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[email protected] Development of Pfizer's Third Generation Turbidimetric Solubility Assay - An Engineering Perspective Brian Bissett Molecular Properties Group Pfizer Global R&D Groton CT
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Development of Pfizer's Third Generation Turbidimetric Solubility Assay - An Engineering Perspective
Brian BissettMolecular Properties Group
Pfizer Global R&DGroton CT
Presentation Overview
History New Assay Overview Engineering: Design Considerations and
Obstacles Testing Performance and Repeatability Project Management Considerations
Purpose:Purpose: The turbidimetric solubility assay The turbidimetric solubility assay mimics typical biology lab solubilization mimics typical biology lab solubilization procedures for an in vivo experiment and procedures for an in vivo experiment and thus is relevant to early discovery stage thus is relevant to early discovery stage absorption problems.absorption problems.
Turbidimetric solubilities are most useful in Turbidimetric solubilities are most useful in the very early stages of discovery. Their the very early stages of discovery. Their value declines as in vivo activity is detected value declines as in vivo activity is detected and as more manning intensive, more and as more manning intensive, more accurate drug metabolism and pharm R&D accurate drug metabolism and pharm R&D resources are invoked.resources are invoked.
Why do we need solubility data anyway?
History of Turbidimetric Assays at PfizerThis first “primitive” assay could only run 6 compounds at a time!
History of Turbidimetric Assays at PfizerG2483B – The first “high throughput” solubility assay at Pfizer.
Desired Improvements over existing 2483B Assay
Septum Piercing Needle Delivery of Compounds in Septum Piercing Needle Delivery of Compounds in DMSO (Safety Issue) .DMSO (Safety Issue) .
Automated Data Reporting (Oracle Database Upload). Automated Data Reporting (Oracle Database Upload). Previous Assay Required Manually Run Macro.Previous Assay Required Manually Run Macro.
Prior Assay could run only one Plate of 45 compounds Prior Assay could run only one Plate of 45 compounds at a time, new assay can run up to 4 Plates of 90 at a time, new assay can run up to 4 Plates of 90 compounds or 360 Consecutive Solubilities.compounds or 360 Consecutive Solubilities.
Automated Generation of Files for High Dose Automated Generation of Files for High Dose Platereader Solubility Assay. Previous Assay required Platereader Solubility Assay. Previous Assay required a separate program run after assay completion to a separate program run after assay completion to generate these files.generate these files.
Total Automation - Place compounds on rack, set up Total Automation - Place compounds on rack, set up software and walk away.software and walk away.
What advantages does this new Assay have?
It is Comparable to a Commercial Unit.It is Comparable to a Commercial Unit. Increased Capacity (4X). Increased Capacity (4X). Increased Sensitivity.Increased Sensitivity. Increased Safety.Increased Safety. Increased Reliability.Increased Reliability. Reduced Operator Time.Reduced Operator Time.
Experimental Differences with Previous Assay Custom Designed Cuvette (Design done internally) Custom Designed Cuvette (Design done internally)
Fabricated by Starna Cells, Inc.Fabricated by Starna Cells, Inc. Custom Designed Septum Piercing Needle (Design Custom Designed Septum Piercing Needle (Design
done internally) Fabricated by Popper & Sons, Inc.done internally) Fabricated by Popper & Sons, Inc. Compound Added Directly to Cuvette. No Compound Added Directly to Cuvette. No
Secondary Mixing Chamber.Secondary Mixing Chamber. Mixing done within the Cuvette via Microstirbar.Mixing done within the Cuvette via Microstirbar. Longer Equilibration Time 90 sec. vs. 60 sec.Longer Equilibration Time 90 sec. vs. 60 sec. Rinse Solvent Changed to DMSO vs. MeOH.Rinse Solvent Changed to DMSO vs. MeOH. Multiple Rinse Methods Dependent Upon Baseline:Multiple Rinse Methods Dependent Upon Baseline:
Simple DMSOSimple DMSO DMSO and Glass Cleaner with EDTADMSO and Glass Cleaner with EDTA Wash Cycle, Multiple DMSO & Glass Cleaner RinsesWash Cycle, Multiple DMSO & Glass Cleaner Rinses
Experimental Differences with Previous Assay
Off Axis & Forward Detector Blocked on original G2483B Assay.Off Axis & Forward Detector Blocked on original G2483B Assay.
Obstacle: Designing the Septum Piercing Needle
Design Requirements:Design Requirements:
Must be Septum PiercingMust be Septum Piercing Coefficients of Variation < 5.0% Coefficients of Variation < 5.0%
between successive additions.between successive additions. Ideally all the compound to be Ideally all the compound to be
utilized in the assay should be utilized in the assay should be contained within the needle as contained within the needle as opposed to being drawn into the opposed to being drawn into the supporting tubing.supporting tubing.
Calculating the volume capacity of a Needle
Assume Needle is a right circular cylinder Assume Needle is a right circular cylinder of height of height hh and radius and radius rr..
2V = r hExample: Needle diameter = 150 microns and Example: Needle diameter = 150 microns and height = 100mm.height = 100mm.
26
3 -9 3
6-9 3
-3 3
150*10 mV = 100*10 m 1.767 * 10 m2
1L 10 L1.767 * 10 m * * 1.767 L10 m 1 L
Obstacle: Designing the Cuvette Holder Hach Designed for Round CellHach Designed for Round Cell Light Ports Must Minimize Light Ports Must Minimize
Noise Created By Backscatter Noise Created By Backscatter from Square Cell Edges.from Square Cell Edges.
Design Requirements:Design Requirements:
Must have Septum Piercing Must have Septum Piercing TopTop
Dual Ports for Solvent/Buffer Dual Ports for Solvent/Buffer AdditionAddition
Micro Magnetic Stirrer for Micro Magnetic Stirrer for CuvetteCuvette
Vent near top of cuvette to Vent near top of cuvette to equilibrate pressure from equilibrate pressure from evacuation and addition of evacuation and addition of liquids. liquids.
Obstacle: Controlling the Hach 2100N Turbidimeter
The Hach Turbidimeter was The Hach Turbidimeter was designed to be operated by designed to be operated by hand. A means had to be hand. A means had to be devised to remotely control devised to remotely control the machine by computer.the machine by computer.
Signals are taken directly Signals are taken directly from the Hach’s internal from the Hach’s internal Circuit Boards and routed to a Circuit Boards and routed to a 50 pin Connector.50 pin Connector.
Signals Pass out the Signals Pass out the connector to a ribbon cable connector to a ribbon cable and are connected to the and are connected to the Interface and Relay Boards.Interface and Relay Boards.
32 Channel Relay board is 32 Channel Relay board is used to simulate Manual used to simulate Manual Keypresses on the Hach, Keypresses on the Hach, automating tasks intended to automating tasks intended to be done by hand.be done by hand.
Obstacle: Controlling the Hach 2100N Turbidimeter
Design Requirements:Design Requirements:
Complete Computer Control of Complete Computer Control of Hach 2100N Turbidimeter by Hach 2100N Turbidimeter by Software, a machine designed to Software, a machine designed to be Operated only by Hand.be Operated only by Hand.
Interface Board with 40 Interface Board with 40 Operational Amplifiers Filters Operational Amplifiers Filters Signals from Hach Turbidimeter Signals from Hach Turbidimeter and Translates them into TTL and Translates them into TTL digital logic signals which are read digital logic signals which are read by a Data Acquisition Board.by a Data Acquisition Board.
Interface Board allows for Error Interface Board allows for Error and State Checking via Software, and State Checking via Software, something not possible with the something not possible with the original unit.original unit.
Obstacle: Keeping the Cuvette Clean
Previous Assay had Separate Mixing Chamber Previous Assay had Separate Mixing Chamber to which Compound was Added. Compound to which Compound was Added. Compound mixed in buffer would then be pumped into mixed in buffer would then be pumped into Hach Chamber for Reading.Hach Chamber for Reading.
Tars and “Gummy” Compounds would stick to Tars and “Gummy” Compounds would stick to the Mixing Chamber but not be pumped into the Mixing Chamber but not be pumped into the Cell in the Hach for Reading. Result, the Cell in the Hach for Reading. Result, Hach cell rarely got dirty but accuracy on Hach cell rarely got dirty but accuracy on some measurements suffered.some measurements suffered.
New Assay Delivers Compounds directly to the New Assay Delivers Compounds directly to the Cell in the Hach Turbidimeter. But the Cell Cell in the Hach Turbidimeter. But the Cell gets Dirty more often. Solution: More gets Dirty more often. Solution: More Aggressive Cleaning Methods ……….Aggressive Cleaning Methods ……….
Obstacle: Keeping the Cuvette CleanSolution:Solution:
Replace MeOH Rinse with DMSO, Replace MeOH Rinse with DMSO, DMSO Rinse works 85% of the DMSO Rinse works 85% of the Time.Time.
Additional Solvent used for Additional Solvent used for “difficult” compounds (tars & “difficult” compounds (tars & gums). Tried several formulations gums). Tried several formulations including DMA, Acetone, and other including DMA, Acetone, and other acids and bases. Cheap Glass acids and bases. Cheap Glass Cleaner was found to be the most Cleaner was found to be the most effective.effective.
Wash Cycle which mimics a Wash Cycle which mimics a washing machine is used for washing machine is used for compounds which leave residues compounds which leave residues difficult to remove. Wash cycle difficult to remove. Wash cycle utilizes both Solvents and lasts utilizes both Solvents and lasts approximately 20 minutes.approximately 20 minutes.
© 1999 Procter & Gamble© 1999 Procter & Gamble
Just how effective is this cleaning method ?
When the Baseline “creeps” upward the wash When the Baseline “creeps” upward the wash cycles beat it back down preserving sensitivity.cycles beat it back down preserving sensitivity.
Baseline Range Over Entire Experiment
0.08
0.085
0.09
0.095
0.1
0.105
0.11
0.115
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43
Sample Number
Bas
elin
e N
TU V
alue
Baseline:
High
Max
Obstacle: Termination of Cable to Syringe PumpsProblem: Line which carries signals to Syringe Pumps Problem: Line which carries signals to Syringe Pumps is long enough that reflections occur.is long enough that reflections occur.
Signals take time to propagate.Signals take time to propagate. Propagating Signals have energy.Propagating Signals have energy. All Wires have an inherent resistance, inductance and All Wires have an inherent resistance, inductance and
capacitance. Such parameters form the capacitance. Such parameters form the “characteristic impedance” (Z“characteristic impedance” (Z00) of the Transmission ) of the Transmission line.line.
If a line is short enough, the inherent resistance, If a line is short enough, the inherent resistance, inductance, and capacitance is small enough to be inductance, and capacitance is small enough to be ignored.ignored.
Ideally, the Load attached to the end of the line must Ideally, the Load attached to the end of the line must match the “characteristic impedance” (Zmatch the “characteristic impedance” (Z00) of the ) of the Transmission line, in which case the line is said to be Transmission line, in which case the line is said to be “matched”. Matching is accomplished through “matched”. Matching is accomplished through “termination”, which is adding a load which may be “termination”, which is adding a load which may be composed of inductors, capacitors, and resistors.composed of inductors, capacitors, and resistors.
Obstacle: Reflections on communication lines.
Without proper termination, energy reaching the end of a transmission line has nowhere to go, so it reflects back to the source. Just as a rubber ball will bounce off a solid surface.
Reflections can Imitate Legitimate Control Signals
Noise Imitation of a Legitimate Signal
-1
0
1
2
3
4
5
6
0 1 2 3 4 5 6 7
TIME
VOLT
AG
E
SignalNoiseClockVIL(CMOS)VIL(TTL)VIH(CMOS)VIH(TTL)
0.8V
1.3V
3.3V
3.7V
Solution: Termination of Cable to Syringe Pumps
Solution: “match” the line to the load so that reflections do Solution: “match” the line to the load so that reflections do not occur. RC termination was determined to be the best not occur. RC termination was determined to be the best solution.solution.
RC Network RC Network will act aswill act as
LPFLPF
c
1 133 kHz2
fRC
Obstacle: Valve Problems
Defective Valves Received from General Valve Corporation, pull in Defective Valves Received from General Valve Corporation, pull in Voltage exceeded that of ability of Driver to Actuate the Valve.Voltage exceeded that of ability of Driver to Actuate the Valve.
Prior Assay Drove Valves with +24VDC. Valves ran hot reducing Prior Assay Drove Valves with +24VDC. Valves ran hot reducing their life and possibly having unknown thermal effects on the their life and possibly having unknown thermal effects on the liquids that passed through them.liquids that passed through them.
Valves on New Assay Driven with Specified Valve Driver which Plugs Valves on New Assay Driven with Specified Valve Driver which Plugs into Custom Designed Board. Each Board contains 4 Valve Drivers into Custom Designed Board. Each Board contains 4 Valve Drivers which are independently fused. Valve Drivers can easily be replaced which are independently fused. Valve Drivers can easily be replaced in the event of Failure by simply plugging in a new module.in the event of Failure by simply plugging in a new module.
Obstacle: Firmware Incompatibility
• Kloehn Syringes used in Assays because they provide twice Kloehn Syringes used in Assays because they provide twice the precision as Cavro Syringe Pumps (48,000 steps vs. 24,000 the precision as Cavro Syringe Pumps (48,000 steps vs. 24,000 steps).steps).
• But Tecan RSP9000 series Robots are designed to be used But Tecan RSP9000 series Robots are designed to be used with Cavro Syringes. A Firmware (“a hardware timing problem”) with Cavro Syringes. A Firmware (“a hardware timing problem”) occurs when more than one Kloehn Syringe is connected to the occurs when more than one Kloehn Syringe is connected to the RS-485 bus off the RSP-9000 Robot. This problem has been RS-485 bus off the RSP-9000 Robot. This problem has been verified by Cavro’s Engineer Roger McIntosh.verified by Cavro’s Engineer Roger McIntosh.
• Solution: A new driver was written to control Multiple Syringe Solution: A new driver was written to control Multiple Syringe Pumps via an independent RS-485 Card plugged into an ISA Pumps via an independent RS-485 Card plugged into an ISA slot on the host computer. Handshaking is performed between slot on the host computer. Handshaking is performed between the Syringe Control Application, the Robotic Control the Syringe Control Application, the Robotic Control Application, and the Hach Instrument Control Application.Application, and the Hach Instrument Control Application.
Testing Performance of the New Assay:
First a standard had to be created which would First a standard had to be created which would add a known quantity of Turbidity (NTUs) with add a known quantity of Turbidity (NTUs) with each addition to the test solution (Heach addition to the test solution (H220) contained 0) contained within the cuvette.within the cuvette.
Formula (from Hach Manual):Formula (from Hach Manual):
2
1 Vol STD NTU Standard2 Vol H 0
Testing Performance of the New Assay:
Example: A single 1.0Example: A single 1.0µL addition of 1000NTU µL addition of 1000NTU solution to a cuvette with a total volume of 2.5 mL.solution to a cuvette with a total volume of 2.5 mL.
1 1 10002 2500
= 0.2 NTUs
3rd Generation Turbidimetric Solubility Assay
Based on 1.0 µL 1000 NTU additions into a 2.5mL cuvette:Based on 1.0 µL 1000 NTU additions into a 2.5mL cuvette:
Each addition causes a "jump" of .003 NTU on the display.Each addition causes a "jump" of .003 NTU on the display.
Each 1.0 µL addition causes a 0.2 NTU rise turbidity.Each 1.0 µL addition causes a 0.2 NTU rise turbidity.
(0.2 NTU) / 3 (0.2 NTU) / 3 0.066 NTU 0.066 NTU
A 0.001 change on the modified Hach 2100N Turbidimeter A 0.001 change on the modified Hach 2100N Turbidimeter represents an "actual" change of approximately 0.066 NTU’s. The represents an "actual" change of approximately 0.066 NTU’s. The variation from the “true” value is the result of using a square cuvette variation from the “true” value is the result of using a square cuvette instead of the circular test tube which the Hach Turbidimeter was instead of the circular test tube which the Hach Turbidimeter was designed to work with. designed to work with.
Revising the Hach 2100N Turbidimeter Specs
Revised Hach 2100N Turbidimeter Specifications:Revised Hach 2100N Turbidimeter Specifications:Measurement Displayed NTU Value True NTU ValueResolution 0.001 .066Repeatability ±0.003*±0.003* 0.2
Measurement Displayed NTU Value True NTU ValueResolution 0.001 N/ARepeatability ±0.01 or 1.0% > ±0.01 or 1.0% >
ofofN/A
**The standard deviation of each successive addition was 0.001 NTUs.The standard deviation of each successive addition was 0.001 NTUs.
Original Hach 2100N Turbidimeter Specifications:Original Hach 2100N Turbidimeter Specifications:
Repeatability: 1000 NTU Testing CV’s 1.4% ~ 1.84%
Eight 1.0 uL Additions of 1000 NTU Standard
0.080
0.085
0.090
0.095
0.100
0.105
0.110
0.115
BaseLine: 1 2 3 4 5 6 7 8
Addition Number
Ntu
Uni
ts
1
2
3
4
5
6
7
8
9
10
11
12
Mean
Testing Assay Performance on “Real” Compounds
““Ideal Conditions” - Compounds are diluted Ideal Conditions” - Compounds are diluted with DMSO, shaken, and run on G2483B and with DMSO, shaken, and run on G2483B and then then immediatelyimmediately run on G5143A - run on G5143A - slack time slack time between runs kept to a minimumbetween runs kept to a minimum..
““Non Ideal Conditions” - Compounds are Non Ideal Conditions” - Compounds are diluted with DMSO, shaken, and run on diluted with DMSO, shaken, and run on 2483B. Compounds then sit in racks 2483B. Compounds then sit in racks (diluted) for an indeterminate period of time (diluted) for an indeterminate period of time (days to several weeks) before being (days to several weeks) before being assayed again on G5143A. (Crystal Formation assayed again on G5143A. (Crystal Formation Possible).Possible).
Parallel Runs with Existing 2483B AssayParallel Runs with Existing 2483B Assay
Parallel Run (2483B Assay) “Ideal” Conditions
2 Assays (45 Compounds) Sensitivity Report
Less Sensitive0% More Sensitive
18%
No Difference82%
Parallel Run (2483B Assay) “Non-Ideal” Conditions
16 Assays (629 Compounds) Sensitivity Pie ChartLess Sensitive
14%More Sensitive
26%
No Difference60%
Although 40% of the compounds had a different solubility, more Although 40% of the compounds had a different solubility, more often than not (75%) the difference was only 5 - 10 µg/µL.often than not (75%) the difference was only 5 - 10 µg/µL.
Parallel Run (2483B Assay) “Non-Ideal” Conditions
Occurrences of Differing Solubility
0
50
100
150
200
250
300
350
400
-65
-55
-45
-35
-25
-15 -5 5 15 25 35 45 55 65
Difference ug/uL (New - Old) [+, G5143A more Sensitive]
Num
ber o
f Sam
ples
Series2
Series1
Repeatability: Midrange Solubility Variation g/L
Standard Error For MidRange Solubilities
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
GS-
0030
70
CP-
6479
54
CP-
6516
74-0
1
CP-
6496
56-0
1
CP-
6516
85
CP-
0000
48
CP-
1638
29-
BH
Compound number
Solu
bilit
y M
ax M
ean
Min
Tota
l Res
pons
e R
ange
MeanMaxMin
“Binning” the results – What do they mean?
Retrain Your ChemistsRetrain Your Chemists<15<15
>50>50
>15>15<50<50
Potential ProblemsPotential Problems
Drug Like MaterialDrug Like Material
Project Management Considerations for New Assays Control of Deliverables
What will be needed ? Who should supply it ? Can they Supply it on time ?
– “past performance is the single best predictor of future behavior”
Accommodation (to Infrastructure) What needs to be changed to bring this screen online ? Who will make these changes ? Can the changes be made within the specified time frame ? Will the changes be made within the specified time frame ?
Project Management Considerations Infrastructure Specific Compound Management
Does an Existing Method Exist for Compound Delivery ? Is the Sample Repository Currently Preparing Samples in the
desired format ? Turnaround Time Required ? Degradation & Stability Issues ?
– Crystal Formation– Solubility in Solvent (DMSO, MeOH, etc.)– Light Sensitivity
Information Transfer of Delivered Compounds ?– Files (xls, csv, txt, etc.)– Web based ?
Will “Backdoor” submissions be allowed ?– Flexibility vs. Conformity issues.– The best and brightest want their results NOW.– Such capability = More Work.
Project Management Considerations Software “The Big 3”
1. Controller Software for Hardware2. Data Analysis Software
Reports for Legal Notebooks Files for Database Uploading/Results Archival
3. Database Upload Software Drag and Drop Web Based File Loading
1. Who is going to write the software ?2. Compatibility Issues ?3. Outsourcing Concerns
Who Owns the source code ? What you know we know - and eventually so will your
competitors. No Vested Interest – It Just has to work upon Delivery.
Project Management Considerations Hardware
1. The Hardware must be designed.2. The Hardware must be prototyped (bread boarded).3. The Prototype must be tested.4. The Prototype must be Laid out using some form of
Hardware Design Tool such as schematic capture.5. The Physical Board must be routed.6. The Gerber Files must be generated and sent to a board
house for fabrication.1. Populated ?2. If Populated, Surface Mount Components ?
7. Does the manufactured Board still work? No – Goto Step 4!8. Common Reasons for Failure.
1. Poor Decoupling and/or Noise Issues.2. Timing Issues (Often Due to Trace Routing)3. Grounding Issues (Ground Loops, Lack of Ground Planes, etc.)
Project Management Considerations Sphere of Influence Prior to System Integration, the Software, Hardware,
Infrastructure, and Compound Management issues must be resolved.
In other words, your deliverables must be delivered. Delivered and Working. The “Sphere of Influence” a person can have will in all
probability not span the entire group of disciplines. Thus any resource required will need to be managed and
sufficiently motivated to deliver on time. Resources fall into two categories:
Those you have direct control over. (Groups and People under your direct supervision.)
Rewards, Motivation, and occasionally Punishment. Those you have limited control over. (Contractors and those
supervised by others.) Reasoning, Praise, and Coercion.
Project Management Considerations System Integration Murphy’s Law of Project Management: “All the pieces may
work perfectly separately, but they will never work together perfectly on the first try.”
System Integration is the art of getting all the components you so meticulously had designed to work in harmony together.
The single most difficult aspect of system integration is estimating an accurate time frame in which a working system can be developed.
This is because in a system of any complexity dependencies will exist, and should a redesign become necessary of any subsystem, its dependant components cannot be tested until the redesign is complete.
Great Project Management Blunders OSFA - One Size Fits All
“It fits my all, but something else is hanging out the back.”- Buddy Hackett
Example: A Pharmaceutical Company Creates a Research Database to store Global Data, yet it is initially modeled using only one type of screen.
Result: Screens with contain any differing parameters cannot have their data uploaded or retrieved until numerous revisions are made.
Great Project Management Blunders NIH – Not Invented Here
Example: A Pharmaceutical Company Creates an Automated Compound handling system from scratch using an industrial contractor rather than purchase a proven commercial compound handling system utilized by its largest competitors.
Result: The contractor was accustomed to working on inventory systems where a lag time of 3 days was sufficient for checking a part in or out of the system. As a result, in the original system, a compound could not be requested if it had been requested by any other lab 36 hours prior to the current request. This was unacceptable and resulted in costly fixes both in terms of redesign and wasted resources.
Project Management Considerations: Communication Many Project Management Failures are a result of poor
Communication. Communication Failures result from a variety of reasons
including: Information was missing Timing was poor Key people are absent Stress and Tension
Sobering Statistic “31% of all communications that occur in Operating Rooms could be categorized as a failure in some way and more than a third of these failures had negative effects on what was happening.”Source: “Communication failures in the operating room: an observational classification of recurrent types and effects.”
3rd Generation Turbidimetric Solubility Assay
Tecan RSP9000 Robotic Sample ProcessorTecan RSP9000 Robotic Sample Processor Kloehn 48,000 Step Syringe Pumps (3 per Assay)Kloehn 48,000 Step Syringe Pumps (3 per Assay) Hach 2100N Turbidimeter (Modified)Hach 2100N Turbidimeter (Modified) Keithley Metrabyte Metrabus Industrial Data Keithley Metrabyte Metrabus Industrial Data
Acquisition InterfaceAcquisition Interface Digital I/O Card (64 TTL Level Inputs/Outputs)Digital I/O Card (64 TTL Level Inputs/Outputs) 8 Channel High Current Relay Card8 Channel High Current Relay Card 32 Channel Standard Relay Card32 Channel Standard Relay Card
Custom Designed Interface CardsCustom Designed Interface Cards
Hardware Specifications:Hardware Specifications:
Acknowledgements
Molecular Properties Group:Dr. Christopher Lipinski – Adj. Senior Research FellowDr. Franco Lombardo – Associate Research FellowAndrea Bunger (Davis) – First Solubility AssayPaul Feeney – 2nd Generation Solubility AssayGus Campos – Molecular Properties GroupChris Caldwell – Molecular Properties GroupVictor Donahue Esq. – Pfizer Legal Dept. NYCStephen Gilbert Esq. – Bryan Cave LLP NYCThomas Freehill P.E. – Eastern CT MicroelectronicsRoger McIntosh – McIntosh Analytical Systems
Additional Resources - USPTO
United States Patent Application “Automated Kinetic Solubility Assay Apparatus and Method” Application Number 20040076546 Filed Oct 18 2002
