Related Substances

Anhydrous sodium propionate; calcium propionate; potassium propionate; propionic acid; zinc propionate.

Anhydrous sodium propionate Empirical formula: C3H5O2Na Molecular weight: 96.06

CAS number: [137-40-6]

Synonyms: E281; propanoic acid, sodium salt, anhydrous.

Safety:

LD50 (mouse, oral): 2.35 g/kg(4) LD50 (rat, oral): 3.92 g/kg

Calcium propionate

Empirical formula: C6H10O4Ca

Molecular weight: 186.22

CAS number: [4075-81-4]

Synonyms: calcium dipropionate; E282; propanoic acid, calcium salt; propionic acid, calcium salt.

211.52

CAS number: [557-28-8]

Synonyms: propanoic acid, zinc salt; propionic acid, zinc salt.

Appearance: white platelets or needlelike crystals (for the monohydrate).

Solubility: the anhydrous form is soluble 1 in 36 of ethanol (95%) at 158C, 1 in 6 of boiling ethanol (95%), and 1 in 3 of water at 158C.

Method of manufacture: prepared by dissolving zinc oxide in dilute propionic acid solution.

Comments: occurs as the anhydrous form and the monohy- drate. Decomposes in moist air to give off propionic acid.

Comments

Propionates are used as antimicrobial preservatives in pre- ference to propionic acid since they are less corrosive.

The therapeutic use of sodium propionate in topical antifungal preparations has largely been superseded by a new generation of antifungal drugs. A specification for sodium propionate is contained in the Food Chemicals Codex (FCC). The EINECS number for sodium propionate is 205-290-4.

Specific References

Bishop Y, ed. The Veterinary Formulary, 6th edn. London: Pharmaceutical Press, 2005: 419–420.

Heseltine WW. A note on sodium propionate. J Pharm Pharmacol

1952; 4: 120–122.

Graham WD, Teed H, Grice HC. Chronic toxicity of bread additives to rats. J Pharm Pharmacol 1954; 6: 534–545.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3276.

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

General References

Doores S. Organic acids. In: Branen AL, Davidson PM, eds. Antimicrobials in Foods. New York: Marcel Dekker, 1983: 85–87. Furia TE, ed. CRC Handbook of Food Additives. Cleveland, OH: CRC

Press, 1972: 137–141.

Authors

SC Owen.

Date of Revision

9 August 2005.

Sodium Starch Glycolate

Nonproprietary Names

BP: Sodium starch glycollate PhEur:Carboxymethylamylum natricum USPNF: Sodium starch glycolate

Synonyms

Carboxymethyl starch, sodium salt; Explosol; Explotab; Glycolys; Primojel; starch carboxymethyl ether, sodium salt; Tablo; Vivastar P.

Chemical Name and CAS Registry Number

Sodium carboxymethyl starch [9063-38-1]

Empirical Formula and Molecular Weight

The USPNF 23 states that sodium starch glycolate is the sodium salt of a carboxymethyl ether of starch, containing 2.8–4.2% sodium.

The PhEur 2005 describes three types of material: Types A and B occur as the sodium salt of a cross-linked partly O- carboxymethylated potato starch, containing 2.8–4.2% and 2.0–3.4% of sodium respectively. Type C is the sodium salt of a cross-linked by physical dehydration, partly O-carboxymethy- lated starch containing 2.8–5.0% sodium.

The JP, PhEur and USPNF monographs have been harmonised for Type A and Type B variants.

Sodium starch glycolate may be characterized by the degree of substitution and crosslinking. The molecular weight is typically 5 × 105–1 × 106.

Structural Formula

 

Functional Category

Tablet and capsule disintegrant.

Applications in Pharmaceutical Formulation or Technology

Sodium starch glycolate is widely used in oral pharmaceuticals as a disintegrant in capsule(1–6) and tablet formulations.(7–10) It is commonly used in tablets prepared by either direct- compression(11–13)  or  wet-granulation  processes.(14–16)  The

usual concentration employed in a formulation is between 2% and 8%, with the optimum concentration about 4%, although in many cases 2% is sufficient. Disintegration occurs by rapid uptake of water followed by rapid and enormous swelling.(17–20)

Although the effectiveness of many disintegrants is affected by the presence of hydrophobic excipients such as lubricants, the disintegrant efficiency of sodium starch glycolate is unimpaired. Increasing the tablet compression pressure also appears to have no effect on disintegration time.(10–14)

Sodium starch glycolate has also been investigated for use as a suspending vehicle.(21,22)

Description

Sodium starch glycolate is a white to off-white, odorless, tasteless, free-flowing powder. The PhEur 2005 states that it consists of oval or spherical granules, 30–100 mm in diameter, with some less-spherical granules ranging from 10–35 mm in diameter.

Pharmacopeial Specifications

See Table I.

 

Table I: Pharmacopeial specifications for sodium starch glycolate.    

Test PhEur 2005 USPNF 23    

Identification + +    

Characters + —    

Appearance of solution + —    

pH + 3.0–5.0 or    

5.5–7.5    

Type A 5.5–7.5 —    

Type B 3.0–5.9 —    

Type C 5.5–7.5 —    

Heavy metals 420 ppm 40.002%    

Iron 420 ppm 40.002%    

Loss on drying + +    

Type A 410.0% —    

Type B 410.0% —    

Type C 47.0% —    

Microbial limits + +    

Sodium chloride + +    

Type A 47.0% 47.0%    

Type B 47.0% 47.0%    

Type C 41.0% —    

Sodium glycolate

Assay (of Na) 42.0%

+ —

2.8–4.2%    

Type A 2.8–4.2% —    

Type B 2.0–3.4% —    

Type C 2.8–5.0% —  

Typical Properties

Acidity/alkalinity: pH = 3.0–5.0 or pH = 5.5–7.5 for a 3.3% w/v aqueous dispersion. See Section 18.

702 Sodium Starch Glycolate

Ash: 415% for Explotab

Density (bulk): 0.756 g/cm3;

0.75 g/cm3 for Explotab;

0.81 g/cm3 for Primojel;

0.67 g/cm3 for Tablo.

Density (tapped): 0.945 g/cm3;

0.88 g/cm3 for Explotab;

0.98 g/cm3 for Primojel;

0.83 g/cm3 for Tablo.

Density (true): 1.443 g/cm3;

1.51 g/cm3 for Explotab;

1.56 g/cm3 for Primojel;

1.49 g/cm3 for Tablo.

Melting point: does not melt, but chars at approximately 2008C.

Particle size distribution: 100% of particles less than 106 mm in size. Average particle size is 35–55 mm for Explotab.

Solubility: sparingly soluble in ethanol (95%); practically insoluble in water. At a concentration of 2% w/v sodium starch glycolate disperses in cold water and settles in the form of a highly hydrated layer.

Specific surface area: 0.24 m2/g;

0.202 m2/g for Explotab;

0.185 m2/g for Primojel;

0.335 m2/g for Tablo;

Swelling capacity: in water, sodium starch glycolate swells to up to 300 times its volume.

Viscosity (dynamic): 4200 mPa s (200 cP) for a 4% w/v aqueous dispersion. Viscosity is 4.26 mPa s for a 2% w/v aqueous dispersion.

SEM 1

Excipient: Sodium starch glycolate (Explotab)

Manufacturer: JRS Pharma Magnification: 300× Voltage: 5 kV

 

SEM 2

Excipient: Sodium starch glycolate (Glycolys)

Manufacturer: Roquettes Fre`res

 

SEM 3

Excipient: Sodium starch glycolate (Primojel) Manufacturer: DMV-International Magnification: 200×

Voltage: 1.5 kV

 

Stability and Storage Conditions

Tablets prepared with sodium starch glycolate have good storage properties.(23–25) Sodium starch glycolate is stable and should be stored in a well-closed container in order to protect it from wide variations of humidity and temperature, which may cause caking.

The physical properties of sodium starch glycolate remain unchanged for up to 3–5 years if it is stored at moderate temperatures and humidity.

Sodium Starch Glycolate 703

SEM 4

Excipient: Sodium starch glycolate (Vivastar P) Manufacturer: JRS Pharma

Magnification: 300×

Voltage: 5 kV

 

Incompatibilities

Sodium starch glycolate is incompatible with ascorbic acid.(26)

Method of Manufacture

Sodium starch glycolate is a substituted derivative of potato starch. Typically, commercial products are also cross-linked.

Starch is carboxymethylated by reacting it with sodium chloroacetate in an alkaline medium followed by neutralization with citric acid or some other acid. Crosslinking may be achieved either by physical methods or chemically by using reagents such as phosphorus oxytrichloride or sodium tri- metaphosphate.(27)

Safety

Sodium starch glycolate is widely used in oral pharmaceutical formulations and is generally regarded as a nontoxic and nonirritant material. However, oral ingestion of large quantities may be harmful.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Sodium starch glycolate may be irritant to the eyes; eye protection and gloves are recommended. A dust mask or respirator is recommended for processes that generate a large quantity of dust.

Regulatory Acceptance

Included in the FDA Inactive Ingredients Guide (oral capsules and tablets). Included in nonparenteral medicines licensed in



the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Pregelatinized starch; starch.

Comments

The physical properties of sodium starch glycolate, and hence its effectiveness as a disintegrant, are affected by the degree of crosslinkage, extent of carboxymethylation, and purity.(28,29)

Sodium starch glycolate has been reported to interact with glycopeptide antibiotics,(30,31) basic drugs, and increase the photostability of norfloxacin.(32) The solubility of the formula- tion matrix and mode of incorporation in wet granulation can affect the disintegration time; disintegration times can be slower in tablets containing high levels of soluble excipients.(33)

Commercially, sodium starch glycolate is available in a number of speciality grades, e.g. low pH (Explotab Low pH, Glycolys Low pH); low viscosity (Explotab CLV, Glycolys LV); enhanced swelling (Explotab V17); low solvent (Vivastar PSF); and viscous (Vivastar P3500, P5000).

Specific References

Newton JM, Razzo FN. The interaction of formulation factors and dissolution fluid and the in vitro release of drug from hard gelatin capsules. J Pharm Pharmacol 1975; 27: 78P.

Stewart AG, Grant DJW, Newton JM. The release of a model low- dose drug (riboflavine) from hard gelatin capsule formulations. J Pharm Pharmacol 1979; 31: 1–6.

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

Botzolakis JE, Augsburger LL. Disintegrating agents in hard gelatin capsules part 1: mechanism of action. Drug Dev Ind Pharm 1988; 14(1): 29–41.

Hannula A-M, Marvola M, Jo¨ ns M. Release of ibuprofen from hard gelatin capsule formulations: effect of modern disintegrants. Acta Pharm Fenn 1989; 98: 189–196.

Marvola M, Hannula A-M, Ojantakanen S, et al. Effect of sodium bicarbonate and sodium starch glycolate on the in vivo disintegra- tion of hard gelatin capsules – a radiological study in the dog. Acta Pharm Nord 1989; 1: 355–362.

Khan KA, Rooke DJ. Effect of disintegrant type upon the relationship between compressional pressure and dissolution efficiency. J Pharm Pharmacol 1976; 28: 633–636.

Rubinstein MH, Price EJ. In vivo evaluation of the effect of five disintegrants on the bioavailability of frusemide from 40 mg tablets. J Pharm Pharmacol 1977; 29: 5P.

Caramella C, Colombo P, Coute U, La Manna A. The influence of disintegrants on the characteristics of coated acetylsalicylic acid tablets. Farmaco (Prat) 1978; 33: 498–507.

Gebre Mariam T, Winnemoller M, Schmidt PC. Evaluation of the disintegration efficiency of a sodium starch glycolate prepared from enset starch in compressed tablets. Eur J Pharm Biopharm 1996; 42(2): 124–132.

Cid E, Jaminet F. Influence of adjuvants on the dissolution rate and stability of acetylsalicylic acid in compressed tablets [in French]. J Pharm Belg 1971; 26: 38–48.

Gordon MS, Chowhan ZT. Effect of tablet solubility and hygroscopicity on disintegrant efficiency in direct compression tablets in terms of dissolution. J Pharm Sci 1987; 76: 907–909.

Kaiho F, Luessen HL, Lehr CM, et al. Disintegration and gel forming behavior of carbomer and its sodium salt used as excipients for direct compression. STP Pharma Sci 1996; 6(6): 385–389.

704 Sodium Starch Glycolate

Sekulovic´ D, Tufegdzˇic´ N, Birmancˇevic´ M. The investigation of the influence of Explotab on the disintegration of tablets. Pharmazie 1986; 41: 153–154.

Bolhius GK, Zuurman K, Te-Wierik GH. Improvement of dissolution of poorly soluble drugs by solid deposition on a super disintegrant. Part 2. Choice of super disintegrants and effect of granulation. Eur J Pharm Sci 1997; 5(2): 63–69.

Joachim J, Kalantzis G, Joachim G, et al. Pregelatinized starches in wet granulation: experimental design and data analysis. Part 2. Case of tablets. STP Pharma Sci 1994; 4(6): 482–486.

Khan KA, Rhodes CT. Disintegration properties of calcium phosphate dibasic dihydrate tablets. J Pharm Sci 1975; 64: 166– 168.

Khan KA, Rhodes CT. Water-sorption properties of tablet disintegrants. J Pharm Sci 1975; 64: 447–451.

Wan LSC, Prasad KPP. Uptake of water by excipients in tablets. Int J Pharm 1989; 50: 147–153.

Thibert R, Hancock BC. Direct visualization of superdisintegrant hydration using environmental scanning electron microscopy. J Pharm Sci 1996; 85: 1255–1258.

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

Smith G, McIntosh IEE. Suspending agents for extemporaneous dispensing [letter]. Pharm J 1976; 217: 42.

Horhota ST, Burgio J, Lonski L, Rhodes CT. Effect of storage at specified temperature and humidity on properties of three directly compressible tablet formulations. J Pharm Sci 1976; 65: 1746–

1749.

Sheen P-C, Kim S-I. Comparative study of disintegrating agents in tiaramide hydrochloride tablets. Drug Dev Ind Pharm 1989; 15(3): 401–414.

Gordon MS, Chowhan ZT. The effect of aging on disintegrant efficiency in direct compression tablets with varied solubility and hygroscopicity, in terms of dissolution. Drug Dev Ind Pharm 1990; 16(3): 437–447.

Botha SA, Lo¨ tter AP, Du Preez JL. DSC screening for drug– excipient and excipient–excipient interactions in polypharmaceu- ticals intended for the alleviation of the symptoms of colds and flu.

III. Drug Dev Ind Pharm 1987; 13(7): 1197–1215.

Bolhuis GK, van Kamp HV, Lerk CF. On the similarity of sodium starch glycolate from different sources. Drug Dev Ind Pharm 1986; 12(4): 621–630.

Rudnic EM, Kanig JL, Rhodes CT. Effect of molecular structure variation on the disintegrant action of sodium starch glycolate. J Pharm Sci 1985; 74: 647–650.

Bolhuis GK, van Kamp HV, Lerk CF. Effect of variation of degree of substitution, crosslinking and purity on the disintegrant efficiency of sodium starch glycolate. Acta Pharm Technol 1984; 30: 24–32.

Claudius JS, Neau SH. Kinetic and equilibrium characterization of interactions between glycopeptide antibiotics and sodium carb- oxymethyl starch. Int J Pharm 1996; 144: 71–79.

Claudius JS, Neau SH. Solution stability of vancomycin in the presence and absence of sodium carboxymethyl starch. Int J Pharm 1998; 168: 41–48.

Cordobo-Borrego M, Cordobo-Diaz M, Cordobo-Diaz D. Valida- tion of a high performance liquid chromatographic method for the determination of norfloxacin and its application to stability studies (photostability study of norfloxacin). J Pharm Biomed Anal 1998; 18: 919–926.

Gordon MS, Rudraraju VS, Dani K, Chowhan ZT. Effect of the mode of super disintegrant incorporation on dissolution in wet granulated tablets. J Pharm Sci 1993; 82: 220–226.

General References

Augsberger LL, Hahm HA, Brzecko AW, Shah U. Superdisintegrants: characterisation and function. In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, 2nd edn. New York: Marcel Dekker, 2002: 2623–2638.

DMV-International. Technical literature: Primojel, 2003.

Edge S, Belu AM, Potter UJ, et al. Chemical characterisation of sodium starch glycolate particles. Int J Pharm 2002; 240: 67–78.

Edge S, Steele DF, Staniforth JN, et al. Powder compaction properties of sodium starch glycolate disintegrants. Drug Dev Ind Pharm 2002; 28(8): 989–999.

Ferrari F, Rossi S, Bonferoni MC, et al. The influence of product brand and batch to batch variability on superdisintegrant performance. STP Pharm Sci 2000; 10(6): 459–465.

JRS Pharma. Technical literature: Explotab, Vivastar P, 2004.

Khan KA, Rhodes CT. Further studies of the effect of compaction pressure on the dissolution efficiency of direct compression systems. Pharm Acta Helv 1974; 49: 258–261.

Mantovani F, Grassi M, Colombo I, Lapasin R. A combination of vapor sorption and dynamic laser light scattering methods for the determination of the Flory parameter chi and the crosslink density of a powdered polymeric gel. Fluid Phase Equilib 2000; 167(1): 63–

81.

Mendell E. An evaluation of carboxymethyl starch as a tablet disintegrant. Pharm Acta Helv 1974; 49: 248–250.

Roquette Fre`res. Technical literature: Glycolys, 2004.

Shah U, Augsberger L. Multiple sources of sodium starch glycolate NF: evaluation of functional equivalence and development of standard performance tests. Drug Dev Ind Pharm 2002; 7(3): 345–359.

Authors

S Edge, RW Miller.

Date of Revision

17 August 2005.

Sodium Stearyl Fumarate

Nonproprietary Names

BP: Sodium stearyl fumarate PhEur: Natrii stearylis fumaras USPNF: Sodium stearyl fumarate

Synonyms

Fumaric acid, octadecyl ester, sodium salt; Pruv; sodium monostearyl fumarate.

Chemical Name and CAS Registry Number

2-Butenedioic acid, monooctadecyl ester, sodium salt [4070- 80-8]

Empirical Formula and Molecular Weight

Table I: Pharmacopeial specifications for sodium stearyl fumarate.

 

Test PhEur 2005 USPNF 23    

Identification + +    

Characters + —    

Water 45.0% 45.0%    

Lead — 40.001%    

Heavy metals — 40.002%    

Related substances + —    

Sodium stearyl maleate — 40.25%    

Stearyl alcohol — 40.5%    

Saponification value (anhydrous — 142.2–146.0  

basis)

Organic volatile impurities — +

Assay (anhydrous basis) 99.0–101.5%  99.0–101.5%

Typical Properties

Acidity/alkalinity: pH = 8.3 for a 5% w/v aqueous solution at 908C.

C22

H39

NaO4

390.5

Density: 1.107 g/cm3

Density (bulk): 0.2–0.35 g/cm3

Density (tapped): 0.3–0.5 g/cm3

Melting point: 224–2458C (with decomposition)

Structural Formula

 

Functional Category

Tablet and capsule lubricant.

Applications in Pharmaceutical Formulation or Technology

Sodium stearyl fumarate is used as a lubricant in capsule and tablet formulations at 0.5–2.0% w/w concentration.(1–9) It is also used in certain food applications; see Section 16.

Description

Sodium stearyl fumarate is a fine, white powder with agglomerates of flat, circular-shaped particles.

Pharmacopeial Specifications

See Table I.

Solubility: see Table II.

Table II: Solubility of sodium stearyl fumarate.

Solvent Solubility at 208C unless otherwise stated

Acetone Practically insoluble

Chloroform Practically insoluble

Ethanol Practically insoluble

Methanol Slightly soluble

Water 1 in 20 000 at 258C 1 in 10 at 808C

1 in 5 at 908C

Specific surface area: 1.2–2.0 m2/g

Stability and Storage Conditions

At ambient temperature, sodium stearyl fumarate is stable for up to 3 years when stored in amber glass bottles with polyethylene screw caps.

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

Incompatibilities

Sodium stearyl fumarate is reported to be incompatible with chlorhexidine acetate.(10)

Method of Manufacture

Stearyl alcohol is reacted with maleic anhydride. The product of this reaction then undergoes an isomerization step followed by salt formation to produce sodium stearyl fumarate.

706 Sodium Stearyl Fumarate

SEM: 1

Excipient: Sodium stearyl fumarate

Manufacturer: JRS Pharma LP

Lot No.: 255-01

Magnification: 300×