Methods of manipulating small amounts of solids

• US 20040146434A1
• Filed: 11/03/2003
• Published: 07/29/2004
• Est. Priority Date: 11/04/2002
• Status: Active Grant

• Current Assignee: TransForm Pharmaceuticals, Inc. (Johnson & Johnson)
• Original Assignee: TransForm Pharmaceuticals, Inc. (Johnson & Johnson)
• Inventors: Gyory, J. Richard, Lemmo, Anthony V., Cima, Michael, Gonzalez-Zugasti, Javier, Cherng, Jeanie, Kane, Nathan
• Granted Patent: US 7,449,342 B2
• Time in Patent Office: Days
• US Class Current: 422/100
• CPC Class Codes: B01F 23/60 Mixing solids with solids
• CPC Class Codes: B01F 27/1121 pin-shaped
• CPC Class Codes: B01F 27/90 with paddles or arms
• CPC Class Codes: B01F 31/55 the materials to be mixed being contained in a flexible bag submitted to periodical deformation
• CPC Class Codes: B01F 33/30 Micromixers
• CPC Class Codes: B01F 33/407 by blowing gas on the material from above
• CPC Class Codes: B01F 33/45 Magnetic mixers; Mixers with magnetically driven stirrers
• CPC Class Codes: B01L 2200/0657 Pipetting powder
• CPC Class Codes: B01L 3/0217 of the plunger pump type medical syringes A61M
• CPC Class Codes: G01F 11/021 of the piston type G01F11/04 takes precedence
• CPC Class Codes: G01F 11/10 with measuring chambers moved during operation
• CPC Class Codes: G01F 11/18 for fluent solid material
• CPC Class Codes: G01G 19/00 Weighing apparatus or methods adapted for special purposes not provided for in the preceding groups electric measuring arrangements involving comparison with a reference value G01R17/00
• CPC Class Codes: G01N 1/286 involving mechanical work, e.g. chopping, disintegrating, compacting, homogenising microtomes G01N1/06; pulverising in general B02C; mixing in general B01F
• CPC Class Codes: G01N 1/36 Embedding or analogous mounting of samples
• CPC Class Codes: G01N 2001/368 Mounting multiple samples in one block, e.g. TMA [Tissue Microarrays]
• CPC Class Codes: G01N 35/0099 comprising robots or similar manipulators robots per se B25J
• CPC Class Codes: Y10T 436/2575 Volumetric liquid transfer

Abstract

The invention relates to methods and apparatuses for manipulating small amounts of solids. Specific embodiments of the invention are particularly suited for the automated transfer of small amounts of solids. In one embodiment, a uniform powder bed is lightly compressed into plugs of powder and dispensed. In another embodiment, the solid is placed in a liquid carrier to form a slurry, dispensed, and the liquid component is subsequently removed. In yet another embodiment, solids are manipulated using adhesive surfaces.

Claims

1. A method of manipulating a solid, which comprises:

(a) providing a bed of powder of known weight and uniform height;

(b) inserting a tube a controlled distance into the bed to obtain a plug of powder, wherein the tube has an interior that accommodates a means of ejecting materials from within the tube;

(c) removing the tube from the bed; and

(d) ejecting the plug of powder.

2. The method of claim 1, wherein:

(a) the tube is inserted completely through the bed;

(b) the plug of powder is obtained by compression;

(c) the means of ejecting the plug is a piston, vibration, pressurized gas, or a liquid;

(d) the means of ejecting the plug of (c) is a piston;

(e) the method does not substantially affect the form of the solid;

or

(f) the powder comprises an active pharmaceutical ingredient.

3. A method for dispensing a controlled mass of a solid, which comprises:

(a) processing the solid into a powder with an average particle size of less than about 200 micrometers;

(b) forming a powder bed with a predetermined mass and uniform height from a portion of the powder;

(c) inserting a tube a controlled distance into the powder bed to obtain a plug of powder, wherein the tube has an interior that accommodates a means for ejecting materials from within the tube;

(d) lifting the tube from the powder bed;

(e) moving the tube over a target location; and

(f) ejecting a plug of powder onto target location.

4. The method of claim 3, wherein:

(a) the method further comprises;

(i) providing a grille plate with an array of holes sized so that the tube can pass through each with a small clearance; and

(ii) holding the grille plate on top of the powder bed;

 

the powder bed is prevented from breaking apart upon insertion of the tube;

(c) a method to form the powder bed comprises;

(i) providing a source receptacle assembly comprising;

(1) a source receptacle with sides, a top surface, a bottom face, and at least one cylindrical hole that passes through and is perpendicular to the bottom face; and

(2) a base plate that is removeably attached to the bottom face;

(ii) dispensing a predetermined mass of the powder into the cylindrical hole;

(iii) providing a cylindrical pin with at least one flat, perpendicular end face;

(iv) inserting the cylindrical pin into the cylindrical hole and pressing the pin into the powder with a predetermined force;

(v) rotating the cylindrical pin through an angle of at least 1 degree of rotation with the predetermined force applied; and

simultaneously rotating and lifting the pin out of the cylindrical hole;

(d) a method is used for forming the powder bed comprising the steps of;

(i) providing a source receptacle assembly comprising;

(1) a source receptacle with sides, a top face, a bottom surface, and at least one cylindrical hole that passes through and is perpendicular to the top face;

(2) a close fitting cylinder disposed inside of the cylindrical hole; and

(3) a cylinder locking means which allows the close fitting cylinder to be either locked to or disengaged from the source receptacle;

(ii) dispensing a predetermined mass of the powder into the cylindrical hole through the top face of the source receptacle;

(iii) providing a slide plate with at least one flat face;

(iv) pressing the flat face of the slide plate against the top face of the source receptacle;

(v) disengaging the cylinder locking means;

(vi) pressing the cylinder into the powder with a predetermined force;

(vii) rotating the cylinder through an angle of at least 1 degree of rotation with the predetermined force applied;

(viii) engaging the cylinder locking means; and

 

sliding the slide plate off of the top face of the source receptacle;

(e) pressures applied to the powder are low enough so as to not substantially affect the form of the powder;

(f) the powder comprises an active pharmaceutical ingredient;

(g) the ejecting means is a close fitting pin disposed in the interior of the tube;

(h) the plug inside the tube is compressed prior to being ejected;

(i) the tube is inserted completely through the powder bed;

(j) the ejecting means is a close fitting pin with sides and a face disposed in the interior of the tube, and the close fitting pin is held stationary relative to the tube while the tube is inserted into the powder bed a predetermined depth sufficient to make the pin face contact the powder;

(k) the tube is inserted into the powder with a predetermined force applied to it;

(l) the tube is inserted into the powder bed a predetermined depth;

(m) the tube is a hollow needle;

or

(n) a wide variety of solids can be dispensed in controlled amounts without substantially affecting their form.

5. An apparatus for manipulating a solid, which comprises:

(a) a punching assembly comprising a tube having an interior, a piston located within the interior of the tube, a first actuator capable of adjusting the vertical position of the tube, and a second actuator capable of moving the piston within the tube;

(b) a powder bed assembly mounted below the punching assembly, comprising a source plate and a receiving plate; and

(c) a means of positioning the punching assembly over the source plate and the receiving plate.

6. An apparatus for dispensing powder which comprises:

(a) a punching assembly comprising a tube having an interior, close fitting pin disposed inside the interior of the tube, a first actuator capable of adjusting the vertical position of the tube, a second actuator capable of moving the pin within the tube;

(b) a source station comprising at least one powder bed of predetermined mass and uniform height, and a structure to support the powder bed;

(c) a receiving plate mounted below the punching assembly; and

(d) a means for positioning the punching assembly over the source plate and the receiving plate.

7. The apparatus of claim 6, wherein:

(a) the first actuator and the second actuator are pneumatically driven linear actuators;

(b) the first actuator and the second actuator are electronically driven linear servos;

(c) the means for positioning the punching assembly comprises perpendicularly mounted electronically driven linear servos;

(d) a wash station is included which contains means for washing away powder from the tube and the pin, and drying the hollow needle and the pin;

(e) a weigh station is included which contains means for weighing powder that is dispensed into it;

(f) the tube is a hollow needle;

or

(g) a wide variety of solids can be dispensed in controlled amounts without substantially affecting their form.

8. A method of manipulating a solid, which comprises:

(a) blending a controlled amount of the solid with a liquid to provide a slurry;

(b) dispensing a controlled amount of the slurry; and

(c) removing the liquid to provide an amount of the solid, wherein the amount of the solid is less than about 1 mg.

9. The method of claim 8, wherein:

(a) the amount of solid is less than about 0.5 mg;

(b) the amount of solid is less that about 100 micrograms;

(c) the means of removing the liquid is evaporation, filtration, or sedimentation;

(d) the solid comprises an active pharmaceutical ingredient;

(d) the solid comprises an active pharmaceutical ingredient;

(e) the method does not substantially affect the form of the solid;

(f) the liquid comprises a wetting agent and water;

(g) the wetting agent is isopropyl alcohol, methanol, PVP, Tween®

, or sodium lauryl sulfate;

or

(h) solid state analysis is performed after removing the liquid to verify that the solid has not changed form.

10. A method of manipulating a solid, which comprises:

contacting particles of the solid with a surface comprising a plurality of discrete adhesive areas separated by non-adhesive areas, wherein the size of the adhesive areas is smaller than about 5 cm², under conditions sufficient to adhere the particles non-electrostatically to an adhesive area; and

adhering the particles non-electrostatically to the adhesive area.

11. The method of claim 10, wherein:

less than about 1 mg of solid is adhered to an adhesive area;

less than about 0.5 mg of solid is adhered to an adhesive area;

(c) less than about 0.25 mg of solid is adhered to an adhesive area;

(d) the adhesive material is a pressure sensitive adhesive, a silicone, or a hydrogel;

(e) the solid comprises an active pharmaceutical ingredient;

or

(f) the method does not substantially affect the form of the solid.

12. An apparatus for manipulating a solid, which comprises:

(a) a surface, comprising a plurality of discrete adhesive areas separated by non-adhesive areas, wherein the size of the adhesive areas is smaller than about 5 cm², under conditions sufficient to adhere the particles non-electrostatically to an adhesive area at least a portion of which is coated with an adhesive;

(b) a container capable of holding powder; and

(c) a means of contacting the adhesive portion of the surface with powder in the container.

13. The apparatus of claim 12, wherein the adhesive material is a pressure sensitive adhesive, a silicone, or a hydrogel.

14. A method for manipulating a solid, which comprises:

dispensing a known amount of solid into a source chamber;

compressing the solid;

moving a slide plate such that a dose chamber traverses the solid;

moving the dose chamber over a target well; and

ejecting a plug of solid.

15. The method for manipulating a solid of claim 14, wherein

(a) the slide plate in step (c) is moved in a criss-cross or in a spiral trajectory;

or

(b) the source chamber is subjected to vibration or mixing in step (c).

16. An apparatus for manipulating a solid, which comprises:

a slide plate comprising a dose chamber;

a powder bed assembly mounted below the slide plate, comprising a source chamber and a receiving plate; and

a means for positioning the slide plate over the source plate and the receiving plate.

17. The apparatus for manipulating a solid of claim 16, wherein:

the apparatus further comprises a microbalance;

or

the slide plate comprises a dose chamber in the form of a grid cutter.

18. A method of manipulating a solid, which comprises:

dispensing a known amount of solid into a source chamber;

compressing the solid;

moving a slide plate directly below the source chamber;

pressing the solid through a grid cutter to make multiple plugs;

moving the slide plate to an ejector pin; and

propelling ejector pin down to eject a solid plug into a target well.

19. The method of claim 18, wherein:

the height of each partition in the grid cutter is controlled by a micrometer;

the target well is controlled by an x servo and a y servo;

or

the target well is controlled by an x linear actuator and a y linear actuator.

20. A method of transferring a solid, which comprises:

gripping a vessel containing a solid with a clamp;

attaching a swing arm to the clamp;

accelerating the swing arm through an arc trajectory until a hard stop is impacted; and

placing a target well directly below the stopped position of the vessel.

21. The method of claim 20, wherein:

a carousel enables simultaneous transferring and weighing;

the target well is controlled by an x servo and a y servo;

the target well is controlled by an x linear actuator and a y linear actuator;

solid transfer is promoted by a vibrating actuator;

or

premature solid transfer is prevented by a retractable shield.

22. An apparatus for transferring a solid, which comprises:

a vessel containing a solid gripped by a clamp;

a swing arm attached to the clamp;

a hard stop;

a target well; and

an x actuator and a y actuator to control the position of the target well.

23. The apparatus of claim 22, wherein:

the actuators are linear servos;

the apparatus further comprises a carousel;

the apparatus further comprises a vibrating actuator;

the apparatus further comprises a retractable shield;

the target vessel is a multi-well plate;

or

the apparatus further comprises a microbalance.

24. A method of transferring a solid, which comprises:

gripping a vessel with a mechanical device mounted to xy linear actuators; and

moving the vessel between a receiving plate and a microbalance using the mechanical device mounted to the xy linear actuators.

25. An apparatus for transferring a solid, which comprises:

a vessel gripped by a mechanical device;

the mechanical device is mounted to xy linear actuators;

a receiving plate; and

a microbalance.

26. A method for mixing small amounts of solids, which comprises:

placing the solid in a filter-bottom well;

sealing the well; and

injecting gas into the well.

27. The method of claim 26, wherein:

the well is sealed with a filter plate;

the well is sealed with a lid;

or

the seal is pierceable.

28. An apparatus for mixing small amounts of solids, which comprises:

a well with a filter bottom containing solids;

a seal; and

a means for injecting gas into the well.

29. A method to weigh a small amount of solid, which comprises:

supporting a low-mass container with a cradle;

positioning the cradle so the low-mass container is above a weigh platform;

lowering the cradle so the low-mass container is supported by the weigh platform; and

weighing the solid.

30. An apparatus to weigh a small amount of solid, which comprises:

a low mass container containing solid and supported by a cradle;

a weigh platform; and

means for lowering the cradle so the low-mass container is supported by the weigh platform.

31. The apparatus of claim 30, further comprising:

xy linear actuators;

or

a two-dimensional array of low-mass containers.

32. A method for measuring the mass of a small amount of solid, which comprises:

coring a plug of powder with a coring tube;

generating a voltage signal;

applying the voltage signal to a piezoelectric actuator affixed to the coring tube; and

measuring the displacement of the coring tube with a laser.

33. The method of claim 32, wherein:

the voltage signal is a swept-sine signal;

or

the frequency of the applied voltage signal is between 6.3 kHz and 7.1 kHz.

34. An apparatus for measuring the mass of a small amount of solid, which comprises:

a coring tube;

a function generator;

a piezoelectric actuator affixed to the coring tube,

a laser aligned with the coring tube.

35. A method for measuring the mass of a small amount of solid, which comprises:

attracting dielectric particles to an electrode by imposing a non-uniform electric field;

generating a voltage signal;

applying the voltage signal to a piezoelectric actuator affixed to the electrode; and

measuring the displacement of the electrode with a laser.

36. The method of claim 35, wherein:

(a) the voltage signal is a swept-sine signal;

or

(b) the frequency of the applied voltage signal is between 3.6 kHz and 4.0 kHz.

37. An apparatus for measuring the mass of a small amount of solid, which comprises:

an electrode;

a function generator;

a piezoelectric actuator affixed to the electrode; and

a laser aligned with the electrode.