Binary and Ternary Phase Diagrams as Routes to Salt Discovery: Ephedrine and Pimelic Acid

Abstract

Despite the commercial importance of molecular salts in pharmaceutical applications, there are few previous studies of their phase behavior in binary and ternary systems. In this current study salt formation is explored in both the binary system (1R,2S)-(-)-ephedrine/pimelic acid and in the related ternary system using water as a solvent. The utility of the binary phase diagram as an aid to full exploration of phase space is demonstrated, and this investigation makes use of both dry techniques (grinding) and crystallization from solutions to access possible solid phases. Inherent problems of isolating a metastable phase in the ternary system are revealed.

High-Throughput Salt Screening of Synthetic Intermediates: Effects of Solvents, Counterions, and Counterion Solubility

“…Our automated intermediate salt screen workflow was developed and optimized over the course of many years and finally reached a stable state in 2014. This workflow took into consideration several key parameters of high-throughput salt screening (e.g., choice of counterions and solvents, compound loadings, crystallization methods, and so forth) that were discussed in great detail in prior publications − ,,− ; Prepare a compound stock solution in tetrahydrofuran (THF) or MeOH (25–100 mg/mL). Prepare counterion stock solutions in water or MeOH (0.1–0.5 M). Add 1.0 equiv of the counterion as a stock solution to the compound stock solution to prepare the respective salt stock solutions. Distribute the salt stock solutions into 96-well plates. Typically, 1–5 mg of the compound is distributed into each well.…”

The effect of carboxylic acids on glycine polymorphism, salt and co-crystal formation. A comparison of different crystallisation techniques

“…The outcome of crystallisation (polymorphism and stoichiometry) can be controlled not only by changing the composition of the starting mixture, but also by varying the crystallisation procedure, resulting from an interplay of thermodynamic and kinetic factors. [54][55][56][72][73][74][75][76] As an example of a detailed comparison of the efficiency of co-crystallisation from the same starting components, comparing the effect of variable conditions within the same technique, and the effect of different techniques, one can mention studies of co-crystallisation in the ''piroxicam-carboxylic acid'' 56 and ''meloxicam-carboxylic acid'' 55,77 systems. Similarly, variations on the co-crystallisation of glycine and oxalic acid under different conditions has been studied.…”

Structural motifs in salts of sulfathiazole: implications for design of salt forms in pharmaceuticals APIs

“…14,18 In contrast comparable studies for salt formers are more unusual and while proton transfer can related to both chemical and crystallographic structure in certain systems, 19 few studies investigating the interaction between molecular structures, intermolecular interactions and formation have been presented. Systematic examples altering the counterions have been reported for ephedrine, [20][21][22] tyramine, 23 gemfibrozil, flurbiprofen, ibuprofen and etodolac salts 24 and studies into series of sulfonic acid salts have also emerged. 25 Unlike cocrystals, salts feature an additional set of unidirectional electrostatic interactions between the charged species (both repulsive and attractive) in addition to the crystal packing directing interactions.…”