Advances in Polymer Design for Enhancing Oral Drug Solubility and

Review Cite This: Bioconjugate Chem. XXXX, XXX, XXX−XXX

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Advances in Polymer Design for Enhancing Oral Drug Solubility and Delivery Jeffrey M. Ting,‡,⊥ William W. Porter, III,§ Jodi M. Mecca,∥ Frank S. Bates,‡ and Theresa M. Reineke*,† †

Department of Chemistry and ‡Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, Minnesota 55455, United States § Food, Pharma, and Medical and ∥Core Research and Development, The Dow Chemical Company, Midland, Michigan 48674, United States ABSTRACT: Synthetic polymers have enabled amorphous solid dispersions (ASDs) to emerge as an oral delivery strategy for overcoming poor drug solubility in aqueous environments. Modern ASD products noninvasively treat a range of chronic diseases (for example, hepatitis C, cystic fibrosis, and HIV). In such formulations, polymeric carriers generate and maintain drug supersaturation upon dissolution, increasing the apparent drug solubility to enhance gastrointestinal barrier absorption and oral bioavailability. In this Review, we outline several approaches in designing polymeric excipients to drive interactions with active pharmaceutical ingredients (APIs) in spray-dried ASDs, highlighting polymer−drug formulation guidelines from industrial and academic perspectives. Special attention is given to new commercial and specialized polymer design strategies that can solubilize highly hydrophobic APIs and suppress the propensity for rapid drug recrystallization. These molecularly customized excipients and hierarchical excipient assemblies are promising toward informing early-stage drug-discovery development and reformulating existing API candidates into potentially lifesaving oral medicines for our growing global population.

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INTRODUCTION In the controlled drug delivery landscape, polymers have played a long-standing role as encapsulating drug carriers in medicinal chemistry, biotechnology, and pharmacology. This is especially pertinent for oral drug delivery, the leading route of administration worldwide due to high patient compliance, affordability, and acceptance. Recent trends show that the highest fraction of drugs succeeding past clinical trials and awaiting regulatory approval are administered via oral routes.1 Inside these tablet and pill formulations, therapeutically inert additives, known as excipients, often include polymers that promote storage and delivery; excipients protect the shelf life of an active pharmaceutical ingredient (API) for long-term use and govern the subsequent controlled release to reach biological targets in the body. Well-defined polymeric attributes can be directly tailored toward APIs in excipients to achieve high drug safety, performance, and quality in oral drug formulations, which can ultimately decrease costs to manufacture and increase likelihood of approval. In oral drug delivery, the bioavailability of APIs is contingent on absorption through the gastrointestinal (GI) tract. For this biological barrier, the Biopharmaceutics Classification System (BCS) provides a framework for relating oral drug absorption to gastric permeability and solubility (Figure 1).2 Marketed drugs show a fairly uniform distribution between the drug classifications, with BCS Class I compounds (high permeability and high solubility) expectedly ranking the highest.3 However, a © XXXX American Chemical Society

troubling disconnect for new pipeline drug candidates is also reported. Only 5−10% of potential drug candidates fall under Class I, and the vast majority (60−70%) are Class II (high permeability and low solubility). It is also important to note that up to 90% of pipeline drugs are in the Class II and Class IV (low solubility and low permeability) categories, where APIs have poor solubility and, therefore, are unreliable in performance and in clinical response. What is the cause of this surprising discrepancy in modern drug discovery? Biomedical and pharmaceutical drug discovery research efforts have been heavily influenced by genomics and molecular biology to adopt automated high-throughput screening (HTS), combinatorial chemistry, and computational drug design methodologies. From the 1990s to 2000s, the capacity of pharmaceutical companies to generate “data points” of molecular targets and compounds grew prolifically from 200 000 to >50 000 000.4 Many promising HTS leads for treating diseases exhibit high drug potency, wherein the driving force of drug-receptor binding is often composed of hydrophobic interactions.5 Consequently, many of these pipeline drugs possess high hydrophobicity (or lipophilicity), limiting their oral delivery applicability. This trend over the past decades has been accompanied by relatively stagnant federal approval of Received: October 24, 2017 Revised: December 11, 2017

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DOI: 10.1021/acs.bioconjchem.7b00646 Bioconjugate Chem. XXXX, XXX, XXX−XXX

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Figure 1. Solubility challenges that plague the oral drug-delivery frontier. The Biopharmaceutics Classification System (BCS) uses drug permeability and solubility as metrics for oral absorption. The four categories include BCS Class I (blue: high solubility, high permeability), Class II (red: low solubility, high permeability), Class III (green: high solubility, low permeability), and Class IV (yellow: low solubility, low permeability). The circle charts to the right show the estimated distribution of marketed and pipeline drugs by BCS classes. The pharmaceutical company data in the circle charts is adapted from ref 3.

reducing the rate of early-stage API attrition11 and (ii) reformulating APIs with suboptimal properties and lost opportunities for oral delivery. Special emphasis is placed on two broad categories in excipient discovery to combat low oral drug absorption: molecular-customized excipients and hierarchical excipient assemblies. Representative examples of these ideas will be highlighted in this Review alongside a brief account of commercial ASD polymers and products that have been successful. We limit our focus to spray drying as a method by which to prepare amorphous solid dispersions (ASDs) but note that the underlying concepts are readily translated to other modes of delivery. Spray drying is a solvent evaporation process in which a polymer−drug solution mixture is converted to a solid mixture using heated inert gas in an evacuated chamber. With process control over spray-drying heating and flow-rate parameters, this technique can be operated to produce material from the milligram to metric ton-scale quantities of consistent material and appreciable yields.12 However, spray drying is not the only method to produce ASDs. For example, hot-melt extrusion (HME) is a viable technology that employs thermal processing of polymers and crystalline drugs. Numerous reviews of this subject have been published elsewhere.13−16 Compared to HME, spray drying can be advantageous if the API or excipient degrades at high processing temperatures or if the API is prohibitively expensive during preclinical development. Williams et al. have chronicled the rise of solubility and dissolution enhancement techniques for poorly water-soluble drugs, which includes an account comparing how pharmaceutical products have adapted solid-dispersion technology as well as other solubility-enhancing techniques over time.17 Additional perspectives on techniques commonly employed to alter the solubility of an API including particle-size reduction,18,19 prodrugs,20,21 polymorphism expression, and co-crystal formation,22,23 lipid-based formulation,24,25 and cyclodextrin complexation26,27 also exist and will not be discussed here. These selected works provide a greater overview of the current oral drug delivery field and cover additional aspects of solubility enhancement. We conclude this Review by suggesting how predictive polymer design, in tandem with advanced characterization techniques, can serve to inform more-successful oral formulations for innovating future medicines.

new drugs. In 2016, only 22 new drugs were approved, the lowest in recent years,6 and the return on investment for R&D expenditure continued to drop to only 3.7%.7 Moreover, the U.S. Government Accountability Office reported a 10 000:1 attrition rate of drug candidates from early stage drug discovery to clinical trials and federal review and approval.8 This has led to tremendous concern over the low research and development productivity coupled with enormous developmental costs in the current pharmaceutical space.9,10 Herein, we discuss precision drug formulation as a potential solution for addressing this difficult drug translation problem, particularly for the solubility problems of BCS Class II drugs (Figure 2). This expression describes how polymers can be rationally designed with specific delivery modalities and harnessed as new excipients to provide insight into what molecular-level attributes can best enhance drug bioavailability. In other words, emphasis is placed on converging polymeric excipient discovery with drug discovery efforts in pursuit of (i)

Figure 2. Illustrative overview of how the convergence of excipient discovery with drug discovery can accelerate precision drug formulations through the pharmaceutical pipeline. For amorphous spray-dried dispersions strategies, knowledge of physiochemical properties for promising active pharmaceutical ingredients can inform the design of molecularly customized excipients or hierarchical excipient assemblies to solubilize otherwise intractable drug candidates. Examples of these excipients are the focus of this Review. Estimated drug attrition data from the U.S. Government Accountability Office are from ref 8. B

DOI: 10.1021/acs.bioconjchem.7b00646 Bioconjugate Chem. XXXX, XXX, XXX−XXX

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AMORPHOUS SPRAY-DRIED SOLID DISPERSIONS In pharmaceutical applications, solid dispersions are typically solid−solid mixtures of drug and polymer. These blended materials can raise the apparent solubility of a drug in solution by orders of magnitude above its equilibrium concentration by maintaining drug molecules at supersaturation.28 Because there is no longer an energetic penalty necessary to disrupt a crystal lattice, i.e., heat of fusion, amorphous drugs can readily interact with surrounding solvent (and the excipient structure) to become solubilized for gastric absorption. The atomization process of spray drying may also impart additional benefits. For instance, the blend of polymer and drug can reduce the effective drug particle size and induce internal particle porosity, thereby increasing the wettability and dissolution rate.29 Furthermore, ASDs have shown distinct advantages over other oral administration strategies for poorly soluble APIs. In one study with an anticancer drug etoposide, ASD formulations exhibited no loss of in vitro permeability through an artificial membrane compared with cyclodextrin, co-solvent, and surfactant-stabilization methods.30 Because an oral drug must first readily dissolve to achieve controlled levels of solubility in the blood, both solubility and permeability are critical factors for achieving effective, reliable, and safe oral administration. However, while the kinetically trapped amorphous state of a drug facilitates supersaturation, it also provides a thermodynamic driving force for precipitation (phase separation, crystallization, etc.). Therefore, an ideal polymeric excipient inhibits such pathways by generating and maintaining supersaturation with noncovalent, stabilizing interactions. The illustration in Figure 3 schematically depicts this concept, often described in the context of a “spring−parachute” analogy.17,31,32 Amorphous drug molecules are the “spring” relative to their crystalline counterparts, while the stabilizing polymer excipient acts as a “parachute” upon drug dissolution

and supersaturation generation to increase the absorption of drugs across the gastrointestinal barrier. In these plots, the area under the dissolution curve (AUCdiss) provides a metric of apparent oral bioavailability. Given the spring−parachute relationship for ASDs, the physical stability of these particles in the solid form is crucial to the formulation shelf life and downstream dissolution performance. The degree of drug amorphicity or crystallinity can be quantified using calorimetric and diffraction techniques, which allows investigators to probe effects of humidity,33 drug molecular mobility,34,35 and material processing. Comprehensive sets of reviews examining solid-state characterization are also important toward developing ASDs and can be found elsewhere.36,37

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COMMERCIAL POLYMERS FOR SOLID-DISPERSION FORMULATIONS In solid oral formulations, there are numerous pharmaceutical excipients approved by the United States Pharmacopeia (USP).38 Amorphous drug products on the market often contain naturally derived or synthetic polymers as inert additives to increase their bioavailability. Table 1 contains a summary of commercial amorphous drug products, compiled from literature sources17,39−42 and organized chronologically by Food and Drug Administration (FDA) approval. Although many of the same excipient(s) recur between these products, the diseases that these medications treat differ widely and include cancer, hypertension, and HIV. Thus, ASDs are versatile in allowing researchers across medical fields to broadly address oral solubility needs. Commercially available and FDA-approved polymeric excipients for solubilizing hydrophobic drugs include synthetics and cellulosics, many of which have been reviewed indepth,43,44 such as polyvinylpyrrolidone (PVP), polyvinylpyrrolidone−vinyl acetate (PVP−VA) or methacrylate (p(MAA− co-MMA)) copolymers, hydroxypropyl methylcellulose (HPMC), and hydroxypropyl methylcellulose acetate succinate (HPMCAS). As shown in Figure 4, these excipients range in chemical diversity to accommodate a wide spectrum of structurally-diverse drugs as ASDs. In addition, new commercial excipients that are not compendial (approved for use by regulatory standards) remain an important area of research and are being pursued. Prominent examples include a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer45 or variants of HPMC.46 Additionally, blends of the above excipients have also shown promise with several APIs,47,48 offering the potential of multidrug delivery for combination therapy treatments. In the following section, we group the most-common synthetic and cellulosic polymers together, summarize their marketed availability, and briefly discuss their properties and applications in the oral drug delivery space. Synthetics. PVP (or synonymously referred to as povidone in the literature) is a neutral homopolymer synthesized using free-radical polymerization of N-vinylpyrrolidone. Pharmaceutical grades of PVP are available from manufacturers such as BASF (Kollidon) and Ashland (Plasdone). In these popular excipient products, the pharmaceutical grades of PVP are available in a range of molecular weights, labeled according to kinematic viscosity (referred to by the USP Convention Kvalue nomenclature) in aqueous solution.49 In general, higher K-values correspond to higher molecular weight and glass transition temperature (Tg) values. These parameters are important in ensuring the processability and shelf life of ASD

Figure 3. Schematic of drug dissolution over time illustrating how solid dispersions enhance the apparent drug solubility. In the plot, purple curves represent polymer, yellow circles depict amorphous drug molecules, and yellow hexagons denote crystallized drug molecules. With a precipitation-inhibiting polymer, supersaturation of amorphized drug can be maintained (green curve, high concentration plateau). With a nonideal polymer, desupersaturation depletes suppressant drug content (orange dashed curve, decreasing concentration). For hydrophobic crystalline drug molecules, limited absorption across the gastrointestinal barrier can occur (red dotted curve, low concentration plateau). C

DOI: 10.1021/acs.bioconjchem.7b00646 Bioconjugate Chem. XXXX, XXX, XXX−XXX

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Bioconjugate Chemistry Table 1. Examples of Commercial Amorphous Drug-Delivery Products by FDA Approval Date trade name

treatment

excipient(s)a

drug(s)

ISOPTIN-SRE

anti-hypertensive

Verapamil

HPC/HPMC

Cesamet

anti-emetic, analgesic

Nabilone

PVP

Nivadil

Nilvadipine

HPMC

Sporanox

anti-hypertensive, major cerebral artery occlusion antifungal

Itraconazole

HPMC

PROGRAF

immunosuppressant

Tacrolimus

HPMC

REZULIN Afeditab

anti-diabetic anti-hypertensive

Troglitazone Nifedipine

GRIS−PEG

antifungal

Griseofulvin

PVP PVP or poloxamer PEG

Nimotop KALETRA

anti-hypertensive HIV

Fenoglide

anti-cholesterol

Nimodipine Lopinavir, Ritonavir Fenofibrate

INTELENCE NORVIR ONMEL

HIV HIV antifungal

Etravirine Ritonovir Itraconazole

CERTICAN and ZORTRESS INCIVEK

immunosuppressant

Everolimus

HPMC PVP−VA PVP−VA or HPMC HPMC

antiviral: hepatitis C

Telaprevir

HPMCAS

ZELBORAF KALYDECO

melanoma skin cancer cystic fibrosis

Vemurafenib Ivacaftor

HPMCAS HPMCAS

NOXAFIL

antifungal

Posaconazole

HPMCAS

PEG PVP−VA PEG

manufacturer (year/method) Abbott Laboratories (1981/melt extrusion) Valeant Pharmaceuticals (1985/melt extrusion) Fujisawa Pharmaceutical Co., Ltd. (1989/ not available) Janssen Pharmaceuticals (1992/spray layering) Astellas Pharma US, Inc. (1994/spray drying) Pfizer/Parke-Davis (1997/melt extrusion) Elan/Watson (2000/melt or absorb) Pedinol Pharmacal Inc., Novartis (2003/ melt extrusion) Bayer (2006/spray drying) AbbVie Inc. (2007/melt extrusion) Veloxis Pharmaceuticals (2007/spray melt) Tibotec, Janssen (2008/spray drying) AbbVie Inc. (2010/melt extrusion) GlaxoSmithKline, Stiefel (2010/melt extrusion) Novartis Pharmaceuticals (2010/spray drying) Vertex Pharmaceuticals, Janssen (2011/ spray drying) Roche (2011/co-precipitation) Vertex Pharmaceuticals (2012/spray drying) Merck (2013/melt extrusion)

ref 17, 39−42 17, 39−42 17, 39−42 17, 39−42 17, 39−42 17, 39, 40, 42 40, 42 17, 39, 40, 42 42 17, 39−42 42 17, 39, 41, 42 17, 40−42 40−42 17, 39−42 17, 40−42 17, 40−42 40−42 41, 42

a

Polymer abbreviations include poly(vinylpyrrolidone) (PVP), polyvinylpyrrolidone−vinyl acetate co-polymers (PVP−VA), variants of poly(ethylene glycol) (PEG), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and hydroxypropyl methylcellulose acetate succinate (HPMCAS).

products. In the commercial oral products tabulated in Table 1, PVP has been used to formulate solid dispersions with troglitazone (REZULIN, prescribed to patients with diabetes mellitus type 2) and nabilone (CESAMET, administered to treat neuropathic pain).43 In the REZULIN formulations, troglitazone served to decrease insulin resistance, but this was withdrawn by the FDA due to hospitalization and acute liver failure.50 For nabilone with PVP, in vivo pharmacological response upon administration to dogs within 3−5 h was reported, which was attributed to PVP disrupting the intramolecular hydrogen bonding interactions of nabilone based on solvent selection for evaporation.51 Beyond homopolymers like PVP, several copolymers have also been approved for pharmaceutical use. Many of these systems offer additional tunable parameters, such as excipient amphiphilicity with PVP−VA or pH responsivity with p(MAA−co-MMA). Pharmaceutical grades of PVP−VA (or sometimes referred to copovidone in the literature) are available from BASF as Kollidon VA64 and from Ashland as Plasdone. Varying the composition of N-vinylpyrrolidone and vinyl acetate in these neutral copolymers effectively increases polymer hydrophobicity and reduces the Tg to the range of 103−106 °C.52,53 Marketed APIs with copovidone in ASDs include KALETRA and NORVIR (lopinavir with ritonavir and ritonavir, respectively).54 These first-line therapy drugs for HIV are on the World Health Organization’s List of Essential Medicines,55 prompting subsequent studies to boost oral bioavailability with new designer excipients.56−58

Figure 4. Chemical structures of four common excipients that are approved for use by regulatory agencies and are frequently used for amorphous solid dispersions. Shown here are (A) polyvinylpyrrolidone (PVP), (B) polyvinylpyrrolidone−vinyl acetate copolymers (PVP−VA), (C) methacrylate copolymers (p(MAA-co-MMA)), and (D) cellulosic polymers such as hydroxypropyl methylcellulose (HPMC, where R groups represent −H, −CH3, −CH2CH(OH)CH3, or −CH2CH(OCH3)CH3) and hydroxypropyl methylcellulose acetate succinate (HPMCAS, where R groups represent −H, −CH3, −COCH3, −COCH2COOH, or −CH2CH(OH)CH3).

D

DOI: 10.1021/acs.bioconjchem.7b00646 Bioconjugate Chem. XXXX, XXX, XXX−XXX

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second two numbers denote the weight percent of hydroxypropyl on the cellulose backbone. Within in each grade of HPMC, there are multiple viscosity grades that impact the dissolution rate of the polymer. Over the range of available viscosity grades of HPMC, the Tg is reported to be in the range of 155−180 °C.69 In part, the high Tg of HPMC is attributed to its effectiveness as an ASD excipient candidate63 providing general physical stability for ASDs. However, it can also limit its processability at industrial scale. For use in solubility-enabling formulations, HPMC 2910 has had the largest impact, as it has better overall solubility in a variety of solvents, enabling greater selection of spray-drying solvents.70 This grade has demonstrated the capability of producing supersaturated solutions71 and retarding the nucleation of crystalline APIs.57 This has resulted in a large number of commercial drug products, such as SPORANOX (itraconazole), PROGRAF (tacroimus), and INTELENCE (etravirine) as listed in Table 1. Recently, The Dow Chemical Company introduced a new grade of HPMC (AFFINISOL HPMC HME), which is outside of the compendia ranges for hydroxypropyl and methoxy substitution. This material has demonstrated the ability to form ASDs, suppress drug nucleation,63 and increase processability due to a reduced Tg of 115 °C.72 In addition to improved thermal processing, the AFFINISOL HPMC HME polymer has higher solubility in organic solvents, making it highly amenable for spray-drying applications as well. Also demonstrating great utility for solubility-enabling formulations, HPMCAS is produced by the esterification of HPMC with acetic acid anhydride and succinic acid anhydride.73 First introduced by Shin Etsu as AQOAT, HPMCAS was originally used for enteric coating applications.74 More recently, Ashland has announced AquaSolve HPMCAS, and The Dow Chemical Company has launched AFFINISOL HPMCAS, with these new manufacturers of HPMCAS entering the market to target solubility-enhancing formulations.75,76 There are three grades of HPMCAS (varying in acetate and succinate substituents) commercially available: HPMCAS 716, HPMCAS 912, and HPMCAS 126, where 7, 9, and 12 represent the acetate content and 16, 12, and 6 represent the succinate content. The ideal physical properties of HPMCAS, such as a relatively low Tg (∼120 °C), amphiphilic nature, broad organic solvent solubility, and ability to ionize, make it a powerful, modular polymer for solubility enhancement applications for a wide portfolio of hydrophobic drug candidates. HPMCAS was discovered to have great utility in solubilizing compounds with poor aqueous solubility compounds in a joint research effort between Bend Research and Pfizer Inc.77 By formulating the polymer with the active drug via spray drying, HPMCAS was demonstrated to offer unique effectiveness for enabling solubility enhancement and preventing nucleation across a broad range of API structures and properties. Here, among six low-solubility drug candidates synthesized by Pfizer (ranging from solubility of 0.004 to 80 μg/mL in water) and three BCS Class II drugs (griseofulvin, nifedipine, and phenytoin), Curatolo et al. concluded that spray-dried dispersions with HPMCAS demonstrated superior solubilization abilities compared with 41 tested excipients, including PVP, HPMC, and its variants.64 In another comprehensive study by Friesen et al., 139 poorly soluble drugs were screened followed by in vitro and in vivo testing. A relationship between the ratio of the API melting temperature (Tm) to Tg and the lipophilicity (log P) was proposed to allow optimal drug

Ionic copolymer excipients are also used in several ASD products. The most-prominent example of this includes a series of methacrylate-based polymers available from Evonik under the trade name Eudragit. These polymers are derived from the copolymerization of (meth)acrylic acids with amino alkyl methacrylates, methacrylic esters, or ammonioalkyl methacrylates. While some types of these polymers can be formulated to be pH-independent, the majority of solubility enhancement research has focused on the pH-dependent polymers in this class. Eudragit L 100 and S 100 are used most often and differ in degree of ionizable carboxylic acid incorporation to control drug delivery. Comparatively, Eudragit L 100 has a greater composition of carboxylic groups and, therefore, begins to swell and dissolve at lower intestinal pH levels. For example, Maghsoodi and Sadeghpoor studied solid-dispersion microparticles of Eudragit S 100 and nonsteroidal anti-inflammatory drug piroxicam at various drug loadings and showed a considerable dissolution dependency between pH 1.2 and 7.4 for in vitro drug release studies.59 This demonstrates how drug release can be formulaically adjusted by regulating the excipient ionizable content in solid dispersions to control the dissolution rate of drugs. Finally, more structurally intricate excipients have been thoroughly investigated in the past decade. Although commercially available from BASF, Soluplus (a polyvinyl caprolactam−polyvinyl acetate−polyethylene glycol graft copolymer) has not yet been used in a commercially approved pharmaceutical product. This excipient has demonstrated versatility as a solubility enhancer for BCS Class II compounds danazol, fenofibrate, and itraconazole during in vitro Caco-2 permeability and in vivo dog model studies.60 In addition to having a record of providing solubility enhancement, Soluplus has gained popularity for pharmaceutical research purposes due to its ease in use for spray drying and HME, imparted by its relatively low Tg (70 °C).61 Cellulosics. Cellulose is a natural-occurring stereoregular polysaccharide consisting of β(1 → 4) linked D-glucose (anhydroglucose) monomers. As processed from plants, cellulose typically has a molecular weight greater than 1 × 106 Daltons.62 Cellulose has three hydroxyl groups per repeat unit that are readily functionalized to yield a wide range of pharmaceutically approved polymers, such as methylcellulose, cellulose acetate phthalate, HPMC, and HPMCAS. Although many of the cellulosics have been utilized as enabling polymers for solubility enhancement, HPMC and HPMCAS have had the greatest amount of interest and success.63−66 Beyond the pharmaceutically approved derivatives of cellulose, several studies suggest that cellulose polymers with optimized designs for solubility enhancement show superior supersaturation properties compared with their commercial counterparts.46,57 HPMC has been regularly employed in oral drug delivery as coatings and modified-release matricies.67 This hydrophilic polymer is produced by the reaction of cellulose with methyl chloride, propylene oxide, and caustic soda. Globally, commercial HPMC is provided by a myriad of providers; however, the current leaders are Ashland (Benecel), The Dow Chemical Company (METHOCEL), and Shin Etsu (METOLOSE).68 The level of hydroxypropyl and methoxy added to the cellulose is defined by the USP monograph, which results in four distinct grades of HPMC for pharmaceutical applications: HPMC 1828, HPMC 2208, HPMC 2906, and HPMC 2910. Here, the first two numbers in the brand name describe the weight percent of methoxy on the cellulose backbone, and the E

DOI: 10.1021/acs.bioconjchem.7b00646 Bioconjugate Chem. XXXX, XXX, XXX−XXX

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Bioconjugate Chemistry

Figure 5. Olefin cross-metathesis represents a versatile technique to selectively functionalize polysaccharides for amorphous solid-dispersion applications. In this representative three-step reaction, commercial methylcellulose (MC1.82, where the degree of CH3 substitution is 1.82) was etherified with 5-bromo-pent-1-ene (structures in blue), metathesized with an assortment of monomer partners (structures in red), and hydrogenated to form saturated cellulose ethers with terminal acid or ester functional groups. Similarly, this synthesis scheme was also extended to ethyl cellulose. Reprinted with permission from ref 83. Copyright 2016 American Chemical Society.

loading to be predicted for ASD solid-state formulation.78 APIs with a low Tm-to-Tg ratio (