Enhancing Dissolution Profile of Domperidone Through Solid Disperstion Integrated Fast Dissolving Films: Formulation, Optimization, and Evaluation

Oral administration is widely preferred because of its convenience, ease of use, and patient acceptability. However, Domperidone has poor aqueous solubility and a slow dissolution rate, which may limit its effective oral delivery.¹

Fast-dissolving oral films (FDOFs) offer a convenient alternative to conventional tablets, particularly for patients with swallowing difficulties. They rapidly disintegrate in the oral cavity and can provide quick drug release without the need for water.^2,3

Solid dispersion technology can improve the solubility and dissolution of poorly water-soluble drugs by incorporating the drug into a hydrophilic polymeric carrier and reducing its crystalline nature. Incorporating the optimized solid dispersion into oral films can therefore enhance drug dissolution while providing a convenient dosage form.⁴

In the present study, Box–Behnken Design (BBD) was employed for systematic formulation optimization. The effects of selected formulation variables on disintegration time and cumulative drug release were evaluated to obtain an optimized fast-dissolving oral film formulation.^5,6

Salient Features of Fast Dissolving Oral Film:

• Ease of administration for patients who are mentally ill-disabled & uncooperative.
• Requires no water; have quick disintegration and dissolution of the dosage form.
• Leaves minimal or no residue in the mouth after administration.
• No risk of choking.
• Provide advantages of liquid medication in the form of solid preparation.
• Amenable and adaptable to existing processing and packaging machinery⁷

Patients who suffer from vomiting cannot be administered the conventional oral formulations and need fast acting formulation. In general, emesis is preceded with nausea and in such condition it is difficult to administer drug with a glass of water; hence it is beneficial to administer drugs as mouth dissolving films with good mouth feel.⁸

This delivery method bypasses hepatic first-pass metabolism, potentially leading to improved bioavailability and faster therapeutic effects compared to traditional oral dosage forms. The route offers several advantages over oral route. The oral cavity has a large surface area, leading to rapid dissolution and disintegration of oral dosage forms. There is no risk of choking⁹. Oral fast-dissolving films (OFDFs) are solid unit dosage forms, providing accurate

dosing and great precision. Pregastric absorption improves the bioavailability of the drug, requiring fewer doses and enhancing patient compliance.¹⁰

This study focuses on the formulation and optimization of Domperidone-loaded fast-dissolving films integrating solid dispersion technology. The integration of solid dispersion with FDOFs offers a novel approach to improving drug delivery and patient outcomes for water-insoluble therapeutic agents.¹¹

Pre-formulation studies

Preformulation studies were carried out to evaluate the physicochemical properties of Domperidone prior to formulation development. These studies included melting point determination to confirm the identity and purity of the drug, solubility analysis in various solvents to assess its solubility profile, determination of the maximum absorption wavelength (λmax) for analytical estimation, and compatibility studies using Fourier Transform Infrared (FTIR) spectroscopy to investigate potential interactions between Domperidone and the selected excipients. The results of these studies provided essential information for the successful development of the formulation.¹²

The melting point of Domperidone was determined using the capillary tube method to confirm its identity and purity. The solubility of Domperidone in different solvents was evaluated by the shake flask method to assess its solubility characteristics and support formulation development.¹³

Drug-Excipient compatibility studies using FTIR spectroscopy

FTIR analysis was carried out using a Shimadzu FTIR spectrophotometer. After initializing the instrument and cleaning the sample holder with acetone, the software was opened and the scan range set to 650–4500 cm⁻¹. A background spectrum was collected, then the sample was placed on the holder and scanned. The obtained spectrum was labeled, saved in ASCII format, and the instrument was turned off after analysis.¹⁴

Determination of λmax

Domperidone 10 µg/ml concentration was prepared by using mixture of phosphate buffer 6.8 and methanol. The solution was scanned from 200-400 nm by UV Spectrometer and a spectrum was observed for absorption maxima.¹⁵

Methods of Preparation Of Solid Dispersion:

I. Preparation of Solid Dispersion; Melting Solvent Method or Melting Fusion method)

A. Solvent evaporation method:

Drug and the polymer were dissolved in 10 ml of methanol and 5ml of dichloromethane. The solvent was stirred on magnetic stirrer at temperature 40°C and then evaporated in oven at 40°C. The solidified mass was then crushed, size reduced in a mortar and pestle and sieved through sieve.no 80.¹⁶

B. Melting Method:

The physical mixture of the drug and hydrophilic carrier is heated until a molten mass is formed. The molten mixture is then rapidly cooled in an ice bath with continuous vigorous stirring. After solidification, the solid mass is crushed, ground into a fine powder, and passed through a sieve.¹⁷

II. Formulation of solid dispersion incorporated fast dissolving oral films. 1. Solvent Casting Method

The required quantity of film-forming polymer is dissolved in distilled water and allowed to hydrate completely. Plasticizer and other excipients are added with continuous stirring to obtain a uniform solution. The prepared solid dispersion (Solid Dispersion containing equivalent 10 mg of Domperidone in 2*2 cm² of Oral films) dispersed uniformly into the polymeric solution. The mixture is stirred to remove air bubbles and poured onto a petriplate or casting surface. The solution is dried at room temperature or in a hot air oven until a thin film is formed. The dried film is carefully peeled off and cut into required sizes for evaluation.¹⁸

Formulation table for the Preperation of solid Dispersion

• SE= Solvent Evaporation method , MM=Melting method

Formulation of PVP K30 SD incorporated Fast Dissolving oral film design by using Box Behnken Design

A. Crosspovidone B. Sodium Starch Glycolate C. PEG 400

Formulation table for the preparation of Fast dissolving Oral Films By incorporating PVP K30 Solid Dispersion.(F1-F16)

Evaluation of solid Dispersion:

1. Solubility:

prepared solid dispersion was separately added into conical flasks containing phosphate buffer pH 6.8 or distilled water. The flasks were shaken continuously in a mechanical shaker for 24 hours at room temperature to attain equilibrium. The solutions were then filtered

through Whatman filter paper, suitably diluted and analyzed using a UV spectrophotometer at 286 nm.¹⁹

2. Drug Content

An accurately weighed quantity of prepared solid dispersion equivalent to 10 mg of Domperidone was transferred into a 100 mL volumetric flask containing phosphate buffer pH 6.8. The volume was made up to 100 mL and shaken thoroughly to obtain a clear solution. The solution was filtered through Whatman filter paper. From the filtrate, 1 mL was withdrawn and diluted to 10 mL with phosphate buffer pH 6.8. The diluted solution was analyzed using a UV spectrophotometer at 284 nm to determine drug content.²⁰

3. Dissolution Studies:

Accurately weigh solid dispersion equivalent to 10 mg of solid dispersion. Fill 500ml of phosphate buffer pH 6.8 into dissolution vessel and maintain temperature at 37±0.5∘C and 50 rpm for 1hr. Add the weighed solid dispersion sample into the Dissolution medium.Withdraw 5ml sample at specific time intervals such as 5,10,15,20,30,45 and 60min.After each withdrawl ,replace with equal volume of fresh dissolution medium maintained at some temperature.Filter the collected sample using whtatsman filter paper to remove undissolved particle.Measure absorbance using uv spectrometer at 286nm.Calculate cumulative % drug release using calibration curve.²¹

4. FTIR Study :

FTIR analysis was carried out using a Shimadzu FTIR spectrophotometer.After initializing the instrument and cleaning the sample holder with acetone, the software was opened and the range set to 400-4000 cm¯¹. A background spectrum was collected, then the sample was placed on the holder and scanned.The obtained spectrum was labeled, saved in ASCII format, and the instrument was turned off after analysis.²²

5. X-Ray Diffractometry Analysis:

X-ray diffractometry analysis of pure Domperidone, physical mixture, and prepared solid dispersion was carried out to determine the crystalline nature of the drug. The samples were finely powdered and analyzed using an X-ray diffractometer with Cu-Kα radiation operated at 40 kV and 30 mA. The diffraction patterns were recorded over a scanning range of 5°–50° (2θ) at a scanning speed of 2°/min. The obtained diffraction peaks of solid dispersion were compared with those of pure drug. Reduction in intensity or disappearance of characteristic crystalline peaks indicated conversion of the drug into amorphous form, which may enhance solubility and dissolution rate.²³

4.6.Evaluation of Fast Dissolving Oral Films

a) Folding endurance

Folding endurance gives the brittleness of a film. It is measured by manually repeated folding of film at some place till it breaks. The number of times the film is folded without breaking is the folding endurance value.²⁴

b) Film thickness

It was measured by using a digital Vernier calliper. The thickness of films was measured at five different points (Four on the corners and in centre), The average thickness of all films

is calculated.25

c) Weight variation

Three films of every 8 films of 2×2 cm² for each formulation were weighed individually and calculated. A calibrated electronic weighing balance is used for weighing buccal film. The

mean weight of all films is calculated.26

d) Percent drug content

A 2 × 2 cm² film was placed in 100 mL of phosphate buffer (pH 6.8) and stirred continuously on a bench-top orbital shaker for 24 hours. The resulting solution was then filtered, suitably diluted, and analyzed using a UV-visible spectrophotometer at 286nm. The drug content was calculated from film samples and reported as the final result.²⁷

e) In vitro drug release

For in vitro drug release study USP type I apparatus (Basket type) dissolution test apparatus containing 500 ml of PB of pH 6.8 as a dissolution medium at 37 ± 0.5°C temperature and speed at 50 rpm. 5 ml of sample solution was withdrawn at time intervals from 2 to 10 min respectively, and equilibrated with a new or fresh dissolution medium to maintain sink state. Drug release was analyzed spectrophotometrically at a λmax of 286 nm using UV visible spectroscopy.²⁸

f) Disintegration Time

the prepared film was placed in a Petri plate containing 10 mL of phosphate buffer pH 6.8, maintained at approximately 37 ± 0.5°C. The time required for the film to completely break down and disperse in the medium was recorded using a stopwatch. The test was performed in triplicate for each formulation, and the results were expressed as mean ± standard deviation (SD).²⁹

g) Stability studies as per ICH (International Conference on Harmonization) guidelines

Stability studies were carried out to investigate the degradation of drug from buccal films formulation during storage. Stability studies are carried out as per ICH guidelines for intermediate study protocol. The formulation was stored at the specific storage condition

30ºC ± 2ºC and 65 ± 5% RH for a period of 6 months. The parameters like % drug content and in vitro drug release were compared at specific time interval of 0, and 6 months as per ICH guidelines.³⁰

Preformulation studies

Preformulation studies were carried out and the results for the experiment conducted are as follows;

a) Identification of drug by Melting point determination

Melting point report of Domperidone

DSC graph of pure Domperidone

b) Solubility analysis

Solubility analysis of Domperidone

c) Determination of λmax Domperidone.

UV spectrum of Domperidone at 10 µg/ml concentration

d) Standard calibration curve of Domperidone

Table 5.3: Data for Standard Calibration Curve of Domperidone

UV spectra of Domperidone at different concentration of 0-40 µg/ml

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Plot of standard calibration curve of Domperidone

• Medium: Phosphate buffer pH 6.8 and Methanol (1:1)
• Standard stock: 1000 µg/ml
• Working stock: 100 µg/ml
• λmax: 286 nm
• Regression coefficient (r²): 0.9994
• Slope (m): 0.024

e) Compatibility studies by FTIR spectrophotometer

FTIR Spectra of Domperidone

FTIR Spectra of SD3 1:5 (PVP K30 and Domperidone)

FTIR Spectra Fast Dissolving Oral Films

FTIR Comparison: Doperidone pure Drug vs PVPK30 Solid Dispersion vs film Physical Mixture

Evaluations studies solid Dispersion

Drug Content of Solid Dispersion

in vitro dissolution study of formulation SD1-SD6

Solubility Analysis of PVP K30 Solid Dispersion

Solubility Analysis Of PEG 4000 Solid Dispersion

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% Drug Content of Solid Dispersion SD1-SD6

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% Cumulative Drug Release of Solid Dispersion SD1-SD6

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Figure 5.10: XRD of Solid Dispersion PVP K30 (1:5)

Evaluation Studies of Solid Dispersion incorporated Fast Dissolving Oral Fims

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Weight variation of formulation F1-F16

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Thickness of formulation F1-F16

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% Drug Content Of Solid Dispersion Incorporated Films F1-F16

Invitro Dissolution Study OF PVP K15 Solid Dispersion incorporated Fast Dissolving Oral Film F1-F16

Invitro Dissolution Study OF PVP K15 Solid Dispersion Incorporated Fast Dissolving Oral Film F9-F16

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% of Cumulative Drug Release of Formulation F1-F16

Optimization By DOE Software – Design Expert

1)optimized formulation composition and Predicted Results

2)Optimized Solid Dispersion Incorporated Fast Dissolving Oral FILMS formulation result

Stability Studies

Results of intermediate stability studies of optimized Solid Dispersion Incorporated Fast Dissolving Oral Films 30ºC ± 2ºC

CONCLUSION:

The present study successfully developed Domperidone solid dispersions using PVP and PEG carriers to improve its solubility and dissolution characteristics. Preformulation studies confirmed the purity, identity, and analytical suitability of the drug. successfully demonstrated the potential of solid dispersion technology combined with fast-dissolving oral films for improving Domperidone delivery. PVP K30 at a 1:5 drug-to-polymer ratio (SD3) provided enhanced solubility (39.41 mg/mL), drug content (96%), and drug release (93.6% at 30 min).

The optimized solid dispersion was successfully incorporated into oral films using the solvent casting method, producing films with acceptable physical characteristics, flexibility, and rapid disintegration. The optimized formulation achieved 26.0 ± 0.20 s disintegration time, 94.12% drug release at 10 min, and 96% drug content, demonstrating rapid drug release and satisfactory formulation performance. Box–Behnken-based optimization enabled systematic evaluation of formulation variables and identification of the optimized film composition. The formulation also showed acceptable stability during the study period, with only minor changes in drug release and drug content. Overall, the developed PVP K30 solid dispersion-incorporated fast-dissolving oral film represents a promising approach for improving the dissolution of Domperidone while providing a convenient and rapidly disintegrating dosage form.

Acknowledgement

I express my sincere gratitude towards Dr. Parthiban S, Head of the department, Department of Pharmaceutics, and Bharathi College of Pharmacy who has been abundantly helpful in numerous ways for this research work. The authors also thank Bharathi College of Pharmacy, Mandya, Karnataka, India, for providing the required facilities to carry out this research work.

Funding

No funding was provided for this study

BIBILOGRAPHY:

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