combined analysis of the size and shape of particles in [email protected] combined...
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Combined Analysis of the Size and Shape of Particles in the Pharmaceutical Industry
015
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
These 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.
Figure 1: Diagram of a laser particle size analyzer [1]
Figure 2: Recommendations for a representative morphological analysis [2]
Standards USP <429>, USP <776> and <1058> Standard 21 CFR Part 11
The 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].
These particle size and morphological data
are also important as they influence the dissolution, bio-availability and therefore
effectiveness of the pharmaceutical
preparations.
Figure 4: Microscopic observations of a sample with an inhomogeneous shape
Figure 3: Influence of the shape on intrinsic viscosity
The benefits of analyzing the size and morphology of particles
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)
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.
0
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0 0.2 0.4 0.6 0.8 1
Aspect Ratio (AR)
Intr
ins
ic v
isc
os
ity,
[ ηη ηη]
AR = 0.2
AR = 0.5AR = 1
AR = 0.1
0
2
4
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24
0 0.2 0.4 0.6 0.8 1
Aspect Ratio (AR)
Intr
ins
ic v
isc
os
ity,
[ ηη ηη]
AR = 0.2
AR = 0.5AR = 1
AR = 0.1
Figure 4: Particle size distributions for an active ingredient and excipients
Most 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
A few examples of particle size distribution measurements for compounds used in the pharmaceutical industry
a) b)
D10 = 7.1 µm, D50 = 11.7 µm, D90 = 16.6 µm
Figure 5: Processing of an image of a microemulsionused in cosmetics
a) original image b) processed image
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.
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:
Figure 6: Particle size distribution of a micro-emulsion
0
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0.1 1 10 100
Particle size (µm)
Vo
lum
e (
%)
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60
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100Histogram
Cumulative curve
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0.1 1 10 100
Particle size (µm)
Vo
lum
e (
%)
Alumina
Silica
Magnesium carbonate
0
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0.1 1 10 100 1000
Particle size (µm)
Vo
lum
e (
%)
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.
Conclusion
References
[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
[8] What is the role of particle morphology in pharmaceutical powder aerosols
Expert Opinion on Drug Delivery, Volume 5, Number 8, pp. 909-914, (2008)
[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)
[9] Divided solids characterization as part of pharmaceutical development
STP Pharma pratiques, Volume 13, Number 4, p. 245-251, (2003)