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The effect of SBE4-/3-CD, a sulfobutyl ether derivative of/3-cyclodextrin on the solubility and a... more The effect of SBE4-/3-CD, a sulfobutyl ether derivative of/3-cyclodextrin on the solubility and aqueous hydrolysis of the antitumor drug O6-benzylguanine (BG) was studied. SBE4-/3-CD is an apparently parenterally safe anionic /3-cyclodextrin derivative with superior solubilizing properties in water. BG has poor aqueous solubility and undergoes rapid hydrolysis to the poorly water soluble guanine. The stability of a parenteral BG formulation was studied after storage at 25, 37 and 50°C. Compared to the intrinsic solubility of BG (0.14 mg/ml, 25°C), 0.05 M SBE4-/3-CD enhanced its solubility to 2.9 mg/ml at 25°C and 3.9 mg/ml at 50°C. Solubility data yielded binding constants (K b) of 565 M-1 at 25°C and 342 M-1 at 50°C. The solubility of guanine was only slightly enhanced by SBE4-/3-CD. Hydrolysis kinetics of BG were studied at 50°C over a pH range of 1-9 and the maximum stability was observed at pH 8-8.5. In the presence of 0.05 M SBE4-/3-CD, hydrolysis was about 9.5-times slower at pH 1, 14.6-times slower at pH 6 and 10-times slower at pH 8. The effect of SBE4-fl-CD concentration was studied at pH 2.2 and 4.8 at 50°C. Hydrolysis rate constants decreased with increasing SBE4-/3-CD concentrations. A non-linear regression analysis of this data yielded K b values of 311 and 270 M-1 at pH 2.2 and 4.8, respectively. A formulation containing 2.5 mg/ml of BG and 0.05 M SBE4-/3-CD in a pH 8 phosphate buffer was stored in ampoules at 25, 37 and 50°C. Guanine production in the samples was measured since its low solubility (2.5/xg/mi) imposed a limitation on the shelf life. Guanine levels exceeded its apparent solubility after 1-2 months of storage at 50°C. At 37°C guanine levels were only 1.6/zg/ml after 343 days of storage whereas those at 25°C were negligible and below the limit of quantitation (approx. 0.1 ~g/ml). The greater stability at room temperature may be attributed to the higher K b value observed and greater intrinsic stability of BG in the complex.
The effect of SBE4-/3-CD, a sulfobutyl ether derivative of/3-cyclodextrin on the solubility and a... more The effect of SBE4-/3-CD, a sulfobutyl ether derivative of/3-cyclodextrin on the solubility and aqueous hydrolysis of the antitumor drug O6-benzylguanine (BG) was studied. SBE4-/3-CD is an apparently parenterally safe anionic /3-cyclodextrin derivative with superior solubilizing properties in water. BG has poor aqueous solubility and undergoes rapid hydrolysis to the poorly water soluble guanine. The stability of a parenteral BG formulation was studied after storage at 25, 37 and 50°C. Compared to the intrinsic solubility of BG (0.14 mg/ml, 25°C), 0.05 M SBE4-/3-CD enhanced its solubility to 2.9 mg/ml at 25°C and 3.9 mg/ml at 50°C. Solubility data yielded binding constants (K b) of 565 M-1 at 25°C and 342 M-1 at 50°C. The solubility of guanine was only slightly enhanced by SBE4-/3-CD. Hydrolysis kinetics of BG were studied at 50°C over a pH range of 1-9 and the maximum stability was observed at pH 8-8.5. In the presence of 0.05 M SBE4-/3-CD, hydrolysis was about 9.5-times slower at pH 1, 14.6-times slower at pH 6 and 10-times slower at pH 8. The effect of SBE4-fl-CD concentration was studied at pH 2.2 and 4.8 at 50°C. Hydrolysis rate constants decreased with increasing SBE4-/3-CD concentrations. A non-linear regression analysis of this data yielded K b values of 311 and 270 M-1 at pH 2.2 and 4.8, respectively. A formulation containing 2.5 mg/ml of BG and 0.05 M SBE4-/3-CD in a pH 8 phosphate buffer was stored in ampoules at 25, 37 and 50°C. Guanine production in the samples was measured since its low solubility (2.5/xg/mi) imposed a limitation on the shelf life. Guanine levels exceeded its apparent solubility after 1-2 months of storage at 50°C. At 37°C guanine levels were only 1.6/zg/ml after 343 days of storage whereas those at 25°C were negligible and below the limit of quantitation (approx. 0.1 ~g/ml). The greater stability at room temperature may be attributed to the higher K b value observed and greater intrinsic stability of BG in the complex.