Macrogol 15 Hydroxystearate

 Nonproprietary Names

BP: Macrogol 15 hydroxystearate PhEur: Macrogoli 15 hydroxystearas

Synonyms

12-Hydroxyoctadecanoic acid polymer with a-hydro-o-hydr- oxypoly(oxy-1,2-ethanediyl);  polyethylene  glycol 660 12-hydroxystearate; Solutol HS 15.

Chemical Name and CAS Registry Number

Polyethylene glycol-15-hydroxystearate [70142-34-6]

Empirical Formula and Molecular Weight

The PhEur 2005 describes macrogol 15 hydroxystearate as a mixture of mainly monoesters and diesters of 12-hydroxystea- ric acid and macrogols obtained by the ethoxylation of 12- hydroxystearic acid. The number of moles of ethylene oxide reacted per mole of 12-hydroxystearic acid is 15 (nominal value). It contains about 30% free macrogols.

Structural Formula

See Section 4.

Functional Category

Dissolution enhancer; nonionic surfactant; solubilizing agent.

Applications in Pharmaceutical Formulation or Technology

Macrogol 15 hydroxystearate is frequently used in preclinical testing of drugs, mainly for IV and other parenteral applica- tions.(1–4) The solubilizing capacity for some tested drugs (clotrimazole, carbamazepine, 17b-estradiol, sulfathiazole, and piroxicam) increases almost linearly with increasing concentra- tion of solubilizing agent; see Figure 1. This is due to the formation of spherical micelles even at high concentrations of macrogol 15 hydroxystearate. Similarly, tests have revealed that viscosity increases with increasing amount of solubilizer, but the amount of solubilized drugs does not have any additional influence on the kinematic viscosity; see Figure 2. Lipid nanocapsules comprising macrogol 15 hydroxystearate and soybean phosphatidylcholine containing 3% docetaxel have been successfully prepared by a solvent-free inversion process.

Description

Macrogol 15 hydroxystearate is a yellowish-white waxy mass at room temperature, which becomes liquid at approximately 308C.

Figure 1: Solubilizing capacity of macrogol 15 hydroxystearate (Solutol HS 15, BASF Plc).

^: Solutol HS 15 with clotrimazole

□: Solutol HS 15 with 17b-estradiol

~: Polysorbate 80 with clotrimazole

Q: Polysorbate 80 with 17b-estradiol

 

Figure 2: Kinematic viscosity of macrogol 15 hydroxystearate (Solutol HS 15, BASF Plc).

^: Solutol HS 15

□: Solutol HS 15 with clotrimazole

~: Polysorbate 80

Q: Polysorbate 80 with clotrimazole

Pharmacopeial Specifications

See Table I.

Typical Properties

Acidity/alkalinity: pH = 6–7 (10% w/v aqueous solution at 208C)

Critical micelle concentration: 0.005–0.02%

Density: 1.03 g/cm3 Flash point: 2728C HLB value: 14–16

Ignition temperature: 3608C

Macrogol 15 Hydroxystearate 417

Table I: Pharmacopeial specifications for macrogol 15 hydroxystearate.

 

Test PhEur 2005    

Identification +    

Characters +    

Solution appearance +    

Acid value 41.0    

Hydroxyl value 90–110    

Iodine value 42.0    

Peroxide value 45.0    

Saponification value 53–63    

Free macrogols 27.0–39.0%    

Ethylene oxide 41 ppm    

Dioxane 450 ppm    

Nickel 41 ppm    

Water 41%    

Total ash 40.3%  

Solidification temperature: 25–308C

Solubility: soluble in ethanol, propan-2-ol, and water to form clear solutions. The solubility in water decreases with increasing temperature. It is insoluble in liquid paraffin.

Viscosity (dynamic): 12 mPa s (12 cP) for a 30% w/v aqueous solution at 258C; 73 mPa s (73 cP) for a 30% w/v aqueous solution at 608C.

Stability and Storage Conditions

Macrogol 15 hydroxystearate has a high chemical stability. The prolonged action of heat may induce physical separation into a liquid and a solid phase after cooling, which can be reversed by subsequent homogenization. Macrogol 15 hydroxystearate is stable for at least 24 months if stored in unopened airtight containers at room temperature (maximum 258C). Aqueous solutions of macrogol 15 hydroxystearate can be heat-sterilized (1218C, 2.1 bar). The pH may drop slightly during heating, which should be taken into account. Separation into phases may also occur, but agitating the hot solution can reverse this. Aqueous solutions can be stabilized with the standard preservatives used in pharmaceuticals.

Incompatibilities

—

Method of Manufacture

Macrogol 15 hydroxystearate is produced by reacting 15 moles of ethylene oxide with 1 mole of 12-hydroxystearic acid.

Safety

Macrogol 15 hydroxystearate is used in parenteral pharma- ceutical preparations in concentrations up to 50% to solubilize diclofenac, propanidid, and vitamin K1. It has also been used in preclinical formulations in preparing supersaturated injectable formulations of water-insoluble molecules. It is generally regarded as a relatively nontoxic and nonirritant excipient.

Macrogol 15 hydroxystearate is reported to not be mutagenic in bacteria, mammalian cell cultures and mammals.

LD50 (rat, oral): >20 g/kg(5)



Handling Precautions

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

Regulatory Status

—

Related Substances

Polyethylene glycol.

Comments

Macrogol 15 hydroxystearate is not restricted solely to parenteral use, but is also suitable for oral applications.

Specific References

von Corswant C, Thoren P, Engstro¨ m S. Triglyceride-based microemulsion for intravenous administration of sparingly soluble substances. J Pharm Sci 1998; 87: 200–208.

Buszello K, Harnisch S, Mu¨ ller RH, Mu¨ ller BW. The influence of alkali fatty acids on the properties and the stability of parenteral O/W emulsions modified with Solutol HS 15. Eur J Pharm Biopharm 2000; 49: 143–149.

Bittner B, Mountfield RJ. Formulations and related activities for the oral administration of poorly water-soluble compounds in early discovery animal studies. Pharm Ind 2002; 64: 800.

Strickley R. Solubilizing excipients in oral and injectable formula- tions. Pharm Res 2004; 21: 201–230.

BASF. Solutol HS 15. http://www.pharma-solutions.basf.com/ (50jqle450ewrum55koxl2kmy)/products.aspx?GrpID=60 (accessed 18 May 2005).

General References

Coon JS, Clodfeller K, Buckingham L, Bines S. Reversal of VP-16 resistance by Solutol HS 15. Proc Am Assoc Cancer Res 1993; 34: 323.

Coon JS, Knudson W, Clodfelter K, et al. Solutol HS 15, nontoxic polyoxyethylene esters of 12-hydroxystearic acid, reverses multi- drug resistance. Cancer Res 1991; 51(3): 897–902.

Fro¨ mming K-H, Kraus C, Mehnert W. Physico-chemical properties of the mixed micellar system of Solutol HS 15 and sodium deoxycholate. Acta Pharm Technol 1990; 36: 214–220.

Lorenz W, Schmal A, Schult H, et al. Histamine release and hypotensive reactions in dogs by solubilizing agents and fatty acids: analysis of various components in Cremophor EL and development of a compound with reduced toxicity. Agents Actions 1982; 12: 64–80.

Smith DB, Ewen C, Mackintosh J, et al. A phase I and pharmacokinetic study of amphethinile. Br J Cancer 1988; 57: 623–627.

Woodburn K, Sykes E, Kessel D. Interactions of Solutol HS 15 and Cremophor EL with plasma lipoproteins. Int J Biochem Cell Biol 1995; 27: 693–699.

Authors

J-P Mittwollen, T Schmeller.

Date of Revision

25 May 2005.

Magnesium Aluminum Silicate

Nonproprietary Names

BP: Aluminium magnesium silicate PhEur: Aluminii magnesii silicas USPNF: Magnesium aluminum silicate

Synonyms

Aluminosilicic acid, magnesium salt; aluminum magnesium silicate; Carrisorb; Gelsorb; Magnabite; magnesium alumino- silicate; magnesium aluminum silicate, colloidal; magnesium aluminum silicate, complex colloidal; Neusilin; Pharmsorb; silicic acid, aluminum magnesium salt; Veegum.

Chemical Name and CAS Registry Number

Aluminum magnesium silicate [12511-31-8] Magnesium aluminum silicate [1327-43-1]

Empirical Formula and Molecular Weight

Magnesium aluminum silicate is a polymeric complex of magnesium, aluminum, silicon, oxygen, and water. The average chemical analysis is conventionally expressed as oxides:

 

Silicon dioxide 61.1%    

Magnesium oxide 13.7%    

Aluminum oxide 9.3%    

Titanium dioxide 0.1%    

Ferric oxide 0.9%    

Calcium oxide 2.7%    

Sodium oxide 2.9%    

Potassium oxide 0.3%    

Carbon dioxide 1.8%    

Water of combination 7.2%  

Structural Formula

The complex is composed of a three-lattice layer of octahedral alumina and two tetrahedral silica sheets. The aluminum is substituted to varying degrees by magnesium (with sodium or potassium for balance of electrical charge). Additional elements present in small amounts include iron, lithium, titanium, calcium, and carbon.

Functional Category

Gum. In tablets, magnesium aluminum silicate is used as a binder and disintegrant in conventional or slow-release formulations.(4,5) See Table I.

Magnesium aluminum silicate may cause bioavailability problems with certain drugs, see Section 12.

Table I: Uses of magnesium aluminum silicate.

Use Concentration (%)

Adsorbent 10–50

Binding agent 2–10

Disintegrating agent 2–10

Emulsion stabilizer (oral) 1–5

Emulsion stabilizer (topical) 2–5

Suspending agent (oral) 0.5–2.5

Suspending agent (topical) 1–10

Stabilizing agent 0.5–2.5

Viscosity modifier 2–10

8  Description

The USPNF 23 describes magnesium aluminum silicate as a blend of colloidal montmorillonite and saponite that has been processed to remove grit and nonswellable ore components. Four types of magnesium aluminum silicate are defined: types IA, IB, IC, and IIA. These types differ according to their viscosity and ratio of aluminum and magnesium content, see Table II.

The PhEur 2005 describes magnesium aluminum silicate (aluminium magnesium silicate) as a mixture of particles with colloidal particle size of montmorillonite and saponite, free from grit and nonswellable ore.

Magnesium aluminum silicate occurs as off-white to creamy white, odorless, tasteless, soft, slippery small flakes, or as a fine, micronized powder. Flakes vary in shape and size from about

0.3 × 0.4 mm to 1.0 × 2.0 mm and about 25–240 mm thick. Many flakes are perforated by scattered circular holes 20–120 mm in diameter. Under dark-field polarized light, innumerable bright specks are observed scattered over the flakes. The powder varies from 45 to 297 mm in size.

Table II: Magnesium aluminum silicate types defined in the USPNF 23.

Adsorbent; stabilizing agent; suspending agent; tablet and capsule disintegrant; tablet binder; viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology

Magnesium aluminum silicate has been used for many years in the formulation of tablets, ointments, and creams. It is used in oral and topical formulations as a suspending and stabilizing agent either alone or in combination with other suspending agents.(1–3) The viscosity of aqueous dispersions may be greatly increased by combination with other suspending agents, such as xanthan gum, owing to synergistic effects, see Xanthan

Type Viscosity

(mPa s)

Pharmacopeial Specifications

See Table III.

Al content/ Mg content

Table III: Pharmacopeial specifications for magnesium aluminum silicate.

 

Test PhEur 2005 USPNF 23    

Identification + +    

Characters + —    

Viscosity (5% w/v suspension) — See Table II    

Microbial limits 4103/g 4103/g    

pH (5% w/v suspension) 9.0–10.0 9.0–10.0    

Acid demand — +    

Loss on drying 48.0% 48.0%    

Arsenic 43 ppm 43 ppm    

Lead 415 ppm 40.0015%    

Assay for Al and Mg content 95.0–105.0 +  

Typical Properties

Acid demand: 6–8 mL of 0.1 N HCl is required to reduce the pH of 1 g to pH 4.

Density: 2.418 g/cm3

Moisture content: 6.0–9.98%.(6) See also Figures 1, 2 and 3.(6)

Particle size distribution: see Section 8.

Solubility: practically insoluble in alcohols, water, and organic solvents.

Swelling capacity: swelling properties are reversible. Magne- sium aluminum silicate swells to many times its original volume in water to form colloidal dispersions and may be dried and rehydrated any number of times.

Viscosity (dynamic): dispersions in water at the 1–2% w/v level are thin colloidal suspensions. At 3% w/v and above, dispersions are opaque. As the concentration is increased above 3% w/v, the viscosity of aqueous dispersions increases rapidly; at 4–5% w/v, dispersions are thick, white colloidal sols, while at 10% w/v firm gels are formed. Dispersions are thixotropic at concentrations greater than 3% w/v. The viscosity of the suspension increases with heating or addition of electrolytes, and at higher concentrations with aging.

 

Figure 1: Equilibrium moisture content of magnesium aluminum silicate (Veegum HV ).

Magnesium Aluminum Silicate 419

 

Figure 2: Sorption–desorption isotherm of magnesium aluminum silicate (Pharmasorb).

 

Figure 3: Sorption–desorption isotherm of magnesium aluminum silicate (Pharmasorb colloidal).

Stability and Storage Conditions

Magnesium aluminum silicate is stable indefinitely when stored under dry conditions. It is stable over a wide pH range, has base-exchange capacity, absorbs some organic substances, and is compatible with organic solvents.

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

420 Magnesium Aluminum Silicate

SEM: 1

Excipient: magnesium aluminum silicate (Veegum)

Manufacturer: RT Vanderbilt Co., Inc.

Lot No.: 61A-1

Magnification: 600×

Voltage: 10 kV

 

SEM: 2

Excipient: magnesium aluminum silicate (Veegum)

Manufacturer: RT Vanderbilt Co., Inc.

Lot No.: 61A-1

Magnification: 2400×

Voltage: 10 kV

SEM: 3

Excipient: magnesium aluminum silicate (Veegum F) Manufacturer: RT Vanderbilt Co., Inc.

Lot No: 61A-2

Magnification: 600×

Voltage: 10 kV

 

SEM: 4

Excipient: magnesium aluminum silicate (Veegum F) Manufacturer: RT Vanderbilt Co., Inc.

Lot No.: 61A-2

Magnification: 2400×

Voltage: 10 kV

   

Magnesium Aluminum Silicate 421

Incompatibilities

Owing to its inert nature, magnesium aluminum silicate has few incompatibilities but is generally unsuitable for acidic solutions below pH 3.5. Magnesium aluminum silicate, as with other clays, may adsorb some drugs.(7,8) This can result in low bioavailability if the drug is tightly bound or slowly desorbed, e.g., amfetamine sulfate,(4) tolbutamide,(9) warfarin sodium,(10) and diazepam.(11)

Method of Manufacture

Magnesium aluminum silicate is obtained from silicate ores of the montmorillonite group, which show high magnesium content. The ore is blended with water to form a slurry to remove impurities and separate out the colloidal fraction. The refined colloidal dispersion is drum-dried to form a small flake, which is then micro-atomized to form various powder grades.

Safety

Magnesium aluminum silicate is generally regarded as nontoxic and nonirritating at the levels employed as a pharmaceutical excipient. Subacute animal feeding studies in rats and dogs fed magnesium aluminum silicate at 10% of the diet, for 90 days, were negative, including autopsy and histopathological exam- inations.(12)

LD50 (rat, oral): > 16 g/kg(13)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended. Adequate ventilation should be provided and dust generation minimized.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (oral granules, solutions, suspensions and tablets; rectal; and topical prepara- tions; vaginal preparations). Included in nonparenteral medi- cines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Attapulgite; bentonite; kaolin; magnesium silicate; magnesium trisilicate; montmorillonite; saponite; talc.

Montmorillonite

Empirical formula: Al2O5·4SiO2·4H2O

CAS number: [1318-93-0]

Comments: a naturally occurring silicate clay.

Comments

The EINECS number for magnesium aluminum silicate is 215- 478-8.



Specific References

Polon JA. The mechanisms of thickening by inorganic agents. J Soc Cosmet Chem 1970; 21: 347–363.

Farley CA, Lund W. Suspending agents for extemporaneous dispensing: evaluation of alternatives to tragacanth. Pharm J 1976; 216: 562–566.

Attama AA, Chuku AJ, Muko KN, Adikwu MU. Effect of Veegum on the suspending properties of Mucuna gum. Boll Chem Farm 1997; 136: 549–553.

McGinity JW, Lach JL. Sustained-release applications of mon- tmorillonite interaction with amphetamine sulfate. J Pharm Sci 1977; 66: 63–66.

McGinity JW, Harris MR. Optimization of slow-release tablet formulations containing montmorillonite I: properties of tablets. Drug Dev Ind Pharm 1980; 6: 399–410.

Grab FL, Johnson JH, Monaco AL, Winfield AJ. Magnesium aluminum silicate. In: Handbook of Pharmaceutical Excipients. Washington, DC and London: American Pharmaceutical Associa- tion and The Pharmaceutical Society of Great Britain, 1986: 166– 169.

McGinity JW, Lach JL. In vitro adsorption of various pharma- ceuticals to montmorillonite. J Pharm Sci 1976; 65: 896–902.

McGinity JW, Harris MR. Increasing dissolution rates of poorly- soluble drugs by adsorption to montmorillonite. Drug Dev Ind Pharm 1980; 6: 35–48.

Varley AB. The generic inequivalence of drugs. J Am Med Assoc

1968; 206: 1745–1748.

Wagner JG, Welling PG, Lee KP, Walker JE. In vivo and in vitro availability of commercial warfarin tablets. J Pharm Sci 1971; 60: 666–677.

Munzel K. The desorption of medicinal substances from adsor- bents in oral pharmaceutical suspensions. Acta Pharmacol Toxicol 1971; 29 (Suppl. 3): 81–87.

Sakai K, Moriguchi K. Effect of magnesium aluminosilicate administered to pregnant mice on pre- and postnatal development of offsprings. Oyo Yakri 1975; 9: 703.

Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. Cincinnati: US Department of Health, 1987.

General References

RT Vanderbilt Co., Inc. Technical literature: Veegum, the versatile ingredient for pharmaceutical formulations, 1992.

Wai K, DeKay HG, Banker GS. Applications of the montmorillonites in tablet making. J Pharm Sci 1966; 55: 1244–1248.

Yokoi H, Enomoto S, Takahashi H. Effect of magnesium aluminosi- licate on fluidity of pharmaceutical powders [in Japanese]. J Pharm Soc Jpn 1978; 98: 418–425.

Authors

A Palmieri.

Date of Revision

8 August 2005.

Magnesium Carbonate

Nonproprietary Names

BP: Heavy magnesium carbonate Light magnesium carbonate

JP: Magnesium carbonate

PhEur: Magnesii subcarbonas ponderosus Magnesii subcarbonas levis

USP: Magnesium carbonate

Synonyms

Carbonic acid, magnesium salt (1:1); carbonate magnesium; hydromagnesite; E504. See Sections 4 and 17.

Chemical Name and CAS Registry Number

Magnesium carbonate anhydrous [546-93-0]

See also Sections 4 and 17.

Empirical Formula and Molecular Weight

Magnesium carbonate is not a homogeneous material but may consist of the normal hydrate, the basic hydrate, and the anhydrous material MgCO3, which is rarely encountered. Basic magnesium carbonate is probably the most common form, and may vary in formula between light magnesium carbonate, (MgCO3)3·Mg(OH)2·3H2O, and magnesium carbonate hydro- xide, (MgCO3)4·Mg(OH)2·5H2O. Normal magnesium carbo- nate is a hydrous magnesium carbonate with a varying amount of water, MgCO3·xH2O.

See also Sections 8, 13 and 17.

Structural Formula

See Section 4.

Functional Category

Adsorbent; antacid; tablet and capsule diluent.

Applications in Pharmaceutical Formulation or Technology

As an excipient, magnesium carbonate is mainly used as a directly compressible tablet diluent in concentrations up to 45% w/w. Heavy magnesium carbonate produces tablets with high crushing strength, low friability, and good disintegration properties.(1–4) However, magnesium carbonate can have varying effects on dissolution and stability.(5,6) See also Section

12. Magnesium carbonate has been incorporated in micro- sphere formulations for the purpose of stabilizing encapsulated proteins.(7) Magnesium carbonate is also used to absorb liquids, such as flavors, in tableting processes.

Magnesium carbonate is additionally used as a food additive and therapeutically as an antacid.

See Table I.

Table I: Uses of magnesium carbonate.

Use Concentration (%)

Absorbent of liquid, in tableting 0.5–1.0

Tablet excipient (direct compression) 445

Description

Magnesium carbonate occurs as light, white-colored friable masses or as a bulky, white-colored powder. It has a slightly earthy taste and is odorless but, since it has a high absorptive ability, magnesium carbonate can absorb odors.

The USP 28 describes magnesium carbonate as either a basic hydrated magnesium carbonate or a normal hydrated mag- nesium carbonate. However, the PhEur 2005 describes magnesium carbonate as being a hydrated basic magnesium carbonate in two separate monographs: heavy magnesium carbonate and light magnesium carbonate. The molecular formulas for heavy magnesium carbonate and light magnesium carbonate vary, but heavy magnesium carbonate may generally be regarded as the tetrahydrate [(MgCO3)3·Mg(OH)2·4H2O], while light magnesium carbonate may be regarded as the trihydrate [(MgCO3)3·Mg(OH)2·3H2O].

The molecular weights of the heavy and light forms of magnesium carbonate are 383.32 and 365.30, respectively.

SEM: 1

Excipient: Magnesium carbonate USP Manufacturer: Mallinckrodt Chemicals Co. Lot No.: KJGJ

Magnification: 60×

Voltage: 20 kV

 

Magnesium Carbonate 423

SEM: 2

Excipient: Magnesium carbonate USP Manufacturer: Mallinckrodt Chemicals Co. Lot No.: KJGJ

Magnification: 600×

Voltage: 20 kV

 

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for magnesium carbonate.

 

Test JP 2001 PhEur 2005 USP 28    

Identification + + +    

Characters — + —    

Microbial limits — — +    

Color of solution — + —    

Soluble salts 410.0 mg 41.0% 41.0%    

Acid-insoluble

substances 42.5 mg 40.05% 40.05%    

Arsenic 45 ppm 42 ppm 44 ppm    

Calcium 40.6% 40.75% 40.45%    

Heavy metals 430 ppm 420 ppm 40.003%    

Iron 4200 ppm 4400 ppm 40.02%    

Chloride — 40.07% —    

Assay (as MgO) 40.0—44.0% 40.0–45.0% 40.0–43.5%  

Note that except where indicated all of the PhEur 2005 test limits apply to both the heavy and light forms of magnesium carbonate.

Typical Properties

Angle of repose:

42–508 for granular heavy magnesium carbonate; 56–608 for spray-dried heavy magnesium carbonate.(3)

Density (bulk):

Heavy magnesium carbonate: 0.207–0.56 g/cm3;(8) Light magnesium carbonate: ≈0.12 g/cm3.

Density (tapped):

Heavy magnesium carbonate: 0.314–0.783 g/cm3;(8) Light magnesium carbonate: ≈0.21 g/cm3.



Density  (true):  Heavy  magnesium  carbonate: 1.966–2.261 g/cm3(8)

Moisture content: at relative humidities between 15% and 65% the equilibrium moisture content of heavy magnesium carbonate at 258C is about 1% w/w; at relative humidities above 75% the equilibrium moisture content at 258C is about 5% w/w.(3)

Particle size distribution:

Heavy magnesium carbonate: 7–43 mm median particle size(8)

Light magnesium carbonate: 99.95% through a 44.5 mm (#350 mesh) sieve for light magnesium carbonate.

Solubility: practically insoluble in water but soluble in water containing carbon dioxide. Insoluble in ethanol (95%) and other solvents. Magnesium carbonate dissolves and effer- vesces on contact with dilute acids.

Specific surface area:

7.8–18.2 m2/g for granular heavy magnesium carbonate;

4.4–15.5 m2/g for spray-dried heavy magnesium carbo- nate;(3)

14.64–14.78 m2/g for basic heavy magnesium carbonate.