Fast-Dissolving Oral Film of Ondansetron for Paediatric Chemotherapy-Induced Nausea: 3² Factorial Optimisation

Children receiving chemotherapy often struggle with nausea and vomiting, and the medicine meant to help can itself be hard to give. Swallowing a tablet while nauseated is difficult for a young child, syrups need accurate measurement, and orally disintegrating tablets can be gritty and fragile. Ondansetron, a 5-HT₃ receptor antagonist, is widely used for chemotherapy-induced nausea and vomiting (CINV) in children. A fast-dissolving oral film that sits on the tongue and disintegrates within seconds without water could make dosing easier for caregivers in paediatric oncology wards and at home.

This M.Pharm dissertation develops a 4 mg ondansetron oral film by solvent casting, using HPMC as film former, PEG 400 as plasticiser, a sweetener and saliva stimulant for palatability, and no ingredients considered unsuitable for young children. After preformulation and compatibility studies (FTIR, DSC), formulation is optimised by a 3² full factorial design in Design-Expert: polymer concentration and plasticiser level are the factors; disintegration time, tensile strength (with folding endurance) and percentage drug released at 2 minutes are the responses.

The optimised film is validated against model predictions, characterised for thickness, weight and content uniformity, surface pH, mechanical properties and morphology, and placed on accelerated stability as per ICH Q1A(R2). The work is written for the PCI M.Pharm Pharmaceutics research scheme (Semester 3 research work and Semester 4 MPH 402P / MPH 403P).

Abstract

Fast-dissolving oral films of ondansetron (4 mg) were developed by solvent casting for paediatric chemotherapy-induced nausea and vomiting. Following preformulation and drug-excipient compatibility studies, a 3² full factorial design evaluated the effects of HPMC concentration and PEG 400 level on disintegration time, tensile strength and drug release at 2 minutes. Polynomial models were fitted and an optimised formulation was selected by desirability and validated experimentally. The optimised film was characterised and subjected to accelerated stability studies as per ICH guidelines.

Introduction

Oral thin films dissolve or disintegrate quickly on the tongue, release drug into saliva and are swallowed without water. They suit patients who have difficulty swallowing, including children and patients with nausea. Regulatory guidance on paediatric medicines emphasises age-appropriate dosage forms, acceptable taste and safe excipients. Ondansetron is a suitable candidate because of its low dose and widespread paediatric use for CINV.

Literature gap

Published ondansetron film studies often use one-factor-at-a-time trials or optimise only disintegration. Fewer apply a factorial design that balances fast disintegration against mechanical strength, which is the central trade-off for films that must survive handling by caregivers. Few studies explicitly design for paediatric use (dose size, excipient choice, film size) or report check-point validation and stability.

Hypothesis

Increasing HPMC concentration increases tensile strength but slows disintegration and early release; increasing PEG 400 improves flexibility and may speed disintegration up to a point. An optimum exists that meets all three response targets.

Feasibility

• Technical: solvent casting needs simple equipment; Design-Expert is named in the PCI syllabus; UV, FTIR, DSC and dissolution apparatus are standard in pharmaceutics departments.
• Economic: ondansetron and excipients can be obtained as gift samples or at modest cost.
• Ethical: in-vitro study only; no human taste panel or animal study, so no ethics committee approval is required.

Children undergoing chemotherapy need reliable antiemetic dosing, but tablets are hard to swallow during nausea, liquids require careful measurement and orally disintegrating tablets are brittle. A fast-dissolving film offers accurate unit dosing without water, but film formulation involves a trade-off: films that disintegrate fastest are often weak and tear when peeled from packaging, while strong films disintegrate slowly. Formulation decisions made by trial and error do not reveal how polymer and plasticiser levels interact. The problem addressed is to develop and optimise a paediatric-appropriate fast-dissolving oral film of ondansetron using a 3² factorial design that balances rapid disintegration and early drug release with adequate mechanical strength, and to confirm its stability.

The study covers in-vitro development of a 4 mg ondansetron oral film for paediatric use, from preformulation to accelerated stability. It does not include in-vivo pharmacokinetic studies, human taste panels or clinical evaluation, which require ethics approval and are listed as future work. Taste masking is addressed through excipient choice and evaluated in vitro only.

Research design

Experimental formulation development using Quality by Design principles and a 3² full factorial design, followed by validation and stability testing.

Semester 3 — research work and proposal

1. Literature and proposal: review of oral films, ondansetron and paediatric formulation guidance; synopsis and proposal presentation (MRM 301T foundations).
2. Preformulation: organoleptic properties, melting point, solubility in water and phosphate buffer pH 6.8, λmax determination by UV scan, calibration curve, method validation (linearity, precision, accuracy, LOD/LOQ) per ICH Q2.
3. Compatibility: FTIR of drug, excipients and physical mixtures; DSC thermograms.
4. Preliminary trials: HPMC E5, HPMC E15, pullulan and PVA as film formers; PEG 400 and glycerol as plasticisers; select system based on film appearance, peelability and disintegration.
5. Quality target product profile (QTPP) and critical quality attributes (CQAs): film size about 2 × 3 cm, 4 mg ondansetron base per film, disintegration < 30 s, adequate tensile strength and folding endurance, rapid release.

Semester 4 — factorial design and evaluation (MPH 402P)

Factors and levels

Responses: Y1 disintegration time (s, petri-dish method in simulated saliva pH 6.8); Y2 tensile strength (MPa) with folding endurance as a supporting response; Y3 % drug released at 2 min (USP type II, simulated saliva pH 6.8, 37 °C).

Other evaluations for all nine batches: weight and thickness variation, surface pH, content uniformity, percentage elongation, moisture uptake.

Analysis in Design-Expert: fit linear, two-factor interaction or quadratic models; ANOVA (model p < 0.05, non-significant lack of fit, adjusted and predicted R² agreement); contour and 3D response-surface plots; numerical optimisation with desirability (minimise Y1, maximise Y3, Y2 in range); prepare the optimised batch in triplicate and compute % prediction error.

Optimised film characterisation: SEM or optical microscopy of surface, dissolution profile with similarity to a marketed orally disintegrating tablet (f2), release kinetics.

Stability: optimised films in aluminium pouches at 40 ± 2 °C / 75 ± 5% RH and 25 ± 2 °C / 60 ± 5% RH for at least 3 months; test appearance, content, disintegration and dissolution at 0, 1, 2 and 3 months.

Statistics

Mean ± SD (n = 3 or 6); ANOVA in Design-Expert; one-way ANOVA or t-tests in GraphPad Prism for stability data; α = 0.05.

Timeline (26 weeks)