Physicochemical charaterization of the anticancer drug camptothecin in acidic environment and design of oral sustained release formulation using hydrophilic polymer NA-CMC

The physicochemical properties of camptothecin (CPT) were investigated by various techniques in an acidic environment in which the drug exist in its stable lactone form. The intrinsic solubility of the CPT-lactone free base was determined to be 1.80 muM at 22°C. The equilibrium solubility of the drug was found to increase with decreasing pH. The enhanced solubility of the drug at very low pH is attributed to the protonation of the nitrogen atom in the ring B and the increased solvency of the highly acid concentrated aqueous media. The pKa of CPT (nitrogen atom of B ring), by nonlinear fitting of the data points, was found to be 1.15, which is similar to the value published earlier by Fassberg and Stella. This value was also verified by partition coefficient and pH-solubility specifically, the pKa and intrinsic partition coefficient (PINT) value was found to be 1.17 and 65 respectively from the slope and intercept of the plot. The logarithmic value of the intrinsic partition coefficient P of the free base CPT-lactone form was estimated to be 1.65, suggesting a drug with a suitable oral absorption profile according to Lipinski's "Rule of five". At pH lower than the pKa there is an amazing transformation of the hydrophobic molecule to a hydrophilic one.; Equilibrium concentration of CPT was found to be 22.9 % +/- 1.3 at pH 7.2 and T = 25 °C which is more likely similar to the equilibrium hydrolysis concentration reported by others (Chourpa et al., 1998, Saetern et al., 2004). The Energy of activation of the hydrolysis of CPT at physiological pH was found to be 114.3 +/- 33.4 KJ/mol. The calculated t½ of the reaction at pH 7.2, 25 °C and 10 °C was found to be 0.07 days and 5.12 days, respectively, whereas the time required for 1% of CPT-lactone to hydrolyze to CPT-carboxylate (t99%)was detetrnined to be 1.8 hours thus offering enough time to safely handle CPT-lactone at low temperatures.; The present formulation work is focused on the effect of sodium carboxymethylcellulose on the CPT rate and mechanism of release from solid dosage forms prepared with different fabrication process. Tablets were compressed and tested for their drug content, weigh variation, hardness and thickness. The analysis of the drug release data was performed with the Korsmeyer-Peppas equation often called power law (Korsmeyer et al., 1983). The (release) exponents obtained indicated that the drug release mechanism is affected by the dissolution medium and the fabrication process, which significantly influence the internal structure of matrix. All release data in acidic medium, as well as in PBS pH 6.8, were a good fit into Korsmeyer-Peppas equation. Interestingly, it was observed that the dissolution rate was very fast for F1, F2 and F4 formulations without swelling or negligible swelling in acidic buffer at pH 1.2 and in PBS pH 6.8. The order of CPT release from fastest to slowest was F1 > F2 > F4 > F3 in acidic buffer at pH 1.2, as well as in PBS pH 6.8. The release from F1 was the faster among all four formulations F3 exhibited the slowest release both in acidic pH 1.2 and in PBS pH 6.8. The release mechanism shifts from an "anomalous" type in acidic medium towards a swelling-controlled, zero-order release in PBS pH 6.8. The very slow drug release from F3 in acidic buffer was due to the acid gel being tough and resistant to erosion as compared to PBS pH 6.8 in which a balance between swelling and erosion of the gel lead to a near zero-order kinetics. F8, F9 and F10 formulations helped understanding reasons behind the sustained release of CPT from the F3 formulation. That is, granulation of sodium CMC with Lactose is necessary for swelling and sustained release properties of the F3 formulation. T80 or F1, F2, F4, and F3 was determined to be 67.5, 113.3, and 310.5 and 1800 minutes, respectively at pH 6.8. Incorporation of DOPC does not affect the equilibrium CPT-lactone content. The half-life obtained from the formulation F1 and F10...