Spray drying process for production of powders with enhanced properties

Abstract

An improved spray drying method for production of amorphous solid dispersions with enhanced bulk density and material attributes comprising the introduction of at least one additional stream in at least one of multiple locations in a spray dryer without interfering with the spray region.

Claims

1. A spray drying apparatus comprising at least one secondary gas stream inlet, for one or more secondary gas streams, in at least one of multiple locations in the spray drying apparatus, wherein the spray drying apparatus comprises a spray dryer chamber comprising an atomization nozzle and a drying gas inlet; and a means for recovering spray dried particles from the spray dryer chamber, wherein the means comprises, immediately downstream from the spray dryer chamber, a cyclone or a filter bag, and a solids container downstream of the cyclone or the filter bag, wherein an outlet of the spray dryer chamber is connected with an inlet of the cyclone or the filter bag via a first connection, wherein an outlet of the cyclone or the filter bag is connected with an inlet of the solids container via a second connection, and wherein at least one of the at least one secondary gas stream inlets is in at least one of the following locations selected from the group consisting of: i) the first connection; ii) the second connection; and iii) the solids container.

2. The spray drying apparatus according to claim 1, wherein the means for recovering spray dried particles from the spray dryer chamber comprises the cyclone connected between the spray dryer chamber and the solids container.

3. The spray drying apparatus according to claim 1, wherein the spray dryer chamber comprises a cylindrical upper section and a conical lower section.

4. The spray drying apparatus according to claim 3, wherein the outlet of the spray dryer chamber is in the conical lower section.

5. The spray drying apparatus according to claim 3, wherein at least one of the at least one secondary gas stream inlets is in at least one of the following locations selected from the group consisting of: i) in the cylindrical upper section of the spray dryer chamber; and ii) in the conical lower section of the spray dryer chamber.

6. The spray drying apparatus according to claim 1, wherein the one or more secondary gas streams are added to the spray drying apparatus in a location outside the spray region.

7. The spray drying apparatus according to claim 3, wherein the outlet of the spray dryer is in the conical lower section, wherein the cyclone or the filter bag is connected to the outlet of the spray dryer in the conical lower section to allow the particles from the spray dryer chamber to pass into the solids container connected to the cyclone or the filter bag via the second connection.

8. The spray drying apparatus according claim 1, wherein the atomization nozzle is of the pressure type, of the two-fluid type, or of the rotary type.

9. The spray drying apparatus according to claim 1, wherein the atomization nozzle is centrally located in the top of the spray dryer chamber.

10. The spray drying apparatus according to claim 8, wherein the atomization nozzle is centrally located in the top of the spray dryer chamber.

11. The spray drying apparatus of claim 1 comprising the filter bag.

12. The spray drying apparatus of claim 1, wherein a distance between the at least one secondary gas stream inlet and the atomization nozzle is from 20 cm to 70 cm.

13. The spray drying apparatus of claim 1, wherein a distance between the at least one secondary gas stream inlet and the atomization nozzle is from 20 cm to 45 cm.

14. The spray drying apparatus of claim 1, wherein a distance between the at least one secondary gas stream inlet and the atomization nozzle is from 45 cm to 70 cm.

15. A method comprising increasing the bulk density of an amorphous solid dispersion of an active pharmaceutical ingredient (API) and, where present, one or more excipients, relative to a corresponding process where one or more secondary gas streams are not present, by spray drying a feed mixture comprising the API and, where present, the one or more excipients with the spray drying apparatus according to claim 1.

16. A method comprising increasing the amorphous physical stability of the particles recovered from a spray dryer chamber, relative to a corresponding process where one or more secondary gas streams are not present by spray drying a feed mixture with the spray drying apparatus of claim 1.

17. A method comprising decreasing the residual solvent content of the particles recovered from a spray dryer chamber, relative to a corresponding process where one or more secondary gas streams are not present by spray drying a feed mixture comprising the solvent with the spray drying apparatus of claim 1.

18. The method of claim 15, wherein a distance between the at least one secondary gas stream inlet and the atomization nozzle is from 20 cm to 70 cm.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a diagram of the process of the present invention.

(2) FIG. 2 is a DSC thermogram of the powder obtained in trial #8.

DETAILED DESCRIPTION OF THE INVENTION

(3) Referring now to the invention in more detail, in FIG. 1 it is shown a spray drying apparatus comprising a spray dryer chamber 10 where a feed mixture in the form of a liquid stream 12 is atomized into droplets in an atomization nozzle and dried with drying gas 14, which is preferably a co-current drying gas. The properties of the dried particles are mostly defined in a region 16 in the vicinity of the nozzle, hereafter referred to as the spray region. The spray region 16 is where the majority of the dried particles are formed. The spray drying apparatus also comprises means for recovering the dried particles from the spray dryer chamber. In FIG. 1, the dried particles are separated from the drying gas in a cyclone 18 and collected in a container 20, while the drying gas exits the cyclone in an outlet stream 24. However, the means for recovering dried particles from the spray dryer chamber may also take the form of other means, which will be known to the person skilled in the art, such as a filter bag.

(4) The spray dryer chamber shown in FIG. 1 preferably comprises a cylindrical upper section and a conical lower section, relative to the drying gas outlet. However, alternative spray dryer chamber shapes and types are also within the scope of the invention. Such suitable alternatives will be known to the skilled person.

(5) The spray dryer chamber also preferably comprises an atomization nozzle of the pressure type, of the two-fluid type, or of the rotary type. The atomization nozzle is preferably centrally located in the top of the spray dryer chamber.

(6) One or more secondary gas streams are added to the process train. Preferably, the one or more secondary gas stream are added to the spray drying apparatus in at least one of the following locations: i) in the straight section of the spray dryer chamber (location 26); ii) in the conical section of the drying chamber (location 28); iii) in the connection between the drying chamber and the cyclone (location 30); iv) in the connection between the cyclone and the solids container (location 32); and v) in the solids container (location 34). However, other locations in the spray drying apparatus for adding the one or more secondary gas streams are not excluded from the scope of the invention.

(7) In an example, the location of the one or more secondary gas streams can be selected depending on what the intended purpose of the one or more gas streams is. For example, it may be desirable to use the one or more secondary gas streams to prevent condensation of the spray dried product in the coldest parts of the spray drying apparatus such as in locations 30, 32 and/or 34, by adding the one or more secondary gas streams in these locations.

(8) In more detail, still referring to the embodiment of the invention discussed in FIG. 1, the flow rate and the temperature of the secondary gas stream added to the process train in any of the locations 26, 28, 30, 32 and 34 can be adjusted independently to meet the desired effect depending on the flow rate and temperature of the liquid stream 12 and drying gas 14. In particular, the flow rate of the stream added in location 34 can be adjusted in a range that at its upper limit promotes the fluidization of the powder in the solids container 20 while preventing the powder to backflow upwards to the cyclone.

(9) In further detail, still referring to the embodiment of the invention of FIG. 1, the liquid stream 12 comprises a solvent system which can be comprised of one solvent, or mixture of solvents. The liquid stream 12 also comprises at least one active pharmaceutical ingredient, or at least one excipient, and preferentially at least one excipient and at least one API. The solvent or solvent mixture in stream 12 can be water, organic solvents, or combinations thereof. Preferably, the solvent system comprises water, acetone, methyl ethyl ketone, ethanol, methanol, isopropanol, ethyl acetate, hexane, heptane, dichloromethane, tetrahydrofuran, or a combination thereof. Upon contact with the drying gas 14 the drying of the droplets of feed mixture produces amorphous solid dispersions of the active pharmaceutical ingredients in the excipients. The atomization system can be of pressure-type, two-fluid-type (either internal or external mixture), rotary-type or any other atomization mechanism known by one skilled in the art.

(10) Preferably, the one or more excipients comprise one or more polymers. Preferably, a solution of one or more active pharmaceutical ingredients and one or more polymers is spray dried to produce an amorphous solid dispersion of the one or more active pharmaceutical ingredients in the one or more polymers. Polymers suitable for use in the formulations of the disclosure include, but are not limited to, N-vinyl lactam, copolymer of N-vinyl lactam, cellulose ester, cellulose ether, polyalkylene oxide, polyacrylate, polymethacrylate, polyacrylamide, polyvinyl alcohol, vinyl acetate polymer, oligosaccharide, polysaccharide, homopolymer of N-vinyl pyrrolidone, copolymer of N-vinyl pyrrolidone, copolymer of N-vinyl pyrrolidone and vinyl acetate, copolymer of N-vinyl pyrrolidone and vinyl propionate, graft copolymer of polyethylene glycol/polyvinyl caprolactam/polyvinyl acetate (e.g., Soluplus), polyvinylpyrrolidone, hydroxyalkylcelluloses, hydroxypropylcellulose, hydroxyalkylalkylcellulose, hydroxypropylmethylcellulose, cellulose phthalate, cellulose succinate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose acetate succinate, polyethylene oxide, polypropylene oxide, copolymer of ethylene oxide and propylene oxide, methacrylic acid/ethyl acrylate copolymer, methacrylic acid/methyl methacrylate copolymer, butyl methacrylate/2-dimethylaminoethyl methacrylate copolymer, poly(hydroxyalkyl acrylate), poly(hydroxyalkyl methacrylate), alkyl acrylate Crosspolymers (e.g. Permulen Carbopol), acrylic acid polymer crosslinked with divinyl glycol (e.g. Noveon), Gelatin, gelatin, copolymer of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, carrageenan, galactomannan, high viscosity gums or xanthan gum, or a combination thereof.

(11) The advantages of the present invention include, without limitation, that it enables the production of high density powders owing to the ability of having very high relative saturation of the drying gas in the spray region without compromising the process yield. High density powders are known to facilitate downstream processes of pharmaceutical operations such for example tableting, capsule filling or sachet filling.

(12) It was found that the powder bulk density can be increased if the additional stream of gas is introduced with increasing distance away from the spray region. Other effects that were identified were that bulk density can be increased by increasing the flow rate of the additional stream of gas, and by decreasing the temperature of the additional stream of gas.

(13) In a specific example, to maximize the bulk density of a spray dried powder, such as a spray dried amorphous solid dispersion, the distance between one of the one or more secondary gas stream inlets and the atomization nozzle is from 20 cm to 70 cm, optionally from 20 to 45 cm, or from 45 to 70 cm.

(14) The bulk density of the spray dried amorphous solid dispersion can also be maximized in certain processes by using one or more secondary gas streams with a temperature of from 25 C. to 75 C., preferably from 25 C. to 50 C.

(15) The bulk density of the spray dried amorphous solid dispersion can also be maximized in certain processes by using one or more secondary gas streams with a flow rate of from 50 litres per minute to 100 litres per minute, such as from 60 litres per minute to 90 litres per minute.

(16) In certain processes, the flow rate of the drying gas into the spray dryer chamber is from 12 kg/hour to 35 kg/hour, such as from 12 kg/hour to 24 kg/hour, or from 12 kg/hour to 20 kg/hour.

(17) The feed mixture can be fed to the spray dryer chamber at any suitable flow rate to achieve optimum spray drying and optimum powder properties. In certain processes, the feed mixture is fed to the spray drying apparatus with a feed rate of from 20 to 30 ml/minute.

(18) In a specific example, the bulk density of the spray dried powder such as a spray dried amorphous solid dispersion is maximized with a distance between the one or more secondary gas stream inlets and the atomization nozzle of from 20 cm to 70 cm, a flow rate of the one or more secondary gas streams of from 50 litres per minute to 100 litres per minute, and a temperature of the one or more secondary gas streams of from 25 C. to 50 C.

(19) The drying gas can be any suitable drying gas known in the art to effectively dry atomized droplets of a feed mixture. Preferably, the drying gas is nitrogen. The one or more secondary gas streams can also comprise any suitable drying gas known in the art to be suitable for use in spray drying processes. Preferably, the one or more secondary gas streams comprise nitrogen.

(20) The process of the present invention provides spray dried particles such as spray dried amorphous solid dispersions of one or more APIs and one or more excipients such as polymers with a bulk density of greater than 0.07 g/ml, preferably, greater than 0.15 g/ml. Preferably, the bulk density of spray dried particles is from 0.1 g/ml to 0.5 g ml, or from 0.1 g/ml to 0.25 g/ml.

(21) In addition to increased bulk density, the produced particles such as amorphous solid dispersions of one or more APIs and one or more excipients such as polymers have improved amorphous physical stability when compared to a conventional corresponding spray drying process where step e. of using the one or more secondary gas streams is not present, since in the present invention these particles are only exposed to high relative saturations for a smaller period of time. The present invention also enables the use of throughputs of feed solution higher than in conventional spray drying, while minimizing typical condensation problems when spray drying high boiling point solvents such as water, or accumulation of the material on the walls of the equipment. It also enhances the cyclone efficiency through an adequate balancing of the flow rate of the added gas streams. An additional benefit of the present invention is that it can reduce the residual solvent of the powders produced since these are exposed to lower relative saturations in the collector owing to the added gas streams.

(22) The advantages of the present invention include, without limitation, that: it enables the production of high density powders owing to the ability of having very high relative saturation of the drying gas in the spray region (region 16) without compromising the process yield. High density powders are known to facilitate downstream processes such as for example tableting and capsule filling. Additionally, the produced particles have improved amorphous physical stability when compared to a conventional corresponding spray drying process where step e. of using the one or more secondary gas stream is not present, since in the present invention these particles are only exposed to high relative saturations for a smaller period of time. The present invention enables the use of very high throughputs of feed solution, while minimizing typical condensation problems when spray drying high boiling point solvents such as water, or accumulation of the material on the walls of the equipment. It also enhances the cyclone efficiency through an adequate balancing of the flow rate of the added gas streams. An additional benefit of the present invention is that it can reduce the residual solvent of the powders produced since these are exposed to lower relative saturations in the collector owing to the added gas streams.

(23) Furthermore, the process of the present invention provides the advantages discussed above by employing a simpler process than prior art attempts to optimize properties of spray dried powders. For example, the process of the present invention preferably does not involve introduction of solid material to the spray dryer chamber such as particles of solid material dispersed within the drying gas. The process of the invention also only requires the use of one solvent system which is the solvent system employed in the feed mixture. The process of the present invention preferably does not comprise additional solvent vapours being introduced to the spray drying process train. For example, preferably, the drying gas does not comprise solvent vapours. The process of the present invention also preferably comprises atomizing the feed mixture into droplets and drying of said droplets with a drying gas, wherein the atomization and drying occurs within the same chamber, such as spray dryer chamber 10.

(24) While the foregoing written description of the invention enables one of ordinary skill to make and use what is considered presently to be the best mode thereof, those of ordinary skill will understand and appreciate the existence of variations, combinations, and equivalents of the specific embodiment, method, and examples herein. The invention should therefore not be limited by the above described embodiment, method, and examples, but by all embodiments and methods within the scope and spirit of the invention as claimed.

EXAMPLES

Example 1

(25) This example demonstrates the impact of process conditions on the production of an amorphous solid dispersion of itraconazole (API) in copovidone (polymer) using the invention herein presented.

(26) Five trials were carried out using a half factorial design of experiments (DoE) (trials #3 to #7). The variables selected in the design of experiment were the location of the added gas stream in relation to the nozzle (20 cm to 70 cm), the feed rate (60 to 90 L/min), and the temperature (25 C. to 75 C.) of the added gas stream. For comparison purposes, one trial was carried out using feasible operating conditions of a conventional spray drying setup (trial #1), without using an additional nitrogen stream. The same throughput used in trials #3 to #7 was used in trial #2 in conventional spray drying mode of operation.

(27) A feed mixture was prepared in each trial by dissolving 2 g of API and 18 g of polymer in a mixture of acetone:water with a 75:25 w/w ratio (735 g of acetone and 245 g of water). A laboratory scale spray dryer (Procept 4M8Trix) equipped with a two-fluid nozzle was used to process the feed mixture at 24 mL/min, with an atomization nitrogen flow rate of 30 L/min. An additional stream of neat nitrogen was added in radially evenly distributed points, tangential to the wall of the drying chamber.

(28) The operating conditions are detailed in the table below. Of note is the drying gas flow rate used in the trials. In trial #1 the minimum drying gas flow rate that could be used to overcome condensation issues was 24 kg/h (the drying gas flow rate was increased in a stepwise fashion until no condensation was observed). The process throughput was increased in trial #2 by reducing the drying gas flow rate to 12 kg/h, which led to condensation and sticking of the solids to the equipment walls. Hence, the results show that an increase in process throughput as in trial #2 is unfeasible in a conventional spray drying process setup.

(29) In the trials of the DoE, the use of an additional nitrogen stream enabled the use of a drying gas flow rate of 12 kg/h and consequently an increase in the local relative saturation conditions in the spray region. The use of an additional stream of nitrogen had an effect of lowering the process dew point (compiled in the table below as T_dew*), which reduced the potential for condensation. Amorphous materials were obtained in all trials in the DoE (#3 to #7), which is indicated by a single glass transition temperature in the DSC analysis (see FIG. 2 related to trial #7). In contrast, amorphous material could not be obtained in conventional spray drying mode in trial #2 due to condensation issues.

(30) The bulk density of the amorphous solid dispersion produced after spray drying was 0.065 g/mL in trial #1. In the DoE trials where an additional stream of nitrogen was added to the process train, bulk density was always larger than in trial #1. The highest bulk density value was observed in trial #4 (0.165 g/mL), with more than a two-fold increase in relation to trial #1. Hence, the use of an improved spray drying process as wherein disclosed enables an increase in bulk density for a fixed mixture feed rate.

(31) The analysis of the results obtained in the DoE trials shows that bulk density increases with increasing distance of the added stream in regards to the spray region (N2_location), with increasing flow rate of the added stream (F_add), and with decreasing temperature of the added stream (T_add).

(32) TABLE-US-00001 Trial 1 2 3 4 5 6 7 Operating conditions N2_location cm 70 70 20 20 45 F_add L/min 60 90 90 60 75 T_add C. 25 75 25 75 50 Relative throughput.sup.a 1 2 2 2 2 2 2 F_drying kg/h 24 12 12 12 12 12 12 F_feed mL/min 24 24 24 24 24 24 24 F_atomiz L/min 30 30 30 30 30 30 30 T_in C. 90 110 110 110 110 110 110 T_out C. 25 NA 21 30 17 27 23 T_dew C. 15 26 26 26 26 26 26 T_dew* C. 21 20 20 21 20 Results Bulk density g/mL 0.065 NA 0.129 0.164 0.160 0.093 0.120 Tg C. 50 NA 39 46 46 42 45 .sup.aRelative throughput is determined by comparing the ratio of F_feed and F_drying in each trial to to trial #1