Effects of inorganic additives on polymorphs of glycine in microdroplets

Abstract

Sodium chloride plays an important role in the selectivity of glycine polymorphs and results in an increased nucleation percentage in microdroplets.

Crystallization and Polymorphism under Nanoconfinement

“…These include microfluidic devices (MFDs), which have been employed for optimizing protein crystallization and crystal quality, wherein crystallization typically occurs in minute water droplets surrounded by a mobile oil phase. − As an example, a multimicrofluidic crystal generator (MMicroCryGen) device featuring MFD technology is shown in Figure . The emergence of MFDs has prompted their use for polymorphs screening as well, particularly pharmaceutical compounds. ,,,, MFDs permit generation of uniform droplets that simplifies statistical analysis of nucleation and polymorphism. ,− MFDs enable solubility determination (of stable and metastable forms) and polymorph screening directly from powder, saving valuable material crucial during early stage development. − Furthermore, droplet-based methods using MFDs can allow access to unstable and metastable polymorphs through confinement in small volumes. Recently, an automated robotics approach based on crystallization in nanosized droplets encapsulated within an inert oil to regulate solvent evaporation was performed in crystallization trays, allowing for hundreds of parallel experiments and the discovery of a new 13th form of ROY …”

“…89,126 This has been amply demonstrated for glycine, the simplest amino acid, which forms three polymorphs. Electrolytes�acids, bases, salts�influence the nucleation and growth of certain glycine polymorphs, 82,90,127 and glycine polymorphism is affected by the pH of the aqueous growth medium. The thermodynamically preferred form γ is favored at neutral pH, but the kinetically preferred form α crystallizes in acidic or basic solutions.…”

“…115 The emergence of MFDs has prompted their use for polymorphs screening as well, particularly pharmaceutical compounds. 90,114,115,153,154 MFDs permit generation of uniform droplets that simplifies statistical analysis of nucleation and polymorphism. 90,155−157 MFDs enable solubility determination (of stable and metastable forms) and polymorph screening directly from powder, saving valuable material crucial during early stage development.…”

Understanding the Salt-Dependent Outcome of Glycine Polymorphic Nucleation

“…However, robust polymorph control has been a challenging task despite the great effort dedicated to fundamental explorations of crystal nucleation and growth [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ], mainly because of the poor understanding of solution crystallization [ 3 , 8 , 9 ]. The challenges faced are perhaps particularly demonstrated by the longstanding puzzles [ 3 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ] of glycine polymorphic crystallization from aqueous solutions with additives including inorganic bases, acids and salts.…”

“…An individual glycine polymorph from a bulk aqueous solution can be produced using various additives [ 8 , 9 , 12 , 20 ] or established techniques [ 21 , 22 , 23 , 24 ]. However, polymorphic crystallization of glycine is still studied extensively by many scientists [ 3 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. One of the reasons [ 3 , 8 , 9 ] behind such extensive studies is that the mechanisms governing the outcome of glycine polymorphic crystallization may provide a clue for robust polymorph control of other polymorphic systems, given that glycine molecules in solution and in solid state exhibit many salient features.…”