(60b) Novel Applications of Light Scattering Techniques for on-Line Characterization of Nano-Particles

Novel Applications of Light Scattering
Techniques for On-Line Characterization of Nano-Particles

Abstract.

As the nature of active
pharmaceutical ingredients changes and more and more biologics are present in
the drug development pipelines, nanoparticles like liposomes and nanoemulsions
are emerging as useful vehicles for drug delivery. Nanoemulsions, consisting of
dispersed colloidal droplets, typically around 50- 600 nm in size, within an
immiscible continuous phase, are used routinely to encapsulate drugs that are
poorly soluble or susceptible to hydrolysis and/or enzymatic breakdown. For
these drugs nanosized micelles act as protective delivery vesicles in vivo,
ensuring successful drug delivery to the target site.

In pharmaceutical
nanoemulsions droplet size typically has a defining influence on in vivo
behavior thereby impacting the pharmacological profile of a drug and its
clinical performance. Droplet size often influences factors such as absorbance,
bioavailability, diffusion rate and stability, and as result tends to be a
critical to quality parameter for the drug product. Understanding how
formulation composition and processing parameters impact droplet size is
therefore a critical step in the development of a robust and well-controlled
nanoemulsification process.

The use of active ingredients that
are only sparingly soluble in solid dosage forms also creates a need to
disperse particles to a very fine size. Increasingly the optimal particle size
for an active ingredient is in the nanometer, rather than the micrometer range.
Nanomilling or micronization processes are applied to grind the particles, in
suspension, and achieve the necessary comminution. Controlling particle size
during the milling process is essential to ensure a safe and efficacious drug.

DLS is a technique used routinely
to measure all types of nanoparticles across the size range 0.3 nm to 10 µm. The principle
that underpins it is a relatively simple one, indeed simplicity is a key
attraction. Small particles in a dispersion or solution are subject to Brownian
motion which is driven by collisions with the solvent
molecules. A DLS instrument determines the rate of diffusion of particles
moving under Brownian motion, from measurements of fluctuations in scattered
light intensity. The resulting diffusion coefficient is used to
calculate particle size through application of the
Stokes-Einstein equation:

Where D = Diffusion coefficient, k = Boltzmann’s constant,
T = absolute temperature, h = viscosity, and D_H = hydrodynamic radius.

This relationship shows clearly how size can be determined
from diffusion speed, provided that the temperature and continuous phase
viscosity of the sample are known however, there are additional features of
modern instrumentation that further enhance the industrial usefulness of the
technique. For example, Non-Invasive Back Scattering technology (NIBS) makes it
possible to achieve high sensitivity across a broad size range and at high
measurement concentrations. It is also possible to apply DLS to measure a
sample in flow, providing that the flow is laminar and of a limited rate.

The conventional way to use DLS in
process development or monitoring is to manually extract a sample and carry out
a measurement in the laboratory to determine particle size. The endpoint of the
process is marked by particle size reaching a target value and this can be
confirmed by offline sampling and analysis. However this approach introduces a
significant lag between an action and any assessment of the impact with the
results often obtained only once the batch is complete. This does not allow for
an assessment of the trajectory of the process, as it progresses, or provide an
opportunity to tune processing parameters to achieve a better result.

For example, in the production of a
pharmaceutical nanoemulsion the endpoint of processing is marked by particle
size reaching a stable value and the top end of the droplet population dropping
below an upper limit. This limit is often guided by the need to achieve certain
performance characteristics in subsequent processing steps, such as sterile
filtration using a 0.2 µm filter, for example. Ensuring that the droplet size
has been sufficiently reduced while minimizing over-processing requires
multiple manual analyses over the course of a batch or during continuous
production. This is a time and labor intensive approach, both at the pilot
scale, when the focus is to scope and optimize processing conditions, and
during commercial production, where precise monitoring is linked directly with
confidence in quality and variable cost management. The need to submit
in-process samples to an analytical lab for analysis results in the loss of
valuable time and inhibits the ability to respond to process deviations.

The use of on-line particle
characterization tools, in contrast, enables rapid, time relevant process
monitoring. Real-time data make it possible to quickly see the impact of
changing a process parameter and efficiently establish conditions that will
deliver a successful outcome. Online measurement therefore brings clarity and
reduces development efforts during the scoping and scale-up studies associated
with QbD, as well as enabling efficient process monitoring and control at the
commercial scale.

The case studies described in this
presentation will  discuss the comparability of manual and automatic analysis
and results achieved from evaluating various formulations with emphasis on
practical value of utilizing Process Analytical Technologies.