Formulation and Optimization of Immediate Release Tablet of Sapropterin Dihydrochloride by Dry Granulation Process

Abstract

The research aims to develop and evaluate an immediate-release dosage form of sapropterin dihydrochloride to improve efficacy, stability, and patient acceptance in treating hyperphenylalaninemia (HPA), ensuring rapid therapeutic action upon administration. Formulation development began with a pre-formulation study to evaluate drug-excipient compatibility, solubility, and compressibility, followed by feasibility trials to create a prototype formulation. Dissolution tests and optimization methods, including DoE and OFAT, were employed to refine the formulation based on critical quality attributes. Process optimization involved identifying and fine-tuning critical parameters through sequential unit operations and risk assessments, ensuring uniformity and quality during scale-up for commercial production. The prototype formulation development for a tablet product based on the reference product Kuvan involved strategic excipient selection to meet critical quality attributes (CQA) and mitigate concerns like mottling. The formulation deviates from the reference by using LH 21 as a binder, colloidal silicon dioxide as a glidant, and omitting anhydrous dibasic calcium phosphate, with Mannitol SD (Pearlitol 200) chosen for its flowability and compressibility. The feasibility trial aimed at achieving pharmaceutical equivalence to Kuvan tablets, focusing on bioequivalence, stability, and API distribution, and involved top spray fluid bed granulation with roller compaction and blending identified as high-risk steps. Optimization of tablet formulation considered drug substance particle size, blend ratios, and excipient selection, with adjustments in intra and extra-granular ratios significantly impacting tablet characteristics. Keywords: Immediate Release, Sapropterin Dihydrochloride, Dry Granulation Process