Green Mechanochemical Strategy for the Discovery and Selective Preparation of Polymorphs of Active Pharmaceutical Ingredient γ-Aminobutyric Acid (GABA)

Abstract

This study exploited a mechanochemical strategy to discover new polymorphs of a drug and meanwhile realize the selective preparation of various polymorphs without using bulk solvents. It is worth noting that in practice, the mechanochemical approach is a unique green and highly efficient method. On the one hand, about 20 years after the last discovery of the γ-aminobutyric acid (GABA) polymorph, we identified a new GABA polymorph (Form-III) by mechanochemical milling. Form-III is available exclusively by milling at present, and its crystal structure is also determined by crystal structure prediction (CSP) methods. On the other hand, through introducing a trace amount of solvents with different hydrogen bond donor/acceptor (α/β) abilities, we can achieve selective control of three GABA polymorphs during the milling process, which is not accessible by the traditional solution-based method. The mechanism of trace solvent-directed polymorphic outcomes was investigated from the change of the stability relationship between different polymorphs under milling conditions. As the milling proceeds, the crystal size decreases and the surface effect becomes significant so that the surface stability will dominate the overall stability. The adsorption of solvents with different α and β values on the crystal surface will affect the surface stability of various GABA polymorphs. Consequently, the polymorph with higher stability is able to survive under milling conditions.

The origin of delayed polymorphism in molecular crystals under mechanochemical conditions

“…22,23,32 However, this concept does not yet account for the striking and often exceptionally long induction periods observed during mechanochemical reactions. 12,33,34 Scheme 1: Schematic representation of the system under study. Formation of carbamazepine (CBZ) and isonicotinamide (INA) cocrystal Forms I or II depending on the energy input (frequency, ball size).…”

Crystal Structure and Thermal Properties of Phenibut, Phenibut H2O and Phenibut HCl: a Case for Phase Stability Based on Structural Considerations

“…A recent study by Wu and Gong reports on the conformation between C β and C γ of the three GABA polymorphs received through different milling conditions. The most frequently obtained form in their experiments posed a gauche conformation in this position [35] . Earlier studies have linked the gauche conformation in GABA to higher stability in the crystal phase possibly because this geometry favors an intramolecular HB.…”

Role of Mechanochemistry in Solid Form Selection and Identification of the Drug Praziquantel

“…Moreover, different polymorphs of a drug molecule can have completely different physiochemical properties such as solubility, permeability, stability, tablettability, hygroscopicity, and so on, properties that are crucial in pharmaceutical formulation development . Thus, screening for all the possible polymorphic forms of a drug and control of the polymorphic form of drug molecules is of considerable importance. − In recent years polymorph screening through mechanochemistry is becoming popular as a greener approach. , Furthermore, liquid-assisted grinding (LAG) is one of the frequently employed strategies for mechanochemical control over cocrystal, polymorphs, etc. − The stabilization of a specific polymorph of γ-aminobutyric acid by using the LAG technique with high-polarity solvents has been reported recently . Emmerling and co-workers demonstrated the formation of a metastable form III of benzamidine by using nicotinamide seeds in a LAG experiment with ethanol .…”