WO2021143414A1 - 一种ponesimod的晶型及其制备方法和用途 - Google Patents

一种ponesimod的晶型及其制备方法和用途 Download PDF

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WO2021143414A1
WO2021143414A1 PCT/CN2020/135824 CN2020135824W WO2021143414A1 WO 2021143414 A1 WO2021143414 A1 WO 2021143414A1 CN 2020135824 W CN2020135824 W CN 2020135824W WO 2021143414 A1 WO2021143414 A1 WO 2021143414A1
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crystal form
csii
preparation
ray powder
present
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French (fr)
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陈敏华
张婧
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苏州科睿思制药有限公司
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Definitions

  • the invention relates to the field of crystal chemistry. Specifically, it relates to the crystal form of Ponesimod and its preparation method and use.
  • Ponesimod is a selective S1P1 receptor agonist (selective S1P1 receptor modulator) developed by Actelion. It was submitted for marketing in the United States and Europe in 2020 for the treatment of multiple sclerosis.
  • the chemical name of Ponesimod is (R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benzo[Z] subunit]-2-([Z]-propylimine Yl)-3-o-tolyl-thiazolidine-4-one (hereinafter referred to as "compound I”), its structural formula is as follows:
  • the crystal form is a solid in which the compound molecules are arranged in a three-dimensional order in the microstructure to form a crystal lattice.
  • the phenomenon of drug polymorphism refers to the existence of two or more different crystal forms of the drug. Because of the different physical and chemical properties, different crystal forms of the drug may have different dissolution and absorption in the body, which may affect the clinical efficacy and safety of the drug to a certain extent. Especially for poorly soluble solid drugs, the crystal form will have a greater impact. Therefore, the crystal form of a drug must be an important content of drug research and an important content of drug quality control.
  • Example 85 discloses a preparation method of Compound I, and WO2010046835A1 discloses that Compound I prepared by this method is in an amorphous form.
  • WO2010046835A1 discloses crystal form A, crystal form C, crystal form III, and crystal form II of compound I. Studies have shown that crystal form III has poor crystallinity and spontaneously transforms into crystal form II at room temperature; the prepared crystal form II contains propionic acid; the thermodynamic stability of crystal form A is inferior to crystal form C. Relatively speaking, the crystal form C is suitable for drug development, but the nuclear magnetic data shows that the crystal form C has residual solvent.
  • WO2017107972A1 discloses crystal form 1, crystal form 2, and crystal form 3. The inventor of the present application found that crystal form 1 is a solvate, and crystal form 2 and crystal form 3 have poor crystallinity.
  • WO2019060147A1 discloses the crystal form T1 and the crystal form T2.
  • the crystal form T2 is a tert-butanol solvate, and the crystal form T1 has poor crystallinity and is presumed to contain an amorphous form.
  • the inventor of the present application unexpectedly discovered the crystalline form CSII of compound I provided by the present invention, which has advantages in physical and chemical properties, preparation processing properties, and bioavailability, such as melting point, solubility, etc.
  • the main purpose of the present invention is to provide a new crystal form of Compound I and its preparation method and application.
  • the present invention provides a crystalline form CSII of Compound I (hereinafter referred to as "crystalline form CSII").
  • the X-ray powder diffraction pattern of the crystal form CSII has characteristic peaks at the diffraction angle 2 ⁇ values of 5.2° ⁇ 0.2°, 10.5° ⁇ 0.2°, and 16.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSII has a diffraction angle 2 ⁇ value of 8.4° ⁇ 0.2°, 12.3° ⁇ 0.2°, 17.5° ⁇ 0.2° at 1 or 2
  • a diffraction angle 2 ⁇ value 8.4° ⁇ 0.2°, 12.3° ⁇ 0.2°, 17.5° ⁇ 0.2° at 1 or 2
  • characteristic peaks at one or three places preferably, the X-ray powder diffraction pattern of the crystal form CSII has 3 places among the diffraction angles 2 ⁇ of 8.4° ⁇ 0.2°, 12.3° ⁇ 0.2°, and 17.5° ⁇ 0.2° Characteristic peaks.
  • the X-ray powder diffraction pattern of the crystal form CSII has a diffraction angle 2 ⁇ value of 22.9° ⁇ 0.2°, 23.5° ⁇ 0.2°, 25.7° ⁇ 0.2° at 1 or 2
  • a diffraction angle 2 ⁇ value of 22.9° ⁇ 0.2°, 23.5° ⁇ 0.2°, 25.7° ⁇ 0.2° at 1 or 2
  • characteristic peaks at one or three places preferably, the X-ray powder diffraction pattern of the crystal form CSII has three places among the diffraction angles 2 ⁇ of 22.9° ⁇ 0.2°, 23.5° ⁇ 0.2°, and 25.7° ⁇ 0.2° Characteristic peaks.
  • the X-ray powder diffraction pattern of the crystal form CSII has diffraction angle 2 ⁇ values of 5.2° ⁇ 0.2°, 10.5° ⁇ 0.2°, 16.9° ⁇ 0.2°, 8.4° ⁇ 0.2° , 12.3° ⁇ 0.2°, 17.5° ⁇ 0.2°, 22.9° ⁇ 0.2°, 23.5° ⁇ 0.2°, 25.7° ⁇ 0.2° any 3, or 4, or 5, or 6, or 7 There are characteristic peaks at, or 8, or 9.
  • the X-ray powder diffraction pattern of the crystal form CSII is basically as shown in FIG. 1.
  • the differential scanning calorimetry diagram of the crystal form CSII is basically as shown in FIG. 2, and the melting endothermic peak begins to appear near 105°C.
  • thermogravimetric analysis chart of the crystal form CSII is basically as shown in FIG. 3, with a mass loss of about 0.3% when heated to 100°C.
  • the crystal type CSII is a crystal-free type.
  • the present invention also provides a preparation method of the crystal form CSII, and the preparation method includes:
  • Compound I crystal form III is placed in an atmosphere of aromatic hydrocarbons, alkanes or alcohol solvents by gas-solid diffusion; or
  • the crystal form III or amorphous form of compound I is stirred in an aromatic hydrocarbon solvent.
  • the crystal form III is characterized in that Cu-K ⁇ radiation is used, and its X-ray powder diffraction pattern has a diffraction angle 2 ⁇ value of 8.5° ⁇ 0.2 °, 10.7° ⁇ 0.2°, 14.7° ⁇ 0.2°, 15.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, 22.4° ⁇ 0.2°, 23.4° ⁇ 0.2°, 26.9° ⁇ 0.2°, there are characteristic peaks.
  • the aromatic hydrocarbon solvent is preferably a C7-C9 aromatic hydrocarbon, more preferably toluene, the alkane solvent is preferably n-hexane, and the alcohol solvent is preferably n-pentanol.
  • the temperature of the gas-solid diffusion is preferably room temperature.
  • the gas-solid diffusion time is preferably 8-42 days.
  • the present invention also provides a pharmaceutical composition, which comprises an effective therapeutic amount of crystalline CSII and pharmaceutically acceptable excipients.
  • the present invention provides the use of crystal form CSII in the preparation of selective S1P1 receptor agonist drugs.
  • the present invention provides the use of crystalline CSII in the preparation of drugs for treating multiple sclerosis.
  • the crystal form CSII provided by the present invention has higher solubility.
  • Higher solubility is conducive to improving the absorption of drugs in the human body, improving bioavailability, and making the drugs play a better therapeutic effect; in addition, higher solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the drug Side effects and improve the safety of medicines.
  • the crystal form CSII provided by the present invention has better in vitro dissolution.
  • the dissolution rate of the crystal form CSII preparation is higher than that of the crystal form A in the prior art.
  • Dissolution is an important prerequisite for drug absorption.
  • a good in vitro dissolution rate indicates that the drug has a higher degree of in vivo absorption and better exposure characteristics in the body, thereby increasing the bioavailability and improving the efficacy of the drug.
  • the crystal form CSII provided by the present invention has lower hygroscopicity.
  • the test results show that the weight gain of crystal form CSII from 40%RH (Relative Humidity) to 80%RH is lower than that of prior art crystal form C, and the crystal form CSII provided by the present invention has hygroscopicity under 80%RH conditions.
  • the weight gain is 0.12%, which is no or almost no hygroscopicity.
  • the hygroscopicity directly affects the physical and chemical stability of the drug, and the high hygroscopicity can easily cause chemical degradation and crystal transformation.
  • high hygroscopicity will reduce the fluidity of the drug, thereby affecting the processing technology of the drug.
  • drugs with high hygroscopicity need to maintain low humidity during production and storage, which puts forward higher requirements on production and requires high costs.
  • high hygroscopicity can easily cause changes in the content of active ingredients in the medicine, which affects the quality of the medicine.
  • the low hygroscopicity crystal type is not harsh on the environment, reduces the cost of material production, storage and quality control, and has strong economic value.
  • the crystalline CSII bulk drugs and preparations provided by the present invention have good stability.
  • the crystal form of the CSII bulk drug is placed under the conditions of 25°C/60%RH, and the crystal form has not changed for at least 6 months, and the chemical purity is above 99%, and the purity remains basically unchanged during storage. It shows that the crystalline CSII bulk drugs and preparations have good stability under long-term conditions.
  • the crystal form of the crystalline CSII bulk drug has not changed after being placed at 40°C/75%RH for at least 6 months, and the crystal form has not changed after being placed at 60°C/75%RH for at least 1 month, and the chemical purity All are above 99%, and the purity remains basically unchanged during storage.
  • the crystal form CSII is mixed with excipients to make a pharmaceutical preparation, it is placed under the condition of 40°C/75% RH, and the crystal form and purity have not changed significantly for at least 3 months. It shows that the crystalline CSII bulk drugs and preparations have better stability under accelerated conditions and more severe conditions. The stability of APIs and preparations under accelerated conditions and more severe conditions is very important for drugs.
  • the crystalline CSII bulk drugs and preparations have good stability under harsh conditions, which is beneficial to avoid the impact of deviation from the storage conditions on the label on the quality of the drugs.
  • the transformation of the crystal form will cause changes in the absorption of the drug, affect the bioavailability, and even cause the toxic and side effects of the drug.
  • Good chemical stability can ensure that there are basically no impurities generated during storage.
  • the crystal form CSII has good physical and chemical stability, ensuring consistent and controllable quality of raw materials and preparations, and minimizing changes in drug quality, bioavailability, and even toxic side effects caused by changes in crystal form or impurities. .
  • the crystal form CSII provided by the present invention has no solvent residues, which effectively overcomes the disadvantages of low drug purity or high solvent residues, such as low drug stability, poor efficacy, and high toxicity.
  • the "stirring” is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, at a stirring speed of 50-1800 revolutions per minute, wherein the magnetic stirring is preferably 300-900 revolutions per minute, and mechanical stirring Preferably it is 100-300 revolutions per minute.
  • the "characteristic peak” refers to a representative diffraction peak used to discriminate crystals, and usually can have an error of ⁇ 0.2°.
  • crystal or “crystal form” can be characterized by X-ray powder diffraction.
  • X-ray powder diffraction pattern is affected by the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with the change of experimental conditions, so the intensity of the diffraction peaks cannot be the only or decisive factor for determining the crystal form.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystals.
  • the intensity of the diffraction peaks shown in the present invention is illustrative and not for absolute comparison. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of the protected crystal form of the present invention does not have to be exactly the same as the X-ray powder diffraction pattern in the embodiment referred to here, and any characteristic peaks in these patterns.
  • the crystal forms of the same or similar X-ray powder diffraction patterns fall within the scope of the present invention.
  • Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with the X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of images reflect the same or different crystal forms.
  • the crystal form CSII of the present invention is pure, and substantially no other crystal forms are mixed.
  • substantially no when used to refer to a new crystal form means that this crystal form contains less than 20% (mass) of other crystal forms, especially less than 10% (mass) of other crystal forms, and even less.
  • Other crystal forms with a content of less than 5% (mass) also refer to other crystal forms with a content of less than 1% (mass).
  • Figure 1 is an XRPD diagram of the crystal form CSII obtained according to Example 1
  • Figure 2 is a DSC chart of the crystal form CSII obtained according to Example 1
  • Figure 3 is a TGA diagram of the crystal form CSII obtained according to Example 1
  • Figure 4 is an XRPD diagram of the crystal form CSII obtained according to Example 2.
  • Figure 5 XRPD comparison diagram of crystal form CSII before and after being placed under 25°C/60%RH (from top to bottom: before placement, placed with closed mouth for 6 months, and placed with open mouth for 6 months)
  • Figure 6 XRPD comparison diagram of crystal form CSII before and after being placed under 40°C/75%RH (from top to bottom: before placement, placed with closed mouth for 6 months, and placed with open mouth for 6 months)
  • Figure 7 XRPD comparison diagram of crystal form CSII before and after being placed at 60°C/75%RH (from top to bottom: before placement, placed with closed mouth for 1 month, and opened for 1 month)
  • Figure 8 is the XRPD comparison diagram of crystal CSII before and after DVS test (from top to bottom: before test, after test)
  • Figure 9 is the XRPD comparison chart of crystal form CSII before and after preparation (from top to bottom: excipient, preparation, crystal form CSII)
  • Figure 10 is the XRPD comparison chart of the stability of crystalline CSII formulations (from top to bottom: before storage, after storage at 40°C/75% RH plus 1g desiccant for 3 months)
  • the X-ray powder diffraction patterns of the samples of the present invention except for the stability of the bulk drug crystal form CSII and the DVS test are collected on a Bruker D2PHASER X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the X-ray powder diffraction patterns of the crystal form CSII stability of the bulk drug of the present invention and the crystal form before and after DVS are collected on a Bruker D8 Discover X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction are as follows:
  • the differential scanning calorimetry (DSC) chart of the present invention was collected on TA Q2000.
  • the method parameters of the DSC are as follows:
  • thermogravimetric analysis (TGA) graph of the present invention is collected on TA Q500.
  • the method parameters of the TGA are as follows:
  • the dynamic moisture adsorption (DVS) map of the present invention is collected on the Intrinsic dynamic moisture adsorption instrument produced by SMS Company (Surface Measurement Systems Ltd.).
  • the instrument control software is DVS-Intrinsic.
  • the method parameters of the dynamic moisture adsorption instrument are as follows:
  • Relative humidity range 0%RH-95%RH
  • Proton nuclear magnetic resonance data ( 1 H NMR) was collected from Bruker Avance II DMX 400M Hz nuclear magnetic resonance spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL of deuterated dimethyl sulfoxide, and make a solution of 2-10 mg/mL.
  • the initial stability of the raw material drug, the 60°C/75% RH storage for 1 month, and the preparation stability detection method are shown in Table 3.
  • room temperature is not a specific temperature value, but refers to a temperature range of 10-30°C.
  • the compound I as a raw material includes, but is not limited to, solid form (crystalline or amorphous), oil form, liquid form and solution.
  • the compound I as a raw material is in a solid form.
  • the compound I used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2010046835A1.
  • the obtained crystalline solid is the crystal form CSII provided by the present invention, and its XRPD pattern is shown in FIG. 1, and its XRPD data is shown in Table 5.
  • the DSC is shown in Figure 2, and the melting endothermic peak begins to appear around 105°C.
  • TGA has a mass loss of about 0.3% when heated to 100°C.
  • the obtained crystalline solid is the crystal form CSII provided by the present invention, and its X-ray powder diffraction pattern is shown in Figure 4, and the X-ray powder diffraction data is shown in Table 6.
  • WO2010046835A1 discloses that crystal form C contains a trace amount of tert-butyl methyl ether.
  • the crystal form CSII provided by the present invention has no solvent residue.
  • SGF simulated gastric juice
  • FaSSIF simulated fasting state intestinal juice
  • FeSSIF simulated feeding state intestinal juice
  • ND Lower than the detection limit of the instrument.
  • the crystal form CSII can be stable for at least 6 months under the conditions of 25°C/60%RH and 40°C/75%RH. It can be seen that the crystal form CSII can maintain good stability under long-term and accelerated conditions. It can be stable for at least 1 month under the condition of 60°C/75%RH. It can be seen that the crystal form CSII also has good stability under more severe conditions.
  • the crystalline CSII has a hygroscopic weight gain of 0.12% under 80% RH conditions, which means it has no or almost no hygroscopicity.
  • the weight gain of crystal form CSII at 40% to 80% RH is 0.07%, and the weight gain of crystal form C at 40% to 80% RH is 0.1%.
  • the moisture absorption of crystal form CSII is better than that of WO2010046835A1 crystal form C.
  • moisture-absorbing weight gain is not less than 15.0%
  • moisture absorption weight gain is less than 15.0% but not less than 2.0%
  • weight gain is less than 2.0% but not less than 0.2%
  • the crystal form CSII prepared by the present invention was prepared using the formulation prescriptions and processes described in Table 11 and Table 12, and the XRPD before and after the crystal form CSII preparation was tested.
  • the XRPD comparison chart is shown in Figure 9, and the purity comparison data is shown in Table 13. Shown. The results showed that the crystal form of the crystal form CSII remained stable before and after the preparation, and the purity of the crystal form remained basically unchanged.
  • the crystal form CSII prepared by the present invention and WO2010046835A1 crystal form A were made into solid capsules according to the formulation and process described in Example 7. After removing the capsule shell, the powder dissolution test was carried out, and the solid capsules were put in a pH 6.8 phosphate buffered saline solution ( PBS) was used to test the cumulative dissolution at different times.
  • PBS pH 6.8 phosphate buffered saline solution
  • the dissolution rate of crystal form CSII is higher than that of WO2010046835A1 crystal form.
  • the crystal form CSII provided by the present invention has better bioavailability.

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Abstract

一种Ponesimod的新晶型及其制备方法，含有该晶型的药物组合物，以及该晶型在制备选择性S1P1受体激动剂药物和治疗多发性硬化症药物中的用途。所述Ponesimod晶型比现有技术具有改进的性质，可应用于对该药物的优化和开发。

Description

一种Ponesimod的晶型及其制备方法和用途 技术领域
本发明涉及晶体化学领域。具体而言，涉及Ponesimod的晶型及其制备方法和用途。
背景技术
Ponesimod是由Actelion公司开发的一种选择性S1P1受体激动剂(selective S1P1 receptor modulator)，2020年在美国和欧洲提交了上市申请，用于治疗多发性硬化症。Ponesimod化学名称是(R)-5-[3-氯-4-(2,3-二羟基-丙氧基)-苯并[Z]亚基]-2-([Z]-丙基亚胺基)-3-邻甲苯基-噻唑烷-4-酮(以下称为“化合物I”)，其结构式如下：
Figure PCTCN2020135824-appb-000001
晶型是化合物分子在微观结构中三维有序排列而形成晶格的固体，药物多晶型现象是指药物存在两种或两种以上的不同晶型。因为理化性质不同，药物的不同晶型可能在体内有不同的溶出、吸收，进而在一定程度上影响药物的临床疗效和安全性。特别是对难溶性固体药物，晶型的影响会更大。因此，药物晶型必然是药物研究的重要内容，也是药物质量控制的重要内容。
WO2005054215A1实例85公开了化合物I的制备方法，WO2010046835A1中披露该方法制备得到的化合物I为非晶形式。
WO2010046835A1公开了化合物I的晶型A、晶型C、晶型III、晶型II。研究表明，晶型III结晶度较差，且在室温下自发转化为晶型II；制备得到的晶型II包含有丙酸；晶型A热力学稳定性劣于晶型C。相对而言，晶型C为适合用于药物开发的晶型，但核磁数据显示晶型C有溶剂残留。
WO2017107972A1公开了晶型1、晶型2和晶型3，本申请发明人研究发现，晶型1为溶剂合物，晶型2和晶型3结晶度差。
WO2019060147A1公开了晶型T1和晶型T2，晶型T2是叔丁醇溶剂合物，晶型T1的结晶度差，推测含无定形。
为克服现有技术的缺点，本申请的发明人意外发现了本发明提供的化合物I的晶型CSII，其在理化性质，制剂加工性能及生物利用度等方面具有优势，例如在熔点，溶解度，引湿性，提纯作用，稳定性，黏附性，可压性，流动性，体内外溶出，生物有效性等方面中的至少一方面存在优势，特别是溶解度高，稳定性好，无溶剂残留，引湿性低，制剂稳定性好、溶出度高，解决了现有技术晶型存在的问题，对含化合物I的药物开发具有非常重要的意义。
发明内容
本发明的主要目的是提供化合物I的新晶型及其制备方法和用途。
根据本发明的目的，本发明提供化合物I的晶型CSII(以下称作“晶型CSII”)。
一方面，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为5.2°±0.2°、10.5°±0.2°、16.9°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为8.4°±0.2°、12.3°±0.2°、17.5°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSII的X射线粉末衍射图在衍射角2θ为8.4°±0.2°、12.3°±0.2°、17.5°±0.2°中的3处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为22.9°±0.2°、23.5°±0.2°、25.7°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSII的X射线粉末衍射图在衍射角2θ为22.9°±0.2°、23.5°±0.2°、25.7°±0.2°中的3处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为5.2°±0.2°、10.5°±0.2°、16.9°±0.2°、8.4°±0.2°、12.3°±0.2°、17.5°±0.2°、22.9°±0.2°、23.5°±0.2°、25.7°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处有特征峰。
非限制性地，晶型CSII的X射线粉末衍射图基本如图1所示。
非限制性地，晶型CSII的差示扫描量热分析图基本如图2所示，在105℃附近开始出现熔化吸热峰。
非限制性地，晶型CSII的热重分析图基本如图3所示，在加热至100℃具有约0.3％的质量损失。
非限制性地，晶型CSII为无水晶型。
根据本发明的目的，本发明还提供所述晶型CSII的制备方法，所述制备方法包括：
将化合物I晶型III置于芳香烃类、烷烃类或醇类溶剂的气氛中气固扩散得到；或
将化合物I晶型III或者无定形置于芳香烃类溶剂中搅拌得到，所述晶型III的特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在衍射角2θ值为8.5°±0.2°、10.7°±0.2°、14.7°±0.2°、15.2°±0.2°、18.0°±0.2°、22.4°±0.2°、23.4°±0.2°、26.9°±0.2°处有特征峰。
所述芳香烃类溶剂优选为C7-C9的芳香烃，进一步优选为甲苯，烷烃类溶剂优选正己烷，醇类溶剂优选正戊醇。
所述气固扩散的温度优选室温。
所述气固扩散的时间优选8-42天。
根据本发明的目的，本发明还提供一种药物组合物，所述药物组合物包含有效治疗量的晶型CSII及药学上可接受的辅料。
进一步地，本发明提供晶型CSII在制备选择性S1P1受体激动剂药物中的用途。
更进一步地，本发明提供晶型CSII在制备治疗多发性硬化药物中的用途。
本发明提供的晶型CSII具有以下有益效果：
(1)与现有技术相比，本发明提供的晶型CSII具有更高的溶解度。更高的溶解度有利于提高药物在人体内的吸收，提高生物利用度，使药物发挥更好的治疗作用；另外，更高的溶解度能够在保证药物疗效的同时，降低药物的剂量，从而降低药品的副作用并提高药品的安全性。
(2)与现有技术相比，本发明提供的晶型CSII具有更优的体外溶出度。在pH6.8磷酸盐缓冲盐溶液(PBS，含0.5％十二烷基硫酸钠)中，晶型CSII制剂溶出度高于现有技术晶型 A。
不同的晶型可能导致药物在体内有不同的溶出速率，直接影响药物在体内的吸收、分布、代谢、排泄，最终因其生物利用度不同而导致临床药效的差异。溶出是药物被吸收的重要前提，良好的体外溶出度预示药物的体内吸收程度较高，在体内暴露特性更好，从而提高生物利用度，提高药物的疗效。
(3)本发明提供的晶型CSII具有较低的引湿性。测试结果表明，晶型CSII在40％RH(Relative Humidity，相对湿度)至80％RH的增重低于现有技术晶型C，且本发明提供的晶型CSII在80％RH条件下引湿性增重为0.12％，属于无或几乎无引湿性。
引湿性直接影响药物的物理化学稳定性，引湿性高易引起化学降解和晶型转变。此外，引湿性高会降低药物的流动性，从而影响药物的加工工艺。不仅如此，引湿性高的药物在生产和保存过程中需要维持低的湿度，对生产提出了更高的要求，需要很高的成本。更重要的是，引湿性高容易造成药物中有效成分含量的变化，影响药物的质量。低引湿性晶型对环境要求不苛刻，降低了物料生产、保存和质量控制成本，具有很强的经济价值。
(4)本发明提供的晶型CSII原料药和制剂均具有良好的稳定性。晶型CSII原料药在25℃/60％RH条件下放置，至少6个月晶型未发生变化，且化学纯度在99％以上，储存过程中纯度基本保持不变。说明晶型CSII原料药和制剂在长期条件下，具有较好的稳定性。
同时，晶型CSII原料药在40℃/75％RH条件下放置至少6个月晶型未发生变化，在60℃/75％RH条件下放置至少1个月晶型未发生变化，且化学纯度均在99％以上，储存过程中纯度基本保持不变。晶型CSII与辅料混合做成药物制剂后，在40℃/75％RH条件下放置，至少3个月晶型和纯度未发生明显变化。说明晶型CSII原料药和制剂在加速条件及更严苛的条件下，具有较好的稳定性。原料药和制剂在加速条件及更严苛的条件下的稳定性对于药物至关重要。原料药和制剂在储存、运输、生产过程中会遇到季节差异、不同地区气候差异和天气因素等带来的高温和高湿条件。晶型CSII原料药和制剂在苛刻的条件下具有较好的稳定性，有利于避免偏离标签上的贮藏条件对药物质量的影响。
晶型的转变会导致药物的吸收发生变化，影响生物利用度，甚至引起药物的毒副作用。良好的化学稳定性可以确保在储存过程中基本没有杂质产生。晶型CSII具有良好的物理化学稳定性，保证原料药和制剂质量一致可控，最大程度地减少药物由于晶型改变或杂质产生引起的药物质量变化，生物利用度改变，甚至引起药物的毒副作用。
(5)本发明提供的晶型CSII无溶剂残留，有效的克服了药物纯度低或溶剂残留高带来的药物稳定性低、疗效差、毒性高等缺点。
本发明中，所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50-1800转/分钟，其中，磁力搅拌优选为300-900转/分钟，机械搅拌优选为100-300转/分钟。
所述“特征峰”是指用于甄别晶体的有代表性的衍射峰，通常可以有±0.2°的误差。
本发明中，“晶体”或“晶型”可以用X射线粉末衍射表征。本领域技术人员能够理解，X射线粉末衍射图受仪器的条件、样品的准备和样品纯度的影响而有所改变。X射线粉末衍射图中衍射峰的相对强度也可能随着实验条件的变化而变化，所以衍射峰强度不能作为判定晶型的唯一或决定性因素。事实上，X射线粉末衍射图中衍射峰的相对强度与晶体的择优取向有 关，本发明所示的衍射峰强度为说明性而非用于绝对比较。因而，本领域技术人员可以理解的是，本发明所保护晶型的X射线粉末衍射图不必和这里所指的实施例中的X射线粉末衍射图完全一致，任何具有和这些图谱中的特征峰相同或相似的X射线粉末衍射图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的X射线粉末衍射图和一个未知晶型的X射线粉末衍射图相比较，以证实这两组图反映的是相同还是不同的晶型。
在一些实施方案中，本发明的晶型CSII是纯的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(质量)的其他晶型，尤其指少于10％(质量)的其他晶型，更指少于5％(质量)的其他晶型，更指少于1％(质量)的其他晶型。
本发明中术语“约”，当用来指可测量的数值时，例如质量、时间、温度等，意味着可围绕具体数值有一定的浮动的范围，该范围可以为±10％、±5％、±1％、±0.5％、或±0.1％。
附图说明
图1为根据实施例1所得晶型CSII的XRPD图
图2为根据实施例1所得晶型CSII的DSC图
图3为根据实施例1所得晶型CSII的TGA图
图4为根据实施例2所得晶型CSII的XRPD图
图5晶型CSII在25℃/60％RH条件下放置前后的XRPD对比图(从上至下依次为：放置前，闭口放置6个月，开口放置6个月)
图6晶型CSII在40℃/75％RH条件下放置前后的XRPD对比图(从上至下依次为：放置前，闭口放置6个月，开口放置6个月)
图7晶型CSII在60℃/75％RH条件下放置前后的XRPD对比图(从上至下依次为：放置前，闭口放置1个月，开口放置1个月)
图8为晶型CSII在DVS测试前后的XRPD对比图(从上至下依次为：测试前、测试后)
图9为晶型CSII在制剂前后的XRPD对比图(从上至下依次为：辅料、制剂、晶型CSII)
图10为晶型CSII制剂稳定性的XRPD对比图(从上至下依次为：放置前、在40℃/75％RH加1g干燥剂放置3个月后)
图11晶型CSII制剂和晶型A制剂在pH6.8磷酸盐缓冲盐溶液中的溶出度曲线
具体实施方式
结合以下实施例对本发明做详细说明，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
DVS：动态水分吸附
1H NMR：液态核磁氢谱
UPLC：超高效液相色谱
采集数据所用的仪器及方法：
本发明所述的除原料药晶型CSII稳定性和DVS测试以外样品的X射线粉末衍射图在Bruker D2PHASER X射线粉末衍射仪上采集。所述X射线粉末衍射的方法参数如下：
X射线光源：Cu,Kα
Kα1
Figure PCTCN2020135824-appb-000002
1.54060；Kα2
Figure PCTCN2020135824-appb-000003
1.54439
Kα2/Kα1强度比例：0.50
电压：30仟伏特(kV)
电流：10毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的原料药晶型CSII稳定性和DVS前后晶型的X射线粉末衍射图在Bruker D8Discover X射线粉末衍射仪上采集。所述X射线粉末衍射的方法参数如下：
X射线光源：Cu,Kα
Kα1
Figure PCTCN2020135824-appb-000004
1.54060；Kα2
Figure PCTCN2020135824-appb-000005
1.54439
Kα2/Kα1强度比例：0.50
电压：40仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自4.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。所述DSC的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述的热重分析(TGA)图在TA Q500上采集。所述TGA的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。仪器控制软件是DVS-Intrinsic。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N 2,200毫升/分钟
相对湿度范围：0％RH-95％RH
核磁共振氢谱数据( 1H NMR)采自于Bruker Avance II DMX 400M Hz核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配成2-10mg/mL的溶液。
本发明中的动态溶解度测试参数如表1。
表1
Figure PCTCN2020135824-appb-000006
Figure PCTCN2020135824-appb-000007
本发明中原料药长期和加速条件放置6个月后的稳定性检测方法如表2。
表2
Figure PCTCN2020135824-appb-000008
本发明中原料药稳定性起始及60℃/75％RH放置1个月及制剂稳定性检测方法如表3。
表3
Figure PCTCN2020135824-appb-000009
Figure PCTCN2020135824-appb-000010
本发明中制剂溶出度检测方法如表4。
表4
Figure PCTCN2020135824-appb-000011
除非特殊说明，以下实施例均在室温条件下操作。所述“室温”不是特定的温度值，是指10-30℃温度范围。
根据本发明，作为原料的所述化合物I包括但不限于固体形式(结晶或无定形)、油状、液体形式和溶液。优选地，作为原料的化合物I为固体形式。
以下实施例中所使用的化合物I可根据现有技术制备得到，例如根据WO2010046835A1所记载的方法制备获得。
具体实施方式
实施例1晶型CSII的制备方法
将8.6mg化合物I晶型III置于4mL玻璃小瓶中，封口并在瓶盖上戳孔，将该玻璃小瓶置于装有5.0mL甲苯的20-mL密封玻璃瓶中，室温下放置42天得到固体。
经检测，所得结晶固体为本发明提供的晶型CSII，其XRPD图如图1所示，XRPD数据如表5所示。
DSC如图2所示，在105℃附近开始出现熔化吸热峰。
TGA如图3所示，将其加热至100℃时，具有约0.3％的质量损失。
表5
衍射角2θ d值 强度％
5.23 16.90 29.87
8.44 10.48 23.14
10.46 8.46 85.01
12.25 7.22 32.70
12.81 6.91 6.66
13.79 6.42 6.69
15.73 5.64 1.32
16.88 5.25 100.00
17.48 5.07 18.90
19.80 4.48 2.33
20.72 4.29 5.51
21.12 4.21 8.03
21.81 4.07 8.05
22.85 3.89 12.90
23.47 3.79 15.47
24.30 3.66 1.53
24.67 3.61 1.98
25.10 3.55 5.54
25.66 3.47 15.58
26.94 3.31 10.77
27.38 3.26 5.77
28.67 3.11 5.76
29.48 3.03 1.47
30.44 2.94 1.13
32.94 2.72 1.48
35.48 2.53 2.01
36.21 2.48 1.86
36.58 2.46 2.38
37.31 2.41 1.73
38.27 2.35 1.89
实施例2晶型CSII的制备方法
称取92.1mg化合物I的无定形和8.8mg晶型CSII晶种，置于20mL玻璃瓶中，加入5mL的甲苯形成悬浊液，将悬浊液在-20℃搅拌约1天，分离固体并在25℃下真空干燥50分钟，得到结晶固体。
经检测，所得结晶固体为本发明提供的晶型CSII，其X射线粉末衍射图如图4，X射线粉末衍射数据如表6所示。
表6
衍射角2θ d值 强度％
5.22 16.94 17.06
6.87 12.87 0.61
8.43 10.49 33.03
10.46 8.46 57.68
12.24 7.23 40.31
12.79 6.92 3.84
13.80 6.42 4.89
15.72 5.64 1.06
16.87 5.26 100.00
17.42 5.09 9.51
17.98 4.93 2.58
19.82 4.48 2.84
20.52 4.33 4.79
20.72 4.29 5.08
21.15 4.20 7.53
21.85 4.07 6.45
22.83 3.89 13.81
23.43 3.80 13.41
24.29 3.66 1.55
24.57 3.62 1.75
25.05 3.55 5.12
25.65 3.47 11.98
26.92 3.31 8.32
27.36 3.26 4.32
27.78 3.21 1.41
28.72 3.11 5.16
29.35 3.04 1.02
30.43 2.94 0.51
31.56 2.84 0.60
32.95 2.72 1.63
34.08 2.63 0.44
35.44 2.53 1.76
36.11 2.49 1.58
36.54 2.46 1.57
37.75 2.38 1.38
38.21 2.36 1.07
39.31 2.29 0.52
实施例3晶型CSII的核磁
称量1-5mg本发明提供的晶型CSII，用0.5mL氘代二甲亚砜溶解，配成2-10mg/mL的溶液。利用核磁共振波谱仪采集核磁共振氢谱数据( 1H NMR)。核磁数据显示晶型CSII结构与化合物I一致，且未检测到任何溶剂，证明本发明提供的晶型CSII无溶残。核磁数据如下： 1H NMR(400MHz,DMSO)δ7.78(d,J＝2.2Hz,1H),7.72(s,1H),7.64(dd,J＝8.7,2.2Hz,1H),7.43–7.21(m,5H),5.03(d,J＝5.1Hz,1H),4.71(t,J＝5.7Hz,1H),4.17(dd,J＝10.1,4.4Hz,1H),4.08(dd,J＝10.1,5.7Hz,1H),3.85(d,J＝5.0Hz,1H),3.50(td,J＝5.6,2.4Hz,2H),3.38–3.32(m,1H),3.30–3.24(m,1H),2.09(s,3H),1.52(dd,J＝14.1,7.2Hz,2H),0.84(t,J＝7.4Hz,3H)。
WO2010046835A1披露晶型C包含微量的叔丁基甲基醚。本发明提供的晶型CSII无溶剂残留。
实施例4晶型CSII的溶解度
进行药物溶解度测试以预测药物体内性能的时候，很重要的一点是尽可能的模拟体内条件。对口服药，用SGF(模拟胃液)、FaSSIF(模拟禁食状态肠液)、FeSSIF(模拟进食状态肠液)可以模拟体内条件并预测进食的影响。在此类介质中测试的溶解度与人体环境中的溶解度更加接近。
以WO2017107972A1记载的方法测试本发明提供的晶型CSII在SGF、FaSSIF、FeSSIF和H 2O中平衡24小时后的溶解度，结果如表7所示。
表7
Figure PCTCN2020135824-appb-000012
Figure PCTCN2020135824-appb-000013
ND：低于仪器的检测限度。
以WO2019060147A1记载的方法测试晶型CSII在pH1.2的缓冲溶液中平衡一小时的溶解度，结果如表8所示。
表8
Figure PCTCN2020135824-appb-000014
结果表明，晶型CSII相较于现有技术具有更高的溶解度。
实施例5晶型CSII的稳定性
称取6份5mg的本发明提供的晶型CSII，分别在25℃/60％RH、40℃/75％RH、60℃/75％RH条件下放置一定时间，采用HPLC和XRPD测定纯度与晶型，结果如表9所示。
表9
Figure PCTCN2020135824-appb-000015
结果表明，晶型CSII在25℃/60％RH和40℃/75％RH条件下至少可稳定6个月，可见，晶型CSII在长期和加速条件下均可保持良好的稳定性。60℃/75％RH条件下放置至少可稳定1个月，可见在更严苛的条件下，晶型CSII也有良好的稳定性。
实施例6晶型CSII的引湿性
称取本发明提供的晶型CSII、晶型C各约10mg，采用动态水分吸附(DVS)仪测试其引湿性，在0-95％-0相对湿度下循环一次，记录每个湿度下的质量变化，并且在DVS测试前后进行XRPD测试。实验结果如表10所示，晶型CSII的引湿性测定前后的XRPD如图8所示。
表10
Figure PCTCN2020135824-appb-000016
晶型CSII在80％RH条件下引湿性增重为0.12％，属于无或几乎无引湿性。晶型CSII在40％至80％RH的增重为0.07％，晶型C在40％至80％RH的增重为0.1％，晶型CSII的引湿性优于WO2010046835A1晶型C。
关于引湿性特征描述与引湿性增重的界定(中国药典2020年版通则9103药物引湿性试验指导原则，实验条件：25℃±1℃，80％±2％相对湿度)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15.0％
有引湿性：引湿增重小于15.0％但不小于2.0％
略有引湿性：引湿增重小于2.0％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
(欧洲药典第九版5.11中对引湿性的界定与中国药典一致)
实施例7晶型CSII制剂的稳定性
将本发明制得的晶型CSII采用表11、表12所述制剂处方和工艺制成制剂，并测试晶型CSII制剂前后的XRPD，XRPD对比图如图9所示，纯度对比数据如表13所示。结果表明，晶型CSII在制剂前后晶型保持稳定，晶型纯度基本不变。
表11
Figure PCTCN2020135824-appb-000017
表12
Figure PCTCN2020135824-appb-000018
Figure PCTCN2020135824-appb-000019
表13
样品 纯度％
晶型CSII原料药 99.61
晶型CSII制剂 99.62
将上述制剂在40℃/75％RH放置，测试该制剂的稳定性，结果如表14所示，XRPD对比图如图10所示。结果表明，晶型CSII制剂在40℃/75％RH条件下至少可以稳定3个月。
表14
放置条件 放置时间 晶型 纯度％
起始制剂样品 —— 晶型CSII 99.62
40℃/75％RH 3个月 晶型CSII 99.64
实施例8晶型CSII制剂的体外溶出度
将本发明制得的晶型CSII和WO2010046835A1晶型A根据实施例7所述制剂处方和工艺制成固体胶囊，去除胶囊壳后进行粉末溶出测试，将其在pH 6.8的磷酸盐缓冲盐溶液(PBS)中测试不同时间的累计溶出度，测试参数如表15所示，测试结果见表16和图11。
表15
Figure PCTCN2020135824-appb-000020
表16
Figure PCTCN2020135824-appb-000021
Figure PCTCN2020135824-appb-000022
在含0.5％十二烷基硫酸钠的pH6.8磷酸盐缓冲盐溶液中，晶型CSII的溶出度高于WO2010046835A1晶型A。本发明提供的晶型CSII具有更优的生物利用度。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (10)

  1. 一种Ponesimod
    Figure PCTCN2020135824-appb-100001
    的晶型CSII，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为5.2°±0.2°、10.5°±0.2°、16.9°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型CSII，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为8.4°±0.2°、12.3°±0.2°、17.5°±0.2°中的1处或2处或3处具有特征峰。
  3. 根据权利要求1所述的晶型CSII，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为22.9°±0.2°、23.5°±0.2°、25.7°±0.2°中的1处或2处或3处具有特征峰。
  4. 一种权利要求1所述的晶型CSII的制备方法，其特征在于：将Ponesimod晶型III置于芳香烃类、烷烃类或醇类溶剂的气氛中气固扩散得到；或
    将Ponesimod晶型III或者无定形置于芳香烃类溶剂中搅拌得到，所述晶型III的特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在衍射角2θ值为8.5°±0.2°、10.7°±0.2°、14.7°±0.2°、15.2°±0.2°、18.0°±0.2°、22.4°±0.2°、23.4°±0.2°、26.9°±0.2°处有特征峰。
  5. 根据权利要求4所述的制备方法，其特征在于所述芳香烃类溶剂为C7-C9的芳香烃。
  6. 根据权利要求4所述的制备方法，所述烷烃类溶剂为正己烷，所述醇类溶剂为正戊醇。
  7. 根据权利要求5所述的制备方法，其特征在于所述C7-C9的芳香烃为甲苯。
  8. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1中所述的晶型CSII及药学上可接受的辅料。
  9. 权利要求1中所述的晶型CSII在制备选择性S1P1受体激动剂药物中的用途。
  10. 权利要求1中所述的晶型CSII在制备治疗多发性硬化症药物中的用途。
PCT/CN2020/135824 2020-01-19 2020-12-11 一种ponesimod的晶型及其制备方法和用途 WO2021143414A1 (zh)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102177144A (zh) * 2008-10-20 2011-09-07 埃科特莱茵药品有限公司 (r)-5-[3-氯-4-(2,3-二羟基-丙氧基)-苯并[z]亚基]-2-([z]-丙基亚胺基)-3-邻甲苯基-噻唑烷-4-酮的晶形
WO2017107972A1 (zh) * 2015-12-25 2017-06-29 苏州晶云药物科技有限公司 一种选择性s1p1受体激动剂的新晶型及其制备方法
WO2019060147A1 (en) * 2017-09-19 2019-03-28 Teva Pharmaceuticals Usa, Inc. NEW CRYSTALLINE POLYMORPHE FROM PONESIMOD

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102177144A (zh) * 2008-10-20 2011-09-07 埃科特莱茵药品有限公司 (r)-5-[3-氯-4-(2,3-二羟基-丙氧基)-苯并[z]亚基]-2-([z]-丙基亚胺基)-3-邻甲苯基-噻唑烷-4-酮的晶形
WO2017107972A1 (zh) * 2015-12-25 2017-06-29 苏州晶云药物科技有限公司 一种选择性s1p1受体激动剂的新晶型及其制备方法
WO2019060147A1 (en) * 2017-09-19 2019-03-28 Teva Pharmaceuticals Usa, Inc. NEW CRYSTALLINE POLYMORPHE FROM PONESIMOD

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