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John F. Bauer ]
Pharmaceutical Solids:
Size, Shape, and Surface Area
“Pharmaceutical Solids” discusses scientific principles odologies. Comparison of data between lots should
associated with pharmaceutical solids useful to prac- utilize the same instrumental method and be accom-
titioners in validation and compliance. We intend panied by microscopic examination
this column to help the understanding of principles • Particle size data is often reported as “equivalent
associated with pharmaceutical solids and to be a spheres” through mathematical calculation
useful resource for daily work applications. The key •C ertain pharmaceutical processes such as milling,
objective for this column: Useful information. wet granulation, and encapsulation may be signifi-
Reader comments, questions, and suggestions are cantly impacted by physical properties
needed to help us fulfill our objective for this column. • International Conference on Harmonisation (ICH)/
Suggestions for future discussion topics or questions Code of Federal Regulations (CFR) guidelines pro-
to be addressed are requested. Case studies illustrat- vide a decision tree to determine whether a particle
ing principles associated with pharmaceutical solids size specification is recommended
submitted by readers are also most welcome. Please • The difficulty of sampling pharmaceutical solids
send your comments and suggestions to column may contribute to data variation. Sampling using
coordinator John Bauer at consultjb@comcast.net process analytical technology (PAT) methods is
or to journal coordinating editor Susan Haigney at recommended.
shaigney@advanstar.com. • Practical implications of particle size may include
active pharmaceutical ingredient (API) biopharma-
KEY POINTS DISCUSSED ceutics, API and product process effects, raw material
The following key points are discussed: supply, and change control
• Physical properties of pharmaceutical solids such • The discussion and recommendations herein are
as particle size, particle shape, and particle surface consistent with the recent US Food and Drug Admin-
characteristics istration draft guidance on process validation.
• Physical properties may have significant effects on
pharmaceutical manufacturing INTRODUCTION
• Particle size is the primary parameter monitored in The large majority of APIs and excipients are solids at
pharmaceutical manufacturing room temperature. Most manufacturing processes for
• Particle shape and particle surface area including both bulk drug and dosage forms involve isolation of
porosity are linked to particle size solids, flowing of solids, mixing of solids, and wetting
• Particle surface area may influence flowabil- and drying of solids. How efficiently and reproducibly
ity, compactability, hygroscopicy, and other solids these operations can be performed is dependent on the
properties characteristics of the solids involved.
• Specific analytical methods are used to determine The last issue of this column discussed extensively
particle size, particle shape, and particle surface the phenomenon of solid form and, specifically, crys-
area tal form. The solid form is important because of the
• Particle size is measured by several different meth- effect it has on the physical properties of the solid.
[
For more Author ABOUT THE AUTHOR
information, John F. Bauer, Ph.D., is president of Consult JB LLC Pharmaceutical Consultants. Dr. Bauer has more
go to than 30 years pharmaceutical industry experience, including work in solid-state chemistry, analytical
gxpandjvt.com/bios chemistry, stability, pharmaceutics, regulatory CMC, patents, and litigation. He may be reached by
e-mail at consultjb@comcast.net.
These properties depend on the nature of the func- meters squared/gram while a cube with a 10-micron
tional groups exposed at dominant faces. More polar edge will have almost twice the surface area at 600
groups on the faces promote wetting by aqueous flu- meters squared/gram. Most particle size detectors will
ids and faster dissolution; non-polar groups hinder see both of these as 10 micron particles. Therefore
these important physical properties and may affect the choice between applying surface area specification
the biopharmaceutics of a drug. or particle size specifications must be made on the
basis of the specific application. Surface area is more
PARTICLE SURFACE AREA appropriate for applications involving hygroscopicity
The relative amount of active groups exposed for an or oxidation concerns. Particle size is more appro-
individual lot of solid is expressed in terms of surface priate for applications involving bulk density and
area. There is no generally accepted definition of mixing concerns. If surface area is found to be the
surface area for an irregular or porous solid. Rather, significant parameter, the porosity of the solid must
the specific surface area of a solid is defined in terms be kept in mind and a validated quantitation method
of an indirect measurement. This is determined by distinguishing the two must be developed.
physical adsorption of a gas, usually helium or nitro- In most cases, particle size is the parameter that
gen, on the surface of the solid. is chosen to be monitored. However, as mentioned
The surface area may be correlated to dissolution previously, the shape of the particle will influence the
rate and other physical parameters. For example, the interpretation of data such as “particles between 10
maintenance of a consistent surface area for the lubri- microns and 100 microns.” These could be particles
cant magnesium stearate may be needed to ensure that are flat plates 100 microns by 100 microns or
that lubrication occurs without overcoating the drug needles 100 microns long. It is critical that particles
particles and impeding dissolution. should always be observed microscopically as a sanity
Processes that may be affected by surface area check on particle size data.
include the following: Particle size is often manipulated during the
• Aggregation/deaggregation of particles during solid (i.e., API or excipient) manufacturing process
blending by controlling precipitation rates, cooling rates, and
• Flowability of drug, excipients and mixed times. These techniques naturally control the size by
powder controlling crystal growth. Particle size is also often
•A mount of granulating liquid required to avoid controlled by mechanically reducing the size through
either overmassing or undermassing either screening (i.e., forcing through a given mesh
• Compactability of powder or granulation size screen) or by milling. The milling operation can
• Hygroscopicity of powder or powder mix. produce uniform particle size but can also produce
high energy areas or areas of disorder in the particles
By nature of the solid form, amorphous solids have that may increase hygroscopicity and decrease sta-
greater surface area and are consequently more prone bility. Therefore, milling should be carefully char-
to problems. acterized and validated and any changes in milling
techniques should require a new validation.
PARTICLE SIZE
A third physical property of solids which can in some ANALYTICAL METHODOLOGY
ways be considered as incorporating the impact of Particle shape or morphology, particle surface area,
both particle shape and surface area is particle size. and particle size can be investigated and quantitated
In some cases, the undesirable properties resulting by the following methods:
from particle shape can be minimized if the size of • Morphology is evaluated by direct microscopic
the particle is controlled. The same can be true of the observation. Image analyzers are used to examine
surface area and, as a result, particle size is the param- a sample of solid and produce images, measure
eter most often specified in control documents. dimensions, and determine aspect ratios (i.e.,
As one might expect, however, particle size and width divided by height).
surface area are not interchangeable. The correlation • Surface area as mentioned previously is quanti-
between surface area and particle size is dependent on tated indirectly by measuring the amount of an
the shape of the particle. For example, a sphere with inert gas that is adsorbed as a monolayer on the
a 10-micron diameter will have a surface area of 310 surface of the solid.
Journal of Validation T echnology [Winter 2009] 39
Pharmaceutical Solids.
A change in morphology can affect the fracture properties of the solid thereby
Sizing/milling Morphology
altering the final particle size obtained
Wet granulation Surface area Increase in surface area may cause increase in massing time or granulation fluid
Wet granulation Particle size Decrease in particle size may cause decrease in massing time or granulation fluid
Compaction Particle size Smaller particles are more brittle than larger particles but have higher bonding index
Suspension Particle size Increase in particle size will increase settling rate and decrease suspension stability
because different techniques and instrument manu- general, the four basic questions can only be accu-
facturers use different algorithms, particle size values rately answered through process justification experi-
should not be compared between techniques or instru- ments. Answering the following questions deter-
ments. Data should be treated as relative values—in mines whether or not a particle size specification is
other words, to compare particle sizes between lots recommended:
and not to determine actual size. The size distribu- • Is the particle size critical to dissolution, solubil-
tions, on the other hand, should be comparable across ity, or bioavailability?
techniques as long as one allows for differences in size • Is the particle size critical to drug product
values and for individual technique limitations (1). In processability?
order to relate particle size measurements to actual • Is particle size critical to drug product stability?
behavior of the solid in a particular manufacturing • Is particle size critical to content uniformity?
process, one must keep sample preparation in mind
and what data are important: Smallest particle size, If the answer to any of the questions is “yes,” a
particle as processed, particle as used, or size distribu- particle size specification is needed. If the answer to
tion. Results must be interpreted in conjunction with all of the questions is “no,” a particle size specifica-
direct microscopic observation. Although there are tion is not needed.
some theoretical correlations between particle size and As mentioned previously, particle size can have
manufacturing performance as the examples in Table I an influence on wettability and dissolution. If one
show, any meaningful correlation between particle size is trying to formulate an active ingredient that falls
and performance must be experimentally determined into BCS class II or IV (i.e., it has low solubility), it
(i.e., through a series of process runs using different is sometimes possible to overcome this obstacle by
particle size material). Only in this manner can one reducing the particle size of the drug greatly using a
determine if particle size is critical and must be con- micronizing mill. This technique has made it possible
trolled for their particular manufacturing process. for several important drugs to be formulated effec-
tively in spite of unfavorable intrinsic properties.
REGULATORY GUIDELINES The decision tree in Figure 5 addresses drug sub-
Figure 5 shows the CFR decision tree (3) on particle stance. However, the same particle size concerns are
size specification requirements. The first question applicable to excipients and granulations.
concerning solubility can in some cases be addressed Snorek, Bauer et al (4), sponsored by the Product
by the Biopharmaceutics Classification System (BCS) Quality Research Institute (PQRI) (5), presented a
category (see Table II) of the drug substance. But in comprehensive discussion of particle size techniques,
Journal of Validation T echnology [Winter 2009] 41
Pharmaceutical Solids.
method validation, and decision trees for particle short time increments, rather than part of the stream
monitoring throughout the development process. being taken for a longer time. Because it is not always
possible to sample batches in this manner, in-line par-
SAMPLING AND PROCESS ANALYTICAL ticle size monitoring offers many advantages. In this
TECHNOLOGY technique, methodology such as Raman spectroscopy
In any of the particle characterization techniques, or a Lasentech instrument is used to continuously
an analyst could be examining less than a gram of monitor particle size during processing.
solid to determine the particle properties of several Sub-sampling for analytical testing is also critical.
kilos of powder. Unlike purity, impurity profile and Allen (7) presents a good comparison of the com-
other characteristics, particle size, shape, and sur- mon methods. He concludes that a spinning riffler
face area are not necessarily uniform throughout a is the best approach. A riffler uses a vibratory feeder
batch of solid. Sampling is critical when determining trough to provide a constant flow of material from a
these properties. This includes sampling from the hopper; then, a dividing head sharply separates the
batch, sub-sampling for the analytical assessment and flowing material into as many as 16 sample vessels.
further sub-sampling for the individual technique. Sampling problems with solids have been recently
According to the “Golden Rule of Sampling” (6), a discussed by Smith (8).
powder should be sampled when in motion, and the
whole sample stream should be taken over multiple
42 Journal of Validation T echnology [Winter 2009] iv thome.com
John F. Bauer.
Raw Material Supply and can be reproducibly manufactured, there are still
High risk API or excipients obtained from outside many potential problems during API and pharma-
sources should be carefully monitored. For example, ceutical product manufacturing because of physical
significant changes in the particle size of material to properties. Practitioners in pharmaceutical valida-
be wet granulated may have a significant affect on tion, manufacturing, quality, technical support, and
the granulation process, resulting in poor subsequent associated functional groups must be aware of this
processing and product dissolution problems. Chang- potential. Fundamental to this awareness is basic
ing suppliers of high-risk materials for cost savings understanding of the materials and processes, iden-
reasons is a common practice with high potential for tification of potential input variation, and strategies
problems. High-risk materials from new suppliers for appropriate control throughout the entire product
should be carefully evaluated. lifecycle. These points are consistent with the recent
FDA draft guidance on process validation (9).
Analytical Data
Particle size may be measured by various analytical
methods. Different methods use different operat- REFERENCES
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differences in measurement method. When compar- 4. Snorek, Sharon M., John F. Bauer, Nallaperumal Chi-
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CONCLUSIONS Autumn 2008.
This discussion has attempted to briefly introduce 9. FDA, Guidance (Draft) for Industry, Process Validation:
important practical concepts associated with particle General Principles and Practices. November 2008. JVT
size and associated pharmaceutical solids physical
properties. Although a drug’s chemical composition ARTICLE ACRONYM LISTING
is the major consideration in the pharmacological API Active Pharmaceutical Ingredient
activity of a pharmaceutical dosage form, the external BCS Biopharmaceutics Classification System
physical properties of the drug solid and excipients are CFR Code of Federal Regulations
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These physical properties are frequently overlooked ICH International Conference on Harmonisation
as a cause of manufacturing problems. After a stable PQRI Product Quality Research Institute
polymorphic form of API is selected for development