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

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.