Influence of the Local Chemical Environment in the Formation of Multicomponent Crystals of L-Tryptophan with N-Heterocyclic Carboxylic Acids: Unusual Formation of Double Zwitterions

Abstract

Formation of multicomponent crystals (MCCs) of L-tryptophan (TRP) with N-heterocyclic carboxylic acids such as 2-picolinic acid (PA) and its 3- or 4-substituent isomers (nicotinic acid or isonicotinic acid), pyrazinecarboxylic acid (PZCA), 2,3-pyrazinedicarboxylic acid (2,3-PZDCA), 2-quinaldic acid (QA), and its 3-subsituent isomer (3-QA) is investigated in this manuscript. The investigation results in four multicomponent solid forms of the amino acid with coformers where the electron withdrawing functional group (−COOH) is present in the ortho-substituent to N-heterocyclic rings. The isomers of PA or QA having −COOH at the meta- or para- position failed to produce new phases. These solid phases were identified by powder X-ray diffraction results, and the MCCs derived from 2-picolinic acid (1) and 2,3-pyrazinedicarboxylic acids (3) were further characterized with single crystal X-ray diffraction. The crystal structure of TRP-PA (1) reveal a rare form of cocrystal where both the amino acid and the picolinic acid are in zwitterionic form. Further, in our surprise, the amino acid appears to undergo change in absolute configuration during cocrystallization. Crystal TRP-2,3-PZDCA (3) is observed as a salt where the amino acid exists in cationic form, and the carboxylic acid exists in anionic form. It is observed that the complementary H-bonding between the py-N/ortho- −COOH of the coformers with the α-NH3 +/α-COO– group of L-tryptophan primarily drives the cocrystallization process. Density functional theory calculations support the experimental observations as lower total energy and higher interaction energy values are obtained for the successfully synthesized MCCs. The solid state fluorescence of TRP (known as intrinsic fluorescence probe) shows that 2,3-PZDCA is an effective quencher.

Interactions of Amino Acids and Aminoxazole Derivatives: Cocrystal Formation and Prebiotic Implications Enabled by Computational Analysis

“…On the basis of a racemic amino acid, we also expected to see a centrosymmetric space group, which turned to be true as complex 6 crystallizes in the monoclinic C2/c group (Z = 4), where amino acid residues of opposite handedness coexist within the unit cell. This structure is similar to that of multicomponent crystals of some amino acids, namely L-Trp, with N-heterocyclic carboxylic acids, for which double zwitterions have been recently reported with change in the absolute configuration during cocrystallization (Das and Srivastava 2017). The term zwitterionic cocrystal is usually applied to systems consisting of a zwitterionic compound and a neutral molecule (Aakeröy et al 2008), which show common features of supramolecular organization and hydrogen bonding (vide infra).…”

Polymorphism in the 1/1 Pterostilbene/Picolinic Acid Cocrystal

“…For instance, the relative bioavailability of quercetin/picolinic acid (coformer in neutral form) with respect to quercetin was 1.75, the apparent aqueous solubility improvement of leflunomide/picolinic acid (coformer in zwitterionic form) in 1/1 and 1/2 stoichiometries were 1.27 and 1.09 respectively, and the relative bioavailability of the hesperetin/picolinic acid (coformer in zwitterionic form) with respect to hesperetin was 1.36. This is compatible 25 cocrystal yes B PAQMEC 28 cocrystal yes B QUJQOE 29 cocrystal yes B RAHKUJ 30 cocrystal yes B NAFZAY 31 cocrystal yes C UBUFIJ 32 cocrystal no C PAQMIG 28 cocrystal no C DEQGAK 33 salt no D PICASC 34 cocrystal yes D ANIMES 35 peroxosolvate yes D BEBCAP 36 cocrystal yes D PICOLA02 37 anhydrous with the "spring and parachute" model, 38 in which a highsolubility coformer is released into the water solution, resulting in cocrystal collapse together with the dissolution of the amorphous, less soluble component of the cocrystal. Thus, the solubility of the cocrystal is directly influenced by the solubility of the coformer.…”

Salt/Cocrystal of Anti-Fibrinolytic Hemostatic Drug Tranexamic acid: Structural, DFT, and Stability Study of Salt/Cocrystal with GRAS Molecules

“…Density functional theory (DFT) calculations were performed for the synthesized salt/cocrystal to understand the geometry of the molecular structure in the synthesized salt/cocrystal and to support the crystal structure determined by SC-XRD analysis. Various research groups have reported DFT calculations on cocrystals to support the experimentally obtained crystal structures. − The molecular structure of TXA and its coformers are displayed in Scheme . The coformers used are salicylic acid (SAL), 3-hydroxybenzoic acid (3HBA), 2,4-dihydroxybenzoic acid (2,4HBA), 2,5-dihydroxybenzoic acid (2,5HBA), 2,6-dihydroxybenzoic acid (2,6HBA), gallic acid (GAA), oxalic acid (TXA), tartaric acid (TTA), fumaric acid (FUM), succinic acid (SUA), and crotonic acid (CRA).…”