**1. Introduction**

Diuretic drugs aim to regulate the volume and composition of body fluids by increasing the rate of urine flow and sodium excretion. They are widely used in clinics for the treatment of edematous disorders, such as those associated with congestive heart failure, as well as liver or renal failure and hypertension [1,2]. Furosemide (FUR, Scheme 1), 4-chloro-2-[(2-furanylmethyl)-amino]-5-sulfamoylbenzoic acid, is classified as a high ceiling loop diuretic drug. Its mechanism of action is related to the inhibition of the sodium-potassium-2chloride co-transporter (Na+-K+-2Cl−) located in the thick ascending limb of the loop of Henle in the renal tubule.

According to the Biopharmaceutics Classification System (BCS), FUR belongs to class IV drug, defined by low solubility and low permeability values [3]. Indeed, furosemide is almost insoluble in water [4], which results in significant intraindividual variations in absorption and very poor oral bioavailability [5]. Despite this relevant drawback, FUR has shown great efficacy, hence it is highly used in therapeutics worldwide, including chronic treatments. Thereby, the development of improved oral formulations of furosemide, which aim to achieve higher bioavailability, are certainly relevant for the pharmaceutical industry.

The design of multicomponent pharmaceutical solids is actually one of the latest research strategies in the development of new drug alternatives in the pharmaceutical

**Citation:** Acebedo-Martínez, F.J.; Alarcón-Payer, C.; Rodríguez-Domingo, L.; Domínguez-Martín, A.; Gómez-Morales, J.; Choquesillo-Lazarte, D. Furosemide/Non-Steroidal Anti-Inflammatory Drug–Drug Pharmaceutical Solids: Novel Opportunities in Drug Formulation. *Crystals* **2021**, *11*, 1339. https://doi.org/10.3390/ cryst11111339

Academic Editor: Aidar T. Gubaidullin

Received: 18 October 2021 Accepted: 31 October 2021 Published: 2 November 2021

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**Copyright:** © 2021 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/).

industry [6]. They can be defined as crystalline materials in which at least one component is an active pharmaceutical ingredient (API). The other components, incorporated in the crystal lattice—so-called coformers—must be found in a stoichiometric ratio and considered pharmaceutically acceptable—i.e., included in the Generally Recognized as Safe (GRAS) list within the FDA's "Substances Added to Food" Inventory. APIs and coformers recognize themselves by different kind of non-covalent intermolecular interactions, so-called supramolecular synthons, mainly H-bonds, which organization has a profound impact on the intimate 3D structure of the solid and therefore on its macroscopic physicochemical properties. The development of this novel strategy is rather interesting because allows industry to save money compared to the traditional drug development scheme, still guarantying the possibility of generating intellectual property rights [7]. In this context, there has been reported several studies devoted to studying pharmaceutical cocrystals and salts of furosemide [8–13].

**Scheme 1.** Chemical formula of furosemide (FUR), ethenzamide (ETZ), and piroxicam (PRX).

One of the most recent approaches in the development of multicomponent pharmaceutical solids is the concurrent administration of two or more APIs, leading to drug–drug or co-drug pharmaceutical solids [14]. APIs within the formulation might have similar or different mechanisms of actions, but always looking for a synergic effect, either targeting one metabolic pathway at different levels or different pathways related to a particular disease.

Along with diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs) are also widely prescribed worldwide. Interestingly, the combination of diuretics—particularly furosemide—and NSAIDs is rather common, especially among the elderly. However, although not contraindicated, there is clinical evidence on the moderate interaction between these two kinds of drugs. The use of NSAIDs may decrease natriuretic response to loop diuretics, thus reducing their efficacy and resulting in adverse effects on patients with different edematous states. In addition, some NSAIDs may also show adverse nephrotoxic effects, which may be exacerbated by diuretic therapy [15–17]. In these cases, dose adjustments or special monitoring of the renal function and blood pressure are required for safety's sake. Unfortunately, the insights of such interactions are still poorly understood because they do not seem to follow the same mechanism for all combination of drugs, some of them being associated with the suppression of plasma renin activity or impaired synthesis of vasodilator prostaglandins.

Since the concurrent prescription of FUR and NSAIDs is quite common, it is worthwhile exploring the formulation of drug–drug multicomponent pharmaceutical solids involving such a combination, seeking new therapeutical alternatives that would improve the bioavailability of the APIs and/or reduce the abovementioned drug–drug interactions. In this work, the synthesis and physicochemical characterization of two different drug– drug pharmaceutical solids, including the loop diuretic furosemide and one NSAID drug: ethenzamide (ETZ, 2-ethoxybenzamide) or piroxicam (PRX, 4-hydroxyl-2- methyl-N-2 pyridinyl-2H-1,2,-benzothiazine-3-carboxamide 1,1-dioxide) are reported (Scheme 1). To the best of our knowledge, there are no conclusive studies on the interaction between furosemide and ethenzamide, while one study was reported on piroxicam–furosemide drug interaction in the late 1980s [18].
