Name: Sulfobutylether b-Cyclodextrin
CAS No: b-Cyclodextrin sulfobutylether, sodium salt [1824100-00-0]
None adopted.
b-Cyclodextrin sulfobutylether, sodium salt; Captisol; (SBE)m-betaCD; SBE7-b-CD; SBECD; sulfobutylether-b-cyclodextrin, sodium salt.
b-Cyclodextrin sulfobutylether, sodium salt [1824100-00-0]
C42H70–nO35(C4H8SO3Na)n 2163 (where n = approximately 6.5)
Cyclodextrins are crystalline, nonhygroscopic, cyclic oligosaccharides derived from starch (see Cyclodextrins). Sulfobutylether bcyclodextrin 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 complexes 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 bcyclodextrin 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 formulations.(13) Sulfobutylether bcyclodextrin 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
b-Cyclodextrin is a cyclic oligosaccharide containing seven D-(þ)- glucopyranose units attached by a(1!4) glucoside bonds (see Cyclodextrins). Sulfobutylether b-cyclodextrin is an anionic bcyclodextrin 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 sulfobutylether (SBE) into b-cyclodextrin can produce materials with different degrees of substitution, theoretically from 1 to 21; the hepta-substituted preparation (SBE7-b-CD) is the cyclodextrin with the most desirable drug carrier properties.(14) Sulfobutylether b-cyclodextrin occurs as a white amorphous powder.
Acidity/alkalinity pH = 4.0–6.8 (30% w/v 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 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 Captisol. Flowability 50 g/s for freeze-dried Captisol. Glass transition temperature 258C(16) 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 3–6% typically; maximum 10%. Osmolarity Solutions of Captisol in the range 9.5–11.4% w/v are isoosmotic with serum.(15) Particle size distribution Typical mean particle size for spraydried sulfobutylether b-cyclodextrin sodium is 70–120 mm. Various processing and handling methods may result in different nominal mean particle sizes. Specific rotation [a]D 20 = þ948 38 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 (1.75 cP) for a 8.5% w/w aqueous solution at 258C, 1.09 mPa s (1.09 cP) at 608C; 528 mPa s (528 cP) for a 60% w/w aqueous solution at 258C, 87 mPa s (87 cP) at 608C.(15)
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. Sulfobutylether b-cyclodextrin is stable in aqueous solutions at values above about pH 1. 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 autoclaved.(15)
The preservative activity of benzalkonium chloride is reduced in the presence of sulfobutylether b-cyclodextrin.
Sulfobutylether b-cyclodextrin is prepared by alkylation of bcyclodextrin 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.
Sulfobutylether b-cyclodextrin is derived from b-cyclodextrin, which is nephrotoxic when administered parenterally (see Cyclodextrins). However, studies have shown that sulfobutylether bcyclodextrin is well tolerated at high doses, when administered via intravenous bolus injections, orally, and by inhalation.(1,8,17) Up to 9 g/day may be administered by IV infusion in a licensed voriconazole formulation.(15) The safety following high doses of sulfobutylether b-cyclodextrin intravenous administration in humans is continually being investigated.(18) 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 biocompatible and exhibits no pharmacological activity. It is rapidly eliminated unmetabolized when administered intravenously.(14)
Observe normal precautions appropriate to the circumstances and quantity of material handled.
Sulfobutylether b-cyclodextrin is included in IV and IM injectable products currently approved and marketed in the USA, Europe, and Japan. It is included in the FDA Inactive Ingredients Database for IM and IV use. Its use by other routes, including SC, oral, inhalation, nasal and ophthalmic, is being evaluated in clinical studies.
a-Cyclodextrin; b-cyclodextrin; g-cyclodextrin; dimethyl-b-cyclodextrin; 2-hydroxyethyl-b-cyclodextrin; hydroxypropyl betadex; 3- hydroxypropyl-b-cyclodextrin; trimethyl-b-cyclodextrin.
Sulfobutylether b-cyclodextrin may be used to reduce the renal damage caused by nephrotoxic drugs.(19) In addition to its use in pharmaceutical formulations, sulfobutylether b-cyclodextrin is also used in chromatographic separations, particularly in chiral separations by HPLC(20) and capillary electrophoresis,(21–24) and in tissue imaging.(25