kywods

The PhEur 2005 describes hydroxyethylmethyl cellulose as a partly O-methylated and O-(2-hydroxyethylated) cellulose. Various different grades are available, which are distinguished by appending a number indicative of the apparent viscosity in millipascal seconds (mPa s) of a 2% w/v solution measured at 208C.

Structural Formula

See Section 4.

Functional Category

Coating agent; suspending agent; tablet binder; thickening agent; viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology

Hydroxyethylmethyl cellulose is used as an excipient in a wide range of pharmaceutical products, including oral tablets and suspensions and topical gel preparations.(1) It has similar properties to methylcellulose, but the hydroxyethyl groups make it more readily soluble in water and solutions are more tolerant of salts and have a higher coagulation temperature.

Description

A white, yellowish-white or grayish-white powder or granules, hygroscopic after drying.

Pharmacopeial Specifications

See Table I.

Typical Properties

Acidity/alkalinity: pH = 5.5–8.0 (2% w/v aqueous solution)

Moisture content: 410%

Solubility: hydroxyethylmethyl cellulose is practically insoluble in hot water (above 608C), acetone, ethanol (95%), ether, and toluene. It dissolves in cold water to form a colloidal solution.

Viscosity (dynamic): 22–30 mPa s (22–30 cP) for a 2% w/v aqueous solution at 208C.

Stability and Storage Conditions

Hydroxyethylmethyl cellulose is hygroscopic and should therefore be stored under dry conditions away from heat.

Incompatibilities

—

Method of Manufacture

—

Safety

Hydroxyethylmethyl cellulose is used as an excipient in various oral and topical pharmaceutical preparations and is generally regarded as an essentially nontoxic and nonirritant material.

See Hypromellose for further information.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of the material handled. Eye protection and gloves are recommended.

Regulatory Status

GRAS listed. Included in nonparenteral medicines licensed in Europe (oral suspensions, tablets, and topical preparations).

Hydroxyethylmethyl Cellulose 335

Related Substances

Ethylcellulose; hydroxyethyl cellulose; hypromellose; methyl- cellulose.

Comments

—

Specific References

1 Bogdanova S. Model suspensions of indomethacin ‘solvent deposited’ on cellulose polymers. Pharmazie 2000; 55(11): 829–

Hydroxypropyl Cellulose

Nonproprietary Names

BP: Hydroxypropylcellulose JP: Hydroxypropylcellulose

PhEur: Hydroxypropylcellulosum USPNF: Hydroxypropyl cellulose

Synonyms

Cellulose, hydroxypropyl ether; E463; hyprolose; Klucel; Methocel; Nisso HPC; oxypropylated cellulose.

Chemical Name and CAS Registry Number

Cellulose, 2-hydroxypropyl ether [9004-64-2]

Empirical Formula and Molecular Weight

The PhEur 2005 and USPNF 23 describe hydroxypropyl cellulose as a partially substituted poly(hydroxypropyl) ether of cellulose. It may contain not more than 0.6% of silica or another suitable anticaking agent. Hydroxypropyl cellulose is commercially available in a number of different grades that have various solution viscosities. Molecular weight has a range of 50 000–1 250 000; see also Section 10.

Structural Formula

R is H or [CH2CH(CH3)O]mH

Functional Category

Coating agent; emulsifying agent; stabilizing agent; suspending agent; tablet binder; thickening agent; viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology

Hydroxypropyl cellulose is widely used in oral and topical pharmaceutical formulations; see Table I.

In oral products, hydroxypropyl cellulose is primarily used in tableting as a binder,(1) film-coating,(2) and extended-release- matrix former.(3–5) Concentrations of hydroxypropyl cellulose of 2–6% w/w may be used as a binder in either wet-granulation or dry, direct-compression tableting processes.(6–10) Concentra- tions of 15–35% w/w of hydroxypropyl cellulose may be used to produce tablets with an extended drug release.(11) The release rate of a drug increases with decreasing viscosity of

hydroxypropyl cellulose. The addition of an anionic surfactant similarly increases the viscosity of hydroxypropyl cellulose and hence decreases the release rate of a drug. Typically, a 5% w/w solution of hydroxypropyl cellulose may be used to film-coat tablets. Aqueous solutions containing hydroxypropyl cellulose along with an amount of methyl cellulose or ethanolic solutions have been used.(12–14) Stearic acid or palmitic acid may be added to ethanolic hydroxypropyl cellulose solutions as plasticizers. Environmental concerns have limited the use of ethanol in film coating solutions. A low-substituted hydroxy- propyl cellulose is used as a tablet disintegrant; see Hydr- oxypropyl Cellulose, Low-substituted.

Hydroxypropyl cellulose is also used in microencapsulation processes and as a thickening agent. In topical formulations, hydroxypropyl cellulose is used in transdermal patches and ophthalmic preparations.(15–17)

Hydroxypropyl cellulose is also used in cosmetics and in food products as an emulsifier and stabilizer.

Table I: Uses of hydroxypropyl cellulose.

Use Concentration (%)

Extended release-matrix former 15–35

Tablet binder 2–6

Tablet film coating 5

Description

Hydroxypropyl cellulose is a white to slightly yellow-colored, odorless and tasteless powder. See also Section 10.

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for hydroxypropyl cellulose.

Test JP 2001 PhEur 2005 USPNF 23

Identification + + +

Characters — + —

Apparent viscosity + + +

Appearance of solution + + —

pH (1 in 100) 5.0–7.5 5.0–8.5 5.0–8.0

Loss on drying 45.0% 47.0% 45.0%

Residue on ignition 40.5% — 40.2%

Sulfated ash — 41.6% —

Arsenic 42 ppm — —

Chlorides + 40.5% —

Lead — — 40.001%

Heavy metals 420 ppm 420 ppm 20 mg/g

Silica — 40.6% —

Organic volatile impurities — — +

Sulfate 40.048% — —

Assay of hydroxypropoxy 53.4–77.5% — 480.5%

groups

Hydroxypropyl Cellulose 337

Typical Properties

Acidity/alkalinity: pH = 5.0–8.5 for a 1% w/v aqueous solution.

Density (bulk): ≈0.5 g/cm3

Interfacial tension: 12.5 mN/m for a 0.1% w/v aqueous solution compared with mineral oil.

Melting point: softens at 1308C; chars at 260–2758C.

Moisture content: hydroxypropyl cellulose absorbs moisture from the atmosphere; the amount of water absorbed depends upon the initial moisture content and the tempera- ture and relative humidity of the surrounding air. Typical equilibrium moisture content values at 258C are 4% w/w at 50% relative humidity and 12% w/w at 84% relative humidity. See Table III. See also Figure I.

Table III: Moisture content of Klucel (Aqualon).

Grade Molecular weight Moisture (%)

Klucel EF ≈80 000 0.59

Klucel LF ≈95 000 2.21

Klucel JF ≈140 000 1.44

Klucel GF ≈370 000 1.67

Klucel MF ≈850 000 1.52

Klucel HF ≈1 150 000 4.27

Figure 1: Equilibrium moisture content of various grades of hydro- xypropyl cellulose.

⃝: Klucel GF (Aqualon, Lot #4996). Q: Klucel JF (Aqualon, Lot #4753). Q: Klucel LF (Aqualon, Lot #4965).

□: Klucel EF (Aqualon, Lot #1223).

Particle size distribution:

Klucel (regular grind), 95% through a US #30 mesh (590 mm), and 99% through a US #20 mesh (840 mm); Klucel (X-grind), 100% through a US #60 mesh (250 mm), and 80% through a US #100 mesh (149 mm).

Refractive index: n20 = 1.3353 for a 2% w/v aqueous solution.

hydrocarbons; carbon tetrachloride; petroleum distillates; glycerin; and oils.

Hydroxypropyl cellulose is freely soluble in water below 388C, forming a smooth, clear, colloidal solution. In hot water, it is insoluble and is precipitated as a highly swollen floc at a temperature between 40 and 458C. Hydroxypropyl cellulose is soluble in many cold or hot polar organic solvents such as dimethyl formamide; dimethyl sulfoxide; dioxane; ethanol (95%); methanol; propan-2-ol (95%); and propylene glycol. There is no tendency for precipitation in hot organic solvents. However, the grade of hydroxypropyl cellulose can have a marked effect upon solution quality in some organic liquids that are borderline solvents, such as acetone; butyl acetate; cyclohexanol; dichloromethane; lactic acid; methyl acetate; methyl ethyl ketone; propan-2- ol (99%); and tert-butanol. The higher-viscosity grades of hydroxypropyl cellulose tend to produce slightly inferior solutions. However, the solution quality in borderline solvents can often be greatly improved by the use of small quantities (5–15%) of a cosolvent. For example, dichloro- methane is a borderline solvent for Klucel HF and solutions have a granular texture, but a smooth solution may be produced by adding 10% methanol.

Hydroxypropyl cellulose is compatible with a number of high-molecular-weight, high-boiling waxes and oils, and can be used to modify certain properties of these materials. Examples of materials that are good solvents for hydroxy- propyl cellulose at an elevated temperature are acetylated monoglycerides, glycerides, pine oil, polyethylene glycol, and polypropylene glycol.

Specific gravity: 1.2224 for particles; 1.0064 for a 2% w/v aqueous solution at 208C.

Surface tension: see Table IV.

Table IV: Surface tension (mN/m) of aqueous solutions of Nisso HPC

(Nippon Soda Co. Ltd.) at 208C.

Grade Surface tension (mN/m) at 208C for aqueous solutions of stated concentration

0.01% 0.1% 1.0% 10.0%

Nisso HPC-L 51.0 49.1 46.3 45.8

Nisso HPC-M 54.8 49.7 46.3 —

Viscosity (dynamic): a wide range of viscosity types are commercially available; see Table V. Solutions should be prepared by gradually adding the hydroxypropyl cellulose to a vigorously stirred solvent. Increasing concentration produces solutions of increased viscosity. See also Section 11 for information on solution stability.

Table V: Viscosity of aqueous solutions of Klucel (Aqualon) at 258C.

Grade Viscosity (mPa s) of various aqueous solutions of

stated concentration

Solubility:

soluble 1 in 10 parts dichloromethane; 1 in 2.5 parts

ethanol (95%); 1 in 2 parts methanol; 1 in 5 parts propan-2-

ol; 1 in 5 parts propylene glycol; and 1 in 2 parts water. Practically insoluble in aliphatic hydrocarbons; aromatic

338 Hydroxypropyl Cellulose

SEM: 1

Excipient: Hydroxypropyl cellulose (Klucel)

Manufacturer: Aqualon

Magnification: 60×

SEM: 2

Excipient: Hydroxypropyl cellulose (Klucel)

Manufacturer: Aqualon

Magnification: 600×

Stability and Storage Conditions

Hydroxypropyl cellulose powder is a stable material, although it is hygroscopic after drying.

Aqueous solutions of hydroxypropyl cellulose are stable at pH 6.0–8.0, with the viscosity of solutions being relatively unaffected. However, at low pH aqueous solutions may undergo acid hydrolysis, resulting in chain scission and hence

a decrease in solution viscosity. The rate of hydrolysis increases with increasing temperature and hydrogen ion concentration. At high pH, alkali-catalyzed oxidation may degrade the polymer and result in a decrease in viscosity of solutions. This degradation can occur owing to the presence of dissolved oxygen or oxidizing agents in a solution.

Increasing temperature causes the viscosity of aqueous solutions to decrease gradually until the viscosity drops suddenly at about 458C owing to the limited solubility of hydroxypropyl cellulose. However, this process is reversible and on cooling the original viscosity is restored.

The high level of substitution of hydroxypropyl cellulose improves the resistance of the polymer to degradation by molds and bacteria.(14) However, aqueous solutions are susceptible to degradation under severe conditions and a viscosity decrease may occur. Certain enzymes produced by microbial action will degrade hydroxypropyl cellulose in solution.(18) Therefore, for prolonged storage, an antimicrobial preservative should be added to aqueous solutions. Solutions of hydroxypropyl cellulose in organic solvents do not generally require pre- servatives.

Ultraviolet light will also degrade hydroxypropyl cellulose and aqueous solutions may therefore decrease slightly in viscosity if exposed to light for several months.

Aqueous hydroxypropyl cellulose solutions have optimum stability when the pH is maintained at 6.0–8.0, and also when the solution is protected from light, heat, and the action of microorganisms.

Hydroxypropyl cellulose powder should be stored in a well- closed container in a cool, dry place.

Incompatibilities

Hydroxypropyl cellulose in solution demonstrates some incompatibility with substituted phenol derivatives, such as methylparaben and propylparaben. The presence of anionic polymers may increase the viscosity of hydroxypropyl cellulose solutions.

The compatibility of hydroxypropyl cellulose with inorganic salts varies depending upon the salt and its concentration; see Table VI. Hydroxypropyl cellulose may not tolerate high concentrations of other dissolved materials.

The balance of the hydrophilic–lipophilic properties of the polymer, which are required for dual solubility, reduces its ability to hydrate with water and it therefore tends to be salted out in the presence of high concentrations of other dissolved materials.

The precipitation temperature of hydroxypropyl cellulose is lower in the presence of relatively high concentrations of other dissolved materials that compete for the water in the system; see Table VII.

Method of Manufacture

A purified form of cellulose is reacted with sodium hydroxide to produce a swollen alkali cellulose that is chemically more reactive than untreated cellulose. The alkali cellulose is then reacted with propylene oxide at elevated temperature and pressure. The propylene oxide can be substituted on the cellulose through an ether linkage at the three reactive hydroxyls present on each anhydroglucose monomer unit of the cellulose chain. Etherification takes place in such a way that hydroxypropyl substituent groups contain almost entirely secondary hydroxyls. The secondary hydroxyl present in the side chain is available for further reaction with the propylene oxide, and ‘chaining-out’ may take place. This results in the

Hydroxypropyl Cellulose 339

Table VI: Compatibility of hydroxypropyl cellulose (Nisso HPC) with inorganic salts in aqueous solutions.(a)

Salt Concentration of salt (% w/w)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Hydroxypropyl cellulose

dust may be irritant to the eyes; eye protection is recommended.

Excessive dust generation should be avoided to minimize the risk of explosions.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (oral capsules and tablets; topical and transdermal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Hydroxyethyl cellulose; hydroxypropyl cellulose, low-substi- tuted; hypromellose.

Table VII: Variation in precipitation temperature of hydroxypropyl cellulose (Klucel H) in the presence of other materials.

Ingredients and concentrations Precipitation temperature (8C)

1% Klucel H 41

1% Klucel H + 1.0% sodium chloride 38

1% Klucel H + 5.0% sodium chloride 30

0.5% Klucel H + 10% sucrose 41

0.5% Klucel H + 30% sucrose 32

0.5% Klucel H + 40% sucrose 20

0.5% Klucel H + 50% sucrose 7

formation of side chains containing more than 1 mole of combined propylene oxide.

Safety

Hydroxypropyl cellulose is widely used as an excipient in oral and topical pharmaceutical formulations. It is also used extensively in cosmetics and food products.

Hydroxypropyl cellulose is generally regarded as an essentially nontoxic and nonirritant material.(19,20) However, the use of hydroxypropyl cellulose as a solid ocular insert has been associated with rare reports of discomfort or irritation, including hypersensitivity and edema of the eyelids. Adverse reactions to hydroxypropyl cellulose are rare. However, it has been reported that a single patient developed contact dermatitis due to hydroxypropyl cellulose in a transdermal estradiol patch.(21)

The WHO has not specified an acceptable daily intake for hydroxypropyl cellulose since the levels consumed were not considered to represent a hazard to health.(22) Excessive consumption of hydroxypropyl cellulose may, however, have a laxative effect.

LD50 (rat, IV): 0.25 g/kg(23)

LD50 (rat, oral): 10.2 g/kg

Comments

Hydroxypropyl cellulose is a thermoplastic polymer that can be processed by virtually all fabrication methods used for plastics. It is also used in hot-melt extruded films for topical use.

When it is produced with chlorpheniramine maleate, the matrix is stabilized, allowing film processing at lower temperatures.(24) Mucoadhesive hydroxypropyl cellulose microspheres have been prepared for powder inhalation preparations.(25) A specification for hydroxypropyl cellulose is included in the Food Chemicals Codex (FCC).

Specific References

Skinner GW, Harcum WW, Barnum PE, Guo JH. The evaluation of fine-particle hydroxypropylcellulose as a roller compaction binder in pharmaceutical applications. Drug Dev In Pharm 1999; 25(10):

1121–1128.

Aqualon. Technical literature: Klucel EF Pharm Hydroxypropyl- cellulose. Use in plasticizer-free aqueous coating, 2000.

Aqualon. Technical literature: Klucel Hydroxypropylcellulose application in a sustained release matrix capsule dosage form, 2004.

Alderman DA. Sustained release compositions comprising Hydro- xypropyl cellulose ethers. United States Patent No. 4,704,285; 1987.

Lee DY, Chen CM. Delayed pulse release hydrogel matrix tablet. United States Patent No. 6,103,263; 2000.

Machida Y, Nagai T. Directly compressed tablets containing hydroxypropyl cellulose in addition to starch or lactose. Chem Pharm Bull 1974; 22: 2346–2351.

Delonca H, Joachim J, Mattha AG. Binding activity of hydro- xypropyl cellulose (200 000 and 1 000 000 mol. wt.) and its effect on the physical characteristics of granules and tablets. Farmaco (Prat) 1977; 32: 157–171.

Delonca H, Joachim J, Mattha A. Effect of temperature on disintegration and dissolution time of tablets with a cellulose component as a binder [in French]. J Pharm Belg 1978; 33: 171– 178.

Stafford JW, Pickard JF, Zink R. Temperature dependence of the disintegration times of compressed tablets containing hydroxy- propyl cellulose as binder. J Pharm Pharmacol 1978; 30: 1–5.

Kitamori N, Makino T. Improvement in pressure-dependent dissolution of trepibutone tablets by using intragranular disin- tegrants. Drug Dev Ind Pharm 1982; 8: 125–139.

Johnson JL, Holinej J, Williams MD. Influence of ionic strength on matrix integrity and drug release from hydroxypropyl cellulose compacts. Int J Pharm 1993; 90: 151–159.

340 Hydroxypropyl Cellulose

Lindberg NO. Water vapour transmission through free films of hydroxypropyl cellulose. Acta Pharm Suec 1971; 8: 541–548.

Banker G, Peck G, Williams E, et al. Evaluation of hydroxypro- pylcellulose and hydroxypropylmethylcellulose as aqueous based film coatings. Drug Dev Ind Pharm 1981; 7: 693–716.

Banker G, Peck G, Williams E, et al. Microbiological considera- tions of polymer solutions used in aqueous film coating. Drug Dev Ind Pharm 1982; 8: 41–51.

Cohen EM, Grim WM, Harwood RJ, Mehta GN. Solid state ophthalmic medication. United States Patent No. 4,179,497; 1979.

Harwood RJ, Schwartz JB. Drug release from compression molded films: preliminary studies with pilocarpine. Drug Dev Ind Pharm 1982; 8: 663–682.

Dumortier G, Zuber M, Chast F, et al. Systemic absorption of morphine after ocular administration: evaluation of morphine salt insert in vitro and in vivo. Int J Pharm 1990; 59: 1–7.

Wirick MG. Study of the enzymic degradation of CMC and other cellulose ethers. J Polym Sci 1968; 6(Part A-1): 1965–1974.

Anonymous. Final report on the safety assessment of hydroxy- ethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxy- propyl methylcellulose and cellulose gum. J Am Coll Toxicol 1986; 5(3): 1–60.

Aqualon. Technical literature: Klucel hydroxypropylcellulose summary of toxicological investigations, 2004.

Schwartz BK, Clendenning WE. Allergic contact dermatitis from hydroxypropyl cellulose in a transdermal estradiol patch. Contact Dermatitis 1988; 18(2): 106–107.

FAO/WHO. Evaluation of certain food additives and contami- nants. Thirty-fifth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1990; No. 789.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2053.

Repka MA, McGinty JW. Influence of chlorpheniramine maleate on topical hydroxypropylcellulose films produced by hot melt extrusion. Pharm Dev Technol 2001; 6(3): 297–304.

Sakagami M, Sakon K, Kinoshita W, Makino Y. Enhanced pulmonary absorption following aerosol administration of mucoadhesive powder microspheres. J Control Release 2001; 77(1–2): 117–129.

General References

Aqualon. Technical literature: Klucel, hydroxypropyl cellulose, a nonionic water-soluble polymer, physical and chemical properties, 1987.

Aqualon. Technical literature: Klucel Hydroxypropylcellulose, Pharm- grade for pharmaceutical uses, 2004.

Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199–265. Ganz AJ. Thermoplastic food production. United States Patent No.

3,769,029; 1973.

Klug ED. Some properties of water-soluble hydroxyalkyl celluloses and their derivatives. J Polym Sci 1971; 36(Part C): 491–508.

Nippon Soda Co. Ltd. Technical literature: Nisso HPC, 1993.

Opota O, Maillols H, Acquier R, et al. Rheological behavior of aqueous solutions of hydroxypropylcellulose: influence of concentration and molecular mass [in French]. Pharm Acta Helv 1988; 63: 26–32.

Hydroxypropyl Cellulose, Low-substituted

Nonproprietary Names

JP: Low-substituted hydroxypropylcellulose USPNF: Low-substituted hydroxypropyl cellulose

Synonyms

Hyprolose, low-substituted; L-HPC.

Chemical Name and CAS Registry Number

Cellulose, 2-hydroxypropyl ether (low-substituted) [78214-41- 2]

Empirical Formula and Molecular Weight

The USPNF 23 describes low-substituted hydroxypropyl cellulose as a low-substituted hydroxypropyl ether of cellulose. When dried at 1058C for 1 hour, it contains not less than 5.0% and not more than 16.0% of hydroxypropoxy groups (—OCH2CHOHCH3). Low-substituted hydroxypropyl cellu- lose is commercially available in a number of different grades that have different particle sizes and substitution levels.

Structural Formula

R is H or [CH2CH(CH3)O]mH

Functional Category

Tablet and capsule disintegrant; tablet binder.

Applications in Pharmaceutical Formulation or Technology

Low-substituted hydroxypropyl cellulose is widely used in oral solid-dosage forms. It is primarily used in tableting as a disintegrant, and as a binder in wet granulation. It has been used in the preparation of rapidly disintegrating tablets produced by direct compression methods.(1,2) In addition, low-substituted hydroxypropyl cellulose has been used to delay the release of drug from a tablet matrix.(3)

There are a number of grades that have different particle sizes and substitution levels. LH-11 has the medium substitu- tion level and the largest particle size, and is typically used as an anticapping agent and disintegrant for direct compression. LH- 21 is used as a binder and disintegrant for tablets through the wet-granulation process. LH-31 is a small-particle grade used especially for extrusion to produce granules, as it has a small particle size that is better for passing a screen. Lower substitution grades LH-22 and LH-32 can be used when high

binding strength is not necessary. If higher binding strength is needed, higher substitution grades LH-20 and LH-30 are also available.

The typical content of low-substituted hydroxypropyl cellulose in a formulation is approximately 5–25%.

Description

Low-substituted hydroxypropyl cellulose occurs as a white to yellowish white powder or granules. It is odorless or has a slight, characteristic odor, and it is tasteless.

SEM: 1

Excipient: Low-substituted hydroxypropyl cellulose, type LH-11 Manufacturer: Shin-Etsu

Magnification: 350×

SEM: 2

Excipient: Low-substituted hydroxypropyl cellulose, type LH-21 Manufacturer: Shin-Etsu

Magnification: 350×

342 Hydroxypropyl Cellulose, Low-substituted

SEM: 3

Excipient: Low-substituted hydroxypropyl cellulose, type LH-31

Table II: Typical properties of hydroxypropyl cellulose, low- substituted, for selected grades.

Manufacturer: Shin-Etsu

Magnification: 350× Grade Hydroxy- propoxy content (%) Angle of repose (8) Average particle size (mm) Density (bulk) (g/cm3) Density (tapped) (g/cm3)

LH-11 11 49 50 0.32 0.56

LH-21 11 45 40 0.36 0.62

LH-31 11 49 25 0.28 0.59

LH-22 8 48 40 0.36 0.62

LH-32 8 53 25 0.28 0.59

LH-20 13 48 40 0.36 0.62

LH-30 13 51 25 0.28 0.59

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for hydroxypropyl cellulose, low substituted.

Test JP 2001 USPNF 23

Identification + +

Chloride 40.335% 40.36%

Heavy metals 410 ppm 40.001%

Arsenic 42 ppm —

pH 5.0–7.5 —

Loss on drying 46.0% 45.0%

Residue on ignition 41.0% 40.5%

Assay (of hydroxypropoxy groups) 5.0–16.0% 5.0–16.0%

Typical Properties

Acidity/alkalinity: pH = 5.0–7.5 for 1% w/v aqueous suspen- sion.

Angle of repose: see Table II.

Ash: 0.3–0.4%

Density (bulk): see Table II.

Density (tapped): see Table II.

Melting point: decomposition at 2758C.

Moisture content:

8% at 33% relative humidity;

38% at 95% relative humidity.

Specific gravity: 1.46

Solubility: practically insoluble in ethanol (95%) and in ether. Dissolves in a solution of sodium hydroxide (1 in 10) and produces a viscous solution. Insoluble, but swells in water.

Stability and Storage Conditions

Low-substituted hydroxypropyl cellulose is a stable, though hygroscopic, material. The powder should be stored in a well- closed container.

Incompatibilities

Alkaline substances may interact. If a tablet formulation contains such a material, its disintegration may be extended after storage.

Method of Manufacture

Low-substituted hydroxypropyl cellulose is manufactured by reacting alkaline cellulose with propylene oxide at elevated temperature. Following the reaction, the product is recrystal- lized by neutralization, washed, and milled.

Safety

Low-substituted hydroxypropyl cellulose is generally regarded as a nontoxic and nonirritant material.

Animal toxicity studies showed no adverse effects in rats fed orally 6 g/kg/day over 6 months. No teratogenic effects were noted in rabbits and rats fed 5 g/kg/day.(4–7)

LD50 (rat, oral): 15 g/kg(4)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Excessive dust generation should be avoided to minimize the risk of explosions.

Regulatory Status

Approved for use in pharmaceuticals in Europe, Japan, USA, and other countries. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Hydroxypropyl cellulose.

Comments

—

Specific References

Kawashima Y, Takeuchi H, Hino T, et al. Low-substituted hydroxypropylcellulose as a sustained-drug release matrix base or disintegrant depending on its particle size and loading in formulation. Pharm Res 1993; 10(3): 351–355.

Ishikawa T, Mukai B, Shiaishi S, et al. Preparation of rapidly disintegrating tablet using new types of microcrystalline cellulose (PH-M series) and low-substituted hydroxypropylcellulose or

Hydroxypropyl Cellulose, Low-substituted 343

spherical sugar granules by direct compression method. Chem Pharm Bull 2001; 49(2): 134–139.

Jeko ZB, Sipos T, Kertai EH, Mezey G. Comparison of dissolution- rate curves of carbamazepine from different hydrophilic matrix tablets. Acta Pharm 1999; 49: 267–273.

Kitagawa H, Yano H, Saito H, Fukuka Y. Acute, subacute and chronic toxicities of hydroxypropylcellulose of low-substitution in rats. Pharmacometrics 1976; 12: 41–66.

Kitagawa H, Saito H, Yokoshima T, et al. Absorption, distribution, excretion and metabolism of 14C-hydroxypropylcellulose of low- substitution. Pharmacometrics 1976; 12: 33–39.

Kitagawa H, Satoh T, Saito H, et al. Teratological study of hydroxypropylcellulose of low substitution (L-HPC) in rabbits. Pharmacometrics 1978; 16: 259–269.

Kitagawa H, Saito H. General pharmacology of hydroxypropyl- cellulose of low substitution (L-HPC). Pharmacometrics 1978; 16: 299–302.

General References

Shin-Etsu Chemical Co. Ltd. Technical literature: L-HPC, low- substituted hydroxypropyl cellulose, 1991.

Shin-Etsu Chemical Co. Ltd. Technical literature: L-HPC, NF Disin- tegrant-binder, 2000.

E1440; hydroxylpropyl starch.

Chemical Name and CAS Registry Number

Hydroxypropyl starch [113894-92-1]

Empirical Formula and Molecular Weight

Hydroxypropyl starch is a derivative of natural starch; it is described in the JPE 2004 as a hydroxypropyl ether of corn starch.

Structural Formula

See Section 4.

Functional Category

Binder; disintegrant; emulsifying agent; thickening agent; viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology

Hydroxypropyl starch is a modified starch and has been used in combination with carrageenan in the production of soft capsules.(1,2) Hydroxypropyl starch has been used experimen- tally in hydrophilic matrices, where it was shown to be an effective matrix for tablets designed for controlled-release drug delivery systems.(3) It has also been used experimentally in the production of hydrophilic matrices by direct compression.(4)

It is used in antiseptics and is used widely in cosmetics. It is also used analytically as a bioseparation aqueous-phase- forming polymer.(5)

Description

Hydroxypropyl starch occurs as a free-flowing white to off- white coarse powder.

Pharmacopeial Specifications

See Section 18.

Typical Properties

Acidity/alkalinity: pH = 4.5–7.0 (10% w/v aqueous disper- sion).

Solubility: practically insoluble in water, ethanol (95%), and ether.

Stability and Storage Conditions

Hydroxypropyl starch is stable at high humidity and is considered to be inert under normal conditions. It is stable in emulsion systems at pH 3–9.

Incompatibilities

See Section 18.

Method of Manufacture

Hydroxypropyl starch is produced industrially from natural starch, using propylene oxide as the modifying reagent in the presence of alkali, adding hydroxypropyl (CH(OH)CH2CH3) groups at the OH positions by an ether linkage.

Safety

Hydroxypropyl starch is widely used in cosmetics and food products. It is also used in oral pharmaceutical formulations. The WHO has set an acceptable daily intake for hydroxypropyl starch at ‘not limited’ since it was well tolerated on oral consumption.(6)

LD50 (rat, oral): 0.218 g/kg(7)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe.

Related Substances

—

Comments

Hydroxypropyl starch–methyl methacrylate (HS-MMA) has been used experimentally in hydrophilic matrices produced by direct compression.(4) Pregelatinized hydroxypropyl starch has been shown to exhibit good disintegrating properties, and can be used as a binder in wet granulation.(8)

Although it is not currently included in the pharmacopeias, a specification for hydroxypropyl starch is included in the Japanese Pharmaceutical Excipients (JPE) 2004; see Table I.(9) Hydroxypropyl starch is compatible with cationic ingredi-

ents (monovalent, divalent), oils, emollients, and silicone.

The EINECS number for hydroxypropyl starch is 232- 679-6.

Hydroxypropyl Starch 345

Table I: JPE 2004 specification for hydroxypropyl starch.

Loss on drying 415.0%

Residue on ignition 40.5%

Content of hydroxypropyl group after drying 2.0–7.0%

Specific References

Draper PR, Tanner KE, Getz JJ, et al. Film forming compositions comprising modified starches and iota-carrageenan and methods for manufacturing soft capsules using the same. International Patent WO 013677; 1999.

Cardinal Health. Vegicaps soft capsules. http://www.cardinal.com/ pts/content/delivery/dd-oral-vegicaps.asp (accessed 26 May 2005).

Goni I, Ferrero MC, Jimenez-Castellanos RM, Gurruchaga M. Synthesis of hydroxypropyl methacrylate/polysaccharide graft copolymers as matrices for controlled release tablets. Drug Dev Ind Pharm 2002; 28(9): 1101–1115.

Ferrero MC, Velasco MV, Mun˜ oz A, et al. Drug release from a family of graft copolymers of methyl methacrylate. I. Int J Pharm 1997; 149: 233–240.

Venacio A, Teixeira JA, Mota M. Evaluation of crude hydroxy- propyl starch as a bioseparation aqueous-phase-forming polymer. Biotechnol Prog 1993; 9(6): 635–639.

FAO/WHO. Fifteenth Report of the Joint FAO/WHO Expert Committee on Food Additives. World Health Organ Tech Rep Ser 1972; No. 488.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2054.

Visavarungroj N, Remon JP. An evaluation of hydroxypropyl starch as disintegrant and binder in tablet formulation. Drug Dev Ind Pharm 1991; 17(10): 1389–1396.

Japan Pharmaceutical Excipients Council. Japanese Pharmaceu- tical Excipients 2004. Tokyo: Yakuji Nippo, 2004: 425–427.

JP: Hydroxypropylmethylcellulose PhEur: Hypromellosum

USP: Hypromellose

Synonyms

Benecel MHPC; E464; hydroxypropyl methylcellulose; HPMC; Methocel; methylcellulose propylene glycol ether; methyl hydroxypropylcellulose; Metolose; Tylopur.

Chemical Name and CAS Registry Number

Cellulose hydroxypropyl methyl ether [9004-65-3]

Empirical Formula and Molecular Weight

The PhEur 2005 describes hypromellose as a partly O- methylated and O-(2-hydroxypropylated) cellulose. It is avail- able in several grades that vary in viscosity and extent of substitution. Grades may be distinguished by appending a number indicative of the apparent viscosity, in mPa s, of a 2% w/w aqueous solution at 208C. Hypromellose defined in the USP 28 specifies the substitution type by appending a four-digit number to the nonproprietary name: e.g., hypromellose 1828. The first two digits refer to the approximate percentage content of the methoxy group (OCH3). The second two digits refer to the approximate percentage content of the hydroxypropoxy group (OCH2CH(OH)CH3), calculated on a dried basis. It contains methoxy and hydroxypropoxy groups conforming to the limits for the types of hypromellose stated in Table I. Molecular weight is approximately 10 000–1 500 000. The JP 2001 includes three separate monographs for hypromellose: hydroxypropylmethylcellulose 2208, 2906, and 2910, respec- tively.

Structural Formula

where R is H, CH , or CH CH(OH)CH

Applications in Pharmaceutical Formulation or Technology

Hypromellose is widely used in oral, ophthalmic and topical pharmaceutical formulations.

In oral products, hypromellose is primarily used as a tablet binder,(1) in film-coating,(2–7) and as a matrix for use in extended-release tablet formulations.(8–12) Concentrations between 2% and 5% w/w may be used as a binder in either wet- or dry-granulation processes. High-viscosity grades may be used to retard the release of drugs from a matrix at levels of 10–80% w/w in tablets and capsules.

Depending upon the viscosity grade, concentrations of 2–20% w/w are used for film-forming solutions to film-coat tablets. Lower-viscosity grades are used in aqueous film-coating solutions, while higher-viscosity grades are used with organic solvents. Examples of film-coating materials that are commer- cially available include AnyCoat C, Spectracel, and Pharma- coat.

Hypromellose is also used as a suspending and thickening agent in topical formulations. Compared with methylcellulose, hypromellose produces aqueous solutions of greater clarity, with fewer undispersed fibers present, and is therefore preferred in formulations for ophthalmic use. Hypromellose at concen- trations between 0.45–1.0% w/w may be added as a thickening agent to vehicles for eye drops and artificial tear solutions.

Hypromellose is also used as an emulsifier, suspending agent, and stabilizing agent in topical gels and ointments. As a protective colloid, it can prevent droplets and particles from coalescing or agglomerating, thus inhibiting the formation of sediments.

In addition, hypromellose is used in the manufacture of capsules, as an adhesive in plastic bandages, and as a wetting agent for hard contact lenses. It is also widely used in cosmetics and food products.

Description

Hypromellose is an odorless and tasteless, white or creamy- white fibrous or granular powder. See also Section 10.

Pharmacopeial Specifications

See Table I.

Typical Properties

Acidity/alkalinity: pH = 5.5–8.0 for a 1% w/w aqueous solution.

Ash: 1.5–3.0%, depending upon the grade and viscosity.

Autoignition temperature: 3608C Density (bulk): 0.341 g/cm3 Density (tapped): 0.557 g/cm3

3 3 2

Functional Category

Coating agent; film-former; rate-controlling polymer for sustained release; stabilizing agent; suspending agent; tablet binder; viscosity-increasing agent.

Density (true): 1.326 g/cm3

Melting point: browns at 190–2008C; chars at 225–2308C. Glass transition temperature is 170–1808C.

Moisture content: hypromellose absorbs moisture from the atmosphere; the amount of water absorbed depends upon the initial moisture content and the temperature and relative humidity of the surrounding air. See Figure 1.

Hypromellose 347

SEM: 1

Excipient: Hypromellose Manufacturer: Dow Chemical Co. Lot No.: ME20012N11

Magnification: 600×

Voltage: 5 kV

SEM: 2

Excipient: Hypromellose Manufacturer: Dow Chemical Co. Lot No.: ME20012N11

Magnification: 60×

Voltage: 5 kV

Solubility: soluble in cold water, forming a viscous colloidal solution; practically insoluble in chloroform, ethanol (95%), and ether, but soluble in mixtures of ethanol and dichloromethane, mixtures of methanol and dichloro- methane, and mixtures of water and alcohol. Certain grades of hypromellose are soluble in aqueous acetone solutions, mixtures of dichloromethane and propan-2-ol, and other organic solvents. See also Section 11.

Specific gravity: 1.26

Table I: Pharmacopeial specifications for hypromellose.

Test JP 2001 PhEur 2005 USP 28

Identification + + +

Characters — + —

Appearance of solution + + —

pH (1% w/w solution) 5.0–8.0 5.5–8.0 —

Apparent viscosity + + +

Loss on drying 45.0% 410.0% 45.0%

Residue on ignition 41.5% — —

For viscosity grade

>50 mPa s — — 41.5%

For viscosity grade — — 43.0%

Sulfated ash — 41.0% —

Chlorides 40.284% 40.5% —

Heavy metals 410 ppm 420 ppm 40.001%

Iron 4100 ppm — —

Arsenic 42 ppm — —

Organic volatile — — +

impurities

Methoxy content

Type 1828 — — 16.5–20.0%

Type 2208 19.0–24.0% — 19.0–24.0%

Type 2906 27.0–30.0% — 27.0–30.0%

Type 2910 28.0–30.0% — 28.0–30.0%

Hydroxypropoxy content

Type 1828 — — 23.0–32.0%

Type 2208 4.0–12.0% — 4.0–12.0%

Type 2906 4.0–7.5% — 4.0–7.5%

Type 2910 7.0–12.0% — 7.0–12.0%

Figure 1: Absorption–desorption isotherm for hypromellose.

^: Sorption

&: Desorption

Viscosity (dynamic): a wide range of viscosity types are commercially available. Aqueous solutions are most com- monly prepared, although hypromellose may also be dissolved in aqueous alcohols such as ethanol and propan- 2-ol provided the alcohol content is less than 50% w/w. Dichloromethane and ethanol mixtures may also be used to prepare viscous hypromellose solutions. Solutions prepared

348 Hypromellose

using organic solvents tend to be more viscous; increasing concentration also produces more viscous solutions; see Table II.

Table II: Typical viscosity values for 2% (w/v) aqueous solutions of

Methocel (Dow Chemical Co.). Viscosities measured at 208C.

Method of Manufacture

A purified form of cellulose, obtained from cotton linters or wood pulp, is reacted with sodium hydroxide solution to produce a swollen alkali cellulose that is chemically more reactive than untreated cellulose. The alkali cellulose is then

treated with chloromethane and propylene oxide to produce

Methocel product USP 28

Nominal viscosity

methyl hydroxypropyl ethers of cellulose. The fibrous reaction

designation (mPa s)

product is then purified and ground to a fine, uniform powder

or granules.

Safety

Hypromellose is widely used as an excipient in oral and topical pharmaceutical formulations. It is also used extensively in cosmetics and food products.

Hypromellose is generally regarded as a nontoxic and nonirritant material, although excessive oral consumption may have a laxative effect.(14) The WHO has not specified an acceptable daily intake for hypromellose since the levels consumed were not considered to represent a hazard to health.(15)

LD50 (mouse, IP): 5 g/kg(16)

LD50 (rat, IP): 5.2 g/kg

To prepare an aqueous solution, it is recommended that hypromellose is dispersed and thoroughly hydrated in about 20–30% of the required amount of water. The water should be vigorously stirred and heated to 80–908C, then the remaining hypromellose should be added. Sufficient cold water should then be added to produce the required volume. When a water-miscible organic solvent such as ethanol (95%), glycol, or mixtures of ethanol and dichloromethane are used, the hypromellose should first be dispersed into the organic solvent, at a ratio of 5–8 parts of solvent to 1 part of hypromellose. Cold water is then added to produce the

required volume.

Stability and Storage Conditions

Hypromellose powder is a stable material, although it is hygroscopic after drying.

Solutions are stable at pH 3–11. Increasing temperature reduces the viscosity of solutions. Hypromellose undergoes a reversible sol–gel transformation upon heating and cooling, respectively. The gel point is 50–908C, depending upon the grade and concentration of material.

Aqueous solutions are comparatively enzyme-resistant, providing good viscosity stability during long-term storage.(13) However, aqueous solutions are liable to microbial spoilage and should be preserved with an antimicrobial preservative: when hypromellose is used as a viscosity-increasing agent in ophthalmic solutions, benzalkonium chloride is commonly used as the preservative. Aqueous solutions may also be sterilized by autoclaving; the coagulated polymer must be redispersed on cooling by shaking.

Hypromellose powder should be stored in a well-closed container, in a cool, dry place.

Incompatibilities

Hypromellose is incompatible with some oxidizing agents. Since it is nonionic, hypromellose will not complex with metallic salts or ionic organics to form insoluble precipitates.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Hypromellose dust may be irritant to the eyes and eye protection is recommended. Excessive dust generation should be avoided to minimize the risks of explosion. Hypromellose is combustible.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (ophthalmic preparations; oral capsules, suspensions, syrups, and tablets; topical and vaginal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Hydroxyethyl cellulose; hydroxyethylmethyl cellulose; hydr- oxypropyl cellulose; hypromellose phthalate; methylcellulose.

Comments

Powdered or granular, surface-treated grades of hypromellose are also available that are dispersible in cold water. These are not recommended for oral use. A specification for hypromellose is contained in the Food Chemicals Codex (FCC).

Specific References

Chowhan ZT. Role of binders in moisture-induced hardness increase in compressed tablets and its effect on in vitro disintegra- tion and dissolution. J Pharm Sci 1980; 69: 1–4.

Rowe RC. The adhesion of film coatings to tablet surfaces – the effect of some direct compression excipients and lubricants. J Pharm Pharmacol 1977; 29: 723–726.

Rowe RC. The molecular weight and molecular weight distribu- tion of hydroxypropyl methylcellulose used in the film coating of tablets. J Pharm Pharmacol 1980; 32: 116–119.

Hypromellose 349

Banker G, Peck G, Jan S, Pirakitikulr P. Evaluation of hydroxy- propyl cellulose and hydroxypropyl methyl cellulose as aqueous based film coatings. Drug Dev Ind Pharm 1981; 7: 693–716.

Okhamafe AO, York P. Moisture permeation mechanism of some aqueous-based film coats. J Pharm Pharmacol 1982; 34 (Suppl.): 53P.

Alderman DA, Schulz GJ. Method of making a granular, cold water dispersible coating composition for tablets. United States Patent No. 4,816,298; 1989.

Patell MK. Taste masking pharmaceutical agents. United States Patent No. 4,916,161; 1990.

Hardy JG, Kennerley JW, Taylor MJ, et al. Release rates from sustained-release buccal tablets in man. J Pharm Pharmacol 1982; 34 (Suppl.): 91P.

Hogan JE. Hydroxypropylmethylcellulose sustained release tech- nology. Drug Dev Ind Pharm 1989; 15: 975–999.

Shah AC, Britten NJ, Olanoff LS, Badalamenti JN. Gel-matrix systems exhibiting bimodal controlled release for oral delivery. J Control Release 1989; 9: 169–175.

Wilson HC, Cuff GW. Sustained release of isomazole from matrix tablets administered to dogs. J Pharm Sci 1989; 78: 582–584.

Dahl TC, Calderwood T, Bormeth A, et al. Influence of physicochemical properties of hydroxypropyl methylcellulose on naproxen release from sustained release matrix tablets. J Control Release 1990; 14: 1–10.

Banker G, Peck G, Williams E, et al. Microbiological considera- tions of polymer solutions used in aqueous film coating. Drug Dev Ind Pharm 1982; 8: 41–51.

FAO/WHO. Evaluation of certain food additives and contami- nants. Thirty-fifth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1990; No. 789.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2054.

General References

Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199–265.

Dow Chemical Company. Technical literature: Methocel cellulose ethers in aqueous systems for tablet coating, 2000.

Li CL, Martini LG, Ford JL, Roberts M. The use of hypromellose in oral drug delivery. J Pharm Pharmacol 2005; 57: 533–546.

Malamataris S, Karidas T, Goidas P. Effect of particle size and sorbed moisture on the compression behavior of some hydroxypropyl methylcellulose (HPMC) polymers. Int J Pharm 1994; 103: 205–

215.

Papadimitriou E, Buckton G, Efentakis M. Probing the mechanisms of swelling of hydroxypropylmethylcellulose matrices. Int J Pharm 1993; 98: 57–62.

Parab PV, Nayak MP, Ritschel WA. Influence of hydroxypropyl methylcellulose and of manufacturing technique on in vitro performance of selected antacids. Drug Dev Ind Pharm 1985; 11: 169–185.

Radebaugh GW, Murtha JL, Julian TN, Bondi JN. Methods for evaluating the puncture and shear properties of pharmaceutical polymeric films. Int J Pharm 1988; 45: 39–46.

Rowe RC. Materials used in the film coating of oral dosage forms. In: Florence AT, ed. Critical Reports on Applied Chemistry, vol. 6. Oxford: Blackwell Scientific, 1984: 1–36.

Sako K, Sawada T, Nakashima H, et al. Influence of water soluble fillers in hydroxypropylmethylcellulose matrices on in vitro and in vivo drug release. J Control Release 2002; 81: 165–172.

Sebert P, Andrianoff N, Rollet M. Effect of gamma irradiation on hydroxypropylmethylcellulose powders: consequences on physical, rheological and pharmacotechnical properties. Int J Pharm 1993; 99: 37–42.

Shin-Etsu Chemical Co. Ltd. Metolose. http://www.metolose.jp/e/ pharmaceutical/metolose.shtml (accessed 25 August 2005).

Shin-Etsu Chemical Co. Ltd. Technical literature: Pharmacoat hydro- xypropyl methylcellulose, 1990.

Wan LSC, Heng PWS, Wong LF. The effect of hydroxypropylmethyl- cellulose on water penetration into a matrix system. Int J Pharm 1991; 73: 111–116.

Hypromellose Acetate Succinate

Nonproprietary Names

USPNF: Hypromellose acetate succinate

Synonyms

Aqoat; Aqoat AS-HF/HG; Aqoat AS-LF/LG; Aqoat AS-MF/ MG; cellulose, 2-hydroxypropyl methyl ether, acetate succi- nate; HPMCAS.

Chemical Name and CAS Registry Number

Cellulose, 2-hydroxypropylmethyl ether, acetate hydrogen butanedioate [71138-97-1]

Empirical Formula and Molecular Weight

Hypromellose acetate succinate is a mixture of acetic acid and monosuccinic acid esters of hydroxypropylmethyl cellu- lose.(1–4) It is available in several grades, which vary in extent of substitution, mainly of acetyl and succinoyl groups, and in particle size (fine or granular). When dried at 1058C for one hour, it contains 12.0–28.0% of methoxy groups; 4.0–23.0% of hydroxypropoxy groups; 2.0–16.0% of acetyl groups; and 4.0–28.0% of succinoyl groups.

The molecular weight of hypromellose acetate succinate is approximately 55 000–93 000 Daltons, measured by gel permeation chromatography using polyethylene oxide as a relative reference standard.

Structural Formula

Where -OR represents one of the following functional groups -hydroxyl, methoxyl, 2-hydroxypropoxyl, acetyl, or succinoyl.

Functional Category

the upper intestine. For aqueous film-coating purposes, a dispersion of hypromellose acetate succinate fine powder and triethyl citrate (as a plasticizer) in water is commonly utilized.(4,8,9) Organic solvents can also be used as vehicles for applying this polymer as a film coating.

Hypromellose acetate succinate may be used alone or in combination with other soluble or insoluble binders in the preparation of granules with sustained drug-release properties; the release rate is pH-dependent.

Dispersions of poorly soluble drugs with hypromellose acetate succinate are prepared using techniques such as mechanical grinding, solvent evaporation, and melt extru- sion.(10–14)

Description

Hypromellose acetate succinate is a white to off-white powder or granules.(4) It has a faint acetic acid-like odor and a barely detectable taste. Hypromellose acetate succinate is available in several grades, according to the pH at which the polymer dissolves (low, L; medium, M; and high, H) and its predominant particle size (cohesive fine powder, F; or free- flowing granules, G).

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for hypromellose acetate succinate.

Loss on drying 40.5.0%

Residue on ignition 40.20%

Heavy metals 40.001%

Limit of free acetic and succinic acids +

Content of acetyl and succinyl groups +

Content of methoxy and 2–hydroxypropoxy groups +

Typical Properties

Density (bulk):

0.2–0.3 g/cm for Aqoat MF (Shin Etsu);

Component of controlled-release or sustained-release dosage forms; enteric coating agent; film-forming agent; solid disper- sion vehicle.

Applications in Pharmaceutical Formulation or Technology

Hypromellose acetate succinate is commonly used in oral pharmaceutical formulations as a film coating, as well as enteric coating material for tablets or granules.(5–7) It is insoluble in gastric fluid but will swell and dissolve rapidly in

0.2–0.5 g/cm3 for Aqoat MG (Shin Etsu).

Density (tapped):

0.3–0.5 g/cm3 for Aqoat MF (Shin Etsu); 0.3–0.6 g/cm3 for Aqoat MG (Shin Etsu).

Density (true): 1.27–1.29 g/cm3(4)

Equilibrium moisture content: 2–3% w/w at ambient tempera- ture and humidity (≈258C, 40% RH).(4) See also Figure 1.

Glass transition temperature: 113 28C (differential scanning calorimetry; dried sample)

Particle size distribution: 10% < 1 mm; 50% < 5 mm; 90%

< 10 mm for Aqoat MF (Shin Etsu).

Hypromellose Acetate Succinate 351

10% < 200 mm; 50% < 800 mm; 90% < 1000 mm for

Aqoat MG (Shin Etsu).

Solubility: practically insoluble in ethanol (95%), hexane, unbuffered water, and xylene. On the addition of acetone, or a mixture of ethanol (95%) and dichloromethane (1 : 1), a clear or turbid viscous liquid is produced. Hypromellose acetate succinate can be dissolved in buffers of pH greater than 4.5 with the rank order of solubility for the various grades (see Section 8) increasing with the ratio of acetyl over succinoyl substitution. The exact pH value at which the polymer dissolves depends on the buffer type and ionic strength, although the rank order for the different grades is independent of the buffer used.

Viscosity (dynamic): see Figure 2.

Figure 1: Viscosity of different grades of Aqoat (Shin-Etsu).(4)

Figure 2: Equilibrium moisture content of Aqoat (Shin-Etsu) at different relative humidities.(4)

SEM: 1

Excipient: Aqoat MF Manufacturer: Shin Etsu Magnification: 1000×

SEM: 2

Excipient: Aqoat MG Manufacturer: Shin Etsu Magnification: 50×

Stability and Storage Conditions

Hypromellose acetate succinate should be stored in a well- closed container, in a cool, dry place. In such storage conditions, hypromellose acetate succinate is a stable material. It is stable for four years after manufacturing.(4) Hypromellose acetate succinate is hygroscopic. It is hydrolyzed to acetic acid and succinic acid, and the hypromellose polymer starts to form if dissolved in 1 mol/L sodium hydroxide for more than two hours.(15) The hydrolysis is the main degradation pathway that is responsible for increasing amounts of free acids in storage, especially upon exposure to moisture.

352 Hypromellose Acetate Succinate

Incompatibilities

Hypromellose acetate succinate is incompatible with strong acids or bases, oxidizing agents, and sustained levels of elevated humidity.

Table II: JPE specification for hypromellose acetate succinate.

Test JPE 1998(1,2)

LG, LF MG, MF HG, HF

Appearance Conforms Conforms Conforms

Method of Manufacture

Identification

Conforms Conforms Conforms

Hypromellose acetate succinate is produced by the esterifica- tion of hypromellose with acetic anhydride and succinic anhydride, in a reaction medium of a carboxylic acid, such as acetic acid, and using an alkali carboxylate, such as sodium acetate, as catalyst.(16) The fibrous reaction product is precipitated out by adding a large volume of water to the reaction medium. Purification is achieved by thorough washing with water. The granular grade of hypromellose acetate succinate that is so obtained can be pulverized to a fine powder if required.

Safety

The safety and pharmacological profiles of hypromellose acetate succinate are similar to those of other ether and ester derivatives of cellulose.(17–21) All nonclinical studies reported in the literature identify no target organs for toxicity by hypromellose acetate succinate.(22,23) It has also been reported that hypromellose acetate succinate does not alter fertility in rats, does not produce any developmental anomalies in rats and rabbits, and does not alter perinatal and postnatal development in rats when assessed up to 2500 mg/kg.(24–27)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Hypromellose acetate succinate dust may be irritant to the eyes. Excessive dust generation should be avoided to minimize the risks of explosions. Avoid contact with open flame, heat, or sparks. Avoid contact with acids, peroxides, and other oxidizing materials. Eye protection is recommended.

Regulatory Status

Included in the FDA Inactive Ingredients Guide for use in oral preparations (capsules, and delayed-action preparations). Hypromellose acetate succinate has been approved for use in commercial pharmaceutical products in the USA and in Japan.

Related Substances

Carboxymethyl cellulose; cellulose acetate; cellulose acetate phthalate; cellulose, microcrystalline; ethylcellulose; hypromel- lose; hypromellose phthalate; hydroxyethyl cellulose; hydroxy- propyl cellulose; methylcellulose.

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