Quality by design approach for fabrication of extended-release buccal films for xerostomia employing hot-melt extrusion technology

The study endeavors the fabrication of extended-release adipic acid (APA) buccal films employing a quality by design (QbD) approach. The films intended for the treatment of xerostomia were developed utilizing hot-melt extrusion technology. The patient-centered quality target product profile was created, and the critical quality attributes were identified accordingly. Three early-stage formulation development trials, complemented by risk assessment aligned the formulation and process parameters with the product quality standards.

Employing a D-optimal mixture design, the formulations were systematically optimized by evaluating three formulation variables: amount of the release-controlling polymer Eudragit® (E RSPO), bioadhesive agent Carbopol® (CBP 971P), and pore forming agent polyethylene glycol (PEG 1500) as independent variables, and % APA release in 1, 4 and 8 h as responses. Using design of experiment software (Design-Expert®), a total of 16 experimental runs were computed and extruded using a Thermofisher ScientificTM twin screw extruder.

All films exhibited acceptable content uniformity and extended-release profiles with the potential for releasing APA for at least 8 h. Films containing 30% E RSPO, 10% CBP 971P, and 20% PEG 1500 released 88.6% APA in 8 h. Increasing the CBP concentration enhanced adhesiveness and swelling capacities while decreasing E RSPO concentration yielded films with higher mechanical strength. The release kinetics fitted well into Higuchi and Krosmeyer-Peppas models indicating a Fickian diffusion release mechanism.

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Adipic acid (APA) purity 99 %, Triethyl citrate (TEC) 99 %, and PEG 1500 were purchased from Fisher Scientific (Hanover Park, IL, USA). Eudragit® RSPO was kindly donated from EVONIK® (NJ, USA). Aqualon EC N14 and Carbomer (Carbopol 971P NF) were generously donated by Lubrizol Corporation (Wickliffe, OH, USA). Affinisol HPMC HME 15LV (molecular weight = 85 kDa), 100LV (molecular weight = 180 kDa) and Hypromellose Methocel K15M (HPMC K15M) (molecular weight = 575 k Da) were graciously donated by IFF.

Rasha M. Elkanayati, Alaa Y. Darwesh, Iman Taha, Honghe Wang, Prateek Uttreja, Sateesh Kumar Vemula, Walter G. Chambliss, Michael A. Repka, Quality by design approach for fabrication of extended-release buccal films for xerostomia employing hot-melt extrusion technology, European Journal of Pharmaceutics and Biopharmaceutics, Volume 200, 2024, 114335, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2024.114335.

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