Improvement of Physicochemical Properties of N-4472. Part III. VC/N-4472 Complex Formation and Self-association in Aqueous Solution.

Abstract

Formation of the counter-ion salt characteristic of higher dissociation constant is one of the promising procedures extensively employed to improve the aqueous solubility of ionic but poorly water-soluble drugs.1) However, it has been reported that the crystal lattice energy varied even in the crystalline salts formed with the same drug depending on kinds of the applied counter ions, leading to different physicochemical properties in the solid state including apparent solubility and dissolution rate, eventually resulting in difference in the oral absorption rate.2) From the comparison of the aqueous solubility of both nicardipine phosphate and nicardipine hydrochloride, Michael et al. reported that approximately 10-fold difference in the solubility was observed between them due to successful solubilization of nicardipine phosphate attributable to self-association and micelle formation in the aqueous solution.3) These findings suggest that difference of the applied counter ions remarkably affected not only the solubility of the salt but also solubilizing behaviors in the aqueous solution. As a consequence, selection of the most appropriate counter ion is significantly outweighed upon the salt formation.Diphenylmethane derivatives as anti-histamine agents 4) and phenothiazine derivatives as psychotropic agents 5,6) were solubilized due to intrinsic self-association in aqueous solution. These drugs had common characteristic that the molecules possessed amphiphilic structures comprising both hydrophilic and hydrophobic moieties.N- [2][3]) is a newly developed drug having a lipid-lowering effect. With its aqueous solubility of less than 0.2 mg/ml (solubility in JP XIV 2nd fluid and distilled water at 37°C), this drug has a drawback to be poorly absorbed after oral administration. In the present study, with an aim to improve the aqueous solubility of N-4472 (solubility in JP XIV 1st fluid at 37°C: 44 mg/ml, pK a : 7.9), we investigated aqueous solubilizing behavior and mechanism of the evaporates of N-4472 which were prepared by addition of various organic acids.

Drug Nanoparticle Formulation Using Ascorbic Acid Derivatives

“…For example, aspasomes were formulated as vesicles composed of various components that interacted with each other [28]. Furthermore, the complex formation between the hydrophobic drug N-4472 and ascorbic acid and the subsequent self-association contributed to form the colloidal particles in aqueous solution (Figure 5) [33]. A novel drug delivery carrier system using ascorbic acid derivatives is going to be developed using this chemical structure-based design.…”