preformulation & solid state - vxp pharma · preformulation & solid state chemistry...
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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: [email protected]