Polycrystalline Company Presentation - Crystallisation by Design

www.polycrystalline.it

2OUTLINE

WHAT IS THE IMPORTANCE OF SOLID FORMS?

THE IMPACT OF SOLID FORMS

WHY POLYCRYSTALLINE WAS FOUNDED?

WHAT WE DO

BRIEF INTRODUCTION TO DRUG DOSAGE FORMS


3DRUG DOSAGE FORMS

Many pharmaceutical delivery technologies are available, such as:

Pulmonary

Delivery

Nasal

Delivery

Transdermal

Delivery

Injectable

Formulation


4DRUG 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.


5

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:


6WHY SOLID?

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. …).


7TYPES 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 RTFree drug Solvent Protonated drug molecule Deprotonated acid


8WHAT 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


9WHAT IS THE IMPORTANCE OF SOLID FORMS?

Process

Optimisation

& Scale-Up

Drug

Discovery

Pre-Clinical

Studies

Routine

Production

Synthetic Route

Selection

Final Dosage

Form

Drug Development Pipeline


10

Process

Optimisation

& Scale-Up

Drug

Discovery

Pre-Clinical

Studies

Routine

Production

Synthetic Route

Selection

Final Dosage

Form




11

Process

Optimisation

& Scale-Up

Drug

Discovery

Pre-Clinical

Studies

Routine

Production

Synthetic Route

Selection

Final Dosage

Form




12

Process

Optimisation

& Scale-Up

Drug

DiscoveryPre-Clinical

Studies

Routine

Production

Synthetic Route

Selection

Final Dosage

Form




13THE IMPACT OF SOLID FORM ISSUES CAN BE COSTLY

Abbott’s Norvir® (Ritonavir) (used to treat HIV/AIDS)its sales topped $1 billion in its first 5 years on the market (1996-2001)

• In early 1998 final product lots failed the dissolution test and were seen to be

precipitated out from the semisolid formulated product

• A new polymorphic form had been discovered that was thermodynamically

more stable and approximately 5 times less soluble than the existing form

• Abbott Laboratories were forced to rapidly develop a new formulation

and crystallisation process

CASE 1

What happened?



Pfizer's Lipitor® (Atorvastatin) (used to treat high cholesterol)the world's best-selling drug, generating nearly $13 billion in 2007 sales

• This drawback delayed the launching of the drug onto the market

and pointing out the weakness of the production procedure and

the amorphous formula produced by the originator's

• It was formulated as an amorphous salt but it was observed to crystallise

during Phase III clinical trials

CASE 2

What happened?



Merck’s Fosamax® (Alendronate) (used to treat osteoporosis)was Merck's No. 3 drug in 2007, with sales totaling $3 billion

• Generic version with a different crystalline form

was launched before patent expiration

CASE 3

What happened?


16POLYCRYSTALLINE

OUR MISSION 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.

Crystal-oriented

synthetic strategies

Understand and control

crystal properties

Crystallisation

by design


17POLYCRYSTALLINE AT A GLANCE

OF LABORATORIES AND

OFFICES IN MEDICINA (ITALY)

750 m2

ANALYTICAL

LABORATORY

cGMPDIFFERENT APIs WE

HAVE OPTIMISED

+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


18REFERENCES



EXTENSIVE IN-HOUSE EQUIPMENT FOR SOLID STATE CHARACHERISATION

− XRPD

− FT-IR

− FT-RAMAN

− Differential Scanning Calorimetry

− Evolved Gas Analysis

− Thermogravimetric Analysis

− Easy Water

− Karl Fischer

− Dynamic Vapour Sorption

− Particle Size Distribution

− Morphologi G3



CHEMICAL SYNTHESIS REACTORS EQUIPPED

WITH pH, TEMPERATURE, FBRM AND

TURBIDITY SENSORS

− CrystalBreeder

− EasyMax 102

− Atlas Syrris

− Glass reactors from 50mL up to 50L


21FROM DISCOVERY TO MANUFACTURING

We support our clients from

early-phase to kilogram supply.

DISCOVER DESIGN DETERMINE DEVELOP

DISCOVER

...to obtain sight or knowledge of

for the first time.


23DISCOVER

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

Salts & Co-Crystals 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

DESIGN

...to devise for a specific function.


25DESIGN

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

DETERMINE

...to bring about as a result.


27DETERMINE

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

DEVELOP

...to work out the possibilities.


29

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, Identification of

the best synthetic route for development


30

PolyCrystalLine SpA

Via F. S. Fabri, 127/1 - 40059 - Medicina (Bologna) - ITALY

Office: +39 051 6970791 Fax: +39 051 851847

E-mail: [email protected]


CONTACT


31CLOSING REMARKS

Thank you for

your attention

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Polycrystalline Company Presentation - Crystallisation by Design