Archives of Pharmacy Practice Review Article

ISSN 2045-080X Vol 3 , Issue 3 , 2012

Basic Concepts Of Cellulose Polymers - A Comprehensive Review

Harika K, Sunitha K, Pavan Kumar P, Maheshwar K and Madhusudan Rao Y* Department of Pharmaceutics, National facilities in Engineering and Technology with Industrial Collaboration (NAFETIC) centre, University College of Pharmaceutical Sciences, Kakatiya University, Warangal – 506 009, A.P. India.

Citation: Harika K, Sunitha K, Pavan Kumar P, Maheshwar K and Madhusudan Rao Y. Basic Concepts Of Cellulose

Polymers- A Comprehensive Review. Archives of Pharmacy Practice. 2012; 3(3)pp202-216.

Abstract

Man’s pursuance for new and improved materials has been should promote innovation. To assist the exploitation expanding with time and it can be said that it is unending. of novel drug delivery systems the need for polymers Though introduced very late in the chain of materials, continues to increase. polymers occupy a major place and pivotal position in our This review serves as a comprehensive source to improve materials map today. Unfolding of the science of polymers and understanding of cellulose derivative polymers and create polymer – based materials had evoked lot of interest and made new avenues in development of a delivery system. In them as a class of materials for their potential use in the field of addition, this review presents in-depth information on pharmaceuticals and industry based products. In recent years, various aspects of polymer chemistry, nomenclature, an awareness and understanding of these polymers has various polymer grades, physical characteristics of increased based upon the following factors. polymers, solubility, and the utility of polymers for  As pharmaceutically active ingredients continue to become various drug delivery systems. more ‘‘potent’’ the effective controlled delivery of doses have become intriguing. As a result, polymers now often Introduction constitute the major portion of many pharmaceutical Cellulose is the most copious naturally occurring dosage forms and as such can have profound impact on the “biopolymer”. The main constituent of various natural reproducibility of drug release and overall performance of fibers such as cotton and higher plants is cellulose. It the dosage forms. consists of long chains of anhydro-D-glucopyranose units  The technical complexities associated with drug (AGU) with each cellulose molecule having three hydroxyl development have increased in controlled delivery due to groups per AGU, except at the terminal ends. Cellulose is challenges such as complex drug actives, and in cases of insoluble in water and most common solvents; the poor biotech products, stabilization of the active ingredient. The solubility is accredited primarily to the strong multidisciplinary understanding of polymers is thus intramolecular and intermolecular hydrogen bonding required including technical, safety, quality, and regulatory between the individual chains. Regardless of its poor aspects, which, prior to this effort, has not been available in solubility characteristics, cellulose is used in a wide range a single resource. of applications including composites, netting, upholstery,  It also proposes new and innovative ways for regulatory coatings, packing, paper, etc. Cellulose is chemically review of polymers, which, if adopted, modified to improve process ability and to produce cellulose derivatives (cellulosics) which can be tailored Key words for specific industrial applications [1-5]. Cellulosics are in

Cellulose Polymers, Premium Product Grades, Viscosities, general strong, reproducible, recyclable and Solubility. biocompatible, being used in various biomedical applications such as blood purification membranes and Manuscript History the like. Thus, through derivatization, cellulosics have Article Received on: 1st Jan, 2012 opened a window of opportunity and have broadened Revised on: 30th April, 2012 their use. Approved for Publication: 10th June, 2012 Cellulose derivatives are a branch of semi-synthetic polymers used in controlled drug delivery. In this review, Corresponding Author we summarize all the critical properties of cellulose ethers Prof. Y. Madhusudan Rao that can be utilized for fulfilling the need of controlling the National facilities in Engineering and Technology with release of active ingredient from a drug delivery system. Industrial Collaboration (NAFETIC) centre, University College of Pharmaceutical Sciences, Kakatiya University Chemically modified derivatives of cellulose: Warangal- 506 009 (A.P), India Tel: +91 870 2438844, Fax: +91 870 2453508 Cellulose (Fig 1) being water insoluble, etherification and esterification at hydroxyl groups bring about drastic Email: [email protected] changes in its original properties making its derivatives

Page 202 Archives of Pharmacy Practice Vol 3 , Issue3 , 2012 Archives of Pharmacy Practice soluble in organic and aqueous solvents [6]. The hydroxyl Table 2: Ester derivatives [6] groups (-OH) of cellulose can be partially or fully reacted with Cellulose Reagent Example Reagent various reagents to afford derivatives with useful properties ester like mainly cellulose esters and cellulose ethers (-OR). Organic Organic Cellulose Acetic acid and esters acids acetate acetic anhydride Cellulose Acetic acid and triacetate acetic anhydride Cellulose Propanoic acid propionate Cellulose Acetic acid and acetate propanoic acid Figure 1: Molecular structure of cellulose propionate Etherification: Cellulose ethers can be prepared by treating Cellulose Acetic acid and alkali cellulose with a number of various reagents including acetate butyric acid alkyl or aryl halides (or sulfates), alkene oxides, and butyrate unsaturated compounds activated by electron-attracting Inorganic Inorganic Nitrocellulose Nitric acid or groups (Eq 1). esters acids (cellulose another nitrate) powerful nitrating agent Cellulose Sulfuric acid or Equation 1: Etherification of cellulose. R’= organic radical (CH3- sulfate another , C2H5–, etc) powerful Table 1: Ether derivatives [6,7] sulfuring agent Cellulose Reagent Example Reagent ethers Cellulose acetate phthalate is obtained by partial Alkyl Halogeno Methylcellulose Chloromethane substitution of cellulose acetate (CA) with phthalic alkanes Ethylcellulose Chloroethane anhydride in the presence of an organic solvent and a Ethyl methyl Chloromethane basic catalyst. cellulose and chloroethane METHOD HOW THE INFORMATION WAS Hydroxy Epoxides Hydroxyethyl Ethylene oxide GATHERED/ CRITERIA FOR THE SELECTION OF alkyl cellulose ARTICLES Hydroxypropyl Propylene  Information was gathered from product cellulose (HPC) oxide brochures of chemical companies (Dow, Hercules, Hydroxyethyl Chloromethane Aqualon, WeKcelo) which are synthesizing these methyl and ethylene polymers. cellulose oxide  Physical description of the materials was Hydroxypropyl Chloromethane obtained from Material safety data sheet (MSDS) methyl and propylene of these particular polymers. cellulose oxide  Other information was also considered from (HPMC) monographs of the different pharmacopeias. Ethyl Chloroethane  Some basic concepts about the cellulosic hydroxyethyl and ethylene polymers were obtained from articles published cellulose oxide in various journals. Carboxy Halogenated Carboxymethyl Chloroacetic alkyl carboxylic cellulose (CMC) acid PROPERTIES OF CELLULOSE DERIVATIVE acids POLYMERS The sodium carboxymethyl cellulose can be cross-linked to Cellulose ethers: The factors associated with polymers, give the croscarmellose sodium (E468) for use as a such as molecular weight, viscosity, concentration, degree disintegrant in pharmaceutical formulations. of substitution and particle sizes have a significant influence on drug release. Hence, it is necessary to have thorough knowledge of the polymer properties to choose Esterification: The esterification can be considered as a the suitable polymer to control the release from a typical equilibrium reaction in which an alcohol and acid react particular dosage form. Among the known polymers, to form ester and water. Cellulose is esterified with certain cellulose ethers are materials of choice for controlled drug acids such as acetic acid, nitric acid, sulfuric acid and release which are discussed in detail in this review. phosphoric acid.

Page 203 Archives of Pharmacy Practice Vol 3 , Issue3 , 2012 Archives of Pharmacy Practice Table 3: A Versatile Range of Polymer Properties [8] METHYL ETHYL HPMC CELLULOSE NITRO PROPERTIES HEC CMC CELLULOSE CELLULOSE &HPC ACETATE CELLULOSE Water soluble     Organo soluble     

Gel forming     Film forming       

Mucoadhesive    

High swelling     Hydrophilic    

Hydrophobic  

Viscosifying       

Thermoplastic   

Drug solubilizer     Table 1 A. Methyl cellulose and hypromellose: Nomenclature: Premium methyl cellulose and hypromellose products are a An example [10]- HPMC E 15 premium LV broad range of water soluble cellulose ethers. They enable Low viscosity pharmaceutical developers to create reliable formulas for tablet coating, granulation, controlled release, extrusion, For pharmaceutical use molding and for controlled viscosity of liquid formulations. Viscosity

(15 mPa.s for a 2% solution Chemistry of methyl cellulose ethers: in water at 20°C) These products are available in two basic types: methyl cellulose (Fig 2) and HPMC (Fig 3). Methyl cellulose is made Chemistry type: E and K are using only methyl chloride. These are methocel A brand hypromellose products. For HPMC products (methocel E, F, J and K brand A is methylcellulose products) propylene oxide is used in addition to methyl The initial letter in the product name identifies the type of chloride to obtain hydroxy propyl substitution on cellulose ether, as follows [11]: anhydroglucose units. Both types have the polymeric backbone  “A” : methyl cellulose products of cellulose but possess different ratios of hydroxypropyl to  “E”, “F”, “J” and “K”: hydroxyl propyl methoxyl substitution. These ratios largely determine the methylcellulose products properties of different product grades and in particular influence hydrophilicity, gelling behavior, rheology, surface The number that follows the initial letter identifies the activity and film forming [9]. viscosity grade in milli-pascal seconds (Note: milli pascals second is equal to centipoises, cP) for the product measured at 2% in water at 20°C. A “C” or an “M” following this number indicates that it is multiplied by the following number:  “C”: 100 times  “M”: 1,000 times

Finally, here are some commonly used suffixes that identify special products:  LV, low viscosity Figure 2: Chemical structure of methyl cellulose  S, surface treated (cold water dispersible) products  G, granular products  CR, controlled release grade  FG, food grade  P, premium grade  PCG or AMC, personal care grade  Developmental grades are denoted by letter “X” plus a second letter (usually U or Y) plus a five

Figure 3: Chemical Structure of Hydroxypropyl digit code Methylcellulose The three digit suffix uniquely identifies particular

Page 204 Archives of Pharmacy Practice Vol 3 , Issue3 , 2012 Archives of Pharmacy Practice products offered which differ in substitution ratio and  In cold water, methylcellulose swells and viscosity. Here are some other examples: disperses slowly to form a clear to opalescent, METHOCEL A 4 CP- methylcellulose product with viscosity of viscous, colloidal dispersion. 400 mPa.s, Premium grade  Soluble in mixtures of ethanol and METHOCEL E 4 M PAMC- hydroxypropyl methyl cellulose dichloromethane, mixtures of methanol and product with viscosity of 4,000 mPa.s, personal care grade that dichloromethane, and mixtures of water and also meets premium grade requirements alcohol.  Certain grades of hypromellose are soluble in Table 4: Methyl cellulose product grades [12,13] aqueous acetone solutions, mixtures of Product Chemica Available Meth Hydr Avg dichloromethane and propan-2-ol, and other l type viscosities oxy oxypr particle organic solvents. , cps % opyl size  Soluble in glacial acetic acid and in a mixture of % (µm) equal volumes of ethanol and chloroform. Methocel Methyl 15, 400, 27.5- 0 85.6  Some grades are swellable in ethanol. A cellulose 1,500, 31.5 premium USP 4,000 In general, binary solvent systems functions more Methocel Hyprom 3, 5, 6, 15, 28.8- 7-12 72.2 effectively with methyl cellulose products than single E ellose 50, 400, 30 solvents. Where alcohols comprise part of binary solvent, premium 2910 10,000 solubility improves as the molecular weight of alcohol Methocel Hyprom 50, 4,000 27- 4-7.5 65 decreases. F ellose 30 Typical nonaqueous solvents used with methyl cellulose premium 2906 ethers [9]: Methocel J 16.5- 23-32 88.4  Furfuryl alcohol premium 20  Dimethyl formamide Methocel Hyprom 3, 100, 19- 4-12 64.7  Dimethyl sulphoxide K ellose 4,000, 25 premium 2208 15,000  Formic acid 1,00,000  Glacial acetic acid Methocel 25 25 100-500  Mixtures of methylene chloride and ethyl, methyl, 310 series or isopropyl alcohols  METHOCEL E Premium products are also available in  Mixtures of chloroform and methanol or ethanol faster hydrating CR (controlled release) grades for 50,  N-methyl pyrrolidone 4,000, and 100,000 cps products Solvent solubility at elevated temperatures [9]: Methocel  METHOCEL K Premium products are also available in E and Methocel J cellulose ether products possess faster hydrating CR (controlled release) grades for structures that provide unusual solubility properties. 100, 4,000, 15,000 and 100,000 cps products They are soluble in certain nonaqueous media at elevated  Viscosities for METHOCEL Premium products are for temperatures. 2% solutions in H2O at 20°C Table 6: Examples of suitable “hot solvents” Table 5: Description of methyl cellulose premium Solvent Boiling Solubility Degree of products (USP specifications) [14] point °C point °C solubility Properties Description Glycols Physical White to slightly off-white, essentially Ethylene glycol 197.3 158 Completely soluble appearance odorless and tasteless powder Diethylene glycol 244.8 135 Completely soluble Propylene glycol 188.2 140 Completely soluble Particle size 100%, No. 30 screen; 1,3-propanediol 214 120 Completely soluble 99%, No. 40 screen Glycerine 290 260 Partially soluble Apparent density, 0.25-0.70 Esters g/cc Ethyl glycolate 160 110 Completely soluble pH (2% w/w 5.0-8.0 Glyceryl 127 100 Completely soluble solution) monoacetate Melting point Glass transition temperature is 170- Glyceryl diacetate 123-133 100 Completely soluble 180°C Amines Monoethanolamine 170-172 120 Completely soluble Max. moisture 5.0 Diethanolamine 268-269 180 Completely soluble content, % Methocel 310 series products: They are granular, high

viscosity materials. Their carefully balanced level of Solubility: substitution renders them soluble in both water and  Practically insoluble in acetone, methanol, chloroform, certain organic solvents or blends of solvents. ethanol (95%), ether, saturated salt solutions, toluene

and hot water. B. Ethyl cellulose: Ethyl cellulose is a family of organo-soluble thermoplastics that have been widely used in

Page 205 Archives of Pharmacy Practice Vol 3 , Issue3 , 2012 Archives of Pharmacy Practice pharmaceuticals. Ethyl cellulose products are among only a Table 7: Ethyl cellulose product grades [15, 16] very small number of water insoluble excipient polymers that Product Viscosi Ethoxyl content, % Mean are approved and accepted globally for pharmaceutical viscosity ty Std Med partic applications [15]. By themselves, they offer an attractive range designation range le of physical properties and they can be blended with other mPa.s size materials to achieve intermediate characteristics. (cP) (µm) ETHOCEL Std 3-5.5 48.0-49.5% 4 premium Chemistry of ethyl cellulose ethers: ETHOCEL Std 6-8 48.0-49.5% 310.0 Like cellulose, the backbone of the molecule of ethyl cellulose 7 premium (Fig 4) is based on repeating anhydroglucose units. Specific ETHOCEL Std 6-8 48.0-49.5% 5.0- properties of the various ethyl cellulose polymers are 7FP premium 15.0 determined by the number of anhydroglucose units in the ETHOCEL Std 9-11 48.0-49.5% 375.0 polymer chain and the degree of ethoxyl substitution. 10 premium ETHOCEL Std 9-11 48.0-49.5% 3.0- 10FP premium 15.0 ETHOCEL Std 12.6- 48.0-49.5% 14 premiuma 15.4 ETHOCEL Std 18-22 48.0-49.5% 10 premium ETHOCEL Std 41-49 48.0-49.5% 45 premium ETHOCEL Med 45-55 45.0-46.5% 50 premiuma ETHOCEL Med 63-77 45.0-46.5% Figure 4: Chemical structure of ethyl cellulose 70 premiuma Nomenclature: ETHOCEL Std 90-110 48.0-49.5% 45.0-46.5% 465.0 An Example- 100 premiuma ETHYL CELLULOSE Std. 10 premium FP ETHOCEL Std 90-110 30-60 100FP Identifies physical premium

form ( fine particle) ETHOCEL Std 180- 48.0-49.5%

Identifies product 200 premium 220 grade (premium or ETHOCEL Std 270- 48.0-49.5% industrial grade) 300 premium 330 (a) Supplied on a restricted, made-to-order basis only. Indicates viscosity

Identifies ethoxyl Fine particle size products were designed specifically for type, content (Std., pharmaceutical formulations when the ethocel is used in Med) an unsolubilized form such as in direct compression The letters following trade mark name (i.e., STD, Med) identify controlled release tablets, granulation and/or the ethoxyl type and ethoxyl content (the chemical agglomeration. In these applications, the particle size designation). “Standard” polymers have an ethoxyl content of distribution influences the release rate and tablet 48.0 to 49.5%; and “medium” polymers have an ethoxyl compressibility. content of 45.0 to 47.0%. Medium polymers are supplied on a very restricted, made-to-order basis only. Table 8: Description of ethyl cellulose premium The number that follows the chemistry designation identifies products (USP specifications) [17] the viscosity of that product in milli Pascals second. Viscosity Properties Description of a 5% solution is measured at 25°C. For medium products Physical appearance White , essentially odorless and solvent is 60% toulene and 40% ethanol. For all other ethyl tasteless powder cellulose products, solvent is 80% toluene and 20% ethanol. Density, g/cc (ethocel 0.4 For example, ethyl cellulose STD. 20 premium polymer STD 4,7,10,20,45,100) describes a product with [16]: Density, g/cc (ethocel 0.3  Standard ethoxyl content (48.0- 49.5%). STD 200& 300)  Nominal viscosity of 20 mPa.s for a 5% solution (in pH Neutral to litmus 80% toluene and 20% ethanol) measured at 25°C. Melting point 165-173°C  Intended use in pharmaceuticals or other regulated Glass transition temperature applications. 129–133°C Max. moisture 5.0 content, %

Specific gravity, g/cc 1.12-1.15

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Solubility: Pine oil Sol clear Sol gels Polyhydric Ethylene glycol, Insol Insol  Ethyl cellulose is practically insoluble in glycerin, alcohols diethylene glycol, propylene glycol, and water, but soluble in varying glycerin proportions in certain organic solvents, depending Triethanolamine Swells Insol upon the ethoxyl content. Ethers Ethyl ether, Sol hazy Swells isopropylether,  Ethylcellulose that contains less than 46.5% of benzyl ether ethoxyl groups is freely soluble in chloroform, methyl Dioxane, Sol clear Sol clear acetate, and tetrahydrofuran, and in mixtures of morpholine aromatic hydrocarbons with ethanol (95%). n-butyl ether Swells Swells  Ethylcellulose that contain not less than 46.5% of Phenyl ether Swells Sol hazy ethoxyl groups is freely soluble in chloroform, ethanol C. ESTERS (95%), ethyl acetate, methanol and toluene [18-24]. Acetates Methyl acetate, Sol clear Sol clear ethyl acetate Table 9: Solubility of ethyl cellulose polymers in a number of Isopropyl acetate, Sol gels Sol clear common single solvents [16] n-butyl acetate, cyclohexyl acetate Solvent Solubilitya of ethyl Sec-butyl acetate, Gels Sol clear ceullulose polymers isobutyl acetate, A. HYDROCARBONS glycol diacetate Type Name of solvent Standard Medium Sec-amyl acetate Swells Sol clear ethoxyl ethoxyl Esters of Ethyl lactate, Sol gels Sol clear Aromatic Toluene, xylene Sol clear Gels hydroxy acids isopropyl lactate, hydrocarbons Ethyl benzene Sol clear Sol gels methyl salicylate Isopropyl benzene Sol clear Swells n-butyl lactate Sol clear Sol clear Diethyl benzene, Sol gels Swells D. KETONES diphenyl ethane Ketones Acetone, methyl Sol clear; Sol gels Cyclo Cyclo hexane, Swells Insol ethyl ketone swells aliphatic methyl cyclohexane Methyl isobutyl Sol clear; Swells hydrocarbons Cyclo hexene Sol clear Sol clear ketone swells Chlorinated Chloroform, Sol clear Sol clear Mesityl oxide, Sol clear Sol gel aliphatic ethylene dichloride, acetophenone hydrocarbons trichloro ethylene, Cyclohexanone, Sol clear Gels propylene methyl dichloride, trichloro cyclohexanone, ethane, tetrachloro diacetone alcohol ethane, methylene chloride asolubility rated on a mixture of 2g ethocel in 18ml of solvent Carbon tetra Sol clear Gels Sol clear- soluble, solution clear of haze and free from gels chloride Sol hazy- soluble, solution hazy and free from gels Perchloroethylene Sol hazy Swells Sol gels- soluble, solution of granular nature due to presence of Chlorinated Monochloro Sol clear Sol hazy gels aromatic benzene, o-dichloro Gels- completely gelatinized hydrocarbons benzene Swells- swollen or incompletely gelatinized Trichloro benzene Sol clear Swells Insol- insoluble B. ALCOHOLS AND ETHERS Monohydric Methanol Sol clear; Sol gels Choice of solvents for intermediate viscosities: aliphatic anhydrous, swells Solutions of ethyl cellulose polymers in aromatic alcohols isobutanol, n- hydrocarbons are highly viscous. Ethanol and methanol butanol yield solution of ethyl cellulose polymers having lower Ethanol, sec- Sol clear; Gels viscosity than do aromatic hydrocarbons, but the butanol, octyl(2- swells properties of films are affected. There are mixtures of ethylhexyl) alcohol aromatic hydrocarbons with methanol or ethanol that Isopropanol Sol clear; Swells yield solution of ethyl cellulose polymers having lower swells viscosity than is obtainable with either solvent type used Monohydric Cycohexanol Gels Sol clear singly. These mixtures also deposit films having good cyclic Furfuryl alcohol, Sol clear Gels alcohols tetrahydro furfuryl strength. acohol, methyl cyclohexanol The low molecular weight aliphatic esters and ketones Benzyl alcohol, Sol clear Sol clear produce solutions of ethyl cellulose polymers that have phenyl ethyl comparatively low viscosities. alcohol

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Table 10: Solvent composition for various solvent mixtures Intended market Grade designation [16] Industrial Industrial Solvent mixture Solvent composition Food F Aromatic/ethanol 20% ethanol Personal care CS Aromatic/ester No change by varying ester pharmaceutical F pharm Esters/ethanol 20% ethanol Ketones/ethanol 20% ethanol Regular grind Fine grind( or X) HF pharm HXF pharm C. Hydroxypropyl cellulose: MF pharm MXF pharm It is non-ionic water-soluble cellulose ether with a versatile GF pharm GXF pharm combination of properties. It combines dual solubility in JF pharm JXF pharm aqueous and polar organic solvents, thermoplasticity, and LF pharm -- surface activity with the thickening and stabilizing properties, EF pharm EXF pharm and can be used in tablet binding, modified release and film coating. For example: KLUCEL H X F pharm Chemistry of hydroxypropyl cellulose: Intended for pharmaceutical HPC (Fig 5) is an ether of cellulose in which some of the purpose hydroxyl groups in the repeating glucose units have been Indicates finely ground grade hydroxypropylated forming -OCH2CH(OH)CH3 groups using propylene oxide. Indicates the viscosity grade The average number of substituted hydroxyl groups per Table 11: Hydroxypropyl cellulose product grades glucose unit is referred to as the degree of substitution (DS). Complete substitution would provide a DS of 3. Because the Different grades of HPC, their viscosities (cps) and hydroxypropyl group added contains a hydroxyl group, this corresponding molecular weights [25]- can also be etherified during preparation of HPC. When this occurs, the number of moles of hydroxypropyl groups per I. Industrial grade glucose ring, moles of substitution (MS), can be higher than 3. Viscosity Concentration in water by Mol wt Because cellulose is very crystalline, HPC must have an MS of types weight, % about 4 in order to reach a good solubility in water. HPC has a 1 2 5 10 combination of hydrophobic and hydrophilic groups, so it has a H 1,275- 1,150,000 lower critical solution temperature (LCST) at 45 °C. At Industrial 3,500 temperatures below the LCST, HPC is readily soluble in water; M 3,500- 850,000 above the LCST, HPC is not soluble. Industrial 7,500 G 125- 370,000 Industrial 450 J 125- 140,000 Industrial 450 L 65- 95,000 Industrial 175 E 250- 80,000 Industrial 800 II. Food grade

Figure 5: Chemical structure of hydroxypropyl cellulose Viscosity Concentration in water by Mol wt types weight, % Nomenclature: 1 2 5 10 Hydroxypropyl cellulose is produced in several grades, GF 150- 370,000 determined by intended markets. For each grade, upto six 400 viscosity types are available designated as H, M, G, J, L, E J F 150- 140,000 [25,26]. 400 LF 75- 95,000 150 EF 200- 80,000 600

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III. Personal care grade, pharmaceutical grade Solubility: Viscosity Concentration in water by Mol wt Hydoxypropylcellulose is soluble in the broadest range of types weight, % solvent systems: cold water, alcohol, and anhydrous 1 2 5 10 systems (e.g., polar organic solvents and glycols). H CS, HF 1,500- 1,150,000 However HPC is generally insoluble in water over 105°F pharm 3000 (40°C); however, this precipitation phenomenon occurs M CS, MF 4000- 850,000 only in water and is fully reversible upon cooling. pharm 6,500 G CS, GF 150- 370,000 HPC will precipitate from water solution at a temperature pharm 400 between 40oC and 45oC. This precipitation is completely J CS, JF 150- 140,000 reversible. The polymer redissolves upon cooling the pharm 400 system below 40oC with stirring and the original is o L CS, LF 75- 95,000 restored. When the temperature reaches 40 to 45 C, this pharm 150 precipitation is evidenced by appearance of cloudiness in E CS, EF 300- 80,000 the solution and reduction in viscosity. pharm 600 Viscosity Concentration in anhydrous Mol wt List of solvents for Hydroxypropyl cellulose [25]: types alcohol by weight, % a) CLEAR AND SMOOTH 1 2 5 10 Glacial acetic acid Ethyl alcohol Propylene glycol Acetone: water Formic acid t-butanol:water H CS, HF 1000- 1,150,000 (9:1) 88% (9:1) pharm 4000 Benzene: Glycerine: Tetra hydro furan M CS, MF 3000- 850,000 methanol(1:1) water(3:7) pharm 6,500 Chloroform Isopropyl Toluene: ethanol G CS, GF 75- 370,000 alcohol 95% (3:2) pharm 400 Cyclohexanone Methanol Water J CS, JF 75- 140,000 Dimethyl Methylene chloride: pharm 400 formamide methanol (9:1) L CS, LF 25- 95,000 pharm 150 Dimethyl Morpholine E CS, EF 150- 80,000 sulphoxide pharm 700 Dioxane Pyridine All viscosities are determined at 25°C using Brookefield LVF b) MODERATELY GRANULAR AND/OR HAZY viscometer with spindle and speed combinations depending on Acetone Methyl acetate viscosity level. Butyl acetate Methyl ethyl ketone Weight- average molecular weight determined by size exclusion Butyl cellosolve Methylene chloride chromatography. Cyclohexanol Naphtha:ethanol (1:1) Isopropyl alcohol 99% Tertiary butanol Table 12: Description of hydroxypropyl cellulose products Lactic acid Xylene: isopropyl alcohol(1:3) (USP specifications) [25,26] c) INSOLUBLE Properties Description Aliphatic hydrocarbon Mineral oils Physical appearance White , essentially odorless and Benzene Soyabean oil tasteless powder Particle size: regular grind Min. 85% through 30 mesh Carbon tetrachloride Toluene Min. 99% through 20 mesh Dichloro benzene Gasoline Industrial grade: xylene Glycerine Min. 80% through 30 mesh Trichloro ethylene Linseed oil Min. 98% through 20 mesh Particle size: fine X-grind Min. 80% through 100 mesh D. Hydroxyethyl cellulose: Min. 90% through 80 mesh Min. 99.9% through 60 mesh Hydroxy ethyl cellulose is a nonionic, water-soluble Bulk Density, g/ml 0.5 (varies with type) polymer that can thicken, suspend, bind, emulsify, form pH Neutral to litmus (1% films, stabilize, disperse, retain water, and provide solution/water) protective colloid action in a variety of pharmaceutical Softening temperature 100-150°C applications. It has outstanding tolerance for dissolved Burn out temperature in N2 or 450-500°C electrolytes. HEC offers narrow viscosity ranges, O2 consistent viscosity reproducibility, and excellent solution Max. moisture content, (as 5.0 clarities. Hydroxyethyl cellulose and methyl cellulose are packed)% frequently used with hydrophobic drugs in capsule Specific gravity, g/cc (2% 1.010 solution at 30°C) formulations, to improve the drugs dissolution in the gastrointestinal fluids. This process is known as

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"Hydrophilization". CELLOSIZE EP 09 hydroxyethyl 90-160 (5% solution) cellulose CELLOSIZE EP 300 hydroxyethyl Chemistry of hydroxyethyl cellulose: 250-400 (2% solution) cellulose Hydroxyethylcellulose polymer is hydroxyl-ethyl ether of CELLOSIZE ER Grades CELLOSIZE ER 100M cellulose. By treating cellulose with sodium hydroxide and 3500-4400 (1% solution) reacting with ethylene oxide, hydroxyethyl groups are hydroxyethyl cellulose CELLOSIZE ER 15M hydroxyethyl introduced to yield a hydroxyethyl ether. In this reaction, the 1100-1500 (1% solution) hydrogen atoms in the hydroxyl groups of cellulose are cellulose CELLOSIZE ER 30M hydroxyethyl replaced by hydroxyethyl groups, which confer water 1500-1900 (1% solution) solubility to the product. The reaction product is purified and cellulose CELLOSIZE ER 37M hydroxyethyl ground to a fine white powder. The maximum value for D.S. in 1900-2400 (1% solution) hydroxyl ethyl cellulose is three [27]. cellulose CELLOSIZE ER 4400 4800-6000 (2% solution) In reacting ethylene oxide with cellulose to form the hydroxyethyl cellulose CELLOSIZE ER 52M hydroxyethyl hydroxyethyl cellulose ether, solubility in water is achieved as 2400-3000 (1% solution) cellulose the degree of substitution is increased. By selecting CELLOSIZE HEC Grades appropriate reaction conditions and moles of substituent, CELLOSIZE HEC-10 hydroxyethyl complete hydration in water is obtained. HEC, which has 4400-6500 (1% solution) cellulose optimum solubility in water, has an MS of 2.5. CELLOSIZE HEC-15 hydroxyethyl 50-80 (2% solution) cellulose CELLOSIZE HEC-18 hydroxyethyl 250-400 (2% solution) cellulose CELLOSIZE HEC-25 hydroxyethyl 4400-6500 (1% solution) cellulose CELLOSIZE HEC-60 hydroxyethyl 180-325 (2% solution) cellulose Figure 6: Chemical structure of hydroxyethyl cellulose CELLOSIZE HEC-10 HV >6000 (1% solution) hydroxyethyl cellulose Nomenclature: CELLOSIZE HEC-25 HV >6000 (1% solution) Two types of HEC are produced for specific dissolving hydroxyethyl cellulose purposes. QP type materials disperse rapidly, while WP types CELLOSIZE HMHEC Grades hydrate quickly. In addition, HEC is available in several grades, CELLOSIZE HMHEC 500 hydrophobe - modified hydroxyethyl which have been specifically developed to improve their cellulose resistance to enzyme attack. They are designated ER type, CELLOSIZE QP Grades enzyme resistant [28]. EP is primarily intended for use in CELLOSIZE QP 09H hydroxyethyl 113-150 (5% solution) emulsion polymerization. To offer longer self-life and protect cellulose cellulose ether from enzyme attack, WeKcelo HEC has Bio- CELLOSIZE QP 09L hydroxyethyl 75-112 (5% solution) stable grade available. These grades are designated by the cellulose letter B (e.g., WeKcelo HEC 30000B) CELLOSIZE QP 10000H hydroxyethyl cellulose CELLOSIZE QP 15000H 1100-1500 (1% solution) Hydroxyethyl cellulose product grades: hydroxyethyl cellulose CELLOSIZE QP 100MH 4400-6000 (1% solution) HEC is manufactured in a variety of viscosity grades. These hydroxyethyl cellulose versions differ principally in their aqueous solution viscosities CELLOSIZE QP 100MHV hydroxyethyl cellulose and are offered to optimize performance in specific HEC CELLOSIZE QP 2000 hydroxyethyl cellulose CELLOSIZE QP 3L hydroxyethyl applications. For a two-percent by weight aqueous solution, 215-282 (5% solution) viscosities range from as low as 10 mPas up to 100,000 mPas. cellulose CELLOSIZE QP 300 hydroxyethyl 300-400 (2% solution) Table 13: HEC Products for Industrial Applications [28,29] cellulose CELLOSIZE QP 30000H 1500-2400 (1% solution) Viscosity Range of hydroxyethyl cellulose Aqueous Solution, LVF CELLOSIZE QP 40 hydroxyethyl CELLOSIZE DCS Grades 80-125 (2% solution) Brookfield at 25°C, cellulose CELLOSIZE QP 4400H mPa•s 4800-6000 (2% solution) CELLOSIZE DCS LV (170 KB PDF) 5000 (2% solution) hydroxyethyl cellulose CELLOSIZE QP 52000H CELLOSIZE DCS HV (170 KB 2400-3000 (1% solution) 50000 (2% solution) hydroxyethyl cellulose PDF) CELLOSIZE WP Grades CELLOSIZE EP Grades CELLOSIZE WP 09H 113-150 (5% solution)

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hydroxyethyl cellulose on the surface is soluble only when the pH is from 8 to 10. CELLOSIZE WP 09L hydroxyethyl 75-112 (5% solution) cellulose Table 15: Solubility Behavior in Organic Solvents [27,29] CELLOSIZE WP 300 hydroxyethyl cellulose CELLOSIZE WP 52000H hydroxyethyl cellulose Solvent Cold 25°C Hot 55- HEC Products for Oilfield Applications 60°C CELLOSIZE HEC-10 hydroxyethyl 4400-6500 (1% solution) Alcohols cellulose Ethanol:water (70:30 by wt) Partially Partially CELLOSIZE HEC-15 hydroxyethyl 50-80 (2% solution) soluble soluble cellulose (60:40 by wt) Partially Partially CELLOSIZE HEC-18 hydroxyethyl 250-400 (2% solution) soluble soluble cellulose (30:70 by wt) Soluble Soluble CELLOSIZE HEC-25 hydroxyethyl 4400-6500 (1% solution) Butanol Insoluble — cellulose CARBITOL™ Solvent Insoluble — CELLOSIZE HEC-60 hydroxyethyl 180-325 (2% solution) Ethanol (95%) Insoluble — cellulose Methyl CELLOSOLVE™ Insoluble — CELLOSIZE HEC-10 HV >6000 (1% solution) Solvent hydroxyethyl cellulose Methanol Insoluble — CELLOSIZE HEC-25 HV >6000 (1% solution) hydroxyethyl cellulose Glycols HEC Products for Personal Care Applications Ethylene glycol Swollen — CELLOSIZE Polymer PCG-10 4400-6000 (1% solution) Glycerin Swollen Partially CELLOSIZE QP 40 hydroxyethyl soluble 80-125 (2% solution) cellulose Propylene glycol Swollen Partially CELLOSIZE QP 300 hydroxyethyl soluble 300-400 (2% solution) cellulose Acids CELLOSIZE QP 4400H Acetic Acid Partially — 4800-6000 (2% solution) hydroxyethyl cellulose soluble CELLOSIZE QP 15000H Glacial acetic Insoluble — 1100-1500 (1% solution) hydroxyethyl cellulose Formic Acid (90%) soluble — CELLOSIZE QP 30000H 1500-2400 (1% solution) Esters hydroxyethyl cellulose Amyl Acetate, Primary Insoluble — CELLOSIZE QP 52000H 2400-3000 (1% solution) Ethyl Acetate Insoluble — hydroxyethyl cellulose Ethyl lactate Insoluble Insoluble CELLOSIZE QP 100MH 4400-6000 (1% solution) Methyl salicylate Insoluble Insoluble hydroxyethyl cellulose Ethers Isopropyl Ether Insoluble — Table 14: Description of hydroxyethyl cellulose products Ethyl Ether Insoluble — (USP specifications) [27,29] 1,4-Dioxane Insoluble — Methyl Cellosolve Insoluble — Properties Description Cellosolve Insoluble Insoluble Physical appearance White to cream-colored, freely Hydrocarbons flowing odourless granules or fine Xylene Insoluble — powder Benzene Insoluble — Particle size 100% through U.S. 80 mesh (177 Petrolene Insoluble — micron) Kerosene Insoluble — Bulk Density, g/cm3 0.3-0.6 Chlorinated Hydrocarbons Apparent density, g/ml 0.35-0.61 Chlorobenzene Insoluble — pH 6.0-8.5 Carbon Tetrachloride Insoluble — Softening Point, °F (°C) >285 (140) Trichloroethylene Insoluble — Decomposition Ethylene Dichloride Insoluble — Temperature, °F (°C) About 400 (205) Methylene Chloride Insoluble — Viscosity(mpa.s), 20°C 5-60000 Aldehydes aqueous solution Butyraldehyde Partially — Specific Gravity at 1.30-1.40 soluble — 20/20°C Formalin soluble Ketones Solubility: Acetone Insoluble — The viscosity become little when the pH ranges from 2 to 12, Diethyl Ketone Insoluble — but the viscosity reduces beyond this range. The HEC treated

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Amines  The "H" signifies a high viscosity grade, there are Ethylenediamine Soluble — "L", "M", and "H" types, representing low, Pyridine Insoluble — medium, and high viscosity respectively. Diethylenetriamine soluble —  "3" is a reference point which defines the Oils maximum viscosity of the gum in a 1% solution at Mineral Oil Insoluble — 25°C (in this case, 3000 centipoise). Cottonseed Oil Insoluble —  The "S" stands for special rheological properties Lard Oil Insoluble — (smooth flow). There are "S" types for smooth Linseed Oil Insoluble — flow and "O" types for tolerance in acidic systems. Miscellaneous  The "X" stands for fine grind material, while a "C" Dimethyl Formamide Soluble — would indicate a coarse particle size, and no letter Dimethyl Acetamide Soluble — would indicate a "regular" particle size. Dimethyl Sulfoxide Soluble Soluble  The "F" represents food grade (FCC), while a "P" Phenol Soluble Insoluble would be pharmaceutical grade (USP). Aniline Insoluble Soluble Ethylene chlorohydrin Soluble Table 16: Carboxymethyl cellulose product grades [30,31] E. Carboxy methyl cellulose: Type Viscosity (mPa s) Carboxymethyl cellulose (CMC) or cellulose gum is a Hercules cellulose gum 7LF 2% 25-50 cellulose derivative with carboxymethyl groups (-CH2-COOH) bound to some of the hydroxyl groups of the glucopyranose 7MF 2% 400-800 monomers that make up the cellulose backbone. It is often 7HF 1% 1500-3000 used as its sodium salt, sodium carboxymethyl cellulose. It is a 9M8F 2% 400-800 low-cost commercial soluble and polyanionic polysaccharide 9H4F 1% 2500-60000 derivative of cellulose. Akucell cellulose gum Akucell AF 0305 1% 10–15 (Low viscosity) Chemistry of Carboxymethyl cellulose: Akucell AF 2785 1% 1500–2500 (Medium viscosity) The manufacture of CMC is a two-step process. In the first step, Akucell AF 3085 1% 8000–12000 (High viscosity) cellulose is suspended in alkali to open the bound cellulose chains, allowing water to enter. Cellulose is then reacted with Table 17: Description of Carboxymethyl cellulose sodium monochloroacetate to yield sodium carboxymethyl products (USP specifications) cellulose. The polar (organic acid) carboxyl groups render the cellulose soluble and chemically reactive by introducing Properties Description carboxymethyl groups along the cellulose chain, which makes Physical appearance White to almost white, hydration of the molecule possible. The functional properties odorless, hygroscopic of CMC depend on the degree of substitution of the cellulose granular powder or fine fibres. structure (i.e., how many of the hydroxyl groups have taken Bulk Density, g/cm3 0.52 g/cm3 part in the substitution reaction), as well as the chain length of Tapped density, g/cm3 0.78 the cellulose backbone structure and the degree of clustering pH (1% w/v solution) 6.0-8.5 of the carboxymethyl substituents. Melting point (°C) Browns at approximately 227°C, and chars at Approximately 252°C. Viscosity(mpa.s), 1% 5–13 000 mPa s w/v aqueous solution

Solubility: CMC is practically insoluble in acetone, ethanol (95%), Figure 7: Chemical structure of Carboxymethyl cellulose ether, and toluene. Easily dispersed in water at all temperatures forming clear colloidal solutions. The Nomenclature [30]: aqueous solubility varies with the degree of substitution An example of nomenclature for Hercules cellulose gum: (DS) (Number of carboxymethyl per glucose unit). The Cellulose gum type 7H3SXF higher the DS, the higher the water solubility, pH  The "7" stands for the degree of substitution. In the resistance, salt compatibility etc. Cellulose gum (CMC) is food industry, there are "7" and "9" types of also soluble in most aqueous mixes such as alcohol/water, substitution. The pharmaceutical industry also has a glycerine/water etc. When other solutes such as salts are "1.2" type to work with. added, it is recommended to dissolve the cellulose gum first.

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APPLICATIONS AND ADVANTAGES OF Table 19 Summarizes the recommendations for CELLULOSE POLYMERS METHOCEL products to be used with selected granulation processes and active ingredients [10,33,34,35]. Polymers offer an outstanding range of controlled release properties for a wide variety of dosage forms and processing S.NO Active METHOCEL Product methods. Ingredient 1. Methyl cellulose and Ethyl cellulose: In 1 High-dose, low- A15 Premium LV; E5 Premium pharmaceuticals, Methyl cellulose has principle solubility drug LV advantages of formulation versatility and the ability to 2 High-dose, high- E5 Premium LV; K3 Premium “fine tune”, improving product appearance, i.e., tablet solubility drug LV physical properties and helps to assure the customer 3 Low-dose, low- A15 Premium LV; K3 Premium acceptance [32]. Ethyl cellulose has excellent solubility drug LV; E5 Premium LV compatability with wide variety of pharmaceutical 4 High-dose, high- A15 Premium LV; K3 Premium systems incorporating an even greater number of solubility drug LV; E5 Premium LV; E15 basic ingredient materials and are used where Premium LV hydrophobic films are needed. 1, 2&3------Recommended granulation process is Low- and Table 18: Applications of methyl and ethyl cellulose [8,12] high-shear granulation; fluid-bed granulation 4------Recommended granulation process is roller- Application Products Typical compaction granulation Recommended Use Level Controlled Release Applications 2. Hydroxy propyl cellulose: The breadth of Controlled Release METHOCEL K100LV, 20 – 55% viscosity grades of HPC can be used for wide Matrix Tablets K4M, K15M, K100M, E4 ranging applications. As a food additive, M, E10M Premium (all hydroxypropyl cellulose is used as a thickener available in Controlled and as an emulsion stabilizer. Lacrisert, Release, CR grade) manufactured by Aton Pharma, is a formulation of Controlled Release ETHOCEL Standard 3 – 20% HPC used for artificial tears. It is used to treat Coatings Premium 4,7,10 medical conditions characterized by insufficient ETHOCEL Premium 3 – 20% tear production such as keratoconjunctivitis sicca blended with METHOCEL , recurrent corneal erosions, decreased corneal E5, E15 Premium sensitivity, exposure and neuroparalytic keratitis. Microencapsulation ETHOCEL Standard 20, 10 – 20% HPC is also used as a lubricant for artificial eyes. 45, 100 Premium HPC is used as a sieving matrix for DNA Tablet Coating Applications separations by capillary and microchip Conventional Tablet METHOCEL E3, E5, E6, 0.5 – 5% electrophoresis. Coating E15LV Premium Solvent-Based Blends of ETHOCEL 1 – 5% Table 20: Applications of hydroxypropyl cellulose [25] Coating for Barrier or Premium and METHOCEL Taste Masking Premium Types of uses Specific Properties Properties applications utilized Granulation Binder Applications Adhesive Solvent-based Thickener, hot-melt thermoplastic Conventional Wet METHOCEL E5LV, E15LV, 2 – 6% Granulation A15LV, K3 Premium Aerosol Emulsions- Stabilizer, cosmetics foaming aid Direct Compression ETHOCEL Standard 7 FP, 5 – 40% Granulation 10 FP, 100 FP Premium Solvent based Film former, binder Solvent-Based ETHOCEL Standard 10, 1 – 6% Granulation 20 or 45 Premium Coatings Edible food Glaze-oil and coating oxygen barrier Liquid Formulations Film coating Solvent-soluble Bulk laxatives METHOCEL A4M, K4M, 5 – 30% film former, heat K100M Premium sealable Creams, gels, and METHOCEL A4M, E4M, 1 – 5% Cosmetics Hair styling aids, Alcohol soluble ointments F4M, K4M Premium alcohol based thickener, and Ophthalmic METHOCEL E4M 0.1 – preparations, film former preparations Premium 0.5% perfumes, etc. Suspensions METHOCEL A4M, E4M, 1 – 2% Emulsions, Emulsion K4M Premium creams, lotions stabilizer, Antacids METHOCEL A15C, A4M, 1 – 2% and shampoos thickener E4M, K4M, K15M, F4M Premium

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Encapsulation Micro and macro Soluble, edible, 4. Carboxymethyl cellulose: Carboxymethyl encapsulation flexible film cellulose sodium is widely used in oral and topical barrier, fast pharmaceutical formulations, primarily for its release viscosity increasing properties. CMC is used as a Extrusion Film and sheet Thermoplastic, lubricant in non-volatile eye drops (artificial profiles and binder, water and tears) and also used in cosmetics, toiletries, filaments solvent soluble surgical prosthetics, and incontinence, personal Molding Injection, Thermoplastic, hygiene, and food products. compression and binder, water and blow molding solvent soluble Table 22: Applications of Carboxy methyl cellulose [31, Pharmaceuticals Tablet binder, Aqueous and 37] tablet coating, solvent solubility, Types of uses Specific Properties modified release thermoplastic applications utilized liquids and semi binder, non-ionic, Adhesive Denture adhesive Wet tack, long solids. pH-insensitive lasting adhesion thickener, Pharmaceuticals Tablet binder, High strength suspending agent, granulation aid binder diffusion barrier, Sustained release Thickener, flexible films diffusion barrier Tablets Film former, 3. Hydroxyethyl cellulose: It can be used in a variety of disintegrant industrial and pharmaceutical applications, including Syrups and Thickener, as a lubricant in preparations for dry eye, contact lens suspensions suspending aid care, and dry mouth. Bulk laxative Physiologically inert, high water Table 21: Applications of Hydroxyethyl cellulose [9,36] binding capacity Types of uses Specific applications Properties utilized Cosmetics Shampoos, Foam stabilizer, Coating Latex paint Texture Thickening and foamed products, suspending aid, paint protective colloid, creams, lotions, thickener, film Water-binding tooth paste former, binder Cosmetics Hair conditioners Thickening and Toothpaste Liquid stabilizing Conclusion soaps and bubble bath The drug development business has become truly global, Hand creams and especially in the area of procurement of components, lotions outsourcing of manufacture, and global Adhesives Wallpaper adhesives Thickening, commercialization. The emergence of controlled release Latex adhesives lubricity, water- Plywood adhesives binding and solids technology as an effective way to enhance patient holdout compliance and extend the life cycle of a drug has led to Pharmaceuticals Lotions and emulsions Thickening, the need for novel ways of controlling the drug release Jellies and ointments stabilizing and profiles. Polymers present a logical and simple approach water-binding to control the release of drugs and also play a key role in Ophthalmic and topical Thickening agent optimizing the therapeutic delivery of drug. The text formulations fulfills a critical need for up-to-date and comprehensive Tablets Binder and film information about a rapidly evolving area of interest. We coating agent encourage readers to learn from this text and to consider Polymerization PVAC and acrylic Protective colloid themselves challenged in helping pharmaceutical latices PVC suspension and surface activity scientists ‘‘what to do and what not to do’’ when selecting Industry Paper, Textiles, Adhesives, a suitable polymer for a specific dosage form. Laundry Aids, decorative and Binders protective coatings, A deeper understanding of polymer properties and its emulsion impact on dosage form functionality is further going to polymerization fuel this trend. Uneducated selection of polymer likely Miscellaneous Joint cements Thickening, water- leads to numerous formulating flaws that require much Hydraulic cements binding, set time and materials. It is therefore logical to select Plaster retarder, rheology polymers by their properties when designing or Caulking compound control, stabilizing, optimizing a formulation, and knowledge of polymer and putty protective coating properties is an important prerequisite for this process. Printing inks and polymerization Selecting polymers with properties that complement the Asphalt emulsions poor qualities of an API or formulation is often an

Page 214 Archives of Pharmacy Practice Vol 3 , Issue3 , 2012 Archives of Pharmacy Practice appropriate first step. Finally, knowledge of polymer 13. Paul J. Sheskey, Tim D. Cabelka, Ryan T. Robb, and properties is essential in creating a robust formulation to Brent M. Boyce; Product Information, Use of manufacture a dosage form that meets specifications in a time Roller Compaction in the Preparation of and material efficient manner. Controlled-Release Hydrophilic Matrix Tablets Containing Methylcellulose and Hydroxypropyl Acknowledgement Methylcellulose Polymers; Reprinted from One of the authors thanks AICTE, New Delhi for granting Pharmaceutical Technology, an ADVANSTAR fellowship during my course. Publication,1994; 1-12. 14. Introducing METHOCELTM DC Grade Conflict of Interest Hypromellose Polymers for Direct Compression The authors report no conflicts of interest. of Controlled Release Dosage Forms: Achieve Excellent Processing, Physical Properties and References Dissolution Profiles without the Need for Wet Granulation; published literature by DowWolf 1. Hinterstoisser B., Salmen L. Application of dynamic 2D Cellulosics, Form No. 198-02173-1008, 2008. FTIR to cellulose. Vibrational Spectroscopy, 2000; 22: 15. Ethocel premium polymers for pharmaceutical 111–118. applications: Proven organosoluble polymers for 2. Bochek A. M. Effect of hydrogen bonding on cellulose controlled release coatings, microencapsulation, solubility in aqueous and nonaqueous solvents. granulation and flavor markings; Form No: 198- Russian Journal of Applied Chemistry, 2003; 76: 02002-1098, 1998. 1711– 1719. 16. Dow Cellulosics, Technical Handbook of 3. Myasoedova V. V. Physical chemistry of non-aqueous ETHOCEL Ethyl cellulose polymers, Form No: solutions of cellulose and its derivatives. John Wiley 192-00818-0905, 2005. and Sons, Chirchester 2000. 17. Majewicz, T.G. “Cellulose ethers,” Encyclopedia of 4. Gross R. A., Scholz C. Biopolymers from polymer science and technology, John Wiley & polysaccharides and agroproteins. American Chemical Sons, Inc., New York, 2002. Society, Washington 2000. 18. Kent, D.J., and Rowe, R.C. Solubility studies on 5. Akira .I. Chemical modification of cellulose. In ‘Wood ethyl cellulose used in film coating. J. Pharm. and Cellulosic Chemistry’ (eds., Hon D. N-S., Shiraishi Pharmacol., 1978; 30: 808-810. N.) Marcel Dekker, New York, 2001; 599–626. 19. Rowe, R.C. The prediction of 6. S. Kamel, N. Ali, K. Jahangir, S. M. Shah, A. A. El-Gendy. compatibility/incompatibility in blends of ethyl Pharmaceutical significance of cellulose: A review. cellulose with hydroxypropyl methylcellulose or eXPRESS Polymer Letters, 2008; Vol.2, No.11: 758– hydroxypropyl cellulose using 2-dimensional 778. solubility parameter maps. J. Pharm. Pharmacol., 7. J. B. Batdorf and P.S.Francls. The Physical Behavior of 1986; 38: 214-5. Water-Soluble Cellulose Polymers. Journal of the 20. Sakellariou, P., Rowe, R.C., and White. The Society of Cosmetic Chemists, 1962; 117-122. solubility parameters of some cellulose 8. An introduction to Dow Pharmaceutical Excipients: An derivatives and polyethylene glycols used in Expanding World of Solutions through Science and tablet film coating. Int. J. Pharm., 1986; 31: 175-7. Polymer Technology; Published literature by Dow 21. Arwidsson, H., and Nicklasson, M. Application of chemicals, Form No. 198-02141 1005. intrinsic viscosity and interaction constant as a 9. Technical handbook of Methocel cellulose ethers; formulation tool for film coating. I. Studies on Published literature by Dow chemicals, Form No: 192- ethyl cellulose 10 cps in organic solvents. 01062-0902, 2002. International Journal of Pharmaceutics, 1989; 56: 10. Sheskey, P.J., and T.P. Dasbach, Evaluation of various 187-193. polymers as dry binders in the preparation of an 22. Robinson, D.H. Ethyl cellulose-solvent phase immediate-release tablet formulation by roller relationships relevant to coacervation compaction; Pharm. Technol. 1995; 19 (10): 98–112. microencapsulation processes. Drug Dev. Ind. 11. Foam enhancement, thickening, gelling, film Pharm., 1989; 15: 2597-2620. formation, and stabilization, Methocel cellulose ethers: 23. Arwidsson, H., and Nicklasson, M., Int. J. Pharm., Multi functional water-soluble polymers that enhance 1990, 58, 73-7. foams, forms films, thicken and stabilize; Amerchol, 24. Archer, W.L. Determination of Hansen solubility The elegance engineers; Form No: 324-00180-0805, parameters for selected cellulose ether 2005; 1-31. derivatives. Ind. Eng. Chem. Res. 1991; 30: 2292- 12. Information brochure of Pharmaceutical Excipients 2298. from Dow Water Soluble Polymers: A broad line of 25. Klucel® Hydroxy propyl cellulose: Physical and products and technologies from a single supplier to chemical properties, Hercules incorporated, help you maximize performance faster; Dow Aqualon division, 2001. chemicals, Form No. 198-02088-0802, 2002.

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26. Product data, KLUCEL® Pharm 34. The Dow Chemical Company, Technotes: Hydroxypropylcellulose; Hercules incorporated, Granulation with Cellulosic Polymers, Part II. Aqualon division, Number 494-9, 2004. High Shear Granulation; Form No. 198-01170- 27. WeKceloTM HEC: Hydroxyethylcellulose, A Nonionic 0702; 28pp. Water-Soluble Polymer: WeKcelo TMHEC and Its 35. The Dow Chemical Company, Technotes: Applications; Information brochure by WeiKem Granulation with Cellulosic Polymers, Part III. Chemicals, 2009; 1-12. Low Shear Granulation; Form No. 198-01181- 28. CELLOSIZE Hydroxyethyl Cellulose for Coatings 0602; 27pp. Applications: High Thickening Efficiency, Excellent 36. Aqualon, Specialties, Natrosol® Formulation Compatibility, and Available with hydroxyethylcellulose, Superior Enzyme Resistance, Form No. 325-00002- http://www.herc.com/aqualon/specialties/prod 1002, 2002. ucts/spec_prod_nathec.html, 2005. 29. CELLOSIZE Hydroxyethyl Cellulose: Thickener, Binder, 37. Hercules Incorporated, Aqualon Division: Stabilizer, Film Former, Protective Colloid, http://www.aqualon.com (16.07.2008). Information brochure by Dow chemicals, Form No. 325-00001-0805, 2005; 1-27. 30. Andrew C. Hoefler; Sodium Carboxymethyl Cellulose: Chemistry, Functionality, and Applications; Food Ingredients Group, Hercules Incorporated Wilmington, Delaware 19808, 1-15. 31. Raymond C Rowe, Paul J Sheskey and Sian C Owen , Handbook of Pharmaceutical Excipients; Fifth edition, 2006. 32. Information brochure of METHOCEL Cellulose Ethers in Aqueous Systems for Tablet Coating; Dow chemicals, Form No. 198-00755-0702, 2002. 33. The Dow Chemical Company, Technotes: Granulation with Cellulosic Polymers, Part I. Fluid Bed Granulation; Form No. 198-01151-0702; 24pp.

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