INTRODUCTION:

The present study was aimed to formulate and evaluate the fast dissolving oral films of Ranitidine hydrochloride by using hydrophilic polymers like HPMC and SCMC by using solvent casting method.

Fast dissolving drug delivery system is a new generation delivery system also known as fast dissolving/ disintegrating film for the oral delivery of the drugs.

It is an alternative to tablets, capsules, syrups and other formulations for paediatric and geriatric patients who experience difficulties in swallowing traditional solid dosage forms which combines both the advantages of conventional tablet and of liquid formulation. The delivery system consists of a thin film of the size of a postage stamp, which is placed on the patient’s tongue or mucosal tissue, where it instantly hydrates by absorbing saliva; the film then rapidly disintegrates and dissolves to release the drug for oral mucosal absorption¹.

Ranitidine HCl, an H2 receptor antagonist which is widely prescribed in active duodenal ulcers, gastric ulcers, Zollinger-Ellison syndrome, gastro esophageal reflux disease, and erosive esophagitis. The recommended adult oral dosage of ranitidine is 150mg four times daily or 300 mg twice daily. Ranitidine HCl is bitter in taste so to provide this drug in a more accessible and patient compliant form and to overcome such problems, in the present study it was decided to mask the bitter taste and formulate into a fast dissolving oral film by using hydrophilic polymers².

MATERIALS AND METHODS:

Various materials and reagents used to carry out the experimental work are given in the following list:

Table 1: List of Materials for Formulation

Material	Procured from
Ranitidine HCl	Mylan Laboratories
HPMC K4M	S. D. Fine Chem. Ltd
SCMC	Oxford laboratory
PEG 400	Fischer- scientific Pvt ltd
Tween 80	Fine - chem industries
Citric acid	S. D. Fine Chem. Ltd
Sodium saccharin	S. D. Fine Chem. Ltd
Menthol	Rolex chemical industries
Ethanol	Central Exise Department
Purified water	Inhouse

Table 2: List of Reagent

Reagent	Procured from
Potassium di hydrogen phosphate	S. D. Fine Chem. Ltd
Sodium hydroxide	S. D. Fine Chem. Ltd
Concentrated Hydrochloric acid	S. D. Fine Chem. Ltd

Formulation of fast Dissolving Oral Films:

Table 3: Composition of various film formulations

Ingredients	F1	F2	F3	F4	F5	F6
Ranitidine HCl(mg)	100	100	100	100	100	100
HPMC K4M (mg)	300	500	---	---	300	500
SCMC (mg)	---	---	300	500	500	300
PEG 400 (ml)	0.5	0.5	0.5	0.5	0.5	0.5
Tween 80 (ml)	0.2	0.2	0.2	0.2	0.2	0.2
Citric acid (mg)	30	30	30	30	30	30
Sodium saccharin (mg)	20	20	20	20	20	20
Menthol (ml)	0.1	0.1	0.1	0.1	0.1	0.1
Ethanol (ml)	1	1	1	1	1	1
Purified water (ml)	5	5	5	5	5	5

Method of preparation of ranitidine hcl fast Dissolving Films:

The fast dissolving films of Ranitidine HCl were prepared by solvent casting technique using film forming polymer HPMC k4 M and SCMC. PEG is used as plasticizer. The required amount of polymer was dispersed in water with continuous stirring using magnetic stirrer. The calculated amount of Ranitidine HCl was dissolved in distilled water and added to polymer solution along with the other excipients and stirred to form homogenous solution. The solution was degassed and then casted on to Petri dish (area of 66.31 cm2) then kept in hot air oven at 40°C for 1 hours. Then the dried films were stored by wrapping in aluminium foil².

Evaluation of Ranitidine hcl fast Dissolving Films:

The prepared film was evaluated for following specifications.

A. Transparency:

Transparency was evaluated by visual appearance of oral film and categorized in various levels such as best, good, medium, bad for transparency⁶.

B. Surface texture:

Surface texture was evaluated by visual appearance of oral film and categorized in smooth to rough surface indicates by mathematical + sign¹.

C. Thickness:

For evaluation of film thickness three films of each formulation were taken and the film thickness was measured using micrometer screw gauge at three different places and the mean thickness of films were calculated and reported².

D. Weight variation:

Three films were taken from each batch and the individual weights were determined by using a digital electronic balance. The mean and standard deviation (S.D) were then calculated³.

E. Moisture absorption:

The film sample is weighed and placed on a pre weighed stainless steel wire mesh. The wire mesh is then submerged in a petridish containing 20 ml distilled water. Increase in weight of the film is determined at regular time intervals (10 min) until a constant weight is obtained the hydration ratio of the film is calculated and average moisture absorption is calculated and reported⁴.

Hydration ratio= Wt-W0×100/W0

Where Wt = weight of film at time t and W0 = weight of film at zero time.

F. Moisture loss:

The percent moisture loss was determined by placing prepared film in desiccators containing anhydrous calcium chloride. After three days, the film was taken and reweighed. Average percent moisture loss was calculated⁴.

Moisture loss=W0/W0-Wt×100

Where

W0= initial weight

Wt = final weight

G. Folding Endurance:

Folding endurance is measured by manual repeated folding of film at same place till it broke. The number of times the film is folded without breaking is known as the folding endurance value. A strip of 3 × 2cm diameter (an area of 6 cm2) was subjected to folding endurance by folding the film at the same place repeatedly several times until a visible crack was observed and the average values were calculated and reported⁴.

H. Surface pH Determination:

Surface pH of the films was determined in order to investigate the possible side effects due to change in pH in vivo, since an acidic or alkaline pH may cause irritation to the buccal mucosa. The film was placed in a petri dish and moistened with 0.5 ml of distilled water and kept for 1 h. pH was noted with the electrode of the pH meter. The average of three determinations for each formulation was done⁵.

I. Drug content:

Drug content determination of the film was carried out by dissolving the film of 4 cm 2 in 100ml of pH 6.8 phosphate buffer using magnetic stirrer for 1 hour. The drug concentration was then evaluated spectrophotometrically at λ_max of 313nm. The determination was carried out in triplicate for all the formulations and average with standard deviation was recorded⁵.

J. In vitro Disintegration Time (DT):

Disintegration test was performed to ensure the disintegration of film in phosphate buffer pH 6.8. Film was placed in beaker containing 10 ml of phosphate buffer pH 6.8. Slight agitation was given at every 10 s, the time at which film starts to disintegrate or break is the disintegration time. The disintegration time for oral films is 5-30 seconds. Although, no official guidance is available for FDFs⁶.

K. In-vitro Dissolution study:

In-vitro dissolution of fast dissolving film was studied in USP paddle dissolution test apparatus using pH 6.8 phosphate buffers as the dissolution medium. The temperature was maintained at 37± 0.5°C throughout the experiment. 5 ml Sample was withdrawn at 2 min intervals and the same quantity was replaced with pH 6.8 phosphate buffer. The cumulative percentage of drug released was determined using UV visible spectrophotometer at 313nm⁵.

RESULTS:

A. Visual inspection:

The prepared films showed uniform distribution of the drug without uneven shape and air entrapments. All the prepared films were pale yellow in colour and transparent.

B. Surface texture:

The prepared films were observed for its surface texture and categorized in smooth to rough surface indicates by mathematical + sign.

Table 4: Surface texture of Films

Formulation	Surface texture
F1	++
F2	++
F3	++
F4	++
F5	+++
F6	+++

C. Thickness test:

The thickness of the film was measured by using vernier callipers at different position of the film and the average thickness of each film was calculated.

Table 5: Thickness of Films

Formulation	Mean Thickness (mm)
F1	1
F2	1.1
F3	1.2
F4	1
F5	1.3
F6	1.2

D. Weight variation:

Two square inch film was cut at five different places in the cast film. The weight of each film/strip was taken and the weight variation was calculated.

Table 6: Weight of Films

Formulation	Mean Weight (mg)
F1	100
F2	101
F3	105
F4	105
F5	110
F6	112

E. Moisture absorption:

Among the formulations were tested for moisture absorption. Results were shown that F6 to F3 shows the maximum and minimum moisture uptake i.e, 8.2 ± 0.06 and 4.2 ± 0.10 respectively. The maximum moisture uptake from films may be due to the high concentration of hydrophilic polymer HPMC K4 M, which readily absorbs moisture when exposed to atmosphere.

Table 7: Moisture absorption of Films

Formulation	% Moisture absorption
F1	5.1
F2	6.5
F3	4.2
F4	5.4
F5	7.8
F6	8.2

F. Moisture loss:

The percent moisture loss was determined for all the formulations. The results were given below

Table 8: Moisture absorption of Films

Formulation	% Moisture loss
F1	2.0
F2	1.2
F3	2.5
F4	1.8
F5	1.3
F6	1.02

G. Folding endurance test:

The folding endurance was measured manually. A strip of film 2 cm2 was cut and subjected for the folding endurance studies until it broke at the same place. The no. of film fold until it broke was reported.

Table 9: Folding Endurance of Films

Formulation	No of folds
F1	120
F2	122
F3	115
F4	118
F5	125
F6	138

H. Surface pH Determination:

The surface pH of films is important because the films are to be placed in the sensitive region of oral mucosa. Highly acidic and highly alkaline substances cause irritation and damage. Therefore the observed pH of all the formulations were found to be in the neutral range shows the suitability of films to be used for oral cavity.

Table 10: Surface pH of Films

Formulation	Surface pH
F1	6.2
F2	6.2
F3	6.2
F4	6.2
F5	6.2
F6	6.5

I. % Drug content:

The prepared film formulations were analyzed for % drug content and it was observed that all the formulation found to contain more than 95% drug content. The data of % drug content was shown in table.

Table 11: % Drug content of Films

Formulation	%Drug content
F1	95.23
F2	96.58
F3	96.25
F4	97.25
F5	98.28
F6	98.44

J. In vitro disintegrationtime:

Test was performed using beaker. One square inch film was dropped in the beaker containing buffer, raised and it is slightly agitated. Time required by the film, when no traces of film remain in buffer was noted.

Table 12: In-vitro Disintegration Time of films

Formulation	In-vitro Disintegration Time (sec)
F1	10
F2	15
F3	12
F4	18
F5	20
F6	19

K. In-vitro drug release studies:

Dissolution of film was studied in 900mL of the medium containing 6.8 pH phosphate buffer. It was shown that within 10 min all the films showed maximum drug release. Percentage of drug release at different time intervals is shown in the Table.

Table 13: In-vitro release studies of Ranitidine HCl Fast Dissolving Oral films

Time (min)	F1	F2	F3	F4	F5	F6
0	0	0	0	0	0	0
2	24.1	23.5	22.0	22.8	25.3	26.2
4	45.5	43.8	44.6	43.5	50.2	52.3
6	60.5	58.5	59.22	58.5	65.8	66.8
8	75.2	74.6	74.5	73.8	82.3	85.26
10	95.6	94.1	94.4	93.8	98.5	99.03

DISCUSSION:

In the present research study, fast dissolving oral films of Ranitidine HCl were prepared by using polymers like HPMC K 4 M and SCMC by solvent casting method.

The drug and the excipients interaction studies were carried out by checking the physical appearance and by FT-IR analysis. The physical mixture of drug with HPMC, SCMC clearly showed the retention of the characteristic peaks of Ranitidine HCl and thus revealing no interaction between the selected drug Ranitidine HCl and other excipients.

Fast dissolving oral films of Ranitidine HCl were prepared by using polymers like HPMC K 4 M and SCMC in different concentrations using plasticizer PEG. Total 6 batches were formulated (F1, F2, F3, F4, F5 and F6).

The prepared films of all the 6 formulations were observed to be in slight yellowish in color, smooth in texture and transparent. The thickness of films varied from 1mm to 1.3mm with small standard deviation ensured uniformity of film prepared by solvent casting method. The observed surface pH was in neutral range shows the suitability of films to be placed in the oral cavity.

The weights of all film were found to be more similar. The drug content of all formulations was within the limits and this indicates the method used for preparing films was reliable.

The folding endurance for all formulations was good. The maximum folding endurance for F6 films was 138 foldings which may be due to presence of HPMC K4 is more tensile.

In vitro disintegration time varies from 10 to 20 seconds for all the formulations. In-vitro disintegration time of the films was found to increase with increase in the amount of polymer.

The In-vitro drug dissolution studies of all six formulations (F1 to F6) were carried out. The amount of Ranitidine HCl released from various formulations F1, F2, F3, F4, F5 and F6 at end of 10 min were 95.6%, 94.1%, 94.4%, 93.8%, 98.56% and 99.03% respectively. Maximum drug release was observed in F6 formulation. So it is considered as optimized formulation.

CONCLUSION:

The fast dissolving films of Ranitidine HCl were prepared by solvent casting method using film-forming polymer HPMC and SCMC using PEG as plasticizer. Based on the in vitro disintegration time and dissolution profile, formulation F6 was found to be promising and showed a disintegration time of 20 s and 99% of drug released in 10 min. However this FDF is useful for the improving of the bioavailability of the drug.

CONFLICT OF INTEREST:

No.

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Received on 13.07.2020 Modified on 26.08.2020

Asian J. Pharm. Tech. 2021; 11(1):13-17.

DOI: 10.5958/2231-5713.2021.00003.9