Schmidt Adrian, de Waard Hans, Moll Klaus-Peter, Krumme Markus, Kleinebudde Peter
Institute of Pharmaceutics and Biopharmaceutics Heinrich-Heine-University Düsseldorf Universitätsstr. 1, Build. 26.22 D-40225 Düsseldorf, Germany; Novartis Pharma AG Novartis Campus, CH-4002 Basel, Switzeerland.
Novartis Pharma AG Novartis Campus, CH-4002 Basel, Switzeerland.
Chimia (Aarau). 2016;70(9):604-9. doi: 10.2533/chimia.2016.604.
In pharmaceutical manufacturing, there is an increasing interest in continuous manufacturing. As an example for fast continuous processes in general of considerable complexity, this study was focussed on improving the understanding of twin-screw wet granulation. The impact of the liquid-to-solid (L/S) mass flow ratio on product quality (granules) as well as on downstream process operations (tableting) was investigated in detail. Initially two methods were used to define L/S ratio boundaries for the granulation regime in twin-screw wet granulation. It was shown that the first method, which is based on measuring the wet granule mass flow variation, can be used to define the upper L/S ratio boundary of the granulation regime. The second method, based on measuring the granule size distribution, can be used to define the lower L/S ratio boundary of the regime. Using these methods, the granulation regime for different formulations could be established. This information was then used to show that the formulation could be optimised such that the process is more robust (i.e. wider L/S ratio boundaries for the granulation regime). Also it could be used to optimise the formulation considering further downstream processing such as drying (using as little water as possible to reduce drying efforts) or tableting (obtain granules with optimised tableting properties). Preferably, the process should be performed close to the lower L/S ratio boundary of the granulation regime. In summary, these tools enabled the quantitative establishment of granulation regime boundaries in a twin-screw wet granulation process and can be used to optimise formulation and to create a robust process. Analogies to other continuous processes in completely different applications can be conceived.
在制药生产中，人们对连续制造的兴趣与日俱增。作为一般具有相当复杂性的快速连续过程的一个例子，本研究聚焦于增进对双螺杆湿法制粒的理解。详细研究了液固（L/S）质量流量比对产品质量（颗粒）以及对下游工艺操作（压片）的影响。最初，使用了两种方法来定义双螺杆湿法制粒中制粒区域的L/S比边界。结果表明，第一种方法基于测量湿颗粒质量流量变化，可用于定义制粒区域的L/S比上限。第二种方法基于测量颗粒尺寸分布，可用于定义该区域的L/S比下限。利用这些方法，可以确定不同配方的制粒区域。然后利用这些信息表明，可以优化配方，使工艺更稳健（即制粒区域的L/S比边界更宽）。它还可用于考虑进一步的下游加工（如干燥，尽可能少用水以减少干燥工作量）或压片（获得具有优化压片性能的颗粒）来优化配方。优选地，该工艺应在接近制粒区域的L/S比下限的条件下进行。总之，这些工具能够在双螺杆湿法制粒过程中定量确定制粒区域边界，并可用于优化配方和创建稳健的工艺。可以设想与完全不同应用中的其他连续过程的类比。
