Purdue University, West Lafayette, IN, USA.
Pharm Dev Technol. 2011 Nov-Dec;16(6):549-76. doi: 10.3109/10837450.2011.611138. Epub 2011 Sep 20.
A case study has been developed to illustrate one way of incorporating a Quality by Design approach into formulation and process development for a small molecule, freeze-dried parenteral product. Sodium ethacrynate was chosen as the model compound. Principal degradation products of sodium ethacrynate result from hydrolysis of the unsaturated ketone in aqueous solution, and dimer formation from a Diels-Alder condensation in the freeze-dried solid state. When the drug crystallizes in a frozen solution, the eutectic melting temperature is above -5°C. Crystallization in the frozen system is affected by pH in the range of pH 6-8 and buffer concentration in the range of 5-50 mM, where higher pH and lower buffer concentration favor crystallization. Physical state of the drug is critical to solid state stability, given the relative instability of amorphous drug. Stability was shown to vary considerably over the ranges of pH and buffer concentration examined, and vial-to-vial variability in degree of crystallinity is a potential concern. The formulation design space was constructed in terms of pH and drug concentration, and assuming a constant 5 mM concentration of buffer. The process design space is constructed to take into account limitations on the process imposed by the product and by equipment capability.
已经开发了一个案例研究，来说明将质量源于设计方法纳入小分子冷冻干燥注射剂的配方和工艺开发的一种方法。选择烯丙基乙基硫脲酸钠作为模型化合物。烯丙基乙基硫脲酸钠的主要降解产物是在水溶液中不饱和酮的水解，以及在冷冻干燥固体状态下通过 Diels-Alder 缩合形成二聚体。当药物在冷冻溶液中结晶时，共晶熔融温度高于-5°C。在 pH 值为 6-8 和缓冲浓度为 5-50 mM 的范围内，结晶受到 pH 的影响，较高的 pH 值和较低的缓冲浓度有利于结晶。鉴于无定形药物的相对不稳定性，药物的物理状态对固体状态稳定性至关重要。在研究的 pH 值和缓冲浓度范围内，稳定性显示出很大的差异，并且结晶度的瓶间变异性是一个潜在的问题。配方设计空间是根据 pH 值和药物浓度构建的，并假设缓冲液的浓度保持在 5 mM 不变。工艺设计空间是为了考虑产品和设备能力对工艺施加的限制而构建的。
