Abstract:
A novel apparatus and process for crystallizing submicron-sized crystals of a pharmaceutical composition. The submicron-sized crystals, which have an average size of less than 1 micron, provide high surface area end product crystals with greatly improved stability and purity, and which afford crystals having improved bioavailability, higher dissolution, decreased decomposition rate and longer shelf-life.

Description:
RELATED APPLICATIONS 
     This application claims priority benefit under Title 35 § 119(e) of U.S. Provisional Application No. 60/117,878, filed Jan. 29, 1999, and entitled SONIC IMPINGING JET CRYSTALLIZATION APPARATUS AND PROCESS, the entire contents of which are incorporated herein by reference. 
    
    
     FIELD OF THE INVENTION 
     The present invention is directed to a crystallization apparatus and process for producing submicron-sized particles. 
     BACKGROUND OF THE INVENTION 
     Producing uniform, very small particles is a common processing challenge for pharmaceutical substances. In general, smaller particles provide two very desirable qualities of pharmaceuticals, namely higher bioavailability and a higher dissolution rate. In U.S. Pat. No. 5,314,506 there is described a method using two impinging jets to achieve uniform particles. However, the particles formed using the process in U.S. Pat. No. 5,314,506 are only as small as 3 microns in size and the majority of the crystals formed are in the range of 3-20 microns. 
     The general process by which these prior art small particles are produced involves two impinging liquid jets positioned within a well stirred flask to achieve high intensity micromixing. At the point where the two jets strike one another a very high level of supersaturation exists. As a result of this high supersaturation, crystallization occurs extremely rapidly within the small mixing volume at the impingement point of the two liquids. Since new crystals are constantly nuceleating at the impingement point, a very large number of crystals are produced. As a result of the large number of crystals formed, the average size remains small, although not all the crystals formed are small in size. 
     The novel apparatus and process of this invention utilizes impinging jets to achieve high intensity micromixing in the crystallization process. The background of high intensity micromixing is discussed in detail in U.S. Pat. No. 5,314,506, which is incorporated by reference herein. 
     SUMMARY OF THE INVENTION 
     The present invention pertains to a novel apparatus and process for crystallizing submicron-sized particles, having an average size of less than 1 micron, and which provides high surface area end product crystals with greatly improved stability and purity. The pure, high surface area particles produced by the process of the present invention display superior crystal structure when compared with particles formed by standard slow crystallization plus milling methods known in the art which use the same quality and kind of feed compounds. These improvements in crystal structure result in decreases in decomposition rate and therefore longer shelf-life for the crystallized product or pharmaceutical composition. Moreover, the smaller size of the pharmaceutical crystals formed using the apparatus of the present invention provide for crystals having a higher bioavailability and higher dissolution rate. 
     More specifically, the novel apparatus and process of this invention relate to the addition of a sonication probe along with impinging jets to achieve high intensity micromixing of fluids so as to form a homogeneous composition prior to the start of nucleation in a continuous crystallization process. 
     The novel apparatus and process of the present invention provide for direct crystallization of high surface area submicron sized particles of high purity and stability. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 is a schematic diagram showing a crystal production system according to the present invention depicting two impinging jets  12 ,  14 , an agitator  18 , and a sonication probe  22  positioned in a flask  16 . 
     FIG. 2 is an enlarged sectional view of the region denoted by A in FIG. 1, illustrating the substantially diametrically opposite positioning of the impinging jet tips and the position of the sonicator probe tip within the same plane of the impinging jet tips. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The novel process of the present invention involves the positioning of a sonication probe or sonicator in a flask wherein liquid jets are positioned to create impinging fluid jet streams to achieve high intensity micromixing of fluids prior to nucleation in a crystallization process. Two or more jets may be used to micromix two or more fluids, although it is preferable to use two jets to micromix the fluids. One liquid jet is generally a solvent saturated with product, and the other liquid jet generally contains an anti-solvent. Maximum micromixing is effected when the two impinging jets are positioned substantially diametrically opposite one another, i.e., at or close to 180° from one another, and advantageously located a distance of 0.4″ apart from each other. 
     As illustrated in FIG. 1, the impinging jet apparatus comprises a first jet  12  and a second jet  14  arranged substantially diametrically opposite one another in a flask  16 , preferably a 1000 ml flask, which is agitated by a overhead stirrer  18 . Flask  16  contains bulk or liquid  13 , which is advantageously the same material as that coming through second jet  14  (anti-solvent). First jet  12  and second jet  14  are provided with jet orifices  12   a  and  14   a  respectively, which are positioned substantially 180° from each other at a distance of 0.4″ from one another. As illustrated in FIG.  1  and more clearly in FIG. 2, the space  20  defined between first and second jet orifices  12   a  and  14   a  defines an impingement point where the fluid from first jet  12  and the fluid from second jet  14  impinge and micromix within flask  16 . 
     The liquids which are pumped through first and second jets  12 ,  14  may be of different solvent composition. One fluid may be a solution of the pharmaceutical compound to be crystallized or a combination of solvents (generally referred to as “feed solution”) and the other fluid may be a solvent or combination of solvents capable of initiating the compound&#39;s precipitation from solution (generally referred to as “anti-solvent”), chosen for its relatively low solvation property with respect to that compound. Such solvents and anti-solvents may include but are not limited to water, methanol, ethanol, DMSO (dimethyl sulfoxide), IPA (isoproplyl alcohol), DMF (dimethylformamide) or acetone. 
     Alternatively, the two fluids used in the process of the present invention may both be solution of the pharmaceutical compound to be crystallized in the same suitable solvent or combination of solvents but each at a different temperature, and nucleation/precipitation can be initiated by instantaneous temperature reduction. A small amount of a suitable surfactant may be added to the fluids used in the process in order to alleviate agglomeration which might occur during the micromixing crystallization process. Suitable surfactants which may be used include, but are not limited, to Tween 80, Cremophor A25, Cremophor EL, Pluronic F68, Pluronic F127, Brij 78, Klucel, Plasdone K90, Methocel E5, and PEG (mw 20,000) and the like. 
     A sonication probe or sonicator  22 , preferably a 20 khz sonication probe, having a probe tip  24  on one end, is positioned in flask  16 . Advantageously, probe tip  24  of a sonication probe  22  is immersed in the crystallization slurry throughout the crystallization process. For maximum effectiveness, probe tip  24  of sonicator  22  is advantageously located as close as possible to the impinging point  20 , as illustrated in FIG.  2 . Depending on several processing parameter, such as temperature, liquid viscosity and percent solids, among others, probe  24  may provide up to 500 watts of power within the crystallization slurry. The addition of ultrasonic energy in the immediate vicinity of the impinging jets  12 ,  14  produces an average particle size of less than 1 micron. 
     In accordance with the present invention, liquid is pumped through first and second jets  12 ,  14  at a minimum linear velocity of 12 m/s. The liquid is comprised of one or more solvents which may include a combination of the pharmaceutical compound and a solvent and an anti-solvent, or simply a combination of solvents and an anti-solvent. When the two jet streams emerge and meet midway between orifice tips  12   a ,  14   a  high intensity micromixing occurs and a disk of crystallization slurry is formed. Depending upon the solvents and pharmaceutical compound(s) being used, each jet stream is advantageously independently maintained at a temperature in the range of 0° to 100° C. To ensure good mixing in the bulk  13 , an agitation rate of &gt;300 RPM is maintained throughout the crystallization procedure using a mixer or agitator  18 , such as a Rushton turbine or other high shear impeller, although the invention is not limited in the type of mixer or agitator used. As illustrated in FIG. 1, agitator  18  is positioned within flask  16  with first and second jets  12 ,  14  and sonicator  22 . Agitator  18  is advantageously positioned proximate first and second jet  12 ,  14 , but should not interfere with the micromixing at impingement point  20 . 
     Proper placement of probe tip  24  of sonicator  22  within impinging point  22  is essential. A comparison of two probe tip  24  placements has demonstrated that locating probe tip  24  lower than the jet orifices  12   a ,  14   a , and hence outside of impinging point  20 , yields slightly larger crystals than if probe tip  24  is located at the same level with jet orifices  12   a ,  14 , and hence within impingement point  20 . For example, in Experiments 44032-006-12 and 44032-006-18, referenced hereinbelow in the Examples, probe tip  24  was positioned approximately one inch below the level of jet orifices  12   a ,  14   a . The resulting crystals from these batches had average sizes of 0.5164 and 0.5178 microns with 97.499% and 97.092% respectively, of the crystals less than 0.500 microns. In contrast, in Experiment 44032-006-27, wherein probe tip  24  was positioned at the same level as jet orifices  12   a ,  14   a  and within impingement point  20 , crystals were formed having an average diameter of 0.5129 microns, with 99.987% less than 0.5000 microns. 
     Regardless of the number of jets used, the jet orifices should be positioned so that the emitted fluid streams will impinge with a high intensity. Impingement of the fluids is essential so that immediate high turbulence impact is created. Thus it is crucial that when two jets are used, they must be positioned such that their orifices are substantially diametrically opposite each other to facilitate proper fluid impingement. 
     The following examples are provided for the purpose of illustrating the present invention and should not be construed as being a limitation on the scope or spirit of the instant invention. It should be understood that there may be other embodiments which fall within the spirit and scope of the invention as defined by the claims appended hereto. 
     EXAMPLE 1 
     Crystallization of (Z-3-[1-(4-chorophenyl)-1-(4-methylsulfonylpenyl)methylene]-dihydrofuran-2-one Experiment No. 42216-195 
     (1) 152.5 grams of the pharmaceutical compound were dissolved in 300 ml of DMSO at 65-75° C. 1200 ml of water (RO quality, filtered) was chilled at 2° C. The rich solution and water were both charged to agitated, jacketed vessels. The respective temperatures of the contents were maintained by heating or chilling the jackets. The process fluids were circulated through the feedlines to attain steady state temperatures and flow rates. 
     (2) 300 ml of water (RO quality, filtered) was charged to the impinging vessel. The jacket temperature was maintained at 2° C. throughout the crystallization. 
     (3) With the mechanical stirrer and sonication power at maximum level, the solution and water jets were impinged at a 1:4 mass flow rate. The rich solution&#39;s flowrate was 0.18 kg/min through a 0.020″ nozzle and the water flowrate was 0.72 kg/min through a 0.040″ nozzle. 
     (4) Upon completion of crystallization, the product was filtered and then washed with approximately 100 ml water (RO quality, filtered). The filter cake was dried in vacuo at 70° C. until dry. Yield is 89.4% excluding 24.19 grams recovered from the solution vessel and circulating lines. 
     (5) The dry product was delumped by passing it through an 80 mesh screen. API aerosizer assays yield a mean particle size of 0.54 microns with 95% of particles under 0.94 microns. 
     Summary of Experiments with BMS-225969 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                 Experiment No. 
                 Mean Size 
                 % &lt;0.5000 μm 
                 95th percentile 
               
               
                   
               
             
             
               
                        42216-157-20 
                 0.5090 microns 
                 99.011 
                 0.5086 microns 
               
               
                 42216-158 
                 0.5124 
                 98.097 
                 0.5087 
               
               
                 42216-195 
                 0.5376 
                 92.224 
                 0.9373 
               
               
                 44032-006-12 
                 0.5164 
                 97.499 
                 0.5087 
               
               
                 44032-006-18 
                 0.5178 
                 97.092 
                 0.5088 
               
               
                 44032-006-27 
                 0.5129 
                 97.987 
                 0.5087 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 2 
     Crystallization of [R-(R*,R*)]-4-[2-[2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl-4-thiazolyl]benzonitrile Experiment No. 42216-027 
     (1) 50 grams of the pharmaceutical compound were dissolved in 150 ml of DMSO at 70° C. and the solution was polish filtered. 1000 ml of water (RO quality, filtered) was tempered to 20° C. The rich solution and water were both charged to agitated, jacketed vessels. The respective temperatures of the contents were maintained by heating or chilling the jackets. The process fluids were circulated through the feed lines to attain steady state temperatures and flow rates. 
     (2) 300 ml of water (RO quality, filtered) was charged through the impinging vessel. The jacket temperature was maintained at 20° C. throughout the crystallization. 
     (3) With the mechanical stirrer and sonication power at maximum level, the solution and water jets were impinged at a 1:4 mass flow rate. The solution&#39;s flow rate is 0.18 kg/min though a 0.020″ nozzle and the water flowrate is 0.72 kg/min through a 0.040″ nozzle. 
     (4) Upon completion of crystallization, the product was filtered and washed with 2 liters of water (RO quality, filtered). The filter cake was dried in vacuo at 70° C. until dry. 
     (5) The dry product was delumped by passing it through an 80 mesh screen. API aerosizer assays yield a mean particle size of 0.5324 microns with 95% of particles under 0.8321 microns. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                 Experiment No. 
                 Mean Size 
                 % &lt;0.5000 μm 
                 95th percentile 
               
               
                   
               
             
             
               
                        42216-028-10 
                 0.5324 microns 
                 91.563 
                 0.8321 microns