Simultaneous Improvement of Dissolution Behavior and Oral Bioavailability of Antifungal Miconazole via Cocrystal and Salt Formation

Abstract

Miconazole shows low oral bioavailability in humans due to poor aqueous solubility, although it has demonstrated various pharmacological activities such as antifungal, anti-tubercular and anti-tumor effects. Cocrystal/salt formation is one of the effective methods for solving this problem. In this study, different methods (liquid-assisted grinding, slurrying and lyophilization) were used to investigate their impact on the formation of the miconazole multicomponent crystals with succinic, maleic and dl-tartaric acids. The solid state of the prepared powder was characterized by differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopy. It was found that lyophilization not only promotes partial amorphization of both salts but also allows obtaining a new polymorph of the miconazole salt with dl-tartaric acid. The lyophilized salts compared with the same samples prepared by two other methods showed better dissolution rates but low stability during the studies due to rapid recrystallization. Overall, it was determined that the preparation method of multicomponent crystals affects the solid-state characteristics and miconazole physicochemical properties significantly. The in vivo studies revealed that the miconazole multicomponent crystals indicated the higher peak blood concentration and area under the curve from 0 to 32 h values 2.4-, 2.9- and 4.6-fold higher than the pure drug. Therefore, this study demonstrated that multicomponent crystals are promising formulations for enhancing the oral bioavailability of poorly soluble compounds.

Novel salts of the antiemetic drug domperidone: synthesis, characterization and physicochemical property investigation

“…[5][6][7][8][9][10][11] The use of cocrystals, salts, and solvates to increase an API's solubility, dissolution profile, bioavailability, and other physicochemical characteristics is becoming more popular. [12][13][14][15][16][17][18][19][20] Domperidone (DOM) (6-chloro-3-[1-[3-(2-oxo-3Hbenzimidazol-1-yl)propyl]piperidin-4-yl]-1H-benzimidazol-2one) is an antiemetic, galactagogue and gastrokinetic that works by blocking the dopamine receptor D2. [21][22][23] Domperidone binds to D2R expressed by peripheral neurons after treatment, inhibiting dopamine binding and D2Rmediated signaling.…”

“…5–11 The use of cocrystals, salts, and solvates to increase an API's solubility, dissolution profile, bioavailability, and other physicochemical characteristics is becoming more popular. 12–20…”

Cocrystal and Coamorphous Solid Forms of Enzalutamide with Saccharin: Structural Characterization and Dissolution Studies

“…Another experimental technique used in this work to attain cocrystallization between Enz and Schr was lyophilization. Freeze-drying or lyophilization is a well-proven technique to develop selective polymorphic forms of drugs, including glycine, , barbital, nilutamide, and new pharmaceutical cocrystals and salts. − The influence of lyophilization conditions on crystallinity, particle size distribution, morphology, and polymorphic outcome of the miconazole multicomponent crystals has been studied by us recently . Due to the extremely low solubility of Enz (cr) in water ((3.9 ± 0.1) × 10 –6 mol·L –1 at 25.0 °C), all of the lyophilization experiments were performed using tert -butanol solutions as described in the Material and Methods section.…”

“…64−66 The influence of lyophilization conditions on crystallinity, particle size distribution, morphology, and polymorphic outcome of the miconazole multicomponent crystals has been studied by us recently. 67 Due to the extremely low solubility of Enz (cr) in water ((3.9 ± 0.1) × 10 −6 mol•L −1 at 25.0 °C8 ), all of the lyophilization experiments were performed using tert-butanol solutions 68 as described in the Material and Methods section. Freeze-drying of the equimolar solution of the components in tert-butanol resulted in a complete amorphization of the sample and the formation of a coamorphous material (further referred to as [Enz +Schr] (am) (1:1)), as shown by PXRD (Figure 2).…”

Cocrystal Prediction of Bexarotene by Graph Convolution Network and Bioavailability Improvement

“…The hydrogen bonding between unlike functional groups is called heterosynthon, which can often be served as a structural design unit for cocrystal synthesis [ 7 ]. As a new type of crystalline material, pharmaceutical cocrystals possess the potential to alter the physical and chemical properties of active pharmaceutical ingredients (API), such as melting point [ 8 ], chemical stability [ 9 , 10 ], solubility [ 11 , 12 ], bioavailability [ 13 , 14 ], and so on.…”