Introduction

Many analytical methods exist for the characterization of products manufactured in the pharmaceutical industry. Measuring the size and shape of particles or emulsions is undoubtedly one of the simplest and quickest methods, but provides indispensable qualitative data to assess the feasibility of a manufacturing process or the final effectiveness of a formulation.

Measuring size and shape is part of the precise requirements of the standards taken as the basis for the assessment of the possibilities for particle size analysis techniques and the benefits of morphological analysis for this application.

The pharmaceutical industry and standards

All of the activities of the pharmaceutical activity are controlled to ensure that the production of drugs is as safe as possible. All of the phases in the manufacture of a drug must therefore meet the requirements of the Food and Drug Administration (FDA).

The most common standards are the USP standards (United States Pharmacopeia). These standards standardize the methods used to measure physical and chemical properties or the use of pharmaceutical products based on ISO standards (International Standardization Organization).

Standards ISO 13320 and 13322

post67These standards indicate the particularities of the equipment required for the analysis of the size of particles by diffraction laser and the analysis of images obtained using optical microscopy.

These standards particularly include a few recommendations on the type of solvents required for the dispersion of particles, recommendations on equipment (figure 1) and the calibration of equipment, the application of the theories of Mie or Fraunhofer and the values of variation coefficients to be applied for repeatability and reproducibility measurements or to statistics for morphological analysis (figure 2).

The table shown in figure 2 indicates an estimation of the number of particles to be analyzed in order to
obtain a statistical measurement of particle size based on image analysis. The measurement of 60,000 particles appears appropriate for a statistical determination of size.

Standards USP <429>, USP <776> and <1058>

The first two USP standards [3-4] include the content of the above ISO standards. Standard USP <1058> [5] covers IQ (Installation Qualification), OQ (Operational Qualification) and PQ (Performance Qualification) processes.

The IQ-OQ-PQ validation plans provided by CILAS are used to install and maintain instruments in accordance with the GMP (Good Manufacturing Practices) required by the WHO (World Health Organization)

Standard 21 CFR Part 11

Regulation 21 CFR Part 11 defines the bases for the electronic signatures on documents transmitted to the FDA (Food and Drug Administration).

This standard:

-Speeds up the exchange of information
-Improves data searches
-Reduces errors and variability
-Reduces data storage costs

SizeExpert software meets the requirements of the standards and mainly manages multi-level access.

The benefits of analyzing the size and morphology of particles

imgg91The importance of the morphology of particles can, for example, be demonstrated by the representation of the intrinsic viscosity of the solution, which influences the thixotropic behavior of a viscous solution [6].

Figure 3 shows changes to this size based on aspect ratio for particles at constant concentrations and volumes. This representation demonstrates a rapid increase in intrinsic viscosity when the particles have a strong shape anisotropy. This property can have a significant impact on the cream or pomade formulation.

Compactation phenomena are directly related to size and shape parameters (figure 4). The control of these parameters therefore enables improvements to manufacturing and compacting processes [7-9].

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These particle size and morphological data are also important as they influence the dissolution, bio-availability and therefore effectiveness of the pharmaceutical preparations.

A few examples of particle size distribution measurements for compounds used in the pharmaceutical industry

post99Most compounds used for their pharmaceutical properties, active ingredients or excipients, are in powder or emulsion form.

Depending on the circumstances, the particle size distributions obtained by diffraction laser can be measured using dry or wet modes.

Figure 5 shows the particle size distributions of an active ingredient, domperidone, and excipients,
aluminum and silicon oxides (alumina and silica) and magnesium carbonate

In the case shown in figure 5.a, a concentrated emulsion has been placed on a microscope plate. The specimen was carefully prepared in view of obtaining fully separated drops and ensuring optimal conditions for the analysis.

For this type of image, digital processing (figure 5.b) involves thresholding to convert the image into black and white. A selection filter was then applied to select isolated particles and exclude agglomerates. In the example shown, the filter applied allowed the most spherical particles to be selected.

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The size of the drops of this emulsion was determined on the basis of the analysis of 1049 particles. The corresponding particle size distribution is shown in figure 6. The typical diameters of this monomode and monodisperse distribution are as follows:

 

 

D10 = 7.1 μm, D50 = 11.7 μm, D90 = 16.6 μm

Conclusion

Whether handling emulsions, dry powders or powders dispersed in a liquid, diffraction laser particle size analysis combined with morphological analysis is an indispensable tool at all phases in the life of a drug.

Research and development phases, the request for marketing authorization or the acceptance inspection of raw materials or the inspection of the quality of the production of pharmaceutical preparations can be analyzed using these methods.

References

[1] International Standard , ISO 13320-1, “Particle Size Analysis – Laser Diffraction Methods”, General Principles

[2] International Standard , ISO 13322-1, “Particle Size Analysis – Image Analysis Methods Part 1 : Static Image Analysis Methods”

[3] United State of Pharmacopeia : USP <429> Light Diffraction Measurement of Particle Size

[4] United State of Pharmacopeia : USP <776> Optical Microscopy

[5] United State of Pharmacopeia : USP <1058> Analytical Instrument Qualification [1] International Standard , ISO 13320-1, “Particle Size Analysis – Laser Diffraction Methods”, General Principles

[6] Intrinsic viscosity and the polarizability of particles having a wide range of shapes Advances in Chemical Physics, Volume XCI, (1995)

[7] Compaction Simulator Studies of a New Drug Substance: Effect of Particle Size and Shape, and Its Binary Mixtures with Microcrystalline Cellulose Pharmaceutical Development and Technology, Volume 1, Issue 2, p. 119-126, (1996)

[8] What is the role of particle morphology in pharmaceutical powder aerosolsExpert Opinion on Drug Delivery, Volume 5, Number 8, pp. 909-914, (2008)

[9] Divided solids characterization as part of pharmaceutical development STP Pharma pratiques, Volume 13, Number 4, p. 245-251, (2003)