LUPIN EX. 1011
`Lupin v. iCeutica
`US Patent No. 9,017,721
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`WO 2006/069419
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`PCT/AU2005/001977
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`Nanoparticle Compositions and Methods for Synthesis Thereof
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`_ 1 _
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`Field of the Invention
`
`The present invention relates to improved therapeutically active nanocomposite
`
`microstructure compositions,
`
`including nanoparticle compositions comprising
`
`nanoparticles of a therapeutically active agent dispersed in a carrier matrix and
`other nanoparticle preparations. The invention also relates to a method for
`
`preparing said compositions and preparations using solid-state mechanochemical
`synthesis.
`Further,
`it relates to therapeutic products produced using said
`
`compositions and to methods of treatment using the compositions.
`
`Background
`
`Poor bioavailability is a significant problem encountered in the development of
`
`therapeutic compositions, particularly those compounds containing an active
`
`agent that is poorly soluble in water. An active agent’s bioavailability is the
`degree to which the active agent becomes available to the target tissue in the
`
`body after systemic administration through, for example, oral or intravenous
`means. Many factors may affect bioavailability, including the form of dosage and
`
`the solubility and dissolution rate of the active agent.
`
`Poorly and slowly water soluble active agents tend to be eliminated from the
`gastrointestinal tract before being absorbed into the circulation.
`In addition, poorly
`
`soluble active agents tend to be disfavored or even unsafe for intravenous
`
`administration due to the risk of particles of agent blocking blood flow through
`
`capillaries.
`
`It is known that the rate of dissolution of a particulate drug can increase with
`
`increasing surface area, that is, decreasing particle size. Consequently, methods
`
`of making finely divided or sized drugs have been studied and efforts have been
`
`made to control the size and size range of drug particles in pharmaceutical
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`compositions. For example, dry milling techniques have been used to reduce
`particle size and hence influence drug absorption. However, in conventional dry
`milling the limit of fineness is reached generally in the region of about 100 microns
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`(100,000 nm), at which point material cakes on the milling chamber and prevents
`
`any further diminution of particle size. Alternatively, wet grinding may be
`
`employed to reduce particle size, but flocculation restricts the lower particle size
`
`limit to approximately 10 microns (10,000 nm). The wet milling process, however,
`
`is prone to contamination, thereby leading to a bias in the pharmaceutical art
`
`against wet milling. Another alternative milling technique, commercial airjet
`
`milling, has provided particles ranging in average size from as low as about 1 to
`
`about 50 microns (1 ,000-50,000 nm).
`
`There are several approaches currently used to formulate poorly soluble active
`
`agents. One approach is to prepare the active agent as a soluble salt. Where
`
`this approach cannot be employed, alternate (usually physical) approaches are
`
`employed to improve the solubility of the active agent. Alternate approaches
`
`generally subject the active agent to physical conditions which change the agent’s
`
`physical and or chemical properties to improve its solubility. These include
`
`process
`
`technologies
`
`such as micro-ionisation, modification of crystal or
`
`polymorphic structure, development of oil based solutions, use of co-solvents,
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`surface stabilizers or complexing agents, micro-emulsions, super critical fluid and
`
`production of solid dispersions or solutions. More than one of these processes
`
`may be used in combination to improve formulation of a particular therapeutic
`
`compound.
`
`These techniques for preparing such pharmaceutical compositions tend to be
`
`complex. By way of example, a principal technical difficulty encountered with
`
`emulsion polymerization is the removal of contaminants, such as unreacted
`
`monomers or initiators (which may have undesirable levels of toxicity), at the end
`
`of the manufacturing process.
`
`Another method of providing reduced particle
`
`size
`
`is
`
`the formation of
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`pharmaceutical drug microencapsules, which techniques include micronizing,
`
`polymerisation and co-dispersion. However,
`
`these techniques suffer from a
`
`number of disadvantages including at least the inability to produce sufficiently
`
`small particles such as those obtained by milling, and the presence of co-solvents
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`and/or contaminants such as toxic monomers which are difficult
`
`to remove,
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`leading to expensive manufacturing processes.
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`Over the last decade intense scientific investigation has been carried out to
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`improving the solubility of active agents by converting the agents to ultra fine
`
`powders by methods such as milling and grinding. These techniques may be
`
`used to increase the dissolution rate of a particulate solid by increasing the overall
`
`surface area and decreasing the average particle size.
`
`Some investigation of the applicability of mechanochemical synthesis (“MCS”)
`
`techniques to active agents has been undertaken. However, these investigations
`
`have focused on providing an alternative manufacturing process that reduces the
`
`need for solvents and improves yields, rather than improving solubility by reducing
`
`particle size.
`
`It is important to note the clear distinction between the MCS method, described
`
`more fully below in the Detailed Description of the Invention, which is one of
`
`building nanoparticles from chemical precursors, as compared to a particle size
`
`reduction methods.
`
`Methods of making nanoparticulate compositions have been described as early as
`
`US Pat. No. 5,145,684. Methods of making nanoparticulate compositions are also
`
`described in U.S. Pat. Nos. 5,534,270; 5,510,118; 5,470,583; 5,591,456;
`
`6,428,814; 6,811,767; and 6,908,626, all of which are specifically incorporated
`
`herein by reference. However, these patents do not teach MCS methods of
`
`forming nanoparticulate compositions. Rather, the techniques described therein
`
`are size reduction techniques. Additionally, these techniques do not result in
`
`nanoparticulate compositions with average particle sizes in the range of the
`
`present invention’s particles, nor do they teach the matrix carrier feature of some
`
`embodiments of the present invention.
`
`Accordingly the present invention seeks to provide improved therapeutically active
`
`nanocomposite microstructure compositions and nanoparticle preparations as well
`
`as methods for their preparation, which at least ameliorate some of the problems
`
`attendant with prior technologies.
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`Summary of the Invention
`
`The present invention is directed to the surprising and unexpected discovery that
`
`improved nanocomposite microstructure compositions can be produced by
`
`mechanochemically synthesising therapeutically active nanoparticles in a carrier
`
`matrix using a solid—state chemical reaction. By mechanochemically synthesising
`
`the therapeutically active nanoparticles in a carrier matrix using mechanochemical
`
`procedures, applicant is able to control the size of the resultant nano particles in
`
`the composition.
`
`As a result,
`
`the improved nanocomposite microstructure
`
`compositions are expected to have several advantages, including improved drug
`
`bioavailability compared to unprocessed or conventional active agents.
`
`Accordingly,
`
`the present
`
`invention relates to an improved nanocomposite
`
`microstructure
`
`composition
`
`comprising therapeutically active nanoparticles
`
`dispersed in a carrier matrix, wherein said composition is mechanochemically
`
`prepared using a solid—state chemical reaction. Preferably, the preparation is a
`
`solid solution or solid dispersion suitable for delivery to an animal.
`
`The present
`
`invention also resides in a method for preparing an improved
`
`nanocomposite microstructure composition, said method comprising the step of:
`
`contacting a precursor compound with a co-reactant under mechanochemical
`
`synthesis conditions to generate a solid-state chemical reaction between the
`
`precursor compound and the co-reactant
`
`to produce therapeutically active
`
`nanoparticles dispersed in a carrier matrix. The carrier matrix produced by this
`
`method will preferably be n0n—toxic or alternatively should be separable from the
`
`therapeutically active nanoparticles.
`
`The present invention also relates to the use of the composition of the invention in
`
`the manufacture of a medicament.
`
`Such a medicament may include the
`
`composition alone or more preferably the composition may be combined with one
`
`or more pharmaceutically acceptable carriers, as well as any desired excipients or
`
`other
`
`like agents commonly used in
`
`the preparation of pharmaceutically
`
`acceptable compositions.
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`The present invention is further directed to methods of treatment of an animal
`
`comprising administering to said animal a therapeutically effective amount of a
`
`composition produced according to a method of the invention, wherein said
`
`animal is in need of said therapeutically active agent.
`
`One aspect of the invention relates to a method for preparing a purified nano-
`
`particulate therapeutically active agent comprising the step of:
`
`(i)
`
`contacting
`
`a
`
`precursor
`
`compound with
`
`a
`
`co-reactant
`
`under
`
`mechanochemical synthesis conditions wherein a solid-state chemical reaction
`
`between the precursor compound and the co-reactant produces therapeutically
`
`active nanoparticles dispersed in a carrier matrix.
`
`In another aspect of the invention, the method further comprises the step of:
`
`(ii)
`
`removing a desired amount of
`
`the carrier matrix to release the
`
`therapeutically active nanoparticles.
`
`The step of removing a desired amount of the carrier matrix to release the
`
`therapeutically active nanoparticles may be performed through means such as
`
`selective dissolution, washing, or sublimation.
`
`The invention also extends to the product of the aforementioned methods and its
`
`use in the preparation of medicaments and therapeutically active compositions
`
`suitable fortreating an animal, such as a human. The invention includes methods
`
`for preparing medicaments and pharmaceutically acceptable compositions
`
`comprising the purified nano-particulate therapeutically active agent.
`
`Thus, in one aspect, the invention includes a method of producing a nanoparticle
`
`composition comprising nanoparticles of a therapeutically effective agent,
`
`comprising the step of: mechanochemical synthesis of a mixture of a precursor
`
`compound and a co-reactant using milling media in a milling apparatus, for a time
`
`period sufficient to produce the nanoparticle composition comprising nanoparticles
`
`of the therapeutically effective agent dispersed within a carrier matrix. The
`
`nanoparticles may have an average size less than 200 nm, 100 nm, 75 nm, 50
`
`nm, or 40 nm. Further, the size distribution of the nanoparticles may be such that
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`at least 50% of the nanoparticles, or 75% of the nanoparticles,
`
`is within the
`
`specified average size range. The time period varies, depending on the nature of
`
`the reactants, and may range from between 5 minutes and 2 hours, 5 minutes and
`
`1 hour, 5 minutes and 45 minutes, 5 minutes and 30 minutes, and 10 minutes and
`
`20 minutes. The milling media may have a diameter between 1 and 20mm, or
`
`between 2 and 15 mm, or between 3 and 10mm.
`
`in another aspect of the invention, the precursor compound may be selected from
`
`biologics, amino acids, proteins, peptides, nucleotides, nucleic acids, and analogs
`
`thereof. Further, the precursor compound may be selected from a variety of
`
`classes of drugs, including anti-obesity drugs, central nervous system stimulants,
`
`carotenoids, corticosteroids, elastase inhibitors, anti—fungals, oncology therapies,
`
`anti-emetics, analgesics, cardiovascular agents, anti~inflammatory agents, such
`
`as NSAIDS and COX-2 inhibitors, anthelmintics, anti—arrhythmic agents, antibiotics
`
`(including
`
`penicillins),
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`anticoagulants,
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`antidepressants,
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`antidiabetic agents,
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`antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents,
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`antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid
`
`agents, antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics),
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`astringents,
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`alpha-adrenergic
`
`receptor blocking
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`agents,
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`beta—adrenoceptor
`
`blocking agents, blood products and substitutes, cardiac inotropic agents, contrast
`
`media, corticosteroids, cough suppressants (expectorants and mucolytics),
`
`diagnostic
`
`agents,
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`diagnostic
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`imaging
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`agents,
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`diuretics,
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`dopaminergics
`
`(antiparkinsonian agents), haemostatics,
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`immunological agents,
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`lipid regulating
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`agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and
`
`biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including
`
`steroids), anti-allergic agents,
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`stimulants and anoretics,
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`sympathomimetics,
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`thyroid agents, vasodilators, and xanthines.
`
`‘
`
`in other aspects,
`
`the precursor
`
`compound may be selected from haloperidol, DL isoproterenol hydrochloride,
`
`terfenadine, propranolol hydrochloride, desipramine hydrochloride, salmeterol,
`
`sildenafil citrate,
`
`tadalafil, vardenafil,
`
`fenamic acids, Piroxicam, Naproxen,
`
`Voltaren
`
`(diclofenac),
`
`rofecoxib,
`
`ibuprofren
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`ondanstetron,
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`sumatriptan,
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`naratryptan, ergotamine tartrate plus caffeine, methylsegide, olanzapine.
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`In another aspect of the invention, the method may comprise an additional step of
`
`removing at
`
`least a portion of the carrier matrix, wherein the nanoparticles
`
`remaining have an average particle size of less than 200 nm. Any portion of the
`
`carrier matrix may be removed, including but not limited to 25%, 50%, 75%, or
`
`substantially all of the carrier matrix removed.
`
`in another aspect, the invention is directed to nanoparticle compositions produced
`
`by any of the foregoing methods. The invention is also directed to pharmaceutical
`
`compositions
`
`having
`
`at
`
`least
`
`the
`
`nanoparticle
`
`compositions
`
`and
`
`a
`
`pharmaceutically acceptable carrier. Medicaments may also be manufactured in
`
`accordance with the methods of the invention, combining a therapeutically
`
`effective amount of a nanoparticle composition produced thereby with a
`
`pharmaceutically acceptable carrier.
`
`In another aspect,
`
`the invention is directed to a nanoparticle composition
`
`comprising nanoparticles of a therapeutically effective agent dispersed in a carrier
`
`matrix, which nanoparticles have an average size selected from less than 200 nm,
`
`less than 100 nm, less than 75 nm, less than 50 nm, and less than 40 nm. The
`
`nanoparticle size distribution may be such that at least 50% of the nanoparticles,
`
`or 75% of the nanoparticles, is within the specified average size range.
`
`In one aspect the invention includes a nanoparticle composition wherein the
`
`carrier matrix is selected from Na2CO3, NaHCO3, NH4Cl, and NaCl, or an
`
`appropriate combination thereof.
`
`In another aspect of the invention, the precursor
`
`compound is selected from diclofenac, naproxen, olanzapine, and sildenafil.
`
`In another aspect
`
`the invention is directed to a nanoparticle composition
`
`comprising nanoparticles of a therapeutically effective agent dispersed in a carrier
`
`matrix, the nanoparticle composition being formed by a process comprising the
`
`step of mechanochemical synthesis of a mixture of a precursor compound and a
`
`co-reactant using milling media in a milling apparatus, for a time period sufficient
`
`to produce the nanoparticle composition. A nanoparticle composition of the
`
`invention may also be produced by a process having an additional step of
`
`removing at least a portion of the carrier matrix. The foregoing options of
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`-3-
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`nanoparticle size, MCS time, precursor compound, and carrier matrix are
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`applicable to these nanoparticle compositions as well.
`
`Other aspects and advantages of the invention will become apparent to those
`
`skilled in the art from a review of the ensuing description.
`
`Brief Description of the Drawings
`
`XRD traces of (a) precipitated diclofenac acid (upper line) and (b) a
`Figure 1:
`stoichiometric mixture of diclofenac sodium and sodium hydrogen sulfate, milled
`
`for 6 hours (lower line).
`
`TG-DSC traces of precipitated diclofenac acid (upper line); and
`Figure 2:
`diclofenac-sodium (2.90g) plus sodium hydrogen sulfate (1.18g), milled for 6
`
`hours (lower line).
`
`Figure 3:
`
`Transmission
`
`electron microscope
`
`image
`
`of
`
`nanoparticle
`
`composition formed by MCS comprising diclofenac sodium salt dispersed in a
`
`matrix carrier comprising sodium carbonate and sodium bicarbonate.
`
`Figure 4:
`
`Transmission
`
`electron microscope
`
`image
`
`of
`
`nanoparticle
`
`composition formed by MCS comprising diclofenac acid dispersed in a matrix
`
`carrier comprising ammonium chloride.
`
`Figure 5:
`
`Transmission
`
`electron microscope
`
`image
`
`of
`
`nanoparticle
`
`composition formed by MCS comprising naproxen acid dispersed in a matrix
`
`carrier comprising ammonium chloride.
`
`Detailed Description of the Invention
`
`General
`
`Those skilled in the art will appreciate that the invention described herein is
`
`susceptible to variations and modifications other than those specifically described.
`It
`is
`to be understood that
`the invention includes all such variations and
`
`modifications. The invention also includes all of the steps, features, compositions
`
`and compounds referred to or indicated in the specification,
`
`individually or
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`collectively and any and all combinations or any two or more of the steps or
`
`features.
`
`The present invention is not to be limited in scope by the specific embodiments
`
`described herein, which are intended for the purpose of exemplification only.
`
`Functionally equivalent products, compositions and methods are clearly within the
`
`scope of the invention as described herein.
`
`The invention described herein may include one or more ranges of values (e.g.
`
`size, concentration etc). A range of values will be understood to include all values
`
`within the range, including the values defining the range, and values adjacent to
`
`the range which lead to the same or substantially the same outcome as the values
`
`immediately adjacent to that value which defines the boundary to the range.
`
`The entire disclosures of all publications (including patents, patent applications,
`
`journal articles, laboratory manuals, books, or other documents) cited herein are
`
`hereby incorporated by reference.
`
`No admission is made that any of the
`
`references constitute prior art or are part of the common general knowledge of
`
`those working in the field to which this invention relates.
`
`As used herein the term “derived” and “derived from” shall be taken to indicate
`
`that a specific integer may be obtained from a particular source albeit not
`
`necessarily directly from that source.
`
`Throughout this specification, unless the context requires othen/vise, the word
`
`"comprise", or variations such as "comprises" or "comprising", will be understood
`
`to imply the inclusion of a stated integer or group of integers but not the exclusion
`
`of any other integer or group of integers.
`
`Throughout this specification, unless the context requires othenNise, the word
`
`“comprise” or variations, such as “comprises” or “comprising” will be understood to
`
`imply the inclusion of a stated integer, or group of integers, but not the exclusion
`
`of any other integers or group of integers.
`
`It is also noted that in this disclosure,
`
`and particularly in the claims and/or paragraphs,
`
`terms such as “comprises”,
`
`“comprised”, “comprising” and the like can have the meaning attributed to it in US
`Patent law; e.g., they can mean “includes”, “included”, “including”, and the like;
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`and that terms such as “consisting essentially of’ and “consists essentially of”
`
`have the meaning ascribed to them in US patent law, for example they allow for
`
`elements not explicitly recited, but exclude elements that are not in the prior art or
`
`that affect a basic or novel characteristic of the invention.
`
`As used herein the term “nanocomposite microstructure” includes nanoparticle
`
`compositions, wherein the composition comprises at least nanoparticles having an
`
`average particle size smaller than 1000 nm. Nanocomposite microstructure as
`
`used herein also includes “nanoparticulate therapeutically active agent" and the
`
`like.
`
`Drug nanoparticles dispersed in a carrier matrix are included in
`
`nanocomposite microstructures, as are embodiments thereof wherein the carrier
`
`matrix has been partially or substantially wholly removed.
`
`“Conventional active agents or drugs” refers to non-nanoparticulate compositions
`
`of active agents or solubilized active agents or drugs. Non-nanoparticulate active
`
`agents have an effective average particle size of greater than about 2 microns,
`
`meaning that at least 50% of the active agent particles have a size greater than
`
`about 2 microns.
`
`(Nanoparticulate active agents as defined herein have an
`
`effective average particle size of less than about 1000 nm.)
`
`“Therapeutica|ly effective amount” as used herein with respect to a drug dosage,
`
`shall mean that dosage that provides the specific pharmacological response for
`
`which the drug is administered in a significant number of subjects in need of such
`
`treatment.
`
`It is emphasized that “therapeutically effective amount,” administered
`
`to a particular subject in a particular instance will not always be effective in
`
`treating the diseases described herein, even though such dosage is deemed a
`
`“therapeutically effective amount" by those skilled in the art.
`
`It is to be further
`
`understood that drug dosages are,
`
`in particular instances, measured as oral
`
`dosages, or with reference to drug levels as measured in blood.
`
`Other definitions for selected terms used herein may be found within the detailed
`
`description of the invention and apply throughout. Unless otherwise defined, all
`
`other scientific and technical
`
`terms used herein have the same meaning as
`
`commonly understood to one of ordinary skill
`
`in the art to which the invention
`
`belongs.
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`Mechanochemical Synthesis
`
`The term "mechanochemical synthesis" (“MCS”) means the use of mechanical
`
`energy to activate,
`
`initiate or promote a chemical reaction, a crystal structure
`
`transformation or a phase change in a material or a mixture of materials, for
`
`example by agitating a reaction mixture in the presence of a milling media to
`
`transfer mechanical energy to the reaction mixture, and includes without limitation
`
`"mechanochemical activation", "mechanochemical processing", "reactive milling",
`
`and related processes. The reaction mixture can be contained in a closed vessel
`
`or chamber. The term "agitating" or "agitation" as used herein means applying at
`
`least one, or any combination of two or more of the fundamental kinematic
`
`motions including translation (e.g., side—to-side shaking), rotation (e.g., spinning or
`
`rotating) and inversion (e.g., end-over—end tumbling) to the reaction mixture.
`
`Preferably, all three motions are applied to the reaction mixture. Such agitation
`
`can be accomplished with or without external stirring of the reaction mixture and
`
`milling media.
`
`In the MCS process of the present invention, a mixture of reactants, in the form of
`
`crystals, powders, or the like,
`
`is combined in suitable proportions with milling
`
`media in a vessel or chamber that is mechanically agitated (i.e., with or without
`
`stirring) for a predetermined period of time at a predetermined intensity of
`
`agitation. Typically, a milling apparatus is used to impart motion to the milling
`
`media by the external application of agitation, whereby various translational,
`
`rotational or inversion motions or combinations thereof are applied to the vessel or
`
`chamber and its contents, or by the internal application of agitation through a
`
`rotating shaft
`
`terminating in a blade, propeller,
`
`impeller or paddle or by a
`
`combination of both actions. Processes that can be mechanically activated by the
`
`methods described herein may include:
`
`initiation of chemical
`
`reactions,
`
`for
`
`example,
`
`solid state reactions such as, oxidation/reduction reactions,
`
`ion-
`
`exchange reactions,
`
`substitution reactions, etc.; dehydration; generation of
`
`dislocations in crystal
`
`lattices;
`
`initiation of polymorphic phase transformations;
`
`formation of metastable phases; refinement of crystallite size; amorphization of
`
`crystalline phases; formation of salts from free acids or bases, and free acids or
`
`bases from salts and the like.
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`Such processes can be promoted under nominally ambient conditions in the
`
`absence of added liquids or solvents.
`
`A detailed description of various aspects of mechanochemical processing is
`
`provided by P. G. McCormick and F. H. Froes
`
`("The Fundamentals of
`
`Mechanochemical Processing", Journal of Metals, vol. 50, 1998, pp 61-65) and E.
`
`M. Gutman ("Mechanochemistry of Materials", Cambridge Internet. Science Publ.,
`
`1998) and references cited therein.
`
`In the method of the present invention, a predetermined amount of milling media,
`
`preferably chemica|ly—inert,
`
`rigid milling media,
`
`is added to an essentially dry
`
`reaction mixture comprising at least a precursor composition (ordinarily a form of
`
`pharmaceutical drug) and a co-reactant, prior to mechanical activation. The
`
`reaction mixture is subjected to mechanical activation, for example,
`
`in a milling
`
`apparatus whereby the reaction mixture is agitated in the presence of milling
`
`media at ambient temperature, that is, without the need for external heating. The
`
`term "chemically-inert" milling media, as used herein, means that the milling
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`media does not react chemically with any of the components of the reaction
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`mixture.
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`Typically, rigid milling media can be in the form of particles desirably having a
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`variety of smooth, regular shapes, flat or curved surfaces, and lacking sharp or
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`raised edges. For example, suitable milling media can be in the form of particles
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`having ellipsoidal, ovoid, spherical or right cylindrical shapes. Preferably, the
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`milling media is in the form of beads, balls, spheres, rods, right cylinders, drums
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`or radius-end right cylinders (i.e., right cylinders having hemispherical bases with
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`the same radius as the cylinder). Depending on the nature of the precursor
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`compound and the co-reactant, the milling media desirably has an effective mean
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`particle diameter (i.e., "particle size") between about 0.1 and 30 mm, more
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`preferably between about 1 and about 15 mm, still more preferably between about
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`3 and 10 mm. As used herein, the term "effective mean particle diameter" is
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`defined as the mean diameter of the smallest circular hole through which a
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`particle can pass freely. For example, the effective mean particle diameter of a
`
`spherical particle corresponds to the mean particle diameter and the effective
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`mean particle diameter of an ellipsoidal particle corresponds to the mean length of
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`the longest minor axis.
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`The rigid milling media advantageously comprises various materials such as
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`ceramic, glass, metal or polymeric compositions, in a particulate form. Suitable
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`metal milling media are typically spherical and generally have good hardness (i.e.,
`
`RHC 60-70), roundness, high wear resistance, and narrow size distribution and
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`can include, for example, balls fabricated from type 52100 chrome steel, type 316
`
`or 4400 stainless steel or type 1065 high carbon steel.
`
`Preferred ceramic materials, for example, can be selected from a wide array of
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`ceramics desirably having sufficient hardness and resistance to fracture to enable
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`them to avoid being chipped or crushed during milling and also having sufficiently
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`high density. Suitable densities for milling media can range from about 1 to 15
`
`g/cm3.
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`Preferred ceramic materials can be selected from steatite, aluminum
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`oxide, zirconium oxide, zirconia-silica, yttria-stabilized zirconium oxide, magnesia-
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`stabilized zirconium oxide,
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`silicon nitride,
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`silicon carbide,
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`cobalt—stabilized
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`tungsten carbide, and the like, as well as mixtures thereof..
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`Preferred glass milling media are spherical (e.g., beads), have a narrow size
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`distribution, are durable, and include, for example, lead—free soda lime glass and
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`borosilicate glass. Polymeric milling media are preferably substantially spherical
`
`and can be selected from a wide array of polymeric resins having sufficient
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`hardness and friability to enable them to avoid being chipped or crushed during
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`milling, abrasion-resistance to minimize attrition resulting in contamination of the
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`product, and freedom from impurities such as metals, solvents, and residual
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`monomers.
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`Preferred polymeric resins,
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`for example, can be selected from crosslinked
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`polystyrenes,
`
`such as polystyrene crosslinked with divinylbenzene, styrene
`
`copolymers, polyacrylates
`
`such as polymethylmethacrylate, polycarbonates,
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`polyacetals, vinyl chloride polymers and copolymers, polyurethanes, polyamides,
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`high density polyethylenes, polypropylenes, and the like. The use of polymeric
`
`milling media to grind materials down to a very small particle size (as opposed to
`
`mechanochemical synthesis)
`
`is disclosed,
`
`for example,
`
`in U.S. Pat. Nos.
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`5,478,705 and 5,500,331. Polymeric resins typically can have densities ranging
`
`from about 0.8 to 3.0 g/cm3. Higher density polymeric resins are preferred.
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`Alternatively, the milling media can be composite particles comprising dense core
`
`particles having a polymeric resin adhered thereon. Core particles can be
`
`selected from materials known to be useful as milling media, for example, glass,
`
`alumina, zirconia silica, zirconium oxide, stainless steel, and the like. Preferred
`
`core materials have densities greater than about 2.5 g/cm3.
`
`In one form of the invention, the milling media are formed from a ferromagnetic
`
`material, thereby facilitating removal of contaminants arising from wear of the
`
`milling media by the use of magnetic separation techniques.
`
`During mechanical activation, the milling media facilitate the direct transfer of
`
`mechanical energy generated by the interaction of the milling media and the
`
`milling apparatus during the rotation, translation, inversion or agitation thereof to
`
`the reactant powders without significant bulk heating of the mixture. Motion
`
`imparted to the milling media can result in application of shearing forces as well
`
`as multiple impacts or collisions having significant intensity between milling media
`
`particles and particles of the reactant powders. The efficiency of mechanical
`
`energy transfer from the milling media to the reactant particles is influenced by a
`
`wide variety of processing parameters including: the type of milling apparatus; the
`
`intensity of the forces generated, the kinematic aspects of the process; the size,
`
`density, shape, and composition of the milling media; the weight ratio of the
`
`reaction mixture to the milling media; the duration of activation; the physical
`
`properties of both reactants and products;
`
`the atmosphere present during
`
`activation; and also others.
`
`The general physical and chemical principles
`
`governing mechanochemical activation are incompletely understood and ordinarily
`
`depend on the specific reactants and products.
`
`The mechanical activation process of the present invention is accomplished most
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`advantageously by a milling apparatus that can repeatedly or continuously apply
`
`mechanical compressive forces and shear stress to the particles of the reaction
`
`mixture. A suitable ‘milling apparatus can be any reactor or vessel that facilitates
`
`energy exchange between the precursor compound and the co-reactant and may
`
`be selected from any known in the art, including but not limited to the following:
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`high—energy ball, sand, bead or pearl mills, basket mill, planetary mill, vibratory
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`action ball mill, multi-axial shaker/mixer, stirred ball mill, horizontal small media
`
`mill, multi-ring pulverizing mill, and the like, including small milling media. The
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`milling apparatus also can contain one or more rotating shafts. Suitable rates of
`
`agitation and total activation times are adjusted for the type and size of milling
`
`apparatus as well as the milling media, the weight ratio of the reaction mixture to
`
`mil