title: Dynamic compatibility testing of DMP 840, an experimental antitumor agent.
abstract: The purpose of this study is to evaluate the potential for DMP 840, a novel experimental antitumor agent, to precipitate during injection or dilution with infusion solutions. The influence of predilution of the drug solution before injection and addition of buffers to the drug vehicle were also investigated. The compatibility of normal saline solution, pH 7.4 phosphate buffers, and human plasma with DMP 840 was examined in vitro under both static conditions and dynamic flow. The combination of DMP 840 solutions with normal saline solution resulted in conversion of the drug to an insoluble dihydrochloride salt. Under conditions of dynamic flow, precipitation, accompanied by large changes in turbidity, occurred at relatively high concentrations of the drug in the injection solution. Dilution of the injection solution below 2 mg/mL or slow injection avoided precipitation. As was the case with the normal saline system, turbidity changes after injection into protein-phosphate buffer (PPB) were dependent on the initial concentration of DMP 840 solution as well as the rate of administration. In addition, the maximum injection rate at which complete miscibility occurred increased exponentially as the drug injection solution was made more dilute. Buffering the DMP 840 injection solution with acetate buffer improved the miscibility of DMP 840 with PPB, which indicated that the turbidity increases were most likely due to conversion of the drug to its insoluble free base form. The observed effects of the buffer on the turbidity response agreed qualitatively with predictions from a graphical approach that considers the effects of dilution and pH changes on drug solubility. Despite these observations, no evidence for the formation of a solid precipitate could be found after injection of the unbuffered drug solution into PPB. Further investigation indicated that the presence of albumin in the PPB prevented the formation of a solid phase during injection. Likewise, fresh human plasma, spiked with 1 and 2 mg/mL solutions of DMP 840, showed no evidence for the formation of a solid precipitate.
authors.affiliation: DuPont Merck Pharmaceutical Company, Wilmington, DE, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Rubino
authors.forename: R
authors.initials: R
authors.lastname: Nellore
authors.forename: B
authors.initials: B
authors.lastname: Parmar
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D002021:Buffers; D002626:Chemistry, Pharmaceutical; D004344:Drug Incompatibility; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007546:Isoquinolines / Q000737:chemistry*; D008698:Mesylates / Q000737:chemistry*; D010949:Plasma
chemical_list: D000970:Antineoplastic Agents; D002021:Buffers; D007546:Isoquinolines; D008698:Mesylates; C084899:bisnafide