throbber
WO 03/026659
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`
`-
`
`64 -
`
`aripiprazole hydrate was identical to the powder x-ray
`
`diffraction spectrum of aripiprazole hydrate presented
`
`at the 4th Joint Japanese-Korean Symposium on Isolation
`
`Technology.
`
`5
`
`Reference Example 4
`
`Preparation of 15 mg tablets containing type
`
`I crystals of aripiprazole--aaj';Lydi;.i-de obtained in
`-:'~:--~- -·
`
`Reference Example 2.
`
`10
`
`Type-I crystals of aripiprazole~
`
`(525 g), lactose (1,995 g), corn starch (350 g) and
`
`crystalline cellulose {350 g) were charged in a
`
`fluidized bed granulating dryer (Flow coater FL0-5,
`
`manufactured by FREUND INDUSTRIAL CO., LTD.), and these
`
`15 granulating ingredients were mixed by fluidizing for
`
`about 3 minutes with an inlet air temperature at 70°C
`
`and air flow rate of 3 m3 /min. Further, the granulating
`
`ingredients were upon continued fluidizing under the
`
`same ~ondition and sprayed about 1,400 g of the aqueous
`
`20
`
`solution to obtained wet granules. The wet granules
`
`were dried under inlet air at temperature at 80°C, for
`
`about 15 minutes. The obtained dried granules
`
`contained 4.3% of water. (Yield: 99%). The dried
`
`granules were subjected to sizing by passing to a sieve
`
`25 of 710 µm.
`
`About 1% by weight of magnesium stearate was
`
`added to the sized granules and mixed, then the
`
`granules were supplied to a tablet machine (Rotary
`
`601 of 1328
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`
`single tablet press 12HUK: manufactured by KIKUSUI
`
`SEISAKUSHO CO., LTD.), there were obtained tablets,
`
`each having 95 mg of weight.
`
`Water content of the tablets was measured
`
`5
`
`according to volumetric titration method (Karl-Fischer
`
`method) described in water content measuring method in
`
`Japanese Pharmacopoea or the electrical quantity
`
`titration method.
`
`10 Water content measuring method:
`
`Sample (0.1 to 0.5 g) (in case of a tablet, 1
`
`tablet was used} was weighed precisely, and the water
`
`content was measured by use of a water content
`
`measuring equipment.
`
`15
`
`Volumetric titration:
`
`Automated water content measuring equipment
`
`Model: KF-06 (manufacture by MITSUBISHI CHEMICAL
`
`CORP.)
`
`Electrical quantity titration method:
`
`20
`
`Automated micro-water content measuring equipment
`
`Model: AQ-7F (manufactured by HIRANUMA SANGYO
`
`CO., LTD.)
`
`Automated water vaporization equipment Model:
`
`LE-20S (manufactured by HIRANUMA SANGYO CO.,
`
`25
`
`LTD.)
`
`Heating temperature: 165+10°c
`
`Nitrogen gas flow rate: about 150 ml/min.
`
`602 of 1328
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`
`Reference Example 5
`
`- 66 -
`
`Preparation of 15 mg tablets containing type
`B crys.tals of aripiprazole~ ..... ,\
`Type B crystals of aripipraole b~~-;~
`(4,500 g), lactose {17,100 g), corn starch (3,000 g)
`
`5
`
`and crystalline cellulose (3,000 g) were charged in a
`
`fluidized bed granulating dryer (NEW-MARUMERIZER Model:
`
`NQ-500, manufactured by FUJI PAUDAL CO., LTD.), and
`
`these granulating ingredients were mixed by fluidizing
`
`10
`
`for about 3 minutes with an inlet air temperature at
`
`70°C, air flow rate of 10 to 15 m3 /min. Further, the
`
`granulating ingredients were upon continued fluidizing
`
`under the same condition, and sprayed about 12,000 g of
`
`5% aqueous solution of hydroxypropyl celulose to
`r
`15 ~btained wet granules. The wet granules were dried
`
`under inlet air at temperature at 85°C, for about 28
`
`minutes. The thus obtained dried granules contained
`
`3.8% of water (measured by the method according to
`
`Reference Example 4).
`
`(Yield: 96%) • The dried
`
`20 granules were subjected to siiing by passing to a sieve
`
`of 850 µm.
`
`About 1% by weight of magnesium stearate was
`
`added to the sized granules and mixed, then the
`
`granules were supplied to a tablet machine (Rotary
`
`25 single tablet press 12HUK: manufactured by KIKUSUI
`
`SEISAKUSHO CO., LTD.), there were obtained tablets,
`
`each having 95 mg of weight.
`
`603 of 1328
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`
`Example 1
`
`- 67 -
`
`500.3 g of the aripiprazole hydrate crystals
`
`obtained in Reference Example 3 were milled using a
`
`sample mill {small atomizer). The main axis rotation
`
`5
`
`rate was set to 12,000 rpm and the feed rotation rate
`
`to 17 rpm, and a 1.0 mm herringbone screen was used.
`
`Milling was completed in 3 minutes, resulting in 474.6
`
`g
`
`(94.9%) of Aripiprazole Hydrate A powder.
`
`The Aripiprazole Hydrate A (powder) obtained
`
`10
`
`in this way had a mean particle size of 20-25 µm. The
`
`melting point (mp) was undetermined because dehydration
`
`was observed beginning near 70°C.
`
`The Aripiprazole Hydrate A {powder) obtained
`
`above exhibited an 1H-NMR
`
`(DMSO-d 6 , TMS) spectrum which
`
`15 was substantially the same as the 1H-NMR spectrum shown
`
`in Figure 2. Specifically, it had characteristic peaks
`
`at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm {m, 2H), 2.35-
`
`2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H + DMSO), 2.78
`ppm (t, J = 7.4 Hz, 2H), 2.97 ppm (brt, J = 4.6 Hz,
`20 4H), 3.92 ppm (t, J = 6.3 Hz, 2H), 6.43 ppm (d, J = 2.4
`Hz, lH), 6.49 ppm (dd, J = 8.4 Hz, J = 2.4 Hz,
`7.04 ppm (d, J = 8.1 Hz, lH), 7.11-7.17 ppm (rn,
`
`lH),
`
`lH),
`
`7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, lH).
`
`The Aripiprazole Hydrate A (powder) obtained
`
`25
`
`above had a powder x-ray diffraction spectrum which was
`
`substantially the same as the powder x-ray diffraction
`
`spectrum shown in Figure 3. Specifically, it had
`
`characteristic peaks at 20 = 12.6°, 15.4°, 17.3°, 18.0°,
`
`604 of 1328
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`-
`
`68 -
`
`18.6°, 22.5° and 24.8°. This pattern is different from
`
`the powder x-ray spectrum of unmilled aripiprazole
`
`hydrate shown in Figure 7.
`
`The Aripiprazole Hydrate A (powder) obtained
`
`5
`
`above had infrared absorption bands at 2951, 2822,
`
`1692, 1577, 1447, 1378, 1187, 963 and 784 cm- 1 on the IR
`
`(KBr) spectrum.
`
`As shown in Figure 1, the Aripiprazole
`
`Hydrate A
`
`(powder) obtained above had a weak peak at
`
`10 71.3°C in thermogravimetric/differential thermal
`
`analysis and a broad endothermic peak {weight loss
`
`observed corresponding ~o one water molecule) between
`
`60-120°C--clearly different from the endothermic curve
`
`of unmilled aripiprazole hydrate (see Figure 6).
`
`15
`
`Example 2
`
`450 g of the Aripiprazole Hydrate A (powder)
`
`obtained in Example 1 was dried for 24 hours at l00°C
`
`using a hot air dryer to produce 427 g (yield 98.7%) of
`
`20 Aripiprazole Anhydride Crystals B.
`
`These Aripiprazole Anhydride Crystals B had a
`
`melting.point (mp) of 139.7°C.
`
`The Aripiprazole Anhydride Crystals B
`
`obtained above had an 1H-NMR spectrum (DMSO-d 6 , TMS)
`
`25 which was substantially the same as the 1H-NMR spectrum
`
`shown in Figure 4. Specifically, they had
`
`characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-
`
`1.78 ppm (m, 2H), 2.35-2.46 ppm {m, 4H), 2.48-2.56 ppm
`
`605 of 1328
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`
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`
`- 69 -
`
`(m, 4H + DMSO), 2.78 ppm (t, J = 7.4 Hz, 2H}, 2.97 ppm
`
`(brt, J = 4.6 Hz, 4H), 3.92 ppm (t, J = 6.3 Hz, 2H),
`
`6.43 ppm (d, J = 2.4 Hz, lH), 6.49 ppm {dd, J = 8.4 Hz,
`
`J = 2.4 Hz, lH), 7.04 ppm (d, J = 8.1 Hz, lH), 7.11-
`
`5 7.17 ppm (m,
`
`lH}, 7.28-7.32 ppm (m, 2H) and 10.00 ppm
`
`{s, lH).
`
`The Aripiprazole Anhydride Crystals B
`
`obtained above had a powder x-ray diffraction spectrum
`
`which was substantially the same as the powder x-ray
`
`10 diffraction spectrum shown in Figure 5. Specifically,
`
`they had characteristic peaks at 28 = 11.0°, 16.6°,
`
`19.3°, 20.3° and 22.1°.
`
`The Aripiprazole Anhydride Crystals B
`
`obtained above had remarkable inf rared absorption bands
`
`15 at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and
`
`779 cm- 1 on the IR (KBr) spectrum.
`
`The Aripiprazole Anhydride Crystals B
`
`obtained above ex_hibited an endothermic peak near about
`
`141.5°C in thermogravimetric/differential thermal
`
`20 analysis.
`
`The Aripiprazole Anhydride Crystals B
`
`obtained above exhibited an endothermic peak near about
`
`140.7°C in differential scanning calorimetry.
`
`Even when the Aripiprazole Anhydride Crystals
`
`25 B obtained above were left for 24 hours in a dessicator
`
`set at humidity 100%, temperature 60°C, they did not
`
`exhibit hygroscopicity exceeding 0.4% {See Table 1
`
`below) .
`
`606 of 1328
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`
`Example 3
`
`- 70 -
`
`44.29 kg of the Aripiprazole Hydrate A
`
`(powder} obtained in Example 1 was dry heated for 18
`
`hours in a 100°C hot air dryer and then heated for 3
`
`5 hours at 120°C to produce 42.46 kg (yield 99.3%) of
`
`Aripiprazole Anhydride Crystals B.
`
`The physicochemical properties of the
`
`resulting Aripiprazole Anhydride Crystals B were the
`
`same as the physicochemical properties of the
`
`10 Aripiprazole Anhydride Crystals B obtained in Example
`
`2.
`
`The Aripiprazole Anhydride Crystals B
`
`obtained in this way did not exhibit hygroscopicity of
`
`more than 0.4% even when left for 24 hours in a
`
`15 dessicator set at humidity 100%, temperature 60°C (see
`
`Table 1 below) .
`
`Example 4
`
`40.67 kg of the Aripiprazole Hydrate A
`
`20
`
`(powder) obtained in Example 1 was dry heated for 18
`
`hours in a 100°C hot air dryer and then heated for 3
`
`hours at 120°C to produce 38.95 kg (yield 99.6%) of
`
`Aripiprazole Anhydride Crystals B.
`
`The physicochemical properties of the
`
`25
`
`resulting Aripiprazole Anhydride Crystals B were the
`
`same as the physicochemical properties of the
`
`Aripiprazole Anhydride Crystals B obtained in Example
`
`2.
`
`607 of 1328
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`- 71 -
`
`The Aripiprazole Anhydride Crystals B
`
`obtained in this way did not exhibit hygroscopicity of
`
`more than 0.4% even when left for 24 hours in a
`
`dessicator set at humidity 100%, temperature 60°C (see
`
`5 Table 1 below} .
`
`Examples 5-10 are useful for injectable or
`
`oral solution formulations but not solid dose
`
`formulations since they were made by heating
`
`Conventional Anhydride or Conventional Hydrate instead
`
`10 of Hydrate A.
`
`Example 5
`
`The hygroscopic aripiprazole anhydride
`
`crystals obtained in Reference Example 1 were heated
`
`15
`
`for 50 hours at 100°C using the same methods as in
`
`Example 2. The physicochemical properties of the
`
`resulting Aripiprazole Anhydride Crystals B were the
`
`same as the physicochemical properties of the
`
`Aripiprazole Anhydride Crystals B obtained in Example
`
`20 2.
`
`The Aripiprazole Anhydride Crystals B
`
`obtained in this way did not exhibit hygroscopicity of
`
`more than 0.4% even when left for 24 hours in a
`
`dessicator set at humidity 100%, temperature 60°C (see
`
`25 Table 1 below).
`
`Example 6
`
`The hygroscopic aripiprazole anhydride
`
`608 of 1328
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`
`

`
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`- 72 -
`
`crystals obtained in Reference Example 1 were heated
`
`for 3 hours at 120°C using the same methods as in
`
`Example 2. The physicochemical properties of the
`
`resulting Aripiprazole Anhydride Crystals B were the
`
`5
`
`same as the physicochernical properties of the
`
`Aripiprazole Anhydride Crystals B obtained in Example
`
`2.
`
`The Aripiprazole Anhydride Crystals B
`
`obtained in this way did not exhibit hygroscopicity of
`
`10 more than 0.4% even when left for 24 hours in a
`
`dessicator set at humidity 100%, temperature 60°C (see
`
`Table 1 below) .
`
`Example 7
`
`15
`
`The hygroscopic aripiprazole anhydride
`
`crystals obtained in Reference Example 2 were heated
`
`for 50 hours at 100°C using the same methods as in
`
`Example 2. The physicochemical properties of the
`
`resulting Aripiprazole Anhydride Crystals B were the
`
`20
`
`same as the physicochemical properties of the
`
`Aripiprazole Anhydride Crystals B obtained in Example
`
`2.
`
`The Aripiprazole Anhydride Crystals B
`
`obtained in this way did not exhibit hygroscopicity of
`
`25 more than 0.4% even when left for 24 hours in a
`
`dessicator set at humidity 100%, temperature 60°C {see
`
`Table 1 below) .
`
`609 of 1328
`
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`
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`
`Example 8
`
`- 73 -
`
`The hygroscopic aripiprazole anhydride
`
`crystals obtained in Reference Example 2 were heated
`
`for 3 hours at 120°C using the same methods as in
`
`5 Example 2. The physicochemical properties of the
`
`resulting Aripiprazole Anhydride Crystals B were the
`
`same as the physicochemical properties of the
`
`Aripiprazole Anhydride Crystals B obtained in Example
`
`2.
`
`10
`
`The Aripiprazole Anhydride Crystals B
`
`obtained in this way did not exhibit hygroscopicity of
`
`more than 0.4% even when left for 24 hours in a
`
`dessicator set at humidity 100%, temperature 60°C (see
`
`Table 1 below) .
`
`15
`
`ExampJe 9
`
`The aripiprazole hydrate crystals obtained in
`
`Reference Example 3 were heated for 50 hours at 100°C
`
`using the same methods as in Example 2. The
`
`20 physicochemical properties of the resulting
`
`Aripiprazole Anhydride Crystals B were the same as the
`
`physicochemical properties of the Aripiprazole
`
`Anhydride Crystals B obtained in Example 2.
`
`The Aripiprazole Anhydride Crystals B
`
`25 obtained in this way did not exhibit hygroscopicity of
`
`more than 0.4% even when left for 24 hours in a
`
`dessicator set at humidity 100%, temperature 60°C (see
`
`Table 1 below) .
`
`610 of 1328
`
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`
`

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`•
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`PCT/JP02/09858
`
`Example JO
`
`- 74 -
`
`The aripiprazole hydrate crystals obtained in
`
`Reference Example 3 were heated for 3 hours at 120°C
`
`using the same methods as in Example 2. The
`
`5 physicochemical properties of the resulting
`
`Aripiprazole Anhydride Crystals B were the same as the
`
`physicochemical properties of the Aripiprazole
`
`Anhydride Crystals B obtained in Example 2.
`
`The Aripiprazole Anhydride Crystals B
`
`10 obtained in this way exhibited hyg~oscopicity of no
`
`more than 0.4% even when left for 24 hours in a
`
`dessicator set at humidity 100%, temperature 60°C (see
`
`Table 1 below) .
`
`15 Example 11 {Preparation of type C crystals of
`
`aripiprazole anhydride)
`
`100 Miligrarns of type-I crystals of
`
`aripiprazole anhydride obtained in Reference Example 2
`
`were heated about 145°C {±3°C).
`
`In this occasion,
`
`20
`
`there was observed the phenomena that the crystals were
`
`once melted, then again crystallized. After that, 100
`
`mg {yield: 100%) of Type C crystals of aripiprazole
`
`anhydride were obtained. The melting point of the
`
`crystals was 150°C. The crystals were colorless prism
`
`25
`
`form.
`
`The type C crystals of aripiprazole anhydride
`
`obtained above had an endothermic curve which was
`
`substantially identical to the endothermic curve of
`
`611 of 1328
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`

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`
`- 75 -
`
`thermogravimetric/differential thermal analysis
`
`(heating rate: S°C/minute) shown in Figure 8.
`
`Specifically, it showed the endothermic curve around
`
`1so.2°c.
`
`5
`
`The type C crystals of aripiprazole anhydride
`
`thus obtained exhibited an 1H-NMR spectrum (DMSO-d 6 ,
`
`TMS) which was substantially identical to the 1 H-NMR
`
`spectrum (DMSO-d6 , TMS) shown in Figure 9.
`
`Specifically, it had the characteristic peaks at 1.55-
`
`10 1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm
`
`(rn, 4H), 2.48-2.56 ppm (m, 4H+DMSO}, 2.78 ppm {t, J=7.4
`
`Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t,
`
`J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, lH), 6.49 ppm
`
`(dd, J=B.4 Hz, J=2.4 Hz,
`
`lH), 7.04 ppm (d, J=8.l Hz,
`
`15
`
`lH), 7.11-7.17 ppm (m,
`
`lH), 7.28-7.32 ppm (m, 2H), and
`
`10.00 ppm (s, lH).
`
`The type C crystals of aripiprazole anhydride
`
`obtained above had a powder X-ray diffraction spectrum
`
`which was substantially identical to the powder X-ray
`
`20 diffraction spectrum shown in Figure 10. Specifically,
`
`it had the characteristic peaks at 29 = 12.6°, 13.7°,
`
`15.4°, 18.1°, 19.0°, 20.6°, 23.5° and 26.4°.
`
`The type C crystals of aripiprazole anhydride
`
`obtained above had an IR spectrum which was
`
`25 substantially identical to the IR (KBr) spectrum shown
`
`in Figure 11. Specifically, it had the characteristic
`
`infrared absorption bands at 2939, 2804, 1680, 1375 and
`
`7 80 cm- 1
`
`•
`
`612 of 1328
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`
`

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`
`- 76 -
`
`The type C crystals of aripiprazole anhydride
`
`obtained above exhibited a solid 13C-NMR spectrum, which
`
`was substantially identical to the solid 13C-NMR
`
`spectrum shown in Figure 12. Specifically, it had the
`
`5 characteristic peaks at 32.8 ppm, 60.8 ppm, 74.9 ppm,
`
`104.9 ppm, 152.2 ppm, 159.9 ppm and 175.2 ppm.
`
`According to the above-mentioned data on
`
`endothermic curve of thermogravimetric/differential
`
`thermal analysis (heating rate: 5°C/minute) and powder
`
`10 X-ray diffraction spectrum, the formation of the type C
`
`crystals of aripiprazole anhydride was confirmed.
`
`When the type C crystals of aripiprazole
`
`anhydride crystals obtained above were left for 24
`
`hours in a dessicator where the conditions were set at
`
`15 humidity 100%, and temperature 60°C, then the crystals
`
`did not exhibit hygroscopicity higher than 0.4%
`
`(see,
`
`Table 1 below) .
`
`Example 12 (Preparation of type D crystals of
`
`20
`
`aripiprazole anhydride)
`
`The type-I crystals of aripiprazole anhydride
`
`obtained in Reference Example 2 were added in 200 ml of
`
`toluene, and dissolved by heating at 74°C. After
`
`confirmed that it was dissolved completely, the toluene
`25 solution was cooled to 7°C, and the precipitated
`
`crystals were collected by filtration. The crystals
`
`were subjected to air-drying as they were so as to
`
`obtain 17.9 g {yield: 89.5%) of type D crystals of
`
`613 of 1328
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`
`aripiprazole anhydride.
`
`- 77 -
`
`The type D crystals of aripiprazole anhydride
`
`obtained above had an endothermic curve substantially
`
`identical to the endothermic curve of
`
`5
`
`thermogravimetric/differential thermal analysis
`
`(heating rate: S°C/minute) shown in Figure 13.
`
`Specifically, it had the endothermic peaks at about
`
`136.8°C and about 141.6°.
`
`The type D crystals of aripiprazole anhydride
`
`10 obtained above exhibited 1H-NMR spectrum (DMSO-d6 , TMS)
`
`which was substantially identical to the 1H-NMR spectrum
`
`(DMSO-d 6 , TMS) shown in Figure 14. Specifically, they
`
`had the characteristic peaks at 1.55-1.63 ppm -(m, 2H),
`
`1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56
`
`15 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm
`
`(brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43
`
`ppm (d, J=2.4 Hz, lH), 6.49 ppm (dd, J=8.4 Hz, J=2.4
`
`Hz, lH), 7.04 ppm (d, J=B.1 Hz,
`
`lH}, 7.11-7.17 ppm {m,
`
`lH}, 7.28-7.32 ppm (m, 2H), and 10.00 ppm {s, lH}.
`
`20
`
`The type D crystals of aripiprazole anhydride
`
`obtained above haq a powder X-ray diffraction spectrum
`
`which was substantially identical to the powder X-ray
`
`diffraction spectrum shown in Figure 15. Specifically,
`
`it had the characteristic ~eaks at 20 = 8.7°, 11.6°,
`
`25 16.3°, 17.7°, 18.6°, 20.3°, 23.4° and 25.0°.
`
`The type D crystals of aripiprazole anhydride
`
`obtained above had an IR spectrum which was
`
`substantially identical to the IR (KBr} spectrum shown
`
`614 of 1328
`
`Alkermes, Ex. 1076
`
`

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`WO 03/026659
`
`PCT/JP02/09858
`
`- 78 -
`
`in Figure 16. Specifically, it had the characteristic
`
`infrared absorption bands at 2946, 1681, 1375, 1273,
`
`117 5 and 862 cm- 1
`
`•
`
`The type D crystals of aripiprazole anhydride
`
`5 obtained above exhibited a solid 13C-NMR spectrum which
`
`was substantially identical to the solid 13C-NMR
`
`spectrum shown in Figure 17. Specifically, it had the
`
`characteristic peaks at 32.1 ppm, 62.2 ppm, 66.6 ppm,
`
`104.1 ppm, 152.4 ppm, 158.5 ppm and 174.1 ppm.
`
`10
`
`According to the above-mentioned data on the
`
`endothermic curve of thermogravirnetric/dif ferential
`
`thermal analysis (heating rate: 5°C/minute) and powder
`
`X-ray diffraction spectrum, the formation of type D
`
`crystals of aripiprazole anhydride was confirmed.
`
`15
`
`When the type D crystals of aripiprazole
`
`anhydride crystals obtained above were left for 24
`
`hours in a dessicator where the conditions were set at
`
`humidity 100%, and temperature 60°C, the crystals did
`
`not have hygroscopicity higher than 0.4% (see, Table 1
`
`20 below) .
`
`Example 13
`
`(Preparation of type D crystals of
`
`aripiprazole anhydride)
`
`1,200 Grams of the type-I crystals of
`
`25 aripiprazole anhydride obtained in Reference Example 2
`
`were dissolved in 18 liters of toluene, with heating.
`
`This toluene solution was cooled to 40°C, and 36 g of
`
`type-D crystals of aripiprazole anhydride obtained in
`
`615 of 1328
`
`Alkermes, Ex. 1076
`
`

`
`WO 03/026659
`
`PCT/JP02/09858
`
`- 79 -
`
`Example 12 were added as seed crystals, then the
`
`solution was cooled to 10°C and allowed to stand as it
`
`is. The precipitated crystals were collected by
`
`filtration, dried at 60°C for 18 hours to obtain 1,073
`
`5
`
`g (yield: 86.8%) of type D crystals of aripiprazole
`
`anhyride (purity: 100%). The crystals were colorless
`
`plate form.
`
`The type D crystals of aripiprazole anhydride
`
`had an endothermic curve substantially identical to the
`
`10 endothermic curve of thermogravimetric/differential
`
`thermal analysis (heating rate: 5°C/minute) shown in
`
`Figure 13. Specifically, it had the endothermic peaks
`
`around about 136.8°C and about 141.6°.
`
`The type D crystals of aripiprazole anhydride
`
`15 obtained above exhibited an 1H-NMR spectrum (DMSO-d 6 ,
`TMS) which was substantially identical to the 1H-NMR
`
`spectrum (DMSO-d6 , TMS) shown in Figure 14.
`
`Specifically, it had the characteristic peaks at 1.55-
`
`1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm
`
`20
`
`(m, 4H}, 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4
`
`Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t,
`
`J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, lH), 6.49 ppm
`
`{dd, J=B.4 Hz, J=2.4 Hz, lH), 7.04 ppm (d, J=B.1 Hz,
`
`lH), 7.11-7.17 ppm (m,
`
`lH), 7.28-7.32 ppm (m, 2H), and
`
`25 10.00 ppm (s, lH).
`
`The type D crystals of aripiprazole anhydride
`
`obtained above had a powder X-ray diffraction spectrum
`
`which was substantially identical to the powder X-ray
`
`616 of 1328
`
`Alkermes, Ex. 1076
`
`

`
`WO 03/026659
`
`PCT/JP02/09858
`
`- 80 -
`
`diffraction spectrum shown in Figure 15. Specifically,
`
`it had the characteristic peaks at 20 = 8.7°, 11.6°,
`
`16. 3 °, 1 7 . 7 °, 18 . 6 °, 2 0. 3 °, 2 3 . 4 ° and 2 5. 0 ° .
`
`The type D crystals of aripiprazole anhydride
`
`5 obtained above had an IR spectrum which was
`
`substantially identical to the IR (KBr) spectrum shown
`
`in Figure 16. Specifically, it had characteristic
`
`infrared absorption bands at 2946, 1681, 1375, 1273,
`
`1175 and 862 cm- 1
`
`•
`
`10
`
`The type D crystals of aripiprazole anhydride
`
`obtained above had a solid 13C-NMR spectrum which was
`
`substantially identical to the solid 13C-NMR spectrum
`
`shown in Figure 17. Specifically, it had the
`
`characteristic peaks at 32.1 ppm, 62.2 ppm, 66.6 ppm,
`
`15 104.1 ppm, 152.4 ppm, 158.5 ppm and 174.1 ppm.
`
`According to the above-mentioned data on the
`
`endothermic curve of thermogravimetric/differential
`
`thermal analysis (heating rate: 5°C/minute) and powder
`
`X-ray diffraction spectrum, the formation of type D
`
`20 crystals of aripiprazole anhydride was confirmed.
`
`When the type D crystals of aripiprazole
`
`anhydride crystals obtained above were left for 24
`
`hours in a dessicator where the conditions were set at
`
`humidity 100%, and temperature 60°C, the crystals did
`
`25 not exhibit hygroscopicity higher than 0.4% (see, Table
`
`1 below).
`
`617 of 1328
`
`Alkermes, Ex. 1076
`
`

`
`WO 03/026659
`
`PCT/JP02/09858
`
`Example 14 (Preparation of type E crystals of
`
`- 81 -
`
`aripiprazole anhydride)
`
`40 Grams of type-I crystals of aripiprazole
`
`anhydride obtained in Reference Example 2 was dissolved
`
`5
`
`in 1000 ml of acetonitrile with heating at 80°C. This
`
`acetonitrile soiution was cooled to about 70°C by
`
`taking for about 10 minutes, and was kept at this
`
`temperature for about 30 minutes to precipitate- the
`
`seed crystals. Next, the temperature of said solution
`
`10 was slowly risen to 75°C, and the crystals were grown
`
`up by keeping this temperature for 1 hour. Then, the
`
`solution was cooled to l0°C by taking about 4 hours,
`
`and the precipitated crystals were collected by
`
`filtration. Thus obtained crystals were subjected to
`
`15 air-drying overnight, there were obtained 37.28 g
`
`(yield: 93.2%} of type E crystals of aripiprazole
`
`anhydride (purity: 100%). The melting point of these
`
`crystals was 145°C, and the crystals were colorless
`
`needle form.
`
`20
`
`The type E crystals of aripiprazole
`
`anhydride had an endothermic curve substantially
`
`identical to the endothermic curve of
`
`thermogravimetric/differential thermal analysis
`
`(heating rate: 5°C/minute) shown in Figure 18.
`
`25 Specifically, it had endothermic peak at about 146.5°.
`
`The type E crystals of aripiprazole anhydride
`
`obtained above exhibited an 1H-NMR spectrum (DMSO-d 6 ,
`
`TMS} which was substantially identical to the 1 H-NMR
`
`618 of 1328
`
`Alkermes, Ex. 1076
`
`

`
`WO 03/026659
`
`PCT/JP02/09858
`
`- 82 -
`
`spectrum (DMSO-d 6 , TMS) shown in Figure 19.
`
`Specifically, it had the characteristic peaks at 1.55-
`
`1. 63 ppm (rn, 2H}, 1.68-1.78 ppm (rn, 2H), 2.35-2.46 ppm
`
`(rn, 4H), 2.48-2.56 ppm (rn, 4H+DMSO), 2.78 ppm {t, J=7.4
`
`5 Hz, 2H}, 2.97 ppm (brt, J=4.6 Hz, 4H}, 3.92 ppm (t,
`
`J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, lH), 6.49 ppm
`
`(dd, J=8.4 Hz, J=2.4 Hz,
`
`lH}, 7.04 ppm (d, J=8.1 Hz,
`
`lH), 7.11-7.17 ppm (m,
`
`lH), 7.28-7.32 ppm (m, 2H), and
`
`10.00 ppm (s, lH).
`
`10
`
`The type E crystals of aripiprazole anhydride
`
`obtained above had a powder X-ray diffraction spectrum
`
`which was substantially identical to the powder X-ray
`
`diffraction spectrum shown in Figure 20. Specifically,
`
`it had the characteristic peaks at 20 = 8.0°, 13.7°,
`
`15 14.6°, 17.6°, 22.5° and 24.0°.
`
`The type E crystals of aripiprazole anhydride
`
`obtained above had an IR spectrum which was
`
`substantially identical to the IR (KBr) spectrum shown
`
`in Figure 21. Specifically, it had the characteristic
`
`20
`
`infrared absorption bands at 2943, 2817, 1686, 1377,
`
`1202, 969 and 774 cm- 1
`
`•
`
`According to the data on the endothermic
`
`curve of thermogravimetric/differential thermal
`
`analysis (heating rate: 5°C/minute) and powder X-ray
`
`25 diffraction spectrum, the formation of type E crystals
`
`of aripiprazole anhydride was confirmed.
`
`When the type E crystals of aripiprazole
`
`anhydride obtained above were left for 24 hours in a
`
`619 of 1328
`
`Alkermes, Ex. 1076
`
`

`
`WO 03/026659
`
`PCT/JP02/09858
`
`- 83 -
`
`dessicator where the conditions were set at humidity
`
`100%, and temperature 60°C, the crystals did not
`
`exhibit hygroscopicity highe~ than 0.4%
`
`(see, Table 1
`
`below) .
`
`5
`
`Example 15 (Preparation of type F crystals of
`
`aripiprazole anhydride)
`
`140 Grams of type-I crystals of aripiprazole
`
`anhydride obtained in Reference Example 2 were
`
`10
`
`suspended in 980 ml of acetone and continued to reflux
`
`for 7.5 hours with stirring. Next, the suspension was
`
`filtered in hot condition, and crystals separated out
`
`were subjected to air-drying for 16 hours at room
`
`temperature, there was obtained 86.19 g (yield: 61.6%)
`
`15 of type F crystals of aripiprazole anhydride {purity:
`
`100%}. The crystals were colorless prism form.
`
`The type F crystals of aripiprazole
`
`anhydride had an endothermic curve substantially
`
`identical to the endothermic curve of
`
`20
`
`thermogravirnetric/dif f erential thermal analysis
`
`(heating rate: S°C/minute) shown in Figure 22.
`
`Specifically, it had the exothermic peaks at about
`
`137.5°C and about 149.8°C.
`
`The type F crystals of aripiprazole anhydride
`
`2 5 obtained above exhibited an 1 H-NMR spectrum ( DMSO-d6 ,
`
`TMS) which was substantially identical to the 1H-NMR
`
`spectrum (DMSO-d 6 , TMS) shown in Figure 23.
`
`Specifically, it had the characteristic peaks at 1.55-
`
`620 of 1328
`
`Alkermes, Ex. 1076
`
`

`
`WO 03/026659
`
`PCT/JP02/09858
`
`- 84 -
`
`1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm
`
`(m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4
`
`Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t,
`
`J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, lH), 6.49 ppm
`
`5
`
`(dd, J=8.4 Hz, J=2 .. 4 Hz, lH), 7.04 ppm (d, J=8.l Hz,
`
`lH), 7.11-7.17 ppm (rn,
`
`lH), 7.28-7.32 ppm (m, 2H), and
`
`10.00 ppm (s, lH).
`
`The type F crystals of aripiprazole anhydride
`
`obtained above had a powder X-ray diffraction spectrum
`
`10 which was substantially identical to the powder X-ray
`
`diffraction spectrum shown in Figure 24. Specifically,
`
`it had the characteristic peaks at 20 = 11.3°, 13.3°,
`
`15.4°, 22.8°, 25.2° and 26.9°.
`
`The type F crystals of aripiprazole anhydride
`
`15 obtained above had an IR spectrum which was
`
`substantially identical to the IR (KBr) spectrum shown
`
`in Figure 25. Specifically, it had the characteristic
`
`infrared absorption bands at 2940, 2815, 1679, 1383,
`
`1273, 1177, 1035, 963 and 790 cm- 1
`
`20
`
`According to the data on endothermic curve of
`
`thermogravimetric/differential thermal analysis
`
`(heating rate: 5°C/minute) and powder X-ray diffraction
`
`spectrum, the formation of type F crystals of
`
`aripiprazole anhydride was confirmed.
`
`25
`
`When the type F crystals of aripiprazole
`
`anhydride crystals obtained above were left for 24
`
`hours in a dessicator where the conditions were set at
`
`humidity 100%, and temperature 60°C, the crystals did
`
`621 of 1328
`
`Alkermes, Ex. 1076
`
`

`
`WO 03/026659
`
`PCT/JP02/09858
`
`not exhibit hygroscopicity higher than 0.4% {see, Table
`
`- 85 -
`
`1 below).
`
`Sample
`
`Reference Example 1
`
`Reference Example 2
`
`Example 2
`
`Example 3
`
`Example 4
`
`Example 5
`
`Example 6
`
`Example 7
`
`Example 8
`
`Example 9
`
`Example 10
`
`Example 11
`
`Example 12
`
`Example 13
`
`Example 14
`
`Example 15
`
`Table 1
`
`Initial Moisture Moisture Content
`After 24 hrs (%)
`Content { % )
`0.04
`3.28
`
`0.04
`
`0.04
`
`0.02
`
`0.02
`
`0.04
`
`0.04
`
`0.04
`
`0.04
`
`0.03
`
`0 .. 05
`
`0.03
`
`0.04
`
`0.04
`
`0.06
`
`0.04
`
`1. 78
`
`0.04
`
`0.02
`
`0.02
`
`0.04
`
`0.04
`
`0.03
`
`0.03
`
`0.01
`
`0.05
`
`0.03
`
`0.03
`
`0.03
`
`0.09
`
`0.04
`
`5 Example 16
`
`a)
`
`Type I crystals of aripiprazole anhydride {10
`
`g) obtained in Reference Example 2 was charged in a
`
`stainless steel round tray {diameter: 80 mm), and
`
`heated to about 170°C so as to melted completely. When
`
`10
`
`this melted liquid was cooled, then it solidified
`
`622 of 1328
`
`Alkermes, Ex. 1076
`
`

`
`WO 03/026659
`
`PCT/JP02/09858
`
`- 86 -
`
`clarity with pale brawn in color, the solid was peeled
`
`off from the stainless steel round tray, there was
`
`obtained 9.8 g (yield: 98%) of _glassy state of
`
`aripiprazole anhydride. The obtained glassy state
`
`5 product was characterized by having no significant peak
`
`observed in a powder X-ray determination. (cf. Figure
`
`31) .
`
`According to the thermogravimetric/
`
`·differental thermal analysis (heating rate: 5°C/
`
`10 minute), as shown in Figure 30, an exothermic peak of
`
`type B crystals of aripiprazole anhydride was observed
`
`at around 86.5°C. While, an endothermic peak of type B
`
`crystals of aripiprazole anhydride owing to melting was
`
`observed at around 140.l°C.
`
`15 b)
`
`When the glassy state of aripiprazole
`
`anhydride obtained in Example 16-a) were charged in a
`
`sealed vessel and left to stand at room temperature for
`
`about 6 months, then type G crystals of aripiprazole
`
`anhydride having white in color was obtained by
`
`20 changing the color from pale brown (25 g, yield: 100%) .
`
`Melting point: 138 to 139°C.
`
`The type G crystals of aripiprazole anhydride
`
`had an endothermic curve which was substantially
`
`identical to the thermogravimetric/differential thermal
`
`25 analysis (heating rate: 5°C/min.) endothermic curve
`
`shown in Figure 26, more particulaly, it has an
`
`endothermic peak around 141.0°C and an exothermic peak
`
`around 122.7°C.
`
`623 of 1328
`
`Alkermes, Ex. 1076
`
`

`
`WO 03/026659
`
`PCT/JP02/09858
`
`- 87 -
`
`The type G crystals of aripiprazole anhydride
`
`obtained as above exhibited an 1H-NMR spectrum which was
`
`substantially identical to the 1H-NMR spectrum (DMSO-d 6 ,
`TMS) shown in Figure 27. Specifically, it has
`
`5 characteristic peaks at 1.55 - 1.63 ppm (m, 2H), 1.68 -
`
`1.78 ppm (m, 2H), 2.35 - 2.46 ppm (m, 4H), 2.48 - 2.56
`
`ppm (m, 4H + DMSO}, 2.78 ppm (t, J=7.4 Hz, 2H), 2.97
`
`ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H),
`
`6.43 ppm (d, J=2.4 Hz, lH), 6.49 ppm {dd, J=8.4 Hz,
`
`10
`
`J=2.4 Hz, lH), 7.04 ppm (d, J=S.1 Hz, lH), 7.11 - 7.17
`
`ppm (m, lH), 7.28 - 7.32 ppm (m, 2H) and 10.00 ppm {s,
`
`lH) .
`
`The type G crystals of aripiprazole anhydride
`
`obtained as above had a powder X-ray diffraction
`
`15
`
`spectrum which was substantially identical to the
`
`powder X-ray diffraction spectrum shown in Figure 28.
`Specifically, it has characteristic peak at 20 = 10.1°,
`
`12.8°, 15.2°, 17.0°, 17.5°, 19.1°, 20.1°, 21.2°, 22.4°,
`
`2 3 _, 3 °, 2 4.

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