Improved spray drying process for producing powders with enhanced properties

Abstract

An improved spray drying process is provided for producing amorphous solid dispersions with enhanced bulk density and material properties. The method includes the steps of: a) providing a feed mixture comprising one or more active pharmaceutical ingredients (APIs), one or more excipients, or a mixture thereof; and a solvent system comprising at least one solvent; b) delivering the feed mixture to a spray-drying apparatus having a spray-drying chamber; c) atomizing the feed mixture into droplets using an atomizing nozzle; d) drying the droplets with a drying gas to produce particles; e) delivering one or more secondary gas streams to the spray-drying apparatus at at least one of a plurality of locations within the spray-drying apparatus; and f) recovering the particles from the spray-drying chamber. At least one additional stream can be introduced into the spray-drying apparatus at at least one of a plurality of locations without interfering with the atomization region.

Description

[Technical field]

[0001] The present invention is in the field of drying methods. More specifically, the present invention relates to drying methods for active pharmaceutical ingredients. In the field of spray drying applied to pharmaceutical ingredients (API), drug product intermediates and drug products It is something. [Background technology]

[0002] In conventional operation of spray dryers used in the pharmaceutical industry, the drying gas is used alone. The dried powder is then pumped into a cyclone and / or filter bag to remove the gas. [Masters, K., "Spray drying handbook" (1991)]. The drying conditions required to obtain the desired properties (e.g. density, grain size) are Often times this limits the throughput of the process and / or results in a higher than desirable solvent / water content. This results in a material having a high content, which is particularly important in the processing of amorphous solid dispersions. Also, the use of very high throughput feed solutions can present stability problems. When spray drying high boiling solvents, problems of condensation and accumulation of material on the equipment walls often occur. Drop.

[0003] In a spray-dried dispersion (SDD), the active pharmaceutical ingredient (API) is dispersed in a polymer matrix. The polymer stabilizes the amorphous and metastable forms of the drug and maintains supersaturation of the API in the solution / biological fluid, thereby increasing bioavailability; The use of intrinsic solvents in the spray drying process has a plasticizing effect. and the corresponding undesirable change in the glass transition temperature (Tg) of the amorphous solid dispersion during the drying process. The Tg is one of the most important characteristics of an amorphous solid dispersion, but g may be essentially related to the molecular mobility of the API, and the spray-dried dispersion formulation may improve the shelf life of the product. This is because it is one of the properties that indicates whether a compound is stable enough to prevent crystallization over a long period of time. be.

[0004] Typical operations downstream of the spray drying step in pharmaceutical processes include blending, roller pressure adjustment, and The SDD material can be compressed downstream without significant operational difficulties. The ability of a powder to flow through and be processed in a given equipment depends on the powder characteristics, i.e. particle size, density and composition. It is closely related to the balance of cohesive-adhesive forces between the equipment and the device. indicates that both the grain size and density should be as large as possible. For example, assume that the powder also has the necessary compressibility to allow a direct compression approach. (as indicated by the relationship between bulk density and tapped density).

[0005] The spray drying literature includes reports of adding an additional fluid flow to the process step to reduce wall accumulation. For example, U.S. Patent Application Serial No. 5,596,817 describes a drying chamber. The gas is injected at a high flow rate at the top of the chamber and at a low flow rate near the wall of the chamber. By allowing efficient blowing effect, product accumulation is minimized. Also, in U.S. Patent Application No. 3,895,994, a method for removing the accumulated product on the cylinder wall is disclosed. The deposit and recirculation to the hot zone are arranged around the injection end of the spray dryer cylinder. By introducing peripheral gas flow from a closed inlet and swirling it inside the cylinder, However, none of these patents disclose a method for spray drying the active pharmaceutical ingredient. The problems associated with spray drying to produce amorphous solid dispersions of ingredients and polymers are specifically addressed. The additional gas flow in these patents is simply formed on the wall of the spray dryer. Used to minimize solid deposits and to provide enhanced powder properties Not used.

[0006] The latest technology is the use of modified spray drying mechanisms to optimize powder properties. Several examples are given. For example, European Patent Application No. 0387950 describes a method for producing a zeolite having a given bulk density. An apparatus for obtaining a spray-dried product is disclosed. A nozzle is provided for supplying a gas with dried particulate material. The ratio of collisions between the gas-solid suspension and the atomizer is The rate and speed make it possible to control the bulk density of the powder. The drying gas supplied to the chamber may be enriched in one or more solvent vapors to determine the properties of the particles, Thus, a spray drying method is disclosed that controls the density and solvent content of the particles.

[0007] U.S. Patent Application No. 8,337,895 describes a method for controlling the drying of droplets and enhancing the enrichment of active ingredients on the surface. a humidity and temperature controlled conditioning zone for applying a pressure to the droplets and for drying the droplets exiting the conditioning zone; A method is disclosed which is intended primarily for inhalation products, including a drying zone of Humidity control, e.g., through a humid air inlet, and / or temperature control, to control conditions in the accommodation strap A temperature control device is provided so that the droplets dry more slowly in the regulating zone than in the dryer. In accordance with the present disclosure, drying kinetics is used to promote diffusion of surface active ingredients at the surface, The amorphous to crystalline conversion can be accelerated during manufacture of a dry powder formulation.

[0008] In summary, the current state of the art involves strategies to prevent product deposition on the walls of the equipment or the use of additional solvents. The adjustment of powder properties by the introduction of a solvent or fine particle size reduction and significant changes in the configuration of the process steps are disclosed. It is just that.

[0009] The inventors of the present invention have demonstrated that the throughput, yield and more importantly the quality of the product of the process, Specifically, to produce materials with higher bulk densities without compromising their amorphous content. It has been recognized that there is a need for a simpler spray drying method that can The present inventors have developed a method for the production of amorphous solid dispersions of active pharmaceutical ingredients and polymers using spray drying. Methods include increased bulk density, lower glass transition temperature and lower residual solvent content. There is a need to produce spray dried particles having enhanced powder properties such as mass. Furthermore, the present inventors have demonstrated that such a method can be easily achieved by a simple spray drying process. It has been recognized that there is a need to provide a spray-dried powder having the following properties: Attempts to improve the properties of spray-dried products are known in the art. The methods are complex and typically involve the use of other solvents in the drying gas or the proximity of the atomizer. Introduction of solid materials adjacent to the chamber (WO2011 / 154014 and EP0387950), or separate conditioning chambers and Use of controlled drying kinetics with multiple chambers in a spray dryer such as a drying chamber The invention disclosed herein overcomes the shortcomings identified in the prior art. This is what we do. Summary of the Invention

[0010] (Summary of the invention) According to an embodiment of the present invention, there is provided a spray drying method comprising: a. providing a feed mixture, the feed mixture comprising: one or more active pharmaceutical ingredients (APIs), one or more excipients, or a mixture thereof; and at least the process further comprising a solvent system comprising at least one solvent; b. feeding the feed mixture into a spray drying apparatus comprising a spray dryer chamber; c. atomizing the feed mixture into droplets with an atomizing nozzle; d. drying the droplets with a drying gas to release the one or more APIs; one or more excipients, or a mixture thereof; producing particles of the compound; e. directing one or more second gas streams at at least one of a plurality of locations within the spray drying apparatus; feeding into said spray drying apparatus; f. recovering the particles from the spray dryer chamber. It will be offered.

[0011] Preferably, the feed mixture comprises one or more APIs and one or more excipients. The above excipients include one or more polymers.

[0012] Preferably, step d. of the method comprises mixing one or more APIs and, if present, one or more excipients. Preferably, the method comprises step e. of claim 1. Amorphous solid dispersions having increased bulk density compared to corresponding non-amorphous spray drying methods. It is for producing things.

[0013] Preferably, step f. comprises collecting the particles in a vessel connected to the spray dryer chamber. and recovering the particles from the spray dryer chamber by a step f. of recovering the particles from the spray dryer chamber; The cyclone or filter bag connected to the chamber is passed through the cyclone or filter bag. This involves entering a container connected to the bag.

[0014] In accordance with another aspect of the present invention, a method for manufacturing a cellular telephone comprising: A spray drying apparatus is provided that includes a second gas inlet.

[0015] Preferably, the apparatus has an increased efficiency compared to a corresponding spray drying apparatus not having a second gas inlet. The objective is to produce a solid dispersion having an increased bulk density.

[0016] According to another aspect of the invention, the method is compared to the corresponding method in the absence of the one or more second gas streams. In comparison, the bulk density of an amorphous solid dispersion of an active pharmaceutical ingredient (API) and one or more excipients is increased. compared to a corresponding method in which one or more secondary gas flows for adding To increase the amorphous physical stability of the particles recovered from the fog dryer chamber, and / or one or more secondary gas streams are not present, compared to a corresponding method Use of the method of the present invention to reduce the residual solvent content of the particles recovered from the chamber. is provided.

[0017] According to another aspect of the present invention, at least one An amorphous solid dispersion is provided that includes an active pharmaceutical ingredient (API) and at least one excipient. .

[0018] In accordance with another aspect of the present invention, a method for treating a pulmonary artery disease comprising administering to a patient a therapeutically effective amount of at least one active pharmaceutical ingredient (API) and at least one and wherein the amorphous solid dispersion has a viscosity of greater than 0.07 g / ml. Preferably, the dispersion has a bulk density of greater than 0.1 g / ml, optionally greater than 0.15 g / ml. Preferably, the dispersion has a density of 0.1 g / ml to 0.5 g / ml, or 0.1 g / ml to 0.5 g / ml. Preferably, the at least one excipient comprises a polymer.

[0019] The present invention relates to pharmaceutical compositions, particularly non-medicinal compositions, having enhanced throughput and enhanced material properties. An improved spray drying method for producing a crystalline solid dispersion. The gas flow is directed at at least one of a plurality of locations in the spray drying apparatus without interfering with the atomization region. This reduces the residual solvent content, thus improving the throughput of the process, powder density, and improve the amorphous physical stability. The end characteristics are optimized to avoid interfering with the position of one or more secondary gas flows. ), is controlled via the feed rate and temperature of the second gas stream.

[0020] The present invention reduces the degree of saturation locally, resulting in amorphous solid dispersions like those produced by spray drying. Reducing the solvent content in such pharmaceutical formulations reduces the plasticizing effect and therefore reduces the undesirable The introduction of a second gas flow is used to reduce the change in amorphous content.

[0021] The bulk density of the powder may be increased by: i) introducing the additional gas flow further away from the atomization region; ii) by increasing the flow rate of the additional gas flow; and iii) by increasing the flow rate of the additional gas flow. It was found that this could be further increased by decreasing the temperature of the gas stream. It was served.

[0022] The method of the present invention is advantageous in that it reduces the time required for spray drying compared to a corresponding method in which one or more secondary gas streams are not used. Increased bulk density, lower glass transition temperature, and / or lower viscosity in the dried product. A spray dried amorphous solid dispersion having a residual solvent content is provided.

[0023] "Corresponding method in the absence of the one or more second gas streams" and "Corresponding spray drying method" The term "process," and similar terms as used herein, refers to the second gas stream (e.g., For example, it refers to the same spray drying process except that process step e.) is absent. For example, a spray drying process is described as "corresponding to another spray drying process in which step e. is absent." If so, this description applies to the same spray drying process using the same equipment and the same spray drying conditions. The only difference between these two methods is the presence of the one or more second gas streams. This refers to the mist drying method. By "atomization zone" we mean the large area located below the atomizer. It is intended to mean the volume inside a spray-drying chamber that contains a number of droplets.

[0024] The term "bulk density" as used herein is a term well known in the art. Bulk materials, e.g., grains of various sizes with irregularly sized voids between the different grains, Bulk density refers to the density of a powder that may have a molecular weight of 1.0 or more. Bulk density is the total mass of a specimen from a material divided by the total mass of the material. It is defined as dividing by a product. [Brief description of the drawings]

[0025] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] FIG. 1 is a diagram of the method of the present invention. [Diagram 2]FIG. 13 is a DSC thermogram of the powder obtained in Trial #8. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] Detailed Description of the Invention Referring now to the present invention in more detail, FIG. 1 shows a feed mixture in the form of a liquid stream 12 being fed to a finely divided Drying gas 14, preferably a co-current drying gas, which is atomized into droplets in the atomizing nozzle. The spray drying apparatus includes a spray dryer chamber 10 in which the powder is dried by The properties of the sprayed particles are primarily defined within a region 16 proximate the nozzle, hereafter referred to as the spray region. The spray area 16 is where the majority of the dried particles are formed. The spray drying apparatus includes a means for recovering the dried particles from the spray dryer chamber. In FIG. 1, the dried particles are isolated from the drying gas in cyclone 18 and placed in vessel 20. while the drying gas exits the cyclone in outlet stream 24. The means for recovering dried particles from the spray dryer chamber may take the form of other means. The container may take any of a variety of forms known to those skilled in the art, such as a filter bag.

[0027] The spray dryer chamber shown in FIG. 1 is preferably cylindrical relative to the drying gas outlet. However, alternative spray dryer chamber shapes and Any such suitable alternatives are within the scope of the present invention.

[0028] The spray dryer chamber is preferably a pressure, two-fluid, or rotary type atomizer. The atomization nozzle is preferably located at the center of the top end of the spray dryer chamber. Located in.

[0029] One or more second gas streams are added to the process sequence. Preferably, the one or more second gas streams are Location: i) the upright portion of the spray dryer chamber (position 26); ii) the cone portion of the drying chamber (position 28); iii) the connection between the drying chamber and the cyclone (position 30); iv) the connection between the cyclone and the solids container (position 32); and v) the solids container (position 34), at least one of which is added to the spray dryer. However, However, other locations in the spray drying apparatus for adding the one or more secondary gas streams are within the scope of the present invention. are not excluded from the

[0030] By way of example, the location of the one or more second gas flows may be determined based on the intended purpose of the one or more gas flows. For example, the one or more second gas streams can be used to In the coolest part of the spray drying apparatus, such as at positions 30, 32 and / or 34, adding said one or more second gas streams at said locations to prevent condensation of the spray-dried product. would be desirable.

[0031] More specifically, and with further reference to the embodiment of the invention depicted in FIG. The flow rate and temperature of the second gas stream added to any of the process steps in 30, 32 and 34 are can be independently adjusted to achieve the desired effect depending on the flow rates and temperatures of the liquid stream 12 and the drying gas 14. In particular, the flow rate of the flow applied at location 34 can be adjusted to the rate at which the powder flows through the cyclone. At its upper limit, the flow of the powder in the solid container 20 is controlled while preventing backflow upwards into the The amount of the oxidative stress can be adjusted within a range that enhances activation.

[0032] More specifically, and with further reference to the embodiment of the present invention in FIG. 1, the liquid stream 12 comprises one solvent. The liquid stream 12 also includes a solvent system which may be comprised of at least one an active pharmaceutical ingredient or at least one excipient, and preferentially at least one excipient and The solvent or mixture of solvents in stream 12 may be water, an organic solvent, or the like. Preferably, the solvent system is water, acetone, methyl ether, or a combination of these. Chile ketone, ethanol, methanol, isopropanol, ethyl acetate, hexane, heptane Drying gases include ethane, dichloromethane, tetrahydrofuran, or combinations thereof. Upon contact with the gas 14, the droplets of feed mixture dry, thereby dissolving the active pharmaceutical ingredient in the excipient. An amorphous solid dispersion of the ingredients is produced. Micronization systems include pressure-based, two-fluid (internal mixture or or external mixing), rotary or any other atomizer known to those skilled in the art. This structure can be adopted.

[0033] Preferably, the one or more excipients comprise one or more polymers. A solution of the drug substance and one or more polymers is spray-dried to release the one or more active ingredients in the one or more polymers. Suitable polymers for use in the formulations of the present disclosure These include, but are not limited to, N-vinyl lactams, copolymers of N-vinyl lactams, Cellulose ester, cellulose ether, polyalkylene oxide, polyacrylate , polymethacrylate, polyacrylamide, polyvinyl alcohol, vinyl acetate polymer -, oligosaccharides, polysaccharides, homopolymers of N-vinylpyrrolidone, copolymers of N-vinylpyrrolidone copolymer of N-vinylpyrrolidone and vinyl acetate, copolymer of N-vinylpyrrolidone and propylene Copolymer of vinyl acetate, polyethylene glycol / polyvinyl caprolactam / polyacetic acid Graft copolymers of vinyl acid (e.g., Soluplus®), polyvinylpyrrolide cellulose, hydroxyalkyl cellulose, hydroxypropyl cellulose, hydroxyalkyl alkyl cellulose, hydroxypropyl methylcellulose, cellulose phthalate, Cellulose chloride, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate cellulose, hydroxypropyl methylcellulose succinate, hydroxypropyl acetate succinate Methylcellulose, polyethylene oxide, polypropylene oxide, ethylene oxide and propylene oxide copolymers, methacrylic acid / ethyl acrylate copolymers, Acrylic acid / methyl methacrylate copolymer, butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymer, poly(hydroxyalkyl acrylate), poly(methacrylate hydroxyalkyl acrylates), alkyl acrylate crosspolymers (e.g., Permulen (registered trademark) Carbopol®, an acrylic acid polymer crosslinked with divinyl glycol (e.g., Noveon®), gelatin, gelatin, vinyl acetate, and crotonic acid Polymers, partially hydrolyzed polyvinyl acetate, carrageenan, galactomannan, high viscosity The gum may be cellulose gum, xanthan gum, or a combination thereof.

[0034] Advantages of the present invention include, but are not limited to, the ability to reduce the amount of Allows the production of dense powders due to the ability to provide very high relative saturation in the drying gas High density powders can be used for example for tableting, capsule filling or sachet filling. It is known to facilitate downstream processes of pharmaceutical manipulation such as

[0035] When an additional gas flow is introduced at a greater distance from the atomization region, the bulk density of the powder increases. It was found that the degree of the gas diffusion can be increased. By increasing the flow rate of the additional gas stream and by decreasing the temperature of the additional gas stream. This resulted in an increase in bulk density.

[0036] In an embodiment, the powder is a spray-dried powder, e.g., a spray-dried amorphous solid dispersion. To maximize the bulk density, the distance between one of the one or more secondary gas inlets and the atomizing nozzle is The distance is 20 cm to 70 cm, optionally 20 to 45 cm, or 45 to 70 cm.

[0037] The bulk density of the spray-dried amorphous solid dispersion is preferably between 25° C. and 75° C. By using one or more second gas streams at temperatures between 25°C and 50°C, it is possible to obtain a maximum It can be.

[0038] The bulk density of the spray dried amorphous solid dispersion is between 50 liters per minute and 10 liters per minute. 0 liters, e.g., one or more second gas streams with a flow rate of 60 liters per minute to 90 liters per minute. By this, it can be maximized in a specific way.

[0039] In certain methods, the flow rate of the drying gas into the spray dryer chamber is between 12 kg / hr and 35 kg / hr. kg / hour, for example, 12 kg / hour to 24 kg / hour, or 12 kg / hour to 20 kg / hour.

[0040] The feed mixture may be fed into the spray dryer chamber at any suitable flow rate to obtain optimal spray drying. Dryness and optimal powder properties can be achieved. In a particular method, the feed mixture comprises: The feed rate into the spray dryer is 20-30 ml / min.

[0041] In an embodiment, the powder is a spray-dried powder, e.g., a spray-dried amorphous solid dispersion. The gas density is such that the distance between the one or more second gas inlets and the atomizing nozzle is 20 cm to 70 cm. The flow rate of the one or more second gas streams is 50 liters / minute to 100 liters / minute, and the one or more second gas streams The maximum occurs when the gas flow temperature is between 25℃ and 50℃.

[0042] The drying gas is known in the art to effectively dry the atomized droplets of the feed mixture. The drying gas may be any suitable drying gas known in the art. Preferably, the drying gas is , nitrogen. The one or more second gas streams are also suitable for use in a spray drying process. The drying gas may comprise any suitable drying gas known in the art. The one or more second gas streams comprise nitrogen.

[0043] The method of the present invention comprises the steps of: Spray-dried particles of the API and one or more excipients, such as a polymer, e.g., spray-dried Preferably, the bulk density of the spray dried particles is 0.1 g / ml to 0.5 g / ml, or 0.1 g / ml to 0.25 g / ml.

[0044] In addition to the increased bulk density, the produced particles, such as one or more APIs and polymers, Step e. is absent in which an amorphous solid dispersion of one or more excipients is used with the one or more second gas streams. It has improved amorphous physical stability compared to the corresponding conventional spray drying methods. This is because, in the present invention, these particles are exposed to high relative saturation for a shorter period of time. This is because the only way to achieve this is to use a spray dryer. Typical condensation problems when spray drying high boiling solvents such as water with a feed solution; This invention also allows for the minimization of material accumulation on the walls of the device. The efficiency of the cyclone is enhanced through proper balancing of the gas flow velocities. An additional benefit is that the present invention reduces the amount of powder produced in the collector due to the added gas flow. The resulting powders can have reduced residual solvent due to exposure to lower relative saturation. That is the thing.

[0045] Advantages of the present invention include, but are not limited to, the following: The present invention provides a very high concentration of the drying gas in the spray zone (zone 16) without compromising process yield. Due to its ability to withstand saturation, it allows the production of high density powders. It is known that such processes facilitate downstream processes such as tabletting and capsule filling. Furthermore, the particles produced are not subject to the conventional process in which step e. using the one or more second gas streams is not present. Improved amorphous physical stability compared to the corresponding spray drying method. This is due to: In the present invention, these particles are only exposed to high relative saturation for a shorter period of time. This is because. The present invention allows for the spray drying of high boiling point solvents such as water while using very high throughput feed solutions. This allows minimizing typical condensation problems during drying or accumulation of material on the equipment walls. do. The present invention also provides a method for balancing the flow rates of the added gas flows to improve the cyclonic efficiency. This increases the efficiency of the An additional benefit of the present invention is that it reduces the amount of powder produced by the added gas flow. The resulting powder is exposed to a lower relative saturation in the collector, reducing residual solvent in the powder. It is possible to make it happen.

[0046] Furthermore, the method of the present invention is useful for optimizing the properties of the spray-dried powders of the prior art. This provides the advantages discussed above by utilizing a methodology that is simpler than previous attempts to The method of the present invention preferably comprises the steps of: introducing solid material, e.g. The method of the present invention does not involve the introduction of dispersed solid material particles. The present invention only requires the use of one solvent system, which is the solvent system utilized in the product. The process preferably does not include additional solvent vapors being introduced into the spray drying process step. For example, preferably the drying gas does not contain solvent vapor. or atomizing the feed mixture into droplets and drying the droplets with a drying gas. wherein the atomizing and drying are performed in the same chamber, e.g. This is done in the spray dryer chamber 10.

[0047] The foregoing description of the present invention is intended to provide a complete understanding of the present invention as presently believed to be the best mode thereof to those skilled in the art. While the present invention enables those of skill in the art to make and use the specific embodiments, methods and methods described herein, It is understood and appreciated that there are variations, permutations, and equivalents to the methods and embodiments. Accordingly, the present invention should not be limited by the embodiments, methods, and examples described above. However, the present invention is not limited by any embodiment or method within the scope and spirit of the claimed invention. should be determined. EXAMPLES

[0048] Example 1 In this example, the preparation of isopropyl alcohol in copovidone (polymer) using the invention presented herein was performed. FIG. 1 shows the effect of process conditions on the production of amorphous solid dispersions of traconazole (API).

[0049] Five trials were performed using a half factorial experimental design (DoE) (Trial The variables selected in the experimental design were the nozzles for the added gas flow. The position (20 cm to 70 cm), the feed rate (60 to 90 L / min), and the temperature (25 For comparison purposes, one trial was performed using a conventional spray dryer without the use of an additional nitrogen flow. A viable operating condition for the drying mechanism was used (Trial #1). The same throughput as that used in Trial #2 in a conventional spray drying configuration was used. .

[0050] The feed mixture consisted of 2 g of API and 18 g of polymer in a 75:25 w / w ratio in acetone for each run. : Prepared by dissolving in a water mixture (735 g acetone and 245 g water). A laboratory-scale spray dryer (Procept 4M8Trix) equipped with a nozzle was used at 24 mL / min. The feed mixture was treated with a flow rate of 30 L / min of atomized nitrogen. The flow was applied circumferentially to the wall of the drying chamber at points uniformly distributed radially.

[0051] The operating conditions are detailed in the table below. Of note, the drying gas used in the trials was In Trial #1, the maximum flow rate that can be used to overcome the condensation problem is The flow rate of the drying gas was 24 kg / h (the flow rate of the drying gas was such that no condensation was observed). In Trial #2, the drying gas flow rate was increased to 12 kg / s. The throughput of the method was increased by decreasing the 1000 saturation temperature / hour. This reduced the condensation and the deposition on the equipment walls. Thus, this result indicates that the method, as in Trial #2, It has been shown that increasing throughput is not feasible with conventional spray drying process mechanisms. is.

[0052] In DoE trials, an additional nitrogen flow was used to achieve 12 kg / hr of drying gas. This allows the use of flow rates of 1000 MPa or less, resulting in increased local relative saturation in the spray region. The use of an additional nitrogen flow reduces the dew point of the process (T_ dew * (edited as "lowering the concentration of Amorphous materials were obtained in all runs (#3~#7) during DoE, which was confirmed by DSC analysis. (See FIG. 2 for Run #7) In contrast, amorphous materials were not spray dried in the conventional manner in Trial #2 due to aggregation issues. It was not possible to obtain this.

[0053] The bulk density of the amorphous solid dispersion produced after spray drying was 0.065 g / m in Trial #1. In DoE trials where an additional nitrogen flow was added to the method procedure, the bulk density was always The bulk density was greater than that in trial #1. The highest bulk density value was observed in trial #4. (0.165 g / mL), with a greater than 2-fold increase relative to trial #1. Thus, Use of the improved spray drying method as disclosed reduces bulk mass fraction for a given mixture feed rate. It is possible to increase the density.

[0054] From the analysis of the results obtained in the DoE trials, it was found that bulk density was added with respect to the spray area. The distance of the added flow (N2_position) is increased, and the flow velocity of the added flow (F_addition) is increased. and decreasing the temperature of the added flow (T_added); This indicates that it will increase.

[0055] [Table 1] a Relative throughput was determined by comparing the ratios of F_feed and F_dry for each trial to Trial #1. It is determined. The present application provides the following invention. (Configuration 1) 1. A spray drying process comprising: a. providing a feed mixture, the feed mixture comprising: one or more active pharmaceutical ingredients (APIs), one or more excipients, or a mixture thereof; and at least the process further comprising a solvent system comprising at least one solvent; b. feeding the feed mixture into a spray drying apparatus comprising a spray dryer chamber; c. atomizing the feed mixture into droplets with an atomizing nozzle; d. drying the droplets with a drying gas to release the one or more APIs; one or more excipients, or a mixture thereof; producing particles of the compound; e. directing one or more second gas streams at at least one of a plurality of locations within the spray drying apparatus; feeding into said spray drying apparatus; and f. recovering the particles from the spray dryer chamber. (Configuration 2) 2. The spray method according to claim 1, wherein the feed mixture comprises one or more active pharmaceutical ingredients and one or more excipients. Drying method. (Configuration 3) Amorphous solids of the one or more APIs, the one or more excipients, or the one or more APIs and one or more excipients. 3. The method of claim 1 or 2, further comprising producing a polymer dispersion. (Configuration 4) 4. The spray formulation of any one of claims 1, 2, or 3, wherein the one or more excipients include one or more polymers. Fog drying method. (Configuration 5) The one or more excipients may be an N-vinyl lactam, a copolymer of an N-vinyl lactam, a cellulose esters, cellulose ethers, polyalkylene oxides, polyacrylates, polymers acrylate, polyacrylamide, polyvinyl alcohol, vinyl acetate polymer, oligo Glycosaccharides, polysaccharides, homopolymers of N-vinylpyrrolidone, copolymers of N-vinylpyrrolidone, N- Copolymer of vinylpyrrolidone and vinyl acetate, N-vinylpyrrolidone and vinyl propionate Nyl copolymer, polyethylene glycol / polyvinyl caprolactam / polyvinyl acetate graft copolymers (e.g., Soluplus®), polyvinylpyrrolidone, hydrochloride, Hydroxyalkylcellulose, Hydroxypropylcellulose, Hydroxyalkylalkyl Cellulose, Hydroxypropyl Methylcellulose, Cellulose Phthalate, Cellulose Succinate cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, succinate Hydroxypropyl methylcellulose acetate succinate, Hydroxypropyl methylcellulose acetate succinate Polyethylene oxide, polypropylene oxide, ethylene oxide and propylene copolymer of ethylene oxide, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / Methyl methacrylate copolymer, butyl methacrylate / 2-dimethylaminoethyl methacrylate acrylate copolymer, poly(hydroxyalkyl acrylate), poly(hydroxymethacrylate) alkyl acrylate crosspolymers (e.g., Permulen®, C arbopol®), acrylic acid polymers crosslinked with divinyl glycol (e.g., N oveon®), gelatin, copolymer of gelatin, vinyl acetate and crotonic acid, part Hydrolyzed polyvinyl acetate, carrageenan, galactomannan, high viscosity gum, xanthate The spray drying method according to any one of configurations 1 to 4, further comprising: Law. (Configuration 6) Increased bulk density compared to a corresponding spray drying method in which step e. of configuration 1 is not present. A spray drying method according to any one of claims 1 to 5 for producing an amorphous solid dispersion having 。 (Configuration 7) Configurations 1-6, wherein the spray dryer chamber comprises a cylindrical upper portion and a cone-shaped lower portion. The spray drying method according to any one of the above. (Configuration 8) Step f. of recovering the particles from the spray dryer chamber comprises recovering the particles from the spray dryer chamber. 8. The spray drying method according to any one of claims 1 to 7, further comprising recovering the mixture in a container connected to the spray drying chamber. method. (Configuration 9) Step f. of recovering the particles from the spray dryer chamber comprises recovering the particles from the spray dryer chamber. The construction includes collection through the use of cyclones or filter bags connected to a filter holder. The spray drying method according to any one of claims 1 to 8. (Configuration 10) Step f. of recovering the particles from the spray dryer chamber comprises recovering the particles from the spray dryer chamber. The cyclone or filter bag connected to the cyclone or filter 10. The method of claim 9, further comprising entering a container connected to the bag. (Configuration 11) The step e) is performed at the following location: i) an upright portion of the spray dryer chamber (position 26); ii) at least one of the cone portions (positions 28) of the spray dryer chamber; 11. The spray drying method according to any one of claims 7 to 10, further comprising feeding a second gas stream. (Configuration 12) The step e) is performed at the following location: i) The connection between the spray dryer chamber and the filter bag or cyclone. 30); ii) the connection between the filter bag or cyclone and the vessel (position 32); iii) said container (position 34); iv) If a cyclone or filter bag is not present, the spray dryer chamber and the and directing at least one second gas stream into at least one of the locations between the vessels. 12. The spray drying method according to any one of aspects 9 to 11. (Configuration 13) The atomizing nozzle is a pressure type, a two-fluid type, or a rotary type. The spray drying method according to any one of the above. (Configuration 14) 14. The method of claim 1, wherein the atomization nozzle is centrally located at the top of the spray dryer chamber. The spray drying method according to any one of claims 1 to 5. (Configuration 15) The solvent system may be water, an organic solvent, such as acetone, methyl ethyl ketone, ethanol, Methanol, isopropanol, ethyl acetate, hexane, heptane, dichloromethane, tetrahydrofuran, or any combination thereof. The spray drying method. (Configuration 16) Configurations 1 to 15, wherein the second gas stream is added to the spray drying apparatus outside the spraying zone. The spray drying method according to any one of the above. (Configuration 17) The flow exiting the spray dryer chamber is the same as that of a corresponding conventional spray dryer without additional gas flow. 17. The spray drying method according to any one of claims 1 to 16, having reduced relative solvent saturation with respect to the process. method. (Configuration 18) The bulk density of the spray dried particles can be chosen from the following: i) increasing the distance of flow added to said spray area; ii) increasing the flow rate of the added flow; and iii) decreasing the temperature of the added stream. 18. The spray drying method according to any one of aspects 1 to 17, (Configuration 19) The throughput of the spray dryer is the same as that of a conventional spray dryer in which step e. of configuration 1 is not present. 19. The spray drying method according to any one of aspects 1 to 18, wherein the drying efficiency is higher than that of the spray drying method. (Configuration 20) 20. Any of claims 1 to 19, wherein the one or more second gas streams and / or the drying gas comprises a nitrogen gas stream. The spray drying method according to any one of claims 1 to 5. (Configuration 21) 21. The method of claim 1, wherein the bulk density of the recovered particles is greater than 0.07 g / ml. The spray drying method. (Configuration 22) 1. The bulk density of the recovered particles is greater than 0.1 g / ml, optionally greater than 0.15 g / ml. 22. The spray drying method according to any one of claims 1 to 21. (Configuration 23) 23. Any of claims 1 to 22, wherein the bulk density of the collected particles is between 0.1 g / ml and 0.25 g / ml. The spray drying method according to any one of claims 1 to 5. (Configuration 24) 24. Any of configurations 1 to 23, wherein the bulk density of the collected particles is between 0.1 g / ml and 0.5 g / ml. The spray drying method according to any one of claims 1 to 5. (Configuration 25) Solid material into the spray dryer chamber, e.g., solid particles dispersed in the drying gas. 25. The spray drying method according to any one of claims 1 to 24, which does not include the introduction of a material. (Configuration 26) The sole solvent system used in the method is the one or more APIs; one or more excipients; or 26. The method according to any one of claims 1 to 25, wherein the mixture is a solvent system in a feed mixture in which the mixture is dissolved. Spray drying method. (Configuration 27) 27. The spray drying method according to any one of claims 1 to 26, wherein the drying gas does not contain any solvent vapor. Drying method. (Configuration 28) atomizing the feed mixture into droplets and drying the droplets to form spray dried 28. The spray drying method according to any one of claims 1 to 27, wherein producing the particles is carried out in the same chamber. Drying method. (Configuration 29) and at least one second gas inlet in at least one of a plurality of locations therein. A spray drying device. (Configuration 30) Increased bulk density compared to a corresponding spray drying apparatus without a secondary gas inlet. 30. The spray drying apparatus of claim 29, for producing a solid dispersion comprising: (Configuration 31) A spray dryer chamber with an atomizing nozzle and a drying gas inlet; and the spray dryer 31. The spray drying method of claim 29 or 30, further comprising a means for recovering the spray-dried particles from the chamber. Device. (Configuration 32) A means for recovering the spray dried particles from the spray dryer chamber comprises: Any of configurations 29 to 31, comprising a filter bag, a container, or any combination thereof. 2. A spray drying apparatus according to claim 1. (Configuration 33) The means for recovering spray dried particles from the spray dryer chamber comprises: 32. The method according to any one of claims 29 to 31, further comprising a cyclone connected between the chamber and the container. Spray drying equipment. (Configuration 34) 29. The spray dryer chamber according to claim 1, wherein the spray dryer chamber has a cylindrical upper end portion and a cone-shaped lower end portion. 34. A spray drying apparatus according to any one of claims 33. (Configuration 35) At least one of the at least one second gas inlet is located at: i) the upright portion of the drying chamber (position 26); and ii) at least one of the cone portions (positions 28) of the drying chamber, 5. A spray drying apparatus according to any one of claims 4 to 4. (Configuration 36) At least one of the at least one second gas inlet is located at: i) the drying chamber and the cyclone, a connection between the means for withdrawing from the chamber (position 30); ii) A device for recovering the spray-dried particles from the spray-drying chamber, such as a cyclone. a connection between the means for inserting the container and the container (position 32); and iii) a solid container (position 34), Spray drying equipment. (Configuration 37) The atomizing nozzle may be a pressure type, a two-fluid type, a rotary type, or any other type of atomizing nozzle. 37. The spray drying apparatus according to any one of aspects 31 to 36, which is a spray drying mechanism. (Configuration 38) 38. The method of claim 31, wherein the atomization nozzle is centrally located at the top of the spray dryer chamber. The spray drying apparatus according to any one of claims 1 to 5. (Configuration 39) 2. The method of claim 1, wherein the active pharmaceutical ingredient (API) is and, if present, one or more excipients to increase the bulk density of the amorphous solid dispersion. Use of the method according to any one of configurations 1 to 28 or the device according to any one of configurations 29 to 38 for For. (Configuration 40) The spray dryer chamber is preferably configured to be sintered in a manner similar to that described above, compared to a corresponding process in which the one or more second gas streams are not present. 29. The method of claim 1, wherein the amorphous physical stability of the particles recovered from the cell is increased. Use of a method according to any one of claims 29 to 38 or a device according to any one of claims 29 to 38. (Configuration 41) The spray dryer chamber is preferably configured to be sintered in a manner similar to that described above, compared to a corresponding process in which the one or more second gas streams are not present. 29. The method according to any one of claims 1 to 28, for reducing the residual solvent content of the particles recovered from the cylinder. 39. Use of the method according to any one of claims 20 to 28 or the device according to any one of claims 29 to 38. (Configuration 42) 23. A method, apparatus or use substantially as herein described with reference to the description and drawings. (Construction 43) At least one active pharmaceutical ingredient obtainable by the method according to any one of configurations 1 to 28. An amorphous solid dispersion comprising an active pharmaceutical ingredient (API) and at least one excipient. (Configuration 44) At least one active pharmaceutical ingredient (API) and at least one excipient, Amorphous solid dispersions having bulk densities of . (Configuration 45) 45. The amorphous solid dispersion of embodiment 44, having a bulk density of greater than 0.1 g / ml, optionally greater than 0.15 g / ml. thing. (Configuration 46) 46. ​​The amorphous solid dispersion of claim 44 or 45, having a bulk density of 0.1 g / ml to 0.5 g / ml. (Configuration 47) 46. ​​The amorphous solid dispersion of claim 44 or 45, having a bulk density of 0.1 g / ml to 0.25 g / ml. (Configuration 48) 47. The amorphous composition of any one of claims 43 to 46, wherein the at least one excipient comprises a polymer. Solid dispersion.

Claims

1. 1. A spray drying process for producing an amorphous solid dispersion, comprising: a. providing a feed mixture, the feed mixture comprising one or more active pharmaceutical ingredients (APIs), one or more excipients, or mixtures thereof; and a solvent system comprising at least one solvent; b. feeding the feed mixture into a spray drying apparatus comprising a spray dryer chamber; c. atomizing the feed mixture into droplets with an atomizing nozzle; d. drying the droplets with a drying gas to produce particles of the one or more APIs; one or more excipients; or a mixture thereof; e. directing one or more second gas streams into the spray dryer at at least one of a plurality of locations within the spray dryer; wherein the method does not have one or more associated gas streams providing fluidizing gas to one or more fluidization chambers and does not have a gas stream associated with return of fine material to the spray dryer chamber; At least one of the at least one second gas flow inlet is located at the following position: i) a connection between the spray dryer chamber and a means for recovering spray dried particles from the spray dryer chamber (position 30); ii) a connection (position 32) between a means for recovering spray dried particles from the spray dryer chamber and a solids container for collecting the particles; and iii) a solid container (position 34) for collecting the particles; wherein the spray drying apparatus does not have one or more fluidization chambers located proximate to the outlet; and f. recovering the particles from the spray dryer chamber; wherein the bulk density of the recovered particles is greater than 0.07 g / ml.

2. 10. The spray drying process of claim 1, wherein the feed mixture comprises one or more active pharmaceutical ingredients and one or more excipients.

3. 3. The spray drying process of claim 1 or 2, comprising producing an amorphous solid dispersion of the one or more APIs, the one or more excipients, or the one or more APIs and one or more excipients.

4. 4. The spray drying method of claim 1, 2, or 3, wherein the one or more excipients comprise one or more polymers.

5. The one or more excipients may be selected from the group consisting of N-vinyl lactams, copolymers of N-vinyl lactams, cellulose esters, cellulose ethers, polyalkylene oxides, polyacrylates, polymethacrylates, polyacrylamides, polyvinyl alcohols, vinyl acetate polymers, oligosaccharides, polysaccharides, homopolymers of N-vinyl pyrrolidone, copolymers of N-vinyl pyrrolidone, copolymers of N-vinyl pyrrolidone and vinyl acetate, copolymers of N-vinyl pyrrolidone and vinyl propionate, graft copolymers of polyethylene glycol / polyvinyl caprolactam / polyvinyl acetate (e.g., Soluplus®), polyvinyl pyrrolidone, hydroxyalkyl cellulose, hydroxypropyl cellulose, hydroxyalkyl alkyl cellulose, hydroxypropyl methyl cellulose, cellulose phthalate, cellulose succinate, cellulose acetate phthalate, hydroxypropyl methyl cellulose ...

5. The spray drying method of claim 1, wherein the excipient is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, polyethylene oxide, polypropylene oxide, copolymers 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 polymers crosslinked with divinyl glycol (e.g., Noveon®), gelatin, copolymers of gelatin, vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, carrageenan, galactomannan, high viscosity gum, xanthan gum, or combinations thereof.

6. The spray drying method of any one of claims 1 to 5, wherein the spray dryer chamber comprises a cylindrical upper section and a cone-shaped lower section.

7. 7. The spray drying method of claim 1, wherein step f. of recovering the particles from the spray dryer chamber comprises recovering the particles in a vessel connected to the spray dryer chamber.

8. 8. The spray drying method of claim 1, wherein step f. of recovering the particles from the spray dryer chamber comprises recovering the particles through the use of a cyclone or a filter bag connected to the spray dryer chamber.

9. 9. The spray drying method of claim 8, wherein step f. of recovering the particles from the spray dryer chamber comprises passing the particles through a cyclone or filter bag connected to the spray dryer chamber and into a container connected to the cyclone or filter bag.

10. The step e) comprises: i) the upright portion of the spray dryer chamber (position 26); ii) the cone portion of the spray dryer chamber (position 28); iii) If no cyclone or filter bag is present, at a location between the spray dryer chamber and the vessel.

10. The spray drying method according to claim 6, further comprising feeding at least one second gas stream into at least one of said first and second gas streams.

11. The spray drying method according to any one of claims 1 to 10, wherein the atomizing nozzle is of a pressure type, a two-fluid type, or a rotary type.

12. The spray drying process of any one of claims 1 to 11, wherein the atomization nozzle is centrally located at the top end of the spray dryer chamber.

13. 13. The spray drying process of any one of claims 1 to 12, wherein the solvent system comprises water, an organic solvent such as acetone, methyl ethyl ketone, ethanol, methanol, isopropanol, ethyl acetate, hexane, heptane, dichloromethane, tetrahydrofuran, or any combination thereof.

14. The spray drying process of any one of claims 1 to 13, wherein the second gas stream is added to the spray drying apparatus at a location outside the atomization region of the spray dryer chamber.

15. 15. The spray drying process of any one of claims 1 to 14, wherein the stream exiting the spray dryer chamber has a reduced relative solvent saturation with respect to a corresponding conventional spray drying process without an additional gas stream.

16. The bulk density of the spray dried particles is selected from the following options: i) increasing the flow distance added to the atomization region within the spray dryer chamber; ii) increasing the flow rate of the added flow; and 16. The spray drying process of claim 1, wherein the temperature is further increased by either: i) increasing the temperature of the added stream; or ii) decreasing the temperature of the added stream.

17. 17. A spray drying process according to any one of claims 1 to 16, wherein the throughput for the spray drying equipment is higher than in a corresponding conventional spray drying process in which step e. according to claim 1 is not present.

18. 18. The spray drying process of any one of claims 1 to 17, wherein the one or more second gas streams and / or the drying gas comprises a nitrogen gas stream.

19. 19. The spray drying process of any one of claims 1 to 18, wherein the bulk density of the recovered particles is greater than 0.1 g / ml, optionally greater than 0.15 g / ml.

20. 19. The spray drying process of any one of claims 1 to 18, wherein the bulk density of the recovered particles is from 0.1 g / ml to 0.25 g / ml.

21. 19. The spray drying process of any one of claims 1 to 18, wherein the bulk density of the recovered particles is from 0.1 g / ml to 0.5 g / ml.

22. A method of spray drying according to any preceding claim, which does not involve the introduction of solid material into the spray dryer chamber, such as solid particulate material dispersed in the drying gas.

23. 23. The spray drying process of any one of claims 1 to 22, wherein the only solvent system used in the process is the one in the feed mixture in which the one or more APIs; one or more excipients, or a mixture thereof, are dissolved.

24. The spray drying process of any one of claims 1 to 23, wherein the drying gas does not contain any solvent vapor.

25. 25. The spray drying process of any one of claims 1 to 24, wherein atomizing the feed mixture into droplets and drying the droplets to produce spray dried particles occur in the same chamber.

26. 1. A spray drying apparatus for producing an amorphous solid dispersion, comprising: at least one second gas inlet at at least one of a plurality of locations within the spray drying apparatus; the spray drying apparatus comprising: a spray dryer chamber comprising an atomizing nozzle and a drying gas inlet; and a means for collecting spray dried particles from the spray dryer chamber comprising a cyclone, a filter bag, a container, or any combination thereof; At least one of the at least one second gas inlet is located at the following position: i) a connection between the spray dryer chamber and a means for recovering spray dried particles from the spray dryer chamber (position 30); ii) a connection (position 32) between a means for recovering spray dried particles from the spray dryer chamber and a solids container for collecting the particles; and iii) a solid container (position 34) for collecting the particles; wherein the spray drying apparatus does not have one or more fluidization chambers located proximate to the outlet.

27. 27. The spray drying apparatus of claim 26, for producing a solid dispersion having an increased bulk density compared to a corresponding spray drying apparatus not comprising a second gas inlet.

28. 28. A spray drying apparatus according to claim 26 or 27, wherein the means for recovering spray dried particles from the spray dryer chamber comprises a cyclone connected between the spray dryer chamber and a vessel.

29. 29. The spray drying apparatus of any one of claims 26 to 28, wherein the spray dryer chamber comprises a cylindrical upper end portion and a cone-shaped lower end portion.

30. The spray drying apparatus is in the following position: i) the upright portion of the spray dryer chamber (position 26); and ii) a cone portion of the spray dryer chamber (position 28); 30. The spray drying apparatus of any one of claims 26 to 29, further comprising at least one second gas inlet in at least one of said first and second gas inlets.

31. The spray drying apparatus according to any one of claims 26 to 30, wherein the atomizing nozzle is a pressure type, a two-fluid type, a rotary type, or any other atomizing mechanism.

32. 32. The spray drying apparatus of any one of claims 26 to 31, wherein the atomization nozzle is centrally located at the top end of the spray dryer chamber.

33. Use of the method according to any one of claims 1 to 25 or use of the apparatus according to any one of claims 26 to 32 to increase the bulk density of an amorphous solid dispersion of an active pharmaceutical ingredient (API) and, if present, one or more excipients, compared to a corresponding method in the absence of the one or more second gas streams.

34. Use of a method according to any one of claims 1 to 25, or use of an apparatus according to any one of claims 26 to 32, to increase the amorphous physical stability of the particles recovered from the spray dryer chamber compared to a corresponding method in which one or more second gas streams are not present.

35. Use of a method according to any one of claims 1 to 25, or use of an apparatus according to any one of claims 26 to 32, to reduce the residual solvent content of the particles recovered from the spray dryer chamber compared to a corresponding method in which one or more second gas streams are not present.

Images