Method of Manufacture

Magnesium oxide occurs naturally as the mineral periclase. It can be manufactured by many processes. Limestone containing the mineral dolomite is calcinated at high temperatures to produce dolime, which then reacts with magnesium chloride- rich sea water to produce magnesium hydroxide and calcium chloride.(18) The magnesium hydroxide is then calcinated to produce magnesium oxide and water. In another process, mined magnesite (MgCO3) is calcinated to produce magnesium oxide and carbon dioxide.(18) Purification methods include crushing and size separation, heavy-media separation, and froth flotation. Producing magnesium oxide from sea water is a process that involves heating magnesium chloride concentrated brine from the Dead Sea. The magnesium chloride decomposes into magnesium oxide and hydrochloric acid.(18) Magnesium oxide may also be produced by the thermal decomposition of magnesium chloride, magnesium sulfate, magnesium sulfite, nesquehonite, and the basic carbonate 5MgO·4CO2·5H2O. Purification of the magnesium oxide produced through thermal degradation is carried out by filtration or sedimentation.

Safety

Magnesium oxide is widely used in oral formulations as an excipient and as a therapeutic agent. Therapeutically, 250–500 mg is administered orally as an antacid and 2–5 g as an osmotic laxative. Magnesium oxide is generally regarded as a nontoxic material when employed as an excipient, although adverse effects, due to its laxative action, may occur if high doses are ingested orally.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Magnesium oxide may be harmful if inhaled, ingested, or absorbed through the skin in quantity and is irritating to the eyes and respiratory system. Gloves, eye protection, and a dust mask or respirator are recommended. In the US and UK, the long-term (8-hour TWA) occupational exposure limits for magnesium oxide, calculated as magnesium, are 10 mg/m3 for total dust and 4 mg/m3 for respirable dust.(18,19) The short-term (15-minute) limit for respirable dust is 10 mg/m3.(18,19)

Regulatory Status

GRAS listed. Accepted for use 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

—



Comments

A specification for magnesium oxide is contained in the Food Chemicals Codex (FCC). The EINECS number for magnesium oxide is 215-171-9.

Specific References

Patel H, Stalcup A, Dansereau R, Sakr A. The effect of excipients on the stability of levothroxine sodium pentahydrate tablets. Int J Pharm 2003; 264: 35–43.

Kirk RE, Othmer DF. Encyclopedia of Chemical Technology, 4th edn, vol 1. New York: Wiley, 1995: 107.

Tugrul TK, Needham TE, Seul CJ, Finnegan PM. Solid-state interaction of magnesium oxide and ibuprofen to form a salt. Pharm Res 1989; 6(9): 804–808.

Nada AH, Etman MA, Ebian AR. In vitro adsorption of mepyramine maleate onto some adsorbents and antacids. Int J Pharm 1989; 53: 175–179.

Khalil SA, Daabis NA, Naggar VF, Motawi MM. The in vitro adsorption of some antibiotics on antacids. Pharmazie 1976; 31: 105–109.

Naggar VF, Khalil SA, Daabis NA. The in-vitro adsorption of some antirheumatics on antacids. Pharmazie 1976; 31: 461–465.

Singh A, Mital H. Adsorption of atropine sulfate and hyoscyamine hydrobromide by various antacids. Acta Pharm Technol 1979; 25(3): 217–224.

Iwuagwu MA, Aloko KS. Adsorption of paracetamol and chloroquine phosphate by some antacids. J Pharm Pharmacol 1992; 44: 655–658.

Monkhouse DC, Lach JL. Drug–Excipient Interactions. Can J Pharm Sci 1972; 7: 29–46.

Shanghavi NM, Bijlani CP, Kamath PR, Sarwade VB. Matrix tablets of salbutamol sulfate. Drug Dev Ind Pharm 1990; 16: 1955–1961.

Racz I, Antal I, Plachy J. Formulation of controlled release drug preparations with antacid effect. Pharmazie 1996; 51(May); 323– 327.

Racz I, Zelko R, Bihari E, Bucsek M. Effect of eudragit type polymers on the drug release from magnesium oxide granules produced by laboratory fluidization. Drug Dev Ind Pharm 1995; 21(18): 2085–2096.

Nagavi BG, Mithal BM, Marwade PR, Dutta R. Solid phase interaction of phenobarbitone sodium with some adjuvants. Indian J Pharm Sci 1983; 45(Jul–Aug): 175–177.

D’Arcy PF, McElnay JC. Drug–antacid interactions: assessment of clinical importance. Drug Intell Clin Pharm 1987; 21: 607–617.

Takahashi H, Watanabe Y, Shimamura H, Sugito K. Effect of magnesium oxide on trichlormethiazide bioavailability. J Pharm Sci 1985; 74: 862–865.

Remon JP, Belpaire F, Van-Severen R, Braeckman P. Interaction of antacids with anti-arrhythmics. Part 5. Effect of aluminum hydroxide and magnesium oxide on the bioavailability of quinidine, procainamide, and propranolol in dogs. Arzneimittel Forschung 1983; 33(1): 117–120.

Jain G, Kakkar A. Interaction of diazepam with excipients in binary powder form. Indian Drugs 1992; 29(Jul): 453–454.

Kirk RE, Othmer DF. Encyclopedia of Chemical Technology, 4th edn., vol. 15. New York: Wiley, 1995: 703–707

Health and Safety Executive. EH40/2002: Occupational Exposure Limits 2002. Sudbury: Health and Safety Executive, 2002.

General References

—

Authors

JT Colvin.

Date of Revision

26 April 2005.

Magnesium Silicate

Nonproprietary Names

JP: Magnesium silicate USPNF: Magnesium silicate

Synonyms

E553a; synthetic magnesium silicate.

Chemical Name and CAS Registry Number

Silicic acid, magnesium salt [1343-88-0]

Empirical Formula and Molecular Weight

MgO·SiO2·xH2O

See also Sections 5 and 17.

Structural Formula

Magnesium silicate is a compound of magnesium oxide and silicon dioxide. See also Section 17.

The JP 2001 states that magnesium silicate contains not less than 45.0% of silicon dioxide (SiO2: molecular weight 60.08) and not less than 20.0% of magnesium oxide (MgO: 40.30), and the ratio of percentage (%) of magnesium oxide to silicon dioxide is not less than 2.2 and not more than 2.5.

The USPNF 23 describes magnesium silicate as a compound of magnesium oxide (MgO) and silicon dioxide (SiO2) that contains not less than 15.0% of MgO and not less than 67.0% of SiO2 calculated on the ignited basis.

Functional Category

Anticaking agent; glidant.

Applications in Pharmaceutical Formulation or Technology

Magnesium silicate is used in oral pharmaceutical formulations and food products as a glidant and an anticaking agent.

Description

Magnesium silicate occurs as an odorless and tasteless, fine, white-colored powder that is free from grittiness.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for magnesium silicate.

Test JP 2001 USPNF 23

 

Identification + +    

pH (10% aqueous suspension) — 7.0–10.8    

Loss on drying — 415%    

Soluble salts 40.02 g 43.0%    

Chloride 40.053% —    

Free alkali + +    

Heavy metals 430 ppm 420 mg/g    

Arsenic 45 ppm —    

Sulfate 40.48% —    

Organic volatile impurities — +    

Loss on ignition 434% 415%    

Fluoride — 410 ppm    

Lead — 40.001%    

Acid-consuming capacity + —    

Ratio of SiO2 to MgO 2.2–2.5 2.5–4.5    

Assay for MgO 520.0% 515%    

Assay for SiO2 545.0% 567%  

Typical Properties

Moisture content: magnesium silicate is slightly hygroscopic.

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

Stability and Storage Conditions

Magnesium silicate should be stored in a well-closed container in a cool, dry place.

Incompatibilities

Magnesium silicate may decrease the oral bioavailability of drugs such as mebeverine hydrochloride,(1) sucralfate, and tetracycline, via chelation or binding, when they are taken together. The dissolution rate of folic acid,(2) erythromycin stearate,(3) paracetamol,(4) and chloroquine phosphate,(4) may be retarded by adsorption onto magnesium silicate. Anti- microbial preservatives, such as parabens, may be inactivated by the addition of magnesium silicate.(5)

Magnesium silicate is readily decomposed by mineral acids.

Method of Manufacture

Magnesium silicate may be prepared from sodium silicate and magnesium sulfate. The silicate also occurs in nature as the minerals meerschaum, parasepiolite, and sepiolite.

Safety

Magnesium silicate is used in oral pharmaceutical formulations and is generally regarded as an essentially nontoxic and nonirritant material.

Orally administered magnesium silicate is neutralized in the stomach to form magnesium chloride and silicon dioxide; some

Magnesium Silicate 429

magnesium is absorbed. Caution should be used when greater than 50 mEq of magnesium is given daily to persons with impaired renal function, owing to the risk of hypermagnesemia. Reported adverse effects include the formation of bladder and renal calculi following the regular use, for many years, of

magnesium silicate as an antacid.(6,7)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection is recom- mended.

Regulatory Acceptance

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (oral tablets). Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Magnesium aluminum silicate; magnesium metasilicate; mag- nesium orthosilicate; magnesium trisilicate; talc.

Magnesium metasilicate

Comments: magnesium metasilicate (MgSiO3) occurs in nature as the minerals clinoenstatite, enstatite, and protoenstatite.

Magnesium orthosilicate

Comments: magnesium orthosilicate (Mg2SiO4) occurs in nature as the mineral forsterite.



Comments

A specification for magnesium silicate is contained in the Food Chemicals Codex (FCC). The EINECS number for magnesium silicate is 215-681-1.

Specific References

Al-Gohary OMN. An in vitro study of the interaction between mebeverine hydrochloride and magnesium trisilicate powder. Int J Pharm 1991; 67: 89–95.

Iwuagwu MA, Jideonwo A. Preliminary investigations into the in- vitro interaction of folic acid with magnesium trisilicate and edible clay. Int J Pharm 1990; 65: 63–67.

Arayne MS, Sultana N. Erythromycin–antacid interaction. Phar- mazie 1993; 48: 599–602.

Iwuagwu MA, Aloko KS. Adsorption of paracetamol and chloroquine phosphate by some antacids. J Pharm Pharmacol 1992; 44: 655–658.

Allwood MC. The adsorption of esters of p-hydroxybenzoic acid by magnesium trisilicate. Int J Pharm 1982; 11: 101–107.

Joekes AM, Rose GA, Sutor J. Multiple renal silica calculi. Br Med J 1973; 1: 146–147.

Levison DA, Crocker PR, Banim S, Wallace DMA. Silica stones in the urinary bladder. Lancet 1982; i: 704–705.

General References

Anonymous. The silicates: attapulgite, kaolin, kieselguhr, magnesium trisilicate, pumice, talc. Int J Pharmaceut Compound 1998; 2(2): 162–163.

Authors

A Palmieri.

Date of Revision

8 August 2005.

Magnesium Stearate

Nonproprietary Names

BP: Magnesium stearate JP: Magnesium stearate PhEur: Magnesii stearas

USPNF: Magnesium stearate

Synonyms

Magnesium octadecanoate; octadecanoic acid, magnesium salt; stearic acid, magnesium salt.

Chemical Name and CAS Registry Number

Octadecanoic acid magnesium salt [557-04-0]

Empirical Formula and Molecular Weight

Table I: Pharmacopeial specifications for magnesium stearate.

C36H

70MgO4

591.34

The USPNF 23 describes magnesium stearate as a com- pound of magnesium with a mixture of solid organic acids that consists chiefly of variable proportions of magnesium stearate and magnesium palmitate (C32H62MgO4). The PhEur 2005 describes magnesium stearate as a mixture of magnesium salts of different fatty acids consisting mainly of stearic acid and palmitic acid and in minor proportions other fatty acids.

Structural Formula

[CH3(CH2)16COO]2Mg

Functional Category

Tablet and capsule lubricant.

Applications in Pharmaceutical Formulation or Technology

Magnesium stearate is widely used in cosmetics, foods, and pharmaceutical formulations. It is primarily used as a lubricant in capsule and tablet manufacture at concentrations between 0.25% and 5.0% w/w. It is also used in barrier creams. See also Section 18.

Description

Magnesium stearate is a very fine, light white, precipitated or milled, impalpable powder of low bulk density, having a faint odor of stearic acid and a characteristic taste. The powder is greasy to the touch and readily adheres to the skin.

Pharmacopeial Specifications

See Table I.



Typical Properties

Crystalline forms: high-purity magnesium stearate has been isolated as a trihydrate, a dihydrate, and an anhydrate.

Density (bulk): 0.159 g/cm3 Density (tapped): 0.286 g/cm3 Density (true): 1.092 g/cm3 Flash point: 2508C

Flowability: poorly flowing, cohesive powder.

Melting range:

117–1508C (commercial samples); 126–1308C (high purity magnesium stearate).

Solubility: practically insoluble in ethanol, ethanol (95%), ether and water; slightly soluble in warm benzene and warm ethanol (95%).

Specific surface area: 1.6–14.8 m2/g

Stability and Storage Conditions

Magnesium stearate is stable and should be stored in a well- closed container in a cool, dry place.

Incompatibilities

Incompatible with strong acids, alkalis, and iron salts. Avoid mixing with strong oxidizing materials. Magnesium stearate cannot be used in products containing aspirin, some vitamins, and most alkaloidal salts.

Magnesium Stearate 431

SEM: 1

Excipient: Magnesium stearate

Magnification: 600×

 

SEM: 2

Excipient: Magnesium stearate

Magnification: 2400×

 

Method of Manufacture

Magnesium stearate is prepared either by the interaction of aqueous solutions of magnesium chloride with sodium stearate or by the interaction of magnesium oxide, hydroxide, or carbonate with stearic acid at elevated temperatures.

Safety

Magnesium stearate is widely used as a pharmaceutical excipient and is generally regarded as being nontoxic following



oral administration. However, oral consumption of large quantities may produce a laxative effect or mucosal irritation. No toxicity information is available relating to normal routes of occupational exposure. Limits for heavy metals in magnesium stearate have been evaluated in terms of mag- nesium stearate worst-case daily intake and heavy metal

composition.(1)

Toxicity assessments of magnesium stearate in rats have indicated that it is not irritating to the skin, and is nontoxic when administered orally or inhaled.(2,3)

Magnesium stearate has not been shown to be carcinogenic when implanted into the bladder of mice.(4)

LD50 (rat, inhalation): >2 mg/L(2) LD50 (rat, oral): >10 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended. Excessive inhalation of magnesium stearate dust may cause upper respiratory tract discomfort, coughing, and choking. Magnesium stearate should be handled in a well- ventilated environment; a respirator is recommended.

Regulatory Acceptance

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

Related Substances

Calcium stearate; magnesium aluminum silicate; stearic acid; zinc stearate.

Comments

Magnesium stearate is hydrophobic and may retard the dissolution of a drug from a solid dosage form; the lowest possible concentration is therefore used in such formula- tions.(5–10) Capsule dissolution is also sensitive to both the amount of magnesium stearate in the formulation and the mixing time; higher levels of magnesium stearate and long mixing times can result in the formation of hydrophobic powder beds that do not disperse after the capsule shell dissolves.(11,12)

An increase in the coefficient of variation of mixing and a decrease in the dissolution rate have been observed following blending of magnesium stearate with a tablet granulation. Tablet dissolution rate and crushing strength decreased as the time of blending increased; and magnesium stearate may also increase tablet friability. Blending times with magnesium stearate should therefore be carefully controlled.(13–29)

The existence of various crystalline forms of magnesium stearate has been established.(30–34) A trihydrate, a dihydrate, and an anhydrate have been isolated,(5,32,33,35) and an amorphous form has been observed.(36) While the hydrate forms are stable in the presence of moisture, the anhydrous form adsorbs moisture at relative humidity up to 50%, and at higher humidities rehydrates to form the trihydrate. The anhydrate can be formed by drying either of the hydrates at 1058C.(33)