**1. Introduction**

In the past years, crystal engineering and, more particularly, cocrystal design has raised the attention of the pharmaceutical industry as an efficient method to develop new pharmaceutical solid forms. The main advantages of such pharmaceutical cocrystals include not only the enhancement of the physicochemical properties of active pharmaceutical ingredients (APIs) but also the potential of obtaining synergic effects in codrug formulations, keeping the options for intellectual property rights open at lower costs.

Lidocaine (2-diethylamino-*N*-(2,6-dimethylphenyl)acetamide), hereafter **(lid)**, is an active pharmaceutical ingredient widely used as an anaesthetic in intravenous injection to treat and prevent pain [1,2] in some medical procedures. It is also used in clinics as an antiarrhythmic drug [3] to treat ventricular arrhythmias, specifically ventricular tachycardia and ventricular fibrillation, or as a vasoconstrictor in topical applications [4].

**(Lid)** shows low solubility in the base form [5]. Therefore, in pharmaceutical formulations, lidocaine is generally used as its hydrochloride derivative **(lidhcl)**. Solubility problems are certainly a big concern regarding the efficacy of oral administration drugs. Hence, if **(lid)** wants to be directly included in drug formulations, one of the best approaches seems to be the development of novel multicomponent pharmaceutical solids, a well-established method able to modulate the physicochemical and biopharmaceutical properties of APIs [6], such as stability, solubility, or manufacturability. In this context, only a few studies can be found in the literature reporting a lidocaine base [7–9], where **(lid)** salts with improved properties were obtained. To build such multicomponent solids, the lidocaine molecule offers different functional groups able to participate in supramolecular synthons (Figure 1), e.g., an amide group that allows hydrogen bonding and an aromatic

**Citation:** Verdugo-Escamilla, C.; Alarcón-Payer, C.; Acebedo-Martínez, F.J.; Fernández-Penas, R.; Domínguez-Martín, A.; Choquesillo-Lazarte, D. Lidocaine Pharmaceutical Multicomponent Forms: A Story about the Role of Chloride Ions on Their Stability. *Crystals* **2022**, *12*, 798. https:// doi.org/10.3390/cryst12060798

Academic Editor: Waldemar Maniukiewicz

Received: 16 May 2022 Accepted: 30 May 2022 Published: 6 June 2022

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moiety that can interact through π interactions. These groups are good candidates for interaction with other aromatic rings and alcohol groups, among others.

**Figure 1.** Molecules used in this investigation (lidocaine as base and chlorhydrate).

Polyhydroxy benzenes (Figure 1) are a group of compounds intensely studied and utilised as coformers with multiple APIs including lidocaine [7]. Indeed, they are included in the Generally Recognised as Safe (GRAS) or Substances Added to Food (EAFUS) lists of the US Food and Drug Administration (FDA). Interestingly, these compounds are quite good H-donors; thus, they can easily form hydrogen bonds with other H-acceptor groups such as amide groups, making them excellent candidates to act as coformers in lidocaine formulations, as already reported for phloroglucinol [7], allowing a comparative study of the structural effect of chlorine in the final products [7].

In this work, we focus on comparing the ability of **(lid)** and **(lidhcl)** to cocrystallise with hydroquinone, resorcinol, and pyrogallol, to form multicomponent pharmaceutical solids, and we study how structure can affect physicochemical properties and usability compared to the parent API. The reported multicomponent solids of **(lid)** and **(lidhcl)** were cocrystallised through liquid-assisted grinding (LAG), a versatile and green synthetic method for obtaining solid forms [10,11] that uses mechanical forces to induce chemical transformations, which is a fast and appropriate tool for multicomponent form screening. The resulting multicomponent forms were characterised by powder X-ray diffraction (PXRD), X-ray differential scanning calorimetry/thermogravimetric analysis (DSC/TGA), Fourier-transform infrared spectroscopy (FTIR), and single-crystal X-ray diffraction (SCXRD). In addition, a thorough analysis of the structural details of the corresponding solids forms obtained for **(lid)** and **(lidhcl)** was carried out to unravel the influence of the structure on some relevant physicochemical properties, i.e., solubility and stability.
