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Determining globule size distributions in injectable liquid emulsions per USP

16 December 2011 No Comment

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Recently a customer pointed to USP <729> GLOBULE SIZE DISTRIBUTION IN LIPID INJECTABLE EMULSIONS. Can Light Scattering help elucidate particle size in parenterals?

The United States Pharmacopeia (USP) is an official public standards-setting authority. Their document USP <729> describes two methods for determining the mean droplet size and size distribution of injectable, oil-in-water, parenteral nutrition emulsions:

  • Method—I Light Scattering Method; subdivided into
    (1) dynamic light scattering (DLS), also known as photon correlation spectroscopy (PCS)
    (2) classical light scattering, based on Mie scattering theory
  • Method II—Measurement of large globule content by Light Obscuration (LO) or Extinction Method

Method I-1 is primarily of interest for Malvern Zetasizer users. Yes, your Zetasizer Nano can perform measurements as described in detail in Method I(1) DLS .There are some minor variations to the procedure stated in that USP method, however these still fall within the definition and allowances of the USP guidance:

a) the scattering angle in the Zetasizer Nano S/ZS is 173 degrees (not the “usually 90degrees”) which provides greater sensitivity combined with wider concentration range than the historical 90 degree optics (as implemented in the S90/ZS90)
b) the suitable detector is an avalanche photodiode (APD) with higher sensitivity than the traditional photomultiplier tube
c) the system does not have a built-in autodilution capability, however it may be found with the use of an autotitrator or on manual dilution testing that consistent and repeatable data require less dilution than in the historical 90 degree optics
d) the postulated Standard Preparation is essentially demonstrated and documented in the IQ/OQ Performance Qualification.

The intensity-weighted mean droplet diameter (MDD) in USP729 is the z-average or cumulant mean size directly obtained from the correlation function in the Malvern DTS software. For lipid injectable emulsions, this parameter must be less than 500 nm diameter. In a research environment, the intensity particle size distribution (PSD) may be transposed to a volume size distribution – for liposomes, a refractive index value of 1.45 and absorption value of 0.001 is typical – which may then provide an additional route to PFAT5, the volume-weighted percentage of fat droplets larger than 5000 nm diameter.

NB: Method I-2 is relevant for laser diffraction, i.e. the Mastersizer (and is the domain of  USP <429> LIGHT DIFFRACTION MEASUREMENT OF PARTICLE SIZE)