Scale-up methods and systems for performing the same

• US 20060024751A1
• Filed: 06/03/2005
• Published: 02/02/2006
• Est. Priority Date: 06/03/2004
• Status: Abandoned Application

• Current Assignee: Fluidigm Corporation
• Original Assignee: Fluidigm Corporation
• Inventors: May, Andy, Nassef, Hany R.
• Application Number:
  US11/145,892
• Publication Number:
  US 20060024751A1
• Time in Patent Office: Days
• US Class Current: 435/7.100
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00315 Microtiter plates
• CPC Class Codes: B01J 2219/00477 Means for pressurising the reaction vessels
• CPC Class Codes: B01J 2219/00495 Means for heating or cooling the reaction vessels
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/00599 Solution-phase processes
• CPC Class Codes: B01J 2219/00695 Synthesis control routines, e.g. using computer programs
• CPC Class Codes: B01J 2219/00698 Measurement and control of process parameters
• CPC Class Codes: B01J 2219/00756 Compositions, e.g. coatings, crystals, formulations
• CPC Class Codes: G01N 2035/00207 Handling bulk quantities of analyte
• CPC Class Codes: G01N 2035/00237 Handling microquantities of analyte, e.g. microvalves, capillary networks
• CPC Class Codes: G16C 20/10 Analysis or design of chemical reactions, syntheses or processes

Abstract

The present invention provides methods of and systems for translating conditions from a small-volume experiment to a larger-volume experiment.

Claims

1. A method of translating conditions from a small-volume to a larger-volume comprising:

(a) identifying one or more first test level(s) of one or more variable(s) that produce a first performance characteristic in a small volume;

(b) adjusting one or more level with an adjustment factor which factor which is based on the first performance characteristic produced in the small volume and the volume differences between the small volume and the larger volume;

thereby producing one or more second test level(s) of one or more variable(s) for producing a second performance characteristic in a larger volume.

3. The method of claim 1 further comprising:

performing a plurality of experiments that vary one or more test level(s) of one or more variable(s) to produce a performance characteristic.

4. A method of claim 1, wherein the ratio of the small-volume to large volume is from about 1:

10 to about 1;

1000.

5. A method of claim 1, wherein the small-volume is at most about 70 nanoliters and the larger-volume is at least about 75 nanoliters.

6. The method of claim 3, wherein said experiments are conducted in a device selected from the group consisting of a larger-volume device and a small-volume device.

7. The method of claim 6, wherein said device is a microfluidic device comprising a plurality of chambers.

8. The method of claim 6, wherein said large-volume device is selected from the group consisting of a microtiter plate, a vapor diffusion plate, a microbatch plate, a microdialysis chamber and a capillary tube.

9. The method of claim 1, wherein the test level is a concentration of a variable or a rate relating to a variable.

2. A method of producing a product in a large-volume comprising:

(a) identifying one or more test level(s) of one or more variable(s) in a small volume that produce a first performance characteristic;

(b) adjusting one or more test level(s) with an adjustment factor which is based on the first performance characteristic produced in the small volume and the volume difference between the small volume and a larger volume;

thereby producing one or more second test level(s) of one or more variable(s);

(c) producing a product using said second test level(s) in a larger-volume.

10. A method of formulating an adjustment factor for translating conditions from a small-volume to a larger-volume comprising:

(a) identifying one or more test level(s) of one or more variables that produce a first performance characteristic in a small volume for further analysis;

(b) identifying one or more test level(s) of one or more variables that produce a second performance characteristic in a large volume for further analysis;

(c) forming an analytical model for obtaining optimum values of the performance characteristic using the identified test levels of variables; and

(e) formulating an adjustment factor using the analytical model.

11. The method of claim 10, wherein the values are obtained from a plurality of experiments that vary one or more test level(s) of one or more variable(s) to produce a performance characteristic.

12. A method of translating crystallization conditions from a small-volume experiment to a larger-volume experiment comprising:

(a) identifying one or more first test level(s) of one or more variable(s) that produce a first crystal property in the small volume;

(b) adjusting one or more test level with an adjustment factor which factor which is based on the first performance characteristic produced in the small volume and the volume differences between the small volume and the larger volume;

thereby producing one or more second test level(s) for producing a second crystal property in a larger volume.

14. A method of claim 12, wherein the test level of a variable is selected from the group consisting of crystallization compound concentration, a precipitation reagent concentration, a pH modifying agent concentration, a salt concentration, a crystallization compound diffusion rate, a crystallization compound nucleation rate, a precipitation reagent diffusion rate, a pH modifying agent diffusion rate, a salt diffusion rate, and combinations thereof.

15. A method of claim 12, wherein the crystal property is selected from the group consisting of crystal density, crystal quality, crystal morphology, crystal size, and combinations thereof.

16. A method of claim 15, wherein the crystal density is selected from the group consisting of low density, medium density and high density;

the crystal quality is selected from the group consisting of low quality, medium quality and high quality.

17. A method of claim 16, wherein when crystals of low density and medium quality are produced in the small-volume said adjusting is selected from the group consisting of:

a) adjusting the salt concentration in the higher volume experiment to a concentration in the range of about 50% to about 100% of the concentration from the low-volume experiment;

b) adjusting the precipitation reagent concentration in the higher volume experiment to a concentration in the range of about 75% to 100% of the concentration from the low-volume experiment; and

c) adjusting the pH in the high volume experiment in increments of 0.5 pH units of the pH of the low-volume experiment.

18. A method of claim 17, wherein when crystals of low density and medium quality are produced in the small-volume said adjusting is selected from the group consisting of;

a) adjusting the precipitation reagent concentration in the higher volume experiment to a concentration in the range of about 90% to 100% of the concentration from the low-volume experiment; and

b) adjusting the pH in the high volume experiment in increments of 0.5 pH units from the pH of the low-volume experiment.

19. A method of claim 16, wherein when crystals of medium density and medium quality are produced in the small-volume said adjusting is selected from the group consisting of;

a) adjusting the salt concentration in the higher volume experiment to a concentration in the range of about 50% to about 100% of the concentration from the low-volume experiment;

b) adjusting the precipitation reagent concentration in the higher volume experiment to a concentration in the range of about 60% to 90% of the concentration from the low-volume experiment; and

c) adjusting the pH in the high volume experiment in increments of 0.5 pH units of the pH of the low-volume experiment.

20. A method of claim 19, wherein when crystals of medium density and medium quality are produced in the small-volume said adjusting is selected from the group consisting of;

a) adjusting the precipitation reagent concentration in the higher volume experiment to a concentration in the range of about 70% to 90% of the concentration from the low-volume experiment; and

b) adjusting the pH in the high volume experiment in increments of 0.5 pH units of the pH of the low-volume experiment.

21. A method of claim 16, wherein when crystals of high density and medium quality are produced in the small-volume said adjusting is selected from the group consisting of;

a) adjusting the salt concentration in the higher volume experiment to a concentration in the range of about 25% to about 75% of the concentration from the low-volume experiment;

b) adjusting the precipitation reagent concentration in the higher volume experiment to a concentration in the range of about 40% to 85% of the concentration from the low-volume experiment; and

c) adjusting the pH in the high volume experiment in increments of 0.5 pH units of the pH of the low-volume experiment.

22. A method of claim 21, wherein when crystals of high density and medium quality are produced in the small-volume said adjusting is selected from the group consisting of;

a) adjusting the salt concentration in the higher volume experiment to a concentration in the range of about 75% of the concentration from the low-volume experiment;

b) adjusting the precipitation reagent concentration in the higher volume experiment to a concentration in the range of about 55% to 85% of the concentration from the low-volume experiment; and

c) adjusting the pH in the high volume experiment in increments of 0.5 pH units of the pH of the low-volume experiment.

23. A method of claim 16, wherein when crystals of low density and high quality are produced in the small-volume said adjusting is selected from the group consisting of;

a) adjusting the salt concentration in the higher volume experiment to a concentration in the range of about 80% to about 100% of the concentration from the low-volume experiment; and

b) adjusting the precipitation reagent concentration in the higher volume experiment to a concentration in the range of about 70% to 100% of the concentration from the low-volume experiment.

24. A method of claim 23, wherein when crystals of low density and high quality are produced in the small-volume the precipitation reagent concentration in the higher volume experiment is adjusted to a concentration in the range of about 85% to 100% of the concentration from the low-volume experiment.

25. A method of claim 16, wherein when crystals of medium density and high quality are produced in the small-volume said adjusting is selected from the group consisting of;

a) adjusting the salt concentration in the higher volume experiment is adjusted to a concentration in the range of about 70% to about 100% of the concentration from the low-volume experiment; and

b) adjusting the precipitation reagent concentration in the higher volume experiment is adjusted to a concentration in the range of about 45% to 100% of the concentration from the low-volume experiment.

26. A method of claim 25, wherein when crystals of medium density and high quality are produced in the small-volume the precipitation reagent concentration in the higher volume experiment is adjusted to a concentration in the range of about 70% to 100% of the concentration from the low-volume experiment.

27. A method of claim 16, wherein when crystals of high density and high quality are produced in the small-volume said adjusting is selected from the group consisting of;

a) adjusting the salt concentration in the higher volume experiment to a concentration in the range of about 60% to about 100% of the concentration from the low-volume experiment; and

b) adjusting the precipitation reagent concentration in the higher volume experiment to a concentration in the range of about 30% to 100% of the concentration from the low-volume experiment.

28. A method of claim 27, wherein when crystals of high density and high quality are produced in the small-volume the precipitation reagent concentration in the higher volume experiment is adjusted to a concentration in the range of about 50% to 100% of the concentration from the low-volume experiment.

13. A method of producing an x-ray quality crystal comprising:

(a) identifying one or more first test level(s) of one or more variable(s) that produce a first crystal property in a small-volume;

(b) adjusting one or more test level(s) with an adjustment factor which is based on the first crystal property produced in the small volume experiment and the volume difference between the small volume experiment and the larger volume experiment;

(c) producing a x-ray quality crystal using said second test level(s) in a larger-volume.

29. A computer implemented method of translating conditions from a small-volume to a larger-volume comprising:

(a) identifying one or more test level(s) of one or more variables that produce a first performance characteristic in a small volume for further analysis;

(b) identifying one or more test level(s) of one or more variables that produce a second performance characteristic in a large volume for further analysis;

(c) recording the values of the test levels, variables and performance characteristics at a particular volume;

(d) forming an analytical model for obtaining optimum values using the recorded values; and

(e) formulating an adjustment factor using the analytical model thereby producing a second set of test levels for producing a second performance characteristic in a larger volume.

30. The method of claim 29, wherein the recording is done in a database.

31. The method of claim 29, wherein the values are obtained from a plurality of experiments that vary one or more test level(s) of one or more variable(s) to produce a performance characteristic.

32. The method of claim 31 wherein the experiments are protein crystallization screening assays.

33. A database formed by the method according to claim 29.

34. A system comprising:

a database of claim 33 and

a computer apparatus having access to said database capable of analyzing the outcome of small-volume and larger volume experiments.

35. A system of claim 34, wherein the system is in communication with an automated crystal detection imaging system.

36. A system of claim 34, wherein the database is in communication with a robotic liquid dispensing system capable of preparing or dispensing new test values of variables.

37. A method for using the system of claim 34 comprising:

(a) identifying in the database one or more test level(s) of one or more variable(s) in a small volume using the computer;

(b) obtaining one or more second test level(s) of one or more variable(s) for a larger-volume;

(c) producing a product using said second test level(s) in a larger-volume.