

79.5±0.154

86±0.171

71.4±0.179

77.5±0.155

74.4±0.256

69±0.019

9.

89.2±0.251

99.2±0.152

89.1±0.181

81.2±0.226

91±0.296

83.7±0.210

80.1±0.158

81.3±0.234

74±0.031

10

98.4±0.011

106.3±0.146

95.11±0.225

92.42±0.113

93.2±0.241

90.27±0.211

87.4±0.025

85.4±0.174

81.5±0.147

(Mean ± S.D., n=3)

 


4.5.6 In- vitro dissolution studies:[1]

It was observed that a higher amount of drug was released from HPMC E5 containing water-soluble polymer. The drug deliverance rate was high in formulation F2 and F1 (99.2±0.152, 98.4±0.114) in 9 and 10 minutes as drug rapidly dissolved. The other dissolution points of other formulations are F3 (95.11±0.225) which contains 750mg of water-soluble polymer HPMC E5. In the case of another formulation prepared with HPMC E15 formulation F4 (92.42±0.113) was released complete drug in 10 minutes whereas formulation F5, F6 released (93.2±0.241, 90.27±0.211) in 10 minutes.

 

Formulation F7 released drug (87.4±0.025) in 10 minutes whereas on the other hand formulation F8 and F9(85.4±0.174, 81.5±0.147) which contains HPMC E50 was unable to dissolve drug completely in 10 minutes due to the increased polymer viscosity. This indicates that drug release from films was mainly dependent on polymer viscosity and concentration of polymer used in the formulation.

 

Fig. No. 3 Graphical representation of Cumulative In-vitro Dissolution of Fast Dissolving Films.

 

5.0 CONCLUSION:

In the present investigation, an attempt was made to develop mouth dissolving films of Labetalol Hydrochloride to achieve fast dissolution characteristics with improved bioavailability by oral route and to improve patient compliance and onset of action.

 

The oral fast dissolving film of Labetalol Hydrochloride was prepared by using the water-soluble polymer as HPMC of different grades (E5, E15, E50) by solvent casting method. The method of the formulation was found to be modest and economic. HPMC was used as a film-forming agent, Propylene Glycol (PG) used as a plasticizer, Citric acid used as a preservative, mannitol used as a sweetening agent, and vanillin used as a flavoring agent.

 

To choose the best formulation various kind of parameters were evaluated physical appearance (transparent), weight variations(512±0.57mg to 698.5±0.71mg) was found to be uniform, thickness (0.186±0.116mm to 0.311±0.065mm), folding endurance (89±0.56 to 265±0.98), surface pH (6.3±0.128 to 6.9±0.165), drug content (95.6±0.051% to 99.06±0.025%) in-vitro drug release and compared.

 

It was concluded that amongst all 9 formulations, F2 was found to be the best and acceptable formulation which contains HPMC E5 whose drug content was about 99.06±0.025% and percentage (%) drug release in 9 min. is about (99.2±0.152%) high as compared to other formulation. The desired level of folding endurance (265±0.98) and pH (6.6±0.126) obtained in simulated saliva (pH buffer 6.7). It indicates that drug release from films mainly depends on polymer viscosity and concentration of polymer used in the formulation.. Fast dissolving film can be a potential novel drug dosage form for pediatric, geriatric, and also for the general population. The films were having much commercial success.

 

6.0 REFERENCE:

1.      Khatoon Naziya, Rao N. G. Raghavendra, Reddy B. Mahipal. Formulation and Evaluation of Oral Fast Dissolving Films of Montelukast Sodium. IJPSR. 2014; 5(5): 1780-1787.

2.      Kothapuvari Pavan Kumar, Rawat Swati, Darna Bhikshapathi. Fast dissolving oral films of almotriptan malate: Preparation and in vitro/in vivo evaluation. Innovations in Pharmacy and Pharmaceutical Technology. 2015; 1(1): 111-125.

3.      Patil Pallavi., Shrivastava S. K. Fast Dissolving Oral Films: an Innovative Drug Delivery System. International Journal of Science and Research (IJSR). July 2014; 3 (7); 996-1060.

4.      Gottumukkala Verma Manoj, Senthil Kumar K, Mohammed Gulzar Ahmed and Krishna K. An approach to formulate and evaluate Labetalol as Fast dissolving tablets. World Journal of Pharmaceutical Research. 2014; 3(6): 735-754.

5.      Nagar Bhanu, Sheorey Sonali, Agrawal Vipul, Shah Nirmal, Shah Jainam. Formulation and Evaluation of Orodispersible Labetalol Tablet for Hypertensive Crisis. Journal of Drug Delivery and Therapeutics. 2013; 3(6): 106-112.

6.      Ali MS, Vijendar C, Kumar D Sudheer and Krishnaveni J. Formulation and Evaluation of Fast Dissolving Oral Films of Diazepam. Journal of Pharmacovigilance. 2016; 4(3): 1-5.

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8.      Bhusnure O.G., Yeote N.S., Shete R.S., Gholve S.B., Giram P.S, Formulation and Evaluation of Oral Fast Dissolving Fim of Gabapentin by QBD approach. International Journal of Pharmacy and Biological Sciences. 2018; 8(2): 426-437.

9.      Narayana P. Raju, Kumar M. Sravan, Reddy Madhusudhan, and Ravishankar K., Formulation and Evaluation of Fast Dissolving Films of Loratidine by Solvent Casting Method. The Pharma Innovation – Journal. 2013; 2 (2): 31-35.

10.   Deepthi A., Reddy B. Venkateswara, and Navaneetha K., Formulation and Evaluation of Fast Dissolving Oral Films of Zolmitriptan. American Journal of Advanced Drug Delivery. 2014; 2(2): 153-163.

11.   Kadbhane N.S, Shinkar D.M, Saudagar R.B, An Overview on: Orally Fast Dissolving Film. International Journal of ChemTech Research. 2017; 10 (7): 815-821.

12.   Pavia D L, Lampman G M, Kriz G S. Introduction to Spectroscopy. Harcourt College Publishers. 2001; 3rd Edition: pp. 13-82.

 

 

 

Received on 19.10.2020         Modified on 07.11.2020

Accepted on 20.11.2020  ©AandV Publications All right reserved

Res. J. Pharmacognosy and Phytochem. 2021; 13(1):1-4.

DOI: 10.5958/0975-4385.2021.00001.7