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Sgs Particle Characterisation en 08
Sgs Particle Characterisation en 08
PARTICLE CHARACTERISATION IN
EXCIPIENTS, DRUG PRODUCTS AND DRUG SUBSTANCES
AUTHOR: HILDEGARD BRÜMMER, PhD, CUSTOMER SERVICE MANAGER, SGS LIFE SCIENCE SERVICES, GERMANY
Particle characterization has significance in many industries. For the pharmaceutical industry, particle size impacts
products in two ways: as an influence on drug performance and as an indicator of contamination. This article will
briefly examine how particle size impacts both, and review the arsenal of methods for measuring and tracking
particle size. Furthermore, examples of compromised product quality observed within our laboratories illustrate why
characterization is so important.
INDICATOR OF CONTAMINATION
Controlling the limits of contaminating • Adverse indirect reactions: particles Particle characterisation of drug
particles is critical for injectable are identified by the immune system as substances, drug products and excipients
(parenteral) solutions. Particle foreign material and immune reaction is an important factor in R&D, production
contamination of solutions can potentially might impose secondary effects. and quality control of pharmaceuticals.
have the following results: It is becoming increasingly important for
In order to protect a patient and to compliance with requirements of FDA and
• Adverse direct reactions: e.g. particles guarantee a high quality product, several European Health Authorities.
are distributed via the blood in the body chapters in the compendia (USP, EP, JP)
and cause toxicity to specific tissues or describe techniques for characterisation
organs, or particles of a given size can of limits. Some of the most relevant
cause a physiological effect blocking blood chapters are listed in Table 1.
flow e.g. in the lungs.
COMPENDIUM TITLE
TABLE 2. CURRENTLY AVAILABLE PARTICLE SIZE ANALYSIS TECHNIQUES AND PARTICLE SIZE RANGE
TECHNIQUE MIN [µM] MAX [µM]
The most common method for particle practice the particles are passed through In our laboratory, we use this instrument
size distribution is the Laser Diffraction a focused laser beam, and these particles for dry powders as well as for well-
Measurement. The laser diffraction scatter light at an angle that is inversely dispersed samples and solutions (e.g.
method is suitable for highly accurate proportional to their size. The angular slurries or samples that need to be
determination of particle sizes in a range intensity of the scattered light is then measured wet in order to achieve good
of 0.02µm to 2000µm. The technique measured by a series of photosensitive particle distribution). Typical diagram of a
is based upon the beam diffraction detectors. particle size distribution investigation is
phenomenon (Fraunhofer diffraction). In shown in Figure 1.
0.2 – 1 mm
VOLUME (%)
5 – 20 µm
VOLUME (%)
In this example, two particle size classes For larger particles, analytical sieving powders. Our laboratory has established
(e.g. 0.1 – 1 mm and 5 – 20 mm) are methods can be used. The European tests for various powders and granulates.
shown. The actual measurement of the Pharmacopeia classifies powders
number of particles in a given range and according to their fineness. Table 3
the cumulative curve is represented. summarizes the different types of
There are two main types of sieving: can be used to gain more information on the focus point of the stage micrometer
Mechanical Sieving and Air-Jet-Sieving. the shape and structure of the particles. scale. Then the distance between
Mechanical sieving is carried out by We utilize microscopy to describe the scales of the two micrometers
stacking the sieves in ascending order of morphological appearance, shape, size is determined and the particle size is
aperture size and placing the powder on of particles and their distribution in APIs calculated. Particle number can also be
top of the sieves. With Air-Jet-Sieving, and excipients. Microscopic investigations calculated by counting particles within
the powder is fluidized and collected by can generally be applied to particles of the grid of the micrometer. Figure 2
application of negative pressure. A wide 1µm and larger. Optical microscopy is illustrates a typical field of a membrane
range of sieve sizes are described in USP, particularly useful for characterisation of filter carrying the particulate matter in a
EP and JP. In general, our laboratories particles that are not spherical. parenteral solution. Several particles of
conduct mechanical sieving for particles different shape are marked by an arrow.
larger than 75µm and for smaller particles In order to measure particle size, an
air-jet sieving or sonic sieving. ocular micrometer is inserted and a
calibrated stage micrometer is placed at
Should further characterisation of particles the centre of the microscope stage and
be required, optical microscopy methods fixed in place. The ocular is adjusted to
LIFE SCIENCE I TECHNICAL BULLETIN 4
Optical microscopy can also be used to investigate particles surfaces for re-crystalization of drug products (e.g. patches). Typical
recrystalization of an API observed during stability storage is shown in Figure 3.
The Environmental Scanning Electron While for conventional SEMs, samples Typical pictures of a filter surface and a
Microscopy (ESEM), with integrated must be suitable for high-vacuum and selected particle are shown in Figure 4.
Energy Dispersive X-ray microanalysis electroconductive. In contrast, using On the left, an overview image is shown
(EDX) for high resolution imaging and ESEM, damp samples, greasy/fatty and with the distribution of particles (bright
element analysis, is a new generation isolating materials can be observed at spots). By EDX it is possible to determine
scanning electron microscope (SEM). high resolutions and analysed without the elemental composition of each
ESEM allows for collecting information the otherwise necessary preparations. particle. On the right a detailed image of
regarding particle size and shape. The image is achieved by secondary one selected particle is depicted which
Consequently, this technique could be electrons (SE - topography contrast) or by shows its crystalline morphology.
used for stable nanosuspensions for back scattered electrons (BSE - material
intravenous injections. In addition, single contrast). The EDX system applied allows
particles can be isolated and evaluated for detecting elements of atomic number
regarding to shape. of 5 (boron) or higher.
SUMMARY
Particle analysis is an increasingly concerning potential contamination of SGS Life Science Services offers the
important parameter in API and excipient injections and infusions is required as techniques reviewed in the article
characterisation. Depending on the part of the safety assessment of the for particle characterisation. With the
formulation, various techiniques and drug. Therefore, an intensive study of established techniques and experience
approaches are available. Pharmacological API and excipient particle size, from the in particle analysis, SGS’s scientific staff
behaviour of drug product can be drug development to manufacturing, can is able to deliver a high quality particle
influenced by changes in particle size facilitate the development of safe, stable analysis on your product.
and structure. In addition, information and efficient products.
LIFE SCIENCE I TECHNICAL BULLETIN 6
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