Continuous-flow, well mixed, microfluidic crystallization device for screening polymorphs, morphologies and crystallization kinetics at controlled supersaturation

Patent metadata

Field	Value
Publication number	US-12370463-B2
Application number	US-202017616761-A
Country	US
Kind code	B2
Filing date	Jun 5, 2020
Priority date	Jun 7, 2019
Publication date	Jul 29, 2025
Grant date	Jul 29, 2025

Abstract

The disclosure relates to a microfluidic system for the screening of polymorphs, morphology, and crystallization kinetics under well-mixed, continuous-flow at controlled supersaturations. The disclosure also relates to a method for screening crystalline polymorphs and morphology, and crystallization kinetics. The microfluidic system includes a microfluidic chamber having one or more inlets, a passive mixing zone, and a trap zone. The passive mixing zone promotes mixing of solvent, solute, and optionally antisolvent under stable, controlled levels of supersaturation. The trap zone similarly has stable, controlled levels of supersaturation and correspondingly low velocity to retain solute crystals formed in the trap zone for time-dependent evaluation.

First claim

What is claimed is:

1. A microfluidic system comprising: (a) a microfluidic chamber comprising: (i) a first inlet zone in fluid communication with a first inlet adapted to receive a first fluid stream comprising a solute dissolved in a solvent,
(ii) a second inlet zone in fluid communication with a second inlet adapted to receive a second fluid stream,
(iii) a passive mixing zone having (A) a first mixing zone boundary and (B) a second mixing zone boundary separate from the first mixing zone boundary, the passive mixing zone being in fluid communication with the first inlet zone via the first mixing zone boundary and the second inlet zone via the first mixing zone boundary, (iv) a trap zone having a trap zone boundary in fluid communication with the second mixing zone boundary, wherein the trap zone is positioned within the microfluidic chamber such that fluid flowing through the microfluidic chamber has a sufficiently low velocity, and configured to retain solute crystals formed in the trap zone within the trap zone, (v) an outlet zone in fluid communication (A) with the passive mixing zone via the first mixing zone boundary, and (B) an outlet adapted to discharge fluid from the microfluidic chamber, and
(vi) a first temperature control means configured to adjust the temperature of the first fluid stream to a first pre-selected value before entering the passive mixing zone.

2. The microfluidic system of claim 1 , wherein:
the microfluidic chamber further comprises a second temperature control means for adjusting the temperature of the second fluid stream to a second pre-selected value before entering the passive mixing zone.

3. The microfluidic system of claim 1 , further comprising: (b) a solvent reservoir in fluid communication with the first inlet zone via the first inlet, the solvent reservoir containing therein the solute dissolved in the solvent; and (c) an antisolvent reservoir in fluid communication with the second inlet zone via the second inlet, the antisolvent reservoir containing therein the antisolvent.

4. The microfluidic system of claim 1 , wherein the first temperature control means comprises a cooling apparatus configured to induce supersaturation and crystallization.

5. The microfluidic system of claim 1 , further comprising: (b) a solvent reservoir in fluid communication with the first inlet zone via the first inlet, the solvent reservoir containing therein the solute dissolved in the solvent.

6. The microfluidic system of claim 1 , wherein the microfluidic system is configured to provide substantially continuous, well-mixed flow for screening crystalline polymorphs and morphology in a supersaturated environment.

7. The microfluidic system of claim 1 , wherein the passive mixing zone is adapted to provide counter diffusion mixing, rotational mixing, oscillatory flow, or a combination thereof.

8. The microfluidic system of claim 7 , wherein the passive mixing zone is adapted to provide rotational mixing.

9. The microfluidic system of claim 8 , wherein:
the microfluidic chamber defines an internal volume having a central axis and a circular cross-section;
the passive mixing zone is positioned within an outer circumferential portion of the internal volume;
the trap zone is positioned at an inner axial portion of the internal volume;
the first inlet zone, the second inlet zone, and the outlet zone are positioned at an outer circumferential portion of the internal volume.

10. The microfluidic system of claim 9 , wherein the microfluidic chamber comprises:
a plurality of first inlet zones in fluid communication with a plurality of first inlets adapted to receive a plurality of first fluid streams each comprising a solute dissolved in a solvent; and
a plurality of first temperature control means for adjusting the temperature of the first fluid streams, when present, to a first pre-selected value before entering the passive mixing zone.

11. The microfluidic system of claim 10 , wherein the plurality of first inlet zones are circumferentially distributed around and tangentially aligned relative to the internal volume of the microfluidic chamber.

12. The microfluidic system of claim 9 , wherein the microfluidic chamber comprises:
a plurality of first inlet zones in fluid communication with a plurality of first inlets adapted to receive a plurality of first fluid streams each comprising a solute dissolved in a solvent; and
a plurality of second inlet zones in fluid communication with a plurality of second inlets adapted to receive a plurality of second fluid streams each comprising an antisolvent.

13. The microfluidic system of claim 12 , wherein the plurality of first inlet zones and the plurality of second inlet zones are circumferentially distributed around and tangentially aligned relative to the internal volume of the microfluidic chamber.

14. The microfluidic system of claim 7 , wherein the passive mixing zone is adapted to provide counter diffusion mixing.

15. The microfluidic system of claim 1 , wherein the microfluidic chamber is sized and shaped to provide unmonitored polymorph screening.

16. The microfluidic system of claim 15 , wherein the system is adapted to provide an autostop mechanism during the screening process.

17. The microfluidic system of claim 1 , wherein the microfluidic chamber is characterized by a Stokes number of less than 1.

18. The microfluidic system of claim 1 , wherein the trap zone is not in direct fluid communication with the outlet zone.

19. The microfluidic system of claim 1 , comprising a plurality of microfluidic chambers, wherein the inlets and outlet(s) of each microfluidic chamber are adapted to be selectively operated at controlled conditions to vary the supersaturation in each microfluidic chamber to facilitate high throughput screening of crystal formation under different conditions.

20. The microfluidic system of claim 1 , further comprising a sensor for detecting one or parameters of the microfluidic system selected from the group consisting of solute concentration, a fluid stream temperature, a fluid stream flow rate, and combinations thereof.

21. The microfluidic system of claim 1 , wherein the microfluidic chamber further comprises a membrane positioned between (A) the outlet zone and (B) the first inlet zone and the second inlet zone, when present.

22. The microfluidic system of claim 1 , wherein the microfluidic chamber further comprises a patterned surface adapted to promote nucleation of crystals.

23. The microfluidic system of claim 1 , wherein the microfluidic chamber further comprises a check valve adapted to permit (i) one-way flow of fluid from the first inlet into the first inlet zone and (ii) one-way flow of fluid from the second inlet into the second inlet zone, when present.

24. The microfluidic system of claim 1 , wherein the microfluidic chamber is sized and shaped to provide a microtiter plate insert.

25. A method for screening crystalline polymorphs and morphology, the method comprising:
(a) providing the microfluidic system of claim 1 ;
(b) introducing a first fluid stream comprising a solute dissolved in a solvent at a first flow rate and a first temperature into the first inlet zone;
(c) optionally, introducing a second fluid stream at a second flow rate and a second temperature in the second inlet zone; and
(d) adjusting at least one of the first flow rate, the first temperature, the second flow rate, and the second temperatu

Assignees

• Univ Illinois

Inventors

• Singh Meenesh R
• Coliaie Paria

Classifications

• B01L2400/0605

  check valves · CPC title

• B01L2300/18

  Means for temperature control · CPC title

• B01L2300/0663

  Whole sensors · CPC title

• B01L2200/16

  Reagents, handling or storing thereof · CPC title

• B01L3/502715 Primary

  characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces · CPC title