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WO2015035817A1 - Cristal d'inositol, son procédé de préparation et son utilisation - Google Patents

Cristal d'inositol, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2015035817A1
WO2015035817A1 PCT/CN2014/080912 CN2014080912W WO2015035817A1 WO 2015035817 A1 WO2015035817 A1 WO 2015035817A1 CN 2014080912 W CN2014080912 W CN 2014080912W WO 2015035817 A1 WO2015035817 A1 WO 2015035817A1
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WIPO (PCT)
Prior art keywords
inositol
crystal form
crystal
ray powder
xrpd
Prior art date
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Ceased
Application number
PCT/CN2014/080912
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English (en)
Chinese (zh)
Inventor
朱理平
梅雪峰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ZHUCHENG HAOTIAN PHARM CO Ltd
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ZHUCHENG HAOTIAN PHARM CO Ltd
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Publication of WO2015035817A1 publication Critical patent/WO2015035817A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
    • C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
    • C07C29/78—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment by condensation or crystallisation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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

  • the present invention relates to the field of chemical pharmaceuticals, and in particular to a novel inositol crystal, a preparation method thereof and use thereof. Background technique
  • the polymorphism phenomenon refers to a phenomenon in which a solid substance is arranged in two or more different spatial manners to form a solid state having different physicochemical properties.
  • polymorphs include multicomponent crystalline forms such as organic solvates and hydrates.
  • Drug polymorphism is widespread in drug development and is an inherent property of organic small molecule compounds. Different crystal forms have different colors, melting points, solubility, dissolution properties, chemical stability, mechanical stability, reactivity, etc. These physicochemical properties and processability sometimes directly affect the safe and effective performance of the drug. Therefore, crystal form research has become an important part of the drug research process.
  • small molecule drugs can have an infinite number of crystal packing methods—polymorphs. Studies have shown that the number of drug polymorphs found is directly proportional to the time and resources of the research they are investigating.
  • the main means of crystal discovery are solution volatilization, melt crystallization, rapid cooling and suspension, etc., which affect the external conditions of drug crystallization by changing the crystallization conditions such as solvent, temperature, speed, and ratio of suspended solvent.
  • High-throughput sample preparation platforms were used to prepare hundreds of crystallization experiments simultaneously, and new crystal forms were prepared and discovered using micro sample preparation techniques and analytical testing methods.
  • Inositol can promote fat metabolism in the liver and is used to treat liver cirrhosis, fatty liver, hepatitis and other diseases. Inositol also has the effect of lowering blood cholesterol, treating fat and cholesterol catabolism disorders; inositol and its derivatives It can also be used to treat depression and obsessive-compulsive disorder.
  • CCD Cambridge Crystal Database
  • MYIINOL ActaCrystallogr. ( 1964 ) , 17, 159 )
  • MYINOL01 ActaCrystallogr. , Sect. E: Struct.Rep.
  • MYTOLD and MYTOLD01 are the same crystal form, both of which are dihydrate crystal forms.
  • MYIINOL is a monoclinic system and MYINOL01 is an orthorhombic system.
  • the present invention aims to provide a novel inositol crystal.
  • Another object of the present invention is to provide a process for the preparation of the novel inositol crystals.
  • a further object of the invention is to provide the use of said novel inositol crystals.
  • a fourth object of the present invention is to provide a pharmaceutical composition containing novel inositol crystals.
  • an inositol crystal form C having a structure as shown in Formula I, wherein said Form C has an X-ray powder diffraction (XRPD) pattern at the following 2 ⁇ ⁇ 0.2° angle Characteristic peaks: 14.86°, 17.82°, 20.38°, 2 8°, 34.33°;
  • the X-ray powder diffraction (XRPD) pattern of the Form C is at the following 2 ⁇ ⁇ 0.2° angle and has a characteristic purlin: 12.53. , 18.04. , 22.06°, 24.04. , 25.78. , 27.80. , 29.50.
  • the X-ray powder diffraction (XRPD) pattern of the Form C has a characteristic peak at the following 2 ⁇ ⁇ 0.2° angle : 5.96°, 6.26°, 6.74°, 8.07°, 14.59°, 18.35°, 19.99°, 24.74°, 30.92°, 33.62°, 36.69°, 38.42. .
  • the crystal C has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Form C differential scanning calorimetry has a characteristic exothermic peak at about 208.2 °C and a characteristic endothermic peak at about 227.4 °C.
  • a process for the preparation of inositol Form C provided by the present invention as described above the method comprising the steps of: cooling 230 to C to molten mentitol to room temperature to obtain the above The inositol crystal form C provided by the present invention is described.
  • it is cooled to room temperature at a rate of 10-100 ° C / minute; more preferably, 50-100 Cool at a rate of °C/min.
  • the method includes the steps of:
  • the inositol crystal form C provided by the present invention as described above is obtained by cooling 230 ° C to molten inositol at a rate of 10-100 ° C /min to room temperature.
  • the inositol is heated to 240 ° C to melt and cooled to room temperature at a rate of 50-100 ° C /min.
  • a pharmaceutical composition comprising the inositol crystalline form C of the invention as described above and a pharmaceutically acceptable carrier.
  • Fig. 1 is an X-ray powder diffraction (XRPD) pattern of the inositol C crystal form obtained in the examples.
  • Fig. 2 is an infrared spectrum (IR) chart of the inositol C crystal form obtained in the examples.
  • Fig. 3 is a Raman spectrum diagram of the inositol C crystal form obtained in the examples.
  • Fig. 4 is a graph showing the thermogravimetric analysis (TG) of the inositol C crystal form obtained in the examples.
  • Fig. 5 is a differential scanning calorimetry (DSC) chart of the inositol C crystal form obtained in the examples.
  • Fig. 6 is a dynamic water vapor adsorption (DFS) diagram of the inositol C crystal form obtained in the examples. detailed description
  • room temperature means 15-30 ° C, preferably 20-25 ° C.
  • treatment or treating includes prophylactic (gp, prophylactic), curative or palliative treatment which results in a desired pharmaceutical and/or physiological effect.
  • treatment is used herein to mean one or more symptoms based on partial or complete mitigation, delayed onset, inhibition of progression, reduction in severity, and/or reduction in a particular disease, disorder, and/or medical condition.
  • the compounds of the present disclosure are administered or applied to an individual in an advanced condition in which the medical condition develops.
  • composition a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • the present inventors further studied the properties of the inositol crystal form C by various means and instruments.
  • X-ray powder diffraction also known as “X-ray polycrystalline diffraction (XRPD)
  • XRPD X-ray polycrystalline diffraction
  • Methods for determining X-ray powder diffraction of crystals are known in the art. For example, using a Bmker DS Advanced model X-ray powder diffractometer, a copper radiation target is used to acquire the spectrum at a scan rate of 2° per minute.
  • the inositol crystal form C of the present invention has a specific crystal form and has a specific characteristic peak in an X-ray powder diffraction (XRPD) chart.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction (XRPD) pattern of the inositol crystal form C of the present invention has a characteristic peak at the following 2 ⁇ ⁇ 0.2° angle: 14.86. , 17.82. , 20.38. 25.32°, 26.42°, 28.39°, 31.28°, 34.33°;
  • the spectrum has a characteristic peak at the following 2 ⁇ ⁇ 0.2° angle: 12.53. , 14.86. , 17.82. , 18.04. , 20.38.
  • the map is 2 ⁇ ⁇ 0.2° below
  • the corners have characteristic peaks: 5.96°, 6.26°, 6.74°, 8.07°, 12.53°, 14.59°, 14.86. , 17.82°, 18.04°, 18.35.
  • the inositol form C has an X-ray powder diffraction (XRPD) pattern substantially identical to that of Figure 1.
  • DSC Differential calorimetric scanning analysis
  • the inositol Form C obtained by the method of the present invention has a characteristic exothermic peak at about 208.2 ° C and a characteristic endothermic peak at about 227.4 ° C, preferably the present invention.
  • Inositol Form C has a DSC pattern substantially consistent with Figure 5.
  • Infrared profiling can also be employed to determine the type of crystal, the method of which is known in the art.
  • the infrared spectrum of the inositol crystal form C of the present invention shows characteristic peaks of the following wave numbers: 3384.46 cm" 1 , 3255.25 cm" 1 , 2933.20 cm” 1 , 1359.57 cm” 1 , 1141.65 cm” 1 , 1039.44 cm” 1 , 881.31 cm “ 1 , 725.10 cm ⁇ preferably has an infrared spectrum substantially identical to that of Fig. 2.
  • Raman's characteristic map (Raman) can also be used to determine the crystal type, and the measurement method is known in the art. For example, Raman measurement can be employed. Different crystal forms of ranitidine hydrochloride and diclofenac sodium.
  • the Raman characteristic map of the inositol crystal form C of the present invention shows characteristic peaks of the following wave numbers: 3409.08 cm” 1 , 2949.24 cm” 1 , 2936.35 cm” 1 , 2913.12 cm “ 1 , 1422.16 cm” 1 , 1260.87 cm” 1 , 1147.70 cm” 1 , 1112.93 cm” 1 , 1088.95 cm” 1 , 1060.58 cm” 1 , 1014.21 cm” 1 , 886.30 cm” 1 , 512.64 cm” 1 , 420.63 cm “ 1. It is preferable to have a Raman characteristic map substantially consistent with FIG.
  • the inositol crystal form C of the present invention has a specific stability and is advantageous for preservation.
  • the inventors showed by the DVS spectrum that in the conventional storage environment (40%-80% RH), Form C has no or almost no hygroscopicity.
  • the DVS profile of the resulting inositol Form C is substantially identical to that of Figure 6. Inositol crystal form C preparation method
  • the inventors have found through intensive studies that it is possible to cool the inositol from 230 ° C to room temperature to obtain inositol crystal form C.
  • the present invention provides a method of preparing the inositol crystal form C, the method comprising the steps of:
  • the inositol as shown in Formula I is heated to 230 ° C to melt;
  • the inositol crystal form c provided by the present invention is obtained by cooling 230 ° C to molten inositol at a rate of 10-100 ° C / minute to room temperature.
  • the inositol can be heated to 230 ° C in a blast oven to melt; preferably heated to 240 ° C to melt.
  • the cooling rate may be 50 - 100 ° C / min.
  • the inositol crystal form C produced by the present invention has better stability, is easy to store and use, and has high purity, and thus can be provided as a drug substance or used for the preparation of a medicament for treating hypercholesterolemia and fatty liver.
  • the present invention is also directed to a composition comprising the inositol Form C of the present invention, the composition comprising an effective amount of inositol Form c, and a pharmaceutically acceptable carrier.
  • the term “containing” or “including” includes “comprising”, “consisting essentially of”, and “consisting of”.
  • the term “effective amount” refers to an amount which is functional or active against a human and/or animal and which is acceptable to humans and/or animals.
  • the term "pharmaceutically acceptable” means a substance that is suitable for use in humans and/or animals without excessive adverse side effects (eg, toxicity, irritability, and allergies; ie, a reasonable benefit/risk ratio) .
  • pharmaceutically acceptable carrier refers to a carrier for the administration of a therapeutic agent, including various excipients and diluents.
  • the term refers to pharmaceutical carriers which are not themselves essential active ingredients and which are not excessively toxic after administration. Suitable carriers are well known to those of ordinary skill in the art. A full discussion of pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences, Mack Pub. Co., N.J. 1991.
  • the "pharmaceutically acceptable carrier” is selected from the group consisting of: a filler, a disintegrant, a lubricant, a glidant, an effervescent agent, a flavoring agent, a coating material, an excipient, or a gentle/ Controlled release agent.
  • the pharmaceutically acceptable carrier can contain liquids such as water, saline, glycerol and ethanol.
  • auxiliary substances such as fillers, disintegrants, lubricants, glidants, effervescent agents, wetting or emulsifying agents, flavoring agents, pH buffering substances and the like may also be present in these carriers.
  • these materials can be formulated in a non-toxic, inert, andpharmaceutically acceptable aqueous carrier medium wherein the pH is usually from about 5 to about 8, preferably, the pH is from about 6 to about 8.
  • the pH is usually from about 5 to about 8
  • the pH is from about 6 to about 8.
  • the novel crystal form provided by the invention has high crystallinity, low hygroscopicity and high solubility, and can improve the bioavailability of inositol.
  • the unit of weight percent by volume in the present invention is well known to those skilled in the art and, for example, refers to the weight of the solute in a 100 ml solution.
  • XRPD All XRPD spectra of this patent are detected by the D8advance X-ray diffractometer from Bruker, Germany.
  • the target is Cu ⁇ (40 kV, 40 mA), and the scanning range is from 3° to 40°. Is 0.1 s / step.
  • the relative intensity of the band may vary due to the dominant orientation effect due to the difference in crystallization conditions, particle size, relative content of the mixture, and other test conditions. Therefore, the crystal to which the relative intensity of the diffraction peak is directed is not characteristic. When judging whether it is the same as the known crystal form, more attention should be paid to the position of the peaks rather than their relative intensities. In addition, care should be taken to maintain the overall concept when determining whether the crystal form is the same, because not a diffraction line represents a phase, but a specific set of "relative intensity can i" data represents a phase.
  • DSC All DSC spectra of this patent were measured by a DSC 8500 differential scanning calorimeter from Elmer, Inc., Platinum, USA, with an atmosphere of nitrogen and a heating rate of 10 degrees Celsius per minute.
  • Inositol is from Shandong Zhucheng Haotian Pharmaceutical Co., Ltd., which belongs to granular crystals.
  • Example 1
  • Example 2 The inositol is heated to 230 ° C to melt, and cooled to room temperature at a cooling rate of 10 ° C /min to obtain crystal form C crystals of inositol.
  • Example 2 The inositol is heated to 230 ° C to melt, and cooled to room temperature at a cooling rate of 10 ° C /min to obtain crystal form C crystals of inositol.
  • Example 3 The inositol is heated to 230 ° C to melt, and cooled to room temperature at a cooling rate of 100 ° C /min to obtain a crystalline form C crystal of inositol.
  • Example 3 The inositol is heated to 230 ° C to melt, and cooled to room temperature at a cooling rate of 100 ° C /min to obtain a crystalline form C crystal of inositol.
  • the inositol is heated to 240 ° C to melt, and cooled to room temperature at a cooling rate of 10 ° C /min to obtain a crystalline form C crystal of inositol.
  • Example 5 The inositol was heated to 240 degrees Celsius to melt, and cooled to room temperature at a cooling rate of 50 degrees Celsius/minute to obtain crystal form C crystals of inositol.
  • Example 5 The inositol was heated to 240 degrees Celsius to melt, and cooled to room temperature at a cooling rate of 50 degrees Celsius/minute to obtain crystal form C crystals of inositol.
  • the inositol is heated to 240 ° C to melt, and cooled to room temperature at a cooling rate of 100 ° C /min to obtain a crystalline form C crystal of inositol.
  • the inositol crystal form C prepared in Example 1 was transmitted by X-rays, and the X-ray powder diffraction peak positions obtained are shown in Table 1.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Diabetes (AREA)
  • Obesity (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un cristal d'inositol, son procédé de préparation et son utilisation. Le diagramme de diffraction des rayons X sur poudre (XRPD) de la forme cristalline C présente des pics caractéristiques aux angles suivants de 2θ±0.2°： 14.86°, 17.82°, 20.38°, 25.32°, 26.42°, 28.39°, 31.28° et 34.33°.
PCT/CN2014/080912 2013-09-10 2014-06-27 Cristal d'inositol, son procédé de préparation et son utilisation Ceased WO2015035817A1 (fr)

Applications Claiming Priority (2)

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CN201310409039.4 2013-09-10
CN201310409039.4A CN103408400B (zh) 2013-09-10 2013-09-10 一种肌醇晶体及其制备方法和用途

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CN105669376B (zh) * 2016-02-27 2019-03-12 诸城市浩天药业有限公司 制备高结晶度、粒径大的肌醇的结晶工艺及应用
CN120574115A (zh) * 2025-08-05 2025-09-02 诸城市浩天药业有限公司 手性肌醇晶型及其制备方法

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JPH1045647A (ja) * 1996-07-30 1998-02-17 Nisso Eng Kk イノシトール無水結晶の製造方法
CN1389447A (zh) * 2002-07-09 2003-01-08 胡中士 无色透明针状晶体肌醇的制取方法及其产品

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GAO, JINMING ET AL.: "Extraction and Application of Inositol", SHAANXI CEREALS & OILS TECHNOLOGY, vol. 16, no. 4, 31 December 1991 (1991-12-31), pages 32 *
GAO, JINMING ET AL.: "Extraction and Application of Inositol", SHANXI GRAINS & OILS TECHNOLOGY, vol. 16, no. 4, 31 December 1991 (1991-12-31), pages 32 - 34 *
KHAN, U. ET AL.: "An Orthorhombic Polymorph of Myo-inositol", ACTA CRYSTALLOGRAPHICA SECTION E: STRUCTURE REPORTS ONLINE, vol. 63, no. 2, 13 February 2007 (2007-02-13), pages 530 - 532 *
REBECCA, O. P. S. ET AL.: "Isolation and Identification of Myo-inositol Crystals from Dragon Fruit (Hylocereus Polyrhizus", MOLECULES, vol. 17, no. 4, 17 April 2012 (2012-04-17), pages 4583 - 4594 *
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