A comparative study on in vitro and in vivo characteristics of enzalutamide nanocrystals versus amorphous solid dispersions and a better prediction for bioavailability based on “spring-parachute” model

Guo, Xueting; Guo, Yibin; Zhang, Maolian; Yang, Bing; Líu, Hao; Yin, Tian; He, Haibing; Wang, Yanjiao; Liu, Dongchun; Gou, Jingxin; Tang, Xing

doi:10.1016/j.ijpharm.2022.122333

Cited by 4 publications

(2 citation statements)

References 55 publications

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“…This supersaturation is explained by temporary prevention of crystallization by the polymer matrix [ 53 , 54 , 55 ]. Thus, the possibly enhanced bioavailability can be assumed [ 24 , 56 , 57 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of Molecular Weight on the Dissolution Profiles of PEG Solid Dispersions Containing Ketoprofen

et al. 2023

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Solid dispersions are typically binary systems with a hydrophilic matrix polymer and a lipophilic active substance. During formulation, the drug undergoes a crystalline to amorphous phase transition, which leads to a supersaturated solution providing enhanced bioavailability. The interaction of the active substance and the polymer is unique and influences the level of supersaturation. We aimed to investigate the relationship between low molecular weight polyethylene glycol derivates PEG 1000, 1500, and 2000 and ketoprofen regarding the effect of molecular weight. The physicochemical properties of solid dispersions prepared with hot melt homogenization and their respective physical mixtures were investigated with Fourier transform infrared spectroscopy, powder X-ray diffraction and scanning electron microscopy techniques. A phase solubility study was carried out in hydrochloric acid media which showed no difference between the three polymers, but the dissolution curves differed considerably. PEG 1000 had higher percentage of released drug than PEG 1500 and 2000, which had similar results. These results indicate that when multiple low molecular weight PEGs are suitable as matrix polymers of solid dispersions, the molecular weight has only limited impact on physicochemical characteristics and interactions and further investigation is needed to select the most applicable candidate.

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Section: Discussionmentioning

confidence: 99%

Effect of Molecular Weight on the Dissolution Profiles of PEG Solid Dispersions Containing Ketoprofen

et al. 2023

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“…The learning has greatly benefited the formulation development. While many industrial precedents focused on the use of polymer (especially for formulations involving amorphous solid dispersions) 46 as a crystallization inhibitor to prevent the neutral form precipitation, we used a cocrystal former (fumaric acid) that serves dual purposes: (1) microenvironmental pH-modulation (pH M ) and (2) formation of a favorable cocrystal that eliminates the freebase produced by disproportionation. The resulting formulation allowed us to achieve target bioavailability by using compendial ingredients in a synergistic way.…”

Section: Introductionmentioning

confidence: 99%

Integrative Salt Selection and Formulation Optimization: Perspectives of Disproportionation and Microenvironmental pH Modulation

Mohan,

Li,

Chu

et al. 2024

Mol. Pharmaceutics

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We report a novel utilization of a pH modifier as a disproportionation retardant in a tablet formulation. The drug molecule of interest has significant bioavailability challenges that require solubility enhancement. In addition to limited salt/cocrystal options, disproportionation of the potential salt(s) was identified as a substantial risk. Using a combination of Raman spectroscopy with chemometrics and quantitative X-ray diffraction in specially designed stress testing, we investigated the disproportionation phenomena. The learnings and insight drawn from crystallography drove the selection of the maleate form as the target API. Inspired by the fumarate form's unique stability and solubility characteristics, we used fumaric acid as the microenvironmental pH modulator. Proof-of-concept experiments with high-risk (HCl) and moderate-risk (maleate) scenarios confirmed the synergistic advantage of fumaric acid, which interacts with the freebase released by disproportionation to form a more soluble species. The resultant hemifumarate helps maintain the solubility at an elevated level. This work demonstrates an innovative technique to mediate the solubility drop during the "parachute" phase of drug absorption using compendial excipients, and this approach can potentially serve as an effective risk-mitigating strategy for salt disproportionation.

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Enhancing the Stability, Solubility, and Antioxidant Activity of Cinchonine through Pharmaceutical Cocrystallization

Zhou,

Tu,

Yang

et al. 2024

Pharm Res

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A comparative study on in vitro and in vivo characteristics of enzalutamide nanocrystals versus amorphous solid dispersions and a better prediction for bioavailability based on “spring-parachute” model

Cited by 4 publications

References 55 publications

Effect of Molecular Weight on the Dissolution Profiles of PEG Solid Dispersions Containing Ketoprofen

Effect of Molecular Weight on the Dissolution Profiles of PEG Solid Dispersions Containing Ketoprofen

Integrative Salt Selection and Formulation Optimization: Perspectives of Disproportionation and Microenvironmental pH Modulation

Enhancing the Stability, Solubility, and Antioxidant Activity of Cinchonine through Pharmaceutical Cocrystallization

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