Patent Application
20090046535
The present invention relates generally to systems and methods for mixing powders and other solid materials, and more particularly to such systems and methods adapted to prepare a plurality of relatively small mixed samples for high-throughput screening.
Automated powder dispensing systems are used in many laboratory and commercial applications. In the pharmaceutical industry, for example, such systems are used to fill capsules with small but accurate doses of drugs, typically using gravimetric or volumetric techniques. These systems suffer various disadvantages, including an inability to handle a wide range of particulate materials at optimal speeds and accuracies, particularly when very small doses are involved (e.g., 20 mg or less). Further, the operation of conventional systems tends to crush the particles being handled.
Automated powder handling systems also have application to high throughput research. For example, they can be used for high throughput catalysis research where catalyst candidates are evaluated using various screening techniques known in the art. See, for example, U.S. Pat. No. 5,985,356, U.S. Pat. No. 6,004,617, U.S. Pat. No. 6,030,917, U.S. Pat. No. 5,959,297, U.S. Pat. No. 6,149,882, U.S. Pat. No. 6,087,181, U.S. Pat. No. 6,063,633, U.S. Pat. No. 6,175,409, and International (PCT) Patent Publications WO 00/09255, WO 00/17413, WO 00/51720, WO 00/14529, each of which is hereby incorporated by reference in its entirety for all purposes.
The efficiency of a high throughput discovery program is, in general, limited by rate-limiting steps of the overall process work flow. One such rate-limiting step has been the mechanical pretreatment and handling of catalyst candidates after synthesis but before screening. U.S. Pat. No. 6,755,364, which is hereby incorporated herein by reference in its entirety for all purposes, is directed to more efficient protocols and systems for effecting the mechanical treatment of materials, and especially, mechanical treatment of catalysis materials such as heterogeneous catalysts and related materials. The disclosed protocols provide an efficient way to prepare catalysis materials having a controlled particle size for optimal screening. The circumstances are similar in the pharmaceutical industry. For example, processes used to screen one or more excipients (i.e., diluents, pH modifiers, viscosity modifiers, stabilizers, flavorings, colorings, fillers and combinations thereof) for suitability for use with one or more active pharmaceutical ingredients can involve preparation and handling of powdered samples. Commonly assigned U.S. Patent Publication No. 2004/0219602, which is hereby incorporated by reference in its entirety for all purposes, describes forced degradation testing of excipients, including a description of analytic methods for using high throughput techniques to screen powdered excipients. Similar methods can be used to screen the compatibility of one powdered active ingredient with one or more other powdered active ingredients. Likewise, high throughput techniques can be applied to the creation and testing of various powdered polymorphs of drug candidates, such as is described in commonly assigned PCT Publication No. WO 03/014732, hereby incorporated by reference in its entirety for all purposes.
In some cases two or more different powders, such as an active ingredient and one or more excipients, are mixed together for further analysis. Many powder handling systems are based on the premise that any powdered ingredients in a sample will be dissolved in a solution, thereby obviating the need to mix powdered ingredients in their powdered form. But some research requires the powders to be mixed while in their powdered form. For example, a powdered mixture may be formed into a tablet for pharmaceutical testing. It may also be desirable to conduct various spectroscopic, X-ray, or other solid-phase analyses on powdered mixtures. Techniques for mixing powders are disclosed in U.S. Pat. No. 7,134,459, hereby incorporated by reference in its entirety for all purposes.
A stirrer, such as the end of a pipette, a stirring bar, or a milling ball can be used to mix powders. Unfortunately, removal of the stirrer after mixing can alter the sample composition because one powder may have more or less affinity for the stirrer than other powders in the sample. Consequently, removal of the stirrer risks disproportionate removal of one or more powders in a residue on the stirrer. When the sample size is small, as is typically the case in combinatorial chemistry, the problem is exacerbated because disproportionate removal of relatively smaller amounts of powder significantly alters the overall sample composition. Thus, it is common practice to leave at least the portion of the stirrer that contacts the powder in the sample to avoid removal of any residue. For example, the tip of a pipette can be broken off and left in the sample container. Likewise, stirring bars and milling balls are often left in the sample after mixing. Not only does this consume the stirrer, but there is also a chance that the continuing presence of the stirrer could affect the sample analysis or limit the types of analyses that can be performed. Furthermore, if mixed powder samples are to be pressed into tablets for ingestion (e.g., in a pharmaceutical trial), it would be preferable to avoid including foreign objects like milling balls and pipette tips in the tablets.
Similar rate limiting steps and/or the need to mix powders can arise whenever a process requires preparation and handling of powdered materials. This can be the case during synthesis or screening of pharmaceuticals and catalysts (as already mentioned) as well as agricultural chemicals, pigments, and flavorings to name just a few of the other applications for powder handling systems.
The invention includes methods and apparatus implementing techniques for mixing solid materials. In some embodiments, one or more fluids are also added to the materials.
In general, in one aspect, the invention includes an apparatus for mixing one or more solid materials. The apparatus includes a powder mixing device mounted above a platform for holding one or more sample vessels, a transport system providing for relative motion of the powder mixing device and the platform and for introduction of a second end of a cannula into the one or more sample vessels, and a fluid delivery system for delivering a fluid to a lumen at a first end of the cannula. The powder mixing device includes a cannula and an actuator for vibrating the cannula.
Particular implementations can include one or more of the following features. The transport system can include a robotic arm holding the powder mixing device. The robotic arm can be operable to move the powder mixing device relative to the platform. The fluid delivery system can include a liquid pump fluidically coupled to the lumen by means of a fluid line extending from the liquid pump to the lumen at the first end of the cannula. The apparatus can include a control device operable to control the operation of the powder mixing device, the transport system and the fluid delivery system. The apparatus can include a powder dispensing device operable to dispense one or more powders into the one or more sample vessels on the platform. The apparatus can include a sample block mounted on the platform, the sample block being configured to receive the one or more sample vessels. The apparatus can include a temperature control system for controlling a temperature of the one or more sample vessels on the platform during operation of the powder mixing device. The transport system can include a detection system for detecting liquid and/or powder levels in the one or more sample vessels. The powder mixing device can include a plurality of cannulae mounted above the platform for simultaneously mixing powder samples in a plurality of sample vessels held on the platform.
In general, in another aspect, the invention provides a method for mixing one or more solid materials in a sample vessel. The method includes, introducing a cannula into the sample vessel, vibrating the cannula to mix the powder sample, and introducing a fluid into the powder sample through an outlet at a second end of the cannula during the vibrating. The cannula has a first end, a second end, and a lumen extending generally from the first end to the second end. The cannula is introduced into the sample vessel such that the second end extends into the powder sample.
Particular implementations can include one or more of the following features. The powder sample can include one or more powders dispensed into the sample vessel by means of a powder dispensing hopper mounted on a robotic arm above the platform. The fluid can be introduced by pumping a liquid through the lumen to the outlet. Vibrating the cannula can include exciting the cannula to a predetermined vibration to mix the powder sample. Introducing the cannula can include positioning the cannula over the sample vessel using a robotic arm. The method can include, after the vibrating and the introducing a fluid, removing the cannula from the sample vessel and positioning the cannula over a second sample vessel holding a second powder sample, lowering the cannula into the second sample vessel, and repeating the vibrating and the introducing a fluid for a second powder sample in the second sample vessel. The method can include heating or cooling the sample vessel during the vibrating and the introducing of a fluid. The introducing a cannula, vibrating the cannula, and introducing a fluid can be performed in parallel (e.g., during overlapping times) for a plurality of powder samples in a plurality of sample vessels.
The invention can be implemented to realize one or more of the following advantages, alone or in the various possible combinations. The apparatus and methods described herein are capable of efficiently mixing small quantities of powder swiftly and accurately. Powder mixing is accomplished without the use of a stir bar or other object that is left behind in the mixture, which facilitates the use of the mixture in further processing steps, such as tablet pressing. The ability to add fluids, and in particular liquids, facilitates processes such as compatibility testing or product development workflows. Powders are handled gently and not subjected to harsh crushing forces which might adversely affect one or more physical characteristics (e.g., size) of the particles. Likewise, any number of relatively small mixed powder samples can be prepared efficiently and accurately. The system can readily be scaled up or down to different sizes, according to need. Further, the system is capable of handling a wide range of powders having different particle sizes and flow characteristics. The system is particularly suited for applications where accuracy and repeatability are important, as in the pharmaceutical, parallel synthesis, and materials research industries.
The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
Corresponding reference characters indicate corresponding parts throughout the drawings.
Referring to
The system 100 includes a powder mixing device 120. The powder mixing device 120 is suitably mounted on a transport system 130, which in the illustrated embodiment includes a robot arm 140 mounted on a track 150 above a work surface 160 (e.g., a platform). In the particular embodiment of
An actuator 230 is operable to vibrate the cannula 210 to mix the powder sample 112 as shown in
The actuator 230 is operable to produce vibrations at a suitable frequency and amplitude which may vary depending on various factors, including the type of powder being handled. Vibration of the cannula 210 can be varied under control of a control system (not shown) that controls operation of the actuator 230. Thus, for example, for relatively dry powders the actuator 230 can be operated to produce a gentle sinusoidal vibration. On the other hand, for particles which tend to agglomerate, a larger amplitude of vibration may be used to promote the free flow of particles. The control system can also vary the frequency of vibration. The frequencies of the vibrations are suitably within the range of about 20 Hz-1000 Hz, and more particularly within the range of about 30 Hz-400 Hz.
The term “vibration” is used in a broad sense to mean the application of alternating or oscillating forces (e.g., tapping or shaking forces) to the cannula 210 tending to disturb the particles in the powder sample to promote mixing. Although the actuator 230 in the illustrated embodiment is an eccentric motor, it is contemplated that other actuators (e.g., piezoelectric actuators) can be used to vibrate the cannula 210. It is also contemplated that vibrations may be transmitted to the cannula 210 to energize its vibration through one or more intermediate non-energizing structures within the scope of the invention.
The sample vessels 110 have an open end 114 and a closed end 116. The sample vessels 110 of the illustrated embodiment have a generally cylindrical shape, but the sample vessel could have practically any shape within the scope of the invention. The system 100 is suitably operable to mix relatively small powder samples 112 in relatively small vessels 110. For example, the sample vessels 110 suitably have a total volumetric capacity of about 50 ml or less, more suitably about 20 ml or less, more suitably in the range of about 0.1 ml to about 20 ml, more suitably in the range of about 0.1 ml to about 10 ml, more suitably in the range of about 0.1 ml to about 2 ml, and even more suitably in the range of about 0.1 ml to about 1 ml. Likewise, the system 100 is suitably operable to mix powder samples 112 comprising less than about 5 grams of powder per sample, more suitably less than about 500 mg of powder per sample, more suitably less than about 100 mg of powder per sample, more suitably less than about 50 mg of powder per sample, more still more suitably less than about 25 mg of powder per sample. The size of the powder samples can vary depending on the particular application and it is possible that the system 100 is adapted to mix only relatively larger samples within the scope of the invention, particularly when the system is used in applications in which the cost and availability of materials used to make the powder samples are not limiting.
Preferably, the size and shape of the sample vessels 110 will be such that there will ample room for mixing of powders in the vessels. For example, if the vessel 110 is cylindrical, it is desirable that its diameter be equal to or greater than the depth of the powder bed 112 to be formed and mixed therein. Likewise, it is desirable that the vessel 110 have sufficient height (e.g., at least three time the height of the powder bed) to provide ample head space for the powder 112 to circulate during mixing. Optionally, the system 100 can include one or more removable closures to seal the open end 114 of the sample vessels 110 around the cannula 210 to prevent loss of powder during mixing. For example a sealing mat or gasket (not shown) can be placed over the sample vessels 110 on the block 170. Alternatively, a septum or other pierceable seal can be positioned over the open end of each sample vessel 110. In the illustrated embodiment, a lateral slit 402 (
It will be appreciated from the foregoing that the vessels 110 may be relatively small and have correspondingly small open ends 114. Also, the cannula 210 can be a relatively flexible and somewhat fragile structure, raising the possibility that damage could result if the cannula is not aligned properly with the open end of a vessel 110 as it is being inserted into the vessel. The bracket 300 in the illustrated embodiment includes a cannula guide 310 operable to guide movement of the cannula 210 into the vessels 110 to reduce the risk that misalignment of the cannula with the open end of the vessel (whether due to positional error, deformation of the cannula, or a combination of these and/or other reasons) will impact insertion of the cannula into the vessel.
As illustrated in
As the mixing device 120 approaches one of the vessels 110, the collar 314 engages the vessel at its open end 114. Continued movement of the mixing device 120 toward the vessel 110 causes the mounting block 302 to slide on the rails 320 toward the collar 314 (carrying the cannula 210 along with it further toward and into the vessel) as the collar and rails are held stationary by the vessel. If the cannula 210 is too far out of alignment, the cannula engages the funnel-shaped inner surface 316 of the collar 314, which guides the cannula toward a more aligned position. This can prevent damage to the cannula 210 and/or vessel 110.
In the illustrated embodiment, the cannula 210 has an internal surface 216 (
In the illustrated embodiment, the cannula outlet 220 comprises a plurality of holes 224 (
As best illustrated in
The fluid delivery system 450 is controlled by the control system to generate a specified flow of fluid through the lumen 218 of cannula 210 during mixing. The type of the fluid flow that is called for can vary depending on the nature of the powder being mixed and the particular application. In the illustrated embodiment, the fluid delivery system 450 (illustrated schematically in
Other fluid delivery systems can be used within the scope of the invention. For example, a pump, such as a syringe pump (not shown) can be used to pump fluid to the outlet 220. Optionally, the fluid delivery system also includes a conventional flow controller in the fluid line for controlling the rate of fluid flow that pumped through the cannula 210 by the pump. In some applications, it may be more desirable to use a pump instead of a pressurized reservoir to produce fluid flow through the cannula. For example, the control system can be used to control a pump (e.g., syringe pump) and/or flow controller to provide a variable and controlled flow rate of fluid from the cannula, particularly in applications in which there is a need or desire to add a relatively larger quantity of fluid to the powder sample 112.
The illustrated embodiment of the system 100 also includes a powder dispensing apparatus 180, such as a Powdernium powder dispensing hopper (Symyx Technologies, Inc., Sunnyvale, Calif.) that can be positioned above each of the sample vessels 110 to dispense measured amounts of various powders into the vessels as described, for example, in U.S. Pat. No. 7,134,459 and/or U.S. Patent Publication 2007/0006942, which are hereby incorporated by reference in their entirety for all purposes. The transport system 130 (e.g., robot) can suitably move the powder dispensing apparatus 180 between various powder supply containers (not shown) if needed and the vessels 110 to transfer one or more powders to the vessels in such combinations as may be required to produce the desired powder samples. For example, the system 100 is suitably able to accommodate different modes of powder transfer, including transfers involving one source to one destination vessel (one-to-one), one source to multiple destination vessels (one-to-many), or multiple sources to multiple destination vessels (many-to-many).
The illustrated embodiment of the system 100 also suitably includes a weighing device 190 (e.g., a scale or balance) that can be used to weigh the vessels to facilitate accurate dispensing of powders and/or fluids to the vessels and/or to confirm that the desired amount of powder and/or fluid has been dispensed to the vessel. Suitable scales, balances, and other weighing devices are disclosed in co-owned U.S. application Ser. No. 11/771,824, U.S. Pat. No. 7,134,459 and/or U.S. Patent Publication 2007/0006942, the contents of which are incorporated by reference.
The system 100 optionally includes a liquid and/or powder detecting apparatus, such as a liquid or powder detecting sensor mounted on cannula 210. The sensor is operable to send signals to the control system that allow the control system to determine that the tip of cannula 210 (and/or outlet 220) is located within powder bed 112 before mixing is commenced. For example, a pressure sensor 260 may be positioned on the cannula (e.g., at the terminal end 214) for this purpose. Other types of sensors (e.g., a dielectric sensor) could also be positioned on the cannula for this purpose. Alternatively, a bed height measuring device (not shown) can be provided for this purpose, in the form of an elongate probe supported on a vertical Z axis rod mounted on a second arm of the transport system 130, so that the probe is movable by the robot along X, Y and Z axes. Other sensors known to those skilled in the art can be adapted to provide information about the position of the cannula 210 relative to the powder sample 112 to the control system within the scope of the invention.
The illustrated embodiment of the system 100 also includes a temperature control system 500 to provide for mixing at reduced and/or elevated temperatures and/or a temperature monitoring system to provide for monitoring of temperature in the sample vessels 110 during mixing. A temperature control and monitoring system can be implemented using known technology, such as heating or cooling fluid conduits 502 embedded in the block 170 to provide for transport of heating and/or cooling fluid into block 170 adjacent to the sample vessels 110.
In a method of the invention, the system 100 is used to mix one or more powdered materials 112. The method suitably includes adding one or more fluids to prepare a sample. The fluid can be a gas or liquid, such as water or other aqueous solution. The system allows one to introduce a controlled amount of well-mixed moisture for accelerated aging, or to mimic a wet granulation process. In some cases the materials are mixed stochastically to provide a heterogeneous mixture. However, the powders 112 can be mixed to a lesser extent if that is all the mixing that is needed for a particular application.
The system 100 is suitably used to mix one or more powder samples 112 weighing about 5 grams or less, more suitably less than about 50 mg, and still more suitably about 10 mg or less. For instance, the system is suitably used to mix one or more samples that are suitably between about 0.1 mg to about 5 grams, more suitably between about 0.1 mg and 1 gram, more suitably between about 0.5 mg to about 1 gram, and still more suitably between about 5 mg to about 1 gram.
The powder samples 112 may comprise particles of any size ranging from about 1 μm to about 1 mm. For example, the average size of the powder particles suitably ranges from about 1 μm to about 400 μm, more suitably from about 100 μm to about 400 μm, more suitably from about 1 μm to about 100 μm, and more suitably from about 1 μm to about 50 μm, and still more suitably from about 1 μm to about 25 μm. The method suitably includes using the powder transfer apparatus to transfer a quantity of a first powder to each sample vessel 110 to form a powder bed in the vessel. Optionally, one or more additional (i.e., second) powders and can be added to each sample vessel 110. Preferably, a different powder transfer device is used to dispense each different powder that is used. If two or more different powders are added to a single vessel 110, this results in the formation of an unmixed powder bed in the sample vessel 110. As shown in
At this point, the sample vessels 110 can be sealed if desired by placing a sealing mat or gasket over the sample vessels 110 on block 170, or positioning a septum or other pierceable seal to seal the open end 114 of each sample vessel 110. For example, removable closures 400 having slits 402 formed therein, as described above, may be placed over the open end 114 of each vessel 110.
The transfer system 130 is used to move the mixing device 120 into a first vessel 110 (e.g., as illustrated in
The fluid may be emitted from the cannula outlet 220 as a fluid stream or spray entering the powder bed 112 in the sample vessel 110. For example, the mixing device 120 can be used to add fluid directly into the powder bed 112 below its surface as indicated in
After mixing the contents of the first vessel 110, the fluid delivery system 450 and the actuator 220 are deactivated and the cannula 210 is removed from the sample vessel 110. If additional samples remain to be mixed, the transport system 130 moves the mixing device 120 to the next sample vessel 110, where the process is repeated. Although a sequential mixing process has been thus described, the system 100 can include multiple mixing devices 120—for example, an array of multiple mixing devices—arranged on robot arm 140, such that the mixing devices can be positioned within multiple sample vessels 110 in parallel, to provide for parallel mixing.
The quantities and identities of the powder(s) and fluid(s) used are generally controlled (e.g., by the control system) and may be selected with the aid of suitable software so the mixed sample has a predetermined composition (e.g., a predetermined mixture of powder(s) and a predetermined moisture content). At any time during preparation of the mixed samples the weighing apparatus 190 may be used to meter addition of the desired amount of powder and/or fluid into a vessel 110 and/or confirm that the desired amount of powder and/or fluid has been added to the vessel to help ensure that the predetermined composition is achieved.
Once the samples 112 have been mixed, they can be subjected to any desired further processing or analysis, such as a parallel imaging operation, or parallel fixed bed screening operation as disclosed in U.S. Pat. No. 6,149,882, U.S. Patent Publication No. 2002/0170976, U.S. Patent Publication No. 2002/0048536, U.S. Patent Publication No. 2002/0045265, and U.S. Patent Publication No. 2002/0042140, each of which is hereby incorporated by reference in its entirety for all purposes. Such further processing may involve transferring the mixtures to separate vessels. Alternatively, the mixtures may be retained in the same vessels 110 for the additional processing or analysis.
The vessels 110 may be heated or cooled by the temperature control system 500 at any point in sample preparation to meet the needs or desires for a particular application. For instance, the vessels 110 may be heated and/or cooled to control temperature of the vessels to a constant temperature or to two or more different temperatures throughout sample preparation. The heating and/or cooling from the temperature control system 500 may be used after the samples 112 are prepared to facilitate further analysis of the characteristics of the samples if desired (e.g., in a forced degradation experiment).
The method suitably includes preparing and screening a plurality of candidate mixtures in relatively small quantities for high-throughput screening of the candidate mixtures for desirable characteristics. The candidate mixtures are suitably candidates for being produced in large quantities (e.g., by a large scale commercial production process). For example, the large scale process may comprise a wet granulation process.
A relatively smaller quantity of a first of said plurality of candidate mixtures is prepared by inserting the cannula 210 of the mixing device 120 into a first powder bed 112 comprising one or more materials. The cannula 210 is vibrated by the actuator to mix the first powder bed 112 and the fluid delivery system 450 is used to add a fluid to the first powder bed via the lumen 218 in the cannula, as described above. The cannula 210 may be vibrated by the actuator 230 to mix the powder bed 112 at the same time fluid is added to the powder bed. The fluid (e.g., a predetermined amount of fluid) is suitably added in a manner selected to mimic the large scale process. For example, if the large scale process is a wet granulation process, the quantity of fluid added by the fluid delivery system may be selected to mimic the wet granulation process. The flow rate and position of the outlet 220 relative to the powder bed 112 may also be controlled in a manner selected to mimic the large scale process. These steps are repeated (which may include being conducted in parallel by a plurality of mixing devices 120) as necessary until a relatively smaller quantity of each of said plurality of candidate mixtures has been prepared.
The candidate mixtures are then subjected to at least one screening test to evaluate one or more characteristics of the candidate mixtures. For example, the candidate mixtures may be subjected to an accelerated aging or forced degradation test. If desired, the candidate mixtures can be pressed into tablets for the screening test to determine how the mixtures perform in tablet form. Advantageously, the mixtures can be pressed into tablets that are substantially devoid of foreign objects used in the mixing process.
In one example, the powder mixing systems and methods of the present invention are used to perform excipient compatibility studies for pharmaceuticals development. In such studies, the apparatus and methods disclosed herein can be used to create arrays of different powders mixtures and mix them to create good contact between an active pharmaceutical ingredient and one or more excipients. The ability to add moisture in such workflows can be important to, for example, accelerate compatibility studies or mimic wet milling operations in process development.
In an exemplary workflow, illustrated in
When introducing elements of the present invention or the preferred embodiments thereof, the articles “a”, “an”, “the”, and “said” are intended to be inclusive and mean that there may be additional elements other than the listed elements.
As various changes could be made in the above constructions and methods without departing from the scope of the invention, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.
This application claims priority to U.S. provisional application No. 60/951,900 filed Jul. 25, 2007, the entire contents of which are hereby incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| 60951900 | Jul 2007 | US |
