United States Patent c191
`Midler, Jr. et al.
`
`I IIIII IIIIIIII Ill lllll lllll lllll lllll lllll lllll lllll lllll llllll Ill lllll llll
`US005314506A
`5,314,506
`[11] Patent Number:
`[45] Date of Patent: May 24, 1994
`
`[75)
`
`[54] CRYSTALLIZATION ME'IHOD TO
`IMPROVE CRYSTAL STRUCTURE AND
`SIZE
`Inventors: Michael Midler, Jr., East Brunswick;
`Edward L. Paul, Chatham Township,
`Morris County; Edwin F.
`Whittington, Linden; Mauricio
`Futran, Westfield, all ofN.J.; Paul D.
`Liu, Concord, Mass.; Jaanpyng Hsu,
`Colonia; Shih-Hsie Pan, Princeton
`Junction, both of N.J.
`[73] Assignee: Merck & Co., Inc., Rahway, N.J.
`[21} Appl. No.: 793,764
`[22] Filed:
`Nov. 18, 1991
`
`[63]
`
`[51]
`[52]
`
`[58]
`
`[56]
`
`Related U.S. Application Data
`Continuation-in-part of Ser. No. 706,682, Jun. 3, 1991,
`abandoned, which is a continuation-in-part of Ser. No.
`538,611, Jun. 15, 1990, abandoned.
`Int. Cl.5 ............................................... BOID 9/02
`U.S. Cl . .................................... 23/295 R; 23/299;
`423/659; 137/896; 239/421; 239/433; 366/173
`Field of Search ............. 137/597, 896; 23/295 R,
`23/293 R, 293 A, 293 S, 299; 241/39; 239/420,
`421,433; 366/172, 173, 176; 422/245; 423/659
`
`References Cited
`U.S. PATENT DOCUMENTS
`2,751,335 6/1956 Carver et al. ..................... 23/293 R
`3,622,496 11/1971 Biribauer et al ...................... 208/35
`4,567,912 2/1986 Levine ................................. 137/606
`4,663,433 5/1987 Pyles et al. .......................... 528/496
`4,783,008 11/1988
`lkeuchi et al. ...................... 239/421
`4,915,302 4/1990 Kraus et al. ........................ 239/14.2
`4,952,224 8/1990 Lilakos .................................. 62/534
`5,011,293 4/1991 Roop et al. ......................... 366/173
`5,074,671 12/1991 Roueche et al ..................... 366/172
`
`FOREIGN PATENT DOCUMENTS
`157562 10/1985 European Pat. Off ..
`
`0344898Al 4/1990 European Pat. Off ..
`393963 10/1990 European Pat. Off ..
`3126854 1/1983 Fed. Rep. of Germany .
`
`OTHER PUBLICATIONS
`R. Pohorecki & J. Baldyga, The Use of a New Model of
`Micromixing for Determination of Crystal Size in Pre(cid:173)
`cipitation, Chem. Eng. Sci. 38 79-83 vol. 38, No. 1 Jan.
`1983.
`J. Garside and N. S. Tavare, Mixing, Reaction and
`Precipation: Limits of Micromising in an MSMPR
`Crystallizer, Chem. Eng. Sc., vol. 40 No. 8 Aug. 1985.
`A Mersmann and M. Kind, Chemical Engineering As(cid:173)
`pects of Precipitation from Solution, Chem. Eng.
`Technol, 11, pp. 264-276 (1988), Aug. 1904.
`M. Midler, et al., Abstract, Annual Meeting American
`Inst. Chem. Eng., San Francisco, Calif. (Nov. 5, 1989).
`P. Liu, et al., (abstract) "The Use of Continuously Im(cid:173)
`pinging Jets to Control Crystallization and Particle Size
`... ", Extended Abstracts. American Institute of Chemical
`Engineers, 1990 Annual Meeting, paper No. 66B, avail(cid:173)
`able to attendees Nov. 11, 1990, at Chicago, IL.
`A. J. Mahajan, et al., (abstract) "Rapid Precipitation of
`Amino Acids", Extended Abstrcts, American Institute of
`Chemical Engineers, 1991 Annual Meeting, paper No.
`74e, available to attendees Nov. 17, 1991, at Los An(cid:173)
`geles, Calif.
`Primary Examiner-Michael Lewis
`Assistant Examiner-Timothy C. Vanoy
`Attorney, Agent, or Firm-Joseph F. DiPrima; Robert J.
`North; Carol S. Quagliato
`ABSTRACT
`[57]
`Impinging fluid jet streams are used in a continuous
`crystallization process to achieve high intensity mi(cid:173)
`cromixing of fluids so as to form a homogeneous com(cid:173)
`position prior to the start of nucleation. This process
`permits direct crystallization of high surface area parti(cid:173)
`cles of high purity and stability.
`
`28 Claims, 4 Drawing Sheets
`
`FLUID l----'-------~
`FEED
`
`4
`
`5
`
`6
`
`PRODUCT
`
`MYLAN EXHIBIT 1014
`
`

`

`U.S. Patent
`
`May 24, 1994
`
`Sheet 1 of 4
`
`5,314,506
`
`FLUID FEED>---~--~~~~~~~---
`
`3
`
`4
`
`5
`
`6
`
`A
`
`PRODUCT
`
`FIG. f
`
`

`

`U.S. Patent
`
`May 24, 1994
`
`Sheet 2 of 4
`
`5,314,506
`
`9
`
`3
`
`10
`
`FIG. 2
`
`FIG. 3
`
`

`

`U.S. Patent
`
`May 24, 1994
`
`Sheet 3 of 4
`
`5,314,506
`
`.
`(!) -LL.
`
`00
`
`..... 1 -.
`:E :
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`:c :
`(!) : - .
`
`:I: :
`
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`~! -·
`....J: ~= 0:
`
`....J:
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`0
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`0
`
`0
`IJ.J
`:I:
`.....
`0
`:z:::C:C
`0 0 0 0
`:E
`G) G) G)
`(/')
`:E :E :E
`~ 0
`~ ~· ~,.,,o
`0 -&no . .
`- vv&nNv
`
`-
`
`U"') u
`(\J .......
`
`-*
`II) -0 -.....
`0
`c:[
`(\J 0::
`z
`0 -.....
`&n c:[
`-
`0::
`.....
`::::)
`<t
`(/')
`0::
`L.LJ
`0...
`::::)
`(/')
`
`0
`-
`
`D ~ <l
`
`<l
`L--L---.Jl...-_JL-----JL-----li..-----l----'----L----'~------' 0
`,.,,
`.
`0
`&n
`0
`0
`U"')
`,...:
`C\.i
`(\J
`SURF AREA sq m PER gm
`
`.
`
`-
`
`

`

`U.S. Patent
`
`May 24, 1994
`
`Sheet 4 of 4
`
`5,314,506
`
`FLUID 1
`FEED 1
`
`127 fFLUID
`lFEED
`
`16
`
`16
`
`PRODUCT
`
`FIG. 5
`
`

`

`CRYSTALLIZATION METHOD TO IMPROVE
`CRYSTAL STRUCTURE AND SIZE
`
`10
`
`25
`
`1
`
`5,314,506
`
`RELATED APPLICATION
`This application is a continuation-in-part of co-pend(cid:173)
`ing U.S. application Ser. No. 706,682, filed Jun. 3, 1991,
`which itself is a continuation-in-part of U.S. application
`Ser. No. 07/538,611, filed on Jun. 15, 1990, and now
`abandoned.
`
`2
`formation and increases impurity entrainment. If a slow
`crystallization technique is employed, more thorough
`mixing of the fluids can be attained prior to crystal
`formation which will improve crystal structure and
`5 purity, but the crystals produced will be large and mill(cid:173)
`ing will be necessary to meet bioavailability require(cid:173)
`ments.
`Another standard crystallization procedure employs
`temperature variation of a solution of the material to be
`crystallized in order to bring the solution to its supersat(cid:173)
`uration point, but this is a slow process that produces
`BACKGROUND OF THE INVENTION
`large crystals. Also, despite the elimination of a solvent
`gradient with this procedure, the resulting crystal char-
`Crystallization from solution of pharmaceutically
`active compounds or their intermediates is the typical
`actcristics of size, purity and stability are difficult to
`method of purification used in industry. The integrity of 15 control and arc inconsistent from batch to batch.
`the crystal structure, or crystal habit, that is produced
`The novel process of this invention utilizes impinging
`and !he p~rticl~ size of the ~nd product are important
`jets to achieve high intensity micromixing in the crystal-
`con~1dera~1ons !n t~7 crystalhzat1on pr~. .
`lization process. High intensity micromixing is a well
`~gh b1oavailab1hty and shoJ: dissolution t1me are
`known technique where mixing-dependent reactions
`des1~able or often necessary attnbutes. of the pha~a- 20 are involved. Feeding strategies as they relate to precip-
`c::cut1cal end ~roduc~. However, the d1rt:Ct crystalhza-
`itation were addressed by Mersmann, A. and Kind, M.,
`t1on of SJ?all s1~ed, h1~h surface area p~rt1cles ~s usually
`Chemical Engineering Aspects of Precipitation from So/u-
`tion, Chem. Eng. Technol., V.11, p. 264 (1988). Notable
`acc.omphshed m a .high supersaturation .env~onm~nt
`~~1ch often results m ma.t7nal of low punty, high fna-
`among other papers recently addressing the effect of
`b1bty, and ~ecreased stability due !0 poor cr~stal stru~-
`micromixing in reaction processes are Garside, J. and
`Tavare N s 11,x· ,·ng, React ·0
`ture formation. Because the bondmg forces m orgamc
`· ·t t ·
`. L ·
`·
`d n..
`·
`h h" h
`f
`f
`,
`·
`,, ,r~,
`1 nan rrec1p1 a 10n. 1mrts
`,
`1 I
`crysta . attices generate a m~c
`. ig e~ ~eq.uency ?
`of Micromixing in an MSMPR Crystallizer, Chem. Eng.
`. 1485 (1985)· Pohorecki R. and B Id
`Sci. V. 40
`am?rphis~. than those found m highly iomc !no~gamc
`solids, "oilmg out" of supersaturated matenal 1s not
`'
`' P
`'
`.
`'. .
`a yg~,
`uncommon, and such oils often solidify without struc- 30 J., 7!'e Use of a N~w ~ode!?! M~crom,xmg for Det~rm1-
`nation of Crystal S1ze m Prec1prtat1on, Chem. Eng. Sc1., V.
`t
`ure.
`79 (1983) H
`h
`·
`·
`·
`38
`.' P·
`. .
`.
`·
`owever, t. e use of high m!en~1ty
`Slow crystallization is a common technique used to
`increase product purity and produce a more stable crys-
`micrormxmg is not the no~ m curr~nt ~I?'stalhzat1on
`tal structure, but it is a process that decreases crystal-
`techn~lo~y ~here no chemical ~eact1?~ is mvo~ved ..
`lizer productivity and produces large, low surface area 35
`Impmg_m~ J~ts are use~ for m1crommng routl~ely m
`react.ion .mJection mouldmg (RIM) technology m ~he
`particles that require subsequent high intensity milling.
`Currently, pharmaceutical compounds almost always
`plastics. m~ustry but not for. the. p~rpo.se of ~au~mg
`require a post-crystallization milling step to increase
`crystall~zat~on. The use of a~ 1m~mgmg Je~ dev1_c~ m .a
`particle surface area and thereby improve their bi-
`crystalhzat10n process to ac~1e~e mte~se m1crom1xm~ 1s
`oavailability. However, high energy milling has draw- 40 novel. Whether _fee~ ~ate~al 1s relat1_vely pure or 1m-
`pu~e,_ the use ?f 1mpmgmg Jets results m crystal charac-
`backs. Milling may result in yield loss, noise and dust-
`ing, as well as unwanted personnel exposure to highly
`ten~t1c~ supenor to those that result from standard crys-
`potent pharmaceutical compounds. Also, stresses gener-
`talhzauon methods.
`ated on crystal surfaces during milling can adversely
`Now with the present invention there is provided a
`affect labile compounds. Overall, the three most desir- 45 method for crystallization of pharmaceutical com-
`able end-product goals of high surface area, high chemi-
`pounds or their intermediates which directly produces
`cal purity, and high stability cannot be optimized simul-
`high surface area end product crystals with greatly
`taneously using current crystallization technology with-
`improved stability and purity and thereby eliminates the
`out high energy milling.
`need for subsequent high intensity milling to meet bi-
`One standard crystallization procedure involves con- 50 oavailability requirements. By removing the need for
`tacting a supersaturated solution of the compound to be
`milling, the novel jet process avoids associated prob-
`crystallized with an appropriate "anti-solvent" in a
`lems of noise and dusting, cuts yield loss, and saves the
`stirred vessel. Within the stirred vessel, the anti-solvent
`time and extra expense incurred during milling. It also
`initiates primary nucleation which leads to crystal for-
`removes an extra opportunity for personnel contact
`mation, sometimes with the help of seeding, and crystal 55 with a highly potent pharmaceutical agent, or for ad-
`digestion during an aging step. Mixing within the vessel
`verse effects on labile compounds. The small particle
`can be achieved with a variety of agitators (e.g., Rush-
`size attained with the jet process is consistent within a
`ton or Pitched blade turbines, Intermig, etc.), and the
`single run and as shown in Table 1, results are reproduc-
`process is done in a batch wise fashion.
`ible between runs. Reproducibility is an attribute of this
`When using current reverse addition technology for 60 process that is not common to "reverse addition" meth-
`direct small particle crystallization, a concentration
`ods typically used to produce small crystals.
`gradient can not be avoided during initial crystal forma-
`The pure, high surface area particles that result from
`tion because the introduction of feed solution to anti-
`the jet process also display superior crystal structure
`solvent in the stirred vessel does not afford a thorough
`when compared to particles formed via standard slow
`mixing of the two fluids prior to crystal formation. The 65 crystallization plus milling methods using the same
`existence of concentration gradients, and therefore a
`quality and kind of feed compound. Improvements in
`heterogeneous fluid environment at the point of initial
`crystal structure result in decreases in decomposition
`crystal formation, impedes optimum crystal structure
`rate and therefore longer shelf-life for the crystallized
`
`

`

`5,314,506
`
`5
`
`3
`product or a pharmaceutical composition containing
`the crystallized material. As shown in Table 2, the mate(cid:173)
`rial produced by the jet process exhibits more consistent
`accelerated stability results than that produced by the
`conventional batch process.
`The purity of crystallized material produced from the
`jet process is superior to that from standard reverse
`addition direct small particle crystallization, as demon(cid:173)
`strated with simvastatin using high performance liquid
`chromatography (HPLC) in Table 3. Standard slow 10
`batch crystallization affords product purity comparable
`to that afforded by the jet process, but the jet process is
`superior because, as noted above, in addition to high
`purity, it also provides higher quality cry~~ ha?it and
`increased particle surface area thereby ehmmatmg the 15
`need for milling.
`Jet process crystallization is suited for continuous
`processing. Standard crystallization methods are gener(cid:173)
`ally run in a batchwise fashion. Continuous processing
`affords two advantages. First, the same amount of feed 20
`compound can be crystallized in significantly less vol(cid:173)
`ume via continuous processing than would be possible
`using a batch by batch method. Second, continuous
`processing enhances reproducibility of results because
`all the material crystallizes under uniform conditions. 25
`Such uniformity is not possible using batch methods in
`which concentration, solubility and other parameters
`change with time.
`
`4
`TABLE 3-continued
`HPLC
`Purity
`(Weight%)
`
`Temp.
`('C.)
`
`969
`Impurity••
`(Weight%)
`
`Simvastatin
`Crystallization
`Method*
`
`Addition
`Slow Batch Process
`99.0
`<0.1
`Product Specification
`>98.5
`<0.5
`•50,50 Volumetric ratio of MeOH:H20 used with impinging jet method; final
`volumetric ratio of 50:50 MeOH:H20 used with reverse addition and slow batch
`methods.
`••Open ring form of simvutatin.
`
`SUMMARY OF THE INVENTION
`This invention concerns a process for crystallization.
`More particularly, this invention relates to the use of
`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. Nucleation and precipitation can be initiated by
`utilizing the effect of temperature reduction on the
`solubility of the compound to be crystallized in a partic(cid:173)
`ular solvent (thermoregulation), or by taking advantage
`of the solubility characteristics of the compound in
`solvent mixtures, or by some combination of the two
`techniques.
`The novel process of this invention provides for the
`direct crystallization of high surface area particles of
`high purity and stability.
`BRIEF DESCRIPTION OF THE ORA WINGS
`
`Batch
`
`______ ......;;T.;..A;.;;.B..;;;L_E_l __ __ ___ 30
`JET CRYSTALLIZED SJMVASTATIN
`Surface Area
`(m2/g) at 45-55' c.
`3.37•
`2.57•
`2.88·
`56
`3
`·
`•
`
`1
`2
`3
`t;;
`4
`~
`3.05
`Mean:
`__ _:S:.:ta:::n=d=ar..:d..:D;..:e_v1=·at;;.io_n_: ______ o._40 ______
`40
`•Run at 50-51· c.
`
`Two embodiments of the invention have been chosen
`for purposes of illustration and description, and are
`shown in the accompanying drawings forming a part of
`35 the specification wherein:
`FIG. 1 is a schematic diagram showing a crystal
`production system depicting the jet chamber 3, the
`transfer line 4, the stirred vessel S, the agitation device
`6 and the entry point of two fluids 1 and 2 into the
`system;
`FIG. 2 is an enlarged sectional view of jet chamber 3
`showing an arrangement for impinging jet introduction
`of two fluids into the system;
`FIG. 3 is an overhead view of the jet chamber 3;
`FIG. 4 shows particle surface area as a function of
`supersaturation ratio using the jet crystallization pro(cid:173)
`cess with simvastatin; and
`FIG. S is a schematic diagram showing a crystal
`production system depicting two fluids, 11 and 12, en-
`50 tering directly into the stirred vessel 13 containing liq(cid:173)
`uid 14 (the liquid being solvent and/or anti-solvent)
`where the jets 16 emit fluid jetstreams that impinge and
`micromix near the effiuent stream of the impeller 15 .
`
`TABLE 2
`60' C. ACCELERATED ST ABILITY TEST
`Weeks (at 60' C.)
`Surface
`2
`4
`0
`Area
`JET CRYSTALLIZED SIMV AST A TIN
`97.2
`98.7
`99.4
`96.8
`95.1
`2.4
`93.3
`98.1
`95.1
`4.0
`98.9
`92.5
`93.4
`85.7
`99.3
`96.5
`88.5
`5.5
`95.l
`86.0
`80.1
`98.8
`96.4
`4.6
`SLOW BATCH CRYSTALLIZED
`SJMV AST A TIN (MILLED)
`95.7
`95.0 95.0
`98.9
`95.5
`94.3
`83.6
`95.0
`99.1
`94.9
`99.0 98.2
`95.9
`93.0
`99.2 98.4 95.3
`95.4
`98.0
`81.3
`99.7
`98.3
`94.0 89.0
`77.8
`99.2
`
`I
`
`6
`
`8
`
`93.5
`82.8
`36.6
`34.0
`
`Batch
`
`I
`2
`3
`4
`
`3.0
`3.3
`2.6
`2.7
`
`I
`2
`3
`4
`5
`6
`•Heat..cool p:ocess used.
`
`Temp.
`'C.
`
`68
`55
`55
`55
`
`•
`•
`•
`•
`•
`
`45
`
`55
`
`60
`
`TABLE 3
`
`Simvastatin
`Crystallization
`Method•
`
`Continuous
`Impinging Jets
`Continous
`Impinging Jets
`Batch Reverse
`
`Temp.
`('C)
`
`HPLC
`Purity
`(Weight%)
`
`969
`Impurity••
`(Weight%)
`
`50
`
`25
`
`25
`
`99.0
`
`<0.1
`
`65
`
`98.6-99.0
`
`0.2-0.4
`
`98.7
`
`0.7
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The novel process of this invention involves the use
`of jets to create impinging fluid jet streams and thereby
`achieve high intensity micromixing of the fluids prior to
`nucleation in a crystallization process. Two or more jets
`may be used to micromix two or more fluids. Prefera(cid:173)
`bly, two jets are used to micromix two fluids. When
`using two jets, preferably the two impinging jet streams
`should be substantially diametrically opposed to each
`other, i.e., they should be at or close to a 180 degree
`angle to each other from an overhead view. FIG. 1
`shows one embodiment of this invention wherein two
`jets are employed; fluids 1 and 2 enter the jet chamber
`
`

`

`5,314,506
`
`s
`6
`rial leaves the stirred vessel, appropriate recovery tech-
`3 where micromixing takes place. FIG. 5, shows an-
`other embodiment of this invention, wherein 2 jets are
`niques are used to isolate the product crystals. The
`material preferably flows through the system in a con-
`employed and the jetstreams impinge and micromix
`tinuous process, although it is possible to hold up the
`directly in the stirred vessel 13. As used herein, the
`terms stirred vessel and age vessel have the same mean- 5 process in a batchwise fashion at the stirred vessel-aging
`ing and are interchangeable.
`step given a vessel of sufficient volume.
`The two fluids used in the novel process of this inven-
`As shown in FIG. 2 and FIG. 3, the jet chamber 3 is
`preferably cylindrical in shape and as shown in FIG. 2
`tion can be of different solvent composition, one fluid
`being a solution of the compound to be crystallized in a
`the jet chamber 3 preferably has a floor 10 which slopes
`suitable solvent or combination of solvents ("feed solu- 10 downward in a conical shape toward the floor's center
`tion"), and the other fluid being a suitable solvent or
`which is open to a connecting transfer line 4 or directly
`combination of solvents capable of initiating that com-
`into a stirred vessel or other appropriate container. The
`pound's precipitation from solution ("anti-solvent"),
`diameter and cylinder wall height of the chamber can
`chosen for its relatively low solvation property with
`vary according to scale needs.
`respect to that compound. Such solvents and anti-sol- 15
`Regardless of the number of jets used, the jet nozzles
`vents can include but are not limited to methanol, ethyl
`should be placed so that the fluid streams they emit will
`acetate, halogenated solvents such as methylene chlo-
`impinge, either inside the jet chamber or directly in the
`ride, acetonitrile, acetic acid, hexanes, ethers, and wa-
`stirred vessel. The fluid jets must impinge to create an
`ter.
`immediate high turbulence impact; concentric or con-
`Or, the two fluids used in the process can both be 20 verging jets generally create insufficient turbulence to
`solutions of the compound to be crystallized in the same
`achieve the required micromixing. When two jets are
`suitable solvent or combination of solvents but each at a
`used with a jet chamber, as shown in FIG. 2 and FIG.
`different temperature, and nucleation/precipitation can
`3, the two jet nozzles 7 are preferably arranged so that
`be initiated by instantaneous temperature reduction.
`they are substantially diametrically opposed to each
`The temperature and composition of each solution are 25 other with their outlet tips directed to face each other;
`chosen so that 1) no material will crystallize upstream of
`i.e., the two jet nozzles are at or close to a 180 degree
`the impinging jets, and 2) sufficient supersaturation will
`angle to each other from an overhead view. Preferably,
`be developed in the impinging jets to cause nucleation.
`each jet outlet nozzle can have a slight downward angle
`Micromixing creates temperature and compositional
`from the horizontal of about 10 degrees to help the
`uniformity throughout the mixture prior to the start of 30 flowing material move down and out of the chamber.
`nucleation.
`Likewise, two jet nozzles placed directly inside the
`The fluids used in the process can also contain a small
`stirred vessel are preferably arranged so that they are
`amount of a suitable surfactant which may alleviate
`substantially diametrically opposed to each other with
`agglomeration which might occur during the jet mix
`their outlet tips directed to face each other. When the
`crystallization process. Thus, one, several or all of the 35 jet nozzles are so placed, each nozzle can have a slight
`fluids employed may contain a surfactant as less than
`upward or downward angle from the horizontal of from
`1 % of its volume. The preferred amount of the surfac-
`0 degrees up to about 15 degrees, but preferably the two
`tant is between 0.05% and 1 % of the volume of the
`nozzles have just enough downward angle from the
`fluid. Since such a surfactant may be incorporated in the
`horizontal (ca. 13 degrees) to ensure that the fluid
`crystalline compound the surfactant should be chosen 4-0 stream of one will not enter the outlet hole of the oppo-
`which will be innocuous to the eventual use of the crys-
`site nozzle.
`talline compound. Suitable surfactants which may be
`One jet nozzle is used to transport one of the two
`included in the fluids employed in the process include
`fluids from an external source into the chamber and the
`but are not limited to Triton X-100, sodium dodecyl
`other jet is used to similarly transport the other fluid.
`sulfate, Witconol-14F, Enthos D70-30C and the like.
`45 The distance between the nozzle tips inside the jet
`The following is a list of compounds that have been
`chamber or stirred vessel should be such that the hydro-
`successfully crystallized to meet particle size and purity
`dynamic form of each fluid jet stream remains essen-
`specifications using the present invention: simvastatin.
`tially intact up to the point of impingement. Therefore,
`lovastatin (crude and pure), omeprazole, PROSCAR ®
`the maximum distance between the nozzle tips will vary
`((5a,17/3)-(l,l-dimethylethyl)-3-oxo-4-azaandrost-
`50 depending on the linear velocity of the fluids inside the
`1-ene-17-carboxamide), diltiazem malate, 17/3-benzoyl-
`jet nozzles. To obtain good results for generally non-
`4-aza-5a-androst-1-ene-3-one, 4" -epi-acetylamino-aver-
`viscous fluids, linear velocity in the jet nozzles should
`mectin Bi, [trans-(-)]-2-[[3-methoxy-2-propoxy-5-[tet-
`be at least about 5 meters/sec., more preferably above
`rahydro-5-(3,4,5-trimethoxyphenyl)-2-furanyl]phenyl]-
`10 meters/sec., and most preferably between about 20
`sulfonyl]ethanol (DevLab, England). However, this is 55 to 25 meters/sec., although the upper limit of linear
`not an exhaustive list of all the compounds that can be
`velocity is only limited by the practical difficulties in-
`used with the present invention.
`valved in achieving it. Linear velocity and flow rate
`After micromixing in a jet chamber, the material
`can both be controlled by various known methods, such
`leaves the jet chamber as depicted in FIG. 1, travels into
`as altering the diameter of the entry tube 8 and/or that
`a stirred vessel 5 either directly or via a transfer line 4, 60 of the nozzle outlet tip 9, and/or varying the strength of
`and after an appropriate age time, the product suspen-
`the external force that moves the fluid into and through
`sion flows out of the vessel as indicated by arrow A.
`the nozzle. Each jet apparatus can be manipulated inde-
`Another embodiment of this invention involves the
`pendently to attain a desired final fluid composition
`micromixing of two impinging jetstreams directly in the
`ratio. When the desired flow ratio of one jet to the other
`stirred vessel without the use of a jet chamber or trans- 65 differs from unity, preferably the difference is compen-
`fer line, as depicted in FIG. 5. For the crystallization of
`sated for by appropriate sizing of the entry tubes. For
`simvastatin, the preferred method is for two jetstreams
`example, if a 4:1 volumetric ratio of feed solution to
`to impinge directly in the stirred vessel. Once the mate-
`anti-solvent is desired, the entry tube delivering feed
`
`

`

`5,314,506
`
`7
`8
`chosen solvent's boiling point and the compound's de-
`solution should be twice the diameter of the entry tube
`composition range. Temperatures above ambient may
`delivering anti-solvent. When the jetstreams impinge
`give improved product characteristics. As an example,
`inside a jet chamber, residence time for the fluid inside
`optimum results with regard to end product surface
`the jet chamber is typically very short, i.e., less than ten
`S area, purity and stability are achieved for simvastatin by
`seconds.
`A transfer line 4 as shown in FIG. 1 may or may not
`running the crystallization at an elevated temperature of
`at least 55• C., more preferably in the range of 60 to 70"
`be used to deliver the fluid mixture into a stirred vessel
`5 from the jet chamber. Solvent, anti-solvent or mix-
`C., and most preferably at 65 to 68" C., in a 41:59 volu-
`metric mixture ofMeOH:H20. In this case, the composi-
`tures thereof optionally containing seed and optionally
`heated to attain optimum crystallization results can be 10 tion in the impinging jetstreams is 50:50 MeOH:H20,
`put inside the stirred vessel FIG. I (5), FIG. 5 (13) at the
`and the composition in the age tank is brought to 41:59
`start of the process before the micromixed fluids enter MeOH:H20 by a separate, additional water injection
`the stirred vessel; this technique is especially preferred
`(not through the impinging jet) directly into the stirred
`when the jetstreams impinge directly in the stirred ves-
`vessel. A 75:25 volumetric mixture of MeOH:H20 used
`sel. Crystal digestion (Ostwald ripening, improvement 15 at room temperature produces crystals essentially the
`of surface structure) takes place inside the stirred vessel.
`same as those from conventional batchwise crystalliza-
`Stirring in the vessel is provided by standard agitators
`tion, i.e, they require milling. A 41:59 volumetric mix-
`ture of MeOH:H2o used at room temperature results in
`6, prefer.ably Rus~ton turbin~s,. lntermig impellers! or
`other .agitators su1ta~l~ for stunn~ a slu':Y s?s~ns1on.
`particles with average surface area above the desirable
`Any impeller prov1dmg good c1rculat1<;>n ms1de the 20 range and decreased purity as shown in FIG. 4. Ambi-
`vessel may 1;>e u~ed. ~oweve~, ~hen the_Jetstreams are
`ent temperature operation using the jet process provides
`arranged to 1mpmge directly ms1de the st1rred vessel, an
`sufficiently good results for PR OSCAR® and there-
`agitator .tha~ d~s n~t interfere. w!th the space °'7upied
`fore elevated temperatures are not necessary.
`by the 1mp1~gmg Jetstreams ms1de t~e vessel 1s. pre-
`The following examples are given for the purpose of
`~erred, espe~1all.y, 7.g., .a Rushton .tu~bme. As depicted 25 illustrating the present invention and should not be
`m FIG. 5, 1mpmgmg Jetstreams ms1de the vessel are
`construed as limitations on the scope or spirit of the
`most preferably placed in the effiuent stream of the
`instant invention.
`agitator, and the height of the liquid in the stirred vessel
`when operated in continuous mode (i.e., flow in equals
`flow out, constant volume maintained), is most prefera- 30
`bly between about two to four times the height of the
`impeller.
`The crystallization is preferably run in a continuous
`process and the appropriate residence time for the com(cid:173)
`pletion of crystal digestion is attained by adjusting the 35
`volume capacity of the stirred vessel, but the mixture
`can be held up in the vessel for any desired length of age
`time if batchwise processing is desired. For example,
`during simvastatin crystallization crystal digestion is
`complete within about 5 minutes and a vessel volume of 40
`roughly 5 liters is sufficient for a residence time of 5
`minutes with a material flow of about 1 liter per minute.
`PROSCAR ® is similar to simvastatin with respect to
`age time. In some instances when the fluids impinge and
`micromix inside a jet chamber, crystallization condi- 45
`tions may be optimized so that crystal precipitation and
`growth are completed within the transfer line itself, or
`even before entering the transfer line, and the crystals
`may be directly collected, bypassing any age time in the
`stirred vessel.
`Manual seeding can be done at any point in the sys(cid:173)
`tem, e.g., in the stirred vessel, the transfer line or the jet
`chamber itself. In some situations, the continuous jet
`process may be ·'self-seeding", i.e., the first crystals to
`form inside the jet chamber (if used), the transfer line (if 55
`used) or the stirred vessel (if used) serve as seed for the
`material that flows through thereafter.
`The micromixed material must be highly supersatu(cid:173)
`rated to attain the beneficial results of the jet crystalliza(cid:173)
`tion process. Aside from thermoregulated initiation of 60
`nucleation, temperature variation also affects product
`results when anti-solvent is used to initiate nucleation
`because of its effect on supersaturation. Generally, good
`results can be achieved for pharmaceutical compounds
`using a volumetric ratio of feed solution to anti-solvent 65
`that provides a high degree of supersaturation in the jet
`chamber in a temperature range of about 24° C. to 70°
`C., although temperature height is limited only by the
`
`EXAMPLE 1
`Crystallization of PROSCAR@
`100 Grams of PROSCAR ® dissolved in 600 ml. of
`glacial acetic acid; once dissolution was complete, 400
`ml. deionized water was added. The solution was fil(cid:173)
`tered through a 0.2 micron membrane into a blow can.
`The blow can outlet was connected to a 1/16 in. OD jet
`nozzle (0.052 in. ID). 5.5 Liters of deionized water was
`filtered through a 0.2 micron membrane into a second
`blow can, and its outlet connected to a l in. OD jet
`nozzle (0.0938 in. ID). Each blow can was pressurized
`to ca. 90 psi with regulated nitrogen. The impinging jets
`were started simultaneously. The desired flow rate of
`the acetic acid solution was 0.2 gpm Oinear velocity ca.
`550 meters/min.) and the desired flow rate of 100%
`H20 was 1.1 gpm Oinear velocity ca. 930 meters/min.).
`The effiuent slurry was collected from the mixing
`chamber in a 12L round-bottom flask equipped with a
`paddle agitator. A minimum age time of two minutes
`was required to complete crystal digestion. The solids
`so were filtered, water washed, then dried.
`Crystals were 10 to 20 microns in diameter and 1
`micron thick, in the form of flakes; specification is 95%
`< smaller than 25 microns.
`EXAMPLE2
`100 Grams of simvastatin were dissolved in 1400 ml.
`methanol, and the solution heated to approximately 55°
`C. Deionized water (1400 ml.) was heated to approxi(cid:173)
`mately 55° C. The heated water was fed to one blow
`can and the heated methanol solution was fed to a sec(cid:173)
`ond blow can. Each blow can outlet was connected to
`a l mm. ID jet nozzle. Each blow can was pressurized
`to 25-35 psi, and impinging jets were started simulta(cid:173)
`neously. The flow from each jet was 1.1 liter/min. (lin(cid:173)
`ear velocity ca. 23 meters/sec.).
`The jet chamber was approximately 2 inches in diam(cid:173)
`eter and 1 inch high with a conical bottom outlet. Effiu(cid:173)
`ent from this chamber was directed to a 4 liter beaker
`
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`

`5,314,506
`
`10
`outlet temperature (43° C.) for 5 minutes, cooled with
`stirring to less than 30° C., and filtered and dried.
`The final product was fine needles with acceptable
`surface area 1.6 m2/gm. Purity was equal to that from
`conventional seeded crystallization.
`
`9
`(approx. 6 inches diameter). The beaker contained 2.5
`grams sim