Solubility enhancement of a bisnaphthalimide tumoricidal agent, DMP 840, through complexation.
The purpose of this research was to enhance the aqueous solubility of DMP 840 by complexation with water-soluble and nontoxic agents, and to understand the nature of the interactions involved in complex formation using nuclear magnetic resonance (1H-NMR). The solubility of DMP 840 in water, saline, acetate buffers, and cosolvent mixtures was determined by high-performance liquid chromatography, and the effect of nicotinamide and pyridoxine concentrations on the solubility of DMP 840 was examined by the phase solubility method. 1H-NMR spectra were acquired in deuterated acetate buffer at 400 MHz on a Varian Unity-400 spectrometer. The aqueous solubility of DMP 840 was sensitive to the presence of chloride and acetate anions in solution, and did not improve in the presence of cosolvents. The use of the nontoxic and water-soluble complex-forming agents nicotinamide and pyridoxine, however, resulted in a linear increase in the aqueous solubility of DMP 840 with both ligands. The solubilization appears to be due to formation of 1:1 complexes between DMP 840 and the bioorganic ligands. The complexation constants were 15.57 M-1 for the DMP 840:nicotinamide complex and 13.36 M-1 for the DMP 840:pyridoxine complex. The NMR results indicate that the interaction is a result of vertical or plane-to-plane stacking and the complexation constants were in agreement with that obtained by phase solubility. The results suggest that the aqueous solubility of a poorly water soluble drug substance such as DMP 840 can be significantly enhanced by its complexation with water-soluble and nontoxic agents.
Raghavan
K S
KS
DuPont Merck Pharmaceutical Company, Experimental Station, Wilmington, Delaware 19880-0400, USA. raghavk@a1.lldmpc.umc.dupont.com
Nemeth
G A
GA
Gray
D B
DB
Hussain
M A
MA
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D007546:Isoquinolines / Q000008:administration & dosage / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008698:Mesylates / Q000008:administration & dosage / Q000737:chemistry*; D011409:Propylene Glycols; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet
D000970:Antineoplastic Agents; D007546:Isoquinolines; D008698:Mesylates; D011409:Propylene Glycols; C084899:bisnafide