Preformulation & Solid State Chemistry Services

Transcription

1 Preformulation & Solid State Chemistry Services VxP Pharma Purdue Research Park 5225 Exploration Drive Indianapolis, IN Tel: Fax:

2 VxP Pharmaprovides 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

3 Accuracy Validity Consistency Quality & Compliance Completeness Data Quality Timeliness Integrity Sponsor Evaluations: Host multiple Sponsor visits and independent facility audits each year 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

4 Services: Solid State Chemistry 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 Solid Form IP Consultancy: Repurposing strategies Second generation strategies Building patent portfolio for IP protection Data package for inclusion in patents Crystallization Process Support: Process development Crystallization process optimization (problem solving) Particle attributes control Purification Polymorphic Isolation Chiral Separation Process Technology Transfer Analytical Research Analytical support for drug product development Method development/validation Prototype/IND stability studies cgmp release testing

5 Services: Preformulation Preformulation Development Solubility measurement and enhancement Physicochemical characterization Vehicle selection (solutions, suspensions) Early formulation development Amorphous solid dispersions Formulatability assessment/risk analysis Molecular Properties pka LogP/LogD Equilibrium solubility Forced degradation and chemical stability Excipient compatibilities Molecular Structure Confirmation Elemental analysis HPLC method development NMR spectroscopy Mass spectroscopy IR/UV-visible spectroscopy Single crystal structure solution Solid State Properties Characterization of selected form Solid state stability studies Karl Fischer and solvent identification Particle morphology Dissolution & intrinsic dissolution

6 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

7 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

8 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

9 Typical Polymorph Screen Solid templates Anti-solvent Vapor diffusion into solution Solvent assisted grinding Amorphization Cooling from solvent mixtures Solubility data enabling screen Long term slurry conversions Conversion by compression Vapor diffusion on solids Evaporation from solvent mixtures Fast & Slow cooling Hydrate formation High boiling point solvents Reflux Experiments chosen based on solubility and compound properties Large range of conditions used in both small and large screens

10 Crystallization of Amorphous Thermocycling Anti-solvent Long term slurry conversion Slow evaporation Refluxing Slow cooling Vapor diffusion Crystals Solid templates

11 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 XRPD, TGA, Raman/FTIR of API Saturated solution API Qualitative solubility Add counter-ion Precipitation Different precipitation methods used to produce salt Characterize solids to determine salt formation, stoichiometry, solvent content Determine crystal forms produced for each salt Dry solids Separate solid from liquid Evaporate liquid Solid characterization XRPD, solution NMR, KF, elemental analysis Review salts produced Determine properties of salts Select lead salt and backup salt based on client needs Review salts Property determination Stability, solubility, hygroscopicity, etc Nominate lead salts

12 Co-crystal Screening Co-crystal formation in relevant solvents Flexible and diverse coformer list Coformers chosen based on API properties and hydrogen bonding networks XRPD, TGA, Raman/FTIR of API API solution Qualitative solubility Add coformer 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 Dry solids Precipitation Separate solid from liquid Evaporate liquid Solid characterization XRPD, solution NMR, KF, elemental analysis, FTIR/Raman Review co-crystals produced Determine properties of co-crystals Select lead cocrystal and backup based on client formulation and development needs Review co-crystals Property determination Stability, solubility, hygroscopicity, etc Nominate co-crystals

13 Amorphous Solid Dispersions Flexible and diverse excipient selection Different API:excipient ratios Binary and ternary mixtures XRPD, TGA, DSC, Raman/FTIR of API API Qualitative solubility Add excipient 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 Mixture Solvent removal or melt Dry solids Solid characterization XRPD, solvent content, KF, DSC, FTIR/Raman Review dispersions produced Determine properties of dispersions Select lead dispersion and backup based on client formulation and development needs Review dispersions Property determination Stability, solubility, hygroscopicity, Tg, etc Nominate amorphous dispersions

14 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)

15 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

16 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

17 Solid-State Equipment DSC-Q200, Q2000 TGA-Q500, Q5000 DVS Intrinsic Panalytical Empyrean XRPD Bruker500 MHz WB SSNMR DXR Raman Microscope MicrotracS-3500 PSD Analyzer CM Protégé PharmD Powder Dispensing System ZeissPolarized Light Microscope

18 Crystallization Equipment EasyMax Crystal 16 OptiMax FBRM G400 ReactIR 45m

19 Analytical and Preformulation Equipment Agilent HPLC 1260, 1100 Agilent 7820A GC Dissolution (Agilent 708-DS) Sirius T3 pka Metrohm 848 Titrino Plus Metrohm 870 Karl Fisher Titrator Water Activity Meter (Aqualab Series 4 TE)

20 Additional Services: Analytical & Bioanalytical VxP Pharmaprovides 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

21 THANK YOU For additional information: VxP Pharma Phone: