(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2006/0160841 A1
`Wei et al.
`(43) Pub. Date:
`Jul. 20, 2006
`
`US 20060160841A1
`
`(54) CRYSTALLIZATION VIA HIGH-SHEAR
`TRANSFORMATION
`
`(76) Inventors: Chenkou Wei, Princeton Junction, NJ
`(US); Bing-Shiou Yang, Dayton, NJ
`(Us)
`
`Correspondence Address:
`LOUIS J. WILLE
`BRISTOL-MYERS SQUIBB COMPANY
`PATENT DEPARTMENT
`p 0 BOX 4000
`PRINCETON, NJ 085434000 (Us)
`
`(21) Appl, NQ;
`
`11/235,327
`
`(22) Filed:
`
`Sep. 26, 2005
`
`Related U.s. Application Data
`
`(60) Provisional application No. 60/645,056, ?led on Jan.
`19, 2005.
`
`Publication Classi?cation
`
`(51) Int. Cl.
`(2006.01)
`C07D 471/02
`(2006.01)
`A61K 31/4745
`(52) us. Cl. .......................................... .. 514/303; 546/118
`
`(57)
`
`ABSTRACT
`
`The invention relates to a process or apparatus for trans
`forming a ?rst polymorph of a chemical material into a
`second polymorph of the same chemical material, utilizing
`an apparatus comprising a vessel connected to a re-circula
`tion system, the process comprising the steps of: suspending
`said ?rst polymorph in a solution to form a slurry in the
`vessel, re-circulating the slurry and removing the slurry from
`the vessel.
`
`MYLAN EXHIBIT 1008
`
`

`

`Patent Application Publication Jul. 20, 2006 Sheet 1 of 4
`
`US 2006/0160841 A1
`
`FIG. 1
`
`Polvmorph Transformation Crvstallization — Batch mode
`
`DC)
`
`I
`
`

`

`Patent Application Publication Jul. 20, 2006 Sheet 2 0f 4
`
`US 2006/0160841 A1
`
`FIG. 2
`
`|
`I
`|
`l
`i I
`l
`L
`I
`1
`
`

`

`Patent Application Publication Jul. 20, 2006 Sheet 3 0f 4
`
`US 2006/0160841 A1
`
`FIG. 4
`
`Polvmorph Transformation Crvstallization — Batch mode
`
`D
`U
`
`

`

`Patent Application Publication Jul. 20, 2006 Sheet 4 0f 4
`
`US 2006/0160841 A1
`
`'\
`
`FIG. 5
`
`

`

`US 2006/0160841 A1
`
`Jul. 20, 2006
`
`CRYSTALLIZATION VIA HIGH-SHEAR
`TRANSFORMATION
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] This application claims a bene?t of priority from
`US. Provisional Application No. 60/645,056 ?led Jan. 19,
`2005, the entire disclosure of Which is herein incorporated
`by reference
`
`FIELD OF THE INVENTION
`
`[0002] The present invention relates to a process for
`preparing small crystals of organic pharmaceutical com
`pounds and more particularly to a crystallization process that
`utilizes high-shear assisted polymorph transformation and to
`the apparatus for practicing such a process.
`
`BACKGROUND OF THE INVENTION
`[0003] It is Well knoWn in the pharmaceutical industry that
`the bioavailability of a sparingly soluble organic compound
`is often enhanced When the compound is very pure and the
`molecules of the compound have a small, uniform particle
`size, high surface area, and short dissolution time. Puri?ca
`tion can be accomplished by crystallization of the compound
`from solution. However, When crystallization takes place
`directly in a high supersaturation environment, the resulting
`material is often unsatisfactory due to loW purity, high
`friability, and lack of stability because the crystal structure
`formation is inadequate. Further, oils commonly produced
`during processing of supersaturated material may solidify
`Without su?icient structure.
`
`[0004] It is possible to sloW doWn the crystallization
`process to obtain a higher purity, more stable product.
`HoWever, sloWing the process decreases crystallizer produc
`tivity and produces particles Which are too large, having loW
`surface area. Such particles require high intensity milling to
`create a useable product.
`[0005] To overcome those problems, and provide crystal
`line particles of high surface area, high chemical purity, and
`high stability, Without the need for post-crystallization mill
`ing, a crystallization process, knoWn as the “impinging ?uid
`jet” process, has been developed.
`[0006] One Well knoWn version of the “impinging ?uid
`jet” process is disclosed in detail in US. Pat. No. 5,314,506
`entitled “Crystallization Method To Improve Crystal Struc
`ture And Size” issued May 24, 1994, to Midler et al., oWned
`by Merck & Co., Inc. of RahWay, N]. The reader is referred
`to that patent for background information and the details of
`the process.
`[0007] Basically, the impinging ?uid jet process utilizes a
`supersaturated solution of the compound to be crystallized in
`solvent and an appropriate “anti-solvent” solution. Diametri
`cally opposed high velocity jet streams of these solutions are
`formed by nozzles and micro mixed in a jet chamber. The
`mixed solutions are then transferred into a vessel Where they
`are stirred to produce the end product. The product, such as
`a neutral molecule or a salt, is crystallized out by mixing the
`solutions Which reduces the solubility of the compound in
`the solvent mixture.
`
`[0008] The impinging ?uid jet stream process has also
`been used for conducting reactive crystallization Wherein a
`
`chemical reaction and controlled crystallization take place
`simultaneously. Patent Application Publication No.: US.
`2002/0016498 A1 of Feb. 7, 2002, entitled “Reactive Crys
`tallization Method to Improve Particle Size” in the name of
`Am Ende et al., oWned by P?zer Inc., provides further
`information in this regard.
`
`[0009] Reactive crystallization involves tWo reactive
`intermediates. Fluid streams of solutions of the reactive
`intermediates are impinged in a chamber under appropriate
`reactive conditions. For example, a ?rst solution containing
`one reagent (for example, an acid) in a solvent is reacted
`With a second solution containing another reagent (for
`example, a base) in a solvent are reacted to form a product,
`such as a salt. The product is not soluble in the solvent
`mixture and thus it rapidly crystallizes out. In the pharma
`ceutical industry, the drug substance is often in a salt form,
`so reactive crystallization is commonly used.
`
`[0010] Recently, Wei et al. disclosed a crystallization
`system using homogenization in WO 03/095059 and another
`crystallization system utilizing atomization in WO
`03/092852. The entire disclosures of each of the aforemen
`tioned patents or patent application publications are incor
`porated herein by reference.
`[0011] There remains a need to develop a robust crystal
`lization process that can produce small and uniform crystals
`With high purity, high stability, and high surface area, and
`Without the necessity of post-crystallization milling.
`
`SUMMARY OF THE INVENTION
`
`[0012] The present invention relates a process for trans
`forming a ?rst polymorph of a chemical material into a
`second polymorph of the same chemical material, utilizing
`an apparatus comprising a vessel connected to a re-circula
`tion system, the process comprising the steps of: suspending
`the ?rst polymorph in a solution to form a slurry in the
`vessel, re-circulating the slurry, and removing the slurry
`from the vessel.
`
`[0013] The present invention relates to apparatus for trans
`forming a ?rst polymorph of a chemical material into a
`second polymorph of the same chemical material.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0014] To these and such other objects Which may here
`inafter appear, the present invention relates to a process
`transforming a polymorph (including solvate) of a chemical
`material into a second polymorph (including solvate) of the
`same chemical material, using a vessel connected to a
`recirculation system. The recirculation can be conducted
`through a homogenization apparatus in Which a high-shear
`force is applied, as described in detail in the folloWing
`speci?cation and recited in the annexed claims, taken
`together With the accompanying draWings, Wherein like
`numerals refer to like parts and in Which:
`
`[0015] FIG. 1 is a schematic draWing of an apparatus
`utilized to perform the process of the present invention;
`
`[0016] FIG. 2 is a cross-sectional vieW of homogenization
`chamber G With rotor H and stator I. J and K are the inlet and
`outlet of the slurry, respectively;
`[0017] FIG. 3 is a cross-sectional vieW taken along line
`1-1 of FIG. 2;
`
`

`

`US 2006/0160841 A1
`
`Jul. 20, 2006
`
`[0018] FIG. 4 is a schematic drawing of an apparatus that
`can be utilized to perform the process of the present inven
`tion; and
`[0019] FIG. 5 is a schematic drawing of an apparatus that
`can be utilized to perform the process of the present inven
`tion.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`[0020] In accordance With one aspect of the present inven
`tion, the process utilizes an apparatus comprising a vessel
`connected to a re-circulation system. The process is useful
`for transforming a ?rst polymorph (including solvate) of a
`chemical material into a second polymorph (including sol
`vate) of the same chemical material. The second polymorph
`can be thermodynamically more stable or thermodynami
`cally less stable than the ?rst polymorph. In addition, the
`?rst polymorph can be in a solvate form, including hydrate
`form and the second polymorph can be in an anhydrous
`form. Further, the present invention can be especially effec
`tive for transforming a ?rst polymorph Which consists of
`large crystals into a second polymorph Which consists of
`small crystals. Generally, large crystals have a particle size
`D[90] greater than about 100 um, and small crystals have a
`particle size D[90] less than about 30 pm. In addition, large
`crystals can have a particle size D[90] greater than about 60
`um, and small crystals can have a particle size D[90] less
`than about 50 pm.
`
`[0021] The recirculation can be conducted through a
`homogenization apparatus in Which a high-shear force is
`applied. The homogenization apparatus comprises a stator
`and a rotatable rotor, and the high-shear mixing force is
`applied by rotating the rotor at a speed of more than 250
`rpm. The rotor can also be rotated as speeds of more than
`500 rpm and more than 1,000 rpm.
`[0022] Re-circulating the slurry comprises regulating the
`How of slurry through the outlet and the inlet of the vessel,
`as illustrated in FIGS. 1 and 5. The energy for the re
`circulation can be provided by a pump. Conventional ?oW
`regulation mechanisms such as metering pumps, valves, and
`the like may be used for this purpose. The process can also
`be conduced in a continuous mode, as illustrated in FIGS.
`1 and 4.
`
`[0023] Suspending the large crystals in a solution to form
`a slurry in the vessel comprises adjusting the temperature of
`the solution in the vessel. This may be achieved by any
`conventional temperature adjusting equipment, such as a
`heater or a cooling bath associated With the vessel.
`
`[0024] In accordance With another aspect of the present
`invention, the process is useful for producing small crystals
`of a chemical material through polymorph transformation,
`utilizing the apparatus as described above and as illustrated
`in FIGS. 1, 4, and 5. The process comprises the steps of: (a)
`mixing a ?rst solution into a second solution in the vessel
`(e.g., vessel A) to form a slurry (i.e., ?rst polymorph),
`Wherein the ?rst solution comprises the material to be
`dissolved in a solvent (e.g., propylene glycol (PG)) and the
`second solution comprises an anti-solvent (e.g., Water); (b)
`re-circulating the slurry, and (c) removing the slurry from
`the vessel after the second polymorph has been formed.
`
`[0025] The ?rst solution may be a supersaturated solution
`comprising the chemical material to be crystallized, such as
`
`a neutral molecule or a salt, dissolved in a solvent. This
`material-containing solution is mixed With a second solu
`tion, Which is an anti-solvent solution. The anti-solvent
`refers to any solvent in Which the chemical material has a
`poor solubility. It may be a mixture of anti-solvents and
`solvents. For example, the anti-solvent may comprise Water
`and PG. Mixing the solutions reduces the solubility of the
`material in the solvent mixture, causing it to crystallize out.
`Optionally, the second solution may contain a limited
`amount of the chemical material.
`
`[0026] The process may also include the step of introduc
`ing seed crystals into the vessel to facilitate crystallization.
`The seed crystals may be placed into the vessel prior to the
`introduction of the solutions or seed crystals may be added
`to one of the solutions prior to its introduction into the
`vessel. These seed crystals must be insoluble in the indi
`vidual solvents and in the solvent mixture.
`
`[0027] As used herein, the terms “?rst” and “second” are
`not intended to denote order or to limit the invention to a
`particular sequence of the combination of the constituents.
`Further, the term “solution” is used generically and should
`be understood to include dispersions, emulsions, multi
`phase systems, and pure solvents, as Well as solutions.
`[0028] Mixing the ?rst solution With the second solution in
`the vessel comprises regulating the How of each of the
`solutions into the vessel. Conventional ?oW regulation
`mechanisms such as metering pumps, valves, and the like
`may be used for this purpose.
`
`[0029] The temperature of one or both of the solutions
`may be adjusted prior to their introduction into the vessel.
`This may be achieved by any conventional temperature
`adjusting equipment, such as a heater or a cooling bath
`associated With the solution source.
`
`[0030] In accordance With another aspect of the present
`invention, the process may also utilize an apparatus com
`prising a ?rst vessel, a second vessel, and a third vessel as
`illustrated in FIG. 5. The process comprising the steps of:
`(a) mixing a ?rst solution into a second solution in the ?rst
`vessel to form a slurry, Wherein the ?rst solution comprises
`the material to be crystallized dissolved in a solvent and the
`second solution comprises an anti-solvent; (b) transferring
`the slurry into the second vessel Wherein a high-shear
`mixing force is applied on the slurry via a homogenizer
`apparatus; (c) transferring the resulting slurry from the
`second vessel into the third vessel and agitating, and (d)
`removing the slurry from the third vessel.
`
`[0031] The temperature of the ?rst and/or second solutions
`may be adjusted prior to their introduction into the ?rst
`vessel. In addition, the temperature of one or more of the
`vessels may be adjusted. This may be achieved by any
`conventional temperature adjusting equipment, such as a
`heater or a cooling bath associated With the solution source
`or the vessel.
`
`[0032] Mixing the ?rst solution With the second solution in
`the ?rst vessel comprises regulating the How of each of the
`solutions into the vessel. Further, transferring the slurry from
`the ?rst vessel into the second vessel and from the second
`vessel into the third vessel comprises regulating the How of
`each of the slurry into each vessel. Conventional ?oW
`regulation mechanisms such as metering pumps, valves, and
`the like may be used for this purpose.
`
`

`

`US 2006/0160841 A1
`
`Jul. 20, 2006
`
`[0033] In accordance With another aspect of the present
`invention, an apparatus is provided for transforming a ?rst
`polymorph (including solvate) of a chemical material into a
`second polymorph (including solvate) of the same chemical
`material, comprising a vessel connected to a re-circulation
`system; a means for suspending the ?rst polymorph in a
`solution to form a slurry in the vessel; a means for re
`circulating the slurry; and optionally a means for removing
`the slurry from the vessel. Removing can be performed by
`decanting or other similar procedures. Thus, a means for
`removing is optional.
`
`[0034] The re-circulation system comprises a homogeni
`zation apparatus; outlet means for transferring the slurry
`from the vessel to the homogenization apparatus; and inlet
`means for receiving the slurry from the homogenization
`apparatus into the vessel. The homogenization apparatus
`comprises a stator and a rotatable rotor, and means for
`applying a high- shear mixing force by rotating the rotor. The
`high-shear mixing force can be applied by rotating the rotor
`at a speed of more than 250 rpm. The rotor can also be
`rotated as speeds of more than 500 rpm and more than 1,000
`rpm.
`
`[0035] The apparatus may include a means for regulating
`the How of slurry through the homogenization apparatus.
`Conventional ?oW regulation mechanisms such as metering
`pumps, valves, and the like may be used for this purpose.
`The apparatus may also include a means for adjusting the
`temperature of the slurry in the vessel. This may be achieved
`by any conventional temperature adjusting equipment, such
`as a heater or a cooling bath associated With the solution
`source or the vessel.
`
`[0036] In accordance With another aspect of the present
`invention, an apparatus is provided for producing small
`crystals of a chemical material through polymorph transfor
`mation, comprising a ?rst source of a ?rst solution; a second
`source of a second solution; a vessel connected to a re
`circulation system; a means for mixing the ?rst solution With
`the second solution in the vessel to form a slurry in the
`vessel; a means for re-circulating the slurry; and optionally
`a means for removing the slurry from the vessel. Removing
`can be performed by decanting or other similar procedures.
`Thus, a means for removing is optional. The ?rst solution
`comprises the material to be crystallized dissolved in a
`solvent and the second solution comprises an anti-solvent.
`The re-circulation system comprises a homogenization
`apparatus; an outlet means for transferring the slurry from
`the vessel to the homogenization apparatus; and an inlet
`means for receiving the slurry from the homogenization
`apparatus into the vessel. The homogenization apparatus
`comprises a stator and a rotatable rotor, and a means for
`applying a high-shear mixing force by rotating the rotor.
`Said means for applying a high-shear mixing force is
`achieved by rotating the rotor at a speed of more than 250
`rpm. The rotor can also be rotated as speeds of more than
`500 rpm and more than 1,000 rpm.
`
`[0037] The apparatus may include a means for regulating
`the How of slurry through the homogenization apparatus.
`Conventional ?oW regulation mechanisms such as metering
`pumps, valves, and the like may be used for this purpose.
`The apparatus may also include a means for adjusting the
`temperature of the slurry in the vessel. This may be achieved
`
`by any conventional temperature adjusting equipment, such
`as a heater or a cooling bath associated With the solution
`source or the vessel.
`
`[0038] In accordance With another aspect of the present
`invention, an apparatus is provided for producing small
`crystals of a chemical material through polymorph transfor
`mation, comprising a ?rst source of a ?rst solution; a second
`source of a second solution; ?rst vessel; a second vessel; a
`third vessel; a means for mixing the ?rst solution With the
`second solution in the ?rst vessel to form a slurry (i.e., ?rst
`polymorph) in the ?rst vessel; a means for transferring the
`slurry from the ?rst vessel into the second vessel; a means
`for applying a high-shear mixing force on the slurry in the
`second vessel via a homogenizer apparatus; a means for
`transferring the resulting slurry from the second vessel into
`the third vessel; a means for applying agitation on the slurry
`in the third vessel; and optionally a means for removing the
`slurry from the third vessel after the second polymorph has
`been formed. Removing can be performed by decanting or
`other similar procedures. Thus, a means for removing is
`optional.
`[0039] The ?rst solution comprises the material to be
`crystallized dissolved in a solvent and the second solution
`comprises an anti-solvent. The re-circulation system com
`prises a homogenization apparatus; outlet means for trans
`ferring the slurry from the vessel to the homogenization
`apparatus; and inlet means for receiving the slurry from the
`homogenization apparatus into the vessel. The homogeni
`zation apparatus comprises a stator and a rotatable rotor, and
`means for applying a high-shear mixing force by rotating the
`rotor. Said means for applying a high-shear mixing force is
`achieved by rotating the rotor at a speed of more than 250
`rpm. The rotor can also be rotated as speeds of more than
`500 rpm and more than 1,000 rpm.
`
`[0040] The apparatus may include a means for regulating
`the How of slurry through the homogenization apparatus.
`Conventional ?oW regulation mechanisms such as metering
`pumps, valves, and the like may be used for this purpose.
`The apparatus may also include a means for adjusting the
`temperature of the slurry in the vessel. This may be achieved
`by any conventional temperature adjusting equipment, such
`as a heater or a cooling bath associated With the solution
`source or the vessel.
`
`EXAMPLES
`
`Example 1
`
`[0041] As illustrated in FIG. 1, 350 grams of 1-(4-meth
`oxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,
`7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3 -carboxamide
`are dissolved in about 4900 mL propylene glycol (PG) at
`about 1100 C. in supply vessel A to form a solution. The
`anti-solvent (i.e., 4200 mL of Water and 420 mL of PG) is
`charged into vessel B. With agitation, provided by mixer C,
`the solution in supply vessel A is pumped in the submerge
`mode, by a pump D, to vessel B, While maintaining the batch
`temperature betWeen 10 to 200 C. At this stage, needle
`shaped crystals are formed in vessel B. The crystals have a
`particle size D[90] greater than about 160 um and are also
`in the dihydrate (H2-2) form.
`[0042] After the charge is over, the slurry (i.e., crystals) in
`vessel B is re-circulated (approximately one tank volume,
`
`

`

`US 2006/0160841 A1
`
`Jul. 20, 2006
`
`i.e., 9520 mL, per minute) through the homogenization
`chamber of an inline homogenization apparatus, such as
`Turrax, designated F, by pump E. The homogenization
`apparatus includes a chamber G With a stator and a rotor.
`After about 24 hours of recirculation, the needle-shaped
`crystals are transformed into small, granular crystals Which
`have a particle size D[90] less than about 20 um and Which
`are in the non-solvate N-1 form. The small crystals are
`?ltered and Washed With the anti-solvent (Water), and dried
`under vacuum at about 60° C.
`
`Example 2
`[0043] As illustrated in FIG. 4, 250 grams of 1-(4-meth
`oxyphenyl) -7 -oxo-6-(4-(2 -oxopiperidin- 1 -yl)phenyl) -4,5 , 6,
`7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide
`are dissolved in about 3500 mL propylene glycol (PG) at
`about 110° C. in supply vessel A to form a solution. The
`anti-solvent (i.e., about 3000 mL of Water and about 300 mL
`of PG) is charged into vessel B. With agitation, provided by
`mixer C, the solution in supply vessel A is pumped in the
`submerge mode, by a pump D, to vessel B, While maintain
`ing the batch temperature betWeen 10 to 20° C. At this stage,
`needle-shaped di-hydrate crystals are formed in vessel B.
`[0044] After the charge is over, the slurry (i.e., crystals) in
`vessel B is recirculated (approximately one tank volume,
`i.e., 6800 mL, per minute) through through the outlet and the
`inlet of vessel B, by pump E. After about 30 hours of
`recirculation, the large needle-shaped crystals are trans
`formed into small, granular crystals Which have a particle
`size D[90] less than about 20 um and Which are in the
`non-solvate N-1 form. The small crystals are ?ltered and
`Washed With the anti-solvent (Water), and dried under
`vacuum at about 60° C.
`
`Example 3
`[0045] As illustrated in FIG. 5, 250 grams of 1-(4-meth
`oxyphenyl) -7 -oxo-6-(4-(2 -oxopiperidin- 1 -yl)phenyl) -4,5 , 6,
`7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide
`are dissolved in about 3500 mL propylene glycol (PG) at
`about 110° C. in supply vessel A to form a solution. The
`anti-solvent (i.e., about 3000 mL of Water and about 300 mL
`of PG) is charged into vessel B. With agitation, provided by
`mixer C, the solution in supply vessel A is pumped in the
`submerge mode, by a pump D, to vessel B, While maintain
`ing the batch temperature betWeen 10 to 20° C. At this stage,
`needle-shaped di-hydrate crystals are formed in vessel B.
`
`[0046] After small N-1 seed crystals are charged into
`transient vessel H, the slurry (i.e., crystals) in vessel B is
`transferred through pump E into the transient vessel H While
`maintaining the tank temperature at 55-65° C. In transient
`tank H, the slurry is strongly sheared and re-circulated by an
`overhead type homogenizer I to ensure fast polymorph
`transformation and production of small granular N-1 crys
`tals. The slurry Was continuously decanted by pump J to
`receiver vessel K While maintaining the residence time of
`the slurry in vessel K for 5-10 minutes. The receiver vessel
`K is agitated by mixer L and the temperature is maintained
`at 55-65° C. during the transfer. After the transfer is over, the
`slurry in vessel K is cooled to room temperature. The small
`crystals are ?ltered, Washed With the anti-solvent (Water),
`and dried under vacuum at about 60° C. to give small,
`granular crystals Which have a particle size D[90] less than
`about 20 um and Which are in the non-solvate N-1 form.
`
`We claim:
`1. A process for transforming a ?rst polymorph of a
`chemical material into a second polymorph of the same
`chemical material, utilizing an apparatus comprising: a
`vessel connected to a re-circulation system, the process,
`comprising:
`(a) suspending the ?rst polymorph in a solution to form a
`slurry in the vessel,
`(b) re-circulating the slurry, and
`(c) removing the slurry from the vessel.
`2. The process of claim 1 Wherein said second polymorph
`is thermodynamically more stable.
`3. The process of claim 1 Wherein said ?rst polymorph is
`a solvate form and said second polymorph is an anhydrous
`form.
`4. The process of claim 1 Wherein the particle size D[90]
`of said ?rst polymorph is greater than about 60 um, and the
`particle size D[90] of said second polymorph is less than
`about 50 pm.
`5. The process of claim 1 Wherein said ?rst polymorph
`consists of large crystals With a particle size D[90] greater
`than about 150 um, and said second polymorph consists of
`small crystals With a particle size D[90] less than about 30
`pm.
`6. The process of claim 1 Wherein said chemical material
`1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1
`is
`yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine
`3-carboxamide.
`7. The process of claim 6 Wherein said ?rst polymorph is
`a dihydrate form and said second polymorph is an anhydrous
`form.
`8. The process of claim 1 Wherein the slurry is re
`circulated through a homogenization apparatus in Which a
`high-shear mixing force is applied.
`9. The process of claim 8 Wherein the homogenization
`apparatus comprises a stator and a rotatable rotor, and the
`high-shear mixing force is applied by rotating the rotor at a
`speed of more than 250 rpm.
`10. The process of claim 9 Wherein the high-shear mixing
`force is applied by rotating the rotor at a speed of more than
`500 rpm.
`11. The process of claim 9 Wherein the high-shear mixing
`force is applied by rotating the rotor at a speed of more than
`1,000 rpm.
`12. The process of claim 11 Wherein said chemical
`material is 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperi
`din-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]py
`ridine-3-carboxamide.
`13. The process of claim 12, Wherein said ?rst polymorph
`is a dihydrate form and said second polymorph is an
`anhydrous form.
`14. A process for transforming a ?rst polymorph of a
`chemical material into a second polymorph of the same
`chemical material, utilizing an apparatus comprising a ves
`sel connected to a re-circulation system, the process com
`prising the steps of:
`
`(a) mixing a ?rst solution into a second solution in the
`vessel to form a slurry of the ?rst polymorph, Wherein
`the ?rst solution comprises the chemical material dis
`solved in a solvent and the second solution comprises
`an anti-solvent;
`
`

`

`US 2006/0160841 A1
`
`Jul. 20, 2006
`
`(b) re-circulating the slurry, and
`(c) removing the slurry from the vessel.
`15. A process for transforming a ?rst polymorph of a
`chemical material into a second polymorph of the same
`chemical material, utilizing an apparatus comprising a ?rst
`vessel, a second vessel, and a third vessel, the process
`comprising the steps of:
`
`(a) mixing a ?rst solution into a second solution in the ?rst
`vessel to form a slurry of the ?rst polymorph, Wherein
`the ?rst solution comprises the chemical material dis
`solved in a solvent and the second solution comprises
`an anti-solvent;
`(b) transferring the slurry into the second vessel Wherein
`a high-shear mixing force is applied on the slurry via a
`homogeniZer apparatus;
`(c) transferring the resulting slurry from the second vessel
`into the third vessel and agitating the slurry; and,
`(d) removing the slurry from the third vessel.
`16. The process of claim 15, Wherein the ?rst vessel is
`connected to a second vessel via a conduit and a pump, and
`the second vessel is further connected to a third vessel via a
`conduit and a pump.
`17. The process of claim 15, Wherein steps (a)-(d) are
`carried out continuously.
`18. An apparatus for transforming a ?rst polymorph of a
`chemical material into a second polymorph of the same
`chemical material, comprising: a vessel connected to a
`re-circulation system; a means for suspending the ?rst
`polymorph in a solution to form a slurry in the vessel; and
`a means for re-circulating the slurry.
`19. The apparatus of claim 18, Wherein said re-circulation
`system, comprises: a homogeniZation apparatus; an outlet
`
`means for transferring the slurry from the vessel to the
`homogenization apparatus; and an inlet means for receiving
`the slurry from the homogeniZation apparatus into the ves
`sel.
`20. The apparatus of claim 19, Wherein said homogeni
`Zation apparatus comprises a stator and a rotatable rotor, and
`means for applying a high-shear mixing force by rotating the
`rotor.
`21. An apparatus for transforming a ?rst polymorph of a
`chemical material into a second polymorph of the same
`chemical material, comprising: a ?rst source of a ?rst
`solution; a second source of a second solution; a vessel
`connected to a re-circulation system; a means for mixing the
`?rst solution With the second solution in the vessel to form
`a slurry of the ?rst polymorph in the vessel; and a means for
`re-circulating the slurry.
`22. The apparatus of claim 21, Wherein the ?rst solution
`comprises the chemical material dissolved in a solvent and
`the second solution comprises an anti-solvent
`23. An apparatus for transforming a ?rst polymorph of a
`chemical material into a second polymorph of the same
`chemical material, comprising: a ?rst source of a ?rst
`solution; a second source of a second solution; a ?rst vessel;
`a second vessel; a third vessel; a means for mixing the ?rst
`solution With the second solution in the ?rst vessel to form
`a slurry of the ?rst polymorph in the ?rst vessel; a means for
`transferring the slurry in the ?rst vessel into the second
`vessel; a means for applying a high-shear mixing force on
`the slurry in the second vessel via a homogeniZer apparatus;
`a means for transferring the resulting slurry from the second
`vessel into the third vessel, and a means for applying
`agitation on the slurry in the third vessel.
`
`