Amino Acids as the Potential Co-Former for Co-Crystal Development: A Review

Abstract

Co-crystals are one of the most popular ways to modify the physicochemical properties of active pharmaceutical ingredients (API) without changing pharmacological activity through non-covalent interactions with one or more co-formers. A “green method” has recently prompted many researchers to develop solvent-free techniques or minimize solvents for arranging the eco-friendlier process of co-crystallization. Researchers have also been looking for less-risk co-formers that produce the desired API’s physicochemical properties. This review purposed to collect the report studies of amino acids as the safe co-former and explored their advantages. Structurally, amino acids are promising co-former candidates as they have functional groups that can form hydrogen bonds and increase stability through zwitterionic moieties, which support strong interactions. The co-crystals and deep eutectic solvent yielded from this natural compound have been proven to improve pharmaceutical performance. For example, l-glutamine could reduce the side effects of mesalamine through an acid-base stabilizing effect in the gastrointestinal fluid. In addition, some amino acids, especially l-proline, enhances API’s solubility and absorption in its natural deep eutectic solvent and co-crystals systems. Moreover, some ionic co-crystals of amino acids have also been designed to increase chiral resolution. Therefore, amino acids are safe potential co-formers, which are suitable for improving the physicochemical properties of API and prospective to be developed further in the dosage formula and solid-state syntheses.

Entropically-Driven Co-assembly of l-Histidine and l-Phenylalanine to Form Supramolecular Materials

“…Molecular self-assembly of amino acids allows the formation of various well-defined supramolecular structures that display optical, mechanical, piezoelectric, and biological properties. − Amino acids are especially attractive building blocks for nanotechnological applications due to their chemical simplicity and inherent biocompatibility. Furthermore, increasing the chemical space by a co-assembly approach provides various supramolecular structures with improved physical, mechanical, and electromechanical properties. − Natural aromatic amino acid building blocks, such as l -Phe, l -Tyr, and l -Trp, self-assemble by noncovalent interactions, including hydrogen bonding, aromatic interactions, and van der Waals interactions, to form amyloid-like well-ordered supramolecular assemblies. − ,, Metal complexes of aromatic amino acids, such as l -Phe with Cu 2+ and Zn 2+ ions, can act as biocatalysts exhibiting high catalytic properties which can be useful in biotechnological, environmental protection, and industrial applications. , Crystal of Cu 2+ -coordinated l -Phe and d -Phe showed significant magnetic properties that can be used in bioelectronics, spintronics, and various technological applications. , Furthermore, amino acids are minimalistic building blocks that allow the design and improvement of the physicochemical properties of pristine supramolecular structures. ,,− The co-assembly of aromatic amino acids and bipyridines in polar organic solvents exhibited 1D crystalline microarchitectures and this well-defined lamellar packing structure could act as a template to accommodate transition metal ions, allowing for the coordinated polymer growth of metal-bipyridine complexes . Furthermore, the co-assembly of l -Phe and bipyridines resulted in smart high-quality hydrogel materials with light irradiation-triggered luminescence .…”

Amino Acid as Co-Crystal Coformer for Ebastine Solubility Enhancement

“…This rule was used as a conformer to prepare cocrystal with EB (pka 8. 19), since According to the"pKa rule", ΔpKa=pKa (acceptor (EB)) − pKa(donor (BENZ)) (16,17,18) According to FDA Δ pKa is considered as a threshold for distinguishing between co-crystals and salt. FDA indicates, the formation of salt will happen in the components having Δ pKa ≥ 1, whereas if the components having Δ pKa < 1 it will result in co-crystal formation (19) .…”

Amorphous Solid Forms of Ranolazine and Tryptophan and Their Relaxation to Metastable Polymorphs

“…The improvement of the physicochemical properties of an API depends also on the co-former when it is part of a multicomponent system. Amino acids are one of the most used types of co-formers in co-amorphous systems, as they are generally recognized as safe (GRAS) Figure b, is an essential amino acid for humans and acts as a biochemical precursor to produce the neurotransmitter serotonin and the vitamin niacin.…”