(T1430-08-52) Overcoming Formulation Challenges of an Unstable Amorphous Prodrug by API Sparing and Enteric Coating Approaches

Purpose: The active pharmaceutical ingredient (API) is a prodrug that undergoes enzymatic conversion to its active metabolite in the intestinal lumen. An amorphous free base was selected for development due to the inability to identify a stable crystalline form through comprehensive polymorph screening. This amorphous form causes severe hydrolytic degradation under acidic conditions as well as gelling upon moisture exposure due to its low Tg (~75°C). This research aims to develop a stable first-in-human (FIH) tablet formulation which can quickly disintegrate in the small intestine, while the critical challenges of API scarcity and inherent physicochemical instability have been addressed.

Methods: API-excipient compatibility study was conducted under stress conditions (elevated temperature/humidity) to identify suitable functional excipients that can maintain the API physical and chemical stability. To address hydration-induced gelation and ensure rapid disintegration, API particle engineering strategies were implemented including jet-milling to micronize the particles and pre-coating with colloidal silicon dioxide to inhibit the directly moisture interaction with the API particles. Enteric coating with optimized thickness was applied to prevent acid-induced hydrolysis in the gastric environment, while keeping balance between gastric protection and fast intestinal release. Stability assessments were focused on the container-closure systems (HDPE bottles containing desiccants versus Alu-Alu blister packs) under different storage conditions (2~8°C and 25°C/60% RH). To overcome the limited API availability, a slugging method with 20 g material was employed with a Styl'One EVO compaction simulator to simulate roller compaction and subsequent compression process parameters, while geometrically equivalent placebo tablets were incorporated to bulk up the active tablets during the enteric coating process development.

Results: Neutral or weak acidic excipients were selected due to the incompatibility of API with common basic excipients (e.g., sodium stearyl fumarate, croscarmellose sodium, etc.).  The API particle size was reduced to D₉₀ ≈10 μm with jet-milling. The pre-coating with colloidal silicon dioxide resulted in rapid tablet disintegration (≤5 min) and complete drug dissolution (85% release within 30 min) in pH 6.8 phosphate buffer. An enteric coating with Eudragit L100-55 at 5 mg/cm² thickness effectively prevented API release in 0.1N HCl (≤10% drug released after 2 h), while maintaining immediate release in the subsequent pH 6.8 media. Based on the stability study results under various packaging configurations, the Alu-alu blister packs stored under 5°C was selected to achieve both chemical and physical stability for the coated tablets. The formulation development was completed with minimal API consumption (~50 g), and the clinical batch was successfully manufactured and released for the FIH study. The PK results will be available in late 2025.

Conclusion: This study overcame the challenges to formulate an unstable amorphous prodrug by using an API-sparing strategy, combined with micronization, enteric coating, and a scale-down slugging method. It also provides a scalable framework for formulating an unstable amorphous drug under resource constraints. The combination of API micronization (D90 ≈10 μm) and the colloidal silicon dioxide pre-coating prevented hydration-induced gelation, enabling rapid disintegration and complete intestinal release. The optimized enteric coating (5 mg/cm² thickness) ensured gastric protection (≤10% release in 0.1N HCl) and fast intestinal dissolution. API consumption was minimized to ~50 g for prototype formulation development with the scale-down slugging method and bulking up with geometrically equivalent placebo tablets during enterica coating development. A stable tablet formulation was successfully delivered for a FIH clinical study.

Parent drug content in the prodrug when stored under different conditions

Two-stage in vitro dissolution profiles of enteric coated tablets with different coating weight gains (USP apparatus II paddle, 100 rpm, 37oC)

Stability results of the enteric coated tablets packaged in Alu-Alu blister packs