Design and Development of Mouth Dissolving Film of Promethazine Hydrochloride

Peer Review Article | Open Access | Published 2nd April 2025

Design and Development of Mouth Dissolving Film of Promethazine Hydrochloride

Pravin Kumar Sharma*, Kuldeep Chaturvedi, Sumeet Dwivedi, Ravi Sharma, G.N. Darwhekar

Acropolis Institute of Pharmaceutical Education and Research, Indore (M.P.) 453771

| EJPPS | 301 (2025) |https://doi.org/10.37521/ejpps30103 | Click to download pdf

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Abstract

The objective of this research was to formulate a mouth dissolving film (MDF) of Promethazine Hydrochloride, aimed at improving its oral bioavailability and providing a quicker onset of action for treating allergic conditions. As a member of BCS Class I, Promethazine Hydrochloride has an oral bioavailability of only about 28% due to first-pass metabolism. To mask its bitter taste, a drug inclusion complex with β-cyclodextrin was created. The MDF was prepared using the solvent casting method and included sodium starch glycolate (as disintegrating agent), mannitol (as a sweetener), citric acid (to stimulate saliva), HPMC E-15 (as a film-forming agent), β-cyclodextrin (for taste masking), PEG-400 (as a plasticizer), peppermint oil (as a flavouring agent), and royal blue colour (as a colouring agent). Optimization was carried out using a three-level (3²) full factorial design, with the concentrations of the disintegrating agent (X2) and polymer (X1) as independent variables. Various parameters were assessed, including weight variation, thickness, folding endurance, surface pH, drug content uniformity, in-vitro disintegration time, in-vitro % drug release, and stability studies. The results indicated that the MDF (F6) achieved an in-vitro drug release of 98.2% and in-vitro disintegration time of 26.56 seconds, suggesting a higher bioavailability and faster onset of action compared to available tablet forms. These findings indicate that mouth dissolving films could be an effective option for treating allergies when rapid action is required.

Key words: Promethazine Hydrochloride, Mouth dissolving film (MDF), Bioavailability, Urticaria, Solvent casting method, Full factorial design, Taste masking.

1. INTRODUCTION

The oral drug delivery system is the most preferred method of medication administration due to its ease of use, convenience, and high patient compliance. However, traditional oral dosage forms like tablets and capsules can pose challenges for certain populations, such as the elderly and children, who may struggle with swallowing. Oral solid dosage forms represent about 60% of all dosage types and often have limitations that can be addressed through innovative alternatives, like mouth dissolving films (MDFs). These films emerged in the late 1970s as a viable substitute for conventional dosage forms. MDFs are thin, flexible, and water-soluble, dissolving quickly in the mouth to release the active ingredient for absorption through the buccal mucosa. This innovative dosage form offers numerous advantages, including the ability to deliver systemic drugs without the first-pass effect in the liver, improved patient compliance due to ease of administration, rapid onset of action, enhanced bioavailability, reduced gastrointestinal side effects, and flexibility in formulation design.

Promethazine Hydrochloride is a first-generation antihistamine that acts primarily as a strong antagonist of the H1 receptor and a moderate antagonist of the muscarinic acetylcholine receptor. This action inhibits histamine receptor activity, making it effective in alleviating allergic conditions. However, its oral bioavailability is limited due to the hepatic first-pass effect, with only about 25% reaching systemic circulation. Currently, Promethazine Hydrochloride is available in conventional forms like tablets and syrups, highlighting the need for a novel approach to develop an optimal dosage form. This research aims to formulate and evaluate a mouth dissolving film of Promethazine Hydrochloride using varying concentrations of polymer and disintegrating agents, employing design of experiments software for optimization.

2. MATERIALS AND METHODS

Promethazine Hydrochloride was received as a gift sample. HPMC E-15, PEG-400, sodium starch glycolate, β-cyclodextrin, citric acid, mannitol, peppermint oil, and royal blue colour were sourced from Loba Chemical Mumbai.

PREFORMULATION STUDIES

Analytical Methods used in Characterisation of Drug

Determination of λ max in distilled water

50 mg of Promethazine Hydrochloride was weighed accurately and transferred to a 100 ml volumetric flask and the volume was made up to 100 ml with distilled water. From this solution, 1 ml was withdrawn and added to the 10 ml volumetric flask and diluted up to 10 ml with distilled water. Finally the sample was scanned in the range of 200-400 nm. The wavelength of the maximum absorption was noted and the UV spectrum was recorded (Sem et al., 2018).

Determination of solubility

The solubility of the drug in distilled water and phosphate buffer at pH 6.8 was assessed using the equilibrium solubility method. In this procedure, 5 mL of solvent was placed in vials, and an excess quantity of the drug was added. The vials were sealed tightly and stirred on a magnetic stirrer for 12 hours, then allowed to equilibrate for an additional 24 hours. Afterward, the solution was filtered, and absorbance was measured at 249 nm using a UV spectrophotometer (Sharma, 2018).

Determination of melting point

A capillary tube was prepared by sealing one end through heating. The sealed tube was then filled with the drug to a height of 1 cm. This tube was placed in a melting point apparatus alongside a thermometer. As the temperature gradually increased, changes in the sample were observed. The temperatures at which the drug began to melt and was fully melted were recorded (Pawar et al., 2019).

Drug – excipient incompatibility study by Differential Scanning Calorimetry (DSC)

DSC-thermogram of Promethazine Hydrochloride and optimized formulation were recorded using DSC to study the incompatibility (Sharma, 2018). The heating rate of 40°C/min in the range of 50−350°C under inert nitrogen environment at a flow rate of 20 ml/min was used. The samples (4 mg) were put in an aluminium sampling pan against a reference standard (Xu et al., 2014).

Formulation of inclusion complex by kneading method

β-cyclodextrin & Promethazine Hydrochloride inclusion complex at weight ratios (1:1) was prepared by a kneading method. Kneaded products were obtained by triturating β-cyclodextrin and Promethazine Hydrochloride in a pestle & mortar by adding a small volume of distilled water. The slurry obtained was dried in a hot air oven at 35℃. Dried complex was passed through sieve number # 60 (Senthilkumar, K. and Vijaya, C., 2015).

Preparation of mouth dissolving film

Mouth dissolving film was prepared using solvent casting method by dissolving a weighed amount of β-cyclodextrin & Promethazine Hydrochloride complex, HPMC E-15 and PEG-400 in 15 ml of distilled water with continuous stirring on a digital magnetic stirrer at 800 rpm for 1 hour. Subsequently, the required amount of sodium starch glycolate, citric acid, mannitol, peppermint oil (Q.s) and royal blue colour (Q.s) was gradually added to the casting solution under constant stirring at 1200 rpm at room temperature until a clear solution was obtained. The list of selected excipients is given in Table 1. As the solution became clear, the casting solution was then stirred for 4 h at 100 rpm to remove entrapped air bubbles. The resulting solution was then cast on a fabricated glass mould lubricated with glycerin and allowed to dry completely at room temperature to form a film. The dried films were carefully separated from the glass mould and cut to produce square shaped films of 2×2cm and were stored in double wrapped aluminum foils (Visser et al., 2015: Thonte et al., 2017).

Table 1 - List of selected excipients

S. No.	Excipients	Purpose
1	HPMC-E-15	Film forming polymer
2	PEG-400	Plasticizer
3	Citric acid	Saliva stimulating agent
4	Mannitol	Sweetening agent
5	Beta-cyclodextrin	Taste masking agent
6	Sodium starch glycolate	Disintegrating agent
7	Pepper mint oil	Flavoring agent
8	Royal blue color	Coloring agent

Optimization of mouth dissolving film using 3² full factorial design

Three level 2 factor (3²) full factorial design was used for optimization of polymer-plasticizer ratio. In this design, 2 factors were evaluated each at 3 levels and experimental trails were performed in all 9 possible combinations (Raza et al., 2019). The amount of HPMC E-15 (X1) and amount of sodium starch glycolate (X2) were selected as independent variables with each factor being studied at low (-1), medium (0), High (+1) level. Table 2 & 3 show the levels of independent variables and in-vitro % drug release, and in-vitro disintegration time used as dependent variable (response). 3² full factorial design layout is given in Table 4 and composition of various fast dissolving films is given in Table 5.

Table 2 - Selected factor and their levels (Independent variable)

S. No	Name of factors	Levels (Concentration of factor)
1	X1: Concentration of HPMC E-15 (mg)	Low	Medium	High
55	60	65
2	X2: Concentration of SSG (mg)	4	6	8

Table 3 - Dependent (Response) variable

S. No	Name of response	Unit
1	In-vitro % drug release	%
2	In-vitro disintegration time	Second

Table 5 - Composition of Promethazine Hydrochloride mouth dissolving film

Evaluation parameters of mouth dissolving film of Promethazine Hydrochloride

Morphological and organoleptic control

The colour, homogeneity, transparency, smell, and appearance of mouth dissolving film were examined visually and sensually (Senthilkumar, K. and Vijaya, C., 2015).

Folding endurance

Folding endurance was evaluated by folding it repeatedly at the same location at a 180° angle until it broke. Before breaking, the number of folds made was recorded. A film is deemed to have exceptional flexibility if it can fold at least 300 times (Vishwkarma et al., 2011).

Surface pH

The surface pH of the mouth dissolving film was measured to assess potential side effects from pH variations, as either acidic or alkaline conditions might cause irritation to the oral mucosa. The measurement was conducted using a pH meter. This test was evaluated by placing the film in a Petri dish. Then it was moistened with 0.5 ml of phosphate buffer and kept for 30 seconds. The pH was noted after bringing the electrode of the pH meter in touch with the surface of the formulation and allowing equilibration for 1 min (Sjöholm and Sandler, 2019).

In-vitro % drug release

The USP paddle apparatus was used to determine the in-vitro dissolution investigation in 900 ml of pH 6.8 phosphate buffer at 37 ±0.5℃ and 50 rpm. A film sample 2×2 cm (equivalent of 25 mg drug) was immersed in the dissolving medium, and at intervals of 0.5, 1, 1.5, 2, 2.5, 3 minutes the aliquots were removed and replaced with the same volume of dissolving fluid to maintain the volume. The samples were filtered with Whatman filter paper and analysis was carried out at 249 nm using a UV-visible spectrophotometer. Sink conditions were kept constant during the trial (Tekade et al., 2017).

Film thickness

A vernier caliper was used to determine the film's thickness. Five points on the film were measured: the centre, four corners, and the mean thickness computed. Six films of each formulation were tested; the maximum thickness variation should be less than 5%, and the mean ± S.E.M was computed (Alhayali et al., 2019).

Drug content uniformity

Drug content uniformity of film was determined by dissolving a 2×2 cm of film (equivalent of 25 mg drug) in 10 ml of phosphate buffer pH 6.8. After extracting an 1 ml of sample, the solution was diluted to 10 ml with buffer pH 6.8 and analyzed by UV-spectrophotometer at 249 nm (Karki et al., 2016).

Weight variation

Weight variation was determined according to the European Pharmacopoeia. Twenty randomly chosen MDF were weighed individually on a digital balance. Subsequently the average mass was calculated (Sharma et al., 2017).

In-vitro disintegration time

Disintegration time of mouth dissolving film was measured by placing the film (2x2cm) in a Petri dish containing 10 ml phosphate buffer pH 6.8. Time required for complete disintegration of the film was noted (Bala and Sharma, 2018).

Stability study

To evaluate the stability of optimised and verified MDF, a stability study was conducted in accordance with ICH Q1A recommendations. MDF were kept for three months under two distinct conditions: 25 ± 2°C/60 ± 5% RH and 40 ± 2°C/75 ± 5% RH. Samples were taken at 0, 30, 60, and 90 days, and the in-vitro disintegration time and in-vitro % drug release were estimated using analytical techniques (Chaudhary et al., 2013).

3. RESULTS AND DISCUSSION

PREFORMULATION STUDIES

Determination of wavelength using UV spectroscopy

The absorbance maximum of Promethazine Hydrochloride in distilled water was found to be 249 nm which matched with that reported in literature. The UV spectrum of Promethazine Hydrochloride is shown in Figure 1.

Figure 1 - Spectrum of Promethazine Hydrochloride

Preparation of calibration curve

Calibration curves of Promethazine Hydrochloride in distilled water and phosphate buffer pH 6.8 were determined and shown in Figures 2 & 3 respectively.

Figure 2 – Calibration curve of Promethazine Hydrochloride in distilled water at 249 nm

Figure 3 – calibration curve for Promethazine Hydrochloride in phosphate buffer at pH 6.8 at wavelength of 249 nm

Determination of solubility

The solubility of Promethazine Hydrochloride was found to be 96±0.6 mg/mL in distilled water and 89.53±0.4 mg/mL in phosphate buffer at pH 6.8. This indicates that Promethazine Hydrochloride is freely soluble in both distilled water and phosphate buffer at pH 6.8.

Melting point determination

The melting point of Promethazine Hydrochloride was found to be 240.5℃±0.01 which was found same as standard range.

Determination of drug-excipients compatibility study

DSC-Thermograms of components are shown in Figures 4 and 5. The thermogram of Promethazine Hydrochloride showed the sharp endothermic peak at 240.08°C, indicating the melting point of Promethazine Hydrochloride and the high intensity of peak. The thermogram of optimized oral formulation (F6) showed a small endothermic peak at 240.08°C indicating the presence of Promethazine Hydrochloride and suggested no incompatibility.

Figure 4 - DSC curve of pure Promethazine Hydrochloride

Figure 5 - DSC of optimized formulation (F6)

FORMULATION AND DEVELOPMENT OF MOUTH DISSOLVING FILM

The mouth dissolving film was formulated using the solvent casting method. A casting solution was prepared in distilled water and poured onto a custom glass mould to produce films of uniform size measuring 2 × 2 cm, with an approximate weight of 149 mg. The results of the optimized formulation are shown in Figure 6 below.

EVALUATION PARAMETERS OF MOUTH DISSOLVING FILM

The mouth dissolving film of Promethazine Hydrochloride was evaluated based on morphological and organoleptic control, film thickness, weight variation, folding endurance, drug content uniformity, surface pH and in-vitro disintegration time.

The results of morphological and organoleptic control appear as circular shape, blue in colour, odourless and transparent and other evaluation parameters are shown below in Table 6. The film thickness and weight variation increased with a higher fraction of polymer, as anticipated. Overall, all formulations demonstrated fast disintegration but exhibited different in-vitro disintegration times due to variations in polymer and disintegrating agent concentrations. The pH of the films was found to be approximately neutral. Most batches met the criteria for drug content uniformity, with the observed drug content ranging from 86.4% to 98.1%, indicating that the drug was evenly distributed throughout the films. Formulation F6 was identified as the optimal formulation based on in-vitro drug release and disintegration time.

Table 6 - Thickness, weight variation, folding endurance, drug content uniformity, surface pH, and in-vitro disintegration time of formulation F1-F9 (n=3).

In-vitro % drug release

The in-vitro % drug release results demonstrated nearly complete drug release (up to 98.2%) within just 3 minutes, indicating a rapid release from the mouth dissolving films (MDFs). The in vitro % drug release data for formulations F1 through F9 is presented in Table 7, while the corresponding drug release graph for these formulations can be found in Figure 7. Additionally, the in-vitro % drug release for the optimized formulation F6 is illustrated in Figure 8.

Figure 7 - In-vitro % drug release profile of film formulation F1-F9

Figure 8 - In-vitro % drug release graph of optimized formulation F6

Stability studies data of optimized formulation of mouth dissolving film

Tables 8 and 9 present the results of the stability analysis of the optimised and validated MDF. After a three-month stability investigation, the in-vitro % drug release and in-vitro disintegration time of the optimised formulation did not significantly alter, according to the stability results.

Table 8 - Stability study data of MDF at 25±2℃/60±5% RH

Table 9- Stability study data of MDF at 40±2℃/75±5% RH

OPTIMIZATION OF MOUTH DISSOLVING FILM

A full factorial experimental design was used to optimize the formulation variable. The 3D response surface plots were obtained using design expert 13 software. These are shown in Figures 9 and 10, and data transformation and response are shown in Table 10. The response in-vitro % drug release (Y1) and in-vitro disintegration time (Y2) were found to be in range from 87.3% to 98.2% & 26.47 to 33.48 sec respectively. The response models were calculated with design expert software by applying coded value of factor level to estimate quantitative effect of the different combination of factors level on in vitro % drug release & in-vitro disintegration time.

Table 10 - Observed response in 3² full factorial design for MDF (n=3)

Figure 9 - 3D surface plot of MDF for in-vitro % drug release

Figure 10 - 3D surface plot of MDF for in-vitro disintegration time

The model described could be represented by full model equations.

In-vitro % drug release = +93.61-3.82A[1]+0.8704A[2]-2.83B[1]+0.3593B[2]+0.3407A[1]B[1]-0.8481A[2]B[1]-0.0148A[1]B[2]-0.4704A[2]B[2]

In-vitro disintegration time = +29.73-1.76A[1]+0.5633A[2]+2.40B[1]-0.3411B[2]

Effect of independent variable on in- vitro disintegration time

The effect of hydroxy propyl methyl cellulose E-15 and sodium starch glycolate on disintegration time were determined and recorded. It suggested decreased disintegration time with increase in concentration of SSG and increase in disintegration time with increase in concentration of HPMC E-15.

Effect of independent variable on in-vitro % drug release

The effect of HPMC E-15 and SSG on % in-vitro drug release were determined and recorded. It suggested increased in % in-vitro drug release with increase in concentration of SSG and HPMC E-15.

4. CONCLUSION

The mouth dissolving film of Promethazine Hydrochloride was developed using the solvent-casting method. Taste masking was achieved by creating a drug inclusion complex with β-cyclodextrin. A 3² factorial design was employed for optimization among the nine formulations prepared according to this design. The formulation containing 60 mg of HPMC E-15 and 8 mg of sodium starch glycolate (F6) demonstrated the highest in-vitro % drug release and suitable in-vitro disintegration time, making it the selected optimized formulation. Accelerated stability studies indicated that the formulation remained stable. Differential scanning calorimetry (DSC) analysis showed no interaction between Promethazine Hydrochloride and the optimized formulation, as evidenced by the comparison of melting point peaks. Thus, this mouth dissolving film formulation is considered potentially effective for treating allergic conditions (urticaria) due to its rapid onset of action, reduced first-pass metabolism, low dosage requirements, enhanced bioavailability, and improved patient compliance.

ACKNOWLEDGEMENT

The Authors are thankful to Acropolis Institute of Pharmaceutical Education and Research, Indore, Madhya Pradesh for providing necessary facilities in the Institute.

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