The Confinement Crystallization Behavior of Isonicotinamide within Functionalized Pores: Correlation between Polymorph Selection and Surface Chemistry

Abstract

Strategically modifying functional groups on pore surfaces of confined materials offers an effective approach to regulating crystal nucleation and growth, which is significant for polymorphic pharmaceuticals. Using isonicotinamide (INA) as a model polymorphic compound, this study systematically investigates the effects of pore surface chemistry─engineered with –CH₃, –OH, –COOH, and –NH₂ groups─on polymorph selection under nanoconfinement. The results reveal distinct pathways: hydroxyl-functionalized pores exclusively yield metastable form VI, methyl-functionalized pores predominantly yield form II, while amine- and carboxyl-functionalized pores yield mixed form II/VI. The OH-modified system demonstrates selectivity for form VI, attributed to specific OH···INA hydrogen-bonding interactions that significantly reduce its nucleation activation energy. This study aims to establish a selective synthesis methodology for polymorphic control of isonicotinamide through spatial confinement and surface chemistry modulation, ultimately achieving high-purity form VI and form II. These findings establish a novel approach for controlling polymorphic outcomes via the rational design of confinement surface chemistry.