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WO2006077584A2 - Nouvelles formes cristallines d'aripiprazole - Google Patents

Nouvelles formes cristallines d'aripiprazole Download PDF

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Publication number
WO2006077584A2
WO2006077584A2 PCT/IL2006/000076 IL2006000076W WO2006077584A2 WO 2006077584 A2 WO2006077584 A2 WO 2006077584A2 IL 2006000076 W IL2006000076 W IL 2006000076W WO 2006077584 A2 WO2006077584 A2 WO 2006077584A2
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Prior art keywords
aripiprazole
crystalline
depicted
aripiprazole form
further characterized
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Ceased
Application number
PCT/IL2006/000076
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English (en)
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WO2006077584A3 (fr
Inventor
Itai Adin
Carmen Iustain
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Wavelength Pharmaceuticals Ltd
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Chemagis Ltd
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    • 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
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2

Definitions

  • the present invention relates to solid state chemistry and more particularly to novel crystalline forms of Aripiprazole and to processes for their preparation.
  • Aripiprazole (Compound 1 below), also known by its chemical names 7-(4-(4- (2,3-dichlorophenyl)-l-piperazinyl)-butoxy)-3,4-dihydro carbostyril or 7-(4-(4-(2,3- dichlorophenyl)-l-piperazinyl)-butoxy)-3,4-dihydro-2(li ⁇ )-quinolinone, is an atypical antipsychotic agent useful for the treatment of schizophrenia.
  • Aripiprazole has shown efficacy in acutely relapsed and longer term schizophrenia and schizoaffective disorder.
  • Aripiprazole is marketed in the United States as AbilityTM by the Bristol-Myers Squibb Company.
  • U.S. Patent No. 5,006,528 The synthetic route disclosed in U.S. Patent No. 5,006,528 includes a crystallization step from ethanol. The reported melting point of the resulting crystals was 139-139.5 0 C.
  • U.S. Patent Application No. 2004/0058935 (hereinafter the '935 application) provides new crystalline modifications of Aripiprazole, including a hydrated form, and some anhydrous modifications. It is stated in the '935 application that Aripiprazole anhydride crystals exist as type I and type II crystals; the type I can be prepared by recrystallization of Aripiprazole from an ethanol solution, or by heating Aripiprazole hydrate at 80°C; and the type II crystals of Aripiprazole anhydride can be prepared by heating the type I crystals of Aripiprazole anhydride at 130° C to 140°C for 15 hours.
  • Aripiprazole is obtained as a highly hygroscopic product.
  • Hygroscopic solids might change their physical and chemical characteristics due to the increased content of water; hence hygroscopicity should be avoided in pharmaceutical products.
  • Table 1 presents the various crystalline forms of Aripiprazole, preparation procedures and some characteristic XRPD peaks thereof, as taught in the '935 application.
  • Aripiprazole form XII is prepared inter alia by crystallization from ethanol (see example 5 in the '835 application), affording "a dry Aripiprazole crystalline form". Noteworthy, ethanol solvates which are the object of the present invention are not mentioned in the '835 application.
  • Application WO 2005/009990 discloses Aripiprazole forms III, IV and V, and application US 2005/0277650 discloses a crystalline hydrate of Aripiprazole and a process of preparing this hydrate form.
  • the present invention provides a novel crystalline form of Aripiprazole, referred to herein as Aripiprazole form AETl.
  • Aripiprazole form AETl This unique form is a stable ethanol hemi-solvate, containing about 5 ⁇ 2 weight percents ethanol.
  • Aripiprazole form AETl undergoes a transition to Aripiprazole form B (disclosed in the '935 application), which involves loss of ethanol.
  • Aripiprazole form AETl is produced by crystallization from ethanol, with or without further treatment. That is, upon crystallization, the filtered crystals can be left in the open air, so as to allow residual amount of ethanol to freely evaporate, or, alternatively, can be gently dried, optionally under reduced pressure, at relatively low temperature (e.g., not exceeding 50 0 C).
  • the present invention provides a novel crystalline form of Aripiprazole, referred to herein as Aripiprazole form AETH.
  • Aripiprazole form AETH This unique form is a stable ethanol solvate containing about 2-3 % ethanol, which corresponds to an Aripiprazole: ethanol ratio of 4:1.
  • Aripiprazole form AETH is obtained by heating Aripiprazole form AETl to temperatures below the minimum temperature of the transition of Aripiprazole form AETl to Aripiprazole form B, e.g., lower than 100 0 C, more preferably lower than 90 0 C, and even more preferably lower than 80 0 C.
  • the observed melting point of Aripiprazole form AETH is about 140 0 C, due to the phase transition to Aripiprazole form B during the melting point measurement procedure.
  • the two ethanol solvates of Aripiprazole namely Aripiprazole form AETl and Aripiprazole form AETH exhibit extended stability, as depicted in figure 9 and Table 5.
  • the data of the experiments demonstrate that Aripiprazole form AETH has better stability, which makes this form most suitable for pharmaceutical compositions.
  • the present invention provides additional novel crystalline forms of Aripiprazole, referred to herein as forms AMI and AM2. Surprisingly, it was found that crystallization from methanol provides solvated forms of Aripiprazole containing either 1 or 2 mole equivalents of methanol per one mole of
  • Aripiprazole form AM2 was obtained only once, using the same method of obtaining form AMI but without drying the crystals, and it was characterized by using the traditional methods. It produces unique powder diffraction pattern, and unique
  • Aripiprazole form AM2 is significantly different from the related form AMI.
  • Aripiprazole form AM2 is thermodynamically less stable than form AMI at room temperature, and is spontaneously transformed into Aripiprazole form AMI after few weeks. Fast transformation of Aripiprazole form AM2 to form
  • AMI was achieved by heating Aripiprazole form AM2 at a temperature higher than room temperature.
  • Figure 1 Powder X-ray diffraction pattern of Aripiprazole form AETl.
  • Figure 2 Infra-red spectrum of Aripiprazole form AETl .
  • Figure 6 Infra-red spectrum of Aripiprazole form AETH.
  • Figure 7 DSC curve of Aripiprazole form AETH.
  • Figure 11 Infra-red spectrum of Aripiprazole form AM2.
  • Figure 12 DSC curve of Aripiprazole form AM2.
  • Figure 14 Powder X-ray diffraction pattern of Aripiprazole form AMI.
  • FIG 16 DSC curve of Aripiprazole form AMI .
  • Figure 17 TGA curve of Aripiprazole form AMI .
  • Aripiprazole form AETl differs from the crystalline form disclosed in the '935 application, which is a hydrate obtained by crystallization from a wate ⁇ ethanol mixture containing significant amounts of water, e.g., ethanol:water ratio of 8:2.
  • Aripiprazole form AETl produces unique powder X-ray diffraction pattern, presented in Figure 1 and in Table 3 below.
  • the diffraction peaks at 8.7, 10.2, 12.6, 18.1, 19.6 and 24.5 ⁇ 0.2 degrees 2 ⁇ are most characteristic of this form.
  • Aripiprazole form AETl further produces a unique infra-red spectrum, presented in Figure 2.
  • the pattern created by the bands in the range of 1000-1200 cm 1 is most characteristic of this form.
  • Aripiprazole form AETl is produced by crystallization from ethanol, with or without further treatment. That is, upon crystallization, the filtered crystals can be left in the open air, so as to allow residual amount of ethanol to freely evaporate, or, alternatively, can be gently dried, optionally under reduced pressure, at relatively low temperature (e.g., not exceeding 50 0 C).
  • Aripiprazole form AETl is an ethanol hemi-solvate, containing about 5 ⁇ 2 weight percents ethanol. Upon heating to about 100 0 C, Aripiprazole form AETl undergoes a transition to form B (disclosed in the '935 application), which involves dissociation of ethanol.
  • the observed melting point of Aripiprazole form AETl is about 139-140 0 C, which is similar to the reported melting point of the crystals obtained from ethanol in U.S. Patent No. 5,006,528. According to the DSC and TGA curves of Aripiprazole form AETl, it may be taught that this melting occurs after a phase transition during which ethanol is emitted and a crystalline form similar to Aripiprazole form B is obtained. A similar phenomenon is observed for the hydrous form, which explains the similarity in the observed melting points, since the discharge of solvents is usually not observed during traditional melting point measurements.
  • the dry Aripiprazole form B may be obtained by heating Aripiprazole form
  • Aripiprazole form AETl was left for 24 hours in a desiccator at 60 0 C and 100 % relative humidity, with no significant record of weight change.
  • the present invention provides a novel crystalline form of Aripiprazole, referred to herein as Aripiprazole form AETH.
  • Aripiprazole form AETH This unique form is a stable novel ethanol solvate containing about 2-3 % ethanol, which corresponds to an Aripiprazole:ethanol ratio of 4:1.
  • the Aripiprazole form AETH produces unique powder X-ray diffraction pattern, presented in Figure 5 and in Table 4 below. The strong diffraction peaks at 8.6, 10.1, 11.0, 16.6, 18.1, 19.3, 19.6, 20.3, 22.1, 23.1 and 24.4 ⁇ 0.2 degrees 2 ⁇ are most characteristic of this form.
  • Table 4 - Aripiprazole form AETH Powder x-ray diffraction peak positions and intensities
  • Aripiprazole form AETH can be prepared by drying form AETl at a temperature lower than the transition temperature (about 100 0 C), preferably lower than 90 0 C, and more preferably at 80 0 C, during a time period longer than two hours.
  • Aripiprazole form AETH Upon heating to a temperature higher than 100 0 C, Aripiprazole form AETH undergoes a transition to Aripiprazole form B.
  • a related endothermic peak at about 95 ⁇ 5 0 C was observed in the DSC curve of this form, presented in Figure 7, followed by melting of the in-situ created Aripiprazole form B.
  • Aripiprazole Form C was not produced by further heating the DSC sample.
  • Form AETH was left for 24 hours in a desiccator at 60 0 C and 100 % relative humidity, with no significant record of weight changes.
  • the two ethanolate forms of Aripiprazole namely Aripiprazole form AETl and Aripiprazole form AETH exhibit extended stability, as depicted in figure 9.
  • Table 5 summarizes the stability tests which were carried out with Aripiprazole forms AETl and AETH, detailing the current stability results of the two Aripiprazole solvates at the experimental temperatures of 25 0 C and 3O 0 C.
  • Aripiprazole form AETH has better stability at the two experimental temperatures. There are changes in the XRPD spectra of the Aripiprazole form AETl although it still contains about 4% ethanol after six months.
  • Aripiprazole forms AM2 and AMI are further provided.
  • Aripiprazole form AM2 was obtained only once, using the same method of obtaining form AMI but without drying the crystals, hence form AM2 can be called a "disappearing polymorph", in analogy to the Ritonavir case.
  • Ritonavir is an anti-AIDS drug, manufactured and marketed by Abbott Laboratories, which was initially marketed as a sole polymorphic form. About two years after entering the market it was surprisingly discovered that several Ritonavir lots contained a second polymorphic material (which is now designated as form II) having reduced solubility, which forced Abbott Laboratories to withdraw the capsules from the market for almost a year and to introduce an oral solution instead. [See for example an article by S.L.Morissette et al., in Proceedings of the National Academy of Sciences of the United States of America, Vol. No. 5, 2180-2184 (2003)]. Aripiprazole form AM2 was characterized by using the traditional methods.
  • Aripiprazole form AM2 produces unique powder diffraction pattern, and unique DSC and TGA curves, typical of a solvated form (see, Figures 12 and 13).
  • the spectral data shows that Aripiprazole form AM2 is significantly different than the related form AMI.
  • Aripiprazole Form AM2 is thermodynamically less stable than form AMI at room temperature, and is spontaneously transformed into Aripiprazole form AMI after few weeks. Fast transformation of Aripiprazole form AM2 to form AMI was achieved by heating Aripiprazole form AM2 at a temperature higher than room temperature.
  • Aripiprazole form AM2 produces a unique powder X-ray diffraction pattern, presented in Figure 10 and in Table 6 below.
  • the strong diffraction peaks at 4.3, 8.5, 16.9, 19.2, 20.6 and 21.7 ⁇ 0.2 degrees 2 ⁇ are most characteristic of this form.
  • Aripiprazole form AM2 produces a unique infra-red spectrum, presented in Figure 11. The pattern created in the range of 750-900 cm "1 is most characteristic of this form.
  • Aripiprazole form AM2 is a solvate, containing about 13 % by weight of methanol (2:1 ratio methanol: Aripiprazole). Upon heating to 50-90 0 C, Aripiprazole form AM2 undergoes a transition to form AMI, which involves dissociation of one mole equivalent of methanol from the crystalline form.
  • the DSC curve of Aripiprazole form AM2, presented in Figure 12, shows two major peaks at the said temperature range: one sharp peak at abount 90 0 C and a second broad peak around 120-140 0 C, each related to the discharge of one mole equivalent of methanol.
  • Aripiprazole form B was not produced during the DSC measurement thereof.
  • Aripiprazole form AMI which produces unique powder diffraction pattern, presented in Figure 14 and in Table 7 below.
  • the diffraction peaks at 9.4, 10.6, 18.2, 18.5 and 24.3 ⁇ 0.2 degrees 2 ⁇ are most characteristic of this form.
  • Aripiprazole form AMI produces a unique infra-red spectrum, presented in Figure 15. The pattern created in the range of 950-1100 cm '1 is most characteristic of this form.
  • Aripiprazole form AMI can be produced by crystallization from methanol.
  • Aripiprazole form AMI is a mono-solvate containing about 6.5 ⁇ 1% by weight of methanol (1:1 ratio methanol :Aripiprazole).
  • methanol 1:1 ratio methanol :Aripiprazole
  • Aripiprazole form AMI undergoes a transition to form B, which involves dissociation of one mole equivalent of methanol therefrom.
  • Aripiprazole form AMI presented in Figure 16 shows a sharp endothermic peak around 110-120 0 C 5 related to the discharge of methanol, followed by melting of the in-situ created Aripiprazole forms B (140 0 C) and Aripiprazole form C (150 0 C).
  • Aripiprazole form AETl was left for 24 hours in a desiccator at 60 0 C and 100
  • Aripiprazole form AMI is stable at room temperature. Upon heating and/or vacuum drying it transforms into a crystalline modification similar to the Aripiprazole form B described above.
  • the novel crystalline forms of Aripiprazole can be efficiently formulated in pharmaceutical compositions and used for treating medical conditions, and particularly psychotic disorders such as schizophrenia, for which treatment with aripiprazole is beneficial. Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention, as delineated hereinabove and as claimed in the claims section below, finds experimental support in the following examples.
  • the novel crystalline forms of Aripiprazole have been characterized by powder X-ray diffraction, which produces a fingerprint of the particular crystalline form. Measurements of 2 ⁇ values are typically accurate to within ⁇ 0.2 degrees.
  • the novel crystalline forms of Aripiprazole described herein were further characterized by infra-red (IR) spectroscopy, run on Nicolet Furrier-transform infrared spectrometer model Avatar 360, with Omnic software version 5.2. All samples were run as KBr disks. The infra-red measurements are accurate to within 4 cm "1 .
  • the novel crystalline forms of Aripiprazole described herein have been further characterized by differential scanning calorimetry (DSC), run on TA instruments model QlOOO, with Universal software version 3.88. Samples were analyzed inside crimped 40 ⁇ l Aluminum pans. Heating rate for all samples was 10 °C/min.
  • the novel crystalline forms of Aripiprazole have been further characterized by thermogravimetric analysis, run on TA instruments model Q500, with universal software version 3.88. Samples were run inside platinum baskets at heating rate of 10 °C/min.
  • Aripiprazole (1.3 grams) was dissolved in 15 ml of ethanol. The solution was heated using an oil bath to reflux, and left to cool down to 25 0 C. The resulting crystals were left to dry inside the hood. 1.1 grams (85 % yield) of Aripiprazole form AETl were obtained.
  • Aripiprazole 4 grams was dissolved in 600 ml of methanol. The solution was heated, using an oil bath, to reflux, and left to cool down to 25 0 C. The resulting crystals were left to dry in a hood. 3.0 grams (75 % yield) of Aripiprazole from AMI were obtained.
  • Aripiprazole form AETl prepared as described in Example 1, was heated under vacuum to 80 0 C for about 24 hours.
  • Aripiprazole form B was obtained, having a powder X-ray diffraction pattern, as depicted in Figure 18.

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  • Organic Chemistry (AREA)
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Abstract

La présente invention concerne de nouvelles formes cristallines d'aripiprazole et leurs procédés de préparation.
PCT/IL2006/000076 2005-01-18 2006-01-18 Nouvelles formes cristallines d'aripiprazole Ceased WO2006077584A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7714129B2 (en) 2003-12-16 2010-05-11 Teva Pharmaceutical Industries Ltd. Methods of preparing anhydrous aripiprazole form II
CN102372672A (zh) * 2010-08-24 2012-03-14 重庆圣华曦药业股份有限公司 低吸湿性阿立哌唑晶体ⅳ、制备方法及其应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006053780A1 (fr) * 2004-11-18 2006-05-26 Synthon B.V. Solvates cristallins d'aripiprazole

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7714129B2 (en) 2003-12-16 2010-05-11 Teva Pharmaceutical Industries Ltd. Methods of preparing anhydrous aripiprazole form II
CN102372672A (zh) * 2010-08-24 2012-03-14 重庆圣华曦药业股份有限公司 低吸湿性阿立哌唑晶体ⅳ、制备方法及其应用
CN102372672B (zh) * 2010-08-24 2014-06-04 重庆圣华曦药业股份有限公司 低吸湿性阿立哌唑晶体iv、制备方法及其应用

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