kywods

Comments

Mannitol is an isomer of sorbitol, the difference between the two polyols occurring in the planar orientation of the OH group on the second carbon atom. Each isomer is characterized by its own individual set of properties, the most important difference being the response to moisture. Sorbitol is hygro- scopic, while mannitol resists moisture sorption, even at high relative humidities.

Granular mannitol flows well and imparts improved flow properties to other materials. However, it usually cannot be used with concentrations of other materials exceeding 25% by weight. Recommended levels of lubricant are 1% w/w calcium stearate or 1–2% w/w magnesium stearate. Suitable binders for preparing granulations of powdered mannitol are gelatin, methylcellulose 400, starch paste, povidone, and sorbitol. Usually, 3–6 times as much magnesium stearate or 1.5–3 times

Mannitol has been reported to sublime at 1308C.

A specification for mannitol is contained in the Food Chemicals Codex (FCC). The EINECS number for mannitol is 200-711-8.

Specific References

Allen LV. Featured excipient: capsule and tablet diluents. Int J Pharm Compound 2000; 4(4): 306–310, 324–325.

Yoshinari T, Forbes RT, York P, Kawashima Y. Improved compaction properties of mannitol after a moisture induced polymorphic transition. Int J Pharm 2003; 258(1–2): 121–131.

Kanig JL. Properties of fused mannitol in compressed tablets. J Pharm Sci 1964; 53: 188–192.

Ward DR, Lathrop LB, Lynch MJ. Dissolution and compatibility considerations for the use of mannitol in solid dosage forms. J Pharm Sci 1969; 58: 1464–1467.

Ghanem AH, Sakr FM, Abdel-Ghany G. Mechanical and physical properties of sulfamethoxazole-mannitol solid dispersion in tablet form. Acta Pharm Fenn 1986; 95: 167–172.

Debord B, Lefebvre C, Guyot-Hermann AM, et al. Study of different crystalline forms of mannitol: comparative behaviour under compression. Drug Dev Ind Pharm 1987; 13: 1533–1546.

Molokhia AM, Al-Shora HI, Hammad AA. Aging of tablets prepared by direct compression of bases with different moisture content. Drug Dev Ind Pharm 1987; 13: 1933–1946.

Mendes RW, Goll S, An CQ. Wet granulation: a comparison of Manni-Tab and mannitol. Drug Cosmet Ind 1978; 122(3): 36, 38,

40, 44, 87–88.

Daoust RG, Lynch MJ. Mannitol in chewable tablets. Drug Cosmet Ind 1963; 93(1): 26–28, 88, 92, 128–129.

Herman J, Remon JP. Aluminium-magnesium hydroxide tablets: effect of processing and composition of granulating solution on the granule properties and in vitro antacid performance. Drug Dev Ind Pharm 1988; 14: 1221–1234.

Couriel B. Advances in lyophilization technology. Bull Parenter Drug Assoc 1977; 31: 227–236.

Williams NA, Lee Y, Polli GP, Jennings TA. The effects of cooling rate on solid phase transitions and associated vial breakage occurring in frozen mannitol solutions. J Parenter Sci Technol 1986; 40: 135–141.

Stella VJ, Umprayn K, Waugh WN. Development of parenteral formulations of experimental cytotoxic agents I: rhizoxin (NSC- 332598). Int J Pharm 1988; 43: 191–199.

Williams NA, Dean T. Vial breakage by frozen mannitol solutions: correlation with thermal characteristics and effect of stereoisomer- ism, additives, and vial configuration. J Parenter Sci Technol 1991; 45: 94–100.

Chan HK, Au-Yeung KL, Gonda I. Development of a mathema- tical model for the water distribution in freeze-dried solids. Pharm Res 1999; 16(5): 660–665.

Pyne A, Surana R, Suryanarayanan R. Crystallization of mannitol below Tg' during freeze-drying in binary and ternary aqueous systems. Pharm Res 2002; 19: 901–908.

Pyne A, Chatterjee K, Suryanarayanan R. Solute crystallisation in mannitol-glycine systems. Implications on protein stabilisation in freeze-dried formulations. J Pharm Sci 2003; 92(11): 2272–2283.

Cavatur RK, Vemuri NM, Pyne A, et al. Crystallization behavior of mannitol in frozen aqueous solutions. Pharm Res 2002; 19: 894–900.

Izutsu K-I, Kojima S. Excipient crystallinity and its protein- structure-stabilizing effect during freeze-drying. J Pharm Pharma- col 2002; 54: 1033–1039.

Johnson RE, Kirchoff CF, Gand HE. Mannitol-sucrose mixtures: versatile formulations for protein lyophilisation. J Pharm Sci 2002; 91(4): 914–922.

Parab PV, Oh CK, Ritschel WA. Sustained release from Precirol (glycerol palmito-stearate) matrix. Effect of mannitol and hydr- oxypropyl methylcellulose on the release of theophylline. Drug Dev Ind Pharm 1986; 12: 1309–1327.

Mannitol 453

Tee SK, Marriott C, Zeng XM, Martin GP. Use of different sugars as fine and coarse carriers for aerosolised salbutamol sulphate. Int J Pharm 2000; 208: 111–123.

Steckel H, Bolzen N. Alternative sugars as potential carriers for dry powder inhalers. Int J Pharm 2004; 270(1–2): 297–306.

Lee KJ, Kang A, Delfino JJ, et al. Evaluation of critical formu- lation factors in the development of a rapidly dispersing capto- pril oral dosage form. Drug Dev Ind Pharm 2003; 29(9): 967–979.

Seager H. Drug development products and the Zydis fast dissolving dosage form. J Pharm Pharmacol 1998; 50: 375–382.

Bauer H, Herkert T, Bartels M, et al. Investigations on polymorphism of mannitol/sorbitol mixtures after spray drying using differential scanning calorimetry, x-ray diffraction and near infrared spectroscopy. Pharm Ind 2000; 62(3): 231–235.

Roquette Fre`res. Technical literature: Pearlitol, 2004.

Murty BSR, Kapoor JN. Properties of mannitol injection (25%) after repeated autoclavings. Am J Hosp Pharm 1975; 32: 826–827.

Jacobs J. Factors influencing drug stability in intravenous infusions. J Hosp Pharm 1969; 27: 341–347.

Epperson E. Mannitol crystallization in plastic containers [letter].

Am J Hosp Pharm 1978; 35: 1337.

Dubost DC, Kaufman MJ, Zimmerman JA, et al. Characterization of a solid state reaction product from a lyophilized formulation of a cyclic heptapeptide. A novel example of an excipient-induced oxidation. Pharm Res 1996; 13: 1811–1814.

Adkin DA, Davis SS, Sparrow RA, et al. The effect of mannitol on the oral bioavailability of cimetidine. J Pharm Sci 1995; 84: 1405–

1409.

Anonymous. Flatulence, diarrhoea, and polyol sweeteners. Lancet

1983; ii: 1321.

Porter GA, Starr A, Kimsey J, Lenertz H. Mannitol hemodilution– perfusion: the kinetics of mannitol distribution and excretion during cardiopulmonary bypass. J Surg Res 1967; 7: 447–456.

McNeill IY. Hypersensitivity reaction to mannitol. Drug Intell Clin Pharm 1985; 19: 552–553.

FAO/WHO. Evaluation of certain food additives and contami- nants. Thirtieth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1987; No. 751.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 1944–1945.

Weast RC, ed. Handbook of Chemistry and Physics, 60th edn. Boca Raton: CRC Press, 1979: c-369.

General References

Armstrong NA. Tablet manufacture. Diluents. In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, 2nd edn, vol.

3. New York: Marcel Dekker, 2002: 2713–2732.

Pikal MJ. Freeze drying. In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 2. New York: Marcel Dekker, 2002: 1299–1326.

Medium-chain Triglycerides

Nonproprietary Names

BP: Medium-chain triglycerides PhEur: Triglycerida saturata media USPNF: Medium-chain triglycerides

Synonyms

Bergabest; caprylic/capric triglyceride; Captex 300; Captex 355; Crodamol GTC/C; glyceryl tricaprylate/caprate; Labrafac CC; MCT oil; Miglyol 810; Miglyol 812; Myritol; Neobee M5; Nesatol; oleum neutrale; oleum vegetable tenue; thin vegetable oil; Waglinol 3/9280.

Chemical Name and CAS Registry Number

Medium-chain triglycerides [73398-61-5]

Empirical Formula and Molecular Weight

≈500 (average)

The PhEur 2005 describes medium-chain triglycerides as the fixed oil extracted from the hard, dried fraction of the endosperm of Cocos nucifera L. or from the dried endosperm of Elaeis guineenis Jacq. They consist of a mixture of triglycerides of saturated fatty acids, mainly of caprylic acid and of capric acid. They contain not less than 95% of saturated fatty acids.

Structural Formula

See also Section 4.

Functional Category

Emulsifying agent; solvent; suspending agent; therapeutic agent.

Applications in Pharmaceutical Formulation or Technology

Medium-chain triglycerides have been used in a variety of pharmaceutical formulations including oral, parenteral, and topical preparations.

In oral formulations, medium-chain triglycerides are used as the base for the preparation of oral emulsions, microemulsions, self-emulsifying systems, solutions, or suspensions of drugs that are unstable or insoluble in aqueous media, e.g. calciferol. Medium-chain triglycerides have also been investigated as intestinal-absorption enhancers(1,2) and have additionally been

used as a filler in capsules and sugar-coated tablets, and as a lubricant or antiadhesion agent in tablets.

In parenteral formulations, medium-chain triglycerides have similarly been used in the production of emulsions, solutions, or suspensions intended for intravenous administration.(3–9) Medium-chain triglycerides have been particularly investigated for their use in total parenteral nutrition (TPN) regimens in combination with long-chain triglycerides.(4)

In cosmetics and topical pharmaceutical preparations, medium-chain triglycerides are used as a component of ointments, creams, and liquid emulsions.(5) In rectal formula- tions, medium-chain triglycerides have been used in the preparation of suppositories containing labile materials.

Therapeutically, medium-chain triglycerides have been used as nutritional agents.(10) Diets containing medium-chain triglycerides are used in conditions associated with the malabsorption of fat, such as cystic fibrosis, since medium- chain triglycerides are more readily digested than long-chain triglycerides. Medium-chain triglycerides provide 35 kJ (8.3 kcal) of energy per gram.

Although similar to long-chain triglycerides, medium-chain triglycerides have a number of advantages in pharmaceutical formulations, which include better spreading properties on the skin; no impedance of skin respiration; good penetration properties; good emollient and cosmetic properties; no visible film on the skin surface; good compatibility; good solvent properties; and good stability against oxidation.

Description

A colorless to slightly yellowish oily liquid that is practically odorless and tasteless. It solidifies at about 08C. The oil is free from catalytic residues or the products of cracking.

Pharmacopeial Specifications

See Table I.

Typical Properties

Acid value:

40.1 for Crodamol GTC/C;

40.1 for Miglyol 810;

40.1 for Miglyol 812;

40.05 for Neobee M5.

Cloud point:

458C for Crodamol GTC/C;

≈108C for Miglyol 810;

≈108C for Miglyol 812.

Color:

460 (Hazen color index) for Crodamol GTC/C;

490 (Hazen color index) for Miglyol 810; 460 (Hazen color index) for Miglyol 812; 4100 (Hazen color index) for Neobee M5.

Density:

0.94–0.96 g/cm3 for Crodamol GTC/C at 208C; 0.94–0.95 g/cm3 for Miglyol 810 at 208C; 0.94–0.95 g/cm3 for Miglyol 812 at 208C;

0.94 g/cm3 for Neobee M5 at 208C.

Medium-chain Triglycerides 455

Table I: Pharmacopeial specifications for medium-chain triglycerides.

Test PhEur 2005 USPNF 23

Identification + +

Characters + —

Appearance + +

Alkaline impurities + +

Relative density 0.93–0.96 0.93–0.96

Refractive index 1.440–1.452 1.440–1.452

Viscosity 25–33 mPa s 25–33 mPa s

Acid value 40.2 40.2

Hydroxyl value 410 410

Iodine value 41.0 41.0

Peroxide value 41.0 41.0

Saponification value 310–360 310–360

Unsaponifiable matter 40.5% 40.5%

Composition of fatty acids

Caproic acid 42.0% 42.0%

Caprylic acid 50.0–80.0% 50.0–80.0%

Capric acid 20.0–50.0% 20.0–50.0%

Lauric acid 43.0% 43.0%

Myristic acid 41.0% 41.0%

Heavy metals(a) 410 ppm 410 ppm

Water 40.2% 40.2%

Total ash 40.1% 40.1%

Chromium 40.05 ppm 40.05 ppm

Copper(a) 40.1 ppm 40.1 ppm

Lead(a) 40.1 ppm 40.1 ppm

Nickel(a) 40.2 ppm 40.1 ppm

Tin(a) 40.1 ppm 40.1 ppm

(a) For medium-chain triglycerides intended for use in parenteral nutrition, the test for heavy metals is replaced by the tests for chromium, copper, lead, nickel, and tin.

Freezing point: —58C for Neobee M5 Hydroxyl value: 48 for Neobee M5 Iodine number:

41.0 for Crodamol GTC/C;

40.5 for Miglyol 810;

40.5 for Miglyol 812;

40.5 for Neobee M5.

Moisture content:

40.15% w/w for Crodamol GTC/C;

40.10% w/w for Miglyol 810;

40.10% w/w for Miglyol 812;

40.15% w/w for Neobee M5.

Peroxide value:

41.0 for Miglyol 810;

41.0 for Miglyol 812;

40.5 for Neobee M5.

Refractive index:

1.4485–1.4500 for Crodamol GTC/C at 208C; 1.4485–1.4505 for Miglyol 810 at 208C;

1.4490–1.4510 for Miglyol 812 at 208C; 1.4480–1.4510 for Neobee M5 at 208C.

Saponification value:

325–345 for Crodamol GTC/C; 335–355 for Miglyol 810;

325–345 for Miglyol 812; 335–360 for Neobee M5.

Solubility: soluble in all proportions at 208C in acetone, benzene, 2-butanone, carbon tetrachloride, chloroform, dichloromethane, ethanol, ethanol (95%), ether, ethyl acetate, petroleum ether, special petroleum spirit (boiling range 80–1108C), propan-2-ol, toluene, and xylene. Mis-

cible with long-chain hydrocarbons and triglycerides; practically insoluble in water.

Surface tension:

32.2 mN/m for Crodamol GTC/C at 258C;

31.0 mN/m for Miglyol 810 at 208C;

31.1 mN/m for Miglyol 812 at 208C;

32.3 mN/m for Neobee M5 at 258C.

Viscosity (dynamic):

27–30 mPa s (27–30 cP) for Miglyol 810 at 208C; 28–32 mPa s (28–32 cP) for Miglyol 812 at 208C; 23 mPa s (23 cP) for Neobee M5 at 258C.

Stability and Storage Conditions

Medium-chain triglycerides are stable over the wide range of storage temperatures that can be experienced in tropical and temperate climates. Ideally, however, they should be stored at temperatures not exceeding 258C and not exposed to tempera- tures above 408C for long periods.

In the preparation of microemulsions and self-emulsifying systems, emulsions, or aqueous suspensions of medium-chain triglycerides, care should be taken to avoid microbiological contamination of the preparation, since lipase-producing microorganisms, which become active in the presence of moisture, can cause hydrolysis of the triglycerides. Hydrolysis of the triglycerides is revealed by the characteristic unpleasant odor of free medium-chain fatty acids.

Medium-chain triglycerides may be sterilized by maintain- ing at 1708C for 1 hour.

At low temperatures, samples of medium-chain triglycerides may become viscous or solidify. Samples should therefore be well melted and mixed before use, although overheating should be avoided.

Medium-chain triglycerides should be stored protected from light in a well-filled and well-closed container. When stored dry, in sealed containers, medium-chain triglycerides remain stable for many years.

Incompatibilities

Preparations containing medium-chain triglycerides should not come into contact with polystyrene containers or packaging components since the plastic rapidly becomes brittle upon contact. Low-density polyethylene should also not be used as a packaging material as the medium-chain triglycerides readily penetrate the plastic, especially at high temperatures, forming an oily film on the outside. High-density polyethylene is a suitable packaging material. Closures based on phenol resins should be tested before use for compatibility with medium- chain triglycerides. Polyvinyl chloride packaging should also be tested for compatibility since medium-chain triglycerides can dissolve some plasticisers, such as phthalates, out of the plastic. Materials recommended as safe for packaging medium- chain triglycerides are low-density polyethylene, polypro-

pylene, glass, and metal.

Method of Manufacture

Medium-chain triglycerides are obtained from the fixed oil extracted from the hard, dried fraction of the endosperm of Cocos nucifera L. Hydrolysis of the fixed oil followed by distillation yields the required fatty acids, which are then re- esterified to produce the medium-chain triglycerides.

Although the PhEur 2005 specifies that medium-chain fatty acids are obtained from coconut oil, medium-chain triglycer- ides are also to be found in substantial amounts in the kernel

456 Medium-chain Triglycerides

oils of certain other types of palm-tree, e.g., palm kernel oil and babassu oil. Some animal products, such as milk-fat, also contain small amounts (up to 4%) of the medium-chain fatty acid esters.

Safety

Medium-chain triglycerides are used in a variety of pharma- ceutical formulations including oral, parenteral, and topical products and are generally regarded as essentially nontoxic and nonirritant materials.

In acute toxicology studies in animals and humans, no irritant or other adverse reactions have been observed; for example, when they were patch-tested on more than 100 individuals, no irritation was produced on either healthy or eczematous skin. Medium-chain triglycerides are not irritating to the eyes.

Similarly, chronic toxicology studies in animals have shown no harmful adverse effects associated with medium-chain triglycerides following inhalation or intraperitoneal, oral, and parenteral administration.

In humans, administration of 0.5 g/kg body-weight medium- chain triglycerides to healthy individuals produced no change in blood or serum triglycerides compared to subjects receiving the same dose of the long-chain triglyceride triolein.

In patients consuming diets based on medium-chain triglycerides, adverse effects reported include abdominal pain and diarrhea.

LD50 (mouse, IV): 3.7 g/kg LD50 (mouse, oral): 29.6 g/kg LD50 (rat, oral): 33.3 g/kg

Handling Precautions

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

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (topical preparations). Included in nonparenteral and parent- eral medicines licensed in Europe. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Suppository bases, hard fat; vegetable oil, hydrogenated.

Comments

—

Specific References

Swenson ES, Curatolo WJ. Intestinal permeability enhancement for proteins, peptides and other drugs: mechanisms and potential toxicity. Adv Drug Del Rev 1992; 8: 39–92.

Spencer SA, Stammers JP, Hull D. Evaluation of a special low birth weight formula, with and without the use of medium chain triglycerides. Early Hum Dev 1986; 13: 87–95.

Bach A, Guisard D, Metais P, Debry G. Metabolic effects following a short and medium-chain triglycerides load in dogs I: infusion of an emulsion of short and medium-chain triglycerides. Arch Sci Physiol 1972; 26: 121–129.

Hatton J, Record KE, Bivins BA, et al. Safety and efficacy of a lipid emulsion containing medium-chain triglycerides. Clin Pharm 1990; 9: 366–371.

Adams U, Neuwald F. Comparative studies of the release of salicylic acid from medium-chain triglyceride gel and paraffin ointment bases: in vitro and in vivo. Pharm Ind 1982; 44: 625– 629.

Pietkiewicz J, Sznitowska M. The choice of lipids and surfactants for injectable extravenous microspheres. Pharmazie 2004; 59: 325–326.

Schaub E, Kern C, Landau R. Pain on injection: a double-blind comparison of propofol with lidocaine pretreatment versus propofol formulated with long- and medium-chain triglycerides. Anaesth Analg 2004; 99: 1699–1702.

Cournarie F, Savelli MP, Rosilio V, Bretez F, et al. Insulin-loaded w/o/w multiple emulsions: comparison of the performances of systems prepared with medium-chain triglycerides and fish oil. Eur J Pharm Biopharm 2004; 58: 477–482.

Holmberg I, Aksnes L, Berlin T, et al. Absorption of a pharmacological dose of vitamin D3 from two different lipid vehicles in man: comparison of peanut oil and a medium chain triaglyceride. Biopharm Drug Dispos 1990; 11: 807–815.

Ruppin DC, Middleton WRJ. Clinical use of medium-chain triglycerides. Drugs 1980; 20: 216–224.

General References

Akkar A, Namsolleck P, Blaut M, Muller RH. Solubilizing poorly soluble antimycotic agents by emulsification via a solvent-free process. AAPS Pharm Sci Tech 2004; 5: E24.

BP: Meglumine JP: Meglumine

PhEur: Megluminum USP: Meglumine

Synonyms

1-Methylamino-1-deoxy-D-glucitol; N-methylglucamine; N-

methyl-D-glucamine.

Chemical Name and CAS Registry Number

1-Deoxy-1-(methylamino)-D-glucitol [6284-40-8]

Empirical Formula and Molecular Weight

Table I: Pharmacopeial specifications for meglumine.

Applications in Pharmaceutical Formulation or Technology

Meglumine is an organic base used as a pH-adjusting agent and solubilizing agent primarily in the preparation of soluble salts of iodinated organic acids used as X-ray contrast media.

Description

Meglumine occurs as a white to slightly yellow-colored crystalline powder; it is odorless or with a slight odor.

Pharmacopeial Specifications

See Table I.

Typical Properties

Acidity/alkalinity: pH = 10.5 (1% w/v aqueous solution).

Dissociation constant: pKa = 9.5 at 208C

Melting point: 128–1328C

Osmolarity: a 5.02% w/v aqueous solution is iso-osmotic with serum.

Solubility: see Table II.

Table II: Solubility of meglumine.

Solvent Solubility at 208C unless otherwise stated

Chloroform Practically insoluble

Ethanol (95%) 1 in 80

1 in 4.8 at 708C

Ether Practically insoluble

Water 1 in 1

Specific rotation [a]20: —16.58 (10% w/v aqueous solution)

Stability and Storage Conditions

Meglumine does not polymerize or dehydrate unless heated above 1508C for prolonged periods.

The bulk material should be stored in a well-closed container in a cool, dry place. Meglumine should not be stored in aluminum containers since it reacts to evolve hydrogen gas; it discolors if stored in containers made from copper or copper alloys. Stainless steel containers are recommended.

458 Meglumine

Incompatibilities

Incompatible with aluminum, copper, mineral acids, and oxidizing materials. Differential scanning calorimeter studies suggest meglumine is incompatible with glipizide.(1)

Method of Manufacture

Meglumine is prepared by the imination of glucose and monomethylamine, in an alcoholic solution, followed by catalytic hydrogenation.

Safety

Meglumine is widely used in parenteral pharmaceutical formulations and is generally regarded as a nontoxic material at the levels usually employed as an excipient.

LD50 (mouse, IP): 1.68 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Meglumine should be handled in a well-ventilated environment and eye protection, gloves, and a respirator are recommended. Exposure to meglumine dust should be kept below 10 mg/m3 for total inhalable dust (8-hour TWA) or 5 mg/m3 for respirable dust (8- hour TWA). There is a risk of explosion when meglumine dust is mixed with air.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (injections; oral tablets). Included in parenteral medicines licensed in the UK.

Related Substances

Eglumine.

Eglumine

Empirical formula: C8H19NO5

Molecular weight: 209.24

CAS number: [14216-22-9]

Synonyms: 1-deoxy-1-(ethylamino)-D-glucitol; N-ethylgluca- mine.

Melting point: ≈1388C

Comments: eglumine is prepared similarly to meglumine except that monoethylamine is used as the precursor, instead of monomethylamine.

Comments

—

Specific References

1 Verma RK, Garg S. Selection of excipients for extended release formulations of glipizide through drug-excipient compatibility testing. J Pharm Biomed Anal 2005; 38: 633–644.

General References

Bremecker KD, Seidel K, Bo¨ hner A. Polyacrylate gels: use of new bases in drug formulation [in German]. Dtsch Apoth Ztg 1990; 130(8): 401–403.

Chromy V, Kulhanek V, Fischer J. D-(–)-N-Methylglucamine buffer for pH 8.5 to 10.5. Clin Chem 1978; 24(2): 379–381.

Chromy V, Zahradnicek L, Voznicek J. Use of N-methyl-D-glucamine as buffer in the determination of serum alkaline phosphatase activity. Clin Chem 1981; 27(10): 1729–1732.

Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical Excipients Directory 1996. Tokyo: Yakuji Nippon, 1996: 305.

BP: Racementhol JP: dl-Menthol

PhEur: Mentholum racemicum USP: Menthol

Synonyms

Hexahydrothymol; 2-isopropyl-5-methylcyclohexanol; 4-iso- propyl-1-methylcyclohexan-3-ol; 3-p-menthanol; p-menthan- 3-ol; dl-menthol; peppermint camphor; racemic menthol.

Chemical Name and CAS Registry Number

(1RS,2RS,5RS)-( )-5-Methyl-2-(1-methylethyl)cyclohexanol [15356-70-4]

Note that the following CAS numbers have also been used: [1490-04-6] and [89-78-1].

Empirical Formula and Molecular Weight

C10H20O 156.27

Structural Formula

Functional Category

Flavoring agent; therapeutic agent.

Applications in Pharmaceutical Formulation or Technology

Menthol is widely used in pharmaceuticals, confectionery, and toiletry products as a flavoring agent or odor enhancer. In addition to its characteristic peppermint flavor, l-menthol, which occurs naturally, also exerts a cooling or refreshing sensation that is exploited in many topical preparations. Unlike mannitol, which exerts a similar effect due to a negative heat of solution, l-menthol interacts directly with the body’s coldness receptors. d-Menthol has no cooling effect, while racemic menthol exerts an effect approximately half that of l-menthol.

When used to flavor tablets, menthol is generally dissolved in ethanol (95%) and sprayed onto tablet granules and not used as a solid excipient.

Menthol has been investigated as a skin-penetration enhancer and is also used in perfumery, tobacco products, chewing gum and as a therapeutic agent. See Table I.

Table I: Uses of menthol.

Use Concentration (%)

Pharmaceutical products

Inhalation 0.02–0.05

Oral suspension 0.003

Oral syrup 0.005–0.015

Tablets 0.2–0.4

Topical formulations 0.05–10.0 Cosmetic products

Racemic menthol is a mixture of equal parts of the (1R,2S,5R)- and (1S,2R,5S)-isomers of menthol. It is a free-flowing or agglomerated crystalline powder, or colorless, prismatic, or acicular shiny crystals, or hexagonal or fused masses with a strong characteristic odor and taste. The crystalline form may change with time owing to sublimation within a closed vessel. The USP 28 specifies that menthol may be either naturally occurring l-menthol or synthetically prepared racemic or dl- menthol. However, the JP 2001 and PhEur 2005, along with other pharmacopeias, include two separate monographs for racemic and l-menthol.

Figure 1: Photomicrograph of large DL-menthol crystals; magnifica- tion 7×. Manufacturer: Charkit Chemical Corp., USA.

Pharmacopeial Specifications

See Table II.

460 Menthol

Table II: Pharmacopeial specifications for menthol.

Test JP 2001 PhEur 2005 USP 28

Identification + + +

Acidity or alkalinity — + —

Congealing range

Melting point 27–288C — +

dl-menthol — ≈348C —

l-menthol

Specific optical 42– 448C ≈438C 41– 448C

rotation

dl-menthol —2 to +28 —0.2 to +0.28 —2 to +28

l-menthol —45 to —518 — —45 to —518

Readily oxidizable — — +

substances

Chromatographic — — +

purity

Related substances — + —

Appearance of — + —

solution

Nonvolatile residue + — 40.05%

Residue on

evaporation — 40.05% —

Organic volatile — — +

impurities

Thymol + — —

Nitromethane or + — —

nitroethane

Assay 598.0% — —

Typical Properties

Boiling point: 2128C Flash point: 918C Melting point: 348C

Refractive index: n20 = 1.4615

Solubility: very soluble in ethanol (95%), chloroform, ether, fatty oils and liquid paraffin; soluble in acetone and benzene; very slightly soluble in glycerin; practically insoluble in water.

Specific gravity: 0.904 at 158C

Specific rotation [a]20: –2 to +28 (10% w/v alcoholic solution)

See also Section 17.

Stability and Storage Conditions

A formulation containing menthol 1% w/w in aqueous cream has been reported to be stable for up to 18 months when stored at room temperature.(1)

Menthol should be stored in a well-closed container at a temperature not exceeding 258C, since it sublimes readily.

Incompatibilities

Incompatible with: butylchloral hydrate; camphor; chloral hydrate; chromium trioxide; b-naphthol; phenol; potassium permanganate; pyrogallol; resorcinol; and thymol.

Method of Manufacture

Menthol occurs widely in nature as l-menthol and is the principal component of peppermint and cornmint oils obtained from the Mentha piperita and Mentha arvensis species. Commercially, l-menthol is mainly produced by extraction

from these volatile oils. It may also be prepared by partial or total synthetic methods.

Racemic menthol is prepared synthetically via a number of routes, e.g. by hydrogenation of thymol.

Safety

Almost all toxicological data for menthol relate to its use as a therapeutic agent rather than as an excipient. Inhalation or ingestion of large quantities can result in serious adverse reactions such as ataxia(2) and CNS depression.(3) Although menthol is essentially nonirritant there have been some reports of hypersensitivity following topical application.(4,5) In a Polish study approximately 1% of individuals were determined as being sensitive to menthol.(6)

The WHO has set an acceptable daily intake of menthol at up to 0.4 mg/kg body-weight.(7)

LD50 (rat, IM): 10.0 g/kg(8)

LD50 (rat, oral): 3.18 g/kg

Handling Precautions

May be harmful by inhalation or ingestion in large quantities; may be irritant to the skin, eyes, and mucous membranes. Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (dental preparations, inhalations, oral aerosols, capsules, solutions, suspensions, syrups, and tablets, also topical preparations). Included in nonparenteral medicines licensed in the UK. Accepted for use in foods and confectionery as a flavoring agent of natural origin. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

d-Menthol; l-menthol; thymol.

d-Menthol

Empirical formula: C10H20O

Molecular weight: 156.27

CAS number: [15356-60-2]

Synonyms: (1S,2R,5S)-(+)-5-methyl-2-(1-methylethyl)cyclo- hexanol.

Appearance: colorless, prismatic or acicular, shiny crystals, without the characteristic odor, taste, and cooling effect of l- menthol. The crystalline form may change with time owing to sublimation within a closed vessel.

Flash point: 918C

Melting point: 43–448C

Specific rotation [a]23: +488 (10% w/v alcoholic solution)

Menthol

Empirical formula: C10H20O

Molecular weight: 156.27

CAS number: [2216-51-5]

Synonyms: levomenthol; levomentholum; (1R,2S,5R)-(–)-5- methyl-2-(1-methylethyl)cyclohexanol.

Appearance: colorless, prismatic, or acicular, shiny crystals, with a strong, characteristic odor, taste, and cooling effect.

Menthol 461

The crystalline form may change with time owing to sublimation within a closed vessel.

Flash point: >1008C

Melting point: 41–448C

Refractive index: n20 = 1.4600

Specific rotation [a]20: —508 (10% w/v alcoholic solution)

Safety:

LD50 (mouse, IP): 6.6 g/kg(8) LD50 (mouse, oral): 3.4 g/kg LD50 (rat, IP): 0.7 g/kg

LD50 (rat, oral): 3.3 g/kg

Comments

It should be noted that considerable variation in the chemical composition of natural menthol oils can occur depending upon their country of origin. The EINECS number for menthol is 201-939-0.

Specific References

Gallagher P, Jones S. A stability and validation study of 1% w/w menthol in aqueous cream. Int J Pharm Pract 1997; 5: 101–104.

Luke E. Addiction to mentholated cigarettes [letter]. Lancet 1962;

i: 110–111.

O’Mullane NM, Joyce P, Kamath SV, et al. Adverse CNS effects of menthol-containing olabas oil [letter]. Lancet 1982; i: 1121.

Papa CM, Shelley WB. Menthol hypersensitivity. J Am Med Assoc

1964; 189: 546–548.

Hayakawa R, Yamamura M, Sugiura M. Contact dermatitis from l-menthol. Cosmet Toilet 1996; 111(7): 28–29.

Rudzki E, Kleniewska D. The epidemiology of contact dermatitis in Poland. Br J Dermatol 1970; 83: 543–545.

FAO/WHO. Evaluation of certain food additives: Fifty-first report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 2000; No. 891.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2297.

General References

Bauer K, Garbe D, Surburg H. Common Fragrance and Flavor Materials. Weinheim: VCH, 1990: 43–46.

Eccles R. Menthol and related cooling compounds. J Pharm Pharmacol 1994; 46: 618–630.

Walker T. Menthol. Properties, uses and some methods of manufacture.

Manuf Chem Aerosol News 1967; 53.

Authors

BA Langdon, MP Mullarney.

BP: Methylcellulose JP: Methylcellulose

PhEur: Methylcellulosum USP: Methylcellulose

Synonyms

Benecel; Culminal MC; E461; Methocel; Metolose.

Chemical Name and CAS Registry Number

Cellulose methyl ether [9004-67-5]

Empirical Formula and Molecular Weight

Methylcellulose is a long-chain substituted cellulose in which approximately 27–32% of the hydroxyl groups are in the form of the methyl ether. The various grades of methylcellulose have degrees of polymerization in the range 50–1000, with molecular weights (number average) in the range 10 000–220 000 Da. The degree of substitution of methylcellu- lose is defined as the average number of methoxyl (CH3O) groups attached to each of the anhydroglucose units along the chain. The degree of substitution also affects the physical properties of methylcellulose, such as its solubility.

Structural Formula

The structure shown is with complete substitution of the available hydroxyl units of methoxyl substitution. Note that methoxyl substitution can occur at any combination of the hydroxyl groups of the anhydroglucose ring of cellulose at positions 2, 3, and 6. See Section 4.

Functional Category

Coating agent; emulsifying agent; suspending agent; tablet and capsule disintegrant; tablet binder; viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology

Methylcellulose is widely used in oral and topical pharmaceu- tical formulations; see Table I.

In tablet formulations, low- or medium-viscosity grades of methylcellulose are used as binding agents, the methylcellulose being added either as a dry powder or in solution.(1–3) High- viscosity grades of methylcellulose may also be incorporated in tablet formulations as a disintegrant.(4) Methylcellulose may be added to a tablet formulation to produce sustained-release preparations.(5)

Tablet cores may also be spray-coated with either aqueous or organic solutions of highly substituted low-viscosity grades of methylcellulose to mask an unpleasant taste or to modify the release of a drug by controlling the physical nature of the granules.(6) Methylcellulose coats are also used for sealing tablet cores prior to sugar coating.

Low-viscosity grades of methylcellulose are used to emulsify olive, peanut, and mineral oils.(7) They are also used as suspending or thickening agents for orally administered liquids, methylcellulose commonly being used in place of sugar-based syrups or other suspension bases.(8) Methylcellulose delays the settling of suspensions and increases the contact time of drugs, such as antacids, in the stomach.

High-viscosity grades of methylcellulose are used to thicken topically applied products such as creams and gels.

In ophthalmic preparations, a 0.5–1.0% w/v solution of a highly substituted, high-viscosity grade of methylcellulose has been used as a vehicle for eye drops.(9) However, hypromellose- based formulations are now preferred for ophthalmic prepara- tions.

Therapeutically, methylcellulose is used as a bulk laxative; it has also been used to aid appetite control in the management of obesity, but there is little evidence supporting its efficacy.

Table I: Uses of methylcellulose.

Use Concentration (%)

Bulk laxative 5.0–30.0

Creams, gels, and ointments 1.0–5.0

Emulsifying agent 1.0–5.0

Ophthalmic preparations 0.5–1.0

Suspensions 1.0–2.0

Sustained-release tablet matrix 5.0–75.0

Tablet binder 1.0–5.0

Tablet coating 0.5–5.0

Tablet disintegrant 2.0–10.0

Description

Methylcellulose occurs as a white, fibrous powder or granules. It is practically odorless and tasteless. It should be labeled to indicate its viscosity type (viscosity of a 1 in 50 solution).

Pharmacopeial Specifications

See Table II.

Typical Properties

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

Methylcellulose 463

Table II: Pharmacopeial specifications for methylcellulose.

Test JP 2001 PhEur 2005 USP 28

Identification + + +

Characters — + —

Appearance of solution + + —

pH 5.0–8.0 5.5–8.0 —

Apparent viscosity + + +

Arsenic 42 ppm — —

Loss on drying 45.0% 410.0% 45.0%

Residue on ignition 41.0% 41.0% 41.5%

Chlorides 40.284% 40.5% —

Iron 4100 ppm — —

Heavy metals 410 ppm 420 ppm 40.001%

Organic volatile — — +

impurities

Assay (of methoxyl 26.0–33.0% — 27.5–31.5%

groups)

Angle of repose: 40–508 Autoignition temperature: ≈3608C Degree of substitution: 1.64–1.92 Density (bulk): 0.276 g/cm3 Density (tapped): 0.464 g/cm3 Density (true): 1.341 g/cm3

Melting point: begins to brown at 190–2008C; begins to char at 225–2308C.

Refractive index of solution:

n20 = 1.336 (2% aqueous solution).

Solubility: practically insoluble in acetone, methanol, chloro- form, ethanol (95%), ether, saturated salt solutions, toluene, and hot water. Soluble in glacial acetic acid and in a mixture of equal volumes of ethanol and chloroform. In cold water, methylcellulose swells and disperses slowly to form a clear to opalescent, viscous, colloidal dispersion.

Surface tension:

53–59 mN/m (53–59 dynes/cm) for a 0.05% w/v solution at 258C;

45–55 mN/m for 0.1% at 208C.

Interfacial tension of solution versus paraffin oil is 19–23 mN/m for 0.1% w/v solution at 208C.

Viscosity (dynamic): various grades of methylcellulose are commercially available that vary in their degree of polymerization. Aqueous solutions at concentrations of 2% w/v will produce viscosities between 5 and 75 000 mPa s. Individual grades of methylcellulose have a stated, narrowly defined viscosity range measured for a 2% w/v solution. The viscosity of solutions may be increased by increasing the concentration of methylcellulose. Increased temperatures reduce the viscosity of solutions until gel formation occurs at 50–608C. The process of thermogela- tion is reversible, with a viscous solution being reformed on cooling. See also Table III.

Table III: Typical viscosity values for 2% w/v aqueous solutions of

Methocel (Dow Chemical Co.) at 208C.

Methocel grade Viscosity (mPa s)

Excipient: Methylcellulose Manufacturer: Dow Chemical Co. Lot No.: KC16012N21

Magnification: 60×

SEM: 2

Excipient: Methylcellulose Manufacturer: Dow Chemical Co. Lot No.: KC16012N21

Magnification: 600×

Stability and Storage Conditions

Methylcellulose powder is stable, although slightly hygro- scopic. The bulk material should be stored in an airtight container in a cool, dry place.

Solutions of methylcellulose are stable to alkalis and dilute acids at pH 3–11, at room temperature. At pH less than 3, acid- catalyzed hydrolysis of the glucose–glucose linkages occurs and the viscosity of methylcellulose solutions is reduced.(10) On heating, solution viscosity is reduced until gel formation occurs at approximately 508C; see Section 10.

Methylcellulose solutions are liable to microbial spoilage and antimicrobial preservatives should therefore be used.

464 Methylcellulose

Solutions may also be sterilized by autoclaving, although this process can decrease the viscosity of a solution.(11,12) The change in viscosity after autoclaving is related to solution pH. Solutions at pH less than 4 had viscosities reduced by more than 20% subsequent to autoclaving.(11)

Incompatibilities

Methylcellulose is incompatible with aminacrine hydrochlor- ide; chlorocresol; mercuric chloride; phenol; resorcinol; tannic acid; silver nitrate; cetylpyridinium chloride; p-hydroxybenzoic acid; p-aminobenzoic acid; methylparaben; propylparaben; and butylparaben.

Salts of mineral acids (particularly polybasic acids), phenols, and tannins will coagulate solutions of methylcellulose, although this can be prevented by the addition of ethanol (95%) or glycol diacetate. Complexation of methylcellulose occurs with highly surface-active compounds such as tetracaine and dibutoline sulfate.

High concentrations of electrolytes increase the viscosity of methylcellulose mucilages owing to the ‘salting out’ of methylcellulose. With very high concentrations of electrolytes, the methylcellulose may be completely precipitated in the form of a discrete or continuous gel. Methylcellulose is incompatible with strong oxidizing agents.

Method of Manufacture

Methylcellulose is prepared from wood pulp (cellulose) by treatment with alkali followed by methylation of the alkali cellulose with methyl chloride. The product is then purified and ground to powder form.

Safety

Methylcellulose is widely used in a variety of oral and topical pharmaceutical formulations. It is also extensively used in cosmetics and food products and is generally regarded as a nontoxic, nonallergenic, and nonirritant material.(13)

Following oral consumption, methylcellulose is not digested or absorbed and is therefore a noncaloric material. Ingestion of excessive amounts of methylcellulose may temporarily increase flatulence and gastrointestinal distension.

In the normal individual, oral consumption of large amounts of methylcellulose has a laxative action and medium- or high-viscosity grades are therefore used as bulk laxatives.

Esophageal obstruction may occur if methylcellulose is swallowed with an insufficient quantity of liquid. Consumption of large quantities of methylcellulose may additionally interfere with the normal absorption of some minerals. However, this and the other adverse effects discussed above relate mainly to the use of methylcellulose as a bulk laxative and are not significant factors when methylcellulose is used as an excipient in oral preparations.

Methylcellulose is not commonly used in parenteral products, although it has been used in intra-articular and intramuscular injections. Studies in rats have suggested that parenterally administered methylcellulose may cause glomer- ulonephritis and hypertension.(13)

The WHO has not specified an acceptable daily intake of methylcellulose since the level of use in foods was not considered to be a hazard to health.(14)

LD50 (mouse, IP): 275 g/kg(15)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Dust may be irritant to the eyes and eye protection should be worn. Excessive dust generation should be avoided to minimize the risk of explosion. Methylcellulose is combustible. Spills of the dry powder or solution should be cleaned up immediately, as the slippery film that forms can be dangerous.

Regulatory Status

GRAS listed. Accepted as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (sublingual tablets; IM injections; nasal preparations; ophthalmic preparations; oral capsules, oral suspensions, and oral 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

Ethylcellulose; hydroxyethyl cellulose; hydroxyethylmethyl cellulose; hypromellose.

Comments

The thermal gelation temperature for methylcellulose decreases as a function of concentration. The presence of additives can increase or decrease the thermal gelation temperature. The presence of drugs can influence the properties of methylcellu- lose gels.(16) In addition, the viscosity of methylcellulose solutions can be modified by the presence of drugs or other additives.(17) Aqueous solutions of methylcellulose can be frozen and do not undergo phase separation upon freezing.

Methylcellulose is best dissolved in water by one of three methods, the most suitable being chosen for a particular application.

The most commonly used method is to add methylcellulose initially to hot water. The appropriate quantity of methylcellu- lose required to produce a solution of specified viscosity is mixed with water at 708C; about half the desired final volume of water is used. Cold water or ice is then added to the hot methylcellulose slurry in order to reduce the temperature to below 208C. A clear, aqueous methylcellulose solution is obtained.

Alternatively, either methylcellulose powder may be dry- blended with another powder prior to mixing with cold water, or methylcellulose powder may be moistened with an organic solvent such as ethanol (95%) prior to the addition of water.

In general, methylcellulose solutions exhibit pseudoplastic flow and there is no yield point. Nonthixotropic flow properties are observed below the gelation temperature.

Note that some cellulose ether products possess hydroxy- propyl substitutions in addition to methyl substitutions but are designated with the same trade name in a product line, differing only by a unique identifier code. These products should not be confused with the products that contain only methyl substitu- tions. A specification for methylcellulose is contained in the Food Chemicals Codex (FCC).

Specific References

Wan LSC, Prasad KPP. Uptake of water by excipients in tablets. Int J Pharm 1989; 50: 147–153.

Methylcellulose 465

Funck JAB, Schwartz JB, Reilly WJ, Ghali ES. Binder effectiveness for beads with high drug levels. Drug Dev Ind Pharm 1991; 17: 1143–1156.

Itiola OA, Pilpel N. Formulation effects on the mechanical properties of metronidazole tablets. J Pharm Pharmacol 1991; 43: 145–147.

Esezobo S. Disintegrants: effects of interacting variables on the tensile strengths and dissolution times of sulfaguanidine tablets. Int J Pharm 1989; 56: 207–211.

Sanghavi NM, Kamath PR, Amin DS. Sustained release tablets of theophylline. Drug Dev Ind Pharm 1990; 16: 1843–1848.

Wan LSC, Lai WF. Factors affecting drug release from drug-coated granules prepared by fluidized-bed coating. Int J Pharm 1991; 72: 163–174.

Wojdak H, Drobnicka B, Zientarska G, Gadomska-Nowak M. The influence of selected properties on the stability of pharma- ceutical emulsions. Pharmazie 1991; 46: 120–125.

Dalal PS, Narurkar MM. In vitro and in vivo evaluation of sustained release suspensions of ibuprofen. Int J Pharm 1991; 73: 157–162.

El Gawad A, Ramadan EM, El Helw AM. Formulation and stability of saluzide eye drops. Pharm Ind 1987; 49: 751–754.

Huikari A, Karlsson A. Viscosity stability of methylcellulose solutions at different pH and temperature. Acta Pharm Fenn 1989; 98(4): 231–238.

Huikari A. Effect of heat sterilization on the viscosity of methylcellulose solutions. Acta Pharm Fenn 1986; 95(1): 9–17.

Huikari A, Hinkkanen R, Michelsson H, et al. Effect of heat sterilization on the molecular weight of methylcellulose determined using high pressure gel filtration chromatography and viscometry. Acta Pharm Fenn 1986; 95(3): 105–111.

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.

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: 2408.

Mitchell K, Ford JL, Armstrong DJ, et al. Influence of drugs on the properties of gels and swelling characteristics of matrices contain- ing methylcellulose or hydroxypropylmethylcellulose. Int J Pharm 1993; 100(1–3): 165–173.

Huikari A, Kristoffersson E. Rheological properties of methylcel- lulose solutions: general flow properties and effects of added substances. Acta Pharm Fenn 1985; 94(4): 143–154.

General References

Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199–265. Hladon T, Gorecki M, Pawlaczyk HJ. Physicochemical interactions of drugs with excipients in suspensions. Acta Pol Pharm 1986; 43(5):

471–480.

Mitchell K, Ford JL, Armstrong DJ, et al. Influence of substitution type on the performance of methylcellulose and hydroxypropylmethyl- cellulose in gels and matrices. Int J Pharm 1993; 100(1–3): 143– 154.

Rowe RC. The molecular weight of methyl cellulose used in pharmaceutical formulation. Int J Pharm 1982; 11: 175–179.

Tapia Villanueva C, Sapag Hagar J. Methylcellulose: its pharmaceutical applications. Acta Farm Bonaerense 1995; 14(Jan–Mar): 41–47.

Wan LS, Prasad KP. Influence of quantity of granulating liquid on water uptake and disintegration of tablets with methylcellulose. Pharm Ind 1989; 51(1): 105–109.

Wan LS, Prasad KP. Studies on the swelling of composite disintegrant– methylcellulose films. Drug Dev Ind Pharm 1990; 16(2): 191–200.

BP: Methyl hydroxybenzoate

JP: Methyl parahydroxybenzoate PhEur: Methylis parahydroxybenzoas USPNF: Methylparaben

Synonyms

E218; 4-hydroxybenzoic acid methyl ester; methyl p-hydroxy- benzoate; Nipagin M; Uniphen P-23.

Chemical Name and CAS Registry Number

Methyl-4-hydroxybenzoate [99-76-3]

Empirical Formula and Molecular Weight

C8H8O3 152.15

Structural Formula

Functional Category

Antimicrobial preservative.

Applications in Pharmaceutical Formulation or Technology

Methylparaben is widely used as an antimicrobial preservative in cosmetics, food products, and pharmaceutical formulations; see Table I. It may be used either alone or in combination with other parabens or with other antimicrobial agents. In cos- metics, methylparaben is the most frequently used antimicro- bial preservative.(1)

The parabens are effective over a wide pH range and have a broad spectrum of antimicrobial activity, although they are most effective against yeasts and molds. Antimicrobial activity increases as the chain length of the alkyl moiety is increased, but aqueous solubility decreases; therefore a mixture of parabens is frequently used to provide effective preservation. Preservative efficacy is also improved by the addition of propylene glycol (2–5%), or by using parabens in combination with other antimicrobial agents such as imidurea; see Section 10.

Owing to the poor solubility of the parabens, paraben salts (particularly the sodium salt) are more frequently used in

formulations. However, this raises the pH of poorly buffered formulations.

Methylparaben (0.18%) together with propylparaben (0.02%) has been used for the preservation of various parenteral pharmaceutical formulations; see Section 14.

Table I: Uses of methylparaben.

Use Concentration (%)

IM, IV, SC injections(a) 0.065–0.25

Inhalation solutions 0.025–0.07

Intradermal injections 0.10

Nasal solutions 0.033

Ophthalmic preparations(a) 0.015–0.2

Oral solutions and suspensions 0.015–0.2

Rectal preparations 0.1–0.18

Topical preparations 0.02–0.3

Vaginal preparations 0.1–0.18

(a) See Section 14.

Description

Methylparaben occurs as colorless crystals or a white crystal- line powder. It is odorless or almost odorless and has a slight burning taste.

SEM: 1

Excipient: Methylparaben Supplier: Bate Chemical Co. Ltd. Magnification: 600×

Pharmacopeial Specifications

See Table II.

Methylparaben 467

Table II: Pharmacopeial specifications for methylparaben.

Test JP 2001 PhEur 2005 USPNF 23

Identification + + +

Characters — + —

Appearance of solution — + +

Acidity — + +

Heavy metals 420 ppm — —

Impurities — + +

Loss on drying 40.5% — —

Parahydroxybenzoic + — —

acid

Chlorides 40.035% — —

Melting range — — 125–1288C

Readily carbonizable + — +

substances

Organic volatile — — +

impurities

Related substances — + —

Residue on ignition 40.10% 40.1% 40.1%

Assay (dried basis) 599.0% 98.0–102.0% 99.0–100.5%

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