Abstract 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.

中文翻译：

---

预制剂研究，以帮助开发PD 144872（一种放射增敏型抗癌药）的可注射制剂

摘要PD 144872是α-[[（（2-溴乙基）氨基]甲基] -2-硝基-1H-咪唑-1-乙醇氢溴酸盐的R对映异构体，是一种双向作用的低氧细胞放射增敏剂，目前正在对其进行评估临床前水平。进行这项研究以帮助开发PD 144872的肠胃外剂型，用于毒理学和临床测试。PD 144872在加速储存条件下显示出良好的固态稳定性；但是，它在25和30°C的水溶液中显示出不可接受的稳定性（用于配制现成的溶液剂型）。通过涉及中性物质的水催化或自发降解的途径很好地描述了pH -k obs曲线，这表明PD 144872在酸性条件下最稳定。与美法仑不同，助溶剂系统不能稳定化合物。假定的降解机理是分子内的亲核攻击，由β-碳上的氨基形成相应的氮丙啶衍生物，该氮丙啶衍生物可以在随后的步骤中被水或其他合适的亲核试剂打开。通过监测降解为PD 144872时形成的氮丙啶产品的手性来确认没有外消旋作用。PD144872的表观溶解度在2–4的pH范围内与pH无关，表明该化合物的极限溶解度阳离子形式在25°C下约为50 mg / ml，在4°C下约为33 mg / ml。根据这些研究，配制工作将首先集中在冻干小瓶的开发上，在pH≤3的条件下进行制造和复原，并且在25或4°C下储存时，最大复原浓度保持在50或33 mg / ml以下C，分别。这应该提供最佳的稳定性和溶解度条件。