Amorphous Content Quantification by DSC and DVS. Comparative Approach to Method Development and Validation

摘要

The presence of various amounts of amorphous material formed either during crystallisation or processing may affect significantly the properties and the stability of the pharmaceutical substances. Some critical properties affecting the bioavailability of product and efficacy, like dissolution rate may be enhanced, while chemical and physical stability will decrease. This can have a direct influence during the lifecycle of the pharmaceutical substance, that is, in the processing steps, storage and delivery to the patient. In order to fully characterise the whole pharmaceutical substance it is therefore necessary to develop methods to quantify the amorphous material. This study shows different approaches to the development and validation of DSC and DVS methods for some drug substances and excipients being developed in our company. Knowledge of the product and its physical behaviour is essential to succeed in the development of an accurate and sensitive method. This study shows a description of the main parameters considered for the development of DSC and DVS methods for amorphous quantification. In DSC methods, the use of the crystallization enthalpy versus the step on the glass transition temperature (Tg) is assessed. Examples of DVS methods are shown using different temperatures, different relative humidity (RH) steps, different solvents and varying times for each step depending on the kinetics of the solvent-product system. The validation strategy followed in this study is based on the principles behind ICH Q2 (Rl) Validation Of Analytical Procedures: Text And Methodology. DSC methods are faster than DVS methods and those may be the selected ones when the amount of amorphous is significant. But for the quantification of small amounts of amorphous DSC methods are used mainly in early stages or as in-process control. For such uses either no validation or a reduced validation is required. DVS methods are used during development phases when an accurate assessment of the amorphous content is required. In late development and commercial phases a DVS method as a limit test may be the most appropriate approach. Comparison of LOQ for different products will be presented. Values for DVS methods are always lower than for DSC methods, as expected. Also a strong product dependence is observed. In some cases the development of a Hyper-DSC method is envisaged as an optimal solution that can provide a fast method with a low LOQ as with DVS methods. That will be shown in future studies.