The solid state forms of the sex hormone 17-β-estradiol

Stevenson, Erin L.; Lancaster, Robert W.; Buanz, Asma; Price, Louise S.; Tocher, Derek A.; Price, Sarah L.

doi:10.1039/c8ce01874j

Cited by 15 publications

(15 citation statements)

References 38 publications

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“…A similar phenomenon has been observed by Stewart et al, where the crystalline solubility of itraconazole in the presence of simulated intestinal fluid was greater than that in pure buffered media . One potential explanation for the increased crystalline solubility in our system could be that the micelles or surfactant molecules may inhibit the formation of the hemihydrate polymorphic form of E2, which is the most stable form of E2 . This hindering of the hemihydrate form would allow for the formation of the unstable anhydrous form of E2, characterized by a greater crystalline solubility.…”

Section: Discussionsupporting

confidence: 87%

Toward Developing Discriminating Dissolution Methods for Formulations Containing Nanoparticulates in Solution: The Impact of Particle Drift and Drug Activity in Solution

et al. 2020

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Enabling formulations are an attractive approach to increase the dissolution rate, solubility, and oral bioavailability of poorly soluble compounds. With the growing prevalence of poorly soluble drug compounds in the pharmaceutical pipeline, supersaturating drug delivery systems (SDDS), a subset of enabling formulations, have grown in popularity due to their properties allowing for drug concentrations greater than the corresponding crystalline solubility. However, the extent of supersaturation generated as the enabling formulation traverses the gastrointestinal (GI) tract is dynamic and poorly understood. The dynamic nature of supersaturation is a result of several competing kinetic processes such as dissolution, solubilization by formulation and endogenous surfactants, crystallization, and absorption. Ultimately, the free drug concentration, which is equivalent to the drug's inherent thermodynamic activity amid these kinetic processes, defines the true driving force for drug absorption. However, in cases where solubilizing agents are present (i.e., surfactants and bile salts), drug molecules may associate with colloidal nanoscale species, complicating drug activity determination. These nanoscale species can drift into the aqueous boundary layer (ABL), increasing the local API activity at the membrane surface, resulting in increased bioavailability. Herein, a novel approach was developed to accurately measure thermodynamic drug activity in complex media containing drug distributed in nanoparticulate species. This approach captures the influence of the ABL on the observed flux and, ultimately, the predicted unbound drug concentration. The results demonstrate that this approach can help to (1) measure the true extent of local supersaturation in complex systems containing solubilizing excipients and (2) elucidate the mechanisms by which colloidal aggregates can modulate the drug activity in solution and potentially enhance the flux observed across a membrane. The utilization of these techniques may provide development scientists with a strategy to evaluate formulation sensitivity to nanospeciation and allow formulators to maximize the driving force for absorption in a complex environment, perhaps enabling the development of dissolution methods with greater discrimination and correlation to pre-clinical and clinical data sets.

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Section: Discussionsupporting

confidence: 87%

Toward Developing Discriminating Dissolution Methods for Formulations Containing Nanoparticulates in Solution: The Impact of Particle Drift and Drug Activity in Solution

et al. 2020

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“…DFT calculations are also often necessary to refine a crystal structure obtained from powder X-ray diffraction (PXRD) experiments. These calculations are mostly consistent with experimental data, as in the case of estradiol ethinyl cocrystals [151].…”

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confidence: 85%

Application of Various Molecular Modelling Methods in the Study of Estrogens and Xenoestrogens

Mazurek

Szeleszczuk

Simonson

et al. 2020

IJMS

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In this review, applications of various molecular modelling methods in the study of estrogens and xenoestrogens are summarized. Selected biomolecules that are the most commonly chosen as molecular modelling objects in this field are presented. In most of the reviewed works, ligand docking using solely force field methods was performed, employing various molecular targets involved in metabolism and action of estrogens. Other molecular modelling methods such as molecular dynamics and combined quantum mechanics with molecular mechanics have also been successfully used to predict the properties of estrogens and xenoestrogens. Among published works, a great number also focused on the application of different types of quantitative structure–activity relationship (QSAR) analyses to examine estrogen’s structures and activities. Although the interactions between estrogens and xenoestrogens with various proteins are the most commonly studied, other aspects such as penetration of estrogens through lipid bilayers or their ability to adsorb on different materials are also explored using theoretical calculations. Apart from molecular mechanics and statistical methods, quantum mechanics calculations are also employed in the studies of estrogens and xenoestrogens. Their applications include computation of spectroscopic properties, both vibrational and Nuclear Magnetic Resonance (NMR), and also in quantum molecular dynamics simulations and crystal structure prediction. The main aim of this review is to present the great potential and versatility of various molecular modelling methods in the studies on estrogens and xenoestrogens.

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“…Computational crystal structure prediction (CSP) is increasingly used to survey the landscape of potential crystal structures as a complement to experimental solid form screening efforts. 31,32 In the pharmaceutical industry, for example, CSP has recently contributed to the discovery and structural determination of new polymorphs of species such as dalcetrapib, 33 aspirin, 34 paracetamol, 35 β-estradiol, 36 galunisertib, 2 and olanzapine. 37 It has similarly helped guide the discovery of new, highly porous organic molecular crystals.…”

Section: Introductionmentioning

confidence: 99%

How many more polymorphs of ROY remain undiscovered

et al. 2022

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The solid state forms of the sex hormone 17-β-estradiol

Abstract: The crystal structure of the female sex hormone has been established despite its high affinity for water.

Cited by 15 publications

References 38 publications

Toward Developing Discriminating Dissolution Methods for Formulations Containing Nanoparticulates in Solution: The Impact of Particle Drift and Drug Activity in Solution

Toward Developing Discriminating Dissolution Methods for Formulations Containing Nanoparticulates in Solution: The Impact of Particle Drift and Drug Activity in Solution

Application of Various Molecular Modelling Methods in the Study of Estrogens and Xenoestrogens

How many more polymorphs of ROY remain undiscovered

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