Assisted particle size reduction process

Abstract

A new scalable process to control the particle size and the particle size distribution, comprising 5 steps: (i) suspension preparation in a mixture of solvents in which the API and/or excipient is partially soluble in one of the solvents; (ii) particle size reduction of the suspension; (iii) aging; (iv) stopping the aging by solvent removal; and (v) optionally, a step of isolating the processed ingredients in the form of powder.

Claims

1. A process for controlling the particle size, while controlling the particle size distribution, of one or more active pharmaceutical ingredients (APIs), or one or more APIs with one or more excipients, which process comprises: a) suspending particles of the one or more APIs and optionally one or more excipients in a mixture of at least two solvents that comprise at least a first solvent and a second solvent; wherein at least the first solvent partially dissolves at least one of the APIs and/or excipients, wherein the API and/or excipient are soluble in the first solvent in an amount of 5,000 volumes or more of solvent per gram of solute, and wherein the API and/or excipient are substantially insoluble in the second solvent; b) reducing the size of the particles in the suspension produced in step a); c) aging the suspension by allowing the suspension to stand over a period of time of at least one hour so as to allow particle size growth to occur via Ostwald ripening; d) stopping the aging by removing the first solvent.

2. The process according to claim 1, wherein the process is for reducing the particle size, while controlling the particle size distribution, of one or more active pharmaceutical ingredients (APIs), or one or more APIs with one or more excipients.

3. The process according to claim 1, wherein the second solvent comprises an anti-solvent of the at least one API and/or excipient partially dissolved in the first solvent.

4. The process according to claim 1, wherein the first solvent is present in proportions of first solvent/second solvent of from 2:1 to 0.01:1 w/w.

5. The process according to claim 1, wherein the first solvent is present in proportions of first solvent/second solvent of from 1:4 to 0.1:1 w/w.

6. The process according to claim 1, wherein step d) of claim 1 of removing the first solvent is performed by distillation, drying, or filtration, or any combination thereof.

7. The process according to claim 1, wherein the particle size reduction of step b) of claim 1 is performed by high pressure homogenization, microfluidization, ball milling, or high shear mixing, or any combination thereof.

8. The process according to claim 1, wherein the suspension is processed using the required number of steps to achieve the target particle size.

9. The process according to claim 1, wherein step d) of claim 1 comprises distillation performed until the first solvent is removed.

10. The process according to claim 1, wherein step d) of claim 1 comprises a membrane filtration until the first solvent is removed.

11. The process according to claim 1, further comprising the step of isolating the products of the process in the form of powder wherein the isolation step comprises a filtration and/or a drying step.

12. The process according to claim 1, further comprising the step of isolating the products of the process in the form of powder wherein the isolation step comprises spray drying.

13. The process according to claim 1, wherein the products of the process have a particle size distribution with a span selected from the group consisting of less than 2.5, below 1.8 and below 1.5.

14. The process according to claim 1, wherein the process is a top down production process.

15. The process according to claim 1, wherein the particles produced by the process comprise microparticles.

16. The process according to claim 1, wherein the one or more APIs comprise one or more corticosteroids.

17. The process according to claim 1, wherein the one or more APIs comprise one or more antibiotics.

18. The process according to claim 1, wherein the one or more APIs is selected from a group consisting of mometasone, fluticasone, tiotropium, ciclesonide, budesonide, formoterol, salmeterol, salbutamol, beclomethasone, betamethasone, ipratropium, terbutaline, hydrocortisone, fosfomycin, tobramycin, doxycycline minocycline, ciprofloxacin, vancomycin, rifampicin, gentamicin, amphotericin, and azithromicin or combinations thereof.

19. The process according to claim 1, wherein the one or more excipients is selected from a group consisting of surfactants, amino acids, lipids, waxes, fatty acids, sugars, flavoring agents, and polymers, or combinations thereof.

20. The process according to claim 1, wherein the concentration of APIs and excipients in the suspension is selected from the group consisting of 30% w/w or less, 15% w/w or less, and 10% w/w or less.

21. The process according to claim 1, wherein the API and/or excipient are soluble in the first solvent in an amount of 10,000 volumes of solvent per gram of solute.

22. The process according to claim 1, wherein the one or more APIs comprise tiotropium bromide, the first solvent is an ester formed from the reaction of a C.sub.1 to C.sub.5 alcohol and a C.sub.1 to C.sub.5 carboxylic acid, and the second solvent is a C.sub.1 to C.sub.9 alkane.

23. The process according to claim 1, wherein the one or more APIs comprise tiotropium bromide, the first solvent is ethyl acetate and the second solvent is heptane.

24. The process according to claim 1, wherein the one or more APIs comprise fluticasone propionate, the second solvent is water, and the first solvent is a C.sub.1 to C.sub.6 ketone.

25. The process according to claim 1, wherein the one or more APIs comprise fluticasone propionate, the second solvent is water and the first solvent is acetone.

Description

EXAMPLE 1

(1) Tiotropium Bromide (40 g) was suspended in a mixture of n-heptane (304 g) and ethyl acetate (456 g) and stirred until a uniform suspension was obtained and fed to a lab scale microfluidizer processor where the suspension was submitted to pressures of 400 bar for 50 cycles. The following particle size results were obtained: Dv10=0.67 m; Dv50=2.98 m; Dv90=7.09 m; span=2.2. After this particle size reduction step, the suspension was transferred to a holding vessel were it was left aging for 20 hours, during which particle size increased, (Dv10=0.78 m; Dv50=3.33 m; Dv90=7.45 m; span=2.0) without stirring at room temperature. After this period, the proportion of ethyl acetate and heptane was changed to approximately 100% heptane by means of a distillation to reduce the amount of material dissolved in suspension. The suspension was fed to a lab scale spray dryer while stirring, with a feed rate of 6 ml/min and a drying temperature of 100 C. The product was collected in a glass flask yielding 30 g.

(2) The product isolated presented an XRPD identical to the one of the starting material and a particle size distribution with Dv10=0.83 m; Dv50=3.02 m; Dv90=7.05 m; span=2.1, which is a size distribution suitable for formulation into an inhalable compound and an appropriate deposition in the lung after inhalation delivery.

EXAMPLE 2

(3) Fluticasone propionate (15 g) was suspended in a mixture of water (256.5 g) and acetone (28.5 g) and stirred until a uniform suspension was obtained and fed to a lab scale microfluidizer processor in which the suspension was submitted to pressures of 750 bar for 45 cycles. The following particle size results were obtained: Dv10=0.92 m; Dv50=1.81 m; Dv90=3.39 m; span=1.4. After this particle size reduction step, the suspension was transferred to a holding vessel where it was left aging for 22 hours, resulting in a larger particle size and a narrower span (Dv10=1.42 m; Dv50=2.53 m; Dv90=4.43 m; span=1.2). After this period, the suspension was fed to a lab scale spray dryer while stirring, with a feed rate of 6 ml/min and a drying temperature of 45 C. The product was collected in a glass flask yielding 12 g.

(4) The product isolated presented an XRPD identical to the one of the starting material and a particle size distribution with Dv10=1.38 m; Dv50=2.42 m; Dv90=4.18 m; span=1.2, which is a size distribution suitable for formulation into an inhalable compound and an appropriate deposition in the lung after inhalation delivery

(5) FIG. 3 presents the narrow particle size distribution curves of fluticasone propionate obtained after the three main steps of this invention (particle size reduction, aging and isolation).

(6) For comparison, the process disclosed in patent WO2011131947 was applied to the processing of fluticasone propionate. Fluticasone propionate (30 g) was suspended in the anti-solvent water (270 g) and stirred until a uniform suspension was obtained and fed to a lab scale microfluidizer processor in which the suspension was submitted to pressures of 750 bar for 45 cycles. The following particle size results were obtained: Dv10=1.28 m; Dv50=2.44 m; Dv90=4.45 m; span=1.3. After this size-reduction step, the suspension was fed to a lab scale spray dryer while stirring, with a feed rate of 6 ml/min and a drying temperature of 45 C. The product was collected in a glass flask yielding 19 g.

(7) The product isolated presented an XRPD identical to the one obtained by the present invention (FIG. 4) and a particle size distribution with Dv10=0.99 m; Dv50=1.94 m; Dv90=3.60 m; span=1.4.

(8) As observed in FIG. 5 the final powder particle size distribution curve obtained using the invention herein disclosed was narrower (span 1.2) than the distribution curve obtained with process described in patent WO2011131947 (span 1.4).

EXAMPLE 3

(9) As an example of the processing of API and excipients, theophylline (4.03 g) and saccharin (4.09 g) were suspended in a mixture of water (367.8 g) and ethanol (32.2 g). Stirring proceeded until a uniform suspension was obtained. Finally the suspension was processed in a lab scale microfluidizer processor submitted to pressures of 755 bar for 25 cycles. After this particle size reduction step, the suspension was transferred to a holding vessel where it was left aging for 48 hours without stirring at room temperature. After this period, the suspension was fed to a lab scale spray dryer while stirring, with a feed rate of 10 ml/min and a drying temperature of 65 C.

(10) The product isolated presented the target crystalline form of theophylline-saccharin co-crystal as described by Enxian et al. (CrystEngComm, 2008, 10, 665-668). FIG. 6 presents the XRPD of the product (before and after drying) and the corresponding raw materials.

(11) The product particle size had a distribution with Dv10=2.03 m; Dv50=4.60 m; Dv90=8.76 m; span=1.5.