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Karin LiltorpKarin Liltorp, Ph.D., is currently working as principal scientist at Particle Analytical Aps., an analytical laboratory performing physical chemical characterization of pharmaceutical drugs.

 
It is well known that blending properties, stability, and dissolution profile of a pharmaceutical drug is highly dependent on size and morphology of the particles. Thus, the “behavior” of the drug during manufacturing —and ultimately in vivo—relies on particle size. In order to secure patients, there is a regulatory requirement to specify acceptance criteria: The need to determine particle sizes is stated in the ICH guidelines 6A, 8, and 9 (amongst others).

For determination of particle sizes, a validated method is necessary. The method most commonly used is laser diffraction. Laser diffraction is known to be a robust method—but one very dangerous pitfall exists: Through laser diffraction, you do not obtain a “direct” measure of the particles. The signals from the measurement are “translated” into a particle size by different calculation methods. These calculation methods are known as “Fraunhofer” and “Mie.” If you are not using the right calculation method and correct parameters, this might lead to large over- or underestimation, especially of the presence of small particles! The consequences might be severe—for instance, a too high or too low exposure in vivo.

Mie Theory

Figure 1. The incident laser light interacts with the particle leading to absorption and scattering. The scattered light is detected and translated into a particle size by mathematical calculations (either Mie or Fraunhofer).

 
In our experience, many people use a “default” value in their “validated” method, which might give a very misleading picture of the actual size distribution. The reason for using default values is most likely due to lack of awareness of the importance of the parameters. An example is the optical properties/refractive index of particles, which affects the interactions with the laser beam. The default value set in a Malvern laser diffraction instrument is 1.5, but even a 0.1 change in this value might lead to drastic changes in the results (the refractive index is usually from 1.3 to 2.1 for organic materials). This implies that the value cannot be assumed, but must be determined experimentally. A method validation should always include evaluation of the calculation method used, even though the suppliers of the instruments usually recommend one of the two calculation methods. Otherwise, a complementary method confirming the results from the laser diffraction should always be applied (i.e., microscopy).

What do you think is the best method validation for particle sizes?