Ultrasound a versatile process analytical tool for quantitative in-line monitoring of pharmaceutical oral/injection formulations

摘要

The pharmaceutical industry follows the quality-by-design approach of the Food and Drug Administration (FDA) that includes the application of process analytical technology (PAT) to guarantee among other the required product quality of drug formulations [1]. Therefore, a variety of methods for the quantification of pharmaceutical formulations have been intensively discussed in recent years [2-5]. These studies have addressed the application of inline PATs, such as NIR, RAMAN, ultrasound spectroscopy. Further studies have assessed the application of FTIR, FBRM, UV, turbidity, or conductivity to measure solution and suspension properties [6-8]. All PATs provide the possibility to monitor process parameters in real time, which leads to more constant product quality by real-time process decision making and process adjustments. However, most of the aforementioned PATs are limited to measuring either solid or liquid phase. Moreover, there are obstacles with electrically non-conducting, dense, concentrated, or optically opaque solutions [9]. Here, the ultrasound-based technologies have clear advantages, because most materials are ultrasonically transparent and hence allow the analysis of a broad variety of sample types (solution, suspension, lotion, emulsion) [2,3,9]. Recent studies have pioneered the use of ultrasound spectroscopy in quantification of drug concentration in different types of formulations [2-4]. However, to the best of our knowledge real-time monitoring of drug concentration in oral/injection pharmaceutical formulations (liquid/suspension) has never been assessed by means of single-frequency ultrasound (US). The aim of this study is to evaluate the application of US as a robust, cost-effective, and small-scale PAT (including control box) to determine and monitor the concentration of commercial, oral/injection pharmaceutical formulations, both solutions and suspensions. The quality and versatility of US are assessed by comparing the results with the outcome of established PATs able to measure solution concentration (conductivity, UV-vis, FlowIR) as well as suspension concentration (FBRM, turbidity) which are relatively small in size (including control box). The latter is important if the PAT should be utilized in small-scale applications with critical space limitations.