VxP Pharma

Purdue Research Park

5225 Exploration Drive

Indianapolis, IN 46241

Tel: 317.759.2299

Fax: 317.713.2950

Preformulation & Solid State

Chemistry Services

VxP Pharma provides manufacturing, testing and

stability services for preformulation and solid state

chemistry development of your product.

Solid Form Modification

-Salt Synthesis and Salt Form Selection

- Polymorph/Salt/Co-crystal Screening and Selection

- Amorphous Dispersion Screening and Selection

-Property Improvement (solubility, stability, bioavailability)

Characterization of Drug Substance and Drug Product

-Solid Form Identification and Quantification,(crystalline, amorphous)

-Solubility and Dissolution (water, organic solvent, pH)

- Physical and Chemical Stability (temperature, relative humidity)

-Thermodynamic Stability

-Process Induced Transformations

• Sponsor Evaluations:– Host multiple Sponsor visits and independent facility audits each year

Quality & Compliance

• Quality Assurance:– To ensure Data and Report Quality

– Rigorous peer review process

– Continuous performance measurements

– SOPs and IOPs in place

– All release testing performed under GMP/GLP requirements

Data

Quality

Data

Quality

ConsistencyConsistency

IntegrityIntegrity

TimelinessTimeliness

CompletenessCompleteness

ValidityValidity

AccuracyAccuracy

• Optimal Solid Form Screening/ Selection:– Polymorph/Salt/Co-crystal screening

– Amorphous solid dispersions

– Solid state characterization

– Thermodynamic phase relationship

– Property evaluation

– Single crystal structure determination

– Form developability assessment

– Form Identification and Quantification

Services: Solid State Chemistry

• Crystallization Process Support:– Process development

– Crystallization process optimization (problem solving)

– Particle attributes control

– Purification

– Polymorphic Isolation

– Chiral Separation

– Process Technology Transfer

• Solid Form IP Consultancy:– Repurposing strategies

– Second generation strategies

– Building patent portfolio for IP protection

– Data package for inclusion in patents

• Analytical Research– Analytical support for drug product

development

– Method development/validation

– Prototype/IND stability studies

– cGMP release testing

• Preformulation Development– Solubility measurement and

enhancement

– Physicochemical characterization

– Vehicle selection (solutions, suspensions)

– Early formulation development

– Amorphous solid dispersions

– Formulatability assessment/risk analysis

Services: Preformulation

• Molecular Properties– pKa

– LogP/LogD

– Equilibrium solubility

– Forced degradation and chemical stability

– Excipient compatibilities

• Solid State Properties– Characterization of selected form

– Solid state stability studies

– Karl Fischer and solvent identification

– Particle morphology

– Dissolution & intrinsic dissolution

• Molecular Structure Confirmation– Elemental analysis

– HPLC method development

– NMR spectroscopy

– Mass spectroscopy

– IR/UV-visible spectroscopy

– Single crystal structure solution

Characterization of API and Drug Product

• Crystallinity:– XRPD

• Reference Data:– IR

– Raman

– Thermal analysis (DSC & TGA)

– Microscopy (optical/SEM)

– Dynamic vapor sorption (hygroscopicity)

– HPLC & LC-MS

– Particle size and morphology

• Phase Purity:– Indexing from single crystal data

• Applications- Identification of

API/starting material

- Characterization of screening and stability samples

- Support of crystallization process development

- Support of formulation process development

- Identification of form changes due to process induced transformations

- Quantification of forms in API and drug product

Solid Form Screening

• Screens tailored to fit your needs throughout development

– Early screens target problem areas (such as solubility) or desired properties (most stable form)

– Late screens target IP and lifecycle management

– Screens of different sizes available to find the optimal form

– Additional property determination used to select the best form

– All data can be added directly to regulatory and IP documents

Screening Strategy

• Screening is part of form selection, formulation development, crystallization development, and lifecycle management

• Form assessment and screening strategy development are provided to help develop the best form

Typical Polymorph

Screen

Solubility data

enabling screen

Anti-solvent

Vapor diffusion into

solution

Long term slurry

conversions

Fast & Slow cooling

RefluxHigh boiling

point solvents

Evaporation from solvent

mixtures

Cooling from solvent

mixtures

Solid templates

Conversion by

compression

Amorphization

Vapor

diffusion

on solids

Hydrate

formation

Solvent

assisted

grinding

• Experiments chosen based on solubility and compound properties

• Large range of conditions used in both small and large screens

Crystallization of

Amorphous

CrystalsVapor diffusion

Refluxing

Thermo-cycling

Anti-solventLong term

slurry conversion

Slow evaporation

Slow cooling

Solid templates

Salt Screening and

Selection

� Internal list of counterions and counterion properties

� Counterions chosen based on formulation and API

properties

� Salt formation in a variety of relevant solvents

� Different precipitation methods used to produce salt

� Characterize solids to determine salt formation,

stoichiometry, solvent content

� Determine crystal forms produced for each salt

� Review salts produced

� Determine properties of salts

� Select lead salt and backup salt based on client needs

XRPD, TGA,

Raman/FTIR of API

Qualitative

solubility

Saturated solution

APIAdd counter-ion

Precipitation

Separate solid from

liquid

Dry solids Evaporate liquid

Solid characterization

XRPD, solution NMR, KF, elemental analysis

Review salts

Property determination

Stability, solubility, hygroscopicity, etc

Nominate lead salts

Co-crystal Screening

� Co-crystal formation in relevant solvents

� Flexible and diverse coformer list

� Coformers chosen based on API properties

and hydrogen bonding networks

� Different precipitation methods used to

optimize co-crystal production

� Characterize solids to determine cocrystal

formation, stoichiometry, solvent content

� Determine crystal forms produced for each

co-crystal

� Review co-crystals produced

� Determine properties of co-crystals

� Select lead cocrystal and backup based on client

formulation and development needs

XRPD, TGA,

Raman/FTIR of API

Qualitative

solubility

API solution Add coformer

Precipitation

Separate solid from

liquid

Dry solids Evaporate liquid

Solid characterization

XRPD, solution NMR, KF, elemental analysis,

FTIR/Raman

Review co-crystals

Property determination

Stability, solubility, hygroscopicity, etc

Nominate co-crystals

Amorphous Solid

Dispersions

� Flexible and diverse excipient selection

� Different API:excipient ratios

� Binary and ternary mixtures

� Relevant production method (melt vs solvent)

� Drying step if needed to remove excess solvent

� Characterize solids to determine dispersion

formation, miscibility, glass transition temperature

(Tg), solvent content

� Review dispersions produced

� Determine properties of dispersions

� Select lead dispersion and backup based on client

formulation and development needs

XRPD, TGA, DSC,

Raman/FTIR of API

Qualitative

solubility

API Add excipient

Mixture

Dry solids

Solvent removal or melt

Solid characterization

XRPD, solvent content, KF, DSC,

FTIR/Raman

Review dispersions

Nominate amorphous dispersions

Property determination

Stability, solubility, hygroscopicity, Tg, etc

Characterization & Selection Tools

• Primary Characterization– Crystallinity by XRPD (x-ray powder diffraction)

– Digital imaging

– Thermal analysis (DSC & TGA)

– Hygroscopicity & physical stability

– Storage under stress conditions (40°C/75%RH, etc)

• Secondary Characterization after scale up:– HPLC & LC-MS

– High resolution XRPD

– Competitive slurry conversions for stable polymorph selection

– XRPD at variable temperature and humidity

– Single crystal X-ray diffraction

– Dynamic vapor sorption (DVS)

– IR & Raman

– Solid-state and solution NMR

– Solubility & dissolution rates

– Particle size distribution (Microtrac, Malvern)

Crystallization

• Identify product quality attributes

• Develop efficient and

robust process

-Small and large

scale crystallizers

- Analytical sensors

(FBRM, ReactIR)

available

-Technology transfer

to API manufacturer

Preformulation

• Traditional analyses

– pKa

– LogP/LogD

– Equilibrium solubility (water, organic solvents, pH)

– Forced degradation and chemical stability

– Excipient compatibilities

• Solid state considerations

– Physicochemical characterization

– Solubility measurement and enhancement

– Solid form suitable for targeted formulation (polymorph, salt, co-crystal, amorphous solid dispersion)

• Early formulation approaches

– Vehicle selection (solutions, suspensions) for toxicology studies and early clinical trials

– Physical and chemical stability in early formulation vehicles

Solid-State Equipment

Panalytical

Empyrean XRPDBruker 500 MHz

WB SSNMR

TGA-Q500, Q5000DSC-Q200, Q2000

DXR Raman Microscope Microtrac S-3500

PSD Analyzer

DVS Intrinsic

Zeiss Polarized Light

Microscope

CM Protégé

PharmD Powder

Dispensing System

Crystallization Equipment

ReactIR 45m

Crystal

16EasyMax

FBRM G400OptiMax

Analytical and Preformulation

Equipment

Metrohm 870 Karl

Fisher Titrator

Agilent HPLC 1260, 1100

Metrohm 848 Titrino Plus

Dissolution

(Agilent 708-DS)

Water Activity Meter

(Aqualab Series 4 TE)

Agilent 7820A GC Sirius T3 pKa

VxP Pharma provides an extensive range of

analytical services and technical support for method

development, validation and testing for multiple

pharmaceutical and biopharmaceutical

applications.

– API Testing

– Product Development Testing

– CMC/Compendial Testing

Additional Services: Analytical & Bioanalytical

THANK YOU

For additional information:

VxP Pharmawww.vxppharma.com

Phone: 317.759.2299

Email: info@vxppharma.com