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01 Excipients Prelims 1..9 244 Docusate Sodium LD50 (mouse, OP): 2.05 g/kg The EINECS number for disodium edetate is 205-358-3. The LD (rabbit, IV): 0.047 g/kg PubChem Compound ID (CID) for disodium edetate includes 8759 50 and 636371. LD50 (rabbit, OP): 2.3 g/kg LD (rat, OP): 2.0 g/kg 50 19 Specific References 1 Ungphaiboon S, Maitani Y. In vitro permeation studies of triamcino- 15 Handling Precautions lone acetonide mouthwashes. Int J Pharm 2001; 220: 111–117. Observe normal precautions appropriate to the circumstances and 2 Kaur IP et al. Formulation and evaluation of ophthalmic preparations D quantity of material handled. Disodium edetate and its derivatives of acetazolamide. Int J Pharm 2000; 199: 119–127. are mild irritants to the mucous membranes. Eye protection, gloves, 3 Bechgaard E et al. Reversibility and clinical relevance of morphological and dust masks are recommended. changes after nasal application of ephedrine nasal drops 1%. Int J Pharm 1997; 152: 67–73. 16 Regulatory Status 4 Morgan BW et al. Adverse effects in 5 patients receiving EDTA at an outpatient chelation clinic. Vet Hum Toxicol 2002; 44(5): 274–276. GRAS listed. Included in the FDA Inactive Ingredients Database 5 FAO/WHO. Toxicological evaluation of certain food additives with a (inhalations; injections; ophthalmic preparations; oral capsules, review of general principles and of specifications. Seventeenth report of solutions, suspensions, syrups, and tablets; rectal topical, and the joint FAO/WHO expert committee on food additives. World Health vaginal preparations). Included in nonparenteral and parenteral Organ Tech Rep Ser 1974; No. 539. medicines licensed in the UK. Included in the Canadian List of 6 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th Acceptable Non-medicinal Ingredients. edn. New York: Wiley, 2004; 1660. 7 Huang YB et al. Effect of antioxidants and anti-irritants on the stability, skin irritation and penetration capacity of captopril gel. Int J Pharm 17 Related Substances 2002; 241: 345–351. Edetic acid. 8 Valenta C et al. Chitosan–EDTA conjugate: novel polymer for topical gels. J Pharm Pharmacol 1998; 50: 445–452. 18 Comments Disodium edetate has been used experimentally to investigate the 20 General References stability and skin penetration capacity of captopril gel, in which — disodium edetate was shown to exert a potent stabilizing effect, and may be used in the development of a transdermal drug delivery 21 Authors (7) system. S Shah, D Thassu. A chitosan–EDTA conjugate has been investigated as a novel polymer for use in topical gels. The conjugate was shown to be stable, colorless, and transparent, and it also demonstrated 22 Date of Revision antimicrobial effects.(8) 30 January 2009. Docusate Sodium 1 Nonproprietary Names 5 Structural Formula BP: Docusate Sodium PhEur: Docusate Sodium USP: Docusate Sodium 2 Synonyms Bis(2-ethylhexyl) sodium sulfosuccinate; dioctyl sodium sulfosuc- cinate; DSS; natrii docusas; sodium 1,4-bis(2-ethylhexyl) sulfosuc- cinate; sodium 1,4-bis[(2-ethylhexyl)oxy]-1,4-dioxobutane-2- sulfonate; sodium dioctyl sulfosuccinate; sulfo-butanedioic acid 6 Functional Category 1,4-bis(2-ethylhexyl) ester, sodium salt; sulfosuccinic acid 1,4-bis(2- Anionic surfactant; fecal softener; wetting agent. ethylhexyl) ester S-sodium salt. 7 Applications in Pharmaceutical Formulation or 3 Chemical Name and CAS Registry Number Technology Sodium 1,4-bis(2-ethylhexyl) sulfosuccinate [577-11-7] Docusate sodium and docusate salts are widely used as anionic surfactants in pharmaceutical formulations. Docusate sodium is mainly used in capsule and direct-compression tablet formulations 4 Empirical Formula and Molecular Weight to assist in wetting and dissolution.(1) Docusate salts are also used in C20H37NaO7S 444.56 oral formulations as laxatives and fecal softeners; see Table I. Docusate Sodium 245 1.5 1.01.0 Table I: Uses of docusate sodium. 1674 2290 Use Concentration (%) 2329 1741 1883 2236 IM injections 0.015 Surfactant (wetting/dispersing/emulsifying agent) 0.01–1.0 a Tablet coating agent 20( ) 0.0 Tablet disintegrant 0.5 (a) Formulation of a tablet coating solution: 20% docusate sodium; 2–15% sodium 2135 log(1/R)log(1/R) 1190 1911 benzoate; 0.5% propylene glycol; solution made in ethanol (70%). 2344 D 1721 2268 1692 2306 1000 x [2nd deriv. log(1/R)] −2.0 −0.1 8 Description 1100 1300 1500 1700 1900 2100 2300 2500 Docusate sodium is a white or almost white, waxlike, bitter tasting, Wavelength/nm plastic solid with a characteristic octanol-like odor. It is hygroscopic and usually available in the form of pellets, flakes, or rolls of tissue- Figure 1: Near-infrared spectrum of docusate sodium measured by thin material. reflectance. Table IV: Solubility of docusate sodium. 9 Pharmacopeial Specifications Solvent Solubility at 208C unless otherwise stated See Table II. Acetone Soluble Chloroform 1 in 1 Table II: Pharmacopeial specifications for docusate sodium. Ethanol (95%) 1 in 3 Ether 1 in 1 Test PhEur 6.0 USP 32 Glycerin Freely soluble Vegetable oils Soluble Identification þþ a Water 1 in 70 at 258C( ) Characters þ — 1in56at308C Alkalinity þ — 1in44at408C Bis(2-ethylhexyl) maleate — 40.4% 1in33at508C Chlorides 4350 ppm — 1in25at608C Clarity of solution — þ 1in18at708C Heavy metals 410 ppm 40.001% þ Related nonionic substances — (a) In water, higher concentrations form a thick gel. Residue on ignition — 15.5–16.5% Sodium sulfate 42.0% — Water 43.0% 42.0% Assay (dried basis) 98.0–101.0% 99.0–100.5% Table V: Surface tension of docusate sodium. Concentration in water at 258C (% w/v) Surface tension (mN/m) 0.001 62.8 0.1 28.7 1.0 26.0 10 Typical Properties Acidity/alkalinity pH = 5.8–6.9 (1% w/v aqueous solution). Acid value 42.5 Critical micelle concentration 0.11% w/v aqueous solution at 11 Stability and Storage Conditions 258C. Docusate sodium is stable in the solid state when stored at room Density 1.16 g/cm3 temperature. Dilute aqueous solutions of docusate sodium between Hydroxyl value 6.0–8.0 pH 1–10 are stable at room temperature. However, at very low pH Interfacial tension In water versus mineral oil at 258C, see Table (<1) and very high pH (>10) docusate sodium solutions are subject III. to hydrolysis. The solid material is hygroscopic and should be stored in an Table III: Interfacial tension of docusate sodium. airtight container in a cool, dry place. Concentration (% w/v) Interfacial tension (mN/m) 12 Incompatibilities 0.01 20.7 Electrolytes, e.g. 3% sodium chloride, added to aqueous solutions 0.1 5.9 (2,3) 1.0 1.84 of docusate sodium can cause turbidity. However, docusate sodium possesses greater tolerance to calcium, magnesium, and other polyvalent ions than do some other surfactants. Docusate Iodine number 40.25 < 8 sodium is incompatible with acids at pH 1 and with alkalis at pH Melting point 153–157 C > 10. Moisture content 1.51% NIR spectra see Figure 1. Saponification value 240–253 13 Method of Manufacture Solubility see Table IV. Maleic anhydride is treated with 2-ethylhexanol to produce dioctyl Surface tension see Table V. maleate, which is then reacted with sodium bisulfite. 246 Docusate Sodium 14 Safety Appearance White amorphous solid with a characteristic octanol- Docusate salts are used in oral formulations as therapeutic agents like odor. for their fecal softening and laxative properties. As a laxative in Solubility Soluble in ethanol (95%) and glycerin; sparingly adults, up to 500 mg of docusate sodium is administered daily in soluble in water. divided doses; in children over 6 months old, up to 75 mg in divided doses is used. The quantity of docusate sodium used as an excipient 18 Comments in oral formulations should therefore be controlled to avoid (4) A convenient way of making a 1% w/v aqueous solution of unintended laxative effects. Adverse effects associated with docusate sodium is to add 1 g of solid to about 50 mL of water and D docusate sodium include diarrhea, nausea, vomiting, abdominal to apply gentle heat. The docusate sodium dissolves in a short time cramps, and skin rashes. As with the chronic use of laxatives, the and the resulting solution can be made up to 100 mL with water. excessive use of docusate sodium may produce hypomagnesemia.(5) Alternatively, 1 g may be soaked overnight in 50 mL of water and Docusate salts are absorbed from the gastrointestinal tract and excreted in bile; they may cause alteration of the gastrointestinal the additional water may then be added with gentle heating and epithelium.(6,7) The gastrointestinal or hepatic absorption of other stirring. drugs may also be affected by docusate salts, enhancing activity and Docusate sodium may alter the dissolution characteristics of possibly toxicity. Docusate sodium should not be administered with certain dosage forms and the bioavailability of some drugs. mineral oil as it may increase the absorption of the oil. A specification for docusate sodium is contained in the Food (9) (8) Chemicals Codex (FCC). LD50 (mouse, IV): 0.06 g/kg The EINECS number for docusate sodium is 209-406-4. The LD50 (mouse, oral): 2.64 g/kg PubChem Compound ID (CID) for docusate sodium is 23673837. LD50 (rat, IP): 0.59 g/kg LD50 (rat, oral): 1.9 g/kg 19 Specific References 1 Brown S et al. Surface treatment of the hydrophobic drug danazol to 15 Handling Precautions improve drug dissolution. Int J Pharm 1998; 165: 227–237. Observe normal precautions appropriate to the circumstances and 2 Ahuja S, Cohen J. Dioctyl sodium sulfosuccinate. Florey K, ed. quantity of material handled. Docusate sodium may be irritant to Analytical Profiles of Drug Substances., vol. 2: New York: Academic the eyes and skin, and when inhaled.
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