(T1330-07-39) Influence of Solid Content and Plasticizer in Formulation of Hypromellose Oral Thin Film – Part 1

Purpose: The study was aimed at exploring the effect of solid content and plasticizer on process and physical properties of oral thin films manufactured via a solvent casting method. Loratadine was selected as a low-dose, poorly water-soluble model drug and hypromellose (hydroxypropyl methylcellulose) as film forming polymer. Loratadine is an anti-allergy, over the counter drug available as chewable, orally disintegrating tablets and solution in 5 and 10 mg doses. It is a suitable candidate for oral thin film formulation due to its low dose and indication. We investigated the effect of solid content, plasticizer type/concentration, and loratadine concentration on manufacturing process and properties of simple oral thin films.

Methods: Formulation systems with a solid content of 5% -25% consisted of hypromellose (METHOCEL^TM E5 Prem LV) as film forming polymer; polyethylene glycol (PG) or glycerol (Gly) (5% -10% w.r.t. polymer) as water soluble plasticizer; loratadine (0% -15% w/w, w.r.t. polymer) as model drug; polysorbate 80 as wetting agent (0.2% w/w) and Foic Blue #1 Dye (0.2% w/w) as coloring agent were designed. Polymeric solutions using a hot/cold method were prepared by dispersing the polymer in 1/5 to 1/3 of the total required volume of water (heated to above 90°C (194°F)). The remainder of the water containing plasticizer/colorant was then added as cold solution to lower the temperature of the dispersion and solubilizes the polymer. For active formulations, loratadine, plasticizer, colorant and surfactant were dispersed in cold water using a high shear mixer and then added to the hypromellose solution. Each formulation was stirred for up to 2 hours and then sonicated at room temperature (RT) for 15 minutes to facilitate removal of air bubbles. For active formulation, mixing was continued at very low speed to remove the air bubbles and prevent settling of the drug. Viscosity of the formulations was measured using a digital rotational viscometer (Brookfield Viscometer DV II+ Pro). Reading was taken at 1 min rotation using spindle # 62 at 20 rpm speed. Then using a draw down technique, films were cast on a glass surface and air dried at RT. The resultant films were cut into 3 X 4 cm pieces, evaluated for appearance, stickiness, and ease of peeling. Thickness was measured at five locations of the films using a micrometer (AMES, Masters of Measurement). Disintegration time (DT, n=10) was measured in 15 mL artificial simulated saliva in a glass Petri dish (6.5 cm diameter, 5 cm height) using a stopwatch. Mechanical strength of the films (n=10) was evaluated via a puncture test method using a texture analyzer (TA. XT. Plus). Loratadine prototype films were selected for drug release evaluation in a follow up study.

Results: The formulation with 5% solid content had low viscosity to cast a proper film, and the formulation with solid content above 15% (i.e. 20%) was too viscous to make acceptable films. Therefore, the study was continued with formulations targeting 10-15% solid content. Viscosity of the placebo formulations with 10% solid content was 139-179 mPa⋅s, and for 15% solid content was 663-1096 mPa⋅s. The viscosity data indicated solid content directly influences formulation viscosity, as solid content increases, viscosity increases. The relationship was reverse for the effect of plasticizer on the solution viscosity. In addition to the plasticizer concentration, type of the plasticizer influenced formulation’s viscosity. For example, viscosity of loratadine dispersions with 5% PG and 5% Gly was 673 mPa⋅s and 1096 mPa⋅s, respectively. All resulting films looked smooth and peelable except for loratadine film made from a dispersion of low solid content (10%) which wasn’t evaluated further (Fig.1). Thickness of the films kept constant between 30-32 µm. The average DT(SD) was 60 (±9.5) and 40 (±7.3) seconds for placebo films w/PG and w/Gly, respectively, indicating faster DT with Gly. The loratadine films showed similar DT regardless of the plasticizer. The average DT was 41.7 (±6.4) and 39 (±7.1) seconds for loratadine films with PG and Gly, respectively. Breaking force (BF) range was 699 g with coefficient of variance (CV) of 17 to 1588 g with CV of 10. Placebo films containing 15% solid and PG as plasticizer indicated higher mechanical strength compared to that of 10% solid and Gly (Fig 2). Mechanical strength of the loratadine films with glycerol was the highest (BF, 1088 g) with the lowest CV of 4, indicating the impact of plasticizer type and concentration on the film properties and uniformity.

Conclusion: Simple film formulations based on hypromellose (METHOCEL™ E5 Prem LV) with loratadine were manufactured via a solvent casting method and studied. The effect of two water soluble plasticizers (propylene glycol and glycerol) and solid content on formulation processability and film properties was investigated. It was demonstrated that solid content and type of plasticizer were critical parameters for formulation processability and film properties. A few loratadine prototype films were selected for dissolution studies and future optimization work.


Figure 1. Effect of solid content and plasticizer on mechanical strength of hypromellose films