METHODS OF PREPARING SOLID PARTICULATE MATERIALS

Abstract

There is described a method of preparing solid particles of a compound, said method comprising controlling provision of a liquid phase, wherein said liquid phase comprises a solution of the compound, in a first flow direction to a membrane, said membrane defining a plurality of pores; and controlling the supersaturation of the liquid phase after it has passed through the membrane via the plurality of pores, to form solid particles of the compound. The method may comprise a continuous method.

Claims

1. A method of preparing solid particles of a compound, said method comprising controlling provision of a liquid phase, wherein said liquid phase comprises a solution of the compound, in a first flow direction to a membrane, said membrane defining a plurality of pores; and controlling the supersaturation of the liquid phase after it has passed through the membrane via the plurality of pores, to form solid particles of the compound.

2. The method according to claim 1 wherein the supersaturation of the liquid is controlled by cooling the liquid phase, antisolvent precipitation or reverse antisolvent precipitation.

3. The method according to claim 2 wherein the supersaturation of the liquid is controlled by cooling the liquid phase after it has passed through the membrane.

4. The method according to claim 2 wherein the supersaturation of the liquid is controlled by antisolvent precipitation after the liquid phase has passed through the membrane.

5. The method according to claim 2 wherein the supersaturation of the liquid is controlled by reverse antisolvent precipitation after the liquid phase has passed through the membrane.

6. The method according claim 1 wherein the method comprises the preparation of solid particles of a compound in crystalline form or amorphous form, or a combination thereof.

7. (canceled)

8. (canceled)

9. A method of preparing solid particles of a compound, said method comprising dispersing a first liquid phase in a second liquid phase; wherein said first liquid phase comprises a solution of the compound and said second liquid phase comprises an antisolvent; or said first liquid phase comprises an antisolvent and said second liquid phase comprises a solution of the compound; 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 to the first flow direction, via the plurality of pores, to form solid particles of the compound.

10. (canceled)

11. (canceled)

12. The method according to claim 9 wherein the method comprises the preparation of solid particles of a compound in crystalline form or amorphous form, or a combination thereof.

13. (canceled)

14. (canceled)

15. A method of preparing solid particles of a compound, said method comprising dispersing a first liquid phase in a second liquid phase; wherein said first liquid phase comprises a solution of the compound and said second liquid phase comprises an antisolvent phase; or said first liquid phase comprises an antisolvent and said second liquid phase comprises a solution of the compound; wherein said method uses a crossflow emulsification apparatus; said crossflow emulsification apparatus (AXF) comprising: an outer tubular sleeve provided with a first inlet at a first end; a particle outlet; and a second inlet, distal from and inclined relative to the first inlet; a tubular membrane provided with a plurality of pores and adapted to be positioned inside the tubular sleeve; and optionally an insert adapted to be located inside the tubular membrane, said insert comprising an inlet end and an outlet end, each of the inlet end and an outlet end being provided with chamfered region; the chamfered region is provided with a plurality of orifices and a furcation plate; and controlling provision of the first liquid phase to the tubular membrane; and controlling provision of a second liquid phase to the tubular membrane via the plurality of pores to form solid particles of the compound.

16. (canceled)

17. (canceled)

18. The method according to claim 15 wherein the method comprises the preparation of solid particles of a compound in crystalline form or amorphous form, or a combination thereof.

19. (canceled)

20. The method according to claim 18 wherein the method comprises the preparation of solid amorphous particles of a compound.

21. (canceled)

22. The method according to claim 15 wherein the solution comprises one or more dissolved organic compounds, the one or more dissolved organic compounds comprising pharmaceutically active compounds or drugs, bioactive agents, nutraceuticals, polymers and the like.

23. (canceled)

24. The method according to claim 1 wherein the compound is of low bioavailability.

25.-27. (canceled)

28. The method according to claim 22 wherein the solution comprises a pharmaceutically active compound is selected from one or more of antifungal agents, such as, itraconazole fluoconazole, terconazole, ketoconazole and saperconazole; anti-infective agents, such as griseofulvin and griseoverdin; antibiotics, such as, amoxicillin, azithromycin, cephalexin, cefixime, cefoperazone, ceftriaxone, ciprofloxacin, clarithromycin, clavulanic acid, clindamycin, doxycycline, erythromycin, gentamycin, levofloxacin, meropenem, metronidazole, neomycin, norfloxacin, ofloxacin, ornidazole, oxytctracycline, piperacillin, rifampicin, streptomycin, sulbactam, sulfadiazine, tazobactam, tetracycline and tinidazole; anti malaria drugs, such as, atovaquone and artesunate; protein kinase inhibitors, such as, afatinib, axitinib, bosutinib, cetuximab.crizotinib, dasatinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, zemurasenib, lapatinib, lenvatinib, mubritinib and nilotinib; immune system modulators, such as, cyclosporine; cardiovascular drugs, such as, digoxin and spironolactone; sterols or steroids, such as, betamethasone; ACE inhibitors, such as, captopril, enalapril, ramipril, quinapril, perindopril, lisinopril, and fosinopril; adenohypophyseal hormones; adrenergic antagonists, such as, phentolamine, phenoxybenzamine, tamsulosin, propranolol, atenolol, metoprolol, timolol and acebutolol; adrenocortical steroids; inhibitors of the biosynthesis of adrenocortical steroids; alpha-adrenergic agonists, such as methoxamine, phenylephrine, methyldopa, norepinephrine; alpha-adrenergic antagonists, such as, phentolamine and phenoxybenzamine; analgesics, such as, aspirin and paracetamol; antipyretics and anti-inflammatory agents, such as, diclofenac, ibuprofen, naproxen and ketoprofen; androgens, local anaesthetics, such as, lidocaine; antiaddictive agents; antiandrogens; antiarrhythmic agents, such as, verapamil and diltiazem; antiasthmatic agents, such as, beclomethasone, budesonide, fluticasone, reproterol, salbutamol and salmeterol; anticholinergic agents, such as, ipratropium and oxybutynin; anticholinesterase agents, such as, donepezil; anticoagulants, such as, dabigatran, rivaroxaban, apixaban, edoxaban and betrixaban; antidiabetic agents, such as, metformin; antidiarrheal agents; antidiuretics; antiemetic and prokinetic agents; antiepileptic agents, such as carbamazepine, gabapentin oxcarbazepine; antiestrogens; antifungal agents; antihypertensive agents, such as, losartan, olmesartan, telmisartan and valsartan; antimicrobial agents; antimigraine agents, such as, zolmitriptan; antimuscarinic agents; antineoplastic agents; antiparasitic agents; antiparkinsons agents, such as, carbidopa and levodopa; antiplatelet agents; antiprogestins; antithyroid agents; antitussives; antiviral agents; antidepressants; azaspirodecanediones; barbiturates; benzodiazepines; benzothiadiazides; beta-adrenergic agonists; beta-adrenergic antagonists; selective adrenergic antagonists; selective agonists; bile salts; butyrophenones; calcium channel blockers; catecholamines and sympathomimetic drugs; cholinergic agonists; cholinesterase reactivators; cognitive enhancers, such as, piracetam; dermatological agents; diphenylbutylpiperidines; diuretics; ergot alkaloids; oestrogens; ganglionic blocking agents; ganglionic stimulating agents; glucocorticoid steroids, such as, dexamethasone and prednisolone; agents for control of gastric acidity and treatment of peptic ulcers; haematopoietic agents; histamines; antihistamine; HMG-CoA reductase inhibitors, e.g. statins, such as, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin; 5-hydroxytryptamine antagonists; hypnotics and sedatives; immunosuppressive agents; laxatives; methylxanthines; monoamine oxidase inhibitors; neuromuscular blocking agents; nutrients or dietary supplements, such as, vitamin B1, vitamin B6 and retinol; organic nitrates; opioid analgesics and antagonists; pancreatic enzymes; phenothiazines; progestins; prostaglandins; agents for the treatment of psychiatric disorders; retinoids; sodium channel blockers; thrombolytic agents; thyroid agents; tricyclic antidepressants; tyrosine kinase inhibitors, such as, axitinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib and vemurafenib; drugs from the group comprising danazol, acyclovir, dapsone, indinavir, lopinavir, nifedipine, nitrofurantion, phentytoin, ritonavir, saquinavir, sulfamethoxazole, valproic acid, trimethoprin, acetazolamide, azathioprine, iopanoic acid, nalidixic acid, nevirapine, praziquantel, rifampicin, albendazole, amitrptyline, artemether, lumefantrine, chloropromazine, clofazimine, efavirenz, iopinavir, folic acid, glibenclamide, haloperidol, ivermectin, mebendazole, niclosamide, pyrantel, pyrimethamine, sulfadiazine, sulfasalazine, triclabendazole, and cinnarizine; and combinations thereof.

29. (canceled)

30. (canceled)

31. The method according to claim 28 wherein the pharmaceutically active compound is an antihypertensive agent, such as, telmisartan.

32. The method according to claim 28 wherein the pharmaceutically active compound is an antihypertensive agent in amorphous form, such as, telmisartan.

33.-39. (canceled)

40. The method according to claim 15 wherein the apparatus includes an insert.

41.-77. (canceled)

78. The method according to claim 1 wherein the method is a continuous process.

79. (canceled)

80. (canceled)

81. A solid particle prepared by the method according to claim 1.

82. A solid particle according to claim 81 wherein the particle comprises an active agent.

83. A solid particle according to claim 81 wherein the solid particles are in crystalline form or amorphous form, or a combination thereof.

84.-89. (canceled)

90. A solid particle according to claim 81 wherein the active agent is selected from one or more of antifungal agents, such as, itraconazole fluoconazole, terconazole, ketoconazole and saperconazole; anti-infective agents, such as griseofulvin and griseoverdin; antibiotics, such as, amoxicillin, azithromycin, cephalexin, cefixime, cefoperazone, ceftriaxone, ciprofloxacin, clarithromycin, clavulanic acid, clindamycin, doxycycline, erythromycin, gentamycin, levofloxacin, meropenem, metronidazole, neomycin, norfloxacin, ofloxacin, ornidazole, oxytctracycline, piperacillin, rifampicin, streptomycin, sulbactam, sulfadiazine, tazobactam, tetracycline and tinidazole; anti malaria drugs, such as, atovaquone and artesunate; protein kinase inhibitors, such as, afatinib, axitinib, bosutinib, cetuximab.crizotinib, dasatinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, zemurasenib, lapatinib, lenvatinib, mubritinib and nilotinib; immune system modulators, such as, cyclosporine; cardiovascular drugs, such as, digoxin and spironolactone; sterols or steroids, such as, betamethasone; ACE inhibitors, such as, captopril, enalapril, ramipril, quinapril, perindopril, lisinopril, and fosinopril; adenohypophyseal hormones; adrenergic antagonists, such as, phentolamine, phenoxybenzamine, tamsulosin, propranolol, atenolol, metoprolol, timolol and acebutolol; adrenocortical steroids; inhibitors of the biosynthesis of adrenocortical steroids; alpha-adrenergic agonists, such as methoxamine, phenylephrine, methyldopa, norepinephrine; alpha-adrenergic antagonists, such as, phentolamine and phenoxybenzamine; analgesics, such as, aspirin and paracetamol; antipyretics and anti-inflammatory agents, such as, diclofenac, ibuprofen, naproxen and ketoprofen; androgens, local anaesthetics, such as, lidocaine; antiaddictive agents; antiandrogens; antiarrhythmic agents, such as, verapamil and diltiazem; antiasthmatic agents, such as, beclomethasone, budesonide, fluticasone, reproterol, salbutamol and salmeterol; anticholinergic agents, such as, ipratropium and oxybutynin; anticholinesterase agents, such as, donepezil; anticoagulants, such as, dabigatran, rivaroxaban, apixaban, edoxaban and betrixaban; antidiabetic agents, such as, metformin; antidiarrheal agents; antidiuretics; antiemetic and prokinetic agents; antiepileptic agents, such as carbamazepine, gabapentin oxcarbazepine; antiestrogens; antifungal agents; antihypertensive agents, such as, losartan, olmesartan, telmisartan and valsartan; antimicrobial agents; antimigraine agents, such as, zolmitriptan; antimuscarinic agents; antineoplastic agents; antiparasitic agents; antiparkinsons agents, such as, carbidopa and levodopa; antiplatelet agents; antiprogestins; antithyroid agents; antitussives; antiviral agents; antidepressants; azaspirodecanediones; barbiturates; benzodiazepines; benzothiadiazides; beta-adrenergic agonists; beta-adrenergic antagonists; selective adrenergic antagonists; selective agonists; bile salts; butyrophenones; calcium channel blockers; catecholamines and sympathomimetic drugs; cholinergic agonists; cholinesterase reactivators; cognitive enhancers, such as, piracetam; dermatological agents; diphenylbutylpiperidines; diuretics; ergot alkaloids; oestrogens; ganglionic blocking agents; ganglionic stimulating agents; glucocorticoid steroids, such as, dexamethasone and prednisolone; agents for control of gastric acidity and treatment of peptic ulcers; haematopoietic agents; histamines; antihistamine; HMG-CoA reductase inhibitors, e.g. statins, such as, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin; 5-hydroxytryptamine antagonists; hypnotics and sedatives; immunosuppressive agents; laxatives; methylxanthines; monoamine oxidase inhibitors; neuromuscular blocking agents; nutrients or dietary supplements, such as, vitamin B1, vitamin B6 and retinol; organic nitrates; opioid analgesics and antagonists; pancreatic enzymes; phenothiazines; progestins; prostaglandins; agents for the treatment of psychiatric disorders; retinoids; sodium channel blockers; thrombolytic agents; thyroid agents; tricyclic antidepressants; tyrosine kinase inhibitors, such as, axitinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib and vemurafenib; drugs from the group comprising danazol, acyclovir, dapsone, indinavir, lopinavir, nifedipine, nitrofurantion, phentytoin, ritonavir, saquinavir, sulfamethoxazole, valproic acid, trimethoprin, acetazolamide, azathioprine, iopanoic acid, nalidixic acid, nevirapine, praziquantel, rifampicin, albendazole, amitrptyline, artemether, lumefantrine, chloropromazine, clofazimine, efavirenz, iopinavir, folic acid, glibenclamide, haloperidol, ivermectin, mebendazole, niclosamide, pyrantel, pyrimethamine, sulfadiazine, sulfasalazine, triclabendazole, and cinnarizine; and combinations thereof.

91. (canceled)

92. (canceled)

Description

[0120] The present invention will now be described by way of example only with reference to the accompanying figures in which:

[0121] FIG. 1 illustrates microscopic images of paracetamol crystals at ×200 magnification from three separate runs;

[0122] FIG. 2 illustrates crystal size distributions obtained by visual particle size analysis of paracetamol crystals formed from three separate CXF runs;

[0123] FIG. 3 illustrates the XRPD pattern of paracetamol produced via CXF with (*) indicating peaks belong to solid PEG P123 surfactant;

[0124] FIG. 4 illustrates a microscopic image of piroxicam produced via CXF at 100× magnification;

[0125] FIG. 5 illustrates crystal size distributions obtained by laser diffraction of piroxicam crystals formed via CXF;

[0126] FIG. 6 illustrates a microscopic image of prednisolone crystals produced via CXF at 200× magnification;

[0127] FIG. 7 illustrates crystal size distribution obtained by visual particle size analysis of prednisolone crystals produced via CXF;

[0128] FIG. 8 illustrates an XRPD pattern of prednisolone produced via CXF;

[0129] FIG. 9 illustrates the effect of changing CXF DPorganic phase flow rate on particle size distributions of telmisartan, obtained by laser diffraction;

[0130] FIG. 10 illustrates the effect of CXF DP flow rate on volume mean size of telmisartan particles to organic phase flow rates;

[0131] FIG. 11 illustrates the effect of membrane pore diameter on particle size distribution of telmisartan, obtained by laser diffraction;

[0132] FIG. 12 illustrates the effect of membrane pore diameter on volume mean size of telmisartan particles;

[0133] FIG. 13 illustrates particle size distributions obtained by laser diffraction of telmisartan produced on three separate LDC runs;

[0134] FIG. 14 illustrates particle size distributions obtained by laser diffraction of telmisartan produced on three separate CXF runs;

[0135] FIG. 15 illustrates a comparison of particle size distributions obtained by laser diffraction of telmisartan produced via LDC and CXF;

[0136] FIG. 16 illustrates microscopic images at ×100 magnification of telmisartan prepared via LDC (a) and CXF (b);

[0137] FIG. 17 illustrates an XRPD pattern of telmisartan collected via LDC (top) and CXF (bottom);

[0138] FIG. 18 illustrates a microscopic image of Carbamazepine crystals at ×100 magnification, produced via the LDC. The aqueous phase used was distilled water with 0.5% P123 surfactant (a) and distilled water with 0.5% HPMC surfactant (b);

[0139] FIG. 19 illustrates an XRPD pattern of carbamazepine produced on the LDC showing form II (top) and form III (bottom);

[0140] FIG. 20 illustrates a microscopic image of Atorvastatin particles produced via the LDC at ×100 magnification;

[0141] FIG. 21 illustrates particle size distribution obtained via laser diffraction of atorvastatin particles produced on the LDC;

[0142] FIG. 22 illustrates an XPRD diffractogram of atorvastatin particles produced on the LDC; and

[0143] FIG. 23 illustrates a microscopic image of metformin crystals at 100× magnification produced via LDC.

EXAMPLES

Example 1

[0144] Reproducibility of the Production of Paracetamol Crystals Via CXF

[0145] A solution of paracetamol in ethanol (0.3 g/ml) was prepared, alongside an aqueous phase consisting of 0.5% wt. PEG P123 in DI water. The CXF was configured with a membrane with 10 μm pores, spaced 200 μm apart in a square grid. A 9.5 mm insert was used. The materials were pumped using gear pumps.

[0146] The aqueous continuous phase was pumped through the annulus at the center of the membrane. The organic disperse phase was pumped through the top port of the device calibrated at a rate of 75 m/min, through the membrane and into the flow of continuous phase at 200 ml/min.

[0147] The solution was collected in a beaker and stirred with an overhead stirrer at 500 rpm for 10-15 minutes.

[0148] The experiment was repeated 3 times. The resultant crystal suspension was examined via microscopy (see FIG. 1), and Jorin Visual Particle Size Analyser (ViPA) for crystal size and uniformity, (FIG. 2 and Table 1).

[0149] The filtered and dried paracetamol crystals were then collected and analysed using X-ray powder diffraction (XRPD), which indicated a highly crystalline material (FIG. 3).

TABLE-US-00001 TABLE 1 Average ± Volume Distribution Run 1 Run 2 Run 3 Standard Deviation D10 (μm) 24.12 25.18 22.13 23.81 ± 0.894 D50 (μm) 41.15 40.82 39.29 40.42 ± 0.573 D90 (μm) 74.81 67.77 62.36 68.31 ± 3.604 Volume Mean 45.37 44.28 41.17 43.61 ± 1.258 D[4,3] μm StDev (μm) 19.09 16.10 15.96 17.05 ± 1.021 Span 1.232 1.044 1.024 1.100 ± 0.066 CV % 42.08 36.35 38.78 39.07 ± 1.660

Example 2

[0150] Production of Piroxicam Crystals Via CXF

[0151] 2.5 g of Piroxicam (PRX) was dissolved in 100 ml of ethanol in a beaker at 32° C. to make up the disperse phase, at a concentration of 25 mg/ml. 0.5% weight hydroxypropyl methylcellulose (HPMC) in deionised water was used as the continuous phase.

[0152] The CXF was configured with a membrane with 5 μm pores, spaced 45 μm apart in a square grid. A 9.5 mm insert was used. The materials were pumped using gear pumps.

[0153] The aqueous continuous phase was pumped at 400 m/min through the annulus at the center of the membrane. The organic disperse phase was pumped at 17 mL/min through the top port of the device, through the membrane and into the flow of continuous phase.

[0154] The solution was collected in a 250 ml beaker and stirred with an overhead stirrer at 500 rpm for 10-15 minutes. The crystals were analyzed via microscopy and Laser Diffraction (Beckmann Coulter LS-230). The results are relayed in FIGS. 4 and 5 and Table 2.

TABLE-US-00002 TABLE 2 Volume Distribution Value D10 (μm) 1.240 D50 (μm) 6.562 D90 (μm) 12.96 Mean (μm) 6.978 SD (μm) 4.307 Span 1.78 CV (%) 61.7

Example 3

[0155] Preparation of Prednisolone Crystals Via CXF

[0156] 8 g of Prednisolone was dissolved in 200 ml of ethanol in a beaker at 55° C. to make up the organic phase. 0.5% PVA (Mowiol 23-88) in DI water was used as the aqueous phase.

[0157] The CXF was configured with a membrane with 10 μm pores, spaced 200 μm apart in a square grid. A 9.5 mm insert was used. The materials were pumped using gear pumps, calibrated so the aqueous continuous phase flow was 230 m/min and the organic disperse phase flow was 28 mL/min.

[0158] The aqueous continuous phase was pumped through the annulus at the center of the membrane. The organic disperse phase, held at 55° C., was pumped through the top port of the device, through the membrane pores and into the flow of continuous phase.

[0159] The resultant solution was collected in a 500 ml beaker and stirred with an overhead stirrer at 500 rpm for 10-15 minutes. The crystals were analyzed via microscopy and Jorin ViPA. The results are relayed in FIGS. 6 and 7 and Table 3.

[0160] The filtered and dried crystals were analyzed by XRPD, (FIG. 8) and indicated a highly crystalline material, in the polymorph form II.

TABLE-US-00003 TABLE 3 Volume Distribution Value D10 (μm) 29.47 D50 (μm) 43.76 D90 (μm) 60.78 Volume Mean (μm) 45.73 SD (μm) 15.29 Span 0.72 CV (%) 33.44

Example 4

[0161] Effect of Disperse Phase Flow Rate on the Size Distribution of Telmisartan Particles

[0162] A solution of telmisartan in DMSO (0.06 g/ml) was prepared as the organic phase. The aqueous phase was composed of distilled water. The CXF was configured with a membrane with 10 μm pores, spaced 200 μm apart in a square grid. A 9.5 mm insert was used. The materials were pumped using gear pumps.

[0163] The aqueous continuous phase was pumped through the annulus at the center of the membrane at 464 m/min. The organic disperse phase was pumped through the top port of the device at rates of 58, 29 and 15 m/min, through the membrane and into the flow of continuous phase that was calibrated.

[0164] The solution was collected in a beaker and stirred with an overhead stirrer at 500 rpm for 5-10 minutes. The crystals were analyzed via laser diffraction, and the results are reported in Table 4 and FIGS. 9 and 10.

TABLE-US-00004 TABLE 4 Volume Distribution 58 mL/min* 29 mL/min 15 mL/min D10 (μm) 7.359 4.981 4.653 D50 (μm) 15.66 10.09 10.11 D90 (μm) 28.00 18.9 15.76 Volume Mean (μm) 17.11 11.79 10.17 S.D. (μm) 8.565 7.943 4.179 Span 1.318 1.379 1.099 *Average of three

Example 5

[0165] Effect of Membrane Pore Diameter on the Size Distribution of Telmisartan Particles

[0166] A solution of telmisartan in DMSO (0.06 g/ml) was prepared as the organic phase. The aqueous phase was composed of distilled water. The CXF was configured with membranes of different pore sizes that included 5, 10, 20 and 40 μm pores, spaced 200 μm apart in a square grid. A 9.5 mm insert was used. The materials were pumped using gear pumps.

[0167] The aqueous continuous phase was pumped through the annulus at the center of the membrane at a rate of 464 ml/min. The organic disperse phase was pumped through the top port of the device at a rate of 58 mL/min, through the membrane pores and into the flow of continuous phase.

[0168] The solution was collected in a beaker and stirred with an overhead stirrer at 500 rpm for 5-10 minutes. The crystals were analyzed via laser diffraction, and the results are reported in Table 5 and FIGS. 11 and 12.

TABLE-US-00005 TABLE 5 Volume 5 μm 10 μm 20 μm 40 μm Distribution pore pore* pore pore D10 μm 6.506 7.359 6.555 8.451 D50 μm 13.01 15.66 18.72 23.16 D90 μm 22.83 28.00 37.68 45.99 Volume Mean μm 14.31 17.11 20.60 25.42 S.D. 7.629 8.565 11.90 14.34 Span μm 1.255 1.318 1.663 1.621 C.V % 53.31 50.06 57.77 56.41 *Average of three

Example 6

[0169] Reproducibility of the Production of Amorphous Telmisartan and Translation from Stirred Cell LDC to Continuous Crossflow CXF Devices A solution of telmisartan in DMSO (0.06 g/ml) was prepared for use as the organic phase. An aqueous phase of 50 ml of DI water was prepared. The LDC was configured with a membrane with 10 μm pores, spaced 200 μm apart in a square grid, in a ring sat underneath a stirrer paddle. A volume of 6 ml of DP was added at an injection rate of 10 ml/min. The CP and DP volume ratio is 8:1. The stirrer was set to 14V (1750 rpm). Once addition of the DP was complete the solution was stirred for 5-10 minutes.

[0170] The LDC runs were repeated three times.

[0171] The particle size distribution curves of the LDC runs were measured via laser diffraction and are shown in FIG. 13.

[0172] Additionally, a solution of telmisartan in DMSO (0.06 g/ml) was prepared as an organic phase. An aqueous phase was composed of distilled water. A CXF was configured with a membrane with 10 μm pores, spaced 200 μm apart in a square grid. A 9.5 mm insert was used. The materials were pumped using gear pumps.

[0173] The aqueous continuous phase was pumped through the annulus at the center of the membrane at a rate of 464 ml/min. The organic disperse phase was pumped through the top port of the device at a rate of 58 mL/min, through the membrane pores and into the flow of continuous phase. This preserved the 8:1 CP:DP ratio used in the LDC experiments and generated a similar shear profile.

[0174] The solution was collected in a beaker and stirred with an overhead stirrer at 500 rpm for 5-10 minutes. The CXF runs were repeated three times.

[0175] The particle size distribution curves of the CXF runs were measured via laser diffraction and are shown in FIG. 14.

[0176] The particle size distributions of material produced on the LDC are shown in Table 6, with errors given as the standard deviations, alongside those for the CXF runs. FIG. 15 shows a crystal size distribution curve from an LDC run alongside a CXF run showing the repeatability in size and distribution.

[0177] Microscope analysis of telmisartan particles produced on the LDC and the CXF was carried out, and an example is shown in FIG. 16.

[0178] Filtered and dried crystals produced by both methods were analyzed by XRPD, (FIG. 17) and indicated an amorphous particle morphology.

TABLE-US-00006 TABLE 6 Volume Distribution LDC CXF D10 (μm) 6.952 ± 0.357 7.359 ± 1.096 D50 (μm) 14.32 ± 0.693 15.66 ± 1.558 D90 (μm) 26.43 ± 1.268  28.0 ± 2.091 Volume Mean 15.79 ± 0.755 17.11 ± 1.538 D[4,3] (μm) StDev (μm) 8.066 ± 0.430 8.565 ± 0.275 Span 1.360 ± 0.028 1.389 ± 0.070 CV (%) 51.07 ± 0.937 50.57 ± 3.09 

Example 7

[0179] Effect of Aqueous Phase Surfactant on Crystal Morphology of Carbamazepine Produced Via LDC

[0180] 0.4 g of Carbamazepine was dissolved in 10 ml methanol in a beaker at 45° C. to make up the organic phase. In one instance, 0.5% Pluronic PEG P123 (Mn˜5,800) in DI water was used as the aqueous phase. In another instance, 0.5% HPMC (Mn˜10,000) in DI water was used as the aqueous phase.

[0181] The LDC was configured with a membrane with 10 μm pores, spaced 200 μm apart in a ring formation. The stirrer speed was set at 14V (1750 rpm), and the organic phase injection rate set at 10 ml/min. The line was primed with organic phase and the aqueous was poured into the stirred cell. The organic phase addition was started and ended when 3 ml of DP was injected.

[0182] The solution was left to stir until precipitation was visible. The crystals were analyzed via microscopy and Jorin ViPA. The results are relayed in FIG. 18 and Table 7.

[0183] The filtered and dried crystals were analyzed by XRPD (FIG. 19), indicating that carbamazepine produced via LDC using an aqueous phase of distilled water with 0.5% P123 surfactant had produced crystalline material of form II, and using an aqueous phase of distilled water with 0.5% HPMC surfactant had produced crystalline material of form III.

TABLE-US-00007 TABLE 7 Volume Distribution 0.5% P123 0.5% HPMC D10 (μm) 29.92 28.90 D50 (μm) 42.37 44.92 D90 (μm) 64.09 78.16 Volume mean (μm) 45.79 48.84 StDev 16.13 18.64 Span 0.81 1.10 CV (%) 35.22 38.18

Example 8

[0184] Preparation of Atorvastatin Particles Via LDC

[0185] 0.6 g of Atorvastatin was dissolved in 10 ml methanol in a beaker at room temperature to make up the organic phase. 0.5% HPMC (Mn˜10,000) in DI water was used as the aqueous phase.

[0186] The LDC was configured with a membrane with 10 μm pores, spaced 200 μm apart in a square grid, in a ring. The stirrer speed was set at 14V (1750 rpm), and the organic phase injection rate set at 10 ml/min. The line was primed with organic phase and the CP was poured into the stirred cell. Addition was started and ended when 3 ml of DP was injected.

[0187] The solution was left to stir until precipitation was visible. The crystals were analyzed via microscopy and Laser Diffraction (Beckmann Coulter LS-230). The results are relayed in FIGS. 20 and 21, and Table 8.

[0188] The resulting solution was filtered and dried to obtain dry atorvastatin. This was analysed via XRPD and indicated an amorphous particle morphology (FIG. 22).

TABLE-US-00008 TABLE 8 Volume Distribution Value D10 (μm) 4.38 D50 (μm) 8.78 D90 (μm) 18.92 Volume mean (μm) 10.24 StDev 5.53 Span 1.66 CV (%) 54.0

Example 9

[0189] Preparation of Metformin Crystals Via LDC

[0190] 0.4 g of Metformin was dissolved in 10 ml methanol in a beaker to make up the organic phase. 0.5% Tween 20 in acetonitrile was used as the aqueous phase.

[0191] The LDC was configured with a membrane with 10 μm pores, spaced 200 μm apart in a ring-shape. The stirrer speed was set at 14V (1750 rpm), and the injection rate set at 10 ml/min. The line was primed with organic phase and the aqueous phase was poured into the dispersion cell. Addition of the organic phase was started and ended when 3 ml of DP was injected.

[0192] The solution was left to stir until precipitation was visible. The crystals were analyzed via microscopy and Jorin ViPA. The results are relayed in FIG. 23 and Table 9.

TABLE-US-00009 TABLE 9 Volume Distribution Value D10 (μm) 25.63 D50 (μm) 50.80 D90 (μm) 81.03 Size Mean (μm) 12.430 Volume Mean (μm) 53.10 StDev 22.04 Span 1.09 CV (%) 41.51