WO2024184724A1

WO2024184724A1 - Dynamic bulk freeze drying devices and methods

Info

Publication number: WO2024184724A1
Application number: PCT/IB2024/051862
Authority: WO
Inventors: Wolfgang BUERGELIN; Thomas Gebhard; Alexander Lukas; Bernhard Luy; Matthias Plitzko; Harry ROESCH
Original assignee: Pfizer Inc.
Priority date: 2023-03-03
Filing date: 2024-02-27
Publication date: 2024-09-12

Abstract

Apparatuses and methods are provided for reducing fluidization of bulk material during dynamic freeze drying. Fluidization is reduced by improving the mixing behavior of the bulk material to increase inter- particulate bulk material porosity during lyophilization processes, which reduces pressure build-up in the bulk material. A new and innovative drum (100) for rotary freeze drying is provided that includes one or more baffles (500) constructed and arranged to form slits through which bulk material can pass as the drum (100) rotates to generate sheets of the bulk material. At least one of the baffles (500) may be disposed in a curved shape, such as a helical shape, along the interior surface of the drum (100). The curved shape directs the bulk material to one of the front and rear end of the drum (100) as the drum (100) rotates.

Description

DYNAMIC BULK FREEZE DRYING DEVICES AND METHODS

TECHNICAL FIELD

[0001 ] The present application relates generally to bulk freeze drying. More specifically, the present application provides apparatuses and methods for dynamic bulk freeze drying that have or use one or more new and innovative structures for generating one or more sheets (or layers) of bulk material.

BACKGROUND

[0002] Freeze drying, also known as lyophilization or cryodesiccation, is a process that removes a solvent or suspension medium from a product. The solvent or suspension medium may be water, though others may be used, such as alcohol. Freeze drying is particularly useful in the pharmaceutical industry, as the integrity of the product is preserved during the freeze drying process and product stability can be guaranteed over relatively long periods of time. The freeze dried product is ordinarily, but not necessarily, a biological substance.

[0003] In a freeze drying process for removing water, the water in the product is frozen to form ice and, under low vacuum conditions in a process chamber, the ice is sublimed into the vapor/gas phase. The sublimation of the ice results in a very significant volume expansion by generating large water vapor volumes. In orderto maintain the low vacuum conditions, the vapors flow to a condenser adjacent to the process chamber and are then de-sublimated again into ice by the condenser. The ice is later removed from the condenser.

[0004] The freeze drying process for removing water is determined, in part, by the diffusion process of the water vapors. For instance, after having effected the sublimation of the ice, the water vapors still have to leave the structure that remains during and after drying. This structure is referred to as lyo cake, which is characterized by typically high porosities. The pore diameters in the lyo cake have a significant impact on the drying process, as the vapor diffusion speed is linked to the pore diameter. Such diffusion is higher in larger pores.

[0005] The freeze drying of frozen bulk material can be performed by conventional shelftype freeze dryers under static conditions utilizing lyo cakes, or by using dynamic bulk freeze drying processes in which the bulk product is kept in motion. The bulk material used in dynamic freeze drying is characterized by significantly smaller frozen particles than the bulk material used in conventional shelf-type freeze dryers, and can be generated by methods like spray freezing of liquids or size reduction of larger frozen structures. The freeze drying of such smaller frozen particles is based on the same principles as for larger lyo cakes in shelf -type freeze dyers. The vapor diffusion processes in these many small frozen particles, however, are different than vapor diffusion processes in larger single piece lyo cakes, which creates challenges for drying the bulk material using dynamic drying processes.

SUMMARY

[0006] The present disclosure provides new and innovative apparatuses and methodsfor reducing fluidization of bulk material during dynamic freeze drying and, therefore, increasing yield. The fluidization, which may be caused by pressure build-up due to vapor diffusion obstruction in bulk freeze drying, is reduced by providing conditions that allow vapor to be released from the bulk material (e.g. , by improving the mixing behavior of the bulk material), which reduces pressure build-up in the bulk material. For example, the conditions increase interparticulate bulk material porosity, and increase opportunitiesfor vapor to be released from the bulk material, during dynamic lyophilization. The provided methods improve the mixing behavior of the bulk material, in part, by generating sheets (or layers) of the bulk material to avoid dense packing of the bulk material. From a sheet, the water vapor can leave the particles directly without being impeded by in ter- particulate diffusion through a porous bulk material. As such, generating the sheets of the bulk material increases in ter- particulate bulk material porosity and therefore reduces fluidization-causing pressure build-up in the bulk material. In embodiments of dynamic drum lyophilization, the provided methods improve the mixing behavior of the bulk material, in part, by effectuating a lateral movement of the bulk material during mixing. The lateral movement takes into account the benefit of the liquid-type flow behavior of the bulk material. The bulk material discussed herein, and the sheets of same discussed herein, include bulk material comprising one or more pharmaceutical compositions, one or more biological materials such as proteins, enzymes, microorganisms, and any thermo- and/or hydrolysis-sensitive material(s).

[0007] In an example implementation, a new and innovative drum for rotary freeze drying is provided that includes baffles constructed and arranged to form slits through which bulk material can pass as the drum rotates to generate sheets of the bulk material. At least one of the baffles may be disposed in a curved (e.g., helical) shape along the interior surface of the drum. The curved shape directs the bulk material to one of the front and rear end of the drum as the drum rotates.

[0008] In one example embodiment, an apparatus (e.g., a freeze-drying apparatus) includes a body (e.g., a freeze-drying body) comprising afirst opening at a first end of the body and a second opening at a second end of the body, wherein the body is adapted to rotate about an axis extending through the first and second openings; and a baffle disposed in a curved (e.g., helical) shape along an interior surface of the body.

[0009] In another example embodiment, an apparatus (e.g., a freeze-drying apparatus) includes a body (e.g., a freeze-drying body) comprising afirst opening at a first end of the body and a second opening at a second end of the body; a baffle comprising a first baffle segment at an angle to a second baffle segment; and a first slit between the first baffle segment and an interior surface of the body. The body is adapted to rotate about an axis extending through the first and second openings.

[0010] In another example embodiment, a method for freeze drying material includes introducing material into a body (e.g., a freeze-drying body) configured to rotate about an axis extending through afirst end of the body and a second end of the body; rotating the body about the axis; and directing a portion of the material towards at least one of the first end of the body and the second end of the body, while the body is rotating, via at least one baffle disposed in a curved (e.g., helical) shape along an interior surface of the body. In some embodiments, the rotating and the directing occurs while the body is positioned at least partially inside a vacuum chamber. In some furtherembodiments, the rotating and the directing occurs while a pressure in the body is within one of the ranges in the group consisting of: 5 to 2500 microbar (pbar), 10 to 1500 pbar, 10 to 750 pbar, 10 to 400 pbar, 10 to 200 pbar, 10 to 100 pbar, and 10 to 50 pbar. [0011] In another example embodiment, a method for dynamically freeze drying material includes supplying material to a freeze-drying apparatus; mixing the material via the freeze-drying apparatus; and generating a sheet of the material during a lyophilization process. In some embodiments, the sheet is generated as some of the material passes through a slit associated with a baffle of the freeze-drying apparatus. The sheet of the material may be generated during mixing the material and/or subsequent to mixing the material. In some embodiments, the mixing and the generating is performed with the freeze-drying apparatus positioned at least partially inside a vacuum chamber. In some further embodiments, the mixing and the generating occurs while a pressure in the freeze-drying apparatus is within a range of 5 to 2500 pbar.

[0012] Additional features and advantages of the disclosed method and apparatus are described in, and will be apparent from, the following Detailed Description and the Figures. The features and advantages described herein are not all-inclusive and, in particular, many additional features and advantages will be apparent to one of ordinary skill in the art in view of the figures and description. Moreover, it should be noted that the language used in the specification has been principally selected for readability and instructional purposes, and not to limit the scope of the inventive subject matter.

[0013] The terms “comprise” (and any form of comprise, such as “comprises” and “comprising”), “have” (and any form of have, such as “has” and “having”), “include” (and any form of include, such as “includes” and “including”), and “contain” (and any form of contain, such as “contains” and “containing”) are open-ended linking verbs. As a result, something that “comprises,” “has,” “includes,” or “contains” one or more elements possesses those one or more elements, but is not limited to possessing only those one or more elements. Likewise, a method that “comprises,” “has,” “includes,” or “contains” one or more steps possesses those one or more steps, but is not limited to possessing only those one or more steps.

[0014] Herein, “or” is inclusive and not exclusive, unless expressly indicated otherwise or indicated otherwise by context. Therefore, herein, “A or B” means “A, B, orboth,” unless expressly indicated otherwise or indicated otherwise by context. Moreover, “and” is both joint and several, unless expressly indicated otherwise orindicated otherwise by context. Therefore, herein, “A and B” means “A and B, jointly or severally,” unless expressly indicated otherwise or indicated otherwise by context. The phrase “and/or” means and or or. T o illustrate, A, B, and/or C includes: A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C. In other words, “and/or” operates as an inclusive or. [0015] Any embodiment of any of the disclosed apparatuses and methods can consist of or consist essentially of — rather than comprise/have/include/contain — any of the described elements, features, and/or steps. Thus, in any of the claims, the term “consisting of” or “consisting essentially of” can be substituted for any of the open-ended linking verbs recited above, in order to change the scope of a given claim from what it would otherwise be using the open-ended linking verb. The feature or features of one embodiment may be applied to other embodiments, even though not described or illustrated, unless expressly prohibited by this disclosure or the nature of the embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The following drawings illustrate by way of example and not limitation. Forthe sake of brevity and clarity, every feature of a given structure is not always labeled in every figure in which that structure appears, and every reference number in a given figure is not always described. Identical reference numbers do not necessarily indicate an identical structure. Rather, the same reference number may be used to indicate a similar feature or a feature with similar functionality, as may non-identical reference numbers. The devices in FIGs. 1 -7 are drawn to scale, and the structures shown in FIGs. 8-14 are from photographs and are also to scale, meaning that, for both groups of figures, the sizes of the depicted elements are accurate relative to each other for at least the depicted elements; but as a person of ordinary skill in the art will understand, this invention is not limited to the depicted embodiments or usage of any of them, and other embodiments that do not possess the depicted sizes also fall within the scope of one or more of the claims.

[0017] FIG. 1 illustrates a side view of a drum for freeze drying, according to an aspect of the present disclosure.

[0018] FIG. 2 illustrates a front view of the drum of FIG. 1 , according to an aspect of the present disclosure.

[0019] FIG. 3 illustrates a rear view of the drum of FIG. 1 , according to an aspect of the present disclosure.

[0020] FIG. 4 illustrates a perspective view of the drum of FIG. 1 , according to an aspect of the present disclosure.

[0021] FIG. 5 illustrates the drum of FIG. 4 with a transparent body, according to an aspect of the present disclosure. [0022] FIG. 6 illustrates a cross-section of the drum of FIG. 1 , according to an aspect of the present disclosure.

[0023] FIG. 7 illustrates a perspective view of helical baffles, according to an aspect of the present disclosure.

[0024] FIG. 8 illustrates a section of the interiorof the drum of FIG. 1 showing holders for the helical baffles, according to an aspect of the present disclosure.

[0025] FIG. 9 illustrates a portion of a helical baffle showing the segments of the helical baffle, according to an aspect of the present disclosure.

[0026] FIG. 10 illustrates a portion of a helical baffle showing the slits of the helical baffle, according to an aspect of the present disclosure.

[0027] FIG. 1 1 illustrates a portion of a helical baffle showing the angles of the segments of the helical baffle, according to an aspect of the present disclosure.

[0028] FIG. 12 illustrates a portion of a non-helical baffle, according to an aspect of the present disclosure.

[0029] FIG. 13 illustrates a sensor for measuring a temperature of the interior surface of a drum, according to an aspect of the present disclosure.

[0030] FIG. 14 illustrates a sensorfor measuring a temperature of the bulk material inside a drum, according to an aspect of the present disclosure.

[0031] FIG. 15 is a flow chart of a method for dynamically freeze drying material, according to an aspect of the present disclosure.

[0032] FIG. 16 is a flow chart of a method for rotary freeze drying material, according to an aspect of the present disclosure.

[0033] FIG. 17 illustrates a sheet (or layer) of material generated by a slit of a baffle, according to an aspect of the present disclosure.

DETAILED DESCRIPTION

[0034] Apparatuses and methods are provided for reducing fluidization of bulk material during dynamicf reeze drying and, therefore, increasing yield. Fluidization is reduced by providing conditions that allow vapor to be released from the bulk material (e.g., by improving the mixing behaviorof the bulk material), which reduces pressure build-up in the bulk material. Forexample, the conditions increase in ter- particulate bulk material porosity during dynamic lyophilization. In another example, the conditions increase opportunities for bulk material particles to emerge at the surface of the bulk material such that entrapped vapor can be released from the bulk material during dynamic lyophilization.

[0035] The bulk material used in dynamic freeze drying is characterized by significantly smaller frozen particles than static freeze drying. The freeze drying of such smaller frozen particles is based on the same principles as for larger lyo cakes used with static freeze drying; however, in dynamic bulk freeze drying of small particles, the water vapor (or other solvent or suspension medium vapor) has to pass through more than intra-particulate pores of a single piece of material. When freeze drying a multiple-particulate bulk material, the void space between the single particles of the bulk material represents another diffusion barrier such that inter-particulate diffusion is also present. Stated differently, after the water vapor leaves a small particle itself (intra-particulate diffusion), the water vapor still has to diffuse through the void space between the particles (inter-particulate diffusion) in orderforthe water vapor to be released from the bulk material. Using typical dynamic freeze-drying equipment, however, and due to certain vacuum pressure levels and frozen particle sizes, the water vapor is impeded from overcoming the interparticulate diffusion barrier and instead accumulates within the bulk material causing fluidization, which causes a portion of the bulk material to leave the process chamber and thereby to be lost, resulting in a yield reduction.

[0036] The provided methods improve the mixing behavior of the bulk material, in part, by generating sheets (or layers) of the bulk material to avoid dense packing of the bulk material and create opportunities for particles of the bulk material to emerge at the surface of the bulk material thereby allowing entrapped vapor to escape. From a sheet, the water vapor can leave the particles directly without being impeded by inter-particulate diffusion through a porous bulk material. As such, generating the sheets of the bulk material increases in ter- particulate bulk material porosity and enables more entrapped vapor to escape from the bulk material, and therefore reduces fluidization-causing pressure build-up in the bulk material. In an example implementation, a new and innovative drum for rotary freeze drying is provided that includes one or more baffles constructed and arranged to form one or more slits through which bulk material can pass to generate one or more sheets of the bulk material. As the drum rotates, bulk material falls through the one or more slits by way of gravity, thus forming one or more sheets of falling particles that allow the water vapor to escape.

[0037] In some embodiments, the provided methods improve the mixing behavior of the bulk material, in part, by effectuating a lateral movement of the bulk material during mixing. The lateral movement takes into account the benefit of the liquid-type flow behavior of the bulk material. In an example implementation, a new and innovative drum for rotary freeze drying is provided that includes at least one baffle disposed in a curved (e.g., helical) shape along the interior surface of the drum. The curved shape directs the bulk material to one of the front and rear end of the drum as the drum rotates. In some aspects, the drum includes at least one helical baffle that directs the bulk material to the front end of the drum and at least one helical baffle that directs the bulk material to the rear end of the drum.

[0038] FIGs. 1 to 4 illustrate various views of the exterior of an example drum 100 for rotary freeze-drying applications. The drum 100 may be utilized to carry out a freeze-drying process of a variety of suitable materials, all of which are within the scope of the present apparatuses and systems. For example, the drum 100 may be utilized to carry out the freeze- drying of pharmaceutical compositions, biological materials such as proteins, enzymes, microorganisms, or any thermo- and/or hydrolysis-sensitive materials. The drum 100 includes a body 102 that has a front end 104 (e.g., first end) opposite a rear end 106 (e.g., second end). The front end 104 includes an opening 200 and the rear end 106 includes an opening 202. The body 102 is adapted so that, when the drum 100 is in use, the body 102 can rotate about an axis 108 extending through the opening 200 and the opening 202. For example, rotation of the body 102 may be driven by a motor (not illustrated) in communication with a controller (not illustrated) having a processorand a memory storing logicforcontrolling the motor. In the illustrated example embodiment, the components of the drum 100 are arranged for the drum 100 to rotate counterclockwise when viewing the drum 100 from the front end 104, as depicted by the arrow 400. In other embodiments, the components of the drum 100 may be arranged for the drum to rotate clockwise. [0039] In various embodiments, and as reflected in FIG. 1 , the drum 100 is inclined toward the front end 104 at an angle 1 10 relative to a horizontal line. The inclination of the drum 100 may help to drain washing fluids during cleaning or steam condensate during sterilization. In various aspects, the angle 1 10 may be within a range of 0.5 to 3 degrees.

[0040] In some embodiments, the drum 100 is a double wall drum such that the body 102 is constructed with a double wall. In such embodiments, the drum 100 may include components for actively controlling the temperature of the interior surface 600 (FIG. 6) of the drum 100, which can transfer heat to the bulk material in order to initiate sublimation of ice . For example, the void space in between the inner wall of the body 102 and the outer wall of the body 102 may be cooled or heated by a flow of a suitable medium (e.g., silicone oil) to control the temperature of the interior surface 600. Such medium may flow through a closed loop (e.g., tubing) positioned at least partially within the space between the two walls of the body 102.

[0041] In at least some embodiments, the drum 100 is positioned within a vacuum chamber 1 12, as depicted in FIG. 1. An interior of the vacuum chamber 1 12 is in fluid communication with a vacuum pump 1 14. The vacuum pump 1 14 may be in communication with the controller (not illustrated) and the memory of the controller may store logic for the processor of the controller to control the vacuum pump 1 14. The vacuum pump 1 14 generates vacuum conditions within the vacuum chamber 1 12 for a freeze-drying process. For instance, the vacuum pump 1 14 may generate a pressure within one of the ranges in the group consisting of: 5 to 2500 microbar (pbar), 10 to 1500 pbar, 10 to 750 pbar, 10 to 400 pbar, 10 to 200 pbar, 10 to 100 pbar, and 10 to 50 pbar. The interior of the drum 100 is in fluid communication with the interior of the vacuum chamber 1 12 such that the vacuum pressure conditions, when present, are present within both the drum 100 and the vacuum chamber 112. While the vacuum chamber 112 and the vacuum pump 114 are shown only in FIG. 1 , it will be appreciated that any of the embodiments supported by the present disclosure may be utilized with vacuum pressure conditions.

[0042] FIG. 5 illustrates the drum 100 with the body 102 transparent in orderto show the baffles arranged in the interiorof the body 102. FIG. 6 illustrates a cross-section of the drum 100 to show a portion of the interiorof the drum 100. Referring to both FIGs. 5 and 6, the baffles are constructed (e.g., curved) and arranged to, while the body 102 is rotating, effectuate lateral movement of the bulk material toward the front end 104 or the rear end 106 and/or generate sheets of the bulk material. In at least some embodiments, the baffles effectuate lateral movement of the bulk material at low rotation speeds (e.g., within a range of 0.5 to 2 rotations per minute (rpm)) of the body 102 of the drum 100. Generally, it can be easier to obtain desired mixing of bulk material with high rotation speeds (e.g., greater than 2 and less than 5 rpm), but high rotations speeds are not desired for freeze drying applications because materials typically used with freeze drying are mechanically sensitive (e.g., lower solid content). As such, low rotation speeds with freeze drying applications, as compared to high rotation speeds, can reduce attrition of the bulk material, leading to improved product yield and less dust, which improves the flow properties of the final product and eases cleaning requirements.

[0043] In the illustrated embodiment, the drum 100 includes baffles 500A-500E that are each disposed in a helical shape along an interior surface 600 of the body 102 such that the baffles 500A-500E direct bulk material toward the rear end 106 while the drum 100 is rotating. As the drum 100 rotates, the curve of the helical shape of each of the baffles 500A-500E influences a portion of the bulk material to flow toward the rear end 106 by way of gravity. For instance, only a portion of the particles of the bulk material contact each of the baffles 500A-500E at a given time. Influencing the portion of the bulk material to flow toward the rear end 106 helps improve the mixing behavior of the bulk material by effectuating lateral movement of the bulk material. While the illustrated embodiment shows five separate baffles 500A-500E, in other embodiments, the drum 100 may include 1 , 2, 3, 4, 6, 10, or any other suitable quantity of baffles 500A-500E, depending on the size of the drum 100.

[0044] The illustrated embodiment of the drum 100 additionally includes baffles 502Aand 502B that are each disposed in a helical shape along an interior surface 600 of the body 102 such that the baffles 502A and 502B direct bulk material toward the front end 104 while the drum 100 is rotating. The curve of the helical shape of each of the baffles 502Aand 502B is the opposite of the curve of the helical shape of each of the baffles 500A-500E and therefore influences a portion of the bulk material to flow toward the front end 104 by way of gravity. For instance, only a portion of the particles of the bulk material contact each of the baffles 502Aand 502B at a given time. Influencing the portion of the bulk material to flow toward the front end 104 helps improve the mixing behavior of the bulk material by effectuating lateral movement of the bulk material. FIG. 7 illustrates the baffle 500A and the baffle 502A to show the opposite curvature of the respective helical shapes, which can be seen in FIG. 6 as well. Returning to FIGs. 5 and 6, while the illustrated embodiment shows two separate baffles 502A and 500B, in other embodiments, the drum 100 may include 1 , 3, 4, 6, 10, or any other suitable quantity of baffles 502A and 502B depending on the size of the drum 100, or might not include any baffles 502A and 502B.

[0045] In at least some embodiments, the drum 100 includes a greater quantity of baffles that direct bulk material toward the rear end 106 (e.g. , baffles 500A-500E) than quantity of baffles that direct bulk material toward the front end 104 (e.g., baffles 502A and 502B). The greater quantity of baffles directing bulk material toward the rear end 106 can compensate for the inclination of the drum 100 toward the front end 104 at the angle 1 10.

[0046] The illustrated embodiment of the drum 100 further includes baffles 504A-504E that reduce slippage of the bulk material while the drum 100 is rotating by improving rolling of the bulk material. In various aspects, one or more of the baffles 504A-504E is inclined relative to the axis 108 to direct bulk material toward the front end 104 or the rear end 106 while the drum 100 is rotating, which helps improve the mixing behavior of the bulk material. For example, FIG. 6 shows that each of the baffles 504A-504C is inclined relative to the axis 108 at an angle 602 such that the bulk material is directed toward the rear end 106 while the drum 100 is rotating. The angle 602 may be within a range of 10-30, 15-25, or 18-22 degrees. In various embodiments, the angle 602 may be 20 degrees. In other examples, a first portion (e.g., one or multiple but less than all) of the baffles 504A-504E may be inclined to direct bulk material toward the rear end 106 while the drum 100 is rotating and a second portion of the baffles 504A-504E may be inclined to direct bulk material toward the front end 104 while the drum 100 is rotating. In some aspects, each of the baffles 504A-504E is not inclined, but is rather parallel to the axis 108. While the illustrated embodiment shows five separate baffles 504A-504E, in other embodiments, the drum 100 may include 1 , 3, 4, 6, 10, or any other suitable quantity of baffles 504A-504E depending on the size of the drum 100, or might not include any baffles 504A-504E.

[0047] In various embodiments, the baffles 504A-504E are disposed in one or more sections of the interior of the drum 100 that are between adjacent, opposing helical baffles. For example, FIG. 6 shows that, in the illustrated embodiment, the baffles 504A-504C are disposed in the section between the baffle 500A and the baffle 502A. In another example, FIG. 5 shows that, in the illustrated embodiment, the baffles 504D-504E are disposed in the section between the baffle 500E and the baffle 502B. In other embodiments, the baffles 504A-504E may be disposed in other sections of the drum 100, such as an intersection with one or more of the baffles 500A-500E or one or more of the baffles 502A and 502B.

[0048] As described above, the baffles of the drum 100 are constructed and arranged to form slits through which bulk material can pass to generate sheets of the bulk material. FIGs. 8 to 10 illustrate sections of the baffle 500A that show the various features of the baffle 500Afor generating the sheets of the bulk material. Each of the described features of the baffle 500A with respect to FIGs. 8 to 10 applies to the baffles 500B-500E and to the baffles 502A and 502B as well.

[0049] In the illustrated embodiment, the baffle 500A includes a baffle segment 800 and a baffle segment 802. Each of the baffle segment 800 and the baffle segment 802 comprises a sheet of material (e.g., metal) curved into a helical shape. The baffle segment 800 and the baffle segment 802 are maintained away from the interior surface 600 of the drum 100 such that a slit 818 is maintained between the baffle segment 800 and the interior surface 600. For example, a primary holder 804 includes a first portion 806 attached to the baffle segment 800, a second portion 808 attached to the baffle segment 802, and a third portion 824 attached to the interior surface 600. The primary holder 804 maintains the baffle segment 800 and the baffle segment 802 apart from the interior surface 600 to thereby maintain the slit 818. A sheet of the bulk material is generated as the bulk material passes through the slit 818. The primary holder 804 maintaining the slit 818, rather than directly connecting the baffle segment 800 to the interior surface 600 at direct connection points, reduces the accumulation of bulk material that would otherwise occur at the direct connection points.

[0050] At least one location on the third portion 824 of the primary holder 804 is separated from at least one location on the baffle segment 800 by a distance 810 in the illustrated embodiment. In some aspects, no portion of the baffle segment 800 (and no portion of the baffle 500A) is closer to the location on the third portion 824 than distance 810. In some aspects, the distance 810 is within a range of 10-30 millimeters (mm). In some aspects, the distance 810 is within a range of 20-30 mm. The distance 810 between the third portion 824 of the primary holder 804 and the baffle segment 800 reduces the accumulation of bulk material at the primary holder 804, though the drum may still operate when the distance 810 is within a range of 0-10 mm.

[0051] In various embodiments, such as the illustrated embodiment, the baffle segment 800 and the baffle segment 802 are maintained away from one another such that a slit 820 is maintained between the baffle segment 800 and the baffle segment 802. Forexample, the primary holder 804 in the illustrated embodiment maintains the baffle segment 800 apart from the baffle segment 802 to maintain the slit 820 for bulk material to pass through the slit 820. As the bulk material passes through the slit 820 during rotation of the drum 100, a sheet of falling bulk material is generated. In some aspects, at least one secondary holder 812 provides further structural support for maintaining the baffle segment 800 apart from the baffle segment 802, as shown in the illustrated embodiment. Forexample, the at least one secondary holder 812 includes a first portion 814 attached to the baffle segment 800 and a second portion 816 attached to the baffle segment 802.

[0052] In various embodiments, such as the illustrated embodiment, the baffle segment 800 includes one or more slits 822 through which bulk material may pass. As the bulk material passes through the one or more slits 822 during rotation of the drum 100, a sheet of falling bulk material is generated. For example, FIG. 17 illustrates a sheet of material 1700 generated by bulk material passing through one of the slits 822. Only the sheet of material 1700 is illustrated in FIG. 17 to maintain clarity in the figure, though it will be appreciated that a similar sheet of material may be formed via the slit 818, the slit 820, or a second slit 822. The one or more slits 822 may be a single continuous slit or multiple slits separated from one another by a portion of the baffle segment 800. In other embodiments, the baffle segment 800 may be solid without any slits, like the baffle segment 802 in the illustrated embodiment. In some aspects, the baffle segment 802 may include one or more slits, such as one or more of the slits 822.

[0053] In at least some aspects, each of the slits 818, 820, and 822 has a width within a range of 1 .5 to 4 mm. In some aspects, each of the slits 818, 820, and 822 has a width within a range of 2 to 3 mm. In at least some aspects, the slit 818 extends for at least 90% of the length of the baffle 500A. In at least some aspects, the slit 818 extends for at least 95% of the length of the baffle 500A. In at least some aspects, the slit 820 extends for at least 90% of the length of the baffle 500A. In at least some aspects, the slit 820 extends for at least 95% of the length of the baffle 500A. In at least some aspects, the one or more slits 822 may cover at least 90% of the length of the baffle 500A. A length of the baffle 500A is understood to be a distance spanning from a furthest most end of the baffle 500A to an opposing furthest most end regardless of whether the ends of the baffle 500A are square.

[0054] FIG. 10 shows that the primary holder 804 maintains the baffle segment 800 at an angle 1000 relative to the interior surface 600 and at an angle 1002 relative to the baffle segment 802. The at least one secondary holder 812 may also maintain the baffle segment 800 at the angle 1002 relative to the baffle segment 802. In various aspects, the angle 1000 is within one of the ranges in the group consisting of 70-1 10, 80-100, and 85-95 degrees. I n some aspects, the angle 1000 is 90 degrees. In various aspects, the angle 1002 is within one of the ranges in the group consisting of 60-120, 70-110, 80-100, and 85-95 degrees. In some aspects, the angle 1002 is 90 degrees.

[0055] Also shown in FIG. 10 is that the interior surface 600, the baffle segment 800, and the baffle segment 802 together form a near U-shape (e.g., a U-shape with 90 degree angles). Stated differently, the baffle 500A and the interior surface 600 togetherform a near U-shape. As the drum 100 rotates, bulk material collects in the space formed within the near U-shape. For example, in the illustrated embodiment, the drum 100 rotates counterclockwise and the space formed by the near U-shape is open with the direction of rotation so that bulk material is collected into the space. While the illustrated embodiment includes a near U-shape formed by the baffle 500A and the interior surface 600, it will be appreciated that other geometrical designs are contemplated for the baffle 500A that enable the baffle 500A to collect bulk material in the space between the baffle 500A and the interior surface 600.

[0056] As the drum 100 rotates and bulk material is collected in the space formed by the baffle 500A and the interior surface 600, the baffle 500A effectuates lateral movement of the bulk material toward the rear end 106 due to gravity and the helical shape of the baffle 500A. The lateral movement of the bulk material provides the advantage of improved mixing behavior of the liquid-type flow of bulk material, which increases homogeneity of the final product. Additionally, as the baffle 500A carries the collected bulk material along the upward portion of a full rotation of the drum 100, a point is reached where the collected bulk material begins to fall through the slits 818, 820, and 822 by way of gravity, which thereby generates sheets of falling particles of the bulk material. The sheets multiply a surface area in which small portions of the bulk material are separated from the main bulk material in a way that allows water vapor to escape the bulk material. The improved conditionsforthe watervaporto escape reduces pressure build-up inside the bulk material, which reduces or eliminates fluidization of the bulk material that causes uncontrollable particle movement and reduced yield.

[0057] Each of the advantages described for the baffle 500A applies to the baffles 500B- 500E and the baffles 502A and 502B as well. For example, FIG. 1 1 illustrates a portion of the interior of the drum 100 that includes portions of the baffles 500A-500D. Although only indicated with a reference numeral in a single instance for the sake of clarity in the figure, as shown in the illustrated embodiment, each of the baffles 500A-500D is attached to at least one primary holder 804 and to at least one secondary holder 812. As the drum 100 rotates, bulk material is collected in the space formed by each of the baffles 500A-500D, lateral movement of the bulk material is effectuated by each of the baffles 500A-500D, and sheets of bulk material are generated through slits of each of the baffles 500A-500D.

[0058] FIG. 12 illustrates a section of the baffle 504A that shows the various features of the baffle 504A for generating the sheets of the bulk material. Each of the described features of the baffle 504Awith respect to FIG. 12 apply to the baffles 504B-504E as well. The baffle 504A is a sheet of material (e.g., metal). The baffle 504A is maintained away from the interior surface 600 of the drum 100 such that a slit 1202 is maintained between the baffle 504A and the interior surface 600. For example, a holder 1200 includes a first portion attached to the baffle 504A and a second portion attached to the interior surface 600. The holder 1200 maintains the baffle 504A apart from the interior surface 600 to thereby maintain the slit 1202. Sheets of the bulk material are generated as the bulk material passes through the slit 1202. The holder 1200 maintaining the slit 1202, rather than directly connecting the baffle 504Ato the interiorsurface 600 at direct connection points, reduces the accumulation of bulk material that would otherwise occur at the direct connection points.

[0059] The holder 1200 maintains the baffle 504A at an angle 1204 relative to the interior surface 600. In various aspects, the angle 1204 is within one of the ranges in the group consisting of 5-50, 5-40, 5-30, 5-20, 10-20, 10-30, 10-40, and 10-50 degrees so that the baffle 504A carries bulk material to a sufficient height as the drum 100 rotates to generate a sheet of the bulk material through the slit 1202 without incurring detrimental process outcomes caused by carrying the bulk material too high (e.g., material getting carried out of the drum 100 through the opening 200 and/or 202 by escaping water vapors). In some aspects, the angle 1204 is 10 degrees.

[0060] In various embodiments, the drum 100 includes sensor(s) for measuring a temperature of the interior surface 600 and/or the bulk material. For example, FIG. 13 illustrates a portion of the interior of the drum 100 showing a temperature sensor 1300. The temperature sensor 1300 includes a tube (e.g., metal tube) housing a thermocouple. The tube is in contact with a block 1302 (e.g., metal block) that is also in contact with the interior surface 600. The block 1302 transfers the temperature of the interior surface 600 to the thermocouple inside the tube via conduction, which therefore allows the temperature of the interior surface 600 to be sensed. [0061 ] FIG. 14 illustrates a portion of the interior of the drum 100 showing atemperature sensor 1400. The temperature sensor 1400 includes a tube (e.g., metal tube) housing a thermocouple. Contrary to the tube of the temperature sensor 1300, the tube of the temperature sensor 1400 is not directly or indirectly in contact with the interior surface 600. As such, the temperature sensor detects atemperature of the bulk material within the drum 100. FIGs. 13 and 14 illustrate the interior of the drum 100 without baffles solely for clarity in the figures.

[0062] At least some of the mechanisms described herein for reducing in ter- particulate bulk material porosity during lyophilization processes to reduce pressure build-up in the bulk material can be used for other dynamic freeze drying techniques in addition to rotary freeze drying. For example, dynamic freeze drying may include inclined vibrating shelves that mix the bulk material due to the vibrations. In such examples, thresholds (e.g., barriers) may be introduced such that when the bulk material passes the thresholds, sheets of the material are generated. In anotherexample, dynamicfreeze drying may include beltdryers. In such examples, mechanical guides may mix the bulk material during static passage and generate a sheet of the material after mixing.

[0063] FIG. 15 shows a flow chart of an example method for dynamically freeze drying material. Although the example method 1500 is described with reference to the flowchart illustrated in FIG. 15, it will be appreciated that other ways of performing the acts associated with the method 1500 may be used in view of the preceding description. For example, in some embodiments, the order of some of the blocks may be changed, certain blocks may be combined with other blocks, and/or certain blocks may be omitted. The method 1500 includes, at block 1502, supplying material to a freeze-drying apparatus. For example, the freeze-drying apparatus may be a rotating drum (e.g., the drum 100), inclined vibrating shelves, belt dryers, or other suitable freeze-drying apparatusesfordynamicfreeze drying. At block 1504, the material is mixed via the freeze-drying apparatus. For example, the material is mixed as the rotating drum rotates, as the shelves vibrate, or as the mechanical guides of the belt dryer mix the material. At block 1506, a sheet of the material is generated, using the apparatus, during a lyophilization process. For example, the sheet of the material is generated as material passes through a slit of a baffle (e.g., the slit 820 of the baffle 500A), as material passes thresholds of vibrating shelves, or via mechanical guides of belt dryers. The sheet of the material is generated during mixing the material (e.g., within the drum 100) or subsequent to mixing the material (e.g., after mechanical guides of the belt dryers mix the material). As described above, generating the sheet of material during the lyophilization process increases inter-particulate bulk material porosity and reduces pressure build-up in the bulk material to prevent extreme fluidization of the bulk material that reduces yield of the dynamic freeze drying process.

[0064] FIG. 16 shows a flow chart of an example method for freeze drying material. In at least some embodiments, the method 1600 may be performed as part of a rotary freeze drying process. Although the example method 1600 is described with reference to the flowchart illustrated in FIG. 16, it will be appreciated that other ways of performing the acts associated with the method 1600 may be used in view of the preceding description. For example, in some embodiments, the order of some of the blocks may be changed, certain blocks may be combined with other blocks, and/or certain blocks may be omitted. [0065] The method 1600 includes, at block 1602 introducing material into a body (e.g., the body 102) configured to rotate about an axis extending through a first end of the body and a second end of the body. At block 1604, the body is rotated about the axis.

[0066] At block 1606, a portion of the material is directed toward at least one of the first end of the body and the second end of the body, while the body is rotating, via at least one baffle (e.g., the baffle 500A or 502A) disposed in a curved (e.g., helical) shape along an interiorsurface (e.g., the interior surface 600) of the body. In some aspects, a first portion of the material is directed toward the first end (e.g., the end 104) of the body via a first baffle (e.g., the baffle 502A) disposed in a curved (e.g., helical) shape along the interior surface of the body, and a second portion of the material is directed toward the second end (e.g., the end 106) of the body via a second baffle (e.g., the baffle 500A) disposed in a curved (e.g., helical) shape along the interior surface of the body. In some aspects, method 1600 further includes generating a sheet of the material, while the body is rotating, via at least one slit (e.g., at least one of the slits 1000, 1002, and 1004) associated with the at least one baffle. In some aspects, method 1600 further includes generating a sheet of the material, while the body is rotating, via the at least one slit (e.g., the slit 1202) associated with at least one second baffle (e.g., the baffle 504A).

[0067] All numerical ranges herein should be understood to include all integers and fractions within the range, inclusive of the ends of the ranges. Moreover, these numerical ranges should be construed as providing supportforaclaim directed to any numberorsubset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 1 to 8, from 3 to 7, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth.

[0068] The scope of this disclosure encompasses all changes, substitutions, variations, alterations, and modifications to the example embodiments described or illustrated herein that a person having ordinary skill in the art would comprehend. The scope of this disclosure is not limited to the example embodiments described or illustrated herein. Moreover, although this disclosure describes and illustrates respective embodiments herein as including particular components, elements, feature, functions, operations, or steps, any of these embodiments may include any combination or permutation of any of the components, elements, features, functions, operations, or steps described or illustrated anywhere herein that a person having ordinary skill in the art would comprehend. Furthermore, reference in the appended claims to an apparatus or system or a component of an apparatus or system being adapted to, arranged to, capable of, configured to, enabled to, operable to, or operative to perform a particular function encompasses that apparatus, system, component, whether or not it orthat particularfunction is activated, turned on, or unlocked, as long as that apparatus, system, or component is so adapted, arranged, capable, configured, enabled, operable, or operative. Additionally, although this disclosure describes or illustrates particular embodiments as providing particular advantages, particular embodiments may provide none, some, or all of these advantages.

[0069] The above specification provides a complete description of the structure and use of illustrative embodiments of this invention. Although certain embodiments have been described above with a certain degree of particularity, or with reference to one or more individual embodiments, those of ordinary skill in the art could make numerous alterations to the disclosed embodiments without departing from the scope of this invention. As such, the various illustrative embodiments of the present apparatuses and methods are not intended to be limited to the particular forms disclosed. Rather, they include all modificationsand alternatives falling within the scope of the claims, and embodiments other than those shown may include some or all of the features of the depicted embodiment. Further, where appropriate, aspects of any of the examples described above may be combined with aspects of any of the other examples described to form further examples having comparable or different properties and/or functions, and addressing the same or different problems. Similarly, it will be understood that the benefits and advantages described above may relate to one embodiment or may relate to several embodiments.

[0070] The claims are not intended to include, and should not be interpreted to include, means-plus- or step-plus-function limitations, unless such a limitation is explicitly recited in a given claim using the phrase(s) “means for” or “step for,” respectively.

Claims

1 . An apparatus comprising: a body comprising a first opening at a first end of the body and a second opening at a second end of the body, wherein the body is adapted to rotate about an axis extending through the first and second openings; and a baffle disposed in a curved shape along an interior surface of the body.

2. The apparatus of claim 1 , wherein the curved shape is a helical shape.

3. The apparatus of claim 1 , wherein the baffle comprises a first baffle segment disposed at an angle to a second baffle segment.

4. The apparatus of claim 3, wherein each of the first and second baffle segments extends an entire length of the baffle.

5. The apparatus of claim 4, wherein the baffle comprises a first slit between the first baffle segment and the second baffle segment.

6. The apparatus of any of claims 3 to 5, wherein a body of the first baffle segment includes at least one second slit and wherein a body of the second baffle segment includes at least one third slit.

7. The apparatus of any of claims 1 to 6, further comprising: at least one fourth slit between the baffle and the interior surface of the body; and a holder attached to the body and to the baffle such that the holder separates the baffle from the interior surface of the body to maintain the at least one fourth slit.

8. The apparatus of claim 7, wherein a position at which the holder is attached to the body is spaced a distance from the baffle.

9. The apparatus of any of claims 1 to 8, wherein the baffle is a first baffle of a plurality of baffles that are each disposed in a curved shape along the interior surface of the body, wherein at least the first baffle of the plurality of baffles is arranged to direct material toward the first end of the body when the apparatus is in operation, and wherein at least one second baffle of the plurality of baffles is arranged to direct material toward the second end of the body when the apparatus is in operation.

10. The apparatus of any of claims 1 to 9, wherein the baffle is a first baffle and the apparatus further comprises: a third baffle disposed along the interior surface of the body and parallel to the axis, wherein the third baffle is at an angle less than ninety degrees to the interior surface along an entire length of the third baffle.

11 . The apparatus of claim 10, wherein the angle is in a range of ten to fifty degrees.

12. The apparatus of claim 10, further comprising: at least one fifth slit between the third baffle and the interior surface of the body; and a plurality of holders attached to the body and to the third baffle such that the plurality of holders separate the third baffle from the interior surface of the body to maintain the at least one fifth slit.

13. The apparatus of any of claims 1 to 12, wherein the body is double-walled.

14. An apparatus comprising: a body comprising a first opening at a first end of the body and a second opening at a second end of the body, wherein the body is adapted to rotate about an axis extending through the first and second openings; a baffle comprising a first baffle segment at an angle to a second baffle segment; and a first slit between the first baffle segment and an interior surface of the body.

15. The apparatus of claim 14, wherein the first slit is between the baffle and the interior surface of the body for at least ninety percent of the length of the baffle.

16. The apparatus of claims 14 or 15, wherein a body of the first baffle segment includes at least one second slit.

17. The apparatus of any of claims 14 to 16, further comprising: a third slit between the first baffle segment and the second baffle segment.

18. The apparatus of claim 17, further comprising: a plurality of holders, wherein each holder is attached to the first baffle segment and to the segment baffle segment such that the plurality of holders maintains the third slit.

19. A method for freeze drying material, comprising: introducing material into a body configured to rotate about an axis extending through a first end of the body and a second end of the body; rotating the body about the axis; and directing a portion of the material toward at least one of the first end of the body and the second end of the body, while the body is rotating, via at least one baffle disposed in a curved shape along an interior surface of the body.

20. The method of claim 19, further comprising: generating a sheet of the material, while the body is rotating, via at least one slit associated with the at least one baffle.

21. The method of claim 19, further comprising: directing a first portion of the material toward the first end of the body via a first baffle disposed in a curved shape along the interior surface of the body; and directing a second portion of the material toward the second end of the body via a second baffle disposed in a curved shape along the interior surface of the body.

22. The method of claim 21 , further comprising: generating a sheet of the material, while the body is rotating, via at least one slit associated with the first baffle.

23. The method of claim 21 , further comprising: generating a sheet of the material, while the body is rotating, via at least one slit associated with the second baffle.

24. The method of any of claims 19 to 23, wherein the rotating and the directing occurs while the body is positioned at least partially inside a vacuum chamber.

25. The method of any of claims 19 to 24, wherein the rotating and the directing occurs while a pressure in the body is within a range of 5 to 2500 pbar.

26. A method for dynamically freeze drying material comprising: supplying material to a freeze-drying apparatus; mixing the material under vacuum via the freeze-drying apparatus; and generating a sheet of the material.

27. The method of claim 26, wherein the sheet of the material is generated during the mixing and/or subsequent to the mixing.

28. The method of any of claims 26 to 27, wherein the freeze-drying apparatus includes at least one of a rotary drum, inclined vibrating shelves, and belt dryers.

29. The method of any of claims 26 to 28, wherein the sheet of the material is returned to a remaining portion of the material during the lyophilization process.

30. The method of any of claims 26 to 29, wherein the freeze-drying apparatus is positioned at least partially inside a vacuum chamber.

31 . The method of any of claims 26 to 30, wherein the mixing and the generating occurs while a pressure in the freeze-drying apparatus is within a range of 5 to 2500 pbar.