Drug Solubility Enhancement through the Preparation of Multicomponent Organic Materials: Eutectics of Lovastatin with Carboxylic Acids

Araya-Sibaja, Andrea Mariela; Vega-Baudrit, José; Guillén-Girón, Teodolíto; Navarro-Hoyos, Mirtha; Cuffini, Silvia Lucía

doi:10.3390/pharmaceutics11030112

Cited by 46 publications

(35 citation statements)

References 35 publications

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“… 27 It has been many times reported that eutectic concentrations play a key role in improving the absorption of many APIs by increasing their solubility and dissolution properties. 28 , 29 With that in mind, one might wonder whether or not the marvelous therapeutic properties observed by Farner et al during the combined therapy with EZB, SVT, and FEN are connected with the accidental employment of the ternary eutectic concentration of these APIs. Finding the answer to this question is the first goal of this paper.…”

Section: Introductionmentioning

confidence: 99%

Ternary Eutectic Ezetimibe–Simvastatin–Fenofibrate System and the Physical Stability of Its Amorphous Form

et al. 2021

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In this study, the phase diagram of the ternary system of ezetimibe–simvastatin–fenofibrate was established. It has been proven that the ternary composition recommended for the treatment of mixed hyperlipidemia forms a eutectic system. Since eutectic mixtures are characterized by greater solubility and dissolution rate, the obtained result can explain the marvelous medical effectiveness of combined therapy. Considering that another well-known method for improving the aqueous solubility is amorphization, the ternary system with eutectic concentration was converted into an amorphous form. Thermal properties, molecular dynamics, and physical stability of the obtained amorphous system were thoroughly investigated through various experimental techniques compared to both: neat amorphous active pharmaceutical ingredients (considered separately) and other representative concentrations of ternary mixture. The obtained results open up a new way of selecting the therapeutic concentrations for combined therapies, a path that considers one additional variable: eutecticity.

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Section: Introductionmentioning

confidence: 99%

Ternary Eutectic Ezetimibe–Simvastatin–Fenofibrate System and the Physical Stability of Its Amorphous Form

et al. 2021

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“…There are several literature reviews on pharmaceutical cocrystals, which can improve the solubility/dissolution rate, stability and bioavailability, alter mechanical properties and mask the taste of bitter drugs (Duggirala et al, 2016;Bolla & Nangia, 2016). In addition, eutectics are equally important in tuning physicochemical properties (Jain et al, 2014;Araya-Sibaja et al, 2019). They are generally formed by cohesive interactions, i.e.…”

Section: Introductionmentioning

confidence: 99%

Multicomponent solid forms of the uric acid reabsorption inhibitor lesinurad and cocrystal polymorphs with urea: DFT simulation and solubility study

Palanisamy

Sanphui

Prakash

et al. 2019

Acta Crystallogr C Struct Chem

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Lesinurad (systematic name: 2-{[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid, C 17 H 14 BrN 3 O 2 S) is a selective uric acid reabsorption inhibitor related to gout, which exhibits poor aqueous solubility. High-throughput solid-form screening was performed to screen for new solid forms with improved pharmaceutically relevant properties. During polymorph screening, we obtained two solvates with methanol (CH 3 OH) and ethanol (C 2 H 5 OH). Binary systems with caffeine (systematic name: 3,7-dihydro-1,3,7trimethyl-1H-purine-2,6-dione, C 8 H 10 N 4 O 2 ) and nicotinamide (C 6 H 6 N 2 O), polymorphs with urea (CH 4 N 2 O) and eutectics with similar drugs, like allopurinol and febuxostat, were prepared using the crystal engineering approach. All these novel solid forms were confirmed by XRD, DSC and FT-IR. The crystal structures were solved by single-crystal and powder X-ray diffraction. The crystal structures indicate that the lesinurad molecule is highly flexible and the triazole moiety, along with the rotatable thioacetic acid (side chain) and cyclopropane ring, is almost perpendicular to the planar naphthalene moiety. The carboxylic acid-triazole heterosynthon in the drug is interrupted by the presence of methanol and ethanol molecules in their crystal structures and forms intermolecular macrocyclic rings. The caffeine cocrystal maintains the consistency of the acid-triazole heterosynthons as in the drug and, in addition, they are bound by several auxiliary interactions. In the binary system of nicotinamide and urea, the acid-triazole heterosynthon is replaced by an acidamide synthon. Among the urea cocrystal polymorphs, Form I (P1, 1:1) consists of an acid-amide (urea) heterodimer, whereas in Form II (P2 1 /c, 2:2), both acidamide heterosynthons and urea-urea dimers co-exist. Density functional theory (DFT) calculations further support the experimentally observed synthon hierarchies in the cocrystals. Aqueous solubility experiments of lesinurad and its binary solids in pH 5 acetate buffer medium indicate the apparent solubility order lesinurad-urea Form I (43-fold) > lesinurad-caffeine (20-fold) > lesinurad-allopurinol (12-fold) ' lesinurad-nicotinamide (11-fold) > lesinurad, and this order is correlated with the crystal structures.

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“…Thus, Araya-Sibaja et al improved the solubility of the drug lovastatin in three binary eutectic mixtures with three different carboxylic acids (benzoic, salicylic, and cinnamic carboxylic acids), being higher for the system formed with salicylic acid. Moreover, the systems showed stability since there was no dissociation and the results achieved indicated that binary eutectic mixtures can be excellent for the preparation of pharmaceutical formulations [44]. Accordingly, another report observed that the use of a DES, composed of betaine and urea, stabilized two therapeutic B-lactam molecules, clavulanic acid and imipenem, with respect to the use of water and with no effect on their antimicrobial activity [52].…”

Section: Eutecticmentioning

confidence: 98%

“…It is well known that solubility has a direct relationship on a therapeutic effect of a drug [43]. In addition, in the last few years, several studies have focused on the use of eutectic mixtures in the pharmaceutical area with the aim of improving the solubility and bioavailability of drugs [40,44]. In Figure 2, a scheme of the evolution of these new solvents is shown.…”

Section: Applications Related To Peculiar Solubility Properties Of Dessmentioning

confidence: 99%

Applications of Deep Eutectic Solvents Related to Health, Synthesis, and Extraction of Natural Based Chemicals

et al. 2021

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Deep eutectic solvents are liquid mixtures of solid components at room temperature, which present exceptional properties: high solvent capacity, high biodegradation, low volatile organic compound character, and relatively low toxicity. Furthermore, there are an important number of DES described, formed by different components and ratios, and thus, the studied applications are also numerous. In this review, we focused on the applications related to health. One of the most promising applications of DES is the development of oral liquid formulations of poorly soluble active pharmaceutical ingredients, although it currently remains at an early stage. We have analyzed the potential and limitations of DES with this regard. Furthermore, DES have been used as synthesis media. In this work, we revised the use of DES to obtain bioactive natural products via synthesis or extraction process. Finally, the usefulness of DES in other interesting applications for promoting health has been also examined: this is the case of genomics studies, nano-carriers for the encapsulation of anticancer drugs or stabilization of samples for medical purposes.

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Drug Solubility Enhancement through the Preparation of Multicomponent Organic Materials: Eutectics of Lovastatin with Carboxylic Acids

Cited by 46 publications

References 35 publications

Ternary Eutectic Ezetimibe–Simvastatin–Fenofibrate System and the Physical Stability of Its Amorphous Form

Ternary Eutectic Ezetimibe–Simvastatin–Fenofibrate System and the Physical Stability of Its Amorphous Form

Multicomponent solid forms of the uric acid reabsorption inhibitor lesinurad and cocrystal polymorphs with urea: DFT simulation and solubility study

Applications of Deep Eutectic Solvents Related to Health, Synthesis, and Extraction of Natural Based Chemicals

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