NZ729479B2 - Crystallization process of aripiprazole derivatives in extended release formulations for treatment of schizophrenia - Google Patents
Crystallization process of aripiprazole derivatives in extended release formulations for treatment of schizophrenia Download PDFInfo
- Publication number
- NZ729479B2 NZ729479B2 NZ729479A NZ72947915A NZ729479B2 NZ 729479 B2 NZ729479 B2 NZ 729479B2 NZ 729479 A NZ729479 A NZ 729479A NZ 72947915 A NZ72947915 A NZ 72947915A NZ 729479 B2 NZ729479 B2 NZ 729479B2
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- New Zealand
- Prior art keywords
- temperature
- mixture
- solvent
- aripiprazole
- formula
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 129
- 230000008569 process Effects 0.000 title claims abstract description 107
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- 238000002425 crystallisation Methods 0.000 title description 70
- 230000008025 crystallization Effects 0.000 title description 70
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical class ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 title description 37
- 238000013265 extended release Methods 0.000 title description 9
- 238000009472 formulation Methods 0.000 title description 9
- 201000000980 schizophrenia Diseases 0.000 title description 8
- 239000002245 particle Substances 0.000 claims abstract description 126
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 239000013078 crystal Substances 0.000 claims abstract description 50
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 81
- 239000002904 solvent Substances 0.000 claims description 67
- 229940079593 drug Drugs 0.000 claims description 60
- 239000003814 drug Substances 0.000 claims description 60
- 238000001816 cooling Methods 0.000 claims description 55
- 238000000265 homogenisation Methods 0.000 claims description 38
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 28
- 229940011051 isopropyl acetate Drugs 0.000 claims description 28
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000013019 agitation Methods 0.000 claims description 15
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- 238000001035 drying Methods 0.000 claims description 14
- 239000012453 solvate Substances 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 12
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 claims description 12
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 12
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 claims description 12
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 8
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 7
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 7
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 7
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 6
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 claims description 6
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 6
- 229940090181 propyl acetate Drugs 0.000 claims description 6
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 5
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 229940043232 butyl acetate Drugs 0.000 claims description 4
- -1 entane Chemical compound 0.000 claims description 4
- 229940093499 ethyl acetate Drugs 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- DDINXHAORAAYAD-UHFFFAOYSA-N aripiprazole lauroxil Chemical compound C1=C2N(COC(=O)CCCCCCCCCCC)C(=O)CCC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC(Cl)=C1Cl DDINXHAORAAYAD-UHFFFAOYSA-N 0.000 abstract description 89
- 229960003798 aripiprazole lauroxil Drugs 0.000 abstract description 89
- 239000007924 injection Substances 0.000 abstract description 25
- 238000002347 injection Methods 0.000 abstract description 25
- 125000001931 aliphatic group Chemical group 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 68
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 50
- 238000001953 recrystallisation Methods 0.000 description 39
- 229960004372 aripiprazole Drugs 0.000 description 32
- 230000000977 initiatory effect Effects 0.000 description 26
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 25
- 238000009826 distribution Methods 0.000 description 20
- PQUGCKBLVKJMNT-UHFFFAOYSA-N SC560 Chemical compound C1=CC(OC)=CC=C1N1C(C=2C=CC(Cl)=CC=2)=CC(C(F)(F)F)=N1 PQUGCKBLVKJMNT-UHFFFAOYSA-N 0.000 description 16
- 230000000694 effects Effects 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 230000003190 augmentative effect Effects 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000013459 approach Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 10
- 229940035044 sorbitan monolaurate Drugs 0.000 description 10
- 238000012546 transfer Methods 0.000 description 10
- 241000700159 Rattus Species 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 9
- 238000010899 nucleation Methods 0.000 description 9
- STDYTJDGBXCCRG-UHFFFAOYSA-N Aripiprazole cavoxil Chemical compound C1=C2N(COC(=O)CCCCC)C(=O)CCC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC(Cl)=C1Cl STDYTJDGBXCCRG-UHFFFAOYSA-N 0.000 description 8
- 230000006911 nucleation Effects 0.000 description 8
- 239000008186 active pharmaceutical agent Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 229940088679 drug related substance Drugs 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 230000006698 induction Effects 0.000 description 6
- 239000007972 injectable composition Substances 0.000 description 6
- 238000010926 purge Methods 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- 238000013461 design Methods 0.000 description 5
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 230000003134 recirculating effect Effects 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
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- 238000013401 experimental design Methods 0.000 description 4
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- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 4
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
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- 208000024714 major depressive disease Diseases 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
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- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
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- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000013529 heat transfer fluid Substances 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- NUKZAGXMHTUAFE-UHFFFAOYSA-N methyl hexanoate Chemical compound CCCCCC(=O)OC NUKZAGXMHTUAFE-UHFFFAOYSA-N 0.000 description 2
- UQDUPQYQJKYHQI-UHFFFAOYSA-N methyl laurate Chemical compound CCCCCCCCCCCC(=O)OC UQDUPQYQJKYHQI-UHFFFAOYSA-N 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 229940068977 polysorbate 20 Drugs 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 229940076279 serotonin Drugs 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
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- WKVZMKDXJFCMMD-UVWUDEKDSA-L (5ar,8ar,9r)-5-[[(2r,4ar,6r,7r,8r,8as)-7,8-dihydroxy-2-methyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5h-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one;azanide;n,3-bis(2-chloroethyl)-2-ox Chemical compound [NH2-].[NH2-].Cl[Pt+2]Cl.ClCCNP1(=O)OCCCN1CCCl.COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3C(O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 WKVZMKDXJFCMMD-UVWUDEKDSA-L 0.000 description 1
- 102000049773 5-HT2A Serotonin Receptor Human genes 0.000 description 1
- 108010072564 5-HT2A Serotonin Receptor Proteins 0.000 description 1
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 1
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 1
- RDYWTOWUSVAZGN-UHFFFAOYSA-N 7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-1-(hydroxymethyl)-3,4-dihydroquinolin-2-one Chemical compound C1=C2N(CO)C(=O)CCC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC(Cl)=C1Cl RDYWTOWUSVAZGN-UHFFFAOYSA-N 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
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- 108090000790 Enzymes Proteins 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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- 206010026749 Mania Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229940056213 abilify Drugs 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
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- 238000000149 argon plasma sintering Methods 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
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- 230000001419 dependent effect Effects 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
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- 239000004744 fabric Substances 0.000 description 1
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- 230000008018 melting Effects 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
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- 239000003960 organic solvent Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Processes for providing depot injections of recrystallized aripiprazole lauroxil in which particles of the aripiprazole lauroxil have a surface area of about 0.50 to about 3.3 m 2/g; and crystals of aripiprazole lauroxil produced by such processes. The present invention provides a process for making a compound of Formula (A) in crystal form wherein Ra is CH20C(O)R and wherein R1 is a substituted or unsubstituted aliphatic moiety. a compound of Formula (A) in crystal form wherein Ra is CH20C(O)R and wherein R1 is a substituted or unsubstituted aliphatic moiety.
Description
LLIZATION PROCESS OF ARIPIPRAZOLE DERIVATIVES IN
EXTENDED RELEASE FORMULATIONS FOR TREATMENT OF
SCHIZOPHRENIA
RELATED APPLICATIONS
This application claims priority to US. Provisional ation Serial No. 62/041 ,341,
filed on August 25, 2014, the content of which is incorporated herein by reference in its
entirety.
FIELD OF THEINVENTION
The present invention is directed to the preparation of crystalline forms of aripiprazole
derivatives including aripiprazole lauroxil and aripiprazole cavoxil. More particularly,
the present invention is directed to lling the recrystallization of aripiprazole
lauroxil and aripiprazole cavoxil to produce particles useful in extended e
injectable formulations for the treatment of schizophrenia and other psychiatric
conditions.
RELATEDART
Aripiprazole is an atypical antipsychotic drug used in the treatment of phrenia
and other psychiatric conditions, such as r disorder and major depressive disorder.
razole, which is a ne D2 and serotonin 5-HT1A receptor t, and an
antagonist of the serotonin 5-HT2A receptor, has been formulated as a tablet and as a
solution, both for oral administration. However, concerns with patient compliance with
oral antipsychotics have been reported, and other methods of delivering ychotics,
such as intramuscular or subcutaneous injection, have been developed.
ABILIFY®, which is a drug containing aripiprazole as the active agent, is available
from Otsuka as an oral tablet (aripiprazole dosage of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg,
or 30 mg), an orally disintegrating tablet (dosage of 10 mg or 15 mg), an oral solution
(dosage of 1 mg/mL), and as an injection for intramuscular use (9.75 mg/1.3 mL in a
single-dose vial). Y® is indicated for schizophrenia, bipolar I disorder,
adjunctive treatment of major depressive disorder, irritability associated with autistic
disorder, and agitation associated with schizophrenia or bipolar mania. Abilify
Maintena® is an extended release inj ectable suspension of aripiprazole available from
Otsuka, and which is indicated for schizophrenia.
There is a need in the art for formulations containing an aripiprazole prodrug that when
administered to a patient can provide for improved therapeutic amounts of aripiprazole.
There is also a need in the art for methods of preparing an razole prodrug that can
be formulated into a long-acting or extended-release formulation that when
administered to a patient can provide for improved eutic amounts of aripiprazole
over an ed period of time.
SUMMARYOF THEINVENTION
The present invention provides a process for making a compound of Formula (A) in
crystal form
CI Nd
Formula (A)
wherein Ra is O)R1 and wherein R1 is a tuted or unsubstituted aliphatic
moiety,
comprising the steps of:
(a) obtaining a drug solution by combining the compound of Formula (A) or a salt or
solvate thereof with a first solvent;
(b) optionally combining the drug solution with a second solvent to form a mixture;
(c) cooling the e; and
((1) when the temperature of the e is within the range of about 0-5 °C above a
target temperature, homogenizing the mixture to form crystallized les of the
compound of Formula (A) having a surface area of about 0.50 m2/g to about 3.3 m2/g.
In another embodiment of the , the compound of Formula (A) is selected from
the group consisting of:
Formula (1) Formula (II).
In a particular embodiment of the method, the compound of Formula (A) has the
structure of Formula (I). In another particular embodiment, the compound of Formula
(A) has the structure of Formula (II).
The present invention provides a process for making a nd of Formula (I) in
crystal form
{IE [‘ifxi‘é’wx '
g; E\VL‘w hixJ
\rr‘fikvr"
Formula (1)
comprising the steps of:
(a) ing a drug solution by ing the compound of Formula (A) or a salt or
solvate thereof with a first solvent;
(b) optionally combining the drug solution with a second solvent to form a e;
(c) cooling the mixture; and
(d) when the temperature of the mixture is within the range of about 0-5 °C above a
target temperature, homogenizing the mixture to form crystallized particles of the
compound of Formula (A) having a surface area of about 0.50 m2/g to about 3.3 mZ/g.
The present ion also provides a s for making a compound of Formula (II)
in crystal form
Formula (11)
comprising the steps of:
(a) obtaining a drug solution by combining the compound of Formula (A) or a salt or
e thereof with a first solvent;
(b) optionally combining the drug solution with a second solvent to form a mixture;
(c) cooling the mixture; and
(d) when the temperature of the mixture is within the range of about 0-5 °C above a
target temperature, homogenizing the mixture to form crystallized particles of the
compound of Formula (A) having a surface area of about 0.50 m2/g to about 3.3 mZ/g.
The processes provided herein encompass a number of embodiments, including the
ing:
In one embodiment, the first solvent of step (a) is a single solvent. In another
embodiment, the first solvent of step (a) is a mixture of two or more solvents. In a
ular embodiment, the first solvent of step (a) is a mixture of two or more solvents
and step (b) is absent. Suitable solvents are known to persons having skill in the art of
crystallization. Examples of solvents are provided infra. In a particular embodiment,
the first t of step (a) is isopropyl e. In another particular embodiment, the
first solvent of step (a) is a mixture of isopropyl acetate and n-heptane.
In one embodiment, step (b) comprises combining the drug solution with a second
solvent to form a mixture. In a particular embodiment, the second solvent of step (b) is
n-heptane. The e of step (b) may be a homogeneous e. In certain
embodiments, homogeneity of the mixture of step (b) is achieved or maintained by
heating or preheating the first solvent of step (a) and/or the drug solution of step (a)
and/or the second solvent of step (b). In a particular embodiment, the temperature of
the mixture of step (b) is in the range of about 55 °C to about 65 °C. In another
embodiment, step (b) is absent. When step (b) is , step (c) ses cooling the
drug solution of step (a), and step (d) comprises homogenizing the drug solution to form
crystallized particles of the compound of Formula (A) having a surface area of about
0.50 m2/g to about 3.3 m2/g when the temperature of the mixture is within the range of
about 0-5 °C above a target temperature,
In one embodiment, step (c) comprises cooling the mixture to the point of
supersaturation. The temperature at which the mixture s aturated may be
in the range of about 50 0C to about 55 0C. In another embodiment, step (c) comprises
cooling to mixture to so that its temperature approaches a target temperature. In a
particular embodiment, the target temperature is about 34 °C.
In one embodiment, the target temperature of step (d) is in the range of about 31 CC to
about 35 °C. In a particular embodiment, the target temperature of step (d) is about 34
CC. In another embodiment of step (d), homogenizing begins when the temperature of
the mixture is about 0 °C to about 4 °C above the target temperature (e.g., at about 31
0C to about 38 oC).
The ing s may further comprise the following steps:
(e) stopping homogenization and re—dissolving the crystallized particles of the
compound of Formula (A) (e.g., compounds having the structure of Formula (I) or
Formula (II)) by heating the mixture;
(f) cooling the mixture; and
(g) when the temperature of the mixture is within the range of about 0-5 °C above the
target temperature, homogenizing the mixture to form crystallized particles of the
compound of Formula (A) (e.g., compounds having the structure of Formula (I) or
Formula (11)) having a surface area of about 0.50 m2/g to about 3.3 m2/g.
Steps (c), (d) and (e) may be performed once, or two or more times, prior to proceeding
to step (f).
Any one or more of steps (a), (b), (c), (d), (e), and (I) may be performed under agitation
The foregoing methods may fitrther se the following steps: filtering the
crystallized particles; rinsing the crystallized particles; and drying the crystallized
particles.
The crystallized particles produced in accordance with the processes described herein
may have a e area of about 0.80 to about 1.1 m2/g. In one ment, the
crystallized les have a surface area of about 1.00 m2/g. In another embodiment,
the Dv[50] of the crystallized les is about 10 to about 30 microns. In still another
embodiment, the Dv[50] of the crystallized particles is about 10 to about 20 microns. In
yet another embodiment, the crystallized les are le for use in a depot
injection.
The invention provides crystallized particles of the compound of Formula (I) and the
compound of Formula (11) ed by the foregoing process. Preferably, the
crystallized particles may have a e area of about 0.80 to about 1.1 m2/g, and more
ably, about 1.00 mZ/g. The Dv[50] of the crystallized particles may be about 10
to about 30 microns, preferably about 10 to about 20 microns.
The present invention provides a process for providing a depot ion comprising the
compound of Formula (I) in crystal form
CE [gmN .M‘xvxe‘fi'xmg '~T§.r"?§<\s
,3 ]
wry -"‘-‘J’\\’«ffifNV-xfl\\l’fi§:’ “‘2’. N \T/x
o 6;}
L”, iv,
Formula (I),
the process comprising the steps of: (a) obtaining a drug solution by combining the
compound of a (I) or a salt or solvate f with a first solvent; (b) combining
the drug solution with a second solvent to form a mixture with reduced solubility
relative to the solubility of the drug solution; (c) g the mixture so that it becomes
supersaturated; (d) cooling the mixture so that its temperature approaches a target
temperature; and (e) when the temperature of the mixture is within the range of about 5
°C above the target temperature, homogenizing the mixture to form crystallized
particles of the compound of Formula (I) having a surface area of about 0.50 to about
3.3 m2/g. Any one or more of steps (a) through (d) of the foregoing process may be
performed under agitation. The foregoing process may fithher comprise the steps of (f)
filtering the crystallized particles, (g) rinsing the crystallized particles, and (h) drying
the crystallized particles.
In the foregoing process, the first solvent may be ethyl acetate, propyl acetate, isopropyl
acetate, butyl acetate, isobutyl acetate, tert—butyl acetate, acetone, and the like, with
isopropyl acetate being preferred; and the second solvent may be pentane, cyclopentane,
hexane, cyclohexane, methyl cyclohexane, heptanes, , nonane, decane, undecane,
ne, ethanol, ol, and the like, with n-heptane being preferred.
Preferably, in step (b), the temperature of the e is in the range of about 55 °C to
about 65 CC. In step (c), the ature at which the mixture becomes supersaturated
may be in the range of about 50 CC to about 55 CC. The target temperature d in
step (d) may be in the range of about 31 °C to about 35 °C, such as about 34 oC.
Preferably, in step (e), the homogenizing begins when the temperature of the mixture is
about 0 °C to about 4 oC above the target temperature.
The invention also provides for crystallized les of the compound of a (I)
produced by the foregoing process. ably, the crystallized particles may have a
surface area of about 0.80 to about 1.1 mZ/g, and more preferably, about 1.00 m2/g. The
Dv[50] ofthe crystallized particles may be about 10 to about 30 s, preferably
about 10 to about 20 microns.
Further, the invention provides a process for providing a depot injection comprising the
compound of Formula (I) in crystal form
CE if TN:
ctr.
a-5L. 3.14;, {J
“IN-‘1‘
K»,-A? ca»\\._f"J... 3
\Nf’ NT._ (x 5,
Lx r
“(v-“N,“'v/- C}
Formula (I),
the process sing the steps of: (a) obtaining a drug solution by combining the
compound of Formula (I) or a salt or solvate thereof with heated pyl acetate; (b)
combining the drug solution with n-heptane to form a mixture with reduced solubility
relative to the solubility of the drug solution; (c) cooling the mixture so that it becomes
supersaturated; (d) cooling the mixture so that its temperature approaches a target
temperature of about 34 °C; and (e) when the temperature of the mixture is within the
range of about 5 °C above the target temperature, homogenizing the mixture to form
crystallized particles of the compound of Formula (I) having a surface area of about
0.50 to about 3.3 m2/g. Any one or more of steps (a) through (d) of the foregoing
process may be performed under agitation. The foregoing process may further
comprise the steps of (f) filtering the crystallized particles, (g) rinsing the crystallized
particles, and (h) drying the llized particles.
Preferably, in step (b), the temperature of the mixture is in the range of about 55 °C to
about 65 °C. In step (c), the temperature at which the mixture becomes supersaturated
may be in the range of about 50 CC to about 55 CC. The target temperature reached in
step (d) may be in the range of about 31 °C to about 35 °C, such as about 34 oC.
Preferably, in step (e), the homogenizing begins when the temperature of the mixture is
about 0 °C to about 4 oC above the target temperature.
The invention also es for crystallized particles of the nd of a (I)
produced by the foregoing process. ably, the llized particles may have a
surface area of about 0.80 to about 1.1 mZ/g, and more preferably, about 1.00 mz/g. The
Dv[50] ofthe crystallized particles may be about 10 to about 30 microns, preferably
about 10 to about 20 microns.
Still further, the invention provides a process for providing a depot injection sing
the compound of Formula (I) in l form
Formula (I),
the process comprising the steps of: (a) obtaining a drug solution by combining the
compound of Formula (I) or a salt or solvate thereof with a first solvent; (b) combining
the drug on with a second solvent to form a mixture with reduced solubility
relative to the solubility of the drug solution; (c) cooling the mixture so that it s
supersaturated; (d) cooling the mixture so that its temperature approaches a target
temperature; (e) when the temperature of the mixture is within the range of about 5 °C
above the target temperature, homogenizing the mixture to form crystallized particles of
the compound of Formula (I); (f) stopping homogenization, and re-dissolVing the
crystallized particles of the compound of Formula (I) by heating the mixture; (g)
cooling the mixture so that its temperature approaches the target ature; and (h)
when the temperature of the mixture is within the range of about 5 °C above the target
temperature, homogenizing the mixture to form crystallized particles of the compound
of Formula (I) having a surface area of about 0.50 to about 3.3 m2/g.
WO 32950
Steps (d), (e), and (f) of the ing process can be performed a second time (or three
times, four times, etc.) prior to proceeding to step (g). For example, the process steps
can be carried out in the order (a), (b), (c), (d), (e), (f), (d), (e), (f), (g), and (h); that is,
steps (d) through (f) are performed twice in succession.
In the foregoing process, the first solvent may be ethyl acetate, propyl acetate, pyl
acetate, butyl acetate, isobutyl acetate, utyl acetate, acetone, and the like, with
isopropyl e being preferred; and the second solvent may be pentane, cyclopentane,
, cyclohexane, methyl cyclohexane, heptanes, octane, nonane, decane, undecane,
ne, ethanol, methanol, and the like, with n-heptane being preferred.
Any one or more of steps (a), (b), (c), (d), (e), (f), and (g) of the foregoing process may
be performed under agitation. The foregoing process may further comprise the steps of
(i) filtering the crystallized particles, (j ) rinsing the crystallized particles, and (k) drying
the crystallized particles.
Preferably, in step (b), the temperature of the mixture is in the range of about 55 °C to
about 65 °C. In step (c), the temperature at which the e becomes supersaturated
may be in the range of about 50 °C to about 55 OC. The target temperature reached in
steps (d) and (g) may be in the range of about 31 °C to about 35 0C, such as about 34
°C. ably, in steps (e) and (h), the homogenizing begins when the temperature of
the mixture is about 0 CC to about 4 °C above the target temperature.
The ion also provides for llized particles of aripiprazole lauroxil produced
by the foregoing process. Preferably, the crystallized particles may have a surface area
of about 0.80 to about 1.1 m2/g, and more preferably, about 1.00 mz/g. The Dv[50] of
the crystallized particles may be about 10 to about 30 microns, preferably about 10 to
about 20 microns.
In alternative embodiments, the homogenizing of the processes described herein can be
replaced with sonicating or the use of an ultrasound device.
The depot injection provided by any of the foregoing processes can provide for
extended release of aripiprazole in viva. Such extended release can occur, for example,
over from a period of about one month to a period of about three months. Preferably,
such extended release can occur, for example, over from a period of about one month to
a period of about two months. The depot injection provided by any of the foregoing
WO 32950
processes can be administered, for example, as a once-monthly injection, a once-every-
two-months injection, or a once-every-three months injection.
BRIEFDESCRIPTIONOF THEDRA WINGS
depicts a typical cooling profile for the recrystallization process of the present
invention.
is a graph showing that homogenizer initiation d llization of
aripiprazole lauroxil at a target temperature.
depicts temperature profiles for recrystallization tests at the 4 kg scale.
is a graph showing the relationship between surface area of particles of
recrystallized razole il and exotherm onset ature.
is a graph showing the relationship between particle size and e area.
FIGS. 6, 7, 8, 9, and 10 show models built from the results of an augmented multi-
factor DOE study used to evaluate the combinatory effect of homogenizer initiation
temperature, homogenizer speed, and heat er temperature gradient on cess
crystal surface area, particle size, and exotherm onset temperature.
shows the relationship between surface area of particles of recrystallized
aripiprazole lauroxil and exotherm onset temperature as revealed by an augmented
multi-factor DOE study.
shows several cooling profiles for runs from a multi—factor DOE (central
composite design) study that used no homogenization.
shows plots of transformed temperature data for the cooling profiles from FIG.
shows a plot of exotherm onset ature (Tmin) versus the calculated
Exponential Primary Cooling Parameter (i.e., cooling rate).
shows particle size distributions for several batches of recrystallized
aripiprazole lauroxil made according to a 200 gram process.
shows particle size distributions for several batches of recrystallized
aripiprazole lauroxil made according to a modified 200 gram process.
shows aripiprazole pK profiles resulting from uscular administration of a
single dose of recrystallized aripiprazole lauroxil (20 mg aripiprazole equivalents)
suspended in either NaCMC or SML vehicle, to male rats to assess the effect of
injection vehicle on the in vivo profile.
shows particle size distribution (PSD) profiles for four lots of aripiprazole
lauroxil recrystallized drug substance.
shows aripiprazole pK profiles resulting from IM administration to male rats of
recrystallized razole lauroxil from the same lots as in suspended in SML
vehicle.
DETAILED DESCRIPTION
Crystallization
Crystallization is a process of forming crystals through precipitation of solids from a
solution, which occurs by variation of the solubility conditions of the solute in the
solvent. The process is governed by both thermodynamic and kinetic s, which can
make it highly variable and difficult to l. These factors include component
concentrations, impurity levels, mixing regime, vessel design, and cooling profile. All
can have a major impact on the size, number, and shape of crystals produced.
dynamically, llization is impossible below the theoretical solution
solubility threshold (saturation). At values above this old, the solution is
supersaturated (contains more solute than could be dissolved by the solvent under
normal stances) and crystallization may proceed. Supersaturation is a
fundamental factor in llization dynamics, where the level of supersaturation
affects the crystallization rate and indicates that crystallization is under kinetic, rather
than thermodynamic, control.
Crystallization consists of two major kinetic driven events: nucleation and crystal
growth. Nucleation is the step where the solute molecules dispersed in the solvent start
to gather into clusters (nuclei) that become stable under the t operating
conditions. The crystal growth is the subsequent growth of the nuclei that d in
producing stable crystals. Nucleation and grth continue to occur aneously
while solution supersaturation exists.
tion is the initiation of crystallization and is the sum effect oftwo categories,
primary and secondary. Primary nucleation is the initial formation of nuclei where
there are no other crystals present. This typically occurs through the influence/presence
of other solids (i.e., walls of the crystallizer vessel and les of any foreign
substance). Secondary nucleation is the formation of nuclei attributable to the influence
of already—existing crystals in the solution. Typically, this is a on of fluid shear
and collisions of crystals and results in the formation of new nuclei. Several factors
used to influence tion rate are use of seed crystals, equipment surface
imperfections, and high shear homogenization.
The combination of solution supersaturation level and factors such as homogenization
governs the tion rate, which in turn influences the crystal particle size and surface
area. In general, a fast nucleation rate leads to smaller crystals, while a slow nucleation
results in larger crystals. This is best understood through the concept of population
e. A fast nucleation rate creates a large number of small nuclei in a specified
period, while a slow nucleation rate creates a lesser number in the same period. After
the nuclei are ted, they then being to grow. Given a finite amount ofmass
available for , and assuming equivalent growth rates, the larger number
population of nuclei will achieve a final particle size that is smaller (conversely larger
surface area) than the lesser number population.
Aripiprazole lauroxil
Aripiprazole lauroxil, an N—lauroyloxymethyl g form of aripiprazole, has been
developed for formulation into extended-release injectable formulations, such as for
intramuscular ion. Aripiprazole lauroxil is a non-hygroscopic white crystalline
solid with a melting point of 81.3 to 83.0 CC, and it exists as a stable form, which has
not been observed in any rphic modifications to date. The compound is
insoluble in water (<4 ng/mL at room temperature) and shows highest room
temperature solubility in the following organic solvents: THF (~400 mg/mL),
dichloromethane (~500 mg/mL), and toluene (~300 mg/mL). The IUPAC name for
aripiprazole lauroxil is (7-(4-(4-(2,3 oropheny1)piperazin- l -yl)butoxy)oxo-3 ,4-
dihydro-ZH—quinolin-l-yl)methyl dodecanoate, corresponding to the molecular formula
C36H51C12N304 and a molecular weight of 660.7. razole lauroxil may also be
referred to as N—lauroyloxymethyl aripiprazole. The chemical structure of aripiprazole
lauroxil is as follows:
{:E [fanN M‘KKVJWHKVJ,‘Q ‘Nfi’fta‘fig
ii ’”’ w» {3 N __,,,l
and is also referred to herein as Formula (I).
Pre-processed aripiprazole lauroxil suitable for the recrystallization process described
herein may be ed, for example, by following the synthesis described in US.
Patent No. 8,431,576. This document is incorporated herein by reference in its entirety.
Salts and es of aripiprazole lauroxil, which are disclosed and described in US.
Patent No. 8,431,576, are also suitable for the recrystallization process described herein.
Aripiprazole lauroxil oes hydrolysis to lauric acid, formaldehyde, and
aripiprazole, which is an important antipsychotic used in the treatment of schizophrenia
and other psychiatric conditions, such as bipolar disorder and major depressive disorder.
Conversion of aripiprazole lauroxil to aripiprazole in vivo is governed by slow
dissolution of the aripiprazole lauroxil drug crystals and subsequent enzyme—mediated
ge to the N—hydroxymethyl aripiprazole intermediate, which spontaneously
converts to aripiprazole.
The slow ution of the aripiprazole lauroxil drug crystals in viva results in systemic
exposure of aripiprazole over several weeks. The rate of aripiprazole il release is
a function of the amount of exposed surface area, ented by particle size
distribution (PSD) and shape/morphology of the drug crystals.
An ed release IM injection offers the potential for an improved safety profile and
ent compliance; therefore, it has the potential to provide more effective
management of schizophrenia.
The present invention provides a process for providing a depot injection comprising
aripiprazole lauroxil, i.e., the compound of Formula (I), in crystal form.
g t ii-‘eg‘ N xxx]
““xjf ”a ~.,/’£‘\‘ w ‘\
x “‘x.”’fl‘PK-"‘-'3 “f
Formula (I)
The process comprises the steps of: (a) obtaining a drug solution by combining the
compound of Formula (I) or a salt or solvate thereof with a first solvent; (b) combining
the drug solution with a second solvent to form a mixture with reduced solubility
ve to the solubility of the drug solution; (c) cooling the mixture so that it becomes
supersaturated; (d) cooling the mixture so that its temperature approaches a target
ature; and (e) when the temperature of the mixture is within the range of about 5
°C above the target temperature, homogenizing the mixture to form llized
particles of the compound of Formula (I) having a surface area of about 0.50 to about
3.3 m2/g. Any one or more of steps (a) through (d) of the foregoing process may be
performed under agitation. The foregoing process may r comprise the steps of (t)
filtering the crystallized particles, (g) rinsing the llized particles, and (h) drying
the crystallized les.
In the foregoing process, the first solvent may be ethyl acetate, propyl acetate, isopropyl
acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, acetone, and the like, with
isopropyl acetate being preferred; and the second solvent may be pentane, cyclopentane,
hexane, cyclohexane, methyl cyclohexane, heptanes, octane, nonane, decane, undecane,
dodecane, ethanol, methanol, and the like, with n-heptane being preferred.
Preferably, in step (b), the temperature of the e is in the range of about 55 °C to
about 65 °C. In step (c), the temperature at which the e becomes supersaturated
may be in the range of about 50 CC to about 55 CC. The target temperature reached in
step (d) may be in the range of about 31 °C to about 35 °C, such as about 34 °C.
ably, in step (e), the homogenizing begins when the temperature of the mixture is
about 0 °C to about 4 °C above the target temperature.
The homogenizing in step (e) initializes and promotes llization, and allows for
control of particle size and surface area. A suitable homogenization speed is from about
4800 to about 9600 rpm. The drying in step (h) can be conducted under nitrogen purge
and vacuum.
The invention also provides for crystallized particles of the compound of a (I)
produced by the foregoing s. Preferably, the crystallized particles may have a
surface area of about 0.80 to about 1.1 mZ/g, and more preferably, about 1.00 m2/g. The
Dv[50] ofthe crystallized particles may be about 10 to about 30 microns, preferably
about 10 to about 20 s.
r, the invention provides a s for providing a depot injection comprising the
compound of Formula (I) in crystal form
CE r“ “*3;
{3; N xxx-“J [
1} «I "“xgtifii‘x.
RM, f,x ”waft.“ 5:: a, J33 if]
L,» a.» o 5:}
Formula (I),
the process comprising the steps of: (a) obtaining a drug solution by combining the
compound of a (I) or a salt or solvate thereof with heated isopropyl acetate; (b)
combining the drug solution with n-heptane to form a mixture with reduced lity
relative to the solubility of the drug solution; (c) cooling the mixture so that it becomes
supersaturated; (d) cooling the mixture so that its temperature approaches a target
temperature of about 34 °C; and (e) when the temperature of the mixture is within the
range of about 5 °C above the target temperature, homogenizing the mixture to form
crystallized particles of the compound of Formula (I) having a surface area of about
0.50 to about 3.3 m2/g. Any one or more of steps (a) through (d) of the foregoing
s may be performed under agitation. The foregoing process may fiarther
comprise the steps of (f) filtering the crystallized particles, (g) rinsing the crystallized
particles, and (h) drying the crystallized particles.
Preferably, in step (b), the temperature of the mixture is in the range of about 55 °C to
about 65 0C. In step (c), the temperature at which the mixture becomes supersaturated
may be in the range of about 50 °C to about 55 CC. The target temperature reached in
WO 32950
step (d) may be in the range of about 31 0C to about 35 0C, such as about 34 OC.
Preferably, in step (e), the homogenizing begins when the temperature of the mixture is
about 0 0C to about 4 oC above the target ature.
The homogenizing in step (e) initializes and promotes crystallization, and allows for
control of particle size and surface area. A suitable homogenization speed is from about
4800 to about 9600 rpm. The drying in step (h) can be conducted under nitrogen purge
and vacuum.
The invention also provides for crystallized particles of the compound of Formula (I)
produced by the foregoing process. ably, the crystallized particles may have a
surface area of about 0.80 to about 1.1 mZ/g, and more preferably, about 1.00 m2/g. The
Dv[50] of the crystallized particles may be about 10 to about 30 microns, preferably
about 10 to about 20 microns.
Still further, the invention provides a process for providing a depot injection sing
the compound of a (I) in crystal form
Formula (I),
the process comprising the steps of: (a) obtaining a drug solution by combining the
compound of a (I) or a salt or solvate thereof with a first solvent; (b) combining
the drug solution with a second solvent to form a mixture with reduced solubility
relative to the solubility of the drug solution; (c) cooling the e so that it becomes
supersaturated; (d) cooling the mixture so that its temperature approaches a target
temperature; (e) when the temperature of the mixture is within the range of about 5 °C
above the target ature, homogenizing the mixture to form crystallized particles of
the compound of Formula (I); (f) stopping homogenization, and re-dissolving the
crystallized particles of the nd of Formula (I) by heating the mixture; (g)
cooling the mixture so that its temperature approaches the target ature; and (h)
when the temperature of the mixture is within the range of about 5 OC above the target
temperature, homogenizing the mixture to form crystallized les of the compound
of a (I) having a surface area of about 0.50 to about 3.3 m2/g.
Steps ((1), (e), and (f) of the foregoing process can be performed a second time (or three
times, four times, etc.) prior to proceeding to step (g). For example, the process steps
can be carried out in the order (a), (b), (c), (d), (e), (f), (d), (e), (f), (g), and (h); that is,
steps ((1) through (f) are performed twice in succession.
In the foregoing s, the first solvent may be ethyl acetate, propyl acetate, isopropyl
e, butyl acetate, isobutyl acetate, tert-butyl acetate, acetone, and the like, with
isopropyl acetate being preferred; and the second solvent may be e, cyclopentane,
hexane, cyclohexane, methyl cyclohexane, heptanes, octane, nonane, decane, undecane,
dodecane, ethanol, methanol, and the like, with n-heptane being preferred.
Any one or more of steps (a), (b), (c), (d), (e), (f), and (g) of the ing process may
be performed under agitation. The foregoing process may further comprise the steps of
(i) filtering the crystallized particles, (1') rinsing the crystallized particles, and (k) drying
the llized particles.
Preferably, in step (b), the temperature of the mixture is in the range of about 55 °C to
about 65 °C. In step (c), the temperature at which the mixture becomes supersaturated
may be in the range of about 50 °C to about 55 CC. The target temperature reached in
steps (d) and (g) may be in the range of about 31 °C to about 35 °C, such as about 34
oC. Preferably, in steps (e) and (h), the homogenizing begins when the temperature of
the mixture is about 0 °C to about 4 °C above the target ature.
The homogenizing in steps (e) and (h) initializes and promotes crystallization, and
allows for control of particle size and surface area. A suitable homogenization speed is
from about 4800 to about 9600 rpm. The drying in step (k) can be conducted under
nitrogen purge and vacuum.
The invention also provides for crystallized particles of the nd of Formula (I)
produced by the foregoing process. Preferably, the crystallized les may have a
surface area of about 0.80 to about 1.1 mZ/g, and more preferably, about 1.00 m2/g. The
Dv[50] ofthe crystallized particles may be about 10 to about 30 microns, preferably
about 10 to about 20 microns.
2015/046525
Each of the foregoing processes may use, instead of the compound of Formula (I), a salt
or solvate thereof such as the salts or es of pre-processed aripiprazole lauroxil
disclosed and described in US. Patent No. 8,431,576.
Aripiprazole cavoxil
Aripiprazole cavoxil, an N—hexanoyloxymethyl prodrug form of aripiprazole, has been
developed for formulation into extended-release injectable formulations, such as for
intramuscular injection. The IUPAC name for aripiprazole cavoxil is (7-(4—(4-(2,3-
dichlorophenyl)piperazin- l -yl)butoxy)oxo-3 ,4-dihydroquinolin- l (2H)-yl)methyl
hexanoate, corresponding to the molecular formula C30H39C12N304 and a molecular
weight of 576.56. The chemical structure of aripiprazole cavoxil is as follows:
C! [JV/RN “FR, “fixv’fl‘v’xxfi
mmi‘ixcxw«AE‘\ 5’3“} If]
"a“, “K vx”‘"\§lx°fl‘\vw : \fr"
9 Q
and is also ed to herein as Formula (II). Aripiprazole cavoxil suitable for the
processes described herein may be obtained, for example, by the synthesis methods
described in US. Patent No. 8,431,576. This document is incorporated herein by
reference in its entirety. Salts and solvates of aripiprazole cavoxil, which are disclosed
and described in US. Patent No. 8,431,576, are also suitable for the ses described
herein.
Process Equipment
The following s equipment was used to recrystallize aripiprazole lauroxil
according to the present invention. Other suitable process equipment may be used, as
would be well understood by one skilled in the art in light of present disclosure.
Drug dissolution vessel: To produce a 4.0 kg batch of tallized aripiprazole
lauroxil, a single closed, jacketed, ed 20 liter vessel was used to dissolve and
er the drug through a sterilizing filter to the ized recrystallization vessel in a
single step. A r pilot process (producing 1.75 kg of recrystallized aripiprazole
lauroxil) used two small stock pots and hot plates to dissolve the drug, and multiple
transfer steps to a 4 liter pressure vessel to sterile filter the solution into the
recrystallization vessel. At both 4.0 kg and 1.75 kg scales, warm isopropyl acetate was
used to dissolve the pre-processed drug crystals of aripiprazole lauroxil. As would be
well understood by one of skill in the art, a “jacket” refers to heat transfer fluid and to
the d space around the vessel containing the heat er fluid that acts as a heat
ger to cool or heat the inside of the vessel, and a “glycol jacket” is a jacket where
the heat transfer fluid is glycol or a mixture of water and glycol. The glycol jacket
temperature s primary cooling, which transitions the system into a meta—stable
zone where crystallization of aripiprazole lauroxil can be initiated with homogenization.
Drug solution filter: The drug solution filter used for both scales was Milliport
Aervent al Cartridge, PTFE Hydrophobic, LAGR04TP6 (112-00783).
Filter heat tape: The filter heat tape used for both scales was Fiberglass Cloth Heating
Tape with Glas-Col Poerrol Controller (10 amps/120 volts).
Recrystallization vessel: The recrystallization vessel used for both scales was a DCI
er Cone Shaped (16” upper ID / 23° angle) Stainless Steel Jacketed Vessel (DCI
Serial #: J82884) with a 3.75” Radial Lower Impeller, 3.75” Axial Upper Impeller on
an angled (non-vertical) agitator.
Homogenizer: The homogenizer used for both scales was a Kinematica Polytron PT—D
50-6 F/G (installed in the recrystallization vessel) with 50 mm Stator Diameter and 45
mm Rotor Diameter.
Sonicator: An exemplary tor le for use with the process of the present
invention is Transsonic T310 from Lab-Line Instruments Inc.
Dryer: The dryer used in the 4.0 kg scale process was a closed, agitated, 15” self-
discharging vacuum filter dryer (Powder Systems Limited; PSL). The 1.75 kg scale
process used two 8” static vacuum filter dryers that required manual aseptic stirring of
the recrystallized drug crystals prior to drying and discharge. The mode of drying was
the same at both scales, namely, the recrystallized drug crystals were dried under
vacuum at room temperature with a dry gas purge to facilitate removal of processing
solvents to acceptably low levels.
Filtrate vessel: The te vessel used in both scales was a DCI 10—gallon Stainless
Steel Jacketed Vessel (DCI Serial #: JS2060).
Recrystallization process
The recrystallization process of the present invention can produce crystallized particles
of aripiprazole lauroxil having a surface area of about 0.50 to about 3.3 m2/g, preferably
about 0.80 to about 1.1 mZ/g, more preferably about 1.00 m2/g. The Dv[50] of the
crystallized particles may be about 10 to about 30 microns, preferably about 10 to about
s.
Recrystallized aripiprazole lauroxil can be produced h the following procedure:
Drug Dissolution: Dissolve pre-processed aripiprazole lauroxil or a salt or solvate
thereof in a first solvent such as isopropyl acetate or another suitable first solvent as
described herein, and sterile filter the result into a recrystallization vessel.
Crystallization: Mix the drug solution (aripiprazole lauroxil dissolved in, e.g.,
isopropyl e) and a second solvent such as heptane or another suitable second
solvent as bed herein and then cool at a controlled rate; initiate homogenization at
a target ature to induce crystallization.
Collection: Transfer contents of recrystallization vessel and filter crystals from the
solvent in a dryer.
Rinsing: Use a fresh portion of the second solvent to recover any crystals remaining in
the tallization vessel and remove gross residual first solvent from the l
surface. Rinsing can also remove residual amounts of acetonitrile, which may have
been present in the ocessed aripiprazole lauroxil.
Drying: Use vacuum drying to reduce levels of both the first and second ts.
The first t may be ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate,
isobutyl acetate, tert-butyl acetate, acetone, or another suitable solvent as would be well
understood by one skilled in the art in light of the present disclosure, or mixtures of the
foregoing ts. Isopropyl acetate is a preferred first t.
The second solvent may be pentane, cyclopentane, hexane, exane, methyl
cyclohexane, es, octane, nonane, decane, undecane, dodecane, ethanol, methanol,
or another suitable solvent as would be well understood by one skilled in the art in light
of the present disclosure, or mixtures of the foregoing solvents. N-heptane is a
preferred second solvent.
A preferred selection and ratio of first solvent and second solvent is isopropyl acetate
and heptanes, in a ratio of 1:2 (V/V).
When the drug solution of aripiprazole lauroxil in a first solvent (such as isopropyl
acetate) is combined with the second solvent (such as e), this forms a e
with reduced solubility relative to the lity of the drug solution. The drug solution
and the second solvent are preferably combined at a ature of from about 55 °C to
about 65 °C, and then the mixture is cooled at a specified rate, such as 1.5 °C per
minute, so that the mixture becomes supersaturated. The temperature at which the
mixture becomes aturated may be in the range of about 50 0C to about 55 °C.
Then the mixture is cooled so that its temperature approaches a target temperature.
This target temperature may be in the range of about 31 °C to about 35 CC, such as
about 34 °C. When the temperature of the mixture is within the range of about 0 °C to
about 4 °C above the target ature, homogenization of the mixture is initiated. A
suitable speed for homogenization is from about 4800 to about 9600 rpm.
Drug dissolution, combining the drug solution and the second solvent, cooling the
mixture of the drug solution and the second t, cooling the mixture once it has
become supersaturated, homogenizing the mixture, and re-dissolving the crystallized
particles of razole lauroxil by heating the mixture can each be performed under
agitation. The agitation may be carried out with an agitator such as an overhead stirrer.
The agitator helps to maintain a uniform l suspension and control over the
temperature.
Suitable salts and solvates of pre-processed aripiprazole lauroxil that can be obtained,
synthesized, and used with the present invention include those disclosed in US. Patent
No. 8,431,576.
Formulations
The recrystallized aripiprazole lauroxil prepared according to the methods disclosed
herein can be ded in injection es to e injectable compositions
suitable, for example, for 1M administration. Such vehicles include a phosphatebuffered
saline injection vehicle comprising sorbitan monolaurate in an amount of
imately 0.37% by weight relative to the weight of the inj ectable composition;
polysorbate 20 in an amount of approximately 0.15% by weight relative to the weight
of the inj ectable composition; and an s carrier. The recrystallized aripiprazole
lauroxil prepared ing to the methods disclosed herein can also be incorporated
into other vehicles and formulations, such as those disclosed in US. Patent Application
ation No. 23 8552.
The following is the formulation of an exemplary depot injection ition
comprising recrystallized aripiprazole lauroxil prepared according to the s
disclosed herein:
Recrystallized Aripiprazole 26.6
Lauroxil Drug Substance
P—hosphateSodium Dibasic
Anhydrous
Sodium D1hydrogen
Phosphate Monobasic
Dihydrate
Water for Injection QS to 100
Relation of particle size and release rate
Particle size of the aripiprazole lauroxil produced from the recrystallization process of
the present invention was shown to relate to release rate in animal studies and thus
required controlling to within an acceptable range. The particle size distribution (PSD)
ofrecrystallized aripiprazole il produced according to the process disclosed
herein can be measured, for e, using a light scattering particle size analyzer such
as those available from HORIBA or Beckman-Coulter, or by other suitable instruments
and methods as would be well understood by one skilled in the art in light of the present
disclosure.
As used herein, “Dv[50]” refers to the 50th percentile of the particle size distribution,
which is hangeable with median diameter or the average particle diameter by
volume. As used herein, “Dv[10]” refers to the 10th percentile of the particle size
distribution, “Dv[90]” refers to the 90th percentile of the particle size distribution, and
“Dv[X]” refers to the Xth percentile of the particle size distribution.
An acceptable Dv[50] range of particles of aripiprazole il produced from the
recrystallization process of the present invention is 10-30 microns, with a DV[50] of 10-
microns being red.
The relation of particle size and release rate is further explained in the studies and
examples further below.
Relation of surface area and release rate
Drug release was found to be proportional to the e area of aripiprazole lauroxil
ed from the recrystallization process of the present invention.
The e area of recrystallized aripiprazole lauroxil particles can be measured, for
example, using an rated surface area and porosimetry analyzer, or by other
suitable instruments and methods as would be well tood by one skilled in the art
in light of the present disclosure.
An acceptable surface area range for particles of aripiprazole lauroxil produced from
the recrystallization process of the present invention is from about 0.50 to about 3.3
m2/g. A surface area range of 0.80 to about 1.1 mZ/g is preferred, and a surface area of
about 1.0 m2/g is more red.
The relation of surface area and release rate is further explained in the studies and
examples further below.
Cooling profile
depicts a typical cooling profile for the recrystallization process of the present
invention. Cooling of a mixture ning razole lauroxil, first solvent, and
second solvent causes the temperature of the mixture to decrease, and the mixture
becomes supersaturated. Aripiprazole lauroxil precipitates, causing an increase in
temperature of the system. This is ed by further cooling of the system. As used
herein, the term “exotherm” refers to the increase in temperature of the system due to
precipitation of the drug. The “precipitation zone,” in which the exotherm occurs,
begins when the temperature starts to increase and covers the entire period during
which aripiprazole lauroxil is precipitating or crystallizing. The “arrest temperature” or
target temperature is the ature at which no further decrease in temperature of the
system is observed and the start (or onset) of crystallization occurs. Homogenization is
preferably initiated when the temperature of the supersaturated mixture of aripiprazole
lauroxil is a few degrees above the arrest or target temperature. nization
promotes crystallization and allows for control of particle size and surface area.
“Tmin” indicates the initial temperature increase due to exothermic heating from the
major crystallization event. Tmin, which defines both the “onset of crystallization” and
the “onset of exotherm,” is ly correlated with particle size and surface area of the
recrystallized particles of aripiprazole lauroxil. “Tmax,” or the exotherm maximum
temperature, denotes the completion of cant exothermic heating from the major
crystallization event. ing the major crystallization event, the slurry is fiarther
cooled in the “final cooling” stage (growth zone). “Tming” is the temperature equal to
Tmin that occurs upon g of the system following the exotherm associated with
crystallization.
STUDIES AND EXAMPLES
Homogenization
As illustrated in homogenizer initiation induces llization at a target
ature. The results of five crystallization tests at the 1.75 kg scale are reflected in
All of the llization tests had the same cooling rate, but each used a
different homogenizer initiation temperatures and resulted in different exotherm onset
temperatures and, as a result, different crystal sizes. In four of the tests, the
homogenizer was turned on at the respective temperature specified in the plot, and
crystallization was induced soon after the initiation of homogenization. The Batch 5
test shows the point when spontaneous crystallization ed, when no
homogenization was used at the given cooling rate.
Impact of homogenizer initiation temperature on crystal size (single factor
screening)
The objective of this study was to screen the impact of homogenization initiation
temperature (“Homogenizer ON”) on the surface area and particle size of recrystallized
aripiprazole lauroxil, as well as the llization induction time and exotherm onset
temperature. The study evaluated homogenizer initiation temperature at three values
(35, 36, and 37 °C) while the following parameters were held constant: Homogenizer
speed — 75% (120 Hz / 7200 rpm); Vessel agitation speed — 375 rpm; Vessel jacket
glycol temperature set-point — 30 0C (this parameter dictates the solution y
g rate).
Table 1 summarizes l tests at the 4 kg scale used to evaluate the effect of
homogenizer initiation temperature enizer ON) on in—process crystal particle
size. By “exotherm onset temperature” is meant the temperature at which dissolved
aripiprazole lauroxil begins to recrystallize.
Table 1: Effect of Homogenizer 0N Temperature (4 kg Scale)
shows the temperature profiles for the tests at the 4 kg scale. The plots showed
that crystallization (observed by the exotherm) occurred shortly after nizer
initiation, as was previously demonstrated at the 1.75 kg scale (.
Impact of crystallization variables on particle size and surface area (multi-factor
screening)
The objective of this study was to characterize the impact of homogenizer initiation
temperature and homogenizer speed on e area and particle size as well as the
llization ion time and exotherm onset temperature. The study evaluated the
two factors of homogenizer initiation temperature and homogenizer speed, both factors
being d at three levels. The study used a fiill factorial experimental design with a
center-point resulting in ten (10) crystallizations. The jacket glycol temperature set-
point was adjusted as a function of the homogenizer initiation temperature. The intent
was to maintain a heat transfer temperature gradient (at crystallization) between 5-7 0C.
This value is defined as the difference n the jacket glycol temperature set-point
and homogenizer initiation temperature.
Table 2 summarizes tests from the multi-factor screening study used to evaluate the
combinatory effect of nizer initiation temperature (Homogenizer ON) and
homogenizer speed on in-process crystal surface area and particle size. The jacket
glycol temperature set-point was varied to maintain the gradient in a range of 5-7 0C in
order to minimize the under-cooling temperature delta.
and present plots of surface area versus rm onset temperature and
particle size versus surface area. The plots demonstrate that the strong relationship
observed between these attributes at the 1.75 kg scale ued to be present at the 4
kg scale.
WO 32950
Screening)
(Multi-factor n—m-nflII—Elna
Parameters
Ch. O.
Crystallization Ln l\
m m
m m
Effect C)
2: H
Table
m m
m m
N m
U U
Impact of crystallization variables on particle size and surface area (multi-factor
DOE)
The objective of this study was to characterize the impact of homogenizer tion
temperature and homogenizer speed on surface area and particle size as well as the
crystallization induction time and exotherrn onset temperature. This study was equivalent
to the study Impact of crystallization variables on particle size and surface area (multi-
factor screening) above, but executed in a different process train. This study evaluated the
two factors of homogenizer initiation temperature and homogenizer speed, each at three
levels. The study used a full factorial experimental design resulting in nine (9)
crystallizations. The jacket glycol temperature set-point was adjusted as a function of the
homogenizer initiation temperature. The intent was to in a heat transfer temperature
gradient (at crystallization) of 6 0C. This value is defined as the ence n the
jacket glycol temperature set-point and homogenizer initiation temperature.
Table 3 summarizes tests fiom the multi—factor DOE (design of ments) study used to
evaluate the combinatory effect of homogenizer initiation ature (Homogenizer ON)
and homogenizer speed on in-process crystal surface area and le size. The jacket
glycol temperature set—point was varied to maintain the gradient at a specified 6 °C in order
to ze the under-cooling temperature delta. The study showed that the impact of
Homogenizer ON temperature and the impact of homogenizer speed parameters were both
statistically significant.
WO 32950 PCT/U52015/046525
nunnun
DOE)
(Multi-factor
Parameters ————
Crystallization '\. 7‘. “3.
\—c m H
m m m
Effect nN <r N
m m m
Table o
m o
£0 00 U)
N N N
N m \—:
N m
D Q
Impact of crystallization variables on particle size and surface area (multi-factor
Augmented DOE)
The objective of this study was to characterize the impact of homogenizer initiation
temperature, homogenizer speed, and heat transfer temperature gradient (at llization)
on surface area and particle size as well as the crystallization induction time and rm
onset temperature. This study augmented the foregoing multi—factor DOE study by
orating the additional parameter of heat transfer temperature gradient. The study
evaluated the three factors of nizer initiation temperature, homogenizer speed, and
heat transfer temperature gradient (at crystallization), each at three levels. The study used a
central composite experimental design with center-point replicates resulting in seventeen
(l7) crystallizations. The jacket glycol temperature set-point was adjusted as a function of
the homogenizer initiation temperature in order to set the heat transfer temperature gradient
(at crystallization). This value is defined as the difference between the jacket glycol
temperature int and homogenizer initiation temperature.
Table 4 summarizes tests from the augmented multi-factor DOE study used to evaluate the
combinatory effect of homogenizer initiation temperature (Homogenizer ON),
homogenizer speed, and heat transfer temperature gradient on in-process crystal surface
area, particle size, and exotherm onset temperature. This DOE ted the immediately
previous experimental design by including heat transfer temperature gradient as a factor.
Again, the jacket glycol temperature set-point was varied to maintain the gradient at
specified values of 4, 6, and 8 0C.
FIGS. 6, 7, 8, 9, and 10 show several models built from the results. Table 5 izes
the findings from these models. All models were statistically significant based on ANOVA
ues < 0.05) and demonstrate no Lack of Fit.
shows the relationship n e area and exotherm onset temperature.
Linear regression analysis trated statistical significance per ANOVA (p-values <
0.05). The excellent relationship of surface area to exotherm onset temperature was
ageous because it provided an in-process measurement of crystallization progression
or performance. Advantageously, in the event that the exotherm onset temperature fell
WO 32950
outside the predicted or target range during a crystallization, the run could be discontinued,
the material re-heated, and the crystallization repeated.
WO 32950 PCT/U52015/046525
DOE) nunnunnun—nn
Augmented
(Multi-factor '\.
Parameters m_
Crystallization 4 4
Effect N
Table Ln
|\ nun—n an34 [In
L|_| Eannual.“fl “man“nunnunnu 26 flflfl
WO 32950 PCT/U82015/046525
nunl-nnl-nn Lnm\—|
Human-n nun—n m_o00NVonLG|\
E15 LO
PCT/U52015/046525
Table 5: Summary of Multi-factor Augmented DOE Models
e area Model
(Multi-factor Augmented DOE)
Exotherm Onset
Temperature Model (Multi-
factor Augmented DOE)
Particle Size (Dv[10])
Model (Multi-factor 0.599 0.0003 No
Augmented DOE)
le Size (Dv[50])
Model (Multi-factor 0.574 0.0004 Yes
Augmented DOE)
: Particle Size (Dv[90])
Model (Multi-factor 0.340 0.0140 No
Augmented DOE)
Characterization of the process operational zone (Multi-factor DOE)
The objective of this study was to characterize the impact of solution cooling rate (as a fimction
ofj acket glycol temperature), homogenization speed, and crystallization type aneous
versus induced) on the crystallization induction time and exotherm onset temperature. The study
used a designed experiment al composite design) consisting of 10 runs that incorporated
two factors at three levels: Vessel Jacket Temperature (3 0C, 16.5 0C, 30 0C); and nizer
Speed (0%, 37.5%, 75%).
Table 6 summarizes tests from the factor DOE (central composite design) consisting of 10
runs that incorporated the two factors at three levels: Vessel Jacket Temperature (3 0C, 16.5 0C,
30 0C); and Homogenizer Speed (0%, 37.5%, 75%). Each run that used a 0% homogenizer
speed (no homogenization) was cooled until it spontaneously crystallized. In the runs that used
homogenizer speeds of 37.5% and 75%, the homogenizer was turned on when the process
ature cooled to 53.6 °C. (This temperature represents the solubility limit of the s
solution below which the solution enters a meta-stable state.) The solution then continued to
cool with homogenization until it crystallized. shows several cooling profiles for runs
that used no nization.
An exotherm onset temperature (Tmin) was recorded for each run and the cooling rate was
calculated. The process cooling followed an exponential decay profile. Therefore, an
Exponential Primary g Parameter (i.e., cooling rate) was calculated by plotting the process
temperature as a function of time using the following data transformation method:
y=m*x+b
Where
T—Ta
3]-_ Ln[T0—Ta]
x [=] Time (Min.)
T [=] Temperature (0C)
To = 58°C
Ta = 20°C
A -regression fit of the data resulted in slope-m (l/°C) and intercept—b, where slope
represents the Exponential Primary Cooling Parameter. displays plots of the
transformed temperature data for the corresponding cooling profiles from .
Table 6: Process Operational Zone Results
shows a plot of exotherm onset temperature (Tmin) versus the calculated Exponential
y g Parameter (i.e., cooling rate). The following terms describe key features of
the plot:
Solubility Limit: The temperature at which the process solution becomes saturated. Below
this temperature, the on is supersaturated. The supersaturated solution is kinetically
persistent since it is ng relatively slowly but has not yet reached thermodynamic
equilibrium, which results in crystallization.
Lower ing Boundary: The lowest process temperature the system can achieve at a
specified cooling rate prior to spontaneous crystallization (i.e., crystallization in the absence of
homogenization).
Upper Operating ry: The highest process temperature the system can achieve at a
specified cooling rate prior to forced crystallization (i.e., crystallization that occurs in the
presence of homogenization). In this case, homogenization was initiated immediately after the
on cooled to the solubility limit (53.6 0C), thereby imparting the maximum
homogenization time within the table zone.
Operational Zone: The temperature range available to the system for a specified cooling rate
where crystallization of the supersaturated solution can be induced through homogenization at
a target temperature. The operational zone provided ce for selection of optimum target
cooling rate and exotherm onset temperature (Tmin) combinations, which ed in robust
sing to target surface areas.
Additional synthesis examples
200 gram scale
Aripiprazole lauroxil was recrystallized using the ing procedure. 246.4 g of isopropyl
acetate was heated in a 1 liter Erlenmeyer flask to 70-75 0C. 383.0 g of heptane was heated in
a 1 liter Erlenmeyer flask to 45—50 c’C. The hot isopropyl acetate was added to a 2 liter
Erlenmeyer flask containing 200 g of aripiprazole lauroxil. The mixture was heated with
swirling until all the white solids dissolved and a clear solution was obtained at 65-70 0C. Hot
e was added to the clear solution in three portions with gentle heating and swirling to
avoid crash-out.
The flask containing the clear solution was placed in a 12 inch sieve pan or equivalent. A
homogenizer probe was placed into the solution and turned on to # 3 (13.5 l/min set on the
machine). Ice was added up to the capacity of the pan. The homogenizer was stopped once the
solution crystallized. The flask was kept in ice until the temperature was 15-20 c’C. The flask
was removed from the ice bath.
A filtration set-up was assembled using a 2 liter filtering flask, Buchner funnel with a rubber
connector, and filter paper. The filter paper was wetted with heptane (~ 5 ml). The
recrystallized white solid was filtered and washed with heptane (~ 60 ml).
The filtered material was spread into a dish. The al was dried inside a vacuum oven at
room temperature for 18-24 hrs with a nitrogen purge. The dried al was transferred into
a 250um sieve. 5 PTFE sieve rings were added to the sieve, a cover with o-ring was placed on
the sieve, and sieving took place using an Analysette 3 PRO at an amplitude set point of 2.7.
Four batches were made following this procedure and combined together to prepare a
suspension of razole lauroxil. Table 7 lists the particle size distribution summary
statistics for each batch as well as the ed t averaged) final batch. shows
the particle size distributions for each batch as well as the combined (weight averaged) final
batch.
Table 7: Particle size distribution summary statistics (post dry and sieving)
Batch Dv[10], DV[50], Dv[90], % Total
um um um
MadiZzed 200 gram scale
Using a graduated cylinder, 280 ml of isopropyl e were measured and transferred to a 2
liter Erlenmeyer flask. Using a ted cylinder, 560 ml of n-heptane were measured and
mixed with the measured isopropyl acetate. 200 g of aripiprazole lauroxil were weighed into a
2 liter Erlenmeyer flask. The solvent mixture was heated to 70 °C and then added to the
WO 32950
aripiprazole lauroxil containing flask. The slurry was heated back to 65 °C to obtain a clear
solution.
The solution was then poured into a 1 liter jacketed glass vessel with a first ulator
ulating water and an overhead high shear mixing probe. The probe was turned on
immediately on setting #3 (13.5 l/min set on the machine). As soon as the internal
temperature reached 2 OC above the target arrest temperature, the recirculating water was
switched to a second recirculator in order to arrest the cooling. As soon as the temperature
started to rise the time was noted and the recirculating water was switched back to the first
recirculator. The probe was then stopped 90 seconds after the start of the temperature rise,
after which it was replaced with an overhead mixer. The slurry was left to cool down to 18 0C.
When the slurry reached 18 °C the slurry was filtered using a Buchner funnel with Whatman
filter paper 4. The solids were then washed with approximately 100 ml of n-heptane. The
solids were spread into a crystallization dish and left to dry in a vacuum oven at room
temperature, house , and a nitrogen purge for approximately 18 hours.
Table 8: Differences between 200 9 scale and modified 200 9 scale processes
_200gram scale Modified 200 gram s
Drug Aripiprazole lauroxil is dissolved in Aripiprazole lauroxil is dissolved in a
dissolution 70-75°C isopropyl acetate and then 65 °C isopropyl acetate/heptane
45-50 °C heptane is added. mixture.
Crystallization 2 liter Erlenmeyer flask in an ice 1 liter jacketed glass vessel with two
vessel bath. recirculating jacket fluid
temperatures.
Manual swirling and homogenizer. Overhead mixer and homogenizer.
Crystallization Homogenizer is switched on and Homogenizer is switched on and
solution is cooled with ice bath until solution cooled with recirculator 1.
it reaches 15'20 OC- As soon as the internal ature
Homogenizer is switched off once reached 2 °C above the target arrest
the solution crystallizes. temperature, the recirculating water
is switched to recirculator 2 in order
to arrest the cooling.
As soon as the ature started
to rise the time the recirculating
water is switched back to recirculator
1 until the slurry reaches 15-20 °C.
nizer is switched off 90 s
after the start of the ature
rise, after which it is replaced with an
ad mixer.
The modified 200 gram process was used successfully in four aripiprazole lauroxil
recrystallization batch campaigns (each consisting of five recrystallization batches). A particle
size distribution similar to that from the (unmodified) 200 gram process was ucibly
ed as seen in . Summary statistics are listed in Table 9. A comparison between
the le size distribution tics of recrystallized aripiprazole lauroxil from the modified
process versus that from the unmodified process revealed a tighter spread in DV[10], DV[SO],
and DV[90], clearly showing an improvement in process robustness and reproducibility.
WO 32950
Table 9: Particle size distribution summary statistics of four batch campaigns
mDv[10], pm Dv[50], pm Dv[90], pm
M1 5 21 36
1.75 kg scale
Aripiprazole lauroxil was recrystallized using the following procedure. 2156.0 g of isopropyl
acetate was added to a recrystallization vessel containing 1750.0 g of aripiprazole lauroxil.
The mixture was heated under agitation to 55-65 0C. When the drug was visibly dissolved in
solution, 3351.0 g of heptane heated to 55-65 °C was added to the recrystallization vessel. The
resulting mixture was heated to 60-65 °C, at which point cold glycol was introduced into the
jacket of the recrystallization vessel in order to cool the mixture. When the temperature of the
mixture of isopropyl acetate, e, and razole lauroxil reached 34 oC, homogenization
was initialized. The temperature was continuously monitored for the onset of the exotherm
(start of precipitation or llization) and the exotherm maximum. When the e
temperature reached the value Tmin after the exotherm (Tming), homogenation was stopped.
More cold glycol was introduced into the vessel jacket in order to cool the mixture to 18 0C, at
which point the mixture was held for 5 minutes.
Then, hot glycol was introduced into the vessel jacket to reheat the mixture toward 60-65 °C, at
which point cold glycol was again introduced into the jacket of the tallization vessel in
order to cool the mixture. When the temperature of the mixture of isopropyl acetate, heptane,
and aripiprazole il reached 34 °C, homogenization was initialized. The ature was
continuously monitored for the onset of the exotherm and the exotherm maximum. When the
mixture temperature reached the value Tmin after the rm (Tminz), homogenation was
stopped. More cold glycol was introduced into the vessel jacket in order to cool the e to
18 °C. The recrystallized aripiprazole lauroxil was filtered under vacuum in a dead end filter
dryer and rinsed with 2187.0 g of heptanes at ambient temperature. The solids were dried
under vacuum (80 torr) for 40 hours in the same vessel and collected.
4 kg scale
Aripiprazole lauroxil was recrystallized using the ing procedure. 4940.0 g of isopropyl
acetate was added to a recrystallization vessel containing 4000.0 g of aripiprazole lauroxil and
mixture under agitation. When the drug was visibly ved in solution (2 55 0C), 7670.0 g
of heptane heated to 55-65 °C was added to the recrystallization vessel. The resulting mixture
was heated to 2 60 oC and then held for 5 minutes. Cold glycol (28 0C) was then introduced
WO 32950
into the jacket of the recrystallization vessel in order to cool the mixture, and when the
temperature of the mixture of isopropyl acetate, e, and aripiprazole lauroxil reached 33.8
c’C, homogenization was initialized. The temperature was continuously monitored for the onset
of the exotherm (start of precipitation or crystallization) and the exotherm maximum. (If Tmin
was less than 33 CC, then another cycle of recrystallization was performed.) When the e
temperature d the value Tmin after the exotherm ), the homogenation was
stopped. More cold glycol was introduced into the vessel jacket in order to cool the mixture to
18 °C.
Then, hot glycol was introduced into the vessel jacket to reheat the mixture toward 60-65 0C, at
which point cold glycol was again uced into the jacket of the recrystallization vessel in
order to cool the mixture. When the temperature of the e of isopropyl acetate, heptane,
and aripiprazole lauroxil reached 33.8 °C, homogenization was initialized. The temperature
was continuously monitored for the onset of the rm and the exotherm maximum. When
the mixture temperature reached the value Tmin after the exotherm (Tmin2), homogenization
was stopped. More cold glycol was introduced into the vessel jacket in order to cool the
mixture to 18 °C. The recrystallized aripiprazole lauroxil was filtered under vacuum in a dead
end filter dryer and rinsed with 9 kg of heptanes at ambient temperature. The solids were dried
under vacuum (20 torr) for 20 hours in the same vessel and collected.
Examgle using sonication instead of homogenization
Aripiprazole lauroxil (10 g) was dissolved in hot isobutyl acetate (14 mL). N—heptane (28 mL)
was added to the hot solution and the mixture was heated fiirther to dissolve all solids. The hot
solution was placed in a sonication bath and sonicated for 2 minutes. Ice was added to the
sonication bath to cool down the mixture. White crystals were formed. The crystals were
filtered using a Buchner funnel and washed with cold n-heptane (10 mL). The white solid was
then dried under vacuum at room temperature overnight and resulted in 9.6 g of recrystallized
razole il (96% yield).
Impact of razole lauroxil particle size distribution (PSD), surface area, and e
on in vivo release profiles
In order to explore the effect of injection vehicle on razole plasma exposure, a single—
dose 1M muscular) rat dosing study was conducted. The closing amount in the study was
29 mg of recrystallized aripiprazole lauroxil prodrug, which is equivalent to 20 mg aripiprazole
base. The following two formulations were prepared and dosed intramuscularly to male rats:
(1) aripiprazole lauroxil bulk recrystallized drug substance suspended in a phosphate-
ed saline injection vehicle with sodium carboxymethylcellulose (NaCMC) (2 wt%) and
polysorbate 20 (0.2 wt%); and
(2) aripiprazole lauroxil recrystallized drug substance suspended in a phosphate-
ed saline injection vehicle using sorbitan monolaurate (SML) (0.5 wt%) and polysorbate
(0.2 wt%).
shows pharmacokinetic profiles of aripiprazole resulting from intramuscular
administration of a single dose of recrystallized aripiprazole lauroxil (20 mg razole
equivalents) suspended in either the NaCMC or SML vehicle, to male rats to assess the effect
of injection vehicle on the in vivo profile. Two lots of recrystallized aripiprazole lauroxil drug
nce were tested. Pharmacokinetic analysis showed that suspensions prepared from the
same drug substance lot resulted in essentially overlapping in vivo pK profiles of aripiprazole,
independent of injection vehicle. The pK parameters, summarized in Table 10, indicated that
the injection vehicle did not significantly impact Cmax, Tmax, or AUC0_T1ast.
Table 10: pK parameters from a single IM administration of
recrystallized aripiprazole lauroxil in male rats
a b AUCo “a“_
drug substance lot, vehicle Cmax (ng/mL) Tmx (day)
(dav*ng/mL)
Lot A, suspended in NaCMC
34.2 1r 6.21 13.8 i 3.66 735 i 82.7
vehicle,
Lot A, suspended in SML
43.1 1r 8.60 16.0 i 1.55 836 i 73.0
vehicle.
Lot B, suspended in NaCMC
22.7 i 1.17 17.2 i 5.74 638 i 53.7
vehicle_
Lot B, suspended in SML
23.4 1r 6.47 17.2 i 3.66 643 1r 146
vehicle.
aCmaxz The maximum precipitated plasma concentration observed.
bTmax: Time at which Cmax occurred.
CAUCMaSg Area under the precipitated plasma tration-time curve from Time 0 to the
last measured precipitated plasma concentration.
The impact of the particle size bution (PSD) and surface area on aripiprazole pK was
further investigated using four lots of recrystallized aripiprazole lauroxil in the rat IM pK
model at the same dose of 29 mg aripiprazole lauroxil equivalent to 20 mg of razole.
PSD and surface area ements for the four lots are presented in Table 11, and the PSD
profiles are illustrated in .
Table 11: PSD and surface area measurements for
aripiprazole lauroxil bulk recrystallized drug nce lots
Surface area
a a a
Lat # Dv[10] um Dv[50] um Dv[90] um
(mZ/g)
aFor a single preparation and measurement, PSD method error for the volume metrics are:
Dv[10]=i0.9 pm, : i3.5 pm, and Dv[90]: $5.7 pm. For an average of three preparations
and measurements, PSD method error would be Dv[10]=i0.5 pm, Dv[50]= $2.0 pm, and
Dv[90]: i3.3 um.
To examine the influences of the PSD and surface area on aripiprazole pK, the characterized
lots of recrystallized aripiprazole lauroxil listed in Table 11 were suspended in SML vehicle
and administered by IM administration to male rats. The aripiprazole pK profiles are plotted in
, and the pK parameters are presented in Table 12. These data show that material with
a smaller PSD and sed surface area (i.e., lot X3) will result in faster release rates (, top—most curve). (Release rate is expressed as razole plasma exposure (dependent on
both the rate of dissolution of recrystallized aripiprazole lauroxil and the rate of esterase
mediated conversion of aripiprazole lauroxil to aripiprazole). Material with larger PSD and
decreased surface area (i.e., lot X2) will result in slower e rates (, bottom-most
curve). Importantly, ation of the calculated AUCinf indicates that systemic exposure
was similar for all groups in this experiment.
Table 12: Aripiprazole pK parameters following a single IM administration of
tallized aripiprazole lauroxil suspended in SML injection vehicle in male rats
Surface AUCo-tlast
area (ml/g) g/mL)
aCmaxz The maximum precipitated plasma concentration observed.
bTmax: Time at which Cmax occurred.
CAUCo_t|ast: Area under the precipitated plasma concentration—time curve from Time 0 to the
last measured precipitated plasma tration.
dAUCinf: Area under the precipitated plasma concentration-time curve from Time 0 to infinity.
The conclusions from these experiments are that both PSD and surface area measurements
were important aspects of the physical ty characterization of the aripiprazole lauroxil
drug ls. Consistent with a release mechanism that is ted by crystal dissolution,
the data obtained from these pK studies highlight the rank order with regard to surface areas
and pK profiles. This ordering is consistent with the character of the insoluble prodrug
crystals, namely, that the particle size distribution and surface area of aripiprazole lauroxil are
the key attributes influencing in vivo performance.
In conclusion, as demonstrated in the pK studies described above, the mance of
recrystallized aripiprazole lauroxil drug product was dominated by the physical properties of
the product crystals. Dissolution of aripiprazole lauroxil following injection was d by
slow dissolution of the drug crystals, and was a function of the amount of exposed surface area
of the aripiprazole il material. The particle size distribution and surface area of
aripiprazole lauroxil were the key attributes influencing in viva mance.
Two-pass recrystallization
A two-pass recrystallization process was developed to fithher improve reproducibility and
particle size control.
As bed earlier, crystallization of aripiprazole lauroxil occurs after cooling the mixture of
the drug, the first solvent (such as isopropyl acetate), and the second t (such as n-
heptane) to a supersaturated condition. Control of the solution temperature to target a specific
onset temperature (exotherm mum” or “Tmin”) for crystallization is important to
control the final particle size distribution and surface area of the aripiprazole lauroxil crystals.
Nucleation and crystallization can be induced by initiating high-shear mixing as the
supersaturated mixture approaches a target temperature. The recrystallization process of the
present invention reproducibly produces crystals of aripiprazole lauroxil with desirable particle
size bution and surface area parameters.
Subsequent to the studies described above ing one-pass recrystallization or a single pass
of tallization, additional studies were performed in ultra-clean equipment.
In sterile pharmaceutical manufacturing, processing is ted in ultra-clean equipment to
ensure quality and reduce ination. Equipment is cleaned and steam sterilized in place
before use. Surface finish is controlled to be very smooth to aid in cleaning. After cleaning
and during use, equipment must be kept totally closed to the environment to prevent
contamination. A first pass of recrystallization may not always behave as predictably as
desired. For instance, variation in llization onset time or crystallization temperature may
be unacceptably large, resulting in tallized particles that have sub-optimal particle size
distribution and surface area parameters. Moreover, since the process is conducted in totally
closed equipment, conventional means of adding solid crystals to facilitate crystallization can
be highly impractical.
Accordingly, a process to fiarther facilitate reproducible recrystallization of razole
lauroxil was developed. ls of aripiprazole lauroxil were first formed by cooling and
itating at supersaturated conditions with or without homogenization. The solution was
then re-warmed and the ls were solved. When the solution was re-cooled, crystals
were precipitated in a reliable , with the aid of high—shear mixing as the target
temperature was ched, much as in the one-pass crystallization process described earlier.
In replicate experiments, the first pass recrystallization resulted in large variation in time from
homogenizer onset to crystal formation. Time to crystallization ranged from about 1 minute to
over 37 minutes. A larger variation in crystallization Tmin was noted. Results of first pass
recrystallization are shown in Table 13.
TABLE 13
Induction time
(Crystallization Homogenize
Crystallization onset time — r ON
Crystallization Homogenizer onset (Tmin) homogenizer
pass ON time time on time) temeperatur
After seeding, the subsequent second pass of recrystallization occurred quickly and
reproducibly around 1 minute or less afler homogenization onset. A much smaller variation in
Tmin was achieved. Results of the second pass of recrystallization are shown in Table 14.
2015/046525
TABLE 14
Induction time
(Crystallization nizer
Crystallization onsettime— ON
Sample Crystallization Homogenizer Tmin) homogenizer temperature,
pass ON time time on time) Tmcin,
While this invention has been particularly shown and described with references to preferred
embodiments thereof, it will be understood in light of the present disclosure by those skilled in
the art that various changes in form and details may be made therein Without departing from
the scope of the invention encompassed by the appended claims.
572570 ALT-024PC
Claims (19)
1. A process for making the compound of Formula (I) in crystal form Formula (I), 5 the process comprising the steps of: (a) obtaining a drug solution by combining the compound of Formula (I) or a salt or solvate thereof with a first solvent; (b) optionally ing the drug solution with a second solvent to form a mixture; (c) g the mixture; and 10 (d) when the temperature of the mixture is within the range of 31 °C to 43 °C, homogenizing the mixture to form crystallized particles of the compound of Formula (I) having a surface area of 0.50 to 3.3 m2/g; wherein the first solvent is ed from the group consisting of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl e, 15 acetone, and a mixture of isopropyl acetate and n-heptane; and the second solvent is selected from the group consisting of pentane, entane, hexane, cyclohexane, methyl cyclohexane, heptane, octane, nonane, decane, undecane, dodecane, ethanol, and methanol.
2. The process of claim 1, r comprising the steps of: 20 (e) stopping homogenization, and re-dissolving the crystallized particles of the compound of Formula (I) by heating the mixture; (f) cooling the mixture; and (g) when the temperature of the e is within the range of 31 °C to 43 °C, homogenizing the mixture to form llized particles of the compound of 25 Formula (I) having a surface area of 0.50 to 3.3 m2/g. 572570 ALT-024PC
3. The process of claim 1 or claim 2, wherein the crystallized les have a surface area of 0.80 to 1.1 m2/g.
4. The process of claim 1 or claim 2, wherein the crystallized particles have a surface area of 1.00 m2/g.
5 5. The process of claim 1 or claim 2, wherein the Dv[50] of the crystallized particles is 10 to 30 microns.
6. The process of claim 5, wherein the Dv[50] of the llized particles is 10 to 20 microns.
7. The process of any one of claims 1 to 6, wherein the first solvent is isopropyl 10 acetate.
8. The process of any one of claims 1 to 6, wherein the first solvent is a e of isopropyl acetate and n-heptane.
9. The process of any one of claims 1 to 8, wherein the second solvent is n-heptane.
10. The process of any one of claims 1 to 9, n in step (b), the temperature of the 15 mixture is in the range of 55 °C to 65 °C.
11. The process of any one of claims 1 to 10, wherein the temperature in step (d) is in the range of 31 °C to 35 °C.
12. The process of any one of claims 1 to 11, wherein the temperature in step (d) is 34 20
13. The process of claim 12, wherein in step (d), the homogenizing begins when the temperature of the mixture is 0 °C to 4 °C above 34 °C.
14. The process of any one of claims 1 to 13, wherein one or more of steps (a) through (c) is performed under agitation.
15. The process of any one of claims 2 to 13, wherein one or more of steps (a), (b), (c), 25 (d), (e), (f), and (g) is performed under agitation. 572570 ALT-024PC
16. The process of any one of claims 1 to 15, further sing the step of filtering the crystallized particles.
17. The process of claim 16, further comprising the step of rinsing the crystallized particles. 5
18. The s of claim 17, further comprising the step of drying the crystallized particles.
19. The process of any one of claims 1 to 10 and 14 to 18, wherein the temperature in step (d) is in the range of 31 °C to 38 °C.
Applications Claiming Priority (3)
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US201462041341P | 2014-08-25 | 2014-08-25 | |
US62/041,341 | 2014-08-25 | ||
PCT/US2015/046525 WO2016032950A1 (en) | 2014-08-25 | 2015-08-24 | Crystallization process of aripiprazole derivatives in extended release formulations for treatment of schizophrenia |
Publications (2)
Publication Number | Publication Date |
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NZ729479A NZ729479A (en) | 2021-03-26 |
NZ729479B2 true NZ729479B2 (en) | 2021-06-29 |
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