Via F.S. Fabri, 127/1 – Medicina (BO) -Tel. +39 051 6970791 – Fax. +39 051 851847 E-mail: info@polycrystalline.it Website: www.polycrystalline.it

PolyCrystalLine was founded in 2005 as a

business idea developed in an academic

context. 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.

In 2007 PolyCrystalLine moved its activities out

of the Department of Chemistry, transferring its

university know-how into a dedicated

laboratory in the suburbs of Bologna.

In September 2009 PCL moved premises into

larger custom-built laboratories and offices in

Medicina.

C o m p a n y Profile

GLP certification was obtained in May 2010 to carry out chemical physics analyses.

In 2014 a new headquarters is being built, increasing further our capabilities in optimization and

synthesis.

C o m p a n y Profile

Our strength:

• Strong link with Crystal Engineering

Group (University of Bologna)

• High competence on solid state

• Dynamic group

• Flexibility and modularity

• Quick response

PolyCrystalLine is a young dynamic company which has established itself as a leader in research

and characterization of solid-state compounds, especially in the pharmaceutical sector.We

have developed a university background into a business venture, blending academic know-

how with business-like agility and flexibility. By working closely with the academic world, we are

able to apply an innovative and avant-garde approach to the solving of scientific, commercial

and patenting problems.

T y p e o f S e r v i c e s

R&D

•Polymorphs Screening

•Salts/Co-crystals Screening

•Amorphous Screening

•Hydrates Screening

•Stability Test (T, M, RH)

•Compatibility Test

•Formulation Study

•Structure Determination by

Single Crystal & Powder

•Dissolution Test (K, TD)

• Tailor-made Project

•Patent, Literature & Consulting

Analytical

•Quality Control

•Certification

•Development method

•Validation Method

•Method Transfer

•Intrinsic Dissolution

•Bioequivalence Test (in vitro)

•SMEPAC/SWAB Test

Optimization &

Synthesis

•Optimization of Crystallization

•Variable Screening (DoE)

•Crystalllization Study

•Impact of Seeding

•Scale-up Study

•Synthesis optimization

PolyCrystalLine provides analyses and studies on Highly Potent and Cytotoxic products.

R e s e a r c h S e r v i c e s - T a i l o r - M a d e P r o j e c t

We are able to satisfy the most varied research

needs and budget requirements, ranging from

in-depth analysis of APIs and

compounds/solvates to quick low-cost

screening and studies involving patent issues.

Our extensive experience in the characterization of solid-state compounds and the study of

polymorphism has led to the development of specific and flexible research protocols (FULL and

FAST). These can be adapted to meet the needs of the pharmaceutical industry.

R e s e a r c h S e r v i c e s - P o l y m o r p h s S c r e e n i n g

A c t i v i t y F A S T F U L L

Solvent N° 20 50

Pre-screening ✓ ✓

Evaporation (RT- LT- HT- LP - SS- Mix) ✓ ✓

Precipitation (Gradient - Anti-solvent) ✓ ✓

Slurry (7 and 30 Days) ✓ ✓

Experiment of Inter-convertion ✗ ✓

Comparative Dissolution Test ✗ ✓

Hydrates Identification ✓ ✓

Hydrates Screening ✗ ✓

Thermal & Mechanical Stabilty ✓ ✓

RH/°C Stability Test (following ICH Guideline) ✓ ✓

E x p e r i m e n t N ° 2 5 0 6 0 0

All the new crystalline forms are characterized with all available techniques.

R e s e a r c h S e r v i c e s – S a l t s / C o - c r y s t a l s S c r e e n i n g

PolyCrystalLine can explore the formation of API salts and co-crystals with pharmaceutically

acceptable guest molecules using different stoichiometric ratios.

Two types of screening can be performed:

• Solvent free screening e.g. grinding,

kneading (solvent drop assistant), melting,

etc.

• Solvent based screening e.g. evaporation,

precipitation, slurry, etc.

New solid forms will be investigated in terms of solubility, polymorphism, and solvate formation.

R e s e a r c h S e r v i c e s – S c r e e n i n g

A m o r p h o u s S c r e e n i n g

Our laboratory can produce amorphous materials using several techniques such as spray drying,

quench cooling, desolvation, etc.

The stability of an amorphous phase is also investigated by solid state NMR and RAMAN

spectroscopy techniques and we are able to evaluate the conditions of conversion into the

crystalline phase.

S t a b i l i t y T e s t

The stability of API with temperature, pressure,

mechanical stress and humidity is assessed by diffraction,

spectroscopic, calorimetric and thermogravimetric

methods.

Conversion and interconversion of polymorph,

amorphous, hydrate or solvate phases are investigated

over a wide temperature range.

DVS Intrinsic analysis gives an important contribution to

determine the stability of an API.

R e s e a r c h S e r v i c e s – F o r m u l a t i o n S t u d y

Formulation studies involve developing a preparation of the drug which is both stable and

acceptable to the patient. It is important to appreciate that a tablet contains a variety of other

substances apart from the drug itself, and studies have to be carried out to ensure that the drug

is compatible with these other substances.

Preformulation involves the characterization of the physical, chemical, and mechanical

properties of the drug in order to choose what other ingredients should be used in the

preparation.

Formulation studies then consider such factors

as particle size, polymorphism, pH,

and solubility, as all of these can

influence bioavailability and hence the activity

of a drug. The drug must be combined with

inactive additives by a method which ensures

that the quantity of drug present is consistent in

each dosage unit e.g. each tablet.

PolyCrystalLine provides tailor-made

formulation studies, to identify excipients and

their solid state behaviour.

R e s e a r c h S e r v i c e s – Patents, literature & Consulting

Patent and literature research is the first step of every project in order to know and identify all

relevant publications and patents. This is possible thanks to our crystallographic, scientific,

technical and patent databases. This information allows us to evaluate the patentability of the

innovation found and suggest the best way for the protection of possible patent rights.

PolyCrystalLine addresses complex issues arising in the preparation of the regCMC section of an

IND. For example, we can optimize characterization research to focus on an API crystalline form

with the most desirable physical properties. By doing so we can guide the customer in choosing

the optimal drug form. If an undesirable polymorph in uncovered in either scale up and/or process

transfer to other site(s), PolyCrystalLine experts will determine the root-cause and will propose

appropriate corrective actions for remediation.

PolyCrystalLine employs a comprehensive multi-technique approach, which encompasses a

range of cutting-edge analytical techniques: X-ray diffraction (PXRD, structure determination,

etc.) Spectroscopy (FTIR, Raman, NMR, etc,) Thermal analysis (DSC, TGA) Microscopy (optical,

electron) Surface characterization (vapor sorption kinetics, specific surface area, etc.)

We help navigate through complex experimental design, parameter choosing, data

interpretation, and data correlation.

Finally we address potential changes, which may occur during physical transformation processes

such as crystallization, drying, spray drying, milling, blending, granulation and tabletting.

A n a l y t i c a l S e r v i c e s – Q u a l i t y C o n t r o l

I n s t r u m e n t s / t e c h n i q u e s Q u a l i t a t i v e Q u a n t i t a t i v e

X-ray powder diffraction ✓ ✓

X-ray powder diffraction at Variable Temperature ✓ ✗

X-ray Single Crystal Determination ✓ ✗

Differencial Scanning Calorimetric (DSC) ✓ ✓

Thermogravimetric Analysis (TGA) ✓ ✗

Evolved Gas Analysis (EGA) ✓ ✗

Hot-stage Microscopy (HSM) ✓ ✗

Dynamic Vapour Sorption (DVS) ✗ ✓

FT-IR ✓ ✓

FT-RAMAN ✓ ✓

UV-Vis ✓ ✓

NMR solid state ✓ ✓

Particle Size Distribution ✓ ✗

Intrinsic dissolution ✗ ✓

Easy-water ✗ ✓

Karl Fischer ✗ ✓

Melting Point ✓ ✗

SEM ✓ ✗

ICP ✗ ✓

BET (N2) ✗ ✓

U(H)PLC ✗ ✓

The XRPD quality assessment results are produced within 24/48 hours of receipt of the sample.

A n a l y t i c a l S e r v i c e s – C e r t i f i c a t i o n

PCL has required GMP certification to perform XRPD Qualitative and Quantitative analysis

PolyCrystalLine is eligible to carry out tests in compliance with the principles of Good Laboratory

Practice laid down in the Annex II of mentioned Legislative Decree, within the following areas of

expertise:

1) PHYSICAL-CHEMICAL TESTING

I n s t r u m e n t s / t e c h n i q u e s

X-ray powder diffraction

Differencial Scanning Calorimetric (DSC)

Thermogravimetric Analysis (TGA)

Evolved Gas Analysis (EGA)

Dynamic Vapour Sorption (DVS)

FT-IR

Particle Size Distribution

Intrinsic dissolution

Karl Fischer

Melting Point

U(H)PLC

A n a l y t i c a l S e r v i c e s – M e t h o d s

M e t h o d s D e v e l o p m e n t

PolyCrystalLine provides the development of analytical methods for

the following applications:

• Quality assessment of APIs, starting material and final product

(XRD - TGA - DSC - FT-IR - HPLC - FT-Raman – PSD);

• Characterization of APIs;

• Quantity assessment of APIs and formulated APIs

(XRD - FT-IR - DSC - FT-Raman);

• Dissolution testing: Ph. Eur. 2.9.3

M e t h o d s V a l i d a t i o n

The methods developed are validated for testing scientific integrity

following ICH guidelines, including preparation and validation

protocols and reports.

M e t h o d T r a n s f e r

PolyCrystalLine provides and follows the transfer of the method

developed where it is needed to perform the analyses within our

company.

A n a l y t i c a l S e r v i c e s – B i o e q u i v a l e n c e D i s s o l u t i o n

The Bioequivalence study is required in order to determine the rate/extent of absorption of each

therapeutic moiety for:

• Potential generic products for which there is a reference listed drug (RLD) approved for

marketing;

• Potential new drug products (new salts, dosage forms) for which adequate clinical studies

have already been conducted;

• Reformulated drug products.

PolyCrystalline provides "In Vitro Bioequivalence

Testing” of solid oral dogase forms according

to ICH Guideline.

O p t & S y n t h S e r v i c e s - O p t i m i z a t i o n of C r y s t a l l i z a t i o n

PolyCrystalLine provides optimization of crystallization projects using a

modular approach ranging from milligrams to half kilogram scale. Our

know-how will optimize the different parameters during the crystallization

processes to obtain the most desirable crystal form, particle size, yield,

etc.

• Synthesys Optimization

• Production of small batches of the API

• Polymorph-salt/cocrystal Screening

• Process Design

• Process Optimization

• Scale-up until 20 Liters

These services are performed using a Design of Experiments (DOE)

approach, a structured, organized method used to determine the

relationship between the different factors affecting a process and the

output of that process. It involves designing a set of experiments in which

all relevant factors are varied systematically. This approach leads to the

identification of all the relevant variables of the studied

system, producing a robust and scalable process.

• Using the DOE method will help pinpoint:

• Key process factors to achieve acceptable results

• Key relationships in the process

• Settings to produce a minimum variable output

O p t & S y n t h S e r v i c e s – A u t o m a t e d R e a c t o r S y s t e m

PolyCrystalLine performs optimized crystallization experiments using Automated Reactor Systems (Atlas Syrris,

EasyMax Mettler). Systems which are designed for chemists who are interested in monitoring or controlling

crystallizations, emulsions, suspensions, etc. They allow turbidity to be examined and modified by controlling

temperature and/or additions to the vessel.

The turbidity system can be used in a wide range of applications such as simple crystallization point detection, or

in more complex studies of metastable crystallization zones, secondary nucleation and polymorphism issues.

A list of typical applications can be seen below:

Crystallization Studies

• Automated metastable zone width studies

• Optimization of product recovery – crystal size, purity and recovery

Crystallization Control

• Crystalline along turbidity ramp

Scale-up Studies

• Batch-to-batch repeatability

• Agitation effects

Polymorphism Studies

• Impact of different solvents, mixture, concentrations and temperatures

• Impact of crystal “seeding”

O p t & S y n t h S e r v i c e s – S y n t h e s i s o p t i m i z a t i o n

The PolyCrystalLine chemical development team

provides you with a complete package of chemical

and analytical services for your pharmaceutical

products. Whatever your requirements, we can support

you with a range of added-value activities – to optimize

the synthetic steps of the production from milligram to

half-kilogram scale of your complex intermediates and

early stage APIs.

Our proven know-how in modern synthesis will find new

cost effective and efficient synthetic routes for your

compounds, enabling you to resolve challenging

synthesis issues, while meeting your deadlines.

C l i e n t s

Abbott

Alfawassermann

ACRAF Angelini

Abiogen

Kalidex

BASF

Cerbios Pharma

Chiesi Farmaceutici

Lusochimica

Menarini

Rottapharm

Chemi

Dipharma Francis

Djada Pharmaceuticals

Finceramica

Italfarmaco

Stragen

Edmond Pharma

Linnea

Polpharma

SIMS

Zambon Group

Novartis

GiulianiPharma

Indena

Alfred E.Tiefenbacher

Procos

Fatro

Lab. Farm. Milanese

Farchemia

Bracco

Eurocoating

PTM

Eratech

Achè

Eurofarma

PCA

Polichem

Recordati

Sigma-tau

Sterling

Prochifar

Developharma

Rivopharm

Dipharma Francis

Lab. Farm. SIT

Helsinn

Farmabios

F.I.S.

PHF

Dompè

Fresenius-Kabi

Sharper

Cristalia

ChemiNova

Industriale Chimica