Crystallisation by design - PolyCrystalLine

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Transcript of Crystallisation by design - PolyCrystalLine

Page 1: Crystallisation by design - PolyCrystalLine

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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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WHO ARE WE?

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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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WHAT IS THE IMPORTANCE OF SOLID FORMS?

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DRUG DOSAGE FORMS

Many pharmaceutical delivery technologies are available, such as:

Pulmonary

Delivery

Nasal

Delivery

Transdermal

Delivery

Injectable

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

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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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WHAT IS CRYSTALLISATION BY DESIGN?

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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?

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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]

www.polycrystalline.it

CONTACT