**1. Introduction**

The multicomponent solid form of the drug is rapidly emerging as an effective way to improve the drug physiochemical properties such as solubility, dissolution rate, bioavailability and other crucial pharmaceutical properties like stability, hygroscopicity, chemical stability, flowability, etc. [1–7]. Eutectic mixtures are multicomponent compounds made up of two or more crystalline solids that show immiscibility in the solid-state and do not combine to generate a new chemical compound but, at a certain ratio, the eutectic composition will exhibit a melting or solidification point significantly lower than its constituents [1,4,8]. The formation of eutectic mixtures can occur via different noncovalent interactions primarily hydrogen bonding, van der Waals forces, and aromatic interactions etc. [9,10]. It is a trial and error approach to get a eutectic composition for enhancing the solubility and bioavailability of medicines with limited water solubility in BCS classes II and IV [1,4]. Eutectic mixtures are frequently used for the design of medicines and delivery methods for administration routes [1,11]. For example, the eutectic mixture of lidocaine and prilocaine cream is a novel formulation of dermal anesthesia which is effective and safe for the treatment option in premature ejaculation patients of various types [11]. Eutectic mixtures generally exhibit high thermodynamic parameters, for example, free energy, enthalpy and entropy etc., which alter the solubility and dissolution behavior [1]. Besides, a higher soluble eutectic mixture component, called coformer in the following, also can favorably influence the wettability of the drug, thus improving the bioavailability [12,13]. When taken orally, curcumin, for example, has low bioavailability and solubility. However, the eutectic mixture of curcumin and nicotinamide in a 1:2 ratio exhibits a 10-fold faster intrinsic dissolution rate [14]. Another aspect is that it is critical to identifying the production of eutectics during the formulation stage to minimize manufacturing difficulties [15,16]. During pharmaceutical research, understanding eutectic mixtures can aid in the discovery of compounds with equivalent melting points.

In this work, we studied the chiral drug aminoglutethimide [3-(4-aminophenyl)-3 ethyl-2, 6-piperidinedione] (AMG), a nonsteroidal aromatase inhibitor drug, used for the treatment of Cushing's syndrome, breast cancer, and prostate cancer [17–19]. According to

**Citation:** Saikia, B.; Seidel-Morgenstern, A.; Lorenz, H. Multicomponent Materials to Improve Solubility: Eutectics of Drug Aminoglutethimide. *Crystals* **2022**, *12*, 40. https://doi.org/10.3390/ cryst12010040

Academic Editors: Duane Choquesillo-Lazarte and Alicia Dominguez-Martin

Received: 29 November 2021 Accepted: 24 December 2021 Published: 28 December 2021

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the Biopharmaceutics Classification System (BCS), AMG is classified as a BCS class II drug because of its poor solubility [20]. Attempts were made in this work to create multidrug eutectics of AMG considering caffeine (CAF, a psychoactive drug [21]), nicotinamide (NIC, a vitamin [22]) and ethenzamide (ZMD, nonsteroidal anti-inflammatory drug [23]) as coformers to improve the aqueous solubility of AMG. Scheme 1 shows the chemical structures of AMG and the three coformers. For the synthesis of eutectics, mainly a mechanochemical solvent-assisted grinding (LAG) method has been used. Differential scanning calorimetry (DSC) data is utilized to establish the precise eutectic composition. X-ray powder diffraction (PXRD), Fourier-transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM) were applied to characterize the eutectic mixtures and their components. Further, the aqueous solubility of the eutectics was determined and found to moderately exceed that of the parent compound AMG.

**Scheme 1.** Molecular structure of Aminoglutethimide and the coformers selected for the study.
