Application of Magnetic Resonance to Assess Lyophilized Drug Product Reconstitution

Abstract

PurposeDynamic in-situ proton (1H) magnetic resonance imaging (MRI) and 1H T2-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.MethodsRapid two-dimensional 1H MRI and diffusion weighted MRI were used to study the temporal changes in solids dissolution and characterise water mass transport characteristics. One-shot T2 relaxation time measurements were also acquired in an attempt to quantify the reconstitution time. Both MRI data and T2-relaxation data were compared to standard visual observations currently adopted by industry. The 1H images were further referenced to MRI calibration data to give quantitative values of protein concentration and, percentage of remaining undissolved solids.ResultsAn algorithmic analysis of the 1H T2-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 1H MRI and 1H T2-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.ConclusionsT2 relaxation time distributions (whose interpretation is validated from the 2D 1H 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 materialThe online version of this article (10.1007/s11095-019-2591-x) contains supplementary material, which is available to authorized users.

Multiparametric magnetic resonance imaging to characterize cabotegravir long‐acting formulation depot kinetics in healthy adult volunteers

“…Although these MRI‐derived parameter assessments have been used previously to examine drug dissolution ex vivo, no reports exist of these applications for in vivo assessment of LA injectable properties. 39 , 40 If drug agglomeration occurred during the initial week postinjection, then either patterns of reduced T2 and ADC or an overall reduction in these values might have been detected. Nevertheless, no patterns or regions of significance were observed in T2 or ADC change in the images, and this was also reflected in the quantitative T2 and ADC values measured in total and IM and SC regional depots.…”

“…T2‐weighted and ADC MRI parameters were assessed to examine whether they could differentiate between physiochemical agglomeration of drug substance and physiologic subacute inflammation. Although these MRI‐derived parameter assessments have been used previously to examine drug dissolution ex vivo, no reports exist of these applications for in vivo assessment of LA injectable properties 39,40 . If drug agglomeration occurred during the initial week postinjection, then either patterns of reduced T2 and ADC or an overall reduction in these values might have been detected.…”