In this presentation are analysed the reasons behind the need to study polymorphism with practical examples.

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Luca Covello
(PolyCrystalLine)
POLYMORPHISM:
opportunity or problem?

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• What is APIs polymorphism?
• What is the impact of polymorphism?
• Disappearing polymorphs
• What are the factors that can affect polymorphism?
• Conclusions
Contents

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WHAT IS APIs
POLYMORPHISM?

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TYPES OF POLYMORPHS: FOR THE SCIENTIST 4
CONCOMITANT POLYMORPHS:
the appearance of two or more polymorphs
within the same crystal batch.
CONFORMATIONAL POLYMORPHS:
the same molecule can adopt different crystal shapes
in different crystals due to internal degrees of freedom.
SOLVATES AND POLYMORPHIC SOLVATES:
occur when a given substance crystallizes with
different amounts or types of solvent molecules.
The packing of a molecule can be arranged in many ways in the crystal in a given
symmetry and polymorphism is a reflection of alternative ways in which molecules in a
crystal strive towards a free energy minimum.

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TYPES OF POLYMORPHS: FOR THE REGULATOR 5
The International Conference on Harmonization (ICH) Guideline Q6A specifications for
new drug substances and products (October 1999) “polymorphism” includes:
Single entity
POLYMORPHS
Molecular adducts
(solvates/hydrates)
Amorphous
forms
PSEUDO-POLYMORPHS

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SOLID
CRYSTALLINE AMORPHOUS
Long range order Short range order
Multi components
POLYMORPHS
Single component
Ionic Non-ionic
SALT MOLECULAR ADDUCTS
SOLVATE/HYDRATE CO-CRYSTAL
Molecule solid at RT
Free drug
Protonated drug molecule
Deprotonated acid
TYPES OF POLYMORPHS: SUMMARY 6
Solvent
PSEUDO-
POLYMORPHS

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WHAT IS THE IMPACT
OF POLYMORPHISM?

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WHAT IS THE IMPACT OF POLYMORPHISM? 8
A critical element of drug discovery and the early stages of drug development
is the identification of the appropriate drug form.
Drug form refers to the nature of the solid drug entity (free acid, free base, salt
or non ionisable compound) and additionally to its solid state (amorphous,
crystalline and polymorphic phase).
Statistically, 85% APIs exhibit
pseudo-polymorphism, and
50% of APIs have multiple forms.

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The drug form impacts on different properties, such as:
Spectral Properties Solubility, Bioavailability
& Dissolution Rate
Physical and
Chemical Stability
Manufacturability
Hygroscopicity Crystal Shape
WHAT IS THE IMPACT OF POLYMORPHISM? 9

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By definition, every new crystal form is novel and IS NOT POSSIBLE TO PREDICT:
• How MANY different crystal forms can be prepared
• How to PREPARE any, as yet unknown, crystal forms
• The PROPERTIES of any, as yet unknown, crystal forms
Therefore, new or additional crystal forms can be patented in order to:
• PROTECT the drug substance from use by competitors
• AVOID infringing a patent
PATENTABILITY OF CRYSTAL FORMS 10
Merck’s Fosamax® (Alendronate)
Its sales in 2002 were $2.2 billion
What happened?
Generic version with a different crystalline form was launched
by Teva Pharmaceutical before Merck’s patent expiration.

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WHAT ARE THE FACTORS THAT
CAN AFFECT POLYMORPHISM?

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FACTORS AFFECTING POLYMORPHISM 12
Many drugs undergo polymorphic transformation during various processes, such as:
TEMPERATURE AND HUMIDITY:
Storage conditions affect physicochemical reactions
which are accelerated at higher temperature.
Humidity act as catalyst on the solid surface.
PHOTOSTABILITY:
Generally light sensitive drugs are protected from
the photolytic degradation by packing them suitably
in light resistant container.
SOLVENT:
Solvent can bring dramatic change in
growth mechanism and morphology.

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FACTORS AFFECTING POLYMORPHISM 13
GRINDING:
During grinding process solid state polymorphic
transformation into non-crystalline or metastable
form is caused by mechanical action.
SURFACTANT:
Surfactant affect solution mediated transformation
of the drug which depends on molecular and
supramolecular structure of the drug.
COMPRESSION:
Stability and compaction behavior form of
the polymorphic form of drug is important.
Many drugs undergo polymorphic transformation during various processes, such as:

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EXAMPLES OF CONVERSIONS BETWEEN FORMS 14
Conversions between crystal forms are possible and often take place. Among the
many possibilities for conversion, specific examples are:
An anhydrous crystalline form can be
transformed into a crystal hydrate via
vapour uptake from the atmosphere.
A metastable crystalline form can convert
into a thermodynamically more stable
crystal over time.
An unsolvated crystal form can form solvates
and co-crystals with other molecules.

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DISAPPEARING
POLYMORPHS

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DISAPPEARING POLYMORPHS 16
When a compound exhibits polymorphism the existence of more than one crystal
structure it may be important to obtain a particular polymorph under controlled and
reproducible conditions.
There are cases where it was difficult to obtain a given polymorphic form even though
this had previously been obtained routinely over long time periods.
WHERE IS
MY FORM?
The worst that can happen for a
pharmaceutical company is if a new
polymorph suddenly appears in the
temperature and humidity conditions
of a blister pack when a compound
is actually on the market.

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WHEN DRUGS GO BAD: THE RITONAVIR STORY 17
Ritonavir was patented in 1993 and marketed in 1996 by Abbott Laboratories. The drug
was on the market for 18 months before a serious problem emerged: the drug began
precipitating out of formulation in large quantities.
The new form was dubbed Form 2 and
was found to be less soluble, greatly
reducing bioavailability.
Abbott was forced to remove Ritonavir
from the market until they solved the
problem, resulting in extreme losses:
• More than $250 million in sales
• Estimated hundreds of millions of
dollars in R&D trying to recover
the original Form 1
What happened?

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CONCLUSIONS

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WHAT IS THE NEED TO STUDY POLYMORPHISM? 19
• Each solid form of a pharmaceutical can be patented. It is, then,
critically important that the company developing the drug knows all
the forms in order to secure intellectual property.
• The knowledge of solid-state properties in an early stage of drug
development helps to avoid manufacturing problems, to fine-tune
the performance of drugs and provides space for innovations.
• Improve the therapeutic activity of drugs.
• Better bioavailability of drugs.

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We support our clients from early-phase to kilogram supply.
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HOW CAN WE HELP YOU? 20

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Thank you
for the Attention
Closing remarks 21
For more information please contact:
luca.covello@polycrystalline.it