WO2019120250A1 - Nouvelle forme cristalline d'hémitartrate de pimavansérine et procédé de préparation de la forme cristalline - Google Patents

Nouvelle forme cristalline d'hémitartrate de pimavansérine et procédé de préparation de la forme cristalline Download PDF

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WO2019120250A1
WO2019120250A1 PCT/CN2018/122359 CN2018122359W WO2019120250A1 WO 2019120250 A1 WO2019120250 A1 WO 2019120250A1 CN 2018122359 W CN2018122359 W CN 2018122359W WO 2019120250 A1 WO2019120250 A1 WO 2019120250A1
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crystal form
tartrate
crystal
hemi
solvent
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PCT/CN2018/122359
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English (en)
Chinese (zh)
Inventor
叶辉青
黄翠
雷鑫
陈勇
黄芳芳
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广东东阳光药业有限公司
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Priority to CN201880065490.XA priority Critical patent/CN111201218A/zh
Publication of WO2019120250A1 publication Critical patent/WO2019120250A1/fr

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4

Definitions

  • the present invention belongs to the field of medicinal chemistry, and in particular, the present invention relates to N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methyl) Crystal form of propoxy)-phenylmethyl)urea hemi-tartrate and preparation method thereof.
  • Pimavanserin N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy)-phenylmethyl)urea, aka Pimavanserin, CAS No. 706779-91-1, is an atypical antipsychotic used to improve the psychotic symptoms of Parkinson's disease, often in the form of pimacillin hemi-tartrate.
  • the structure of Pimavanserin hemi-tartrate is as shown in formula (1):
  • Patent application WO2008144326 or patent CN101035759B reports Form A, Form B, Form C, Form D, Form E, Form F and amorphous of pemasiline hemi-tartrate, and Piperazine is reported by CN107021917.
  • Tartrate salt form II and pemasiline tartrate are amorphous
  • CN106916098 reports the hemihydrate of pemasiline monotartrate
  • CN104961671 reports pimezerine tartrate form I.
  • Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in physical properties such as appearance, fluidity, solubility, storage stability, bioavailability, etc., and may have great differences, which may affect drug storage, application, stability, and efficacy. Different effects are produced; in order to obtain an effective crystal form suitable for production or for pharmaceutical preparations, it is necessary to conduct a comprehensive examination of the crystallization behavior of the drug to obtain a crystal form that satisfies the production requirements.
  • the invention obtains a new crystal form of the compound by conducting a large number of experimental studies on the pimacillin hemi-tartrate compound, and the new crystal form has high solubility, good stability, low wettability, simple preparation process and the like. Superiority, superior in industrial production; research on its crystal form provides opportunities to improve the overall performance of the pharmaceutical product (such as easy synthesis or treatment, improve dissolution or improve stability and shelf life), while expanding the formulation
  • the variety of materials available to scientists when designing the drug is critical to drug development.
  • the present invention aims to solve at least one of the technical problems in the related art to some extent. To this end, it is an object of the present invention to provide a new crystalline form of pembelline hemi-tartrate and a process for the preparation thereof which have good solubility and stability.
  • the invention provides a new crystalline form of pemasiline hemi-tartrate, referred to as Form VI.
  • the novel crystal form of the present invention as described above is studied, and the crystal form VI has good properties in terms of stability, wettability, and the like, and can be used for preparation of a pharmaceutical preparation.
  • the crystal form VI is characterized by having an X-ray powder diffractometer using Cu-K ⁇ radiation having diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 5.37, 7.02, 10.62, 14.07, 16.79, 18.66, 20.60, 21.65.
  • the Form VI has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle by using an X-ray powder diffractometer of Cu-K ⁇ radiation: 9.44, 13.14, 15.71, 17.71 , 19.61, 21.11, 23.23, 25.00, 28.19.
  • the Form VI has a diffraction peak at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle by using an X-ray powder diffractometer of Cu-K ⁇ radiation: 5.37, 7.02, 9.44, 10.62 , 13.14, 14.07, 15.71, 16.79, 17.71, 18.66, 19.61, 20.60, 21.11, 21.65, 23.23, 25.00, 28.19.
  • the X-ray powder diffraction pattern of the pimacillin hemi-tartrate salt form VI is shown in Figure 1, wherein the relative intensity of the peak at 2 ⁇ of 18.66 degrees is greater than 70%, or greater than 80. %, or greater than 90%, or greater than 99%.
  • the Form VI has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG.
  • the differential scanning calorimetry curve (DSC) of the Form VI has an endothermic peak at 70 ° C - 100 ° C and 165 ° C - 175 ° C, wherein the sample is dried to 70 ° C - The peak at 100 °C has a slight effect.
  • the Form VI has a differential scanning calorimetry curve (DSC pattern) as shown in FIG.
  • thermogravimetric analysis curve (TGA) of Form VI shows weight loss between 25 ° C and 100 ° C with a weight loss of about 2.55%.
  • the Form VI has a thermogravimetric analysis curve (TGA map) substantially as shown in FIG.
  • the urea hemi-tartrate crystal form VI can be used for the preparation of an antipsychotic pharmaceutical preparation or a pharmaceutical composition, such as a pharmaceutical preparation or a pharmaceutical composition for improving psychotic symptoms of Parkinson's disease.
  • Another object of the present invention is to provide a therapeutically effective amount of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropane).
  • a pharmaceutical composition of oxy)-phenylmethyl)urea hemi-tartrate salt form VI and a pharmaceutically acceptable adjuvant or excipient is provided.
  • a therapeutically effective amount of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy)-phenyl is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation which can be prepared in a manner well known in the pharmaceutical art.
  • the pharmaceutical composition or formulation can be used to treat a psychiatric disorder, such as for improving psychotic symptoms of Parkinson's disease.
  • the crystal form VI provided by the invention has better stability than the crystal form A of CN101035759B.
  • a more stable crystal form is important for improving the quality of the drug.
  • the crystal form VI provided by the invention has lower hygroscopicity, is not easy to deliquesce under high humidity conditions, and is convenient for long-term storage and placement of the drug.
  • the crystal form C of the patent CN101035759B is a relatively stable crystal form, the preparation process is complicated and difficult to operate. It is difficult to obtain the crystal form C with high crystal purity under the conventional crystallization process, and the raw material requirement in the process production. Higher, the moisture, dissolving, and related substances in the raw materials will have a great influence on the preparation of the crystalline form C, and it is necessary to add a seed crystal, and it takes a long time to obtain a pure crystalline form C.
  • the crystal form VI provided by the invention is simpler and easier to operate, does not require seed crystals in production, is more favorable for industrial production, and has good crystal form stability.
  • the invention provides a process for the preparation of the picometholin hemi-tartrate salt form VI described above.
  • a method for preparing the crystalline form VI of pemasiline hemi-tartrate comprises: feeding the crude pimacillin hemi-tartrate into a mixed solvent containing a good solvent and a poor solvent, heating to 25 ° C to 50 ° C, and dissolving completely The temperature was lowered to -10 ° C to 40 ° C, crystals were precipitated, crystals were collected, and the solvent was removed to obtain a crystal form VI. In some embodiments, after the dissolution is completed, the temperature is lowered to 0 ° C to 20 ° C, crystals are precipitated, crystals are collected, and the solvent is removed to obtain Form VI.
  • the crude pemasiline hemi-tartrate may be in any form of pemasiline hemi-tartrate, including, but not limited to, Form A, Form B, Form C, Form D disclosed in Patent Application WO2008144326 or Patent CN101035759B. , Form E, Form F or amorphous.
  • the good solvent is water.
  • the poor solvent is one or more of methanol and ethanol. In some embodiments, the poor solvent is methanol or ethanol.
  • the mass is calculated in grams (g). When the volume is calculated in milliliters (mL), the mass to volume ratio of the crude product of the pimacillin hemi-tartrate to the solvent is 1:1 to 1:50, more preferably 1:1. 1:10.
  • the mixed solvent is water and ethanol. In some embodiments, the volume ratio of water to ethanol in the mixed solvent is from 1:10 to 10:1. In some embodiments, the volume ratio of water to ethanol in the mixed solvent is from 4:1 to 8:1.
  • a method of preparing the pimacillin hemi-tartrate salt form VI comprises: piperazine color penta-tartrate crystal form A, Form B, Form C, Form D, Form E
  • One or more of the crystalline form F or the amorphous form (disclosed in the patent application WO2008144326 or the patent CN101035759B) is put into a mixed solvent containing a good solvent and a poor solvent, and the suspension is equilibrated, the crystal is collected, and the solvent is removed to obtain a crystal form.
  • the good solvent is water.
  • the poor solvent is methanol, ethanol or a combination thereof. The mass is calculated in grams (g).
  • the mass to volume ratio of the crude product of the pimacillin hemi-tartrate to the solvent is 1:1 to 1:50; more preferably 1:1. 1:10.
  • the mixed solvent is water and ethanol. In some embodiments, the volume ratio of water to ethanol in the mixed solvent is from 1:10 to 10:1. In some embodiments, the volume ratio of water to ethanol in the mixed solvent is from 4:1 to 8:1. In some embodiments, the mixed solvent is water and methanol. In some embodiments, the volume ratio of water to methanol in the mixed solvent is from 1:10 to 10:1. In some embodiments, the volume ratio of water to methanol in the mixed solvent is 4:1 or 8:1.
  • the "crystal form” of the present invention may be present in the sample at 0.0001% to 100%, and thus, as long as the sample contains even a trace amount of, for example, more than 0.0001%, more than 0.001%, more than 0.001%, or more than 0.01%, as described in the present invention.
  • the “crystal form” should be understood to fall within the scope of the present invention.
  • the present invention tests various parameters and conducts the crystal form on a sample containing a substantially "some crystal form”. Characterization and identification.
  • the differential scanning calorimetry (DSC) of the crystal form has experimental errors and is slightly affected by the degree of dryness of the sample, between one machine and another, and between one sample and another.
  • the position and peak value of the thermal peak may be slightly different.
  • the value of the experimental error or difference may be less than or equal to 10 ° C, or less than or equal to 5 ° C, or less than or equal to 4 ° C, or less than or equal to 3 ° C, or less than or equal to 2 ° C, or less than It is equal to 1 ° C, so the value of the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.
  • RH is a relative humidity
  • Figure 1 X-ray powder diffraction (XRPD) pattern of Form VI of the compound of formula (1).
  • FIG. 1 Differential scanning calorimetry (DSC) curve for Form VI of the compound of formula (1).
  • reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
  • ml or mL means milliliter
  • ul means microliter
  • mg means milligram
  • the weight gain of the crystal form A at 80% relative humidity and the weight gain of 95% relative humidity are 10.73% and 28.47%, respectively, thereby showing that the form VI has a lower index than the form A. Wet.
  • the crystal form VI and the crystal form A or the crystal form C sample of the present invention were respectively placed under high humidity (98% RH) conditions for 3 days, and the experimental results are shown in Table 3 below.
  • the crystal form VI was separately placed at a high temperature of 60 ° C and the humidity condition was not controlled, 90% RH ⁇ 2% RH condition and ultraviolet light 4500 Lux 1.7 w * h / m 2 , under illumination conditions of about 25 ° C, respectively, in 5 days, XRPD was detected for 10 days and 15 days, and the results are shown in Table 5 below.
  • the crystal form VI was placed in a PE (polyethylene bag) and an aluminum foil package, and allowed to stand under an accelerated condition of 40 ° C and 75% RH for 3 months, and the XRPD was examined.
  • the results are shown in Table 6 below.
  • X-ray powder diffraction (XRPD) patterns were collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with a transflective sample stage equipped with an automated 3*15 zero background sample holder.
  • the radiation source used is (Cu, k ⁇ , K ⁇ 1 1.540598; K ⁇ 2 1.544426; K ⁇ 2/K ⁇ 1 intensity ratio: 0.50), wherein the voltage is set at 45KV, the current is set at 40 mA.
  • X-ray beam divergence, ie the effective size of the X-ray constraint on the sample is 10 mm. Using ⁇ - ⁇ In the continuous scan mode, an effective 2 ⁇ range of 3° to 40° is obtained.
  • DSC measurements were performed using TA Instruments TM Model Q2000 sealing disk apparatus.
  • the sample (about 1-3 mg) was weighed in an aluminum pan, capped with a Tzero, accurately recorded to one hundredth of a milligram, and the sample was transferred to an instrument for measurement.
  • the instrument was purged with nitrogen at 50 mL/min. Data were collected at room temperature to 300 ° C at a heating rate of 10 ° C/min. The endothermic peak was drawn down and the data was analyzed and displayed using TA Universal Analysis.
  • TGA measurements were performed in a TA Instruments TM model Q500. The operation steps are empty and peeled, take about 10 mg of the solid sample, and peel it in the peeled open space. After the instrument was operated stably, data was collected at room temperature to 300 ° C at a heating rate of 10 ° C / min under a nitrogen purge, and the spectra were recorded.

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Abstract

La présente invention se rapporte au domaine de la chimie pharmaceutique, et concerne une forme cristalline VI d'hémitartrate de pimavansérine ainsi qu'un procédé de préparation de la forme cristalline. Le motif XRPD de la forme cristalline comprend les pics caractéristiques suivants à 2θ (avec une plage d'erreur de ± 0,2 degrés) : 5,37, 7,02, 10,62, 14,07, 16,79, 18,66, 20,60 et 21,65. La forme cristalline a une bonne solubilité et une bonne stabilité, est bénéfique pour des opérations dans des processus de stockage, de transfert et de production, et peut être préparée dans une préparation pharmaceutique.
PCT/CN2018/122359 2017-12-22 2018-12-20 Nouvelle forme cristalline d'hémitartrate de pimavansérine et procédé de préparation de la forme cristalline WO2019120250A1 (fr)

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Citations (8)

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Publication number Priority date Publication date Assignee Title
CN101035759B (zh) * 2004-09-27 2011-06-15 阿卡蒂亚药品公司 N-(4-氟苄基)-n-(1-甲基哌啶-4-基)-n’-(4-(2-甲基丙氧基)苯基甲基)脲及其酒石酸盐的合成和晶形
CN104961671A (zh) * 2014-09-05 2015-10-07 苏州晶云药物科技有限公司 N-(4-氟苄基)-n-(1-甲基哌啶-4-基)-n’-(4-(2-甲基丙氧基)-苯基甲基)脲半酒石酸盐的晶型及其制备方法
CN105924381A (zh) * 2015-12-18 2016-09-07 重庆两江药物研发中心有限公司 一种哌马色林晶型c的制备方法
CN106008323A (zh) * 2016-05-30 2016-10-12 成都百裕制药股份有限公司 一种制备哌马色林半酒石酸盐晶型c的方法
CN106699637A (zh) * 2015-11-17 2017-05-24 重庆医药工业研究院有限责任公司 一种匹马色林单酒石酸盐晶型及其制备方法
CN106916098A (zh) * 2017-03-07 2017-07-04 江苏艾立康药业股份有限公司 一种哌马色林单酒石酸盐半水合物及制备方法
CN106946764A (zh) * 2017-05-11 2017-07-14 成都百裕制药股份有限公司 一种制备哌马色林半酒石酸盐晶型b的方法
CN107021917A (zh) * 2016-02-02 2017-08-08 江苏恩华药业股份有限公司 哌马色林半酒石酸盐的新晶型及其制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105859608B (zh) * 2016-05-27 2018-12-28 成都百裕制药股份有限公司 一种制备哌马色林半酒石酸盐晶型b的方法

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101035759B (zh) * 2004-09-27 2011-06-15 阿卡蒂亚药品公司 N-(4-氟苄基)-n-(1-甲基哌啶-4-基)-n’-(4-(2-甲基丙氧基)苯基甲基)脲及其酒石酸盐的合成和晶形
CN104961671A (zh) * 2014-09-05 2015-10-07 苏州晶云药物科技有限公司 N-(4-氟苄基)-n-(1-甲基哌啶-4-基)-n’-(4-(2-甲基丙氧基)-苯基甲基)脲半酒石酸盐的晶型及其制备方法
CN106699637A (zh) * 2015-11-17 2017-05-24 重庆医药工业研究院有限责任公司 一种匹马色林单酒石酸盐晶型及其制备方法
CN105924381A (zh) * 2015-12-18 2016-09-07 重庆两江药物研发中心有限公司 一种哌马色林晶型c的制备方法
CN107021917A (zh) * 2016-02-02 2017-08-08 江苏恩华药业股份有限公司 哌马色林半酒石酸盐的新晶型及其制备方法
CN106008323A (zh) * 2016-05-30 2016-10-12 成都百裕制药股份有限公司 一种制备哌马色林半酒石酸盐晶型c的方法
CN106916098A (zh) * 2017-03-07 2017-07-04 江苏艾立康药业股份有限公司 一种哌马色林单酒石酸盐半水合物及制备方法
CN106946764A (zh) * 2017-05-11 2017-07-14 成都百裕制药股份有限公司 一种制备哌马色林半酒石酸盐晶型b的方法

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