title: Excipient hydrolysis and ester formation increase pH in a parenteral solution over aging.
abstract: Recently, the number of drug substances that are poorly water-soluble has increased dramatically. This makes improving solubility one of the most critical tasks in pharmaceutical development today. In this study, the physicochemical stability of an injectable solution of conivaptan hydrochloride salt was investigated. Because its free form is hydrophobic, the drug substance was solubilized in a co-solvent system, 40% of which was composed of different alcohols. Since the free form is also alkaline, lactic acid was added to the co-solvent system to further improve its solubility. Remarkably, the pH of the solution was found to increase gradually over time. Considering the physicochemical nature of the drug substance, uncontrolled increases in pH would pose a potential threat of reducing solubility and forming precipitates. For this reason, a risk evaluation was performed. The evaluation revealed that the pH increase was caused by the hydrolysis of lactic acid oligomers as well as by the ester formation occurring between lactic acid and the alcohols. High concentrations of lactic acid supplied as an excipient usually contain lactic acid oligomers, which are hydrolyzed into lactic acid monomers upon dilution with water. Commercial software was used to determine the pK(a) values of the lactic acid oligomers, which were found to be lower than that of lactic acid monomers. This indicates that hydrolysis causes the pH to increase. Ester formation consumes the acid, which also causes the pH to increase. However, both hydrolysis and ester formation equilibrated by the 16-month time point when stored at 25 degrees C. This information allowed the upper limit of the pH increase to be determined molecularly, thereby ensuring product quality through the prevention of precipitate formation due to reduced solubility. Increased awareness of the importance of risk evaluation in pharmaceutical development is critical as these kinds of chemical reactions between excipients constitute a potential risk factor, but tend to be overlooked.
authors.affiliation: Pharmaceutical Research and Technology Laboratories, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan. yutaka.hirakura@jp.astellas.com
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hirakura
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Nakamura
authors.forename: Tatsuyoshi
authors.initials: T
authors.lastname: Wakasawa
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Ban
authors.forename: Shoji
authors.initials: S
authors.lastname: Yokota
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kitamura
mesh_terms: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000008:administration & dosage / Q000737:chemistry; D002853:Chromatography, Liquid / Q000379:methods; D004355:Drug Stability; D004952:Esters / Q000737:chemistry*; D000431:Ethanol / Q000737:chemistry; D005079:Excipients / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007267:Injections / Q000592:standards; D019344:Lactic Acid / Q000737:chemistry; D013058:Mass Spectrometry / Q000379:methods; D015394:Molecular Structure; D019999:Pharmaceutical Solutions / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D019946:Propylene Glycol / Q000737:chemistry; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods / Q000592:standards; D013997:Time Factors
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D004952:Esters; D005079:Excipients; D019999:Pharmaceutical Solutions; D011108:Polymers; C106389:conivaptan; D019344:Lactic Acid; D000431:Ethanol; D019946:Propylene Glycol