6-Carboxycellulose Acetate Butyrate: Effectiveness as an Amorphous Solid Dispersion Polymer.

Amorphous solid dispersion (ASD) in a polymer matrix is a powerful method for enhancing the solubility and bioavailability of otherwise crystalline, poorly water-soluble drugs. 6-Carboxycellulose acetate butyrate (CCAB) is a relatively new commercial cellulose derivative that was introduced for use in waterborne coating applications. As CCAB is an amphiphilic, carboxyl-containing, high glass transition temperature (Tg) polymer, characteristics essential to excellent ASD polymer performance, we chose to explore its ASD potential. Structurally diverse drugs quercetin, ibuprofen, ritonavir, loratadine, and clarithromycin were dispersed in CCAB matrices. We evaluated the ability of CCAB to create ASDs with these drugs and its ability to provide solubility enhancement and effective drug release. CCAB/drug dispersions prepared by spray drying were amorphous up to 25 wt % drug, with loratadine remaining amorphous up to 50% drug. CCAB formulations with 10% drug proved effective at providing in vitro solubility enhancement for the crystalline flavonoid drug quercetin as well as ritonavir, but not for the more soluble APIs ibuprofen and clarithromycin and the more hydrophobic loratadine. CCAB did provide slow and controlled release of ibuprofen, offering a simple and promising Long-duration ibuprofen formulation. Formulation with clarithromycin showed the ability of the polymer to protect against degradation of the drug at stomach pH. Furthermore, CCAB ASDs with both loratadine and ibuprofen could be improved by the addition of the water-soluble polymer poly(vinylpyrrolidone) (PVP), with which CCAB shows good miscibility. CCAB provided solubility enhancement in some cases, and the slower drug release exhibited by CCAB, especially in the stomach, could be especially beneficial, for example, in formulations containing known stomach irritants like ibuprofen.

Polysaccharide Aldehydes and Ketones: Synthesis and Reactivity.

Polysaccharides are biodegradable, abundant, sustainable, and often benign natural polymers. The achievement of selective modification of polysaccharides is important for targeting specific properties and structures and will benefit future development of highly functional, sustainable materials. The synthesis of polysaccharides containing aldehyde or ketone moieties is a promising tool for achieving this goal because of the rich chemistry of aldehyde or ketone groups, including Schiff base formation, nucleophilic addition, and reductive amination. The obtained polysaccharide aldehydes or ketones themselves have rich potential for making useful materials, such as self-healing hydrogels, polysaccharide-protein therapeutic conjugates, or drug delivery vehicles. Herein, we review recent advances in synthesizing polysaccharides containing aldehyde or ketone moieties and briefly introduce their reactivity and corresponding applications.

Dextran Macroinitiator for Synthesis of Polysaccharide-b-Polypeptide Block Copolymers via NCA Ring-Opening Polymerization.

Synthesis of polysaccharide-b-polypeptide block copolymers represents an attractive goal because of their promising potential in delivery applications. Inspired by recent breakthroughs in N-carboxyanhydride (NCA) ring-opening polymerization (ROP), we present an efficient approach for preparation of a dextran-based macroinitiator and the subsequent synthesis of dextran-b-polypeptides via NCA ROP. This is an original approach to creating and employing a native polysaccharide macroinitiator for block copolymer synthesis. In this strategy, regioselective (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) oxidation of the sole primary alcohol located at the C-6 position of the monosaccharide at the nonreducing end of linear dextran results in a carboxylic acid. This motif is then transformed into a tetraalkylammonium carboxylate, thereby generating the dextran macroinitiator. This macroinitiator initiates a wide range of NCA monomers and produces dextran-b-polypeptides with a degree of polymerization (DP) of the polypeptide up to 70 in a controlled manner (D < 1.3). This strategy offers several distinct advantages, including preservation of the original dextran backbone structure, relatively rapid polymerization, and moisture tolerance. The dextran-b-polypeptides exhibit interesting self-assembly behavior. Their nanostructures have been investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM), and adjustment of the structure of block copolymers allows self-assembly of spherical micelles and worm-like micelles with varied diameters and aspect ratios, revealing a range of diameters from 60 to 160 nm. Moreover, these nanostructures exhibit diverse morphologies, including spherical micelles and worm-like micelles, enabling delivery applications.

Silica-Biomacromolecule Interactions: Toward a Mechanistic Understanding of Silicification.

Silica-organic composites are receiving renewed attention for their versatility and environmentally benign compositions. Of particular interest is how macromolecules interact with aqueous silica to produce functional materials that confer remarkable physical properties to living organisms. This Review first examines silicification in organisms and the biomacromolecule properties proposed to modulate these reactions. We then highlight findings from silicification studies organized by major classes of biomacromolecules. Most investigations are qualitative, using disparate experimental and analytical methods and minimally characterized materials. Many findings are contradictory and, altogether, demonstrate that a consistent picture of biomacromolecule-Si interactions has not emerged. However, the collective evidence shows that functional groups, rather than molecular classes, are key to understanding macromolecule controls on mineralization. With recent advances in biopolymer chemistry, there are new opportunities for hypothesis-based studies that use quantitative experimental methods to decipher how macromolecule functional group chemistry and configuration influence thermodynamic and kinetic barriers to silicification. Harnessing the principles of silica-macromolecule interactions holds promise for biocomposites with specialized applications from biomedical and clean energy industries to other material-dependent industries.

Chitosan as a Canvas for Studies of Macromolecular Controls on CaCO3 Biological Crystallization.

A mechanistic understanding of how macromolecules, typically as an organic matrix, nucleate and grow crystals to produce functional biomineral structures remains elusive. Advances in structural biology indicate that polysaccharides (e.g., chitin) and negatively charged proteoglycans (due to carboxyl, sulfate, and phosphate groups) are ubiquitous in biocrystallization settings and play greater roles than currently recognized. This review highlights studies of CaCO3 crystallization onto chitinous materials and demonstrates that a broader understanding of macromolecular controls on mineralization has not emerged. With recent advances in biopolymer chemistry, it is now possible to prepare chitosan-based hydrogels with tailored functional group compositions. By deploying these characterized compounds in hypothesis-based studies of nucleation rate, quantitative relationships between energy barrier to crystallization, macromolecule composition, and solvent structuring can be determined. This foundational knowledge will help researchers understand composition-structure-function controls on mineralization in living systems and tune the designs of new materials for advanced applications.

Synthesis and Characterization of Multi-Reducing-End Polysaccharides.

Site-specific modification is a great challenge for polysaccharide scientists. Chemo- and regioselective modification of polysaccharide chains can provide many useful natural-based materials and help us illuminate fundamental structure-property relationships of polysaccharide derivatives. The hemiacetal reducing end of a polysaccharide is in equilibrium with its ring-opened aldehyde form, making it the most uniquely reactive site on the polysaccharide molecule, ideal for regioselective decoration such as imine formation. However, all natural polysaccharides, whether they are branched or not, have only one reducing end per chain, which means that only one aldehyde-reactive substituent can be added. We introduce a new approach to selective functionalization of polysaccharides as an entrée to useful materials, appending multiple reducing ends to each polysaccharide molecule. Herein, we reduce the approach to practice using amide formation. Amine groups on monosaccharides such as glucosamine or galactosamine can react with carboxyl groups of polysaccharides, whether natural uronic acids like alginates, or derivatives with carboxyl-containing substituents such as carboxymethyl cellulose (CMC) or carboxymethyl dextran (CMD). Amide formation is assisted using the coupling agent 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM). By linking the C2 amines of monosaccharides to polysaccharides in this way, a new class of polysaccharide derivatives possessing many reducing ends can be obtained. We refer to this class of derivatives as multi-reducing-end polysaccharides (MREPs). This new family of derivatives creates the potential for designing polysaccharide-based materials with many potential applications, including in hydrogels, block copolymers, prodrugs, and as reactive intermediates for other derivatives.

Interaction of Polymers with Enzalutamide Nanodroplets-Impact on Droplet Properties and Induction Times.

Amorphous solid dispersions (ASDs), which consist of a drug dispersed in a polymeric matrix, are increasingly being applied to improve the in vivo performance of poorly water-soluble drugs delivered orally. The polymer is a critical component, playing several roles including facilitating drug release from the ASD, as well as delaying crystallization from the supersaturated solution generated upon dissolution. Certain ASD formulations dissolve to produce amorphous drug-rich nanodroplets. The interaction of the polymer with these nanodroplets is poorly understood but is thought to be important for inhibiting crystallization in these systems. In this study, the impact of ionic polymers on the crystallization kinetics of enzalutamide from supersaturated solutions containing different amounts of amorphous nanodroplets was evaluated by determination of nucleation induction times. The amount of the polymer associated with the drug nanodroplets was also determined. When comparing two polymers, hydroxypropylmethyl cellulose acetate succinate (HPMCAS) and Eudragit E PO, it was found that the crystallization tendency and physical properties of the drug nanodroplets varied in the presence of these two polymers. Both polymers distributed between the aqueous phase and the drug-rich nanodroplets. A greater amount of Eudragit E PO was associated with the drug-rich nanodroplets. Despite this, Eudragit E PO was a less-effective crystallization inhibitor than HPMCAS in systems containing nanodroplets. In conclusion, in supersaturated solutions containing amorphous nanodroplets, the extent of association of a polymer with the drug nanodroplet does not solely predict crystallization inhibition.

Selective Oxidation of 2-Hydroxypropyl Ethers of Cellulose and Dextran: Simple and Efficient Introduction of Versatile Ketone Groups to Polysaccharides.

Oxidation of polysaccharides has been a useful approach to new materials. However, selectivity in oxidation of polysaccharide macromolecular polyols remains a significant challenge with few methods for the synthesis of ketone-substituted polysaccharides. We report here a selective, practical, and efficient process, beginning with 2-hydroxypropyl ethers of polysaccharides that are simple and economical to prepare. We demonstrate this approach herein using commercial 2-hydroxypropyl cellulose (HPC) and 2-hydroxypropyl dextran (HPD) that we prepared. We oxidize the terminal, secondary alcohols of the oligo(2-hydroxypropyl) substituents with sodium hypochlorite so that the product has an oligo(2-hydroxypropyl) side chains terminated by a ketone. We demonstrate the high chemo- and regioselectivity of this oxidation by analytical methods including hydrolysis to monosaccharides and mass spectrometry of the resulting mixture. We provide an initial demonstration of the potential utility of these keto-polysaccharides by reacting Ox-HPC with primary amines to form Schiff base imines, providing proactive polymers.

All-Polysaccharide, Self-Healing Injectable Hydrogels Based on Chitosan and Oxidized Hydroxypropyl Polysaccharides.

Polysaccharide-based hydrogels are attractive materials for biomedical applications for reasons that include their polyfunctionality, generally benign nature, and biodegradability. However, the use of polysaccharide-based hydrogels may be limited by toxicity arising from small-molecule crosslinkers, or may involve undesired chemical modification [Hennink, W. E.; et al. Adv. Drug Delivery Rev. 2012, 64, 223-236]. Here, we report a green, simple, efficient strategy for the preparation of polysaccharide-based, in situ forming hydrogels. The Edgar group reports in the accompanying manuscript that chemoselective oxidation of oligo(hydroxypropyl)-substituted polysaccharides introduces ketone groups at the termini of the side chains [Nichols, B. L. B.; et al]. Amine-containing moieties can condense with ketones to form imines. The imine linkage is dynamic in the presence of water, providing the potential for self-healing [Wei, Z.; et al. Adv. Funct. Mater. 2015, 25, 1352-1359], injectability [Wei, Z.; et al. Adv. Funct. Mater. 2015, 25, 1352-1359], and pH responsiveness [Yao, K.; et al. J. Appl. Polym. Sci. 1993, 48, 343-354]. In this work, we designed and prepared two different types of hydrogels, oxidized hydroxypropyl cellulose/chitosan (Ox-HPC-Chitosan) and oxidized hydroxypropyl dextran/chitosan (Ox-HPD-Chitosan), each cross-linked by imine bonds. The mechanical properties of these hydrogels were characterized by rheometry, revealing that hydrogel storage modulus could be tuned from 300 Pa to 13 kPa simply by controlling the degree of substitution (DS) of ketone groups. Rheological characterization also illustrated the rapid self-healing property of these all-polysaccharide hydrogels. Moreover, these hydrogels exhibited high swelling rates and facile injectability. Therefore, this work reveals a potential strategy for the construction of hydrogels that require no small-molecule crosslinkers and are therefore highly attractive for biomedical, agricultural, controlled release, and other applications.

Regioselective Bromination of the Dextran Nonreducing End Creates a Pathway to Dextran-Based Block Copolymers.

Preparation of polysaccharide-based block copolymers with linear architectures is an important goal, opening up clear application potential and requiring significant advances in polysaccharide regio- and chemoselectivity. Herein we report a simple approach to prepare dextran-based block copolymers. Reaction with N-bromosuccinimide (NBS)/triphenyl phosphine (PPh3) regioselectively brominates the sole primary alcohol of linear, unbranched dextran at C-6 of the nonreducing end monosaccharide. The resulting dextran, monofunctionalized with a terminal C-6 bromide, was coupled with various amine terminated polymers to prepare block copolymers, including dextran-b-poly(ethylene glycol), dextran-b-polystyrene, and dextran-b-poly(N-isopropylacrylamide). These renewable-based block copolymers, prepared in two selective, high-yielding steps from native linear dextran, exhibit various interesting properties. Dextran-b-poly(N-isopropylacrylamide) undergoes thermally induced micellization as revealed by dynamic light scattering (DLS), forming micelles upon exceeding 33 °C. We also observed microphase separation in dextran-b-polystyrene by using small-angle X-ray scattering (SAXS). Overall, this methodology provides a new, highly chemo- and regioselective, versatile route to diverse dextran-based block copolymers with useful properties, enabling drug delivery, compatibilization, and other applications.

Efficient Synthesis of Glycosaminoglycan Analogs.

Glycosaminoglycans (GAGs) are among the most complex, biologically active polysaccharides in nature. The complexity of GAGs greatly impedes their synthesis, thus complicating the structure-property studies that are so necessary for us to understand the roles of GAGs in natural processes, in pathogen invasion, and to understand how to develop effective interventions, for example, to prevent undesired GAG hijacking by pathogens. Total synthesis of GAG oligomers from monosaccharide building blocks is useful, but incredibly labor-intensive, expensive, and inefficient. In this study, we report a regiospecific synthetic route to two types of designed GAG analogs by chemical modification of commercially available, inexpensive cellulose acetate. Cellulose acetate was first brominated, followed by azide displacement to introduce azides as the GAG amine precursors. The resulting 6-N3 cellulose acetate was then saponified to liberate 6-OH groups. Subsequent oxidation of the liberated primary hydroxyl groups to carboxyl groups was smoothly effected by a TEMPO-catalyzed process. Finally, the azides were reduced to amines using an aqueous process, new to polysaccharide chemistry, employing reduction by dithiothreitol (DTT). Alternatively, another process new to polysaccharide chemistry could be employed to convert most of the azides to acetamido groups (mimicking those present, for example, in native hyaluronic acid) by reduction with thioacetic acid. All the intermediates and products were characterized by 1H NMR, 13C NMR, and FT-IR spectroscopy. This synthetic route provides access to GAG analogs that will be of great interest for exploring structure-property relationships in various biomedical applications.

Influence of Polymer and Drug Loading on the Release Profile and Membrane Transport of Telaprevir.

During the dissolution of amorphous solid dispersions (ASDs), various phase transformations can occur, which will ultimately impact the degree of supersaturation. This study employed dissolution and diffusion measurements to compare the performance of various ASD formulations based on the maximum amount of free drug in the solution that was able to permeate through a cellulose-based membrane. Telaprevir (TPV) was used as the model drug compound, and ASDs were prepared with different drug loadings and with four different polymers. Four possible scenarios that can influence TPV mass flow rates upon ASD dissolution were described and supported with experimental data: (1) a system dissolves readily and completely undergoes phase separation via glass-liquid phase separation (GLPS), forming drug-rich aggregates, and reaches the maximum anticipated mass flow rate; (2) where the maximum mass flow rate decreases due to substantial mixing of the polymer into the drug-rich phase, and/or due to the formation of soluble polymer-drug complexes; (3) a system does not undergo GLPS due to slow drug release and/or matrix crystallization; and (4) a system does not undergo GLPS due to rapid crystallization from the supersaturated solution generated during dissolution. The results described herein support the importance of the combined use of the dissolution-diffusion measurements to determine the maximum level of supersaturation achievable for diverse drug formulations.

Pharmaceutical Applications of Cellulose Ethers and Cellulose Ether Esters.

Cellulose ethers have proven to be highly useful natural-based polymers, finding application in areas including food, personal care products, oil field chemicals, construction, paper, adhesives, and textiles. They have particular value in pharmaceutical applications due to characteristics including high glass transition temperatures, high chemical and photochemical stability, solubility, limited crystallinity, hydrogen bonding capability, and low toxicity. With regard to toxicity, cellulose ethers have essentially no ability to permeate through gastrointestinal enterocytes and many are already in formulations approved by the U.S. Food and Drug Administration. We review pharmaceutical applications of these valuable polymers from a structure-property-function perspective, discussing each important commercial cellulose ether class; carboxymethyl cellulose, methyl cellulose, hydroxypropylcellulose, hydroxypropyl methyl cellulose, and ethyl cellulose, and cellulose ether esters including hydroxypropyl methyl cellulose acetate succinate and carboxymethyl cellulose acetate butyrate. We also summarize their syntheses, basic material properties, and key pharmaceutical applications.

Crystallization Inhibition Properties of Cellulose Esters and Ethers for a Group of Chemically Diverse Drugs: Experimental and Computational Insight.

Amorphous solid dispersions are widely used to enhance the oral bioavailability of poorly water-soluble drugs. Polymeric additives are commonly used to delay crystallization of the drug from the supersaturated solutions formed upon ASD dissolution by influencing the nucleation and growth of crystals. However, there is limited evidence regarding the mechanisms by which polymers stabilize supersaturated drug solutions. The current study used experiments and computational modeling to explore polymer-drug interactions in aqueous solutions. Nucleation induction times for supersaturated solutions of nine drugs in the presence of five newly synthesized cellulose-based polymers were evaluated. The polymers had carboxylic acids substituents with additional variations in the side-chain structure: (1) one with a single side chain and a carboxylic acid termination, (2) three with a branched side chain terminated with a carboxylic and an alcohol group (varying the cellulose linkage and the length of the hydrocarbon side chain), and (3) one with a branched side chain with two carboxylic acid end groups. The polymers with a short side chain and one carboxylic acid were effective, whereas the polymers with the two carboxylic acids or a long hydrocarbon chain were less effective. Atomic force microscopy experiments, evaluating polymer adsorption onto amorphous drug films, indicated that the effective polymers were uniformly spread across the surface. These results were supported by molecular dynamics simulations of a polymer chain in the presence of a drug aggregate in an aqueous environment, whereby the effective materials had a higher probability of establishing close contacts and more negative estimated free energies of interaction. The insights provided by this study provide approaches to design highly effective polymers to improve oral drug delivery.

Multidrug, Anti-HIV Amorphous Solid Dispersions: Nature and Mechanisms of Impacts of Drugs on Each Other's Solution Concentrations.

Drug therapy has been instrumental in prolonging the lives of patients infected by human immunodeficiency virus (HIV). In order to combat development of resistance, therapies involving three or more drugs in combination are recommended by the World Health Organization (WHO) to suppress HIV and prevent development of acquired immune deficiency syndrome (AIDS). It is desirable for multidrug combinations to be coformulated into single dosage forms where possible, to promote patient convenience and adherence to dosage regimens, for which amorphous solid dispersion (ASD) is particularly well-suited. We investigated multidrug ASDs of three model anti-HIV drugs, ritonavir (Rit), etravirine (Etra), and efavirenz (Efa), in cellulosic polymer matrices. We hypothesized that the presence of multiple drugs would reduce crystallization tendency, thereby providing stable, supersaturating formulations for bioavailability enhancement. We explored new ASD polymers including cellulose acetate suberate (DSSub 0.9, CASub) and cellulose acetate adipate propionate (DSAd 0.9, CAAdP), and control commercial cellulosic polymers including 6-carboxycellulose acetate butyrate (CCAB) and carboxymethyl cellulose acetate butyrate (CMCAB). We succeeded in preparing three-drug ASDs containing very high drug loadings (45% drug total; 15% of each drug); each polymer tested was effective at stabilizing the amorphous drugs in the solid phase, as demonstrated by XRD, SEM, and DSC studies. In pH 6.8 dissolution studies ASDs released each anti-HIV drug over 8 h, affording supersaturated solutions of each drug, but unexpectedly failing in some cases to reach maximum possible supersaturation. In a second set of dissolution studies (pH 6.8), the cause of the observed solution concentration limitations was investigated by studying release from single- and two-drug ASDs. Concentrations of Rit, Etra, and Efa achieved from three-drug ASDs were higher than those achieved from crystalline drugs. Surprisingly, however, there was a decrease in the achieved drug concentrations of both Rit and Efa when they dissolved together, while Etra solution concentration was enhanced by the presence of Rit and Efa in the ASD. We demonstrate that these effects have to do primarily with solution phase interactions between the anti-HIV drugs, rather than from the drugs influencing each other's release rate, and we suggest that such observations may indicate an important, previously inadequately recognized, and general phenomenon for ASDs containing multiple hydrophobic drugs.

Olefin Cross-Metathesis in Polymer and Polysaccharide Chemistry: A Review.

Olefin cross-metathesis, a ruthenium-catalyzed carbon-carbon double bond transformation that features high selectivity, reactivity, and tolerance of various functional groups, has been extensively applied in organic synthesis and polymer chemistry. Herein, we review strategies for performing selective cross-metathesis and its applications in polymer and polysaccharide chemistry, including constructing complex polymer architectures, attaching pendant groups to polymer backbones and surfaces, and modifying polysaccharide derivatives.

An Efficient, Regioselective Pathway to Cationic and Zwitterionic N-Heterocyclic Cellulose Ionomers.

Cationic derivatives of cellulose and other polysaccharides are attractive targets for biomedical applications due to their propensity for electrostatically binding with anionic biomolecules, such as nucleic acids and certain proteins. To date, however, relatively few practical synthetic methods have been described for their preparation. Herein, we report a useful and efficient strategy for cationic cellulose ester salt preparation by the reaction of 6-bromo-6-deoxycellulose acetate with pyridine or 1-methylimidazole. Dimethyl sulfoxide solvent favored this displacement reaction to produce cationic cellulose acetate derivatives, resulting in high degrees of substitution (DS) exclusively at the C-6 position. These cationic cellulose derivatives bearing substantial, permanent positive charge exhibit surprising thermal stability, dissolve readily in water, and bind strongly with a hydrophilic and anionic surface, supporting their potential for a variety of applications such as permeation enhancement, mucoadhesion, and gene or drug delivery. Expanding upon this chemistry, we reacted a 6-imidazolyl-6-deoxycellulose derivative with 1,3-propane sultone to demonstrate the potential for further elaboration to regioselectively substituted zwitterionic cellulose derivatives.

Functionalized Celluloses with Regular Substitution Pattern by Glycosynthase-Catalyzed Polymerization.

Control of the monomer sequence in polymers is extraordinarily difficult by chemical synthesis, though Nature routinely exerts such control, including in the biosynthesis of polysaccharides. This inability has prevented us from being able to match the exquisite structure-activity control exhibited in biosynthesis of bioactive natural polysaccharides. We here address a powerful approach, whereby enzyme-catalyzed polymerization of properly modified building blocks is introduced as a simple route affording polysaccharides with controlled sequence and functionalization pattern. Targeting cellulose as a versatile scaffold for novel biomaterials, we describe the preparation of a perfectly alternating polysaccharide with repeat unit 6'-azido-6'-deoxycellobiose by a glycosynthase-catalyzed polymerization using the Humicola insolens cellulase Cel7B E197A mutant, and its further functionalization to give novel modified cellulose derivatives with a regular substitution pattern.

Amphiphilic Cellulose Ethers Designed for Amorphous Solid Dispersion via Olefin Cross-Metathesis.

The design of cellulose ether-based amphiphiles has been difficult and limited because of the harsh conditions typically required for appending ether moieties to cellulose. Olefin cross-metathesis recently has been shown to be a valuable approach for appending a variety of functional groups to cellulose ethers and esters, provided that an olefin handle for metathesis can be attached. This synthetic pathway gives access to these functional derivatives under very mild conditions and at high efficiency. Modification of ethyl cellulose by metathesis to prepare useful derivatives, for example, for solubility and bioavailability enhancement of drugs by amorphous solid dispersion (ASD), has been limited by the low DS(OH) of commercial ethyl cellulose derivatives. This is problematic because ethyl cellulose is otherwise a very attractive substrate for synthesis of amphiphilic derivatives by olefin metathesis. Herein we explore two methods for opening up this design space for ether-based amphiphiles, for example, permitting synthesis of more hydrophilic derivatives. One approach is to start with the more hydrophilic commercial methyl cellulose, which contains much higher DS(OH) and therefore is better suited for introduction of high DS of olefin metathesis "handles". In another approach, we explored a homogeneous one-pot synthesis methodology from cellulose, where controlled DS of ethyl groups was introduced at the same time as the ω-unsaturated alkyl groups, thereby permitting complete control of DS(OH), DS(Et), and ultimately DS of the functional group added by metathesis. We describe the functionalized derivatives available by these successful approaches. In addition, we explore new methods for reduction of the unsaturation in initial metathesis products to provide robust methods for enhancing product stability against further radical-catalyzed reactions. We demonstrate initial evidence that the products show strong promise as amphiphilic matrix polymers for amorphous solid dispersion and other applications.

Mechanistic Design of Chemically Diverse Polymers with Applications in Oral Drug Delivery.

Polymers play a key role in stabilizing amorphous drug formulations, a recent strategy employed to improve solubility and bioavailability of drugs delivered orally. However, the molecular mechanism of stabilization is unclear, therefore, the rational design of new crystallization-inhibiting excipients remains a substantial challenge. This article presents a combined experimental and computational approach to elucidate the molecular features that improve the effectiveness of cellulose polymers as solution crystallization inhibitors, a crucial first step toward their rational design. Polymers with chemically diverse substituents including carboxylic acids, esters, ethers, alcohols, amides, amines, and sulfides were synthesized. Measurements of nucleation induction times of the model drug, telaprevir, show that the only effective polymers contained carboxylate groups in combination with an optimal hydrocarbon chain length. Computational results indicate that polymer conformation as well as solvation free energy are important determinants of effectiveness at inhibiting crystallization and show that simulations are a promising predictive tool in the screening of polymers. This study suggests that polymers need to have an adequate hydrophilicity to promote solvation in an aqueous environment, and sufficient hydrophobic regions to drive interactions with the drug. Particularly, the right balance between key substituent groups and lengths of hydrocarbon side chains is needed to create effective materials.