Codesigning Tubular Flow and Noncontact Sonication for Antisolvent Crystallization: Rapid Fouling-Free Production of Uniform Rifapentine Crystals with Reduced Aspect Ratios

Rifapentine (RPT), a critical antituberculosis active pharmaceutical ingredient (API), faces persistent supply shortages compounded by crystallization challenges. Conventional antisolvent crystallization often produces RPT crystals with high aspect ratios (>7) and sizes outside the preferred 5–20 μm range. RPT’s strong adhesion to solid surfaces further increases fouling risk, and makes conventional milling impractical due to equipment damage. To avoid fouling, prior processes have relied on low supersaturation (≤1.5), resulting in long residence times of 4–6 hours. This study introduces a modular, continuous, fouling-free crystallization process that simultaneously addresses these limitations by codesigning precise antisolvent injection, controlled supersaturation, and dynamic noncontact ultrasonication within a tubular slug-flow platform. We establish design criteria enabling reproducible antisolvent (water) injection into flowing RPT solution slugs (in tetrahydrofuran) via continuous droplet formation and merging, minimizing needs for feedback control or complex operation. Guided by simplified semiempirical models and rapid droplet/slug tests, noncontact sonication is strategically applied at three stages─nucleation, growth, and breakage─to suppress fouling and enhance uniformity, without needing milling. Within 0.5 hour of residence time, these steps collectively reduce crystal dimensions while maintaining small variations (e.g., length from 81 μm to 6 μm, coefficient of variation or CVL ∼ 0.20; aspect ratio from 33 to 3.5, CVAR ∼ 0.29) and 100% form purity. This integrated approach offers a scalable pathway toward reliable RPT crystallization and supply resilience.