Analytical Sciences , Merck & Co., Inc. , Rahway , New Jersey 07065 , United States.
Pharmacokinetics, Pharmacodynamics, and Drug Metabolism , Merck & Co., Inc. , Kenilworth , New Jersey 07033 , United States.
Mol Pharm. 2020 Feb 3;17(2):530-540. doi: 10.1021/acs.molpharmaceut.9b00958. Epub 2020 Jan 14.
Novel treatment routes are emerging for an array of diseases and afflictions. Complex dosage forms, based on active pharmaceutical ingredients (APIs) with previously undesirable physicochemical characteristics, are becoming mainstream and actively pursued in various pipeline initiatives. To fundamentally understand how constituents in these dosage forms interact on a molecular level, analytical methods need to be developed that encompass selectivity and sensitivity requirements previously reserved for a myriad of in vitro techniques. The knowledge of precise chemical interactions between drugs and excipients in a dosage form can streamline formulation development and process screening capabilities through the identification of properties that influence rates and mechanisms of drug release in a cost-effective manner, relative to long-term in vivo studies. Through this work, a noncompendial in vitro release (IVR) method was developed that distinguished the presence of individual components in a complex crystalline nanosuspension environment. Doravirine was formulated as a series of long-acting injectable nanosuspensions with assorted excipients, using low- and high-energy wet media milling methods. IVR behavior of all formulation components were monitored using a robust continuous flow-through (CFT) dissolution setup (USP-4 apparatus) with on-line H NMR end-analysis (flow-NMR). Results from this investigation led to a better understanding of formulation parameter influences on nanosuspension stability, surface chemistry, and dissolution behavior. Flow-NMR can be applied to a broad range of dosage forms in which specific molecular interactions from the solution microenvironment require further insight to enhance product development capabilities.
新的治疗方法正在涌现，可用于治疗一系列疾病和不适。基于具有先前不理想理化特性的活性药物成分 (API) 的复杂剂型正在成为主流，并在各种管道计划中积极推进。为了从根本上了解这些剂型中的成分在分子水平上如何相互作用，需要开发分析方法，这些方法需要涵盖以前保留用于多种体外技术的选择性和灵敏度要求。通过以具有成本效益的方式识别影响药物释放速率和机制的性质，相对于长期的体内研究，可以了解药物和赋形剂在剂型中的精确化学相互作用，从而简化配方开发和工艺筛选能力。通过这项工作，开发了一种非药典体外释放 (IVR) 方法，该方法可区分复杂结晶纳米混悬液环境中单个成分的存在。多伟拉韦被配制成一系列具有各种赋形剂的长效注射用纳米混悬剂，使用低能和高能湿法介质研磨方法。使用具有在线 H NMR 末端分析 (流-NMR) 的强大连续流动 (CFT) 溶解装置 (USP-4 装置) 监测所有制剂成分的 IVR 行为。该研究的结果使人们更好地了解了制剂参数对纳米混悬剂稳定性、表面化学和溶解行为的影响。流-NMR 可应用于广泛的剂型，其中需要进一步了解溶液微环境中的特定分子相互作用，以增强产品开发能力。
