Oral Dissolving Films of Chlorpheniramine Maleate: Formulation and Evaluation

The oral route is the most desired one for systemic effect which is attributed to its ease of administration, adaptability, non-invasiveness, patient compliance, and acceptability.¹ Tablet is the most recommended dosage because of ease in manufacturing, transporting, and higher patient compliance.² Generally, geriatric, nauseous, pediatric, bedridden, and noncompliant patients have trouble swallowing the traditional oral dosage form and do not take medicines as directed.³ Hence therapy becomes noncompliant and ineffective. Therefore, ODFs were developed that dissolve or disintegrate fast (within three minutes) in mouth, without requiring water.⁴ ODFs resemble postage stamps in their shape, thickness, and size, that dissolve or disintegrate quickly in the oral cavity when contact with saliva, and form solution or suspension which helps in rapid absorption.⁵ ODFs are very suited for the drugs with high first-pass metabolism. These are used for improving bio-availability, minimizing adverse or side effects and, also making it cost-effective.⁶

Chlorpheniramine maleate, an anti-histamine drug is indicated in the management of allergic reactions related to skin and mucous membranes.⁷ According to the Biopharmaceutical Classification System (BCS), CM belongs to Class I. CM was especially designed to provide a fast onset of action, increase patient compliance for pediatrics, elderly and patients who find difficulty in swallowing.⁸ The present study was an attempt to give pleasant taste, along with good bioavailability.

A series of dilutions 10, 20, 30, 40, and 50 μg/mL was measured for absorbance against a blank phosphate buffer pH 6.8 at the λ_max of 262 nm.

The dose of CM is 4 mg. Hence the amount of CM required in 2 cm x 2 cm square film is 4 mg. The diameter of pertiplate is 9 cm.¹⁰

Therefore, 63.58 cm² of petri plate should contain 63.6 mg of the CM which is fixed for all the formulations.

Chlorpheniramine maleate was selected as a drug based on its physicochemical and biological properties and also based on its suitability for Oral dissolving films. HPMC E15, PVA, and PVP K-30 were selected as film-forming polymers. PEG 400 was selected as a permeation enhancer and plasticizer. Citric acid was selected as saliva-stimulating agent. Mannitol was selected as a sweetening agent. ODFs were prepared using solvent-casting method. Eight Formulations (F1-F8) were created, the compositions of which are listed in Table 1. The Drug CM, citric acid, and mannitol were suitably dissolved in water and methanol. An aqueous preparation of polymer was separately prepared by dissolving in suitable quantity of water and methanol. Aqueous solution of polymers was then added to the previously prepared solution, thereafter PEG 400 (Plasticizer) was added to the mixture to make a transparent solution with constant stirring for 1 hour until a uniformly viscous solution was obtained. Thereafter kept in a sonicator for degassing for 10 min. The finished product was cast onto a Petri dish and dried in a hot air oven at 50°C for 24 hr. The dried ODFs were cut into square-shaped films. Each film had approximate surface area of about 4 cm² (2 cm x 2 cm) with a dose of 4 mg of chlorpheniramine maleate.^11,12

Table 1:
Formulation table of CM oral dissolving Film.

The films of about 2×2 cm² dimension (3 films each from 3 different polymeric films) were used to determine the thickness using Vernier caliper at three different positions.¹⁴

The average weight of prepared ODFs was determined by taking three 2×2 cm² dimension films from each formulated batch and weighing them on a digital balance. Thereafter average weight was calculated.¹⁴

Three ODFs of about 2×2 cm² from each batch were taken. Each ODF was folded at the same place repeatedly until cracks were visible. The folding endurance was calculated for ODFs of each formulation.¹⁵

This parameter was determined by initially weighing the ODF and, then putting this ODF in a desiccator (containing calcium carbonate) for about three days. Later, strips were taken out of the desiccator and reweighed. Moisture content was estimated using the below formula.¹⁶

Three ODFs of about 2×2 cm² from each batch were taken. Each ODF was moistened with 2 mL of pH 6.8 phosphate buffer in a Petri plate for 30 sec. The pH was noted after equilibrating the solution for 1 min using pH meter.¹⁷

The Limit of content uniformity should be 85-115%.¹⁸ The ODFs of about 2×2 cm² from each batch was placed in a beaker containing 50 mL of pH 6.8 phosphate buffer. The contents were stirred to dissolve the film and then filtered. The absorbance of the solution was measured against the corresponding blank solution at 262 nm wavelength using UV-visible spectrophotometer. The average drug content was calculated.

Disintegration time is the time when an oral film starts breaking when brought in contact with water or saliva. For a fast-dissolving film, the time of disintegration should be in the range of 5-30 sec. The test was performed using USP disintegration test apparatus, using 250 mL phosphate buffer pH 6.8 at 37±0.5°C as a medium, 2 cm²×2 cm² strips was placed in the tube, and the disks were placed over it. Three oral films of each formulation were kept in the disintegration apparatus and the average of three disintegration time was calculated.¹⁹ Every formulated oral dissolving film was cut into 2×2 cm² dimension and its in vitro disintegration times was determined visually in a beaker of 20 mL containing distilled water with swirling every 10 sec. The mean of three readings was determined.²⁰

The dissolution time is the time when the film completely dissolves. The in vitro dissolution test was carried out in a USP-I rotating basket dissolution apparatus. Drug-loaded films were cut into 2 cm diameter and placed in the basket of the dissolution apparatus. The volume of dissolution medium (simulated saliva fluid i.e., phosphate buffer pH 6.8) was 500 mL and was maintained at the temperature of 37±4°C and the basket was rotated at 50 revolutions per min (rpm). Samples of 5 mL were withdrawn at predetermined time intervals and replaced with 5 mL of fresh medium. The absorbance was recorded at the wavelength of 262 nm against blank using a UV-visible spectrophotometer.²¹

An in vitro diffusion study through a cellophane membrane was carried out using a modified Franz diffusion cell with internal diameter 2.5 cm. The cellophane membrane was mounted between the donor and the receptor compartments. The donor compartment was filled with the drug dissolved in 20 mL of simulated salivary fluid of pH 6.8, which was maintained at 37±0.2°C, and hydrodynamics were maintained using a magnetic stirrer. Samples (1 mL) were withdrawn from the receptor compartment (phosphate buffer pH 6.8) at suitable time intervals of 2 min and replaced with an equal amount in the receptor compartment with phosphate buffer. The percentage amount of drug presence (diffused from the donor to the receptor compartment) in the receptor compartment was determined by measuring the absorbance in UV-visible spectrophotometer at λ_max of 262 nm.^18,22

The final optimized formulation was subjected to aggravated conditions of temperature and relative humidity by wrapping it in aluminum foil and packaging it in a glass container. The films were kept in stability chamber, at 40°±2°C temperature and 75±5% RH for 3 months. After 3 months the films were tested.²³

The authors would like to acknowledge Principal and management of MRM College of Pharmacy for providing us all the outstanding facilities for carrying this research.

The authors declare that there is no conflict of interest.