Scholarly Works, Sustainable Biomaterials
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Browsing Scholarly Works, Sustainable Biomaterials by Department "Chemistry"
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- Amorphous solid dispersions of enzalutamide and novel polysaccharide derivatives: investigation of relationships between polymer structure and performanceWilson, Venecia R.; Lou, Xiaochun; Osterling, Donald J.; Stolarik, DeAnne F.; Jenkins, Gary J.; Nichols, Brittany L. B.; Dong, Yifan; Edgar, Kevin J.; Zhang, Geoff G. Z.; Taylor, Lynne S. (Nature Research, 2020-10-28)Amorphous solid dispersion (ASD) is a widely employed formulation technique for drugs with poor aqueous solubility. Polymers are integral components of ASDs, but mechanisms by which polymers lead to the generation and maintenance of supersaturated solutions, which enhance oral absorption in vivo, are poorly understood. Herein, a diverse group of newly synthesized cellulose derivatives was evaluated for their ability to inhibit crystallization of enzalutamide, a poorly soluble compound used to treat prostate cancer. ASDs were prepared from selected polymers, specifically a somewhat hydrophobic polymer that was extremely effective at inhibiting drug crystallization, and a less effective, but more hydrophilic, crystallization inhibitor, that might afford better release. Drug membrane transport rate was evaluated in vitro and compared to in vivo performance, following oral dosing in rats. Good correlation was noted between the in vitro diffusion cell studies and the in vivo data. The ASD formulated with the less effective crystallization inhibitor outperformed the ASD prepared with the highly effective crystallization inhibitor in terms of the amount and rate of drug absorbed in vivo. This study provides valuable insight into key factors impacting oral absorption from enabling ASD formulations, and how best to evaluate such formulations using in vitro approaches.
- Amphiphilic hydroxyalkyl cellulose derivatives for amorphous solid dispersion prepared by olefin cross-metathesisDong, Yifan; Mosquera-Giraldo, Laura I.; Troutman, Jacob; Skogstad, Brittny; Taylor, Lynne S.; Edgar, Kevin J. (Royal Society of Chemistry, 2016-07-07)Olefin cross-metathesis (CM) has enabled design and synthesis of diverse, amphiphilic cellulose ether derivatives (e.g. of ethyl and methyl cellulose). In this paper, hydroxyalkyl cellulose was selected as a hydrophilic starting material, with the additional advantage that it has DS (OH) 3.0 that allows targeting of a full range of DS of selected functional groups. Hydroxypropyl cellulose (HPC) was first etherified with 5-bromopent-1-ene to attach olefin “handles” for metathesis, whereby control of molar ratios of sodium hydride and 5-bromopent-1-ene permits full DS control of appended olefin. These olefin-terminated HPC ethers then were subjected to CM with acrylic acid and different acrylates, followed by diimide hydrogenation to reduce the resulting α,β-unsaturation. NMR and FT-IR spectroscopies were useful tools for following reaction progress. One of the product carboxyl-functionalized HPC derivatives, designated HPC-Pen106-AA-H, showed high promise as a crystallization inhibitor of the antiviral drug telaprevir. Its nucleation-induction inhibitory ability was compared to those of commercial controls, HPC and HPMCAS. All three polymers were very effective for inhibiting telaprevir crystallization, increasing induction time up to 8-fold. HPC did not effectively prevent amorphous particle growth, whereas the carboxyl-containing HPC-Pen106-AA-H and HPMCAS were able to prevent formation of agglomerates of amorphous drugs.
- Imparting functional variety to cellulose ethers via olefin cross-metathesisDong, Yifan; Edgar, Kevin J. (The Royal Society of Chemistry, 2015-04-09)Olefin cross-metathesis is a valuable new approach for imparting functional variety to cellulose ethers. Starting from commercially available ethyl cellulose, terminally unsaturated alkyl groups were appended as metathesis handles by reaction with allyl chloride, 5-bromo-1-pentene, 7-bromo-1-heptene and 11-bromo-1-undecene, employing sodium hydride catalyst. These olefin-terminal ethyl cellulose derivatives were then subjected to olefin cross-metathesis with a variety of electron-poor olefin substrates, including acrylic acid and acrylate esters under optimized conditions (5–10 mol% Hoveyda-Grubbs’ 2nd generation catalyst, 37 °C, 2 h). The effects of varying the length of the ω-unsaturated alkyl handle, and of the solvent systems used were evaluated. Ethyl cellulose containing a pent-4-enyl substituent performed best in cross metathesis reactions and a hept-6-enyl substituent gave similarly good results. Ethyl cellulose with allyl substituents gave low to moderate metathesis conversion (<50%), possibly due to steric effects and the proximity of the ether oxygen to the terminal olefin. Interestingly, longer tethers (undec-10-enyl) gave high conversions (up to 90%) but relatively slow reactions (ca. 12 h needed for high conversion). While limited in this study by the relatively low DS (OH) of the starting commercial ethyl cellulose materials, this methodology has strong promise for introduction of diverse functionality to cellulose ethers in chemospecific and mild fashion, enabling amorphous solid dispersion and other applications.
- Multifunctional cellulose esters by olefin cross-metathesis and thiol-Michael additionMeng, Xiangtao; Roy Choudhury, Shreya; Edgar, Kevin J. (Royal Society of Chemistry, 2016-04-25)Olefin cross-metathesis (CM) has been shown to be a versatile, mild, modular, and efficient approach to polysaccharide modification. One issue with regard to this approach is the susceptibility of the initial α,β-unsaturated CM derivatives to H-atom abstraction in the γ-position, followed by radical recombination that leads to insoluble, crosslinked products. In our original approach, we resolved this problem through removing the offending unsaturation by hydrogenation. In the current study, we describe a method to exploit these reactive conjugated olefins, by post-CM thiol-Michael addition, thereby appending additional functionality. CM substrates and thiols bearing various functional groups were combined and reacted, employing amine catalysis. Up to 100% conversion was achieved under proper conditions (e.g. catalyst and reaction time), with minimal side reactions observed. The combination of the two modular reactions creates versatile access to cellulose derivatives equipped with a wide diversity of functional groups.