Posaconazole-amino acid cocrystals for improving solubility and oral bioavailability while maintaining antifungal activity and low In vivo toxicity

Vemuri, Venkata Deepthi; Srinivas, Leela; Reddy, Purna Chandra

doi:10.1016/j.jddst.2022.103491

Cited by 4 publications

(4 citation statements)

References 39 publications

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“…The cocrystals with 4aminobenzoic acid, L-glutamine, and L-asparagine are the only three examples of posaconazole cocrystals reported in the literature. 4,36 However, several cocrystals of itraconazole, which is structurally similar to posaconazole, with dicarboxylic acids are known. 47,48 cocrystal screening for PSZ could reveal new multicomponent crystalline forms of the compound.…”

Section: ■ Resultsmentioning

confidence: 99%

“…The cocrystals with 4-aminobenzoic acid, l -glutamine, and l -asparagine are the only three examples of posaconazole cocrystals reported in the literature. , However, several cocrystals of itraconazole, which is structurally similar to posaconazole, with dicarboxylic acids are known. , This information suggested that a cocrystal screening for PSZ could reveal new multicomponent crystalline forms of the compound. To test this hypothesis, we screened potential coformers, including acidic and neutral compounds, by combining the mentioned computational tools with high-throughput screening experiments (Figure ).…”

Section: Resultsmentioning

confidence: 99%

“…As shown in Figure 2, PSZ interaction sites are represented by the triazole and triazolone rings, which possess both hydrogen bond donors (N�C−H) and acceptors (N and C�O), and by the amine and hydroxyl groups. To the best of the authors' knowledge, one cocrystal of posaconazole with 4-aminobenzoic acid 4 and two cocrystals with amino acids (Lglutamine and L-asparagine 36 ), which displayed supersaturation and higher solubility compared to the free base, are reported in the literature.…”

Section: ■ Introductionmentioning

confidence: 99%

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Exploring the Cocrystal Landscape of Posaconazole by Combining High-Throughput Screening Experimentation with Computational Chemistry

Guidetti¹,

Hilfiker²,

Kuentz

et al. 2022

Crystal Growth & Design

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The development of multicomponent crystal forms, such as cocrystals, represents a means to enhance the dissolution and absorption properties of poorly water-soluble drug compounds. However, the successful discovery of new pharmaceutical cocrystals remains a time-and resource-consuming process. This study proposes the use of a combined computational-experimental high-throughput approach as a tool to accelerate and improve the efficiency of cocrystal screening exemplified by posaconazole. First, we employed the COSMOquick software to preselect and rank cocrystal candidates (coformers). Second, high-throughput crystallization experiments (HTCS) were conducted on the selected coformers. The HTCS results were successfully reproduced by liquid-assisted grinding and reaction crystallization, ultimately leading to the synthesis of thirteen new posaconazole cocrystals (7 anhydrous, 5 hydrates, and 1 solvate). The posaconazole cocrystals were characterized by PXRD, 1 H NMR, Fourier transform-Raman, thermogravimetry−Fourier transform infrared spectroscopy, and differential scanning calorimetry. In addition, the prediction performance of COSMOquick was compared to that of two alternative knowledge-based methods: molecular complementarity (MC) and hydrogen bond propensity (HBP). Although HBP does not perform better than random guessing for this case study, both MC and COSMOquick show good discriminatory ability, suggesting their use as a potential virtual tool to improve cocrystal screening.

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Section: ■ Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Exploring the Cocrystal Landscape of Posaconazole by Combining High-Throughput Screening Experimentation with Computational Chemistry

Guidetti¹,

Hilfiker²,

Kuentz

et al. 2022

Crystal Growth & Design

View full text Add to dashboard Cite

show abstract

“…Several methods have been established to address this concern, including the use of prodrugs [ 1 , 2 , 3 , 4 , 5 ], nanosuspensions, [ 6 , 7 , 8 , 9 ] or complexation of APIs [ 10 , 11 , 12 , 13 , 14 ], and modification of the solid API phase itself. The latter approach can be achieved through the formation of API salts, co-crystals, or amorphous systems to enhance the targeted drug’s solubility properties [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Product solubility is influenced by various thermodynamic and kinetic factors, such as the solubilities of the co-formers, solvent environment, and molecular characteristics like polarization or ionization [ 17 , 26 , 27 ].…”

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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Elucidating of Fluconazole Cocrystallization With a Cutting-Edge Nutraceutical Coformer for Enhanced Formulation Strategies

Vithlapara,

Chotaliya,

Mori

et al. 2024

J Pharm Innov

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Posaconazole-amino acid cocrystals for improving solubility and oral bioavailability while maintaining antifungal activity and low In vivo toxicity

Cited by 4 publications

References 39 publications

Exploring the Cocrystal Landscape of Posaconazole by Combining High-Throughput Screening Experimentation with Computational Chemistry

Exploring the Cocrystal Landscape of Posaconazole by Combining High-Throughput Screening Experimentation with Computational Chemistry

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

Elucidating of Fluconazole Cocrystallization With a Cutting-Edge Nutraceutical Coformer for Enhanced Formulation Strategies

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