title: Importance of early characterization of physicochemical properties in developing high-dose intravenous infusion regimens for poorly water-soluble compounds.
abstract: TECHNICAL ABSTRACT: The aim of this work is to highlight the importance of the early characterization of physico-chemical properties to design an intravenous infusion regimen for a poorly water-soluble model compound. Compound X is a crystalline, poorly water-soluble weak base with a pH-dependent solubility profile. Due to its extremely low solubility above pH 6, the main challenge was to develop a suitable intravenous formulation for delivering high doses of compound X while minimizing the risk of precipitation upon injection into the blood (pH 7.4). A systematic approach, including formulation screening using minimum amounts of drug substance and evaluation of precipitation potential at the injection site, was employed in early discovery stages to identify a suitable infusion regimen for compound X in various preclinical models. More than 60 formulation variants were screened for solubility, pH, and precipitation potential using less than 150 mg of compound. Evaluation of precipitation potential upon injection was based on the calculation of the effective concentration at the injection site. Based on the results from formulation screening and the calculation of the effective concentration at the injection site, an intravenous infusion regimen was designed to overcome the precipitation upon injection risk associated with the poor physico-chemical properties of this compound.
  This work highlights the impact of the physico-chemical properties of a poorly water-soluble compound on the design of high-dose intravenous infusion regimens for preclinical development. Crystalline compounds, especially weak bases, with poor aqueous solubility have a high tendency to precipitate upon injection into the blood (pH 7.4). The main challenge was to develop a suitable intravenous formulation for delivering high doses of such crystalline, poorly water-soluble, weakly basic compounds. A combination approach, including formulation screening using minimum amounts of drug substance and evaluation of precipitation potential at the injection site, was employed in early discovery stages to identify a suitable infusion regimen for various animal models. Based on the results from formulation screening and the calculation of the effective concentration at the injection site, a suitable intravenous infusion regimen was designed to overcome the precipitation upon injection risk associated with the poor physico-chemical properties of this compound.
authors.affiliation: Chemical and Pharmaceutical Profiling, Novartis Institutes for Biomedical Research, Inc., Cambridge, MA 02139, USA.
authors.forename: Akash
authors.initials: A
authors.lastname: Jain
authors.forename: Weijia
authors.initials: W
authors.lastname: Zheng
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Garad
authors.forename: Margaret
authors.initials: M
authors.lastname: Weaver
authors.forename: Riccardo
authors.initials: R
authors.lastname: Panicucci
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: D014867:Water