The role of ionic vs. non-ionic excipients in APIs-based eutectic systems

Martins, Mónia A.R.; Silva, Liliana P.; Jorge, Patrícia S.; Abranches, Dinis O.; Pinho, Simão P.; Coutinho, J.

doi:10.1016/j.ejps.2020.105583

Cited by 15 publications

(18 citation statements)

References 54 publications

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“…The solid systems were then powdered in a mortar and pestle until a fine powder, capable of being inserted in a glass capillary, was obtained. Alternatively, if at least one of the compounds degraded with heat, the system was directly crushed, skipping the heating process [10,34,44].…”

Section: Mixture Preparationmentioning

confidence: 99%

Liquefying Flavonoids with Terpenoids through Deep Eutectic Solvent Formation

et al. 2022

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The formation of deep eutectic solvents (DES) is tied to negative deviations to ideality caused by the establishment of stronger interactions in the mixture than in the pure DES precursors. This work tested thymol and menthol as hydrogen bond donors when combined with different flavonoids. Negative deviations from ideality were observed upon mixing thymol with either flavone or flavanone, two parent flavonoids that only have hydrogen bond acceptor (HBA) groups, thus forming non-ionic DES (Type V). On the other hand, the menthol systems with the same compounds generally showed positive deviations from ideality. That was also the case with the mixtures containing the more complex hydroxylated flavonoid, hesperetin, which resulted in positive deviations when mixed with either thymol or menthol. COSMO-RS successfully predicted the behavior of the solid-liquid phase diagram of the studied systems, allowing for evaluation of the impact of the different contributions to the intermolecular interactions, and proving to be a good tool for the design of DES.

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Section: Mixture Preparationmentioning

confidence: 99%

Liquefying Flavonoids with Terpenoids through Deep Eutectic Solvent Formation

et al. 2022

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“…Therefore, we can only say there is a possibility that these systems are protic ionic liquids and not molecular liquids. This possibility also explains the high increase of the solubility of both APIs [ 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

Solids Turn into Liquids—Liquid Eutectic Systems of Pharmaceutics to Improve Drug Solubility

et al. 2022

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The low solubility of active pharmaceutical ingredients (APIs) is a problem in pharmaceutical development. Several methodologies can be used to improve API solubility, including the use of eutectic systems in which one of the constituents is the API. This class of compounds is commonly called Therapeutic Deep Eutectic Systems (THEDES). THEDES has been gaining attention due to their properties such as non−toxicity, biodegradability, and being non−expensive and easy to prepare. Since the knowledge of the solid liquid diagram of the mixture and the ideal eutectic point is necessary to ascertain if a mixture is a deep eutectic or just a eutectic mixture that is liquid at ambient temperature, the systems studied in this work are called Therapeutic Liquid Eutectic Systems (THELES). Therefore, the strategy proposed in this work is to improve the solubility of chlorpropamide and tolbutamide by preparing THELES. Both APIs are sulfonylurea compounds used for the treatment of type 2 diabetes mellitus and have low solubility in water. To prepare the THELES, several coformers were tested, namely, tromethamine, L(+)−arginine, L−tryptophan, citric acid, malic acid, ascorbic acid, and p−aminobenzoic acid, in molar ratios of 1:1 and 1:2. To improve viscosity, water was added in different molar ratios to all systems. THELES were characterized by mid−infrared spectroscopy (MIR), and differential scanning calorimetry. Their viscosity, solubility, and permeability were also determined. Their stability at room temperature and 40 °C was accessed by MIR. Cytocompatibility was performed by metabolic activity and cell lysis evaluation, according to ISO10993−5:2009, and compared with the crystalline APIs. THELES with TRIS were successfully synthesized for both APIs. Results showed an increased solubility without a decrease in the permeability of the APIs in the THELES when compared with the pure APIs. The THELES were also considered stable for 8 weeks at ambient temperature. The cells studied showed that the THELES were not toxic for the cell lines used.

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“…The impact of ionic and non-ionic excipients on API-DES formation was also investigated attempting to understand what type of compounds should be preferably selected. To this purpose, thymol, coumarin and quaternary ammonium chloride salts were studied in combination with acetylsalicylic acid, acetaminophen, ibuprofen, ketoprofen and lidocaine [88]. By using COSMO-RS, it was possible to predict the solid-liquid equilibrium phase diagrams of the API and excipients mixtures.…”

Section: Api-des Formulationsmentioning

confidence: 99%

“…Based on the same diagrams, it was possible to verify that quaternary ammonium chloride salts, such as tetraalkylammonium chlorides, do not allow temperature depressions (from the melting temperature of the API) in the same degree as the non-ionic compounds studied. Regarding the use of non-ionic excipients, while the systems containing coumarin follow a quasi-ideal behavior, the strong interactions between these APIs and thymol lead to negative deviations to thermodynamic ideality [88]. Despite the study of non-ionic excipients by computational methods being seen as a promising tool to be considered for the design of API-DES formulations, more experimental data on this topic is still necessary.…”

Section: Api-des Formulationsmentioning

confidence: 99%

Deep Eutectic Solvents and Pharmaceuticals

et al. 2021

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Deep eutectic solvents (DES) are eutectic mixtures that present a deviation from the ideal thermodynamic solid–liquid phase behavior, where a significant depression in the melting temperature occurs. If properly designed and chosen, DES may be liquid at room and the human body’s temperatures and display a biocompatible character, thus representing relevant options in the pharmaceutical field. Accordingly, DES have been studied as alternative solvents or in formulations of pharmaceuticals to improve their solubility and stability. Depending on the DES components, these mixtures might exhibit interesting biological activities compatible with several applications. The use of DES as functional agents or as novel liquid forms of active pharmaceutical ingredients (API-DES) with the goal of improving bioavailability, permeability and therapeutic efficacy of a given API stands as alternative strategies in the pharmaceutical field for drug delivery purposes.

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The role of ionic vs. non-ionic excipients in APIs-based eutectic systems

Cited by 15 publications

References 54 publications

Liquefying Flavonoids with Terpenoids through Deep Eutectic Solvent Formation

Liquefying Flavonoids with Terpenoids through Deep Eutectic Solvent Formation

Solids Turn into Liquids—Liquid Eutectic Systems of Pharmaceutics to Improve Drug Solubility

Deep Eutectic Solvents and Pharmaceuticals

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