Methods and systems for preparing feed solutions for spray drying

Abstract

Provided herein is a method for preparing a batch of feed solution for spray drying from at least one solvent and two or more solid components comprising at least one excipient and at least one active pharmaceutical ingredient (API), wherein the method is performed in a system comprising a deagglomeration device and a tank that are fluidly connected to form a fluid loop, the method comprising: (i) charging the solvent into the system (ii) charging the two or more solid components into the system, wherein at least one solid component of the two or more solid components is charged into the system through the deagglomeration device, (iii) circulating the solvent and the two or more solid components around the fluid loop through the tank and the deagglomeration device while mixing with the deagglomeration device to dissolve the two or more solid components in the at least one solvent, to prepare the batch of feed solution, wherein the batch has a volume of 50 L to 500 L. Related methods for delivering a continuous supply of feed solution for a spray dryer and systems for preparing batches of feed solution for a spray dryer are also provided.

Description

[0001] METHODS AND SYSTEMS FOR PREPARING FEED SOLUTIONS FOR SPRAY DRYING

[0002] Field of the Invention

[0003] The present disclosure generally relates to the field of spray drying. More specifically the present disclosure relates to methods and systems for preparing feed solutions that are delivered to a spray dryer in the preparation of spray dried dispersions comprising active pharmaceutical ingredients.

[0004] Background of the Invention

[0005] A spray dried dispersion (SDD) is a particulate formulation where one or more active ingredients are dispersed at the molecular level within an amorphous system, consisting of a matrix of carrier materials. Spray dried dispersions are commonly used in various industries, including pharmaceuticals, food, and chemicals, due to their ability to improve the solubility, stability, and bioavailability of active ingredients. Within pharmaceutical spray dried dispersions, the active pharmaceutical ingredient (API) is molecularly dispersed, typically, within a polymeric matrix. This polymer serves the dual purpose of stabilizing the amorphous and metastable state of the drug, while also prolonging the supersaturation of the active ingredient in solution or biological fluids, thereby enhancing bioavailability. In pharmaceutical applications, spray dried dispersions are often used to formulate poorly soluble drugs (BCS class 2 and 4 drugs) into easily dispersible powders or granules, enabling more effective drug delivery and absorption in the body.

[0006] Spray dried dispersions are typically produced through a multi-step process involving feed solution preparation, and spray drying. Conventional spray drying processes often involve upstream and downstream batch operations, which can be time-consuming and resource intensive. These processes typically necessitate large-scale equipment and lengthy changeover times, limiting production efficiency and flexibility. Moreover, the conventional approach may result in prolonged feed solution preparation times, leading to challenges in meeting manufacturing demands. In the conventional spray drying manufacturing approach, feed solution preparation is carried out in large volume stirred tanks, a time-consuming process lasting between 8 to 36 hours, in some cases extending to over 48 hours. The extended dissolution times are attributed to the lengthy dissolution of common polymers used in spray dried dispersions, such as hydroxypropyl methylcellulose acetate succinate (HPMCAS), copovidone, hydroxypropyl methylcellulose (HPMC), and Eudragit®, which tend to agglomerate into large lumps when charged directly into the tanks. These lumps necessitate considerable time for de-lumping and dissolution. Despite efforts to expedite this process, e.g. through slower and gradual feeding of polymers, the feed solution still demands a considerable amount of time, often surpassing several hours. This duration is associated with the scale of operations, which includes the utilization of feeding stirred tanks ranging in capacity, in most commercial processes, from 500 to 15,000 L.

[0007] The inefficiencies inherent in the conventional process, including prolonged feed solution preparation times and large-scale equipment requirements, pose significant challenges to manufacturers seeking to enhance production efficiency, reduce operational costs, and improve product quality of spray dried dispersions.

[0008] The preparation of feed solutions for spray drying is disclosed for example in WO 2019 / 207086 Al, which describes a setup for spray drying a powder dispersion, involving an evaporator and a mixing unit connected in a loop configuration, and continuous feeding of compositions into the loop, mixing, removal and spray-drying to obtain particles. It is reported that this process is particularly suited for encapsulating fat-soluble compounds like beta-carotene, yielding spray- dried powders with high concentrations of the compound.

[0009] US 2005 / 0031692 Al discloses a process for producing a pharmaceutical composition containing a solid amorphous dispersion of a low-solubility drug and a polymer. This involves forming a spray solution by dissolving the drug and polymer in a solvent, atomizing the solution into droplets in a drying chamber, and solidifying the droplets to form the dispersion. The resulting dispersion enhances drug concentration or dissolution rate compared to the drug alone. Parameters such as feed rate, gas temperature, and droplet size are controlled to ensure proper powder properties and solvent removal. In this document it is described that the solution of the drug, polymer and solvent is preferably mixed (including using submerged impellers or agitators) for a relatively long period of time, such as from four to eight hours, to ensure that all the polymer and the drug have dissolved. While these publications involve spray drying processes, they do not emphasize the operation of preparing a feed solution to a spray dryer or address the inefficiencies inherent in the conventional process that are mentioned above.

[0010] The inventors of the present invention have appreciated that there is a need for a more efficient method for the preparation of feed solutions to produce spray dried dispersions. Although prior art attempts are known, these processes involve the use of elevated temperatures with the aid of heat exchangers to achieve supersaturated solutions upon feeding to the spray dryer (as described in WO 2010 / 111132 A2), or the use of microfluidization devices to assist suspension dissolution (as described in WO2019 / 162688 Al), in which the suspension is pushed through very narrow channels, leading to high turbulence due to large pressure differences, and in some cases cavitation. It also imparts significant energy to the suspension.

[0011] Accordingly, there remains a need in the art for alternative and improved methods and systems for feed solution preparation in the production of spray dried dispersions.

[0012] Summary of the Invention

[0013] Accordingly, in a first aspect, the present invention provides a method for preparing a batch of feed solution for spray drying from at least one solvent and two or more solid components comprising at least one excipient and at least one active pharmaceutical ingredient (API), wherein the method is performed in a system comprising a deagglomeration device and a tank that are fluidly connected to form a fluid loop, the method comprising:

[0014] (i) charging the solvent into the system

[0015] (ii) charging the two or more solid components into the system, wherein at least one solid component of the two or more solid components is charged into the system through the deagglomeration device,

[0016] (iii) circulating the solvent and the two or more solid components around the fluid loop through the tank and the deagglomeration device while mixing with the deagglomeration device to dissolve the two or more solid components in the at least one solvent, to prepare the batch of feed solution, wherein the batch has a volume of 50 L to 500 L.

[0017] In a further aspect, the present invention provides a method for delivering a continuous supply of a feed solution for a spray dryer, the method comprising preparing the batch of the feed solution as described above, supplying the prepared batch from the system towards the spray dryer while preparing the subsequent batch of the feed solution in the system, and supplying the prepared subsequent batch from the system towards the spray dryer in a consecutive manner.

[0018] In addition, the present invention provides a system for preparing batches of feed solution for a spray dryer and for supplying the batches to the spray dryer in a consecutive manner to provide a continuous supply of feed solution for the spray dryer, wherein each batch is to be prepared by dissolving at least two solid components in at least one solvent in the system, the system comprising:

[0019] (a) at least two tanks;

[0020] (b) at least one deagglomeration device;

[0021] (c) at least one inlet conduit for charging at least one of the solid components into the system through the at least one deagglomeration device;

[0022] (d) an arrangement of conduits such that at least one of the at least two tanks, which has a volume of 50 L to 500 L, is fluidly connected to the at least one deagglomeration device in a fluid loop, around which the at least two solid components and the at least one solvent can be circulated while mixing with the deagglomeration device in order to dissolve the at least two solid components in the at least one solvent to prepare the batches of the feed solution, and

[0023] (e) one or more outlet conduit(s) for supplying the batches of feed solution from the system towards the spray dryer, wherein the system is configured to accommodate a prepared batch of the feed solution in one of the at least two tanks during supply of the prepared batch to the spray dryer through the one or more outlet conduits while a subsequent batch of the feed solution is being prepared in the system.

[0024] Preferred features of all aspects of the present invention are defined in the dependent claims. The methods and systems defined herein are useful for the efficient preparation of feed solutions that can be fed to a spray dryer for the preparation of spray dried dispersions. The inventors have surprisingly found that the use of a smaller feed solution batch volume in combination with the use of a circulation loop and deagglomeration device as set out in the claims, significantly expedites dissolution times. This enables a “mini-batch” method to be used to provide a continuous supply of feed solution for a spray dryer. The invention allows a first batch of feed solution having a volume of 50 L to 500 L to be prepared, and while this batch is being fed to the spray dryer a second batch of the feed solution is prepared. Due to the short feed solution preparation times achieved with the present invention, the second batch of the feed solution is ready and can be supplied to the spray dryer directly after the first batch, providing a continuous supply of feed solution. Multiple batches can therefore be prepared and supplied to the spray dryer in a consecutive manner, thus enabling the spray dryer to be operated continuously.

[0025] The use of smaller batch sizes in the present invention, also advantageously enables the use of smaller system components and, as a result, more compact and versatile processing units. Additionally, the methods and systems allow the batch sizes to be varied within the same process train, enabling flexibility and scalability in manufacturing.

[0026] Brief Description of Figures

[0027] To assist understanding of the present disclosure and to show how embodiments may be put into effect, reference is made, by way of example only, to the accompanying Figures in which:

[0028] Figure 1 is a schematic representation of an example of the system of the present invention in which the system is arranged for the polymer (excipient) and API for making a batch of feed solution to be charged into the system using a LIW feeder metering system that feeds into a buffer hopper and then into the high- shear pump (deagglomeration device). The solvent required for the batch can be fed into tank 1. A PAT tool is present for monitoring the solid concentration in the fluid loop. When the batch is ready it can be transferred to tank 2, from where it can be fed on to the spray dryer while a further batch is prepared in tank 1. A solvent stabilization tank is also present to supply stabilizing solvent to the spray dryer. Spray drying with the stabilizing solvent can be performed between spray drying of batches of feed solution. Figure 2 is a schematic representation of another example of the system of the present invention similar to that shown in Figure 1. In this example the polymer (excipient) is fed using a loss-in- weight feeder (LIW feeder metering device) into the high shear pump, while the API is fed using another loss-in- weight feeder (LIW feeder metering device) into tank 1. The solvent is also fed into the tank 1. As in Figure 1, a PAT tool monitors the solid concentration in the fluid loop. When the batch is ready it can be transferred to tank 2, from where it can be fed on to the spray dryer while a further batch is prepared in tank 1.

[0029] Figure 3 is a schematic representation of a further example of the system of the present invention. Both tank 1 and tank 2 are arranged such that they are fluidly connected or capable of being fluidly connected via a fluid loop and a second fluid loop, respectively, to the deagglomeration device. Once a batch of feed solution is prepared using the fluid loop involving the deagglomeration device and the tank, it can be supplied from the tank to the spray dryer, while a subsequent batch of the feed solution is prepared using the second fluid loop, the deagglomeration device and tank 2. As in Figures 1 and 2, a PAT tool monitors the solid concentration in the fluid loops to determine feed solution readiness.

[0030] Detailed Description of the Invention

[0031] As highlighted above, the present invention relates to methods and systems for preparing a feed solution for a spray drying process from at least one solvent and two or more solid components comprising at least one excipient and at least one active pharmaceutical ingredient (API).

[0032] In a first aspect the present invention provides a method for preparing the batch of feed solution in a system comprising a deagglomeration device and a tank that are fluidly connected to form a fluid loop, the method comprising:

[0033] (iv) charging the solvent into the system

[0034] (v) charging the two or more solid components into the system, wherein at least one solid component of the two or more solid components is charged into the system through the deagglomeration device, (vi) circulating the solvent and the two or more solid components around the fluid loop through the tank and the deagglomeration device while mixing with the deagglomeration device to dissolve the two or more solid components in the at least one solvent, to prepare the batch of feed solution, wherein the batch has a volume of 50 L to 500 L.

[0035] The deagglomeration device is used to break up any agglomerates of the solid component(s), to ensure efficient mixing with the at least one solvent. Preferably the deagglomeration device is a high shear mixer or a high shear pump. High shear mixers / high shear pumps are also known as high shear reactors, rotor- stator mixers, and high shear homogenizers and are characterized by high rotor tip speeds (ranging from 10 to 50 m / s), and very high shear rates (ranging from 20,000 to 100,000 s'1) (Zhang et al., Chemical Engineering and Processing: Process Intensification, July- August 2012, volumes 57-58, pages 25-41). Such devices use shear to disperse the solid components within the solvent. The shear force occurs when part of the mixture is pushed in one direction, while the other part is pushed in the opposite direction simultaneously.

[0036] However, ultrasonic deagglomeration devices, fluidized bed systems, sifting devices, milling devices or grinding devices can also be used as the deagglomeration device to achieve the same mixing effects.

[0037] It is noted that the deagglomeration device is not a microfluidization / high-pressure homogeneization device and the deagglomeration device does not utilize microfluidization channels, i.e., any fluid channels for the at least one solvent and the two or more solid components in the deagglomeration device are 2 mm or more in diameter. A microfluidization device is not conventionally considered to be a deagglomeration device and in particular not a high shear device (e.g. high shear mixer / pump) as the flow of fluid through such a device is different from that in a deagglomeration device. In a microfluidization device microfluidization occurs in which fluid is pushed through very narrow channels, leading to high turbulence due to large pressure differences, and the imparting of high energy to the fluid, orders of magnitude above conventional deagglomeration devices. Suitable deagglomeration devices are commercially available, such as the CMX (recirculation) 2000 inline mixer that is available from IKA. Most devices are available in a range of sizes and the size can be selected based on the volume of the batch being prepared.

[0038] The deagglomeration device is positioned in-line in a fluid loop that connects the device to the tank. In the method the at least one solvent and the two or more solid components that have been charged into the system circulate around the fluid loop, through the tank to the deagglomeration device and back again while being mixed with the deagglomeration device, i.e. the at least one solvent and the two or more solid components are recirculated multiple times around the fluid loop, in order to dissolve the two or more solid components in the at least one solvent. In this manner, the at least one solvent and the two or more solid components, i.e., the suspension, are subjected to mixing by the deagglomeration device multiple times, as dictated by the recirculation flow rate and the total recirculation time.

[0039] As noted above, in the method the prepared batch has a volume of 50 L to 500 L (or 50 L to less than 500 L), preferably 50 L to 400 L (or 50 L to less than 400 L), and more preferably 50 L to 200 L (or 50 L to less than 200 L). In particular, the present inventors have found that the combination of performing the method in a system comprising the deagglomeration device and a tank that are fluidly connected to form a fluid loop as described above, and the use of a small batch volume, allows the batch of feed solution to be prepared rapidly, i.e., in 60 minutes or less.

[0040] The method is performed in a system that comprises a tank for containing the at least one solvent and the two or more solid components while they are repeatedly passed through the deagglomeration device and, as discussed further below, optionally also for accommodating the prepared batch of feed solution while the batch is being fed to the spray dryer. The tank may also comprise an agitation device for mixing of the at least one solvent and the two or more solid components to assist in dissolving the two or more solid components in the solvent, and optionally also for maintaining the batch solution is homogenous form while it is being fed to the spray dryer.

[0041] Accordingly, the methods described herein may comprise mixing the at least one solvent and the two or more solid components, or may comprise mixing the prepared batch of feed solution with the agitation device. In one example the methods described herein comprise mixing with the agitator during the circulating in (iii). The agitation device may be a mechanical agitator, such as a rotating stirrer or blade, a paddle type mixer or a static agitator.

[0042] The tank may be of any size suitable for handling the 50 L to 500 L batch volume. Normally, the tank volume, i.e., the maximum volume that the tank is designed to contain, will not be less than 5 % of the batch volume. In general, smaller tanks are preferred as these are considered to provide more efficient mixing and a process that is more readily controlled, i.e., with improved quality assurance. In particular, it is noted that mixing may be more efficient where the tank volume more closely matches the batch volume. Therefore, preferably the tank volume is 50 L to 500 L (or 50 L to less than 500 L), preferably 50 L to 400 L (or 50 L to less than 400 L), and more preferably 50 L to 200 L (or 50 L to less than 200 L).

[0043] In the method of the present invention the at least one solvent is charged into the system. The at least one solvent may be charged into the system from a solvent tank under the action of gravity or may be pumped from the solvent tank into the system. The location of charging into the system is not particularly limited and the solvent may be charged into the system at any location around the fluid loop. However, preferably the at least one solvent is charged into a tank (e.g., as shown in Figures 1 to 3), or into a fluid conduit, e.g., pipe, leading directly into a tank.

[0044] The at least one solvent is charged to the system in (i) in an amount necessary for the batch volume described above. This amount may be charged in (i) one go, or the amount may be split and charged into the system in two or more portions, i.e., in two or more steps. Preferably 80 to 90% of the volume of the solvent is charged into the system at the beginning of the method, followed by the final 10 to 20% of the solvent towards the end of the method, to wash down interior surfaces of the system to remove any residual solid components.

[0045] In the method of the present invention, the two or more solid components are charged into the system, wherein at least one of these is charged into the system through the deagglomeration device. The other solid component may also be charged into the system through the deagglomeration device or may be charged into the system at another location around the fluid loop, for example into the tank or into a fluid conduit, e.g., pipe, leading directly into a tank.

[0046] Normally, the at least one solid component that is charged into the system through the deagglomeration device is the at least one excipient, since this is usually prone to clumping / agglomeration. However, the API can also be charged through the deagglomeration device (e.g., as shown in Figure 1) if this component also has the potential to agglomerate. Alternatively, if the API is not problematic in this way, the API can be charged into the tank (e.g., as shown in Figures 2 and 3).

[0047] The two or more solid components are charged into the system in (ii) in amounts necessary to prepare the batch described above. The amount may be charged in (ii) in a continuous stream until the amount is charged, or in two or more portions, i.e., in two or more steps. The rate of charging of the two or more solid components can be controlled to avoid clumping.

[0048] The at least one solvent may be charged into the system before, concurrently with, or after the charging of the two or more solid components. In a preferred example, the solvent is charged into the system before or concurrently with the at least one solid component that is charged into the system through the deagglomeration device. In this way, the at least one solvent is circulating from the tank to the deagglomeration device while the at least one solid component is being charged into the system through this device, such that the solvent picks up the solid component as it passes through the device and is circulated back to the tank. Ensuring that the solvent is present in sufficient quantity when the solid components enter the system can be helpful to prevent the formation of gel-type clumps of the solid components at the bottom of the tank.

[0049] The system may preferably comprise one or more metering system(s) for measuring and charging the amounts of the two or more solid components necessary for preparing a batch of the feed solution into the system. Accordingly, the method may comprise the steps of metering an amount of the excipient and metering an amount of the API that are to be used in the method of preparing the batch. The one or more metering system(s) can be selected from a loss-in- weight feeder, a gain-in- weight hopper, a rotary valve, a pneumatic conveyor, or a vibratory feeder. Preferably the one or more metering system(s) is one or more loss-in- weight feeder(s). In one example, a loss-in- weight feeder is used to meter the at least one excipient and a second loss-in-weight feeder is used to meter the at least one API (e.g., as shown in Figures 1 and 2). Use of the one or more of such feeders is preferred to ensure efficient preparation of multiple batches of feed solution as discussed below.

[0050] A container, such as a buffer hopper (e.g., as shown in Figures 1 and 2), may be used to hold the metered amounts of the excipient(s) and / or the metered API(s) prior to these entering the fluid loop of the system.

[0051] The method of the invention may also comprise conveying the two or more solid component to the one or more metering system(s) using gravity or a vacuum.

[0052] As noted above, the two or more solid components comprise at least one excipient and at least one API. The two or more solid components may be in powdered form or in granular form. In particular, the solid components may have a particle size less than 0.5 mm (i.e., a maximum dimension of the particles is less than 0.5 mm). Preferably, the two or more solid components are in powdered form.

[0053] The at least one excipient is one or more excipients that are suitable for a pharmaceutical use. The at least one excipient is normally a polymer and may be a polysaccharide, for example a cellulosic polysaccharide or derivative / cellulose-based polymer, a polymer comprising vinyl groups, for example polyvinyl pyrrolidone, or a polymer comprising acrylic groups, for example polymethyl acrylate. Preferably the at least one excipient is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), copovidone (a synthetic copolymer consisting of A-vinyl-2-pyrrolidone and vinyl acetate), hydroxypropyl methylcellulose (HPMC), polymethacrylate (such as Eudragit®), or a combination thereof.

[0054] The at least one excipient may be selected based on the active pharmaceutical ingredient and the desired characteristics of the spray dried dispersions that are to be prepared. The at least one solvent may be selected from water, methanol, ethanol, propanol, acetone, butanone, tetrahydrofuran, dichloromethane, hexane, ethyl acetate, n-heptane, other organic solvents and combinations thereof. Suitable solvents for the pharmaceutically acceptable excipients and APIs, i.e., solvents in which the excipients and APIs are soluble, are known in the art, and therefore the solvent should be selected based on the excipient(s) and API(s) being used (see, for example, Patra et al., “Pharmaceutical significance of Eudragit: a review”, June 2017, Future Journal of Pharmaceutical Sciences; 3(1): 33-45).

[0055] The method of the present invention may comprise monitoring and controlling feed solution concentration using Process Analytical Technology (PAT) tools integrated within the method. In particular, the method may comprise monitoring the concentration of the two or more solid components dissolved in the at least one solvent during the method to determine when the batch of feed solution is ready for use, i.e., to determine when the two or more solid components are sufficiently dissolved in the at least one solvent for spray drying. Such monitoring can be done using one or more turbidimeter(s) and / or one or more viscometer(s).

[0056] The PAT tools for monitoring the solids concentration may be positioned on the fluid loop(s) (e.g., as shown in Figures 1-3).

[0057] Normally the solids concentration of the prepared batch of feed solution is 3 wt. % to 45 wt. % and may be 10 wt. % to 45 wt. % or 10 wt.% to 25 wt. %.

[0058] As demonstrated by the Example included herein, the present inventors have found that using the method of the present invention the two or more solid components can be dissolved rapidly in the at least one solvent. Preferably, the batch of feed solution is prepared by dissolving the two or more solid components in the at least one solvent within 60 minutes, and preferably within 30 minutes.

[0059] Once the batch of feed solution is prepared, the method of the present invention may comprise supplying the prepared batch from the system to the spray dryer. This may be done at the same time (simultaneously, at least in part) as preparing a subsequent batch of the same feed solution in the system.

[0060] This preparation of a subsequent batch in the system may be achieved with a second tank in the system. In one embodiment, the method comprises moving the prepared batch (i.e., the first batch) to the second tank where it can be accommodated while it is being supplied to the spray dryer. This allows the tank (i.e., the first tank), the deagglomeration device and the fluid loop at the same time to be reused to prepare the subsequent (second) batch of the feed solution. In this method the steps (i) to (iii) as described above are repeated to prepare the subsequent batch.

[0061] Alternatively, the system may comprise a second tank that is connected or connectable (e.g. through the use of valves) to the deagglomeration device or to a second deagglomeration device, to form a second fluid loop. This can be used to prepare the subsequent (second) batch of the feed solution, while the already prepared batch (the first batch, which is accommodated in the first tank) is being supplied to the spray dryer. In this embodiment preparing the subsequent (second) batch of the same feed solution may comprise:

[0062] (iv) repeating (i), (i.e., charging the solvent into the system)

[0063] (v) repeating (ii) (i.e., charging the two or more solid components into the system), wherein the at least one solid component of the two or more solid components is charged into the system through the deagglomeration device as in (ii) or wherein the at least one solid component of the two or more solid components is charged into the system through the second deagglomeration device; and

[0064] (vi) circulating the solvent and the two or more solid components around a second fluid loop through a second tank and the deagglomeration device or the second deagglomeration device while mixing with the deagglomeration device or the second deagglomeration device to dissolve the two or more solid components in the at least one solvent to prepare the subsequent (second) batch of feed solution.

[0065] The volume of the subsequent (second) batch prepared by the method is 50 L to 500 L (or 50 L to less than 500 L), preferably 50 L to 400 L (or 50 L to less than 400 L), and more preferably 50 L to 200 L (or 50 L to less than 200 L). The subsequent (second) batch may have the same volume as the first batch, or it may be different. Preferably the subsequent (second) batch has the same volume as the first batch.

[0066] The details of the batch and the method of parts (i) to (iii) given above also apply to parts (iv) to (v).

[0067] In particular, the second tank may have the same features as the first tank with respect to tank volume and the optional presence of an agitation device. Accordingly, the methods described herein may comprise mixing the contents of the second tank with the agitation device.

[0068] Based on the above method, the present invention also provides in a further aspect a method for delivering a continuous supply of a feed solution for a spray dryer. This method comprises preparing a batch (a first batch) of feed solution as described above and supplying the prepared batch from the system to the spray dryer while preparing the subsequent batch (a second batch) of the feed solution in the system as described above. The method comprises supplying the batches to the spray drying in a consecutive matter so as to deliver the continuous supply of the feed solution.

[0069] By repeating the above method, multiple batches of the feed solution can be prepared and supplied to the spray dryer in a consecutive manner, e.g., three or more batches. This can be used to achieve the spray drying of a large volume of feed solution in an efficient manner, i.e., without the need to prepare the large volume of feed solution in one go, and the wait time that this necessarily entails.

[0070] In particular, the methods of the present invention can be used to provide feed solution feed rates to the spray dryer that enable the normal operation of an industrial scale spray dryer. This can be defined as the ratio of the flow rate of the drying gas (F_drying) used in the spray dryer, to feed rate of the feed solution (F_feed) to the spray dryer. The method of the present invention enables the ratio F_drying / F_feed to be equal to or greater than 5. (This includes for F_drying rates of 80 kg / h (pilot scale), and for rates of 360 kg / h, 650 kg / h and 1250 kg / h (PSD2, PSD3 and PSD4 scales, respectively).) Accordingly, the methods of the present invention may further comprise a step of spray drying the feed solution in a spray dryer using a drying gas. As per the above paragraph, the step of spray drying may use a ratio F_drying / F_feed that is equal to or greater than 5.

[0071] The method may comprise stabilizing the spray dryer with a stabilization solvent and a drying gas. For example, as shown in Figure 1 , the system may comprise a solvent stabilization tank connected or connectable to the spray dryer for supplying the stabilizing solvent to the spray dryer. In one embodiment of the method the stabilizing solvent is supplied to the spray dryer between the prepared batches of feed solution. This enables each batch of the spray dried dispersion prepared with each batch of feed solution to be separated if necessary.

[0072] In a further aspect the present invention provides a system that may be used for performing the methods described above. Specifically, the present invention provides a system for preparing batches of feed solution for a spray dryer and for supplying the batches to the spray dryer in a consecutive manner to provide a continuous supply of feed solution for the spray dryer, wherein each batch is to be prepared by dissolving at least two solid components in at least one solvent in the system, the system comprising:

[0073] (a) at least two tanks;

[0074] (b) at least one deagglomeration device;

[0075] (c) at least one inlet conduit for charging at least one of the solid components into the system through the at least one deagglomeration device;

[0076] (d) an arrangement of conduits such that at least one of the at least two tanks, which has a volume of 50 L to 500 L, is fluidly connected to the at least one deagglomeration device in a fluid loop, around which the at least two solid components and the at least one solvent can be circulated while mixing with the deagglomeration device in order to dissolve the at least two solid components in the at least one solvent to prepare the batches of the feed solution, and

[0077] (e) one or more outlet conduit(s) for supplying the batches of feed solution from the system towards the spray dryer, wherein the system is configured to accommodate a prepared batch of the feed solution in one of the at least two tanks during supply of the prepared batch to the spray dryer through the one or more outlet conduits while a subsequent batch of the feed solution is being prepared in the system.

[0078] In one embodiment of the system, the at least two tanks comprise a first tank that is fluidly connected to the at least one deagglomeration device in the fluid loop in (d) and a second tank to accommodate the prepared batch of the feed solution while the subsequent batch of the feed solution is being prepared in the system using the fluid loop. This type of arrangement is shown for example in Figures 1 and 2.

[0079] In an alternative embodiment, the at least two tanks comprise a first tank that is fluidly connected to the at least one deagglomeration device in the fluid loop in (d), and a second tank having a volume of 50 L to 500 L and capable of being fluidly connected (e.g. using values) or fluidly connected to the at least one deagglomeration device to form a second fluid loop around which the at least two solid components and the at least one solvent can be circulated while mixing with the at least one deagglomeration device in order to dissolve the at least two solid components in the at least one solvent to prepare the batches of the feed solution, such that the batch of feed solution prepared using the fluid loop can be supplied to the spray dryer through the one or more outlet conduit(s) while the subsequent batch of the feed solution is being prepared using the second fluid loop. This type of arrangement is shown for example in Figure 3.

[0080] The earlier description of the features of the system in relation to the method set out earlier in this disclosure also apply to the features of the system. In particular, we refer to the earlier description of the deagglomeration device, the tanks (including volume and the presence of the agitation device), the one or more metering systems for charging the two or more solid components into the system, and the one or more monitoring devices. In one example, as shown in Figures 1 to 3, the monitoring devices (PAT tool) may be positioned on the fluid loop (and / or on the second fluid loop if present) to determine batch readiness for spray drying.

[0081] The following are intended as examples only and do not limit the present disclosure. EXAMPLES

[0082] Example 1

[0083] In this example, we demonstrate the efficiency of the expedited feed solution process described above, showing the dissolution of feed solutions for spray dried dispersions (SDD) in less than 10 minutes. The experiment was conducted using a scaled-down setup to mimic industrial conditions.

[0084] Experimental Setup:

[0085] • Solid raw materials (excipients) in powder form: HPMCAS MG, HPMC E5, Copovidone and Eudragit® L100. (The experiment was performed without API as this is not expected to add any complexity to the operation. Specifically, based on our experience, the API readily dissolves as it is charged to the tank, and does not confer significant changes to the solution transport properties.)

[0086] • Solvents: Dichloromethane, Methanol, Acetone, Ethanol and Water.

[0087] • Feed solution tank volume: 30 L

[0088] • Metering system: Coperion K-Tron K2-ML-D5-T35 loss-in-weight feeder.

[0089] • Deagglomeration Device: IKA CMX 2000 high shear pump for aiding powder deagglomeration .

[0090] • PAT monitoring tools: viscometer and turbidimeter.

[0091] The overall setup was similar to that shown in Figure 2, without the presence of the API hopper and feeder.

[0092] Procedure:

[0093] 1. Set up the feed solution preparation system with the tank, metering system, deagglomeration device (high shear pump), and PAT monitoring tools. (The overall setup was similar to that shown in Figure 2, without the presence of the API hopper and LIW feeder, and without tank 2.)

[0094] 2. Weigh and charge 18.4 kg of the solvent into the feed tank.

[0095] 3. Weigh and charge 1.6 kg of solid raw material (excipient) into the loss-in-weight feeder.

[0096] 4. Start the loss-in-weight feeder to dispense the solid raw material (excipient) into the high shear pump. 5. Initiate the high shear pump to aid in powder deagglomeration and incorporate the solid raw material (excipient) into the recirculation line (fluid loop).

[0097] 6. Continuously recirculate the mixture in the feed tank to ensure thorough dissolution.

[0098] 7. Monitor the dissolution progress using PAT tools integrated within the system.

[0099] 8. Assess completion of dissolution based on predetermined acceptance criteria.

[0100] 9. Final time for dissolution considers the duration of steps 5 and 6 above.

[0101] Experimental Results:

[0102] The results with different combinations of solvent and polymers (excipients) are shown in Table 1 below.

[0103] • As shown in Table 1, the feed solution dissolution process was completed in less than 10 minutes for all investigated feed solution systems.

[0104] • PAT tools indicated full dissolution of the solid raw materials within this timeframe.

[0105] • The expedited process achieved a significant reduction in preparation time compared to conventional methods, which typically take several hours.

[0106] Table 1: Experimental data for the expedited feed solution process The results show that using the system and method of the present invention batches of feed solution can be rapidly prepared to achieve a continuous supply of feed solution for the spray dryer.

[0107] Other variants or use cases of the disclosed techniques may become apparent to the person skilled in the art once given the disclosure herein. The disclosure is not limited by the described embodiments but only by the accompanying claims.

Claims

CLAIMS1. A method for preparing a batch of feed solution for spray drying from at least one solvent and two or more solid components comprising at least one excipient and at least one active pharmaceutical ingredient (API), wherein the method is performed in a system comprising a deagglomeration device and a tank that are fluidly connected to form a fluid loop, the method comprising:(i) charging the solvent into the system(ii) charging the two or more solid components into the system, wherein at least one solid component of the two or more solid components is charged into the system through the deagglomeration device,(iii) circulating the solvent and the two or more solid components around the fluid loop through the tank and the deagglomeration device while mixing with the deagglomeration device to dissolve the two or more solid components in the at least one solvent, to prepare the batch of feed solution, wherein the batch has a volume of 50 L to 500 L.

2. The method according to claim 1, wherein the batch has a volume of 50 L to 200 L.

3. The method according to claim 1 or claim 2, wherein the deagglomeration device is a high shear pump, a high shear mixer, an ultrasonic deagglomeration device, a fluidized bed system, a sifting device, a milling device, or a grinding device.

4. The method according to claim 3, wherein the deagglomeration device is a high shear pump or a high shear mixer.

5. The method according to any of claims 1 to 4, wherein the tank comprises an agitation device and in (iii) the at least one solvent and the two or more solid components being circulated around the fluid loop are mixed in the tank with the agitation device.

6. The method according to any of claims 1 to 5, wherein the agitation device in the tank is a stirrer.

7. The method according to any of claims 1 to 6, wherein the at least one solvent is charged in (i) into the tank.

8. The method according to any of claims 1 to 7, wherein the at least one solvent is charged to the system before, concurrently with, or after the charging of the two or more solid components.

9. The method according to any of claims 1 to 8, wherein charging into the system of the two or more solid component and / or the at least one solvent occurs in more than one step.

10. The method according to claim 9, wherein the at least one solid component of the two or more solid components that is charged into the system through the deagglomeration device is the excipient.

11. The method according to any of claims 1 to 10, wherein the system comprises one or more metering system(s) for charging the two or more solid components into the system.

12. The method according to claim 11, wherein the one or more metering system(s) is selected from a loss-in- weight feeder, a gain-in- weight hopper, a rotary valve, a pneumatic conveyor, or a vibratory feeder.

13. The method according to claim 11 or claim 12, wherein the one or more metering system(s) is one or more loss-in-weight feeder(s).

14. The method of any of claims 11 to 13, comprising conveying the two or more solid component to the one or more metering system(s) using gravity or a vacuum.

15. The method of any of claims 1 to 14, wherein the tank volume is 50 L to 500 L, and optionally wherein the tank volume is 50 L to 200 L.

16. The method of any of claims 1 to 15, wherein the two or more solid components are in powdered form or in granular form, preferably in powdered form.

17. The method according to any of claims 1 to 16, wherein the at least one excipient is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), copovidone, hydroxypropyl methylcellulose (HPMC), polymethacrylate (such as Eudragit®), or a combination thereof.

18. The method according to any of claims 1 to 17, comprising monitoring the concentration of the two or more solid components dissolved in the at least one solvent, optionally wherein the monitoring is performed using a viscometer and / or a turbidimeter.

19. The method according to any of claims 1 to 18, wherein the two or more solid components are dissolved in the at least one solvent within 60 minutes, and preferably within 30 minutes.

20. The method according to any of claims 1 to 19, wherein the solids concentration of the prepared batch of feed solution is 3 wt. % to 45 wt. %.

21. The method according to any of claims 1 to 20, wherein the method comprises supplying the prepared batch from the system to the spray dryer while preparing a subsequent batch of the feed solution in the system.

22. The method according to claim 21, wherein the method comprises accommodating the prepared batch of the feed solution in a second tank while supplying the prepared batch from the system to the spray dryer, and comprises repeating (i) to (iii) according to any of claims 1 to 20 to prepare the subsequent batch of the feed solution in the system.

23. The method according to claim 21, wherein preparing the subsequent batch of the feed solution in the system comprises:(iv) repeating (i)(v) repeating (ii), wherein the at least one solid component of the two or more solid components is charged into the system through the deagglomeration device as in (ii) or wherein the at least one solid component of the two or more solid components is charged into the system through a second deagglomeration device; and(vi) circulating the solvent and the two or more solid components around a second fluid loop through a second tank and the deagglomeration device or the second deagglomeration device while mixing with the deagglomeration device or the second deagglomeration device to dissolve the two or more solid components in the at least one solvent, to prepare the subsequent batch of the feed solution, wherein the subsequent batch of the feed solution has a volume of 50 L to 500 L.

24. The method of claim 22 or claim 23, wherein the second tank has a volume of 50 L to 500 L, optionally wherein the second tank has a volume of 50 L and 200 L.

25. The method of any of claims 22 to 24, wherein the second tank comprises an agitation device, optionally a stirrer, and the method comprises mixing with the agitation device.

26. A method for delivering a continuous supply of a feed solution for a spray dryer, the method comprising preparing the batch of the feed solution according to any of claims 1 to 20, supplying the prepared batch from the system to the spray dryer while preparing the subsequent batch of the feed solution in the system according to any of claims 21 to 25, and supplying the prepared subsequent batch from the system to the spray dryer in a consecutive manner.

27. The method of claim 26, comprising repeating the preparing and supplying so as to prepare and supply three or more batches of the feed solution, preferably so as to prepare and supply 1500 L to 15 000 L of feed solution.

28. The method of claim 26 or claim 27, wherein the continuous supply of the feed solution enables a feed solution feed rate to the spray dryer such that a ratio of a drying gas flow rate (F_drying) in the spray dryer to feed solution feed rate (F_feed) rate is greater than or equal to 5.

29. The method of any of claims 26 to 28, the method comprising spray drying the prepared batch of feed solution and then the subsequent prepared batch(es) of feed solution in a consecutive manner, optionally wherein a step of spray drying with a stabilizing solvent is performed between spray drying of each batch of feed solution.

30. A system for preparing batches of feed solution for a spray dryer and for supplying the batches to the spray dryer in a consecutive manner to provide a continuous supply of feed solution for the spray dryer, wherein each batch is to be prepared by dissolving at least two solid components in at least one solvent in the system, the system comprising:(a) at least two tanks;(b) at least one deagglomeration device;(c) at least one inlet conduit for charging at least one of the solid components into the system through the at least one deagglomeration device;(d) an arrangement of conduits such that at least one of the at least two tanks, which has a volume of 50 L to 500 L, is fluidly connected to the at least one deagglomeration device in a fluid loop, around which the at least two solid components and the at least one solvent can be circulated while mixing with the deagglomeration device in order to dissolve the at least two solid components in the at least one solvent to prepare the batches of the feed solution, and(e) one or more outlet conduit(s) for supplying the batches of feed solution from the system to the spray dryer, wherein the system is configured to accommodate a prepared batch of the feed solution in one of the at least two tanks during supply of the prepared batch to the spray dryer through the one or more outlet conduits while a subsequent batch of the feed solution is being prepared in the system.

31. The system according to claim 30, wherein the at least two tanks comprise a first tank that is fluidly connected to the at least one deagglomeration device in the fluid loop in (d) and a second tank to accommodate the prepared batch of the feed solution while the subsequent batch of the feed solution is being prepared in the system using the fluid loop.

32. The system according to claim 30, wherein the at least two tanks comprise a first tank that is fluidly connected to the at least one deagglomeration device in the fluid loop in (d), and a second tank having a volume of 50 L to 500 L and capable of being fluidly connected to the at least one deagglomeration device to form a second fluid loop around which the at least two solid components and the at least one solvent can be circulated while mixing with the at least one deagglomeration device in order to dissolve the at least two solid components in the at least one solvent to prepare the batches of the feed solution, such that the batch of feed solution prepared using the fluid loop can be supplied to the spray dryer through the one or more outlet conduit(s) while the subsequent batch of the feed solution is being prepared using the second fluid loop.

33. The system according to any one of claims 30 to 32 wherein the at least one deagglomeration device is a high shear pump, a high shear mixer, an ultrasonic deagglomeration device, a fluidized bed system, a sifting device, a milling device, or a grinding device, and preferably wherein the at least one deagglomeration device is a high shear pump or a high shear mixer.

34. The system according to any one of claims 30 to 33, wherein one or more of the at least two tanks comprise an agitation device, preferably a stirrer.

35. The system according to any one of claims 30 to 34, wherein the system comprises one or more metering system(s) for charging the two or more solid components into the system.

36. The system according to claim 35, wherein the one or more metering system(s) is selected from a loss-in- weight feeder, a gain-in- weight hopper, a rotary valve, a pneumatic conveyor, or a vibratory feeder, and preferably wherein the one or more metering system(s) is one or more loss- in- weight feeder(s).

37. The system according to any one of claims 30 to 36, wherein the volume of the first tank and / or the volume of the second tank is 50L to 200 L.

38. The system according to any one of claims 30 to 37, wherein the system comprises one or more monitoring devices for monitoring the concentration of the two or more solids dissolved in the at least one solvent, optionally wherein the one or more monitoring devices are selected from a viscometer and a turbidimeter.

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