Crystallisation of chemical molecules

Patent metadata

Field	Value
Publication number	US-11781239-B2
Application number	US-202017616920-A
Country	US
Kind code	B2
Filing date	Jun 11, 2020
Priority date	Jun 11, 2019
Publication date	Oct 10, 2023
Grant date	Oct 10, 2023

Abstract

This invention relates to a method of forming crystals of chemical molecules. The methods are effective even when only very small amounts of a compound are available and can be used to explore the experimental crystallisation space including screening for optimal crystallisation conditions such as for polymorphic phases, salts, solvates and co-crystals of chemical molecules and to provide single crystals for structural determination of unknown molecules by single crystal X-ray crystallography.

First claim

The invention claimed is:

1. A method forming a crystal of a chemical molecule or a salt thereof, the method comprising:
a) forming a droplet, the droplet comprising a first liquid and a second liquid; wherein the first liquid comprises the chemical molecule or a salt thereof dissolved in an organic medium; and the second liquid is an oil; and
b) allowing a crystal comprising the chemical molecule to form in the droplet.

2. A method of claim 1 , wherein the chemical molecule is an organic molecule.

3. A method of claim 1 , wherein the chemical molecule is a small molecule.

4. A method of claim 1 , wherein the organic medium comprises at least one organic solvent.

5. A method of claim 4 wherein the total amount of organic solvent is greater than 75% by volume of the organic medium.

6. A method of claim 1 , wherein at least one organic solvent in the organic medium has a boiling point greater than 80° C.

7. A method of claim 6 wherein at least one organic solvent in the organic medium has a boiling point greater than 125° C.

8. A method of claim 1 , wherein the first liquid comprises less than 1 mg of the organic molecule, or salt thereof.

9. A method of claim 8 , wherein the first liquid comprises less than 100 μg of the organic molecule, or salt thereof.

10. A method of claim 1 , wherein the total volume of the first liquid in the droplet may be less than 1 μL.

11. A method of claim 10 , wherein the total volume of the first liquid in the droplet may be less than 200 nL.

12. A method of claim 1 , wherein the oil is a perfluorinated oil.

13. A method of claim 1 , wherein in the droplet, the second liquid forms a coating over the first liquid.

14. A method of claim 13 , wherein the second liquid encapsulates the first liquid.

15. A method of claim 1 , wherein the ratio first liquid:second liquid is in the range from 2:1 to 1:20 by volume.

16. A method of claim 1 , wherein the droplet is a sitting droplet.

17. A method of claim 1 , wherein the droplet is a hanging droplet.

18. A method of claim 1 , wherein the droplet is formed by first forming a droplet of the second liquid and then injecting the first liquid into the second liquid to form the droplet.

19. A method of claim 1 , wherein step b) is conducted in the presence of an antisolvent.

20. A method of claim 1 , wherein the surface on which the droplet is formed is a well of a multi-well plate.

21. A method of claim 1 , wherein the method comprises the steps:
recovering a crystal; and
performing single crystal X-ray crystallography on the crystal.

22. A method of determining the structure of a chemical molecule, or salt thereof, the method comprising:
forming a plurality of droplets according to claim 1 ;
allowing crystals to form from said plurality of droplets;
looking for signs of crystal formation;
recovering any crystal that are formed;
performing single crystal X-ray crystallography on the crystal that are formed; and
using the results of the single crystal X-ray crystallography to determine the structure of the chemical molecule, or salt thereof.

23. A method of screening for polymorphs of a chemical molecule, or salt thereof, the method comprising:
forming a plurality of droplets according to claims 1 ;
allowing crystals to form from said plurality of droplets;
looking for signs of crystal formation;
recovering any crystal that are formed;
performing single crystal X-ray crystallography on the crystal that are formed; and
optionally, comparing the results of the single crystal X-ray crystallography for each crystal to the results of the single crystal X-ray crystallography for each other crystal and/or to known polymorphic forms of the chemical molecule or salt thereof;
wherein at least two of the plurality droplets are different.

24. A method of claim 22 , wherein each droplet is formed in a respective well of a multiwall plate.

25. A method of claim 22 , wherein the plurality of droplets may each be different.

Assignees

• Univ Newcastle

Inventors

• Hall Michael
• Probert Michael
• Tyler Andrew

Classifications

• C30B7/06 Primary

  using non-aqueous solvents · CPC title

• B01D9/0054

  Use of anti-solvent · CPC title

• B01D9/0077 Primary

  Screening for crystallisation conditions or for crystal forms · CPC title

• C30B29/58

  Macromolecular compounds · CPC title

• C30B7/00 Primary

  Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions (from molten solvents C30B9/00; by normal or gradient freezing C30B11/00; under a protective fluid C30B27/00) · CPC title