In-line derivative spectroscopy as a promising application to a small-scale in vitro transfer model in biorelevant supersaturation and precipitation testing

Abstract

Abstract Objectives Dissolution testing of poorly soluble and precipitating drugs is of great importance for pharmaceutical industry. As offline HPLC analytics is time-consuming and labour-intensive, the development of suitable in-line analytics to measure drug concentration allows better predictions of drug dissolution and precipitation. The purpose of this study was to develop an in-line derivative spectroscopic method which facilitates drug concentration measurements in suspensions without additional sample preparation. Methods Solubility, dissolution and precipitation of ketoconazole were analysed using derivative spectroscopy and HPLC. Key findings Results of solubility and dissolution experiments were highly comparable. Due to higher sampling frequency and lack of sample preparations, supersaturation in a pH-shift experiment was more accurately captured by UV in-line analytics. The application of a prefiltration step and flow-through cuvettes facilitates implementation of in-line derivative spectroscopy into an in vitro transfer model with changing UV-active media and high supersaturation in highly turbid samples. Conclusions Although the application of derivative spectroscopy has been described previously, the approach described herein is novel and well-suited for the application in an automated in vitro transfer model. Moreover, it represents a promising tool for drug substance characterisation, candidate selection and formulation development.