| Popis: |
PD 144872, the R -enantiomer of α-[[(2-bromoethyl)amino]methyl]-2-nitro-1H-imidazole-1-ethanol hydrobromide, is a dual-action hypoxic cell radiosensitizer which is currently being evaluated at the preclinical level. This study was performed to aid in the development of a parenteral dosage form of PD 144872 for use in toxicologic and clinical testing. PD 144872 shows good solid-state stability under accelerated storage conditions; however, it shows unacceptable stability (for the formulation of a ready-made solution dosage form) in aqueous solution at 25 and 30°C. The pH -k obs profile is well described by a pathway involving water-catalyzed or spontaneous degradation of the neutral species which implies that PD 144872 is most stable under acidic conditions. Unlike melphalan, co-solvent systems do not stabilize the compound. The postulated degradation mechanism is intramolecular, nucleophilic attack by the amino group at the β-carbon to form the corresponding aziridine derivative which can be opened, in a subsequent step, by water or other suitable nucleophiles. The absence of racemization was confirmed by monitoring the chirality of the aziridine product formed upon the degradation of to PD 144872. The apparent solubility of PD 144872, in the pH range of 2–4, is independent of pH and suggests that the limiting solubility of the cationic form is about 50 mg/ml at 25°C and about 33 mg/ml at 4°C. Based on these studies, formulation efforts will focus initially on the development of a lyophilized vial where manufacture and reconstitution will be conducted at pH ≤ 3 and where the maximum reconstitution concentration is kept below 50 or 33 mg/ml when stored at 25 or 4°C, respectively. This should provide optimal stability and solubility conditions. |
