US20040058935A1 - Low hygroscopic aripiprazole drug substance and processes for the preparation thereof - Google Patents
Low hygroscopic aripiprazole drug substance and processes for the preparation thereof Download PDFInfo
- Publication number
- US20040058935A1 US20040058935A1 US10/333,244 US33324403A US2004058935A1 US 20040058935 A1 US20040058935 A1 US 20040058935A1 US 33324403 A US33324403 A US 33324403A US 2004058935 A1 US2004058935 A1 US 2004058935A1
- Authority
- US
- United States
- Prior art keywords
- aripiprazole anhydride
- aripiprazole
- anhydride crystals
- crystals
- solid oral
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
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Definitions
- FIG. 13 shows a thermogravimetric/differential thermal analysis endothermic curve of the type D crystals of aripiprazole anhydride obtained in Example 12 or Example 13.
- FIG. 21 shows an IR spectrum of the type E crystals of aripiprazole anhydride obtained in Example 14.
- Hydrate A defined according to one or more of the embodiments described herein wherein said Hydrate is made by a process as described herein.
- aripiprazole drug substance of low hygroscopicity is provided.
- aripiprazole drug substance of low hygroscopicity wherein said drug substance is Aripiprazole Anhydride Crystals B and will not substantially convert to a hydrous form of aripiprazole when properly stored even for an extended period.
- said Aripiprazole Anhydride Crystals B can be stored under a relative humidity (RH) of 60% and at a temperature of 25° C., even for a period not less than 4 years.
- the mean particle size of the Aripiprazole Hydrate A obtained by milling should normally be 50 ⁇ m or less, preferably 30 ⁇ m or less. Mean particle size can be ascertained by the particle size measurement method described hereinafter.
- the Aripiprazole Anhydride Crystals B of the present invention can be prepared with certainty by heating Aripiprazole Hydrate A for about 18 hours at 100° C., and then heating it for about 3 hours at 120° C.
- the Aripiprazole Anhydride Crystals B of the present invention can also be obtained if the heating time is extended still further, but this may not be economical.
- Aripiprazole Anhydride Crystal B can be also obtained the following process.
- the present invention relates to aripiprazole anhydride crystals (hereinafter referred to as “type E crystals of aripiprazole anhydride”) having the following physicochemical properties (11) to (14):
- the present invention relates a process for preparing aripiprazole anhydride crystals stated in the aforementioned item 2, characterized by recrystallizing from toluene.
- the present invention relates to a process for preparing aripiprazole anhydride crystals stated in the aforementioned item 4, characterized by heating a suspension of aripiprazole anhydride crystals in acetone.
- the present invention relates to a pharmaceutical solid oral preparation obtained by drying a pharmaceutical solid oral preparation comprising conventional Aripiprazole Hydrate Crystals and one or more pharmaceutically acceptable carriers at 70 to 100° C., and the pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes.
- Type C crystals of aripiprazole anhydride of the present invention have the following physicochemical properties (1) to (5):
- Aripiprazole anhydride used as the raw material may be conventional aripiprazole anhydride crystals, for example, type-I crystals of aripiprazole anhydride, type-II crystals of aripiprazole anhydride crystals and the like, and these anhydrides may be either purified products or crude materials.
- Type D crystals of aripiprazole anhydride of the present invention is prepared, for example, by recrystallization of aripiprazole anhydride from toluene. Specifically, an aripiprazole anhydride is added to toluene, further heated and dissolved, then thus obtained solution is cooled. By such procedures, type D crystals of aripiprazole anhydride of the present invention is separated out as crystals in toluene.
- type D crystals of aripiprazole may be added as a seed crystal to said solution. Further, the seed crystal may be formed by cooling gradually said solution being obtained by heating and dissolving. In the presence of the seed crystal, type D crystals of aripiprazole anhydride may be separated out.
- type B crystals of aripiprazole anhydride, type C crystals of aripiprazole anhydride, type D crystals of aripiprazole anhydride, type E crystals of aripiprazole anhydride, or type G crystals of aripiprazole anhydride prepared in the present invention can be used as the raw materials for aripiprazole anhydrides.
- aripiprazole anhydrides can be used singly or in combination of at least 2 kinds thereof.
- Aripiprazole anhydride used as the raw material may be well-known aripiprazole anhydride crystals, for example, any one of type-I crystals of aripiprazole anhydride and type-II crystals of aripiprazole anhydride and the like, and these anhydrides may be either purified products or crude materials.
- aripiprazole anhydride crystals which are the raw material for preparing the Aripiprazole Anhydride Crystals B to G of the present invention are prepared for example by Method a or b below.
- the powder x-ray diffraction pattern was measured at room temperature using a Cu Ka filled tube (35 kV 20 mA) as the x-ray source with a wide-angle goniometer, a 1° scattering slit, an 0.15 mm light-intercepting slit, a graphite secondary monochromator and a scintillation counter. Data collection was done in 2 ⁇ continuous scan mode at a scan speed of 5°/minute in scan steps of 0.02° in the range of 3° to 40°.
- TOSS method (TOSS is a program name of the apparatus) among CP/MAS method.
- Test tube made of zirconia, having the outside diameter of 7.5 mm, and inside capacity of 0.8 ml
- the Aripiprazole Hydrate A (powder) obtained above had infrared absorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and 784 cm ⁇ 1 on the IR (KBr) spectrum.
- the Aripiprazole Hydrate A (powder) obtained above had a weak peak at 71.3° C. in thermogravimetric/differential thermal analysis and a broad endothermic peak (weight loss observed corresponding to one water molecule) between 60-120° C.—clearly different from the endothermic curve of unmilled aripiprazole hydrate (see FIG. 6).
- the Aripiprazole Anhydride Crystals B obtained above had remarkable infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and 779 cm ⁇ 1 on the IR (KBr) spectrum.
- 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).
- 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).
- 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).
- the type D crystals of aripiprazole anhydride obtained above had an IR spectrum which was substantially identical to the IR (KBr) spectrum shown in FIG. 16. Specifically, it had characteristic infrared absorption bands at 2946, 1681, 1375, 1273, 1175 and 862 cm ⁇ 1 .
- test solutions obtained respectively from 10 minutes, 20 minutes, 30 minutes, 45 minutes and 60 minutes after the start of test are named as T10, T20, T30, T45 and T60.
- Example 19-a Tablet (30 mg) of — 79.8%
- Example 19-b Tablet (30 mg) of — 85.9%
- the intragranulation was placed in the blender and the Avicel® PH 200 and crospovidone added thereto and blended for five minutes. The magnesium stearate was then added and the mixture blended for an additional three minutes to form the final blend. Tablets compressed therefrom had a breaking force of 2.3 kP (3.5 SCU) and disintegrated in 10 seconds in 5 ml of water. The final blend formulation demonstrated excellent flow and was free of other problems such as chipping, capping and sticking. It has been found that utilizing Avicel® PH 102 for the intragranulation and Avicel® PH 200 for the extragranulation ingredient enhanced the quality of the resultant tablets.
- Intragranulation Mg. per Ingredient Percent w/w tablet Xylitol (300) Xylisorb 26 52 Avicel ® PH 102 12 24 Calcium Silicate (crystalline, alpha 33.35 66.7 triclinic) Hubersorb 600 NF 10 20 (amorphous calcium silicate) Crospovidone 3 6 Amorphous silica 2 4 Aspartame 2 4 Wild cherry flavor 0.15 0.3 Tartaric acid 2 4 Acesulfame K 2 4 Magnesium stearate 0.25 0.5 Total weight 92.75 185.5
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Priority Applications (20)
Application Number | Priority Date | Filing Date | Title |
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US11/790,606 US7910589B2 (en) | 2001-09-25 | 2007-04-26 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US11/790,603 US20070213343A1 (en) | 2001-09-25 | 2007-04-26 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US11/790,604 US8399469B2 (en) | 2001-09-25 | 2007-04-26 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US11/790,605 US8017615B2 (en) | 2001-09-25 | 2007-04-26 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US11/797,030 US20070203152A1 (en) | 2001-09-25 | 2007-04-30 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US11/797,024 US20070203151A1 (en) | 2001-09-25 | 2007-04-30 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US11/797,019 US20070203150A1 (en) | 2001-09-25 | 2007-04-30 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US13/067,750 US8642760B2 (en) | 2001-09-25 | 2011-06-23 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US13/067,838 US8901303B2 (en) | 2001-09-25 | 2011-06-29 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US13/217,636 US8703772B2 (en) | 2001-09-25 | 2011-08-25 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US13/350,117 US8580796B2 (en) | 2001-09-25 | 2012-01-13 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US13/476,758 US8901130B2 (en) | 2001-09-25 | 2012-05-21 | Low hygroscopic aripiprazole drug substance and processes for the preparation |
US13/476,773 US8703773B2 (en) | 2001-09-25 | 2012-05-21 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US13/749,753 US8993761B2 (en) | 2001-09-25 | 2013-01-25 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US14/049,777 US9359302B2 (en) | 2001-09-25 | 2013-10-09 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US14/624,595 US10150735B2 (en) | 2001-09-25 | 2015-02-18 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US15/149,522 US20160251315A1 (en) | 2001-09-25 | 2016-05-09 | Low hygroscopic aripiprazole drug substance and proce3sses for the preparation thereof |
US16/169,255 US20190225584A1 (en) | 2001-09-25 | 2018-10-24 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US16/718,281 US20200123110A1 (en) | 2001-09-25 | 2019-12-18 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US17/160,716 US20210395204A1 (en) | 2001-09-25 | 2021-01-28 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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JP2001290645 | 2001-09-25 | ||
JP2001348276 | 2001-11-14 | ||
CA 2379005 CA2379005A1 (en) | 2001-09-25 | 2002-03-27 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
PCT/JP2002/009858 WO2003026659A1 (en) | 2001-09-25 | 2002-09-25 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
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PCT/JP2002/009858 A-371-Of-International WO2003026659A1 (en) | 2001-09-25 | 2002-09-25 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
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US11/790,606 Division US7910589B2 (en) | 2001-09-25 | 2007-04-26 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US11/790,605 Division US8017615B2 (en) | 2001-09-25 | 2007-04-26 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US11/790,604 Division US8399469B2 (en) | 2001-09-25 | 2007-04-26 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US11/797,030 Division US20070203152A1 (en) | 2001-09-25 | 2007-04-30 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US11/797,024 Division US20070203151A1 (en) | 2001-09-25 | 2007-04-30 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US11/797,019 Division US20070203150A1 (en) | 2001-09-25 | 2007-04-30 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US13/350,117 Continuation US8580796B2 (en) | 2001-09-25 | 2012-01-13 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
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US11/790,605 Expired - Lifetime US8017615B2 (en) | 2001-09-25 | 2007-04-26 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US11/790,603 Abandoned US20070213343A1 (en) | 2001-09-25 | 2007-04-26 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
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US11/797,019 Abandoned US20070203150A1 (en) | 2001-09-25 | 2007-04-30 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
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US13/067,750 Expired - Lifetime US8642760B2 (en) | 2001-09-25 | 2011-06-23 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US13/067,838 Expired - Fee Related US8901303B2 (en) | 2001-09-25 | 2011-06-29 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US13/350,117 Expired - Lifetime US8580796B2 (en) | 2001-09-25 | 2012-01-13 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US13/476,758 Expired - Fee Related US8901130B2 (en) | 2001-09-25 | 2012-05-21 | Low hygroscopic aripiprazole drug substance and processes for the preparation |
US13/476,773 Expired - Lifetime US8703773B2 (en) | 2001-09-25 | 2012-05-21 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US13/749,753 Expired - Fee Related US8993761B2 (en) | 2001-09-25 | 2013-01-25 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US14/049,777 Expired - Fee Related US9359302B2 (en) | 2001-09-25 | 2013-10-09 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US14/624,595 Expired - Fee Related US10150735B2 (en) | 2001-09-25 | 2015-02-18 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US15/149,522 Abandoned US20160251315A1 (en) | 2001-09-25 | 2016-05-09 | Low hygroscopic aripiprazole drug substance and proce3sses for the preparation thereof |
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US16/718,281 Abandoned US20200123110A1 (en) | 2001-09-25 | 2019-12-18 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US17/160,716 Abandoned US20210395204A1 (en) | 2001-09-25 | 2021-01-28 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
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US11/790,603 Abandoned US20070213343A1 (en) | 2001-09-25 | 2007-04-26 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US11/790,606 Expired - Lifetime US7910589B2 (en) | 2001-09-25 | 2007-04-26 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US11/790,604 Expired - Lifetime US8399469B2 (en) | 2001-09-25 | 2007-04-26 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US11/797,019 Abandoned US20070203150A1 (en) | 2001-09-25 | 2007-04-30 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US11/797,030 Abandoned US20070203152A1 (en) | 2001-09-25 | 2007-04-30 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US11/797,024 Abandoned US20070203151A1 (en) | 2001-09-25 | 2007-04-30 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US13/067,750 Expired - Lifetime US8642760B2 (en) | 2001-09-25 | 2011-06-23 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US13/067,838 Expired - Fee Related US8901303B2 (en) | 2001-09-25 | 2011-06-29 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US13/350,117 Expired - Lifetime US8580796B2 (en) | 2001-09-25 | 2012-01-13 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US13/476,758 Expired - Fee Related US8901130B2 (en) | 2001-09-25 | 2012-05-21 | Low hygroscopic aripiprazole drug substance and processes for the preparation |
US13/476,773 Expired - Lifetime US8703773B2 (en) | 2001-09-25 | 2012-05-21 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US13/749,753 Expired - Fee Related US8993761B2 (en) | 2001-09-25 | 2013-01-25 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US14/049,777 Expired - Fee Related US9359302B2 (en) | 2001-09-25 | 2013-10-09 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US14/624,595 Expired - Fee Related US10150735B2 (en) | 2001-09-25 | 2015-02-18 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US15/149,522 Abandoned US20160251315A1 (en) | 2001-09-25 | 2016-05-09 | Low hygroscopic aripiprazole drug substance and proce3sses for the preparation thereof |
US16/169,255 Abandoned US20190225584A1 (en) | 2001-09-25 | 2018-10-24 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US16/718,281 Abandoned US20200123110A1 (en) | 2001-09-25 | 2019-12-18 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
US17/160,716 Abandoned US20210395204A1 (en) | 2001-09-25 | 2021-01-28 | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
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EP (6) | EP1927356B1 (no) |
JP (3) | JP3760264B2 (no) |
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SI (4) | SI1927356T1 (no) |
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WO (1) | WO2003026659A1 (no) |
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