WO2003049845A1

WO2003049845A1 - High strength magnetic stir bar

Info

Publication number: WO2003049845A1
Application number: PCT/US2002/037983
Authority: WO
Inventors: Royal J. Haskell
Original assignee: Pharmacia Corporation
Priority date: 2001-12-05
Filing date: 2002-11-27
Publication date: 2003-06-19
Also published as: AU2002352946A1

Abstract

There is provided a high strength, custom-sizable magnetic stir bar useful in, inter alia, processes for reducing particle size of a drug. The stir bar comprises a substantially inert case having a longitudinal axis and a magnetic assembly comprising one to a plurality of magnets. At least one of the magnets has a maximum energy product of not less than about 21 MGO, the assembly is completely enclosed in and substantially fills the case, and the assembly has a polarity substantially aligned with the longitudinal axis of the case.

Description

HIGH STRENGTH MAGNETIC STIR BAR

FIELD OF THE INVENTION

The present invention relates to a high strength magnetic stir bar useful for, inter alia, milling drugs and/or agrochemicals on a small scale. BACKGROUND OF THE INVENTION

Magnetic stirring of liquids enclosed within a bottle is a well known technique in the chemical and biological arts. Typically, such magnetic stirring involves rotating or revolving a magnetic field beneath the bottom of a container so as to cause a magnetically susceptible mixing member (e.g. a stir bar) to rotate in a generally circular path in a plane inside of the container. For many liquid stirring applications, stir bars composed of low strength magnets, for example ferrite or AlNiCo magnets, are suitable. Illustratively, United States Patent No. 5,586,823 to Carr provides a magnetic stirrer wherein a relatively weakly magnetized disposable stir bar composed of molded ferrite is moved in a closed container with a relatively powerful magnetic driver outside of the container.

A novel technique for lab-scale milling of drugs, described in co-assigned United States Patent Publication No. 2002-0119200 to the present inventor, has recently been developed. This patent publication discloses a process for reducing particle size of a drug comprising (a) a step of dispersing about 10 g or less of the drug in a suitable volume of a hquid dispersion medium to form a suspension; (b) a step of bringing together in a vessel the suspension, grinding media and a stir bar; (c) a step of magnetically activating the stir bar to effect milling of the suspension to a weight average particle size not greater than about 1 μm; and (d) a step of separating the resulting milled suspension from the grinding media and the stir bar. Stir bars described in that publication are traditional ferrite stir bars and samarium cobalt stir bars. Typically, such ferrite stir bars have a maximum energy product of about 2 - 3 mega-gauss-oersted (MGO) and such samarium cobalt stir bars have a maximum energy product of about 18 - 20 MGO.

For several reasons, however, traditional commercially available stir bars, both traditional ferrite and traditional samarium cobalt stir bars, are less than desirable when used in the above-described process. For example, traditional stir bars are only available in certain pre-determined sizes, shapes and having limited maximum energy products. In performing the above lab-scale milling process, it is sometimes desirable to use a stir bar having only a slightly shorter length than the interior diameter of the grinding vessel being used and/or having a shape approximating the shape of the vessel bottom. Such a vessel length or shape may not correspond to the size or shape of any commercially available stir bar and are thus not suitable for small scale milling operations (e.g. in 1 ml cryogenic vials or 20 ml scintillation vials).

Traditional commercial stir bars purportedly can be made-to-order (e.g. size and/or shape) from some suppliers, but such stir bars have important disadvantages of high cost and substantial delay between time of order and time of delivery. Furthermore, some firms which provide such stir bars often require a minimum order of thousands of bars which is not practical or economical in situations where no more than a few or several stir bars are needed.

Traditional commercially available stir bars also can easily de-couple from an external rotating magnet, even when the external rotating magnet is of high power. Such de-coupling is a particular problem when stirring at higher rotational speeds or when milling dispersions comprising grinding media as is the case when performing the above described milling process. De-coupling can be a problem in the above described milling process even when using commercially available samarium cobalt stir bars, typically only commercially available in lengths of 10 mm or greater. Therefore, a significant need exists for a stir bar that overcomes at least some of the problems associated with traditional, commercially available stir bars.

SUMMARY OF THE INVENTION Accordingly, the present invention provides an affordable, custom-sizable, and high powered stir bar which overcomes at least some of the above described limitations. This invention represents a significant improvement over the prior art.

A stir bar according to the present invention comprises a substantially inert case having a longitudinal axis and a magnetic assembly comprising one to a plurality of magnets. At least one, preferably at least a substantial portion, and more preferably all of the magnets, have a maximum energy product of not less than about 21 MGO. The assembly is completely enclosed in and substantially fills the case and has a polarity substantially aligned with the longitudinal axis of the case. In another embodiment, the invention provides a stir bar comprising a substantially inert case having a longitudinal axis and a magnetic assembly completely enclosed in and substantially filling the case. In this embodiment, the magnetic assembly comprises a plurality of magnets linearly and contiguously arranged, at least two of which magnets have a maximum energy product of not less than about 15 MGO. Each magnet has a first face disposed in orientation of a north pole and an opposing second face disposed in orientation of a south pole and adjoining faces of contiguous magnets have opposite polarity. The first and second faces are disposed substantially perpendicular to the longitudinal axis of the case. Other features of the invention will be in part apparent and in part laid out hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows in diagrammatic form an illustrative apparatus in which a stir bar of the invention can be used. Fig. 2 shows a perspective representation of an illustrative stir bar of the invention.

Fig. 3 shows a cross section view of an illustrative stir bar of the invention. Fig. 4 shows a side view of an illustrative stir bar of the invention.

DETAILED DESCRIPTION OF THE INVENTION In a first embodiment, the present invention provides a stir bar which comprises a substantially inert case having a longitudinal axis and a magnetic assembly. The magnetic assembly is completely enclosed in and substantially fills the case and the assembly has a polarity substantially aligned with the longitudinal axis of the case. In this embodiment, the magnetic assembly comprises one to a plurality of magnets at least one of which, preferably a substantial portion of which, and more preferably all of which individually have a maximum energy product of not less than about 21 MGO, preferably not less than about 23 MGO, still more preferably not less than about 25 MGO, and even more preferably not less than about 27 MGO. A plurality herein can be 2, 3, 4, 5 or more. Illustratively, such magnets will individually have a maximum energy product of about 21 to about 100 MGO, about 23 to about 75 MGO, about 25 to about 50 MGO or about 27 to about 40 MGO. It will be understood that while it is preferred that each magnet present in a magnetic assembly has a maximum energy product of at least about 21 MGO, the mere replacement of a de minimus portion of magnets with magnets exhibiting a maximum energy product of less than 21 MGO is within the scope of the present invention.

A suitable magnetic assembly can include magnets comprising any magnetic material or composition. Non-limiting examples of such materials include rare earth metals, transition metals, rare earth-transition metal alloys, rare earth-iron-boron alloys, and combinations thereof. Particularly preferred rare earth metals include Ce, Pr, Nd, and Sm. Preferred transition metals include Fe, Co, Pt, Ag, and Cu. Illustrative alloy materials suitable for use in a magnetic assembly include, without limitation, NdFeB, PtCo, BiMn, AgMnAl, and CoFeCuSm. Particularly preferably, magnets present in a magnetic assembly present in a stir bar of the invention will remain magnetized at temperatures of at least about 75 °C and more preferably at least about 80 °C.

Magnets suitable for use in a magnetic assembly can be of any desired shape, for example box-, doughnut-, triangular-, bar- or disk-shape. Preferably the magnets are of disk- or doughnut-shape. Most preferably the magnets are of disk-shape. Where the magnets are of disk- or doughnut-shape, they preferably have a diameter of about 2 to about 25 mm, preferably about 2 to about 20 mm, more preferably about 2 to about 12.5 mm, and still more preferably about 2 to about 8 mm. Such magnets preferably have a thickness of about 0.5 to about 20 mm, more preferably about 1 to about 10 mm, still more preferably about 1 to about 5 mm, and even more preferably about 1 to about 2 mm. Where the magnetic assembly comprises more than one magnet, it is preferred that all of the magnets have substantially the same peripheral shape and that individual faces present on each magnet are of substantially the same cross-sectional area. Preferably, all magnets present in a magnet assembly have cross- sectional faces of substantially identical surface shape and area.

Stir bars according to the present invention comprise a case. The case is preferably substantially inert (non-reactive) and abrasion-resistant. Furthermore, the case is preferably water-impermeable and resistant to cracking or leaking during use. A suitable case can comprise one continuous piece or of two or more pieces sealed or bonded together. Non-limiting illustrative examples of suitable materials for use in a case include rubber, metals, epoxy, glue, plastics and other polymers, and combinations thereof. Illustrative polymers include RheFlex® tubing (Rheodyne), polypropylene, polymethylmethacrylate, fluoropolymers such as polytetrafluoroethylene (PTFE, available commercially as Teflon®), ethylene-tetrafluoroethylene fluoropolumer (e.g. Tefzeϊ®), perfluoroalkoxy copolymer resin (Teflon® PFA), fluorinated ethylene propylene, polychlorotrifluoroethylene, polyvinylidene fluoride fluoroplastic (e.g. Kynar), etc. Fluoropolymers are particularly preferred. An especially preferred case comprises PTFE tubing whereby the ends of the tube are sealed with PTFE discs and epoxy cement.

In another embodiment, the invention provides a stir bar comprising a substantially inert case having a longitudinal axis and a magnetic assembly comprising a plurahty of magnets, at least two of which, preferably substantially all of which, and more preferably all of which have a maximum energy product of not less than about 15 MGO. The magnets are completely enclosed in and substantially fill the case, and are linearly and contiguously arranged. Each magnet has a first face disposed in orientation of a north pole and an opposing second face disposed in orientation of a south pole. Adjoining faces of adjacent magnets have opposite polarity and the first and second faces are disposed substantially perpendicular to the longitudinal axis of the case.

Preferably, at least one, more preferably at least a substantial portion, and still more preferably all of the magnets present in the assembly of this embodiment have a maximum energy product of not less than about 15 MGO, preferably not less than about 21 MGO, more preferably not less than about 23 MGO, still more preferably not less than about 25 MGO, and even more preferably not less than about 27 MGO. Illustratively, each magnet present in the assembly has a maximum energy product of about 15 to about 100 MGO, about 21 to about 75 MGO, about 25 to about 50 MGO or about 27 to about 40 MGO.

In another embodiment, the invention provides a stir bar comprising a substantially inert case having a longitudinal axis and a magnetic assembly comprising one to a plurahty of magnets. In this embodiment, at least one of the magnets has a maximum energy product of not less than about 15 MGO, preferably not less than about 21 MGO, more preferably not less than about 23 MGO, and still more preferably not less than about 25 MGO. The assembly is completely enclosed in and substantially fills the case; the assembly has a polarity substantially aligned with the longitudinal axis of the case, and the longitudinal axis of the case has a length of not more than about 9 mm, preferably not more than about 8 mm, more preferably not more than about 7 mm, and more preferably not more than about 5 mm.

An illustrative milling apparatus in which a stir bar of the present invention can be used is described in United States Patent Publication No. 2002-0119200 to HaskelL hereby incorporated by reference herein in its entirety, and is shown diagrammatically in Fig. 1. In such an apparatus, a vessel 11 is adapted to receive a suspension comprising the hquid dispersion medium 12 for the drug, grinding media 13 and magnetically activatable means 14 (e.g. a stir bar) for stirring the dispersion medium with grinding media therein. The vessel 11 is illustratively a vial having a capacity of about 0J ml to about

40 ml and preferably has a cover 15 to prevent spillage during milling. The vessel is held in place by suitable support means such as a clamp 16.

The grinding media 13 are illustratively spherical beads, about 0.2 mm to about

5 mm in diameter, and are illustratively of latex, glass or zirconium oxide. The magnetically activatable means for stirring illustratively comprises a magnetic stir bar 14, illustratively a stir bar of the present invention. An activating device 17, illustratively a magnetic stir plate, preferably with the cover plate removed to increase field strength, is placed near, preferably immediately under, the stirring means. EXAMPLES

The following examples illustrate aspects of the present invention but should not be construed as limitations.

Example 1

A stir bar 20 was prepared as illustrated in Fig. 2 (perspective representation), Fig. 3 (section view), and Fig. 4 (side view). As shown in these figures, four discshaped NdFeB magnets 1 (nickel coated, 3 mm diameter/1 mm thickness) were linearly stacked to a desired length and press fit into a piece of PTFE tubing 2 which was of slightly greater length than the stacked magnets. The ends of the tubing were then sealed by placing adhesive 3, for example epoxy cement, in the end of the tube and press fitting a pre-cut PTFE disk 4 thereon. An additional layer of adhesive 5 was placed on the outside of the disk as needed. Alternatively, the ends of the sleeve can be sealed with adhesive and no disk or with a disk and one layer of adhesive. To reduce rotational friction, a piece of external tubing 6, for example Tygon tubing, was slipped over the tube so that the bar balanced evenly when placed on a flat, horizontal surface. Preferably such external tubing is of lesser length than the stir bar and is fixably located around the midsection of the stir bar, for example as illustrated in Fig 2. Example 2

Dispersions D1-D4 containing 5% by weight celecoxib were prepared by the process described below. The dispersions differed only in the particle size range of the celecoxib.

1. Celecoxib was micronized in an air jet mill to form a drug powder. 2. The drug powder was added to an aqueous solution containing 2.5% low viscosity hydroxypropylcellulose (HPC-SL) and 0.12% sodium dodecyl sulfate, to form a suspension.

3. The suspension was wet milled to form a milled suspension according to the following protocol. A sample amount of 6.0 ml of the suspension (containing 20% celecoxib), a 19 mm traditional magnetic stir bar (ferrite or AlNiCo), 8 ml of lead-free glass beads, and 50 μl of antifoaming agent (Sigma Antifoam A Concentrate) were added to a 20 ml scintillation vial. To provide a milled suspension having a target particle size range of 6-7 μm (i.e., the size range achieved in the micronizing step, used to provide a comparative composition), the vial was shaken for two minutes. To provide a milled suspension having smaller target particle size ranges, the vial was suspended over a high-strength rotating magnet so that milling occurred upon agitation of the glass beads by rotation of the magnetic stir bar. Target particle size ranges were varied by controlling magnet rotation rate, n- lling time and/or bead size, as shown in Table 1. Small aliquots were removed at intervals in order to monitor progress of particle size reduction.

4. The resulting milled suspension in each case was transferred to a larger vial and diluted with fresh vehicle to form a final milled suspension. Nominal celecoxib concentration in final suspensions was 5% by weight. Table 1. Milling conditions used to produce milled suspensions D1-D4.

In general, for the larger 19 mm length stir bars, milling speeds greater than about 900 to about 1000 rpm could not be exceeded without experiencing de-coupling. At least in part due to these relatively slow milling speeds, extended milling times of 25 to 52 hours were required to achieve desired drug particle size ranges. Example 3

Valdecoxib, linezolid, phenytoin, griseofulvin and carbamazepine were milled according to the general procedure described for celecoxib in Example 2. However, stir bars of the invention prepared substantially as described in Example 1 were used in order to achieve increased milling speeds without experiencing decoupling and to reduce overall milling time for a given drug particle size range. Milling parameters are shown in Table 2.

Size Detection Method: ^α Turbidimetry, ² Optical Microscopy, ³ X-Ray Diffraction.

Table 2, continued.

As is seen in Table 2, milling speeds of 1500 to 3000 rpm were achieved and milling time was less than that utilized in Example 2.

Claims

WHAT IS CLAIMED IS:

1. A stir bar comprising:

(i) a substantially inert case having a longitudinal axis; and (ii) a magnetic assembly comprising one to a plurahty of magnets; wherein at least one of the magnets has a maximum energy product of not less than about 21

MGO; the assembly is completely enclosed in and substantially fills the case; and the assembly has a polarity substantially aligned with the longitudinal axis of the case.

2. The stir bar of Claim 1 wherein the magnetic assembly comprises a plurahty of magnets.

3. The stir bar of Claim 1 wherein at least a substantial portion of said one to a plurahty of magnets has a maximum energy product of not less than about 21 MGO.

4. The stir bar of Claim 1 wherein each of said one to a plurahty of magnets has a maximum energy product of not less than about 21 MGO.

5. The stir bar of Claim 1 wherein the magnetic assembly comprises one or more materials selected from the group consisting of rare earth metals, transition metals, rare earth-transition metal alloys, or rare earth-iron-boron alloys.

6. The stir bar of Claim 1 wherein the magnetic assembly comprises a rare earth metal selected from the group consisting of Ce, Pr, Nd, and S .

7. The stir bar of Claim 1 having a longitudinal axis of about 0.5 to about 25 mm.

8. The stir bar of Claim 1 having a longitudinal axis of about 0.5 to about 9 mm.

9. The stir bar of Claim 1 wherein the case comprises a polymer.

10. The stir bar of Claim 1 wherein the case comprises a fluoropolymer selected from the group consisting of polytetrafluoroethylene, ethylene-tetrafluoroethylene fluoropo αmer, perfluoroalkoxy copolymer resin, fluorinated ethylene propylene, polychlorotrifluoroethylene, or polyvinyhdene fluoride fluoroplastic.

11. A stir bar comprising:

(i) a substantially inert case having a longitudinal axis; and (ii) a magnetic assembly completely enclosed in and substantially filling the case; wherein the magnetic assembly comprises a plurahty of magnets linearly and contiguously arranged; at least two ofthe magnets have a maximum energy product of not less than about 15 MGO; each magnet has a first face disposed in orientation of a north pole and an opposing second face disposed in orientation of a south pole; adjoining faces of contiguous magnets have opposite polarity; and said first and second faces are disposed substantially perpendicular to the longitudinal axis ofthe case.

12. The stir bar of Claim 11 wherein at least two ofthe magnets in said magnetic assembly have a maximum energy product of not less than about 25 MGO.

13. The stir bar of Claim 11 wherein at least substantially ah ofthe magnets in said magnetic assembly have a maximum energy product of not less than about 15 MGO.

14. The stir bar of Claim 11 wherein at least substantially ah ofthe magnets in said magnetic assembly have a maximum energy product of not less than about 25 MGO.

15. The stir bar of Claim 11 wherein the magnetic assembly comprises a material selected from the group consisting of rare earth metals, transition metals, rare earth-transition metal alloys, or rare earth-iron-boron alloys.

16. The stir bar of Claim 11 wherein the magnetic assembly comprises a rare earth metal selected from the group consisting of Ce, Pr, Nd, and Sm.

17. The stir bar of Claim 11 having a longitudinal axis of about 0.5 to about 20 mm.

18. The stir bar of Claim 11 having a longitudinal axis of about 0.5 to about 9 mm.

19. The stir bar of Claim 11 wherein the case comprises a polymer.

20. The stir bar of Claim 11 wherein the case comprises a fluoropolymer selected from the group consisting ofpolytetrafluoroethylene, ethylene- tetrafluoroethylene fluoropofαmer, perfluoroalkoxy copolymer resin, fluorinated ethylene propylene, polychlorotrifluoroethylene, or polyvinylidene fluoride fluoroplastic.

21. A stir bar comprising:

(i) a substantially inert case having a longitudinal axis; and (ii) a magnetic assembly comprising one to a plurahty of magnets; wherein at least one ofthe magnets has a maximum energy product of not less than about 15 MGO; the assembly is completely enclosed in and substantially fills the case; the assembly has a polarity substantiaUy ahgned with the longitudinal axis ofthe case; and said longitudinal axis has a length of not more than about 9 mm.

22. The stir bar of Claim 21 wherein said longitudinal axis has a length of not more than about 5 mm.