Polymorphism—A Critical Consideration in Pharmaceutical ...

]Pharmaceutical Solids.
John F. Bauer

Polymorphism—A
Critical Consideration in
Pharmaceutical Development,
Manufacturing, and Stability

Welcome to “Pharmaceutical Solids.” This first installment of “Pharmaceutical Solids”
This column discusses scientific principles associated addresses the potential solid polymorphic forms of
a drug which in turn determine many of the solid
with pharmaceutical solids useful to practitioners in physical properties. A thorough understanding of the
validation and compliance. This column has been solid state chemistry of a new drug should be a critical
developed with the intention to help readers under- component of pharmaceutical development, and will
stands the principles associated with pharmaceutical serve throughout the entire product lifecycle.
solids, and to be a useful resource for daily work
applications. Enhanced process understanding is an Reader comments, questions, and suggestions
important objective of the quality by design initiative. are needed to help us fulfill our objective for this
The key objective for this column: Usefulness. column. Suggestions for future discussion top-
ics or questions to be addressed are requested.
The topic of pharmaceutical solids is broad and com- Case studies illustrating principles associated with
plex. Its importance is unquestioned. Understanding pharmaceutical solids submitted by readers are
the basic properties of pharmaceutical solids is fun- also most welcome. We need your help to make
damental to pharmaceutical discovery, development, “Pharmaceutical Solids” a useful resource. Please
clinical studies, manufacturing, processing, problem send your comments and suggestions to column
investigations, and stability. Unfortunately this topic coordinator John Bauer at [email protected]
often requires understanding the higher level of prin- or to journal coordinating editor Susan Haigney at
ciples of chemistry, physics, and mathematics. These [email protected].
may include thermodynamics, crystallization, analyti-
cal DSC, X-Ray diffraction, and other research meth- KEY POINTS
ods. Finally, the language of pharmaceutical solids
may be esoteric and intimidating. • Pharmaceutical solids may be crystals, crystal
solvates or hydrates, crystal desolvated solvates
These considerations make discussion of pharma- or dehydrated hydrates, or amorphous solids
ceutical solids a difficult task. This column addresses
the various topics of pharmaceutical solids with these • All crystal forms described can exist in different
considerations in mind. It is our challenge to present forms called polymorphs
these topics in a meaningful way so that our readers
will be able to understand and apply the principles • Polymorphs can have significant differences in
discussed in their daily work applications. their physical properties even though they are
chemically identical. Physical properties include

[For more AuthorABOUT THE AUTHOR
information,
go to ivthome.John F. Bauer, Ph.D., is president of Consult JB LLC Pharmaceutical Consultants. Dr. Bauer has more than 30 years

pharmaceutical industry experience, including work in solid state chemistry, analytical chemistry, stability, pharmaceutics,

com/bios regulatory CMC, patents, and litigation. He may be reached at 847.738.0856 and at [email protected].

Journal of Validation Technology [Autumn 2008] 15

Pharmaceutical Solids.

solubility, melting point, particle size, dissolution solubility change for the drug, which in turn resulted in a
rate, hygroscopicity, and others. bioavailability change and affected the therapeutic effect
• Polymorphs may interconvert depending on condi- of the drug. The Norvir product was withdrawn from the
tions. Usually the metastable kinetic form converts market. An intensive research effort was undertaken to
to the stable thermodynamic form. understand and solve the problem. A new capsule formu-
• Laboratory studies are key to determining the poten- lation was eventually introduced that overcame the physi-
tial of a compound to form multiple polymorphs, cal problems. After implementing the new formulation,
determining under what conditions the polymorphs Norvir Capsules were returned to the marketplace (1).
are formed, what are the physical properties of
each polymorph, and what is the stability of each This unexpected change in physical properties had a
polymorph dramatic impact on patients, the pharmaceutical manu-
• T he primary analytical method to characterize poly- facturer, and the US Food and Drug Administration.
morphs is x-ray diffraction. Other methods used Since this crisis, FDA has become much more aware and
include solid state NMR, Raman and NIR spectros- concerned about the physical properties of drugs and the
copy, and thermal methods such as DSC and TGA. measures taken to ensure that physical properties do not
• Seeding is used to facilitate manufacturing of the change during the product shelf life. The compound that
desired polymorph was present in the Norvir formulation before and after the
• P olymorph interconversions in pharmaceutical prod- sudden manufacturing problem was chemically the same.
uct manufacturing have been reported for grind- So what caused the problem, the inability to produce
ing, milling, tablet compressing, and other processes capsules, and the subsequent global consequences?
involving moisture or other solvents
• ICH Q6A addresses specifications for API and phar- PHYSICAL FORMS OF
maceutical products and includes several decision PHARMACEUTICAL SOLIDS
trees
• Awareness, knowledge, and understanding of poly- The cause of the ritonavir problem was a change in poly-
morphism are important throughout the product morphic solid form. Most pharmaceuticals are funda-
lifecycle. Polymorphism may impact product devel- mentally organic compounds, and organic compounds
opment, clinical studies, product manufacturing, can often exist in a variety of solid forms. This means
product quality, and product stability. that although a drug will remain as the same chemical
• Change management and validation in API manufac- entity and have the same chemical properties of stability,
turing and product manufacturing should address the reactivity, etc., it may not always act in the same way in
potential impact of formulation and process changes the solid state. These differences may or may not cause
on API polymorphism. a difference in pharmacological effect (i.e., how the drug
may work in the human body such as inhibiting proteases
INTRODUCTION or reducing blood pressure). In the Norvir example, the
change in solid form had a great effect on solubility, which
In June 1998 at the Geneva International AIDS Confer- in turn reduced bioavailability.
ence, ritonavir, the active ingredient in Norvir Capsules
(Abbott), was identified as the key component in various Pharmaceutical solids can exist in two general forms:
protease inhibitor cocktails (combination therapies) used Crystalline and non-crystalline forms.
for the successful treatment of HIV infections. This find-
ing enhanced the therapeutic effectiveness of many AIDS Crystalline Forms
therapies, and caused Norvir to be used in combination In order to form a solid, a compound must have internal
with many other marketed AIDS products around the attraction between molecules that is sufficient to restrict
world. By that time, 240 lots of the Norvir Capsules had the free movement that exists in liquids and gases, but
been successfully manufactured. However, in the sum- how strong the internal attractions are can vary. There are
mer of 1998, a sudden change in physical properties of multiple well-known solid forms that have been identified
ritonavir brought production to a halt and eventually in pharmaceuticals. A crystalline solid form or crystal
led to an interruption of the supply of Norvir capsules to exists when the molecules of the drug are arranged in
the millions of HIV patients who relied on the product the solid in a three-dimensional repeating pattern or
for its therapeutic effects. The crystal form of ritonavir unit cell (see Figure 1).
had unexpectedly changed. This change resulted in a
Crystalline solids are usually highly stable and have
a well-established solubility and dissolution rate. Most
drugs are used in the crystalline form.

16 Journal of Validation Technology [Autumn 2008] ivthome.com

John F. Bauer

Figure 1: Example of crystal arrangement. Figure 2: Example of crystal hydrate.

z

Water

y
x

Amorphous Solid Crystal Desolvated Solvate/Dehydrated
A second type of solid form that is non-crystalline is referred Hydrate
to as the amorphous form. This type of solid is randomly Although hydrates can have benefits in manufactur-
arranged with a high degree of disorder in the molecular ing, they can also present a significant problem from
arrangement. The amorphous state is usually much faster the standpoint of drying. Many hydrates will dehydrate
dissolving than the crystalline state, and has a variable or lose the water from the crystal under normal drying
solubility that is usually higher than the crystalline form. conditions forming a dehydrated hydrate. This creates
The amorphous form is often less stable than the crystal- what amounts to an activated hole in the crystal, and the
line form and is usually hygroscopic (i.e., the amorphous active sites exposed have a tendency to either reabsorb
form will absorb water from the atmosphere under ambient water or to bind to other available moieties. Over drying
humidity conditions). In actuality, solids can exist on a erythromycin dihydrate can cause it to dehydrate and bind
continuum between amorphous and crystalline whereby to an excipient. This binding slows the dissolution rate
they contain varying degrees of disorder—the solid may sufficiently to causes stability failures and notification
be partly crystalline and partly amorphous. of FDA (2). If the crystal loses solvent such as ethanol
or other solvent other than water, the resulting crystal is
Crystal Solvate/Hydrate called a desolvated solvate.
The solubility that is of the most importance as far as phar-
maceuticals are concerned is the aqueous solubility. Some All solid forms described above can have significant
drugs can dissolve rapidly in water but then incorporate differences in their physical properties even though they
water molecules into a different solid form that has water are chemically identical. Physical properties include
systematically distributed within the molecular arrange- solubility, melting point, particle size, dissolution rate,
ment (see Figure 2). This solid form is known as a hydrate. hygroscopicity and others. All of these properties can
Depending on the number of molecules of water incor- have a dramatic impact on manufacturability, stabil-
porated, this crystal can be a monohydrate, dihydrate, ity, and sometimes bioavailability of the commercial
trihydrate, etc. These hydrates will have reduced solubility formulation.
in water and often precipitate out of an aqueous solution
of drug. It is critical to know if a particular drug substance POLYMORPHISM
can form hydrates because this reduced solubility in water
can also lead to reduced bioavailability and to manufactur- The ritonavir problem was caused by a change in the
ing problems. Finally, it is also possible for some drugs to solubility of ritonavir that caused the drug to precipi-
form solid forms analogous to hydrates but that incorporate tate from the capsule formulation, and reduced its
other solvents such as ethanol or ethyl acetate into the solid bioavailability to less than 5%. The reason for this
rather than water. These are known as solvates. Solvates change is a phenomenon known as polymorphism.
and hydrates can be very stable solid forms and may have As described previously, solids can exist as crystal-
definite benefits in regard to manufacturing. line, amorphous, solvate (hydrate), and desolvated
(dehydrated) forms. Complicating this situation is the
fact that crystalline solids (and solvates/hydrates and

Journal of Validation Technology [Autumn 2008] 17

Pharmaceutical Solids.

desolvated/dehydrated solvates/hydrates) can exist in LABORATORY STUDIES TO DETERMINE
what are known as polymorphs. Crystals exist with POLYMORPHISM
the molecules arranged in a repeating pattern with an
identifiable symmetry. However, there can be more Which polymorph of a crystalline drug will form under
than one possible repeating pattern for many drugs. certain conditions cannot be predicted. However, labora-
This can be demonstrated by visualizing a number of tory experiments can be conducted that will determine
identical Lego pieces of a specific shape. Each Lego the potential for formation of multiple polymorphs.
piece represents a drug molecule. These individual These studies are performed by crystallizing the drug
Lego pieces can be assembled in several different ways from multiple solvents of differing polarities, different
to form different symmetrical patterns. Each of the solvent combinations, at different temperatures, at differ-
different patterns contains the same number and type ent rates of cooling, and other experimental conditions.
of individual Lego pieces. These studies are conducted in solid state laboratories
using a laboratory robot system.
Each of these different patterns would represent
a different polymorph of the drug. These various The crystal form that will be easiest to form is the one
polymorphs are chemically identical but can have closest in arrangement to the drug in solution under the
significantly different physical properties. Because same environmental conditions. This transition requires
the molecules are arranged differently in the different the least energy, and the form produced is called the
polymorphs, it is possible to have different portions kinetic form. There may also be other forms that are
or functional groups of the molecule exposed at the not as closely related to the dissolved drug but can also
surfaces of the crystal. These differences, especially form under the specific environmental conditions. The
when they involve hydrogen bonding groups, can form that has the strongest internal attractions within the
cause the crystal to interact differently with solvents crystal is the most stable form under these conditions and
and therefore change the solubility of the drug. This is referred to as the thermodynamic form. Given enough
was the case with ritonavir. A much less soluble poly- time and especially if solvent mediated, the thermody-
morph having five times lower solubility was formed. namic form of the crystal would be the final and most
The significantly different solubility of the new rito- stable polymorphic crystal form produced. When dif-
navir polymorph made it impossible to manufacture ferent temperatures are involved, more complexity may
the original Norvir formulations. be introduced. For example, the simplest situations are
those in which a single polymorph is always the most
Different crystal arrangements or crystal lattices stable polymorph regardless of temperature; these systems
are possible for any particular compound. Under are called monotropic systems. However, there may be
particular temperature, pressure, and humidity condi- situations in which a different polymorph is the most
tions, the various polymorphs of a drug have different stable polymorph at a higher temperature; these systems
energies. There is one polymorph that has the lowest are called enantiotropic systems.
energy and is considered the most stable. All other
forms are referred to as metastable, although they may When multiple polymorphs of a drug are formed
be quite stable under that particular combination of it is necessary to understand their conditions of for-
temperature, pressure, and humidity. Theoretically mation and the physical properties associated with
any metastable form will convert to the stable form each form. Polymorphic interconversions have been
under particular conditions. However, this conver- reported in the solid state, caused by mechanical
sion will be extraordinarily slow unless mediated by stress and/or high temperature. The stability of each
a solvent. In the case of ritonavir, the solvent system form must be studied. The information learned in
in the capsule mediated the crystal form change. The these studies is used in the selection of the appro-
stability referred to here is the ease with which one priate form for development. Thereafter, labora-
solid form converts to another solid form, for example, tory information is useful for development of the
conversion of amorphous solid to crystalline form or active pharmaceutical ingredient (API) manufactur-
one polymorph to another. Crystal polymorphs can ing process. When multiple polymorphic forms are
also differ in chemical stability because the groups possible, it is critical to understand the conditions
present on the surface of the molecule will be more or under which they can interconvert. In many cases
less labile or reactive. The tendency of a compound to the forms do not differ enough to affect the manu-
attract water from the atmosphere (i.e., hygroscopic- facture, stability, and/or efficacy of the compound.
ity) is also the result of surface groups. However, this information is only known through
appropriate laboratory investigations.

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John F. Bauer

One other important benefit of understanding the Figure 3: X-ray of forms I and II of a drug.
various polymorphs and methods of preparation of dif-
ferent polymorphs is that polymorphs are patentable. 120
This knowledge may thus provide commercial benefit 110
for the organization. 100

CHARACTERIZING POLYMORPHS 90Relative intensity

Polymorphs are characterized by techniques and methods 80 40.0
that provide particulate level characterization of phar-
maceutical solids. The “gold standard” for this type of 70
investigation is X-ray diffraction. The x-ray beam is dif-
fracted or reflected as it collides with atoms in the crys- 60
tal. The different atoms will bend the x-rays at different
angles that indicate the distances between the atoms. 50
The exiting beams can be detected. This can be plot-
ted as a graph of intensity versus angle that represents a 40
unique fingerprint for a particular crystal form of a drug.
Amorphous solids are not crystalline and do not give a 30
characteristic x-ray pattern. Figure 3 illustrates an X-ray
diffraction pattern for two different crystal polymorphs 20
of the same drug—chemically identical but having two
different polymorphic crystal forms. 10

Other techniques that can be used to distinguish 0
and identify crystal forms are solid state nuclear 5.0 10.0 15.0 20.0 25.0 30.0 35.0
magnetic resonance (ssNMR), Raman spectroscopy,
and near-infrared spectroscopy (NIR). Of these tech- 2 Theta
niques, Raman and NIR spectroscopy are adaptable to
process analytical technology (PAT). These techniques solution of the drug to act as a template or starting point
are useful for in process monitoring of the manufac- for further crystallization. Such crystals are called seeds
turing process (i.e., the formation of the actual desired and in many instances can be used to direct the crystal-
or undesired polymorph can be detected during the lization to the desired solid form. This technique, known
manufacturing process and appropriate controlling as seeding, is commonly used in bulk drug synthesis.
adjustments can be made). In these cases, the seeding is intentional and controlled.
It is possible, however, to inadvertently seed processes,
MANUFACTURING THE DESIRED API producing undesired solid forms. In some cases, such as
POLYMORPH the aforementioned ritonavir example, it is possible for an
undesired polymorphic form to be seeded by a compound
Laboratory studies provide information regarding desired different from the drug itself. In the case of ritonavir, the
polymorph solubility, preferred crystallization solvent, less soluble polymorph (called Form 2) was never seen
optimized concentrations in mixed solvent systems, crys- in laboratory studies. It was inadvertently seeded by a
tallization conditions, and other processing parameters. degradation product with a similar crystal structure to
One very important phenomenon related to solid form Form 2 ritonavir.
manufacturing control is seeding. As mentioned previ-
ously, the various solid forms possible for a compound POLYMORPHS IN PHARMACEUTICAL
include polymorphs, solvates, and amorphous. As also PRODUCT MANUFACTURING
mentioned, the surfaces of these various forms can have
different functional groups or active portions of the mol- There are many reported examples of changes in solid
ecule exposed. The mechanism for crystal growth is for form due to conditions typical of product manufacturing
further molecules to attach themselves to the surface of processes. Examples of processing that may cause poly-
existing crystals and continue the crystal symmetry. This morphic changes including grinding, milling, heating,
mechanism can be exploited by providing crystals of and compressing. Manufacturing conditions that include
the desired solid polymorphic form to a supersaturated a solvent (e.g., wet granulation, polymorphs in solution,
polymorphs in suspension) may also facilitate conversion
to the thermodynamic polymorph. An often-cited article
entitled “Disappearing Polymorphs” (3) describes mul-
tiple cases where a crystal form was developed and even

Journal of Validation Technology [Autumn 2008] 19

Pharmaceutical Solids.

patented and marketed when a new polymorph suddenly investigated early in the drug development process. The
appeared, and the first form could no longer be produced. potential for multiple polymorphs, the properties of
The extreme example of ritonavir (Norvir) exemplifies the the individual polymorphs, the desired polymorph for
criticality of solid state investigations during the develop- development, its stability, solid state reactivity, and so on
ment of a new drug entity and manufacturing process must be understood. This information will be of service
development. This has been an important area of concern throughout the product lifecycle from API and product
and emphasis by FDA and International Conference on development through commercial distribution. Consider
Harmonisation (ICH) in recent years. the following possible consequences if adequate informa-
tion regarding polymorphs is not known and polymorph
REGULATORY DOCUMENTS ADDRESSING changes occur:
POLYMORPHISM
• F ormulation development work may have prob-
The following are several regulatory documents address- lems because of changes in polymorph physical
ing polymorphs and changes in polymorphs: properties

• FDA ANDAs: Pharmaceutical Solid Polymorphism (4) • A clinical study may be affected due to solubility and
• ICH Q6A Specifications: “Test procedures and Accep- bioavailability changes

tance Criteria for New Drug Substances and New • Stability problems such as precipitation from solution
Drug Products: Chemical Substances” (5) may occur in the commercial dosage form
• ICH Guideline Q6A has also been published in the
FDA Federal Register (6). • Manufacturing problems such as tablet compressing
problems may occur
The FDA and ICH guidelines both provide a series of
decision trees that can be followed in determining if a speci- • P roduct quality changes such as grittiness in a topical
fication is required to confirm the nature of the polymorph cream formulation may occur
present in both bulk substance and product. These deci-
sion trees are very useful and reflect the current approach • S olidification of ointments and/or suppositories over
to evaluating the concern that should exist around poly- time.
morphs for any particular product. The decisions trees
are built on information gathered in the initial laboratory A good development process should address the solid
studies on the drug crystal form (see Figure 4). state properties of the API. The API manufacturing pro-
cess should be well controlled to yield the intended crystal
The important questions to be answered in the deci- polymorph. The product manufacturing process should
sion trees either eliminate potential solid form changes likewise be well understood and appropriately controlled
as a concern (i.e., changes have no effect on product) or to assure that it does not cause change in the API crystal
demonstrate that the manufacturer has control of the solid form. Product stability studies should assure there are
form throughout the process. The analytical methodol- no polymorphic changes during the product shelf life of
ogy to detect undesirable solid forms in the presence of the commercial package.
the desired form must be validated.
Any changes to the API manufacturing process or to
The Norvir polymorph example discussed previously the product manufacturing process should address the
suggests an additional concern in the formulation of potential for polymorphic changes to the API crystal.
liquid solution products. Conventional wisdom suggests The original API development work is helpful in address-
that since the drug is in solution, polymorphic forms ing the impact of these changes. Experimental research
should be of no concern. However, extraneous materials and development studies should indicate whether there
can sometimes seed new thermodynamic crystal forms is potential for the API molecule to form multiple poly-
that may precipitate from solution. When solution prod- morphs, and the ease of interconversion between poly-
ucts are formulated, the drug concentrations should be morphic forms. This information will form the basis for
well below the saturation concentrations of any of the appropriate testing in process validation.
known drug product polymorphs.
CONCLUSIONS
PRACTICAL IMPLICATIONS OF
POLYMORPHISM Although the chemical and physiological properties of
a pharmaceutical compound determine the potential of
In light of the problems that can be caused by changes in the compound as a commercially viable drug product,
solid form, it is imperative polymorphism be thoroughly the solid state properties of the compound are extremely
important in determining whether it can be reproduc-
ibly manufactured. Laboratory studies are key to deter-
mining the potential of a compound to form multiple

20 Journal of Validation Technology [Autumn 2008] ivthome.com

John F. Bauer

Figure 4: Example decision tree from FDA and ICH guidelines.

Drug substance

1. Conduct polymorphism Can NO
screen on drug substance different
polymorphs No further action
be formed?

YES GO TO 2.

Characterize the forms:
e.g.,
-X-ray powder diffraction
-DSC/thermoanalysis
-Microscopy
-Spectroscopy

2. Do the NO
forms have

different properties?

(solubility, stability,

melting point)

YES No further test or
acceptance criterion for
Is drug drug substance
product safety,
performance or NO

efficacy GO TO 3.
affected?

YES

Set acceptance criterion
for polymorph content
in drug substance

3. Does drug
product

performance testing YES Establish acceptance
criteria for the relevant
provide adequate performance test(s).

control if polymorph

ratio changes

(e.g., dissolution)?

NO

Monitor polymorph form
during stability of drug
product.

Does a NO No need to set acceptance
change occur criteria for polymorph
which could change in drug product.
affect safety
or efficacy? Journal of Validation Technology [Autumn 2008] 21

YES

Establish acceptance
criteria which are consistent
with safety and/or efficacy.

Pharmaceutical Solids.

polymorphs, under what conditions the polymorphs good understanding of a manufacturing process. Good
are formed, the physical properties of each polymorph, understanding of manufacturing processes is consistent
and the stability of each polymorph. Awareness, knowl- with recent quality by design principles.
edge, and understanding of polymorphism is important
throughout the product lifecycle. Polymorphism may REFERENCES
impact product development, clinical studies, product
manufacturing, product quality, and product stability. 1. John Bauer, John Morris, Rodger Henry, et al., “Ritonavir
The large majority of manufacturing problems encoun- Crystal Forms—An Extraordinary Example of Conforma-
tered in commercial scale manufacturing are related tional Polymorphism,” Pharmaceutical Research 18, 859-
to the physical properties of the API and/or excipients. 866, 2001.
These problems may be caused by polymorphic changes.
Change management and validation in API manufac- 2. Bauer, J., W. Dziki, W., and J. Quick, “The Role of an Iso-
turing and product manufacturing should address the morphic Desolvate in Dissolution Failures of an Erythro-
potential impact of formulation and process changes on mycin Tablet Formulation,” J. Pharmaceutical Sciences, 88
API polymorphism. (11), 1222-1227, 1999.

FUTURE INSTALLMENTS OF “PHARMA- 3. Dunitz, Jack D. and Joel Bernstein, “Disappearing Poly-
CEUTICAL SOLIDS” morphs,” Acc. Chemical Research 28, 193-200, 1995.

The properties of pharmaceutical solids are generally 4. FDA, ANDAs: Pharmaceutical Solid Polymorphism, “Chem-
categorized at three levels: Molecular level properties, istry, Manufacturing, and Controls Information,” July
particulate level properties, and bulk level properties. 2007.
Molecular level properties are those properties that could
be measured for a small group of individual molecules. 5. International Conference on Harmonisation (ICH) Q6A.
These properties are spectroscopic in nature, such as those “Specifications: Test procedures and Acceptance Criteria for
determined by ultraviolet spectroscopy, vibrational spec- New Drug Substances and New Drug Products: Chemical
troscopy such as infrared spectroscopy and nuclear mag- Substances,” Step 4, October 1999.
netic resonance spectroscopy. Particulate level properties
are those characteristics which can be determined on a 6. FDA, Federal Register, ICH, “Draft Guidance on Specifica-
small number of particles or crystals. These properties tions: Test Procedures and Acceptance Criteria for New
are determined by microscopic methods, particle size Drug Substances and New Drug Products: Chemical Sub-
methods, x-ray, and thermal methods such as differential stances,” Vol. 65, #251, 12-29-2000.
scanning calorimetry and thermogravimetric analysis.
Bulk level properties are those determined on a relatively GENERAL REFERENCES
large sample of material. These include surface area deter-
mination, porosity, powder flowability, angle of repose, Brittain, Harry G., editor, Physical Characterization of Pharma-
solubility, water sorption, and powder bulk density. ceutical Solids, Marcel Dekker, New York, 1995.

Several of the above methods and their relevant appli- Byrn, Stephen R., Ralph R. Pfeiffer, and Joseph G. Stowell,
cations will be discussed in future installments of “Phar- Solid State Chemistry of Drugs, 2nd ed. SSCI, Inc., West La-
maceutical Solids.” Solid polymorphic form is only one fayette, Indiana, 1999. JVT
of several physical properties of the drug substance that
can be critical to manufacturing and control. Future GLOSSARY
discussions in this column will address other properties
of pharmaceutical solids such as particle size and surface Amorphous solid: A solid in which there is no long-
area. Pharmaceutical solids include the active drug as well range order of the positions of the atoms.
as the inactive excipients in the dosage form. Manufac-
turers often forget that excipients are also pharmaceuti- Crystal: A solid formed by the solidification of a chemical
cal solids and that the solid form of major excipients and having a highly regular atomic structure, has regu-
can also have an impact on stability, compressibility, larly repeating internal structure.
wetability, and other properties that are important to a
reproducible manufacturing process. The solid proper- Dehydrated hydrate: The activated species that exists
ties of active drugs and excipients must be considered for when the water molecules are removed from the crystal-
line structure of a hydrate without destroying the crystal
structure.

Desolvated solvate: The activated species that exists
when the solvent molecules are removed from the

22 Journal of Validation Technology [Autumn 2008] ivthome.com

John F. Bauer

crystalline structure of a solvate without destroying the Polymorph, thermodynamic form: The polymorphic
crystal structure. form that is of lowest energy under a particular set of
temperature/humidity conditions and therefore is the
Enantiotropic system: A set of polymorphic forms in most stable form and will not convert to other forms.
which the different forms are most stable depending on
temperature and humidity. Seeding: A process that uses a small crystal to start and
direct a crystallization process.
Hydrate: A crystalline solid with molecules of water in-
corporated in the solid state structure, which can often Solvate: A crystalline solid with molecules of a solvent
be removed partly or completely by relatively gentle incorporated in the solid state structure, which can often
heating. be removed partly or completely by relatively gentle
heating.
Hygroscopic material: A material that readily absorbs
moisture from the atmosphere. Stable polymorph: Polymorph with the lowest energy
under a defined set of conditions.
Metastable polymorph: Polymorph that can exist but
does not have the lowest energy under a defined set of Unit cell: The smallest building block of a crystal, whose
temperature and humidity conditions. A polymorph that geometric arrangement defines a crystal’s characteristic
is considered metastable under one set of conditions can symmetry and whose repetition in space produces a crys-
also be the stable polymorph under a different set of tal lattice.
conditions.
X-Ray powder diffraction: An analytical test method X-
Monotropic system: A set of polymorphic forms in which Ray diffraction on powder or microcrystalline samples
the same form is most stable regardless of temperature for structural characterization of the materials. Can often
and humidity. supply a fingerprint for each individual polymorph of a
compound.
Polymorph: One of several distinct crystal packing ar-
rangements, potentially having a different energy of for- ARTICLE ACRONYM LISTING
mation and melting point than other polymorphic forms
of the same molecule. API Active Pharmaceutical Ingredient
FDA US Food and Drug Administration
Polymorph, kinetic form: The polymorphic form that ICH International Conference on Harmonisation
requires the least energy to form and therefore is usually NIR Near-Infrared Spectroscopy
the first and fastest form to crystallize. It is not always PAT Process Analytical Technology
the most stable form and can convert to a different poly- ssNMR Solid State Nuclear Magnetic Resonance
morph over time.

Journal of Validation Technology [Autumn 2008] 23