Identification of critical parameters for an automatic film applicator to produce orodispersible hydrocortisone hemisuccinate films

Objective
Orodispersible films (ODFs) offer various advantages, both in terms of ease of administration for some populations (i.e., pediatric and geriatric) and in terms of dosage adjustment options. However, few pharmaceutical specialties are available, and the production of ODFs in hospital pharmacies is underdeveloped. The use of an automatic suction-heating film applicator (AAF) appears to be a promising solution for producing ODFs directly in hospitals.
The study focuses on identifying and evaluating the critical parameters of the manufacting process of ODFs containing 1.0 mg of hydrocortisone hemisuccinate (HCS) using the AFF.

Materials and Methods
HCS ODFs are composed of sterile water, hydroxypropyl methylcellulose, corn starch, calcium carbonate, sucralose, propylene glycol, and injectable HCS (Upjohn^®) used at 10 mg/g.
The AAF (TQC Sheen^®) was adjusted to obtain a 200 cm2 film, from which 2 cm2 samples were cut manually and then packaged in a Medi-Dose^® system.
A complete 24-factorial design was used to study the AAF parameters: spreader knife height (300-700 µm), application speed (5-25 mm/s), drying temperature (60-70°C) and drying time (30-50 min) with a triplicated center point. The response factors were: film thickness, film mass, HCS degradation impurities (HPLC-UV), relative deviation from the expected dose, dissolution time (t80%, USP IV) and residual moisture (halogen desiccator).

Results
The significant factors common to all responses are the height of the knife, the application speed, and the interactions between both. There is an expected correlation between thickness, mass, and dose. The drying time only affects the residual moisture content while the drying temperature has no influence on the results under the conditions studied. There is no degradation of the active ingredient at Day-0 (stability study in progress). Almost all experiments comply with the mass uniformity test except for conditions combining a knife height of 700 µm with an application speed of 5 mm/s (3/4 invalid). The central point has a content of 1.01 ± 0.05 mg, which is in line with the expected dose, complies with mass uniformity assay, and shows a t80% of 5.8 ± 0.4 min, equivalent to the dissolution time of Setofilm^® (ondansetron ODF).

Conclusion
Two factors stand out as important for controlling the content and uniformity of the masses when producing ODFs with an automatic film applicator: the height of the knife and the application speed. However, the height of the knife does not appear to be a relevant parameter for adjusting the dose of HCS in ODFs.
These initial results confirm the potential of this process for producing ODFs within hospital pharmacies for compatible active pharmaceutical ingredients.

Keywords: Drug development, Experimental plan, Hydrocortisone

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