Co-Crystals of Etravirine by Mechanochemical Activation

Mureşan-Pop, Marieta; Vulpoi, Adriana; Simon, V.; Todea, M.; Magyari, Klára; Pap, Zsolt; Simion, Andrea; Filip, Claudiu; Simon, S.

doi:10.1016/j.xphs.2021.09.023

Cited by 5 publications

(5 citation statements)

References 47 publications

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“…PROG–IPA possessed a monoclinic crystal system, with the space group C 2 . The benzoic acid family possesses robust hydrogen bonding capacity and is widely used in the formation of organic cocrystals [ 25 , 26 ]. Most of the hydrogen bonding modes involved the combination of strong (e.g., O–H···O, O–H···N or N–H···O) and weak (e.g., C–H···O) interactions [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

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Improving the Solubility and Bioavailability of Progesterone Cocrystals with Selected Carboxylic Acids

Xiong,

Xu,

Zhang

et al. 2024

Pharmaceutics

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Progesterone (PROG) is a natural steroid hormone with low solubility and high permeability that belongs to biopharmaceutics classification system class II. In this study, novel pharmaceutical cocrystals of PROG were successfully prepared by solvent evaporation or a liquid-assisted grinding process aimed at enhancing its solubility and bioavailability. The cocrystal formers selected based on crystal engineering principles were carboxylic acids, namely, 4-formylbenzeneboronic acid (BBA), isophthalic acid (IPA), and 3-nitrophthalic acid (NPA). The cocrystal structures were characterized using multiple techniques. Single-crystal X-ray diffraction results showed that the carbonyl group, acting as a hydrogen bond acceptor, was pivotal in the cocrystal network formation, with C–H···O interactions further stabilizing the crystals. The cocrystals exhibited improved solubility and dissolution profiles in vitro, with no significant changes in hygroscopicity. The parallel artificial membrane permeability assay (PAMPA) models indicated that the cocrystals retained PROG’s high permeability. Pharmacokinetic studies in Sprague–Dawley rats revealed that all cocrystals increased PROG exposure, with AUC(0~∞) values for PROG–BBA, PROG–IPA, and PROG–NPA being 742.59, 1201.72 and 442.67 h·ng·mL−1, respectively. These values are substantially higher compared to free PROG, which had an AUC(0~∞) of 301.48 h·ng·mL−1. Notably, PROG–IPA provided the highest AUC improvement, indicating a significant enhancement in bioavailability. Collectively, the study concludes that the cocrystal approach is a valuable strategy for optimizing the physicochemical properties and oral bioavailability of PROG, with potential implications for the development of other poor water-soluble drugs.

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Section: Resultsmentioning

confidence: 99%

“…PROG-IPA possessed a monoclinic crystal system, with the space group C 2 . The benzoic acid family possesses robust hydrogen bonding capacity and is widely used in the formation of organic cocrystals [25,26] 2D layer modes were formed. The sheet structure was similar to that of the isophthalic acid:bipy-pr cocrystal [27].…”

Section: D-h•••mentioning

confidence: 99%

Improving the Solubility and Bioavailability of Progesterone Cocrystals with Selected Carboxylic Acids

Xiong,

Xu,

Zhang

et al. 2024

Pharmaceutics

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“…Briefly, excess PZQ and PZQ cocrystals (the corresponding amount of 6 mg of PZQ) were added to 2 mL vials containing 2 mL of the dissolution medium. The slurry samples were placed in an orbital shaker to achieve uniform mixing at 37 °C for 24 h. At different time intervals (10,20,30,40,50,60, and 90 min), an aliquot of 200 μL of each sample was collected after centrifugation, filtered, and analyzed concerning the PZQ content by HPLC-UV analysis.…”

Section: Differential Scanning Calorimetry (Dsc) and Thermogravimetri...mentioning

confidence: 99%

“…In the pharmaceutical industry, the development of innovative drugs with improved effects is a real necessity due to the emergence of various infectious diseases resistant to usually administered drugs. Such new drug forms can be obtained by combining an active pharmaceutical ingredient (API) with other substances, resulting in new solid forms or supramolecular complexes such as salts or cocrystals. − Mechanochemistry is a frequent technique used in the synthesis of these new materials that display improved physicochemical properties due to its simplicity, noninvasive effects on the environment, scalability, and low process costs such as time and energy. − Diverse experiments have shown that parameters selected in the process of mechanical mortaring, such as the vibration frequency, ball size and weight, time of mechanical action, amount of solvent, or temperature, influence the resulting outcomes . The structural and chemical changes of the materials are directly influenced by the mechanical energy stored during the process: as this energy increases, the coherence energy of the particles will decrease, resulting in the appearance of defects inside the material or even its amorphization .…”

Section: Introductionmentioning

confidence: 99%

Mechanochemical Synthesis of New Praziquantel Cocrystals: Solid-State Characterization and Solubility

Mureşan-Pop,

Simon,

Bodoki

et al. 2024

Crystal Growth & Design

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New cocrystals of praziquantel with suberic, 3-hydroxybenzoic, benzene-1,2,4,5-tetracarboxylic, trimesic, and 5-hydroxyisophthalic acids were obtained through ball milling experiments. The optimal conditions for the milling process were chosen by changing the solvent volume and the mechanical action time. Supramolecular interactions in the new cocrystals are detailed based on single-crystal X-ray diffraction analysis, confirming the expected formation of hydrogen bonds between the praziquantel carbonyl group and the carboxyl (or hydroxyl) moieties of the coformers. Different structural characterization techniques were performed for all samples, but the praziquantel:suberic acid cocrystal includes a wider range of investigations such as thermal analysis, infrared and X-ray photoelectron spectroscopies, and SEM microscopy. The stability for up to five months was established by keeping it under extreme conditions of temperature and humidity. Solubility studies were carried out for all the new forms disclosed herein and compared with the promising cocrystals previously reported with salicylic, 4-aminosalicylic, vanillic, and oxalic acids. HPLC analyses revealed a higher solubility for most of the new cocrystal forms, as compared to pure praziquantel.

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“…Over the years, various theories on crystallization mechanisms during grinding have been proposed. These include local temperature increases inducing melt-like crystallization or local defects caused by mechanic stress, leading to particle diffusion through changes in surface energy [ 64 , 65 , 66 , 67 ].…”

Section: Introductionmentioning

confidence: 99%

Maleic Acid as a Co-Former for Pharmaceutically Active GABA Derivatives: Mechanochemistry or Solvent Crystallization?

2023

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In this study, we compare the mechanochemical and classical solvent crystallization methods for forming maleates of GABA and its pharmaceutically active derivatives: Pregabalin, Gabapentin, Phenibut, and Baclofen. Common characterization techniques, like powder and single crystal X-ray diffraction, IR-spectroscopy, differential scanning calorimetry, thermogravimetric analysis and 1H-NMR spectroscopy, are used for the evaluation of structural and physicochemical properties. Our work shows that maleate formation is possible with all investigated target compounds. Large increases in solubility can be achieved, especially for Pregabalin, where up to twentyfold higher solubility in its maleate compared to the pure form can be reached. We furthermore compare the mechanochemical and solvent crystallization regarding quickness, reliability of phase production, and overall product quality. A synthetic route is shown to have an impact on certain properties such as melting point or solubility of the same obtained products, e.g., for Gabapentin and Pregabalin, or lead to the formation of hydrates vs. anhydrous forms. For the GABA and Baclofen maleates, the method of crystallization is not important, and similarly, good results can be obtained by either route. In contrast, Phenibut maleate cannot be obtained pure and single-phase by either method. Our work aims to elucidate promising candidates for the multicomponent crystal formation of blockbuster GABA pharmaceuticals and highlight the usefulness of mechanochemical production routes.

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Co-Crystals of Etravirine by Mechanochemical Activation

Cited by 5 publications

References 47 publications

Improving the Solubility and Bioavailability of Progesterone Cocrystals with Selected Carboxylic Acids

Improving the Solubility and Bioavailability of Progesterone Cocrystals with Selected Carboxylic Acids

Mechanochemical Synthesis of New Praziquantel Cocrystals: Solid-State Characterization and Solubility

Maleic Acid as a Co-Former for Pharmaceutically Active GABA Derivatives: Mechanochemistry or Solvent Crystallization?

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