Pentamorphs of Acedapsone

Abstract

Acedapsone is a long acting prodrug of Dapsone, the diacetyl derivative of diaminophenyl sulfone. It exhibits superior bioavailability compared to the parent drug. Dapsone occupies a preeminent position in the treatment of leprosy since the 1940s. Surprisingly no X-ray crystal structure or polymorphs of acedapsone are reported. Five novel polymorphs of acedapsone are reported (I–V) of which crystal forms I and II are characterized by single X-ray diffraction. These novel polymorphs were crystallized from solution, slow cooling of the melt, and spray-drying of the powder. Solution crystallization afforded Acedapsone Forms I and II. Slow cooling of the melt phase resulted in an amorphous phase, which transformed to a new Form IV slowly at room temperature, and then to Form III. Fast cooling or quick quench of the amorphous solid gave Form I. Spray drying resulted in a new metastable polymorph V, but this polymorph also converted to Form III at room temperature after 6 h. In addition to five crystalline polymorphs of acedapsone, an amorphous phase was also obtained from the melt. XPac analysis of polymorphs I and II (space group P21/n and C2/c) showed 2D isostructurality, and Hirshfeld surface analysis revealed subtle differences in the molecular environment of the two crystal structures. The stability of five polymorphs by DSC, VT-PXRD, and upon heating in a sealed tube suggested that the kinetic stability order is Form I (most stable) > II > III > IV > V > amorphous (least stable), whereas competitive slurry and liquid-assisted grinding experiments gave the thermodynamic stability as Form II (most stable) > I > III > IV > V > amorphous (least stable). Solventless methods such as quench cooling of the melt and holding in a sealed tube at high temperature and pressure yielded the kinetically stable Form I. Spray drying of the powder gave metastable Forms III and V (which transformed over time), and slurry conditions gave the thermodynamic Form II. The pentamorphic system follows Ostwald’s law of stages. The role of solvent selection in the direct crystallization of Acedapsone polymorphs after diacetylation of Dapsone is also discussed.

An Investigation into the Polymorphism and Crystallization of Levetiracetam and the Stability of its Solid Form

“…Solution crystallization, humidity, melt cooling, freeze‐dryer, quench cooling, sublimation, and milling were applied to investigate the crystallization and polymorphism of LEV in detail. To the best of our knowledge, several techniques, including melt cooling, quench cooling, and milling, can convert solid drugs to amorphous and metastable forms . However, the results reveal that no new solid forms were formed when various methods of solid‐state transformation were performed.…”

“…Pharmaceutical solid form screening has rapidly developed into a general approach to improve the physicochemical properties of drugs, which can remarkably affect the solubility, bioavailability, hygroscopicity, melting point, stability, compressibility, and other performance characteristics of pharmaceutical products . A large number of methods can be applied to produce polymorphs of APIs, such as high‐temperature‐triggered transformation, cooling crystallization, pressure‐induced transformation, milling, humidity, and solution crystallization by changing the crystallization temperature, solution concentration, cooling rate, solvent types, pH, and additive . Studies aimed at obtaining solid forms of relevant drug are greatly essential and meaningful to develop optimal drug crystals and to control the quality of the final state of the drug .…”

Towards medicinal mechanochemistry: evolution of milling from pharmaceutical solid form screening to the synthesis of active pharmaceutical ingredients (APIs)

“…49 Liquid-assisted grinding was used by the Nangia group as a part of the investigation of the pentamorphic system of acedapsone. 91 Systematic comparison of different polymorph screening techniques, using the cocrystallisation of phenazine and mesaconic acid as a model reaction, established LAG as the most prolific one, enabling the observation of three out of five crystal forms encountered in this study. 92 Seeding-assisted grinding A different approach to screen and selectively synthesise polymorphs of organic molecular solids has been demonstrated by the Cinc ˇic ´group, 93,94 who explored the role of seeding 95 on the polymorphic outcome of mechanochemical synthetic organic reactions.…”

Preparation, characterization, intrinsic dissolution studies and microbiological assessment of dapsone tosylate polymorphs

“…Four polymorphs of DAP-flavone co-crystals have been reported [10]. Acedapsone, a commercial derivative of DAP, has five polymorphs [11]. In both cases, the selection of the solvent for crystallization is crucial for achieving a single polymorph.…”