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ADME SOLUTIONS

ADME SOLUTIONS. ADME. Line of automated workstations for drug screening in discovery and development. Installed base at big pharma, strong current interest, clear product expansion route. Structural Signature Technology.

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ADME SOLUTIONS

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  1. ADME SOLUTIONS

  2. ADME • Line of automated workstations for drug screening in discovery and development. • Installed base at big pharma, strong current interest, clear product expansion route. StructuralSignatureTechnology • Breakthrough technology for rapid assessment of structural changes to proteins. • Very significant potential application base in both biotech and pharma. Initial commercial feasibility underway. Proteomics • First true adjustable third dimension. • Studies in clinical marker discovery underway. CORE TECHNOLOGIES/PRODUCTS

  3. Technologies

  4. Spectrum of Solutions Automated Discovery Workstation Automated Solubility Workstation Automated LogD Workstation Solubility Solubility LogD Permeability LogD Permeability Blood-Brain Barrier Permeability Available Included Option Metabolic Stability Plasma Protein Binding R&D Completed

  5. ADME in Discovery and Development (1) • Discovery: • Objective: Fail hits early • Samples: Dry and DMSO-dissolved • Throughput: Up to 200 samples/day (typically) • Accuracy: (Supposedly) not high – rank order is sometime sufficient • Development: • Objective: Optimize lead (better ADME parameters), salt & excipient selection, QSAR, etc. • Samples: Dry • Throughput: Typically up to 100/day, but increasing • Accuracy: High, must use gold-standard validated assays

  6. ADME in Discovery and Development (2) • State-of-the-art today: • Discrete instruments, each performing a single assay • Data consistency between different assays non-existent • Significant interaction required from trained personnel • No process engineering methodologies: • When assay is not required, the system is idle • When a system is down, there is no replacement • To double the capacity, each system must be duplicated • Automated Discovery Workstation: The modern approach to the entire lab

  7. same sample Automated Discovery Workstation - ADW • Not an instrument: It is an integrated solution (lab-on-a-bench) • Machine work – people think • Turnkey, automated, multi-assay workstation • Performs (presently) discovery/development assays: • True LogD/LogP vs. pH • True aqueous solubility vs. pH • Identity and purity of compound • Compound concentration w/o standard • Scalable, Flexible, Extendable technology • Standardized, validated data

  8. ADW - Automated Discovery Workstation ANALIZA’sIn-house DevelopmentSystem (2002)

  9. Add solute Sample andanalyze Phases Settle Mix Octanol sat. w/buffer Buffer sat. w/octanol Ctop Cbot Two Key ADME Assays1. LogD/LogP • P is the partition coefficient between octanol and a buffer, that is obtained under equilibrium • Important for multiple ADME processes in discovery and development, and for QSAR lead optimization • Very extensive database exists  well validated method • Direct LogP assay (shake flask = gold standard):

  10. ADW:LogD/LogP Assay

  11. Two Key ADME Assays2. Solubility • Solubility is the concentration of the compound in solution in equilibrium with its solid • Important for bioavailability and other ADME processes • Very sensitive to measurement methodology • Current profiling solubility indicators are frequently different from the true values • Direct solubility assay (shake flask = gold standard) • Unique features: • No sample weighting • No assay calibration required to calculate solubility as mass/volume

  12. ADW:Solubility Assay

  13. Validation: LogD Accuracy LogDADW = 0.002(± 0.008) + 1.011(± 0.005)*LogDmanual N = 179; r2 = 0.9960; standard error of estimate = 0.1022

  14. Validation: Solubility Accuracy

  15. Validation: Precision Allopurinol in 0.15M NaCl in 0.01M Universal buffer, pH 6.6

  16. ADW Control and Analysis Software

  17. LogD Assay: Main screen with optional information windows

  18. Solubility Assay: Setup, imported data

  19. Data Viewer: Full featured archival data re-display andre-analyze GUI, which runs from any computer on the network

  20. Data Viewer: Display of archived raw PDA data – sample spectraYou Never Lose Your Data!

  21. ADW Hardware • Robotic liquid handler (Hamilton 4200, four computer-controlled syringes, custom valves). • Custom computer-controlled valve system (Rheodyne). • UV/VIS photo-diode array spectrophotometer (Groton Technologies) • Chemiluminescence total nitrogen detector (Antek Instruments) • Custom electronics, bar-code reader, and high-end control computer • Vacuum and HPLC pumps • Deckware: plate and filter holders, buffer racks, etc.

  22. ADW Hardware: Assay Specific LogD • Customized plate vortexer • Customized plate sealer • Refrigerated plate centrifuge Solubility • Custom filter plate holders • Customized filter plate presser • Customized shaker • Buffer containers holder • Temperature option (heated shaker, on-deck water bath )

  23. ADW Supplies Consumables: • LogD systems: • Loaded in 96 deep well plates, bar-coded, QC’ed • Ready-to-use in 6 standard pH levels • Solubility: • Filter vials Optional/Maintenance: • Nitrogen-detector calibration plates • Extra filter plates • Repair kits, parts Always Available: A direct hot-line to our scientists and system developers – you always get a timely answer, advice, and dedicated service

  24. ADW Key Specifications * Typical for 1-50 µg/ml range. Proportional with required upper range** Depending on user-selected settings and compound

  25. The ADW Solution Vs. Competition

  26. ADW: The Integrated ADME Environment

  27. AUTOMATED SOLUBILITY WORKSTATIONASolW in Pre-Formulation/Development All Slides Confidential

  28. Solubility • Solubility is the concentration of the compound in solution in equilibrium with its solid • Solubility takes several forms and is a function of multiple parameters (crystalline form, temperature, pH, co-solvent, etc.) • Important for bioavailability • Very sensitive to measurement methodology • Current profiling solubility indicators in early discovery are frequently different from the true values obtained during development • A direct solubility assay is defined by the shake flask method and is recognized as the gold standard

  29. Who Are The Users? • Discovery: • Obtain a measure of solubility of relevance to HTS and early ADMET • Can we determine if the compound will crash out of solution? • Obtain ADMET information of relevance for selecting amongst hits • Development: • Early lead characterization • Lead optimization • Formulation excipient selection

  30. Who Are The Users? (2) • Will the compound crash out?  solubility • Everyone else needs good data: • For promoting a compound: binning may be sufficient • For lead optimization: accurate data • For formulation development: accurate data • For anything regulatory: accurate data

  31. Alternative Techniques for Measuring SolubilityA Comparison (1/2)

  32. Alternative Techniques for Measuring SolubilityA Comparison (2/2)

  33. The ASolWAssay

  34. ASolW with Whatman’s MiniPrep Filter

  35. Options for Measuring Solubility ASolW: Dedicated Instrument ADW: Multi-Assay Instrument

  36. ASolW – Automated Solubility Workstation ANALIZA’s ASolW In-house development system

  37. ASolW: Assay setup

  38. ASolW: Data Check

  39. ASolW: Runtime Panel

  40. ASolW: Accuracy

  41. ASolW: Precision Allopurinol in 0.15M NaCl in 0.01M Universal buffer, pH 6.6

  42. Total Nitrogen Detection • Exceptions: • N2 – nothing is detected! • Nitrosamine (for GC) • Azides (1/3 response) • Double bonds (partial response) Separate calibration

  43. ASolW: Assay Using Nitrogen Content

  44. Basic Issue:What is the Effect of DMSO?

  45. Basic Issues:What is the Effect of DMSO?

  46. Basic Issue:What is the Effect of DMSO? Typically: • DMSO is a fact of life during screening • DMSO solubility is > or >> than true solubility • But just because we relaxed one experimental parameter does not mean that we can dispense with everything else • Make sure you know what you are using the data for – especially in lead promotion decisions

  47. ASolW Hardware • Robotic liquid handler (Hamilton 4000, two computer-controlled syringes, custom valves). • Custom computer-controlled valve system (Rheodyne). • Chemiluminescence total nitrogen detector (Antek Instruments CLND 8600) • Custom electronics, bar-code reader, and high-end control computer. • Custom filter plate compressor • 4-filter plate shaker/heater incubator • Miscellaneous accessories: Vacuum pumps, HPLC pump • Deck accessories: Filter plates, buffer racks

  48. ASolW Options, Kits, and Consumables Options: • Temperature option (to 37 deg.C) Kits: • Starter filter pack (included) • Maintenance kit • Additional filter plates, buffer/co-solvent bottles, etc. Consumables: • Filter packs • Nitrogen-free buffers

  49. Why ADME with ANALIZA? • We are experienced • We provide innovations with gold-standard assays • We don’t just automate • We report archival-quality data while minimizing material consumption and at high throughput • We guard your investment and offer flexibility and extendibility to our workstations • We pride ourselves with a personal, responsive, first-class organization before and after the installation

  50. Thank You

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