Taking the "Suspense" out of Nanosuspension Specifications

Formulators currently face numerous challenges in nanosuspension development in terms of ensuring safety, efficacy, and stability. Presenters at Wednesday's AAPS symposium offered strategies for addressing these challenges, including setting meaningful particle-size specifications, selecting the method to measure particles in nanosuspensions (especially for nonspherical particles), gaining a meaningful particle-size distribution, and determining the particle size from such distributions.

As Stanley Hem, PhD, observed, obtaining stable nanosuspensions is especially challenging because of their tendency to aggregate. "This is a major problem with nanosuspensions," he says, because of the interparticle forces among the particles. In particular, as particle size decreases, interparticle distance decreases, so aggregations are more likely to occur. In particular, formulators must pay close attention to the interparticular forces, especially the electrostatic repulsive force (which can be modified with the addition of a surfactant) and steric repulsive forces.

For example, says Hem, aggregation in nanosuspensions (for particles less than 100 nm) can be prevented with the addition of appropriate stabilizers (such as Tween 80) in the formulations. These stabilizers can increase the effective distance of repulsive forces, even to distances beyond those at which the strong Van der Waals attractive forces are in effect.

Hem also showed that viscosity is not directly related to the degree of disaggregation in polymers, pointing out that the rate of disaggregation is heavily dependent on shear stress, temperature, and ionic strength. Understanding the ideal conditions of these parameters is critical because the process must not be stopped until the formulation is completely disaggregated.

Demonstrating the effect of autoclaving on the stability of polymers, Hem presented studies conducted on guar gum, xanthan gum, Carbomer 940P, and hydroxyethylcellulose. For example, for guar gum, if it is to be autoclaved, the effect is highly dependent on concentration. Ideal stability, says Hem, occurs at concentrations of 0.5% or higher. With xanthan gum, however, the impact of autoclaving on stability is more complex. Hem showed that the addition of NaCl (even after autoclaving for 15 minutes) can be used to recover the double-helix structure of xanthan gum.

Hem also pointed out that whenever one has a charged particle, there is going to be a "double layer" and the microenvironment surrounding the double layer may have a pH different from that of the bulk, which may have a significant influence on stability. For example, in glucose 1 phosphate, the pH of the microenvironment differed significantly from the bulk substance's as the temperature changed. Therefore, the behavior of the substance will be governed by the microparticle pH as opposed to that of the bulk. Hem also demonstrated that the stability of methylparaben, which degrades by both acid- and base-catalyzed hydrolysis, was greatest at pH 4.5 after the surface charge was modified.

Right now, the industry is still trying to figure out how to measure and report particle sizes. Mark BuMiller, PhD, demonstrated several approaches for determining what the particle size should be based on. Ideally, says BuMiller, the particle-size rating should be based on performance. In actuality, he says, industry usually bases it on historical data.

Currently available technology, like microscopy (automatic image analysis) and particle counters, can be useful, says BuMiller. The industry standard sample for particle counters is about 600 particles, but the standard is not firm. BuMiller notes that although USP offers some guidance, the industry now has a better standard, ISO 13322-1. "In my humble opinion, this provides better guidance than the USP equations," he says.

BuMiller also advised on reporting mean diameters and the various techniques to obtain meaningful particle sizes. In particular, he advised using the D[4,3] data, often referred to as the "volume mean diameter" and strongly suggested not taking the number mean. "Instead, formulators should take the number mean, [and] convert it to the volume mean. This number is much more useful." He also advised never using the D[1,0] value when using laser diffraction such as photon correlation spectroscopy. For laser diffraction, multiple measurements should be taken, specifically Dv10, Dv50, and Dv90. If there is an error, says BuMiller, specifications (which were based on performance of the instrument) should be tightened.

Mansoor Khan, RPh, PhD, (FDA, Rockville, MD, and a Pharmaceutical Technology Editorial Advisory Board member) concluded the presentation by describing a regulatory perspective on the challenges of particle-size distribution with meaningful specifications. Khan first reviewed the US Food and Drug Administration's paradigm changes for testing to quality, and the usefulness of several ICH quality guidelines, including Q6A, Q8, Q9, and Q10.

During his presentation, Khan listed questions that must be addressed, including: When is particle size important? Which method should be used? How should the method be validated? What specifications should be reported? And what should be expected when specifications change? In some cases, Khan said, particle size may not need to be specified as long as product performance can be otherwise scientifically justified.

Khan concluded his presentation with an FDA study of how three methods - laser diffraction, "Rapidvue" image analysis, and light obscuration - demonstrated deviations in particle size. Acknowledging "no one technique does everything," formulators can use complementary techniques to obtain better specifications, thereby reducing the need to tighten specifications later in the process.

Presenters in "Current Challenges in Pharmaceutical Suspension Dosage Forms - Formulation Development, Relevant Particle-Size Specification and Bioavailability Evaluation" were:

Moderator: Alok Kulshreshtha, PhD, Alcon Research.

Current Challenges in the Development of Stable Pharmaceutical Suspensions, Stan Hem, PhD, Purdue University.

Various Measurement Techniques for Particle-size distributions in Pharmaceutical Suspensions and Meaningful Specifications, Mark BuMiller, PhD, Malvern Instruments.

Regulatory Perspectives on the Challenges of Particle-Size Distribution with Meaningful Specifications, Mansoor Khan, PhD, US Food and Drug Administration.