**1. Introduction**

Crystal engineering is the rational design of functional molecular solids from neutral or ionic building blocks, using intermolecular interactions in the design strategy [1]. This field has its origins in organic chemistry and in physical chemistry. The expansion of crystal engineering during the last years as a research field parallels significant interest in the origin and nature of intermolecular interactions and their use in the design and preparation of new crystalline structures [2].

The concept of crystal engineering, mainly cocrystal, is gaining an extensive interest of pharmaceutical researchers of both academia and industry during the last decade [3], the prominent reason being its ability to enhance the physicochemical and biopharmaceutical properties of active pharmaceutical ingredients without altering chemical structure, thus maintaining its therapeutic activity. With the new guidelines issued by United States Food and Drug Administration and European Medicines Agency for the regulatory aspect of cocrystal, the development of pharmaceutical cocrystal has gained a high impetus [4].

**Citation:** Castiñeiras, A.; Frontera, A.; García-Santos, I.; González-Pérez, J.M.; Niclós-Gutiérrez, J.; Torres-Iglesias, R. Multicomponent Solids of DL-2-Hydroxy-2 phenylacetic Acid and Pyridinecarboxamides. *Crystals* **2022**, *12*, 142. https://doi.org/10.3390/ cryst12020142

Academic Editor: Klaus Merz

Received: 10 December 2021 Accepted: 5 January 2022 Published: 20 January 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

A supramolecular synthesis is used to prepare cocrystals, and the design of homo and supramolecular heterosynthons is particularly one of the most exploited [5,6]. Although the preparation of cocrystals does not involve great complexity, the selection of the solvent can be critical in obtaining a particular crystal phase of cocrystal. The role of the solvent in the nucleation of crystals and cocrystals is still far from being completely understood.

The three isomers of pyridinecarboxamide: 2-pyridine carboxamide or picolinamide (**pic**), 3-pyridinecarboxamide or nicotinamide (**nam**) and 4-pyridinecarboxamide or isonicotinamide (**inam**) (Scheme 1), are a class of medicinal agents that can be classified as GRAS compounds (generally regarded as safe). Nicotinamide and isonicotinamide are popular cocrystal formers, **nam** is vitamin B3 and therefore of pharmaceutical relevance [7], whilst isonicotinamide is one of the most effectively used cocrystallizing compounds [8], as the pyridine N atom of the isonicotinamide molecule readily acts as a hydrogen bond acceptor when faced with good hydrogen bond donors such as carboxylic acids and alcohols [9]. In fact, the carboxylic acid···pyridine hydrogen bond has been identified as a robust yet versatile hydrogen bond and persists even in the presence of other good donors [10]. Cocrystals of picolinamide are rarely seen in the literature, despite being a structural isomer of **nam** and **inam** and a strong inhibitor of poly(ADP-ribose)synthetase [11], showing important biological activity with a coenzyme called NAD (nicotinamide adenine dinucleotide), which plays important roles in more than 200 amino acid and carbohydrate metabolic reactions [12]. Apart from pharmaceutical value, in general, pyridinecarboxamides are excellent cocrystallizing compounds. The amide group features two hydrogen bond donors and two lone pairs on the carbonyl O atom. A second hydrogen bond acceptor is the lone pair on the N atom of the pyridine ring. Consequently, these molecules are very versatile for a variety of hydrogen bonding interactions, especially in pharmaceutical cocrystals [13]. The crystal and molecular structures of the three isomers have been the subject of recent studies, and from the crystal structure point of view, all isomer compounds exhibit polymorphism. Two polymorphs are known of picolinamide [14] nicotinamide, which is a highly polymorphic compound with nine solved single-crystal structures [15], and isonicotinamide has six polymorphs in monoclinic and orthorhombic forms [16–19].

**Scheme 1.** Molecular diagrams of pyridinecarboxamides and mandelic acid. θ1, θ<sup>2</sup> and θ<sup>3</sup> indicate angles of torsion.

DL-Mandelic acid (Scheme 1) is a useful precursor to various drugs, for example homatropine and cyclandelate, which are esters of mandelic acid, and it is also known to have antibacterial properties [20]. Generally, the profile of **DL-H2ma** allows us to envisage this compound as an excellent coformer for cocrystals with the aforementioned carboxamides. Indeed, given that **DL-H2ma** is a substituted carboxylic acid containing a hydroxyl group on the adjacent carbon, it also possesses a set of sites capable of hydrogen bonding, both of donor and acceptor character.

For racemate of mandelic acid **DL-H2ma** and its enantiomers **L-H2ma** and **D-H2ma**, different polymorphs are known. Racemic **DL-H2ma** occurs as orthorhombic form I and also as polymorph II, monoclinic, metastable at normal conditions [21,22]. From **D-H2ma** only one monoclinic form is known [23] and for **L-H2ma** two polymorphs are known, both monoclinic [22].

Taking into account the previous considerations, the main objective of this work is the preparation, characterization, study of physicochemical properties, and identification of recurrent supramolecular patterns, within a new set of multicomponent pharmaceutical crystals that involve the three isomers of pyridinecarboxamide with DL-mandelic acid as coformer (Scheme 1), as well as to evaluate the effect of position isomerism of cocrystal formers on the formation and robustness of the supramolecular structures and subsequent physicochemical properties of cocrystals.
