Patent Publication Number: US-6991191-B2

Title: Method of using a small scale mill

Description:
RELATED APPLICATIONS 
     This application is a continuation of application Ser. No. 10/037,566, filed on Oct. 19, 2001, now U.S. Pat. No. 6,745,962, which is a divisional of application Ser. No. 09/583,893, filed on May 31, 2000, now U.S. Pat. No. 6,431,478, which is based on Provisional Application No. 60/137,142, filed on Jun. 1, 1999, the disclosures of which are specifically incorporated by reference. 
    
    
     BACKGROUND 
     Wet media mills, such as the ones described in U.S. Pat. No. 5,797,550 issued to Woodall, et al, and U.S. Pat. No. 4,848,676 issued to Stehr, are generally used to mill or grind relatively large quantities of materials. These rather large media mills are not generally suitable for grinding small or minute quantities. U.S. Pat. No. 5,593,097 issued to Corbin recognizes the need for milling small quantities, as small as 0.25 grams, to a size less than 0.5 micron to about 0.05 micron in terms of average diameter in about 60 minutes. 
     The media mill described in the Corbin patent comprises a vertically oriented open top vessel, a vertically extending agitator with pegs, a motor for rotating the agitator, and a controller for controlling the rotational speed. The vessel is a cylindrical centrifuge or test tube formed of a glass, plastic, stainless steel, or other suitable material having an inner diameter of between 10 to 20 mm. The media suitable is described as any non-contaminating, wear resistant material, sized between about 0.17 mm to 1 mm in diameter. 
     The particulates to be ground and the grinding media are suspended in a dispersion and poured into the vessel. The agitator, with the peg end inserted in the vessel, is spun. The Corbin patent also discloses that the pegs should extend to within between about 1–3 mm of the sides of the vessel to provide the milling desired in the shortest possible time without damaging the materials and producing excessive heat. To avoid splattering created by vortexing of the material during mixing, the top peg of the mixer is positioned even with the top of the dispersion. No seal or cover is deemed needed during mixing or agitation if this practice is followed. 
     The Corbin patent also discloses that its micro media can be useful for forming medicinal compounds, food additives, catalysts, pigments, and scents. Medicinal or pharmaceutical compounds can be expensive and require much experimentation, with different sizes and quantities. The Corbin patent discloses that the preferred media for medicinal compounds are zirconium oxide and glass. Moreover, pharmaceutical compounds are often heat sensitive, and thus must be maintained at certain temperatures. In this respect, the Corbin patent discloses using a temperature control bath around the vessel. 
     In the media mill of the type described in the Corbin patent, even if the vessel is filled to the top peg, however, the rotating agitator in the dispersion creates a vortex, which undesirably draws air into the dispersion and foams the dispersion. Moreover, the open top configuration draws in contamination, making the mill unsuitable for pharmaceutical products. The temperature-controlled bath could spill into the open top container and further contaminate the product. 
     There is a need for a micro or small-scale media mill that avoids these problems. The present invention is believed to meet this need. 
     SUMMARY 
     The present invention relates to a small-scale or micro media-mill and a method of milling materials, such as pharmaceutical products. The present small-scale mill, which can be vertically or horizontally oriented, can use a dispersion containing attrition milling media and the product to be milled. The milling media can be polymeric type, such as formed of polystyrene or cross-linked polystyrene having a nominal diameter of no greater than 500 microns. Other sizes include 200 microns and 50 microns and a mixture of these sizes. 
     In one embodiment, the mill has a relatively small vessel having an opening, an agitator, and a coupling, and a rotatable shaft mounted for rotation about a shaft mount. The agitator is dimensioned to be inserted in the vessel through the opening. Specifically, the agitator can have a rotor and a rotor shaft extending from the rotor. The rotor shaft is connected to the rotatable shaft. The rotor is dimensioned to be inserted in the vessel with a small gap formed between an outer rotating surface of the rotor and an internal surface of the vessel. The coupling detachably connects the vessel to the shaft mount. The coupling has an opening through which a portion of the agitator, such as the rotor shaft, extends. The shaft mount seals the vessel opening to seal the dispersion in the vessel. A seal can be provided to seal the portion of the agitator or the rotor shaft while permitting the agitator to rotate. The rotatable shaft can be driven by a motor or can be a motor shaft of a motor, preferably a variable speed motor capable of 6000 RPM. 
     In one embodiment; the coupling can have a threaded portion for detachably mounting to the shaft mount and a flange portion for detachably coupling to the vessel. In another embodiment, the coupling is integrally formed with the vessel and has a threaded portion for detachably mounting to the shaft mount. 
     The mill can include a cooling system connected to the vessel. In one embodiment, the cooling system can comprise a water jacket. Specifically, the vessel comprises a cylindrical inner vessel and an outer vessel spaced from and surrounding the inner vessel. The inner and outer vessels form a chamber therebetween. The chamber can be vessel shaped or annular. A flange connects the upper ends of the inner and outer vessel. The outer vessel (jacket) has at least first and second passages that communicate with the chamber. The cooling system comprises the outer vessel with the first and second passages, which is adapted to circulate cooling fluid. 
     In an alternative embodiment, the vessel can comprise an inner cylindrical wall having a bottom and an open top and an outer cylindrical wall spaced from and surrounding the inner vessel. The inner and outer cylindrical walls are connected together so that an annular chamber is formed therebetween. At least the first and second passages are formed at the outer cylindrical wall and communicate with the chamber to pass coolant. The bottom extends radially and covers the bottom end of the outer cylindrical wall. The bottom can have an aperture that allows samples of the dispersion to be withdrawn. A valve can close the aperture. Alternatively, the bottom can have an observation window for observing the dispersion. 
     In another embodiment, the vessel can include at least one port through which the dispersion is filled. The vessel includes at least two ports through which the dispersion is circulated. In this respect, the cooling system comprises the ports on the vessel for circulating the dispersion. The vessel can be horizontally oriented. 
     The rotor can be cylindrical, and can have tapered end surfaces. In one embodiment, the rotor is dimensioned so that its outer periphery is spaced no larger than 3 mm away from an inner surface of the vessel, particularly when the dispersion contains attrition media having a nominal size of no larger than 500 microns. The spacing or the gap is preferably no larger than 1 mm, particularly when the dispersion contains attrition media having a nominal size of no larger than 200 microns. 
     In another embodiment, the cylindrical rotor can have a cavity and a plurality of slots that extend between an inner surface of the cavity and an outer surface of the cylindrical rotor. In another embodiment, the cylindrical rotor can have a plurality of channels extending to an outer surface of the cylindrical rotor. In another embodiment, the cylindrical rotor can have a plurality of passageways extending between the tapered end surfaces of the cylindrical rotor. 
     One method according to the present invention comprises providing a dispersion containing a non-soluble product to be milled and attrition milling media having a nominal size of no greater than 500 microns; inserting the dispersion into a cylindrical vessel; providing an agitator and a coupling that closes the vessel, the coupling having an opening through which a portion of the agitator extends, the agitator comprising a cylindrical rotor and a shaft extending therefrom, wherein the cylindrical rotor is dimensioned so that an outer periphery is no greater than 3 mm away from an inner surface of the cylindrical wall; inserting an agitator into cylindrical vessel and sealingly closing the coupling, wherein the amount of dispersion inserted into the vessel is so that the dispersion eliminates substantially all of the air in the vessel when the agitator is fully inserted into the vessel; and rotating the agitator for a predetermined period. 
     Another method according to the present invention comprises providing a dispersion containing a non-soluble product to be milled and attrition milling media having a nominal size of no greater than 500 microns; providing an agitator having a cylindrical rotor and shaft extending therefrom; inserting the agitator in a horizontally oriented cylindrical vessel and sealing the cylindrical vessel, the cylindrical rotor being dimensioned to provide a gap of no greater than 3 mm between an outer surface of the rotor and an inner surface of the vessel; providing at least one port through the cylindrical vessel and maintaining the port at a highest point of the horizontally oriented cylindrical vessel; filling the cylindrical vessel with the dispersion until the dispersion drives out substantially all of the air in the vessel; and rotating the agitator for a predetermined period. 
     The method further includes cooling the vessel by jacketing the vessel and flowing water between the jacket and the vessel. Another method comprises externally circulating the dispersion through a plurality of ports formed through the horizontally oriented vessel to thereby cool the dispersion or refresh the dispersion. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       These and other features, aspects, and advantages of the present invention will become more apparent from the following description, appended claims, and accompanying exemplary embodiments shown in the drawings. 
         FIG. 1  illustrates a small-scale or micro-media mill according to one embodiment of the present invention. 
         FIG. 1A  illustrates an enlarged detailed view of the mill shown in  FIG. 1 . 
         FIG. 2  illustrates the media mill of  FIG. 1 , but with a different vessel. 
         FIG. 3  illustrates a small-scale or micro-media mill according to another embodiment of the present invention. 
         FIG. 3A  illustrates an enlarged detailed view of the mill shown in  FIG. 3 . 
         FIG. 3B  illustrates an enlarged detailed view taken along area  3 B of  FIG. 3A . 
         FIG. 4  illustrates a side view of a small scale or micro media mill according to another embodiment of the present invention. 
         FIG. 5  illustrates another embodiment of an agitator and another embodiment of a vessel that can be used with the media mill of  FIGS. 1–4 . 
         FIG. 6  illustrates the agitator of the type illustrated in the embodiments of  FIGS. 1–4 . 
         FIG. 7–13D  illustrate various agitator configurations that can be used with the media mill of  FIGS. 1–4 . 
     
    
    
     DETAILED DESCRIPTION 
     Although references are made below to directions in describing the structure, they are made relative to the drawings (as normally viewed) for convenience. The directions, such as top, bottom, upper, lower, etc., are not intended to be taken literally or limit the present invention. 
     A small-scale mill  1 ,  1 A,  2  ( FIGS. 1–4 ) according to the present invention is designed to mill relatively small amounts of dispersion to a size ranging from microns to nanometers in a relatively short time, i.e., a few hours or less, using attrition milling media, such as polymer type, e.g., cross linked polystyrene media, having nominal size no greater than about 500 microns (0.5 mm) to about 50 microns or mixtures of the sizes ranging between them. The performance of the present scale mill is designed to provide the results comparable to the DYNO-MILL and the NETZSCH ZETA mills. The mill  1 ,  1 A,  2  according to the present invention can have a provision for cooling the dispersion, which allows increased agitator tip speed without overheating, to increase its efficiency and allow milling of heat sensitive pharmaceutical products. 
     A vertically oriented mills  1 ,  1 A is exemplified in  FIGS. 1–3A . The mill  1 ,  1 A generally comprises a container or vessel  10 ,  10 A,  10 B,  10 C, an agitator or mixer  30 , a coupling  50 , and a rotatable journaled shaft  120 , which can be that of a motor  100 . The vessel  10 ,  10 A,  10 B,  10 C has a substantially cylindrical milling chamber and can be single walled  10 C, as shown in  FIGS. 5 and 6 , or jacketed (double-walled)  10 ,  10 A,  10 B, as shown in  FIGS. 1–3A , to allow water cooling. The agitator  30 , which comprises a rotor  32  and a shaft  40  extending from one end of the rotor  32 , is preferably a single piece to ease cleaning, and is adapted to be connected to a conventional electric motor  100 , which preferably is capable of rotating up to 6000 RPM. A conventional motor controller  101  ( FIGS. 1 ,  3 ,  4 ), such as SERVODYNE Mixer Controller available from Cole-Parmer Instrument Co. of Vernon Hills, Ill., can control the motor speed and duration. The coupling  50  is mounted to the motor  100  and is coupled to the vessel  10  using a sanitary fitting and a clamp C (shown in phantom in  FIG. 3 ) to seal the vessel  10 ,  10 A,  10 B,  10 C. 
     Referring to  FIG. 1A , the vessel  10  in this embodiment is double walled or jacketed to circulate a coolant. Specifically, the vessel  10  comprises an inner cylindrical wall  12  and an outer cylindrical wall  14  spaced from and concentric with the inner cylindrical wall  12 . The outer wall  14 , however, need not be cylindrical or concentric relative to the inner wall  12 . It can have any configuration that allows water circulation to the inner cylindrical wall  12 . An annular mounting flange  16  holds together top end of the inner and outer cylindrical walls  12 ,  14 . The inner cylindrical wall  12  has a bottom wall  13  enclosing its bottom end to form an inner vessel ( 12 ,  13 ). The outer cylindrical wall  14  also has a bottom wall  15  enclosing its bottom end and spaced from the bottom wall  13  to form an outer vessel ( 14 ,  15 ). The outer vessel ( 14 ,  15 ) is spaced from the inner vessel ( 12 ,  13 ) and forms a vessel shaped chamber  17  that can be filled with water and circulated to cool the dispersion during milling. 
     The outer cylindrical wall  14  has two openings  20 , preferably positioned diametrically opposite to each other and a pair of coolant connectors  22  aligned with the openings  20 . Either of these connectors  22  can serve as a coolant inlet or outlet. These connectors  22  can extend substantially radially outwardly. The free end of each connector can have a sanitary fitting, which includes an annular mounting flange  24  and a complementary fitting (essentially mirror image thereof—not shown), adapted to be clamped with, for example, a TRI-CLAMP available from Tri-Clover Inc. of Kenosha, Wis. These mounting flanges  24  are configured substantially similar to the mounting flanges  16 ,  52  connecting the vessel  10 ,  10 A,  10 B,  10 C to the motor  100 . All of these mounting flanges  16 ,  24 ,  52  can be adapted for a TRI-CLAMP, as described below. Each of these flanges  16 ,  24 ,  52  has an annular groove G for seating an annular gasket  60  and a beveled or tapered surface B. The mounting flanges and the gasket  60 , which is FDA approved, adapted for the TRI-CLAMP are also available from Tri-Clover Inc. 
       FIG. 2  shows another embodiment of the double walled vessel  10 A, which is substantially similar to that shown in  FIGS. 1 and 1A . The difference is that the bottom wall  13  of the inner cylindrical wall  12  in  FIG. 2  is exposed. In other words, the alternative vessel  10 A of  FIG. 2  has no outer bottom wall  15  of  FIG. 1A . The alternative vessel  10 A has its bottom wall  13  extending radially outwardly to the outer cylindrical wall  14 . The chamber  17  is annular instead of being vessel shaped ( FIG. 2 ). The bottom wall  13  can have a heat sink or a Peltier coolant (not shown) attached. The bottom wall  13  also can have an observation window or an opening  205 , which can be sealed or can have a valve  210  that vents excess pressure build up and/or allows a sample withdrawal. This way, minute amounts of dispersion can be taken out and examined without having to take off the coupling  50 . Alternatively, the opening can be sealed using a self-sealing resilient material that permits insertion of a syringe for withdrawing samples. The window  205  can have a small chamber extending outwardly from the bottom (not shown). This chamber can hold a small amount of dispersion so that it can be viewed through an observation device. This chamber can be configured so that the dispersion is constantly circulated, such as placing the window  205  in a location where the dispersion is constantly moving. 
       FIGS. 3 and 3A  show another embodiment of the double walled vessel  10 B, which is substantially similar to that shown in  FIGS. 1 and 1A . The primary difference is that the outer bottom wall  15 A can be threaded or screwed (or sealingly mounted) into the outer cylindrical wall  14 . In this respect, the outer bottom wall  15 A can have an annular groove (not numbered) that seats an O-ring  74  or the like to provide a better water seal. Another difference from the vessel of  FIGS. 1 and 1A , is that a quick couple fitting  22 A,  24 A,  24 B is used. The connectors  22 A are threadlingly mounted to the openings  20  formed in the outer cylindrical wall  14 . The connectors  22 A can use a commercially available quick connector or couple  24 A, such as ⅛″ PARKER series 60 Quick Couple. The quick couple  24 A can be connected to a flexible hose barb  24 A, such as a commercially available stainless steel ⅛″ NPT×¼″ hose barb. The double-walled vessels  10  and  10 A can also use the quick couple fitting  22 A,  24 A,  24 B instead of the sanitary fitting type described above and illustrated in  FIGS. 1–2 . 
     Alternative to the double walled vessel is a single walled vessel  10 C shown in  FIGS. 5 and 6 . The single walled vessel  10 C can be used when the product to be milled is not heat sensitive or for milling a short period. The single walled vessel is constructed similar to the inner vessel ( 12 ,  13 ) of the double walled vessel  10 . A heat sink (not shown) can be attached to its cylindrical wall  12  and bottom wall  13 . The heat sink also can be fan cooled. Another alternative cooling system can be a Peltier cooler, which operates on the Peltier effect theory (cooling by flowing an electric current through a Peltier module made of two different types of conductive or semiconductive materials attached together). A Peltier module with a heat sink (Peltier coolant) can be detachably attached to the vessel. 
     In the embodiments of  FIGS. 1–3 ,  5 , and  6 , the mounting flange  52  of the coupling  50  is configured substantially the same as or complementary to the annular mounting flange  16 . The mounting flanges  16  and  52  are coupled facing each other with the gasket  60 , such as a Tri-Clamp EPDM black, FDA approved gasket, sandwiched therebetween, as shown in  FIGS. 1A ,  2 , and  3 A. The gasket  60  has annular lower  62  and upper  64  protrusions that engage the respective grooves G formed in the mounting flanges  16 ,  52 , and align the flanges  16  and  52 . A TRI-CLAMP C (see  FIG. 3 ) can engage the periphery P and the beveled surfaces B of the mounting flanges  16 ,  52 . When these flanges are aligned, they form a trapezoidal profile. Tightly wrapping the TRI-CLAMP around the periphery and the beveled surfaces B squeezes the flanges  16 ,  52  together to provide a sealed connection. 
     The mounting flanges  24  of the connectors  22  ( FIGS. 1 ,  1 A,  2 ) can be connected to their respective water source and drain pipes (not shown) in the same way as the vessel  10 ,  10 A,  10 B,  10 C is connected to the coupling  50 , as just described, using a gasket  60  and a TRI-CLAMP C. 
     Referring to the embodiments of  FIGS. 1–3A , the coupling  50  also has a cylindrical portion  54  extending from its mounting flange  52 . The flange  52  has a central opening  56  and a stepped recess  58  concentric with the opening  56 . The recess  58  seats a seal, which can be a lip or mechanical seal ring  70  having a complementary configuration. Specifically, the seal ring  70  can be made from PTFE with a Wolastonite filler and can have an L-shaped (cross-sectional) profile as shown in detail in  FIG. 3B . The seal ring  70  also can include a concentric O-ring  71  or the like, as shown in  FIG. 3B . The opening  56  is dimensioned only slightly larger than the agitator&#39;s shaft  40 . The seal ring  70  is adapted to engage the shaft  40  and seal the same while permitting the agitator  30  to rotate. 
     Referring to  FIGS. 1A ,  2 ,  3 A, the cylindrical portion  54  is threaded on its inner side so that it can be attached to the motor  100 . Specifically, the coupling  50  is attached to a shaft mount  110 , which comprises an annular flange  112  and a downwardly extending cylindrical member  114 . The cylindrical member  114  has an outer threading for threadingly mating with the threaded cylindrical portion  54  of the coupling  50 . The flange  112  is mounted to the motor using bolts  200  or the like. The motor  100  can be mounted to a stand or fixture  150  via the flange  112 , using bolts  200 . The stand  150  allows the motor  100  and the vessel  10 ,  10 A,  10 B,  10 C to be oriented vertically, as shown in  FIGS. 1 ,  1 A,  2 , and  3 . 
     The shaft mount  110  has a central through hole  115  dimensioned larger than the shaft  40 . The distal (lower) end of the cylindrical member  114  has an annular projection  116  that bears against the seal ring  70  (see  FIG. 3B ) and holds the seal ring  70  in place. The coupling  50  has an annular end face  55  that abuts against a complementary face or shoulder  117  formed on the distal (lower) end of the cylindrical member  114 , adjacent to the annular projection  116 . The end face  55  provides a positive stop and maintains proper seal compression when the coupling  50  is mounted to the shaft mount  110 . In this respect, referring to  FIG. 3A , the mounting flange  52  can also include an O-ring  72  positioned in an annular groove  59  formed on the upper end face  55  to provide additional seal. As the temperature of the dispersion increases during milling, expanding air under pressure is designed to escape through the seal ring  70 , while maintaining liquid seal. In this respect, the cylindrical member  114  has a vent opening  118  to vent any air seeping through the seal ring  70 . 
     The rotor shaft  40  comprises a larger diameter portion  42  and a smaller diameter portion  44  having a threaded free end  45 . A tapered section  46  extends between these portions  42 ,  44 . The rotor  30  is attached to the motor  100  by inserting the smaller diameter portion  44  into a hollow motor shaft  120  and threading a nut  49  or a manual knob  49 A ( FIG. 3 ) onto the threaded end  45 , which tightly pulls the tapered section  46  against the lower end or mouth of the hollow shaft  120 , compressively attaching the agitator shaft  40  to the hollow motor shaft  120 . The nut  49  or the knob  49 A can be covered with a safety cap  47  ( FIG. 3 ), which can be mounted to the top end of the motor  100  using a base  48 . The cap  47  can be threadedly mounted to the base  48 . The tapered section  46  also eases the insertion of the shaft  40  through the seal ring  70  and prevents tear or damage to the seal ring  70 . At least around a section CP of the large diametered shaft portion  42  contacting the seal  70  is preferably coated with a wear resistant coating, such as a hard chrome coating to prevent wear. 
     Although the above-described mill  1  ( FIGS. 1–3B ) has been described and shown in a vertical configuration, the present invention also contemplates a horizontally oriented mill  2 , as shown in  FIG. 4 . The horizontally oriented mill  2  is substantially similar to the vertically oriented mill  1  shown in  FIGS. 1–3 , except for the vessel and coupling configuration. In the horizontally oriented mill, a mounting bracket  160  is attached to the motor  100  via the shaft mount  110  so that the mill  2  is stably supported in the horizontal position, as shown in  FIG. 4 . In the horizontally oriented mill  2 , its vessel  10 D can be attached to the motor via a threaded coupling  16 ′, and the shaft  40  can be sealed via a single or double mechanical seal, or a lip seal  70 ′ (shown in phantom). 
     Referring to  FIG. 4 , the vessel  10 D for the horizontally oriented mill  2  is substantially similar to the singled walled vessel  10 C ( FIGS. 5 and 6 ), except that the flange  16  ( FIGS. 5 and 6 ) has a threaded coupling  16 ′, substantially similar to the threaded coupling  50  shown in  FIGS. 1–3A . The vessel  10 D has an open cylindrical wall  12 , with one closed by an end wall  13 . The threaded coupling  16 ′ is integrally or monolithically formed at the opposite open end. The vessel  10 D, however, can be configured like the singled walled vessel  10 C for use with the afore-described sanitary fitting. 
     The vessel  10 D is illustrated with four fill/drain/cooling ports P 1 –P 4  for illustrative purposes only. Only one port is needed in the horizontally oriented mill  2 . The ports P 2 –P 4  are radially extending through the cylindrical wall  12  of the vessel  10 B, whereas the port P 1  is axially extending from the end wall  13  of the vessel  10 B. In one embodiment, the vessel  10 D can have a single top fill port P 2  or P 3 . In such an embodiment, it is especially desirable for the top port P 2  or P 3  to be located at or along the highest point of the milling chamber, i.e., at 12 O&#39;clock position for a cylindrical vessel  10 D, as this allows the chamber to be filled so that all of the air is displaced from the chamber. The absence of air in the milling chamber during operation prevents the formation of foam and enhances milling performance. 
     Alternatively, the horizontally oriented vessel  10 D can contain two or more ports, such as two top radial ports P 2  and P 3 , a single axial port P 1  and a single top radial port P 3 , or a single top radial port P 3  and a single bottom radial port P 4 . In such embodiments, the dispersion can be externally circulated through the vessel  10 D, where one port acts as an outlet and the other an inlet. The dispersion can be cooled or replenished during the circulating process. Using two ports, one can recirculate (or add) the process fluid and/or attrition media via an external vessel and pump (not shown). If the attrition media has to remain in the vessel, the outlet port can be fitted with a suitable screen or filter to retain the media during operation. 
     Referring to  FIGS. 5–13D , the rotor  32 ,  32 A– 32 J (collectively “32”) for both the vertically and horizontally oriented mills  1 ,  1 A,  2  can have different geometric configurations. The agitator  30  is preferably made of stainless steel or teflon or stainless steel with a teflon coating. In this respect, the TRI-CLAMP can be made of 304 stainless steel. The components that are exposed to the dispersion also can be made of 316 stainless steel. In fact, all of the metal components, except the clamp and the motor can be made of 316 stainless steel. Alternatively, all metal components that become exposed to the dispersion can be made of any material that is resistant to crevice corrosion, pitting, and stress corrosion, such as an AL-6XN stainless steel alloy. An AL-6XN alloy meets ASME and ASTM specifications, and is approved by the USDA for use as a food contact surface. 
     The rotor  32  also can comprise a variety of geometries, surface textures, and surface modifications, such as channels or protrusions to alter the fluid flow patterns. For example, the rotor  32  can be cylindrical (straight), as shown in  FIG. 5 , or cylindrical (tapered ends T 1 , T 2 ) as shown in  FIGS. 1–4  and  6 . In other illustrated embodiments, the rotor  32  can be hexagonal ( FIG. 7 ), ribbed ( FIG. 8 ), square ( FIG. 9 ), cylindrical with channels ( FIGS. 10 and 11 ), cylindrical with passageways ( FIG. 12 ), and cylindrical with a cavity and slots ( FIGS. 13–13D ). All of these embodiments can have tapered end surfaces T 1 , T 2 . 
     Specifically, the hexagonal rotor  32 A ( FIG. 7 ) has six planar sides  202 . The ribbed rotor  32 B ( FIG. 8 ) has hexagonal sides  202  as shown in  FIG. 7 , but with six ribs  204  extending respectively from the middle of each of the six sides  202 . The square rotor  32 C ( FIG. 9 ) has four planar sides  206 . The cylindrical rotor  32 D ( FIG. 10 ) has four channels  208  that are perpendicular to each adjacent channels  208 . The cylindrical rotor  32 E ( FIG. 11 ) is substantially identical to the cylindrical rotor  32 D of  FIG. 10 , but has six channels  208  instead of four, symmetrically angled and spaced apart. The cylindrical rotor  32 F ( FIG. 12 ) has four angled passageways  210 , extending from the tapered or conical end surfaces T 1 , T 2 . These angled passageways have four openings at the first tapered end surface T 1  and four openings at the second tapered end surface T 2 . An imaginary circle intercepting the four openings at the first tapered end surface T 1  has a greater diameter than an imaginary circle intercepting the four openings at the second tapered end surface T 2 . 
     The cylindrical rotors  32 G,  32 H,  32 I,  32 J ( FIGS. 13–13D ) each have a concentrical cylindrical cavity  212  opening to the second tapered surface T 2 . Depending on the material and the media mill size, these rotors can have at least three (not shown) equally spaced apart axially extending flow modifying channels  214 . The rotors  32 G– 23 J are respectively shown with four, six, eight, and nine channels  214 . These slots  214  can also be angled as shown, or spiraled or helically configured (not shown) relative to the rotational axis. In the embodiment of  FIG. 13A , four channels  214  can be angled 90° relative to the adjacent channels. In the embodiment of  FIG. 13B , the six channels  214  can be angled 60°. In the embodiment of  FIG. 13C , the eight channels  214  can be angled 45°. In the embodiment of  FIG. 13D , the nine channels  214  can be angled 40° relative to the vertical. In alternative embodiments (not shown), the channels  214  can radially extend from the axis of the rotor  41 . 
     The rotors  32 G– 32 J of  FIGS. 13A–13D  can act as a pump. That is, these rotors can withdraw fluid into the cavity  212  and eject fluid outwardly through the channels  214 , or conversely withdraw fluid into the cavity through the channels  214  and eject fluid outwardly through the cavity  212 , depending on the direction of the rotation, to modify the dispersion flow pattern. 
     In other embodiments (not shown), rotors also can contain pegs, agitator discs, or a combination thereof. 
     Referring to the cylindrical rotor  32  shown in  FIGS. 1–6 , its outer peripheral cylindrical surface  36  and the inner cylindrical surface  12 ″ of the inner cylindrical wall  12  of the vessel  10 ,  10 A,  10 B,  10 C,  10 D are dimensioned to provide a small gap X. The gap X is preferably no greater than 3 mm and no smaller than 0.3 mm. In general, this gap X should be approximately 6 times the diameter of the milling media, which is preferably made of cross linked polystyrene or other polymer as described in U.S. Pat. No. 5,718,388 issued to Czekai, et al. The largest attrition milling media preferably is nominally sized no greater than 500 microns (0.5 mm). Presently, the smallest attrition milling media contemplated is about 50 microns. Nonetheless, it is envisioned that a smaller attrition milling media can be suitable for milling certain non-soluble products, such as pharmaceutical products, which means that the gap X can be made smaller accordingly. 
     The vessel size can vary for milling small amounts of dispersion. Although the present invention is not limited to particular sizes, in the preferred embodiment, the inner diameter of the vessel is between ⅝ inch to 4 inches. By way of examples only, milling chamber of the vessel  10 ,  10 A,  10 B,  10 C, and  10 D and the cylindrical rotor  32  can have the dimensions specified in Tables 1 and 2. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 (STRAIGHT ROTORS) 
               
            
           
           
               
               
            
               
                   
                 CYLINDRICAL VESSEL Size 
               
            
           
           
               
               
               
               
            
               
                   
                 #1 
                 #2 
                 #3 
               
            
           
           
               
               
            
               
                   
                 TRI-CLAMP Size VESSEL/COUPLING 
               
            
           
           
               
               
               
               
            
               
                   
                 2″ TC 
                 2.5″ TC 
                 3″ TC 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                 R-vessel (inch) (1/2 DC) 
                 0.685 
                 0.935 
                 1.185 
               
               
                 H-vessel (inch) (HC) 
                 1.125 
                 1.125 
                 1.125 
               
               
                 R-rotor (inch) (1/2 DR) 
                 0.567 
                 0.817 
                 1.063 
               
               
                 H-rotor (inch) (HR) 
                 0.890 
                 0.890 
                 0.890 
               
               
                 R-shaft (inch) (1/2 DS) 
                 0.313 
                 0.313 
                 0.313 
               
               
                 H-shaft (inch) (HS) 
                 0.118 
                 0.118 
                 0.118 
               
               
                 Volume Vessel (in 3 ) 
                 1.658 
                 3.090 
                 4.963 
               
               
                 Volume Rotor (in 3 ) 
                 0.899 
                 1.866 
                 3.156 
               
               
                 Volume Shaft (in 3 ) 
                 0.036 
                 0.036 
                 0.036 
               
               
                 Working Volume (in 3 ) 
                 0.723 
                 1.187 
                 1.770 
               
               
                   
                 11.855 ml 
                 19.458 ml 
                 29.012 ml 
               
               
                 Typical Dispersion Volume 
                  8.299 ml 
                 13.621 ml 
                 20.309 ml 
               
               
                 @ 50% media charge 
               
               
                 Typical Dispersion Volume 
                  5.453 ml 
                  8.951 ml 
                 13.346 ml 
               
               
                 @ 90% media charge 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 (TAPERED ROTORS) 
               
            
           
           
               
               
            
               
                   
                 VESSEL Size 
               
            
           
           
               
               
               
               
            
               
                   
                 #1 
                 #2 
                 #3 
               
            
           
           
               
               
            
               
                   
                 TRI-CLAMP Size VESSEL/COUPLING 
               
            
           
           
               
               
               
               
            
               
                   
                 2″ TC 
                 2.5″ TC 
                 3″ TC 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                 R-vessel (inch) (1/2 DC) 
                 0.685 
                 0.935 
                 1.185 
               
               
                 H-vessel (inch) (HC) 
                 1.190 
                 1.190 
                 1.190 
               
               
                 R-rotor (inch) (1/2 DR) 
                 0.567 
                 0.817 
                 1.063 
               
               
                 H-rotor (inch) (HR) 
                 1.018 
                 1.018 
                 1.018 
               
               
                 H-top taper (inch) (HTT) 
                 0.064 
                 0.120 
                 0.120 
               
               
                 H-bottom taper (inch) (HBT) 
                 0.064 
                 0.075 
                 0.075 
               
               
                 R-shaft (inch) (1/2 DS) 
                 0.313 
                 0.313 
                 0.313 
               
               
                 H-shaft (inch) (HS) 
                 0.086 
                 0.086 
                 0.086 
               
               
                 Volume Vessel (in 3 ) 
                 1.754 
                 3.268 
                 5.250 
               
               
                 Volume Rotor Body (in 3 ) 
                 0.899 
                 1.726 
                 2.919 
               
               
                 Volume Upper Cone (in 3 ) 
                 0.040 
                 0.128 
                 0.196 
               
               
                 Volume Lower Cone (in 3 ) 
                 0.040 
                 0.080 
                 0.122 
               
               
                 Volume Shaft (in 3 ) 
                 0.026 
                 0.026 
                 0.026 
               
               
                 Volume Complete Rotor (in 3 ) 
                 0.979 
                 1.934 
                 3.237 
               
               
                 Working Volume (in 3 ) 
                 0.749 
                 1.308 
                 1.986 
               
               
                   
                 12.274 ml 
                 21.429 ml 
                 32.548 ml 
               
               
                 Typical Dispersion Volume 
                  8.592 ml 
                 15.001 ml 
                 22.784 ml 
               
               
                 @ 50% media charge 
               
               
                 Typical Dispersion Volume 
                  5.646 ml 
                  9.858 ml 
                 14.972 ml 
               
               
                 @ 90% media charge 
               
               
                   
               
            
           
         
       
     
     It was mentioned that the gap X between the rotor  32  and the inner surface  12 ″ of the cylindrical wall  12  should be approximately 6 times the diameter of the attrition milling media. Nonetheless, the vessel and rotor combination can be used with 50, 200, 500 and mixtures of 50/200, 50/500, or 50/200/500 micron media These milling media also can be used with a gap X of 1 mm. The rotor speed is correlated to the rotor diameter to produce different tip speeds, which are related to the milling action. A too high tip speed can generate much heat and can evaporate the dispersion. A too low tip speed causes inefficient milling. 
     Tapering the ends of the rotor  32 , as illustrated in  FIGS. 1–4  and  6 – 13 D can provide more uniform shear throughout the milling chamber. Although the shear rate between two concentric cylinders is relatively constant if the gap is narrow, a flat end (bottom or top) surface cylinder will produce less uniform shear stress. Referring to  FIG. 6 , by equating the shear rate for concentric cylinders and a cone shape surface T 2  revolving about a flat bottomed vessel surface  13 ″, one can calculate a tip angle β=arc tan(1−D R /D C ), where D R  represents an outer cylindrical surface  36  of the rotor  32  and D C  represents an inner cylindrical surface  12 ″ of the vessel  10 ,  10 A,  10 B,  10 C,  10 D. Ideally, the cone should “touch” the bottom (or the top or the ends) to maintain a constant shear. This, however, is not practical. Instead, a cone is truncated, forming a gap d between the truncated bottom surface T 2  and the opposing bottom vessel surface  13 ″. The gap d is preferably defined by D T /2×tan β, where D T /2 is the distance between the center of rotation and the truncation edge. If D T /2 is sufficiently small in comparison with D R /2, a substantially uniform shear can be maintained. A uniform shear rate would allow the user to better estimate shearing effect in the milling of colloidal dispersions, although constant shear in the mill is not necessary to produce a colloidal dispersion. Another benefit to having a tapered bottom surface T 2  is that it prevents the accumulation of suspended particles on the bottom near the center of rotation where the speed is at its minimal. 
     U.S. Pat. No. 5,145,684 issued to Liversidge et al., U.S. Pat. No. 5,518,187 issued to Bruno et al., and U.S. Pat. Nos. 5,718,388 and 5,862,999 issued to Czekai et al. disclose milling pharmaceutical products using polymeric milling media. These patents further disclose dispersion formulations for wet media milling. The disclosures of these patents are incorporated herein by reference. 
     In operation of the vertically oriented mill  1 ,  1 A, an appropriate dispersion formulation containing the milling media and the product to be milled is prepared, which can be prepared according to the aforementioned patents. The dispersion is poured into the vessel  10 ,  10 A,  10 B,  10 C to a level that would cause the dispersion to fill to the brim or the top face  61  (see  FIGS. 5 and 6 ) of the gasket  60  (or even overflow) when the rotor  30  fully inserted to the vessel  10  to minimize trapping of air within the vessel. After filling appropriate amount of the dispersion into the vessel  10 ,  10 A,  10 C, the vessel is aligned with the coupling  50 , which is premounted to the shaft mount  110 , and raised until the vessel and coupling flanges  16 ,  52  line up. The aligned coupling flanges  16 ,  52  are held together using, for instance, a TRI-CLAMP C or the like, which couples the vessel  10 ,  10 A,  10 B,  10 C to the coupling  50  and seals the dispersion. Similarly, the connectors  22 ,  22 A are connected to a coolant inlet and outlet respectively using two TRI-CLAMPs or quick coupling  24 A, one for each connector  22 ,  22 A. Coolant, such as water, is circulated to cool the vessel  10 ,  10 A,  10 B,  10 C. The motor controller  101  can be set to rotate the rotor for a predetermined period, depending on the dispersion formulation. 
     Because the coupling  50  seals the vessel  10 ,  10 A,  10 B,  10 C, and because only a very small amount of air is trapped in the vessel, vortexing and contamination problems are minimized or avoided. Thus, the mill according to the present invention can prevent the dispersion formulation from foaming. Further, because the vessel is cooled, either by the cooling jacket or by circulating the dispersion, the rotor  32  can be spun faster. Thus, a higher energy can be transferred to the dispersion. 
     In the operation of the horizontally oriented mill  2 , the vessel  10 D is first mounted to the shaft mount  110  with either a threaded coupling  16 ′ (as shown in  FIG. 4 ) or a sanitary fitting (as shown in  FIGS. 1–3 ) and with the rotor  32  positioned inside the vessel  10 D as shown in  FIG. 4 . The dispersion formulation containing the milling media and the product to be milled is poured or injected through the top port P 2  or P 3  (only one being required) until all or substantially all of the air is displaced with the dispersion. The motor controller  101  then can be set to rotate the rotor  32  for a predetermined period, depending on the dispersion formulation. If the vessel  10 D has multiple ports, such as P 1 , P 3  or P 2 , P 3 , or P 3 , P 4 , the dispersion can be circulated via an external vessel and pump (not shown) during milling. 
     Because virtually all or substantially all of the air can be displaced in the horizontally oriented mill  2 , vortexing and contamination problems are minimized or avoided. Thus, the mill according to the present invention can prevent the dispersion formulation from foaming. Further, because the dispersion can be circulated, where it can be cooled with external cooling system, the rotor can be spun faster and high energy can be transferred to the dispersion. Moreover, the dispersion can be refreshed or made in batches or inspected without having to disassemble the vessel  10 D from the shaft mount  110 . 
     Exemplary Pharmaceutical Products 
     The pharmaceutical products herein include those products described in the aforementioned patents incorporated herein by reference and any human or animal ingestable products and cosmetic products. 
     As disclosed in U.S. Pat. No. 5,145,684 for “Surface Modified Drug Nanoparticles” to Liversidge et al., the drug substance must be poorly soluble and dispersible in at least one liquid medium. By “poorly soluble” it is meant that the drug substance has a solubility in the liquid dispersion medium of less than about 10 mg/ml, and preferably of less than about 1 mg/ml. 
     A preferred liquid dispersion medium is water. However, other liquid media in which a drug substance is poorly soluble and dispersible can be employed in the milling process, such as, for example, aqueous salt solutions, safflower oil, and solvents such as ethanol, t-butanol, hexane, and glycol. 
     Suitable drug substances can be selected from a variety of known classes of drugs including, for example, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (antiparkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, xanthines, and antiviral agents. Preferred drug substances include those intended for oral administration and intravenous administration. 
     A description of these classes of drugs and a listing of species within each class can be found in Martindale,  The Extra Pharmacopoeia , Twenty-ninth Edition (The Pharmaceutical Press, London, 1989), the disclosure of which is hereby incorporated by reference in its entirety. The drug substances are commercially available and/or can be prepared by techniques known in the art. 
     As taught in U.S. Pat. No. 5,518,187, the invention is also applicable for the grinding of particles for cosmetic and photographic compositions. 
     In addition, as taught in U.S. Pat. No. 5,718,388 for “Continuous Method of Grinding Pharmaceutical Substances” to Czekai et al.; U.S. Pat. No. 5,518,187 for “Method of Grinding Pharmaceutical Substances” to Bruno et al.; and U.S. Pat. No. 5,862,999 for “Method of Grinding Pharmaceutical Substances” to Czekai et al., other suitable drug substances include NSAIDs described in U.S. patent application Ser. No. 897,193, filed on Jun. 10, 1992, and the anticancer agents described in U.S. patent application Ser. No. 908,125, filed on Jul. 1, 1992. U.S. patent application Ser. No. 897,193 was abandoned and refiled on Mar. 13, 1995, as U.S. patent application Ser. No. 402,662, now U.S. Pat. No. 5,552,160 for “Surface Modified NSAID Nanoparticles.” U.S. patent application Ser. No. 908,125 issued as U.S. Pat. No. 5,399,363 for “Surface Modified Anticancer Nanoparticles.” 
     U.S. Pat. No. 5,552,160 states that useful NSAIDS can be selected from suitable acidic and nonacidic compounds. Suitable acidic compounds include carboxylic acids and enolic acids. Suitable nonacidic compounds include, for example, nabumetone, tiaramide, proquazone, bufexamac, flumizole, epirazole, tinoridine, timegadine, and dapsone. Suitable carboxylic acid NSAIDs include, for example: (1) salicylic acids and esters thereof, such as aspirin; (2) phenylacetic acids such as diclofenac, alclofenac, and fenclofenac; (3) carbo- and heterocyclic acetic acids such as etodolac, indomethacin, sulindac, tolmetin, fentiazac, and tilomisole; (4) propionic acids such as carprofen, fenbufen, flurbiprofen, ketoprofen, oxaprozin, suprofen, tiaprofenic acid, ibuprofen, naproxen, fenoprofen, indoprofen, and pirprofen; and (5) fenamic acids such as flufenamic, mefenamic, meclofenamic, and niflumic. Suitable enolic acid NSAIDs include, for example: (1) pyrazolones such as oxyphenbutazone, phenylbutazone, apazone, and feprazone; and (2) oxicams such as piroxicam, sudoxicam, isoxicam, and tenoxicam. 
     U.S. Pat. No. 5,399,363 states that useful anticancer agents are preferably selected from alkylating agents, antimetabolites, natural products, hormones and antagonists, and miscellaneous agents, such as radiosensitizers. 
     Examples of alkylating agents include: (1) alkylating agents having the bis-(2-chloroethyl)-amine group such as, for example, chlormethine, chlorambucile, melphalan, uramustine, mannomustine, extramustinephoshate, mechlore-thaminoxide, cyclophosphamide, ifosfamide, and trifosfamide; (2) alkylating agents having a substituted aziridine group such as, for example, tretamine, thiotepa, triaziquone, and mitomycine; (3) alkylating agents of the alkyl sulfonate type, such as, for example, busulfan, piposulfan, and piposulfam; (4) alkylating N-alkyl-N-nitrosourea derivatives, such as, for example, carmustine, lomustine, semustine, or streptozotocine; and (5) alkylating agents of the mitobronitole, dacarbazine, and procarbazine type. 
     Examples of antimetabolites include: (1) folic acid analogs, such as, for example, methotrexate; (2) pyrimidine analogs such as, for example, fluorouracil, floxuridine, tegafur, cytarabine, idoxuridine, and flucytosine; and (3) purine derivatives such as, for example, mercaptopurine, thioguanine, azathioprine, tiamiprine, vidarabine, pentostatin, and puromycine. 
     Examples of natural products include: (1) vinca alkaloids, such as, for example, vinblastine and vincristine; (2) epipodophylotoxins, such as, for example, etoposide and teniposide; (3) antibiotics, such as, for example, adriamycine, daunomycine, doctinomycin, daunorubicin, doxonibicin, mithramycin, bleomycin, and mitomycin; (4) enzymes, such as, for example, L-asparaginase; (5) biological response modifiers, such as, for example, alpha-interferon; (6) camptothecin; (7) taxol; and (8) retinoids, such as retinoic acid. 
     Examples of hormones and antagonists include: (1) adrenocorticosteroids, such as, for example, prednisone; (2) progestins, such as, for example, hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate; (3) estrogens, such as, for example, diethylstilbestrol and ethinyl estradiol; (4) antiestrogens, such as, for example, tamoxifen; (5) androgens, such as, for example, testosterone propionate and fluoxymesterone; (6) antiandrogens, such as, for example, flutamide; and (7) gonadotropin-releasing hormone analogs, such as, for example leuprolide. 
     Examples of miscellaneous agents include: (1) radiosensitizers, such as, for example, 1,2,4-benzotriazin-3-amine 1,4-dioxide (SR 4889) and 1,2,4-benzotriazine-7-amine 1,4-dioxide (WIN 59075); (2) platinum coordination complexes such as cisplatin and carboplatin; (3) anthracenediones, such as, for example, mitoxantrone; (4) substituted ureas, such as, for example, hydroxyurea; (5) and adrenocortical suppressants, such as, for example, mitotane and aminoglutethimide. 
     In addition, the anticancer agent can be an immunosuppressive drug, such as, for example, cyclosporine, azathioprine, sulfasalazine, methoxsalen, and thalidomide. 
     Surface Modifiers 
     Also as disclosed in U.S. Pat. No. 5,145,684, the drug particles comprise a discrete phase of a drug substance having a surface modifier adsorbed on the surface thereof. Useful surface modifiers are believed to include those which physically adhere to the surface of the drug substance but do not chemically bond to the drug. 
     Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants. 
     Representative examples of excipients include gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, e.g., the commercially available Tweens, polyethylene glycols, polyoxyethylene stearates, colloidol silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethycellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). 
     Most of these excipients are described in detail in the  Handbook of Pharmaceutical Excipients , published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, the Pharmaceutical Press (1986), the disclosure of which is hereby incorporated by reference in its entirety. The surface modifiers are commercially available and/or can be prepared by techniques known in the art. 
     Particularly preferred surface modifiers include polyvinylpyrrolidone, Pluronic® F68 and F108, which are block copolymers of ethylene oxide and propylene oxide, Tetronic® 908, which is a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine, dextran, lecithin, Aerosol OT® (American Cyanamid), which is a dioctyl ester of sodium sulfosuccinic acid, Duponol P® (DuPont), which is a sodium lauryl sulfate, Triton X-200® (Robin and Haas), which is an alkyl aryl polyether sulfonate, Tween® 80 (ICI Specialty Chemicals), which is a polyoxyethylene sorbitan fatty acid ester, and Carbowax® 3350 and 934 (Union Carbide), which are polyethylene glycols. Surface modifiers which have found to be particularly useful include polyvinylpyrrolidone, Pluronic® F-68, and lecithin. 
     The surface modifier does not chemically react with the drug substance or itself. Furthermore, the individually adsorbed molecules of the surface modifier are essentially free of intermolecular crosslinkages. 
     The drug particles can be reduced in size in the presence of a surface modifier. Alternatively, the particles can be contacted with a surface modifier after attrition. 
     The relative amount of drug substance and surface modifier can vary widely and the optimal amount of the surface modifier can depend, for example, upon the particular drug substance and surface modifier selected, the critical micelle concentration of the surface modifier if it forms micelles, etc. The surface modifier preferably is present in an amount of about 0.1–10 mg per square meter surface area of the drug substance. The surface modifier can be present in an amount of 0.1–90%, preferably 20–60% by weight based on the total weight of the dry particle. 
     Particle Size 
     Also disclosed in U.S. Pat. No. 5,145,684 is the particle size of the milled pharmaceutical substances. As used herein, particle size refers to a number average particle size as measured by conventional particle size measuring techniques well known to those skilled in the art, such as sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation. By “an effective average particle size of less than about 400 nm” it is meant that at least 90% of the particles have a weight average particle size of less than about 400 nm when measured by the above-noted techniques. In other embodiments of the invention, the effective average particle size is less than about 250 nm. In some embodiments of the invention, an effective average particle size of less than about 100 nm has been achieved. 
     As disclosed in U.S. Pat. Nos. 5,862,999, 5,518,187, and 5,718,388, the particle size of the milled compound can be submicron or nanoparticulate. In other embodiments described by these patents, the average particle size of the milled compound can be less than about 500 nm, less than about 400 nm, less than about 300 nm, or less than about 100 nm. 
     With reference to the effective average particle size, it is preferred that at least 95% and, more preferably, at least 99% of the particles have a particle size less than the effective average, e.g., 400 nm. In particularly preferred embodiments, essentially all of the particles have a size less than 400 nm. In some embodiments, essentially all of the particles have a size less than 250 nm. 
     Grinding Media 
     As disclosed in U.S. Pat. Nos. 5,145,684 and 5,862,999, the grinding media for the particle size reduction step can be selected from rigid media, preferably spherical or particulate in form, having an average size less than about 3 mm and, more preferably, less than about 1 mm. However, grinding media in the form of other non-spherical shapes are expected to be useful in the practice of this invention. Such media desirably can provide the particles of the invention with shorter processing times and impart less wear to the milling equipment. 
     As disclosed in U.S. Pat. No. 5,862,999, the grinding media can range in size up to about 100 microns. For fine grinding, the grinding particles preferably have a mean size of less than about 75 microns, more preferably, less than about 50 microns, and, most preferably, less than about 25 microns, in size. Excellent particle size reduction has been achieved with media having a particle size of about 5 microns. 
     As disclosed in U.S. Pat. No. 5,518,187, the grinding media can range in size from about 0.1 to 3 mm. For fine grinding, the grinding particles preferably are from 0.2 to 2 mm, more preferably, 0.25 to 1 mm in size. 
     As disclosed in U.S. Pat. No. 5,718,388, the grinding media can range in size up to about 1000 microns. Other useful sizes of grinding media include media having a particle size of less than about 300 microns, less than about 75 microns, or less than about 50 microns. 
     As disclosed in U.S. Pat. No. 5,718,288, grinding media having mixed media sizes can be utilized. For example, larger media may be employed in a conventional manner where such media is restricted to the milling chamber. Smaller grinding media may be continuously recirculated through the system and permitted to pass through the agitated bed of larger grinding media. In this embodiment, the smaller media is preferably between about 1 and 300 microns in mean particle size and the larger grinding media is between about 300 and 1000 microns in mean particle size. 
     As disclosed in U.S. Pat. Nos. 5,145,684, 5,862,999, and 5,718,388, the selection of material for the grinding media is not believed to be critical. It has been found that zirconium oxide, such as 95% ZrO stabilized with magnesia, zirconium silicate, glass, stainless steel, titania, alumina, and 95% ZrO stabilized with yttrium grinding media provide particles having levels of contamination which are believed to be acceptable for the preparation of pharmaceutical compositions. Preferred media have a density greater than about 3 g/cm 3 . 
     As disclosed in U.S. Pat. Nos. 5,862,999, 5,518,187, and 5,718,388, the grinding media can comprise particles, preferably substantially spherical in shape, e.g., beads, of a polymeric resin. 
     In general, polymeric resins suitable for use herein are chemically and physically inert, substantially free of metals, solvent and monomers, and of sufficient hardness and friability to enable them to avoid being chipped or crushed during grinding. Suitable polymeric resins include crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene, styrene copolymers, polyacrylates such as polymethyl methylcrylate, polycarbonates, polyacetals, such as Delrin™., vinyl chloride polymers and copolymers, polyurethanes, polyamides, poly(tetrafluoroethylenes), e.g., Teflon™, and other fluoropolymers, high density polyethylenes, polypropylenes, cellulose ethers and esters such as cellulose acetate, polyhydroxymethacrylate, polyhydroxyethyl acrylate, silicone containing polymers such as polysiloxanes and the like. 
     The polymer can be biodegradable. Exemplary biodegradable polymers include poly(lactides), poly(glycolide) copolymers of lactides and glycolide, polyanhydrides, poly(hydroxyethyl methacrylate), poly(imino carbonates), poly(N-acylhydroxyproline)esters, poly(N-palmitoyl hydroxyproline) esters, ethylene-vinyl acetate copolymers, poly(orthoesters), poly(caprolactones), and poly(phosphazenes). In the case of biodegradable polymers, contamination from the media itself advantageously can metabolize in vivo into biologically acceptable products which can be eliminated from the body. 
     The polymeric resin can have a density from 0.8 to 3.0 g/cm 3 . Higher density resins are preferred inasmuch as it is believed that these provide more efficient particle size reduction. 
     As disclosed in U.S. Pat. No. 5,518,187, the grinding media can comprise particles comprising a core having a coating of the polymeric resin adhered thereon. The core material preferably can be selected from materials known to be useful as grinding media when fabricated as spheres or particles. Suitable core materials include zirconium oxides (such as 95% zirconium oxide stabilized with magnesia or yttrium), zirconium silicate, glass, stainless steel, titania, alumina, ferrite and the like. Preferred core materials have a density greater than about 2.5 g/cm 3 . The selection of high density core materials is believed to facilitate efficient particle size reduction. 
     Useful thicknesses of the polymer coating on the core are believed to range from about 1 to about 500 microns, although other thicknesses outside this range may be useful in some applications. The thickness of the polymer coating preferably is less than the diameter of the core. 
     The cores can be coated with the polymeric resin by techniques known in the art. Suitable techniques include spray coating, fluidized bed coating, and melt coating. Adhesion promoting or tie layers can optionally be provided to improve the adhesion between the core material and the resin coating. The adhesion of the polymer coating to the core material can be enhanced by treating the core material to adhesion promoting procedures, such as roughening of the core surface, corona discharge treatment, and the like. 
     Milling Process 
     As disclosed in U.S. Pat. No. 5,718,388, the milling process can be continuous. In such a process, the active agent to be milled and rigid grinding media are continuously introduced into a milling chamber, the active agent is contacted with the grinding media while in the chamber to reduce the particle size of the active agent, the agent and the grinding media are continuously removed from the milling chamber, and thereafter the active agent is separated from the grinding media. 
     Given the disclosure of the present invention, one versed in the art would appreciate that there may be other embodiments and modifications within the scope and spirit of the present invention. Accordingly, all modifications attainable by one versed in the art from the present disclosure within the scope and spirit of the present invention are to be included as further embodiments of the present invention. The scope of the present invention accordingly is to be defined as set forth in the appended claims.