Application of Magnetic Resonance to Assess Lyophilized Drug Product Reconstitution

PURPOSE: Dynamic in-situ proton ((1)H) magnetic resonance imaging (MRI) and (1)H T(2)-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 (1)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(2) relaxation time measurements were also acquired in an attempt to quantify the reconstitution time. Both MRI data and T(2)-relaxation data were compared to standard visual observations currently adopted by industry. The (1)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 (1)H T(2)-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 (1)H MRI and (1)H T(2)-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(2) relaxation time distributions (whose interpretation is validated from the 2D (1)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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11095-019-2591-x) contains supplementary material, which is available to authorized users.