www.polycrystalline.it
OUTLINE
WHO ARE WE?
WHAT IS THE IMPORTANCE OF SOLID FORMS?
SOLID FORMS AND DRUG DEVELOPMENT
WHAT IS CRYSTALLISATION BY DESIGN?
HOW CAN WE HELP YOU?
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POLYCRYSTALLINE IN A NUTSHELL
LEVEL OF CONTAINMENT
FOR HPAPIs
OEB5ANALYTICAL LABORATORY
AND INSTRUMENTS
cGMPDIFFERENT APIs
WE HAVE STUDIED
+300
The company was born out of the Molecular Crystalline Engineering
(MCE) group of research coordinated by Professor Dario Braga in the
Department of Chemistry “G. Ciamician” of the University of Bologna. POLYCRYSTALLINE
WAS FOUNDED
2005
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OUR PROVEN STRENGTH
WE ARE A HIGH PERFORMING COHESIVE
TEAM OF CHEMISTS AND ANALYSTS.
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EVOLVING THROUGH RESEARCH
WE CARE ABOUT RESULTS AND
INNOVATION BASED ON THE USE OF
MODERN TECHNOLOGIES.
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HOW DO WE PERFORM OUR SERVICES?
Manual/Semi-Automated Screening
(PolyCrystalLine)
• Driven by science not robotics
• Scientific investigation tailored to your API
properties, development phase and budget
High-Throughput Screening
(other CRO)
• Rapid but limited by its settings
• Fully automated and usually subject to large number of experiments required
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REFERENCES
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INSTRUMENTS FOR CRYSTALLISATION DEV. AND OPTIMIZATION
PANalytical X'Pert3 Powder SMS DVS Intrinsic Malvern Morphologi G3
Mettler-Toledo DSC 1 Beckman Coulter Particle Size Analyzer LS100Q Thermo Scientific Nicolet™ iS™50 (FT-IR/FT-RAMAN)
Mettler-Toledo TGA/DSC1 Thermo Scientific Nicolet™ iS™10 TGA-IR Module
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INSTRUMENTS FOR SOLID-STATE RESEARCH
Mettler-Toledo EasyMax 102 Atlas Syrris Mettler-Toledo FBRM G400
Avantium Crystalbreeder
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INSTRUMENTS FOR ANALYTICAL RESEARCH
Berghof EasyH2O Agilent 708-DS Dissolution Test Mettler-Toledo Karl-Fischer DL31
Mettler-Toledo MP70 Melting Point System Thermo Scientifics Multiskan FC Thermo Scientifics UltiMate 3000 LC system with
Coulochem III Electrochemical Detector
Agilent HPLC 1260
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DRUG DOSAGE FORMS
Many pharmaceutical delivery technologies are available, such as:
Pulmonary
DeliveryNasal
DeliveryTransdermal
DeliveryInjectable
Formulation
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DRUG DOSAGE FORMS
Year Oral Injection Other
2012 54% 28% 18%
2013 63% 26% 11%
2014 46% 37% 17%
2015 53% 40% 7%
Route of Administration of Novel Drug Approvals by U.S. FDA
However, oral administration is still the
preferred route when developing a
conventional dosage form for a new drug.
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60% of novel drug approved by the U.S. FDA in 2015
were solid dosage products.
Year Tablet Capsule Powder Solution Other Solid Dosage Forms
2012 15 5 5 13 1 64%
2013 12 5 2 7 1 70%
2014 10 9 3 19 0 54%
2015 15 7 5 18 0 60%
Dosage Forms of Novel Drug Approvals by U.S. FDA
DRUG DOSAGE FORMS
Oral dosage forms can have a variety of choices, but most common are solids:
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WHY SOLID FORM?
Solid is more stable than its liquid counterpart.
Active Pharmaceutical Ingredients (APIs) are usually
manufactured, transported and stored as solid.
They are easy to administer (i.e. tablet, capsule,
powder, etc. …).
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TYPES OF SOLID FORMS
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
Solvent
Protonated drug molecule
Deprotonated acid
The concept of pseudopolymorphism
is used for crystalline forms which
also comprise solvent molecules as
an integral part of their structure.
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WHAT IS THE IMPORTANCE OF SOLID FORMS?
Different solid forms show different properties, such as:
Spectral Properties Solubility, Bioavailability
& Dissolution Rate
Physical and
Chemical Stability
Manufacturability
Hygroscopicity Crystal Shape
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SOLID FORMS AND DRUG DEVELOPMENT
Process
Optimisation
& Scale-Up
Drug
Discovery
Pre-Clinical
Studies
Routine
Production
Synthetic Route
Selection
Final Dosage
Form
Drug Development Pipeline
Drug development is a lengthy, complex, and costly process, entrenched with a
high degree of uncertainty that a drug will actually succeed.
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Process
Optimisation
& Scale-Up
Drug
Discovery
Pre-Clinical
Studies
Routine
Production
Synthetic Route
Selection
Final Dosage
Form
Drug Development Pipeline
SOLID FORMS AND DRUG DEVELOPMENT
Many issues can affect the final dosage form, altering its appearance, friability,
bioavailability, shelf-life, assay, etc.
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Process
Optimisation
& Scale-Up
Drug
DiscoveryPre-Clinical
Studies
Routine
Production
Synthetic Route
Selection
Final Dosage
Form
Drug Development Pipeline
SOLID FORMS AND DRUG DEVELOPMENT
Often problems observed in the final dosage form may find their root causes in
drug discovery and in a sub-optimal solid form screening.
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1. What might go wrong?
If anything can go wrong, it will.
3. What are the consequences?
It will be all your fault, and everyone will know it.
2. What is the likelihood it will go wrong?
If anything just cannot go wrong, it will anyway.
MURPHY’S LAWS FOR DRUG DEVELOPMENT
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The properties of products and processes are affected by many factors:
TRADITIONAL APPROACH TO CRYSTALLISATION
Physical StabilityDissolution Chemical Stability
Process parameters
Crystal form properties
Crystallisation
What influences my solid form?
TemperaturePressureMixing speed
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CRYSTALLISATION BY DESIGN
Our mission is to support our clients during drug development, helping them to
reduce batch failure, avoiding costly crystallisation issues and overall
offering greater confidence in drug quality during manufacturing.
Prepare the
building blocks
Crystal-oriented
synthetic strategies
Understand and control
crystal properties
Crystallisation
by Design
Arrange the building
blocks in a desired way
Understand and control over
properties related to solid form
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MOLECULE PARTICLE POWDER
Chemistry Physics Functional
• Structure
• Molecular weight
• Melting point
• pKa
• Partition coefficient
• Solubility
• Particle size
• Surface properties
• Crystallinity
• Porosity
• Dissolution
• Flowability
• Mixability
• Wettability
• Compressibility
The final goal to achieve with Crystallisation by Design is to understand and link
together all the interconnections between properties of interest.
CRYSTALLISATION BY DESIGN
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After Crystallisation by Design the process is not seen as a black box anymore:
CRYSTALLISATION BY DESIGN
Input factors (X)
Output responses (Y)
TemperaturePressureMixing speed
Physical StabilityDissolution Chemical Stability
Crystallisation
Y=f(X)
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BENEFTIS OF CRYSTALLISATION BY DESIGN
• Proactive approach to drug development to quickly get to the root
cause and resolution of any issue related to crystal form.
• Better understanding and control of solid form properties of APIs and
how they affect the final drug product.
• Improve the manufacturing efficiency and product quality.
• Identify critical chemical, physical and functional properties which are
crucial for specific formulation requirements.
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HOW CAN WE HELP YOU?
We support our clients from
early-phase to kilogram supply.
DISCOVER DESIGN DETERMINE DEVELOP
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DISCOVER
«...to obtain sight or knowledge of
for the first time.»
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DISCOVER
Determination and control of
polymorphs is crucial to understand
your product/process and enhance
your patenting strength.
Salts & Co-Crystals
Screening
Identification of
Hydrates
Polymorph Screening
Hydrates usually show a wide range of
properties that can be very different
from the parent, anhydrous material.
They present new possibilities
for drug patenting also
enhancing the physiochemical
profile of existing drugs.
Generation of
Amorphous Material
Amorphous materials can
significantly increase bioavailability
of poorly-water soluble drugs.
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DESIGN
«...to devise for a specific function.»
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DESIGN
Stability evaluation of various forms
at different conditions.
Solid Form Selection
API-Excipient
Compatibility
Stability Studies
Obtain an in-depth understanding
of physical or chemical API-
excipient interactions.
Identification of the best physical
form by evaluating physical and
chemical changes.
Consulting &
Patent Support
Evaluation of the patentability of
new forms and processes.
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DETERMINE
«...to bring about as a result.»
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DETERMINE
Particle MorphologyStructure Analysis
Content &
Activity of Water
Thermal Analysis Physicochemical
Analysis
cGMP Quality Control
cGMP QC testing for raw materials,
active pharmaceutical ingredients
(API) and intermediates.
ICP-MS, pKa, LogP, LogD,
Solubility.
PSD, SEM, Bulk Density, Tap Density,
Morphologi G3, Optical Microscopy.
XRPD, XRPD Single Crystal, FT-
IR, FT-RAMAN, Solid/Liquid-state
NMR, Solid Form Quantitation,
Structure Determination.
VT-XRPD, DSC, TGA, TG-
EGA, HSM, Melting Point.
Easy Water, Karl Fischer Titrations,
DVS, Loss on Drying.
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DEVELOP
«...to work out the possibilities.»
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Process Development
& Scale-Up
Process Validation
Investigation of the effect of
crystallisation parameters and seeding
on final PSD and morphology.
Ensure that your process is properly
designed executing DOE studies and
statistical assessment utilising QbD.
Standard Reference of
Crystalline Forms
Reproduce and scale-up the selected
procedure to obtain the desired form.
DEVELOP
Synthetic Route Scouting
Resolving synthesis issues, determine best
synthesis conditions and identification of
the best synthetic route for development.
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PolyCrystalLine SpA
Via F. S. Fabri, 127/1 - 40059 - Medicina (Bologna) - ITALY
Office: +39 051 6970791 Fax: +39 051 851847
E-mail: [email protected]
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CONTACT
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