KR20050085035A - Media milling using nonspherical grinding media - Google Patents

Abstract

The present invention relates to a milling method in which nonspherical grinding media is used to produce small particles useful in pharmaceuticals, nutraceuticals, and diagnostic agents.

Description

Milling media using non-spherical grinding media {MEDIA MILLING USING NONSPHERICAL GRINDING MEDIA}

The present invention relates to a media milling method in which non-spherical grinding media are used to produce small particles that are particularly useful in the pharmaceutical, nutraceutical, and diagnostic fields.

Methods of making fine particles have many commercial applications, for example in the manufacture of oral, transdermal, injectable or inhalable drugs and herbals, nutraceuticals, diagnostic test ingredients and diagnostic agents. For example, it is known that the dissolution rate of a solid compound increases with increasing surface area of the solid. As a result, particle dissolution rates can be increased by increasing the surface area to weight ratio of the particles making up the solid through particle size reduction techniques. Because bioavailability is associated with dissolution kinetics and membrane permeability, in many cases the bioavailability of low-soluble drugs or diagnostic compounds in water can also be increased through reduction in particle size. Also, in many cases, a method of reducing the particle size of the drug is particularly preferred because most of the small molecule drug (grade 2 and grade 4 drugs) are poorly soluble in water or gastric juice. Thus, successful preparation of small particles can produce end products with shorter dissolution times, increased bioavailability and potentially faster treatment initiation effects.

In the pharmaceutical and other industries, media milling is a frequently used method for producing fine and ultra fine (nano) particles. Media milling methods generally include filling the milling chamber with grinding media together with the material to be ground. In the case of wet medium milling, the material to be ground is generally added to the mill as a slurry consisting of a solid suspended in a liquid. Often, surfactants are added to stabilize the slurry. Some form of stirring device is then used to agitate the grinding media to break up the solid particles. Alternatively, the grinding media can be brought into motion by applying planetary motion, tumbling, or vibrational motion to the milling chamber, or when the magnetic grinding medium filled in the milling chamber receives an alternating / swinging magnetic field. Common wet mills include colloid mills, pressure homogenizers, rotor stators, and media mills. See, for example, "Technical Aspects of Dispersion" by DA Wheeler, Chapter 7 "Dispersion of Powders in Liquids", edited by GD Parfitt, 3 ^rd edition, Applied Science Publishers.

The type of grinding media filled in the media mill is generally selected from any dense, tough, hard material, such as sand, stainless steel, zirconium silicate, zirconium oxide, yttrium oxide, glass, alumina, titanium and the like. In situations involving metal (oxide) contamination, or shifts in pH, polymer grinding media are used.

Generally, the grinding media filled in the milling chamber consists of spherical media milling beads. Spherical grinding media were considered to be the most mechanically stable form of hard grinding media because they have theoretically no wear or shaving edges. Typically, spherical hard, rigid grinding media have been used in the milling method where it is necessary to prevent or reduce the grinding or wear of the hard grinding media.

US Pat. No. 5,145,684 to Liversidge et al., And EPO 498,492, disclose dispersible particles of drug substance or x-ray contrast agent with surface modifiers absorbed on their surface in an amount sufficient to maintain an effective average particle size of less than about 400 nm. List it. The particles are prepared by dispersing the drug substance or contrast agent in a liquid dispersion medium and wet grinding in the presence of a rigid spherical or particulate grinding medium.

U. S. Patent No. 5,518, 187 to Bruno et al. Describes a method of making a drag material or diagnostic imaging agent particle comprising grinding the drag material or imaging agent in the presence of a grinding media consisting essentially of a polymer resin. The grinding media is characterized in that it is substantially spherical in the disclosure.

US Pat. No. 5,862,999 to Czekai et al. Describes a method for preparing therapeutic and diagnostic imaging agent particles having an average particle size of less than about 500 nm by grinding the therapeutic or diagnostic imaging agent in the presence of a rigid grinding media having an average particle size of less than about 100 microns. do. The grinding media is characterized in that it is substantially spherical in the disclosure.

U.S. Patent Application 2002/0003179 A1 to Verhoff et al. Describes a process for preparing a solid particle dispersion of a milled substrate comprising using a plurality of large and small size media together in the same milling chamber.

U. S. Patent No. 3,210, 016 discloses an apparatus and method for a method similar to ball milling using a milling agent having a planar surface rather than a round surface.

US Pat. No. 6,634,572 B2 discloses a method of milling a solid substrate in the presence of two or more different milling media.

PCT International Application No. PCT / US02 / 16159 is a co-owned co-pending application that discloses an apparatus and method for high pressure media milling.

U. S. Patent No. 5,891, 231 relates to a grinding method for producing colorants for inks in which the grinding media can be spherical, cylindrical or cubic.

Co-owned co-pending patent application WO 03/040245 discloses the use of cubic grinding media for producing colorant particles for the ink industry.

Summary of the Invention

According to the present invention, there is provided a method for producing fine particles of a drug, nutraceutical, or diagnostic agent comprising grinding a drug, nutraceutical, or diagnostic agent using a non-spherical grinding medium.

The grinding media can be made essentially of any tough elastic material. Or in the alternative, the grinding media may comprise particles comprising a core having a tough elastic material attached thereon. The type of material selected to include the medium is determined in part by the toughness and hardness needed to effectively mill the particular particle to be milled.

1 is an optical micrograph at 80X magnification showing 500 micron cubic nylon ground particles (purchased from Norstone Inc., Wyncote, PA, USA).

FIG. 2 is an optical micrograph at 80 × magnification showing 500 micron spherical polystyrene ground particles (purchased from Norstone Inc., Wyncote, PA, USA).

3 is an electron micrograph showing the starting ibuprofen used in Example 2. FIG.

4 is an electron micrograph showing ibuprofen after grinding according to the method of Example 2. FIG.

All documents cited in this disclosure are particularly cited in their entirety.

The present invention is a medium milling method using non-spherical grinding media to produce small particles useful in many commercial applications, particularly pharmaceuticals, nutraceuticals, and diagnostic agents.

The term "nonspherical" as used by the applicant means any three-dimensional shape that is not substantially spherical. The term “spherical” is given the usual meaning and is defined as any three-dimensional shape in which all points are equidistant when measured in a straight line from the center of the object to the surface of the object. For example, non-spherical media may include media shapes that are substantially cubic, rectangular, hexagonal, rod-shaped, needle-shaped, or elliptical. Applicants point out that in the use of the term "non-spherical", the grinding media is not necessarily made of "perfect shape" cubic, rectangular, hexagonal, rod-shaped, needle-shaped, etc. as used classically in the field of geometry. do. In addition, media consisting of a combination of the above-mentioned non-spherical shapes are used in the method of the present invention.

Applicant media mills, or media mills, generally describe any apparatus or method for reducing the size of a solid particulate material through a grinding method using grinding media. The media milling method embodied in the present invention comprises an attritor, a tumbling ball mill, a vibratory ball mill, a planetary ball mill, a horizontal media mill, a vertical media mill, or an annular media mill. It may be any wet or dry grinding method used. In dry tumbling, vibrating, or planetary motion ball milling methods, the carrier fluid may be a gas such as air or nitrogen, or an inert or reactive gas. A common wet milling method is called slurry milling where a liquid is used as the carrier fluid. Possible liquids include water, salt solutions, buffer solutions, solvents (ethanol, hexane, glycols, and the like), solvent / water mixtures, solvent / solvent mixtures, and the like.

In another aspect, the carrier fluid may be a pressurized gas, such as pressurized nitrogen, or a gas under supercritical pressure or temperature conditions, for example CO ₂ pressurized above a critical point. In this embodiment, the invention may be practiced according to the high pressure medium milling method described in the name “high pressure medium milling” (co-owned, co-pending patent application PCT / US02 / 16159), which is incorporated herein by reference.

In general, the non-spherical media milling beads of the present invention may be composed of any material having greater hardness and stiffness than the material to be ground into particles. Thus, the grinding material may consist of almost all tough, hard materials, including, for example, nylon and polymer resins, metals, and various naturally occurring materials such as chitin obtained from sand, silica, or crab shells. Preferably, the non-spherical grinding media of the present invention consist of a tough elastic material having a low wear rate and thus a low incidence of contamination of the ground material by the worn media pieces. In addition, the non-spherical grinding media may consist entirely of a single material that is tough and elastic, or may alternatively comprise a core portion having a coating of one or more materials, ie, a tough elastic material attached thereon. In addition, the non-spherical grinding media may consist of a mixture of any materials suitable for grinding.

 Polymeric resins suitable for use herein as the grinding media are chemically and physically inert so as not to chip or break during grinding, and are preferably substantially free of metals, solvents and monomers, and have sufficient hardness and friability. . Suitable polymer resins are crosslinked polystyrenes such as polystyrene crosslinked with divinylbenzene, styrene copolymers, polycarbonates, polyacetals such as Delrin (trade name), vinyl chloride polymers and copolymers, polyurethanes , Polyamide, poly (tetrafluoroethylene), eg Teflon (trade name), and other fluoropolymers, high density polyethylene, polypropylene, cellulose ethers and esters such as cellulose acetate, polyhydroxymethacrylate, Silicone-containing polymers such as polyhydroxyethyl acrylate, polysiloxane, and the like.

Biodegradable polymer resins are also suitable for use herein. Exemplary biodegradable polymers include poly (lactide), poly (glycolide), copolymers of lactide and glycolide, polyanhydrides, poly (hydroxyethyl methacrylate), poly (imino carbonate) , Poly (N-acylhydroxyproline) ester, poly (N-palmitoyl hydroxyproline) ester, ethylene-vinyl acetate copolymer, poly (orthoester), poly (caprolactone), and poly (phosphazene) It includes.

In the case of biodegradable polymers, media contaminants can be advantageously metabolized in vivo into biologically acceptable products that can be removed from the body. Additional grinding media materials include extinguishing components having a "GRAS" (generally recognized as safe) condition. For example, there are starch based materials or other carbohydrates, protein based materials, and salt based materials such as cubic sodium chloride crystals.

In grinding media comprising a core of one or more materials, the core material (s) may be selected from materials known to be useful as grinding media, preferably when produced as spheres or particles. Suitable core materials include, but are not limited to, zirconium oxide (eg, 95% zirconium oxide stabilized with magnesia or yttrium), zirconium silicate, glass, stainless steel, titania, alumina, ferrite, and the like. The core material (s) can also be magnetic.

The size of the particles produced according to the method of the present invention can vary widely depending on the desired application. However, in many pharmaceutical, nutraceutical and diagnostic applications, the desired size is in the range of 100 μm to nanometers. Often, the size range useful in the pharmaceutical field is especially below about 500 nm.

Surprisingly, non-spherical grinding media can allow large particles to be produced in pharmaceuticals, nutraceuticals, and diagnostic agents. In addition, non-spherical grinding media can shorten the milling time, especially when the production of very fine particles is required. As demonstrated in Example 1, the Applicant noted that when the grinding conditions and the grinding material are the same, grinding can proceed faster by the non-spherical grinding media than the spherical grinding media. In particular, it has been found that when the same volume of cubic polystyrene grinding media and spherical polystyrene grinding media are used in the same milling method under the same milling conditions, the grinding proceeds at a faster rate by the cubic polystyrene grinding media than the spherical polystyrene grinding media. .

Any size grinding media suitable to achieve the desired particle size can be used. However, in many applications the preferred size of the grinding media ranges from 15 mm to 20 microns for continuous media milling where the media stay in the mill. In the case of batch media milling (in the etitor) or circulating milling, where the slurry and grinding media are circulated, smaller non-spherical grinding media can often be used.

Various manufacturing methods can be used to produce the non-spherical grinding media used according to the method of the present invention. For example, the media material may be cryogenically ground and then subjected to screening or air sorting techniques to obtain the desired size grade / fraction. Additionally, 1) extrusion through different die designs, 2) various cutting techniques may be applied, or 3) cast through available casting methods to form non-spherical grinding media. In many cases, non-spherical grinding media having the desired size and material properties can be commercially available.

The invention may be practiced to produce a wide variety of particle sizes, particularly in the fields of medicine, nutraceuticals, and diagnostics. In the case of dry milling, the drug, nutraceutical, and diagnostic agent must be able to form into solid particles. In the case of wet milling, the drug, nutraceutical, and diagnostic agent are preferably dispersible and low in solubility in one or more fluid media. "Low soluble" means that the drug, nutraceutical, or diagnostic agent has a solubility of less than about 10 mg / ml, and in most cases less than about 1 mg / ml, in a liquid dispersion medium, such as water, at room temperature. However, compounds that are not low in solubility can still be milled using a fluid saturated with the compound. The term “fluid” used by the applicant in wet milling means that the continuous phase can be a liquid, gas, pressurized gas, liquefied gas, supercritical fluid, subcritical fluid, or any combination thereof.

Water-soluble and water-insoluble drugs suitable for use in the present invention are anabolic steroids, stimulants, analgesics, anesthetics, antacids, antiarrhythmics, anti-asthmatics, antibiotics, anti-caring agents, anticoagulants, anticholinergics, anticonvulsants, antidepressants, antidiabetics Antidiabetic, anti-epileptic, antiepileptic, antifungal, antiparasitic, hemorrhoidal, antihistamine, anti-hormonal, antihypertensive, antihypertensive, anti-inflammatory, anti-muscarinic, antifungal, anti-tumor, anti-obesity, anti-plaque, Antiprotozoal agents, antipsychotics, antiseptics, anticonvulsants, antithrombotic agents, antitussives, antiviral agents, antianxiety agents, astringents, beta-adrenergic receptor blockers, bile acids, mouthwashes, bronchospasm inhibitors, bronchodilators, calcium channel blockers, cardiac glycosides, Contraceptives, corticosteroids, decongestants, diagnostics, digestives, diuretics, dopamine, electrolytes, nausea, expectorants, hemostatics, hormones, hors Alternative therapies, sleeping pills, hypoglycemic agents, immunosuppressants, erectile dysfunction agents, laxatives, fat control agents, mucolytic agents, muscle relaxants, nonsteroidal anti-inflammatory drugs, nutraceuticals, analgesics, parasympathetic agents, parasympathetic nerve agents, prostagladins, mental Stimulants, psychiatric agents, sedatives, sex steroids, antispasmodics, steroids, stimulants, sulfonamides, sympathomimetic agents, sympathomimetic agents, sympathomimetic agents, thyroids, thyreostatic drugs, vasodilators, vitamins, xanthines, And mixtures thereof.

Suitable herbal substances are any therapeutic compound derived from a biological source or chemically synthesized as equivalent to a product from a biological source, eg proteins, peptides, bexins, nucleic acids, immunoglobulins, polysaccharides, cell products, plant extracts, plants Phytochemicals, animal extracts, recombinant proteins, enzymes or combinations thereof.

Suitable drugs and herbal substances include those delivered through pulmonary delivery mechanisms, parenteral delivery mechanisms, percutaneous delivery mechanisms, oral delivery mechanisms, ocular delivery mechanisms, suppository or vaginal delivery mechanisms, ear delivery mechanisms, nasal delivery mechanisms and implanted delivery mechanisms. Include.

Suitable diagnostic agents are ethyl-3,5-bisacetoamido-2,4,6-triiodobenzoate (WIN 8883), ethyl (3,5-bis (acetylamino) -2,4,6-tri Iodobenzoyloxy) acetate (WIN 12901), ethyl-2- (bis (acetylamino) -2,4,6-triiodobenzoyloxy) butyrate (WIN 16318), 6-ethoxy-6-oxohexyl- 3,5-bis (acetylamino) -2,4,6-triiodobenzoate (WIN 67722), but is not limited thereto. Other suitable imaging agents are described in the disclosure EPO 498,482, which is incorporated herein by reference. Diagnostic agents also include any other particulate matter useful in vivo or ex vivo in the detection or quantification of health or disease.

Suitable nutraceuticals include dietary supplements such as vitamins and minerals, herbal remedies such as Asian ginseng, bilberry, black cohash, cascara, cat's claw, Cayenne, cranberry, devil's claw, dong quai, echinacea, evening primrose oil, feverfew, garlic, ginger, ginkgo biloba ginkgo biloba, ginseng, golden seal, gotu kola, grape seed, green tea, hawthorn, kava, licorice, milk thistle, cow palmetto, Siberian ginseng, St. John's wort, valerian root, probiotics, and functional foods such as, but not limited to, yogurt, high calcium milk, and high fiber bread. Do not. In addition, any substance normally digested by humans or animals for optimal sustaining, growth and maintenance is considered a food or food substance that can be used as a source of nutraceuticals.

Those skilled in the art will be able to identify other fields and applications in which many different types of articles can be milled according to the method of the present invention.

The material to be ground by means of the invention is often milled at a temperature that does not significantly reduce or lose the efficacy of the material. If the ground material is a chemical, a treatment temperature of less than about 30-40 ° C. is generally preferred. At the end of the method, the processing equipment can be cooled using conventional cooling equipment. Supercooling conditions may also be used if the fluid selected is a gas at ambient temperature.

The media milling method can be performed under various pressure conditions. For example, general media milling can typically be performed under conditions of ambient pressure. Ambient processing pressures are common in balls, eritators and vibratory mills. Processing pressures up to about 20 psi (1.4 kg / cm 2) are common in conventional media milling.

The process according to the invention can also be carried out at elevated pressures using a gas pressurized above a critical pressure, for example using the name “high pressure medium milling” (generally co-owned application PCT / US02 / 16159). See.

The carrier fluid may be pressurized gas, pressurized liquid or supercritical fluid.

The present invention can also be used to produce any of a variety of small, high surface area particles that can be used as carrier particles for liquids or as seeds for crystallization or precipitation. Particles formed by the method of the present invention may in many cases also be coated simultaneously or subsequently with moisture barriers, taste shields, or other additives or encapsulating agents that improve the properties of the drug, nutraceutical or diagnostic agent.

Particles of drugs, nutraceuticals and diagnostic agents may also be combined with other materials during the milling process. Most other materials are inerts, which may include, for example, surfactants, dispersants, and the like. Thus, in the process of the invention, surface modifiers such as surfactants, emulsifiers, or stabilizers may be adsorbed on the surface of the drug, nutraceutical or diagnostic particles during the milling process. Useful surface modifiers are believed to include those chemically bound to the surface of the drug, nutraceutical or diagnostic particle as well as those physically attached. The surface modifier may be present in an amount of 0.1 to 90% by weight, preferably 1 to 10% by weight, of the total weight of each material and surface modifier.

Preferred proportions of the grinding media, drugs, nutraceuticals and / or diagnostic agents, any liquid dispersion media, and the inert agent (s) present in the mill's grinding vessel are, for example, the particular drug, nutraceutical, or diagnostic agent selected. It can vary widely depending on the size and density of the grinding media, the type of mill selected and the like.

The process can be carried out continuously, batch or semi-batch. In high energy medium mills, it may be desirable for 70-90% of the grinding chamber volume to be filled with grinding media. Conversely, in the case of a roller mill it may often be desirable for the grinding chamber volume of 50% to consist of air and the remaining 50% to the grinding medium and, if present, to a liquid dispersion medium. This allows a cascade effect in the container of the roller, allowing the solid product to be effectively milled. However, if foaming is a problem during wet grinding, the container may be completely filled with a liquid dispersion medium.

The treatment or milling time may also vary widely depending on the particular mechanical means selected and the treatment conditions. In the case of ball mills, treatment times of up to 5 days or more may be required. On the other hand, high shear media mills can be used to achieve the desired results with treatment times of less than one day (retention times of one minute or several hours).

After milling is complete, the grinding media is separated into milled particulate product (in dry or liquid dispersion form) using conventional separation techniques such as sieving through filtration, mesh screens and the like. When using a high pressure medium mill containing a supercritical fluid, the grinding fluid is advantageously separated from the grinding medium and the ground particles by evaporation after the high pressure medium milling process returns to ambient pressure.

The invention is further defined in the following examples, all parts and proportions being based on weight. It should be understood that these examples of the present invention are given by way of illustration only, although they represent preferred embodiments. From the foregoing discussion and these embodiments, those skilled in the art can identify essential features of the present invention and can make various changes and modifications to adapt to various uses and conditions without departing from the spirit and scope of the present invention.

<Example 1>

Grinding of Naproxen in a SPEX Mill Using Cubic Polymer Grinding Media

Cubic nylon grinding media with a size of 500 microns (Norstone Inc., Wyncote, PA, USA) was added to a 2 oz glass jar, and 50% of the jar was filled with cubic nylon grinding media (bulk volume). An aqueous dispersion containing 5 wt% USP grade naproxen (Spectrum Chemicals) and 3 wt% Pluronic (VWR Scientific) was formed. 8 grams of the dispersion was then added to a 2 oz glass jar containing grinding media and placed in a holder in a SPEX 8000 mixer / mill (SPEX, Rexton, VA, USA).

The dispersion was milled at the default mill speed (60 Hz). Naproxen particles were measured at 8 and 18 hour intervals using a Malvern Mastersizer 2000 (Malvern Instruments, Worcestershire, UK). The results are listed in Table 1 below. After 8 hours milling, the cubic nylon grinding media produced particles with a particle size of 2,986 nm. After 18 hours milling, fine naproxen particles having a median particle size of 363 nm were prepared. The final product was a milky material with no noticeable discoloration.

Particle Size of Naproxen Milled Using Cubic Nylon Media (w / Malvern MS2000) Milling time Medium granularity 8 hours 2,986 nm 18 hours 363 nm

<Example 2>

Milling of Ibuprofen in High Pressure Medium Mills

Cubic nylon grinding media (Norstone Inc., Wyncote, PA, USA) with a particle size of 500 microns were added to a 1 L high pressure medium mill (Dupont, WO 02/094443 A2). 72% of the grinding chamber was filled with cubic nylon grinding media (bulk volume). 150 grams of ibuprofen (Spectrum Chemicals) was charged to the grinding chamber. The mill was then pressurized with carbon dioxide under supercritical conditions. The mill was operated for 4 hours at a pressure of 1450 psi and a temperature of 35 ° C. The mill speed was kept constant at 1750 RPM. The product was collected from the mill after completion of the run. The particle size of the feedstock and the milled product was measured by forward light scattering (Mastersizer 2000, Malvern Instruments, England). Particle size data is listed in Table 2. Particle scanning micrographs (SEM, Hitachi S-4700, San Jose, Calif.) Were taken of the feedstock (FIG. 3) and the milled product (FIG. 4). The grain size of the milled product increased. However, scanning electron micrographs show that the milled product is agglomerated and composed of fine primary crystals.

Cumulative undersize of feedstock and milled ibuprofen 10% 50% 90% Feedstock (microns) 4.3 41.2 105.6 Milled Ibuprofen (micron) 17.2 58.2 119.9

<Example 3>

Grinding of Naproxen in Netzsch High Speed Medium Mills

The following components shown in Table 3 were mixed to prepare a 1-liter naproxen dispersion.

Preparation of Naproxen Dispersion ingredient density Deionized water 92 wt% Pluronic F68 (BASF) 3 wt% Naproxen (Spectrum Chemicals) 5 wt%

The dispersion was charged to a feed tank of a Netzsch Labstar medium mill (Netzsch Inc., Exton, PA). The mill chamber was filled with 80% cubic nylon grinding media. The dispersion was circulated through a medium mill operated at 3000 RPM. 1 g of sample was taken from the mill return line at a fixed time point for particle analysis with Mastersizer 2000 (Malvern, England). The results are listed in Table 4. After 960 minutes the median size was 230 nanometers.

Particle Size Distribution of Naproxen Milled on a NETZSCH Labstar 10% 50% 90% Sample (Nm) (Nm) (Nm) 0 minutes (supply) 5,214 17,182 189,291 4 mins 2,520 4,943 11,160 32 mins 1,482 2,926 5,457 128 minutes 658 1,615 3,701 240 minutes 128 633 2,930 480 minutes 98 271 2,278 720 minutes 96 246 2,079 960 minutes 94 230 1,718

This application claims the benefit of US Provisional Application No. 60 / 427,122, filed November 18,2002, which is incorporated herein by reference.

Claims (20)

A method of pulverizing a drug, nutraceutical, or diagnostic material comprising pulverizing the material in the presence of a non-spherical grinding medium using a media mill. The method of claim 1 wherein the media mill is a dry media mill. The method of claim 1 wherein the media mill is a wet media mill. The method of claim 1 wherein the media mill contains a fluid pressurized above a critical pressure of the fluid. The method of claim 4, wherein the non-spherical grinding media is cubic. 6. The method of claim 5, wherein the cubic non-spherical grinding media comprises a polymeric material. The method of claim 6, wherein the substance is a drug. 8. The method of claim 7, wherein the drug is ibuprofen or naproxen. The method of claim 1 wherein the media mill contains one or more fluids selected from the group consisting of liquids, gases, liquefied / cooled gases, supercritical fluids and subcritical fluids. The method of claim 1 wherein the non-spherical grinding media is cubic. The method of claim 10, wherein the cubic non-spherical grinding media comprises a material selected from the group consisting of polymeric materials, ceramic materials, and mixtures thereof. The method of claim 11, wherein the substance is a drug. The method of claim 11, wherein the polymeric material is polystyrene. The method of claim 13, wherein the substance is a drug. The method of claim 11, wherein the polymeric material is nylon. The method of claim 15, wherein the substance is a drug. The method of claim 1 wherein the substance is a drug. A method of increasing the solubility of a low soluble drug, nutraceutical, or diagnostic substance, comprising grinding the substance in the presence of non-spherical grinding media using a media mill. A pharmaceutical, nutraceutical, or diagnostic imaging agent comprising the particles crushed according to the method of claim 1. Naproxen or ibuprofen comprising the particles ground according to the method of claim 1.