NMR Method Characterizes Nanoparticle Surface Area

Mon, 11/05/2012 - 2:39pm
XiGo Nanotools, Bethlehem, Penn.

There is an increasing need for adaptable methods and technologies as nanoparticle surface area measurements are becoming more and more essential.

Figure 1 depicts the competitive adsorption of a surfactant and a polymer onto 15-nm silica.Nanotechnology has drawn much attention since there is tremendous potential for the development of nanoparticles that will deliver enhanced performance capabilities to products. For example, nanoparticles are being used for automotive coatings (to improve scratch resistance) and in the growing field of printed electronics (lower curing temperature and finer lines). 

Understanding the nature and the extent of nanoparticle surfaces is an essential element in particulate dispersion formulation. For example, the wetted surface area determines the quantity of surfactant required to ensure complete particle coverage and accordingly, optimal particle dispersion. Irrespective of the industry in which you work, optimizing product performance and ensuring end-product quality requires knowledge and control of the particle-liquid interface. Despite the importance of the particle surface-liquid interface on product performance, no direct technique was available to determine the wetted surface area of suspensions and slurries, until now.

Traditional surface area measurement using BET gas adsorption is only possible for dry powders. Unfortunately, gas adsorption on a dried particle surface has little relevance to the behavior of those particles when dispersed in liquids. With formulated suspensions, particles need to be separated from the liquid in which they were created or used. This can be a non-trivial process, especially in the case of nanoparticle dispersions that are created directly by a condensation (sometimes termed “bottom-up”) method; particles aggregate on drying, thus the total surface extent measured in the dry state is different from the same particle surface area properly dispersed in a liquid. This complicated and time-consuming sample preparation and measurement process has limited the use of surface area measurements in dispersion formulation development. 

Measurements of particle size and distribution are much more rapid and do provide some information, but have several limitations: they are confined to very dilute systems; they assume that the particles are spherical; they are not sensitive to measuring small particles among large ones; and they provide no information about the particle surface chemistry.

Relaxation Time and Rate versus weight % for 100nm TiO2Unfortunately, most industrially relevant suspensions are not dilute, many real particles are not spherical, most real particles are not monodisperse and surface chemistry can have a significant impact on dispersion performance.  

A new approach to quantifying the extent and nature of nanoparticle surfaces using nuclear magnetic resonance (NMR) is available that could prove an invaluable tool to scientists working in product formulation and development, process development or quality control. 

The Acorn Area, from XiGo Nanotools, uses a patented approach that interrogates the nanoparticle surface–liquid interface that requires no sample preparation and takes less than 5 minutes to measure not only wetted surface area but other attributes of nanoparticle dispersion behavior.

The Acorn Area method relies on the observation that liquid in close proximity to the particle surface has a relaxation time, T2s , that is orders of magnitude shorter than the relaxation time, T2bulk, of liquid far away from the particle surface. Liquid molecules exchange between the particle surface and the bulk liquid very rapidly. When the relaxation time of a particulate dispersion is measured, an average relaxation time is observed that is a weighted average of the volume of liquid on the particle surface and the volume of liquid far away from the particle surface. 

This approach has several practical advantages. It works well for concentrated systems. In fact, the higher the particle concentration, the greater the volume of surface-associated liquid and, hence, the larger the relaxation time shift in comparison with the liquid without particles. The second advantage is time: it typically takes less than 2 minutes to complete a relaxation measurement on a particle suspension. Finally, the measurement is agnostic to the size and shape of particles dispersed and can work with any liquid that contains protons. 

Particle Surface Area and Size as a function of Milling Time

In contrast to measurements of particle size by dynamic light scattering or light diffraction, where the raw scattered/diffracted intensity data has to be deconvoluted by means of complex algorithms, the NMR relaxation time can be converted into the absolute surface area by means of a straightforward calculation. 

The presence of API fines in a drug product can significantly alter the pharmacokinetics of drug absorption and, in some cases, result in cytotoxicity. While it has long been known that drug dissolution is controlled by API surface area, there is a growing body of evidence that, specifically with nanoparticles, it is the surface area and not particle size that is the defining metric that controls toxicological interaction. In addition, the presence of fines can cause issues with the physical stability of the drug product. The surfactant loading required to stabilize a colloidal dispersion is directly related to the available wetted surface of the particle, hence direct measurement of the wetted surface area is critical to formulation development. 

Time mode

Area Quant software, the operating software supplied with Acorn Area, has a Time Mode function that can be used to study changes in dispersion properties. Relaxation measurements are very sensitive to changes in particle concentration. Sedimentation can pose serious issues for formulation stability. As settling particles pass out of the Acorn Area measuring zone, the relaxation time increases, enabling the Area to be used to measure particle settling for hours, days, weeks or even months, irrespective of suspension concentration. Further, since the measurement is non-invasive, samples can be stored and re-measured at any future date. This makes it extremely useful for studying accelerated aging.

The Time Mode can also be used to study flocculation and coagulation. As particles floc, or coagulate, the aggregates formed immobilize liquid, increasing the effective volume of bound liquid, resulting in a reduction of relaxation time.

Sedimentation of a 10% aqueous suspension of Barium TitanateFlow-Thru option

The Acorn Area also has an (optional) flow module. By flowing the sample suspension through the instrument, the effects of additives on the particle-liquid interface can be studied. In actual practice, the flow is continuous, but the sample flow is stopped by a bypass valve to allow the dispersion to reach equilibrium in the static magnetic field. Measurements can be made every minute to determine, for example, equilibrium adsorption times. 

The Flow-Thru option also keeps samples (that would otherwise settle) suspended during the measurement. Flow-Thru measurements enable a much larger sample volume to be measured than would ordinarily be available using the manually filled NMR tubes. By continuous circulation and averaging the relaxation times, a more “representative” value can be obtained—important when the suspension under test is heterogeneous. 

The following information compares data for a sample of an industrial dispersion where T2 (msec) Static and T2 (msec) Flow was measured, respectively, for each sample—Sample 1: 112.1, 113.6; Sample 4: 95.5, 94.2; Sample 5: 100.9, 101.3; Sample 6: 107.9, 109.6; Sample 7: 144.8, 144.9; Sample 8: 120.6, 122.2; and Sample 9: 133.6, 135.2.

 The material is a very heterogeneous mix and obtaining a “representative”sample can be problematic. The static measurements were made by manually filling NMR tubes and the relaxation values are the average of five repeat measurements on 10 separate aliquots of dispersion. The total analysis time (sample preparation and measurement) was almost two hours. The flow measurements were obtained from five passes of bulk dispersion through the Acorn, each “sample” was measured three times; and total analysis time was less than 30 minutes.

NMR relaxation

In addition to determining the wetted surface area of suspensions, NMR relaxation can be used to characterize the strength of interaction between water (and other additives) and particle surface functional groups. The measured relaxation time is changed as a dispersant (surfactant or polymer) is added to a suspension; the dispersant adsorbs at the surface, displacing initial surface-associated water.

This effect can be exploited in formulation to determine, for example, the optimum amount of dispersant needed for particle surface coverage. Adsorption of surfactants onto particles is often a key step in the preparation of stable dispersions. Surfactants can be a significant cost in formulations and so the goal is to find the most economical, or “optimum,” coverage. 

Real-world formulations often utilize multiple additives; and the order of their addition is critical to obtaining stable dispersion conditions. Very frequently, polymers are used in conjunction with surfactants. NMR relaxation measurements can be used to study the effect of this process. In Figure 1, the graph on the left shows the adsorption of a polymer (PVP) onto a silica surface. The graph on the right shows the dramatic destabilizing effect of post-adding an anionic surfactant (SDS) to that same PVP-stabilized silica suspension—the SDS complexes with the PVP causing it to desorb, resulting in uncoated (and unstable) silica particles. The economic impact of incorrect mixing can be considerable. 

Finally, relaxation measurements in aqueous media can also be correlated with the number of hydroxyl groups on a pure oxide surface; a sample with a richer content of hydroxyl groups should possess a smaller relaxation time. 


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