Verification of solid dissolution in robotic drug preparation

Abstract

The present invention relates to automated operations for the preparation of medicaments, in particular image-based progression and / or result verification, and / or detection of fault conditions related to dissolution of a medicament material contained in a vial. In some examples, imaging and image processing are used to track the progression of a process that converts solids and / or concentrated materials (e.g., crystallized and / or lyophilized) to fluid solutions and / or suspensions. The dilution time may change along with the change of conditions; detection of fault conditions may reduce risk and / or reduce waste. In some examples, the amount of fluid used in dissolution / dilution itself is monitored at one or more stages. The invention also relates to methods of evaluating the fluid content of vials, including vials dispensed for manual manipulation, which may include viewing obstructions, such as labels.

Description

[0001] Related applications

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 455,117, filed March 28, 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] In some embodiments of the invention, the invention relates to the field of apparatus for the robotic preparation of pharmaceuticals, and more specifically, but not exclusively, to the mixing of substances by such apparatus. Background Technology

[0004] The challenges of automating drug preparation have been recognized in conventional technologies, and various technologies have been developed to provide solutions. Summary of the Invention

[0005] According to one aspect of some examples of this disclosure, a method for evaluating the contents of a vial, the contents comprising a pharmaceutical ingredient, wherein the method comprises: manipulating the vial to change the tilt angle of the vial relative to a boundary region of the contents of the vial; acquiring at least one image of the vial during a time period in which the tilt angle is changed; calculating the location of the boundary region in the at least one image by performing image processing with a processing circuit system; comparing the location of the boundary region with the target criterion, wherein the target criterion takes into account the displacement of the location of the boundary region due to the tilt angle; and automatically determining, based on the result of the comparison, whether to use or reject the contents of the vial in the automated preparation of a pharmaceutical formulation.

[0006] According to some examples of this disclosure, the manipulation changes the tilt angle such that the boundary region in the at least one image of the vial extends along the bottom surface of the vial.

[0007] According to some examples of this disclosure, the target criterion includes a target location extending along the bottom surface, and the comparison determines the position of the boundary region relative to the target location.

[0008] According to some examples of this disclosure, the label obstructs the view of the contents through the obstructed side of the vial, and the change in the tilt angle causes the boundary region to move from the obstructed side of the vial to an unobstructed surface region, the boundary region being visible through the unobstructed surface region.

[0009] According to some examples of this disclosure, the target criteria include target positioning along the unobstructed surface area of ​​the vial, and the comparison determines the position of the boundary area relative to the target positioning.

[0010] According to some examples of this disclosure, the target positioning extends along a portion of the surface of the vial, and when the vial is upright, the portion is positioned above or below the label.

[0011] According to some examples of this disclosure, during the time period in which the tilt angle is changed, the height of the inclusion is a non-linear function of the inclusion volume.

[0012] According to some examples of this disclosure, the manipulation includes rotating the vial while keeping the boundary region horizontal.

[0013] According to some examples of this disclosure, the manipulation includes moving the vial, the movement changing the angle of the boundary region away from the horizontal plane.

[0014] According to some examples of this disclosure, at least one of the comparison and the automatic determination includes calculating the volume of the contents of the vial, and the automatic determination selects to use or reject the contents of the vial based on how close the volume is to a target volume.

[0015] According to some examples of this disclosure, the target criterion defines the target location, the result of the comparison includes the distance between the location of the boundary region and the target location, and the determination to use or reject the contents of the vial based on the distance.

[0016] According to some examples of this disclosure, the boundary region indicates the difference in optical properties between the lower material phase of the contents of the vial and the material above the lower material phase.

[0017] According to some examples of this disclosure, the optical property is at least one of refractive index, light absorption coefficient, and turbidity.

[0018] According to some examples of this disclosure, the at least one image includes multiple images obtained at different tilt angles of the vial.

[0019] According to some examples of this disclosure, the calculations and comparisons are performed for each of the plurality of images.

[0020] According to some examples of this disclosure, the automatic determination includes using the positioning representation of each of the plurality of images to determine the parameters of the bottle's geometry.

[0021] According to some examples of this disclosure, at least one image was obtained when the tilt angle changed by at least 45° from the upright and static position of the vial.

[0022] According to some examples of this disclosure, at least one image was obtained when the vial was tilted to within 15° relative to the horizontal plane.

[0023] According to some examples of this disclosure, the contents of the vial contain a fluid.

[0024] According to some examples of this disclosure, the vial includes a generally cylindrical lower region, an inwardly curved top region leading to a capped neck, and a circular bottom surface of the lower region; wherein the tilt angle adjusts a portion of the boundary region such that the boundary region extends along the bottom surface.

[0025] According to some examples of this disclosure, the at least one image images the boundary region through the optical irregularities of the bottom surface.

[0026] According to some examples of this disclosure, determining the use of the contents of the vial includes determining to adjust the amount of fluid in the vial to correct for discrepancies between the target location and the location representation of the boundary region.

[0027] According to some examples of this disclosure, the method includes manipulating the vial to a new position based on the determined use.

[0028] According to some examples of this disclosure, the new positioning returns the vial to an upright position.

[0029] According to one aspect of some examples of this disclosure, a method for evaluating the fluid contents of a vial, the fluid contents comprising a pharmaceutical ingredient, the method comprising: receiving at least one image of the vial, wherein the at least one image has an image of the vial when the vial is tilted to position a portion of a boundary layer of the fluid contents below a label portion on the surface of the vial; using computerized image processing, comparing the positioning of the boundary layer extending along the bottom surface of the vial with a target positioning corresponding to a target fluid volume in the vial and an angle of tilt of the vial; and, based on the result of the comparison, automatically determining whether to use or reject the contents of the vial in the automated preparation of a pharmaceutical formulation.

[0030] According to some examples of this disclosure, the fluid contents contain a solvent in which the pharmaceutical ingredient is dissolved.

[0031] According to some examples of this disclosure, the comparison includes determining the liquid volume of the inclusion and comparing the determined volume of the inclusion with the target liquid volume.

[0032] According to some examples of this disclosure, determining the volume includes measuring at least one parameter of the geometry of the vial using at least one image of the vial.

[0033] According to one aspect of some examples of this disclosure, a method for evaluating the contents of a vial, the contents comprising a pharmaceutical ingredient, wherein the method comprises: manipulating the vial to change the tilt angle of the vial; acquiring at least one image of the vial during a time period in which the tilt angle is changed; detecting the presence or absence of a fluid boundary region in the at least one image by performing image processing with a processing circuit system; and automatically determining, based on the result of the detection, whether the contents of the vial should be used or rejected in the automated preparation of the pharmaceutical formulation.

[0034] According to some examples of this disclosure, when the contents of the vial comprise a target volume of fluid, the tilt angle is selected to position the fluid boundary region to extend along a surface region of the vial, the surface region being located above or below the label of the vial when the vial is upright.

[0035] According to some embodiments of this disclosure, the surface area is located below the label on the vial and extends along the bottom surface of the vial.

[0036] According to one aspect of some embodiments of this disclosure, a system for evaluating vial contents comprising a pharmaceutical ingredient is provided. The system includes: a processing circuitry system and a memory, wherein the memory includes instructions that command the processing circuitry system to: control a manipulator to change the tilt angle of the vial relative to an upper boundary layer of the vial contents; access at least one image of the vial acquired during a time period in which the tilt angle is changed; calculate a localization characterization of a boundary region of the vial contents in the at least one image; compare the localization characterization of the boundary region with a target localization, wherein the target localization takes into account boundary region displacement due to the tilt angle; and, based on the result of the comparison, command the system to use or reject the vial contents in the automated preparation of the pharmaceutical formulation.

[0037] According to some examples of this disclosure, the system includes the manipulator.

[0038] According to some examples of this disclosure, the instructions command the processing circuitry system to control the imager to obtain the at least one image of the vial.

[0039] According to one aspect of some embodiments of this disclosure, a system for evaluating vial contents comprising a pharmaceutical ingredient is provided, the system comprising: a manipulator configured to hold the vial at a variably selectable tilt angle relative to an upright orientation; an imager positioned relative to the manipulator to image the vial while it is held at the tilt angle relative to the upright orientation, including viewing the bottom surface of the vial; a processing circuitry system and a memory storing instructions, wherein the instructions command the processing circuitry system to: control the manipulator to change the tilt angle of the vial relative to the upright orientation; control the imager to acquire at least one image of the vial during a time period in which the tilt angle is changed; calculate a localization characterization of a boundary region of the vial contents in the at least one image; compare the localization characterization of the boundary region with a target localization, wherein the target localization takes into account the displacement of the boundary region due to the tilt angle; and, based on the result of the comparison, command the system to use or reject the vial contents in the automated preparation of a pharmaceutical formulation.

[0040] According to one aspect of some embodiments of this disclosure, a method is provided for controlling the dissolution of a solute in a solvent in a vial held by a vial holder in a pharmaceutical preparation apparatus, the method comprising: stirring the vial holder by a stirrer operably connected to the vial holder, thereby agitating the solute and the solvent in the vial held by the vial holder; accessing at least one image of the vial contents captured after the stirring has commenced by a processing circuitry system; evaluating the characteristics of the vial contents by performing image processing with the processing circuitry system; comparing the evaluated characteristics of the vial contents with target characteristics; and adjusting the stirring performed by the stirrer by the processing circuitry system based on the result of the comparison.

[0041] According to some examples of this disclosure, the adjustment includes stopping the stirring.

[0042] According to some examples of this disclosure, the adjustment includes restarting the stirring process.

[0043] According to some examples of this disclosure, the adjustment includes modifying at least one parameter of the stirring motion.

[0044] According to some examples of this disclosure, the solute is a solid.

[0045] According to some examples of this disclosure, the solvent is a fluid.

[0046] According to some examples of this disclosure, the evaluated characteristics assess the solute's dissolution in the solvent, the target characteristics of the vial contents include dissolution appearance standards, and the adjustments include stopping the operation of the stirrer or extending the operating time of the stirrer.

[0047] According to some examples of this disclosure, the adjustments include stopping the operation of the stirrer if the target dissolution appearance standard is not yet met; and issuing an alarm.

[0048] According to some examples of this disclosure, the adjustment includes extending the operation of the stirrer when the target dissolution appearance standard has not yet been met.

[0049] According to some examples of this disclosure, the dissolution appearance criteria include a measure of at least one of the following: the transparency of the solvent, the color of the solvent, and the clarity of the solvent.

[0050] According to some examples of this disclosure, the dissolution appearance criteria include a measure of the color of the solvent selected according to the type of solute.

[0051] According to some examples of this disclosure, the evaluated characteristics assess the clumping of the solute, the target characteristics of the solvent in the vial include clumping appearance criteria, and the adjustment includes modifying parameters governing the movement mode of the stirrer.

[0052] According to some examples of this disclosure, the movement pattern is adjusted in at least one of the following: amplitude, acceleration, rotation of the vial, and geometry of the path along which the vial moves.

[0053] According to some examples of this disclosure, the evaluated characteristics assess the presence of foreign particles in the solvent, the target characteristics of the vial contents include a foreign particle presence standard, and the adjustment includes stopping stirring; and the processing circuitry also issues an alarm based on the results of the comparison.

[0054] According to some examples of this disclosure, the evaluated characteristics assess the presence of foreign particles in the solvent, the target characteristics of the vial contents include a foreign particle presence standard, and the adjustment includes stopping stirring; and the processing circuitry also issues an alarm based on the results of the comparison.

[0055] According to some examples of this disclosure, the evaluated characteristics assess the volume of the vial contents, the target characteristics of the solvent in the vial include the expected amount of the vial contents, and the adjustment includes stopping stirring; and the processing circuitry also issues an alarm based on the results of the comparison.

[0056] According to some examples of this disclosure, the evaluation of at least one of the features and the comparison includes classifying the at least one image based on a pre-trained machine learning model.

[0057] According to some examples of this disclosure, the adjustment includes adjusting the stirring of at least the second flask based on the result of the comparison.

[0058] According to some examples of this disclosure, the adjustment is made based on the results of the corresponding plurality of comparisons.

[0059] According to some examples of this disclosure, the at least one image of the contents of the vial is imaged from a location below the vial.

[0060] According to one aspect of some embodiments of this disclosure, a system for controlling the dissolution of a solute in a solvent in a vial held by a vial holder in a pharmaceutical preparation apparatus is provided. The system includes a processing circuitry configured to: control a stirrer operably connected to the vial holder, thereby agitating the solute and the solvent in the vial held by the vial holder; access at least one image of the vial contents captured after the stirring has commenced; evaluate the characteristics of the vial contents; compare the evaluated characteristics with target characteristics of the solvent in the vial; and adjust the stirring of the stirrer based on the result of the comparison.

[0061] According to some examples of this disclosure, the evaluated characteristics assess the solute's dissolution in the solvent, the target characteristics of the solvent in the vial include dissolution appearance standards, and the processing circuitry adjusts the stirring by stopping the operation of the stirrer or extending the operating time of the stirrer.

[0062] According to some examples of this disclosure, the evaluated characteristics assess the agglomeration of the solute, the target characteristics of the solvent in the vial include agglomeration appearance criteria, and the processing circuit system adjusts the stirring by modifying parameters governing the movement mode of the stirrer.

[0063] According to some examples of this disclosure, the evaluated characteristics assess the presence of foreign particles in the solvent, the target characteristics of the solvent in the vial include a foreign particle presence standard, and the processing circuitry adjusts the stirring by stopping the stirring; and the processing circuitry also issues an alarm based on the results of the comparison.

[0064] According to some examples of this disclosure, the evaluated characteristics assess the presence of foreign particles in the solvent, the target characteristics of the solvent in the vial include a foreign particle presence standard, and the processing circuitry adjusts the stirring by stopping the stirring; and the processing circuitry also issues an alarm based on the results of the comparison.

[0065] According to some examples of this disclosure, the evaluated characteristics assess the volume of solvent in the vial, the target characteristics of the solvent in the vial include the expected amount of solvent in the vial, and the processing circuitry adjusts the stirring by stopping the stirring; and also, based on the results of the comparison, the processing circuitry issues an alarm.

[0066] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. While similar or equivalent methods and materials described herein may be used in the practice or testing of embodiments of this disclosure, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including its definitions, shall prevail. Furthermore, materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0067] As those skilled in the art will understand, aspects of this disclosure can be embodied as a system, method, or computer program product. Therefore, aspects of this disclosure can take the form of a completely hardware embodiment, a completely software embodiment (including firmware, resident software, microcode, etc.), or an embodiment combining software and hardware aspects that can all be generally referred to herein as a “circuit,” “module,” or “system” (e.g., a method can be implemented using a “computer circuit system”). Furthermore, some embodiments of this disclosure can take the form of a computer program product embodied in one or more computer-readable media having computer-readable program code embodied thereon. Implementations of methods and / or systems of some embodiments of this disclosure can involve performing and / or completing selected tasks manually, automatically, or in combination thereof. Furthermore, based on the actual instruments and equipment of some embodiments of methods and / or systems of this disclosure, several selected tasks can be implemented by hardware, by software, or by firmware and / or by a combination thereof, for example, using an operating system.

[0068] For example, hardware for performing selected tasks according to some embodiments of this disclosure may be implemented as a chip or circuit. As software, selected tasks according to some embodiments of this disclosure may be implemented as a plurality of software instructions executable by a computer using any suitable operating system. In some embodiments of this disclosure, one or more tasks performed in the method and / or by the system are executed by a data processor (also referred to herein as a “digital processor,” meaning a data processor operating using digital bit sets), such as a computing platform for executing multiple instructions. The instruction execution element of the processor may include, for example, one or more microprocessor chips, ASICs, and / or FPGAs. Optionally, the data processor includes volatile and / or non-volatile memory for storing instructions and / or data, such as magnetic hard disks and / or removable media for storing instructions and / or data. Optionally, network connectivity is also provided. Optionally, a display and / or a user input device such as a keyboard or mouse are also provided. Any of these embodiments is more generally referred to herein as an example of a computer circuit system.

[0069] Any combination of one or more computer-readable media may be used in some embodiments of this disclosure. A computer-readable medium may be a computer-readable signal medium or a computer-readable storage medium. A computer-readable storage medium may be, for example, but not limited to, electronic, magnetic, optical, electromagnetic, infrared, or semiconductor systems, devices, or apparatuses, or any suitable combination thereof. More specific examples (a non-exhaustive list) of computer-readable storage media will include: electrical connections having one or more wires, portable computer disks, hard disks, random access memory (RAM), read-only memory (ROM), erasable programmable read-only memory (EPROM or flash memory), optical fiber, portable optical disc read-only memory (CD-ROM), optical storage devices, magnetic storage devices, or any suitable combination thereof. In the context of this document, a computer-readable storage medium may be any tangible medium that may contain or store programs for use by or in conjunction with an instruction execution system, device, or apparatus. A computer-readable storage medium may also contain or store information for use by such programs, such as data constructed in a manner recorded in the computer-readable storage medium such that a computer program can access it as, for example, one or more tables, lists, arrays, data trees, and / or other data structures. In this document, a computer-readable storage medium that records data in a form that can be retrieved as a group of digital bits is also referred to as a digital memory. It should be understood that in some embodiments, a computer-readable storage medium may optionally also be used as a computer-writable storage medium when the computer-readable storage medium is not inherently read-only and / or is in a read-only state.

[0070] In this document, a data processor is referred to as being "configured" to perform data processing actions, provided that it is coupled to a computer-readable medium to receive instructions and / or data from it, process them, and / or store the processing results in the same or another computer-readable medium. The processing performed (optionally with respect to data) is specified by instructions, the effect of which is that the processor operates according to the instructions. The actions of processing may be referred to by one or more other terms, either additionally or alternatively; for example: comparison, estimation, determination, calculation, identification, association, storage, analysis, selection, and / or transformation. For example, in some embodiments, a digital processor receives instructions and data from a digital memory, processes the data according to the instructions, and / or stores the processing results in the digital memory. In some embodiments, "providing" the processing results includes one or more of transmitting, storing, and / or presenting the processing results. Presentation optionally includes displaying on a display, providing audio instructions, printing on a printout, or giving the results in a form acceptable to human senses.

[0071] Computer-readable signal media may include propagated data signals embodying computer-readable program code therein, for example, in baseband or as part of a carrier wave. Such propagated signals may take any of a variety of forms, including, but not limited to, electromagnetic, optical, or any suitable combination thereof. A computer-readable signal medium may be any computer-readable medium that is not a computer-readable storage medium but can convey, propagate, or transmit a program for use by or in conjunction with an instruction execution system, device, or apparatus.

[0072] Program code embodied on a computer-readable medium and / or data used therefrom may be transmitted using any suitable medium, including but not limited to wireless, wired, fiber optic cable, RF, or any suitable combination thereof.

[0073] Computer program code used to perform operations of some embodiments of this disclosure may be written in any combination of one or more programming languages, including object-oriented programming languages ​​such as Java, Smalltalk, and C++, and conventional procedural programming languages ​​such as C or similar programming languages. Additionally or alternatively, sequences of logical operations (optionally corresponding to computer instructions) may be embodied in the design of an ASIC and / or the configuration of an FPGA device. The program code may execute entirely on the user's computer, partially on the user's computer (e.g., as a standalone software package), partially on the user's computer and partially on a remote computer, or entirely on a remote computer or server. In the latter case, the remote computer may be connected to the user's computer via any type of network including a local area network (LAN) or a wide area network (WAN), or may be connected to an external computer (e.g., via the Internet using an Internet service provider).

[0074] The following description may refer to flowchart illustrations and / or block diagrams of methods, apparatus (systems), and computer program products according to embodiments of this disclosure. It should be understood that each block of the flowchart illustrations and / or block diagrams, and combinations of blocks in the flowchart illustrations and / or block diagrams, can be implemented by computer program instructions. These computer program instructions can be provided to a processor of a general-purpose computer, special-purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions / actions specified in one or more blocks of the flowchart illustrations and / or block diagrams.

[0075] These computer program instructions may also be stored in a computer-readable medium that can direct a computer, other programmable data processing device or other apparatus to operate in a particular manner, such that the instructions stored in the computer-readable medium produce an article of writing comprising instructions that implement functions / actions specified in one or more blocks of a flowchart and / or block diagram.

[0076] Computer program instructions may also be loaded onto a computer, other programmable data processing apparatus or other device to cause a series of operational steps to be executed on the computer, other programmable apparatus or other device to produce a computer-implemented process, such that the instructions, which execute on the computer or other programmable apparatus, provide for implementing the functions / actions specified in one or more boxes of a flowchart and / or block diagram.

[0077] Some of the methods described in this paper are typically designed for use by computers only; and may be infeasible or impractical for human experts to perform entirely manually. Human experts who wish to perform similar tasks manually (such as inspecting objects) might expect to use entirely different methods, such as leveraging expert knowledge and / or the pattern recognition capabilities of the human brain, which would be far more efficient than manually performing the steps of the methods described in this paper. Attached Figure Description

[0078] Some embodiments of this disclosure have been described herein by way of example only with reference to the accompanying drawings. Detailed reference is now made to the drawings, and it should be emphasized that the details shown are by way of example and for the purpose of illustrative discussion of embodiments of this disclosure. In this regard, the description made with reference to the drawings will make it apparent to those skilled in the art how embodiments of this disclosure can be practiced.

[0079] In the attached diagram:

[0080] Figure 1 A block diagram of an example system 100, representing some instances of the subject matter currently disclosed, is schematically shown, the system being configured for the controlled dissolution of solids into a fluid;

[0081] Figures 2A-2F Various methods for controlling the dissolution of solids into liquids are demonstrated, based on some examples of the currently disclosed subject matter;

[0082] Figure 3 Flowcharts illustrate, based on some examples of the currently disclosed subject matter, the monitoring and control of solid dissolution into fluid as part of the drug preparation process in a robotic drug preparation system, as well as example general methods for detecting and reporting faults;

[0083] Figure 4A These are photographic images (captured from below) of vials containing solid agglomerates, based on some instances of the currently disclosed subject.

[0084] Figure 4B These are photographic images of vials containing foreign particles, based on some examples of currently published topics;

[0085] Figures 5A-5B These are photographic images of the same vial containing agglomerated solids, based on some instances of the currently disclosed subject matter;

[0086] Figure 5C This is based on some examples of the currently disclosed topics. Figures 5A-5B The difference image (absolute value) obtained by subtracting the images of each other;

[0087] Figures 6A-6BThese are photographic images of vials containing foreign particles, based on some examples of currently published topics;

[0088] Figure 6C It is based on some examples of the currently published topics. Figures 6A-6B The absolute value difference image is constructed from the image;

[0089] Figure 7 This is a flowchart schematically illustrating a method for determining the amount of fluid contained in a vial by performing an image-based examination based on some instances of the currently disclosed subject matter.

[0090] Figure 8 This is a flowchart schematically illustrating a method for determining the presence of fluid by image-based examination of a vial, based on some instances of the currently disclosed subject matter.

[0091] Figure 9A The photographs reproduce some examples of fluid-containing vials held by clamps at an angle of approximately 90°, based on the currently disclosed subject matter;

[0092] Figure 9B The photographs reproduce some examples of the subject currently disclosed, showing vials containing solids held by clamps at an angle of approximately 90°.

[0093] Figure 9C The photographs reproduce some examples of fluid-containing vials held by clamps at an angle of approximately 90°, based on the currently disclosed subject matter;

[0094] Figures 10A-10B The diagram schematically illustrates a side view cross-section of a fluid-containing vial 115 with a slanted tilt angle α, representing some examples of the subject matter currently disclosed. Figure 10A ) and bottom view ( Figure 10B );

[0095] Figure 11 A side view cross section of a fluid-containing vial with varying tilt angle α is schematically shown, based on some examples of the subject matter currently disclosed.

[0096] Figure 12A-12B The schematic representation shows a side view cross-section of a labeled fluid-containing vial 115, based on some examples of the subject matter currently disclosed. Figure 12A ) and side view ( Figure 12B );

[0097] Figure 12C The diagram schematically illustrates a side view cross-section of a fluid-containing vial with a 90° tilt angle α, representing some examples of the subject matter currently disclosed; and

[0098] Figure 13This is a schematic diagram of the geometric parameters of a small bottle based on some examples of the currently disclosed topic. Detailed Implementation

[0099] In some embodiments of the invention, the invention relates to the field of apparatus for the robotic preparation of pharmaceuticals, and more specifically, but not exclusively, to the mixing of substances by such apparatus.

[0100] Overview

[0101] Monitoring and control of drug substance mixtures

[0102] One aspect of some examples of the currently disclosed subject matter relates to the automated monitoring and control of the mixing of pharmaceutical substances. Specifically, the dissolution of pharmaceutical substances into solutes is described. Monitoring and control of mixing into suspension forms (e.g., emulsions) are not excluded, and modifications may be made as necessary and / or according to instructions relevant to a particular instance (e.g., a standard for consistent turbidity and / or opacity may be sought instead of a standard for transparency). In some instances, monitoring and control are implemented by a robotic drug preparation system that operates to prepare pharmaceutical formulations via measured fluid transfer between multiple containers.

[0103] In some instances, for the initial or intermediate state of containers used in automated drug preparation, the containers contain an undissolved solute and its intended solvent. For example, the solvent may have recently been added to the solute (or the solute may have been added to the solvent), and / or a portion of the solute may have precipitated from the solvent (e.g., during a refrigeration period). The solute may be in liquid or solid form.

[0104] The amount of time and action required for solute dissolution is potentially variable; for example, it depends on the chemical properties of the solute and / or solvent, the presence of other solutes in the solvent, the initial size of the solute particles, and / or the temperature and / or other parameters of the solute / solvent mixture. Furthermore, different mixing actions can potentially have different effects on the mixing rate, depending specifically on aspects of the inclusions, such as comparing agglomerated solid inclusions with those that readily achieve suspension.

[0105] In some instances, the dissolution method includes first monitoring dissolution in one or more vials, pausing the stirring process multiple times to allow imaging to measure the state of solute dissolution in the solvent. Once a sufficient overall time period for dissolution is determined, the method continues mixing one or more additional vials, omitting one or more pauses during the pausing process. In some embodiments, the first pause during the mixing of one or more additional vials occurs after the entire time period for which sufficient dissolution of the solute in the solvent is expected to be achieved.

[0106] In some instances, it is necessary to detect and respond to anomalous conditions (e.g., mitigate these conditions and / or issue alerts). Examples of anomalous conditions include fluid loss (e.g., due to inadequate sealing and / or container damage), failure of solids to dissolve as expected (e.g., failing to achieve expected completion and / or within the expected timeframe), and / or residual particles that do not conform to the expected visual characteristics of the dissolved solids (e.g., solid contaminants, such as beads, glass fragments, filter residue, metal particles, or other foreign particle types).

[0107] Indication and measurement of the mixing state of pharmaceutical substances

[0108] In some instances, a key indicator of the progress and / or completion of mixing is the reduction and / or substantial disappearance of the solid material in the mixing vial as the solute dissolves into the solvent. Optionally, the reduction / disappearance of the solute is monitored optically, for example, using imaging of the vial and / or measurements of light interacting with the vial and its contents. Measurements (e.g., images and / or other measurements) optionally characterize the vial when it is in motion and / or stationary. Measurements of stationary vials optionally include measurements of light interacting with the vial, and the solute and / or solvent contents of the vial: completely dissolved in the solute, mechanically mixed with the solute but not completely dissolved (e.g., suspended), or completely or partially agglomerated and / or precipitated from the solute.

[0109] Optionally (alternatively or alternatively), non-optical measurements are performed on the mixed state. For example, measurements can be performed using ultrasound as a source of radiant energy, where the measurements are taken in the form of images, or in another form that assesses the interaction of acoustic energy with the contents of the vial. In some instances, an alternative method is used, for example, to assess the mixed state by measuring the temperature change caused by dissolution.

[0110] Optionally, the assessment of the mixed state includes determining the turbidity of the solution. Depending on the measurement method, there may be a period of time during which a decrease in turbidity cannot be measured. Optionally, there may be a period of time during which the measurement results indicate a change in turbidity (e.g., a decrease in turbidity).

[0111] For solutes expected to dissolve completely in the solute, the assessment of the mixing state optionally includes determining whether the contained inclusions have become completely transparent. In some instances, as mixing tends to be complete, the absorption, transmission, and / or reflection spectra of the vial inclusions may shift (e.g., color change). Optical measurements optionally measure the spectral shift. Optionally, the amount of spectral shift is quantified as part of the assessment of the mixing state of the vial inclusions.

[0112] Optionally, the assessment of the mixing state includes determining, based on the material collected during settling after stirring (e.g., after a pause period allowing such settling, such as 1-10 seconds, 1-30 seconds, 1-60 seconds, or other time periods), the presence of remaining undissolved solute and / or material still unaffected by stirring (e.g., agglomeration on the vial surface). In some instances, unmixed material may be collected even during stirring, for example, due to density separation within the vial's contents vortex. Optionally, monitoring the mixing state includes obtaining measurements of the material in areas where such vortices are expected to cause material agglomeration.

[0113] In some instances, a mixing phase may exist, during which the fluid inclusions are essentially clear, but this also includes the presence of small amounts of undissolved particles (e.g., large crystals of solute) or virtually undissolved particles (e.g., impurities or other inclusions). In some instances, measurements are taken to identify such particles; and they are assessed based on their importance to the mixing state of the inclusions. For example, there may be thresholds for particle number and / or size below which the vial inclusions are considered mixed, even if the particle number is not zero.

[0114] In some instances, images of vials used for drug preparation are used to help set system requirements. In some instances, the system operator approves the results of system operations used to mix the drug formulation, e.g., approves the final result, and images taken during mixing are optionally considered valid results representing intermediate drug preparation operations. Alternatively or additionally, the system operator approves images or other measurements that directly indicate the results of intermediate operations. For example, the system operator examines an image of the boundary layer in a fluid vial and approves it as a benchmark. Alternatively or additionally, the system operator confirms that the starting conditions are valid, and based on this confirmation, the vial image is accepted as a relevant indication of the effective fluid volume in the vial. For example, the system operator may be someone who directly provides instructions to the system or someone who assists in monitoring system operations. In some instances, an additional automated system is provided in place of the system operator, e.g., an automated system specifically configured to validate the drug formulation according to appropriate criteria based on measured volume, composition, and / or other inputs.

[0115] In some embodiments, manipulation, such as the agitation of subsequent vials, is adjusted based on desired values ​​set during agitation of one or more initial vials. Specifically, agitation of one or more earlier vials can be monitored more closely (e.g., divided into more sub-time periods, with a pause in agitation between these sub-time periods to allow imaging), while subsequent vials are agitated more continuously, potentially reducing their processing time relatively.

[0116] Factors that could potentially confound measurement results

[0117] Furthermore, in some instances, a situation may arise where a portion of the solvent in the vial appears completely clear, while other parts of the vial retain one or more noticeable solute particles. In such cases, a sampling window containing only a portion of the vial contents may be insufficient to determine the overall state of the mixture within the vial contents. Optionally, this situation can be mitigated and / or avoided by using measurements with an image that substantially includes the entire contents of the vial.

[0118] One or more visible particles may contain "clumps" of solute (many smaller particles agglomerated, melted by the solvent, sintered, or otherwise bound together). Clumps of solute may adhere to the surface of the vial, preventing movement relative to the vial during stirring, and / or may move freely in the solvent. In some instances, clumps are assessed by examining the shape of the transparent portions of the vial to confirm that these portions encompass the entire volume of the vial. In other instances, the presence of clumps and / or other residual particles is assessed by looking for areas that create a stark contrast in the measured light level and / or areas that experience changes in the measured light level indicating that one or more particles have moved through these areas.

[0119] The vial contents may potentially contain gaseous inclusions (bubbles and / or foams) that are pre-existing and / or generated through mixing and agitation. In some instances, the potential confounding effects of such bubbles and / or foams on measurements are mitigated, for example, by observing bubble behavior (e.g., rising rather than sinking over a period of time, the location of foams at the interface layer) and / or based on expectations of bubble formation and / or foaming, such as expectations for calibration against specific solute-solvent systems and / or mixing conditions.

[0120] It should be noted that different methods for measuring mixing progress have different potential advantages and disadvantages. For example, a potential advantage of measuring during continuous fluid agitation is that it does not interrupt the mixing process to be performed, thus potentially allowing mixing to continue and complete more quickly. However, it is optional to temporarily slow down and / or adjust the mixing movement to present the appropriate aspects of the vial to a camera or other imaging and / or measuring device. In some instances, mixing progress is assessed while the fluid and / or solid contents within the vial remain in motion, for example, while vortices still exist within the contents and / or while the contents are splashing within the vial.

[0121] Artifacts can occur in images of such moving systems; for example, motion blur can make particles appear indistinct, while bubbles may be particularly difficult to distinguish from particles and / or more prevalent overall. In some instances, stroboscopic illumination can be used to partially mitigate, for example, motion blur, while retaining the potential advantage of allowing mixing motion to continue. Conversely, measuring the solution after stirring has stopped is potentially suitable for collecting information about remaining solute particles as a concentrate by sedimentation and / or slowing its movement, in order to better track and evaluate them.

[0122] In some instances, a measurement scheme is chosen such that a measurement method that favors uninterrupted mixing (but is potentially susceptible to confounding effects) is used during the early stages of the mixing process. The timing for using a different (e.g., validated and / or potentially more reliable) measurement method is then optionally selected based on the decision made regarding the estimation of mixing progress.

[0123] Dynamic System Response of Hybrid Progress

[0124] In response to measurements indicating any state, the actions of the hybrid subsystem itself and / or the entire robotic drug preparation system can potentially be adjusted.

[0125] In some instances, the estimated time to completion of mixing is calculated based on measurements of mixing progress during the initial phase of mixing. This estimated completion time may optionally be used as a basis for selecting additional actions that relate to the vial and / or mixing subsystem itself, and / or another element of the overall functionality of the drug preparation system.

[0126] For example, early in the mixing process, stubborn agglomerates may be optionally identified, allowing for relatively efficient replacement of vials with new ones and minimizing lost time (optionally, the vials may be reused after a period of "pre-soaking" or another mitigation action). In some instances, the estimated time to complete mixing is used to estimate the value of a particularly violent oscillation period (from the perspective of time savings), which may lead to foaming and / or bubble formation, resulting in additional settling waiting periods. In some instances, the bubble formation rate and / or bubble dissipation rate are simultaneously tracked with the material to obtain a suitable high-energy mixing scheme that requires a post-mixing settling time not exceeding the time saved by accelerating the mixing rate itself. In some instances, a delay period for transport or other preparation following the completion of active mixing agitation can be used as the time to complete mixing, e.g., the time period allowing the final remaining crystals of the solute to dissolve. In some instances, measurements of the mixing rate are used to calculate how much final mixing is expected to occur within the anticipated time period of such a delay.

[0127] In another instance, the coordination with other activities in the drug preparation process may be optionally adjusted to account for the expected time of mixing completion. For example, the timing of removing reagents from refrigeration and / or radiation shielding may be optionally adjusted such that the reagents reach a state and / or be positioned to interact with the mixed contents of the vial, as if they were ready.

[0128] In some instances, mixing progress is tracked over time, and this progress is correlated with actions and / or events that may have occurred during the previous treatment of the vials. For example, positioning and movement parameters may be optionally modified when initially injecting the solvent into the vial containing the dry solute, based on indications of which injection methods are most effective for achieving rapid mixing. Examples of this operation include adjusting the relative depth of the injection cannula insertion into the vial, and / or adjusting the relative orientation of the vial and cannula to guide the fluid jet toward the walls and / or corners of the vial. Optionally, arbitrary variation of at least some of these parameters is taken for granted during device operation, and successful variations in movement are generalized to larger uses (and potential additional variations). Optionally, for example, an initial experiment for a period of time may be conducted using different batches of vials, based on an injection mode that has been identified as potentially preferred.

[0129] Non-solution mixture

[0130] In some instances, mixing is used to form mixtures and / or homogenize them (e.g., emulsify and / or suspend them), without necessarily producing an optically clear solution. In some instances, an optically clear solution is the desired result, but there may be an operational phase during which the solute and solvent are in a fully mixed suspension, which may depend on adequate homogenization to end active stirring (e.g., such that dissolution will reliably complete on its own within a given available time). Optionally, the potential benefit of doing so is reduced processing time and allows for more efficient use of drug preparation equipment.

[0131] In some instances, measurements of the mixing state determine that the distribution of undissolved (e.g., suspended) matter is sufficiently uniform to be considered complete mixing. In some instances, this involves imaging the texture of the suspended matter portions, which can be observed at the surface of the turbid mixture. For example, the texture of the visible surface of the mixture can be determined to be uniformly composed of particles smaller than a certain size over a period of time (and optionally during motion and / or agitation), said period of time being long enough that the matter visible at the surface can be considered representative of the entire volume.

[0132] Fluid content monitoring in vials

[0133] One aspect of the currently disclosed subject matter involves the automated verification of fluid contents in vials during automated mixing of pharmaceutical formulations.

[0134] When vials are provided and / or manipulated as containers for pharmaceutical substances, the volume of fluid may need to be verified during operations using the contained pharmaceutical substance. For example, the contained pharmaceutical substance may be distributed in solid form and intended to dissolve in a certain amount of injectable fluid (e.g., saline) before being removed from the vial (e.g., at a known concentration of solution). In automated systems, there may be an assessment risk that needs to be mitigated, namely, that an incorrect amount of fluid may be injected into the vial for this purpose. Additionally or alternatively, there may also be an assessment risk that needs to be mitigated, namely, that the solid contents vial may inadvertently replace the dissolved contents vial.

[0135] As a mitigation measure and / or as part of sensing control, non-visual means (e.g., scaling) are a typical solution for automatically verifying the volume of fluid contents. This offers the potential advantage of sensitive quantitative verification of material movement within a system. However, this is associated with potential calibration issues involving sensor precision and / or system time for material placement and / or for scaling readings to stabilize.

[0136] Some examples of the currently disclosed subject matter utilize optically identifiable (visual) indicators of the amount of liquid contents in a transparent-walled container. An important type of such indicator involves a contrasting boundary region at the interface between the liquid phase of the vial's contents and (typically) the gaseous phase (e.g., air or another gas) of the vial's contents. In some instances (in addition to or alternative to the gaseous phase), there are liquid / liquid boundaries between unmixed liquids; for example, the boundary between a denser liquid (such as an aqueous solution) and a less dense liquid (such as oil or other non-aqueous liquid). This boundary region is also referred to herein as an "upper" boundary region because it is the boundary region located above the bottom of the vial and is the boundary region located above the material phase of the vial's contents. It is not necessarily a "topmost" such boundary; for example, there may be three material phases in the vial, with a boundary layer between each pair of sequential material phases.

[0137] In images of vials obtained using an optical camera, the boundary region is visible at the location where it extends through the inner surface of the vial's transparent wall. While this location is visible, its precise positioning can be somewhat inaccurate. For example, the optical properties of the container wall can distort the container's appearance, and / or it can be affected by the 3-D shape of the fluid meniscus formed by the liquid at its surface. The meniscus shape bends according to the balance between the fluid's surface tension and the attractive force of the liquid on the container wall. These forces can vary depending on the specific properties of both; for example, they can sometimes be affected even when the amount of solute in the liquid is relatively small.

[0138] The visibility of the boundary region (i.e., its impact on pixel intensity in the vial image) is a result of differences in one or more optical properties of the material phases constituting the vial's contents. Examples include differences in refractive index (especially for boundaries between optically transparent materials), optical absorption, scattering, and / or reflection at one or more wavelengths. Differences in refractive index between the liquid contents and the container wall material itself can also affect the actual and / or imaged shape of the boundary region. The effects of refraction can also introduce uncertainties to the container's structure, inferred solely from the image. For example, the vial wall thickness may undergo optical distortion, the amount of which collectively depends on the vial's geometry and the refractive index of its material.

[0139] Furthermore, the utility of visually assessing fluid volume (e.g., verifying) using boundary areas can be hampered by the presence of labels that obscure much of the vial wall. If there are gaps in the label, these gaps may be small, and / or inconveniently and / or unpredictably oriented. This, coupled with the confusion effects described above, can render visual assessments of the vial's liquid contents unreliable.

[0140] Nevertheless, the inventors of this disclosure have identified that in certain potentially significant cases in the field of automated drug preparation, image-based assessment of the fluid volume in vials (including labeled vials) can potentially reduce or eliminate the need for secondary verification of symmetrical quantities and / or other methods of the fluid volume in vials.

[0141] In short, in some instances, image-based evaluation involves imaging the vial while the boundary region is tilted and / or vertically oriented relative to the bottom of the vial. This is also referred to herein as the variation of the vial's tilt angle relative to the boundary region. Typically, the vial itself tilts from a vertical (upright) orientation (e.g., while the boundary region remains horizontal). However, it is not excluded that the vial may be affected by movement (e.g., rotational movement), the forces exerted by these movements causing the boundary region itself to tilt relative to the direction of gravity, regardless of whether the vial itself is tilted away from its upright orientation. For example, the tilt angle is chosen to place at least a portion of the boundary layer outside the label-occluded area, and / or optionally satisfy other conditions of the imaging, calibration, and / or processing algorithms; for example, as described herein. In some instances, the tilt angle is chosen to place the boundary layer in a position visible (and / or expected to be visible) through the bottom of the vial.

[0142] The ability to detect a boundary layer at least indicates that the vial contains fluid. For example, this allows verification, at least, whether a initially dry substance placed in a vial within a drug preparation system has undergone an earlier step involving fluid reception. The boundary layer can be identified, for example, by characteristic shape, by characteristic intensity distribution, and / or by characteristic behavior in response to vial movement; for example, when the vial is at different tilt angles, and / or when the vial undergoes acceleration. These are examples of target criteria that can be compared to images.

[0143] In some instances, and in conjunction with the bottle's tilt angle (and optionally with appropriate assumptions about the bottle's internal geometry), the location of the boundary region can be used to estimate the volume of the fluid contents within the bottle. This estimation can optionally be performed at a selectable level of expected accuracy.

[0144] For example, even a rough estimate of the volume (e.g., within ±20% of the precise figure) is often sufficient for verification purposes. A target volume (optionally represented as a range and / or tolerance specification) is also an instance of a target standard to which measurements derived from the image can be compared, for example, a comparison based on converting the boundary layer into a relevant volume estimate using appropriate calculations, optionally involving the location of the boundary layer in the image.

[0145] The original active pharmaceutical ingredient in the vial can be a solid in a separately validated amount (e.g., already well validated), where the added fluid serves primarily to dissolve it. Minor deviations in the fluid volume are negligible (e.g., when the entire contents of the vial are to be used in a single, larger volume anyway), and can be adjusted during the remaining steps of drug preparation, and / or at the time of drug administration.

[0146] In some instances, the calibration status of one or more calibration vials and / or vials known and / or confirmed to contain certain (e.g., target) fluid volumes and / or compositions is used as a reference. This allows for the evaluation of fluid volumes and / or vial status in other imaging vials based solely on boundary region positioning and vial angles.

[0147] The calibration state can optionally be represented as, for example, the localization of the boundary layer, a comparison of images showing the boundary layer (e.g., subtracting, correlating, or otherwise comparing two images to establish a measure of similarity or difference), or another state. In some instances, the comparison is performed using a machine learning product (e.g., a machine learning product trained based on the evaluation results of the boundary layer localization). Each of these is also an instance of a target standard that can be compared with the boundary layer localization.

[0148] In some instances, images of vials used for drug preparation are used to help set system requirements, for example, in high-risk scenarios where the focus is on mitigating rare or intermittent deviations relative to typical fluid volumes. In some instances, the system operator approves the results of system operations used to mix the drug formulation, for example, approving the final result, and images taken during mixing are optionally considered valid results representing intermediate drug preparation operations. Alternatively or additionally, the system operator approves images or other measurements that directly indicate the results of intermediate operations. For example, the system operator examines an image of the boundary layer in a fluid vial and approves it as a benchmark. Alternatively or additionally, the system operator confirms that the starting conditions are valid, and based on this confirmation, the image of the vial is accepted as a relevant indication of the effective fluid volume in the vial. For example, the system operator may be someone who directly provides instructions to the system or someone who assists in monitoring system operations. In some instances, an additional automated system is provided in place of the system operator, for example, an automated system specifically configured to validate the drug formulation according to appropriate criteria based on measured volumes, compositions, and / or other inputs, in place of the system operator.

[0149] Alternatively or additionally, the accuracy of volume estimation can be optionally improved by considering more potential confounding factors, such as parameters of the vial's internal shape and / or the fluid meniscus shape (optionally with or without calibration vials). The ability to flexibly switch between quantitative and qualitative validation levels (with optionally different levels of accuracy) has potential advantages, as it allows for adjustments to the time and / or effort required for measurements to meet specific validation and / or risk mitigation requirements.

[0150] Where further characterization of the vial's "upright" orientation is required to dispel doubt, this orientation can be identified by features such as the vial being oriented to allow (when unsupported) stable placement on a substantially horizontal bottom or part thereof, for example, on a flat surface, a complete or partial ring, and / or on a small protrusion such as a bulge or spherical protrusion. Alternatively or additionally, in the case of a vial with a septum, the septum is located at the top and is generally oriented horizontally. Typically, but not necessarily, a vial in an upright position comprises a lower volume containing contents that is cylindrical or prismatic (e.g., a constant cross-section, ignoring minor deviations in volume, such as a recessed bottom surface). The cross-section is typically circular, but other cross-sectional shapes are not excluded, such as oval, elliptical, triangular, quadrilateral, or other shapes. In this case, at least when the vial also has a flat bottom and a horizontally oriented bottom, the longitudinal axis of the cylinder or prism extends vertically when the vial is upright. Optionally, the orientation of the vial label (e.g., text) provides an indication of the vial's orientation.

[0151] In some instances, one or more automated actions performed using the vial are based on image-based assessments of the vial's contents, such as the presence and / or quantity of fluid (e.g., liquid fluid). In some instances, the automated action is determined to be one or more uses of the vial's contents, or to reject the use of the vial's contents. In some preferred instances, use / rejection is related to the use of the contents in the automated preparation of pharmaceutical formulations. For example, it may not be possible to determine whether to continue using the vial until the quantity of the fluid contents in the vial is validated.

[0152] In some instances, vial determination is used in conjunction with additional adjustments to the vial's contents. For example, optional inclusions may be used to add more fluid to compensate for deficiencies. Alternatively, (e.g., in cases where the ingredient is found to be over-diluted to an excessively large volume), the fluid is mixed with the contents of another vial, where the volume of added fluid is intentionally or unintentionally reduced so that the combined concentration is corrected to the target level. In some instances, vial determination uses inclusions to orient the vial to a specific location in preparation for further activities. For example, the vial is returned to an upright position to allow fluid to be drawn from it; or the vial is placed in a completely inverted position to achieve the same purpose. In some instances, the vial is returned to an upright position and moved to be placed in a rejection area, or returned to its original location (as a rejection object) and no longer used.

[0153] the term

[0154] The subject matter of this disclosure generally relates to robotic drug preparation systems, and more specifically, to fluid transfer stations within robotic drug preparation systems. It should be understood that, for the sake of brevity and clarity, the examples described herein (with reference to the accompanying drawings and others) are described with reference to a subset of components of a drug preparation system; for example, a specific aspect of an entire fluid transfer device assembly. Furthermore, examples directly similar to those described herein should be understood to be covered within the scope of this disclosure. This includes, for example, specific embodiments and / or combinations of elements and / or subsystems that differ in detail from those explicitly described but are similar in function and / or functional role.

[0155] Drug preparation system: Embodiments of the robotic drug preparation system and its fluid delivery station described herein are configured to perform operations related to the transfer of drugs between different fluid delivery devices.

[0156] A robotic drug preparation system according to the subject matter of this disclosure (which may alternatively be referred to as a "robotic system") includes components and / or subsystems such as a robotic station, robotic arm, motors, control units, and / or other mechanisms that operate to perform, control, and / or verify fluid delivery. These components are optionally designed and / or described as constituting units and / or subsystems and / or comprised of units and / or subsystems operable to perform activities related to the preparation of a drug intended for administration to a patient. For example, a robotic system may include one or more automated or partially automated subsystems comprising at least one manipulator at least partially controlled by a controller unit (equivalently referred to as a controller or control unit). The controller units themselves may be arranged, for example, hierarchically and / or communicatively in a network to coordinate the overall operation of the drug preparation system.

[0157] The drug preparation system described herein delivers fluid between a container and a fluid delivery unit specified by a fluid delivery device, where the latter typically acts as an intermediate element (typically, but not necessarily, an "active" element, e.g., an element that causes fluid movement by generating pressure), and the former is considered either a fluid source or a fluid receiving element (typically, but not necessarily, a "passive" element). Fluid delivery may be assisted by a fluid delivery connector. However, a typical intermediate fluid delivery unit may still optionally operate as an initial source of fluid (e.g., in the form of a pre-filled syringe provided at the start of drug preparation) and / or as a final container of fluid (e.g., in the form of a filling unit, which is then forwarded to another process, such as delivery to a patient, storage, or another purpose). The intermediate role of the container as both a fluid source and a fluid receiver is also not excluded.

[0158] Embodiments of delivery devices may include, for example, one or more catheters, pumps, syringes, vials, intravenous bags, adapters, and / or needles. Optionally, these elements are consumables and / or accessories of a drug preparation system. However, alternatively, such elements are considered components of a drug preparation system. The term vial is specifically used herein as a term for a container in which contents, beginning in a solid and / or relatively concentrated form, are initially dissolved and / or diluted. In other instances, the vial contains a certain amount of fluid, regardless of whether it was initially intended as a container for solids and / or concentrates. In other instances, the vial may still retain substances in solid and / or concentrated forms. However, the term vial is not limited to this list of examples.

[0159] Fluid: As used herein, “fluid” generally includes pharmaceuticals, diluents, saline solutions, water, or any other fluid used in the preparation of pharmaceuticals. More specifically, fluid can be understood as being provided as a liquid, although the use of gaseous fluids is not excluded, provided their properties are consistent with those described herein.

[0160] Fluid transfer: "Fluid transfer" between a container assembly and a fluid transfer assembly is carried out through openings formed in the ports of the container assembly or fluid transfer assembly and / or through openings formed in the diaphragms of the container assembly or fluid transfer assembly.

[0161] Diaphragm: In this document, "diaphragm" generally refers to a membrane configured to close an inlet to a part of its constituent device. A diaphragm on a container or container connector (also known as a container diaphragm) seals the container. A diaphragm on a fluid transfer assembly (also known as a fluid transfer connector diaphragm) prevents or blocks entry into and / or through a fluid transfer conduit. Typically, diaphragms are made of a resilient, puncture-resistant material. Such materials can be polymers with elastic properties, like rubber. For example, vials are often fitted with caps that integrate diaphragms.

[0162] Container: In performing fluid transfer, the robotic system operating according to this disclosure optionally manipulates and / or inspects containers embodied differently. As described herein, "container" optionally refers to any one or more of the following: syringe, IV bag, elastic pump, vial, bottle, ampoule, syringe, tubing, conduit, or generally any vessel or container suitable for containing fluid or liquid. It should also be understood that a container can be any other element operating as a component of a fluid transfer device, with or without a connector (or "adapter") for establishing fluid communication between the container and other fluid transfer components. For example, a container can be a vial with a vial adapter, or an intravenous bag with a point adapter. Access to the container can be through a container diaphragm, which can be a diaphragm of the container cap or part of a connector. In fluid transfer using fluid pressure changes and / or differential pressure, the container characteristically experiences fluid transfer due to pressure changes within and / or generated by the fluid transfer assembly to which the container is connected.

[0163] Vial: As described herein, a “vial” (e.g., a container) can include, for example, a sealable vessel made of glass or plastic containing a drug in liquid or powder form, such as an ampoule or bottle. Vials can be single-use or reusable. Vials can be tubular or bottle-shaped, with a neck near the opening. The top of the vial can be capped, for example, with a septum. The shape of a vial is generally fixed, and specifically, a constant internal volume remains constant, although the volume can be filled to a greater or smaller extent. In some instances, a vial is also a preparation container in which the supplied substance is dissolved, diluted, and / or reconstituted in preparation for further operations, such as transfer to a syringe. Therefore, operations performed on a vial typically involve injecting a fluid and removing one or both of the fluid. Between these two, there may be mixing operations, such as dissolving and / or diluting the originally contained substance with the injected fluid. Vials are typically supplied for manual preparation options and are not necessarily standardized in size. Vials can be labeled to suit manual operation, but this presents potential disadvantages for automated operations, such as obstructing the view of the vial's contents.

[0164] Container Assembly: As described herein, a “container assembly” may include: a separate container, or a container to which a container connector is mounted. The term “vial assembly” is used equivalently, although examples embodying aspects of this disclosure do not necessarily include vials in the strict sense (e.g., ampoules may be present instead). A diaphragm for at least partially sealing the vial inlet may be positioned as part of the vial itself and / or part of the container connector (equivalently referred to as a “vial adapter” or “container adapter”). The container connector may include means that can be mounted to the vial to facilitate the transfer of the vial itself (by gripping the adapter rather than gripping the vial) and / or facilitate the transfer of fluid into or out of the vial. The container connector may provide protected (e.g., “closed” and / or sterile) contact with the contents of the vial. The container connector may be a single-use or reusable sterile device. The vial in the container assembly may be partially shielded by elements attached thereto (e.g., a manipulator that holds it for operations such as oscillation or fluid exchange).

[0165] Manipulator: As described herein, a “manipulator” can include structures and / or mechanisms configured to controllably interact with at least one container (e.g., a container loaded onto a system) and / or other components or structures of a drug preparation system. A manipulator can be configured to move at least one container. A manipulator can be configured to induce or facilitate a fluid transfer process; for example, transferring fluid from one container to another, involving, for example, aspirating and / or inserting (e.g., injecting) fluid. A manipulator can include a robotic arm, platform, robotic station, or a combination thereof configured to manipulate the container and / or fluid transfer assembly. A manipulator can include actuators, such as motors, for facilitating its operation. Some manipulators are also referred to herein as “stirring.” In some instances, a stirrer includes a manipulator that provides stirring-specific capabilities (e.g., the ability to oscillate, separate from the ability of the manipulator to selectively position the container to be manipulated at a target location). In some instances, a simpler feature of a stirrer is the ability to hold the container (e.g., vial) in place while the stirrer itself moves in a stirring manner, for example, oscillating at appropriate positioning to move the contents within the container. In some instances, the movement of the agitator introduces vortex motion into the fluid contents of the container. In some instances, the agitator moves to disturb the surface boundary regions of the fluid contents of the container; for example, to produce splashing and / or momentary droplet separation. In some instances, the agitator generates an electric current within the fluid contents of the container. In some instances, the agitator introduces motion into the contents of a vial, causing the mixing of two material phases of the vial's contents, for example, suspending and / or dissolving a solid material in a liquid material, and / or suspending and / or dissolving two liquid materials in a common material phase.

[0166] A manipulator is not necessarily implemented as an "arm" itself, even in cases where such terms are used. Fluid transfer can occur when a container is engaged (e.g., clamped) by a manipulator. In one instance, a manipulator (e.g., a "clamp" or "plunger arm") may include one or more actuators for engaging a syringe and / or pulling or pushing a plunger of the syringe. The syringe may then engage a vial. Manipulators are optionally configured to manipulate other types of fluid containers, such as vials, IV bags, tubing, and / or another suitable container.

[0167] Controller: In this document, the equivalent terms "controller" and "controller unit" generally refer to a circuit system configured to command certain aspects of the behavior of a controlled element, such as the operation of an actuator (which may in turn be the actuator of a manipulator), the operation of a sensor, and / or the operation of an imager. In some instances, the controller includes a computerized circuit system (also referred to herein as a "processing circuit system") configured to perform operations according to a set of instructions stored in a controller-readable memory, which may be executed, for example, by a central processing unit (CPU), one or more processors, processor units, and / or microprocessors. Additionally or alternatively, in some instances, the controller uses a digital signal processor (DSP), a field-programmable gate array (FPGA), a specialized application-specific integrated circuit (ASIC), or other means. Additionally or alternatively, in some instances, the controller or controller unit includes one or more analog circuits (e.g., amplifier-based feedback) and / or low-level logic gate-based control circuits. In some instances, the control unit may include one or more mechanism controllers. The controller unit may include any means for controlling elements in a robotic drug delivery system and may include at least one of an analog control circuit system, a synchronization unit, and a processor.

[0168] Imager: In this document, the term "imager" refers to any device that operates to produce an image of a target. "Optical" imaging can generally be understood as including imaging with light (including visible light), but this is not mandatory. For example, infrared and / or ultraviolet wavelengths, in addition to or alternative to visible light wavelengths, may be used for imaging as appropriate. An example of an imager is an optical camera; for example, a camera equipped with one or more transparent lenses and a light sensor capable of readout to produce a digital image. Optionally, scanning imaging methods are used, for example, imaging the reflectivity of laser illumination scanned from the target back to the sensor. Optionally, interferometric imaging is used, for example, for tracking small deformations and / or movements. Imaging with radiant energy other than visible light is not excluded; for example, acoustic energy, electromagnetic wavelengths outside the visible spectrum, and / or particle (with mass) radiation imaging. Optionally, contact imaging is performed, for example, moving a contact probe along the imaging target to confirm the accuracy of its positioning and / or measure one or more contours of its shape.

[0169] In this document, characteristics and / or values ​​may be referred to as “expected” or “targeted.” It should be understood that these terms refer to the technical representation of the appropriate corresponding state and / or quantity. Optionally, such representation is digital, for example, as in the case of a target stored by a digital computing circuit system. Optionally, such representation is analog and / or mechanical; for example, represented by a pointer, knob, weight, or other element or arrangement of elements.

[0170] Before explaining at least one embodiment of this disclosure in detail, it should be understood that this disclosure is not necessarily limited in its application to the details of the construction and arrangement of components and / or methods set forth in the following description and / or shown in the accompanying drawings and / or given in the examples. The features described in this disclosure, including those of the invention, can have other embodiments or can be practiced or carried out in various ways.

[0171] Visual inspection of solute dissolution in solvent

[0172] Now for reference Figure 1 The diagram schematically illustrates a block diagram of an example system 100, representing some instances of the subject matter currently disclosed, configured to controllably dissolve a solid into a fluid. In some instances, system 100 is a subsystem of a robotic drug preparation system that operates to prepare drug formulations via measured fluid transfer between multiple containers.

[0173] In some instances, vial 115 is a container containing a fluid-solid mixture. It is introduced for manipulation by system 100, for example, by prior robotic pickup from a storage area and / or by manual placement.

[0174] In some instances, vial 115 initially contains powdered (e.g., lyophilized and / or ground) and / or crystalline material. This may be mixed with a fluid solvent (e.g., a saline solution or Ringer's solution), for example, a fluid solvent injected into vial 115 in an early stage of processing by a robotic drug preparation system.

[0175] In some instances, the vial manipulator / stirrer 110 includes a mechanical component 110A that operates to grip (or otherwise hold, e.g., accommodate) and move the vial 115. As a non-limiting example, the vial manipulator / stirrer 110 may be a robotic arm with a gripping tool at its end end suitable for gripping and manipulating the vial.

[0176] In some instances, the stirring assembly of the vial manipulator / stirrer 110 is operable to apply rotational motion to the vial 115, such as cyclic (e.g., circular) and / or reciprocating rotational motion on one, two, or three axes in a clockwise or counterclockwise direction, as well as movement between 0 degrees and 360 degrees (or larger angles for repeated cycles).

[0177] As a non-limiting example: the vial manipulator / stirrer 110 optionally rotates the vial 115 in an alternating manner, first moving the vial 115 90° clockwise in the x-direction, then 180° counterclockwise in the x-direction, and finally moving it 90° clockwise back to its original position. This movement may optionally be repeated any suitable number of times.

[0178] As another non-limiting example, the vial manipulator / stirrer 110 can rotate the vial 115 360° in the z direction, for example, by rotating it to flip the vial 115 over, and then continue rotating it to return the vial 115 to its original orientation.

[0179] In some instances, the stirring assembly of the vial manipulator / stirrer 110 can cause the manipulated vial 115 to move (e.g., linear movement) (i.e., reciprocating motion) in the forward and / or backward directions along one, two, or three axes. The distance and speed of movement can optionally have any suitable values.

[0180] In some instances, the vial manipulator / stirrer 110 is operable to cause the manipulated vial 115 to move simultaneously and / or continuously in a sequence including any of the movements described above.

[0181] As used herein, the term "oscillation" refers to any type of movement applied to vial 115 that can be adapted to accelerate the rate of dissolution of a solid or fluid solute into a fluid solvent. For example, such acceleration of the dissolution rate can be at least in part due to, for example, the movement of the solvent through the material during dissolution, flushing away the solute and thereby maintaining a relatively steep concentration gradient, allowing the remaining material to continue diffusing into it. Optionally, the acceleration of the dissolution rate is at least in part due to mechanical forces (e.g., shear forces and / or impact forces) acting on the solute to break it up and / or increase its effective surface area. The latter mode of acceleration can potentially have variable effectiveness, for example, depending on how the fluid is moved within its container and / or how the dissolved material responds to the mechanical forces.

[0182] Optionally, illumination 125 is positioned to illuminate the contents 160 of vial 115. For example, illumination 125 may optionally include annular illumination around vial 115. Optionally, illumination 125 is provided by another light source (e.g., a panel light source or a point light source). Regardless of the configuration, illumination 125 provides illumination suitable for an imager 120 (e.g., an optical camera) to capture images of the fluid 160A and / or solid 160B contained in vial 115.

[0183] Imager 120 can be any suitable type of digital camera or other imaging device. Imager 120 can be positioned, for example, below vial 115 to allow viewing of its contents from the bottom surface of the vial. A potential advantage of doing so is avoiding obstruction from labels or other items on the walls of vial 115. In some instances, imager 120 is positioned in another suitable location.

[0184] The processing circuitry 130 can be operatively connected to the imager 120 and to the vial manipulator / stirrer 110. In some instances, the processing circuitry 130 can, for example, command the imager 120 to capture an image of the vial 115, and then receive the captured image.

[0185] In some instances, the processing circuitry 130 can command the vial manipulator / stirrer 110 to start or stop oscillation, or to change oscillation parameters.

[0186] The processing circuitry system 130 may include a processor 150 and a memory 155. In some instances, instructions for execution by the processor 150 to carry out one or more methods of the present disclosure are provided on a non-transitory digital storage medium. Specifically, it should be understood that, regarding Figure 2A-3 and / or Figure 7-8 Any operation performed by the computer as described may optionally be associated with a corresponding instruction provided on a non-transitory digital storage medium and executed by the processor 150.

[0187] Processor 150 can be a suitable hardware-based electronic device with data processing capabilities, such as a general-purpose processor, a digital signal processor (DSP), a dedicated application-specific integrated circuit (ASIC), one or more cores of a multi-core processor, etc. Processor 150 can also consist of, for example, multiple processors, multiple ASICs, virtual processors, combinations thereof, etc.

[0188] Memory 155 may be, for example, a suitable type of volatile and / or non-volatile memory, and may include, for example, a single physical memory component or multiple physical memory components. Memory 155 may also include virtual memory. Memory 155 may be configured to, for example, store various types of data used in computation.

[0189] The processing circuit system 130 can be configured to execute several functional modules according to computer-readable instructions implemented on a non-transitory computer-readable storage medium. Hereinafter, such functional modules are referred to as being contained within the processing circuit system. These modules may include, for example, a stirring control unit 142, a global control unit 145, a fluid analysis subsystem 135, and a machine learning model 140.

[0190] The global control unit 145 can perform global control functions, such as moving the vial 115 to different positions in the drug preparation device after the solid has completely dissolved into the fluid.

[0191] The stirring control unit 142 can control the bottle manipulator / stirrer 110.

[0192] The fluid analysis subsystem 135 can perform image processing on captured images of the fluid in vial 115 and determine, based on the images, whether the fluid and / or solid exhibit certain properties. Vial 115 can then be further processed according to appropriate processing methods suitable for the determined fluid properties, which will be described in detail below.

[0193] As a non-limiting example, in various instances, the fluid analysis subsystem 135 can determine one or more of the following types of properties of fluids and / or solids:

[0194] The transparency or lack thereof of the fluid / solid mixture. For example, an image can be analyzed to determine the degree of attenuation of illumination intensity as it passes through the vial (smaller attenuation is associated with greater transparency). This could include, as needed, measuring the intensity of light traveling from the backlight through the vial to the imager, the intensity of light entering the vial from the side of the imager and then returning to the imager, and / or the intensity of light from another path.

[0195] The degree of clarity of the fluid / solid mixture, or whether the fluid / solid mixture meets certain clarity requirements. Under some lighting conditions, light intensity may decrease as clarity decreases; under other lighting conditions, light intensity may increase, for example, when more light is reflected back from a turbid suspension. Optionally, the uniformity of the image can also be evaluated, such as the uniformity of particle size, particle velocity, or another metric. For example, under stirring, particles in a suspension may reflect laser speckle patterns that vary with common and / or unique time-dependent statistics. Optionally, the exposure time or another parameter can be selected to distinguish between “blurred” and unblurred areas of laser speckle motion. Unblurred areas may indicate areas compacted rather than suspended by material.

[0196] It should be noted that fluid clarity refers to the amount of light that can pass through a non-transparent fluid. For example, fluid clarity may indicate whether there are clumps on the inner surface of vial 115.

[0197] Alternatively or additionally, a mismatch may exist between the observed fluid color and the expected or target fluid color. For example, this could indicate that the type of solid is incorrect, or that the amount of solid or fluid is incorrect. It should be noted that the expected fluid color itself can be variable, depending on, for example, the type of solid and / or fluid in the vial.

[0198] In another example, the fluid analysis subsystem 135 is configured to measure the presence of foreign particles in the fluid. This potentially indicates contamination of the solution or damage to internal components of the vial. Foreign particles can be, for example, particles whose size, shape, or color is inexplicable. Foreign particles can be particles that remain in the vial after other particles have dissolved. Optionally, such particles can be distinguished from air bubbles, for example, based on their apparent density (e.g., settling rather than rising) and / or lack of transientity.

[0199] In another instance, there may be a mismatch between the liquid level and the expected liquid level. This could potentially indicate that the vial has leaked.

[0200] It should be noted that the expected (target) liquid level can be variable, for example, selected based on the initial amount of fluid in the vial.

[0201] In some instances, the fluid analysis subsystem 135 utilizes a machine learning model 140. In this case, the machine learning model 140 can be pre-trained to classify images as needed.

[0202] For example, machine learning model 140 can be trained using images of transparent and opaque fluids (e.g., using appropriate labels in the case of a supervised model). Fluid analysis subsystem 135 can then classify the runtime images to categorize them as transparent or opaque. In some instances, training (and therefore classification) can be specific to a particular solid type (i.e., a particular drug) or a particular fluid type.

[0203] In various instances, the machine learning model 140 can be similarly trained to perform classification, thereby distinguishing fluids that meet a specific level of clarity from those that do not. Similarly, the machine learning model 140 can be trained to identify the presence of foreign particles, the color or hue of the fluid, and the presence of agglomerates on the vial 115. In some instances, the fluid analysis subsystem 135 and / or the machine learning model 140 are used for, for example... Figures 2A-2F and / or Figure 3 Methods such as these.

[0204] Alternatively or concurrently, the fluid analysis subsystem 135 may use mechanisms known in the art to estimate the fluid volume. In some embodiments, the estimation is performed using a machine learning model 140, which is trained to perform classification to distinguish the presence and / or level of fluid in the vial. In some instances, the fluid analysis subsystem 135 and / or the machine learning model 140 are used for, for example... Figure 7-8 Methods such as these.

[0205] In some instances, the fluid analysis subsystem 135 uses non-machine learning image processing methods on the captured images to determine the properties of the fluid.

[0206] In some instances, the fluid analysis subsystem 135 uses measurement and / or analysis arrangements, such as those described herein related to visually inspecting the presence and / or volume of fluid.

[0207] Figures 2A-2F Various methods for controlling the dissolution of solids into liquids are demonstrated. It should be noted that individual examples may utilize some or all of these methods, or a combination of different methods.

[0208] Figure 2A The flowchart illustrates an example method for ensuring the dissolution of a solid into a fluid as part of a drug preparation process in a robotic drug preparation system, based on some instances of the currently disclosed subject matter.

[0209] Figure 2A The method shown can be applied, for example, to the preparation of completely transparent drug solutions, which are the result of powdered substances being completely dissolved in a fluid (such as a saline solution or a glucose solution).

[0210] Figure 2A The method shown can be operated on, for example, vials containing powdered material, in which an appropriate amount of fluid has already been injected.

[0211] The processing circuitry 130 (e.g., stirring control unit 142) can control the vial manipulator / stirrer 110 to oscillate 205A on the vial 115 held by the vial manipulator or stirrer 110.

[0212] For example, after a specific time interval (e.g., time sufficient for a specific solid to dissolve in a specific fluid) has elapsed, the processing circuitry 130 (e.g., the fluid analysis subsystem 135) can assess (e.g., through machine learning classification, as described above) whether the fluid is currently transparent 210A. In another instance, transparency is assessed by examining the ratio of light scattering to light passing directly through the vial. In yet another instance, transparency is assessed based on the contrast and / or legibility of an image target positioned on opposite sides of the vial.

[0213] It should be noted that in some instances, transparent fluids can be colored. In such instances, spectral parameters may exist as characteristics of the dissolved fluid and / or its concentration, such as the ratio of light measured at two different wavelengths.

[0214] If the processing circuitry 130 (e.g., the fluid analysis subsystem 135) determines that the fluid in vial 115 is indeed transparent, the processing circuitry 130 (e.g., the global control unit 145) can control the vial manipulator / stirrer 110 to continue 215A to the next stage of the drug preparation process.

[0215] If the processing circuitry 130 (e.g., the fluid analysis subsystem 135) determines that the fluid is not transparent (at least according to the transparency criterion used), the processing circuitry 130 (e.g., the global control unit 145) can issue a 220A alarm indicating that the solid has not dissolved properly in the fluid (e.g., by displaying a message on the management display unit). In some instances (alternatively or alternatively), another form of exception handling is performed; for example, the use of the vial can be refused, and alternatively, the use of another vial can be selected to continue operation.

[0216] It should be noted that the teachings of the topics currently being presented are not subject to Figure 2A The constraints of the flowchart shown. It should also be noted that although the flowchart is for reference... Figure 1 The system's elements are described, but this is by no means restrictive, and operations can be performed by elements other than those described herein.

[0217] Figure 2B A flowchart illustrating another example method for controlling the dissolution of solids into a fluid as part of a drug preparation process in a robotic drug preparation system, based on some instances of the currently disclosed subject matter.

[0218] Figure 2B The method shown can be applied, for example, to the preparation of drug solutions that are not completely transparent after the powdered substance has been completely dissolved in the fluid.

[0219] therefore, Figure 2B The steps of the method are similar to Figure 2A The steps of the method. However, after the oscillation and time interval expires 205B, the processing circuit system 130 (e.g., fluid analysis subsystem 135) can assess (e.g., by machine learning classification as described above) whether the fluid clarity meets the fluid clarity standard 210B.

[0220] If so, the processing circuitry 130 (e.g., global control unit 145) can continue processing 215B; if not, the processing circuitry 130 (e.g., global control unit 145) can issue an alarm 220B. In some instances (alternatively or alternatively), another form of exception handling is performed; for example, the use of the vial can be refused, and alternatively, the use of another vial can be selected to continue operation.

[0221] It should be noted that the teachings of the topics currently being presented are not subject to Figure 2B The constraints of the flowchart shown. It should also be noted that although the flowchart is for reference... Figure 1 The system's elements are described, but this is by no means restrictive, and operations can be performed by elements other than those described herein.

[0222] Now for a brief reference Figure 4B These are photographic images of vials containing foreign matter particles, based on some instances of the currently disclosed subject matter. Under the current lighting conditions, clear (transparent) areas appear as black, while foreign matter particles appear as particles, such as particle 160B. Identification of these particles is optionally performed using machine vision methods such as edge detection, thresholding, and / or granular filtering. Optionally, machine learning methods are used to train the distinction between foreign matter particles and other image elements of less particular interest, such as microbubbles and reflections from the vial surface.

[0223] Also, a brief reference Figures 6A-6B These are photographic images of vials containing foreign particles, based on some examples of the currently disclosed subject matter. Further brief references are available. Figure 6C It is based on some examples of the currently disclosed topic. Figures 6A-6B The absolute value difference image is constructed from the image. Despite the different features and imaging conditions (e.g., illumination 125 is located at...), Figures 6A-6B In the bottom left corner, and the large, bright label 610 wraps around the small bottle 115, but... Figure 6C Large particles can still be easily distinguished. Optional additional processing can be performed, such as masking, filtering, and / or otherwise improving particle visibility. Optionally, machine learning classification can be applied to the original and / or preprocessed images to improve the visibility of potential fault conditions.

[0224] Figure 2C Flowcharts show additional example methods for controlling the dissolution of solids into fluids as part of a drug preparation process in a robotic drug preparation system, based on some instances of the currently disclosed subject matter.

[0225] Optionally, use Figure 2C The method shown in the paper optimizes the processing time used for dissolving solids into fluids and detects dissolution failures. Alternatively, when the dissolution time is unknown or variable, the method can be utilized... Figure 2C The method shown dissolves solids into a fluid.

[0226] The processing circuit system 130 (e.g., stirring control unit 142) can control the vial manipulator / stirrer 110 to initiate the oscillation 205C of the vial 115 held by the vial manipulator or stirrer 110.

[0227] Processing circuitry 130 (e.g., fluid analysis subsystem 135) can periodically evaluate (e.g., through machine learning classification as described above) whether the fluid is currently transparent 210C. In instances where the fluid is expected to become opaque, processing circuitry 130 (e.g., fluid analysis subsystem 135) can instead evaluate whether the fluid clarity meets fluid clarity criteria.

[0228] If the processing circuitry 130 (e.g., the fluid analysis subsystem 135) determines that the fluid in vial 115 is indeed transparent (or meets the clarity criteria), then the processing circuitry 130 (e.g., the stirring control unit 142) can stop the oscillation of vial 115 by the vial manipulator / stirrer 110. The processing circuitry 130 (e.g., the global control unit 145) can then control the vial manipulator / stirrer 110 to continue to the next stage of the drug preparation process.

[0229] If the processing circuitry 130 (e.g., the fluid analysis subsystem 135) determines otherwise that the fluid is opaque (or its clarity does not meet the clarity criterion), then the processing circuitry 130 (e.g., the global control unit 145) can assess whether 215C has reached the oscillation limit (e.g., the time limit), and if so, the processing circuitry 130 (e.g., the global control unit 145) can issue an alarm 225C. If the oscillation limit has not been reached, the processing circuitry 130 (e.g., the fluid analysis subsystem 135) can continue oscillating 205C of vial 115 and then reassess whether the fluid is transparent (or whether its clarity meets the clarity criterion).

[0230] therefore, Figure 2C The demonstrated method achieves a close match between the oscillation period and the actual time required for the solid to dissolve into the fluid. It should be noted that, compared to existing systems for assessing fluid transparency / clarity while vial 115 is stationary, Figure 2C The method demonstrated utilizes the capabilities of the fluid analysis subsystem 135 to assess fluid transparency / clarity during oscillation, thereby providing an efficient process that maintains processing continuity and reduces dissolution time.

[0231] It should be noted that the teachings of the topics currently being presented are not subject to Figure 2C The constraints of the flowchart shown. It should also be noted that although the flowchart is for reference... Figure 1 The system's elements are described, but this is by no means restrictive, and operations can be performed by elements other than those described herein.

[0232] Figure 2DA flowchart illustrating an example method for handling solid agglomeration on a vial surface during the dissolution of a solid into a fluid, as part of a drug preparation process in a robotic drug preparation system, based on some instances of the currently disclosed subject matter.

[0233] The processing circuitry 130 (e.g., stirring control unit 142) can control the vial manipulator / stirrer 110 to oscillate 205D on the vial 115 held by the vial manipulator or stirrer 110.

[0234] For example, after a specific time interval (e.g., time sufficient for a specific solid to dissolve into a specific fluid) has elapsed, the processing circuitry 130 (e.g., the fluid analysis subsystem 135) can assess (e.g., by machine learning classification as described above) the presence of solid agglomerates 210D on the surface of the vial. It should be noted that in some instances, the processing circuitry 130 (e.g., the fluid analysis subsystem 135) can also assess other conditions (such as the transparency or clarity of the fluid) (continuously or simultaneously).

[0235] Now for reference Figure 4A This is a photographic image (captured from below) of a vial containing solid agglomerates, based on some instances of the currently disclosed subject matter. This image is an example of an image measurement obtained by imager 120 when viewing the contents upwards from a position located below the vial 115. See also... Figures 5A-5B The image shows a photographic image of the same vial containing a clump of solid, based on some instances of the currently disclosed subject matter. Further references. Figure 5C It is based on some examples of the currently disclosed subject matter through Figures 5A-5B The difference image (absolute value) is obtained by subtracting the images from each other.

[0236] In some instances, the processing circuitry system 130 (e.g., the fluid analysis subsystem 135) determines whether a vial image is clumped based on a classification of the vial image by a machine learning model, which is pre-trained using images of vials with and without solid clumps (with appropriate labels).

[0237] In some other instances, if dissolution is incomplete (e.g., the fluid is not transparent), the processing circuitry 130 (e.g., the fluid analysis subsystem 135) determines the presence of agglomerates. For example, Figure 5C The (absolute) difference image shows a "white" motion signal, which is due to the subtle difference in reflectivity of the circulating fluid inclusions 160A, while the solid 160B remains dark because there is no relative motion there.

[0238] It should be further noted that in some instances, the processing circuitry 130 (e.g., the stirring control unit 142) can stop the oscillation of the vial 115 after the time interval expires and before assessing whether clumping is present, while in other instances, the oscillation can continue during the assessment of whether clumping is present.

[0239] If the processing circuitry 130 (e.g., the fluid analysis subsystem 135) determines that the fluid in vial 115 is free of agglomerates, then, where appropriate, the processing circuitry 130 (e.g., the stirring control unit 142) can stop the oscillation of vial 115 by the vial manipulator / stirrer 110. The processing circuitry 130 (e.g., the global control unit 145) can then control the vial manipulator / stirrer 110 to continue 215D for the next stage of the drug preparation process.

[0240] If the processing circuitry 130 (e.g., the fluid analysis subsystem 135) determines that agglomeration is present, the processing circuitry 130 (e.g., the stirring control unit 142) can alter parameters of the oscillation behavior of the vial manipulator / stirrer 110. For example, the vial can be stirred with greater amplitude, greater acceleration, and / or with altered motion patterns (e.g., along the bottom-to-top axis of the vial, in a figure-eight pattern, in a circular motion, in a random pattern, or in other oscillation patterns).

[0241] As a non-limiting example: if the vial manipulator / stirrer 110 oscillates the vial 115 in a linear motion at a specific angle in the x and z planes, the manipulator / stirrer 110 can change the stirring angle 220D to remove and dissolve the agglomerated solids and continue oscillation. Optionally, if continued oscillation does not resolve the agglomeration, the processing circuitry 130 (e.g., the fluid analysis subsystem 135) can issue an alarm indicating that the solids are not properly dissolved in the fluid.

[0242] It should be noted that the teachings of the topics currently being presented are not subject to Figure 2D The constraints of the flowchart shown. It should also be noted that although the flowchart is for reference... Figure 1 The system's elements are described, but this is by no means restrictive, and operations can be performed by elements other than those described herein.

[0243] Figure 2E Flowcharts show additional example methods for controlling the dissolution of solids into fluids as part of a drug preparation process in a robotic drug preparation system, based on some instances of the currently disclosed subject matter.

[0244] Figure 2E The method shown can be applied, for example, to the preparation of a drug solution obtained by completely dissolving a powdered substance in a fluid, wherein the dissolution of the solid continues even after the oscillation has stopped.

[0245] As a non-limiting example, cyclophosphamide is a drug used in chemotherapy. In some cases, cyclophosphamide may not dissolve completely and immediately. In such cases, it is recommended to let the vial stand for a period of time.

[0246] The processing circuitry 130 (e.g., stirring control unit 142) can control the vial manipulator / stirrer 110 to oscillate 205E on the vial 115 held by the vial manipulator or stirrer 110 for a certain amount of time (e.g., the time appropriate for a particular solid to dissolve in the fluid).

[0247] After a specific time interval (e.g., time sufficient to dissolve a specific solid into a specific fluid) has elapsed, the processing circuitry 130 (e.g., the stirring control unit 142) can wait 210E for a certain duration to allow the solution to “settle.” In some instances, the settling time is 0.

[0248] The processing circuitry system 130 (e.g., the fluid analysis subsystem 135) can then evaluate (e.g., by machine learning classification as described above) whether the fluid is currently transparent 215E (or, in some instances, whether the fluid clarity meets the clarity criteria).

[0249] If the processing circuitry 130 (e.g., the fluid analysis subsystem 135) determines that the fluid in vial 115 is indeed transparent, the processing circuitry 130 (e.g., the global control unit 145) can control the vial manipulator / stirrer 110 to continue 220E to the next stage of the drug preparation process.

[0250] If the processing circuitry 130 (e.g., the fluid analysis subsystem 135) determines otherwise that the fluid is opaque (or, if appropriate, does not meet the clarity criteria), the processing circuitry 130 (e.g., the global control unit 145) may issue a 225E alarm indicating that the solids are not properly dissolved in the fluid.

[0251] It should be noted that in some instances, the processing circuitry 130 (e.g., the fluid analysis subsystem 135) may assess the transparency (or clarity criterion) multiple times (e.g., with pauses in between) before issuing an alarm indicating that the solid has not dissolved.

[0252] It should be noted that the teachings of the topics currently being presented are not subject to Figure 2E The constraints of the flowchart shown. It should also be noted that although the flowchart is for reference... Figure 1 The system's elements are described, but this is by no means restrictive, and operations can be performed by elements other than those described herein.

[0253] Figure 2F The flowchart illustrates an example method for detecting and reporting faults in the process of solids dissolving into a fluid as part of a drug preparation process in a robotic drug preparation system, based on some examples of the currently disclosed subject matter.

[0254] The processing circuitry 130 (e.g., stirring control unit 142) can control the vial manipulator / stirrer 110 to oscillate 205F on the vial 115 held by the vial manipulator or stirrer 110.

[0255] The processing circuitry system 130 (e.g., the fluid analysis subsystem 135) can assess whether a specific fault has occurred in the 210F.

[0256] As a non-limiting example, the processing circuit system 130 (e.g., the fluid analysis subsystem 135) can evaluate one or more of the following types of faults:

[0257] ● The fluid color does not match the expected fluid color (this may indicate that the solid type is incorrect, or that the amount of solid or fluid is incorrect). It should be noted that the expected fluid color can be variable and depends on the type of solid and / or fluid in the vial.

[0258] ● The presence of foreign particles (e.g., particles that have fallen from the diaphragm) in the fluid (this can indicate contamination of the solution or damage to internal components of the vial). For example, Figure 4B Example images depicting a vial containing foreign particles (captured from below the vial).

[0259] ● The liquid level does not match the expected level (this can indicate a leak in the vial). In some instances, the imager can be placed next to vial 115 to monitor fluid volume. In some instances, it uses, for example, regarding... Figure 7 The method described (and other related figures) is used to assess the liquid level.

[0260] It should be noted that the expected liquid level can be variable and depends, for example, on the initial amount of fluid in the vial, the amount of fluid ordered and / or observed to be injected into the vial, and / or the amount of fluid adjusted in consideration of the operation of withdrawing fluid from the vial.

[0261] The processing circuit system 130 (e.g., the fluid analysis subsystem 135) can assess whether one or more of these faults have occurred, for example, through machine learning classification as described above.

[0262] If the processing circuitry 130 (e.g., the fluid analysis subsystem 135) determines that a fault has actually occurred, the processing circuitry 130 (e.g., the global control unit 145) can issue a 215F alarm indicating that a fault has occurred (and in some instances, include details of the fault).

[0263] It should be noted that the teachings of the topics currently being presented are not subject to Figure 2F The constraints of the flowchart shown. It should also be noted that although the flowchart is for reference... Figure 1 The system's elements are described, but this is by no means restrictive, and operations can be performed by elements other than those described herein.

[0264] Figure 3 Flowcharts illustrate, based on some examples of the currently disclosed subject matter, the monitoring and control of solid dissolution into fluids as part of the drug preparation process in a robotic drug preparation system, as well as example general methods for detecting and reporting faults.

[0265] The processing circuit system 130 (e.g., stirring control unit 142) can control the initiation 305 of the vial manipulator / stirrer 110 (e.g., stirring of the vial 115 held by the vial manipulator or stirrer 110).

[0266] The processing circuitry system 130 (e.g., the fluid analysis subsystem 135) can then receive images of the fluid in the vial 115 captured by the camera 310.

[0267] It should be noted that in some instances, the processing circuitry 130 (e.g., the stirring control unit 142) can stop the oscillation of the vial 115 before the image is captured, while in other instances, the oscillation can continue during the image capture, and in some instances, it can continue during subsequent image processing.

[0268] The processing circuitry system 130 (e.g., the fluid analysis subsystem 135) can then classify 315 the received images to determine the properties of the fluid / solid in the vial 115. Optionally, the properties can be determined by measuring the image shape, intensity, dynamic characteristics (e.g., the magnitude of difference between two or more images), or in another manner.

[0269] As a non-limiting example, the processing circuit system 130 (e.g., the fluid analysis subsystem 135) can determine the presence of one or more of the following types of properties of a fluid and / or solid:

[0270] ● The transparency or lack of transparency of fluid / solid mixtures.

[0271] ● The degree of clarity of the fluid / solid mixture, or whether the fluid / solid mixture meets certain clarity requirements.

[0272] ● Check if there are any lumps on the inner surface of the small bottle 115.

[0273] ● The fluid color does not match the expected fluid color (this may indicate that the solid type is incorrect, or that the amount of solid or fluid is incorrect). It should be noted that the expected fluid color can be variable and depends on the type of solid and / or fluid in the vial.

[0274] ● The presence of foreign particles in the fluid (this can indicate contamination of the solution or damage to internal components of the vial).

[0275] ● The liquid level does not match the expected level (this can indicate that the vial is leaking).

[0276] It should be noted that the expected liquid level can be variable and depends on the initial amount of fluid in the vial.

[0277] As described in detail above, see reference. Figure 1 In some instances, the processing circuit system 130 (e.g., the fluid analysis subsystem 135) uses a trained machine learning model to classify the image to determine the presence of one or more features among the characteristics.

[0278] In some other instances, the processing circuitry 130 (e.g., the fluid analysis subsystem 135) uses other image processing methods to determine the presence of one or more characteristics among the features.

[0279] The processing circuit system 130 (e.g., stirring control unit 142 or global control unit 145) can then perform the subsequent steps 320 based on the determined characteristics.

[0280] As a non-limiting example, the processing circuit system 130 (e.g., the stirring control unit 142 or the global control unit 145) may perform one or more of the following steps in response to the determined characteristics:

[0281] ●Stop the mixer.

[0282] ● Modify the operating parameters of the stirrer 110, for example, change the oscillation angle.

[0283] ●Move vial 115 to the next stage of the preparation process (e.g., control a robotic arm to remove the vial from the vial holder).

[0284] ● Issue an alarm.

[0285] Figures 2A-2FAn example method for controlling the dissolution of solids into liquids is described, the method involving performing specific subsequent steps in response to the determination of specific fluid properties.

[0286] It should be noted that the teachings of the topics currently being presented are not subject to Figure 3 The constraints of the flowchart shown. It should also be noted that although the flowchart is for reference... Figure 1 The system's elements are described, but this is by no means restrictive, and operations can be performed by elements other than those described herein.

[0287] Visual inspection of fluid presence and / or volume

[0288] Image assessment of contents in liquid vials

[0289] Now for reference Figure 7 This is a flowchart schematically illustrating a method for determining the amount of fluid contained in a vial through image-based examination, based on some instances of the currently disclosed subject matter. See also... Figure 8 This is a flowchart schematically illustrating a method for determining the presence of fluid by image-based examination of a vial, based on some instances of the currently disclosed subject matter. Both methods will be described simultaneously, with reference to specific boxes as appropriate. Optionally, both methods are performed. Optionally, both methods are performed concurrently (e.g., using the same image of the vial). Optionally, the two methods are performed separately, or only one method is performed.

[0290] The tilt angle of the vial used for imaging contents

[0291] In box 705 ( Figure 7 ) and / or 805 ( Figure 8 At this location, in some instances, an inspection image of the vial is obtained and / or accessed. The inspection image shows the vial with an applied tilt angle. The tilt angle tilts the vial away from a vertical orientation in which the bottom side of the vial is oriented perpendicular to the direction of gravitational acceleration. It is expected that the inspected vial contains a certain amount of liquid contents, and computational image analysis of the inspection image is used to verify that the amount of liquid contents is within specifications. Optionally, at Figure 8 In cases where the examined vial is expected to be free of liquid contents, the operation should be appropriately reversed in the reported results.

[0292] Brief Reference Figure 12A-12B It schematically represents a side view cross-section of a labeled fluid-containing vial 115 according to some examples of the subject matter currently disclosed. Figure 12A ) and side view ( Figure 12BThe vial 115 is upright and not tilted. Despite the presence of fluid 160 and the formation of an optically distinct boundary region 600A, the presence of the label 610 leaves no gap or only a very small gap 611 through which the boundary region 600A can be visualized in a side view of the vial 115. The boundary region is formed due to the characteristics of the contents of the vial, such as the difference in optical density between the fluid and the gas, and / or another characteristic, for example, as described in the overview.

[0293] Even if it exists, the gap 611 may be unreliably located, and / or even if located, the gap may be too narrow to reliably and automatically detect the boundary region 600A. However, it is understood that if the boundary region 600A is identified, the volume of the fluid 160 can be at least approximately determined based on the knowledge of the inner radius r602 of the vial and the height h601 of the boundary region above the inner bottom of the vial 115.

[0294] In some instances, the tilted vial 115 is imaged through the surface of the bottom 115B of the vial, which is typically circular and flat enough to allow the vial to be placed upright on the surface. Deviations from the ideal flatness of the bottom surface can affect image quality, including texture (e.g., raised or convex dots around the edges), slight concavity, indentations or raised markings (e.g., lettering, numbering, and / or logos) and / or manufacturing defects. It should be noted that despite these potential drawbacks when imaging through the contents, the bottom of the vial is typically not labeled, such as label 610.

[0295] Therefore, the small bottle is not like Figure 12A-12B It appears vertically as shown, but is tilted relative to the vertical at an angle α.

[0296] Also, a brief reference Figure 12C This schematically illustrates a side view cross-section of a fluid-containing vial 115 with a 90° tilt angle α, based on some examples of the subject matter currently disclosed. This has a height h601 ( Figure 12A-12B The effect of lowering the height to h″601B is due to the fluid 160 spreading into a larger containment area. Label 610 still obscures most of the side view (although it has been removed in the cross-sectional view).

[0297] Typically, the tilt angle of the vial in the image is chosen such that the boundary region 600A is positioned as a visible area in the detection image that passes through (or is intended to pass through) the vial. For example, in the example shown, it passes through the bottom 115B of the vial from an advantageous position of the imager 620 and is within the imager's field of view 621. Thus, in some instances, the measurement area on the vial surface forms the bottom or top of a cylinder or prism, but does not itself follow the rising wall of such a shape.

[0298] In some instances, the measurement area on the surface of the vial (outside of which the boundary area is imaged) does not form part of the main straight cylindrical or right prismatic shape of the vial. For example, the boundary area 600A can be partially seen through the top 605 of the vial, and this area (in the upright positioning of the vial 115) would be located above the more regular cylindrical portion of the vial 115.

[0299] Brief Reference Figure 9A It reproduces a photograph of a fluid-containing vial 115 held by a clamp 110 at an angle of approximately 90°, according to some examples of the subject matter currently disclosed. The presence of fluid inclusions 160A is automatically determined based on the presence and / or positioning of the boundary region 600A (considering...). Figure 8 ) and / or level (considering Figure 7 It is visible through the difference in refractive index between the fluid contents 160A and the gas in the rest of the filling vial 115.

[0300] Brief Reference Figure 9B It reproduces a photograph of a vial 115 containing solids held by a clamp 110 at an angle of approximately 90°, based on some examples of the subject matter currently disclosed. Based on the absence of boundary regions and / or image characteristics indicating the presence of solids 160B, it is automatically determined that no fluid inclusions are present.

[0301] Brief Reference Figure 9C It reproduces a photograph of a fluid-containing vial 115 held by a clamp 110 at an angle of approximately 90°, according to some examples of the subject matter currently disclosed. The presence of fluid inclusions 160A is automatically determined based on the presence and / or positioning of the boundary region 600A (considering...). Figure 8 ) and / or level (considering Figure 7 It is visible through the color difference (i.e., optical density at at least one wavelength) between the fluid contents 160A and the gas in the remaining portion of the vial 115.

[0302] Return boxes 705, 805: In instances using bottom-view images, the tilt angle is optionally any angle that deviates the vial from the vertical to a degree sufficient to make the boundary area of ​​interest make the desired contact with the bottom of the vial (visible through the bottom of the vial). This condition is preferably selected when the vial is filled with liquid as specified during the preparation of a pharmaceutical formulation, for example, to fill at least 20%, at least 30%, at least 50% (substantial filling), or another relative (or absolute) filling amount by volume.

[0303] The tilt angle can be, for example, about 90° (i.e., the vial is oriented sideways, such as...). Figure 12C and / or Figure 9A –9C is shown).

[0304] Alternatively or concurrently, a different tilt angle is used. In some instances, for example, a tilt angle of 75°–90° is used. In some instances, the tilt angle deviating from the vertical direction is at least 45°, at least 60°, or at least 75°. In some instances, a tilt angle that is at least partially reversed is used, i.e., a tilt angle greater than 90°. For example, a tilt angle of 90°–105° is used.

[0305] Optionally, images of the vial at multiple tilt angles are obtained, for example, to help ensure that at least one tilt angle displays the boundary region in a position suitable for measurement by image processing. The tilt angle is optionally selected based on the expected liquid volume in the vial and / or according to program presets.

[0306] Brief Reference Figure 11 The diagram schematically illustrates a side view cross-section of a fluid-containing vial 115 with varying tilt angles α, according to some examples of the subject matter currently disclosed. In position 801, the tilt angle is approximately 60°; in position 802, the tilt angle is approximately 90°. The diagram between the two shown positions represents the variation of height h from height 801A in position 801 to height 802A in position 802. Optionally, imaging may be performed at any one, two, or more positions within this range. Each of these positions should show the boundary region 600A intersecting with the bottom 115B of the vial.

[0307] Return boxes 705 and 805: Using an angled placement of the boundary region within the viewing area of ​​the vial offers potential advantages, for example, in situations where much of the vial wall may be obscured by the label and therefore unreliable and / or unusable for verifying the presence and / or volume of fluid contents.

[0308] In some instances, the tilt angle actually applied to the vial (i.e., for assessing the presence / amount of fluid contents) is known from the data separated from the image of the boundary layer. For example, the tilt angle is set by the operation of the drug preparation system and is known based on encoder measurements, gravity sensing, or another data source. Optionally, the tilt angle is determined by pre-arrangement: for example, a processing algorithm is designed assuming that the image it receives always corresponds to a vial held at a specific tilt angle, or otherwise ensures that the image corresponds to a pre-determined tilt angle.

[0309] Alternatively or, in some instances, the tilt angle is inferred and / or confirmed by the image itself, for example, based on the apparent eccentricity of the bottom of the circular vial due to image foreshadowing. A potential advantage of relying on inferring the tilt angle from the imaged shape of the vial is that this conveniently decouples the operation of the vial manipulation from the imaged observation of the vial, for example, to reduce the risk of data skew, and / or provides independent verification that the mechanical aspects of the operation are within the expected parameter range.

[0310] Brief Reference Figures 10A-10B It schematically represents a side view cross-section of a fluid-containing vial 115 with a slanted tilt angle α, according to some examples of the subject matter currently disclosed. Figure 10A ) and bottom view ( Figure 10B In the example shown, α is approximately 60°. Fluid 160 fills vial 115 to level h′601A. It should be noted that the angle results in… Figure 10B The view of the bottom 115B of the vial is selectively projected forward along the vertical axis. This eccentricity, along with the assumption that the bottom 115B of the vial is actually circular, allows the inference of the tilt angle based on measurements of the vertical and horizontal axes of the bottom 115B of the vial. Depending on the field of view setup used for imaging, the receding of the bottom 115B of the vial in the lower part of the image may also affect the geometry of the imaged image. This is also optionally taken into account.

[0311] Returning to the operations in boxes 705 and 805: In some instances, the contents of the tilted vial are in a positional equilibrium during imaging: that is, the vial does not move relative to the imager, does not accelerate (unless it is subject to gravity), and more specifically, the boundary region of interest remains in a stable position during image exposure. This has potential advantages for the accuracy and repeatability of measurement results.

[0312] However, a stable equilibrium is not necessarily required. For example, in cases where the vial itself is in a stable, non-accelerated position after a recent stop, the characteristics of this movement can be determined by measuring sufficient images to account for residual sloshing of a certain amount of fluid contents (and especially movement of the boundary region on the bottom view of the vial). For example, the center point of the range can be determined; and / or the settling state to which the movement of the vial contents tends can be determined. Conversely, the absence of such movement at the boundary is optionally used as evidence of a complete lack of fluid.

[0313] In another example, the vial can be dynamically rotated by a series of angles α (e.g., around an internal point of the vial), during which images are acquired with different exposure cycles. The rotation rate is optionally low enough that the non-equilibrium aspect of the condition can be neglected in the calculation.

[0314] Alternatively (refer to boxes 705, 805), dynamic effects can be fully or partially compensated for during computation. Potential advantages of imaging during the dynamic movement of the vial include faster measurement processes and / or integration of the measurement process into other operations performed by the drug preparation system, where vial positioning potentially suitable for measurement may occur incidentally and / or when it does not significantly impact program time as it might be if the volume measurement stage were performed separately.

[0315] In some instances, the vial is accelerated during image exposure. For example, it is linearly accelerated and / or moves along an arc centered on a point outside the vial (e.g., circular motion, such as in a centrifuge). This can result in a displacement of the boundary region perpendicular to the direction of gravity acting alone, potentially even accompanied by the vial itself remaining vertically oriented. The camera used for imaging is optionally synchronized with the motion of the vial in any suitable manner, for example, translated to follow the motion of the vial, or fixed to a manipulator that also moves the vial.

[0316] In some instances (e.g., as about Figure 12C As mentioned, images providing a view of the top of the vial are optionally used to verify the presence of fluid and / or accommodating fluid volume requirements. Optionally, this can be used instead of a bottom-view image. Specifically, a bottom side view has a potential advantage because the shape of the bottom of the vial is generally relatively flat and regular (circular) compared to the typically curved (e.g., elliptical) surface of the top of the vial, which may also include interruptions including the neck and cap. Especially at lower tilt angles, more fluid contents can be retained in the cylindrical region of the vial, potentially reducing the number of assumptions required to account for the internal shape of the vial in volume estimation. Similarly, while clamping the bottom and / or sidewalls of the vial during implementation is not excluded, the top of the vial may be obscured when the vial is held in place for operation.

[0317] However, for example, once the boundary region rises above the level of the obscuring label, a top side view (if available) can provide information suitable for determining the presence of fluid. A quantitative volume estimate can be obtained where the vial shape is modeled and / or can be adequately modeled. Similarly, a side view of the vial can optionally be used to estimate fluid contents (optionally exclusively), provided that the boundary region (e.g., the area where the fluid meniscus contacts the vial wall) has been moved by tilting to a position where it can be observed. Furthermore, any of the views can optionally be combined. Combinations of imaged views can potentially provide information that helps to determine the fluid volume more accurately, for example, as described with respect to box 710.

[0318] Optionally, in box 805 and Figure 8 In this method, the vial is not tilted, but rather viewed from an angle intended to bring any potential solid contents of the vial to an unobstructed area of ​​the vial wall. For example, the vial is held vertically and viewed from the bottom surface. Potential advantages of tilting the vial in any way include that this causes the powder inside the vial to move (indicating the presence of solid material), and / or that this also allows confirmation of the presence of boundary areas.

[0319] Confirmation of fluid volume indication

[0320] In some instances, in box 710 ( Figure 7 ) and / or 810 ( Figure 8 At point 705, the fluid volume indication is determined based on one or more images obtained and / or accessed at points 705 and 805.

[0321] In this document, the term "fluid volume indication" refers to an indication of how much fluid is in a vial, whether absolute (e.g., expressed in volume units proportional to milliliters) or relative to a fluid volume requirement specified in another way (e.g., a reference volume). In box 715 ( Figure 7 In some instances, the fluid volume indication matches the requirements.

[0322] Figure 7 The two boxes are introduced together because the definition of fluid volume indication is related to the implementation that matches the operational requirements. Specifically, the two types of implementation schemes can be characterized as "relative volume" implementation schemes and "absolute volume" implementation schemes.

[0323] Relative volume implementation scheme

[0324] In some instances of relative volume implementations, the fluid volume indicates the location of a boundary region relative to a visible surface area of ​​a vial. For example, it can be predetermined that, for a certain tilt angle and vial type (i.e., a specific internal geometry of the vial), a target fluid content will achieve a specific location of the boundary region relative to a vial surface marker (e.g., the outer periphery of the circular shape at the bottom of the vial). The bottom of the vial and / or other vial surface markers can be identified using, for example, image segmentation techniques. In some instances, the location of the boundary region is identified relative to another reference, such as coordinate axes established by the mechanical arrangement of the drug preparation system itself (e.g., a vertical axis with a known relative positioning of a gripper holding the vial and a camera imaging the vial).

[0325] The boundary region itself can be identified, for example, as a linear (narrow rectangular) region extending laterally (or as intended) through the bottom of the vial, characterized, for example, by having a distinct contrast gradient (for a line), either through two such contrast gradients (for a bright or dark line), or optionally selected and implemented using an edge detector or other image processing algorithm, depending on the specific lighting and imaging conditions used. Optionally, the boundary region detector is selected to be stable against the average level of viewing distortion imposed by relatively small irregularities in the vial wall portion viewed through it.

[0326] In cases where the image of the boundary region is not typically linear (e.g., when the boundary region is expected to be imaged at a location where it contacts the curved top or side of a vial), the image processing algorithm optionally models the boundary region as a curve that is appropriately parameterized. For example, the curve can be parameterized to fit the intersection of a sloping surface projected onto the camera's imaging plane with a cylindrical and / or elliptical wall portion. In some instances, the image itself is geometrically transformed before the detection algorithm is applied to normalize the shape of the imaged boundary region (e.g., to make it more linear).

[0327] The target location of the boundary region may be optionally defined as, for example, a straight line or curve contained in (or beyond) the boundary region, an area where the boundary regions intersect, or otherwise defined.

[0328] Even if it is not necessary to access data indicating the actual amount of the target fluid content (e.g., in milliliters), the image processing algorithm can determine that the geometrically specified criteria are met based on this amount.

[0329] Therefore, as part of the operation of box 715, it can convert the fluid volume indication into a through / non-through indication. Optionally, other categories (e.g., "empty" or "too full") can be added to such determination. Optionally, the amount of deviation relative to the expected value can be provided as an indication, for example, as a positioning deviation. Optionally, such deviation can be statistically reported, for example, as a multiple of the standard deviation or other statistical measure. Optionally, the positioning deviation can be calibrated in other ways, for example, expressed as a percentage and / or in absolute volume units (e.g., milliliters).

[0330] In some instances, calibrations are coarsely calculated to indicate overfilling or underfilling; for example, deviations in millimeters relative to the target location of the boundary region are converted to milliliters via a linear scale, although this conversion may become increasingly inaccurate as the deviation distance from the boundary region increases. It is understood that, according to this approach, the types and number of corrections applied to relative volume implementations can increase until it actually becomes an instance of the absolute volume implementation category, further details of which will be described below.

[0331] The acceptability of evaluating fluid volumes through purely relative and / or coarse calibration can vary depending on the type of pharmaceutical preparation being mixed, regulatory requirements, reagent values, and / or other parameters. Therefore, the ability to adjust calibration procedures and / or the amount of prior knowledge used to meet such requirements is a potential advantage.

[0332] Optionally, as part of the normal operation of the drug preparation system, a reference for evaluating fluid volume indications can be determined, and this is one of the potential advantages of a relative volume implementation. For example, the system may operate for a period of time, processing several vials during which a cumulative fluid volume indication is accumulated for each vial. Assuming that errors during this time period are small, nonexistent, negligible, and / or excluded, these results can be used (e.g., statistically) to: assess the amount of fluid contents in the vials imaged during this time period, and to set criteria that can be used to specifically evaluate fluid volume indications in other vials. In particular, during future vial processing, even if there is optionally no target in milliliters and / or a direct representation of the current fluid volume contained in the vial, an alert and / or mitigation action can be immediately triggered when a relative difference in fluid contents is sensed.

[0333] Absolute volume implementation scheme

[0334] Turning now to the absolute volume implementation categories of boxes 710, 715: optionally specifying the amount of the target liquid content as a volume requirement proportional to milliliters (e.g., a specific volume, a specific volume with an acceptable range of error, and / or a volume range). In the following description, it is assumed that the calibration between image pixels and spatial size is known and / or can be calculated based on system dimensions, reference markers, and / or other suitable constraints.

[0335] As described for the relative volume implementation, the determination of the fluid volume indication can begin by finding its location relative to the visible surface area in an image of the boundary region. To convert this to a milliliter-scale volume, the operation of box 710 optionally uses any suitable combination of modeled and measured parameters that (at least approximately) describe the internal geometry of the vial. Depending on the requirements, these parameters can more or less accurately approximate the actual internal geometry of the vial.

[0336] A simple case applies, for example, when the fluid volume is relatively low compared to the height of the roughly straight cylindrical portion of the vial. The internal volume of the vial can be simply modeled as a straight cylinder with a circular cross-section extending infinitely upwards from the bottom.

[0337] The circular cross-section is optionally determined based on an image of the bottom of the vial, for example, assuming the diameter to be used is approximately equal to the maximum horizontal width of the vial (as imaged), minus twice the “reasonable” vial wall thickness (e.g., 1.5 mm, or another value, for example, also estimated from the image). Optionally, for example, based on the known vial model used, any or all vial geometry values ​​are provided separately from the image.

[0338] For a relatively small tilt angle (i.e., as long as the “upper” extent of the boundary region does not extend beyond the cylindrical region of the vial), the amount of fluid contained can be calculated as the volume of the model cylinder located below the plane extending through and parallel to the boundary region.

[0339] When low volume / low tilt conditions are not applied, the vial model can be enhanced, for example, by assuming a maximum height of the vial, a curved (e.g., elliptical) upper portion, and / or a cylindrical neck (as the case may be). Optionally, parameters of any of these are measured via imaging, although direct measurement of the vial wall thickness may be prone to error due to optical distortion. Even in this case, corrections to the wall thickness are optionally determined based on empirical measurements and / or a physical model containing reasonable assumptions about the refractive index of the vial wall material. Optionally, parameters of any of these are provided separately from the image, for example, as parameters describing a known vial model. The model can be further extended as needed, for example, to include corrections for meniscus shape and / or container irregularities (such as the concavity of the vial bottom). With sufficiently complete modeling, either in this or other ways, any tilt angle of the boundary region and the imaged location can be correlated with a specific fluid volume expressed in milliliters. Optionally, the description of the model is limited to parameters that are meaningful within a specific tilt angle range.

[0340] Furthermore, it is noted that when there are free (unknown) parameters in the model (e.g., wall thickness), a potential source of information that can help assign values ​​to these parameters can be obtained by measuring how the location of the boundary region changes with the tilt angle. For example, given the external dimensions of the vial (optionally determined directly from imaging), an unknown constant vial wall thickness, and the image measurement dependence of the boundary region location on the tilt angle (e.g., for at least two tilt angles), the wall thickness can be fixed to a certain value (or a constrained range of values) such that the calculated volume remains constant with changes in the tilt angle.

[0341] Brief Reference Figure 13 This is a schematic diagram of the geometric parameters of a vial based on some examples of this disclosure. Regarding Figure 12AThe bottom radius r602 of the internal volume geometry of vial 115 is described. In some instances, one or more additional geometric parameters of the vial are described and / or considered when calculating the volume of the fluid contents. For example, in some instances, the estimated bottom radius r602 is obtained by subtracting the vial wall thickness w ~ 1 907 from the outer radius of the vial. Optionally, the internal height of the cylindrical portion of vial 115 is calculated by subtracting the estimated, known, or image-measured bottom thickness w ~ 2 906 of the vial from the total (external) height measured from the image of the cylindrical portion. In some instances, parameters of other parts of the internal geometry of vial 115 are estimated, such as the height radius r ~ t903 of the top portion of vial 115. In some instances, the volume calculation considers a correction function ε ~ 2(r,θ,α)904 for distortion caused by the fluid meniscus shape of the boundary region, where θ is a parameter of the angle of the vial wall about a plane parallel to the boundary region that contacts the vial wall, and α is the tilt angle. In some instances, the correction takes into account the deviation of the bottom inner surface of vial 115 from the planar shape ε~2(r,θ)906, where θ is a parameter of the angle around the vial wall.

[0342] Response to fluid volume indication

[0343] At box 720, in some instances, and based on the results of matching the fluid volume indication with the requirements at box 715, it is determined whether the fluid volume indication meets expectations (requirements). If yes, then at box 730, processing continues using the contents of the now-validated vial. Otherwise, at box 725, an anomaly has occurred.

[0344] The anomaly in box 725 may optionally be functionally related to one or more consequences associated with the operation of the drug preparation system. For example, the anomaly may trigger any one or more of the following:

[0345] ● User alarms, which signal to the device operator that requires their attention (e.g., by visual, tactile, auditory or other signal transmission; optionally using the system’s own hardware and / or remotely connected hardware that communicates with it wirelessly).

[0346] ● An internal fault that causes the system to stop operating (or at least bypass the suspected faulty function) until the fault condition is cleared.

[0347] ● Self-check, for example, to determine if an unexpected fluid volume indication can be traced back to a specific condition.

[0348] ● Adjustments, such as correcting the volume in the vial by injecting more fluid or removing fluid, to place the vial in a waste area or special storage area, and / or to use a replacement vial and retry the faulty part of the drug mixing procedure.

[0349] It should be noted that system self-checks and / or adjustments are optional operations that the system can perform on its own, but they are usually not performed when system resources are sufficiently intensive, until an exception such as box 725 occurs. This makes Figure 7 This method of operation becomes a gating method for other operations, allowing the system to self-recover and / or potentially reducing the direct monitoring requirements of some other system components. For example, when the rated capacity of a brine storage bag is reached, it may be in a partially uncertain state, unsure how much more brine can be drawn from it. Rather than replacing the storage bag prematurely, it is better to use it until it reaches its limit. Figure 7 The operation clearly identifies a fluid shortage. At this point, the system can continue with the specified operations to correct (and re-verify as appropriate) the state of the empty brine reservoir and the state of the underfilled vials.

[0350] Overview

[0351] As used herein, the term “about” with respect to quantity or value means “within ±10% of”.

[0352] The terms “comprises,” “comprising,” “includes,” “including,” “having,” and their enumerated variants mean “including but not limited to.”

[0353] The term "composed of" means "including and limited to".

[0354] The term "consistently made up of" means that a composition, method, or structure may include other components, steps, and / or portions, provided that the additional components, steps, and / or portions do not substantially alter the fundamental and novel characteristics of the claimed composition, method, or structure.

[0355] As used herein, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” include plural indicators. For example, the terms “compound” or “at least one compound” can include a variety of compounds, including mixtures thereof.

[0356] As used herein, the terms “example” and “exemplary” mean “serving as an example, instance, or illustration.” Any embodiment described as “example” or “exemplary” is not necessarily to be construed as superior to or superseding other embodiments and / or as excluding the incorporation of features of other embodiments.

[0357] As used herein, the term “optionally” means “provided in some embodiments and not in others.” Any specific embodiment of this disclosure may include a number of “optional” features, except where such features conflict to some extent.

[0358] As used herein, the term "method" refers to the manner, means, techniques, and procedures used to accomplish a given task, including but not limited to those known to practitioners in the fields of chemistry, pharmacology, biology, biochemistry, and medicine, or those that are readily developed based on known manner, means, techniques, and procedures.

[0359] As used herein, the term “treatment” includes eliminating, substantially inhibiting, slowing or reversing the progression of a condition, substantially improving the clinical or aesthetic symptoms of a condition, or substantially preventing the occurrence of the clinical or aesthetic symptoms of a condition.

[0360] Throughout this application, embodiments may be presented with reference to a range format. It should be understood that the use of a range format is for convenience and brevity only and should not be construed as a rigid limitation on the scope of this disclosure. Therefore, a range description should be considered as specifically disclosing all possible subranges and individual numerical values ​​within those ranges. For example, a description of a range such as “1 to 6” should be considered as specifically disclosing subranges such as “1 to 3”, “1 to 4”, “1 to 5”, “2 to 4”, “2 to 6”, “3 to 6”, etc., and individual numbers within those ranges, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range.

[0361] Whenever a range of numbers is indicated herein (e.g., “10-15”, “10 to 15”, or any pair of numbers connected by such range indications), it means any number (fraction or integer) included within the indicated range boundaries, including the range boundaries, unless the context explicitly states otherwise. The phrases “range” / “variable range” / “ranges” between the first and second indicating numbers, and “to,” “at most,” “until,” or “through” (or another such range indication term) for the first indicating number and “range” / “variable range” / “ranges” for the second indicating number, are used interchangeably herein and mean including the first and second indicating numbers and all fractions and integers in between.

[0362] Although the description of this disclosure has been provided in conjunction with specific embodiments, it will be apparent to those skilled in the art that many variations, modifications, and alterations will be readily apparent. Therefore, it is intended to cover all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0363] It should be understood that, for clarity, certain features described in the context of individual embodiments in this disclosure may also be provided in combination in a single embodiment. Conversely, for simplicity, different features described in the context of a single embodiment may also be provided individually or in any suitable sub-combination or, where appropriate, in any other described embodiment of this disclosure. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments unless the embodiments would not function without those elements.

[0364] The applicant intends that all publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety, as if each individual publication, patent, or patent application were specifically and separately attributed and incorporated herein by reference. Furthermore, any reference or identification of any reference in this application should not be construed as an admission that such reference is available as prior art as disclosed herein. The use of section headings should not be interpreted as a necessary limitation. Additionally, any priority documents of this application are hereby incorporated herein by reference in their entirety.

Claims

1. A method for evaluating the contents of a vial, the contents comprising a pharmaceutical ingredient, wherein the method comprises: Manipulate the vial to change the tilt angle of the vial relative to the boundary region of the contents of the vial; At least one image of the vial is obtained during the time period during which the tilt angle is changed; The location of the boundary region in the at least one image is calculated by performing image processing using a processing circuit system; The positioning of the boundary region is compared with a target standard, wherein the target standard takes into account the displacement of the positioning of the boundary region due to the tilt angle; and Based on the results of the comparison, the use or rejection of the contents of the vial in the automated preparation of the pharmaceutical formulation is automatically determined.

2. The method of claim 1, wherein the manipulation changes the tilt angle such that the boundary region in the at least one image of the vial extends along the bottom surface of the vial.

3. The method of claim 2, wherein the target criterion comprises a target location extending along the bottom surface, and the comparison determines the position of the boundary region relative to the target location.

4. The method according to any one of claims 1 to 3, wherein the label obstructs the view of the contents through the obstructed side region of the vial, and the change of the tilt angle causes the boundary region to move from the obstructed side region of the vial to an unobstructed surface region, the boundary region being visible through the unobstructed surface region.

5. The method of claim 4, wherein the target criterion comprises a target location along the unobstructed surface region of the vial, and the comparison determines the position of the boundary region relative to the target location.

6. The method of claim 5, wherein the target positioning extends along a portion of the surface of the vial, and the portion is positioned above or below the label when the vial is upright.

7. The method according to any one of claims 1 to 6, wherein during the time period in which the tilt angle is changed, the height of the inclusion is a non-linear function of the volume of the inclusion.

8. The method according to any one of claims 1 to 7, wherein the manipulation comprises rotating the vial while the boundary region remains horizontal.

9. The method according to any one of claims 1 to 7, wherein the manipulation comprises moving the vial, the movement changing the angle of the boundary region away from the horizontal plane.

10. The method according to any one of claims 1 to 9, wherein at least one of the comparison and the automatic determination comprises calculating the volume of the contents of the vial, and the automatic determination selects to use or reject the contents of the vial based on how close the volume is to a target volume.

11. The method according to any one of claims 1 to 9, wherein the target criterion defines a target location, the result of the comparison includes the distance between the location of the boundary region and the target location, and the determination to select or reject the contents of the vial based on the distance.

12. The method according to any one of claims 1 to 11, wherein the boundary region indicates an optical property difference between the lower material phase of the contents of the vial and the material above the lower material phase.

13. The method of claim 12, wherein the optical property is at least one of refractive index, light absorption coefficient, and turbidity.

14. The method according to any one of claims 1 to 13, wherein the at least one image comprises a plurality of images obtained at different tilt angles of the vial.

15. The method of claim 14, wherein the calculation and the comparison are performed for each of the plurality of images.

16. The method of claim 14, wherein the automatic determination comprises parameters for determining the geometry of the vial using a localization representation of each of the plurality of images.

17. The method according to any one of claims 1 to 16, wherein at least one image is obtained when the tilt angle changes by at least 45° from the upright and static positioning of the vial.

18. The method of claim 17, wherein at least one image is obtained when the vial is tilted to within 15° relative to the horizontal plane.

19. The method according to any one of claims 1 to 17, wherein the contents of the vial comprise a fluid.

20. The method of any one of claims 1 to 19, wherein the vial comprises a generally cylindrical lower region, an inwardly curved top region leading to a capped neck, and a circular bottom surface of the lower region; wherein the tilt angle adjusts a portion of the boundary region such that the boundary region extends along the bottom surface.

21. The method of claim 20, wherein the at least one image images the boundary region through the optical irregularities of the bottom surface.

22. The method of any one of claims 1 to 21, wherein determining the use of the contents of the vial comprises determining to adjust the amount of fluid in the vial to correct the difference between the target location and the location representation of the boundary region.

23. The method according to any one of claims 1 to 22, comprising manipulating the vial to a new position according to the determined use.

24. The method of claim 23, wherein the new positioning returns the vial to an upright position.

25. A method for evaluating the fluid contents of a vial, the fluid contents comprising a pharmaceutical ingredient, the method comprising: Receive at least one image of the vial, wherein the at least one image has an image of the vial when the vial is tilted to position a portion of the boundary layer of the fluid contents below a label portion on the surface of the vial; Using computerized image processing, the location of the boundary layer extending along the bottom surface of the vial is compared with the target location corresponding to the target fluid volume in the vial and the tilt angle of the vial. as well as Based on the results of the comparison, the use or rejection of the contents of the vial in the automated preparation of the pharmaceutical formulation is automatically determined.

26. The method of claim 19, wherein the fluid inclusion comprises a solvent in which the pharmaceutical ingredient is dissolved.

27. The method according to any one of claims 19 to 26, wherein the comparison comprises determining the liquid volume of the inclusion and comparing the determined volume of the inclusion with a target liquid volume.

28. The method of claim 27, wherein determining the volume comprises measuring at least one parameter of the geometry of the vial using the at least one image of the vial.

29. A method for evaluating the contents of a vial, the contents comprising a pharmaceutical ingredient, wherein the method comprises: Manipulate the vial to change its tilt angle; At least one image of the vial is obtained during the time period during which the tilt angle is changed; The presence or absence of a fluid boundary region in the at least one image is detected by image processing using a processing circuit system; and Based on the results of the detection, the use or rejection of the contents of the vial in the automated preparation of the pharmaceutical formulation is automatically determined.

30. The method of claim 29, wherein when the contents of the vial comprise a target volume of fluid, the tilt angle is selected to position the fluid boundary region to extend along a surface region of the vial, the surface region being above or below the label of the vial when the vial is upright.

31. The method of claim 30, wherein the surface region is located below the label of the vial and extends along the bottom surface of the vial.

32. A system for evaluating vial contents containing a pharmaceutical ingredient, the system comprising: a processing circuit system and a memory, wherein the memory includes instructions that command the processing circuit system to: Control the manipulator to change the tilt angle of the vial relative to the upper boundary layer of the vial contents; Access at least one image of the vial obtained during the time period in which the tilt angle is changed; Calculate the localization representation of the boundary region of the contents of the vial in the at least one image; The positioning representation of the boundary region is compared with the target positioning, wherein the target positioning takes into account the displacement of the boundary region due to the tilt angle; as well as Based on the results of the comparison, the system is instructed to use or reject the vial contents in the automated preparation of pharmaceutical formulations.

33. The system of claim 32, comprising the manipulator.

34. The system of claim 32, comprising an imager; and wherein the instructions command the processing circuitry system to control the imager to obtain the at least one image of the vial.

35. A system for evaluating vial contents, the vial contents containing a pharmaceutical ingredient, the system comprising: A manipulator configured to hold the vial at a variably selectable tilt angle relative to the upright orientation of the vial; An imager, positioned relative to the manipulator, for imaging the vial while it is held at an angle of inclination relative to the upright orientation, including viewing the bottom surface of the vial; A processing circuit system and a memory, the memory storing instructions, wherein the instructions command the processing circuit system to: Control the manipulator to change the tilt angle of the vial relative to the upright orientation; The imager is controlled to acquire at least one image of the vial during the time period during which the tilt angle is changed; Calculate the localization representation of the boundary region of the contents of the vial in the at least one image; The positioning representation of the boundary region is compared with the target positioning, wherein the target positioning takes into account the displacement of the boundary region due to the tilt angle; as well as Based on the results of the comparison, the system is instructed to use or reject the vial contents in the automated preparation of pharmaceutical formulations.

36. A method for controlling the dissolution of a solute in a vial into a solvent, said vial being held by a vial holder in a pharmaceutical preparation apparatus, the method comprising: The vial holder is agitated by a stirrer operably connected to the vial holder, thereby agitating the solute and the solvent in the vial held by the vial holder; The processing circuit system stores at least one image of the contents of the vial captured after the stirring begins; The characteristics of the contents of the vial are evaluated by image processing using the aforementioned processing circuit system; The evaluated characteristics of the contents of the vial are compared with the target characteristics; as well as Based on the results of the comparison, the processing circuit system adjusts the stirring performed by the stirrer.

37. The method of claim 36, wherein the adjustment includes stopping stirring.

38. The method of claim 36, wherein the adjustment comprises restarting the stirring.

39. The method of claim 36, wherein the adjustment comprises modifying at least one parameter of the stirring motion.

40. The method according to any one of claims 36 to 39, wherein the solute is a solid.

41. The method according to any one of claims 36 to 40, wherein the solvent is a fluid.

42. The method of claim 36, wherein the evaluated characteristic assesses the solute's dissolution in the solvent, the target characteristic of the vial contents includes a dissolution appearance standard, and the adjustment includes stopping the operation of the stirrer or extending the operating time of the stirrer.

43. The method of claim 42, wherein the adjustment includes stopping the operation of the stirrer if the target dissolution appearance standard is still not met; and issuing an alarm.

44. The method of claim 42, wherein the adjustment includes extending the operation of the stirrer if the target dissolution appearance standard is still not met.

45. The method of claim 42, wherein the dissolution appearance criterion comprises a measure of at least one of the following: The transparency of the solvent, The color of the solvent, and The clarity of the solvent.

46. ​​The method of claim 45, wherein the dissolution appearance criterion comprises a measure of the color of the solvent selected according to the type of the solute.

47. The method of claim 36, wherein the evaluated characteristics assess the clumping of the solute, the target characteristics of the solvent in the vial include a clumping appearance standard, and the adjustment includes modifying a parameter governing the movement mode of the stirrer.

48. The method of claim 47, wherein the movement mode is adjusted in at least one of the following: amplitude, Acceleration, The rotation of the vial, and The geometry of the path along which the vial moves.

49. The method of claim 36, wherein the evaluated characteristic assesses the presence of foreign particles in the solvent, the target characteristic of the vial contents includes a foreign particle presence criterion, and the adjustment includes stopping stirring; and the processing circuitry also issues an alarm based on the result of the comparison.

50. The method of claim 36, wherein the evaluated characteristic assesses the presence of foreign particles in the solvent, the target characteristic of the vial contents includes a foreign particle presence criterion, and the adjustment includes stopping stirring; and the processing circuitry also issues an alarm based on the result of the comparison.

51. The method of claim 36, wherein the evaluated characteristics assess the volume of the vial contents, the target characteristics of the solvent in the vial include the expected amount of the vial contents, and the adjustment includes stopping stirring; and the processing circuitry also issues an alarm based on the result of the comparison.

52. The method according to any one of claims 36 to 51, wherein at least one of evaluating the feature and the comparison comprises classifying the at least one image according to a pre-trained machine learning model.

53. The method of claim 36, wherein the adjustment comprises adjusting the stirring of at least the second vial based on the result of the comparison.

54. The method of claim 53, wherein the adjustment is made based on the results of the respective plurality of comparisons.

55. The method of claim 36, wherein the at least one image of the contents of the vial is imaged from a position below the vial.

56. A system for controlling the dissolution of a solute in a vial into a solvent, the vial being held by a vial holder in a pharmaceutical preparation apparatus, the system comprising a processing circuit system configured to: A stirrer operably connected to the vial holder is controlled to agitate the solute and solvent in the vial held by the vial holder. Access at least one image of the contents of the vial captured after the stirring begins; Evaluate the properties of the contents of the vial; The evaluated characteristics are compared with the target characteristics of the solvent in the vial; and Adjust the agitator's stirring based on the results of the comparison.

57. The system of claim 56, wherein the evaluated characteristics assess the solute's dissolution in the solvent, the target characteristics of the solvent in the vial include a dissolution appearance standard, and the processing circuitry adjusts the stirring by stopping the operation of the stirrer or extending the operating time of the stirrer.

58. The system of claim 56, wherein the evaluated characteristics assess the agglomeration of the solute, the target characteristics of the solvent in the vial include agglomeration appearance criteria, and the processing circuitry adjusts the stirring by modifying parameters governing the movement mode of the stirrer.

59. The system of claim 56, wherein the evaluated characteristics assess the presence of foreign particles in the solvent, the target characteristics of the solvent in the vial include a foreign particle presence criterion, and the processing circuitry adjusts stirring by stopping stirring; and the processing circuitry also issues an alarm based on the result of the comparison.

60. The system of claim 56, wherein the evaluated characteristics assess the presence of foreign particles in the solvent, the target characteristics of the solvent in the vial include a foreign particle presence criterion, and the processing circuitry adjusts stirring by stopping stirring; and the processing circuitry also issues an alarm based on the result of the comparison.

61. The system of claim 56, wherein the evaluated characteristics assess the volume of solvent in the vial, the target characteristics of the solvent in the vial include the expected amount of solvent in the vial, and the processing circuitry adjusts stirring by stopping stirring; and also issues an alarm based on the result of the comparison.

Images