WO2020244148A1 - Forme cristalline a de doramectine, forme cristalline b de doramectine et procédé de préparation associé - Google Patents

Forme cristalline a de doramectine, forme cristalline b de doramectine et procédé de préparation associé Download PDF

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Publication number
WO2020244148A1
WO2020244148A1 PCT/CN2019/117678 CN2019117678W WO2020244148A1 WO 2020244148 A1 WO2020244148 A1 WO 2020244148A1 CN 2019117678 W CN2019117678 W CN 2019117678W WO 2020244148 A1 WO2020244148 A1 WO 2020244148A1
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WIPO (PCT)
Prior art keywords
doramectin
crystal form
preparing
solvent
characteristic peaks
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PCT/CN2019/117678
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English (en)
Chinese (zh)
Inventor
李亚玲
吴燕子
孙元杰
王彪
张朋丽
栗栖凤
夏雪林
刘爱玲
李守军
Original Assignee
天津瑞普生物技术股份有限公司
瑞普（天津）生物药业有限公司
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Publication of WO2020244148A1 publication Critical patent/WO2020244148A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This application belongs to the technical field of veterinary medicine and chemical engineering crystallization, and specifically relates to doramectin crystal form A, crystal form B and preparation methods thereof.
  • Doramectin is a new generation of macrolide antiparasitic drugs developed by Pfizer in the United States in the 1990s. It is considered to be one of the most outstanding drugs among abamectins.
  • Doramectin is a sixteen-membered macrolide semi-synthetic antibiotic produced by a new strain of genetically recombined Streptomyces avermitilis by adding cyclohexanoic acid as a precursor substance. It belongs to the third generation.
  • Avermectin drugs are easily soluble in organic solvents, such as methanol, ethanol, acetone, 1,2-propylene glycol, ethyl acetate, dimethyl sulfoxide, and isopropyl acetate.
  • the structural formula is as follows:
  • Doramectin is a new, broad-spectrum antiparasitic drug, effective against gastrointestinal nematodes, lung nematodes, mites, ticks and wound maggots, etc. It is used for the treatment of ectoparasitic diseases such as livestock nematodes and mites, mainly applicable For cattle and pigs.
  • the different solid forms of pharmaceutical or veterinary compounds determine their different physical properties.
  • the difference in physical properties will have an impact on the preparation, processing, formulation or application of pharmaceutical or veterinary compounds.
  • Different crystal forms will cause its stability, solubility, dissolution rate, bulk density, fluidity, suspension stability, stability during grinding, vapor pressure, optical and mechanical properties, hygroscopicity, crystal size, filtration properties, dryness, density Physicochemical properties such as melting point, degradation stability, and stability to prevent conversion to other crystal forms have an important influence, which may cause different efficacy and bioavailability during use. Therefore, for solid medicines, the development of different solid forms is more conducive to choosing a suitable crystal form according to the characteristics of the pharmaceutical preparation.
  • Patent CN 109651465 A discloses that the organic solvents used in the crystallization process are ethyl acetate, ethanol, acetone, preferably ethyl acetate; but these solvents have relatively high solubility , Resulting in lower refined yield.
  • Patent CN 108976270A discloses a purification method that uses acetone/water recrystallization. Due to the high solubility of acetone, a small amount of water is added, and the yield is about 70%, resulting in low purification yield and high production cost.
  • Patent CN104693254A discloses a crystallization method of doramectin to obtain high-purity doramectin.
  • the recrystallization solvent is methanol, ethanol, acetone, isobutanol, isopropanol, or any mixed solvent thereof.
  • Patent CN 104418927 A discloses a purification method in which the crystallization solvent is an alcohol/water mixed solvent.
  • the alcohol aqueous solution has an alcohol content of more than 90% (V/V), preferably more than 95%, and the amount is 5-10 times (V/W) of the weight of the filter cake. Due to the large proportion of alcohol, the refining yield is low. None of the patents involved the study of crystal forms, which greatly restricted the use of this species in veterinary medicine.
  • This application provides a polymorph of doramectin and a preparation method thereof.
  • the obtained crystal form A and crystal form B have good stability, high purity, and good fluidity; the crystal yield obtained by the preparation process is good, which is suitable for industrial production. It overcomes the shortcomings of related technologies and provides more options for doramectin in the development of new dosage forms.
  • the X-ray powder diffraction pattern of the crystal form A ( Figure 1) at 2 ⁇ is 6.5 ⁇ 0.2°, 9.4 ⁇ 0.2°, 10.5 ⁇ 0.2°, 11.2 ⁇ 0.2°, 11.5 ⁇ 0.2°, 12.7 ⁇ 0.2°, 13.4 ⁇ 0.2°, 13.9 ⁇ 0.2°, 14.4 ⁇ 0.2°, 15.2 ⁇ 0.2°, 15.7 ⁇ 0.2°, 16.7 ⁇ 0.2°, 17.1 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.2 ⁇ 0.2°, 18.5 ⁇ 0.2°, 19.1 ⁇
  • the X-ray powder diffraction pattern of the crystal form B ( Figure 2) at 2 ⁇ is 4.4 ⁇ 0.2°, 6.1 ⁇ 0.2°, 6.3 ⁇ 0.2°, 8.7 ⁇ 0.2°, 9.3 ⁇ 0.2°, 10.4 ⁇ 0.2°, 10.7 ⁇ 0.2°, 11.0 ⁇ 0.2°, 11.2 ⁇ 0.2°, 11.5 ⁇ 0.2°, 12.5 ⁇ 0.2°, 13.3 ⁇ 0.2°, 13.8 ⁇ 0.2°, 14.2 ⁇ 0.2°, 14.4 ⁇ 0.2°, 16.9 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.2 ⁇ 0.2°, 18.5 ⁇ 0.2°, 18.9 ⁇ 0.2°, 19.8 ⁇ 0.2°, 21.4 ⁇ 0.2°, 22.0 ⁇ 0.2°, 22.5 ⁇ 0.2°, 26.8 ⁇ 0.2°, 28.1 ⁇ There are exclusive characteristic absorption peaks at 0.2°, 33.0 ⁇ 0.2°, and 45.1 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of doramectin crystal form A provided in this application is shown in FIG. 1.
  • the X-ray powder diffraction pattern of doramectin crystal form B provided in this application is shown in FIG. 2.
  • this application also provides a method for preparing doramectin crystal form A and crystal form B, the steps are as follows:
  • the crystallization equipment used can be a conventional crystallization kettle with stirring effect in this field.
  • the good solvent in step (1) is selected from one or more organic solvents such as halogenated hydrocarbons, alcohols, esters, ketones or tetrahydrofuran.
  • the good solvent in step (1) is selected from one or more of tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, acetone, isopropanol, n-butanol, methanol or ethanol.
  • the dosage ratio (m:v) of the doramectin to the good solvent in step (1) is 1:3-1:5.
  • Step (2) Concentrate under reduced pressure until the remaining liquid volume is 1-5 times the weight of the solid doramectin, preferably 2-3 times; the volume of the added poor solvent is 1-5 times the weight of the solid doramectin, preferably It is 1-2 times.
  • the poor solvent for preparing crystal form A in step (2) is selected from one or more of aliphatic hydrocarbon solvents, aromatic hydrocarbons, and ether solvents.
  • the poor solvent for preparing crystal form A in step (2) is selected from n-hexane, cyclohexane, n-heptane, diethyl ether, dimethyl ether, diisopropyl ether, petroleum ether, methyl tert-butyl One or more of ether and toluene.
  • the poor solvent for preparing crystal form A in step (2) is selected from one or more of n-hexane, n-heptane, petroleum ether, methyl tert-butyl ether, toluene, and acetonitrile.
  • the poor solvent for preparing crystal form B in step (2) is acetonitrile.
  • the thermal dissolution temperature in step (1) is 20-60°C;
  • step (2) The temperature reduction range of step (2) is -5-15°C, and the drying temperature is 30-80°C.
  • the refining process of this application is simple, easy to operate, and suitable for industrialized production.
  • the purity of doramectin crystals obtained by using this refining process is all above 99%, even up to 99.5%, which greatly improves the efficacy of the drug;
  • the polymorphic form obtained by the crystallization process has good stability, no crystal form transformation and no moisture absorption.
  • Figure 1 is an X-ray powder diffraction pattern of doramectin crystal form A prepared in Example 1 of the present application;
  • Figure 2 is an X-ray powder diffraction pattern of doramectin crystal form B prepared in Example 2 of the present application;
  • Example 3 is an X-ray powder diffraction pattern of doramectin crystal form A prepared in Example 3 of the present application;
  • Figure 4 is an HPLC chart of Example 1 of the doramectin crystal prepared by the application.
  • Fig. 5 is an HPLC chart of Example 2 of doramectin crystals prepared in this application;
  • Fig. 6 is an HPLC chart of the raw material doramectin in the examples of the present application.
  • X-ray powder diffraction (XRD) instrument Japanese Rigaku D/Max-2500: radiation source: copper target scanning at room temperature: scanning range: 2.0 ⁇ 50.0°, scanning rate: 8°/min, step size: 0.02 °;
  • Fig. 1 is an X-ray powder diffraction chart of the doramectin crystal form obtained in Example 1
  • Fig. 4 is an HPLC chart of purity detection. It can be seen from Figure 4 that the normalized purity of the main peak is 99.16%.
  • the XRD diffraction 2 ⁇ value 6.5°, 9.4°, 10.5°, 11.2°, 11.5°, 12.7°, 13.4°, 13.9°, 14.4°, 15.2°, 15.7°, 16.7°, 17.1 °, 17.6°, 18.2°, 18.5°, 19.1°, 19.8°, 21.3°, 21.8°, 22.3°, 22.7°, 25.3°, 27.2°, 30.4° have exclusive characteristic absorption peaks.
  • Example 1 obtained doramectin crystal form A.
  • Fig. 2 is an X-ray powder diffraction pattern of the doramectin crystal form obtained in Example 2, and Fig. 5 is an HPLC pattern of purity detection.
  • the 2 ⁇ values are 4.4°, 6.1°, 6.3°, 8.7°, 9.3°, 10.7°, 11.0°, 11.2°, 11.5°, 12.5°, 13.3°, 13.8°, 14.2° , 14.4°, 16.9°, 17.6°, 18.0°, 18.2°, 18.5°, 18.9°, 19.8°, 21.4°, 22.0°, 22.5°, 26.8°, 28.1°, 33.0°, 45.1° with exclusive characteristic absorption peak.
  • the normalized purity of the main peak is 99.54%.
  • Example 2 obtained doramectin crystal form B.
  • Example 3 obtained doramectin crystal form A.
  • the doramectin crystal form obtained in this application has no obvious changes in content, appearance and crystal form, and has good stability. It has no hygroscopicity and can be better applied to pharmaceutical preparations.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur un polymorphe de doramectine. Plus particulièrement, la présente invention concerne une forme cristalline A de doramectine, une forme cristalline B de doramectine et un procédé de préparation associé. Le polymorphe peut être obtenu par dissolution de doramectine dans un bon solvant organique, suivi par l'ajout d'un solvant médiocre pour précipiter les cristaux, refroidissement, filtrage et séchage. Le polymorphe de doramectine selon la présente invention présente des caractéristiques remarquables en termes de propriétés physiques et chimiques stables, d'une pureté élevée, d'une excellente fluidité, d'un excellent rendement du procédé de préparation et d'une aptitude à la production industrielle.
PCT/CN2019/117678 2019-06-05 2019-11-12 Forme cristalline a de doramectine, forme cristalline b de doramectine et procédé de préparation associé WO2020244148A1 (fr)

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CN201910484778.7 2019-06-05
CN201910484778.7A CN110256515A (zh) 2019-06-05 2019-06-05 多拉菌素晶型a、晶型b及其制备方法

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CN110256515A (zh) * 2019-06-05 2019-09-20 天津瑞普生物技术股份有限公司 多拉菌素晶型a、晶型b及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104418927A (zh) * 2013-08-29 2015-03-18 重庆乾泰生物医药有限公司 一种多拉菌素的分离纯化方法
CN108976270A (zh) * 2017-12-08 2018-12-11 北大方正集团有限公司 一种高纯度多拉菌素的制备方法
CN109651465A (zh) * 2019-01-17 2019-04-19 北大方正集团有限公司 一种多拉菌素的纯化工艺
CN110256515A (zh) * 2019-06-05 2019-09-20 天津瑞普生物技术股份有限公司 多拉菌素晶型a、晶型b及其制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104693254B (zh) * 2013-12-10 2018-03-27 重庆乾泰生物医药有限公司 一种多拉菌素的制备方法
CN104311611B (zh) * 2014-08-13 2017-01-18 广东东阳光药业有限公司 一种制备固态大环内酯的方法
US9643991B2 (en) * 2015-06-08 2017-05-09 Rotam Agrochem International Company Limited Process for preparing a novel crystalline form of emamectin benzoate and use the same

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104418927A (zh) * 2013-08-29 2015-03-18 重庆乾泰生物医药有限公司 一种多拉菌素的分离纯化方法
CN108976270A (zh) * 2017-12-08 2018-12-11 北大方正集团有限公司 一种高纯度多拉菌素的制备方法
CN109651465A (zh) * 2019-01-17 2019-04-19 北大方正集团有限公司 一种多拉菌素的纯化工艺
CN110256515A (zh) * 2019-06-05 2019-09-20 天津瑞普生物技术股份有限公司 多拉菌素晶型a、晶型b及其制备方法

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