Enantiomeric separation of racemic amlodipine by sequential fractional crystallization through formation of diastereomeric salt solvates and co‐crystals of solvate‐like compounds with specific structure — A tandem resolution

Abstract

A new resolution method of racemic amlodipine has been developed. The racemic compound is reacted in a suitable solvent with 0.25-mol equivalent of (R,R)-tartaric acid. After the decomposition of the diastereomeric salt, the remaining racemic fraction is precipitated with half-equivalent of fumaric acid, and the pure amlodipine enantiomer is obtained. A quarter equivalent of the same resolving agent, (R,R)-tartaric acid has been also added to the mother liquor to obtain the other enantiomer. The advantage of this method is that both of the enantiomers of amlodipine could be obtained with high enantiomeric excess with the same resolving agent. The racemic excess can also be isolated and re-resolved. Achiral reagents (urea and thiourea) have been added to the resolving agent. These neutral additives are incorporated as co-crystals in the structure of the diastereomeric salts. The used solvate-former solvents and achiral additives are structurally similar, and their presence can enable the fractional separation of the diastereomers. In addition, the racemate, the enantiomers, and some intermediate salts with high diastereomeric excess obtained in the resolution process of amlodipine have been also subjected to thermal (DSC, TG/DTA-EGA-MS, and -FTIR), analytical (FTIR spectroscopic), and structural (XRD) comparisons, which indicate that the key-intermediate crystalline diastereomeric salts-as solvates and co-crystals-inherit a kind of structural similarity from their related additives-solvents (DMF, DMAA, and DMSO) or (thio)ureas, respectively.

Optical Resolution of Two Pharmaceutical Bases with Various Uses of Tartaric Acid Derivatives and Their Sodium Salts: Racemic Ephedrine and Chloramphenicol Base

“…Meanwhile, the application range of the powder XRD pattern-indexing and crystal structure modelling/solving opportunities connected to the DASH software package [ 16 ] have been also tested on pure initial materials and diastereomeric salt samples of high diastereomeric excess [ 17 ].…”

Overcoming a Solid Solution System on Chiral Resolution: Combining Thermodynamics of Crystallization and Kinetics of Enantioselective Dissolution

“…[1] It is therefore important to separate the two enantiomers and investigate their respective properties. In this context, chiral resolution by crystallization methods such as preferential crystallization, [2][3][4][5][6][7][8][9][10][11][12] diastereomeric salt formation, [13][14][15][16][17] co-crystallization [2,7,11,[18][19][20] and deracemization, [18,[21][22][23][24] has been widely utilized due to its economic advantage and simplicity of the operation. However, these methods require crystallization conditions yielding precipitate containing only the desired enantiomer such as eutectic system.…”

Diastereomeric salts of (S,S)-sertraline with l- and d-tartaric acids: an investigation into chiral supramolecular discrimination

“…26 In CBR methods, the diastereomeric salts of TA and derivatives have been used in many successful resolution cases (33% for TA and 25% for derivatives). 24,27 For example, diastereomeric separation of amlodipine, 28 epinephrine (or adrenaline) 29 and aminodiol (AD) and ephedrin 30 and α-phenylethylamine 31 is achieved using l -(+)-tartaric acid as a resolving agent. Multistage crystallization is able to resolve citalopram using (+)- O , O ′-di- p -toluoyl- d -tartaric acid (DTTA).…”