432 Magnesium Stearate

It has not been conclusively established which form of pure magnesium stearate possesses the best lubricating proper- ties.(31,32,36,37) Commercial lots of magnesium stearate gen- erally consist of mixtures of crystalline forms.(32,34,36–40) Because of the possibility of conversion of crystalline forms during heating, consideration should be given to the pretreat- ment conditions employed when determining physical proper- ties of magnesium stearate powders such as surface area.(41)

Physical properties of magnesium stearate can vary among batches from different manufacturers(40) because the solid-state characteristics of the powder are influenced by manufacturing variables.(31) Variations in the physical properties of different lots of magnesium stearate from the same vendor have also been observed.(40) Presumably because of these variations, it has not been possible to conclusively correlate the dissolution rate retardation with observed lubricity.(42)

However, various physical properties of different batches of magnesium stearate such as specific surface area, particle size, crystalline structure, moisture content, and fatty acid composition have been correlated with lubricant effi- cacy.(32,36,39,40,43–47) Due to variations in the specific surface area, the USPNF 23 labeling states that specific surface area and the method specified for its determination should be listed on the label. Reduction in dissolution caused by the effects of magnesium stearate in some cases can be overcome by including a highly swelling disintegrant in the formulation.(48) There is evidence to suggest that the hydrophobic nature of magnesium stearate can vary from batch to batch owing to the presence of water-soluble, surface-active impurities such as sodium stearate. Batches containing very low concentrations of these impurities have been shown to retard the dissolution of a drug to a greater extent than when using batches that contain higher levels of impurities.(42) One study related lubricity to the fatty acid composition (stearate : palmitate) of lubricant lots for tablet formulations based on compaction data and tablet material properties.(47) However, other studies have indicated that fatty acid composition has no influence on lubricant activity(32) and high-purity magnesium stearate was as effective a lubricant as the commercial material.(10) Moisture sorption at different relative humidities can result in morphological

changes in the magnesium stearate.(49,50)

A specification for magnesium stearate is included in the Food Chemicals Codex (FCC). The EINECS number for magnesium stearate is 209-150-3.

Specific References

Chowhan ZT. Harmonization of excipient standards. In: Weiner ML, Kotkoskie LA, eds. Excipient Toxicity and Safety. New York: Marcel Dekker, 2000: 321–354.

Anonymous. Final report of the safety assessment of lithium stearate, aluminum distearate, aluminum stearate, aluminum tristearate, ammonium stearate, calcium stearate, magnesium stearate, potassium stearate, sodium stearate, and zinc stearate. J Am Coll Toxicol 1982; 1: 143–177.

Sondergaard D, Meyer O, Wurtzen G. Magnesium stearate given perorally to rats: a short term study. Toxicology 1980; 17: 51–55.

Boyland E, Busby ER, Dukes CE, et al. Further experiments on implantation of materials into the urinary bladder of mice. Br J Cancer 1964; 18: 575–581.

Levy G, Gumtow RH. Effect of certain formulation factors on dissolution rate of the active ingredient III: tablet lubricants. J Pharm Sci 1963; 52: 1139–1144.

Ganderton D. The effect of distribution of magnesium stearate on the penetration of a tablet by water. J Pharm Pharmacol 1969; 21 (Suppl.): 9S–18S.

Caldwell HC. Dissolution of lithium and magnesium from lithium carbonate capsules containing magnesium stearate. J Pharm Sci 1974; 63: 770–773.

Chowhan ZT, Amaro AA, Chow YP. Tablet-to-tablet dissolution variability and its relationship to the homogeneity of a water- soluble drug. Drug Dev Ind Pharm 1982; 8: 145–168.

Lerk CF, Bolhuis GK, Smallenbroek AJ, Zuurman K. Interaction of tablet disintegrants and magnesium stearate during mixing II: effect on dissolution rate. Pharm Acta Helv 1982; 57: 282–286.

Hussain MSH, York P, Timmins P. Effect of commercial and high purity magnesium stearates on in-vitro dissolution of paracetamol DC tablets. Int J Pharm 1992; 78: 203–207.

Samyn JC, Jung WY. In vitro dissolution from several experi- mental capsule formulations. J Pharm Sci 1970; 59: 169–175.

Murthy KS, Samyn JC. Effect of shear mixing on in vitro drug release of capsule formulations containing lubricants. J Pharm Sci 1977; 66: 1215–1219.

Ragnarsson G, Holzer AW, Sjogren J. The influence of mixing time and colloidal silica on the lubricating properties of magnesium stearate. Int J Pharm 1979; 3: 127–131.

Bolhuis GK, Lerk CF, Broersma P. Mixing action and evaluation of tablet lubricants in direct compression. Drug Dev Ind Pharm 1980; 6: 573–589.

Bossert J, Stamm A. Effect of mixing on the lubrication of crystalline lactose by magnesium stearate. Drug Dev Ind Pharm 1980; 6: 573–589.

Bolhuis GK, Smallenbroek AJ, Lerk CF. Interaction of tablet disintegrants and magnesium stearate during mixing I: effect on tablet disintegration. J Pharm Sci 1981; 70: 1328–1330.

Sheikh-Salem M, Fell JT. The influence of magnesium stearate on time dependent strength changes in tablets. Drug Dev Ind Pharm 1981; 7: 669–674.

Stewart PJ. Influence of magnesium stearate on the homogeneity of a prednisone granule ordered mix. Drug Dev Ind Pharm 1981; 7: 485–495.

Jarosz PJ, Parrott EL. Effect of tablet lubricants on axial and radial work of failure. Drug Dev Ind Pharm 1982; 8: 445–453.

Mitrevej KT, Augsburger LL. Adhesion of tablets in a rotary tablet press II: effects of blending time, running time, and lubricant concentration. Drug Dev Ind Pharm 1982; 8: 237–282.

Khan KA, Musikabhumma P, Rubinstein MH. The effect of mixing time of magnesium stearate on the tableting properties of dried microcrystalline cellulose. Pharm Acta Helv 1983; 58: 109–

111.

Johansson ME. Investigations of the mixing time dependence of the lubricating properties of granular and powdered magnesium stearate. Acta Pharm Suec 1985; 22: 343–350.

Johansson ME. Influence of the granulation technique and starting material properties on the lubricating effect of granular magnesium stearate. J Pharm Pharmacol 1985; 37: 681–685.

Chowhan ZT, Chi LH. Drug–excipient interactions resulting from powder mixing III: solid state properties and their effect on drug dissolution. J Pharm Sci 1986; 75: 534–541.

Chowhan ZT, Chi LH. Drug–excipient interactions resulting from powder mixing IV: role of lubricants and their effect on in vitro dissolution. J Pharm Sci 1986; 75: 542–545.

Johansson ME, Nicklasson M. Influence of mixing time, particle size and colloidal silica on the surface coverage and lubrication of magnesium stearate. In: Rubinstein MH, ed. Pharmaceutical Technology: Tableting Technology. Chichester: Ellis Horwood, 1987: 43–50.

Wang LH, Chowhan ZT. Drug–excipient interactions resulting from powder mixing V: role of sodium lauryl sulfate. Int J Pharm 1990; 60: 61–78.

Muzikova J, Horacek J. The dry binders, Vivapur 102, Vivapur 12 and the effect of magnesium stearate on the strength of tablets containing these substances. Ceske Slov Farm 2003; 52(4): 176–

180.

Muzikova J. Effect of magnesium stearate on the tensile strength of tablets made with the binder Prosolv SMCC 90. Ceska Slow Farm 2002; 51(1): 41–43.

Muller BW. The pseudo-polymorphism of magnesium stearate.

Zbl Pharm 1977; 116(12): 1261–1266.

Magnesium Stearate 433

Miller TA, York P. Physical and chemical characteristics of some high purity magnesium stearate and palmitate powders. Int J Pharm 1985; 23: 55–67.

Ertel KD, Carstensen JT. Chemical, physical, and lubricant properties of magnesium stearate. J Pharm Sci 1988; 77: 625–629.

Ertel KD, Carstensen JT. An examination of the physical properties of pure magnesium stearate. Int J Pharm 1988; 42: 171–180.

Wada Y, Matsubara T. Pseudo-polymorphism and crystalline transition of magnesium stearate. Thermochim Acta 1992; 196: 63–84.

Sharpe SA, Celik M, Newman AW, Brittain HG. Physical characterization of the polymorphic variations of magensium stearate and magnesium palmitate hydrate species. Struct Chem 1997; 8(1): 73–84.

Leinonen UI, Jalonen HU, Vihervaara PA, Laine ESU. Physical and lubrication properties of magnesium stearate. J Pharm Sci 1992; 81(12): 1194–1198.

Muller BW. Polymorphism of magnesium stearate and the influence of the crystal structure on the lubricating behavior of excipients. Acta Pharm Suec 1981; 18: 74–75.

Brittain HG. Raw materials. Drug Dev Ind Pharm 1989; 15(13): 2083–2103.

Dansereau R, Peck GE. The effect of the variability in the physical and chemical properties of magnesium stearate on the properties of compressed tablets. Drug Dev Ind Pharm 1987; 13: 975–999.

Barra J, Somma R. Influence of the physicochemical variability of magnesium stearate on its lubricant properties: possible solutions. Drug Dev Ind Pharm 1996; 22(11): 1105–1120.

Phadke DS, Collier JL. Effect of degassing temperature on the specific surface area and other physical properties of magnesium stearate. Drug Dev Ind Pharm 1994; 20(5): 853–858.

Billany MR, Richards JH. Batch variation of magnesium stearate and its effect on the dissolution rate of salicylic acid from solid dosage forms. Drug Dev Ind Pharm 1982; 8: 497–511.

Frattini C, Simioni L. Should magnesium stearate be assessed in the formulation of solid dosage forms by weight or by surface area? Drug Dev Ind Pharm 1984; 10: 1117–1130.

Bos CE, Vromans H, Lerck CF. Lubricant sensitivity in relation to bulk density for granulations based on starch or cellulose. Int J Pharm 1991; 67: 39–49.

Phadke DS, Eichorst JL. Evaluation of particle size distribution and specific surface area of magnesium stearate. Drug Dev Ind Pharm 1991; 17: 901–906.

Steffens KJ, Koglin J. The magnesium stearate problem. Manuf Chem 1993; 64(12): 16, 17, 19.



Marwaha SB, Rubinstein MH. Structure-lubricity evaluation of magnesium stearate. Int J Pharm 1988; 43(3): 249–255.

Desai DS, Rubitski BA, Varia SA, Newman AW. Physical interactions of magnesium stearate with starch-derived disinte- grants and their effects on capsule and tablet dissolution. Int J Pharm 1993; 91(2–3): 217–226.

Swaminathan V, Kildisig DO. An examination of the moisture sorption characteristics of commercial magnesium stearate. AAPS PharSciTech 2001; 2(4): 28.

Bracconi P, Andres C, Ndiaye A. Structural properties of magnesium stearate pseudopolymorphs: effect of temperature. Int J Pharm 2003; 262 (1–2): 109–124.

General References

Bohidar NR, Restaino FA, Schwartz JB. Selecting key pharmaceutical formulation factors by regression analysis. Drug Dev Ind Pharm 1979; 5: 175–216.

Butcher AE, Jones TM. Some physical characteristics of magnesium stearate. J Pharm Pharmacol 1972; 24: 1P–9P.

Ford JL, Rubinstein MH. An investigation into some pharmaceutical interactions by differential scanning calorimetry. Drug Dev Ind Pharm 1981; 7: 675–682.

Johansson ME. Granular magnesium stearate as a lubricant in tablet formulations. Int J Pharm 1984; 21: 307–315.

Jones TM. The effect of glidant addition on the flowability of bulk particulate solids. J Soc Cosmet Chem 1970; 21: 483–500.

Pilpel N. Metal stearates in pharmaceuticals and cosmetics. Manuf Chem Aerosol News 1971; 42(10): 37–40.

York P. Tablet lubricants. In: Florence AT, ed. Materials Used in Pharmaceutical Formulation. London: Society of Chemical Industry 1984: 37–70.

Zanowiak P. Lubrication in solid dosage form design and manufacture. In: Swarbick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, vol. 9. New York: Marcel Dekker, 1990: 87–112.

Authors

LV Allen, PE Luner.

Date of Revision

9 August 2005.

Magnesium Trisilicate

Nonproprietary Names

BP: Magnesium trisilicate PhEur: Magnesii trisilicas USP: Magnesium trisilicate

Synonyms

E553(a); magnesium mesotrisilicate; silicic acid, magnesium salt (1 : 2), hydrate.

Chemical Name and CAS Registry Number

Magnesium trisilicate [14987-04-3]

Empirical Formula and Molecular Weight

Mg2Si3O8·xH2O 260.86 (anhydrous)

Structural Formula

2MgO·3SiO2·xH2O

Functional Category

Anticaking agent; glidant; therapeutic agent.

Applications in Pharmaceutical Formulation or Technology

Magnesium trisilicate is used in oral pharmaceutical formula- tions and food products as a glidant. It is also used therapeutically as an antacid, and also for the treatment of ciprofloxacin overdose or toxicity.(1)

Description

The USP 28 describes magnesium trisilicate as a compound of magnesium oxide and silicon dioxide with varying proportions of water. It contains not less than 20% of magnesium oxide and not less than 45% of silicon dioxide. The PhEur 2005 similarly describes magnesium trisilicate as having a variable composi- tion corresponding to the approximate formula Mg2Si3O8·xH2O. It contains not less than 29% of magnesium oxide and not less than the equivalent of 65% of silicon dioxide, both calculated with reference to the ignited substance. Magnesium trisilicate 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 trisilicate.

 

Test PhEur 2005 USP 28    

Identification + +    

Ratio of SiO2 to MgO — 2.10–2.37    

Loss on ignition 17.0–34.0% 17.0–34.0%    

Water-soluble salts 41.5% 41.5%    

Chloride 4500 ppm 40.055%    

Sulfates 40.5% 40.5%    

Alkalinity + +    

Arsenic 44 ppm 48 ppm    

Heavy metals 440 ppm 40.003%    

Acid-absorbing capacity 4100.0 mL 140–160 mL    

Assay of MgO 529.0%(a) 520.0%    

Assay of SiO2 565.0%(a) 545.0%    

(a) With reference to the ignited substance.  

Typical Properties

Moisture content: magnesium trisilicate is slightly hygroscopic. At relative humidities of 15–65%, the equilibrium moisture content at 258C is 17–23% w/w; at relative humidities of 75–95%, the equilibrium moisture content is 24–30% w/w. Solubility: practically insoluble in diethyl ether, ethanol (95%)

and water.

Stability and Storage Conditions

Magnesium trisilicate is stable if stored in a well-closed container in a cool, dry place.

Incompatibilities

Magnesium trisilicate, when taken with drugs such as mebeverine hydrochloride,(2) proguanil,(3) norfloxacin,(4) sucralfate, and tetracycline, may cause a reduction in bioavail- ability via binding or chelation. The dissolution rate of folic acid,(5) erythromycin stearate,(6) paracetamol, and chloroquine phosphate(7) may be retarded by adsorption onto magnesium trisilicate. Antimicrobial preservatives, such as the parabens, may be inactivated by the addition of magnesium trisilicate.(8)

Magnesium trisilicate is also readily decomposed by mineral acids.

Method of Manufacture

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

Safety

Magnesium trisilicate is used in oral pharmaceutical formula- tions and is generally regarded as an essentially nontoxic and nonirritant material.

When administered orally, magnesium trisilicate is neutra- lized in the stomach to form magnesium chloride and silicon

Magnesium Trisilicate 435

dioxide; some magnesium may be absorbed. Caution should be used when concentrations greater than 50 mEq of magnesium are given daily to persons with impaired renal function, owing to the risk of hypermagnesemia.

Therapeutically, up to about 2 g of magnesium trisilicate may be taken daily as an antacid.

Reported adverse effects include the potential for osmotic diarrhea in the elderly using antacids containing magnesium trisilicate;(9) and the potential for the formation of bladder and renal calculi following the long-term use of magnesium trisilicate as an antacid.(10,11)

Handling Precautions

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

Regulatory Status

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

Related Substances

Calcium silicate; magnesium aluminum silicate; magnesium silicate; magnesium trisilicate anhydrous; talc.

Calcium silicate

Appearance: white to off-white-colored, free-flowing powder that remains free-flowing after absorbing relatively large amounts of water or other liquids.

Solubility: practically insoluble in water. Forms a gel with mineral acids.

Handling precautions: in the UK, the long-term (8-hour TWA) occupational exposure standards for calcium silicate are 10 mg/m3 for total inhalable dust and 4 mg/m3 for respirable dust.(12)

Comments: many different forms of calcium silicate are known such as CaSiO3, Ca2SiO4, and Ca3SiO5. Usually these occur in the hydrated form and contain varying amounts of water of crystallization. Calcium silicate is used in pharmaceutical formulations as a glidant and anticaking agent.(13) Also used in food products (GRAS listed). The EINECS number for calcium silicate is 215-710-8.

Magnesium trisilicate anhydrous Empirical formula: Mg2Si3O8 Molecular weight: 260.86

CAS number: [14987-04-3]



Comments

Magnesium trisilicate is regarded as a type of magnesium silicate. The EU food additive code E553(a) has been applied to both. The EINECS number for magnesium trisilicate is 239- 076-7.

Specific References

Ofoefule SI, Okonta M. Adsorption studies of ciprofloxacin: evaluation of magnesium trisilicate, kaolin and starch as alter- natives for the management of ciprofloxacin poisoning. Boll Chim Farm 1999; 138: 239–242.

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

Onyeji CO, Babalola CP. The effect of magnesium trisilicate on proguanil absorption. Int J Pharm 1993; 100: 249–252.

Okhamafe AO, Akerele JO, Chukuka CS. Pharmacokinetic interactions of norfloxacin with some metallic medicinal agents. Int J Pharm 1991; 68: 11–18.

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(8): 655–658.

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

Ratnaike RN, Jones TE. Mechanisms of drug-induced diarrhoea in the elderly. Drugs & Aging 1998; 13: 245–253.

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.

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

Asano T, Tsubuku S, Sugawara S, et al. Changes in volume and compression energy upon compression of calcium silicate tablets. Drug Dev Ind Pharm 1997; 23: 679–685.

General References

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

Authors

AS Kearney.

Date of Revision

19 August 2005.

Malic Acid

Nonproprietary Names

PhEur: Acidum malicum USPNF: Malic acid

Synonyms

Apple acid; E296; 2-hydroxy-1,4-butanedioic acid; hydroxy- butanedioic acid; 1-hydroxy-1,2-ethanedicarboxylic acid; hydroxysuccinic acid; 2-hydroxysuccinic acid; DL-malic acid.

Chemical Name and CAS Registry Number

Hydroxybutanedioic acid [6915-15-7]

(RS)-( )-Hydroxybutanedioic acid [617-48-1]

Empirical Formula and Molecular Weight

C4H6O5 134.09

Structural Formula

 

Functional Category

Acidulant; antioxidant; chelating and buffering agent; flavoring agent; therapeutic agent.

Applications in Pharmaceutical Formulation or Technology

Malic acid is used in pharmaceutical formulations as a general- purpose acidulant. It possesses a slight apple flavor and is used as a flavoring agent to mask bitter tastes and provide tartness. Malic acid is also used as an alternative to citric acid in effervescent powders, mouthwashes, and tooth-cleaning tablets.

In addition, malic acid has chelating and antioxidant properties. It may be used with butylated hydroxytoluene as a synergist in order to retard oxidation in vegetable oils. In food products it may be used in concentrations up to 420 ppm.

Therapeutically, malic acid has been used topically in combination with benzoic acid and salicylic acid to treat burns, ulcers, and wounds. It has also been used orally and parenterally, either intravenously or intramuscularly, in the treatment of liver disorders, and as a sialagogue.(1)

Description

White or nearly white, crystalline powder or granules having a slight odor and a strongly acidic taste. It is hygroscopic. The synthetic material produced commercially in Europe and the USA is a racemic mixture, whereas the naturally occurring

material found in apples and many other fruits and plants is levorotatory.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for malic acid.

Test PhEur 2005 USPNF 23

Identification + +

Characters + —

Residue on ignition 40.1% 40.1%

Appearance of solution + — Water-insoluble substances 40.1% 40.1%

Heavy metals 420 ppm 40.002%

Fumaric acid — 40.1%

Maleic acid — 40.05%

Optical rotation –0.18 to +0.18 — Organic volatile impurities — +

Related substances + —

Water 42.0% —

Assay 99.0–101.0% 99.0–100.5%