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Pharmaceutical Solids.
John F. Bauer
Wettability
John F. Bauer
“Pharmaceutical Solids” discusses scientific principles
associated with pharmaceutical solids useful to practitioners in validation and compliance. We intend
this column to be a useful resource for daily work
applications. The key objective for this column:
Usefulness.
Reader comments, questions, and suggestions are
needed to help us fulfill our objective for this column. Case studies illustrating principles associated
with pharmaceutical solids submitted by readers
are most welcome. Please send your comments and
suggestions to column coordinator John Bauer at
[email protected] or to journal coordinating
editor Susan Haigney at [email protected].
KEY POINTS
The following key points are discussed in this
article:
•Wetting is an important phenomenon in the
manufacture of pharmaceutical dosage forms
•Wetting is also related to drug dissolution, drug
bioavailability and in vivo performance—the efficacy of the drug product
•Wettability of a solid is dependent on the nature
of the functional groups on the solid surface and
more polar surfaces increase wettability
•Wettability is characterized by the contact angle
of the liquid (usually water) with the solid surface. The smaller the contact angle—the greater
the wettability of the solid.
•The formation of a well wetted solid surface is a
fundamental step in the formation of acceptable
pharmaceutical granulations using a wet granulation process
•The wettability of any particular drug substance can
vary with crystal form, crystal habit, surface roughness surface area, porosity, and particle size
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•The addition of surfactants as well as the formation of salts can increase the wettability of poorly
wettable solids
•Validation and compliance personnel should be
knowledgeable of the problem tendencies of their
products and be vigilant of changes in bulk drug
manufacturing, particle size reduction processes,
certain dosage form manufacturing processes,
and certain major excipient changes.
INTRODUCTION
Solid pharmaceutical dosage forms are heterogeneous
mixtures prepared from several individual solid powders (i.e., active drug and excipients) having varying
physical properties.
Granulation is one of the most important unit
operations in drug product manufacturing. It is a
size enhancing process by which small particles are
formed into larger agglomerates. The smaller particles
can still be individually identified and are chemically
unchanged in the resulting granules. However, they
exist in more uniformly sized and dispersed particles
that can be further manipulated into dosage forms.
There are both dry and wet granulation processes, but
wet granulation is much more prevalent.
The following are main objectives of the granulation process:
•Improve the flow properties of the mixture
•Prevent segregation of the components
•Improve the compressibility of the mixture.
Previous columns (1, 2) discuss specific individual
physical properties of pharmaceutical solids such as
crystal form, particle size, surface area, and morphology, and how these properties influence stability and
manufacturing performance. This column addresses
a property that is in effect the result of positive or
ABOUT THE AUTHOR
John F. Bauer, Ph.D., is president of Consult JB LLC Pharmaceutical Consultants. Dr. Bauer has more
than 30 years of pharmaceutical industry experience, including work in solid-state chemistry, analytical chemistry, stability, pharmaceutics, regulatory CMC, patents, and litigation. He may be reached at
[email protected].
Validation T echnology [Winter 2010]
iv thome.com
John F. Bauer.
negative synergism among these individual properties.
The phenomenon is wetting or the physical interaction
of a solid with a liquid where there is no chemical
reaction. This discussion focuses on the interaction of
solids with water, although the concepts are applicable to other liquids, especially polar liquids. Wetting
ability is critical in the granulation process as well as
subsequent dosage form dissolution.
DEFINITION OF WETTING AND
WETTABILITY
Compounds or drugs attract water to the solid surface
to varying extents. Some moderately attract moisture while others seek water so extensively that they
become excessively wet (hygroscopic compounds)
and some even to the point of self dissolving (deliquescence). The large majority of pharmaceutical
compounds will simply be wetted to some degree
when brought into contact with water. Wetting can
be defined in various ways but the following seems
appropriate at this point. Wetting is the continued
contact between a liquid and a solid surface resulting
from physical interactions when the two are brought
together. In other words, the liquid is in some way
physically attached to the surface of the solid because
of some bonding force. This phenomenon of wetting
and the strength of the interaction are important in a
wide range of practical applications from watering a
garden to wet granulating a pharmaceutical preparation. The term used to describe the ease and extent of
wetting for an individual solid is wettability. While
watering a flower bed, one can observe how the water
appears differently and spreads differently on the
surface of different kinds of flowers. It also appears
to stay longer and bead up more on the surface of
some plants than on others. This is a reflection of
the different wettabilities of the various plants and
is a result of their physical surfaces.
WATER AND WETTING
In the oxygen-hydrogen bonds in water, the bonding
electrons are not located equidistant from the two
elements. This results in a partial negative charge on
oxygen and partial positive charge on hydrogen. This
uneven distribution of charge is known as a dipole.
Because of these dipoles, the hydrogen atoms of one
water molecule will be highly attracted to the oxygen atoms of neighboring molecules forming a weak
“hydrogen bond.” This allows water to produce an
extensive intramolecular network. This tendency of
water molecules to attract each other is called cohegxpandjv t.com
sion. The lowest energy or most stable state for such
a system is when each water molecule is surrounded
by the maximum number of other water molecules.
This situation results in a drop shape with the minimum amount of surface area, i.e., a sphere. This can
be seen as a droplet forms at the end of a faucet prior
to gravity distorting the shape and making the drop
fall (see Figure 1).
Because of this high cohesion it often appears as
if a membrane or thin skin has formed around the
drop (see Figure 2).
This skin is what allows insects to scurry across a
pond without sinking. The cohesion is strong enough
to support their weight as long as it is well distributed
across the water surface (see Figure 3).
This property that causes the surface of a liquid to
behave as a skin or stretched membrane is referred to
as surface tension. The relationship between surface
tension and the pull of gravity is what determines if an
object will float. Unfortunately, golf balls always sink.
This same innate ability of water to hydrogen bond
leads to a tendency for water to interact with solid
surfaces through adhesion, a process where the surface
molecules of water bond to the solid surface.
At this point we can expand our definition of wetting to be the contact between a liquid and a solid
surface resulting from the intermolecular interactions
when the solid and liquid are brought together. The
Figure 1: Spherical shape assumed by water drops.
Figure 2: Representation of “skin” on water surface.
“skin” due to surface
tension reflecting water
molecule cohesion
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Pharmaceutical Solids.
extent of wetting is dependent on the energies or surface tensions of the interfaces involved.
The degree of wetting of a solid surface, therefore, is
a balance between the forces of cohesion and adhesion.
This balance exists at the point of contact. Consequently the ideally spherical water drop on a surface
becomes distorted and appears as a truncated sphere.
The amount of wetting will result in greater or lesser
truncation. Figure 4 depicts varying degrees of wetting
and subsequent drop shape. This distortion is reflected
by the contact angle (theta), which is the angle between
the surface and a line drawn tangent to the curved
surface of the drop. The larger the contact angle, the
more spherical character is maintained and the less
the surface is wetted.
Table I presents the relationship between the contact
angle, the wettability of the surface, and the relative
cohesive and adhesive forces between the solid and
the liquid. Although the contact angle is measured
on the liquid drop, the wettability is a characteristic
of the solid surface and can vary from solid to solid,
from crystal form to crystal form, and even from batch
to batch.
Surfaces that have high contact angles and resist wetting with water are referred to as hydrophobic (water
Figure 3: Insect supported by water surface tension.
hating). Conversely, surfaces with low water contact
angles are hydrophilic (water loving). Table II summarizes the properties of these two types of solids.
IMPORTANCE OF WETTABILITY
Non-wetting surfaces (i.e., materials with very low
adhesion to water and consequently high contact
angles) can be beneficial for products that are designed
to repel water, such as foul weather clothing. However,
high wettability is desired in many situations. Wetting
is important in the bonding and adherence of two
materials. For example the presence and quantity of
water in mortar is critical to its bonding strength and
spreadability. In pharmaceutical manufacturing, wetting plays a crucial part in granulation.
Granulation Process
The mechanism of granulation is directly related to the
phenomena of cohesion and adhesion and, therefore,
wettability. Reasonably strong physical bonds must
be formed between the various powder particles in
order to form granules. These bonds must be strong
enough to assure that the granules will not break down
during subsequent unit operations such as drying and
compression. The strength of these bonds is related to
Figure 4: Truncation of water drop as adhesion to surface increases (left to right).
Amount of wetting is proportional to 1/θ.
Table I: Relationship of contact angle to wettability, cohesion, and adhesion.
Contact angle θ
Wettability
Adhesion strength
Cohesion strength
θ=0
Perfect wetting
Strong
Weak
0 < θ < 90
High wettability
Strong/weak
Strong/weak
90 • θ <180
Low wettability
Weak
Strong
θ = 180
Completely non-wetting
Weak
Strong
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John F. Bauer.
Table II: Summary of properties and terminologies related to wettability.
Hydrophobic surface
Solid property (with water as wetting liquid) Hydrophilic surface
High
Contact angle
Low
Low
Adhesiveness
High
Poor
Wettability
Good
Low
Solid surface free energy
High
particle size, moisture content, and the surface tension
of the granulation fluid.
The wettability of the solids involved is critical in the
mechanism. Ideally the first step will be the formation
of a thin immobile layer of liquid (water) on the solids.
The efficiency and effectiveness of this coating is very
dependent on the wettabilities involved. Good wetting
properties are required to get uniform liquid distribution and well controlled granule growth. If the solids
have low wetting (i.e., high contact angles) the film will
not be created and the necessary adhesion will not be
obtained. If the solid wets too extensively or is highly
soluble in the liquid, an excessive water layer may form
restricting adhesion of the powders. Another concern
may be the formation of hydrates on the surface of the
solid that would have different adhesion properties
than the original drug substance.
The possible formation of hydrates is a property that
should be thoroughly investigated earlier in development so that the risk of problems during granulation
can be anticipated and avoided.
Once the liquid layer is formed, there will be an
increase in contact between particles, and bond
strength will increase through Van der Waal forces.
The contact area will depend on the wettability of all
powders involved and not just the active drug. Therefore, it is important to be aware of the wetting characteristics of all ingredients in the formulation (i.e.,
active drug and excipients).
There are three stages of moisture content during
the granulation process. At first, when the moist content is low, the particles are held together by surface
tension forces and hydrostatic pressure through liquid
bridges between the solids. In other words the liquid
will bind to the different solids involved and the surface tension of the water will be strong enough that
the water will act as a bridge between the solids. This
is called the pendular state. As the air on the surfaces
is displaced from between the particles, the capillary
state, where water spreads more evenly across the surfaces, is reached. Particles are held together by this
capillary action. Throughout these stages the tensile
strength increases significantly. These liquid bridges
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are prerequisite to solid bridges that are formed as the
liquid is dried away in the final stage. As the water
evaporates the solid suspended in the liquid phase
as well as the material dissolved will settle out and
form solid bridges or a mortar-like binder between the
solids. As can be understood from this mechanism,
how well a solid wets is a critical element in its ability
to be well formulated.
Dosage Form Dissolution
Additionally as one might expect, the first step in
dissolving a solid is also wetting of the material’s
surface. Consequently, the wettability will not only
effect how a compound formulates but also the rate
of dissolution of the drug from the dosage form.
The wettability of the solid is dependent on the
nature of both the solid and the wetting liquid. Consequently, the wetting step of the granulation can
be enhanced by the use of surfactants. These are
compounds that can be added to the liquid phase to
lower the surface tension. They generally consist of
molecules that have a hydrophobic end and a hydrophilic end. This dual nature helps create the effective
liquid bridges necessary for granulation.
NATURE OF THE SOLID
Solids are traditionally divided into high energy and
low energy solids. Materials such as metals, hard
molecular crystals, and ceramics are held together by
strong covalent and ionic bonds and have hard surfaces
that require a high amount of energy to disrupt. The
polar or semi-polar nature of these bonds generally
make the surface completely wettable. Weak molecular
crystals held together mostly by hydrogen bonds and
Van der Waal forces are considered low energy and
are often only partially wetted. In other words, the
wettability of a solid surface can be influenced by the
distribution and charge of the surface groups, number
of hydrogen bonding sites, and configuration at the
molecular level. An increase in the polarity of the
solid surface will increase the wettability.
Although the number of polar groups in the molecule is controlled by the drug structure, the exposure
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Pharmaceutical Solids.
of these groups on the surface of the solid can be
greatly influenced by crystal form. In any crystal form
there will be a balance between internal association of
polar groups usually through hydrogen bonding and
the presence of polar groups on the crystal surface.
For example, the protease inhibitor, ritonavir can
exist in at least two crystal forms. Form I has polar
groups exposed on the crystal surface. Form II has
all the polar groups occupied in internal hydrogen
bonding and they are not accessible from the crystal
surface. As a result, Form II has very poor wettability
compared to Form I.
Because crystal form can have a significant effect on
wettability, a less thermodynamically stable crystal form
may be preferred as an active drug substance because of
improved granulation properties. The primary impact on
wettability comes from the outermost chemical groups
and crystal packing. In some cases, the polarity of the
outermost groups can be altered by the formation of a
salt or complex as the active ingredient and consequently
improve granulation reproducibility.
As discussed in an earlier column (1), the same
crystal form can be isolated in different crystal habits
or external particle shapes (morphology). It is the
surface of this crystal habit that is exposed to the
liquid and consequently affects the wettability. A
number of pharmaceutical companies are investing
in the ability to manufacture drugs in specific crystal
habits usually nearer spherical. This is called crystal
engineering and their goal is to avoid problem habits
such as needles that can cause flow and blending
problems. Reliable control of the crystal habit can
be of significant importance in effecting wettability
as well. For example, while working with a fluoroquinone antibiotic that can exist in several polymorphic forms, our lab encountered an unusual wetting
event. After several dozen successful granulation runs
using multiple active ingredient lots, a single batch
became dry and crispy during drying indicating that
the granulation process had failed. The active drug
particles had not wetted as expected. A thorough
investigation into crystal form, particle size, surface
area, purity, water content, etc., was conducted and
revealed no difference between this lot and other
well-behaved batches. The only testing that indicated
a difference in this lot was dielectric analysis (DEA).
This technique applies a current to the surface of a
material and records the ability of the surface to accept
and maintain a charge (capacitance). In this case
the problem lot, although the same crystal form as
previous successful lots, showed no ability to accept
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a charge (Figure 5). This indicated an absence of
polarity on the surface and explained the very poor
wettability. Because this was the same crystal form
previously used, the explanation was the unexpected
formation of a crystal habit that successfully masked
the polar groups but was not significantly different
when observed microscopically. Because crystal habit
can be influenced by isolation techniques, it is important to control the entire synthetic process including
the final isolation steps.
Physical manipulation can also impact the wettability of solids. Surface roughness and porosity (Figure 6)
can both lower the wettability of the solid as a result of
water being drawn into the pores by capillary action and
not remaining on the smoother surface areas. Drying
techniques such as tray drying and tumble drying as
well as size reduction by milling can impact the roughness and porosity of the solid surface. Size reduction by
milling can be especially significant because the friction
involved can create varying amounts of static charge
on the particle surface. Since wettability is dramatically influenced by the polarity of the solid surface, the
presence of non-reproducible charges can affect the
dependability of granulation.
These possible changes in wettability should be
considered when evaluating possible manufacturing
changes or process improvements.
ANALYTICAL ASPECTS
The standard measure of wettability is the contact
angle. This is usually determined using a combination of microscopy and projection instruments. Table
I shows how these contact angle measurements can
be correlated to water wetting. In actuality, this is
the only straightforward measurement of wettability. However, there are other less routine techniques
that can be used to estimate how well a solid will
wet. Surface tension is another important parameter
when judging wettability. As a general rule, acceptable bonding adhesion is achieved when the surface
energy of the solid is at least 10 dynes/cm greater
than the surface tension of the liquid. Pure water
has a surface tension of approximately 73 dynes/cm.
Therefore, analytically the surface tension of the solid
is important as well as the contact angle. The surface
tension of a solid is estimated by interaction with a
set of established test liquids that have known surface tension values. The force required to remove
the liquid from the solid surface can be measured
by a number of various ways and a practical surface
tension estimated.
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John F. Bauer.
Figure 5: Dielectric analysis curves for problem and typical drug lots.
C
a
p
a
c
i
t
a
n
c
e
Figure 6: Photomicrograph of solid surface
showing roughness and porosity.
1.2
1
0.8
0.6
Typical lot
Problem lot
0.4
0.2
0
20
40
60
80
100
120
Other techniques have some applicability in evaluating wettability but are more difficult to perform.
Atomic force microscopy (AFM) is a microscopic technique that traces the surface of a solid using a probing
tip. The adhesive force between the AFM tip and the
solid surface can give an estimate of how strongly a
liquid would adhere to the solid surface. Inverse gas
chromatography in which a column is packed with the
solid to be studied and the extent to which water vapor
is retarded as it flows through the column gives insight
into the adhesive force between the solid surface and
water. Lastly, DEA can be used as a fingerprint for the
type of polarity expected on the solid surface and can
be used to identify nonconforming lots.
IMPLICATIONS FOR VALIDATION AND
COMPLIANCE
This article has discussed the importance of solid molecule surface properties on wetting. Effects on wetting
are important in both dosage form manufacturing
and drug dissolution. Effects on drug manufacturing
can cause failed batches with significant economic
consequences. Drug dissolution is directly related
to drug bioavailability and in vivo performance—the
efficacy of the drug product. Solid molecular surface
properties are thus directly related to the pharmacological performance of the drug product.
Validation and compliance personnel with responsibility for solid products must be knowledgeable of
the problem tendencies of their products. Development personnel will likely have addressed the surfaced properties of drug molecules during product
and process development. Their findings and precautions should be communicated to validation and
compliance personnel with product responsibilities.
Thereafter, the validated processes that have been used
to successfully manufacture bulk drugs and products
must be maintained.
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When a drug molecule with problematic tendencies
has been identified, validation and compliance personnel should be watchful for process and material
changes. The following general areas are especially
prone to problem effects:
•Bulk drug manufacturing. Changes in bulk
drug manufacturing processes may affect the
surface properties and wetting of pharmaceutical solids. These changes may in turn affect
dosage form manufacturing when the bulk drug
content is a quantitatively significant part of the
formulation. Bulk drug changes affecting wetting
may adversely affect drug dissolution. If drug
dissolution is affected, there may be subsequent
effects on in vivo bioavailability and pharmacologic response.
•Particle size reduction processes. Bulk drugs
particle size is typically reduced prior to subsequent granulation processes. These processes may
occur as part of bulk drug manufacturing or as the
first step in dosage form manufacturing. Particle
size reduction is accomplished by use of specific
equipment with specific process parameters. If
different equipment is used or if different process parameters are needed, the effects of these
changes on the solid surface properties should
be evaluated. Any changes to the particle size
reduction equipment or process parameters used
for particle size reduction of susceptible molecules
should be carefully evaluated prior to implementation and subsequently monitored.
•Dosage form manufacturing granulation
processes. Dosage form granulation processes,
especially wet granulation processes, involve the
interaction of multiple process parameters. Even
relatively simple granulation processes with water
require control of the amount of water added, the
rate of addition, equipment operational paramJournal
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Pharmaceutical Solids.
eters such as mixer speed, massing time, end point
judgment, and so on. Manual granulation processes in which manufacturing operators control
these parameters are especially prone to variation in granule properties. Changes in granule
properties are reflected in subsequent processes
such as tablet compressing. Changes to granule
properties may also affect drug dissolution and
in vivo performance. Any changes to the granulation processes of susceptible molecules should be
carefully evaluated prior to implementation and
subsequently monitored.
•Dosage form drying processes. Drying processes may have significant effect on the surface
properties of pharmaceutical solids. For example,
lyophilized solids, fluidized-bed dried solids, and
oven-dried solids will be chemically identical, but
will likely have markedly different surface properties. Any changes to the drying processes of
susceptible molecules should be carefully evaluated prior to implementation and subsequently
monitored.
•Dosage form sizing processes. Dried granulation particle size is typically modified prior
to subsequent mixing and blending processes.
This process accomplishes particle size reduction
of large granules and enables formation of the
target granule size distribution for the formulation. Sizing is accomplished by use of specific
equipment such as impact mills with specific
process parameters. If different equipment is
used or if different process parameters are needed,
the effects of these changes on the solid surface
properties should be evaluated. Any changes to
the sizing equipment or process parameters used
for particle size reduction of dried granulations
should be carefully evaluated prior to implementation and subsequently monitored.
•Excipient changes. Most of the above discussion addressed wettability of active drugs. How-
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ever, in formulations containing highly potent
drugs (i.e., low dose drugs such as 1 mg per tablet)
the inactive excipients are more critical to processing than the active drug. For example, for a tablet weighing 150 mg and containing 5 mg active
drug, the formulation contains 145 mg inactive
excipients or more than 95% inactive excipients.
Validation and compliance personnel should be
wary of changes to the major inactive excipients
such as by sourcing from new vendors. These
changes should be carefully evaluated prior to
implementation and subsequently monitored.
CONCLUSION
The ability to form a uniform layer of water on the
surface of a solid can be a critical step in some unit
operations of the pharmaceutical manufacturing process, especially granulation.
Poor wettability can require the use of special formulation techniques such as direct compression or the
addition of excess surfactants. Therefore, wettability
is a significant property of drug substances and should
be evaluated during drug development. Wettability
must also be considered whenever process changes are
being introduced and considered as a possible cause
if granulation problems are encountered.
REFERENCES
1. Bauer, J.F., “Pharmaceutical Solids: Polymorphism—A
Critical Consideration in Pharmaceutical Development,
Manufacturing, and Stability,” Journal of Validation Technology, Vol. 14, #5, Autumn 2008.
2. Bauer, J.F., “Drying Pharmaceutical Solids—Hydrates
and Enantiotropic Polymorphs,” Journal of Validation
Technology, Vol. 15, #2, Spring 2009. JVT
ARTICLE ACRONYM LISTING
AFMAtomic Force Microscopy
DEADielectric Analysis
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