# Background Information for the 

# October 2002 ACPS Meeting

# Scientific Considerations of Polymorphism in Pharmaceutical Solids: Abbreviated New Drug Applications 

INTRODUCTION

Many pharmaceutical solids can exist in different physical forms.
Polymorphism is often characterized as the ability of a drug substance
to exist as two or more crystalline phases that have different
arrangements and/or conformations of the molecules in the crystal
lattice (1). Amorphous solids consist of disordered arrangements of
molecules and do not possess a distinguishable crystal lattice. Solvates
are crystalline solid adducts containing either stoichiometric or
nonstoichiometric amounts of a solvent incorporated within the crystal
structure. If the incorporated solvent is water, the solvates are also
commonly known as hydrates. Polymorphism refers to the occurrence of
different crystalline forms of the same drug substance. Polymorphism in
this commentary is defined as in the International Conference on
Harmonization (ICH) Guideline Q6A (2), to include solvation products and
amorphous forms.

Polymorphs and/or solvates of a pharmaceutical solid can have different
chemical and physical properties such as melting point, chemical
reactivity, apparent solubility, dissolution rate, optical and
electrical properties, vapor pressure, and density. These properties can
a direct impact on the process-ability of drug substances and the
quality/performance of drug products, such as stability, dissolution,
and bioavailability. A metastable pharmaceutical solid form can change
crystalline structure or solvate/desolvate in response to changes in
environmental conditions, processing, or over time.

Several regulatory documents and literature reports (2-4) address issues
relevant to the regulation of polymorphism. The concepts and principles
outlined in these are applicable for an ANDA. However, certain
additional considerations may be applicable in case of ANDAs. Often at
the time FDA receives an ANDA a monograph defining certain key
attributes of the drug substance and drug product may be available in
the Unites States Pharmacopoeia (USP). These public standards play a
significant role in the ANDA regulatory review process and in case of
polymorphism, when some differences are noted, lead to additional
requirements and considerations. This commentary is intended to provide
a perspective on polymorphism in pharmaceutical solid in the context of
ANDAs. It highlights major considerations for monitoring and controlling
drug substance polymorphs and describes a framework for regulatory
decisions regarding drug substance \"sameness\" considering the role and
impact of polymorphism in pharmaceutical solids.

POLYMORPHISM IN PHARMACEUITCAL SOLID DRUG SUBSTANCE AND THE ISSUE OF
"SAMENESS"

FDA may refuse to approve an ANDA referencing a listed drug if the
application contains insufficient information to show that the drug
substance is the \"same\" as that of the reference listed drug. A drug
substance in a generic drug product is generally considered to be the
same as the drug substance in the reference listed drug if it meets the
same standards for identity. In most cases, the standards for identity
are described in the USP although FDA may prescribe additional standards
when necessary. Because drug product performance depends on the product
formulation, the drug substance in a proposed generic drug product need
not have the same physical form (particle size, shape, or polymorph
form) as the drug substance in the reference listed drug. An ANDA
applicant is required to demonstrate that the proposed product meets the
standards for identity, exhibits sufficient stability and is
bioequivalent to the reference listed drug.

Over the years FDA has approved many generic drug products based upon a
drug substance with different physical form from that of the drug
substance in the respective reference listed drug (e.g., warfarin
sodium, famotidine, and ranitidine). Also many ANDAs have been approved
in which the drug substances differed from those in the corresponding
reference listed drugs with respect to solvation or hydration state
(e.g., terazosin hydrochloride, ampicillin, and cefadroxil).

Since polymorphs exhibit certain differences in physical (e.g., powder
flow and compactability, apparent solubility and dissolution rate) and
solid state chemistry (reactivity) attributes that relate to stability
and bioavailability it is essential that the product development and the
FDA review process pay close attention to this issue. This scrutiny is
essential to ensure that polymorphic differences (when present) are
addressed via design and control of formulation and process conditions
to physical and chemical stability of the product over the intended
shelf-life, and bioavailability/bioequivalence.

## 

## CHARACTERIZATION OF POLYMORPHS

A number of methods have been employed for characterizing polymorphs in
pharmaceutical solids (5). Polarizing optical microscopy and
thermomicroscopy have proven to be useful tools. Thermal analysis
procedures, such as differential scanning calorimetry (DSC) and
thermogravimetric analysis (TGA), can be used to obtain additional
information, including phase changes, and to deduce whether each
isolated form is a solvate or anhydrate. These thermal methodologies are
employed to distinguish between enantiotropic and monotropic systems.
For an enantiotropic system, the relative stability of a pair of solid
forms inverts at some transition temperature beneath the melting point
while a single form is always more stable beneath the melting point in a
monotropic system (5).

The utility of solid-state spectroscopy for characterization of
polymorphic systems is becoming exceedingly important. Nuclear magnetic
resonance (NMR), infrared absorption, and Raman spectroscopy are used to
study crystal structures. These methods require that either the nuclei
of the pair of substances being examined exist in magnetically
inequivalent environments or the vibrational modes are sufficiently
different between the structural forms to permit differentiation.

It should be emphasized that the definitive criterion for the existence
of polymorphism is via demonstration of a nonequivalent crystal
structure, usually by comparison of the x-ray diffraction patterns.
Microscopy, thermal analysis methodology, and solid state NMR are
generally considered as sources of supporting information.

PROPERTIES OF POLYMORPHS

Solubility and Dissolution

The solid state characteristics of drugs are known to potentially exert
a significant influence on the *solubility parameter*. Polymorphs of a
drug substance can have different apparent aqueous solubility and
dissolution rate, when such differences are sufficiently large
bioavailability is altered and it is often difficult to formulate a
bioequivalent drug product using a different polymorph.

Solubility at a defined temperature and pressure is the saturation
concentration of the dissolved drug in equilibrium with the solid drug.
Aqueous solubility of drugs is traditionally determined using the
equilibrium solubility method that involved suspending an excess amount
of a solid drug in a selected aqueous medium. The equilibrium solubility
method may not be suitable to determine the solubility of a metastable
form, since the metastable form may convert to the stable form during
the experiment.

When the solubility of metastable forms of a drug substance can not be
determined by the equilibrium method, the intrinsic dissolution method
may be useful to deduce the relative solubilities of metastable forms
(6). Use of the intrinsic dissolution method assumes that the intrinsic
dissolution rate is proportional to the solubility - the proportionality
constant being the transport rate constant, which is constant under the
same hydrodynamic conditions in a transport-controlled dissolution
process.

Polymorphic differences and transformation that result in different
apparent solubility and dissolution rate are generally detected by
dissolution testing. This test provides a suitable means to identify and
control the quality of a product from both bioavailability and
(physical) stability perspectives. When solubility and dissolution rate
of the relevant polymorph forms are sufficiently high and controlled via
dissolution regulatory concerns with respect to bioavailability and
stability are minimum. The Biopharmaceutics Classification (7,8)
criteria of high solubility and rapid dissolution should be considered
in regulatory decisions.

Stability and Manufacture-ability

Polymorphs of a pharmaceutical solid may have different physical and
solid state chemical (reactivity) properties (9). The most stable
polymorphic form of a drug substance is often used because it has the
lowest potential for conversion from one polymorphic form to another
while the metastable form may be used to enhance the bioavailability.
Gibbs free energy, thermodynamic activity, and solubility provide the
definitive measures of relative polymorphic stability under defined
conditions of temperature and pressure. The relative polymorphic
stability may be determined by an iterative examination of the relative
apparent solubility of supersaturated solutions of polymorphic pairs.
Since the rate of conversion to the more stable form is often rapid when
mediated by the solution phase, the less stable polymorph with the
greater apparent solubility dissolves, while the more stable polymorph
with the lower apparent solubility crystallizes out upon standing.

Solid-state reactions include solid-state phase transformations,
dehydration/desolvation processes, and chemical reactions. One polymorph
may convert to another during manufacturing and storage, particularly
when a metastable form is used. Since an amorphous form is
thermodynamically less stable than any crystalline form, inadvertent
crystallization from an amorphous drug substance may occur. As a
consequence of the higher mobility and ability to interact with
moisture, amorphous drug substances are also more likely to undergo
solid-state reactions.

In addition, phase conversions of some drug substances are possible when
exposed to a range of manufacturing processes (10).
Milling/micronization operations may result in polymorphic form
conversion of a drug substance. In the case of wet granulation
processes, where the usual solvents are aqueous, one may encounter a
variety of interconversions between anhydrates and hydrates, or between
different hydrates. Spray-drying processes have been shown to produce
amorphous drug substances. However, phase conversions should not be of
concern if they occur consistently.

CONSIDERATIONS OF POLYMORPHISM IN ANDAs

Decision Trees #1 - #3, as shown in Figure 1, provide a process for
evaluating when and how polymorphs of drug substances in ANDAs should be
monitored and controlled. These decision trees were developed based on
the ICH Guideline Q6A decision trees on polymorphism (2) and adopt the
concepts from the Biopharmaceutics Classification System (7, 8).

Decision Tree #1 considers whether there is a need to set polymorphic
acceptance criteria in drug substances and drug products. If no known
polymorphs exist or all known polymorphs are highly soluble and
sufficiently stable, it is expected that polymorphism is unlikely to
have an effect on bioavailability and stability. This approach assumes
that adequate knowledge of drug substance polymorphs is available by the
time an ANDA is filed.

Decision Tree #2 discusses how to set a polymorph specification for a
drug substance, given the fact that at least one polymorph is known to
have low solubility based on the BCS. If an ANDA has the same polymorph
specification as the U. S. Pharmacopoeia (USP), and the USP
specification is adequate, no further polymorphic test or acceptance
criteria for the drug substance beyond the existing USP methodology
would be necessary. Otherwise, an ANDA applicant should set a new
polymorphic acceptance criterion for the drug substance.

Decision Tree #3 discusses if there is a need to set a polymorph
specification for a drug product. It is not necessary to have a
polymorph specification for a drug product if the most stable
polymorphic form is used or the form is used in a previously approved
product(s) that was developed *without extraordinary formulation or
manufacturing process development effort*. Furthermore, drug product
dissolution testing can frequently detect polymorphic conversions. In
rare cases, solid state characterization may have to be employed.

######  

###### REFERENCES

1.  D. J. W. Grant. Theory and origin of polymorphism. In H. G. Brittain
    (ed.) Polymorphism in Pharmaceutical Solids. Marcel Dekker, Inc.,
    New York, 1999, pp. 1-34.

2.  International Conference on Harmonization Q6A Guideline:
    Specifications for New Drug Substances and Products: Chemical
    Substances, October 1999.

3.  Center for Drug Evaluation and Research Guidance: Submitting
    Supporting Documentation in Drug Applications for the Manufacture of
    Drug Substances, February 1987.

4.  S. Byrn, R. Pfeiffer, M. Ganey, C. Hoiberg, and G. Poochikian.
    Pharmaceutical solids: A strategic approach to regulatory
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5.  H. Brittain. Methods for the characterization of polymorphs and
    solvates. In H. G. Brittain (ed.) Polymorphism in Pharmaceutical
    Solids. Marcel Dekker, Inc., New York, 1999, pp. 227-278.

6.  L. X. Yu and G. L. Amidon GL. Analytical Solutions to Mass Transfer.
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    23-54.

7.  G. L. Amidon, H. Lennernas, V. P. Shah, and J. R. Crison. A
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    bioavailability. *Pharm. Res*. 12:413-420 (1995).

8.  L. X. Yu, G. L. Amidon, J. E. Polli, H. Zhao, M. Mehta, D. P.
    Conner, V. P. Shah, L. J. Lesko, M.-L. Chen, V. H. L. Lee, and A. S.
    Hussain. Biopharmaceutics Classification System: The scientific
    basis for biowaiver extension. *Pharm. Res.* 19:921-925 (2002).

9.  S. R. Byrn, R. R. Pfeiffer, and J. G. Stowell. Solid-State Chemistry
    of Drugs. 2^nd^ Edition, SSCI, Inc., West Lafayette, Indiana, pp.
    259-366.

10. H. G. Brittain and E. F. Fiese. Effect of pharmaceutical processing
    on drug polymorphs and solvates. In H. G. Brittain (ed.)
    Polymorphism in Pharmaceutical Solids. Marcel Dekker, Inc., New
    York, 1999, pp. 331-362.

    **LEGEND**

Figure 1(a): Decision Tree #1. Investigating the need to set acceptance
criteria for polymorphs in drug substances and drug products in ANDAs
for solid dosage forms or liquids containing undissolved drug substance

Figure 1(b): Decision Tree #2. Investigating how to set acceptance
criteria for polymorphs in drug substances in ANDAs for solid dosage
forms or liquids containing undissolved drug substance

Figure 1(c): Decision Tree #3. Investigating the need to set acceptance
criteria for polymorphs in drug product in ANDAs for solid dosage forms
or liquids containing undissolved drug substance

Figure 1(a): Decision Tree \# 1

Figure 1(b): Decision Tree \# 2

Figure 1(c): Decision Tree \# 3