Patent Publication Number: US-11020352-B2

Title: Systems and methods for the fabrication of tablets, including pharmaceutical tablets

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of U.S. patent application Ser. No. 15/898,010, entitled “SYSTEMS AND METHODS FOR THE FABRICATION OF TABLETS, INCLUDING PHARMACEUTICAL TABLETS” filed on Feb. 15, 2018, which claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application Ser. No. 62/460,626, entitled “SYSTEMS AND METHODS FOR THE FABRICATION OF TABLETS, INCLUDING PHARMACEUTICAL TABLETS” filed on Feb. 17, 2017, and U.S. Provisional Application Ser. No. 62/619,638, entitled “SYSTEMS AND METHODS FOR THE FABRICATION OF TABLETS, INCLUDING PHARMACEUTICAL TABLETS” filed on Jan. 19, 2018, and U.S. Provisional Application Ser. No. 62/621,429, “SYSTEMS AND METHODS FOR THE FABRICATION OF TABLETS, INCLUDING PHARMACEUTICAL TABLETS” filed on Jan. 24, 2018, the entire contents of each of which are incorporated herein by reference. 
    
    
     GOVERNMENT SPONSORSHIP 
     This invention was made with Government support under Contract No. N66001-11-C-4147 awarded by the Space and Naval Warfare Systems Center. The Government has certain rights in the invention. 
    
    
     TECHNICAL FIELD 
     Systems and methods for fabricating tablets, including pharmaceutical tablets, are generally described. 
     BACKGROUND 
     Recently, pharmaceutical and biotechnology industries have experienced periods of slowed growth and increased costs associated with the development of new pharmaceutical products. While individual processes involved in certain pharmaceutical manufacturing are transitioning to continuous-like processes, pharmaceutical facilities generally still rely on batch or semi-batch techniques to produce complex chemical products. Current processes are typically tailored to manufacture a single specific type of pharmaceutical tablet and generally require large, expensive, and static setups. While continuous processes are suggested to offer numerous benefits, including reduced cost, complete infrastructure and systems capable of complex continuous manufacturing of pharmaceutical tablets do not exist. The ability to fabricate pharmaceutical tablets (and, in some cases, compositionally different types of pharmaceutical tablets) in a single self-contained system remains elusive. 
     SUMMARY 
     Systems and methods for fabricating tablets, including pharmaceutical tablets, are provided. Certain of the systems and methods described herein are capable of manufacturing tablets of different dosages without the need to fluidically connect or disconnect unit operations when switching from a tablet having a first dosage to a tablet having a second, different dosage. Certain of the systems and methods described herein are capable of manufacturing compositionally tablets, e.g., tablets with different active pharmaceutical ingredients (APIs). The subject matter of the present invention involves, in some cases, interrelated products, alternative solutions to particular problem, and/or a plurality of different uses of one or more systems and/or articles. 
     According to one aspect, a method for producing an ingestible pharmaceutical composition is provided. The method can comprise, in some embodiments, receiving, with a controller, instructions regarding a first tablet dosage and a second tablet dosage. The method may also include dispensing a first amount of a solid active pharmaceutical ingredient and dispensing a first amount of an excipient. The method may also include blending the first amount of the solid active pharmaceutical ingredient and the first amount of the excipient to form a first mixture having a volume of less than 10 L. The method may also include forming a first tablet from the first mixture, dispensing a second amount of the solid active pharmaceutical ingredient and dispensing a second amount of the excipient. The method may also include blending the second amount of the solid active pharmaceutical ingredient and the second amount of the excipient to form a second mixture and forming a second tablet from the second mixture, wherein a dosage of the active pharmaceutical ingredient of the first tablet is different from a dosage of the active pharmaceutical ingredient of the second tablet. 
     According to another aspect, a method of producing an ingestible pharmaceutical composition is provided. The method can comprise, in some embodiments, receiving, with a controller, instructions regarding a first tablet dosage and a second tablet dosage. The method may also include providing a first dispenser, a second dispenser, a blender and a frame, wherein the first dispenser, the second dispenser and the blender are coupled to the frame. The method may also include dispensing a first amount of a solid active pharmaceutical ingredient, dispensing a first amount of an excipient, and blending the first amount of the solid active pharmaceutical ingredient and the first amount of the excipient to form a first mixture, and forming a first tablet from the first mixture. The method may also include dispensing a second amount of the solid active pharmaceutical ingredient, dispensing a second amount of the excipient, blending the second amount of the solid active pharmaceutical ingredient and the second amount of the excipient to form a second mixture and forming a second tablet from the second mixture. 
     According to yet another aspect, a method of producing an ingestible pharmaceutical composition is provided. The method can comprise, in some embodiments, receiving, with a controller, instructions regarding a first drug type and a second drug type. The method may also include dispensing a first solid active pharmaceutical ingredient, dispensing a first excipient, blending the first solid active pharmaceutical ingredient and the first excipient to form a first mixture having a volume of less than 10 L, and forming a tablet from the first mixture. The method may also include dispensing a second solid active pharmaceutical ingredient, the second solid active pharmaceutical ingredient being compositionally different from the first solid active pharmaceutical ingredient, dispensing a second excipient, blending the second solid active pharmaceutical ingredient and the second excipient to form a second mixture, and forming a tablet from the second mixture. 
     According to yet another aspect, a system for producing an ingestible pharmaceutical composition is provided. The system can comprise, in some embodiments, a plurality of dispensers, a first weigh scale configured to weigh material dispensed from the plurality of dispensers, and a blender configured to receive and mix the material dispensed from the plurality of dispensers to form a first mixture, the blender having a volume of less than 10 L. 
     According to yet another aspect, a system for producing an ingestible pharmaceutical composition is provided. The system can comprise, in some embodiments, a frame, a plurality of dispensers, a weigh scale configured to weigh material dispensed from the plurality of dispensers, and a blender configured to receive and mix the material dispensed from the plurality of dispensers to form a first mixture, wherein the plurality of dispensers, the weigh scale and the blender are coupled to the frame. 
     Other advantages and novel features of the present invention will become apparent from the following detailed description of various non-limiting embodiments of the invention when considered in conjunction with the accompanying figures. In cases where the present specification and a document incorporated by reference include conflicting and/or inconsistent disclosure, the present specification shall control. If two or more documents incorporated by reference include conflicting and/or inconsistent disclosure with respect to each other, then the document having the later effective date shall control. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Non-limiting embodiments of the present invention will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to be drawn to scale. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the invention shown where illustration is not necessary to allow those of ordinary skill in the art to understand the invention. In the figures: 
         FIG. 1  is a schematic illustration of a system for producing pharmaceutical tablets according to one set of embodiments; 
         FIG. 2  is a block diagram of a method of producing pharmaceutical tablets according to one set of embodiments; 
         FIG. 3  is a perspective view of a system for producing pharmaceutical tablets according to one set of embodiments; 
         FIG. 4  is a front view of the system shown in  FIG. 3 ; 
         FIG. 5  depicts a system for producing pharmaceutical tablets; 
         FIG. 6  depicts a system for producing pharmaceutical tablets in a portable arrangement according to one set of embodiments; 
         FIG. 7  is a perspective view of an array of dispensers according to one set of embodiments; 
         FIGS. 8A-8D  depict graphs indicating dispenser performance; 
         FIG. 9  is a perspective view of a material carrying unit according to one set of embodiments; 
         FIG. 10  depicts a material carrying unit; 
         FIG. 11  depicts a chart indicating carrying unit performance; 
         FIG. 12  is a perspective view of a blender according to one set of embodiments; 
         FIG. 13  depicts a blender; 
         FIGS. 14A-14B  depict a blender impeller; 
         FIG. 14C  is a perspective view of a blender impeller; 
         FIG. 15  depicts a chart indicating blender mixing performance; 
         FIG. 16  is a perspective view of a lower stream process arrangement according to one set of embodiments; 
         FIG. 17  depicts a lower stream process arrangement; 
         FIG. 18  is a perspective view of a mixed blend dispenser according to one set of embodiments; 
         FIG. 19  depicts a mixed blend dispenser; 
         FIGS. 20A-B  depict graphs indicating dispenser performance; 
         FIG. 21  is a perspective view of a tableting unit and weigh scale according to one set of embodiments; 
         FIG. 22  depicts tablets produced by the tableting unit; 
         FIG. 23  is a block diagram of an illustrative computing device that may be used to implement a method of producing pharmaceutical tablets; 
         FIG. 24  is a block diagram of a method of producing pharmaceutical tablets; 
         FIG. 25  depicts a dispenser with a discharge chute and a vibratory mechanism; 
         FIG. 26  depicts a dispenser discharge chute; 
         FIG. 27  depicts a vibratory mechanism; 
         FIG. 28  depicts a plurality of glass beads to help with dispensing of material; 
         FIG. 29A  is an optical microscope image of ibuprofen particles used in a tableting process; 
         FIG. 29B  is an optical microscope image of diazepam particles used in a tableting process; 
         FIG. 30  depicts ibuprofen and diazepam tablets manufactured using a system for producing pharmaceutical tablets; 
         FIG. 31A  illustrates the dissolution results for the manufactured ibuprofen tablets; and 
         FIG. 31B  illustrates the dissolution results for the manufactured diazepam tablets. 
     
    
    
     DETAILED DESCRIPTION 
     Systems and methods related to fabricating tablets, including pharmaceutical tablets, are generally described. 
     The ability to fabricate pharmaceutical tablets in a portable, self-contained, and/or readily reconfigurable system remains generally elusive. In the pharmaceutical industry, pharmaceutical tablets are typically made from large formulated blend batches on the scale of kilos to tons. Such processes require a large investment in equipment, space and materials. Also, with substantial expense tied to each batch, substantial financial losses are associated with the loss of a batch due to quality problems. With high production volumes, a longer shelf-life of several years or months may be required. As a result, comprehensive and rigorous final product testing must be conducted to measure shelf life/stability (active pharmaceutical ingredient degradability, sensitivity to temperature and moisture, etc.). Coatings are sometimes needed to prolong shelf life of mass-produced tablets. Developing suitable coating formulations can be a significant challenge, as coatings introduce potential issues such as adherence, cracking, degree of moisture protection, effect on dissolution rate and compatibility with active pharmaceutical ingredients (APIs) and excipients. Such considerations may limit the choice of acceptable APIs and/or excipients. When shelf-life is of concern, additional testing may be required. Packaging appropriate to sustain a long shelf-life may be designed and tested. This can introduce additional compatibility concerns (e.g., between the packaging and the coating material). High production volumes can also come with the downside of high expense and down-time associated with any product changes. It may therefore be difficult, for example, for typical pharmaceutical facilities to be flexible to customer demand, or to accommodate market demand for “orphan” drugs. 
     Described herein is a system and method for making pharmaceutical, finished dosage form tablets. The unit may provide various benefits over conventional batch processes. The inventors have appreciated that, in some cases, the unit may provide various benefits; for example, it may: (1) help address regional drug shortages, (2) provide a solution for drugs with a short shelf life, (3) be reconfigurable to produce multiple drug products, (4) be located at locations where drug products are required, (5) be put into immediate production of drugs based on demand, bypassing the need to stockpile drugs, and/or (6) reduce formulation complexity relative to products needing yearlong stability. 
     According to one aspect, the system is a compact, portable unit. In some embodiments, the system holds and processes volumes of material that are much smaller than those of traditional batch processes. In some embodiments, multiple components of the system are coupled together to a common frame, as opposed to having large components independent of one another spread out over a facility floor. 
     According to one aspect, the method involves using a system to fabricate a first tablet and a second tablet, the two tablets being different from one another. In some embodiments, the two tablets may include the same API, but be of different dosages. In some cases, the system may automatically switch between production of the two different dosages without any physical changes to the system components. In some embodiments, the first tablet may include an API that is compositionally different from the API of the second tablet. In some cases, touch points in the system, i.e., components of the system that come into contact with API, may be substituted with clean components when the system switches from producing tablets that include one API to producing tablets that include a compositionally different API. According to one aspect, the tablets may be created on-demand, e.g., a user may input an instruction to the system specifying the desired dosage and/or desired API of the tablet. In some embodiments, a user may specify the number of desired tablets. In response, the system will dispense the appropriate type and amount of API and excipient to form a blended mix for the tablet in accordance with the user&#39;s instruction. In some embodiments, the system includes a controller that receives the user&#39;s instruction and controls the system components to carry out steps in accordance with the instruction. 
     In one set of embodiments, systems and methods related to producing one or more pharmaceutical tablets are described.  FIG. 1  depicts a schematic illustration of system  1  according to one set of embodiments, which can be used to produce one or more pharmaceutical tablets. In some embodiments, the system comprises one or more modules. Each module can contain at least one unit operation. The unit operation can be used to perform a step of a tablet fabrication process. 
     In some embodiments, the system comprises a plurality of modules that interact with one another. For example, in certain embodiments, the system comprises multiple modules that interact with one another. In some such embodiments, each of the modules within the system can be used to perform one or more steps of a multi-step tablet production process. 
     Referring to  FIG. 1 , for example, system  1  comprises modules  110 ,  124 ,  130 ,  210  and  230 . In some embodiments, module  110  comprises a plurality of dispensers, module  124  comprises a weigh scale, module  130  comprises a blender, module  210  comprises a dispenser, and module  230  comprises a tableting unit. Dispensers  110  can be used to dispense tablet materials, and a weigh scale  124  can be used to weigh the dispensed material, a blender  130  can be used to mix the dispensed materials, a blended mix dispenser  210  can be used to dispense the blended mix, and a tableting unit  230  can be used to form a tablet  2  from the blended mix. In some embodiments, material dispensed from the dispensers  110  is conveyed to the blender  130 . According to one aspect, the weighing function and conveying function may be integrated into one material carrying unit. In some embodiments, a controller  300  controls the operation of the system. The controller  300  may receive feedback from one or more modules of the system and/or may provide control instructions to one or more modules of the system. The dashed lines in  FIG. 1  between controller  300  and each of the modules indicate that the controller  300  may communicate with one or more of the modules of the system. In some embodiments, the modules of the system (e.g., the dispensers, the blender, the carriage, etc.) may also communicate with one another, with and/or independently of the controller. 
       FIG. 2  depicts a schematic illustration of a process of producing pharmaceutical tablets according to one set of embodiments. In such embodiments, API and excipient are dispensed, then weighed. In some embodiments, the API and/or excipients may be solid, such as in a powder form. The API and excipient may be dispensed and weighed at different times, such that the system is able to determine the mass of each type of dispensed material. For example, the system may first dispense API and then weigh the dispensed API. The system may then subsequently dispense excipient and then weigh the dispensed excipient. In some embodiments the API may be dispensed into a carriage, and the excipient may be dispensed into the same carriage holding the dispensed API. The system may determine the mass of the excipient based on the increase in weight detected after the excipient was added. In other embodiments, each of the materials may be weighed separately. For example, the API and excipient may be weighed in different carriages. Or, the same carriage may be emptied out between receipt of each type of material. For example, in some embodiments, the API is first weighed, then the API is removed from the carriage. After the carriage is emptied, in some embodiments, the excipient is received and weighed in the carriage. For the above discussion, it should be appreciated that the order of dispensing can be changed, e.g., reversed such that the excipient is dispensed before the API. Or, in case where a plurality of excipients and/or APIs are used in a tablet, any order of dispense may be used. 
     In some embodiments, after weighing, the API and excipient are conveyed to a blender. In such embodiments, weighing occurs prior to conveying the API and excipient to the blender. However, in other embodiments, weighing may occur in the blender itself. In either case, with the API and excipient present in the blender, the blender mixes the API and excipient together into a mixed blend. In some embodiments, the mixed blend is then dispensed into smaller, discrete amounts that are received by a tableting machine, which forms and outputs a completed tablet. In some embodiments, the tableting machine may use a direct compression method to compact the mixed blend and form the tablet. In some embodiments, the final tablet may be weighed to check that it is of a desired mass. 
     One illustrative embodiment of a system for producing pharmaceutical tablets is shown in  FIGS. 3 and 4 , and an illustrative embodiment of one system is shown in  FIG. 5 . Each of the components mentioned in this section will be described in greater detail in a subsequent section. The tablet production system  1  includes a plurality of dispensers  110 . In the embodiment of  FIGS. 3 and 4 , the system includes five dispensers,  111 ,  112 ,  113 ,  114  and  115 . In this embodiment, the weigh module includes a weigh scale  124 , a carriage  120  that receives material to be weighed, and an arm  122  connecting the weigh scale  124  to the carriage  120 . In some embodiments, the weigh module also serves to convey dispensed material to the blender. For example, in the embodiment shown in  FIGS. 3-5 , the weigh scale is coupled to an actuator  126  such that the carriage  120  can be moved to various positions beneath each of the dispensers  110  and to the blender  130 . In some embodiments, to facilitate delivery of material from the carriage  120  to the blender, the carriage is configured to tilt such that material in the carriage slides out into the blender. In some embodiments, the system may include a tilting mechanism  121  that tilts the carriage. In some embodiments, the blender  130  includes a rotating impeller that mixes the dispensed API and excipient together into a blended mix. 
     The blended mix is then transferred from the blender  130  to a dispenser  210 . In some embodiments, the bottom of the blender  130  opens up and feeds into the dispenser  210  located below. In some embodiments, the blended mix dispenser  210  dispenses discrete amounts of the blended mix into a tableting unit  230 , which compresses the blended mix into a tablet and ejects the tablet into a tablet output tray  238 . 
     According to one aspect, the system may be divided into two process streams: an upper process stream  100  and a lower process stream  200 . In the embodiment shown in  FIGS. 3-5 , the upper process stream  100  begins with the dispensers  110  and ends with the blender  130  mixing the API and excipient into a blended mix. The lower process stream  200  begins with the blended mix dispenser  210  receiving a blended mix and ends with the tableting unit  230  forming and outputting a tablet. The step of transferring the blended mix from the blender  130  to the blended mix dispenser  210  connects the upper and lower process streams. In the embodiment shown in  FIGS. 3-5 , this transfer step occurs via an opening of the blender  130  to allow blended mix inside the blender  130  to fall into the dispenser  210  below. In some embodiments, the upper and lower process streams can operate simultaneously, and, in some cases, independently of one another. For example, while API and excipient are being dispensed, weighed, and mixed in the blender in the upper process stream, tablets can be formed in the lower process stream. The two process streams may be controlled by either the same controller or separate controllers. 
     In the embodiment shown in  FIGS. 3-5 , the upper and lower process streams occur at the same physical location. In addition, with the blender directly ejecting blended mix into the dispenser  210  below, the two process streams also interact directly with one another. 
     However, it should be appreciated that the upper and lower process streams may be physically separated from one another. For example, the two process streams may occur in separate facilities in different parts of the world. The upper process stream may result in a mixed blend that is transported to the location of the lower process stream, and the mixed blend is fed into the dispenser of the lower process stream. The two process streams may also occur in the same facility, but in separated positions such that the blender of the upper process stream is not directly above the dispenser of the lower process stream. 
     In some embodiments, the upper and lower process streams need not be tied together. For example, in some embodiments, the upper process stream can supply an unrelated tableting stream. As another example, in some embodiments, the lower process stream can be supplied by an unrelated blending stream. 
     According to one aspect, each of the upper and lower stream processes are integrated systems. In contrast to conventional large-scale batch processes, in which the components are spread out over the floor of the facility due to their large-volume nature, for each of the upper and lower stream processes, in some embodiments, the components are sized and positioned such that they can be coupled to a common frame, making the system compact, and in some cases, portable. For example, in the embodiment shown in  FIG. 3 , the components of the upper process stream  100 , e.g., the dispensers  110 , weigh scale  124 , carriage  120  and blender  130  are coupled to an upper frame  10 . As also seen in  FIG. 3 , the components of the lower process stream  200 , e.g., the dispenser  210  and the tableting unit  230 , are coupled to a lower frame  20 . 
     According to one aspect, the tablet production system is a compact, portable unit. In some embodiments, the tablet production system occupies a volume of less than 10,000 liters, less than 5000 liters, less than 2000 liters, or less than 1000 liters. As used herein, the “volume” of the system corresponds to the smallest rectangular prism that encompasses all components of the system. In some embodiments, the tablet production system has a footprint of less than 10 square meters, less than 5 square meters, less than 2 square meters, or less than 1 square meter. In one embodiment, the tablet production system is approximately 72.4 cm×53.3 cm×134.6 cm (length by width by height). 
     According to one aspect, the tablet production system can be one complete integrated system, with both the upper and lower process streams contained within one compact, portable unit. In some embodiments, the tablet production system can sit atop a rolling assembly, such that the system can be easily moved and transported. In one illustrative embodiment shown in  FIG. 6 , the tablet production system  1  is integrated with a rolling assembly having wheels  42 . The rolling assembly may include locks on the wheels that can be engaged to prevent inadvertent movement of the system and disengaged to permit movement of the system. 
     In some embodiments, the assembly may include a removable access covering that can be moved to provide access to the production system. In the illustrative embodiment shown in  FIG. 6 , the assembly includes a covering  30 . The covering  30  may be mounted to the sides of the system via arms  32  that can rotate up and down to permit the covering  30  to move between closed and open positions. In the open position, a user is able to access the components of the system  1  and can proceed with any appropriate manipulations of the system, e.g., for maintenance, cleaning, changing of components, etc. In some embodiments, the covering  30  may be transparent in order to allow a user to see the tablet production system while the covering  30  is in the closed position. In some embodiments, a storage/equipment cabinet  40  may be provided with the production system  1 . 
     In some embodiments, the system may be configured to manufacture on-demand pharmaceutical tablets on a scale of one hundred to thousands a day. Examples of different types of drugs that may be manufactured by such a unit include, but are not limited to: ibuprofen, doxycycline monohydrate, diphenhydramine hydrochloride, diazepam, ciprofloxacin HCl, azithromycin and fluoxetine hydrochloride. In some embodiments, the same system may be configured to produce two or more different drugs, even if the drugs are from different drug classes and have differing chemical structures, bulk physical properties, flow behaviors, and/or require different formulation strategies to make tablets. According to one aspect, the tablet production system is designed to accommodate a wide range of materials and tablet formulations. 
     Each of the components of the tablet production system will now be discussed in more detail below. 
     One illustrative embodiment of dispensers that may be used with the tablet production system is shown in  FIG. 7 . A plurality of dispensers may be used—each containing a different material. In some embodiments, the dispensers contain API, excipients or other suitable tablet ingredients. Although five dispensers are used in the  FIG. 7  embodiment, it should be appreciated that any suitable number of dispensers may be used. For example, 2, 3, 4, 5, 6 or more dispensers may be used. 
     In some embodiments, the dispensers are volumetric feeders in which feed rate is inferred from feeder speed based on prior calibration. In other embodiments, the dispensers are gravimetric feeders in which feed rate is controlled based on direct weight measurement. 
     In the embodiment shown in  FIG. 7 , the dispensers are Orbetron 50 Series dispensers (ORBETRON, Hudson, Wis.). Such dispensers operate by rotating a feeding disc within a storage container. An illustrative disc  500  is shown in  FIG. 25 . In some embodiments, the feeding disc has a small hole into which material can fall. With each rotation of the feeding disc, the material that is positioned in the hole of the feeding disc becomes aligned with an outlet hole of the dispenser, allowing the material in the disc hole to exit the dispenser. In this manner, with each rotation, the feeding disc permits a limited amount of material to exit the dispenser. In some embodiments, a “flicker” component may be added to a dispenser to aid in dispensing of cohesive materials. Such a component may help to break powder bridges and enhance flow. 
     The inventors have appreciated other arrangements to help with decreasing compaction of powder and/or otherwise preventing clogging of dispensers. 
     In some embodiments, as shown in  FIGS. 25-26 , the dispenser may include a chute  510  downstream of the outlet of the dispenser. The chute may be attached directly to the dispenser outlet. The chute may aid in dispensing material out of the dispenser. 
     In some embodiments, as shown in  FIGS. 25 and 27 , a vibratory mechanism  520  may be added to the dispenser. The vibratory mechanism may help to prevent compaction of material being dispensed and/or help to prevent clogging of the dispenser outlet. The vibratory mechanism may help to reduce powder accumulation on one or more components of the dispenser. The vibratory mechanism may be positioned directly on the dispenser outlet itself, or on a component attached to the dispenser outlet, such as the chute  510 . One example of a vibratory mechanism is an ADAFRUIT vibrating mini motor disc. In some embodiments, the operating voltage of the vibrating mini motor disc is 2 to 5 volts. 
     In some embodiments, beads may be added inside the dispenser to help decrease compaction of powder. The beads may be sized such to remain inside the dispenser without jamming the dispenser. For example, the beads may be larger than the dispenser outlet. In some embodiments, in dispensers that utilize a rotation disc, the beads may be sized larger than the spaces between the teeth of the disc such that they do not fall into the spaces between the teeth of the disc. The beads may move as the disc rotates, which may help to break any compacted material and keep the powder flow continuous. An illustrative example of such beads is shown in  FIG. 28 , which depicts a plurality of glass beads. In some embodiments, the beads may be 5 mm in diameter. However, other diameter sizes may be used as well. In some embodiments, 10 to 30 grams of the glass beads may be used. In some embodiments, about 18 grams of the glass beads may be used. 
     In some embodiments, the dispensers may operate at a feed as low as 2 gm/hour and as high as 5 kg/hour. The flow rate of the dispensers may be sufficient for a thousand doses a day. 
     It should be appreciated that other types of dispensers may be used, such as screw feeders, vibrator feeders, roller feeders, belt feeders, etc. 
       FIGS. 8A-8D  depict graphs indicating performance of the Orbetron 50 Series dispensers using an open-loop arrangement (i.e., no feedback from a weigh scale was used to control the dispensers). Tests were conducted with API, free-flowing excipients, cohesive excipients, and blends. The outcome of the tests indicated that higher variations in feed rate were observed for API and cohesive excipients, lower variations in feed rate were observed with free-flowing excipients and blends, and that feed rate varied with the change of fill level or powder height. 
     In some embodiments, to resolve these types of variations, a closed-loop control of dispensed powder may be included in the tablet production system. As one example, a weigh scale may be used to provide closed-loop feedback control. The weigh scale arrangement will be discussed in more detail in the next section. 
     In some embodiments, the tablet production system may include a weigh scale to provide a closed-loop control of dispensed powder. In some embodiments, the weigh scale takes the form of a load cell. It should be appreciated that other types of weigh scales may be used, such as a piezoresistive sensor, force restoration balances, etc. 
     In some embodiments, API and excipients are fed from multiple dispensers to a carriage suspended from a load cell. In some embodiments, the API and excipients from the plurality of dispensers are dispensed directly into a blender. In such an arrangement, the entire blender itself may be suspended from a load cell or other weigh scale such that material being dispensed into the blender may be weighed. 
     In some embodiments, material dispensed from the dispensers must be conveyed to a blender. In some embodiments, the component of the tablet production system that performs a weighing function of dispensed material also performs an additional function of conveying dispensed material to the blender for mixing. 
     One illustrative embodiment of a weigh scale module is shown in  FIG. 9 , and an actual weigh scale module is shown in  FIG. 10 . The module of  FIGS. 9-10  includes a weigh scale  124  and a carriage  120  suspended from the weigh scale  124  via an arm  122 . In the embodiment shown in  FIGS. 9 and 10 , the weigh scale  124  comprises a load cell. In some embodiments, the weigh scale module also performs an additional function of conveying material. In some embodiments, the module may include a linear actuator  126  to move the weigh scale  124 , arm  122  and carriage  120  to different locations. In some embodiments, the carriage  120  can be commanded to move to any dispenser, in any sequence, and the required amounts of powder or other material may be dispensed at each dispenser location. The carriage  120  may then transfer material to a blender. In some embodiments, the module may include a track along which the components can slide. 
     The inventors have appreciated that one potential challenge in transferring material from one container to another, particularly where the material is a powder, is the tendency for some of the material to remain in the starting container, resulting in incomplete transfer of material. This may lead to improper ingredient ratios and/or waste. 
     In some embodiments, where an intermediate carriage is used to carry material from dispensers to a blender, the carriage is arranged to tilt to aid in transfer of material. In some embodiments, such as the embodiments of  FIGS. 9 and 10 , the carriage  120  may be pivotally attached to the arm. 
     In some embodiments, the system may include a tilting mechanism, which could be, for example, on the blender, in a stationary position above the blender, or on the carriage itself. When the carriage reaches the blender, the tilting mechanism may be actuated to tilt the carriage. In the embodiment shown in  FIGS. 3-5 , the system includes a powered tilting mechanism in the form of a forklift  121  positioned above the blender  130 . When the carriage  120  reaches the blender, the forklift  121  lifts the trailing end of the carriage to tilt the leading edge of the carriage downward toward the mixing vessel of the blender. 
     In other embodiments, the tilting of the carriage may be done in a passive manner instead of by a powered tilting arrangement. For example, as the carriage moves toward the blender, the carriage may interact with a physical obstruction, such as a sloped wedge, that pushes one end of the carriage upward to tilt the carriage. 
     According to another aspect, material may be dispensed from the dispensers into the carriage in a particular order to facilitate transfer of material out of the carriage. In some embodiments, a controller controls the system to specifically dispense the least cohesive material into the carriage first. Without wishing to be bound by theory, when in contact with the originating container, cohesive materials tend to leave more residue than less cohesive materials during transfer. Thus, having the least cohesive material in direct contact with the carriage may help to facilitate a cleaner transfer. 
     Tests were conducted of the amount of residue remaining in the material carrying carriage when used to transfer a powder material. As seen in the test results depicted in  FIG. 11 , around 1% of the starting powder remained stuck to the carriage after transfer. 
     According to one aspect, the tablet ingredients are mixed until a desired amount of blend uniformity is reached. In some embodiments, the mixing can be performed by a blender. 
     One illustrative embodiment of a blender is shown in  FIGS. 3, 4, 5, 12 and 13 . As best seen in  FIGS. 12-13 , the blender  130  may include a mixing vessel  131 , motor  134 , an actuator  133 , and a gearbox  132 . 
     According to one aspect, the mixing vessel of the blender may be sized to be much smaller than the mixers used in traditional large-scale batch processing. In some embodiments, the mixing vessel of the blender may have a volume of less than or equal to 10 L, 1 L, 500 mL, 200 mL, or 100 mL. In some embodiments, the mixing vessel of the blender has a volume of about 200 mL. In some cases, the blender can mix about 50 gm of powder at a time with 40-50% capacity. 
     In some embodiments, the materials dispensed from the dispensers  110  form a mixture in the blender having a combined volume of less than or equal to 10 L, 1 L, 500 mL, 200 mL, or 100 mL. 
     According to one aspect, the blender is configured to be easily cleanable and re-configurable. In some embodiments, the blender includes a magnetic drive coupling, quick detach mount, and enclosed drive. 
     One illustrative embodiment of a blender impeller is shown in  FIGS. 14A-C . The impeller includes a shaft  136  and a plurality of impeller blades  137 . The blades  137  may be arranged at rotated angles relative to one another. Alternatively or in addition, for each group of blades (one on each side of the shaft), the blades  137  may be positioned at different heights relative to one another and/or at different circumferential positions along the drive shaft relative to one another. In some embodiments, the impeller may give rise to convective mixing to achieve a uniform blend. 
     In some embodiments, the blender may include a mechanism that allows for release of contents through the bottom of the blender mixing vessel to facilitate transfer of mixed material out of the blender. 
     In some embodiments, the blender mixing vessel has an outlet valve, such as a bottom plug, that can be opened to permit release of material. In one embodiment, a solenoid actuator pushes down on a shaft that is co-axial with the blender impeller shaft to move the bottom plug downwards so the mixed blend can be transferred to a dispenser below. 
     Mixing performance of the blender was tested using 4.48% fluoxetine HCl+0.5% SiO2+95.02% corn starch. As seen in the test results depicted in  FIG. 15 , after about 15 minutes of mixing, the RSD (Relative Standard Deviation) reached &lt;6%. 
     The lower process stream will now be discussed.  FIGS. 16 and 17  depict one illustrative embodiment of a lower process stream, including a dispenser  210  and a tableting unit (which may include, in part, a tablet die  231  and a tablet punch  232 ). 
     In some embodiments, a second dispensing step is used to dispense the mixed blend into smaller, discrete portions of material that are each ultimately compressed to form a single tablet. 
     In one illustrative embodiment shown in  FIGS. 18 and 19 , blended mix dispenser  210  includes a hopper  212 , a mechanical vibration unit  214  and a dispense head  216 . The blended mix from the blender  130  sits within the hopper  212 . In some embodiments, the vibration unit  214  operates based on a tapping mechanism in which an actuator  215  causes the vibration unit to move up and down. In some embodiments, the tapping mechanism includes a mallet or other device that strikes the hopper itself or a component that is in contact with the hopper, causing the hopper to move up and down. The dispense head  216  may include one or more holes. Up and down movement of the hopper may cause material to exit the hole(s) of the dispense head  216 . Without wishing to be bound by theory, the tapping mechanism may build powder micro-bridges which break down on impact and then re-build. 
     Dispense performance of the dispenser was tested using dispense heads of different hole sizes. As seen in the test results depicted in  FIG. 20A , a linear relationship was observed with mass flow rate and number of holes. As seen in the test results depicted in  FIG. 20B , measurements of mass fed per tap (i.e. mass dispensed per tap) were found to be sufficiently consistent, and increased with an increase in the number of holes in the dispense head. 
     It should be appreciated that other dispensing mechanisms may be used, such as those enumerated above with regard to the API and excipient dispensers upstream from the blender. 
     In some embodiments, the tableting process comprises a direct compaction method in which powder (e.g., API powder and/or excipient powder) and/or other tablet ingredients are pressed into the final tablet shape. In some embodiments, the tableting assembly may include a tablet die and a tablet punch that cooperate to create tablets. The punch may be lowered into the tablet die to compact tablet ingredients to form a tablet. In some embodiments, the tableting assembly may also include a die actuator that moves the die from a receiving position in which it receives a discrete amount of blended mix from the blended mix dispenser  210  to a compaction position in which it is aligned with the tablet punch. In some embodiments, the die actuator may also move the die to an ejection position in which the completed tablet is ejected from the die. 
     In some embodiments, the system may include different tablet die sizes and punches depending on the tablet dosage size. The system may switch between different die and punch sizes automatically, or may require a manual adjustment. 
     In some embodiments, after the tablet is formed and ejected, it is weighed by a weigh scale to determine whether or not the tablet has the desired amount of mass. If the weigh scale determines that the tablet does not satisfy mass requirements, the system may reject and discard the tablet. 
     One illustrative embodiment of a tableting unit  230  is shown in  FIG. 16 , and a portion of the tableting unit is shown in  FIG. 21  (the tablet punch  232  is omitted in  FIG. 21 ). In some embodiments, the tableting unit  230  may include a tablet die  231 , a die carriage  220  (best seen in  FIG. 21 ), a die actuator  222  and a tablet punch  232 . 
     In some embodiments, first, powder is dispensed into the tablet die  231  from the blended mix dispenser  210 . A die actuator  222  may move the tablet die  231  and the die carriage  220  until the die  231  is positioned below the tablet punch  232  (the die carriage  220  is best seen in  FIG. 21 ). A press  233  associated with the tablet punch  232  is seen in  FIG. 5 . In some embodiments, a GAMLEN tableting press, punch and die (Gamlen, Nottingham UK) may be used. 
     In some embodiments, with the tablet die  231  and the tablet punch  232  aligned, the tablet punch  232  is lowered into the tablet die  231  and compacts the tablet ingredients within the die  231  to form a tablet. In  FIG. 16 , for example, the tablet punch  232  and tablet die  231  are shown in the aligned position. In some embodiments, the formed tablet is then ejected into the tablet output tray  238 . 
     In some embodiments, the tablet punch is configured to apply varying amounts of compaction pressure depending on hardness requirements, the tablet formulation, and/or tablet size. In some embodiments, the controller may communicate to the tablet punch the appropriate compaction pressure to apply. In some embodiments, one or more sensors such as transducers (e.g., piezoelectric transducers) may be used to monitor and/or control tablet press compaction pressure. For example, in some embodiments, one or more sensors may be located within the tablet punch and/or the tablet die during compaction. 
     In some embodiments, such as the embodiment shown in  FIG. 5  and  FIG. 21 , a weigh scale  240  may be used to determine the weight of each formed tablet. In some embodiments, the tablet output tray  238  is positioned on the weigh scale, and the weigh scale detects the weight of each formed tablet by detecting the change in weight each time a tablet is output in the tray. 
     In some embodiments, if the tablet is measured to be of the expected weight for the tablet, the tablet is retained, and if the tablet is not of the expected weight, the tablet is discarded. An example of resulting tablets  2  produced by a tablet production system is shown in  FIG. 22 . 
     In some embodiments, the tableting unit requires only an upper punch  232 , and does not require a lower punch. However, in other embodiments, a lower punch may be used. 
     In some embodiments, techniques described herein may be carried out using one or more computing devices, including, but not limited to, network databases, storage systems, and central plant controllers. For example, the system may include a controller that includes one or more computing devices. Embodiments are not limited to operating with any particular type of computing device. 
       FIG. 23  is a block diagram of an illustrative computing device  1000  that may be used to implement any of the above-described techniques. Computing device  1000  may include one or more processors  1001  and one or more tangible, non-transitory computer-readable storage media (e.g., memory  1003 ). Memory  1003  may store, in a tangible non-transitory computer-recordable medium, computer program instructions that, when executed, implement any of the above-described functionality. Processor(s)  1001  may be coupled to memory  1003  and may execute such computer program instructions to cause the functionality to be realized and performed. 
     Computing device  1000  may also include a network input/output (I/O) interface  1005  via which the computing device may communicate with other computing devices (e.g., over a network), and may also include one or more user I/O interfaces  1007 , via which the computing device may provide output to and receive input from a user. The user I/O interfaces may include devices such as a keyboard, a mouse, a microphone, a display device (e.g., a monitor or touch screen), speakers, a camera, and/or various other types of I/O devices. 
     The above-described embodiments can be implemented in any of numerous ways. For example, the embodiments may be implemented using hardware, software or a combination thereof. When implemented in software, the software code can be executed on any suitable processor (e.g., a microprocessor) or collection of processors, whether provided in a single computing device or distributed among multiple computing devices. It should be appreciated that any component or collection of components that perform the functions described above can be generically considered as one or more controllers that control the above-discussed functions. The one or more controllers can be implemented in numerous ways, such as with dedicated hardware, or with general purpose hardware (e.g., one or more processors) that is programmed using microcode or software to perform the functions recited above. In some embodiments, a combination of programmable hardware and dedicated hardware may also be used. 
     In this respect, it should be appreciated that one implementation of the embodiments described herein comprises at least one computer-readable storage medium (e.g., RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, digital versatile disks (DVD) or other optical disk storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or other tangible, non-transitory computer-readable storage medium) encoded with a computer program (i.e., a plurality of executable instructions) that, when executed on one or more processors, performs the above-discussed functions of one or more embodiments. The computer-readable medium may be transportable such that the program stored thereon can be loaded onto any computing device to implement aspects of the techniques discussed herein. In addition, it should be appreciated that the reference to a computer program which, when executed, performs any of the above-discussed functions, is not limited to an application program running on a host computer. Rather, the terms computer program and software are used herein in a generic sense to reference any type of computer code (e.g., application software, firmware, microcode, or any other form of computer instruction) that can be employed to program one or more processors to implement aspects of the techniques discussed herein. 
     According to one aspect, the tablets may be created on-demand, e.g., a user may input an instruction to the system specifying the desired dosage and/or desired drug type. In response, the system will dispense the appropriate type and amount of API and excipient in accordance with the user&#39;s instruction. In some embodiments, the system may include a controller that receives the user&#39;s instructions and controls the system components to carry out the instructions. 
     For example, the system may receive instructions to produce 100 tablets of ibuprofen having a dosage of 500 mg and 50 tablets of ibuprofen having a dosage of 100 mg. The system controller receives the instructions and commands the various components of the system to produce tablets accordingly. For example, in some embodiments, the controller may instruct the blended mix dispenser (the dispenser downstream from the blender) to dispense a suitable mass of the mixed blend for the 500 mg tablets 100 times, and then dispense a suitable mass of the mixed blend for the 100 mg tablets 50 times. In this manner, in some embodiments, the system may seamlessly switch from production of a first tablet dosage to a second tablet dosage of the same drug without the need for production pauses or disconnecting/connecting modules or unit operations. 
     As another example, the system may receive instructions to produce 100 tablets of a first drug type (e.g., ibuprofen) and 50 tablets of a second, compositionally different drug type (e.g., azithromycin). The system controller receives the instructions and commands the various components of the system to produce tablets accordingly. In some embodiments, the dispensers upstream from the blender may already include all of the APIs and excipients required for both drugs. For example, three dispensers may hold the API(s) and excipient(s) required to make the first drug type, and three other dispensers may hold the API(s) and excipients required to make the second drug type. In other embodiments, the dispensers holding the ingredients needed for the second drug type are not connected to the system until after production of the first drug type has finished. 
     In some embodiments, when switching between production of different drug types, the “touch points” of the system may be replaced with clean components. Touch points of the system include any component of the system that came into contact with dispensed tablet ingredients (e.g., API or excipients). Examples of touch points include the carriage, blender impeller and mixing vessel, the blended mix dispenser hopper, the tablet die, the tablet press, and the tablet output tray. These components may be swapped out automatically by the system, manually by an operator, or a mix of both. However, production of both types of drug may still be considered to be run on the same physical system, as the overall infrastructure the system has not changed. For instance, the frames to which components are coupled may remain the same, the weigh scale and the actuator moving the carriage may remain the same, the blender motor and actuator may remain the same, the blended mix dispenser actuator may remain the same, and/or the tablet die actuator may remain the same. 
     A schematic flow chart of one such process according to one embodiment is shown in  FIG. 24 . First, the system receives dosage and/or drug type instructions  410 . Such instructions may be input by a user, e.g., a user interacting with a control panel of the system, a user sending instructions from a remote location, etc. In some embodiments, the system may be pre-programmed with instructions. In response to the instructions, the system dispenses  420  the appropriate API(s) and excipient(s) needed to make the specified drug type. The dispensed material is weighed  430  and conveyed  440  to a blender. The blender creates a mixed blend  450 , and a dispenser dispenses appropriately-sized portions of the mixed blend to satisfy the specified dosage  460 . The tableting machine then receives material from the dispenser and forms and ejects tablets  470 . Step  480  indicates that, if new instructions are received, the cycle restarts. 
     In some embodiments, at least one of the dispensing, blending and tableting steps are carried out at least partially in response to the instructions. 
     As noted above, certain of the systems and methods described herein include the use of an active pharmaceutical ingredient (“API”). As used herein, the term “active pharmaceutical ingredient” refers to an agent that is administered to a subject to treat a disease, disorder, or other clinically recognized condition, or for prophylactic purposes, and has a clinically significant effect on the body of the subject to treat and/or prevent the disease, disorder, or condition. Active pharmaceutical ingredients include, without limitation, agents listed in the United States Pharmacopeia (USP), Goodman and Gilman&#39;s The Pharmacological Basis of Therapeutics, 10th Ed., McGraw Hill, 2001; Katzung, B. (ed.) Basic and Clinical Pharmacology, McGraw-Hill/Appleton &amp; Lange, 8th edition (Sep. 21, 2000); Physician&#39;s Desk Reference (Thomson Publishing); and/or The Merck Manual of Diagnosis and Therapy, 17th ed. (1999), or the 18th ed (2006) following its publication, Mark H. Beers and Robert Berkow (eds.), Merck Publishing Group, or, in the case of animals, The Merck Veterinary Manual, 9th ed., Kahn, C. A. (ed.), Merck Publishing Group, 2005. Preferably, though not necessarily, the active pharmaceutical ingredient is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, APIs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; APIs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. All listed APIs are considered acceptable for use in accordance with the present invention. 
     In certain embodiments, the active pharmaceutical ingredient is a small molecule. Exemplary active pharmaceutical ingredients include, but are not limited to, anti-cancer agents, antibiotics, anti-viral agents, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or non-steroidal anti-inflammatory agents, antihistamine, immunosuppressant agents, antigens, vaccines, antibodies, decongestant, sedatives, opioids, pain-relieving agents, analgesics, anti-pyretics, hormones, prostaglandins, etc. 
     As used herein, the term “small molecule” refers to molecules, whether naturally-occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight. Typically, a small molecule is an organic compound (i.e., it contains carbon). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain embodiments, the molecular weight of a small molecule is at most about 1,000 g/mol, at most about 900 g/mol, at most about 800 g/mol, at most about 700 g/mol, at most about 600 g/mol, at most about 500 g/mol, at most about 400 g/mol, at most about 300 g/mol, at most about 200 g/mol, or at most about 100 g/mol. In certain embodiments, the molecular weight of a small molecule is at least about 100 g/mol, at least about 200 g/mol, at least about 300 g/mol, at least about 400 g/mol, at least about 500 g/mol, at least about 600 g/mol, at least about 700 g/mol, at least about 800 g/mol, or at least about 900 g/mol, or at least about 1,000 g/mol. Combinations of the above ranges (e.g., at least about 200 g/mol and at most about 500 g/mol) are also possible. 
     Non-limiting examples of APIs include diphenhydramine, ciprofloxacin, diazepam, fluoxetine, ibuprofen, doxycycline, and azithromycin. Those of ordinary skill in the art, given the present disclosure, would be capable of applying the synthesis methods and systems described herein to other pharmaceutical active ingredients. 
     Also as noted above, certain of the systems and methods described herein can be used to produce ingestible pharmaceutical compositions. Generally, ingestible pharmaceutical compositions refer to those compositions including an active pharmaceutical ingredient and a pharmaceutically acceptable excipient. As used herein, the term “pharmaceutically acceptable excipient” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some non-limiting examples of materials which can serve as pharmaceutically acceptable excipients are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, methylcellulose, hydroxypropylmethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; detergents such as Tween 80; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; water (e.g., pyrogen free water); isotonic saline; citric acid, acetate salts, Ringer&#39;s solution; ethyl alcohol; and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. Other possible excipients include glidant and solubilizer. 
     In some embodiments, the ingestible pharmaceutical composition comprises at least about 2.5 mg, at least about 5.0 mg, or at least about 20 mg of an active pharmaceutical ingredient per milliliter of a pharmaceutically acceptable excipient. In some embodiments, the active pharmaceutical ingredient is dissolved in the pharmaceutically acceptable excipient. In certain embodiments, the active pharmaceutical ingredient is suspended in the pharmaceutically acceptable excipient. In some embodiments, the ingestible pharmaceutical composition is in the form of a tablet. 
     In some embodiments, the system is configured to produce at least about 1000 doses of API per day. In certain embodiments, the system is configured to produce at least about 2000 doses per day, at least about 4000 doses per day, at least about 8000 doses per day, at least about 10000 doses per day, or at least about 20000 doses per day. As will be generally understood by one skilled in the art, the term dose generally refers to an amount of an active pharmaceutical ingredient which is administered to an organism (e.g., a person, an animal, a plant, an insect, and/or a bacterium) to stimulate a biological response. In certain embodiments, the system is configured to produce at least about 20 grams/day, at least about 50 grams/day, at least about 100 grams/day, at least about 200 grams per day, or at least about 400 grams per day of an ingestible pharmaceutical composition. 
     In certain embodiments, the system is configured to produce a relatively high amount of an active pharmaceutical ingredient in a small footprint. For example, in some cases, the system may be configured to produce at least about 5 grams of an active pharmaceutical ingredient per square foot footprint area per day. In some embodiments, the system is configured to produce at least about 7 g/day/ft 2 , at least about 10 g/day/ft 2 , at least about 20 g/day/ft 2 , at least about 30 g/day/ft 2 , at least about 50 g/day/ft 2 , at least about 60 g/day/ft 2 , at least about 70 g/day/ft 2 , at least about 90 g/day/ft 2 , at least about 100 g/day/ft 2 , at least about 120 g/day/ft 2 , at least about 150 g/day/ft 2 , or at least about 200 g/day/ft 2  of an active pharmaceutical ingredient per day per footprint area. In certain embodiments, the system is configured to produce at least about 1 gram of an active pharmaceutical ingredient per cubic feet of a housing (e.g., as described above) per day. For example, in some embodiments, the system is configured to produce at least about 2 g/day/ft 3 , at least about 3 g/day/ft 3 , at least about 4 g/day/ft 3 , at least about 5 g/day/ft 3 , at least about 7 g/day/ft 3 , at least about 10 g/day/ft 3 , at least about 15 g/day/ft 3 , at least about 20 g/day/ft 3 , or at least about 25 g/day/ft 3  of an active pharmaceutical ingredient per volume of a housing per day. 
     Example 
     A tableting system for producing pharmaceutical tablets was used to manufacture ibuprofen (IBU) and diazepam (DIZ) tablets. 
     The system was divided into an upper process stream and lower process stream. The upper process stream began with individual powder (API and excipients) feeding and ended with blending. The lower process stream began with dispensing of the powder blend to the compression of tablets. A direct compression method was used to make the tablets. These two process streams operated independently under high-level software control. 
     The dimensions of the system measure approximately 72.4 cm (length) by 53.3 cm (width) by 134.6 cm (height). API and excipients were fed from multiple volumetric feeders to a carriage consisting of a boat suspended from a load cell. The feeders were modified to dispense cohesive APIs and excipients, when necessary. The carriage could be commanded to move to any volumetric feeder, in any sequence, and the required amounts of powder may be dispensed at each feeder location. The carriage transferred powder (any number of transfers may be possible) from the boat to a conical blender with an impeller. The blender mixed powder via convective mixing to achieve a blend. After mixing, the blend was dispensed into the hopper of a blended mix dispenser having a tapping feeder. CAPSUGEL (South Carolina, USA) dispense heads were used on the tapping feeder to regulate the amount of powder fed. Powder was then dispensed in pre-determined amounts (depending on the desired dosage size) into a tablet press die. The actuator would slide the die into position underneath the actuated punch of a laboratory tablet press (Gamlen PCA-500D, Gamlen Tableting Ltd, UK). The blend was then compressed to make the tablet. The tablet was ejected from the die, then transferred to a weighing station. Finally, the tablet was collected. 
     The materials used for making the ibuprofen and diazepam tablets, along with their specific functions, are presented in Table 1 below. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Materials used for making tablets and their functionality. 
               
            
           
           
               
               
               
               
            
               
                   
                 Trade name/ 
                   
                 Manufacturer/ 
               
               
                 Material 
                 CAS number* 
                 Functionality 
                 supplier 
               
               
                   
               
               
                 Ibuprofen (IBU) 
                 15687-27-1 
                 Drug/API 
                 Spectrum Chemical 
               
               
                   
                   
                   
                 Mfg. Corp. 
               
               
                 Diazepam (DIZ) 
                 439-14-5 
                 Drug/API 
                 Sigma Aldrich 
               
               
                 Anhydrous lactose 
                 SuperTab ® 21AN 
                 Filler/Diluent 
                 DFE Pharma 
               
               
                 Fumed silica 
                 CAB-O-SIL ® 
                 Glidant/Flow 
                 Cabot Corporation 
               
               
                   
                 M-5P 
                 aid 
                   
               
               
                 Magnesium 
                 Kosher Passover 
                 Lubricant 
                 Mallinckrodt 
               
               
                 stearate NF/EP/JP 
                 HyQual ™ 
                   
                 Pharmaceuticals 
               
               
                   
               
               
                 *Chemical Abstracts Service (CAS) 
               
            
           
         
       
     
     Physical properties of ibuprofen and diazepam APIs are presented in Table 2 below. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Physical properties of Active  
               
               
                 Pharmaceutical Ingredients (APIs) studied. 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Molecular 
                 Solubility 
               
               
                   
                   
                   
                 weight 
                 in water 
               
               
                   
                 APIs 
                 Function 
                 g/mol 
                 (mg/ml) 
               
               
                   
                   
               
               
                   
                 Ibuprofen (IBU) 
                 Anti-inflammatory 
                 206.285 
                 0.021 
               
               
                   
                 Diazepam (DIZ) 
                 Anxiolytic  
                 284.743 
                 0.050 
               
               
                   
                   
                 and sedative 
               
               
                   
                   
               
            
           
         
       
     
     A simplified approach in formulation development was considered by minimizing number of excipients required for tableting. Hence, only one filler/diluent, flow aid/glidant and lubricant were considered as part of the formulations for both model drugs. Anhydrous lactose (SuperTab® 21AN) was used as the filler/diluent, fumed silica (CAB-O-SIL® M-5P) was used as the glidant, and magnesium stearate (Kosher Passover HyQual™) was used as the lubricant. This grade of anhydrous lactose was selected as the filler in the formulations. 
     The formulated blends were used for the manufacturing of tablets. The compositions of the formulations used are presented in Table 3 below. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Formulations used for making 
               
               
                 IBU and DIZ tablets. 
               
            
           
           
               
               
               
               
            
               
                   
                 Tablet properties 
                 IBU 
                 DIZ 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 API strength (mg) 
                 200 
                 10 
               
               
                   
                 Tablet weight (mg) 
                 340 
                 250 
               
               
                   
                 Tablet formulation  
                   
                   
               
               
                   
                 compositions (%) 
                   
                   
               
               
                   
                 API 
                 58.82 
                 4.00 
               
               
                   
                 Anhydrous lactose 
                 40.18 
                 95.00 
               
               
                   
                 Fumed silica 
                 0.50 
                 0.50 
               
               
                   
                 Magnesium stearate 
                 0.50 
                 0.50 
               
               
                   
                   
                 100.00 
                 100.00 
               
               
                   
                 Blend formulation  
                   
                   
               
               
                   
                 compositions (g) 
                   
                   
               
               
                   
                 API 
                 30.59 
                 1.74 
               
               
                   
                 Anhydrous lactose 
                 20.89 
                 41.42 
               
               
                   
                 Fumed silica 
                 0.26 
                 0.22 
               
               
                   
                 Magnesium stearate 
                 0.26 
                 0.22 
               
               
                   
                   
                 52.00 
                 43.60 
               
               
                   
                   
               
            
           
         
       
     
     The particle sizes of the API and excipients, except fumed silica, are presented in Table 4 below. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Properties of Active Pharmaceutical Ingredients 
               
               
                 (APIs) and excipients used for tableting. 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Flow 
               
               
                   
                   
                 Bulk 
                   
                 function 
               
               
                   
                   
                 den- 
                 Compress- 
                 coeffi- 
               
               
                 API, 
                 Particle size (μm) 
                 sity 
                 ibility 
                 cient 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Excipients 
                 d 10   
                 d 50   
                 d 90   
                 g/cm 3   
                 (%) 
                 (ffc) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Ibuprofen 
                 4.86 
                 21.87 
                 75.31 
                 0.53 
                 25.07 
                 3.87 
               
               
                 (IBU) 
               
               
                 Diazepam 
                 5.74 
                 23.12 
                 110.75 
                 0.52 
                 32.73 
                 2.78 
               
               
                 (DIZ) 
               
               
                 Anhydrous 
                 26.03 
                 188.75 
                 425.90 
                 0.74 
                 13.10 
                 5.69 
               
               
                 lactose 
               
               
                 Magnesium 
                 2.76 
                 6.86 
                 15.10 
                 0.31 
                 38.97 
                 5.18 
               
               
                 stearate 
               
               
                   
               
            
           
         
       
     
     Microscopy images showing the morphology of IBU and DIZ particles are shown in  FIGS. 29A and 29B , respectively. Particle and bulk properties of IBU and DIZ are summarized in Table 4 above. IBU and DIZ both are fine particles with a d 50  of 21.87 μm and 23.12 μm, respectively. The microscopy image shows IBU as plate-like rectangular shape particles ( FIG. 29A ), whereas DIZ particles are irregular shaped, agglomerated particles ( FIG. 29B ). 
     Flow properties of powder blends prepared for tablets were measured using FT4 Powder Rheometer and are presented in Table 5 below. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Properties of powder blends prepared for tableting. 
               
            
           
           
               
               
               
               
            
               
                   
                 Bulk  
                 Compres- 
                 Flow  
               
               
                   
                 density 
                 sibility 
                 function co- 
               
               
                 Blends 
                 g/cm 3   
                 (%) 
                 efficient (ffc) 
               
               
                   
               
               
                 Ibuprofen (IBU) 
                 0.65 
                  5.18 
                 &gt;10 
               
               
                 Diazepam (DIZ) 
                 0.72 
                 12.27 
                 &gt;10 
               
               
                   
               
            
           
         
       
     
     Lactose, API, and silica were fed consecutively into the blender for IBU blending. Lactose was split into two equal quantities for DIZ blend. Half was fed into blender at the beginning and the remaining half was fed the end of feeding sequence. The blender was operated at 80 RPM and blended all materials for 26 minutes. Then magnesium stearate was added into the blender and blended for an additional 4 minutes at 80 RPM. The magnesium stearate was not added at the beginning to prevent over-lubrication of the formulation. A total of 52.0 g of IBU blend and a total of 43.6 g of DIZ blend were produced in each blend batch. 40% of the total blender volume was used for blending based on the measured conditioned bulk density of each final blend. 
     The final blend was transferred into the tapping feeder hopper. The powder was dispensed into a 10 mm die to make tablets of 340 mg and 250 mg total weight for IBU and DIZ, respectively. The number of taps required to obtain the necessary fill weight was 53 (±5) for IBU and 35 (±5) for DIZ. The accepted weight variation was considered ±10% of target tablet weight. Dispensed powder was compressed at a force of 450 kg to make tablets using a flat and round punch with a diameter of 10 mm. The punch speed was programmed at 1.0 mm/s. Each tablet was weighed and its dimensions (diameter and thickness) were measured using a digital slide caliper (Fowler 54-100-000-2, Fowler Company Inc., Newton, Mass.). Twenty-two tablets for IBU and forty-two tablets for DIZ were manufactured and analyzed. Some of the manufactured ibuprofen and diazepam tablets are shown in  FIG. 30 . 
     Properties of the resulting manufactured IBU and DIZ tablets were measured (weight, tensile strength, assay, and content uniformity) and are presented in Table 6 below. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Properties of tablets (weight, tensile strength, assay  
               
               
                 and acceptance value) prepared using blends. 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Tensile  
                   
                   
               
               
                   
                   
                 strength 
                   
                   
               
               
                   
                 Tablet  
                 (Aver- 
                 Assay 
                   
               
               
                   
                 weight 
                 age ± 
                 (% of the 
                 Acceptance 
               
               
                   
                 (Average,  
                 STDEV 
                 labeled con- 
                 value 
               
               
                 Blends 
                 % RSD) (mg) 
                 MPa 
                 tent) (%) 
                 (AV) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ibuprofen 
                 334.07, 2.58 
                 1.14 ± 0.09 
                 98.81 
                 6.12 
               
               
                 (IBU) 
                   
                   
                   
                   
               
               
                 Diazepam 
                 258.06, 2.99 
                 0.52 ± 0.07 
                 103.69 
                 9.36 
               
               
                 (DIZ) 
               
               
                   
               
            
           
         
       
     
     The average weight of 10 tablets manufactured are reported with % RSD value. The average weight of IBU and DIZ were 334.07 mg and 258.06 mg, respectively. The weight variation was within the ±10% of target tablet weight 340 mg for IBU and 250 mg for DIZ. The RSD value was below 3% for both drug tablets. The low RSD indicates uniform dispense of blend into the die and low weight variation among tablets. 
     The average tensile strength of IBU and DIZ tablets were 1.14 MPa and 0.52 MPa, respectively. The diameter and thickness of six tablets were measured. For IBU tablets, the average values for diameter and thickness were 10.06 (±0.03) mm and 3.8 (±0.12) mm, respectively. For DIZ tablets, the average values for diameter and thickness were 10.11 (±0.02) mm and 2.59 (±0.06) mm, respectively. 
     According to USP-39, official monograph IBU/DIZ tablets must contain not less than 90% and not more than 110% of the labeled amount meet the assay standard. Similarly, if the calculated acceptance value of the active ingredient, based on 10 dosage units, is less than or equal to 15.0, then the product meets the USP quality standard. As shown in Table 6, the assay values of the IBU and DIZ tablets are within the range of 90-110%. Both the IBU and DIZ tablets meet the content uniformity/weight variation criteria, as the acceptance value (AV) is below 15. 
       FIGS. 31A and 31B  illustrate the dissolution results for the manufactured IBU and DIZ tablets, respectively. Average and standard deviation are depicted (n=6). According to USP monograph, 80% IBU should dissolve within 60 minutes, and 85% DIZ should dissolve within 30 minutes. The time it takes for 80% of the drug to dissolve (t 80 ) for IBU tablets and DIZ tablets is 23 minutes and 4 minutes, respectively. Hence, dissolution results of both drug tablets meet the USP monograph. 
     While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the functions and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, and/or methods, if such features, systems, articles, materials, and/or methods are not mutually inconsistent, is included within the scope of the present invention. 
     The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.” 
     The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified unless clearly indicated to the contrary. Thus, as a non-limiting example, a reference to “A and/or B,” when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A without B (optionally including elements other than B); in another embodiment, to B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc. 
     As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. 
     As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc. 
     In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.