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.
Highlights
Tumanova et al conducted a study on the ability of co-crystal formation between flurbiprofen and L-proline using the liquid-assisted grinding (LAG) method with five different solvents, i.e., methanol, ethanol, isopropanol, acetonitrile, and water; both compounds are soluble in methanol and ethanol; only flurbiprofen is soluble in isopropanol and acetonitrile, and only L-proline is soluble in water
This study showed that the choice of the solvent used for the LAG method is a factor that can affect the rate of reaction and the reaction pathway, as five co-crystal structures were found with different types of supramolecular synthon [86]
The salt co-crystals asymmetric unit consisted of L-proline, which coordinated with the alkaline ion and interacted with water and diclofenac molecules via hydrogen bonding, as shown in Figure 6 [22]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Many researchers have been developing ways to modulate API physicochemical properties to enhance their therapeutic effectiveness [3]. The co-crystal formation has become a field of interest because of its potential to modulate API physicochemical properties, such as solubility, chemical stability, and physical stability, affecting the shelf life of the drug and its therapeutic effects in the body [6]. Researchers are looking for the less dangerous co-formers with hydrogen bonding sites that can interact with the API’s functional groups, including amino acids [4]. A new category of multicomponent crystal, namely ionic co-crystal, is garnering much attention due to its advantages, such as the simplicity and functionality to improve physicochemical properties of pharmaceuticals, food, fertilizers, and chiral resolution [15]. L-proline is discussed in depth due to it becoming the most used co-former with some advantages over the other amino acids [17,20,21,22]
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