Stability and Storage Conditions

Magnesium carbonate is stable in dry air and on exposure to light. The bulk material should be stored in a well-closed container in a cool, dry place.

Incompatibilities

Incompatible with phenobarbital sodium,(4,9) diazepam solu- tion at a pH 55,(10) some binary powder mixtures,(11) lansoprazole,(5) and formaldehyde.(12) Acids will dissolve magnesium carbonate, with the liberation of carbon dioxide. Slight alkalinity is imparted to water. Magnesium carbonate was also found to increase the dissolution of acetazolamide formulations at a pH of 1.12; however, dissolution was retarded at a pH of 7.4.(6)

Method of Manufacture

Depending upon the manufacturing process used, the composi- tion of the magnesium carbonate obtained may vary from normal hydrated magnesium carbonate to basic hydrated magnesium carbonate.

Light magnesium carbonate may be manufactured by saturating an aqueous suspension of dolomite, CaMg(CO3)2, with carbon dioxide under pressure. On increase of the temperature, calcium carbonate precipitates almost entirely. The filtered solution is then heated to boiling; the magnesium bicarbonate in the solution loses carbon dioxide and water, and light magnesium carbonate precipitates.

Heavy magnesium carbonate may be manufactured by mixing a hot concentrated solution of magnesium chloride or magnesium sulfate with a solution of sodium carbonate. The heavy magnesium carbonate may be either precipitated to produce a granular material or spray-dried. Varying the temperature of the reaction solutions produces heavy magne- sium carbonate with differing physical properties: e.g., material with a higher specific surface area is produced at a lower reaction temperature. Low processing temperature provided the largest surface area, which produced optimum granules or spray-dried powder.(3) If dilute magnesium chloride or mag- nesium sulfate solutions are used for the reaction, a less dense material is produced.

424 Magnesium Carbonate

Magnesium carbonates in varying states of hydration are also found as minerals in nature.

Safety

Magnesium carbonate is used as an excipient in oral solid- dosage pharmaceutical formulations and is generally regarded as an essentially nontoxic and nonirritant material. However, the use of magnesium salts, such as magnesium carbonate, is contraindicated in patients with renal impairment. In addition, the probable oral lethal dose in humans has been estimated at 0.5–5.0 g/kg body weight.(12)

On contact with gastric acid, magnesium carbonate reacts in the stomach to form soluble magnesium chloride and carbon dioxide. Magnesium carbonate should therefore not be used as an antacid by those individuals whose stomachs cannot tolerate the evolution of carbon dioxide. Some magnesium is absorbed but is usually excreted in the urine. As with other magnesium salts, magnesium carbonate has a laxative effect and may cause diarrhea.

Therapeutically, the usual dose of magnesium carbonate as an antacid is 250–500 mg, and 2.0–5.0 g as a laxative.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Magnesium carbonate may be irritant to the eyes; eye protection is recommended. OSHA standards state that IPA 8-hour time weighted airborne average is 10 mg/m3.(12)

Regulatory Acceptance

GRAS listed. 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.

Related Substances

Magnesium carbonate anhydrous; magnesium carbonate hydroxide; normal magnesium carbonate.

Magnesium carbonate anhydrous Empirical formula: MgCO3 Molecular weight: 84.31

CAS number: [546-93-0]

Synonyms: carbonic acid, magnesium salt anhydrous (1 : 1); E504; magnesite.

Appearance: odorless, white-colored bulky powder or light, friable masses.

Melting point: decomposes at 3508C.

Magnesium carbonate hydroxide

Empirical formula: (MgCO3)4·Mg(OH)2·5H2O

Molecular weight: 485.65

CAS number: [39409-82-0]

Synonyms: carbonic acid, magnesium salt (1 : 1), mixture with magnesium hydroxide and magnesium hydrate; dypingite; E504.

Appearance: odorless, white-colored bulky powder or light, friable masses.

Melting point: on heating at 7008C it is converted into magnesium oxide.

Specific gravity: 1.45

Comments: the EINECS number for magnesium carbonate hydroxide is 235-192-7.

Normal magnesium carbonate Empirical formula: MgCO3·xH2O CAS number: [23389-33-5]

Synonyms: carbonic acid, magnesium salt (1 : 1), hydrate; magnesium carbonate, normal hydrate; E504.

Appearance: odorless, white-colored bulky powder or light, friable masses.

Comments

Magnesium carbonate has been found to increase the dissolu- tion of acetazolamide formulations at a pH of 1.12; however, dissolution was retarded at a pH of 7.4.(6) Magnesium carbonate has also been shown to alter the pharmacokinetics of halofantrine, increasing the time to reach maximum plasma concentration and reducing maximum plasma concentra- tions.(13) Because drug interactions can occur with a variety of antacids,(14) the potential for these effects should be considered when designing pharmaceutical formulations con- taining magnesium carbonate.

A specification for magnesium carbonate is contained in the Food Chemicals Codex (FCC). The EINECS number for magnesium carbonate is 208-915-9.

Specific References

Haines-Nutt RF. The compression properties of magnesium and calcium carbonates. J Pharm Pharmacol 1976; 28: 468–470.

Armstrong NA, Cham T-M. Changes in the particle size and size distribution during compaction of two pharmaceutical powders with dissimilar consolidation mechanisms. Drug Dev Ind Pharm 1986; 12: 2043–2059.

Cham T-M. The effect of the specific surface area of heavy magnesium carbonate on its tableting properties. Drug Dev Ind Pharm 1987; 13(9–11): 1989–2015.

Peterson CL, Perry DL, Masood H, et al. Characterization of antacid compounds containing both aluminum and magnesium. II: Codried powders. Pharm Res 1993; 10(7): 1005–1007.

Tabata T, Makino T, Kikuta J, et al. Manufacturing method of stable enteric granules of a new antiulcer drug (lansoprazole). Drug Dev Ind Pharm 1994; 20(9): 1661–1672.

Hashim F, El-Din EZ. Effect of some excipients on the dissolution of phenytoin and acetazolamide from capsule formulations. Acta Pharm Fenn 1989; 98: 197–204.

Sandor M, Riechel A, Kaplan I, Mathiowitz E. Effect of lecithin and MgCO3 as additives on the enzymatic activity of carbonic anhydrase encapsulated in poly(lactide-co-glycolide) (PLGA) microspheres. Biochimica et Biophysica Acta 2002; 1570(1): 63–

74.

Freitag F, Kleinebudde P. How do roll compaction / dry granulation affect the tabletting behaviour of inorganic materials? Comparison of four magnesium carbonates. Eur J Pharm Sci 2003; 19: 281–289.

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

Jain GK, Kakkar AP. Interaction study of diazepam with excipients in liquid and solid state. Indian Drugs 1992; 29(July): 545–546.

Jain GK, Kakkar AP. Interaction study of diazepam with excipients in binary powder form. Indian Drugs 1992; 29(July): 453–454.

Hazardous Substances Data Bank (2005). Magnesium carbonate, http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB (accessed 7

June 2005).

Magnesium Carbonate 425

Aideloje SO, Onyeji CO, Ugwu NC. Altered pharmacokinetics of halofantrine by an antacid, magnesium carbonate. Eur J Pharm Biopharm 1998; 46(3): 299–303.

Sadowski DC. Drug interactions with antacids: mechanisms and clinical significance. Drug Safety 1994; 11(6): 395–407.

General References

Freitag F, Kleinebudde P. How do roll compaction / dry granulation affect the tableting behaviour of inorganic materials? Microhard- ness of ribbons and mercury porosimetry measurements of tablets. Eur J Pharm Sci 2004; 22: 325–333.

Jaiyeoba KT, Spring MS. The granulation of ternary mixtures: the effect of solubility of the excipients. J Pharm Pharmacol 1980; 32: 1–5.



Khaled KA. Formulation and evaluation of hydrochlorothiazide liquisolid tablets. Saudi Pharm J 1998; 6(Jan): 39–46.

Law MFL, Deasy PB. Effect of common classes of excipients on extrusion-spheronization. J Microencapsul 1997; 14(May): 647–

657.

Authors

BF Truitt.

Date of Revision

7 June 2005.

Magnesium Oxide

Nonproprietary Names

BP: Heavy magnesium oxide and Light magnesium oxide JP: Magnesium oxide

PhEur: Magnesii oxidum ponderosum (Magnesium oxide, heavy) and Magnesii oxidum leve (Magnesium oxide, light) USP: Magnesium oxide

See Section 8.

Synonyms

Calcined magnesia; calcinated magnesite; Destab; E530; Magcal; Magchem 100; Maglite; magnesia; magnesia mon- oxide; magnesia usta; Magnyox; Marmag; Oxymag; periclase.

Chemical Name and CAS Registry Number

Magnesium oxide [1309-48-4]

Empirical Formula and Molecular Weight

MgO 40.30

Table I: Pharmacopeial specifications for magnesium oxide.

Test JP 2001 PhEur 2005 USP 28

Identification + + +

Loss on ignition 410.0% 48.0% 410.0%

Color of solution — + —

Free alkali and soluble salts + — 42.0% Soluble substances — 42.0% —

Acid-insoluble substances 40.1% 40.1% 40.1% Arsenic 410 ppm 44 ppm —

Calcium — 41.5% 41.1%

Calcium oxide + — —

Carbonate + — —

Heavy metals 440 ppm 430 ppm 420 mg/g

Iron 4500 ppm + 40.05% Heavy magnesium oxide — 40.07% —

Light magnesium oxide — 40.1% — Chloride — + — Heavy magnesium oxide — 40.1% —

Light magnesium oxide — 40.15% — Fluoride 40.08% — —

Sulfate — 41.0% —

Structural Formula

MgO

Functional Category

Assay 596.0% 98.0–

100.5%

10 Typical Properties

96.0–

100.5%

Anticaking agent; emulsifying agent; glidant; tablet and capsule diluent.

Applications in Pharmaceutical Formulation or Technology

Magnesium oxide is used as an alkaline diluent in solid-dosage forms to modify the pH of tablets.(1) It can be added to solid- dosage forms to bind excess water and keep the granulation dry. In combination with silica, magnesium oxide can be used as an auxiliary glidant.(2) It is also used as a food additive and as an antacid, either alone or in conjunction with aluminum hydroxide. Magnesium oxide is additionally used as an osmotic laxative and a magnesium supplement to treat deficiency states.

Description

Two forms of magnesium oxide exist: a bulky form termed light magnesium oxide and a dense form termed heavy magnesium oxide. The USP 28 defines both forms in a single monograph, while other pharmacopeias have separate monographs for each form. For the heavy variety, 5 g occupies a volume of about 10–20 mL; for the light variety, 5 g occupies a volume of about 40–50 mL as defined by the USP 28.

Both forms of magnesium oxide occur as fine, white, odorless powders. They possess a cubic crystal structure.

Pharmacopeial Specifications

See Table I.

Acidity/alkalinity: pH = 10.3 (saturated aqueous solution)

Boiling point: 36008C

Melting point: 28008C

Particle size distribution: 99.98% less than 45 mm in size (light magnesium oxide).

Refractive index: 1.735

Solubility: soluble in dilute acids and ammonium salt solutions; very slightly soluble in pure water (solubility is increased by carbon dioxide); practically insoluble in ethanol (95%).

Specific gravity: 3.581 g/cm3 at 258C

Stability and Storage Conditions

Magnesium oxide is stable at normal temperatures and pressures. However, it forms magnesium hydroxide in the presence of water. Magnesium oxide is hygroscopic and rapidly absorbs water and carbon dioxide on exposure to the air, the light form more readily than the heavy form.

The bulk material should be stored in an airtight container in a cool, dry place.

Incompatibilities

Magnesium oxide is a basic compound and as such can react with acidic compounds in the solid state to form salts such as Mg(ibuprofen)2 or degrade alkaline-labile drugs.(3) Adsorption of various drugs onto magnesium oxide has been reported, such as antihistamines,(4) antibiotics (especially tetracyclines),(5) salicylates,(6) atropine sulfate,(7) hyoscyamine hydrobromide,(7) paracetamol, chloroquine,(8) and anthranilic acid derivatives have been reported to adsorb onto the surface of magnesium

Magnesium Oxide 427

oxide.(9) Magnesium oxide can also complex with polymers,

e.g. Eudragit RS, to retard drug release(10–12) and can interact in the solid state with phenobarbitone sodium.(13) Magnesium oxide can also reduce the bioavailability of phenytoin,(14) trichlormethiazide,(15) and anti-arrhythmics.(16) The presence of magnesium oxide can also have a negative impact on the solid-state chemical stability of drugs, such as diazepam.(17)