Lien Vermeir

Effect of molecular exchange on water droplet size analysis in W/O emulsions as determined by diffusion NMR

Using NMR diffusometry, the diffusion of water and tetramethylammonium chloride was recorded in order to determine the water droplet size distribution in W/O emulsions. This study aimed at evaluating the effect of extradroplet diffusion of water on the estimated droplet size distribution upon comparison to the real droplet size distribution. The latter originated from the diffusion behavior of the tetramethylammonium cation (TMA+), which is known to have a much lower permeability through the oil phase as compared to water. Whereas both low-resolution and high-resolution pulsed field gradient NMR revealed that the water droplet size overestimation could be reduced selecting either a lower measurement temperature during diffusion analysis, or a smaller diffusion delay value Δ, still comparison to TMA+ diffusion indicated that artefacts were unavoidable even at low Δ and temperature. In order to correct for this extradroplet water diffusion phenomenon, different data analysis methods were evaluated. The previously described Pfeuffer exchange model could only partly compensate for the effect of extradroplet diffusion on the water droplet size determination. On the other hand, accurate water droplet size analysis results were obtained by correcting the experimentally determined diffusion distances based on Einsteins diffusion law. As such, reliable data could be obtained by low resolution NMR based on water diffusion at or even above room temperature.

Effect of molecular exchange on water droplet size analysis as determined by diffusion NMR: The W/O/W double emulsion case.

HYPOTHESIS The accuracy of the inner water droplet size determination of W/O/W emulsions upon water diffusion measurement by diffusion NMR was evaluated. The resulting droplet size data were compared to the results acquired from the diffusion measurement of a highly water soluble marker compound with low permeability in the oil layer of a W/O/W emulsion, which provide a closer representation of the actual droplet size. Differences in droplet size data obtained from water and the marker were ascribed to extra-droplet water diffusion. EXPERIMENTS The diffusion data of the tetramethylammonium cation marker were measured using high-resolution pulsed field gradient NMR, whereas the water diffusion was measured using both low-resolution and high-resolution NMR. Different data analysis procedures were evaluated to correct for the effect of extra-droplet water diffusion on the accuracy of water droplet size analysis. FINDINGS Using the water diffusion data, the use of a low measurement temperature and diffusion delay Δ could reduce the droplet size overestimation resulting from extra-droplet water diffusion, but this undesirable effect was inevitable. Detailed analysis of the diffusion data revealed that the extra-droplet diffusion effect was due to an exchange between the inner water phase and the oil phase, rather than by exchange between the internal and external aqueous phase. A promising data analysis procedure for retrieving reliable size data consisted of the application of Einsteins diffusion law to the experimentally determined diffusion distances. This simple procedure allowed determining the inner water droplet size of W/O/W emulsions upon measurement of water diffusion by low-resolution NMR at or even above room temperature.

In situ nondestructive sediment characterization and resuspendability evaluation of concentrated aqueous paliperidone palmitate suspensions in prefilled syringes by low-field one-dimensional pulsed-field gradient NMR profilometry

This work aims to demonstrate the usefulness of a low-field one-dimensional pulsed-field gradient NMR (1D pfg NMR) profilometry technique to enable in situ nondestructive sediment characterization and resuspendability quantification of concentrated prefilled injectable suspensions. Aqueous paliperidone palmitate suspensions were used as model samples and low-intensity centrifugation was evaluated as a long-term gravity simulation approach. The low-field 1D pfg NMR technique allowed a detection zone of 2.5 cm in height for water content measurement of syringe samples using a Teflon syringe holder. Thus, the sediment compactness could be deduced from its water content. Quantitative evaluation of resuspendability was realized by front tracking of the NMR profile signals, which yielded the exponential sediment volume decay constant as a resuspendability quantification parameter. The study shows that both active ingredient particle size distribution and storage temperature had significant effects on the sedimentation rate and the resuspendability of the suspensions. The centrifugation method proved to be useful as a long-term gravity simulation and screening method, although the results should be interpreted with caution due to its higher acceleration and compression force imposed on the active ingredient particles.

Simple and straightforward determination of the enclosed water volume fraction of W/O/W double emulsions by analytical photocentrifugation

ABSTRACT During the preparation of W/O/W-type double emulsions, a part of the internal water phase is often released to the external water phase. Thus, it is important that the enclosed water volume fraction can be determined in a simple and straightforward manner after preparation. In this work, a method is developed to determine the enclosed water volume fraction of W/O/W-type double emulsions using analytical photocentrifugation after which the results are compared to the enclosed water volume fraction as determined using pulsed field gradient Nuclear Magnetic Resonance (NMR). From the results, it can be concluded that analytical photocentrifugation is indeed a simple and straightforward method to determine the enclosed water volume fraction of double emulsions.

Increasing water solubility with decreasing droplet size limits the use of water NMR diffusometry in submicron W/O-emulsion droplet size analysis

HYPOTHESIS Water droplet size analysis of water-in-oil emulsions using water NMR diffusometry yielded values that were, from a certain shear intensity onwards, independent from the shear which was used during production. It was assumed that the constant water droplet size, obtained for samples prepared at higher shear, were only apparent droplet diameters. Considering the well-known increased solubility of the dispersed phase in the continuous phase at smaller droplet sizes, it is hypothesized that water diffusion in the oil phase was responsible for the fact that apparent rather than real sizes were obtained. EXPERIMENTS W/O-emulsions, prepared with a varying shear intensity, were characterized using dynamic light scattering, light microscopy, T2-relaxometry and PFG-NMR diffusometry. The latter measurements were conducted on both a low- and a high-resolution device and was based on either water (LR- and HR-NMR) or a water-soluble marker (HR-NMR). FINDINGS Low-resolution PFG-NMR is incapable of accurately determining the droplet size of W/O-emulsions containing (sub)micron sized droplets. On the other hand, using high-resolution PFG-NMR diffusometry and the addition of an oil insoluble marker to the water phase, the application window could be extended towards smaller droplet sizes. Finally, it was shown that T2-relaxometry was capable of detecting differences in droplet size between (sub)micron sized W/O-emulsions.

Influence of the NMR receiver gain on the enclosed water volume fraction of W/O/W double emulsions as determined by low-resolution NMR diffusometry and T2 relaxometry

Hereby, W/O/W emulsions can be obtained upon in-corporation of water within the emulsified oil phase of an oil-in-water emulsion. The enclosed water volume fraction (EV) isthe fraction of the total water that is present as internal waterdroplets and is an important measure of both the effectivenessof W/O/W emulsion preparation, as well as of W/O/W emulsionstability upon storage.In this study, the effect of NMR RG parameter setting on thequantitative determination of the EV of W/O/W type doubleemulsions by T

Statistical analysis of the effects of polyethylene glycol concentration and molecular weight on the sedimentation and resuspendability behavior of model aqueous dispersions

This work investigates the flocculation effect of polyethylene glycol (PEG) on typical aqueous dispersions, such as O/W emulsions and solid/liquid suspensions. Hereby, sunflower oil and flubendazole were selected as model ingredients, whereas microfluidization at variable driving air pressure was used to enable particle size distribution variations for both systems. The molecular weight of PEG varied from 2000 to 12,000g/mol while its concentration ranged from 50 to 100mg/ml. Statistical analysis revealed that both PEG concentration and molecular weight showed a flocculation enhancing effect. Hereby the inhibiting effect of particle size toward the formation of voluminous and easily resuspendable sediment could at least partially be overcome by selecting appropriate PEG characteristics.