Pharmaceutical Applications of Cellulose Ethers and Cellulose Ether

Subscriber access provided by Kaohsiung Medical University

Review

Pharmaceutical Applications of Cellulose Ethers and Cellulose Ether Esters Hale Cigdem Arca, Laura I. Mosquera-Giraldo, Vivian Bi, Daiqiang Xu, Lynne S. Taylor, and Kevin J. Edgar Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.8b00517 • Publication Date (Web): 05 Jun 2018 Downloaded from http://pubs.acs.org on June 5, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

Pharmaceutical Applications of Cellulose Ethers and Cellulose Ether Esters

Hale Cigdem Arca1,2, Laura I. Mosquera-Giraldo4, Vivian Bi3, Daiqiang Xu3, Lynne S. Taylor4, and Kevin J. Edgar1,2*

1

Macromolecules and Interfaces Institute, Virginia Tech, Blacksburg, VA 24061, USA

2

Department of Sustainable Biomaterials, Virginia Tech, Blacksburg, VA 24061, USA

3

Ashland Specialty Ingredients, 500 Hercules Rd., Wilmington, DE 19808, USA

4

Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN

47907, USA

*Corresponding author, E-mail: [email protected]; Tel: 1.540.231.0674 Abstract 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 US 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,

1 ACS Paragon Plus Environment

Biomacromolecules 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 81

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. Introduction Commercial cellulose ethers are widely used and extremely valuable in pharmaceutical applications, playing roles from the rather straightforward (e.g., as coatings that control rate of release by their rate of dissolution), to the highly complex and challenging (e.g., enhancing solubility and bioavailability of otherwise poorly soluble drugs). We focus herein on current commercial cellulose ethers and those that were manufactured in the recent past, and include some important cellulose ether esters. We further choose to focus herein on pharmaceutical applications, while recognizing that cellulose ethers are useful in many other non-pharma applications. We begin the review in Section 1 by discussing the general chemistry of cellulose and cellulose ethers, then giving a brief overview (Section 1.4) of some of the most important pharmaceutical applications. Then in Section 2 we discuss the most important cellulose ether types individually, since they differ significantly from one another in terms of structure, properties, and application areas; in Section 3 we similarly consider cellulose ether esters. Finally we provide in Section 4 a future outlook for cellulose ethers, in particular for pharmaceutical applications. 1. Cellulose and cellulose ethers overview 1.1 Cellulose and processing: Cellulose is an abundant, naturally-occurring biopolymer, with a linear polymer chain comprising entirely glucopyranose monosaccharides 2 ACS Paragon Plus Environment

Page 3 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

(anhydroglucose units, or AGU) linked by equatorial 1,4-glycosidic bonds without any branching (repeat unit →4)-β-D-Glcp-(1→). These rather rigid chains have the ability to hydrogen bond to one another, and can pack tightly into a crystal lattice1. Cellulose has good mechanical properties (Young’s modulus as high as 15 GPa)2, biocompatibility with many tissues including those of the gastrointestinal (GI) tract, and is the polymer standard for biodegradability3,4, being mineralized to CO2 and water. Despite being entirely biodegradable, cellulose cannot be metabolized by humans and is poorly absorbed from the GI tract5. The renewable nature, low toxicity, and strength properties of cellulose make it an important biomaterial. Due to its hydrophilic nature and crystalline structure, cellulose is not soluble in water, or in any single organic solvent, and cannot be melt-processed because it decomposes before melting4. Chemists have addressed these poor processing issues of infusible, insoluble cellulose by utilizing its hydroxyl groups at the 2-, 3- and 6-positions for appending substituents, creating derivatives with much different physical properties than those of crystalline cellulose6. Etherification and esterification are the most common methods used to enhance cellulose processability and properties. Solubility properties of derivatives are frequently improved vs. cellulose, permitting processing into various forms such as fibers, coatings, or particles, and thus opening up the potential for a variety of applications. Cellulose esters, because of how they are most often manufactured (peracylation followed by hydrolysis to the desired DS), tend to have a high DS of a relatively hydrophobic substituent, good organic solvent (but not water) solubility, and thermoplasticity; cellulose ester properties and applications have been summarized previously7. Cellulose ethers are manufactured in different fashion, by direct etherification to the desired DS. These DS targets are often lower, leading to more water-soluble derivatives. As a result, they are designed for different commercial applications; in particular, they are important materials for 3 ACS Paragon Plus Environment


Page 4 of 81

pharmaceutical applications where water affinity can be a great advantage. Cellulose ethers, and especially their pharmaceutical applications, have not been the topic of comprehensive recent scientific review8–10. Rinaudo has written an insightful recent review on the chemistry and applications of methyl cellulose11. We attempt herein to provide a broad review of pharmaceutical applications and structure-property-function relationships of cellulose ethers and ether esters. 1.2 Cellulose ether chemistry: Cellulose ethers are polymers typically prepared by nucleophilic reaction of cellulose hydroxyl groups with electrophiles such as alkyl halides or epoxides. They find use in a wide range of applications including as thickeners, binders, lubricants, emulsifiers, rheology modifiers, and film formers in many industries including food12,13, pharmaceuticals8 and personal care products14, oil field chemicals15, construction16, paper17, adhesives18, batteries19, and textiles20. Among commercial cellulose ethers, carboxymethyl cellulose (CMC) is most heavily used worldwide (over half of the total cellulose ether consumption). Methyl cellulose (MC) and its derivatives have the second largest consumption by volume21. We will discuss the general characteristics of cellulose ethers, their preparation chemistry, and how these afford properties that influence pharmaceutical applications in particular.

Theoretically, all three hydroxyl groups of cellulose per anhydroglucose unit (AGU) can be fully etherified, resulting in a degree of substitution (DS) slightly in excess of 3.00 (considering that the end group hydroxyls at C1 and C4 can also be reacted), but frequently complete substitution is not achieved, either because it is not desirable due to the properties being targeted, and/or due to insufficient reactivity of cellulose hydroxyl groups. As noted above, the partially substituted cellulose ethers of commerce are obtained by being reacted 4 ACS Paragon Plus Environment

Page 5 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

directly to the desired DS. This has implications with regard to variability of DS along the chain of ethers vs. that observed for cellulose esters. In contrast to ether synthesis, the required back-hydrolysis reaction of cellulose triesters to the desired final DS is an equilibrium reaction that affords products that are believed to have relatively random distributions along and between the chains and between the hydroxyl groups of the monosaccharides. Detailed substituent distributions between and along chains of cellulose esters cannot be determined, and distributions among hydroxyl groups also cannot be determined when there are multiple substituent types, using current analytical methods. For commercial cellulose esters the investigator therefore infers random distributions from those analytical hints that are available22,23, from theory, and from product properties. In the case of cellulose ethers, where substituents are appended by ether bonds that are stable to hydrolytic conditions that cleave anomeric linkages (for example, trifluoroacetic acid (TFA)/water), other analytical tools are available that can shed light on these issues. Because of the heterogeneous nature of commercial cellulose etherification reactions (generally a slurry of cellulose in aqueous sodium hydroxide, sometimes with an alcohol diluent, along with the desired electrophile), reaction with the electrophile tends to proceed faster in areas of the cellulose fiber that are relatively amorphous, and more slowly in crystalline regions24. For this reason cellulose ethers, especially those with relatively low DS values, are believed to have relatively uneven distributions of substituents, with highly substituted and nearly unsubstituted regions existing on the same cellulose chain25. This has been shown with methyl cellulose by observing cellulose crystallinity (which must arise from unsubstituted regions26) even at DS(Me) of 1.0. In addition, Mischnick and her co-workers have demonstrated uneven substitution in some cases, by partial hydrolysis of cellulose ethers (TFA/water) to oligosaccharides, and comparison of the monosaccharide distribution 5 ACS Paragon Plus Environment


Page 6 of 81

vs. those expected from modeling hydrolysis of random, blocky, and other idealized structures27,28. These functionalization patterns along the cellulose chain have been investigated for various etherification reactions and conditions, since they impact polymer physical properties including solubility and gelation. Ether substituents may prevent crystallization or induce water solubility to different extents depending on whether they are randomly or heterogeneously distributed. Cellulose ether gelation may be induced by “junction zones” existing in the co-polymer, which are highly substituted, and so are able to engage in hydrophobic interactions in water to form a stable network29. While distribution of ether substituents is thus influential upon polymer properties, it can be somewhat challenging to study. Besides heterogeneity along the polymer chain or between polymer chains, the possibility also exists for heterogeneity with regard to position of substitution within the AGU30. The three cellulose hydroxyl groups at positions 2, 3, and 6 are chemically non-equivalent

to

one

another,

as

shown

in

Fig.

1.

CH2OR’ H

R = CH3, CH2CH3, CH2CO2X = Halide (typically Cl)

O R’O

OH

RX H

CH2OH 6 O

O 4 HO 3

OH

2 OH

O

1 n

n

OR’

NaOH, H2O

5

+ NaX

O

R’ = H, R

R

NaOH, H2O R = H, CH3

CH2OR’ H

O

O R’O

OH n

OR’

R O

R’ = H,

m

OH

R


Page 7 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

Figure 1. General commercial methods for preparation of cellulose ethers For the ideal case, it is assumed that the rates of reaction of all hydroxyl groups are unequal, but do not change throughout the reaction in spite of changes in local environment with partial substitution; this model was developed by Spurlin31. The monosaccharide content of a particular cellulose ether can usually be quantified, since complete TFA/water hydrolysis affords monosaccharides which may be analyzed by chromatographic techniques, and identified by comparison with authentic standards or by methods like mass spectrometry32. Since cellulose etherification is essentially irreversible, the monosaccharide composition of a cellulose ether directly and specifically reflects the results of competition between the three hydroxyl groups for a particular type and amount of electrophile. Detailed investigations of the monosaccharide compositions of various cellulose ethers prepared under different reaction conditions have shown that the cellulose hydroxyl groups do not possess equal reactivity towards electrophiles; in addition, substituents do in fact influence the reactivities of nearby hydroxyls, resulting in deviations from the Spurlin model33. Figure 2 illustrates various types of variations which may be observed from the Spurlin model, caused by solution vs. slurry reaction, variable accessibility of different areas of the fiber, and other conditions

or

morphological

features.



Page 8 of 81

Figure 2. Possible substituent distribution patterns (random, more heterogeneous, more regular, distorted, and bimodal) for a sample with DP 4 and substituent DS 1.5. n (R) is the number of substituents R. Amounts are given in mol% AGU. Adapted from ref. 28, Copyright 2010, with permission from Elsevier, Inc. Generally speaking the 2-OH is most reactive followed by the 6-OH; the order of these two may differ in some cases, but they are always more reactive than the 3-OH4. The observed order of reactivity is attributed to the fact that the 2-OH is more acidic (due to proximity to C1, the most electropositive carbon of the AGU) and the 6-OH is least sterically encumbered (wider available approach angles) resulting in the observed general reactivity order (O2 > O6 >> O3)34. Conventional cellulose etherification reactions with reagents that have wide approach angles usually provide products with at best only modestly regioselective substitution; protection and deprotection reactions, generally impractical in manufacturing processes, are required to obtain highly regioselectively substituted cellulose ethers35. This is 8 ACS Paragon Plus Environment

Page 9 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

significant since product properties can vary greatly depending upon position of modification36. The extent of an etherification reaction can be controlled by varying the temperature, catalyst, solvent system and the molar ratio of electrophile to AGU. Cellulose ethers are relatively stable under the required alkaline reaction conditions (although some loss in degree of polymerization (DP) occurs due to so-called alkaline peeling, in which one monosaccharide at a time is lost in a base-catalyzed reaction from the reducing end of the chain6). Molecular weight, DS (and molar substitution, MS, defined as number of substituents per monosaccharide, where appropriate (see section 2.4.1)), and position and pattern of etherification determine the properties of the product cellulose ether37. Often molecular weight has a greater effect on mechanical properties, while physical properties (e.g. solubility and water absorption) depend more upon the type of substituent and its DS18. 1.3 General properties: Cellulose ethers possess certain characteristic features that contribute to their value in pharmaceutical and other applications. Most commercial cellulose ethers are water-soluble, the exceptions being ethyl cellulose polymers with rather high DS(ethyl), and all have high affinity for water. Even those cellulose ethers that have hydrophobic substituents (e.g. methyl or ethyl) at low DS are water-soluble, since the substituents contribute to structural irregularity, impede hydrogen bonding, and thereby limit crystallinity, which is the main source of poor solubility for cellulose. Therefore these watersoluble ethers can be used to modify the rheology of aqueous solutions (e.g., the shearthinning properties of hydroxyethyl cellulose aqueous solutions contributing to both pigment dispersion at low shear and reduced brush drag at high shear, in latex paints)7. Commercial cellulose ethers tend to have high molecular weights and possess many hydrogen bond acceptors and donors, therefore violating at least three of Lipinski’s rules for ready permeation through the gastrointestinal (GI) epithelium38. As a result, cellulose ethers 9 ACS Paragon Plus Environment


Page 10 of 81

typically remain within the GI tract and are unlikely to permeate into the bloodstream. Cellulose ethers are also even more stable to ultraviolet (UV) radiation than are cellulose esters, since they do not possess ester chromophores14. Finally, commercial cellulose ethers typically possess some degree of amphiphilicity, due to the combination of hydrophilic OH groups and the hydrophobic backbone (and in some cases, substituents). Each cellulose ether type has other important properties that influence pharmaceutical usage, as will be discussed for individual cases below. We summarize (Table 1) composition and key physical properties of selected, representative cellulose ethers used in pharmaceutical applications.

Table 1. Selected, comparative properties of representative cellulose ethers used in pharmaceutical applications Cellulose

Substituent*

DS

MS

ether

Solubility (examples)

MC

Me

1.839

N/A

EC CMC

Et CM

2.639 0.9

N/A N/A

HPC

HP

2.241

4.4

HPMC

Me, HP

1.9142 0.23

Water, pyridine, DMAc, DMF Acetone, toluene, EtOH Water, mixtures of water with EtOH, acetone Water, MeOH, EtOH, iPrOH, pyridine, acetic acid, mixtures of water with EtOH, MeOH, or acetone Water, mixtures of water with EtOH, MeOH, or acetone, mixtures of CH2Cl2/EtOH MeOH, acetone, THF, CH2Cl2

Tg

SPa

1/2 (°°C) (MPa )

20040

25.02

140

19.85 33.18

130

24.88

164

23.88

Me, 1.87,42 120 21.73 HP, 0.25, Ac, 0.47, Su 0.40 Cellulose ether abbreviation definitions: MC methyl cellulose, EC ethyl cellulose, CMC carboxymethyl cellulose HPC hydroxypropyl cellulose, HPMC hydroxypropyl methyl cellulose, HPMCAS hydroxypropyl methyl cellulose acetate succinate. HPMCAS


Page 11 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

*Substituent shorthand: Me = CH3; Et = CH3CH2; CM = CH2CO2H; HP = CH2(CH3)CHOH; Ac = CH3CO; Su = CO(CH2)2CO2H. N/A not applicable. a Solubility parameters were calculated using the Fedor’s method43. The SP calculation procedure is described in detail in the Supporting Information in the paper by Dong et al. 39 1.4 Types of pharmaceutical application: Drug delivery systems have gained importance in medicine since the early 1970s, with polymers playing crucial roles, and cellulose derivatives being of special importance. Cellulose ethers are used in several types of pharmaceutical applications, including oral, transdermal, and transmucosal systems. Polymers must be biocompatible (defined as the ability of the material to invoke a tolerable host response upon application44) with the biological systems with which they come into contact; e.g. the GI enterocytes in the case of oral drug delivery. In addition, drug delivery follows the rule that “what goes in must come out”; polymers used in pharmaceutics must be cleared from the body, by degradation of the polymer into non-toxic and readily cleared materials, or by clearance intact from the body45. Cellulose ethers, as semi-synthetic polymers prepared from the natural polysaccharide cellulose, are usually suitable for oral4642,47–49, transdermal,50–52 or transmucosal52,53 drug delivery systems, but not for intravenous (IV) or inhalation applications since humans do not possess cellulase enzymes in circulation, and so cellulose ethers in the bloodstream cannot be broken down at an acceptable rate into fragments small enough to be cleared or metabolized.

1.4.1 Oral administration: Early attention focused on oral controlled release systems, which are designed to deliver drugs at controlled rate and duration while maintaining drug plasma concentrations at therapeutic levels. Controlled release systems may enable reduction in dosage frequency, thereby improving patient adherence to dosage regimes54. In controlled release systems, the cellulose ether may influence drug release rate by the rate of polymeric 11 ACS Paragon Plus Environment


Page 12 of 81

erosion/degradation, and/or by drug diffusion rate through the polymeric material, or through gels formed by contact of the material with water55. After release, polymeric delivery systems may also protect the drug from degradation or prevent drug crystallization. Cellulose ethers have found use as hydrophobic coatings that control rates of drug diffusion (e.g. EC), as amphiphilic matrices that form miscible blends with drug (e.g. HPC or HPMC), as pHresponsive release agents (e.g. CMCAB or HPMCAS), or as rapidly dissolving agents that accelerate pill disintegration (e.g. CMC).

1.4.1.1 Cellulose Ethers in Amorphous Solid Dispersions (ASDs): Drugs with low solubility (Biopharmaceutical Classification System Classes II and IV)56 present a great challenge to formulation scientists, since they often have poor and/or variable oral bioavailability57. As we summarize in this review, cellulose ethers and cellulose ether esters may be useful in ASD applications. We provide formulation details, and describe how ASDs can enhance solution concentration dramatically, especially for highly crystalline drugs, by eliminating drug crystallinity and stabilizing the amorphous drug against recrystallization both in the solid dispersion and after dissolution. In most ASDs, the drug is trapped in a thermodynamically unstable amorphous form, and accordingly tends towards recrystallization to reach the lower energy crystalline state. This tendency may lead to formulation stability problems58. Crystallization can occur either in the solid state during transport and storage of formulations, accelerated by exposure to high ambient moisture and/or temperature, or from solution (or drug-rich phases)59,60 after drug dissolution in the GI tract. In order to stabilize against crystallization, strong drug-polymer interactions are key, to overcome attractive forces between drug molecules and keep them separate61. Therefore, in this review we emphasize the ability of cellulose ethers to impart 12 ACS Paragon Plus Environment

Page 13 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

stability against drug crystallization. Cellulose ether physical properties are thoroughly described in the synthesis sections; these properties will strongly influence the type and extent of interaction with drug molecules. In addition to chemical interactions, high polymer Tg can also increase formulation stability in the solid state by limiting drug mobility, thus retarding recrystallization62. It is thus essential to have a formulation Tg higher than ambient temperature even in highly humid conditions, and even when the drug is a plasticizer for the polymer; this is promoted by high polymer Tg. Moreover, the polymer should prevent recrystallization after drug release in the GI tract for maximum bioavailability63. The polymer must therefore be at least partially soluble in the aqueous medium to permit stabilization against crystallization from solution. 1.4.2 Transdermal administration: Transdermal drug delivery systems have been in use for more than 40 years, initially being limited to a few compounds such as nitroglycerin64 and estradiol65. As transdermal technology improved, systems have been developed for a modest number of drugs, and transdermal patches have become a billion-dollar industry. The biggest advantage of transdermal systems is their ability to release a fairly constant amount of drug over a prolonged period. In this way narrow therapeutic windows (as with nitroglycerin) can be accommodated, and application frequency is low, enhancing patient convenience and compliance. Transdermal dosage forms are non-invasive and self-administered, enhancing patient appeal and reducing medical costs. They avoid the first pass effect of oral administration, in which absorbed drug first travels to the liver and is exposed to metabolic enzymes; likewise, exposure to stomach enzymes and low stomach pH is eliminated. Transdermal systems have the additional attraction that they can be readily removed if problems make it necessary to halt drug administration66. Cellulose ethers are most



Page 14 of 81

frequently used in transdermal systems as matrices or matrix additives to maintain drug distribution in the film, and to inhibit drug crystal formation. The stratum corneum layer of skin is an effective barrier against drug penetration. The resulting very slow passive permeation by most drug molecules is the primary limitation on development of transdermal systems; as a result, only about a dozen drugs have marketed transdermal forms. For drugs that do have adequate inherent skin permeation rates, the polymer components of the transdermal delivery system can strongly influence the rate of drug permeation through the skin, thereby controlling delivery rates67. Cellulose ethers can be used in the systems in various roles such as a skin adhesive68 or gelation agent69 as discussed in the following parts of this review. 1.4.3 Transmucosal administration: Transmucosal drug delivery systems are applied to promote drug delivery via nasal, rectal, vaginal, ocular, buccal, or sublingual mucosa for systemic or topical administration. Transmucosal administration has a number of advantages; it avoids the oral first pass effect, can afford enhanced permeation, and in some instances does not require sterile formulations. Mucosa are rich in blood supply, more permeable than the gastrointestinal epithelium and the stratum corneum, and have short recovery times after application stress or damage. The buccal mucosa for example is far more permeable than the skin70. In topically applied transmucosal systems cellulose ethers are sometimes used as bioadhesives, where the adhesion ability has been found to depend on polymer absorption of water from the mucosa and the pH of the target location, and frequently is greater for ionic polymers71. Bioadhesion is defined as attachment to a biological substrate that can


Page 15 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

prolong the contact time of the drug delivery system, and has been explored in both systemic and topical applications. While bioadhesion is a concept of uncertain value in oral delivery, where adhesion to mucus particles suspended in the GI lumen competes with adhesion to the mucus of the epithelium, it is valuable in transmucosal systems. In those systems, adhesion to the mucosa (e.g. nasal, vaginal, buccal, or ocular) keeps the drug in close proximity to the membrane which must be crossed. Typically in transmucosal systems, rapid clearance from the application site can be an issue (for example by the cilia of the nose72, or through tearing of the eye73), limiting and causing variability in the dose absorbed, but the high viscosity imparted by a water-soluble cellulose ether, in conjunction with any bioadhesive properties (e.g. for CMC) can help retain the dosage form in the proper location for a longer duration. Cellulose ethers have advantages as transmucosal formulation components, including the ability of most of them to increase aqueous solution viscosity, bioadhesive properties of some cellulose ethers, relative lack of toxicity, low bioavailability, and film-forming ability. In ocular delivery for example, the ability of cellulose ethers like HPMC to impart viscosity, or of ionic cellulose ethers like NaCMC to enhance bioadhesion, can help enhance the duration of corneal exposure to the drug, and therefore its uptake into the eye74. In some cases, blends have been investigated to combine, for example, the ability to enhance solution viscosity (e.g. MC) with the bioadhesive properties of some ionic polymers (e.g. poly(acrylic acid)73. Transmucosal formulations comprise an adhesive layer to attach to the wet mucous surface, and additive polymers that swell upon moistening. Depending on the design, at least one of the layers contains drug substances and, in response to polymer swelling or disintegration, drug is released over time75. In addition to the slow release, cost, and convenience advantages previously mentioned, for certain maladies transmucosal delivery can be an extremely helpful, critically important treatment modality. 15 ACS Paragon Plus Environment


Page 16 of 81

Examples include neurodegenerative diseases (such as advanced Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, spinal muscular atrophy, multisystem atrophy and Friedreich's ataxia), or brain injury. For these patients, oral drug administration is a challenge, and thus transmucosal formulations may be more suitable, providing prolonged release that may provide faster uptake and work for a much broader variety of drugs than transdermal patches.76

2. Common Types of Cellulose Ethers; Syntheses, Properties, and Applications We discuss each of the important commercial cellulose ether classes; CMC, MC, EC, HPC, and HPMC. Cellulose ether esters including HPMCAS and carboxymethyl cellulose acetate butyrate (CMCAB), which are of growing interest for applications involving enhancement of solution concentrations of otherwise poorly water-soluble drugs, will be discussed in Section 3.

2.1 Sodium Carboxymethyl Cellulose (NaCMC) CH2OH H

ClCH2COONa

O

O HO

OH n

CH2OH H

O

O NaOH, H2O

HO

OH n

OH

NaCMC

OCH2CO2Na

Figure 3. NaCMC synthesis and structure. This structure and others in this review are not meant to indicate regioselective substitution; depictions of substituent location are merely for convenience and clarity of depiction.


Page 17 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

2.1.1 NaCMC Synthesis and General Polymer Properties NaCMC is a commercial, physiologically inert, water-soluble, polyanionic derivative of cellulose. The polyelectrolyte has high affinity for water, and poor solubility in organic solvents, but, if predissolved in water, can tolerate addition of some proportion of watermiscible solvents to the solution without precipitation. To prepare NaCMC, cellulose is treated with sodium hydroxide, then reacted with chloroacetic acid (Fig. 3). In this Williamson ether synthesis77, stoichiometric NaOH is required and consumed, NaCl is a co-product, and glycolic acid is a by-product, formed by displacement of Cl- from chloroacetic acid by NaOH. The method used has a great impact on the functionalization pattern, highest achievable DS, and solubility, where a relatively low DS of this polar substituent is enough to make the polymer water-soluble78. Heinze et al. have shown that even DS(CMC) 0.4 was sufficient to make NaCMC water soluble79 under homogeneous solution conditions (e.g, N-methyl morpholine oxide/water). Production of commercial NaCMC is carried out by the slurry method, where cellulose is dispersed into a water, NaOH, and alcohol mixture, and then the solvent distributes the chloroacetate and dissolved base to the hydroxyl groups of cellulose, disturbs the crystalline structure of cellulose by breaking hydrogen bonds, and thus activates hydroxyl groups towards etherification. Alternatively, a dry process can be used where alkali cellulose is prepared first, followed by the addition of monochloroacetate in the solid state. As already noted, NaCMC can be also synthesized in homogeneous solution. Cellulose can for example be dissolved in DMAc/LiCl9, then reacted with powdered NaOH and chloroacetic acid to afford a product that reportedly contains a significantly higher amount of tricarboxymethylated and unsubstituted monosaccharides than by the slurry method80. In another study, Heinze et al. presented a fully homogeneous carboxymethylation method in one phase, where cellulose 17 ACS Paragon Plus Environment


Page 18 of 81

was dissolved in Ni(tren) and HPLC analysis after depolymerization showed that the distribution of the functional groups has a pattern similar to that of NaCMC prepared by the conventional slurry method, O6 ≥ O2 > O379. This implies that these homogeneous conditions surprisingly did not significantly impact the regioselectivity of CMC synthesis; heterogeneous activation of cellulose by mercerization and complete dissolution provide similar accessibility, and there appears to be no particular advantage of the latter method in the case of CMC. On the other hand, Bhandari et al. proposed a new method for synthesis of NaCMC, reactive extrusion, where the continuous, convenient process takes less than 2 min and reduces solvent usage81. It is important to note that it is difficult to drive DS(CMC) higher than about 1.5 in a single reaction step, regardless of the number of equivalents of chloroacetic acid used82. We attribute this difficulty to the fact that both chloroacetic acid and CMC, once some CM substitution has occurred, are fully ionized and anionic in aqueous NaOH. Thus, the higher the DS(CM), the greater the electrostatic repulsion between the anionic polyelectrolyte and the approaching sodium chloroacetate. This limits the DS range of CMC polymers that are practically available. 2.1.2 NaCMC Pharmaceutical Applications NaCMC has found use in pharmaceutical formulations as a thickener83, stabilizer84, disintegration agent85, bioadhesive material86 and film-former87,88. Cross-linked NaCMC, known as croscarmellose, is widely used as a superdisintegrant in tablet and capsule formulations89. NaCMC has been used in matrix-controlled drug release in combination with other cellulose


Page 19 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

ethers such as EC or HPMC. Rapidly dissolving NaCMC has been used as co-excipient in many pharmaceutical dosage forms to enhance release rate. EC-NaCMC wet granulated tablets released diclofenac potassium in vitro over 4-6 h, vs. > 24 h from an ethyl cellulose – diclofenac potassium formulation90. In another study, NaCMC osmotically controlled release tablets were formulated for sustained release of glipizide by hot melt granulation, and in dissolution studies a zero-order release profile was observed over 16 h91, showcasing the ability of ionized NaCMC to create osmotic pressure. “Zero-order” release rate refers to zero-order kinetics with respect to time; that is, release rate is constant over time until the drug is virtually exhausted in the dosage form. Zero-order release can often provide nearconstant blood levels over prolonged time periods, which is conducive to once-daily oral dosing; this can help to promote patient adherence to the prescribed dosage regime92. NaCMC has been also investigated for use in oral controlled delivery tablets, e.g. of losartan93, metoprolol94 and ibuprofen95. NaCMC has excellent film forming ability due in part to the fact that commercial NaCMC products have higher DP than most other commercial cellulose ethers. Commercial NaCMC is available at molecular weights of 700K (and higher), which corresponds to DP of approximately 3K. NaCMC was used for oral thin film preparation for probiotic delivery purposes and probiotic viability was maintained for 150 days88. In another study, NaCMC films were found to be nontoxic towards human keratinocytes and fibroblasts96, and thus useful for transdermal delivery of acetylsalicylic acid and stratifin for wound healing (postburn scar treatment) purposes. NaCMC has been also used in preparation of film blends. Starch based films are odorless, semi-permeable to CO2, and resistant to oxygen passage, but have poor mechanical properties. Starch-NaCMC solvent-cast films were prepared and the blended edible films were shown to have higher mechanical strength, but lower moisture 19 ACS Paragon Plus Environment


Page 20 of 81

absorption and lower solubility than starch films97. Badwaik, et al. showed that antimicrobial and antioxidant materials could be loaded into edible alginate/starch/NaCMC films, which were uniform and had good thermal stability for coating purposes87. In addition, the polyanionic nature of NaCMC can be exploited for the preparation of polyelectrolyte multilayer (PEM) films by layer-by-layer assembly. Microparticles loaded with drugs (such as ibuprofen) can be embedded into the PEM98. Several polyanionic polymers have been found to possess bioadhesive properties, which as we have noted may have value in a number of drug delivery applications. Anionic NaCMC can adhere more strongly to some biological surfaces than most of the nonionic cellulose derivatives, making NaCMC attractive for transmucosal and transdermal applications. For example, NaCMC tablets were designed for oral delivery of a water-soluble drug, sotalol HCl. The tablets were evaluated in vitro, releasing drug for 14 hours, and showing good bioadhesive attachment ex vivo to rabbit stomach or small intestinal tissue99. NaCMC adheres to the mucosal surface better than non-ionic MC and HPMC, as investigated by coating the polymers containing acetyl salicylic acid onto glass beads, and testing adhesion of the modified beads to gastric and intestinal mucosa100. Bioadhesive NaCMC matrices have been studied for their ability to lengthen the stay of water soluble drugs such as ciprofloxacin101 in the absorptive portion of the GI tract. For oral mucosal (buccal) delivery102, bucco-adhesive NaCMC tablets have been prepared with poorly water-soluble drugs86,103 including glipizide104 and pindolol105, and water-soluble drugs106,107 such as lignocaine HCl108, miconazole nitrate109, and triamcinolone acetonide110. Nifedipine bucco-adhesive formulations showed zero-order drug release kinetics; adhesive force increased with increasing NaCMC percentage, adhering to the upper gums of human volunteers for over 8 h, releasing almost 100% of the nifedipine86. The FDA permits up to 242 mg NaCMC for oral formulations, up to 10.95 mg 20 ACS Paragon Plus Environment

Page 21 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

for buccal applications, and up to 0.5% for ophthalmic solutions111. NaCMC has been also used in ophthalmic applications as a lubricant and thickener, taking advantage of its aqueous solubility, high molecular weight, and rheological properties. Aqueous NaCMC is a clear lubricant with cytoprotective properties and has low propensity to cause eye irritation. Therefore it has been used in artificial tears and lens lubricant rewetting products, usually at low concentration (ca. 0.5%)112. NaCMC can bind to corneal epithelial cells, increase corneal wound healing39, and the high viscosity of aqueous NaCMC solutions prolongs residence time on the eye surface. There are multiple NaCMC-containing commercial products for ophthalmic applications. NaCMC formulations were developed for genitourinary tract infection treatment, anticipating that its bioadhesive property would enhance vaginal residence time. For mixed infections, clotrimazole and metronidazole bioadhesive NaCMC tablets showed stronger in vitro antimicrobial effects vs. commercial products, Infa-V TM, Candid-VTM and Canesten 1 TM, 113

. In another study, clotrimazole tablets were designed for daily application, where

bioadhesive strength was tested on porcine vaginal mucosal membranes; they were shown to have strong attachment and good stability114. NaCMC was also used for acyclovir115 and ketoconazole116 vaginal bioadhesive tablet preparations. Although these results are quite promising, they require further in vivo studies since the high rate of drug elimination from the application area is a key limitation on vaginal mucosal applications. 2.2 Methyl cellulose (MC):



CH2OH H O HO

CH3Cl

O

CH2OH H

O

O HO

OH OH

Page 22 of 81

OH

H2O, NaOH

n

MC

OCH3

n

Figure 4. MC synthesis and structure. 2.2.1 Synthesis and General Polymer Properties Commercially, MC is synthesized (Fig. 4) by reaction of alkali cellulose (cellulose treated with sodium hydroxide) in a Williamson ether synthesis77 with methyl chloride as electrophile117. Like CMC, manufacture of MC can be performed using the so-called dry process, or by the slurry process. Diluents such as dimethyl ether, ethylene glycol dimethyl ether, or toluene are generally utilized for the slurry process. MC water solubility is heavily influenced by DS (Me) (see Supplementary Information for description of method for calculating DS(Me) from percent methyl values. Similar methods can be used to calculate DS of other cellulose ether alkyl or carboxyalkyl groups (Et, CM)). For commercially prepared MC, when DS (Me) is between 0.1-1.1 the polymer swells, becoming water soluble between DS (Me) 1.4-2.0, but losing water solubility at DS (Me) ≥ 2.1118. MC with DS of 1.5 has very good solubility in cold119 or hot (> 60 °C) water, and it can be dissolved in polar aprotic solvents like pyridine, DMI, DMAc, or DMF. It is not soluble in lower polarity solvents such as THF, acetone, or alcohols, limiting available drug delivery formulation methods. MC aqueous solutions are stable across a wide range of pH values (2-12) without apparent changes in viscosity. Commercial MC is available with viscosity 4-3,500 mPa-s (measured at 20 °C with 2-4 mg/ml solutions by capillary viscometry), corresponding to a molecular weight range of ca. 46,000 - 300,000117.


Page 23 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

Aqueous MC solutions exhibit the interesting property of thermo-reversible gelation. They gel upon heating to approximately 55 °C, and then redissolve upon cooling. It appears to be well-accepted that gelation of MC solutions is primarily caused by hydrophobic interactions between methyl groups120. At low temperatures, molecules are hydrated and water forms an ice-like structure around the hydrophobic methoxy groups, making the polymer soluble. As temperature is increased, water mobility increases, decreasing its close association with the methoxyl groups, due to decreased relative viscosity and increased entropy of the solution121. As temperature continues to rise, hydrophobic groups interact by van der Waals forces, a network forms between hydrophobic polymer sites, relative viscosity increases sharply, and a gel forms. Gels redissolve upon cooling with a hysteresis loop, and this cycle can be repeated times122,123.

multiple



Page 24 of 81

Figure 5. G’ of 2.1 wt% MC-300 (DS(Me) = 1.8) at several continuous (not stepwise) heating rates measured at 5% strain and 1 rad/s. The crossover of G’ and G’’ at each heating rate is noted (filled stars on heating, open stars on cooling) and serves to approximate the Tgel for each condition. Adapted with permission from ref 124. Copyright 2012, American Chemical Society. Gel formation and gelation temperature depend on variables including DS (Me), solution concentration, salt content, heating rate, and polymer molecular weight. Lodge and coworkers124 have examined the dependence of gelation temperature on heating rate, concluding that the strong dependence on heating rate (Figure 5) supports a gelation mechanism involving nucleation and growth, rather than spinodal decomposition. Polymers with higher DS (Me) and higher molecular weight can form firmer gels125 in an entropy


Page 25 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

driven process. MC fine structure (random vs. non-random distribution), resulting from the synthesis method, also strongly impacts gelation. For example, MC prepared under homogeneous conditions shows much higher temperature and weaker thermal transitions; methyl distribution of these derivatives around the glucose ring is more statistical, though distribution along the chain has not been carefully evaluated (but is assumed to be more even due to the homogeneous methods used)126–129. 2.2.2 MC Pharmaceutical Applications The U.S. Food and Drug Administration (FDA) classifies MC as Generally Recognized As Safe (GRAS), and approves its use in formulations within the following limits; up to 183 mg for oral, up to 4 mg for buccal, up to 102 mg for vaginal, and up to 0.5 % (v/v) for ophthalmic applications111. In addition, MC is metabolically inert, non-digestible, forms viscous aqueous solutions, and is soluble in cold water. For these reasons, MC has been widely used in the pharmaceutical industry, including as a thickener130, binder131, stabilizer132 , suspending agent133, and film former134. MC has been used in controlled release formulations as a polymeric carrier, where its amphiphilicity and ability to dissolve to create viscous aqueous solutions are valuable. It has been shown that MC mixtures can be good carriers for ibuprofen, where tablets were prepared by direct compression of MC, HPMC, and microcrystalline cellulose in order to extend drug release; these formulations displayed linear release profiles, lasting at least 12-16 h. In addition, mixtures of MC and ι-carrageenan afforded zero-order release. Water insoluble microcrystalline cellulose helped prevent tablet matrix disintegration, swelling upon contact with water. On the other hand, water-soluble MC enhances water absorption penetration rate, promoting dosage form swelling135. 25 ACS Paragon Plus Environment


Page 26 of 81

MC has been shown to stabilize nanoparticles132, for example where gold nanoparticles are generated in the presence of MC by reduction of HAuCl4•4H2O (H2, 85°C). In this study, the gold nanoparticle size was stable at 30-50 nm as demonstrated by X-ray photoelectron spectroscopy (XPS) and energy dispersive X-ray spectroscopy. Control gold nanoparticles without MC agglomerated during formulation preparation, illustrating the ability of MC to stabilize nanoparticles, presumably by hydrophobic interactions as well as by increasing viscosity. These particles have potential for diagnostic and therapeutic applications. MC can form water-soluble films that have low permeability for non-polar gases such as oxygen and carbon dioxide. These have potential to be used as film dosage forms, or for coating other delivery systems for various purposes, e.g. taste masking136. Stand-alone MC films have poor mechanical properties and processing characteristics, so are commonly plasticized. Solvent-cast edible films of MC were prepared with plasticizers, e.g. the polymeric plasticizer polyethylene glycol (PEG) 400, where it was observed that water absorption by the films increases with increasing concentration of the hydrophilic PEG. Addition of PEG plasticizer decreases film Tg in predictable fashion137, and increases the rate of water, oxygen, and aroma permeation. If PEG concentration is < 30%, the film remains transparent138. MC has also been blended with starch in order to form flexible and transparent edible films with moderate mechanical strength. Starch alone does not form films with adequate mechanical properties and good moisture barrier performance. MC is a good candidate material to prepare blends with water-soluble, extrudable (with water or other plasticizer) starch via various methods such as hot extrusion, or hot pressing. Although a single Tg value was observed for the starch/MC/plasticizer (45/45/10) blend by thermal analysis (DSC, 2nd heating), it is difficult to conclude on this basis whether there is phase


Page 27 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

separation139; according to Olabisi, it is not possible to distinguish a phase separated system from a miscible one if the Tg values of individual components are separated by less than 20°C140. Starch itself does not have an observable glass transition (most native polysaccharides do not) and it is unlikely that MC and starch are truly miscible. 2.3 Ethyl cellulose (EC)

CH2OH H O HO

CH3CH2Cl

O

O

O HO

OH OH

CH2OH H

OH

NaOH, H2O

n

EC

n OCH2CH3

Figure 6. EC synthesis and structure 2.3.1 Synthesis and General Polymer Properties EC is prepared in a fashion similar to the method used for MC, by Williamson ether synthesis (Fig. 6). Ethylation of cellulose is less efficient than methylation under heterogeneous conditions due to the higher molar volume and hydrophobicity of ethyl halides, which can retard the diffusion-controlled reaction. Generally speaking, synthesis of EC requires more harsh conditions than for MC; higher alkalinity, higher reaction temperature, and longer reaction time. In commercial methods, ≥ 50% sodium hydroxide is used for alkalization, and then the alkali cellulose is reacted with ethyl chloride at < 50 °C for 10-20 h141,142. The resulting EC has almost equal partial DS(Et) at O2 and O6, with lower DS(Et) at O3143.

Table 2. EC Physical Properties 27 ACS Paragon Plus Environment


Page 28 of 81

DS(Et)

2.2-2.8

Tg

140 °C (DS(Et) 2.3)

Tm

140-160 °C

Viscosity (5% solution, 25 °C,

40-52 mPa-s (AqualonTM N50)

Ubbelohde viscometer)144

250-350 mPa-s (AqualonTM N300)

Solubility

Stability

Soluble in esters, aromatic hydrocarbons, alcohols, ketones and aromatic solvents. Insoluble in water. Light stable (visible or UV), relatively stable to alkaline conditions, but not to strongly acidic media.

Increasing DS(Et) has a dramatic impact upon solubility; at low DS(Et), EC is water-soluble due to disruption of H-bonding and structural regularity by the ethyl groups, while at high DS(Et) it becomes insoluble in water, and soluble even in solvents as non-polar as aromatic hydrocarbons. EC solubility parameter thus decreases with increasing DS(Et). In general, commercial EC grades have high DS(Et), and so are soluble in a variety of solvents such as esters, aromatic hydrocarbons, alcohols, ketones, and aromatic solvents, but unlike other commercial cellulose ethers are insoluble in water (Table 2). EC is thermoplastic; commercial EC is typically amorphous with Tg values reported from 128 °C (EC analysis not reported)145 to 140 °C142 (DS(Et) 2.55, 48.5% ethyl content). Due to its high Tg, EC is often plasticized for extrusion. Commercial, high DS(Et) EC is a tasteless, odorless powder with low water affinity, relatively hydrophobic, and can form tough, flexible films. EC is generally non-toxic10,146, and no significant biodegradation was recorded when exposed to


Page 29 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

Aureobacterium saperdae or Pseudomonas lemoignei for 30 days147. EC physical properties are summarized in Table 1. 2.3.2 EC Pharmaceutical Applications As a material that is more hydrophobic than other commercial cellulose ethers, EC is often used in different ways in pharmaceutical applications than the other ethers. EC forms films and matrices with lower water affinity and can be readily thermally extruded into films or EC/drug matrices. EC has been used in drug delivery systems as a binder148,149, film forming agent,150 or coating material151. It is also used to mask the bitter taste of drugs to increase patient compliance152. According to FDA, the EC daily maximum allowable dose is 308 mg for oral, 80 mg for transdermal, and 50 mg for vaginal applications111. It can be processed by melt extrusion145,153,154, spray drying155, co-precipitation,148 or emulsification/solvent evaporation152, and formed into tablets by either direct compression156 or wet granulation157. NaCMC95,158, HPMC95,149, Eudragit copolymers (e.g. ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate copolymer with a ratio of 1:2:0.2)

148,159,160

, and

starch95,158 are hydrophilic co-excipients frequently used in combination with EC in oral dosage forms to increase drug release rates. EC in matrix systems can be used to modify drug diffusion and release. Directly compressed tablets of EC (mixed with ethyl acrylate, methyl methacrylate, or trimethylammonioethyl methacrylate copolymer) and didanosine (anti-HIV drug)159,160 allowed sustained release of 60-70% of the drug in vitro over 6 h. In these studies drug load had the most significant effect on increasing dissolution efficiency, and drug release was inversely proportional to EC particle size159. Matrices of EC with diclofenac potassium were prepared and subjected to in vitro dissolution studies, showing that EC significantly decreased diclofenac release rate, and 29 ACS Paragon Plus Environment


Page 30 of 81

that zero-order release was observed90. Controlled release of ibuprofen from EC matrices was investigated95,149, showing for directly compressed formulations that EC molecular weight did not significantly impact ibuprofen release rate. On the other hand, when a wet granulation method was used, ibuprofen release rate increased with lower molecular weight EC. Drug content however more significantly impacted drug release rate, with release rate increasing with higher ibuprofen content (moving from polymer-controlled to drugcontrolled release rate)149. Generally, hydrophobic EC can reduce release rates of hydrophilic drugs by reducing the rate of water permeation into the formulation and that of drug solution in water out of the formulation. Manipulating the hydrophilic drug/EC ratio can be used to tune release rate, with increasing proportion of EC resulting in slower release rate. Increasing the ratio of the high Tg, thermoplastic, compressible EC to drug caused decreased tablet porosity, and increased tablet hardness. It also reduced tablet wettability, drug release rate, water absorption, and drug diffusion149,161. Thus, more hydrophilic co-excipients are sometimes added to EC formulations to provide increased release rates. EC has been used in oral drug delivery systems as a carrier in order to improve drug bioavailability162,163. For example, the anti-ulcer drug ranitidine hydrochloride was formulated in EC-based porous particles of 350-750 µm diameter, with encapsulation efficiencies up to 96% when prepared by an oil-in-oil method; paraffin and Span 60 comprised the dispersion medium for the drug and polymer mixture. These EC solvent evaporated particles were orally dosed to New Zealand rabbits, resulting in extended drug release (more than 12 h), achieving drug plasma concentration around 15 µg/mL, and increasing drug bioavailability 2.4-fold relative to pure drug164. In another study, tramadol EC microcapsules were prepared by spray drying, and the effects of EC viscosity, solvent system, and plasticizer addition were 30 ACS Paragon Plus Environment

Page 31 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

investigated155. The hydrophobic EC is miscible with many hydrophobic drugs, but ASD formulations using EC could suffer from slow release, since EC contains no ionizable groups. EC is a good film former, and commercial EC has a relatively low solubility parameter (Table 1), thus it has found use in film coating of drug formulations. Often water-insoluble EC films function to slow drug release, particularly of hydrophilic drugs; they may also provide an oxygen barrier and/or mask drug taste. Granules of theophylline, cellulose, and lactose coated with EC were investigated and zero order theophylline release from the coated granules was reported165. Moreover, 5-aminosalicylic acid was formulated in ethyl cellulose – amylose coated pellets for colon specific drug delivery, mediated by colonic bacterial degradation of the (no doubt immiscible) amylose component. The EC portion limited swelling and thereby drug release rate, relative to other coatings (EC/amylose aqueous dispersion, and (ethyl acrylate/methyl methacrylate/trimethylammonioethyl methacrylate) copolymer-amylose coating)166. While EC is thermally processable, therefore creating the potential to extrude drug/polymer blends for ASD to enhance solubility and bioavailability of otherwise poorly soluble drugs, the hydrophobicity of EC means that there is no obvious trigger for drug release from such ASDs. Hence EC is often co-extruded with a hydrophilic material to provide the release mechanism, where release rate is controlled by the ratio of hydrophilic to hydrophobic polymers. Some drugs plasticize EC, resulting in even more moderate extrusion temperatures; thus EC/metoprolol tartrate was extruded in the range 110-140°C167, while 30% ibuprofen in EC formulations could be extruded at 82°C, and 60% ibuprofen-EC formulations gave smooth extrudates at 60-62°C168–170, all far below the Tg of the EC used 31 ACS Paragon Plus Environment


Page 32 of 81

(133°C)170. EC solubility and film-forming properties have also been exploited to prepare spray-on transdermal delivery films from relatively benign solvents like acetone and ethanol150. Fluconazole-containing films were prepared from EC only, and from blends with an acrylate copolymer. Increasing amounts of EC restricted fluconazole release rate predictably, with moderate adhesion to skin that was improved by blending with the acrylate copolymer. Tests with healthy human volunteers showed that the films displayed adequate dermal adhesion, flexibility, and complete, slow drug release over ca. 12 h. 2.4 Hydroxypropyl Cellulose (HPC)

CH3 OH O

CH2OH H

O CH2 CH3

O O HO

OH OH

n

H2O, NaOH, cosolvent

H

O O HO

OH HPC

O

n CH3 O

H3C

OH

Figure 7. HPC synthesis and structure. 2.4.1 Synthesis and General Polymer Properties HPC is manufactured by reacting alkali cellulose with propylene oxide at elevated temperatures and pressures, leading to nucleophilic ring opening, predominantly though not exclusively at the less hindered end of the epoxide. This affords hydroxypropyl (HP) 32 ACS Paragon Plus Environment

Page 33 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

substituents that contain almost entirely alkali salts of secondary hydroxyl groups. These anions are available for further reaction with propylene oxide, and in fact have much wider available approach angles than do the cellulose main chain hydroxyls. The side chain alkoxyl can react with further molecules of propylene oxide (PO), forming oligo(propylene oxide) side chains that can each contain more than one combined PO (note that the 2-carbons of both PO and of the hydroxyalkyl substituents of HPC are asymmetric; however, the PO used commercially is racemic). At higher values of DS/MS(HP), it is probable that most of the primary hydroxyls on the cellulose have been substituted and that the reactive groups remaining are secondary hydroxyls171. An idealized structure for a portion of an HPC molecule with MS(HP) of 3 and DS(HP) of 2 is given in Fig. 7. While DS is the average number of hydroxyl positions substituted per AGU with a maximum of ca. 3, MS is the average number of substituents per AGU and is theoretically unlimited, potentially exceeding 3 for oligo(hydroxyalkyl) adducts of cellulose with epoxides (like HPC). Both DS and MS significantly influence cellulose hydroxyalkyl ether properties. HPC is a non-ionic, amphiphilic cellulose ether which is soluble in aqueous and polar organic solvents. The somewhat hydrophobic HP substituents impart thermoplasticity172 and some degree of surface activity. At the same time, HPC modifies aqueous rheological properties as do other water-soluble cellulose ethers, thickening those solutions and imparting colloidal stabilization. Commercial HPC (MS 3.0-4.0)173 is soluble in water below 38°C, but has the interesting thermal gelation property in common with MC121 and some other cellulose ethers174. As a result of this thermal gelation, HPC is insoluble in water above ca. 45°C. HPC is available in a range of molecular weights, which influence solution properties in predictable ways. The



Page 34 of 81

same amphiphilic properties lead to miscibility with a number of plasticizers and other polymers175. HPC is primarily supplied by two manufacturers, Ashland Specialty Ingredients and Nippon Soda Co., Ltd. Ashland HPC is trademarked as KlucelTM; within the pharmaceutical grade there are seven viscosity types designated as H, M, G, J, L, E and EL. Table 3 gives the water and ethanol viscosity specifications of pharmaceutical grade for each available viscosity type171. Nippon Soda NissoTM HPC is available in five viscosity types; aqueous viscosity information can be found in Table 4176. Table 3. Klucel HPC Viscosity Types, Viscosities, and Molecular Weights Klucel Pharmaceutical Grade ELF

Viscosities, mPa-s# 1%*

2%*

5%*

300-600; 150-700

~80,000

75-150; 25-150 150-400; 75-400

LF and LXF JF and JXF

MF and MXF

10%* ~40,000

EF and EXF

GF and GXF

Mw**

95,000 370,000

150-400; 75-400 4000-6500; 3000-6000

140,000 850,000

1500-3000; 1,150,000 1000-4000 mPa-s = millipascal seconds. Viscosities in water are presented in black regular font; viscosities in absolute ethanol are in red italic font. HF and HXF

*All viscosities determined at 25°C using a Brookfield LVF viscometer with spindle and speed combinations depending on viscosity level **Weight average molecular weight determined by size exclusion chromatography.

Table 4. Nisso HPC Viscosity Types and Viscosities (mPa-s) Nisso HPC type

SSL

SL

L

M

H 34

ACS Paragon Plus Environment

Page 35 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

Viscosity @ 20°C/2% aq Mw

10002-2.9 3-5.9 6-10 150-400 4000 ~40,000 ~100,000 ~140,000 ~620,000 ~910,000

HPC is thermoplastic, unlike the less thermally stable hydroxyethyl cellulose (HEC), with a reported Tg of ~130°C.177 HPC does not begin to decompose until ca. 300ºC178 (by thermogravimetric analysis); HEC decomposition begins at ca. 200ºC. Therefore, for HPC there is a sufficient melt processing window. The melt flow behavior of HPC depends in predictable fashion upon its molecular weight, with lower MW grades having higher melt flow indices (Fig. 8)171.

Figure 8. HPC melt flow index as a function of MW at 150°C.



Page 36 of 81

HPC is, like many other cellulose derivatives, a good film former. Its films are somewhat less brittle than those from cellulose and certain of its derivatives because of the relatively flexible oligo(hydroxypropyl) substituents, making it a useful material for fabrication of films and sheets by casting or extrusion techniques. HPC coatings have been extruded onto paper, fabrics, food products and other substrates. Its high Tg means that HPC films stay in the glassy phase (non-tacky) even when humidity is rather high and/or even when containing a plasticizer (or drug that plasticizes the film). Extrusion of some HPC grades can lead to impractical melt viscosities179; plasticizers (vide infra) can be useful in this regard.

2.4.2 HPC Pharmaceutical Applications HPC is frequently employed as a tablet binder, because of its high Tg, thermal plasticity, and relatively broad compatibility that are a result of its balance of hydrophilic and hydrophobic properties, leading also to its organic solvent and aqueous solubility. These properties allow tablet preparation using a variety of formulation techniques. Levels of ca. 2-8 wt% HPC in the formulation bind the tablet, affording fast release, whereas higher levels of HPC (ca. 2030 wt%) promote formation of a gel layer upon exposure to water, thereby affording extended release (vide infra)180. Picker-Freyer and Dürig have studied physical mechanical and tablet properties of HPC in pure form and in mixtures. They observed that compactability and plasticity increase as molecular weight and particle size decrease. Conversely, elastic deformation is more pronounced at higher molecular weight and particle size180.


Page 37 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

Fine HPC particle size grades (ca. 80 µm mean size) are most suitable for dry binder applications, while regular particle size grades (ca. 250 µm mean size) are more readily dispersible, making them more useful in solution binding applications. Skinner et al. evaluated HPC as a roller compaction binder in pharmaceutical applications using poorly compressible acetaminophen (APAP) as model drug. Fine-particle HPC at 4-8 wt% overcame capping and friability problems, affording useful tablet dosage forms181. Fine particle HPC levels of at least 20% of the matrix form a gel layer upon water contact, retarding drug release, either by diffusion or erosion182. For poorly soluble drugs, where erosion is the predominant release mechanism, low molecular weight grades of HPC dissolve and release faster. Drug release from HPC matrices is sensitive to HPC molecular weight, particle size, and drug/polymer proportions; co-excipients may also impact release profiles. In a study aiming to attain 100% drug release of water-soluble caffeine after 24 h from HPC tablet matrices, it was shown that increasing HPC/caffeine ratios significantly decreased caffeine release rate183. Hydration rates, matrix erosion, and drug release from HEC and HPC physical blend matrices were compared184. The more hydrophilic HEC swelled and eroded faster than HPC. Drug release from HEC matrices occurred by non-Fickian transport, i.e., a combination of drug diffusion and polymer erosion and swelling, while drug release from HPC matrices was controlled primarily by diffusion through the HPC gel. Saša et al. investigated cellulose ether surface properties by inverse GC and correlated with matrix drug release rates185. Relative cellulose ether polarity by GC was HEC > HPMC > HPC, which correlated well with water sorption rate and swelling degree. They did not



Page 38 of 81

report the ether MS and DS values, making it difficult to evaluate the structure-property relationship in detail. Release of pentoxifylline and vancomycin from the cellulose ether matrices followed the same order as the polarity of polymers. They found that drug release from HPC is governed mainly by Fickian diffusion, whereas from HEC relaxation of polymer chains is also important. Uekama et al. used a combination of cyclodextrin and HPC to develop bi-layer controlled release tablets for poorly soluble compounds186,187. Hydrophilic β-cyclodextrin derivatives complexed and solubilized the drug, while HPC or HPC/EC matrices provided slow release. These were combined in a double-layer tablet to optimize release profile and solubility. Exemplifying HPC/drug melt extrusion, Lakshman et al. combined the hydrophilic, poorly compactable drug metformin HCl with HPC using a twin-screw extruder above HPC Tg, but below metformin Tm. Compared with wet and solvent granulation, melt granulation provided highest compactability and lowest friability, that were insensitive to changes in atmospheric moisture level. HPC permitted formulation of decreased tablet size of the highdose drugs; remarkably < 10% by weight HPC was sufficient to achieve compactability and friability targets. HPC was superior to HPMC in this instance due to enhanced hardness, and afforded higher release rate than HEC188. HPC has suitable properties for the most commonly used methods (e.g., spray drying and melt extrusion) for preparing ASDs of drugs in order to enhance solubility and bioavailability. Inoue and co-workers examined a variety of polymers as ASD matrices for the immunosuppressant drug cyclosporine A (CsA)189. They found that HPC formed ASDs with CsA, even at > 75% drug. Other cellulose ethers including MC and HPMC also formed ASDs at similar CsA levels, but dissolution from the HPC formulation was faster and the 38 ACS Paragon Plus Environment

Page 39 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

supersaturation achieved was much greater. HPC with Mw of ≤ 70,000 released CsA almost immediately, while delayed release was observed with high Mw HPC (250K – 400K). The relative HPC hydrophobicity (solubility parameters (Table 1) MC 25.0, HPMC 23.9, HPC 24.8 MPa1/2) may enhance interactions with the hydrophobic drug, promoting stabilization against recrystallization. The complex HPC structure can be an advantage in ASD since it essentially eliminates any tendency for HPC to crystallize. Studies of HPC vs. PEG in felodopine190 ASD showed that release from the hydrophilic PEG matrix was much faster and more complete. However, PEG tends to crystallize, which would be unacceptable variation in a marketed formulation, whereas the HPC does not (XRD, DSC). Mohammed et al. reported the use of HPC for ketoprofen solubility enhancement by forming a solid dispersion via thermal extrusion, which is attractive for ASD since no organic solvents are involved191. Drug release rate from extruded pellets depended upon HPC molecular weight, with faster ketoprofen release observed at lower molecular weight (40K vs. 80K Mw). Tablets compressed from milled extrudates exhibited rapid release. HPC may also impact growth rate of in vivo precipitated crystals, influencing their redissolution rate and bioavailability. Sugita et al. noted192 that a tablet formulation of pioglitazone HCl showed higher bioavailability when HPC was present as a binder, than when the polymer was absent. Given that pioglitazone is a weakly basic compound and is expected to precipitate upon transit from the stomach to the small intestine, the particle size of the precipitate becomes an important consideration. The authors demonstrated that crystalline pioglitazone free base precipitated in the presence of HPC had a population of particles with size smaller than 1 µm. These smaller particles were absent following 39 ACS Paragon Plus Environment

Biomacromolecules

precipitation when HPC was not present, and lower bioavailability was observed, attributed to the absence of the small particles.

Certain plasticizers are miscible with HPC, facilitating extrusion of higher molecular weight/melt

viscosity

grades

10000

apparent viscosity, Pas

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 40 of 81

(Fig.

9)199.

No Plasticizer 5% PEG 4600 5% PEG 400 5% Triacetin 5% Dibutylsebecate 5% Glycerin 5% Stearic acid

1000

100 10

100

1000

apparent shear rate, sec-1

Figure 9. Effect of plasticizer on melt viscosity of HPC (Mw ~ 850,000) at 180°C.

Repka et al. studied melt extrusion of HPC/drug formulations in the presence of plasticizers including PEG 8000 (2%), triethyl citrate (2%), acetyl tributyl citrate (2%), and PEG 400 (1%). Tg values predictably decreased with the inclusion of drugs and plasticizers, though the Tg of the film containing the lowest Mw PEG (400) was not stable (rose) over 6 months aging, possibly due to plasticizer evaporation. Plasticizers were important; the researchers could not extrude a consistent HPC film in the absence of drugs or plasticizers due to excessive melt viscosity179, and they observed profound degradation of the model drug 40 ACS Paragon Plus Environment

Page 41 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

hydrocortisone during extrusion of unplasticized HPC, which was presumably exacerbated by high melt temperatures and viscosity.

2.5 Hydroxypropyl methyl cellulose (HPMC):

CH3

O

CH2OH

O CH2

CH3Cl, H

CH3

O O HO

OH OH

n

NaOH, H2O, cosolvent

H

O O HO

OH O

HPMC

R

n

O m H3C

Figure 10. HPMC synthesis and structure (R= –H, -CH3, or –CH2CH(OH)CH3). 2.5.1 Synthesis and General Polymer Properties HPMC (or hypromellose, Fig. 10) is a cellulose ether formed by base catalyzed heterogeneous reaction of cellulose with methyl chloride and propylene oxide

117,193,194

.

Reaction with methyl chloride is a simple Williamson ether reaction, resulting in formation of methyl ethers as described for MC. Reaction with propylene oxide is more complicated, potentially resulting in chain extension as described for HPC (2.4.1). Methylation at the oligo(propylene oxide) chain terminus is also possible. Consequently, the final product HPMC contains more than 5 substituent types; 1) H-, 2) Me-, 3) 2-hydroxy-1-propyl (major isomer), 4) 1-hydroxy-2-propyl (minor isomer), 5) methyl-terminated HP, as well as HP oligomers with or without methyl termination, so that it is a remarkably complex copolymer



Page 42 of 81

(of potentially > (53 or 125) different monosaccharides). It can be readily appreciated that controlled synthesis of this complex sequence of monomers is difficult, as is complete structural analysis. It has been determined that the oligomeric side chains stop at rather low DP value (2-3); this is at first surprising since one might assume that higher DP would further increase steric freedom and thus reactivity of the extended-length alkoxide195.

H3C O Na H OHO

O O

OH n

O CH3 Figure 11. Hypothetical structure of chelated terminal HPMC cation

Mischnick in well-designed deuteromethylation/ partial hydrolysis/ gas chromatography (GC)/ mass spectrometry experiments196 has shown that distribution of methyl groups along the chain is actually more regular than predicted by random models, while HP distribution closely followed those models31,33. We speculate that the growing polyether chain may coordinate the terminal cation and thus reduce terminal anion reactivity (Fig. 11). Mischnick observed greater sodium cation coordination and thus ion intensities for hydroxypropylated mono- and oligosaccharides196, which would be consistent with this hypothesis.

The hydroxypropyl substituent is sufficiently hydrophilic to contribute to the hydration rate, while the methyl substituent is relatively hydrophobic, thus HPMC is an amphiphilic


Page 43 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

polymer. For example, HPMC is known to accumulate at the air-water interface, reducing the surface tension of water197. It also adsorbs at other interfaces, such as drug crystal-water interfaces198. Therefore levels of methyl and HP substitution impact HPMC hydration rate, and likely impact drug delivery system performance. HPMC can form thermoreversible gels upon heating, by a mechanism similar to that described for MC. Highly methylated HPMC chains can form crosslinks due to van der Waals interactions between the hydrophobic methoxy groups upon heating, but hydroxypropyl and oligomeric groups can inhibit crosslinking and gelation122,199. Therefore, MC can form firmer films at lower gelation temperature than can HPMC, even if the particular HPMC has similar molecular weight and DS(Me) to the MC of interest. As DS(Me) content of HPMC is reduced, gelation temperature increases. HPMC is soluble in water or water/solvent mixtures, e.g. ethanol/water and isopropyl alcohol/water. In addition, HPMC (DS (Me) 1.8-2.0, DS (HP) 0.2-0.34) can be dissolved in non-aqueous solvents with medium to high polarity, such as mixtures of methylene chloride and methyl, ethyl or isopropyl alcohols, pyridine, N-methyl pyrrolidone, mixtures of chloroform and methanol or ethanol, glacial acetic acid, dimethyl formamide, or dimethyl sulfoxide200, permitting fabrication of HPMC formulations by various methods including solvent casting and spray drying. AFFINISOL™ HPMC HME is a modified HPMC grade recently introduced by Dow Chemical which has improved thermal processing properties, and improved solubility in a variety of organic solvents201. In addition to its complex structure, HPMC is hygroscopic, further complicating analysis, e.g. of thermal properties. HPMC glass transition is thus not sharp, and difficult to measure by conventional DSC. Modulated DSC is often required to observe HPMC Tg, which has been reported as ca. 180 °C (powder) 142,202, but in the case of solvent cast films HPMC (DS 43 ACS Paragon Plus Environment


Page 44 of 81

(Me) 1.8-2.0, DS (HP) 0.2-0.34, viscosity 5,000 mPa-s) has Tg 157 °C 202. 2.5.2 HPMC Pharmaceutical Applications HPMC is used in the pharmaceutical industry as a film-coating agent203, thickener204, hydrophilic matrix material205, tablet binder, and as an ASD carrier. In addition, it has bioadhesive properties206 and resists microbial attack207. Table S1 (Supplementary Information) displays various HPMC applications with specific drugs and methods of administration. FDA classifies HPMC as GRAS, based on toxicology studies using oral and intraperitoneal routes of administration208. Dosage forms containing up to 20 mg/kg HPMC were non-toxic to mice, rats, dogs and cynomolgus monkeys209. FDA approved drug products can contain HPMC at levels up to 670 mg in oral, up to 54 mg for vaginal, up to 24 mg for buccal, and up to 2.25% for ophthalmic solution formulations111. HPMC pharmacokinetics, distribution, and elimination were investigated in rats and humans, revealing that approximately 97% of orally dosed HPMC was recovered from the feces208; thus it does not significantly biodegrade in the GI tract, nor does it permeate through the enterocytes into the bloodstream to any significant extent. In the National Formulary (USP30-NF25,) HPMC is recognized as an excipient to be used as a coating agent, suspending or viscosity increasing agent, and as a tablet binder210. BenecelTM, MethocelTM and MetoloseTM are HPMC trade names for products of Ashland Chemical, Dow Chemical, and Shin-Etsu Chemical Companies, respectively. HPMC is available in a wide range of molecular weights, with viscosities of 2% w/w aqueous solutions ranging from 3 to 200,000 mPa-s188,199, corresponding to Mw of 8 – 200 X 103 Dalton (DP 40-1000)213. In the USP nomenclature, four-digit numbers represent substituent percent, where the first two digits refer to the methyl group and last two digits refer to the


Page 45 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

hydroxypropyl group (see Supplementary Material for example calculation for conversion of percent substituent into DS); HPMC commercial product properties are summarized in Table 5. In controlled release applications, the E (HPMC 2910) and K types (HPMC 2208) are most commonly used.



Page 46 of 81

Table 5. Methyl and hydroxypropyl (%) contents of BencelTM HPMC commercial products200,214,215 Benecel HPMC Type E4M E10M F50 F4MC K4M K100M K400M

2% Viscosity*, mPas 2700-5040 7500-14000 40-60 2700-5040 2700-5040 75000-140000 150000-280000

Characteristics Methoxyl content, % 28-30 28-30 19-30 19-30 20-24 20-24 20-24

Hydroxpropyl content, % 7-12 7-12 3-12 3-12 7-12 7-12 7-12

*All viscosities determined at 25°C using a Brookfield LVF viscometer with spindle and speed combinations depending on viscosity level

Viriden et al., observed only a small impact of functional group DS upon solubility within HPMC types, but found that the substituent distribution along the polymer chain was impactful. Cellulose ethers containing more- and less-substituted sequences have lower solubility than do more homogeneously substituted analogs, even at similar degrees of substitution216. Substituted segments have a tendency to associate in water and form gel-like components, increasing viscosity; as temperature increases, these gel-like components grow in size. This may impact polymer dissolution from the dosage form, where the higher solubility of homogeneously substituted HPMC may lead to faster tablet erosion216,217, and consequently drug release. Greater heterogeneity may slow release of hydrophobic drugs (erosion controlled), e.g. carbamazepine, but has no effect on release rate of drugs whose release is diffusion controlled, e.g. theophylline218. Thus, erosion-controlled drug release is sensitive to alterations in HPMC chemical composition.


Page 47 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

The impact of polymer viscosity upon drug release rates has also been investigated. For water-soluble drugs such as aminophylline219, promethazine HCl220, and others221,222, it was shown that there is no release rate dependence on HPMC viscosity205. On the other hand, HPMC solution viscosity, which depends upon molecular weight, does impact release of poorly water soluble drugs such as indomethacin. Higher HPMC molecular weight led to slower indomethacin release; a wet granulated formulation with 15,000 mPa viscosity HPMC (K type, water, 20°C) taking 12 h to release 90 % of drug, while 4000 mPa viscosity HPMC under otherwise equivalent conditions reached 90% release within 8 h223. HPMC has been found to be a useful hydrophilic carrier in drug delivery systems. By absorption of water, it creates osmotic pressure, which leads to rupture of the polymer matrix and thus enhances drug release95 either by diffusion or by erosion of the gel layer. High swellability and surface activity are key parameters that impact drug release rate. Hydration of HPMC upon contact with water or other biological fluids leads to polymer chain relaxation and volume expansion. In addition, cellulose ethers with methyl and/or hydroxypropyl groups can be adsorbed onto hydrophobic drug surfaces224,225, producing a steric stabilizing effect226. For these reasons, HPMC has been applied in solid dispersions as a rate controlling and stabilizing polymer. High viscosity HPMC grades extended release of metformin hydrochloride, a very hydrophilic drug with a variable but short half-life (1.5 – 4 h). Solid dispersions were prepared by solvent casting or co-grinding methods; dispersions prepared at 1:4 drug to HPMC ratio by either method prolonged metformin release for 10 h in vitro227. Direct compression of tablets

228

and gel formation for hydrophilic matrix tablets

229,230

are other

methods used to prepare HPMC rate-controlling formulations. Tablets from high molecular weight HPMC are harder, less plastic, and less likely to deform by compression than those 47 ACS Paragon Plus Environment


Page 48 of 81

from lower molecular weight HPMC231. HPMC has been also used for wet granulation. In case studies of wet granulation of acetaminophen, ibuprofen, and ascorbic acid using low viscosity HPMC and MC215, HPMC tablets were less fragile than MC tablets. Although wet granulated HPMC tablets have good potential, the preparation method is costly. Direct compression of controlled-release formulations has also traditionally been a challenge, due to poor compressibility and low final product content uniformity. Low viscosity HPMC grades permit higher solids solutions, making them preferred for tablet film coating203,205. HPMC is the most widely used cellulose derivative in pharmaceutical film coating, probably because it has better solvent solubility than most other commercial cellulose ethers while retaining high water affinity, and because its flexible substituents can dissipate energy, thereby reducing friability232. In some formulations, film coating properties (e.g. moisture permeability, mechanical properties, ductility) were improved by addition of plasticizers (e.g. low MW polyethylene glycol233,234, propylene glycol234, or glycerol203). HPMC is suitable for encapsulation of oxidatively labile and hygroscopic drugs as a result of its low oxygen permeability. HPMC was investigated as a component of tablet coatings with potential for colon specific delivery in combination with pectin and chitosan (which are degraded by colonic bacteria, providing the colon-targeting)235,236. HPMC is resistant to colonic bacterial degradation, delaying release time. Due to its reasonable solvent solubility and thermoplastic nature, respectively, HPMC-based formulations can be also prepared by spray drying237–239 and thermal extrusion240,241. Spray drying polymer and drug from a common solvent can be an efficient method to prepare ASDs of poorly soluble crystalline drugs (e.g. naproxen237,239 or indomethacin239), or watersoluble drugs (e.g. sodium pantoprazole238 or acetaminophen242). On the other hand, only 48 ACS Paragon Plus Environment

Page 49 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

some specific grades of HPMC can be melt-extruded. HPMC E50 2910 (Tg 174°C) extrusion led to an increase in back pressure and the melt-extrusion process was troubled, while HPMC 100 (Tg 110°C) is readily extrudable at temperatures between 150-205°C, with minimal color change even at the higher temperatures. Extruded HPMC formulations have been prepared with lidocaine 243 and itraconazole240.

HPMC is an effective crystallization inhibitor in some supersaturated ASD systems. Paclitaxel showed minimal precipitation and improved pharmacokinetics after oral dosing in HPMC ASD to rats. HPMC has been used to prevent or retard precipitation of various other poorly soluble drugs such as tacrolimus, AMG 009, and PNU-91325244. Yamashita et al. reported that HPMC is a more effective and appropriate ASD polymer for tacrolimus than PEG 6000 or polyvinylpyrrolidone (PVP)245, where all three polymers formed miscible formulations according to XRD results. ASD in HPMC generated a supersaturated tacrolimus concentration of about 50 µg/mL (crystalline tacrolimus solubility 1-2 µg/mL) and maintained this concentration for more than 24 h. On the other hand, drug solution concentrations decreased rapidly from ASDs with the more hydrophilic PVP and PEG 6000, which apparently were less effective tacrolimus crystallization inhibitors. It is interesting that HPMC has proven to be an effective ASD polymer, since it lacks the carboxyl groups that have been found by many investigators41,49,246 to be so useful for enhancing drug-polymer interactions . Presumably HPMC amphiphilicity is well-suited to strong polymer-drug interactions.

Several HPMC-based ASDs have been commercialized. Prograf® capsules contain an ASD of tacrolimus prepared by solvent impregnation of the drug into the polymer245. Sporanox® 49 ACS Paragon Plus Environment


Page 50 of 81

capsules contain an ASD of the antifungal compound itraconazole in an HPMC matrix. This product is prepared by spray coating a solution of the drug and polymer onto sugar beads. Itraconazole is also prepared as an ASD with HPMC using melt extrusion to produce Onmel tablets™. Etravirine, a drug used to treat HIV infections, is commercially available as Intelence™ tablets which contain the drug as an ASD with HPMC.

Due to its ability to form films, its water solubility, and its ability to form miscible dispersions with many drugs, HPMC has been used in numerous mucosal drug delivery formulations. HPMC buccal delivery systems with various drugs247,248,249 including chlorhexidine hydrochloride250 and insulin251 adequately adhered to oral mucosa. Taylan et al. showed that an HPMC and polycarbophil (8:2) formulation afforded buccal sustained release, with long duration effect54. The solubility of HPMC in water is particularly important in buccal formulations, since even tiny amounts of residual solvent in a buccal film could cause an unacceptable, unpleasant taste. HPMC vaginal drug delivery systems have been developed, for example for delivery of antiviral drugs. HPMC films can adhere to porcine vaginal tissue for 6 h, releasing 70% of the drug load (sodium dodecyl sulfate)252. In another study, acyclovir vaginal tablets were prepared with MC, NaCMC, HPMC, or HPC by direct compression and wet granulation. HPMC stayed physically attached to cow vagina for 6 h while the other tablets swelled rapidly, leading to disintegration67. Directly compressed clotrimazole tablets using HPMC combined with polyanionic NaCMC showed higher mucoadhesive strength and more controlled vaginal drug release than when HPMC was combined with neutral guar gum253. Furthermore, vaginal thermosensitive gels were prepared with HPMC 2208 and cyclodextrin, providing slow release of the anticancer drug 5fluorouracil (5-FU) over 90 h in vitro; a human cervical carcinoma cancer (HeLa cells) study 50 ACS Paragon Plus Environment

Page 51 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

showed anticancer efficacy for these gels at much lower 5-FU dose, with controlled and prolonged 5-FU release254. Unlike tablets, in situ gelling systems in the vaginal cavity offer the advantage of reduced outflow from the vagina. Although HPMC-based approaches are promising for vaginal delivery, their usefulness is still limited by the short vaginal residence time of the dosage forms, which necessitates frequent application. Ophthalmic mucoadhesive systems based on HPMC have also been developed, exploiting its water solubility, high solution viscosity, gel forming ability, and bioadhesive nature to afford longer eye retention and reduced eye irritation. Ophthalmic delivery faces the challenge that ocular formulations are typically eliminated from the eye within the first 5-20 min after administration, and the therapeutic dose must penetrate the cornea within this short time frame. Liu et al. showed that HPMC/alginate formulations of gatifloxacin, an antibacterial agent, kept the drug in the eye longer in vitro and in vivo without causing any irritation, also providing increased gatifloxacin bioavailability204. In vitro studies showed that drug release was sustained over 8 h, while in vivo formulation half-life was limited to 44 min, still significantly longer than with conventional systems. HPMC has also been used for the preparation of commercial artificial tear products for dry eyes.

3. Cellulose Ether Esters 3.1 Carboxymethylcellulose Acetate Butyrate (CMCAB) 3.1.1 Synthesis and General Properties



Page 52 of 81

O HO

O

CH2

H O HO

(CH3CO)2O (CH3(CH2)2CO)2O

O OH

O H2SO4

n

O

CH2

H

O

O

OH

O

CMC

n

O CMCAB

O

O

OR

OR

Figure 12. CMCAB synthesis and structure (R = H or Na) Hydrophobically modified CMC derivatives, prepared by esterification of CMC hydroxyl groups, have been explored for waterborne coatings and as drug delivery polymers. CMCAB synthesis by reaction of CMC with acetic and butyric anhydrides under strong acid catalysis was reported by Eastman Chemical Co255. DS values obtained depend in predictable fashion upon reaction conditions and reactant mole ratios. The resulting CMCAB polymer (Fig. 12) has three substituent types (other than hydrogen), with DS (CMC) 0.33, DS butyrate (Bu) 1.64, and DS acetyl (Ac) 0.44. The carboxymethyl groups impart pH sensitivity; CMCAB swells at neutral pH or higher, i.e. at intestinal pH. 3.1.2 Pharmaceutical Applications CMCAB has potential use in different drug delivery dosage forms, playing roles such as matrix, binder, or film former with poorly water-soluble drugs, e.g. ibuprofen, glyburide, griseofulvin256, and clarithromycin48, as well as with water-soluble drugs such as fexofenadine HCl256 and moderately soluble drugs like rifampin. CMCAB ASDs can be prepared through spray drying, co-precipitation, film casting, or solvent rotary evaporation256. Extrusion of CMCAB has not been reported and may be difficult, since the high Tg polymer (137°C) 52 ACS Paragon Plus Environment

Page 53 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

contains both free OH and carboxyl groups and may be prone to thermal cross-linking by ester formation. Direct compression with CMCAB gave zero-order release of ibuprofen, and this otherwise modestly soluble drug displayed much higher solution concentrations upon release from a CMCAB matrix at pH 6.8. In vitro experiments showed that zero-order release was prolonged for more than 20 h, promising for a simple, once-daily form of ibuprofen. Edgar et al. studied controlled release of ibuprofen, glyburide, griseofulvin and fexofenadine HCl from CMCAB ASDs prepared by different techniques, which provided pH-controlled release and enhanced drug solution concentration. Some formulations afforded zero-order drug release (ibuprofen-CMCAB solid dispersion) and enhanced stabilization against drug crystallization. Clarithromycin/CMCAB ASDs were investigated to increase drug solubility and prevent its degradation at acidic pH48. ASD in CMCAB afforded considerable protection against clarithromycin decomposition at low pH; as a result, a total of approximately 55% of the drug was released intact during simulated passage through the absorptive zone of the GI tract (vs. 0% for clarithromycin in the absence of polymer, or in ASD with HPMCAS). Similarly, CMCAB/rifampin ASDs were prepared in order to increase rifampin bioavailability and investigated by in vitro dissolution studies. The hydrophobic protonated CMCAB matrix prevented any measurable drug release under gastric-simulating conditions (pH 1.2), but at pH 6.8, upon deprotonation of the CMCAB carboxylic acid groups and resulting matrix swelling, the CMCAB ASDs released around 70% of the rifampin intact within 8 h (Fig. 13), showing an initial burst release upon pH switch to 6.8257.



Page 54 of 81

Figure 13. Dissolution of rifampin from ASD in various carboxyl-containing cellulose derivatives. Error bars indicate 1 standard deviation (n = 3). Rif: crystalline rifampin. CMCAB: carboxymethyl cellulose acetate butyrate. CAAdP: cellulose acetate adipate propionate. CASub: cellulose acetate suberate. CABSeb: cellulose acetate butyrate sebacate. Adapted from ref. 257. Copyright 2018, with permission from American Pharmacists Association. The amphiphilic CMCAB has sufficiently broad affinity for different drug structures that it is also useful for multi-drug ASDs prepared, in the case cited, by dissolving three structurally diverse anti-HIV drugs in an organic solvent with CMCAB, then casting a film. Each drug was miscible with CMCAB and each drug was released from the ASD in pH 6.8 buffer, with two of the three achieving supersaturation258. 3.2 Hydroxypropyl Methyl Cellulose Acetate Succinate (HPMCAS)


Page 55 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

O O

O (CH3CO)2O,

CH2

H O AcO

O

HPMC

O

CH3

O

O

O

O

O

NaOOCCH3, CH3CO2H

OH

O

n

AcO

OH

O CH2 O

O

HPMCAS R

HO O

m

Figure 14. HPMCAS synthesis and structure (R = H, acetyl, methyl, succinyl)

3.2.1 Synthesis and General Properties HPMCAS is a complex co-polymer prepared by reaction of HPMC with acetic and succinic anhydrides. Many more than four types of moiety (excluding hydrogen; acetyl, succinoyl, methyl, the isomeric hydroxypropyl groups, and the many possible permutations of oligo(hydroxypropyl) groups, not to mention oligo(hydroxypropyl) groups capped by methyl ethers, or acetate or succinate esters) are presumably relatively randomly substituted around the AHG ring and along and between chains (Fig. 14). HPMCAS has modest water solubility at acidic pH due to the hydrophobic methyl and acetyl substituents but swells when its succinate groups (4-14%) are ionized at intestinal pH (6-7.5). There are also HPMCAS grades with higher % succinate (14-18%) that can ionize at lower pH (5.5-6)259. Due to its amphiphilic nature, HPMCAS is frequently used in ASD formulations with hydrophobic drugs. HPMCAS, along with cellulose acetate trimellitate (CAT), cellulose acetate

phthalate

(CAP),

hydroxypropyl

cellulose

acetate

phthalate

(HPCAP),



Page 56 of 81

hydroxypropylmethyl cellulose acetate phthalate (HPMCAP), and methyl cellulose acetate phthalate (MCAP) were patented by Pfizer Inc. for their ability to increase drug solution concentration and hence bioavailability from ASDs, and their use in pH-controlled drug delivery systems260. 3.2.2 Pharmaceutical Applications HPMCAS has now been used as the matrix polymer in many ASDs of poorly water soluble drugs, in order to increase their solution concentrations and prevent recrystallization, including AMG 517261, nifedipine262, felodipine263, quercetin47, naringenin264, clarithromycin48, teleprevir265, and itraconazole266. HPMCAS was identified as the most efficient polymer among HPMC, hypromellose phthalate (HPMCP), methacrylic acid/ethyl acrylate copolymer (MAEA), and povidone (PVP) for nifedipine stabilization in ASDs. ASD in HPMCAS increased nifedipine solution concentration, and prevented its recrystallization after dissolution at pH 6.8262. HPMCAS can be combined with drugs by solvent-free (thermal extrusion) methods, or by co-dissolution followed by spray drying or other methods of isolation from solution266,267. HPMCAS bulk physicochemical properties are not strongly affected by hot melt extrusion, but thermal processing does cause the polymer to release acetic and succinic acids, potentially leading to longer dissolution times due to loss of ionizable succinate groups. Lower molecular weight HPMCAS is relatively more suitable for thermal processing than higher molecular weight grades because of its lower processing temperature (160-180°C); as a result it loses fewer carboxylic acid groups and did not exhibit reduction in dissolution time268. Felodipine/HPMCAS solid dispersions were prepared by both spray drying and


Page 57 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

thermal extrusion. HPMCAS has Tg of 120°C and begins to degrade at ca. 200°C (Mw 17,000-20,000). In this study, materials were extruded at 130°C. Alternatively, HPMCAS/felodipine solutions in acetone were spray dried at 65°C with 1:1, 1:2, and 1:3 polymer:drug ratios. Spray dried particles released drug faster than the melt-extruded formulations, which might be related to lower density and larger surface area of spray dried particles, thereby enhancing contact with the dissolution medium. On the other hand, the 1:1 polymer:drug melt extruded samples had higher stability against recrystallization than spray dried particles267. Taylor et al. showed by mid-infrared studies that HPMCAS more effectively prevented crystallization of certain model drugs (quercetin and naringenin) than HPMC, CMCAB, or poly(acrylic acid) (PAA)264. Many commercial ASD formulations are prepared with HPMCAS. These include products such as Harvoni®, used to treat hepatitis C infections, containing the poorly soluble drug ledipasvir, and the cystic fibrosis treatment, Kalydeco®, an ASD with the active ingredient ivacaftor. HPMCAS dispersions are typically manufactured by spray drying, but products prepared by alternative manufacturing methods have also been developed. Noxafil delayedrelease tablets contain the weakly basic drug, posaconazole, and are prepared as an ASD with HPMCAS using hot melt extrusion. The anticancer drug, vemurafenib, is highly insoluble, exhibiting extremely low bioavailability when dosed as a crystalline form. Due to its high melting point, this compound cannot be processed using hot melt extrusion. Further, spray drying is inefficient due to its low solubility in volatile organic solvents. An ASD formulation, Zelboraf®, was successfully commercialized using a microprecipitation approach. Here, the drug and polymer were dissolved in an organic solvent and added to acidified water, leading to coprecipitation of drug and polymer269. The ASD formulation was shown to dramatically improve vemurafenib bioavailability. 57 ACS Paragon Plus Environment


Page 58 of 81

4. Conclusions and Future Perspectives Both ethers and ether esters of cellulose have been applied to pharmaceutical formulations and have utility that can be systematically related to their structural features. Etherification of cellulose, and in some cases subsequent esterification, can provide polymers with enhanced hydrophobicity,

increased

thermoplasticity,

high

glass

transition

temperature,

compressibility, and compatibility with drugs, to name just a few pharmaceutically useful properties. All of these properties can be controlled by modulation of substituent type and DS/MS in predictable fashion, as we demonstrate in this review. The investigations discussed herein show that these renewable-based polymer derivatives can increase drug bioavailability, thereby decreasing drug costs, variability, dosage form size, and potentially side effects of the formulation relative to the crystalline drug. They can control drug release rate, enhance adhesion to mucosal tissues, form films as controlled and/or targeted release vehicles, and stabilize drugs. What are the primary limits upon the scope of cellulose ether utility in pharmaceutical applications, and how might we overcome those limitations? We would argue that two of the primary limitations that have restrained understanding and exploitation of cellulose ether structure property relationships have been 1) limited synthetic tools, and 2) limited analytical tools. Synthetic tools: To date the scope of available cellulose ethers has been limited by the demands of the standard aqueous processes in which strong alkali catalysts are used. Electrophiles for reaction with cellulose must possess some water solubility, be able to penetrate swollen cellulose fibers, and react sufficiently slowly with water or alkali. As a result, the list of commonly employed ether substituents is extremely short; methyl, ethyl, hydroxyethyl, 58 ACS Paragon Plus Environment

Page 59 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

hydroxypropyl, carboxymethyl. There is a strong need for modern, practical, selective (chemoselective and/or regioselective) synthetic methods that can expand the scope of available cellulose ethers and the functional groups they may contain. One straightforward, recent approach270 has been to extend the cellulose ether ester paradigm, reacting cellulose alkyl ethers (MC and EC) with protected ω-carboxyalkanoyl chlorides, ultimately producing alkyl cellulose ω-carboxyalkanoates that show in vitro promise for amorphous solid dispersion. A more broadly applicable approach to this objective may be to use more conventional (that is to say, Williamson ether synthesis) methods to append functional “handles” such as allyl, propargyl, or ω-unsaturated alkyl groups to the polysaccharide (Figure 15). Then Huisgen click reactions could be used to append azide-terminated chains to the propargyl groups271– 273

, or ω-unsaturated alkyl groups could be elaborated via olefin cross methathesis

(CM)39,41,274,275. Thiol-Michael reactions can be used to further functionalize the CM products276,277, while thiol-ene reactions could be used to functionalize allyl278 or other ωunsaturated handles. Experience to date with the Huisgen, CM, and thiol-Michael approaches indicates that each can be mild and quantitative with the proper match of polysaccharide “handle” and small molecule reagent. Furthermore, the functional group borne by the small molecule reagent can vary across a wide latitude due to the mild and selective nature of these reactions. This “handle” approach is currently the subject of initial exploration, with great promise for efficient, practical expansion of the cellulose ether structural repertoire. These novel abilities to functionalize cellulose ethers have already provided valuable derivatives for challenging applications like high-performance ASD polymers. 59 ACS Paragon Plus Environment


X

OH

OH

or

H

O

O HO

OH

H

X

OH

1

+ NaX

O

O HO

NaOH, H2O

n

Page 60 of 81

OH n

2

O

or

CM OH H

O

O HO

CO2R

Huisgen RN3

Thiol-ene RSH hν

OH n

O

OH H

R’SH, Et3N Thiol-Michael OH O

O HO

OH n

O

CO2R

H

O

O HO

3 OH H

O

O HO

OH n

OH

4

N

5

N N R

O

n 6

O

SR’

SR

CO2R

Figure 15. “Handle” approach to synthesis of broad range of functional cellulose ethers

Analytical tools: In order to acquire deep understanding of structure-property relationships of cellulose ethers, of course structure first must be known. Yet, these semi-synthetic derivatives are prepared in such a way (processes that begin as heterogeneous mixtures) that many types of variability may be present. These include differences in distribution around the glucopyranose ring, in distribution along the chain, and in distribution between chains. Current analysis methods for cellulose ethers are advantaged by the fact that C-O ether bonds are stable across a wide pH range (as cellulose esters are not); thus the investigator has


Page 61 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

good methods for determining identity and total DS of substituents, and even overall monosaccharide composition (e.g. quantities of 3-monosubstituted monosaccharide, and of 2,6-disubstituted monosaccharide). Polysaccharide analytical chemists can even estimate substituent distributions along the chain by partial hydrolysis of cellulose ethers to oligosaccharides (OS), determination of OS molecular weight and even identity by MS, and comparison of the OS distribution to that expected for random, blocky, and other model distributions28. However, precise monosaccharide sequences of cellulose ethers are largely black boxes, as are variations between polysaccharide chains, because we lack the necessary tools to measure them. Can we improve upon this analytical situation in order to more deeply understand cellulose ether structure, and thereby relate to things like preparative conditions, properties, and performance? Can mass spectrometric methods be developed that work more reliably for intact polysaccharide chains (whose DP values can be in the hundreds or higher, vs. limits of ca. 30 for MALDI-TOF MS)279,280? Can we go even further and analyze individual polysaccharide chains, e.g. by pulling chains through an aperture, as individual DNA chains are being analyzed today in genomic analyses281? Could analysis of such individual chains, averaged sensibly, afford far deeper structural understanding? Clearly analysis is an area of great future challenge and opportunity in polysaccharide chemistry in general, and in cellulose ether chemistry in particular. We anticipate that currently accessible cellulose ethers and cellulose ether esters, and the new functional derivatives of the future, will continue to grow in importance to pharmaceutical formulators as a result of their sustainable, renewable sources, and their appropriate structural, toxicity, and performance characteristics. Supporting Information



Page 62 of 81

The supporting information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.biomac. This information includes a table listing HPMC-containing pharmaceutical products, as well as the formula for calculating DS of an ether substituent from % substituent values.


Page 63 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

References: (1)

Nishiyama, Y.; Langan, P.; Chanzy, H. Crystal Structure and Hydrogen-Bonding System in Cellulose Iβ from Synchrotron X-Ray and Neutron Fiber Diffraction. J. Am. Chem. Soc. 2002, 124 (31), 9074–9082.

(2)

S. Yamanaka; K. Watanabe; N. Kitamura; M. Iguchi; S. Mitsuhashi; Y. Nishi; Uryu, M. The Structure and Mechanical Properties of Sheets Prepared from Bacterial Cellulose. J. Mater. Sci. 1989, 24 (9), 3141–3145.

(3)

Gross, R. A.; Kalra, B. Biodegradable Polymers for the Environment. Science 2002, 297 (5582), 803–807.

(4)

Chandra R.; Rustgi R. Biodegradable Polymers. Prog. Polym. Sci. 1998, 23, 1273– 1335.

(5)

Liu, H.; Ilevbare, G. A.; Cherniawski, B. P.; Ritchie, E. T.; Taylor, L. S.; Edgar, K. J. Synthesis and Structure-Property Evaluation of Cellulose ω-Carboxyesters for Amorphous Solid Dispersions. Carbohydr. Polym. 2014, 100, 116–125.

(6)

Cunha, A. G.; Gandini, A. Turning Polysaccharides into Hydrophobic Materials: A Critical Review. Part 1. Cellulose. Cellulose 2010, 17 (5), 875–889.

(7)

Edgar, K. J.; Buchanan, C. M.; Debenham, J. S.; Rundquist, P. A.; Seiler, B. D.; Shelton, M. C.; Tindall, D. Advances in Cellulose Ester Performance and Application. Prog. Polym. Sci. 2001, 26 (9), 1605–1688.

(8)

Aminabhavi, T. M.; Patil, G. V.; Balundgi, R. H.; Harlapur, S. F.; Manvi, F. V.; Bhaskar, C. A Review on the Sustained Release of Cardiovascular Drugs through Hydroxypropyl Methylcellulose and Sodium Carboxymethylcellulose Polymers. Des. Monomers Polym. 1998, 1 (4), 347–372.

(9)

Shojaei, A. H. Buccal Mucosa As A Route For Systemic Drug Delivery: A Review. J. Pharm. Pharm. Sci. 1998, 1 (1), 15–30.

(10)

Murtaza G. Ethylcellulose Microparticles: A Review. Acta Pol. Pharm. Drug Res. 2012, 69, 11–22.

(11)

Nasatto, P.; Pignon, F.; Silveira, J.; Duarte, M.; Noseda, M.; Rinaudo, M. Methylcellulose, a Cellulose Derivative with Original Physical Properties and Extended Applications. Polymers (Basel). 2015, 7 (5), 777–803.

(12)

Miller, K. S.; Krochta, J. M. Oxygen and Aroma Barrier Properties of Edible Films: A Review. Trends Food Sci. Technol. 1997, 8 (7), 228–237.

(13)

Cha, D. S.; Chinnan, M. S. Biopolymer-Based Antimicrobial Packaging: A Review. Crit. Rev. Food Sci. Nutr. 2004, 44 (4), 223–237.

(14)

Schultz, G. J. Grinding Process for High Viscosity Cellulose Ethers. 4,820,813, 1989.

(15)

Dolz, M.; Jiménez, J.; Hernández, M. J.; Delegido, J.; Casanovas, A. Flow and Thixotropy of Non-Contaminating Oil Drilling Fluids Formulated with Bentonite and Sodium Carboxymethyl Cellulose. J. Pet. Sci. Eng. 2007, 57 (3–4), 294–302.

(16)

Plank, J. Applications of Biopolymers and Other Biotechnological Products in Building Materials. Appl. Microbiol. Biotechnol. 2004, 66 (1), 1–9.

(17)

Gardnera, D. J.; Oportob, G. S.; Millsc, R.; Samir, A. S. Adhesion and Surface Issues in Cellulose and Nanocellulose. J Adhes. Sci Technol. 2008, 22 (5–6), 545–567.



Page 64 of 81

(18)

Petit, J.-Y.; Wirquin, E. Evaluation of Various Cellulose Ethers Performance in Ceramic Tile Adhesive Mortars. Int. J. Adhes. Adhes. 2013, 40, 202–209.

(19)

Spirk, S. Polysaccharides in Batteries; Springer, Cham, 2018; pp 9–57.

(20)

Badulescu, R.; Vivod, V.; Jausovec, D.; Voncina, B. Grafting of Ethylcellulose Microcapsules onto Cotton Fibers. Carbohydr. Polym. 2008, 71 (1), 85–91.

(21)

Cellulose Ethers Market By Derivative [Methyl, Ethyl & Carboxymethyl Cellulose] & Application [Pharmaceuticals, Personal Care, Construction, Food & Beverages, Surface Coatings & Paints] – Global Trends & Forecasts to 2017 .

(22)

Buchanan, C. M.; Edgar, K. J.; Hyatt, J. A.; Wilson, A. K. Preparation of Cellulose [1-C13]acetates and Determination of Monomer Composition by NMR Spectroscopy. Macromolecules 1991, 24 (11), 3050–3059.

(23)

Buchanan, C. M.; Edgar, K. J.; Wilson, A. K. Preparation and Characterization of Cellulose Monoacetates - the Relationship between Structure and Water Solubility. Macromolecules 1991, 24 (11), 3060–3064.

(24)

Mazeau, K.; Heux, L. Molecular Dynamics Simulations of Bulk Native Crystalline and Amorphous Structures of Cellulose. J. Phys. Chem. B 2003, 107 (10), 2394–2403.

(25)

Klemm, D.; Heublein, B.; Fink, H.-P.; Bohn, A. Cellulose: Fascinating Biopolymer and Sustainable Raw Material. Angew. Chemie Int. Ed. English 2005, 44, 3358–3393.

(26)

Ioelovich, M. Cellulose as a Nanostructured Polymer: A Short Review. BioResources 2008, 3, 1403–1418.

(27)

Mischnick, P.; Adden, R. Fractionation of Polysaccharide Derivatives and Subsequent Analysis to Differentiate Heterogeneities on Various Hierarchical Levels. Macromol. Symp. 2008, 262 (1), 1–7.

(28)

Mischnick, P.; Momcilovic, D. Chemical Structure Analysis of Starch and Cellulose Derivatives. In Advances in Carbohydrate Chemistry and Biochemistry; Elsevier: London, 2010; pp 117–210.

(29)

Schupper, N.; Rabin, Y.; Rosenbluh, M. Multiple Stages in the Aging of a Physical Polymer Gel. Macromolecules 2008, 41 (11), 3983–3994.

(30)

Volkert, B.; Wagenknecht, W. Substitution Patterns of Cellulose Ethers - Influence of the Synthetic Pathway. Macromol. Symp. 2008, 262, 97–118.

(31)

Spurlin, H. M. Arrangement of Substituents in Cellulose Derivatives. J. Am. Chem. Soc. 1939, 61 (8), 2222–2227.

(32)

Mischnick, P. Mass Spectrometric Characterization of Oligo- and Polysaccharides and Their Derivatives. In Mass Spectrometry of Polymers - New Techniques; Hakkarainen, M., Ed.; Springer Berlin Heidelberg: Berlin, Heidelberg, 2012; pp 105–174.

(33)

Reuben, J. Analysis of the 13C-N.m.r. Spectra of Hydrolyzed and Methanolyze OMethylcelluloses: Monomer Compositions and Models for Their Description. Carbohydr. Res. 1986, 157, 201–213.

(34)

Heinze, T.; Koschella, A. Carboxymethl Ethers of Cellulose and Stach- A Review. Macromol. Symp. 2005, 223 (1), 13–40.

(35)

Koschella, A.; Klemm, D. Silylation of Cellulose Regiocontrolled by Bulky Reagents and Dispersity in the Reaction Media. Macromol. Symp. 1997, 120 (1), 115–125.

(36)

Fox, S. C.; Li, B.; Xu, D.; Edgar, K. J. Regioselective Esterification and Etherification of


Page 65 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

Cellulose - A Review. Biomacromolecules 2011, 12, 1956–1972. (37)

Lorand, E. J. Cellulose Ethers Variations of Physical Properties with Composition. Ind. Eng. Chem. 1938, 30 (5), 527–530.

(38)

Lipinski, C. A. Rule of Five in 2015 and beyond: Target and Ligand Structural Limitations, Ligand Chemistry Structure and Drug Discovery Project Decisions. Adv. Drug Deliv. Rev. 2016, 101, 34–41.

(39)

Dong, Y.; Mosquera-Giraldo, L. I.; Taylor, L. S.; Edgar, K. J. Amphiphilic Cellulose Ethers Designed for Amorphous Solid Dispersion via Olefin Cross-Metathesis. Biomacromolecules 2016, 17 (2), 454–465.

(40)

Park, J.-S.; Ruckenstein, E. Viscoelastic Properties of Plasticized Methylcellulose and Chemically Crosslinked Methylcellulose. Carbohydr. Polym. 2001, 46 (4), 373–381.

(41)

Dong, Y.; Mosquera-Giraldo, L. I.; Troutman, J.; Skogstad, B.; Taylor, L. S.; Edgar, K. J. Amphiphilic Hydroxyalkyl Cellulose Derivatives for Amorphous Solid Dispersion Prepared by Olefin Cross-Metathesis. Polym. Chem. 2016, 7 (30), 4953–4963.

(42)

Marks, J. A.; Wegiel, L. A.; Taylor, L. S.; Edgar, K. J. Pairwise Polymer Blends for Oral Drug Delivery. J. Pharm. Sci. 2014, 103 (9), 2871–2883.

(43)

Fedors, R. F. A Method for Estimating Both the Solubility Parameters and Molar Volumes of Liquids. Polym. Eng. Sci. 1974, 14 (2), 147–154.

(44)

O’Donnell, P. The Williams Dictionary of Biomaterials; The Liverpool University Press: Liverpool L69 3BX, 1999.

(45)

Safari J.; Zarnegar, Z. Advanced Drug Delivery Systems: Nanotechnology of Health Design A Review. J. Saudi Chem. Soc. 2014, 18, 85–99.

(46)

Posey-Dowty, J. D.; Watterson, T. L.; Wilson, A. K.; Edgar, K. J.; Shelton, M. C.; Lingerfelt, L. R. Zero-Order Release Formulations Using a Novel Cellulose Ester. Cellulose 2007, 14 (1), 73–83.

(47)

Li, B.; Konecke, S.; Harich, K.; Wegiel, L.; Taylor, L. S.; Edgar, K. J. Solid Dispersion of Quercetin in Cellulose Derivative Matrices Influences Both Solubility and Stability. Carbohydr. Polym. 2013, 92 (2), 2033–2040.

(48)

Pereira, J. M.; Mejia-Ariza, R.; Ilevbare, G. A.; McGettigan, H. E.; Sriranganathan, N.; Taylor, L. S.; Davis, R. M.; Edgar, K. J. Interplay of Degradation, Dissolution and Stabilization of Clarithromycin and Its Amorphous Solid Dispersions. Mol. Pharm. 2013, 10 (12), 4640–4653.

(49)

Liu, H.; Ilevbare, G. A.; Cherniawski, B. P.; Ritchie, E. T.; Taylor, L. S.; Edgar, K. J. Synthesis and Structure–property Evaluation of Cellulose ω-Carboxyesters for Amorphous Solid Dispersions. Carbohydr. Polym. 2014, 100 (0), 116–125.

(50)

Bigucci, F.; Abruzzo, A.; Cerchiara, T.; Gallucci, M. C.; Luppi, B. Formulation of Cellulose Film Containing Permeation Enhancers for Prolonged Delivery of Propranolol Hydrocloride. Drug Dev. Ind. Pharm. 2014, 1–9.

(51)

Gupta, V.; Singh, S.; Srivarstava, M.; Ahmad, H.; Pachauri, S. D.; Khandelwal, K.; Dwivedi, P.; Dwivedi, A. K. Effect of Polydimethylsiloxane and Ethylcellulose on in Vitro Permeation of Centchroman from Its Transdermal Patches. Drug Deliv. 2016, 23, 113–122.

(52)

Fini, A.; Bergamante, V.; Ceschel, G. C. Mucoadhesive Gels Designed for the Controlled Release of Chlorhexidine in the Oral Cavity. Pharmaceutics 2011, 3 (4), 665–679.



Page 66 of 81

(53)

Sushma, M.; Raju, Y. P.; Sundaresan, C. R.; Vandana, K. R.; Kumar, N. V; Chowdary, V. H. Transmucosal Delivery of Metformin- a Comprehensive Study. Curr. Drug Deliv. 2014, 11 (2), 172–178.

(54)

Serlin, M. J.; Orme, M. L.; MacIver, M.; Green, G. J.; Sibeon, R. G.; Breckenridge, A. M. The Pharmacodynamics and Pharmacokinetics of Conventional and Long-Acting Propranolol in Patients with Moderate Hypertension. Br. J. Clin. Pharmacol. 1983, 15 (5), 519–527.

(55)

Brazel, C. S.; Peppas, N. A. Modeling of Drug Release from Swellable Polymers. Eur. J. Pharm. Biopharm. 2000, 49 (1), 47–58.

(56)

Kasim, N. A.; Whitehouse, M.; Ramachandran, C.; Bermejo, M.; Lennernas, H.; Hussain, A. S.; Junginger, H. E.; Stavchansky, S. A.; Midha, K. K.; Shah, V. P.; et al. Molecular Properties of WHO Essential Drugs and Provisional Biopharmaceutical Classification. Mol. Pharm. 2004, 1 (1), 85–96.

(57)

Murdande, S. B.; Pikal, M. J.; Shanker, R. M.; Bogner, R. H. Aqueous Solubility of Crystalline and Amorphous Drugs: Challenges in Measurement. Pharm. Dev. Technol. 2011, 16 (3), 187–200.

(58)

Williams, H. D.; Trevaskis, N. L.; Charman, S. A.; Shanker, R. M.; Charman, W. N.; Pouton, C. W.; Porter, C. J. Strategies to Address Low Drug Solubility in Discovery and Development. Pharmacol. Rev. 2013, 65 (1), 315–499.

(59)

Ilevbare, G. A.; Liu, H.; Pereira, J.; Edgar, K. J.; Taylor, L. S. Influence of Additives on the Properties of Nanodroplets Formed in Highly Supersaturated Aqueous Solutions of Ritonavir. Mol. Pharm. 2013, 10 (9).

(60)

Ilevbare, G. A.; Taylor, L. S. Liquid–Liquid Phase Separation in Highly Supersaturated Aqueous Solutions of Poorly Water-Soluble Drugs: Implications for Solubility Enhancing Formulations. Cryst. Growth Des. 2013, 13 (4), 1497–1509.

(61)

N. Shah D. Choi, H. Chokshi, Malick A.W., H. S. Amorphous Solid Dispersions Theory and Practice; Rathbone, M., Ed.; Advances in Delivery Science and Technology: London, 2014.

(62)

Hancock, B. C.; Zografi, G. Characteristics and Significance of the Amorphous State in Pharmaceutical Systems. J. Pharm. Sci. 1997, 86 (1), 1–12.

(63)

Ilevbare, G. A. .; Liu, H. .; Edgar, K. J. .; Taylor, L. S. Maintaining Supersaturation in Aqueous Drug Solutions: Impact of Different Polymers on Induction Times. Cryst. Growth Des. 2013, 13 (2), 740–751.

(64)

Shaw, J.; Urquhart, J. Programmed, Systemic Drug Delivery by the Transdermal Route. Trends Pharmacol. Sci. 1979, 1 (1), 208–211.

(65)

Chetkowski, R. J.; Meldrum, D. R.; Steingold, K. A.; Randle, D.; Lu, J. K.; Eggena, P.; Hershman, J. M.; Alkjaersig, N. K.; Fletcher, A. P.; Judd, H. L. Biologic Effects of Transdermal Estradiol. N. Engl. J. Med. 1986, 314 (25), 1615–1620.

(66)

Prausnitz, M. R.; Langer, R. Transdermal Drug Delivery. Nat. Biotechnol. 2008, 26 (11), 1261–1268.

(67)

Valenta, C. The Use of Mucoadhesive Polymers in Vaginal Delivery. Adv. Drug Deliv. Rev. 2005, 57 (11), 1692–712.

(68)

Kanios, D. Compositions and Methods to Effect the Release Profile in the Transdermal Administration of Active Agents. 6,638,528 B1, 2003.


Page 67 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

(69)

Alderman, D. Sustained Release Dosage Form Based on Highly Plasticized Cellulose Ether Gels. 4,695,464, 1987.

(70)

Morales, J. O.; McConville, J. T. Manufacture and Characterization of Mucoadhesive Buccal Films. Eur. J. Pharm. Biopharm. 2011, 77 (2), 187–199.

(71)

Abruzzo, A.; Bigucci, F.; Cerchiara, T.; Cruciani, F.; Vitali, B.; Luppi, B. Mucoadhesive Chitosan/gelatin Films for Buccal Delivery of Propranolol Hydrochloride. Carbohydr. Polym. 2011, 87, 581–588.

(72)

Hansen, K.; Kim, G.; Desai, K.-G. H.; Patel, H.; Olsen, K. F.; Curtis-Fisk, J.; Tocce, E.; Jordan, S.; Schwendeman, S. P. Feasibility Investigation of Cellulose Polymers for Mucoadhesive Nasal Drug Delivery Applications. Mol. Pharm. 2015, 12 (8), 2732– 2741.

(73)

Khutoryanskaya, O. V.; Morrison, P. W. J.; Seilkhanov, S. K.; Mussin, M. N.; Ozhmukhametova, E. K.; Rakhypbekov, T. K.; Khutoryanskiy, V. V. Hydrogen-Bonded Complexes and Blends of Poly(acrylic Acid) and Methylcellulose: Nanoparticles and Mucoadhesive Films for Ocular Delivery of Riboflavin. Macromol. Biosci. 2014, 14 (2), 225–234.

(74)

Khare, A.; Grover, K.; Pawar, P.; Singh, I. Mucoadhesive Polymers for Enhancing Retention in Ocular Drug Delivery: A Critical Review. Rev. Adhes. Adhes. 2014, 2 (4), 467–502.

(75)

Suzuki, Y.; Ikura, H.; Yamashita, G. Slow-Releasing Medical Preparation to Be Administered by Adhering to a Wet Mucous Surface. 4,292,299, 1981.

(76)

Schneider, J. S.; Koleng, J. J.; Florentine, R.; Anderson, D. W. Ganglioside Transmucosal Formulations. 13/407,296, 2012.

(77)

Williamson, A. W. XXII.—On Etherification. J. Chem. Soc. 1852, 4, 229–239.

(78)

Kamel, S.; Ali, N.; Jahangir, K.; Shah, S. M.; El-Gendy, A. A. Pharmaceutical Significance of Cellulose: A Review. eXPRESS Polym. Lett. 2008, 2 (11), 758–778.

(79)

Heinze, T.; Liebert, T.; Klüfers, P.; Meister, F. Carboxymethylation of Cellulose in Unconventional Media. Cellulose 1999, 6 (2), 153–165.

(80)

Heinze, T.; Erler, U.; Nehls, I.; Klemm, D. Determination of the Substituent Pattern of Heterogeneously and Homogeneously Synthesized Carboxymethyl Cellulose by Using High-Performance Liquid Chromatography. Die Angew. Makromol. Chemie 2003, 215 (1), 93–106.

(81)

Bhandaria, P. N.; Jones, D. D.; Hanna, M. A. Carboxymethylation of Cellulose Using Reactive Extrusion. Carbohydr. Polym. 2012, 87, 2246–2254.

(82)

Baar, A.; Kulicke, W.-M.; Szablikowski, K.; Kiesewetter, R. Nuclear Magnetic Resonance Spectroscopic Characterization of Carboxymethylcellulose. Macromol. Chem. Phys. 1994, 195 (5), 1483–1492.

(83)

Garrett, Q.; Simmons, P. A.; Xu, S.; Vehige, J.; Zhao, Z.; Ehrmann, K.; Willcox, M. Carboxymethylcellulose Binds to Human Corneal Epithelial Cells and Is a Modulator of Corneal Epithelial Wound Healing. Invest. Ophthalmol. Vis. Sci. 2007, 48 (4), 1559– 1567.

(84)

He, F.; Zhao, D. Manipulating the Size and Dispersibility of Zerovalent Iron Nanoparticles by Use of Carboxymethyl Cellulose Stabilizers. Environ. Sci.Technol. 2007, 41 (17), 6216–6221.



Page 68 of 81

(85)

Wan, L. S. C.; Prasad, K. P. P. Uptake of Water into Tablets with Low-Substituted Carboxymethyl Cellulose Sodium as Disintegrant. Int. J. Pharm. 1989, 55 (2–3), 115– 121.

(86)

Varshosaz, J.; Dehghan, Z. Development and Characterization of Buccoadhesive Nifedipine Tablets. Eur. J. Pharm. Biopharm. 2002, 54 (2), 135–141.

(87)

Badwaik, L. S.; Borah, P. K.; Deka, S. C. Antimicrobial and Enzymatic Antibrowning Film Used as Coating for Bamboo Shoot Quality Improvement. Carbohydr. Polym. 2014, 103, 213–220.

(88)

Saha, S.; Tomaro-Duchesneau, C.; Daoud, J. T.; Tabrizian, M.; Prakash, S. Novel Probiotic Dissolvable Carboxymethyl Cellulose Films as Oral Health Biotherapeutics: In Vitro Preparation and Characterization. Expert Opin. Drug Deliv. 2013, 10 (11), 1471–1482.

(89)

Desai, P. M.; Liew, C. V.; Heng, P. W. S. Review of Disintegrants and the Disintegration Phenomena. J. Pharm. Sci. 2016, 105 (9), 2545–2555.

(90)

Shah, S. U.; Shah, K. U.; Rehman, A.; Khan, G. M. Investigating the in Vitro Drug Release Kinetics from Controlled Release Diclofenac Potassium-Ethocel Matrix Tablets and the Influence of Co-Excipients on Drug Release Patterns. Pak. J. Pharm. Sci. 2011, 24 (2), 183–192.

(91)

Panda, R. R.; Tiwary, A. K. Formulation and Optimization of Osmotically Controlled Release Tablets of Glipizide: Hot Melt Granulation. Ther. Deliv. 2010, 1 (6), 763–774.

(92)

Sotthivirat, S.; Haslam, J. L.; Lee, P. I.; Rao, V. M.; Stella, V. J. Release Mechanisms of a Sparingly Water-Soluble Drug from Controlled Porosity-Osmotic Pump Pellets Using Sulfobutylether-Beta-Cyclodextrin as Both a Solubilizing and Osmotic Agent. J. Pharm. Sci. 2009, 98 (6), 1992–2000.

(93)

Chen, R. N.; Ho, H. O.; Yu, C. Y.; Sheu, M. T. Development of Swelling/floating Gastroretentive Drug Delivery System Based on a Combination of Hydroxyethyl Cellulose and Sodium Carboxymethyl Cellulose for Losartan and Its Clinical Relevance in Healthy Volunteers with CYP2C9 Polymorphism. Eur. J. Pharm. Sci. 2010, 39 (1–3), 82–89.

(94)

Varshosaz, J.; Tavakoli, N.; Eram, S. A. Use of Natural Gums and Cellulose Derivatives in Production of Sustained Release Metoprolol Tablets. Drug Deliv. 2006, 13 (2), 113–119.

(95)

Khan, G. M.; Zhu, J. B. Ibuprofen Release Kinetics from Controlled-Release Tablets Granulated with Aqueous Polymeric Dispersion of Ethylcellulose II: Influence of Several Parameters and Coexcipients. J. Control. Release 1998, 56 (1–3), 127–134.

(96)

Rahmani-Neishaboor, E.; Jallili, R.; Hartwell, R.; Leung, V.; Carr, N.; Ghahary, A. Topical Application of a Film-Forming Emulgel Dressing That Controls the Release of Stratifin and Acetylsalicylic Acid and Improves/prevents Hypertrophic Scarring. Wound Repair Regen. 2013, 21 (1), 55–65.

(97)

Ghanbarzadeha, B.; Almasia, H.; Entezamib, A. A. Physical Properties of Edible Modified Starch/carboxymethyl Cellulose Films. Innov. Food Sci. Emerg. Technol. 2010, 11 (4), 697–702.

(98)

Qiu, X.; Leporatti, S.; Donath, E.; Möhwald, H. Studies on the Drug Release Properties of Polysaccharide Multilayers Encapsulated Ibuprofen Microparticles. Langmuir 2001, 17 (17), 5375–5380.


Page 69 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

(99)

Jiménez-Castellanos, M. R.; Ziaa, H.; Rhodesa, C. T. Design and Testing in Vitro of a Bioadhesive and Floating Drug Delivery System for Oral Application. Int. J. Pharm. 1994, 105 (1), 65–70.

(100) Ranga Rao, K. V.; Buri, P. A Novel in Situ Method to Test Polymers and Coated Microparticles for Bioadhesion. Int. J. Pharm. 1989, 52 (2), 265–270. (101) Varshosaz, J.; Tavakoli, N.; Roozbahani, F. Formulation and in Vitro Characterization of Ciprofloxacin Floating and Bioadhesive Extended-Release Tablets. Drug Deliv. 2006, 13 (4), 277–285. (102) Sudhakar, Y.; Kuotsu, K.; Bandyopadhyay, A. K. Buccal Bioadhesive Drug Delivery — A Promising Option for Orally Less Efficient Drugs. J. Control. Release 2006, 114 (1), 15–40. (103) Nafee, N. A.; Ismail, F. A.; Boraie, N. A.; Mortada, L. M. Mucoadhesive Buccal Patches of Miconazole Nitrate: In Vitro/in Vivo Performance and Effect of Ageing. Int. J. Pharm. 2003, 264, 1–14. (104) Semalty, M.; Semalty, A.; Kumar, G. Formulation and Characterization of Mucoadhesive Buccal Films of Glipizide. Indian J. Pharm. Sci. 2008, 70 (1), 43–48. (105) Dortunc, B.; Ozer, L.; Uyanik, N. Development and in Vitro Evaluation of a Buccoadhesive Pindolol Tablet Formulation. Drug Dev. Ind. Pharm. 1998, 24 (3), 281–288. (106) Ali, J.; Khar, R.; Ahuja, A.; Kalra, R. Buccoadhesive Erodible Disk for Treatment of OroDental Infections: Design and Characterisation. Int. J. Pharm. 2002, 238 (1–2), 93– 103. (107) Perioli, L.; Ambrogi, V.; Rubini, D.; Giovagnoli, S.; Ricci, M.; Blasi, P.; Rossi, C. Novel Mucoadhesive Buccal Formulation Containing Metronidazole for the Treatment of Periodontal Disease. J. Control. Release 2004, 95 (3), 521–533. (108) Parvez N.; Ahuja A. Development and Evaluation of Muco-Adhesive Buccal Tablets of Lignocaine Hydrochloride. Indian J. Pharm. Sci. 2002, 64 (6), 563–567. (109) Mohammed, F. A.; Khedr, H. Preparation and in Vitro/in Vivo Evaluation of the Buccal Bioadhesive Properties of Slow-Release Tablets Containing Miconazole Nitrate. Drug Dev. Ind. Pharm. 2003, 29 (3), 321–337. (110) Ali, J.; Khar, R. K.; Ahuja, A. Formulation and Characterisation of a Buccoadhesive Erodible Tablet for the Treatment of Oral Lesions. Pharmazie 1998, 53 (5), 329–334. (111) FDA Inactive Ingredient Database for Approved Drug Products https://www.fda.gov/drugs/informationondrugs/ucm113978.htm. (112) Vehige, J. G.; Simmons, P. A.; Anger, C.; Graham, R.; Tran, L.; Brady, N. Cytoprotective Properties of Carboxymethyl Cellulose (CMC) When Used prior to Wearing Contact Lenses Treated with Cationic Disinfecting Agents. Eye Contact Lens 2003, 29 (3), 177–180. (113) Alam, M. A.; Ahmad, F. J.; Khan, Z. I.; Khar, R. K.; Ali, M. Development and Evaluation of Acid-Buffering Bioadhesive Vaginal Tablet for Mixed Vaginal Infections. AAPS PharmSciTech 2007, 8 (4), E109. (114) Sharma, G.; Jain, S.; Tiwary, A. K.; Kaur, G. Once Daily Bioadhesive Vaginal Clotrimazole Tablets: Design and Evaluation. Acta Pharm. 2006, 56 (3), 337–345. (115) Genc, L.; Oguzlar, C.; Guler, E. Studies on Vaginal Bioadhesive Tablets of Acyclovir.



Page 70 of 81

Pharmazie 2000, 55 (4), 297–299. (116) Karasulu, H. Y.; Hilmioglu, S.; Metin, D. Y.; Guneri, T. Efficacy of a New Ketoconazole Bioadhesive Vaginal Tablet on Candida Albicans. Farmaco 2004, 59 (2), 163–167. (117) Keary, C. M. Characterization of METHOCEL Cellulose Ethers by Aqueous SEC with Multiple Detectors. Carbohydr. Polym. 2001, 45 (3), 293–303. (118) Kondo, T. The Relationship between Intramolecular Hydrogen Bonds and Certain Physical Properties of Regioselectively Substituted Cellulose Derivatives. J. Polym. Sci. Part B Polym. Phys. 1997, 35 (4), 717–723. (119) Bock, L. H. Water Soluble Cellulose Ethers. Ind. Eng. Chem. 1937, 29 (9), 985–988. (120) Nakagawa, A.; Fenn, D.; Koschella, A.; Heinze, T.; Kamitakahara, H. Physical Properties of Diblock Methylcellulose Derivatives with Regioselective Functionalization Patterns: First Direct Evidence That a Sequence of 2,3,6-Tri-OMethyl-Glucopyranosyl Units Causes Thermoreversible Gelation of Methylcellulose. J. Polym. Sci. Part B Polym. Phys. 2011, 49 (21), 1539–1546. (121) Kobayashi, K.; Huang, C.-I.; Lodge, T. P. Thermoreversible Gelation of Aqueous Methylcellulose Solutions. Macromolecules 1999, 32, 7070–7077. (122) Sarkar, N. Kinetics of Thermal Gelation of Methylcellulose and Hydroxypropylmethylcellulose in Aqueous Solutions. Carbohydr. Polym. 1995, 26 (3), 195–203. (123) Li, L. Thermal Gelation of Methylcellulose in Water: Scaling and Thermoreversibility. Macromolecules 2002, 35 (15), 5990–5998. (124) Arvidson, S. A.; Lott, J. R.; McAllister, J. W.; Zhang, J.; Bates, F. S.; Lodge, T. P.; Sammler, R. L.; Li, Y.; Brackhagen, M. Interplay of Phase Separation and Thermoreversible Gelation in Aqueous Methylcellulose Solutions. Macromolecules 2013, 46 (1), 300– 309. (125) Balaghi, S.; Edelby, Y.; Senge, B. Evaluation of Thermal Gelation Behavior of Different Cellulose Ether Polymers by Rheology. AIP Conf. Proc. 2014, 1593. (126) Desbrières, J. A Calorimetric Study of Methylcellulose Gelation. Carbohydr. Polym. 1998, 37 (2), 145–152. (127) Takahashi, S. I.; Fujimoto, T.; Miyamoto, T.; Inagaki, H. Relationship between Distribution of Substituents and Water Solubility of O-Methyl Cellulose. J. Polym. Sci. Part A Polym. Chem. 1987, 25 (4), 987–994. (128) Desbrières, J.; Hirrien, M.; Rinaudo, M. Thermogelation of Methylcellulose: Rheological Considerations. Polymer (Guildf). 2000, 41 (7), 2451–2461. (129) Hirrien, M.; Desbrières, J.; Rinaudo, M. Physical Properties of Methylcelluloses in Relation with the Conditions for Cellulose Modification. Carbohydr. Polym. 1996, 31 (4), 243–252. (130) Landoll, L. M. Modified Nonionic Cellulose Ethers. US4228277 A, October 1980. (131) Nyström, C.; Mazur, J.; Sjögren, J. Studies on Direct Compression of Tablets II. The Influence of the Particle Size of a Dry Binder on the Mechanical Strength of Tablets☆. Int. J. Pharm. 1982, 10 (3), 209–218. (132) Sahoo, G. P.; Bhui, D. K.; Bar, H.; Sarkar, P.; Samanta, S.; Pyne, S.; Misra, A. Synthesis and Characterization of Gold Nanoparticles Adsorbed in Methyl Cellulose Micro


Page 71 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

Fibrils. J. Mol. Liq. 2010, 155 (2–3), 91–95. (133) Johnston, D.; Gray, M. R.; Reed, C. S.; Bonner, F. W.; Anderson, N. H. A Comparative Evaluation of Five Common Suspending Agents Used in Drug Safety Studies. Drug Dev. Ind. Pharm. 1990, 16 (12), 1893–1909. (134) Kanig, J. L.; Goodman, H. Evaluative Procedures for Film-Forming Materials Used in Pharmaceutical Applications. J. Pharm. Sci. 1962, 51 (1), 77–83. (135) Nerurkar, J.; Jun, H. W.; Price, J. C.; Park, M. O. Controlled-Release Matrix Tablets of Ibuprofen Using Cellulose Ethers and Carrageenans: Effect of Formulation Factors on Dissolution Rates. Eur. J. Pharm. Biopharm. 2005, 61 (1–2), 56–68. (136) Sharma, V.; Chopra, H. Role Of Taste And Taste Masking Of Bitter Drugs In Pharmaceutical Industries An Overview. Int. J. Pharm. Pharm. Sci. 2010, 2 (4), 14–18. (137) Debeaufort, F.; Voilley, A. Methyl Cellulose-Based Edible Films and Coatings I. Effect of Plasticizer Content on Water and 1-Octen-3-Ol Sorption and Transport. Cellulose 1995, 2 (3), 205–2013. (138) Debeaufort, F.; Voilley, A. Methylcellulose-Based Edible Films and Coatings: 2. Mechanical and Thermal Properties as a Function of Plasticizer Content. J. Agric. Food Chem. 1997, 45 (3), 685−689. (139) Arvanitoyannis, I.; Biliaderis, C. G. Physical Properties of Polyol-Plasticized Edible Blends Made of Methyl Cellulose and Soluble Starch. Carbohydr. Polym. 1999, 38 (1), 47–58. (140) Olabisi, O.; Robeson, L. M.; Shaw, M. T. Polymer-Polymer Miscibility; Academic Press.: New York, 1979. (141) Lilienfeld, A. Manufacture of Cellulose Derivatives. US2265917 A, December 1941. (142) Rekhi, G. S.; Jambhekar, S. S. Ethylcellulose - A Polymer Review. Drug Dev. Ind. Pharm. 1995, 21, 61–77. (143) Donges, R. Non-Ionic Cellulose Ethers. Br. Polym. J. 1990, 23 (4), 315–326. (144) Dow Chemical Company Ethyl Cellulose Polymers Technical Handbook. (145) Verhoeven, E.; De Beer, T. R. M.; Van den Mooter, G.; Remon, J. P.; Vervaet, C. Influence of Formulation and Process Parameters on the Release Characteristics of Ethylcellulose Sustained-Release Mini-Matrices Produced by Hot-Melt Extrusion. Eur. J. Pharm. Biopharm. 2008, 69 (1), 312–319. (146) Murtaza G.; Ahmad A.; Waheed A. A.; M., N. A. Salbutamol Sulphate-Ethylcellulose Microparticles: Formulation and in-Vitro Evaluation with Emphasis on Mathematical Approaches. DARU J. Pharm. Sci. 2009, 17 (3), 209–217. (147) Finelli L.; Scandola M.; P., S. Biodegradation of Blends of Bacterial poly(3Hydroxybutyrate) with Ethyl Cellulose in Activated Sludge and in Enzymatic Solution. Macromol. Chem. Phys. 1998, 199 (4), 695–703. (148) Huang, J.; Wigent, R. J.; Schwartz, J. B. Nifedipine Molecular Dispersion in Microparticles of Ammonio Methacrylate Copolymer and Ethylcellulose Binary Blends for Controlled Drug Delivery: Effect of Matrix Composition. Drug Dev. Ind. Pharm. 2006, 32 (10), 1185–1197. (149) Khan, G. M.; Meidan, V. M. Drug Release Kinetics from Tablet Matrices Based upon Ethylcellulose Ether-Derivatives: A Comparison between Different Formulations.



Page 72 of 81

Drug Dev. Ind. Pharm. 2007, 33 (6), 627–639. (150) Gohel, M. C.; Nagori, S. A. Fabrication of Modified Transport Fluconazole Transdermal Spray Containing Ethyl Cellulose and Eudragit RS100 as Film Formers. AAPS PharmSciTech 2009, 10 (2), 684–691. (151) Muschert, S.; Siepmann, F.; Leclercq, B.; Carlin, B.; Siepmann, J. Prediction of Drug Release from Ethylcellulose Coated Pellets. J. Control. Release 2009, 135 (1), 71–79. (152) Avanço, G. B.; Bruschi, M. L. Preparation and Characterisation of Ethylcellulose Microparticles Containing Propolis. Rev. Ciênc. Farm. Básica Apl., 2008, 29 (2), 129– 135. (153) Vynckier, A. K.; Dierickx, L.; Saerens, L.; Voorspoels, J.; Gonnissen, Y.; De Beer, T.; Vervaet, C.; Remon, J. P. Hot-Melt Co-Extrusion for the Production of Fixed-Dose Combination Products with a Controlled Release Ethylcellulose Matrix Core. Int. J. Pharm. 2014, 464 (1–2), 65–74. (154) Verhoeven, E.; De Beer, T. R.; Schacht, E.; Van den Mooter, G.; Remon, J. P.; Vervaet, C. Influence of Polyethylene Glycol/polyethylene Oxide on the Release Characteristics of Sustained-Release Ethylcellulose Mini-Matrices Produced by Hot-Melt Extrusion: In Vitro and in Vivo Evaluations. Eur. J. Pharm. Biopharm. 2009, 72 (2), 463–470. (155) Zhang, Z. Y.; Ping, Q. N.; Xiao, B. Microencapsulation and Characterization of Tramadol-Resin Complexes. J. Control. Release 2000, 66 (2–3), 107–113. (156) Desai, R. P.; Neau, S. H.; Pather, S. I.; Johnston, T. P. Fine-Particle Ethylcellulose as a Tablet Binder in Direct Compression, Immediate-Release Tablets. Drug Dev. Ind. Pharm. 2001, 27 (7), 633–641. (157) Shah, S.; Shah, K.; Jan, S. U.; Ahmad, K.; Rehman, A.; Hussain, A.; Khan, G. M. Formulation and in Vitro Evaluation of Ofloxacin-Ethocel Controlled Release Matrix Tablets Prepared by Wet Granulation Method: Influence of Co-Excipients on Drug Release Rates. Pak. J. Pharm. Sci. 2011, 24 (3), 255–261. (158) Wahab A; Khan G.M.; Akhlaq M.; Khan N.R.; Hussain A.; Zeb A.; Rehman A.; Shah K.U. Pre-Formulation Investigation and in Vitro Evaluation of Directly Compressed Ibuprofen-Ethocel Oral Controlled Release Matrix Tablets: A Kinetic Approach. African J. Pharm. Pharmacol. 2011, 5 (19), 2118–2127. (159) Sanchez-Lafuente, C.; Furlanetto, S.; Fernandez-Arevalo, M.; Alvarez-Fuentes, J.; Rabasco, A. M.; Faucci, M. T.; Pinzauti, S.; Mura, P. Didanosine Extended-Release Matrix Tablets: Optimization of Formulation Variables Using Statistical Experimental Design. Int. J. Pharm. 2002, 237 (1–2), 107–118. (160) Sanchez-Lafuente, C.; Teresa Faucci, M.; Fernandez-Arevalo, M.; Alvarez-Fuentes, J.; Rabasco, A. M.; Mura, P. Development of Sustained Release Matrix Tablets of Didanosine Containing Methacrylic and Ethylcellulose Polymers. Int. J. Pharm. 2002, 234 (1–2), 213–221. (161) Pollock, D. K. Influence of Filler/binder Composition on the Properties of an Inert Matrix CR System. Proc. Int. Symp. Control. Release Bioact. Mater. 1997, 24, 481–482. (162) Eichie F.L.; Okor R.S. Parameters to Be Considered in the Simulation of Drug Release from Aspirin Crystals and Their Microcapsules. Trop. J. Pharm. Res. 2002, 1 (2), 99– 110. (163) Dailey O.D.; Dowler C.C. Polymeric Microcapsules of Cyanazine: Preparation and


Page 73 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

Evaluation of Efficacy. J. Agric. Food Chem 1998, 46 (9), 3823–3827. (164) Mastiholimath, V. S.; Dandagi, P. M.; Gadad, A. P.; Mathews, R.; Kulkarni, A. R. In Vitro and in Vivo Evaluation of Ranitidine Hydrochloride Ethyl Cellulose Floating Microparticles. J. Microencapsul. 2008, 25 (5), 307–314. (165) Palmieri G. F.; Wehrle P. Evaluation of Ethylcellulose-Coated Pellets Optimized Using the Approach of Taguchi. Drug Dev. Ind. Pharm. 1997, 23 (11), 1069–1077. (166) Milojevic S.; Newton J.M.; Cummings J.H.; Gibson G.R.; Botham R.L.; Ring S.G.; Stockham M.; Allwood M.C. Amylose as a Coating for Drug Delivery to the Colon: Preparation and in Vitro Evaluation Using 5-Aminosalicylic Acid Pellets. J. Control. Release 1996, 38, 75–84. (167) Quinten, T.; De Beer, T.; Vervaet, C.; Remon, J. P. Evaluation of Injection Moulding as a Pharmaceutical Technology to Produce Matrix Tablets. Eur. J. Pharm. Biopharm. 2009, 71 (1), 145–154. (168) De Brabander, C.; Vervaet, C.; Remon, J. P. Development and Evaluation of Sustained Release Mini-Matrices Prepared via Hot Melt Extrusion. J. Control. Release 2003, 89 (2), 235–247. (169) Verhoeven, E.; Vervaet, C.; Remon, J. P. Xanthan Gum to Tailor Drug Release of Sustained-Release Ethylcellulose Mini-Matrices Prepared via Hot-Melt Extrusion: In Vitro and in Vivo Evaluation. Eur. J. Pharm. Biopharm. 2006, 63 (3), 320–330. (170) De Brabander, C.; Van Den Mooter, G.; Vervaet, C.; Remon, J. P. Characterization of Ibuprofen as a Nontraditional Plasticizer of Ethyl Cellulose. J. Pharm. Sci. 2002, 91 (7), 1678–1685. (171) Klucel Hydroxypropylcellulose Physical and chemical properties. (172) Guo, J.-H.; Skinner, G. .; Harcum, W. .; Barnum, P. . Pharmaceutical Applications of Naturally Occurring Water-Soluble Polymers. Pharm. Sci. Technolo. Today 1998, 1 (6), 254–261. (173) Imeson, A. Thickening and Gelling Agents for Food; Springer Science & Business Media, 2012. (174) Kamitakahara, H.; Funakoshi, T.; Nakai, S.; Takano, T.; Nakatsubo, F. Synthesis and Structure/property Relationships of Regioselective 2-O-, 3-O- and 6-O-Ethyl Celluloses. Macromol. Biosci. 2010, 10 (6), 638–647. (175) Dubolazov, A. V; Nurkeeva, Z. S.; Mun, G. A.; Khutoryanskiy, V. V. Design of Mucoadhesive Polymeric Films Based on Blends of Poly(acrylic Acid) and (Hydroxypropyl)cellulose. Biomacromolecules 2006, 7 (5), 1637–1643. (176) Nisso HPC at http://www.nissoexcipients.com/. (177) Crowley, M. M.; Zhang, F.; Repka, M. A.; Thumma, S.; Upadhye, S. B.; Battu, S. K.; McGinity, J. W.; Martin, C. Pharmaceutical Applications of Hot-Melt Extrusion: Part I. Drug Dev. Ind. Pharm. 2008, 33 (9), 909–926. (178) El-Zaher, N. A.; Osiris, W. G. Thermal and Structural Properties of Poly(vinyl Alcohol) Doped with Hydroxypropyl Cellulose. J. Appl. Polym. Sci. 2005, 96 (5), 1914–1923. (179) Repka, M. A.; Gerding, T. G.; Repka, S. L.; McGinity, J. W. Influence of Plasticizers and Drugs on the Physical-Mechanical Properties of Hydroxypropylcellulose Films Prepared by Hot Melt Extrusion. Drug Dev. Ind. Pharm. 1999, 25 (5), 625–633.



Page 74 of 81

(180) Picker-Freyer, K. M.; Dürig, T. Physical Mechanical and Tablet Formation Properties of Hydroxypropylcellulose: In Pure Form and in Mixtures. AAPS PharmSciTech 2007, 8 (4), E92. (181) Skinner, G. W.; Harcum, W. W.; Barnum, P. E.; Guo, J. H. The Evaluation of FineParticle Hydroxypropylcellulose as a Roller Compaction Binder in Pharmaceutical Applications. Drug Dev. Ind. Pharm. 1999, 25 (10), 1121–1128. (182) Klucel Hydroxypropylcellulose Hydrophilic Matrix System http://www.ashland.com/file_source/Ashland/Product/Documents/Pharmaceutical /PC_11229_Klucel_HPC.pdf. (183) Teixeira, A. Z. A. Hydroxypropylcellulose Controlled Release Tablet Matrix Prepared by Wet Granulation: Effect of Powder Properties and Polymer Composition. Brazilian Arch. Biol. Technol. 2009, 52 (1), 157–162. (184) Sinha Roy, D.; Rohera, B. D. Comparative Evaluation of Rate of Hydration and Matrix Erosion of HEC and HPC and Study of Drug Release from Their Matrices. Eur. J. Pharm. Sci. 2002, 16 (3), 193–199. (185) Sasa, B.; Odon, P.; Stane, S.; Julijana, K. Analysis of Surface Properties of Cellulose Ethers and Drug Release from Their Matrix Tablets. Eur. J. Pharm. Sci. 2006, 27 (4), 375–383. (186) Uekama, K.; Matsubara, K.; Abe, K.; Horiuchi, Y.; Hirayama, F.; Suzuki, N. Design and in Vitro Evaluation of Slow-Release Dosage Form of Piretanide: Utility of βCyclodextrin:cellulose Derivative Combination as a Modified-Release Drug Carrier. J. Pharm. Sci. 1990, 79 (3), 244–248. (187) Wang, Z.; Horikawa, T.; Hirayama, F.; Uekama, K. Design and In-Vitro Evaluation of a Modified-Release Oral Dosage Form of Nifedipine by Hybridization of Hydroxypropyl-β-Cyclodextrin and Hydroxypropylcellulose. J. Pharm. Pharmacol. 1993, 45 (11), 942–946. (188) Lakshman, J. P.; Kowalski, J.; Vasanthavada, M.; Tong, W.-Q.; Joshi, Y. M.; Serajuddin, A. T. M. Application of Melt Granulation Technology to Enhance Tabletting Properties of Poorly Compactible High-Dose Drugs. J. Pharm. Sci. 2011, 100 (4), 1553–1565. (189) Onoue, S.; Sato, H.; Ogawa, K.; Kawabata, Y.; Mizumoto, T.; Yuminoki, K.; Hashimoto, N.; Yamada, S. Improved Dissolution and Pharmacokinetic Behavior of Cyclosporine A Using High-Energy Amorphous Solid Dispersion Approach. Int. J. Pharm. 2010, 399 (1–2), 94–101. (190) Ozeki, T.; Yuasa, H.; Kanaya, Y. Application of the Solid Dispersion Method to the Controlled Release of Medicine. IX. Difference in the Release of Flurbiprofen from Solid Dispersions with Poly(ethylene Oxide) and Hydroxypropylcellulose and the Interaction between Medicine and Polymers. Int. J. Pharm. 1997, 155 (2), 209–217. (191) Mohammed, N. N.; Majumdar, S.; Singh, A.; Deng, W.; Murthy, N. S.; Pinto, E.; Tewari, D.; Durig, T.; Repka, M. A. KlucelTM EF and ELF Polymers for Immediate-Release Oral Dosage Forms Prepared by Melt Extrusion Technology. AAPS PharmSciTech 2012, 13 (4), 1158–1169. (192) Sugita, M.; Kataoka, M.; Sugihara, M.; Takeuchi, S.; Yamashita, S. Effect of Excipients on the Particle Size of Precipitated Pioglitazone in the Gastrointestinal Tract: Impact on Bioequivalence. AAPS J. 2014, 16 (5), 1119–1127. (193) Chan, L. W.; Wong, T. W.; Chua, P. C.; York, P.; Heng, P. W. Anti-Tack Action of


Page 75 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

Polyvinylpyrrolidone on Hydroxypropylmethylcellulose Solution. Chem. Pharm. Bull. (Tokyo). 2003, 51 (2), 107–112. (194) Li, C. L.; Martini, L. G.; Ford, J. L.; Roberts, M. The Use of Hypromellose in Oral Drug Delivery. J. Pharm. Pharmacol. 2005, 57 (5), 533–546. (195) Arisz, P.; Thai, H. T. T.; Boon, J. J.; Salomons, W. G. Changes in Substituent Distribution Patterns during the Conversion of Cellulose to O-(2-Hydroxyethyl)celluloses. Cellulose 1996, 3, 45–61. (196) Adden, R.; Müller, R.; Mischnick, P. Analysis of the Substituent Distribution in the Glucosyl Units and along the Polymer Chain of Hydroxypropylmethyl Celluloses and Statistical Evaluation. Cellulose 2006, 13 (4), 459–476. (197) Persson, B.; Nilsson, S.; Sundelof, L.-O. On the Characterization Principles of Some Technically Important Water-Soluble Nonionic Cellulose Derivatives. Part II: Surface Tension and Interaction with a Surfactant. Carbohydr. Polym. 1996, 29 (96), 119– 127. (198) Schram, C. J.; Taylor, L. S.; Beaudoin, S. P. Influence of Polymers on the Crystal Growth Rate of Felodipine: Correlating Adsorbed Polymer Surface Coverage to Solution Crystal Growth Inhibition. Langmuir 2015, 31 (41), 11279–11287. (199) Haque, A.; Richardson, R. K.; Morris, E. R.; Gidley, M. J.; Caswell, D. C. Thermogelation of Methylcellulose. Part II: Effect of Hydroxypropyl Substituents. Carbohydr. Polym. 1993, 22 (3), 175–186. (200) Dow Chemical Co. Chemistry of METHOCEL Cellulose Ethers - A Technical Review http://msdssearch.dow.com/PublishedLiteratureDOWCOM/dh_08e5/0901b803808 e5f58.pdf?filepath=dowwolff/pdfs/noreg/198-02289.pdf&fromPage=GetDoc. (201) Huang, S.; O’Donnell, K. P.; Keen, J. M.; Rickard, M. A.; McGinity, J. W.; Williams, R. O. A New Extrudable Form of Hypromellose: AFFINISOLTM HPMC HME. AAPS PharmSciTech 2016, 17 (1), 106–119. (202) Ford, J. L. Thermal Analysis of Hydroxypropylmethylcellulose and Methylcellulose: Powders, Gels and Matrix Tablets. Int. J. Pharm. 1999, 179 (2), 209–228. (203) Hanhijarvi, K.; Majava, T.; Kassamakov, I.; Heinamaki, J.; Aaltonen, J.; Haapalainen, J.; Haeggstrom, E.; Yliruusi, J. Scratch Resistance of Plasticized Hydroxypropyl Methylcellulose (HPMC) Films Intended for Tablet Coatings. Eur. J. Pharm. Biopharm. 2010, 74 (2), 371–376. (204) Liu, Z.; Li, J.; Nie, S.; Liu, H.; Ding, P.; Pan, W. Study of an alginate/HPMC-Based in Situ Gelling Ophthalmic Delivery System for Gatifloxacin. Int. J. Pharm. 2006, 315 (1–2), 12–17. (205) Melia, C. D. Hydrophilic Matrix Sustained Release Systems Based on Polysaccharide Carriers. Crit. Rev. Ther. Drug Carr. Syst. 1991, 8 (4), 395–421. (206) Jaipal, A.; Pandey, M. M.; Charde, S. Y.; Sadhu, N.; Srinivas, A.; Prasad, R. G. Controlled Release Effervescent Buccal Discs of Buspirone Hydrochloride: In Vitro and in Vivo Evaluation Studies. Drug Deliv. 2014, 1–7. (207) Cha, D. S.; Chinnan, M. S. Biopolymer-Based Antimicrobial Packaging: A Review. Crit. Rev. Food, Sci. Nutr. 2004, 44 (4), 223–237. (208) Drozen M.S. GRAS Notification for Hydroxypropyl Methylcellulose https://www.fda.gov/downloads/Food/IngredientsPackagingLabeling/GRAS/Notic



Page 76 of 81

eInventory/ucm269093.pdf. (209) Thackaberry, E. A.; Kopytek, S.; Sherratt, P.; Trouba, K.; McIntyre, B. Comprehensive Investigation of Hydroxypropyl Methylcellulose, Propylene Glycol, Polysorbate 80, and Hydroxypropyl-Beta-Cyclodextrin for Use in General Toxicology Studies. Toxicol. Sci. 2010, 117 (2), 485–492. (210) Al-Tabakha, M. M. HPMC Capsules: Current Status and Future Prospects. J. Pharm. Pharm. Sci. 2010, 13 (3), 428–442. (211) Ashland. Pharmaceutical Excipients and Coating Systems http://www.ashland.com/industries/pharmaceutical/oral-solid-dose/film-coatings. (212) Dow Chemical. METHOCEL Cellulose Ethers Techical Handbook. (213) Ashland Inc. Benecel TM hydroxypropyl methlcellulose for personal care. (214) Shin-Etsu Chemical Co., L. Metolose (Hypromellose* & Methylcellulose) http://www.metolose.jp/en/pharmaceutical/metolose.html. (215) Ashland Inc. BenecelTM methylcellulose, hypromellose and methylhydroxyethyl cellulose (Number 4391-15) http://www.ashland.com/industries/food-andbeverage/pet-food/benecel-methylcellulose-and-hydroxypropylmethylcellulose. (216) Viriden, A.; Larsson, A.; Wittgren, B. The Effect of Substitution Pattern of HPMC on Polymer Release from Matrix Tablets. Int. J. Pharm. 2010, 389 (1–2), 147–156. (217) Viriden, A.; Wittgren, B.; Andersson, T.; Larsson, A. The Effect of Chemical Heterogeneity of HPMC on Polymer Release from Matrix Tablets. Eur. J. Pharm. Sci. 2009, 36 (4–5), 392–400. (218) Viriden, A.; Abrahmsen-Alami, S.; Wittgren, B.; Larsson, A. Release of Theophylline and Carbamazepine from Matrix Tablets--Consequences of HPMC Chemical Heterogeneity. Eur. J. Pharm. Biopharm. 2011, 78 (3), 470–479. (219) Ford, J. L.; Rubinstein, M. H.; Hogan, J. E. Propranolol Hydrochloride and Aminophylline Release from Matrix Tablets Containing Hydroxypropylmethylcellulose. Int. J. Pharm. 1985, 24 (2–3), 339–350. (220) Ford, J. L.; Rubinstein, M. H.; Hogan, J. E. Formulation of Sustained Release Promethazine Hydrochloride Tablets Using Hydroxypropyl-Methylcellulose Matrices. Int. J. Pharm. 1985, 24 (2–3), 327–338. (221) Vueba, M. L.; Batista de Carvalho, L. A.; Veiga, F.; Sousa, J. J.; Pina, M. E. Influence of Cellulose Ether Polymers on Ketoprofen Release from Hydrophilic Matrix Tablets. Eur. J. Pharm. Biopharm. 2004, 58 (1), 51–59. (222) Campos-Aldrete, M. E. Influence of the Viscosity Grade and the Particle Size of HPMC on Metronidazole Release from Matrix Tablets. Eur. J. Pharm. Biopharm. 1997, 43 (2), 173–178. (223) Pradhan, R.; Budhathoki, U.; Thapa, P. Formulation of Once a Day Controlled Release Tablet of Indomethacin Based on HPMC-Mannitol. Kathmandu Univ. J. Sci. Eng. Technol. 2008, 4 (1). (224) Nochos, A.; Douroumis, D. In Vitro Release of Bovine Serum Albumin from alginate/HPMC Hydrogel Beads. Carbohydr. Polym. 2008, 74 (3), 451–457. (225) Rasenack, N.; Hartenhauer, H.; Muller, B. W. Microcrystals for Dissolution Rate Enhancement of Poorly Water-Soluble Drugs. Int. J. Pharm. 2003, 254 (2), 137–145.


Page 77 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

(226) Law, S. L.; Kayes, J. B. Adsorption of Non-Ionic Water-Soluble Cellulose Polymers at the Solid-Water Interface and Their Effect on Suspension Stability. Int. J. Pharm. 1983, 15 (3), 251–260. (227) Patil, S.; Kuchekar, B.; Chabukswar, A.; Jagdale, S. Formulation and Evaluation of Extended-Release Solid Dispersion of Metformin Hydrochloride. J. Young Pharm. 2010, 2 (2), 121–129. (228) Pradhan, R.; Kim, Y. I.; Chang, S. W.; Kim, J. O. Preparation and Evaluation of OnceDaily Sustained-Release Coated Tablets of Tolterodine-L-Tartrate. Int. J. Pharm. 2014, 460 (1–2), 205–211. (229) Pygall, S. R.; Kujawinski, S.; Timmins, P.; Melia, C. D. Mechanisms of Drug Release in Citrate Buffered HPMC Matrices. Int. J. Pharm. 2009, 370 (1–2), 110–120. (230) Avalle, P.; Pygall, S. R.; Gower, N.; Midwinter, A. The Use of in Situ near Infrared Spectroscopy to Provide Mechanistic Insights into Gel Layer Development in HPMC Hydrophilic Matrices. Eur. J. Pharm. Sci. 2011, 43 (5), 400–408. (231) Hardy, I. J.; Cook, W. G.; Melia, C. D. Compression and Compaction Properties of Plasticised High Molecular Weight Hydroxypropylmethylcellulose (HPMC) as a Hydrophilic Matrix Carrier. Int. J. Pharm. 2006, 311 (1–2), 26–32. (232) Obara, S.; Kokubo, H. Application of HPMC and HPMCAS to Aqueous Film Coating of Pharmaceutical Dosage Forms, Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, Informa Healthcare; 2008. (233) J.T. Heinaimaiki; V.M. Lehtola; P. Nikupaavo; Yliruusi, J. K. The Mechanical and Moisture Permeability Properties of Aqueous-Based Hydroxypropyl Methylcellulose Coating Systems Plasticized with Polyethylene Glycol. Int J Pharm. 1994, 112 (2), 191–196. (234) Roy, A.; Ghosh, A.; Datta, S.; Das, S.; Mohanraj, P.; Deb, J.; Bhanoji Rao, M. E. Effects of Plasticizers and Surfactants on the Film Forming Properties of Hydroxypropyl Methylcellulose for the Coating of Diclofenac Sodium Tablets. Saudi Pharm J 2009, 17 (3), 233–241. (235) G.S. MacLeod; J.T. Fell; J.H. Collett; H.L. Sharma; Smith, A. M. Selective Drug Delivery to the Colon Using Pectin:chitosan:hydroxypropyl Methycellulose Film Coated Tablets. Int. J. Pharm. 1999, 187, 251–257. (236) G.S. MacLeod J.H. Collett, J. T. F. An in Vitro Investigations into the Potential for Biomodal Drug Release from Petin/chitosan HPMC-Coated Tablets. Int. J. Pharm. 1999, 188, 11–18. (237) Adibkia, K.; Barzegar-Jalalia, M.; Maheri-Esfanjanib, H.; Ghanbarzadehb, S.; Shokrib, J.; Sabzevarie, A.; Javadzadeha, Y. Physicochemical Characterization of Naproxen Solid Dispersions Prepared via Spray Drying Technology. Powder Technol. 2013, 246, 448– 455. (238) Raffin, R. P.; Jornada, D. S.; Re, M. I.; Pohlmann, A. R.; Guterres, S. S. Sodium Pantoprazole-Loaded Enteric Microparticles Prepared by Spray Drying: Effect of the Scale of Production and Process Validation. Int. J. Pharm. 2006, 324 (1), 10–18. (239) Kumar, S.; Xu, X.; Gokhale, R.; Burgess, D. J. Formulation Parameters of Crystalline Nanosuspensions on Spray Drying Processing: A DoE Approach. Int. J. Pharm. 2014, 464 (1–2), 34–45.



Page 78 of 81

(240) Verreck, G.; Six, K.; Van den Mooter, G.; Baert, L.; Peeters, J.; Brewster, M. E. Characterization of Solid Dispersions of Itraconazole and Hydroxypropylmethylcellulose Prepared by Melt Extrusion--Part I. Int. J. Pharm. 2003, 251 (1–2), 165–174. (241) Six, K.; Berghmans, H.; Leuner, C.; Dressman, J.; Van Werde, K.; Mullens, J.; Benoist, L.; Thimon, M.; Meublat, L.; Verreck, G.; et al. Characterization of Solid Dispersions of Itraconazole and Hydroxypropylmethylcellulose Prepared by Melt Extrusion, Part II. Pharm. Res. 2003, 20 (7), 1047–1054. (242) Zhao, M.; Barker, S. A.; Belton, P. S.; McGregor, C.; Craig, D. Q. Development of Fully Amorphous Dispersions of a Low T(g) Drug via Co-Spray Drying with Hydrophilic Polymers. Eur. J. Pharm. Biopharm. 2012, 82 (3), 572–579. (243) Repka, M. A.; Gutta, K.; Prodduturi, S.; Munjal, M.; Stodghill, S. P. Characterization of Cellulosic Hot-Melt Extruded Films Containing Lidocaine. Eur. J. Pharm. Biopharm. 2005, 59 (1), 189–196. (244) Xu, S.; Dai, W. G. Drug Precipitation Inhibitors in Supersaturable Formulations. Int. J. Pharm. 2013, 453 (1), 36–43. (245) Yamashita, K.; Nakate, T.; Okimoto, K.; Ohike, A.; Tokunaga, Y.; Ibuki, R.; Higaki, K.; Kimura, T. Establishment of New Preparation Method for Solid Dispersion Formulation of Tacrolimus. Int. J. Pharm. 2003, 267, 79–91. (246) Ilevbare, G. A.; Liu, H.; Edgar, K. J.; Taylor, L. S. Understanding Polymer Properties Important for Crystal Growth Inhibition-Impact of Chemically Diverse Polymers on Solution Crystal Growth of Ritonavir. Cryst. Growth Des. 2012, 12 (6), 3133–3143. (247) Agarwal, V.; Mishra, B. Design, Development, and Biopharmaceutical Properties of Buccoadhesive Compacts of Pentazocine. Drug Dev. Ind. Pharm. 1999, 25 (6), 701– 709. (248) Taylan, B.; Capan, Y.; Guven, O.; Kes, S.; Hincal, A. A. Design and Evaluation of Sustained-Release and Buccal Adhesive Propranolol Hydrochloride Tablets. J. Control. Release 1996, 38 (1), 11–20. (249) El- Nabarawi, M. A.; Makky, A. M.; El-Setouhy, D. A.; Abd-Elmoniem, R. A.; Amin, M. G.; Jasti, B. A. Fabrication, Evaluation And Preliminary Clinical Study Of Bi-Layer Orobuccal Devices Containing Ketorolac Tromethamine And Chlorhexidine Hcl For Treatment Of Oral Inflammation. Int. J. Pharm. Pharm. Sci. 2014, 6 (2), 851–857. (250) BERMOCOLL® Cellulose Ethers https://celluloseethers.akzonobel.com/brands/bermocoll/. (251) Hosny, E. A.; Elkheshen, S. A.; Saleh, S. I. Buccoadhesive Tablets for Insulin Delivery: In-Vitro and in-Vivo Studies. Boll. Chim. Farm. 2002, 141 (3), 210–217. (252) Yoo, J. W.; Dharmala, K.; Lee, C. H. The Physicodynamic Properties of Mucoadhesive Polymeric Films Developed as Female Controlled Drug Delivery System. Int. J. Pharm. 2006, 309 (1–2), 139–145. (253) SR Bhat; Shivakumar, H. G. Bioadhesive Controlled Release Clotrimazole Vaginal Tablets. Trop. J. Pharm. Res. 2010, 9 (4), 339–346. (254) Bilensoy, E.; Rouf, M. A.; Vural, I.; Sen, M.; Hincal, A. A. Mucoadhesive, Thermosensitive, Prolonged-Release Vaginal Gel for Clotrimazole:beta-Cyclodextrin Complex. AAPS PharmSciTech 2006, 7 (2), E38.


Page 79 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

(255) Allen, J. M.; Wilson, A. K.; Lucas, P. L.; Curtis, L. G. Carboxyalkyl Cellulose Esters. US5668273, 1996. (256) Shelton, M. C. .; Posey-Dowty, J. D. .; Lingerfelt, L. R. .; Kirk, S. K. .; Klein, S. .; Edgar, K. J. Enhanced Dissolution of Poorly Soluble Drugs from Solid Dispersions in Carboxymethylcellulose Acetate Butyrate Matrices; American Chemical Society, 2009; Vol. 1017. (257) Arca, H. Ç.; Mosquera-Giraldo, L. I.; Pereira, J. M.; Sriranganathan, N.; Taylor, L. S.; Edgar, K. J. Rifampin Stability and Solution Concentration Enhancement Through Amorphous Solid Dispersion in Cellulose ω-Carboxyalkanoate Matrices. J. Pharm. Sci. 2018, 107, 127–138. (258) Arca, H. Ç.; Mosquera-Giraldo, L. I.; Dahal, D.; Taylor, L. S.; Edgar, K. J. Multidrug, AntiHIV Amorphous Solid Dispersions: Nature and Mechanisms of Impacts of Drugs on Each Other’s Solution Concentrations. Mol. Pharm. 2017, 14 (11), 3617–3627. (259) AquaSolve TM Hypromellose Acetate Succinate ( HPMCAS ) http://www.ashland.com/industries/pharmaceutical/oral-solid-dose/aquasolvehypromellose-acetate-succinate. (260) Curatolo, W. J.; Nightingale, J. A. S.; Shanker, R. M.; Sutton, S. C. Solubility in Small Intestines; Hydroxypropyl Methyl Cellulose Acetate Succinate Polymer and Zwitterion Drug; US6548555 B1, April 2003. (261) Kennedy, M.; Hu, J.; Gao, P.; Li, L.; Ali-Reynolds, A.; Chal, B.; Gupta, V.; Ma, C.; Mahajan, N.; Akrami, A.; et al. Enhanced Bioavailability of a Poorly Soluble VR1 Antagonist Using an Amorphous Solid Dispersion Approach: A Case Study. Mol. Pharm. 2008. (262) Tanno, F.; Nishiyama, Y.; Kokubo, H.; Obara, S. Evaluation of Hypromellose Acetate Succinate (HPMCAS) as a Carrier in Solid Dispersions. Drug Dev. Ind. Pharm. 2004, 30 (1), 9–17. (263) Konno, H.; Handa, T.; Alonzo, D. E.; Taylor, L. S. Effect of Polymer Type on the Dissolution Profile of Amorphous Solid Dispersions Containing Felodipine. Eur. J. Pharm. Biopharm. 2008, 70 (2), 493–499. (264) Wegiel, L. A.; Mauer, L. J.; Edgar, K. J.; Taylor, L. S. Mid-Infrared Spectroscopy as a Polymer Selection Tool for Formulating Amorphous Solid Dispersions. J. Pharm. Pharmacol. 2014, 66 (2), 244–255. (265) Kwong, A. D.; Kauffman, R. S.; Hurter, P.; Mueller, P. Discovery and Development of Telaprevir: An NS3-4A Protease Inhibitor for Treating Genotype 1 Chronic Hepatitis C Virus. Nat. Biotechnol. 2011, 29 (11), 993–1003. (266) Lang, B.; McGinity, J. W.; Williams 3rd, R. O. Dissolution Enhancement of Itraconazole by Hot-Melt Extrusion Alone and the Combination of Hot-Melt Extrusion and Rapid Freezing--Effect of Formulation and Processing Variables. Mol. Pharm. 2014, 11 (1), 186–196. (267) Mahmah, O.; Tabbakh, R.; Kelly, A.; Paradkar, A. A Comparative Study of the Effect of Spray Drying and Hot-Melt Extrusion on the Properties of Amorphous Solid Dispersions Containing Felodipine. J. Pharm. Pharmacol. 2014, 66 (2), 275–284. (268) Sarode, A. L.; Obara, S.; Tanno, F. K.; Sandhu, H.; Iyer, R.; Shah, N. Stability Assessment of Hypromellose Acetate Succinate (HPMCAS) NF for Application in Hot Melt Extrusion (HME). Carbohydr. Polym. 2014, 101, 146–153.



Page 80 of 81

(269) Shah, N.; Iyer, R. M.; Mair, H. J.; Choi, D. S.; Tian, H.; Diodone, R.; Fähnrich, K.; PabstRavot, A.; Tang, K.; Scheubel, E.; et al. Improved Human Bioavailability of Vemurafenib, a Practically Insoluble Drug, Using an Amorphous Polymer-Stabilized Solid Dispersion Prepared by a Solvent-Controlled Coprecipitation Process. J. Pharm. Sci. 2013, 102 (3), 967–981. (270) Arca, H. C.; Mosquera-Giraldo, L. I.; Taylor, L. S.; Edgar, K. J. Synthesis and Characterization of Alkyl Cellulose ω-Carboxyesters for Amorphous Solid Dispersion. Cellulose 2017, 24 (2), 609–625. (271) Vega, B.; Wondraczek, H.; Bretschneider, L.; Näreoja, T.; Fardim, P.; Heinze, T. Preparation of Reactive Fibre Interfaces Using Multifunctional Cellulose Derivatives. Carbohydr. Polym. 2015, 132, 261–273. (272) Kamitakahara, H.; Suhara, R.; Yamagami, M.; Kawano, H.; Okanishi, R.; Asahi, T.; Takano, T. A Versatile Pathway to End-Functionalized Cellulose Ethers for Click Chemistry Applications. Carbohydr. Polym. 2016, 151, 88–95. (273) Meng, X.; Edgar, K. J. “Click” reactions in Polysaccharide Modification. Prog. Polym. Sci. 2016, 53, 52–85. (274) Dong, Y.; Edgar, K. J. Imparting Functional Variety to Cellulose Ethers via Olefin Cross-Metathesis. Polym. Chem. 2015, 6 (20), 3816–3827. (275) Dong, Y.; Matson, J. B.; Edgar, K. J. Olefin Cross-Metathesis in Polymer and Polysaccharide Chemistry: A Review. Biomacromolecules 2017, 18 (6), 1661–1676. (276) Dong, Y.; Mosquera-Giraldo, L. I.; Taylor, L. S.; Edgar, K. J. Tandem Modification of Amphiphilic Cellulose Ethers for Amorphous Solid Dispersion via Olefin CrossMetathesis and Thiol-Michael Addition. Polym. Chem. 2017, 8 (20), 3129–3139. (277) Meng, X.; Roy Choudhury, S.; Edgar, K. J. Multifunctional Cellulose Esters by Olefin Cross-Metathesis and Thiol-Michael Addition. Polym. Chem. 2016, 3848–3856. (278) Hu, H.; You, J.; Gan, W.; Zhou, J.; Zhang, L. Synthesis of Allyl Cellulose in NaOH/urea Aqueous Solutions and Its Thiol–ene Click Reactions. Polym. Chem. 2015, 6 (18), 3543–3548. (279) Kabel, M. A.; Bos, G.; Zeevalking, J.; Voragen, A. G. J.; Schols, H. A. Effect of Pretreatment Severity on Xylan Solubility and Enzymatic Breakdown of the Remaining Cellulose from Wheat Straw. Bioresour. Technol. 2007, 98 (10), 2034– 2042. (280) Anastyuk, S. D.; Shevchenko, N. M.; Dmitrenok, P. S.; Zvyagintseva, T. N. Structural Similarities of Fucoidans from Brown Algae Silvetia Babingtonii and Fucus Evanescens, Determined by Tandem MALDI-TOF Mass Spectrometry. Carbohydr. Res. 2012, 358, 78–81. (281) Jain, M.; Fiddes, I. T.; Miga, K. H.; Olsen, H. E.; Paten, B.; Akeson, M. Improved Data Analysis for the MinION Nanopore Sequencer. Nat. Methods 2015, 12 (4), 351–356.


Page 81 of 81 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

Biomacromolecules

Amorphous Solid Dispersion

O H Bioadhesion

O

R O

O

R O O

OH O

H

O

O

R

pH Response

ACS Paragon Plus Environment

O

R

R

Controlled Release

Pharmaceutical Applications of Cellulose Ethers and Cellulose Ether

Recommend Documents