title: Solubilization and preformulation of poorly water soluble and hydrolysis susceptible N-epoxymethyl-1,8-naphthalimide (ENA) compound.
abstract: N-Epoxymethyl-1,8-naphthalimide (ENA) is a novel antiproliferative drug candidate with potent anticancer and antifungal activity. It has an aqueous solubility of 0.0116mg/mL and also exhibits hydrolytic instability with a first-order hydrolysis rate of 0.051 h(-1). The present preformulation study aimed to characterize the physicochemical properties of ENA and develop an early injectable solution formulation for preclinical studies. To minimize hydrolysis, ENA is proposed to be formulated as either lyophilized powders or nonaqueous solutions followed by solubilization/reconstitution prior to administration. ENA solubilization was investigated in both aqueous media (by cosolvency, micellization and complexation) and nonaqueous solutions (mixture of Cremophor EL and ethanol). It is found that none of the solubilization techniques in aqueous media could increase ENA solubility to a desired level of several hundreds microg/mL at pharmaceutically acceptable excipient concentrations (< or =10%). In contrast, a combination of 70% Cremophor EL and 30% ethanol (v/v) proved effective in solubilizing ENA at 4 mg/mL, which exhibited good physical and chemical stability on storage at both 4 degrees C and room temperature over 4 months. No precipitation was observed upon 5-20 times dilution by the saline; in addition, less than 5% of ENA was hydrolyzed in 4h for the saline-diluted aqueous solutions. This nonaqueous ENA formulation is thus proposed for further preclinical studies, which can be reconstituted, prior to administration, by the 5-20 times infusion fluids (saline, 5% dextrose, etc.) to the desired drug dosing concentration at the acceptable excipient level. The approach used in this work could serve as a useful reference in formulating nonpolar drugs with hydrolytic instability.
authors.affiliation: Institute of Chemical and Engineering Sciences, (A*STAR) Agency for Science, Technology and Research, 1 Pesek Road, Jurong Island, Singapore 627833, Singapore. dong_yuancai@ices.a-star.edu.sg
authors.forename: Yuancai
authors.initials: Y
authors.lastname: Dong
authors.forename: Wai Kiong
authors.initials: WK
authors.lastname: Ng
authors.forename: Uttam
authors.initials: U
authors.lastname: Surana
authors.forename: Reginald B H
authors.initials: RB
authors.lastname: Tan
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D011232:Chemical Precipitation; D004355:Drug Stability; D004356:Drug Storage; D000431:Ethanol / Q000737:chemistry; D005079:Excipients / Q000737:chemistry*; D005990:Glycerol / Q000031:analogs & derivatives / Q000737:chemistry; D006868:Hydrolysis; D008823:Micelles; D053644:Naphthalimides / Q000737:chemistry*; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry; D013696:Temperature
chemical_list: D000970:Antineoplastic Agents; D005079:Excipients; D008823:Micelles; C530699:N-epoxymethyl-1,8-naphthalimide; D053644:Naphthalimides; D013501:Surface-Active Agents; D000431:Ethanol; C000515:cremophor EL; D005990:Glycerol