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In powder form, ascorbic acid is relatively stable in air. In the absence of oxygen and other oxidizing agents it is also heat stable. Ascorbic acid is unstable in solution, especially alkaline solution, readily undergoing oxidation on exposure to the air.(2,3) The oxidation process is accelerated by light and heat and is catalyzed by traces of copper and iron. Ascorbic acid solutions exhibit maximum stability at about pH 5.4. Solutions may be sterilized by filtration.

The bulk material should be stored in a well-closed nonmetallic container, protected from light, in a cool, dry place.

Incompatibilities

Incompatible with alkalis, heavy metal ions, especially copper and iron, oxidizing materials, methenamine, phenylephrine hydrochloride, pyrilamine maleate, salicylamide, sodium nitrite, sodium salicylate, theobromine salicylate, and picot- amide.(4,5) Additionally, ascorbic acid has been found to interfere with certain colorimetric assays by reducing the intensity of the color produced.(6)

Method of Manufacture

Ascorbic acid is prepared synthetically or extracted from various vegetable sources in which it occurs naturally, such as rose hips, blackcurrants, the juice of citrus fruits, and the ripe fruit of Capsicum annuum L. A common synthetic procedure involves the hydrogenation of D-glucose to D-sorbitol, followed by oxidation using Acetobacter suboxydans to form L-sorbose. A carboxyl group is then added at C1 by air oxidation of the diacetone derivative of L-sorbose and the resulting diacetone-2- keto-L-gulonic acid is converted to L-ascorbic acid by heating with hydrochloric acid.

50 Ascorbic Acid

Safety

Ascorbic acid is an essential part of the human diet, with 40 mg being the recommended daily dose in the UK(7) and 60 mg in the US.(8) However, these figures are controversial, with some advocating doses of 150 or 250 mg daily. Megadoses of 10 g daily have also been suggested to prevent illness although such large doses are now generally considered to be potentially harmful.(9–11)

The body can absorb about 500 mg of ascorbic acid daily with any excess immediately excreted by the kidneys. Large doses may cause diarrhea or other gastrointestinal distur- bances. Damage to the teeth has also been reported.(12) However, no adverse effects have been reported at the levels employed as an antioxidant in foods and pharmaceuticals. The WHO has set an acceptable daily intake of ascorbic acid, potassium ascorbate, and sodium ascorbate, as antioxidants in food, at up to 15 mg/kg body-weight in addition to that naturally present in food.(13)

LD50 (mouse, IV): 0.52 g/kg(14) LD50 (mouse, oral): 3.37 g/kg LD50 (rat, oral): 11.9 g/kg

Handling Precautions

Ascorbic acid may be harmful if ingested in large quantities and may be irritating to the eyes. Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and rubber or plastic gloves are recommended.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (inhalations, injections, oral capsules, suspensions, tablets, topical prepara- tions, and suppositories). Included in medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Ascorbyl palmitate; erythorbic acid; sodium ascorbate.

Comments

Many dosage forms for ascorbic acid have been developed for its administration to patients, including microencapsulation.(15) A specification for ascorbic acid is contained in the Food

Chemicals Codex (FCC).

The EINECS number for ascorbic acid is 200-066-2.

Specific References

Hammad MA, Muller BW. Solubility and stability of tetrazepam in mixed micelles. Eur J Pharm Sci 1998; 7: 49–55.

Hajratwala BR. Stability of ascorbic acid. STP Pharma 1985; 1: 281–286.

Touitou E, Gilhar D, Alhaique F, et al. Ascorbic acid in aqueous solution: bathochromic shift in dilution and degradation. Int J Pharm 1992; 78: 85–87.

Botha SA, Lo¨ tter AP, du Preez JFL. DSC screening for drug–drug interactions in polypharmaceuticals intended for the alleviation of the symptoms of colds and flu. Drug Dev Ind Pharm 1987; 13: 345–354.

Mura P, Bettinetti GP, Faucci MT, et al. Differential scanning calorimetry in compatibility testing of picotamide with pharma- ceutical excipients. Thermochim Acta 1998; 321: 59–65.

Krishnan G, Talwar SK, Sharma SC, Sharma RG. Estimation of phenylephrine hydrochloride in multi-component pharmaceutical preparations. Eastern Pharmacist 1990; 33: 143–145.

Department of Health. Dietary reference values for food energy and nutrients for the United Kingdom: report of the panel on dietary reference values of the committee on medical aspects of food policy. Report on Health and Social Subjects 41. London: HMSO, 1991.

Subcommittee on the tenth edition of the RDAs, Food and Nutrition Board, Commission on Life Sciences. National Research Council. Recommended Dietary Allowances, 10th edn. Washing- ton, DC: National Academy Press, 1989.

Ovesen L. Vitamin therapy in the absence of obvious deficiency: what is the evidence? Drugs 1984; 27: 148–170.

Bates CJ. Is there a maximum safe dose of vitamin C (ascorbic acid)? Br Med J 1992; 305: 32.

Mason P. Vitamin C. Dietary Supplements, 2nd edn. London: Pharmaceutical Press, 2001: 227–233.

Giunta JL. Dental erosion resulting from chewable vitamin C tablets. J Am Dent Assoc 1983; 107: 253–256.

FAO/WHO. Toxicological evaluation of certain food additives with a review of general principles and of specifications. Seventeenth report of the joint 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: 309–310.

Esposito E, Cervellayi F, Menegatti E, et al. Spray-dried Eudragit microparticles as encapsulation devices for vitamin C. Int J Pharm 2002; 242: 329–334.

General References

Abramovici B, Molard F, Seguin B, Gromenil JC. Comparative study of the tabletability of different grades of vitamin C [in French]. STP Pharma 1987; 3: 16–22.

Allwood MC. Factors influencing the stability of ascorbic acid in total parenteral nutrition infusions. J Clin Hosp Pharm 1984; 9: 75–85. Bhagavan HN, Wolkoff BI. Correlation between the disintegration time and the bioavailability of vitamin C tablets. Pharm Res 1993; 10:

239–242.

Davies MB, Austin J, Partridge DA. Vitamin C—Its Chemistry and Biochemistry. London: Royal Society of Chemistry, 1991.

Hu F, Wang H, Wu X. Effects of different adhesives on the stability of vitamin C buccal tablets. Zhejiang Yike Daxue Xuebao 1997; 26: 108–110.

Krishna G, Mao J, Almassian B. Development of a parenteral formulation of an investigational anticancer drug, 3-aminopyr- idine-2-carboxaldehyde thiosemicarbazone. Pharm Dev Technol 1999; 4: 71–80.

Nebuloni M, Pifferi G, Munna E. Thermal analysis in preformulation studies of a lyophilized form of an antibiotic. Boll Chim Farm 1996; 135: 94–100.

Pinsuwan S, Alvarez-Nunez FA, et al. Degradation kinetics of 4- dedimethylamino sancycline, a new anti-tumor agent, in aqueous solutions. Int J Pharm 1999; 181: 31–40.

Saleh SI, Stamm A. Evaluation of some directly compressible L-ascorbic acid forms. STP Pharma 1988; 4: 10–14.

Saleh SI, Stamm A. Contribution to the preparation of a directly compressible L-ascorbic acid granular form: comparison of granules prepared by three granulation methods and evaluation of their corresponding tablets. STP Pharma 1988; 4: 182–187.

Seta Y, Higuchi F, Otsuka T, et al. Preparation and pharmacological evaluation of Captopril sustained-release dosage forms using oily semisolid matrix. Int J Pharm 1988; 41: 255–262.

BP: Ascorbyl palmitate PhEur: Ascorbylis palmitas USPNF: Ascorbyl palmitate

Synonyms

Table I: Pharmacopeial specifications for ascorbyl palmitate.

Test PhEur 2005 USPNF 23

Identification + +

Characters + —

Appearance of solution + —

Melting range — 107–1178C

L-Ascorbic acid 6-palmitate; E304; 3-oxo-L-gulofuranolactone 6-palmitate; vitamin C palmitate.

Chemical Name and CAS Registry Number

L-Ascorbic acid 6-hexadecanoate [137-66-6]

Empirical Formula and Molecular Weight

C22H38O7 414.54

Structural Formula

Specific rotation (10% w/v in methanol)

Typical Properties

Solubility: see Table II.

+218 to +248 +218 to +248

Functional Category

Antioxidant.

Applications in Pharmaceutical Formulation or Technology

Ascorbyl palmitate is primarily used either alone or in combination with alpha tocopherol as a stabilizer for oils in oral pharmaceutical formulations and food products; generally 0.05% w/v is used. It may also be used in oral and topical preparations as an antioxidant for drugs unstable to oxygen. The combination of ascorbyl palmitate with alpha tocopherol shows marked synergism, which increases the effect of the components and allows the amount used to be reduced.

The solubility of ascorbyl palmitate in alcohol permits it to be used in nonaqueous and aqueous systems and emulsions.

Description

Ascorbyl palmitate is a practically odorless, white to yellowish powder.

Pharmacopeial Specifications

See Table I.

Table II: Solubility of ascorbyl palmitate.

Solvent Solubility at 208C unless otherwise stated(1)

Acetone 1 in 15

Chloroform 1 in 3300

1 in 11 at 608C Cottonseed oil 1 in 1670

Ethanol 1 in 8

1 in 1.7 at 708C

Ethanol (95%) 1 in 9.3

Ethanol (50%) 1 in 2500

Sunflower oil 1 in 3300

Water Practically insoluble 1 in 500 at 708C

1 in 100 at 1008C

Stability and Storage Conditions

Ascorbyl palmitate is stable in the dry state, but is gradually oxidized and becomes discolored when exposed to light and high humidity. In an unopened container, stored in a cool place, it has a shelf life of at least 12 months. During processing, temperatures greater than 658C should be avoided.

The bulk material should be stored in an airtight container at 8–158C, protected from light.

52 Ascorbyl Palmitate

Incompatibilities

Incompatibilities are known with oxidizing agents, e.g., in solution oxidation is catalyzed by trace metal ions such as Cu2+ and Fe3+.

Method of Manufacture

Ascorbyl palmitate is prepared synthetically by the reaction of ascorbic acid with sulfuric acid followed by reesterification with palmitic acid.

Safety

Ascorbyl palmitate is used in oral pharmaceutical formulations and food products and is generally regarded as an essentially nontoxic and nonirritant material. The WHO has set an estimated acceptable daily intake for ascorbyl palmitate at up to 1.25 mg/kg body-weight.(2)

LD50 (mouse, oral): 25 g/kg(3) LD50 (rat, oral): 10 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Ascorbyl palmitate dust may cause irritation to the eyes and respiratory tract. Eye protection is recommended.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (oral, rectal, topical preparations). Included in nonparenteral medicines licensed in the UK.

Related Substances

Ascorbic acid; sodium ascorbate.

Comments

The EINECS number for ascorbyl palmitate is 205-305-4.

In order to maximize the stability and efficacy of ascorbyl palmitate the following precautions are recommended: stainless

steel, enamel, or glass should be used; deaeration (vacuum) procedures and inert gas treatment are recommended where feasible; protect from light and radiant energy.

The formation of ascorbyl palmitate vesicles (Aspasomes) and their pharmaceutical applications has recently been investigated.(4)

Specific References

Kla¨ ui H. Tocopherol, carotene and ascorbyl palmitate. Int Flavours Food Addit 1976; 7(4): 165–172.

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

Gopinath D, Ravi D, Rao BR, et al. Ascorbyl palmitate vesicles (Aspasomes): formation, characterization and applications. Int J Pharm 2004; 271: 95–113.

General References

Austria R, Semenzato A, Bettero A. Stability of vitamin C derivatives in solution and topical formulations. J Pharm Biomed Anal 1997; 15: 795–801.

Daniel JW. Metabolic aspects of antioxidants and preservatives.

Xenobiotica 1986; 16(10–11): 1073–1078.

Johnson DM, Gu LC. Autoxidation and antioxidants. In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, vol. 1. New York: Marcel Dekker, 1988: 415–449.

Pongracz G. Antioxidant mixtures for use in food. Int J Vitam Nutr Res 1973; 43: 517–525.

Sˇpiclin P, Gasˇperlin M, Kmetec V. Stability of ascorbyl palmitate in

topical microemulsions. Int J Pharm 2001; 222: 271–279.

Weller PJ, Newman CM, Middleton KR, Wicker SM. Stability of a novel dithranol ointment formulation, containing ascorbyl palmi- tate as an anti-oxidant. J Clin Pharm Ther 1990; 15: 419–423.

BP: Aspartame PhEur: Aspartamum USPNF: Aspartame

Synonyms

3-Amino-N-(a-carboxyphenethyl)succinamic acid N-methyl ester; 3-amino-N-(a-methoxycarbonylphenethyl)succinamic acid; APM; aspartyl phenylamine methyl ester; Canderel; E951; Equal; methyl N-a-L-aspartyl-L-phenylalaninate; NutraSweet; Pal Sweet; Pal Sweet Diet; Sanecta; SC-18862; Tri-Sweet.

Chemical Name and CAS Registry Number

N-a-L-Aspartyl-L-phenylalanine 1-methyl ester [22839-47-0]

Empirical Formula and Molecular Weight

Applications in Pharmaceutical Formulation or Technology

Aspartame is used as an intense sweetening agent in beverage products, food products, and table-top sweeteners, and in pharmaceutical preparations including tablets,(1,2) powder mixes, and vitamin preparations. It enhances flavor systems and can be used to mask some unpleasant taste characteristics; the approximate sweetening power is 180–200 times that of sucrose.

Unlike some other intense sweeteners, aspartame is meta- bolized in the body and consequently has some nutritive value:

SEM: 1

Excipient: Aspartame Magnification: 70× Voltage: 3 kV

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for aspartame.

Test PhEur 2005 USPNF 23

Characters + —

Identification + +

Appearance of solution + — Conductivity 430 mS/cm —

Specific optical rotation +14.58 to +16.58 +14.58 to +16.58

Related substances + —

Heavy metals 410 ppm 40.001%

Loss on drying 44.5% 44.5%

Sulfated ash 40.2% 40.2%

Impurities + —

Transmittance — +

1 g provides approximately 17 kJ (4 kcal). However, in practice, the small quantity of aspartame consumed provides a minimal

Limit of 5-benzyl-3,6-dioxo-

2-piperazineacetic acid

— 41.5%

nutritive effect.

Therapeutically, aspartame has also been used in the treatment of sickle cell anemia.(3)

Description

Aspartame occurs as an off white, almost odorless crystalline powder with an intensely sweet taste.

Organic volatile impurities — +

Assay 98.0–102.0% 98.0–102.0%

Typical Properties

Acidity/alkalinity: pH = 4.5–6.0 (0.8% w/v aqueous solution).

Brittle fracture index: 1.05(4)

54 Aspartame

Bonding index:

0.8 × 102 (worst case)(4)

2.3 × 102 (best case)(4)

Flowability: 44% (Carr compressibility index)(4)

Density (bulk):

0.5–0.7 g/cm3 for granular grade;

Incompatibilities

Differential scanning calorimetry experiments with some directly compressible tablet excipients suggests that aspartame is incompatible with dibasic calcium phosphate and also with the lubricant magnesium stearate.(10) Reactions between

aspartame and sugar alcohols are also known.

0.2–0.4 g/cm for powder grade;

0.17 g/cm3 (Spectrum Quality Products).(4)

Density (tapped): 0.29 g/cm3 (Spectrum Quality Products)(4)

Density (true): 1.347 g/cm3

Effective angle of internal friction: 43.08(4)

Melting point: 246–2478C

Solubility: slightly soluble in ethanol (95%); sparingly soluble in water. At 208C the solubility is 1% w/v at the isoelectric point (pH 5.2). Solubility increases at higher temperature and at more acidic pH, e.g., at pH 2 and 208C solubility is 10% w/v.

Specific rotation [a]22: —2.38 in 1 N HCl

Stability and Storage Conditions

Aspartame is stable in dry conditions. In the presence of moisture, hydrolysis occurs to form the degradation products L-aspartyl-L-phenylalanine and 3-benzyl-6-carboxymethyl-2,5- diketopiperazine. A third-degradation product is also known, b-L-aspartyl-L-phenylalanine methyl ester. For the stability profile at 258C in aqueous buffers, see Figure 1.

Stability in aqueous solutions has been enhanced by the addition of cyclodextrins,(5,6) and by the addition of poly- ethylene glycol 400 at pH 2.(7) However, at pH 3.5–4.5 stability is not enhanced by the replacement of water with organic solvents.(8)

Aspartame degradation also occurs during prolonged heat treatment; losses of aspartame may be minimized by using processes that employ high temperatures for a short time followed by rapid cooling.

The bulk material should be stored in a well-closed container, in a cool, dry place.

Figure 1: Stability profile of aspartame in aqueous buffers at 258C.(9)

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