METHODS FOR REACTIVE CRYSTALLISATION

Abstract

There is described a method of preparing solid particles of a material, said method comprising controlling provision of a first liquid phase, wherein said first liquid phase comprises a solution of a first material through a membrane, said membrane defining a plurality of pores; and controlling provision of a second liquid phase, wherein said second liquid phase comprises a solution of a second material; reacting the first a second materials to produce a third liquid phase comprising a solution of a third material; and supersaturating the third liquid phase to form solid particles of the third material.

Claims

1. A method of preparing solid particles of a material, said method comprising controlling provision of a first liquid phase, wherein said first liquid phase comprises a solution of a first material through a membrane, said membrane defining a plurality of pores; and controlling provision of a second liquid phase, wherein said second liquid phase comprises a solution of a second material; reacting the first a second materials to produce a third liquid phase comprising a solution of a third material; and supersaturating the third liquid phase to form solid particles of the third material.

2. A method of preparing solid particles of a material, said method comprising controlling provision of a first liquid phase, wherein said first liquid phase comprises a solution of a first material, in a first flow direction to a membrane, said membrane defining a plurality of pores; and controlling provision of a second liquid phase, wherein said second liquid phase comprises a solution of a second material; introduction of the second liquid phase being substantially perpendicular to the introduction of the first liquid phase; reacting the first and second materials to produce a third liquid phase comprising a solution of a third material; and supersaturating the third liquid phase to form solid particles of the third material.

3. A method according to claim 1 wherein the method comprises reactive preparation of solid particles of a material in crystalline form or amorphous form, or a combination thereof.

4. (canceled)

5. (canceled)

6. A method of reactive preparation of solid particles of a third material, said method comprising reacting a first liquid phase with a second liquid phase by dispersing the first liquid phase in the second liquid phase; wherein said first liquid phase comprises a solution of a first material and said second liquid phase comprises a solution of a second material; said method comprising controlling provision of the first liquid phase in a first flow direction to a membrane, said membrane defining a plurality of pores; and controlling provision of the second liquid phase to the membrane in a crossflow (AXF) to the first flow direction, via the plurality of pores, to reactively form a solution of a third material; and optionally supersaturating the solution of the third material in order to produce particles of the third material.

7. A method according to claim 6 wherein the crossflow of the second liquid phase is at an angle of 90 degrees to the flow direction of the first liquid phase, plus or minus 45 degrees.

8. (canceled)

9. (canceled)

10. A method according to claim 1 wherein the method comprises preparing solid particles of more than one material, e.g. as co-crystals, comprising two or more components.

11. A method according to claim 1 wherein the prepared reactive solution (i.e. after reaction) includes one or more dissolved materials wherein the dissolved materials include one or more organic compounds, which may include, for example, pharmaceutically active compounds, bioactive agents, nutraceuticals, polymers and the like; metal-organic frameworks; or inorganic materials.

12.-14. (canceled)

15. A method of according to claim 1 wherein the method comprises the reactive preparation of solid amorphous particles of a material.

16. A method according to claim 1 wherein the dissolved prepared material (i.e. after reaction) comprises a material of low solubility.

17. A method according to claim 1 wherein the prepared reacted solution (i.e. after reaction) includes a dissolved material, wherein the material comprises one or more organic compounds, the one or more organic compounds comprising pharmaceutically active compounds or drugs, bioactive agents, nutraceuticals, polymers and the like.

18. (canceled)

19. A method according to claim 1817 wherein the solution comprises a pharmaceutically active compound of low bioavailability.

20. (canceled)

21. A method according to claim 1 wherein the prepared reacted solution (i.e. after reaction) include a dissolved material, wherein the material is an inorganic material.

22. (canceled)

23. (canceled)

24. A method according to claim 1 wherein the apparatus includes an insert.

25-35. (canceled)

36. A method according to claim 1 wherein the crossflow apparatus comprises a plurality of tubular membranes.

37. (canceled)

38. A method according to claim 14 wherein a plurality of membranes is grouped as a cluster of membranes positioned alongside each other.

39.-42. (canceled)

43. A method according to claim 1 wherein the membrane pores are laser drilled.

44.-47. (canceled)

48. A method according to claim 16 wherein the interpore distance is from about 1 m to about 5,000 m.

49. A method according to claim 16 wherein the surface porosity of the membrane may be from about 0.001% to about 20% of the surface area of the membrane.

50.-55. (canceled)

56. A method according to claim 81 wherein the furcation plate is a bi-furcation plate or a tri-furcation plate.

57.-67. (canceled)

68. A reactive crystallisation apparatus for reactively dispersing a first phase in a second phase, comprising: a membrane defining a plurality of apertures connecting a first liquid phase, wherein said first liquid phase comprises a solution of a first material, on a first side of the membrane; to a second liquid phase, wherein said second liquid phase comprises a solution of a second material, on a second different side of the membrane; the apparatus being adapted to generate a reactive mixture through egression of the first liquid phase into the second liquid phase via the plurality of apertures; the apparatus also comprising a reaction chamber arranged to receive the first and second liquid phases and/or the reactive mixture from the membrane.

69.-73. (canceled)

Description

[0116] The present invention will now be described by way of example only with reference to the accompanying figures in which:

[0117] FIG. 1(a) illustrates the particle diameters for CaSO.sub.4.Math.2H.sub.2O via batch crystallisation;

[0118] FIG. 1(b) illustrates the particle diameters for CaSO.sub.4.Math.2H.sub.2O via reactive crystallisation using AXF mini;

[0119] FIG. 1(c) illustrates microscopic images for reactively crystallised CaSO.sub.4.Math.2H.sub.2O (100 magnification);

[0120] FIG. 1(d) illustrates FTIR spectra for reactive crystallised CaSO.sub.4.Math.2H.sub.2O (*) with vibrational peaks in the spectrum matching those of the reference CaSO.sub.4.Math.2H.sub.2O (A) obtained from NIST;

[0121] FIG. 1(e) illustrates X-ray diffraction patterns of S-1) batch reactive crystallisation of CaSO.sub.4.Math.2H.sub.2O, S-2) AXF-mini reactive crystallisation of CaSO.sub.4.Math.2H.sub.2O;

[0122] FIG. 2 illustrates particle diameters for CaHPO.sub.4.Math.2H.sub.2O crystallisation using batch reactive crystallisation;

[0123] FIG. 3(a) illustrates particle diameters for CaHPO.sub.4.Math.2H.sub.2O crystallisation using AXF-mini stoichiometric reactive crystallisation with CP:DP at 5:1 ml/min;

[0124] FIG. 3(b) illustrates microscopic images for reactive crystallised CaHPO.sub.4.Math.2H.sub.2O (100 magnification);

[0125] FIG. 3(c) illustrates FTIR spectra for reactive crystallised CaHPO.sub.4.Math.2H.sub.2O (*) with vibrational peaks in the spectrum matching those of the reference CaHPO.sub.4.Math.2H.sub.2O () obtained from NIST;

[0126] FIG. 4(a) illustrates particle diameters for CaHPO.sub.4.Math.2H.sub.2O crystallisation using AXF-mini via non-stoichiometric reactive crystallisation with CP:DP at 10:0.5 ml/min;

[0127] FIG. 4(b) illustrates microscopic images of CaHPO.sub.4.Math.2H.sub.2O crystals from reactive crystallisation using AXF-mini via non-stoichiometric reaction with CP:DP 10:0.5 ml/min (100 magnification). Initial images show amorphous CaHPO.sub.4.Math.2H.sub.2O crystals with stirring causing crystalline CaHPO.sub.4.Math.2H.sub.2O crystals to form;

[0128] FIG. 4(c) illustrates FTIR spectra of amorphous and crystalline CaHPO.sub.4.Math.2H.sub.2O from reactive crystallisation using AXF mini (non-Stoichiometric reaction concentrations);

[0129] FIG. 5(a) illustrates particle diameters for CaHPO.sub.4.Math.2H.sub.2O crystallisation using AXF-mini via stoichiometric reactive crystallisation with CP:DP at 10:0.5 ml/min;

[0130] FIG. 5(b) illustrates microscopic images of CaHPO.sub.4.Math.2H.sub.2O crystals from reactive crystallisation using AXF-mini via stoichiometric reaction with CP:DP 10:0.5 ml/min (100 magnification). Initial images show amorphous CaHPO.sub.4.Math.2H.sub.2O crystals with stirring causing crystalline CaHPO.sub.4.Math.2H.sub.2O crystals to form;

[0131] FIG. 5(c) illustrates particle diameters for CaHPO.sub.4.Math.2H.sub.2O crystallisation using AXF-mini via stoichiometric reactive crystallisation with CP:DP at 10:0.5 ml/min;

[0132] FIG. 5(d) illustrates microscopic images for amorphous CaHPO.sub.4.Math.2H.sub.2O from stoichiometric reactive crystallisation using AXF mini (100 magnification);

[0133] FIG. 5(e) illustrates X-ray diffraction patterns of P-1) batch reactive crystallisation of CaHPO.sub.4.Math.2H.sub.2O, P-2) LDC-1 reactive crystallisation of CaHPO.sub.4.Math.2H.sub.2O, P-3) AXF-mini reactive crystallisation of amorphous non-stoichiometric Ca.sub.5(PO.sub.4).sub.3OH, P-4) AXF-mini reactive crystallisation of crystalline non-stoichiometric CaHPO.sub.4.Math.2H.sub.2O, P-5) AXF-mini reactive crystallisation of amorphous stoichiometric CaHPO.sub.4.Math.2H.sub.2O, P-6) AXF-mini reactive crystallisation of crystalline stoichiometric CaHPO.sub.4.Math.2H.sub.2O;

[0134] FIG. 6(a) illustrates particle diameters for CaCO.sub.3 from batch reactive crystallisation;

[0135] FIG. 6(b) illustrates particle diameters for CaO.sub.3 using AXF-mini reactive crystallisation;

[0136] FIG. 6(c) illustrates microscopic images for reactively crystallised CaCO.sub.3 (400 magnification);

[0137] FIG. 6(d) illustrates FTIR spectra for reactive crystallised CaCO.sub.3 (*) with vibrational peaks in the spectrum matching those of the reference CaCO.sub.3 () obtained from NIST;

[0138] FIG. 6(e) illustrates particle diameters for CaCO.sub.3 from reactive crystallisation using AXF-1 with flow rates of 250:50 ml/min using 10200 m membrane and inserts of 9.5, 9.7 and 9.8 mm; and

[0139] FIG. 6(f) illustrates X-ray diffraction patterns of C-1) batch reactive crystallisation of CaO.sub.3 calcite and vaterite mixture, C-2) AXF-mini reactive crystallisation of CaO.sub.3 calcite and vaterite, C-3) AXF-1 with 9.5 mm insert reactive crystallisation of CaO.sub.3 calcite and vaterite, C-4) AXF-1 with 9.7 mm insert reactive crystallisation of CaO.sub.3 calcite, C-5) AXF-1 with 9.8 mm insert reactive crystallisation of CaO.sub.3 calcite.

[0140] As a case study the formation of CaSO.sub.4.Math.2H.sub.2O, CaHPO.sub.4.Math.2H.sub.2O and CaCO.sub.3 has been carried out.

[0141] CaSO.sub.4.Math.2H.sub.2O, CaHPO.sub.4.Math.2H.sub.2O and CaCO.sub.3 are all readily used in the pharmaceutical industry as excipients (inactive ingredient). Good size and CSD control makes the blending and mixing with Active Pharmaceutical Ingredients (APIs) better as well as the general particle handling process.

[0142] Other applications of these materials include, but shall not be limited to: [0143] CaSO.sub.4.Math.2H.sub.2Oconstruction materials, fertilizers, dentistry fillers; [0144] CaHPO.sub.4.Math.2H.sub.2Otreatment of wastewater and polluted soil, source of calcium and phosphorus, high-end nutrients; and [0145] CaCO.sub.3fillers in adhesives and sealants, plastics, paper manufacturing, paints and inks, catalysts and gas filters.

[0146] Inorganic reactive crystallisation studies were conducted with the following reactions: [0147] CaCl.sub.2+Na.sub.2SO.sub.4.fwdarw.CaSO.sub.4.Math.2H.sub.2O+2NaCl [0148] CaCl.sub.2)+NaH.sub.2PO.sub.4.Math.2H.sub.2O.fwdarw.CaHPO.sub.4.Math.2H.sub.2O+NaCl+HCl+2H.sub.2O [0149] CaCl.sub.2+Na.sub.2CO.sub.3.fwdarw.CaCO.sub.3+2NaCl

[0150] All reactions were carried out in aqueous conditions and based on solubility. For example, CaCl.sub.2, Na.sub.2SO.sub.4, NaH.sub.2PO.sub.4.Math.2H.sub.2O, Na.sub.2CO.sub.3, NaCl and HCl are all soluble in water. CaSO.sub.4.Math.2H.sub.2O, CaHPO.sub.4.Math.2H.sub.2O and CaCO.sub.3 are all poorly soluble in water.

Example 1

CaSO.sub.4.Math.2H.sub.2O Crystallisation

[0151] Reactive crystallisation was conducted via a standard batch process then in a mini-crossflow membrane emulsification apparatus (AXF mini). This had the continuous phase (CP) and dispersed phase (DP) contain the reagents that would undergo reactive crystallisation towards CaSO.sub.4.Math.2H.sub.2O. This was compared to a batch reactive crystallisation process to observe the benefits of the crossflow membrane methodology.

1.1 Batch Run

[0152] 14 V stirrer, 10 ml/min rate [0153] DP CaCl.sub.2)/DI water 0.100 g/ml, 10 ml added [0154] CP Na.sub.2SO.sub.4/Di water 0.0256 g/ml, 50 ml total [0155] Flux 1842.2 ml/min/cm2, Shear 24.577 Pa

1.2 AXF-Mini Run

[0156] 5100 m membrane, 9.8 mm [0157] Flow rates-CP 5 ml/min, DP 1 ml/min [0158] Pore Velocity (m/s)=0.0270, Annulus Velocity (m/s)=0.0268 [0159] Momentum Flux Ratio=1.02, Re (annulus)=5.36

[0160] The results are provided in FIGS. 1(a) to 1(e).

[0161] FTIR spectroscopy and X-ray diffraction analysis show reactive crystallisation of CaSO.sub.4.Math.2H.sub.2O has been successful using both batch and continuous AXF-mini runs. Particle size analysis shows the AXF-mini apparatus has reduced the size of the crystals.

Example 2

CaHPO.sub.4.Math.2H.sub.2O Crystallisation

[0162] Reactive crystallisation was conducted via a standard batch process than in a mini-crossflow membrane emulsification apparatus (AXF mini). This had the continuous phase (CP) and dispersed phase (DP) contain the reagents that would undergo reactive crystallisation towards CaHPO.sub.4.Math.2H.sub.2O. This was compared to a batch reactive crystallisation process to observe the benefits of the crossflow membrane methodology.

2.1 Batch Process

[0163] DP CaCl.sub.2)/DI water 0.100 g/ml, 10 ml added [0164] CP NaH.sub.2PO.sub.4.Math.2H.sub.2O/Di water 0.0281 g/ml, 50 ml total [0165] Flux 1842.2 ml/min/cm2, Shear 24.577 Pa

[0166] NoteCP solution was raised to pH=6.51 with 4M NaOH, this was due to CaHPO.sub.4.Math.2H.sub.2O being unable to precipitate under acidic conditions 14 V stirring, 10 ml/min rate

[0167] The results are provided in FIG. 2.

2.2 AXF Mini Run

[0168] DP CaCl.sub.2)/DI water 0.100 g/ml, [0169] CP NaH.sub.2PO.sub.4.Math.2H.sub.2O/Di water 0.0281 g/ml,

[0170] 10200 m membrane, 9.8 mm membrane

[0171] NoteCP solution was raised to pH=6.51 with 4M NaOH

[0172] Both stoichiometric and non-stoichiometric reactions were carried out

Stoichiometric (5:1) Reaction

[0173] 5 parts NaH.sub.2PO.sub.4.Math.2H.sub.2O solution reacting with 1 part CaCl.sub.2) solution based on flow rate and concentration.

[0174] Pore Velocity (m/s)=0.0270, Annulus Velocity (m/s)=0.0268

[0175] Momentum Flux Ratio=1.02, Re (annulus)=5.36

Non-Stoichiometric (10:0.5) Reaction

[0176] 20 parts NaH.sub.2PO.sub.4.Math.2H.sub.2O solution reacting with 1 part CaCl.sub.2) solution based on flow rate and concentration.

[0177] Pore Velocity (m/s)=0.0135, Annulus Velocity (m/s)=0.0536

[0178] Momentum Flux Ratio=0.0636, Re (annulus)=10.72

[0179] The results are provided in FIGS. 3(a) to 4(c).

2.3 AXF Mini Run

[0180] DP CaCl.sub.2/DI water 0.200 g/ml, 0.5 ml/min [0181] CP NaH.sub.2PO.sub.4.Math.2H.sub.2O/Di water 0.01425 g/ml, 10 ml/min

[0182] 10200 m membrane, 9.8 mm membrane

[0183] NoteCP solution was raised to pH=6.51 with 4M NaOH

Stoichiometric (5:1) Reactions

[0184] CP:DP flow rates 10:0.5 ml/min

[0185] 5 parts NaH.sub.2PO.sub.4.Math.2H.sub.2O solution reacting with 1 part CaCl.sub.2 solution based on flow rate and concentration.

[0186] Pore Velocity (m/s)=0.0135, Annulus Velocity (m/s)=0.0536

[0187] Momentum Flux Ratio=0.0636, Re (annulus)=10.72

[0188] The results are provided in FIGS. 5(a) to 5(e).

[0189] FTIR spectroscopy and X-ray diffraction analysis showed reactive crystallisation of CaHPO.sub.4.Math.2H.sub.2O has been successful using both batch and continuous AXF-mini runs towards crystalline materials. The continuous AXF-mini setup initially produced amorphous crystals that under stirring would arrange into long-ranged ordered crystalline forms. The different crystalline forms were also confirmed using FTIR spectroscopy and X-ray diffraction analysis. XRPD analysis showed the amorphous non-stoichiometric material was Ca.sub.5(PO.sub.4).sub.3OH whilst the amorphous stoichiometric material was a mixture of CaHPO.sub.4.Math.2H.sub.2O and Ca.sub.5(PO.sub.4).sub.3OH.

[0190] Particle size analysis shows the AXF-mini apparatus has reduced the size of the crystals and improved the CSD compared to batch. This improvement was possible either through changing the concentrations and flow rate for a stoichiometric reaction. Or through just changing the flow rate resulting in a non-stoichiometric reaction.

Example 3

CaCO.SUB.3 .Crystallisation

[0191] Reactive crystallisation was conducted in a mini-crossflow membrane emulsification apparatus (AXF mini) and a crossflow membrane emulsification apparatus (AXF). This had the continuous phase (CP) and dispersed phase (DP) contain different reagents that would undergo reactive crystallisation towards CaCO.sub.3. The scaled up of equipment and reactive crystallisation was shown to be successful with repeatable particle size results and levels of purity.

3.1 Batch Process

[0192] DP CaCl.sub.2/DI water 0.100 g/ml, 10 ml added [0193] CP NaCO.sub.3/Di water 0.0212 g/ml, 50 ml total [0194] Flux 1842.2 ml/min/cm2, Shear 24.577 Pa

[0195] The results are provided in FIG. 6(a).

3.2 AXF Mini Run

[0196] DP CaCl.sub.2/DI water 0.111 g/ml, [0197] CP Na.sub.2CO.sub.3/Di water 0.0212 g/ml,

[0198] 10200 m membrane, 9.8 mm

[0199] Flow rates-CP 5 ml/min, DP 1 ml/min

[0200] Pore Velocity (m/s)=0.0270, Annulus Velocity (m/s)=0.0268

[0201] Momentum Flux Ratio=1.02, Re (annulus)=5.36

[0202] The results are provided in FIGS. 6(b) to 4(d).

3.3 AXF-1 Run

[0203] DP CaCl.sub.2/DI water 0.111 g/ml, [0204] CP Na.sub.2CO.sub.3/Di water 0.0212 g/ml,

[0205] 10200 m membrane, 9.8, 9.7 and 9.5 mm inserts

[0206] Flow ratesCP=250 ml/min, DP=50 ml/min

9.5 mm Insert

[0207] Pore Velocity (m/s)=0.135, Annulus Velocity (m/s)=0.544

[0208] Momentum Flux Ratio=0.0616, Re (annulus)=272.06

9.7 mm Insert

[0209] Pore Velocity (m/s)=0.135, Annulus Velocity (m/s)=0.898

[0210] Momentum Flux Ratio=0.0226, Re (annulus)=269.30

9.8 mm Insert

[0211] Pore Velocity (m/s)=0.135, Annulus Velocity (m/s)=1.340

[0212] Momentum Flux Ratio=1.02, Re (annulus)=267.94

[0213] The results are provided in FIGS. 6(e) to 6(f).

[0214] FTIR spectroscopy and X-ray diffraction analysis showed reactive crystallisation of precipitated CaCO.sub.3 has been successful through AXF-mini runs with a mixture of calcite and vaterite polymorphs. The scale up of the reactive crystallisation through the AXF-1 has been investigated and was shown to be successful with repeatable crystal sizes to the AXF-mini results. This was possible through investigating different insert sizes and the effect these have on the crystal sizes and overall reactive crystallisation process. It was found that inserts of 9.7 and 9.8 mm diameter would result in pure calcite formation, however, would eventual result in blockages of the CaCO.sub.3 crystal flow. However, when an insert of 9.5 mm was used this was ran with no blockages observed but the XRPD result showed a mixture of vaterite and calcite.