kywods

Isomalt is produced from food-grade sucrose in a two-stage process. Beet sugar is converted by enzymatic transglucosida- tion into the reducing disaccharide isomaltulose. This under- goes catalytical hydrogenation to produce isomalt.

Safety

Isomalt is used in oral pharmaceutical formulations, confec- tionery, and food products. It is generally regarded as a nontoxic, nonallergenic, and nonirritant material.

Toxicological and metabolic studies on isomalt(5–10) have been summarized in a WHO report prepared by the FAO/ WHO Expert Committee (JECFA), resulting in an acceptable daily intake of ‘not specified’.(11)

The glycosidic linkage between the mannitol or sorbitol moiety and the glucose moiety is very stable, limiting the hydrolysis and absorption of isomalt in the small intestine. There is no significant increase in the blood glucose level after oral intake, and glycemic response is very low, making isomalt suitable for diabetics. The majority of isomalt is fermented in the large intestine. In general, isomalt is tolerated very well, although excessive consumption may result in laxative effects.(12–14)

Isomalt is not fermented by bacteria present in the mouth, therefore no significant amount of organic acid is produced that attacks tooth enamel.(15–17)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection, gloves, and a dust mask or respirator are recommended.

Regulatory Status

GRAS listed. Accepted as a food additive in Europe.

Related Substances

—

Comments

Compression of isomalt without lubrication is difficult, and problems such as die wall sticking, capping, and lamination have been observed. The addition of a lubricant such as magnesium stearate will reduce die wall adhesion. Co-extrusion of isomalt with paracetamol (acetaminophen) significantly improved the tableting properties of the mixtures, compared to physical mixtures of drug and isomalt.(18) Direct molding is also a potentially suitable technique for producing isomalt- based tablets.(18)

It is anticipated that a specification for isomalt will soon be included in the USPNF.(19)

A variety of different grades of isomalt are commercially available that have different applications, e.g. GalenIQ 720 and 721 are used in direct compression, GalenIQ 810 is used in wet granulation, GalenIQ 981 is used in coatings, and GalenIQ 990 is used in boilings.

Specific References

Ndindayino F, Henrist D, Kiekens F, et al. Characterization and evaluation of isomalt performance in direct compression. Int J Pharm 1999; 189: 113–124.

Palatinit GmbH. Technical literature: Isomalt, GalenIQ, 2005.

Cerestar. Technical literature: IsoMaltidex, 2002.

Schiweck H. Palatinit—Production, technological characteristics and analytical study of foods containing Palatinit. Alimenta 1980;

(19): 5–16.

Livesey G. The energy values of dietary fibre and sugar alcohols for man. Nutr Res Rev 1992; (5): 61–84.

Waalkens-Berendsen DH, Koeter HB, van Marwijk MW. Embry- otoxicity/teratogenicity of isomalt in rats and rabbits. Food Chem Toxicol 1990; 28(1): 1–9.

Smits-Van Prooije AE, De Groot AP, Dreef-Van Der Meullen HC, Sinkeldam EJ. Chronic toxicity and carcinogenicity study of isomalt in rats and mice. Food Chem Toxicol 1990; 28(4): 243– 251.

Waalkens-Berendsen DH, Koeter HB, Sinkeldam EJ. Multigenera- tion reproduction study of isomalt in rats. Food Chem Toxicol 1990; 28(1): 11–19.

Waalkens-Berendsen DH, Koeter HB, Schlu¨ ter G, Renhof M. Developmental toxicity of isomalt in rats. Food Chem Toxicol 1989; 27(10): 631–637.

Pometta D, Trabichet D, Spengler M. Effects of a 12 week administration of isomalt on metabolic control in type-II-diabetics. Akt Erna¨ hrung 1985; 10: 174–177.

FAO/WHO. Toxicological evaluation of certain food additives and contaminants. Twentieth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1987; No. 539.

Livesey G. Tolerance of low-digestible carbohydrates: a general view. Br J Nutr 2001; 85: S1, S7–S16.

Paige DM, Bayless TM, Davis LR. Palatinit digestibility in children. Nutr Res 1992; 12: 27–37.

Storey DM, Lee A, Zumbe A. The comparative gastrointestinal response of young children to the ingestion of 25 g sweets containing sucrose or isomalt. Br J Nutr 2002; 87(4): 291–297.

Featherstone DB. Effect of isomalt sweetener on the caries process: A review. J Clin Dent 1995; 5: 82–85.

Van de Hoeven JS. Influence of disaccharide alcohols on the oral microflora. Caries Res 1979; 13: 301–306.

Gehring F, Karle EJ. The sugar substitute Palatinit with special emphasis on microbial and caries-preventing aspects. Z Erna¨ rung 1981; 20: 96–106.

Ndindayino F, Vervaet C, Van den Mooter G, Remon JP. Direct compression and moulding properties of co-extruded isomalt/drug mixtures. Int J Pharm 2002; 235: 159–168.

Isomalt. Pharmacopeial Forum 2005; 31(1): 89–92.

General References

Bauer KH, Lehmann K, Osterwald HP, Rothgang G. Coated Pharmaceutical Dosage Forms: Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials. Stuttgart: Medpharm Scientific Publications, 1998: 280.

Do¨ rr T, Willibald-Ettle I. Evaluation of the kinetics of dissolution of tablets and lozenges consisting of saccharides and sugar substitutes. Pharm Ind 1996; 58: 947–952.

Fritzsching B, Schmidt T. A survey of isomalt as a sugarfree excipient for nutraceuticals. Pharmaceutical Manufacturing and Packing Sourcer 2000(Sept); 70–72.

Iida K, Leuenberger H, Fueg LM, et al. Effect of mixing of fine carrier particles on dry powder inhalation property of salbutamol sulfate (SS). Yakugaku-zasshi, J Pharm Soc Jpn 2000; 120(1): 113– 119.

O’Brien Nabors L, ed. Alternative Sweeteners: An Overview, 3rd edn.

New York: Marcel Dekker, 2001: 553.

370 Isomalt

Ndindayino F, Henrist D, Kiekens F, et al. Direct compression properties of melt-extruded isomalt. Int J Pharm 2002; 235(1–2): 149–157.

Ndindayino F, Vervaet C, Van-den-Mooter G, Remon JP. Bioavail- ability of hydrochlorothiazide from isomalt-based moulded tablets. Int J Pharm 2002; 246: 199–202.

Palatinit GmbH. http://www.palatinit.com/en/Homepage/ (accessed 1 September 2005).

Authors

B Fritzsching, O Luhn, A Schoch.

BP: Isopropyl alcohol JP: Isopropanol

PhEur: Alcohol isopropylicus USP: Isopropyl alcohol

Synonyms

Dimethyl carbinol; IPA; isopropanol; petrohol; 2-propanol;

sec-propyl alcohol.

Chemical Name and CAS Registry Number

Propan-2-ol [67-63-0]

Empirical Formula and Molecular Weight

C H O 60.1

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for isopropyl alcohol.

Test JP 2001 PhEur 2005 USP 28

3 8

Structural Formula

Functional Category

Disinfectant; solvent.

Applications in Pharmaceutical Formulation or Technology

Typical Properties

Antimicrobial activity: isopropyl alcohol is bactericidal; at concentrations greater than 70% v/v it is a more effective antibacterial preservative than ethanol (95%). The bacter- icidal effect of aqueous solutions increases steadily as the concentration approaches 100% v/v. Isopropyl alcohol is ineffective against bacterial spores.

Autoignition temperature: 4258C

Boiling point: 82.48C

Dielectric constant: D = 18.62

Isopropyl alcohol (propan-2-ol) is used in cosmetics and pharmaceutical formulations primarily as a solvent in topical formulations.(1) It is not recommended for oral use owing to its toxicity; see Section 14.

Although it is used in lotions, the marked degreasing properties of isopropyl alcohol may limit its usefulness in preparations used repeatedly. Isopropyl alcohol is also used as a solvent both for tablet film-coating and for tablet granula- tion,(2) where the isopropyl alcohol is subsequently removed by evaporation. It has also been shown to significantly increase the skin permeability of nimesulide from carbomer 934.(3)

Isopropyl alcohol has some antimicrobial activity (see Section 10) and a 70% v/v aqueous solution is used as a topical disinfectant. Therapeutically, isopropyl alcohol has been investigated for the treatment of postoperative nausea or vomiting.(4)

Description

Isopropyl alcohol is a clear, colorless, mobile, volatile, flammable liquid with a characteristic, spirituous odor resembling that of a mixture of ethanol and acetone; it has a slightly bitter taste.

Explosive limits: 2.5–12.0% v/v in air.

Flammability: flammable.

Flash point: 11.78C (closed cup); 138C (open cup). The water azeotrope has a flash point of 168C.

Freezing point: —89.58C

Melting point: —88.58C

Moisture content: 0.1–13% w/w for commercial grades (13% w/w corresponds to the water azeotrope).

Refractive index:

n20 = 1.3776;

n25 = 1.3749.

Solubility: miscible with benzene, chloroform, ethanol (95%), ether, glycerin, and water. Soluble in acetone; insoluble in salt solutions. Forms an azeotrope with water, containing 87.4% w/w isopropyl alcohol (boiling point 80.378C).

Specific gravity: 0.786

Vapor density (relative): 2.07 (air = 1)

Vapor pressure:

133.3 Pa (1 mmHg) at —26.18C;

4.32 kPa (32.4 mmHg) at 208C;

5.33 kPa (40 mmHg) at 23.88C;

13.33 kPa (100 mmHg) at 39.58C.

Viscosity (dynamic): 2.43 mPa s (2.43 cP) at 208C

372 Isopropyl Alcohol

Stability and Storage Conditions

Isopropyl alcohol should be stored in an airtight container in a cool, dry place.

Incompatibilities

Incompatible with oxidizing agents such as hydrogen peroxide and nitric acid, which cause decomposition. Isopropyl alcohol may be salted out from aqueous mixtures by the addition of sodium chloride, sodium sulfate, and other salts, or by the addition of sodium hydroxide.

Method of Manufacture

Isopropyl alcohol may be prepared from propylene; by the catalytic reduction of acetone, or by fermentation of certain carbohydrates.

Safety

Isopropyl alcohol is widely used in cosmetics and topical pharmaceutical formulations. It is readily absorbed from the gastrointestinal tract and may be slowly absorbed through intact skin. Prolonged direct exposure of isopropyl alcohol to the skin may result in cardiac and neurological deficits.(5) In neonates, isopropyl alcohol has been reported to cause chemical burns following topical application.(6,7)

Isopropyl alcohol is metabolized more slowly than ethanol, primarily to acetone. Metabolites and unchanged isopropyl alcohol are mainly excreted in the urine.

Isopropyl alcohol is about twice as toxic as ethanol and should therefore not be administered orally; isopropyl alcohol also has an unpleasant taste. Symptoms of isopropyl alcohol toxicity are similar to those for ethanol except that isopropyl

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Isopropyl alcohol may be irritant to the skin, eyes, and mucous membranes upon inhalation. Eye protection and gloves are recommended. Isopropyl alcohol should be handled in a well-ventilated environment. In the UK, the long-term (8-hour TWA) exposure limit for isopropyl alcohol is 999 mg/m3 (400 ppm); the short- term (15-minute) exposure limit is 1250 mg/m3 (500 ppm).(10) OSHA standards state that IPA 8-hour time weighted average airborne level in the workplace cannot exceed 400 ppm. Isopropyl alcohol is flammable and produces toxic fumes on combustion.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (oral capsules, tablets, and topical preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Propan-1-ol.

Propan-1-ol

Empirical formula: C3H8O

Molecular weight: 60.1

CAS number: [71-23-8]

Synonyms: propanol; n-propanol; propyl alcohol; propylic alcohol.

Autoignition temperature: 5408C

Boiling point: 97.28C

Dielectric constant: D25 = 22.20 Explosive limits: 2.15–13.15% v/v in air. Flash point: 158C (closed cup)

Melting point: –1278C

Refractive index: n20 = 1.3862

alcohol has no initial euphoric action and gastritis and vomiting are more prominent; see Alcohol. Delta osmolality may be

Solubility:

miscible with ethanol (95%), ether, and water.

useful as rapid screen test to identify patients at risk of complications from ingestion of isopropyl alcohol.(8) The lethal oral dose is estimated to be about 120–250 mL although toxic symptoms may be produced by 20 mL.

Adverse effects following parenteral administration of up to 20 mL of isopropyl alcohol diluted with water have included only a sensation of heat and a slight lowering of blood pressure. However, isopropyl alcohol is not commonly used in parenteral products.

Although inhalation can cause irritation and coma, the inhalation of isopropyl alcohol has been investigated in therapeutic applications.(3)

Isopropyl alcohol is most frequently used in topical pharmaceutical formulations where it may act as a local irritant.(9) When applied to the eye it can cause corneal burns and eye damage.

LD50 (dog, oral): 4.80 g/kg(9) LD50 (mouse, oral): 3.6 g/kg LD50 (mouse, IP): 4.48 g/kg LD50 (mouse, IV): 1.51 g/kg LD50 (rabbit, oral): 6.41 g/kg LD50 (rabbit, skin): 12.8 g/kg LD50 (rat, IP): 2.74 g/kg

LD50 (rat, IV): 1.09 g/kg LD50 (rat, oral): 5.05 g/kg

Specific gravity: 0.8053 at 208C

Viscosity (dynamic): 2.3 mPa s (2.3 cP) at 208C

Comments: propan-1-ol is more toxic than isopropyl alcohol. In the UK, the long-term (8-hour TWA) exposure limit for propan-1-ol is 500 mg/m3 (200 ppm); the short-term (15- minute) exposure limit is 625 mg/m3 (250 ppm).(10)

Comments

A specification for isopropyl alcohol is contained in the Food Chemicals Codex (FCC).

The EINECS number for isopropyl alcohol is 200-661-7.

Specific References

Rafiee Tehrani H, Mehramizi A. In vitro release studies of piroxicam from oil-in-water creams and hydroalcoholic gel topical formulations. Drug Dev Ind Pharm 2000; 26(4): 409–414.

Ruckmani K, Muneera MS, Vijaya R. Eudragit matrices for sustained release of ketorolac tromethamine: formulation and kinetics of release. Boll Chim Form 2000; 139: 205–208.

Guengoer S, Bergisadi N. Effect of penetration enhancers on in vitro percutaneous penetration of nimesulide through rat skin. Pharmazie 2004; 59: 39–41.

Merritt BA, Okyere CP, Jasinski DM. Isopropyl alcohol inhalation: alternative treatment of postoperative nausea and vomiting. Nurs Res 2002; 51(2): 125–128.

Isopropyl Alcohol 373

Leeper SC, Almatari AL, Ingram JD, Ferslew KE. Topical absorption of isopropyl alcohol induced cardiac neurological deficits in an adult female with intact skin. Vet Hum Toxicol 2000; 42: 15–17.

Schick JB, Milstein JM. Burn hazard of isopropyl alcohol in the neonate. Pediatrics 1981; 68: 587–588.

Weintraub Z, Iancu TC. Isopropyl alcohol burns. Pediatrics 1982;

69: 506.

Monaghan MS, Ackerman BH, Olsen KM, et al. Use of delta osmolality to predict serum isopropanol and acetone concentra- tions. Pharmacotherapy 1993; 13(1): 60–63.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2148–2149.

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

BP: Isopropyl myristate PhEur: Isopropylis myristas USPNF: Isopropyl myristate

Synonyms

Crodamol IPM; Estol IPM; isopropyl ester of myristic acid; Kessco IPM 95; Lexol IPM-NF; myristic acid isopropyl ester; Rita IPM; Stepan IPM; Tegosoft M; tetradecanoic acid, 1- methylethyl ester; Waglinol 6014.

Chemical Name and CAS Registry Number

1-Methylethyl tetradecanoate [110-27-0]

Empirical Formula and Molecular Weight

C17H34O2 270.5

Structural Formula

Functional Category

Emollient; oleaginous vehicle; skin penetrant; solvent.

Applications in Pharmaceutical Formulation or Technology

Isopropyl myristate is a nongreasy emollient that is absorbed readily by the skin. It is used as a component of semisolid bases and as a solvent for many substances applied topically. Applications in topical pharmaceutical and cosmetic formula- tions include bath oils; make-up; hair and nail care products; creams; lotions; lip products; shaving products; skin lubricants; deodorants; otic suspensions; and vaginal creams; see Table I. For example, isopropyl myristate is a self-emulsifying compo- nent of a proposed cold cream formula,(1) which is suitable for use as a vehicle for drugs or dermatological actives; it is also used cosmetically in stable mixtures of water and glycerol.(2)

Isopropyl myristate is used as a penetration enhancer for transdermal formulations and has been used in conjunction with therapeutic ultrasound and iontophoresis.(3) It has been used in a water-oil gel prolonged-release emulsion and in various microemulsions. Isopropyl myristate has also been used in microspheres, and significantly increased the release of drug from etoposide-loaded microspheres.(4)

Table I: Uses of isopropyl myristate.

Use Concentration (%)

Detergent 0.003–0.03

Otic suspension 0.024

Perfumes 0.5–2.0

Microemulsions <50

Soap 0.03–0.3

Topical aerosols 2.0–98.0

Topical creams and lotions 1.0–10.0

Description

Isopropyl myristate is a clear, colorless, practically odorless liquid of low viscosity that congeals at about 58C. It consists of esters of propan-2-ol and saturated high molecular weight fatty acids, principally myristic acid.

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for isopropyl myristate.

Test PhEur 2005 USPNF 23

Identification + +

Appearance of solution + —

Specific gravity — 0.846–0.854

Relative density ≈ 0.853 0.846–0.854

Refractive index 1.434–1.437 1.432–1.436

Residue on ignition 40.1% 40.1%

Acid value 41.0 41.0

Saponification value 202–212 202–212

Iodine value 41.0 41.0

Appearance of solution + —

Viscosity 5–6 mPa s —

Water 40.1% —

Organic volatile impurities — +

Assay (as C17H34O2) 590.0% 590.0%

Typical Properties

Boiling point: 140.28C at 266 Pa (2 mmHg)

Flash point: 153.58C (closed cup)

Freezing point: ≈58C

Solubility: soluble in acetone, chloroform, ethanol (95%), ethyl acetate, fats, fatty alcohols, fixed oils, liquid hydrocarbons, toluene, and waxes. Dissolves many waxes, cholesterol, or lanolin. Practically insoluble in glycerin, glycols, and water.

Viscosity (dynamic): 5–7 mPa s (5–7 cP) at 258C

Stability and Storage Conditions

Isopropyl myristate is resistant to oxidation and hydrolysis and does not become rancid. It should be stored in a well-closed container in a cool, dry place and protected from light.

Isopropyl Myristate 375

Incompatibilities

When isopropyl myristate comes into contact with rubber, there is a drop in viscosity with concomitant swelling and partial dissolution of the rubber; contact with plastics, e.g. nylon and polyethylene, results in swelling. Isopropyl myristate is incompatible with hard paraffin, producing a granular mixture. It is also incompatible with strong oxidizing agents.

Method of Manufacture

Isopropyl myristate may be prepared either by the esterification of myristic acid with propan-2-ol or by the reaction of myristoyl chloride and propan-2-ol with the aid of a suitable dehydrochlorinating agent. A high-purity material is also commercially available, produced by enzymatic esterification at low temperature.

Safety

Isopropyl myristate is widely used in cosmetics and topical pharmaceutical formulations and is generally regarded as a nontoxic and nonirritant material.(5–7)

LD50 (mouse, oral): 49.7 g/kg(8) LD50 (rabbit, skin): 5 g/kg

Handling Precautions

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

Regulatory Status

Included in the FDA Inactive Ingredients Guide (otic, topical, transdermal, and vaginal preparations). Used in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Isopropyl palmitate.

Comments

The EINECS number for isopropyl myristate is 203-751-4.

Specific References

Jimenez SMM, Fresno CMJ, Selles Flores E. Proposal and pharmacotechnical study of a modern dermo-pharmaceutical formulation for cold cream. Boll Chim Farm 1996; 135: 364–373.

Ayannides CA, Ktistis G. Stability estimation of emulsions of isopropyl myristate in mixtures of water and glycerol. J Cosmet Sci 2002; 53(3): 165–173.

Fang JY, Fang CL, Huang YB. Transdermal iontopheresis of sodium nonivaride acetate III: combined effect of pretreatment by penetration enhancers. Int J Pharm 1997; 149: 183–195.

Schaefer MJ, Singh J. Effect of isopropyl myristic acid ester on the physical characteristics and in vitro release of etoposide from PLGA microspheres. AAPS PharmTechSci 2000; 1(4): 32.

Stenba¨ ck F, Shubik P. Lack of toxicity and carcinogenicity of some commonly used cutaneous agents. Toxicol Appl Pharmacol 1974; 30: 7–13.

Opdyke DL. Monographs on fragrance raw materials. Food Cosmet Toxicol 1976; 14(4): 307–338.

Guillot JP, Martini MC, Giauffret JY. Safety evaluation of cosmetic raw materials. J Soc Cosmet Chem 1977; 28: 377–393.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2164.

General References

Fitzgerald JE, Kurtz SM, Schardein JL, Kaump DH. Cutaneous and parenteral studies with vehicles containing isopropyl myristate and peanut oil. Toxicol Appl Pharmacol 1968; 13: 448–453.

Nakhare S, Vyas SP. Prolonged release of rifampicin from internal phase of multiple w/o/w emulsion systems. Indian J Pharm Sci 1995; 57: 71–77.

BP: Isopropyl palmitate PhEur: Isopropylis palmitas USPNF: Isopropyl palmitate

Synonyms

Crodamol IPP; Emerest 2316; hexadecanoic acid isopropyl ester; hexadecanoic acid 1-methylethyl ester; isopropyl hexa- decanoate; Kessco IPP; Lexol IPP-NF; Liponate IPP; palmitic acid isopropyl ester; Protachem IPP; Rita IPP; Stepan IPP; Tegosoft P; Unimate IPP; Waglinol 6016; Wickenol 111.

Chemical Name and CAS Registry Number

Methylethyl hexadecanoate [142-91-6]

Empirical Formula and Molecular Weight

C19H38O2 298.51

Structural Formula

Functional Category

Emollient; oleaginous vehicle; skin penetrant; solvent.

Applications in Pharmaceutical Formulation or Technology

Isopropyl palmitate is a nongreasy emollient with good spreading characteristics, used in topical pharmaceutical formulations and cosmetics such as: bath oils; creams; lotions; make-up; hair care products; deodorants; lip products; suntan preparations; and pressed powders; see Table I.

Isopropyl palmitate has also been used in controlled-release percutaneous films, and has also been investigated in the production of reversed sucrose ester vesicles, as well as microemulsions.(1)

Table I: Uses of isopropyl palmitate.

Use Concentration (%)

Detergent 0.005–0.02

Perfume 0.2–0.8

Soap 0.05–0.2

Topical aerosol spray 3.36

Topical creams and lotions 0.05–5.5

Description

Isopropyl palmitate is a clear, colorless to pale yellow-colored, practically odorless viscous liquid that solidifies at less than 168C.

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for isopropyl palmitate.

Test PhEur 2005 USPNF 23

Identification + +

Acid value 41.0 41.0

Appearance of solution + —

Characters — +

Iodine value 41.0 41.0

Organic volatile impurities — +

Relative density 0.850–0.855 0.850–0.855

Residue on ignition 40.1% 40.1%

Refractive index 1.436–1.440 1.435–1.438

Saponification value 183–193 183–193

Viscosity 5–10 mPa s —

Water 40.1% —

Assay (of C19H38O2) 590.0% 590.0%

Typical Properties

Boiling point: 1608C at 266 Pa (2 mmHg)

Freezing point: ≈13–158C

Solubility: soluble in acetone, chloroform, ethanol (95%), ethyl acetate, mineral oil, propan-2-ol, silicone oils, vegetable oils, and aliphatic and aromatic hydrocarbons; practically insoluble in glycerin, glycols, and water.

Surface tension: ≈29 mN/m for Tegosoft P at 258C

Viscosity (dynamic): 5–10 mPa s (5–10 cP) at 258C

Stability and Storage Conditions

Isopropyl palmitate is resistant to oxidation and hydrolysis and does not become rancid. It should be stored in a well-closed container, above 168C, and protected from light.

Incompatibilities

See Isopropyl Myristate.

Method of Manufacture

Isopropyl palmitate is prepared by the reaction of palmitic acid with propan-2-ol in the presence of an acid catalyst. A high- purity material is also commercially available, which is produced by enzymatic esterification at low temperatures.

Isopropyl Palmitate 377

Safety

Isopropyl palmitate is widely used in cosmetics and topical pharmaceutical formulations, and is generally regarded as a relatively nontoxic and nonirritant material.(2–4)

LD50 (mouse, IP): 0.1 g/kg(5)

Handling Precautions

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

Regulatory Status

Included in the FDA Inactive Ingredients Guide (topical and transdermal preparations). Used in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Isopropyl myristate.

Comments

The EINECS number for isopropyl palmitate is 205-571-1.

Specific References

Mollee H, De Vrind J, De Vringer T. Stable reversed vesicles in oil: characterization studies and encapsulation of model compounds. J Pharm Sci 2000; 89(7): 930–939.

Frosch PJ, Kligman AM. The chamber-scarification test for irritancy. Contact Dermatitis 1976; 2: 314–324.

Guillot JP, Martini MC, Giauffret JY. Safety evaluation of cosmetic raw materials. J Soc Cosmet Chem 1977; 28: 377–393.

Opdyke DL, Letizia C. Monographs on fragrance raw materials.

Food Cosmet Toxicol 1982; 20 (Suppl.): 633–852.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2165.

BP: Heavy kaolin JP: Kaolin

PhEur: Kaolinum ponderosum USP: Kaolin

Note that the PhEur 2005 contains a monograph on heavy kaolin (kaolinum ponderosum). The BP 2004 in addition to the monograph for heavy kaolin also contains monographs for light kaolin (natural) and light kaolin.

See also Section 8.

Empirical Formula and Molecular Weight

C3H6O3 90.08

Structural Formula

Functional Category

Acidifying agent; acidulant.

Applications in Pharmaceutical Formulation or Technology

Lactic acid is used in beverages, foods, cosmetics, and pharmaceuticals (see Table I) as an acidifying agent and acidulant.

In topical formulations, particularly cosmetics, it is used for its softening and conditioning effect on the skin. Lactic acid may also be used in the production of biodegradable polymers and microspheres, such as poly(D-lactic acid), used in drug delivery systems.(1,2) See also Aliphatic Polyesters.

Lactic acid is also used as a food preservative. Therapeu- tically, lactic acid is used in injections, in the form of lactate, as a source of bicarbonate for the treatment of metabolic acidosis; as a spermicidal agent; in pessaries for the treatment of leukorrhea; in infant feeds; and in topical formulations for the treatment of warts.

Table I: Uses of lactic acid.

Use Concentration (%)

Injections 0.012–1.16

Topical preparations 0.015–6.6

Description

Lactic acid consists of a mixture of 2-hydroxypropionic acid, its condensation products, such as lactoyllactic acid and other polylactic acids, and water. It is usually in the form of the racemate, (RS)-lactic acid, but in some cases the (S)-(+)-isomer is predominant.

Lactic acid is a practically odorless, colorless or slightly yellow-colored, viscous, hygroscopic, nonvolatile liquid.

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for lactic acid.

Test JP 2001 PhEur 2005 USP 28

Identification + + +

Appearance of solution — + —

Specific rotation — — —0.058 to

Heavy metals 410 ppm 410 ppm 40.001%

Iron 45 ppm — —

Sulfate 40.01% 4200 ppm +

Chloride 40.036% — +

Citric, oxalic, phosphoric, + + +

and tartaric acids

Ether-insoluble substances — + —

Cyanide + — —

Sugars and other reducing + + +

substances

Glycerin and mannitol

—

Methanol and methyl esters — 450 ppm —

Reducing substances — + —

Readily carbonizable + — +

substances

Bacterial endotoxins — 45 IU/g — Volatile fatty acids + + — Residue on ignition 40.1% 40.1% 43.0 mg

Sulfated ash — 40.1% 40.05%

Assay + 88.0–92.0% 88.0–92.0%

Typical Properties

Boiling point: 1228C at 2 kPa (15 mmHg) Dissociation constant: pKa = 4.14 at 22.58C Flash point: >1108C

Heat of combustion: 15.13 kJ/kg (3615 cal/kg)

Melting point: 178C

382 Lactic Acid

Osmolarity: a 2.3% w/v aqueous solution is isoosmotic with serum.

Refractive index: n20 = 1.4251

Solubility: miscible with ethanol (95%), ether, and water; practically insoluble in chloroform.

Specific heat: 2.11 J/g (0.505 cal/g) at 208C

Specific gravity: 1.21

Specific rotation [a]21:

—2.68 (8% w/v aqueous solution) for (R)-form;

+2.68 (2.5% w/v aqueous solution) for (S)-form.

Viscosity (dynamic): 28.5 mPa s (28.5 cP) for 85% aqueous solution at 258C.

Stability and Storage Conditions

Lactic acid is hygroscopic and will form condensation products such as polylactic acids on contact with water. The equilibrium between the polylactic acids and lactic acid is dependent on concentration and temperature. At elevated temperatures lactic acid will form lactide, which is readily hydrolyzed back to lactic acid.

Lactic acid should be stored in a well-closed container in a cool, dry place.

Incompatibilities

Incompatible with oxidizing agents, iodides, and albumin. Reacts violently with hydrofluoric acid and nitric acid.

Method of Manufacture

Lactic acid is prepared by the fermentation of carbohydrates, such as glucose, sucrose, and lactose, with Bacillus acidi lacti or related microorganisms. On a commercial scale, whey, corn starch, potatoes, or molasses are used as a source of carbohydrate. Lactic acid may also be prepared synthetically by the reaction between acetaldehyde and carbon monoxide at 130–2008C under high pressure, or by the hydrolysis of hexoses with sodium hydroxide.

Lactic acid prepared by the fermentation of sugars is levorotatory; lactic acid prepared synthetically is racemic. However, lactic acid prepared by fermentation becomes dextrorotatory on dilution with water owing to the hydrolysis of (R)-lactic acid lactate to (S)-lactic acid.

Safety

Lactic acid occurs in appreciable quantities in the body as an end product of the anaerobic metabolism of carbohydrates and, while harmful in the concentrated form (see Section 15), can be considered nontoxic at the levels at which it is used as an excipient. A 1% v/v solution, for example, is harmless when applied to the skin.

There is evidence that neonates have difficulty in metaboliz- ing (R)-lactic acid and this isomer and the racemate should therefore not be used in foods intended for infants aged less than 3 months old.(3)

There is no evidence that lactic acid is carcinogenic, teratogenic, or mutagenic.

LD50 (guinea pig, oral): 1.81 g/kg(4) LD50 (mouse, oral): 4.88 g/kg

LD50 (mouse, SC): 4.5 g/kg LD50 (rat, oral): 3.73 g/kg

Handling Precautions

Lactic acid is caustic in concentrated form and can cause burns on contact with the skin and eyes. It is harmful if swallowed, inhaled, or absorbed through the skin. Observe precautions appropriate to the circumstances and quantity of material handled. Eye protection, rubber gloves, and respirator are recommended. It is advisable to handle the compound in a chemical fume hood and to avoid repeated or prolonged exposure. Spillages should be diluted with copious quantities of water. In case of excessive inhalation, remove the patient to a well-ventilated environment and seek medical attention. Lactic acid presents no fire or explosion hazard but emits acrid smoke and fumes when heated to decomposition.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (IM, IV, and SC injections, oral syrups and tablets, topical and vaginal preparations). Included in medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Aliphatic polyesters; sodium lactate.

Comments

A specification for lactic acid is contained in the Food Chemicals Codex (FCC). The EINECS number for lactic acid is 200-018-0.

Specific References

Brophy MR, Deasy P. Biodegradable polyester polymers as drug carriers. In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, vol. 2. New York: Marcel Dekker, 1990: 1–25.

Kim IS, Jeong YI, Cho CS, Kim SH. Core–shell type polymeric nanoparticles composed of poly(L-lactic acid) and poly(N-isopro- pylacrylamide). Int J Pharm 2000; 211: 1–8.

FAO/WHO. Toxicological evaluation of certain food additives with a review of general principles and specifications. Seventeenth report of the FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1974; No. 539.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2196.

General References

Al-Shammary FJ, Mian NAZ, Mian MS. Lactic acid. In: Brittain HG, ed. Analytical Profiles of Drug Substances and Excipients, vol. 22. San Diego: Academic Press, 1993: 263–316.

BP: Lactitol monohydrate

PhEur: Lactitolum monohydricum USPNF: Lactitol

Synonyms

E966; b-galactosido-sorbitol; Finlac DC; lactil; lactite; lacto- biosit; lactosit; Lacty.

Chemical Name and CAS Registry Number

4-O-(b-D-Galactopyranosyl)-D-glucitol [585-86-4]

4-O-(b-D-Galactopyranosyl)-D-glucitol monohydrate [81025-

04-9]

4-O-(b-D-Galactopyranosyl)-D-glucitol dihydrate [81025-

03-8]

Empirical Formula and Molecular Weight

C12H24O11 344.32 (anhydrous)

C12H24O11·H2O 362.34 (monohydrate)

C12H24O11·2H2O 380.35 (dihydrate)

Structural Formula

Functional Category

Sweetening agent; tablet and capsule diluent.

Applications in Pharmaceutical Formulation or Technology

Lactitol is used as a noncariogenic replacement for sucrose. It is also used as a diluent in solid dosage forms.(1) A direct- compression form is available,(2,3) as is a direct-compression blend of lactose and lactitol. Lactitol is also used therapeutically in the treatment of hepatic encephalopathy and as a laxative; see Section 14.

Description

Lactitol occurs as white orthorhombic crystals. It is odorless with a sweet taste that imparts a cooling sensation. It is available in powdered form and in a range of crystal sizes. The directly compressible form is a water-granulated product of microcrystalline aggregates.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for lactitol.

Test PhEur 2005 USPNF 23

Identification + +

Characters + —

Appearance of solution + —

Acidity or alkalinity + —

Specific optical rotation +13.58 to +15.58 —

Related substances 41.0% 41.5%

Reducing sugars 40.2% 40.2% as dextrose

Lead 40.5 ppm —

Nickel

Water 41 ppm —

Microbial contamination 4103/g —

Residue on ignition 40.1% 40.5%

Heavy metals — 45 mg/g

Organic volatile impurities — +

Assay 96.5–102.0% 98.0–101.0%

Typical Properties

Acidity–alkalinity: pH = 4.5–7.0 (10% w/v solution).

Density: 1.54 g/cm3

Heat of solution: —54 J/g

Loss of water of crystallization: 145–1858C

Moisture content: 4.5–5.5% for the monohydrate; 40.5% for the anhydrous.

Osmolarity: a 7% w/v aqueous solution is isoosmotic with serum.

Refractive index:

n20 = 1.3485 (10% solution);

n20 = 1.3650 (20% solution);

n20 = 1.3827 (30% solution);

n20 = 1.4018 (40% solution);

n20 = 1.4228 (50% solution);

n20 = 1.4466 (60% solution).

Solubility: slightly soluble in ethanol (95%) and ether. Soluble 1 in 1.75 of water at 208C; 1 in 1.61 at 308C; 1 in 1.49 at

408C; 1 in 1.39 at 508C.

Specific rotation [a]20: +14.58 to +158

Viscosity (dynamic):

1.3 mPa s (1.3 cP) for 10% solution at 208C;

1.9 mPa s (1.9 cP) for 20% solution at 208C;

384 Lactitol

3.4 mPa s (3.4 cP) for 30% solution at 208C;

6.9 mPa s (6.9 cP) for 40% solution at 208C;

18.9 mPa s (18.9 cP) for 50% solution at 208C;

80.0 mPa s (80.0 cP) for 60% solution at 208C.

Stability and Storage Conditions

Lactitol as the monohydrate is nonhygroscopic and is stable under humid conditions. It is stable to heat and does not take part in the Maillard reaction. In acidic solution, lactitol slowly hydrolyzes to sorbitol and galactose. Lactitol is very resistant to microbiological breakdown and fermentation. Store in a well- closed container. When the compound is stored in an unopened container at 258C and 60% relative humidity, a shelf-life in excess of 3 years is appropriate.

Incompatibilities

—

Method of Manufacture

Lactitol is produced by the catalytic hydrogenation of lactose.

Safety

Lactitol is regarded as a nontoxic and nonirritant substance. It is not fermented significantly in the mouth, and is not cariogenic.(4) It is not absorbed in the small intestine, but is broken down by microflora in the large intestine,(5) and is metabolized independently of insulin. In large doses it has a laxative effect; therapeutically, 10–20 g daily in a single oral dose is administered for this purpose.

LD50 (mouse, oral): >23 g/kg(6) LD50 (rat, oral): 30 g/kg

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.

Related Substances

—

Comments

Finlac DC is a commercially available water-granulated directly compressible lactitol.(2)

Lactitol has a sweetening power about one-third that of sucrose. It does not promote dental caries and has a caloric value of 9.9 J/g (2.4 cal/g).

The EINECS number for lactitol is 209-566-5.

Specific References

Allen LV. Featured excipient: capsule and tablet diluents. Int J Pharm Compound 2000; 4(4): 306–310, 324–325.

Armstrong NA. Direct compression characteristics of lactitol.

Pharm Technol Eur 1998; 10(2): 42–46.

Muzikova J. A study of compressibility of directly compacting forms of lactitol. Ceska Slov Form 2003; 52(5): 241–243.

Grenby TH, Philips A, Mistry M. Studies on the dental properties of lactitol compared with five other bulk sweeteners in vitro. Caries Res 1989; 23: 315–319.

Grimble GK, Patil DH, Silk DBA. Assimilation of lactitol, an unabsorbed disaccharide in the normal human colon. Gut 1988; 29: 1666–1671.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2198.

General References

Armstrong NA. Tablet manufacture. In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 3. New York: Marcel Dekker, 2002: 2713–2732.

van Uyl CH. Technical and commercial aspects of the use of lactitol in foods as a reduced-calorie bulk sweetener. Dev Sweeteners 1987; 3: 65–81.

van Velthuijsen JA. Food additives derived from lactose: lactitol and lactitol palmitate. J Agric Food Chem 1979; 27: 680–686.

BP: Anhydrous lactose JP: Anhydrous lactose

PhEur: Lactosum anhydricum USPNF: Anhydrous lactose

Synonyms

Anhydrous Lactose NF 60M; Anhydrous Lactose NF Direct Tableting; Lactopress Anhydrous; lactosum; lattioso; milk sugar; Pharmatose DCL 21; Pharmatose DCL 22; saccharum lactis; Super-Tab Anhydrous.

Chemical Name and CAS Registry Number

O-b-D-galactopyranosyl-(1→4)-b-D-glucopyranose [63-42-3]

Empirical Formula and Molecular Weight

C12H22O11 342.30

Structural Formula

The PhEur 2005 describes anhydrous lactose as O-b-D- galactopyranosyl-(1→4)-b-D-glucopyranose; or a mixture of O-b-D-galactopyranosyl-(1→4)-a-D-glucopyranose and O-b-D- galactopyranosyl-(1→4)-b-D-glucopyranose. The USPNF 23 describes anhydrous lactose as being primarily b-lactose or a mixture of a- and b-lactose. The JP 2001 describes anhydrous lactose as b-lactose or a mixture of b-lactose and a-lactose.

Functional Category

Binding agent; directly compressible tableting excipient; lyophilization aid; tablet and capsule filler.

Applications in Pharmaceutical Formulation or Technology

Anhydrous lactose is widely used in direct compression tableting applications and as a tablet and capsule filler and binder. Anhydrous lactose can be used with moisture-sensitive drugs due to its low moisture content.

See also Lactose, Monohydrate; Lactose, Spray-Dried.

Description

Lactose occurs as white to off-white crystalline particles or powder. Several different brands of anhydrous lactose are commercially available which contain anhydrous b-lactose and anhydrous a-lactose. Anhydrous lactose typically contains 70–80% anhydrous b-lactose and 20–30% anhydrous a- lactose.

SEM: 1

Excipient: Pharmatose DCL 21 Manufacturer: DMV International Magnification: 200×

Voltage: 1.5 kV

Pharmacopeial Specifications

See Table I.

386 Lactose, Anhydrous

SEM: 2

Excipient: Pharmatose DCL 22 Manufacturer: DMV International Magnification: 55×

Voltage: 1.5 kV

SEM: 3

Excipient: Super-Tab Anhydrous Manufacturer: New Zealand Lactose Magnification: 500×

Voltage: 10 kV

Typical Properties

Angle of repose: 398 for Pharmatose DCL 21 and 388 for

Super-Tab Anhydrous.

Table I: Pharmacopeial specifications for lactose anhydrous.

Test JP 2001 PhEur 2005 USPNF 23

Identification + + +

Appearance/color of + + +

solution

Characters — + —

Optical rotation +54.4 to +54.4 to +54.4 to

+55.98 +55.98 +55.98

Acidity or alkalinity + + +

Heavy metals 45 ppm 45 ppm 45 mg/g

Absorbance

210–220 nm 40.25 40.25 40.25

270–300 nm 40.07 40.07 40.07

Loss on drying 40.5% +(a) 40.5%

Water 41.0% 41.0% 41.0%

Residue on ignition 40.1% — 40.1%

Sulfated ash — 40.1% —

Fungi and yeast 450/g — 450/g

Escherichia coli + + +

Salmonella + — —

Isomer ratio + +(a) +

(a) Not a mandatory test.

Melting point:

223.08C for anhydrous a-lactose;

252.28C for anhydrous b-lactose;

232.08C (typical) for commercial anhydrous lactose.

Particle size distribution: see Table II.

Permanent deformation pressure: 521.0 MPa (at compression pressure 177.8 MPa)(a)

Reduced modulus of elasticity: 5315 (at compression pressure 177.8 MPa)(a)

Solubility: soluble in water; sparingly soluble in ethanol (95%) and ether.

Specific surface area: 0.41 m2/g for Pharmatose DCL 22;

0.37 m2/g for Super-Tab Anhydrous.

Specific rotation [a]25 : 54.48 to 55.98

Tensile strength: 2.577 MPa (at compression pressure 177.8 MPa)(a)

Water content: 40.5% loss on drying and 41.0% water content for Anhydrous Lactose NF Direct Tableting and Anhydrous Lactose NF 60M; 0.2% loss on drying and 0.5% water content for Pharmatose DCL 21 (typical); 0.2% loss on drying and 0.2% water content for Pharmatose DCL 22 (typical); 0.15% loss on drying for Super-Tab Anhydrous (typical).

(a) Methods for characterizing the mechanical properties of compacts of pharmaceutical ingredients are specified in the Handbook of Pharmaceutical Excipients, 3rd edn.(1)

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