Monitoring of the sedimentation kinetics of vaccine adjuvants using water proton NMR relaxation

Abstract

Suspensions of solid particles find applications in many areas—mining, waste treatment, and in pharmaceutical formulations. Pharmaceutical suspensions include aluminum‐adjuvanted vaccines are widely administered to millions of people worldwide annually. Hence, the stability parameters of such suspensions, for example, sedimentation rate and the compactness of the formed sediments, are of great interest to achieve the most optimal and stable formulations. Unlike currently used analytical techniques involving visual observations and/or monitoring of several optical properties using specialized glassware, water proton nuclear magnetic resonance (wNMR) used in this work allows one to analyze samples in their original sealed container regardless of its opacity and/or labeling. It was demonstrated that the water proton transverse relaxation rate could be used to monitor in real time the sedimentation process of two widely used aluminum adjuvants—Alhydrogel® and Adju‐Phos®. Using wNMR, we obtained valuable information on the sedimentation rate, dynamics of the supernatant and sediment formation, and the sedimentation volume ratio (SVR) reflecting the compactness of the formed sediment. Results on SVR from wNMR were verified by caliper measurements. Verification of the sedimentation rate results from wNMR by other analytical techniques is challenging due to differences in the measured attributes and even units of the reported rate. Nonetheless, our results demonstrate the practical applicability of wNMR as an analytical tool to study pharmaceutical suspensions, for example, aluminum‐adjuvanted vaccines, to provide higher quality and more efficient vaccines. Such analyses could be carried out in the original container of a suspension drug product to study its colloidal stability and to monitor its quality over time without compromising product integrity.

Analysis of the Adsorbed Vaccine Formulations Using Water Proton Nuclear Magnetic Resonance—Comparison with Optical Analytics

“…Another important parameter derived from the sedimentation kinetics, the sedimentation volume ratio (SVR), indicates the sediment compactness, which relates to the redispersion of aluminum-adjuvanted vaccines; sediments with smaller SVR are more compact and hence might be more difficult to redisperse. As has been shown previously [27], the water proton transverse relaxation rate R 2 ( 1 H 2 O) consistently decreases during the sedimentation of aluminum adjuvant suspensions.…”

“…Additionally, the higher plateau value of R 2 F (T) for the HD sample after completion of sedimentation suggests higher compaction of the sediment layer compared to the LD sample (the two batches have the same amount of aluminum adjuvant microparticles, at 0.66 mg/mL of Al(III)). Indeed, in more compact aluminum sediment, the concentration of AlPO 4 microparticles will be higher, and higher concentrations of aluminum adjuvants are known to result in much higher values of the water proton transverse relaxation rate R 2 ( 1 H 2 O) [27,31].…”

“…This difference between high-and low-dose formulations could be explained based on the difference in electrostatic repulsion effects between AlPO 4 particles. In the absence of adsorbed antigen, repulsion between similarly charged adjuvant microparticles would result in rather slow sedimentation which takes multiple days to reach plateau [27]. Antigens and adjuvants typically are oppositely charged in a formulation.…”

“…Our previous research has demonstrated the capability of wNMR to provide important information on the dynamic behavior of pharmaceutical suspensions containing aluminum adjuvants. We explored the concentration-dependent differences in the sedimentation kinetics of two commercially available aluminum adjuvant suspensions, Alhydro-gel® and Adju-Phos® [27]. wNMR was successfully used to analyze freezing susceptibility and to detect prior freezing history of aluminum-adjuvanted vaccines in their original containers [28].…”

Inspecting Insulin Products Using Water Proton NMR. I. Noninvasive vs Invasive Inspection

“…We have applied w NMR to a variety of systems, including biomaterials, 13,14 surfactants, 15 small molecules, 16 nanoparticles, 17 dendrimers, 12,18 insulin, 2,19 proteins, 15,20,21 monoclonal antibodies, 22,23 vaccine adjuvants 24,25 and vaccines. 26 We also discussed applications of w NMR in the development, 27,28 inspection, 29 and distribution 30 of drugs and vaccines.…”