Application of Magnetic Resonance to Assess Lyophilized Drug Product Reconstitution.

Purpose: Dynamic in-situ proton (H) magnetic resonance imaging (MRI) and H T-relaxometry experiments are described in an attempt to: (i) understand the physical processes, that occur during the reconstitution of lyophilized bovine serum albumin (BSA) and monoclonal antibody (mAb) proteins; and (ii) objectify the reconstitution time.

Methods: Rapid two-dimensional H MRI and diffusion weighted MRI were used to study the temporal changes in solids dissolution and characterise water mass transport characteristics. One-shot T relaxation time measurements were also acquired in an attempt to quantify the reconstitution time. Both MRI data and T-relaxation data were compared to standard visual observations currently adopted by industry. The H images were further referenced to MRI calibration data to give quantitative values of protein concentration and, percentage of remaining undissolved solids.

Results: An algorithmic analysis of the H T-relaxation data shows it is possible to classify the reconstitution event into three regimes (undissolved, transitional and dissolved). Moreover, a combined analysis of the 2D H MRI and H T-relaxation data gives a unique time point that characterises the onset of a reconstituted protein solution within well-defined error bars. These values compared favourably with those from visual observations. Diffusion weighted MRI showed that low concentration BSA and mAb samples showed distinct liquid-liquid phase separation attributed to two liquid layers with significant density differences.

Conclusions: T relaxation time distributions (whose interpretation is validated from the 2D H MR images) provides a quick and effective framework to build objective, quantitative descriptors of the reconstitution process that facilitate the interpretation of subjective visual observations currently adopted as the standard practice industry.