med 5

For this reason, its use in oral pharmaceutical formulations is declining.

Although sucrose has been associated with obesity, renal damage, and a number of other diseases, conclusive evidence linking sucrose intake with some diseases could not be established.(12,13) It was, however, recommended that sucrose intake in the diet should be reduced.(13)

LD50 (mouse, IP): 14 g/kg(14) LD50 (rat, oral): 29.7 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended. In the UK, the occupational exposure limit for sucrose is 10 mg/m3 long-term (8-hour TWA) and 20 mg/m3 short-term.(15)

Regulatory Status

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

Related Substances

Compressible sugar; confectioner’s sugar; invert sugar; sugar spheres.

Invert sugar

Empirical formula: C6H12O6

Molecular weight: 180.16

CAS number: [8013-17-0]

Comments: an equimolecular mixture of dextrose and fructose prepared by the hydrolysis of sucrose with a suitable mineral acid such as hydrochloric acid. Invert sugar may be used as a stabilizing agent to help prevent crystallization of sucrose syrups and graining in confectionery. A 10% aqueous solution is also used in parenteral nutrition.

Comments

For typical boiling points of sucrose syrups, without inversion of the sugar, see Table V. A specification for sucrose is contained in the Food Chemicals Codex (FCC).

The EINECS number for sucrose is 200-334-9.

Table V: Boiling points of sucrose syrups.

Sucrose concentration (% w/v) Boiling point (8C)

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

Mullarney MP, Hancock BC, Carlson GT, et al. The powder flow and compact mechanical properties of sucrose and three high intensity sweeteners used in chewable tablets. Int J Pharm 2003; 257(1–2): 227–236.

Salazar DSM, Saavedra C. Application of a sensorial response model to the design of an oral liquid pharmaceutical dosage form. Drug Dev Ind Pharm 2000; 26(1): 55–60.

Cooper J. A question of taste: uses of sucrose. Manuf Chem 2003;

74(10): 71–72, 74.

Izutsu K, Kojima S. Excipient crystallinity and its protein structure stabilizing effect during freeze-drying. J Pharm Pharmacol 2002; 54(8): 1033–1039.

Johnson RE, Kirchoff CF, Gand HE. Mannitol-sucrose mixtures: versatile formulations for protein lyophilisation. J Pharm Sci 2002; 91(4): 914–922.

Middleton KR, Seal D. Sugar as an aid to wound healing. Pharm J 1985; 235: 757–758.

Thomas S. Wound Management and Dressings. London: Pharma- ceutical Press, 1990: 62–63.

Hancock BC, Dalton CR. Effect of temperature on water vapour sorption by some amorphous pharmaceutical sugars. Pharm Dev Technol 1999; 4(1): 125–131.

Tressler LJ. Medicine bottle caps [letter]. Pharm J 1985; 235: 99.

Golightly LK, Smolinske SS, Bennett ML, et al. Pharmaceutical excipients: adverse effects associated with ‘inactive’ ingredients in drug products (part II). Med Toxicol 1988; 3: 209–240.

Yudkin J. Sugar and disease. Nature 1972; 239: 197–199.

Anonymous. Report on Health and Social Subjects 37. London: HMSO, 1989.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3318.

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

General References

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

Barry RH, Weiss M, Johnson JB, DeRitter E. Stability of phenylpro- panolamine hydrochloride in liquid formulations containing sugars. J Pharm Sci 1982; 71: 116–118.

Jackson EB, ed. Sugar Confectionery Manufacture. Glasgow: Blackie, 1990.

Lipari JM, Reiland TL. Flavors and flavor modifiers. In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 2. New York: Marcel Dekker, 2002: 1255–1263.

Wolraich ML, Lindgreen SD, Stumbo PJ, et al. Effects of diets high in sucrose or aspartame on the behavior and cognitive performance of children. N Engl J Med 1994; 330: 301–307.

USPNF: Compressible sugar

Synonyms

Di-Pac; direct compacting sucrose.

Chemical name and CAS Registry Number

See Sections 4 and 18.

Empirical Formula and Molecular Weight

The USPNF 23 states that compressible sugar contains not less than 95.0% and not more than 98.0% of sucrose (C12H22O11). It may contain starch, maltodextrin, or invert sugar, and may contain a suitable lubricant.

Structural Formula

See Section 4.

Functional Category

Sweetening agent; tablet and capsule diluent.

Applications in Pharmaceutical Formulation or Technology

Compressible sugar is used primarily in the preparation of direct-compression chewable tablets. Its tableting properties can be influenced by small changes in moisture level;(1,2) see Table I.

Table I: Uses of compressible sugar.

Use Concentration (%)

Dry binder in tablet formulations 5–20

Filler in chewable tablets 20–60

Filler in tablets 20–60

Sweetener in chewable tablets 10–50

Description

Compressible sugar is a sweet-tasting, white, crystalline powder.

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for compressible sugar.

Loss on drying 0.25–1.0%

Residue on ignition 40.1%

Microbial limits +

Organic volatile impurities +

Sulfate 40.010%

Assay 95.0–98.0%

Typical Properties

Density (bulk): 0.492 g/cm3 Density (tapped): 0.6 g/cm3 Moisture content: 0.57%

Particle size distribution: for Di-Pac, 3% maximum retained on a #40 (425 mm) mesh; 75% minimum through a #100 (150 mm) mesh; 5% maximum through #200 (75 mm) mesh.

Solubility: the sucrose portion is water-soluble.

Specific surface area: 0.13–0.14 m2/g

Stability and Storage Conditions

Compressible sugar is stable in air under normal storage conditions of room temperature and low relative humidity. The bulk material should be stored in a well-closed container in a cool, dry place.

Incompatibilities

Incompatible with dilute acids, which cause hydrolysis of sucrose to invert sugar, and with alkaline earth hydroxides, which react with sucrose to form sucrates.

Method of Manufacture

Compressible sugar is prepared by cocrystallization of sucrose with other excipients such as maltodextrin.(1) Compressible sugar may also be prepared using a dry granulation process.

Safety

Compressible sugar is generally regarded as a relatively nontoxic and nonirritant material. See also Sucrose.

Handling Precautions

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

Sugar, Compressible 749

Regulatory Status

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

Confectioner’s sugar; sucrose; sugar spheres; Sugartab.

Sugartab

Appearance: Sugartab (JRS Pharma LC) is a compressible sugar that does not conform to the USPNF 23 specification. It is an agglomerated sugar product containing approximately 90–93% sucrose, the balance being invert sugar.

Density (bulk): 0.60 g/cm3 Density (tapped): 0.69 g/cm3 EINECS number: [64333-34-2]

Flowability: 42.7 g/s

Moisture content: 0.20–0.57%.

Particle size distribution: 30% through a #20 (850 mm) mesh; 3% through a #30 (600 mm) mesh.

Comments

—

Specific References

Rizzuto AB, Chen AC, Veiga MF. Modification of the sucrose crystal structure to enhance pharmaceutical properties of excipient and drug substances. Pharm Technol 1984; 8(9): 32, 34, 36, 38–

39.

Tabibi SE, Hollenbeck RG. Interaction of water vapor and compressible sugar. Int J Pharm 1984; 18: 169–183.

General References

JRS Pharma LC. Technical literature: Sugartab, 2003.

Mendes RW, Gupta MR, Katz IA, O’Neil JA. Nu-tab as a chewable direct compression carrier. Drug Cosmet Ind 1974; 115(6): 42–46,

130–133.

Ondari CO, Kean CE, Rhodes CT. Comparative evaluation of several direct compression sugars. Drug Dev Ind Pharm 1983; 9: 1555– 1572.

Ondari CO, Kean CE, Rhodes CT. Comparative evaluation of several direct compression sugars. Drug Dev Ind Pharm 1988; 14: 1517– 1527.

Shangraw RF, Wallace JW, Bowers FM. Morphology and functionality in tablet excipients for direct compression. Pharm Technol 1981; 5: 69–78.

Sugar, Confectioner’s

Nonproprietary Names

USPNF: Confectioner’s sugar

Synonyms

Icing sugar; powdered sugar.

Chemical Name and CAS Registry Number

See Section 4.

Empirical Formula and Molecular Weight

The USPNF 23 describes confectioner’s sugar as a mixture of sucrose (C12H22O11) and corn starch that has been ground to a fine powder; it contains not less than 95.0% sucrose.

Structural Formula

See Section 4 and Sucrose.

Functional Category

Sugar coating adjunct; sweetening agent; tablet and capsule diluent.

Applications in Pharmaceutical Formulation or Technology

Confectioner’s sugar is used in pharmaceutical formulations when a rapidly dissolving form of sugar is required for flavoring or sweetening. It is used as a diluent in solid-dosage formulations when a small particle size is necessary to achieve content uniformity in blends with finely divided active ingredients. In solutions, at high concentrations (70% w/v), confectioner’s sugar provides increased viscosity along with some preservative effects. Confectioner’s sugar is also used in the preparation of sugar-coating solutions and in wet granula- tions as a binder/diluent. See Table I.

Table I: Uses of confectioner’s sugar.

Use Concentration (%)

Sweetening agent in tablets 10–20

Tablet diluent 10–50

See also Section 18.

Description

Confectioner’s sugar occurs as a sweet-tasting, fine, white, odorless powder.

SEM: 1

Excipient: Confectioner’s sugar

Excipient: Confectioner’s sugar

Sugar, Confectioner’s 751

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for confectioner’s sugar.

Organic volatile impurities +

Residue on ignition 40.08%

Specific rotation 5+62.68

Sulfate 40.006%

Assay 495.0%

Typical Properties

Density (bulk): 0.465 g/cm3 Density (tapped): 0.824 g/cm3 Moisture content: 0.1–0.31%

Particle size distribution: various grades with different particle sizes are commercially available, e.g., 6X, 10X, and 12X grades of confectioner’s sugar from the Domino Sugar Corp. Mean particle size is 14.3 mm.

For 6X, 94% through a #200 (75 mm) mesh.

For 10X, 99.9% through a #100 (150 mm) mesh and 97.5% through a #200 (75 mm) mesh.

For 12X, 99% through a #200 (75 mm) mesh and 96% through a #325 (45 mm) mesh.

Solubility: the sucrose portion is water-soluble while the starch portion is insoluble in water, although it forms a cloudy solution.

Stability and Storage Conditions

Confectioner’s sugar is stable in air at moderate temperatures but may caramelize and decompose above 1608C. It is more hygroscopic than granular sucrose. Microbial growth may occur on dry storage if adsorbed moisture is present or in dilute aqueous solutions.

Confectioner’s sugar should be stored in a well-closed container in a cool, dry place.

Incompatibilities

Confectioner’s sugar is incompatible with dilute acids, which cause the hydrolysis of sucrose to invert sugar. It is also incompatible with alkaline earth hydroxides, which react with sucrose to form sucrates.

Method of Manufacture

Confectioner’s sugar is usually manufactured by grinding refined granulated sucrose with corn starch to produce a fine powder. Other anticaking agents, such as tricalcium phosphate and various silicates, have also been used but are less common.

Safety

Confectioner’s sugar is used in confectionery and oral pharmaceutical formulations. It is generally regarded as a relatively nontoxic and nonirritant material. See also Sucrose.

Handling Precautions

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

Regulatory Status

Included in the FDA Inactive Ingredients Guide (capsules and tablets). Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Compressible sugar; sucrose; sugar spheres.

Comments

Confectioner’s sugar is not widely used in pharmaceutical formulations because the poor-flow characteristics prevent its use in direct-compression blends. However, confectioner’s sugar is used when a smooth mouth feel or a rapidly dissolving sweetener is required, and when a milled/micronized active ingredient must be blended with a diluent of similar particle size for powders or wet granulations.

Low-starch grades of confectioner’s sugar containing 0.01% w/w starch are also commercially available.

Specific References

General References

Barry RH, Weiss M, Johnson JB, DeRitter E. Stability of phenyl- propanolamine hydrochloride in liquid formulations containing sugars. J Pharm Sci 1982; 71: 116–118.

Czeisler JL, Perlman KP. Diluents. In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, vol. 4. New York: Marcel Dekker, 1988: 37–84.

Edwards WP. The Science of Sugar Confectionery. Cambridge: Royal Society of Chemistry, 2000.

Jackson EB, ed. Sugar Confectionery Manufacture. Glasgow: Blackie, 1990.

Onyekweli AO, Pilpel N. Effect of temperature changes on the densification and compression of griseofulvin and sucrose powders. J Pharm Pharmacol 1981; 33: 377–381.

Wolraich ML, Lindgren SD, Stumbo PJ, et al. Effects of diets high in sucrose or aspartame on the behavior and cognitive performance of children. N Engl J Med 1994; 330: 301–307.

BP: Sugar spheres PhEur: Sacchari spheri USPNF: Sugar spheres

Synonyms

Non-pareil; non-pareil seeds; NPTAB; Nu-Core; Nu-Pareil PG; sugar seeds; Suglets.

Chemical Name and CAS Registry Number

—

Empirical Formula and Molecular Weight

Tablet and capsule diluent.

Applications in Pharmaceutical Formulation or Technology

Sugar spheres are mainly used as inert cores in capsule and tablet formulations, particularly multiparticulate sustained- release formulations.(1–4) They form the base upon which a drug is coated, usually followed by a release-modifying polymer coating.

Alternatively, a drug and matrix polymer may be coated onto the cores simultaneously. The active drug is released over an extended period either via diffusion through the polymer or through to the controlled erosion of the polymer coating.

Complex drug mixtures contained within a single-dosage form may be prepared by coating the drugs onto different batches of sugar spheres with different protective polymer coatings.

Sugar spheres are also used in confectionery products.

Description

The USPNF 23 describes sugar spheres as approximately spherical granules of a labeled nominal-size range with a uniform diameter and containing not less than 62.5% and not more than 91.5% of sucrose, calculated on the dried basis. The remainder is chiefly starch.

The PhEur 2005 states that sugar spheres contain not more than 92% of sucrose calculated on the dried basis. The remainder consists of corn (maize) starch and may also contain starch hydrolysates and color additives. The diameter of sugar spheres varies from 200 to 2000 mm and the upper and lower limits of the size of the sugar spheres are stated on the label.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for sugar spheres.

Test PhEur 2005 USPNF 23

Identification + +

Heavy metals 45 ppm 45 ppm

Loss on drying 45.0% 44.0%

Microbial limits + +

Organic volatile impurities — +

Particle size distribution + +

Residue on ignition 40.2% 40.25%

Specific rotation — +418 to +618

Sucrose (dried basis) 492% 62.5–91.5%

Typical properties

Density:

1.57–1.59 g/cm3 for Suglets less than 500 mm in size;

1.55–1.58 g/cm3 for Suglets more than 500 mm in size.

Flowability: <10 seconds, free flowing.

Particle size distribution: sugar spheres are of a uniform

diameter. The following sizes are commercially available from various suppliers (US standard sieves):

45–60 mesh (250–355 mm)

40–50 mesh (300–425 mm)

35–45 mesh (355–500 mm)

35–40 mesh (420–500 mm)

30–35 mesh (500–600 mm)

25–30 mesh (610–710 mm)

20–25 mesh (710–850 mm)

18–20 mesh (850–1000 mm)

16–20 mesh (850–1180 mm)

14–18 mesh (1000–1400 mm)

Solubility: solubility in water varies according to the sucrose-to- starch ratio. The sucrose component is freely soluble in water, whereas the starch component is practically insoluble in cold water.

Specific surface area:

0.1–0.2 m2/g for Suglets less than 500 mm in size;

>0.2 m2/g for Suglets more than 500 mm in size.

Stability and Storage Conditions

Sugar spheres are stable when stored in a well-closed container in a cool, dry place.

Incompatibilities

See Starch and Sucrose for information concerning the incompatibilities of the component materials of sugar spheres.

Method of Manufacture

Sugar spheres are prepared from crystalline sucrose, which is coated using sugar syrup and a starch dusting powder.

Sugar Spheres 753

Safety

Sugar spheres are used in oral pharmaceutical formulations. The sucrose and starch components of sugar spheres are widely used in edible food products and oral pharmaceutical formula- tions.

The adverse reactions and precautions necessary with the starch and sucrose components should be considered in any product containing sugar spheres. For example, sucrose is generally regarded as more cariogenic than other carbo- hydrates, and in higher doses is also contraindicated in diabetic patients.

See Starch and Sucrose for further information.

Handling Precautions

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

Regulatory Status

Included in the FDA Inactive Ingredients Guide (oral capsules and tablets). Included in nonparenteral medicines licensed in the UK and Europe. The sucrose and starch components of sugar spheres are individually approved for use as food additives in Europe and the USA. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Compressible sugar; confectioner’s sugar; starch; sucrose.

Comments

—

Specific References

Narsimhan R, Labhasetwar VD, Lakhotia CL, Dorle A. Timed- release noscapine microcapsules. Indian J Pharm Sci 1988; 50: 120–122.

Bansal AK, Kakkar AP. Solvent deposition of diazepam over sucrose pellets. Indian J Pharm Sci 1990; 52: 186–187.

Ho H-O, Su H-L, Tsai T, Sheu M-T. The preparation and characterization of solid dispersions on pellets using a fluidized- bed system. Int J Pharm 1996; 139: 223–229.

Miller RA, Leung EM, Oates RJ. The compression of spheres coated with an aqueous ethylcellulose dispersion. Drug Devel Ind Pharm 1999; 25(4): 503–511.

General References

Birch GG, Parker KJ, eds. Sugar: Science and Technology. London: Applied Science Publications, 1979.

Sulfobutylether b-Cyclodextrin

Nonproprietary Names

None adopted.

Synonyms

b-Cyclodextrin sulfobutylether, sodium salt; Captisol; (SBE)7m- beta-CD; SBE7-b-CD; SBECD; sulfobutylether-b-cyclodextrin, sodium salt.

Chemical Name and CAS Registry Number

b-Cyclodextrin sulfobutylether, sodium salt [1824100-00-0]

Empirical Formula and Molecular Weight

C42H70–nO35·(C4H8SO3Na)n 2163 (where n = approxi- mately 6.5)

Structural Formula

R = H21–n or (CH2CH2CH2CH2SO2ONa)n where n = 6.0–7.1

Note: the substitution pattern is random, yielding a heterogeneous mixture both in terms of the site of substitution as well as degree of substitution. The n value is an average number derived from the average degree of substitution.

Functional Category

Dissolution-enhancing agent; drug delivery system; osmotic agent; solubilizing agent; stabilizing agent; tablet and capsule diluent; viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology

Cyclodextrins are crystalline, nonhygroscopic, cyclic oligo- saccharides derived from starch (see Cyclodextrins). Sulfo- butylether b-cyclodextrin is an amorphous, anionic substituted b-cyclodextrin derivative (see Section 8); other substituted cyclodextrin derivatives are also available (see Section 17).

Sulfobutylether b-cyclodextrin can form noncovalent com- plexes with many types of compounds including small organic molecules, peptides,(1) and proteins.(2) It can also enhance their solubility(3,4) and stability(4–6) in water. The first application of sulfobutylether b-cyclodextrin was in injectable preparations;(7) it can also be used in oral solid(8,9) and liquid(10) dosage forms, and ophthalmic,(11,12) inhalation, and intranasal formula- tions.(13) Sulfobutylether b-cyclodextrin can function as an osmotic agent and/or a solubilizer for controlled-release delivery,(9) and has antimicrobial preservative properties when present at sufficient concentrations.

The amount of sulfobutylether b-cyclodextrin that may be used is dependent on the purpose for inclusion in the formulation, the route of administration, and the ability of the cyclodextrin to complex with the drug being delivered. The minimum amount required for solubilization is, in general, a cyclodextrin/drug molar ratio of approximately 1–5 (the exact ratio being experimentally determined from complexation data). The maximum use in a formulation may be limited by physicochemical constraints such as viscosity (e.g. syringeable concentrations may be considered up to 50% w/v), tonicity, or the total weight and size of solid dosage forms (e.g. less than a gram in an individual tablet). It may also be limited by pharmacokinetic/pharmacodynamic (PK/PD) considerations. As dilution of a cyclodextrin formulation leads to an increase in the amount of uncomplexed drug, formulations that are not diluted upon administration, such as ophthalmic formulations, are sensitive to cyclodextrin concentration. In formulations such as these, cyclodextrin concentrations greater than the minimum required for solubilization can reduce the availability of uncomplexed drug and thereby affect PK/PD expectations by producing effects such as slower onset, lower Cmax, and bioavailability.

Description

b-Cyclodextrin is a cyclic oligosaccharide containing seven D- (+)-glucopyranose units attached by a(1→4) glucoside bonds (see Cyclodextrins). Sulfobutylether b-cyclodextrin is an anionic b-cyclodextrin derivative with a sodium sulfonate salt separated from the hydrophobic cavity by a butyl spacer group. The substituent is introduced at positions 2, 3, and 6 in at least one of the glucopyranose units in the cyclodextrin structure. Introducing the SBE into b-cyclodextrin can produce materials with different degrees of substitution, theoretically from 1 to 21; the hepta-substituted preparation (SBE7-b-CD) being the cyclodextrin with the most desirable drug carrier properties.(14)

Sulfobutylether b-cyclodextrin occurs as a white amorphous powder.

Pharmacopeial Specifications

—

Sulfobutylether b-Cyclodextrin 755

Typical Properties

Acidity/alkalinity: pH = 6 (30% w/w aqueous solution)(15)

Angle of repose:

20.58 for freeze-dried Captisol;

31.68 for spray-dried Captisol.

Appearance of solution: a 30% w/v solution in water is clear, colorless, and essentially free from particles of foreign matter.

Average degree of substitution: 6.0–7.1(15)

Compressibility: see Figure 1.

Density (bulk):

0.446–0.482 g/cm3 for freeze-dried Captisol;

0.524 g/cm3 for spray-dried Captisol;

0.482 g/cm3 for spray-agglomerated reprocessed Captisol.

Density (tapped):

0.565–0.597 g/cm3 for freeze-dried Captisol; 0.624 g/cm3 for spray-dried Captisol;

0.595 g/cm3 for spray-agglomerated reprocessed Captisol.

Flowability: 50 g/s for freeze-dried Captisol.

Hygroscopicity: reversibly picks up water at relative humidities (RH) up to 60%. Equilibration at RH equal to or above 60% will result in deliquescence and a water content of approximately 16%w/w. See Figure 2.

Melting point: decomposition at 2758C.

Moisture content: 2–5% typically; maximum 10%.

Osmolarity: a 12.7% w/v solution of Captisol is iso-osmotic with serum.

Particle size distribution: typical mean particle size for spray- dried sulfobutylether b-cyclodextrin sodium is 70–120 mm. Various processing and handling methods may result in different nominal mean particle sizes.

Specific rotation [a]20: +948

Solubility: soluble 1 in less than 2 of water; 1 in 30–40 of methanol; practically insoluble in ethanol, n-hexane, 1-butanol, acetonitrile, 2-propanol, and ethyl acetate.

Viscosity (dynamic): 1.75 mPa s for a 8.5% w/w aqueous solution at 258C, 1.09 mPa s at 608C;

528 mPa s for a 60% w/w aqueous solution at 258C, 87 mPa s at 608C.(15)

SEM: 1

Excipient: Freeze-dried sulfobutylether b-cyclodextrin sodium (Captisol)

Manufacturer: CyDex

Magnification: 150×

SEM: 2

Excipient: Spray-dried

(Captisol) sulfobutylether b-cyclodextrin sodium

Manufacturer: CyDex

Magnification: 150×

SEM: 3

Excipient: Spray-agglomerated sulfobutylether b-cyclodextrin sodium (reprocessed Captisol)

Manufacturer: CyDex

Magnification: 150×

Stability and Storage Conditions

Sulfobutylether b-cyclodextrin is stable in the solid state and should be protected from high humidity. It should be stored in a tightly sealed container in a cool, dry place.

It will reversibly take up moisture without any effect on the appearance of the material at humidities up to 60% RH. Equilibration at RH values above 60% will result in deliquescence. Once in this state, the material can be dried, but will give a glasslike product. This water absorption behavior is typical of amorphous hygroscopic materials.

756 Sulfobutylether b-Cyclodextrin

Figure 1: Compression characteristics of sulfobutylether b-cyclodex- trin sodium.

⃝: Spray-dried (CyDex, Captisol, Lot No.: CY-03A-

02046)

0: Spray-agglomerated (Reprocessed CyDex Lot No.: CY- 03A-099020)

□: Freeze-dried (CyDex, Captisol, Lot No.: RPP-96-

CDSBE-BA#1)

Mean tablet weight: 220 mg

Tablet dimensions: 5/16 inch std concave Lubricated with 0.5% magnesium stearate

Tablet machine: Instrumented Stokes Model F, Single Punch Press

Figure 2: Moisture sorption–desorption isotherm of sulfobutylether b- cyclodextrin sodium, at 308C.

&: Freeze-dried (native moisture content: 3.7%)

Q: Spray-dried (native moisture content: 5.2%)

Sulfobutylether b-cyclodextrin is stable in aqueous solutions at values above about pH1. It can degrade in highly acidic (pH

< 1) solutions, particularly at elevated temperatures; producing the ring-opened form, followed by hydrolysis of the a(1→4) glucoside bonds.

Sulfobutylether b-cyclodextrin solutions may be auto- claved.(15)

Incompatibilities

The preservative activity of benzalkonium chloride is reduced in the presence of sulfobutylether b-cyclodextrin.

Method of Manufacture

Sulfobutylether b-cyclodextrin is prepared by alkylation of b- cyclodextrin using 1,4-butane sultone under basic conditions. The degree of substitution in b-cyclodextrin is controlled by the stoichiometric ratio of b-cyclodextrin to sultone used in the process.

Safety

Sulfobutylether b-cyclodextrin is derived from b-cyclodextrin, which is toxic when administered parenterally (see Cyclodex- trins). However, studies have shown that sulfobutylether b- cyclodextrin is well tolerated at high doses, when administered via intravenous bolus injections, orally, and by inhala- tion.(1,8,16) Up to 9 g/day may be administered by IV infusion in a licensed voriconazole formulation.(15)

Sulfobutylether b-cyclodextrin has been subjected to an extensive battery of in vitro and in vivo genotoxicity and pharmacological evaluations. No genotoxic or mutagenic changes were observed with sulfobutylether b-cyclodextrin administration. Sulfobutylether b-cyclodextrin is biocompati- ble and exhibits no pharmacological activity. It is rapidly eliminated unmetabolized when administered intravenously.

Handling Precautions

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

Regulatory Status

Sulfobutylether b-cyclodextrin is included in IV and IM injectable products currently approved and marketed in the USA and Europe. It is included in the FDA inactive ingredient guide for IM and IV use. Its use by other routes, including oral, inhalation, and ophthalmic, is being evaluated in clinical studies.

Related Substances

a-Cyclodextrin; b-cyclodextrin; g-cyclodextrin; dimethyl-b- cyclodextrin; 2-hydroxyethyl-b-cyclodextrin; 2-hydroxypro- pyl-b-cyclodextrin; 3-hydroxypropyl-b-cyclodextrin; tri- methyl-b-cyclodextrin.

Comments

In addition to its use in pharmaceutical formulations, sulfobutylether b-cyclodextrin is also used in chromatographic separations, particularly in chiral separations by HPLC(17) and capillary electrophoresis(18–21) and in tissue imaging.(22)

Specific References

Johnson MD, Hoesterey BL, Anderson BD. Solubilization of a tripeptide HIV protease inhibitor using a combination of ioniza-

Sulfobutylether b-Cyclodextrin 757

tion and complexation with chemically modified cyclodextrins. J Pharm Sci 1994; 83(8): 1142–1146.

Tokihiro K, Irie T, Uekama K. Varying effects of cyclodextrin derivatives on aggregation and thermal behavior of insulin in aqueous solution. Chem Pharm Bull 1997; 45(3): 525–531.

Zia V, Rajewski RA, Stella VJ. Effect of cyclodextrin charge on complexation of neutral and charged substrates: comparison of (SBE)7m-Beta-CD to HP-Beta-CD. Pharm Res 2001; 18(5): 667–

673.

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General References

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Authors

GL Mosher, JD Pipkin.

PhEur: Acidum sulfuricum USPNF: Sulfuric acid

Synonyms

E513; hydrogen sulfate; oil of vitriol.

Chemical Name and CAS Registry Number

Sulfuric acid [7664-93-9].

Empirical Formula and Molecular Weight

med 5

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Wednesday, November 6, 2024

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