Characterizing Drug–Polymer Interactions in Aqueous Solution with Analytical Ultracentrifugation

Amponsah-Efah, Kweku K.; Demeler, Borries; Suryanarayanan, Raj

doi:10.1021/acs.molpharmaceut.0c00849

Cited by 5 publications

(3 citation statements)

References 59 publications

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“…To determine the extent of generalizability of the hypothesis, a wider range of drug–polymer systems needs to be studied. We have noticed from our ongoing studies that other techniques that can provide complementary information on interaction patterns in aqueous solution will likely be required because of the challenge posed by the poor aqueous solubility of the model drugs . The next step would be to investigate if the dissolution enhancement observed in vitro due to strong interactions translates to enhanced bioavailability in vivo .…”

Section: Significancementioning

confidence: 99%

The Influence of the Strength of Drug–Polymer Interactions on the Dissolution of Amorphous Solid Dispersions

et al. 2020

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In an earlier report, ionic interactions between ketoconazole (KTZ), a weakly basic drug, and poly(acrylic acid) (PAA), an anionic polymer, resulted in a dramatic decrease in molecular mobility as well as reduced crystallization propensity of amorphous solid dispersion (ASD) in the solid state. On the other hand, weaker dipole−dipole interactions between KTZ and polyvinylpyrrolidone (PVP) resulted in ASDs with higher crystallization propensity (Mistry et al. Mol Pharm., 2015, 12 (9), 3339−3350). In this work, we investigated the behavior of the ketoconazole (KTZ) solid dispersions in aqueous media. In vitro dissolution tests showed that the PAA ASD maintained the level of supersaturation for a longer duration than the PVP ASD at low polymer contents (4−20% w/w polymer). Additionally, the PAA ASDs were more resistant to drug crystallization in aqueous medium when measured with synchrotron X-ray diffractometry. Two-dimensional 1 H nuclear Overhauser effect spectroscopy (NOESY) NMR cross peaks between ketoconazole and PAA confirmed the existence of drug−polymer interactions in D 2 O. The interaction was accompanied by a reduced drug diffusivity as monitored by 2D diffusion ordered spectroscopy (DOSY) NMR and enthalpy-driven when characterized by isothermal titration calorimetry (ITC). On the other hand, drug−polymer interactions were not detected between ketoconazole and PVP in aqueous solution, with NOESY, DOSY, or ITC. The results suggest that interactions that stabilize ASDs in the solid state can also be relevant and important in sustaining supersaturation in solution.

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Section: Significancementioning

confidence: 99%

The Influence of the Strength of Drug–Polymer Interactions on the Dissolution of Amorphous Solid Dispersions

et al. 2020

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“…In vivo, these bound drug species, along with free drug, constitute a gastric milieu that is dynamic in nature due to continuous drug removal by absorption. Biopredictive (non-QC) in vitro assessment of ASD performance, on the other hand, is commonly performed under closed, nonsink conditions afforded by the standard United States Pharmacopeia (USP) dissolution testing apparatus, which allows only static equilibria between various drug species. − It has also been shown in an earlier study that a closed dissolution testing apparatus increases the crystallization propensity of supersaturated solutions . This would prevent the assessment of the full potential of ASDs or, worse, may underestimate their efficacy.…”

Section: Introductionmentioning

confidence: 99%

An Artificial Gut/Absorption Simulator: Understanding the Impact of Absorption on In Vitro Dissolution, Speciation, and Precipitation of Amorphous Solid Dispersions

Jain,

Hou,

Siegel

2024

Mol. Pharmaceutics

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Upon dissolution, amorphous solid dispersions (ASDs) of poorly water-soluble compounds can generate supersaturated solutions consisting of bound and free drug species that are in dynamic equilibrium with each other. Only free drug is available for absorption. Drug species bound to bile micelles, polymer excipients, and amorphous and crystalline precipitate can reduce the drug solute's activity to permeate, but they can also serve as reservoirs to replenish free drug in solution lost to absorption. However, with multiple processes of dissolution, absorption, and speciation occurring simultaneously, it may become challenging to understand which processes lead to an increase or decrease in drug solution concentration. Closed, nonsink dissolution testing methods used routinely, in the absence of drug removal, allow only for static equilibrium to exist and obscure the impact of each drug species on absorption. An artificial gut simulator (AGS) introduced recently consists of a hollow fiber-based absorption module and allows mass transfer of the drug from the dissolution media at a physiological rate after tuning the operating parameters. In the present work, ASDs of varying drug loadings were prepared with a BCS-II model compound, ketoconazole (KTZ), and hypromellose acetate succinate (HPMCAS) polymer. Simultaneous dissolution and absorption testing of the ASDs was conducted with the AGS, and simple analytical techniques were utilized to elucidate the impact of bound drug species on absorption. In all cases, a lower amount of crystalline precipitate was formed in the presence of absorption relative to the nonsink dissolution "control". However, formation of HPMCAS-bound drug species and crystalline precipitate significantly reduced KTZ absorption. Moreover, at high drug loading, inclusion of an absorption module was shown to enhance ASD dissolution. The rank ordering of the ASDs with respect to dissolution was significantly different when nonsink dissolution versus AGS was used, and this discrepancy could be mechanistically elucidated by understanding drug dissolution and speciation in the presence of absorption.

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“…Despite the growing interest in understanding drug-carrier interactions at a molecular level, prediction of the drug release kinetics remains challenging due to many interrelated physicochemical processes that occur simultaneously in the aqueous environment [14,15]. Therefore, studies on the interaction of active substances (drugs) and their carriers in hydrous medium are important as they provide the basic foundation for their application [16][17][18][19][20]. The influence of hydrogen bond interactions on the drug release kinetics need to be determined in order to understand the fundamental mechanisms governing the release process [21,22].…”

Section: Introductionmentioning

confidence: 99%

The Role of Hydrogen Bonding in Paracetamol–Solvent and Paracetamol–Hydrogel Matrix Interactions

et al. 2021

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The photophysical and photochemical properties of antipyretic drug – paracetamol (PAR) and its two analogs with different substituents (acetanilide (ACT) and N-ethylaniline (NEA)) in 14 solvents of different polarity were investigated by the use of steady–state spectroscopic technique and quantum–chemical calculations. As expected, the results show that the spectroscopic behavior of PAR, ACT, and NEA is highly dependent on the nature of the solute–solvent interactions (non-specific (dipole-dipole) and specific (hydrogen bonding)). To characterize these interactions, the multiparameter regression analysis proposed by Catalán was used. In order to obtain a deeper insight into the electronic and optical properties of the studied molecules, the difference of the dipole moments of a molecule in the ground and excited state were determined using the theory proposed by Lippert, Mataga, McRae, Bakhshiev, Bilot, and Kawski. Additionally, the influence of the solute polarizability on the determined dipole moments was discussed. The results of the solvatochromic studies were related to the observations of the release kinetics of PAR, ACT, and NEA from polyurethane hydrogels. The release kinetics was analyzed using the Korsmayer-Peppas and Hopfenberg models. Finally, the influence of the functional groups of the investigated compounds on the release time from the hydrogel matrix was analyzed.

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Characterizing Drug–Polymer Interactions in Aqueous Solution with Analytical Ultracentrifugation

Cited by 5 publications

References 59 publications

The Influence of the Strength of Drug–Polymer Interactions on the Dissolution of Amorphous Solid Dispersions

The Influence of the Strength of Drug–Polymer Interactions on the Dissolution of Amorphous Solid Dispersions

An Artificial Gut/Absorption Simulator: Understanding the Impact of Absorption on In Vitro Dissolution, Speciation, and Precipitation of Amorphous Solid Dispersions

The Role of Hydrogen Bonding in Paracetamol–Solvent and Paracetamol–Hydrogel Matrix Interactions

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