Impact of a Single Hydrogen Substitution by Fluorine on the Molecular Interaction and Miscibility between Sorafenib and Polymers

Abstract

We aim to understand the potential impact of a modest chemical modification of a drug molecule on the downstream design of its amorphous solid dispersion (ASD) formulation. To this end, we used sorafenib (SOR) and its fluorinated form, regorafenib (REG), as model drugs, to assess the impact of a single hydrogen substitution by fluorine on the molecular interaction and miscibility between drug and PVP or PVP–VA, two commonly used polymers for ASDs. In this study, we observed that the T g values of PVP or PVP–VA based ASDs of SOR deviated positively from the Gordon–Taylor prediction, which assumes ideal mixing, yet the T g of REG ASDs deviated negatively from or matched well with the ideal mixing model, suggesting much stronger drug–polymer interactions in SOR ASDs compared with the REG ASDs. Using solution NMR and computational methods, we proved that a six-member-ring formed between the carbonyl groups on the polymers and the uramido hydrogen of SOR or REG, through intermolecular hydrogen bonding. However, steric hindrance resulting from fluorination in REG caused weaker interaction between REG–polymer than SOR–polymer. To further confirm this mechanism, we investigated the molecular interactions of other two uramido-containing model compounds, triclocarban (TCC) and gliclazide (GCZ), with PVP. We found that TCC but not GCZ formed a hexatomic ring with PVP. We concluded that PVP based polymers can easily interact with N,N′-disubstituted urea compounds with a trans–trans structure in the form of hexatomic rings, and the interaction strength of the hexatomic ring largely depended on the chemistry of drug molecules. This study illustrated that even a slight chemical modification on drug molecules could result in substantial difference in drug–polymer interactions, thus significantly impacting polymer selection and pharmaceutical performance of their ASD formulations.

Analytical and Computational Methods for the Determination of Drug-Polymer Solubility and Miscibility

“…Forster et al have reported the composition dependent presence of single or multiple T g values in the system of lacidipine and indomethacin with PVP . Apart from the presence of multiple T g values, reports also state the presence of a single T g as a sign of the molecularly dispersed ASD. ,− This is one of the commonly used qualitative predictors of drug-polymer miscibility with more than 50 instances in the reviewed literature. In a most recent report, Blasi et al have reported the presence of multiple T g values for ASD with ketoprofen content more than 35% w/w in poly­(D, L-lactide- co -glycolide) …”

Engineering of hybrid anticancer drug-loaded polymeric nanoparticles delivery system for the treatment and care of lung cancer therapy

“…Owing to its ecofriendly accountability and bio-competitiveness, bio-degradable polymeric nanoparticles with appropriate dimensions, even surface diameter, and increased aqueous solubility have gotten a lot of attention (Liu et al, 2016 ; Zhang & Tung, 2017 ; Liu et al, 2019 ; Li et al, 2020a , 2020b ). In anticancer therapy, biomaterial fields, and medical diagnosis, a number of environmentally friendly NMs have been widely used.…”

Co-drug delivery of regorafenib and cisplatin with amphiphilic copolymer nanoparticles: enhanced in vivo antitumor cancer therapy in nursing care

“…Some commercial products of non-biodegradable microspheres have come into the market already such as DC Beads and Hepasphere™ for TACE. Drugs especially the positively charged were usually shielded by ion exchange approach, and the drug elution kinetics were determined by the ionic environment of physiological fluids (Liu et al., 2019 ).…”

“…Combination therapy can be performed via co-administration of a supplementary cancer drug along with a sensitizer. The interfaces within potential anticancer drugs rely on the dose ratios between the two medications and can be potentially incompatible (Li and Finley, 2018 ; Liu et al., 2019 ; Yang et al., 2019 ). Consequently, the importance of preserving a beneficial ratio to maintain a synergistic relationship between two drugs through nanoparticles (NPs) formulations cannot be ignored.…”

“…Consequently, the importance of preserving a beneficial ratio to maintain a synergistic relationship between two drugs through nanoparticles (NPs) formulations cannot be ignored. The procedure of encapsulating several anticancer drugs in individual NPs has proved to be problematic because the drugs have to preserve their important physicochemical properties (Li & Finley, 2018 ; Liu et al., 2019 ; Yang et al., 2019 ). Hence, nanoformulations that are prepared by encapsulating numerous medications with varied physico-chemical belongings while preserving controlled ratios are preferred for drug delivery within the body tissues.…”