Incompatibilities

Shellac is chemically reactive with aqueous alkalis, organic bases, alcohols, and agents that esterify hydroxyl groups. Therefore, shellac should be used with caution in the presence of such compounds.

Method of Manufacture

Shellac or lac is obtained by purification of the resinous secretion of the insect Laccifero (Tachardia) lacca Kerr (Homoptera, Coccidae). The insect lives on the sap of the stems of various trees; secretions are found most abundantly on the smaller branches and twigs, which are broken off and constitute sticklac. After scraping of the twigs and soaking in water, the water-soluble components are removed by treatment with dilute alkali. The resulting water-insoluble material is called seed lac.

Historically, seed lac was processed into shellac by melting the seed lac in a muslin bag suspended over a fire. Shellac could then be squeezed from the bag by hand and poured into molds to produce button shellac. Alternatively, the molten shellac was collected and allowed to cool as discs or wafer-thin sheets.

Today, most shellac is produced on a commercial scale using machine processes involving extraction from seed lac using steam heat or solvent extraction with hot ethanol. Shellac produced by the heat and solvent extraction processes cannot usually be differentiated by chemical tests.

Various different grades of modified or refined shellac are available, which may be broadly defined as either bleached or orange shellac. Orange shellac is essentially the crude shellac obtained from seed lac, as described above. It may retain most of its wax or be dewaxed, and may contain less of the natural color than was originally present. The quantities of wax, coloring material, and other impurities present may vary; the

�physical properties of orange shellac may therefore also vary depending upon its source or the processing methods used.

Bleached or white shellac is obtained by dissolving shellac in aqueous sodium carbonate, bleaching the solution with sodium hypochlorite, and precipitating the bleached shellac with 2 N sulfuric acid. Removal of wax by filtration results in a refined bleached shellac.

Most commercial shellac is produced in India and Thailand; smaller amounts come from Burma and Malaysia.

Safety

Shellac is used in oral pharmaceutical formulations, food products, and cosmetics. It is generally regarded as an essentially nonirritant and nontoxic material at the levels employed as an excipient. However, excessive consumption of shellac may be harmful.

Handling Precautions

Shellac may be harmful if ingested in large quantities. It is irritating to the eyes, and to the respiratory system if inhaled as dust. Observe normal precautions appropriate to the circum- stances and quantity of material handled. Eye protection, gloves, and a dust respirator are recommended. Shellac should be handled in a well-ventilated environment.

Regulatory Status

Accepted as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (oral capsules and tablets). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Aleuritic acid; pharmaceutical glaze; polyvinyl acetate phtha- late; shellolic acid.

Aleuritic acid

Empirical formula: C16H32O5

Molecular weight: 304.42

CAS number: [533-87-9]

Synonyms: DL-erythro-9,10,16,-trihydroxyhexadecanoic acid; 9,10,16-trihydroxypalmitic acid; 8,9,15-trihydroxypenta- decane-1-carboxylic acid.

Melting point: 100–1018C

Solubility: soluble in methanol.

Comments: component of shellac. The EINECS number for aleuritic acid is 208-578-8.

Pharmaceutical glaze

Comments: pharmaceutical glaze is a specially denatured alcoholic solution of shellac containing between 20% and 57% of anhydrous shellac. It may be prepared using either ethanol or ethanol 95% and may contain waxes and titanium dioxide as an opacifing agent.

Shellolic acid

Empirical formula: C15H20O6

Molecular weight: 296.33

CAS number: [4448-95-7]

Synonyms: 10b,13-dihydroxycedr-8-ene-12,15-dioic acid; 2,3,4,7,8,8a-hexahydro-4-hydroxy-8-(hydroxymethyl)-8- methyl-1H-3a,7-methanoazulene-3,6-dicarboxylic acid.

Melting point: 204–2078C

Comments: component of shellac.

Shellac 651

Comments

Shellac is insoluble in acidic conditions but is soluble at higher pH; it therefore appears to be a suitable enteric-coating material. However, in practice, delayed disintegration and drug release may occur in vivo as shellac is insoluble in the slightly acidic environment of the upper intestine. Additives such as lauric acid may be added to plasticize and improve disintegration of shellac films, although shellac tends not to be used in new drug formulations as an enteric-coating agent.

Studies using the USP disintegration test for enteric-coated tablets have indicated that there is a marked increase in the disintegration time over a 6-month storage period for shellac- coated tablets.(4) It is likely that this effect is due to the polymerization of shellac, which occurs over storage periods of this duration. A specification for shellac is contained in the Food Chemicals Codex (FCC).

The EINECS number for shellac is 232-549-9.

Specific References

Yates P, Field GF. Lac—I: the structure of shellolic acid.

Tetrahedron 1970; 26: 3135–3158.

Yates P, Burke PM, Field GF. Lac—II: the stereochemistry of shellolic and epishellolic acids. Tetrahedron 1970; 26: 3159–3170.

�

Specht F, Saugestad M, Waaler T, Muller BW. The application of shellac acidic polymer for enteric coating. Pharm Technol Eur 1998; 10(9): 20, 22, 24, 27, 28.

Luce GT. Disintegration of tablets enteric coated with CAP. Manuf Chem Aerosol News 1978; 49(7): 50, 52, 67.

General References

Chang RK, Iturrioz G, Luo CW. Preparation and evaluation of shellac pseudolatex as an aqueous enteric coating system for pellets. Int J Pharm 1990; 60: 171–173.

Cockeram HS, Levine SA. The physical and chemical properties of shellac. J Soc Cosmet Chem 1961; 12: 316–323.

Labhasetwar VD, Puranik PK, Dorle AK. Study of shellac-glycerol esters as anhydrous binding agents in tablet formulations. Indian J Pharm Sci 1988; 50: 343–345.

Limmatrapirat S, Limmatrapirat C, Luangtana-Anan M, et al. Modification of physicochemical and mechanical properties of shellac by partial hydrolysis. Int J Pharm 2004; 278(1): 41–49.

Authors

X Li, BR Jasti.

Date of Revision

18 August 2005.

Simethicone

Nonproprietary Names

BP: Simeticone PhEur: Simeticonum USP: Simethicone

Synonyms

Dow Corning Q7-2243 LVA; Dow Corning Q7-2587; poly- dimethylsiloxane–silicon dioxide mixture; Sentry Simethicone; simeticone.

Chemical Name and CAS Registry Number

a-(Trimethysilyl-o-methylpoly[oxy(dimethylsilylene)], mixture with silicon dioxide [8050-81-5]

Empirical Formula and Molecular Weight

See Section 8.

Structural Formula

 

where n = 200–350

Functional Category

Antifoaming agent; tablet diluent; water-repelling agent.

�Description

The PhEur 2005 and USP 28 describe simethicone as a mixture of fully methylated linear siloxane polymers containing repeating units of the formula [–(CH3)2SiO–]n, stabilized with trimethylsiloxy end-blocking units of the formula [(CH3)3 SiO–

], and silicon dioxide. It contains not less than 90.5% and not more than 99.0% of the polydimethylsiloxane [–(CH3)2SiO–]n, and not less than 4.0% and not more than 7.0% of silicon dioxide. The PhEur 2005 additionally states that the degree of polymerization is between 20–400.

Simethicone occurs as a translucent, gray-colored, viscous fluid. It has a molecular weight of 14 000–21 000.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for simethicone.

Test PhEur 2005 USP 28

Identification + +

Characters + —

Acidity + —

Defoaming activity 415 seconds 415 seconds

Loss on heating — 418%

Volatile matter 41.0% —

Heavy metals 45 ppm 45 mg/g Organic volatile impurities — +

Mineral oils + —

Phenylated compounds + —

Assay (dimethicone) + —

Assay (silicon dioxide) — 4.0–7.0% Assay (silica) 47.0% —

Assay (polydimethylsiloxane) 90.5–99.0% 90.5–99.0%

Typical Properties

Boiling point: 358C

Refractive index: n20 = 0.965–0.970

Applications in Pharmaceutical Formulation or Technology

�Solubility:

�D

practically insoluble in ethanol (95%) and water.

The main use of simethicone as an excipient is as an antifoaming agent in pharmaceutical manufacturing processes, for which 1–50 ppm is used.

Therapeutically, simethicone is included in a number of oral pharmaceutical formulations as an antiflatulent, although its therapeutic benefit is questionable.(1) It is also included in antacid products such as tablets or capsules.(2–6) In some types of surgical or gastroscopic procedures where gas is used to inflate the body cavity, a defoaming preparation containing simethicone may be used in the area to control foaming of the fluids.

When simethicone is used in aqueous formulations, it should be emulsified to ensure compatibility with the aqueous system and components.

In the USA, up to 10 ppm of simethicone may be used in food products.

�The liquid phase is soluble in benzene, chloroform, and

ether, but silicon dioxide remains as a residue in these solvents.

Specific gravity: 0.95–0.98 at 258C

Viscosity (kinematic): 370 mm2/s at 258C for Dow Corning Q7-2243 LVA.

Stability and Storage Conditions

Simethicone is generally regarded as a stable material when stored in the original unopened container. A shelf-life of 18 months from the date of manufacture is typical. However, some simethicone products have a tendency for the silicon dioxide to settle slightly and containers of simethicone should therefore be shaken thoroughly to ensure uniformity of contents before sampling or use. Simethicone should be stored in a cool, dry, location away from oxidizing materials.

Simethicone 653

Simethicone can be sterilized by dry heating or autoclaving. With dry heating, a minimum of 4 hours at 1608C is required.

Incompatibilities

Simethicone as supplied is not generally compatible with aqueous systems and will float like an oil on a formulation unless it is first emulsified. It should not be used in formulations or processing conditions that are very acidic (below pH 3) or highly alkaline (above pH 10), since these conditions may have some tendency to break the polydimethylsiloxane polymer. Simethicone cannot normally be mixed with polar solvents of any kind because it is very minimally soluble. Simethicone is incompatible with oxidizing agents.

Method of Manufacture

Silicon dioxide is initially rendered hydrophobic in one of a variety of proprietary processes specific to a particular manufacturer. It is then slowly mixed with the silicone fluids in a formulation. After mixing, the simethicone is milled to ensure uniformity.

Safety

Simethicone is used in cosmetics, foods, and oral and topical pharmaceutical formulations and is generally regarded as a relatively nontoxic and nonirritant material when used as an excipient. Direct contact with the eye may cause irritation.

Therapeutically, oral doses of 125–250 mg of simethicone, three or four times daily, have been given as an antiflatulent. Doses of 20–40 mg of simethicone have been given with feeds to relieve colic in infants.(7)

LD50 (dog, IV): 0.9 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended. Simethicone should be handled in areas with adequate ventilation.

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (oral emulsions, powders, solutions, suspensions, tablets, and

�

rectal and topical preparations). Included in nonparenteral medicines licensed in the UK.

Related Substances

Cyclomethicone; dimethicone.

Comments

—

Specific References

Anonymous. Simethicone for gastrointestinal gas. Med Lett Drugs Ther 1996; 38: 57–58.

Sox T. Simethicone and sulfasalazine for treatment of ulcerative colitis. United States Patent 6,100,245; 1999.

Holtman G, Gschossmann J, Karaus M, et al. Randomized double- blind comparison of simethicone with cisapride in functional dyspepsia. Aliment Pharmacol Ther 1999; 13(11): 1459–1465.

Tiongson A. Process of making an aqueous calcium carbonate suspension. International Patent WO 9945937; 1999.

Luber J, Madison G, McNally G. Antifoam oral solid dosage forms comprising simethicone and anhydrous calcium phosphate. European Patent 891776; 1999.

Devlin BT, Hoy MR. Semisolid composition containing an antiflatulent agent. European Patent 815864; 1998.

Metcalf TJ, Irons TG, Sher LD, Young PC. Simethicone in the treatment of infant colic: randomized, placebo-controlled, multi- center trial. Pediatrics 1994; 84: 29–34.

General References

Daher L. Lubricants for use in tabletting. United States Patent 5,922,351; 1999.

Rider JA, Roorda AK, Rider DL. Further analysis of standards for antacid simethicone defoaming properties. Curr Ther Res 1997; 58(12): 955–963.

Authors

RT Guest.

Date of Revision

22 August 2005.