1. Field of the Disclosure
The disclosure relates to compositions, apparatuses and systems for use in the removal of magnetic material from compositions, particularly pharmaceutical compositions.
2. Background
Many applications require the separation of particles from a composition. Filtration is a widely used method to remove particulate matter. In one commonly used version of this method, a membrane is inserted into the flow of the preparation and particles are unable to pass through the pores of the membrane due to their size. The filtration membrane may also include materials such that the particles absorb to the membrane. The composition with reduced amounts of particles is collected as the filtrate. However, filtration may not be desirable in situations where small particles are present and membranes with very small pore sizes are required because an unacceptably large increase in mechanically applied pressure may be necessary to maintain the flow rate. In addition, filtration may be difficult where the initial viscosity of the solution is high or where the one or more of the components of the composition is not compatible with the membrane. Also, filtration may be completely impossible in situations where the active agent is itself in the form of particles in suspension. In these cases, filtration may remove the active agent particles as well as undesirable particles.
An alternative method of separating particles takes advantage of their magnetic properties. Generally, if a magnetic field is applied to a solution containing material with magnetic properties, then that material will be drawn to the source of the magnetic field and will be separated from the solution. The use of magnetic fields to separate components from solution has been exploited in applications where it is necessary to purify a particular component from a solution. For example, an antibody may be linked to a magnetic particle and the antibody-particle complex mixed with blood. The antibody will interact with its corresponding antigen in the solution. When a magnetic field is applied, the antibody-antigen-magnetic particle complex can be separated from the blood.
Material with magnetic properties may also arise during the production of a composition. For example, during the production of pharmaceutical compositions, one source of metal particles comes from the metal used in devices such as reaction vessels, stirrers, homogenizers, grinders and ball milling apparatus. The presence of these particles even at very low levels is undesirable and the use of magnetic fields presents one method to remove them and achieve the required purity for the composition. These metal particles may arise from metals such as allotropes of iron (e.g., ferrite, austenite, martensite), alloys of iron and carbon (such as stainless steel, with or without added elements such as nickel, cobalt, molybdenum, chromium or vanadium), lanthanides (such as gadolinium, europium, and dysprosium), or paramagnetic materials such as aluminum, titanium, and their alloys. Ceramic materials may also be magnetic. Magnetic ceramics may be generated by mixing metal oxides (e.g., ZnO, FeO, MnO, NiO, BaO, or SrO) with Fe2O3. These ceramics find use in permanent magnets, computer memory, and in telecommunications.
Stainless steel is defined as a ferrous alloy with a minimum of 10.5% chromium content. The presence of chromium results in a higher resistance to rust and corrosion. The magnetic properties of stainless steel vary depending on the elemental composition of the steel. Alloys with relatively low concentrations of nickel or manganese are ferromagnetic. In these alloys, a martensite crystalline structure predominates and the steel will respond strongly to magnetic fields. Steel alloys with higher concentrations of nickel or manganese assume a stabilized austenite crystalline configuration. The austenitic steels are generally considered non-magnetic but in fact are paramagnetic and will respond to strong magnetic fields (on the order of 1 TESLA). Pure titanium or aluminum are paramagnetic and are expected to respond to strong magnetic fields.
U.S. Published Patent Application No. 2003/0108613 by Weitschies et al, which is herein incorporated by reference, describes a device for the magnetic separation of pharmaceutical preparations. The device consists of a separation space in which a magnetic field prevails and which has an inlet and an outlet. However, the device is intended to be used only as an attachment filter for infusion and injection instruments or to be integrated into such instruments. There remains a need for apparatuses, systems and methods for using them which are able to separate magnetic material and which are more easily adapted into processes for formulating compositions.
The disclosure provides for apparatuses, systems and methods to substantially remove magnetic material from compositions, particularly pharmaceutical compositions.
In one embodiment, the disclosure provides for a conduit through which a composition passes or is maintained. The conduit passes adjacent to an arrangement of magnets and the composition is subject to a magnetic field that substantially removes material with magnetic properties.
In one embodiment, an arrangement of magnets is formed from magnets that are arranged in at least one double Halbach array. The conduit passes through a space between the halves of the array, substantially removing material with magnetic properties from a composition that flows through the conduit.
In another embodiment, a column contains magnetic beads. A composition passes through the column, and material with magnetic properties is substantially removed.
The disclosure also provides for systems that incorporate the apparatuses of the disclosure as well as methods for using the apparatuses.
a and 1b show cross-sectional views of apparatuses according to the disclosure.
a and 3b show schematics of two possible arrangements of magnets according to the disclosure.
a to 4e show schematics of the possible orientations of the magnetic fields of split ring magnets according the disclosure.
a and 6b are schematics showing an arrangement of magnets that form a double Halbach array, in an (a) aligned or (b) opposed arrangement according to the disclosure.
a and 9b are schematics showing an arrangement of magnets forming multiple double Halbach arrays according to the disclosure.
a (double Halbach aligned), 10b (double Halbach opposed) and 10c (diametrically oriented array elements as shown in
a and 12b show a side view of an embodiment of an apparatus according to the disclosure.
As required, detailed embodiments of the present disclosure are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the disclosure, which may be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present disclosure in virtually any appropriate manner.
This disclosure concerns apparatuses and systems for the separation or removal of ferromagnetic, ferrimagnetic, paramagnetic, or superparamagnetic particulate material from compositions that are in the form of a fluid or solid. The fluid may be either a solution or a fluid containing dispersed particles. The composition may be solid such as a finely divided powder that can be passed through the apparatuses of the disclosure using a stream of carrier gas. The present disclosure can be used in numerous applications where it is desirable to remove material that is responsive to magnetic fields, including magnetic material of a very small size. These applications include petroleum products, pharmaceutical compositions, magnetic recording media, food products and drinking water purification. In one embodiment, the apparatuses and methods of the disclosure are used with pharmaceutical compositions.
The present disclosure can also be used in any industrial process in which magnetic particles are intentionally added as a catalyst or manufacturing aid that needs to be removed at the end of the manufacturing process. In biotechnology, for example, the disclosure is applicable to situations where desired biochemicals or biologicals including cells or tissue should be separated from other components during or at the end of a process (e.g., fermentation). For example, magnetic beads coated with molecules (e.g., antibodies) that specifically interact with the desired product are added, the interaction occurs, and the magnetic beads with the attached desired product are removed. The final product is detached from the beads, which can then be recycled. This is exemplified in U.S. Pat. No. 4,628,037 which is herein incorporated by reference. Another example is in U.S. Pat. No. 5,916,743 which is also herein incorporated by reference. This latter patent discloses a cell-separation method combining the techniques of immunoaffinity separation and continuous flow centrifugal separation for selective separation of a nucleated heterogeneous cell population from a heterogeneous cell mixture. The heterogeneous cell mixture is intimately contacted to promote binding thereto by particles having attached a substance that actively binds to a specific desired type of cell out of the cell mixture. The particles are selected so that the sedimentation velocity of the particle/cell conjugate differs sufficiently from those of other cells in the cell mixture to allow its separation by means of a continuous flow cell separator. The method rapidly processes large volumes of cell mixture with the high accuracy expected of immunoaffinity separation and can be used to separate, for example, various types of leukocytes from whole blood, bone marrow concentrate, or a peripheral blood stem cell concentrate; or precursors of lymphokine activated killer cells, tumor infiltrating lymphocyte cells, or activated killer monocytes from lymphocyte or monocyte cell concentrates or from a tissue cell preparation. In this case, the present disclosure can be used as an alternative separation method to immunoaffinity purification and separation techniques.
In general, the apparatuses provide for a separation zone to which a magnetic field is applied and through which a composition passes or is maintained. The apparatuses include an arrangement of magnets that produce a magnetic field of sufficient force to remove magnetic material such that the treated composition is rendered substantially free of magnetic material or at least within required limits. The apparatuses described here are capable of being physically integrated into systems used to make compositions such that the separation of magnetic material becomes an easily accomplished step in the process of the commercial production of compositions. Alternatively, the apparatuses of the disclosure may be used separately from the other processes during production of compositions.
The apparatuses and methods disclosed here are capable of removing material with magnetic properties including material with ferromagnetic, ferrimagnetic, paramagnetic and superparamagnetic properties. In one embodiment, the composition is a pharmaceutical composition, and the active agent or agents of the composition are generally non-magnetic or diamagnetic, whether the active agent forms a homogeneous solution or is in the form of dispersed particles in suspension. In this embodiment, undesirable magnetic material is removed and the active agent is substantially retained in the composition. In an alternative embodiment, the active agent may have magnetic properties and the apparatuses are used to separate out the active agent from other components of the composition.
It is generally noted that the disclosure can be especially efficient in removing smaller particles from a composition that includes different sizes of particles to be removed.
In one embodiment, the apparatuses may separate particles of stainless steel or other metals that may originate from the machinery used during the production of pharmaceutical compositions, including particles that originate from alloys of stainless steel that are generally considered non-magnetic. Although not wishing to be bound by theory, these alloys may be non-magnetic on a large scale but the smaller magnetic particles that originate from abrasive processes may have magnetic properties. On a large scale, there may be no net magnetization because randomly oriented magnetic domains within the molecular structure of the steel cancel each other. However, particles may have a single isolated domain or a small collection of domains and have net magnetic properties. Domain sizes vary considerably from a few nm to over 10 microns, depending on the type of material and how it was processed (Fourlaris G; Maylin M G; Gladman T. Magnetic domain imaging and mechanical/magnetic property characterization of a 2507 type duplex austenitic-ferritic stainless steel. Materials Science Forum, 1999, Vol 318-320, pp 823-828). In addition, abrasive stress is known to cause a transition from an austenitic crystalline form found in many stainless steels to a martensitic form. The latter form has ferromagnetic properties and responds to magnetic fields. Furthermore, austenite is paramagnetic and responds to very strong magnetic fields.
Magnets formed from a number of elements can be used for the disclosed magnetic separations depending on the nature of the material to be separated. The removal of small particles by magnetic attraction is enhanced by the use of magnets with very strong magnetic fields. In this case, the rare earth composite neodymium-iron-boron (NdFeB) typically is an advantageous choice. NdFeB has the highest residual magnetic flux density (Br) and resistance to demagnetization (also called coercivity [Hc]) of any magnet formula. The maximum flux density at the surface of NdFeB is approximately 10,000 gauss (1 Tesla). Samarium Cobalt (SmCo) is another preferred material. The magnets may be bar-shaped, horseshoe-shaped or ring-shaped, for example.
a shows one embodiment of an apparatus that can achieve the separation of magnetic material. The apparatus has a conduit 21 with an interior volume 22 that carries a composition, such as a pharmaceutical composition. The conduit 21 passes through a zone 24 containing a magnetic field. The magnetic field is generated by an arrangement 25 of at least one magnet. In this and other embodiments, the conduit passes through a gap 26 in the arrangement of magnets where the magnetic field prevails.
The removal of magnetic material is achieved when the composition containing the magnetic material passes through the conduit and the magnetic particles are drawn to the interior surface of the conduit by the magnetic field. As shown in
The conduit, for example, may be non-magnetic tubing that is compatible with pharmaceutical compositions. The conduit may be adapted such that it can be integrated into a system for production of a pharmaceutical composition. For example, one end of the conduit may be adapted to receive the pharmaceutical composition from a previous step in processing and the second end may be adapted to re-circulate the pharmaceutical composition through the first end of the conduit to repeat the magnetic separation step or to the next step in processing of the pharmaceutical composition. The effluent contains no magnetic particles, or a quantity of magnetic particles significantly lower than that in the initial composition. Alternatively, the apparatus may be separate from the other components of the production system.
In the embodiment shown in
In
For example, in one embodiment of an array of magnets (
In a further embodiment, the magnetic field results from a series of ring magnets such that each split pair comprises one segment. Each half of the pair may have any magnetic field orientation.
In one embodiment, the composition flows through a conduit that passes through a gap in a series of magnets in which the magnetization vectors of the magnets are arranged according to a modification of a simple Halbach array. In a Halbach array, a series of permanent magnets is arranged such that the magnetic field on one side of the array is augmented while reducing the field to very low values on the other side. In a typical Halbach array of block magnets, the magnetization direction of each magnet in the series is rotated a specified angle in either a clockwise or counterclockwise direction.
In another embodiment utilizing a split ring design, each half of the array comprises a series of complete magnetic circuits (a double Halbach design). In
In a further embodiment (“double Halbach, opposed”), the axial split elements are aligned and the alternating diametric elements are antipodal (see
As shown in
a and 9b show two embodiments of double Halbach arrangements that were experimentally tested in the Examples. Each array was composed of twenty elements. This double Halbach arrangement may be thought of as a composite of two Halbach arrays, each comprised of a series of half magnets, or combinations of split pair elements (antipodal) and whole magnets. In the first embodiment (the Halbach Aligned design), the magnetization vectors for the stack of ring magnets are oriented as shown in
In a further embodiment (the Halbach opposed design), the magnetization vectors for the array are oriented as shown in
As shown in
Areas with a stronger magnetic field are represented by closer line spacing. As shown, the double Halbach array opposed (
equation:
Fμ is the magnetic force between two dipoles, χ is the magnetic susceptibility, ρ is the particle density, μ0 is the magnetic permeability of free space, dB/dt is the magnetic field gradient along a direction perpendicular to the field lines, and |Bx| is the field strength at the particle position. Therefore, at similar magnetic gradients, higher field strengths should result in larger forces between the magnetic particles and the walls of the magnet array.
Compared with the Halbach opposed design (
In
A yet further embodiment is shown in
This Example describes purification of pharmaceutical solid in a liquid process stream. Three magnetic array separators were tested, each of the following types:
(a) Whole magnet array (diametric, alternating antipodal segments)
(b) Double Halbach array aligned
(c) Double Halbach array opposed.
Each magnetic element (split or whole ring magnet), was fabricated from neodymium-iron-boron (NdFeB) alloy (DuraMagnetics, Sylvania, Ohio). The magnetic field strength of a whole magnet was measured on its outside surface using a DC magnetometer (AlphaLab Inc.), and was found to have a maximum field strength of approximately 5,000 gauss (0.5 tesla). Finite element analysis estimated field strengths as high as 5,700 gauss for each magnet, and strong gradients near the inner surface of the central bore of the ring magnet (see
Systems as shown in
The syringe pump 70 (see
To recirculate the composition through the magnetic arrays (5 passes), a system using a peristaltic pump was used (see
Drug particle size populations were determined by static laser diffraction (Horiba LA-920). The method is described in the following article: J. Wong, P. Papadopoulos, J. Werling, C. Rebbeck, M. Doty, J. Kipp, J. Konkel and D. Neuberger,” Itraconazole Suspension for Intravenous Injection: Determination of the Real Component of Complete Refractive Index for Particle Sizing by Static Light Scattering,” PDA J. Pharm. Sci. Technol., 60, 302-313 (2006) and D. Neuberger and J. Wong, “Suspension for Intravenous Injection: Image Analysis of Scanning Electron Micrographs of Particles to Determine Size and Volume,” PDA J. Pharm. Sci. Technol., 59, 187-199 (2005). Measurements were obtained using five milliliters of each collected sample. The remaining five milliliters of each sample were centrifuged at 10,000 RCF for 1 hour (Beckman Coulter, Allegra™ 64R Centrifuge with C1015 Rotor) and the centrifuge tubes were visually examined for separation of dense, dark metal particles. These samples were resuspended and analyzed for iron content by emission spectroscopy (Perkin-Elmer Aanalyst™ 600 Atomic Absorption Spectrometer with THGA Graphite Furnace). Table 2 shows the iron content (in ppb) of each sample. The data are plotted in
The effect of higher flow rate on particle removal was examined in this Example. The system shown in
The results are presented in
This Example examined the effect of multiple passes on particle separation (double Halbach opposed). A 1% (w/v) pharmaceutical suspension with metal particles was passed once, 10 times, and 100 times, through the double Halbach opposed array at a flow rate of either 100 or 300 cc/min. The experimental setup in
In this Example, water was used to wash a system that is used to manufacture pharmaceutical compositions. This Example also indicates the efficiency of this invention for removing magnetic material from solutions. The water was flushed through the system and a sample of the flushed water examined for the presence of magnetic material. In Control experiments, no magnetic array was included in the system and in Experimental samples a magnetic array was included as indicated in Table 4.
Water was flushed through the system at 15000 psi for 60 minutes or pumped using a peristaltic pump. A sample of the flushed or pumped water was removed and magnetic particle size populations were determined by static laser diffraction. In Table 4, results of magnetic particle numbers and sizes are shown both as differential and cumulative counts are shown for three separate experiments.
It will be understood that the embodiments of the present disclosure which have been described are illustrative of some of the applications of the principles of the present disclosure. Numerous modifications may be made by those skilled in the art without departing from the true spirit and scope of the disclosure. Various features which are described herein can be used in any combination and are not limited to procure combinations that are specifically outlined herein.
The benefit under 35 U.S.C. §119(e) of U.S. provisional patent application Ser. No. 60/871,781 filed Dec. 23, 2006, the entire disclosure of which is incorporated herein by reference, is hereby claimed.
Number | Date | Country | |
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60871781 | Dec 2006 | US |