WO2022052969A1 - 环丝氨酸晶型及其制备方法 - Google Patents

环丝氨酸晶型及其制备方法 Download PDF

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WO2022052969A1
WO2022052969A1 PCT/CN2021/117351 CN2021117351W WO2022052969A1 WO 2022052969 A1 WO2022052969 A1 WO 2022052969A1 CN 2021117351 W CN2021117351 W CN 2021117351W WO 2022052969 A1 WO2022052969 A1 WO 2022052969A1
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cycloserine
crystal form
volume ratio
present
isopropanol
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PCT/CN2021/117351
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English (en)
French (fr)
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李娜
陈连蔚
施珍娟
赵美玉
郑剑锋
苏笛
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浙江海正药业股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • 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
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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

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  • the present invention relates to the field of chemical pharmacy. More specifically, the present invention relates to crystal forms I and II of cycloserine and a method for preparing the crystal forms.
  • the cycloserine prepared by the method of the present invention has a larger average particle size and good fluidity.
  • D-cycloserine is a broad-spectrum polypeptide antibiotic produced by Streptomyces lavendulae and S. orchidaceus or chemically synthesized.
  • Cycloserine has a broad antibacterial spectrum.
  • Mycobacterium tuberculosis it also has inhibitory effects on most Gram-positive and negative bacteria, rickettsia and some protozoa. Acid, isoniazid, pyrazinamide and other drug-resistant Mycobacterium tuberculosis also have a role.
  • D-alanine Because it is a structural analog of D-alanine, it can compete with D-alanine to inhibit two important enzymes in the synthesis of peptidoglycan, alanine racemase and D-alanyl- D-alanine synthase. Its anti-mycobacterium tuberculosis (Mycobacterium tuberculosis) ability is weak, only 1/10 ⁇ 1/20 of streptomycin. The advantage is that it is effective against drug-resistant strains of the bacteria, and it is not easy to develop drug resistance to it. This product can be used in combination with other anti-tuberculosis drugs to treat tuberculosis caused by drug-resistant Mycobacterium tuberculosis.
  • Mycobacterium tuberculosis Mycobacterium tuberculosis
  • the antibacterial mechanism of cycloserine is to inhibit the synthesis of bacterial cell wall mucopeptides, thereby causing cell wall defects.
  • the main structural component of bacterial cell wall is cell wall mucopeptide, which is composed of N-acetylglucosamine (GNAc) and N-acetylmuramic acid (MNAc) linked to pentapeptide.
  • GAAc N-acetylglucosamine
  • MNAc N-acetylmuramic acid
  • the formation of intracytoplasmic mucopeptide precursors can be blocked by cycloserine, which blocks the formation of N-acetylmuramic acid pentapeptides by inhibiting D-alanine racemase and synthase.
  • oral administration still accounts for about 80% of human administration routes.
  • tablets are the main oral administration method, and most of the domestic tablet production methods are wet granulation processes.
  • wet granulation may affect the quality of the drug; on the other hand, the wet granulation and drying processes have strict requirements on process parameters, and slight changes in process parameters have a negative impact on the quality of the final product. Influence, it is difficult to grasp in the large-scale production process, which will bring hidden risks to product quality.
  • the direct mixing process is derived from the direct powder compression method, and compared with the wet granulation and tableting method, the significant advantage of the powder direct compression method is its economy, which greatly reduces the production and testing costs.
  • the direct mixing process reduces the wet granulation and drying processes, improves the process adaptability, reduces the risk of product quality, shortens the production cycle, saves production time and energy, has strong operability, small batch differences, and continuous production is guaranteed.
  • the key to the direct mixing process is whether the mixed material has the fluidity and compressibility required for tableting. Therefore, the fluidity requirements of API are relatively high. Liang Fenglin et al. described in the journal "Application of Direct Mixing Process in Oral Preparations and Analysis of Influencing Factors": In the direct mixing process, the powder with a particle size of about 300 ⁇ m has good fluidity, The extruded tablets have high hardness, better drug uniformity and solubility, and are similar to wet granulation tablets in terms of friability, dissolution and hardness.
  • the preparation of cycloserine tablets by the direct mixing process has high requirements on the crystal habit, particle size and fluidity of cycloserine.
  • the cycloserine crystals obtained by the prior art CN110183391A have small particles, poor fluidity, and low yield;
  • CN105646385A has a long refining time, and the preparation method is a repetitive process of standing-stirring-standing-stirring, and the crystals are easy to agglomerate, stick to walls, Sticky paddle, uneven particles.
  • the existing technology cannot meet the requirements of the direct mixing process for cycloserine API. To this end, it is necessary to develop new cycloserine crystal forms with good fluidity to solve the above problems.
  • the present invention provides cycloserine crystal forms I and II with good fluidity.
  • the crystal form I of cycloserine according to the present invention is referred to as crystal form I in the present invention.
  • the X-ray powder diffraction pattern of the crystal form I of the present invention has characteristic peaks at the following diffraction angles 2 ⁇ : 11.88 ⁇ 0.2°, 15.40 ⁇ 0.2°, 17.08 ⁇ 0.2°, 18.42 ⁇ 0.2°, 23.72 ⁇ 0.2°, 24.48 ⁇ 0.2°, 27.66 ⁇ 0.2°, 28.66 ⁇ 0.2°, 34.40 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form I of the present invention has the 2 ⁇ value, the interplanar spacing d value and the relative intensity data as shown in Table 1 below:
  • the X-ray powder diffraction pattern of Form I of the present invention is substantially as shown in FIG. 1 .
  • the differential scanning calorimetry (DSC) pattern of the crystal form I of the present invention has an endothermic peak with a Peak value of 70.8°C and a decomposition peak with a Peak value of 154.9°C.
  • the crystal form I of the present invention has a DSC pattern as shown in FIG. 2 .
  • thermogravimetric analyzer (TGA) spectrum of the crystal form I of the present invention has two steps, and the weight loss of the first step is 15.44%.
  • the crystal form I of the present invention has a TGA pattern as shown in FIG. 3 .
  • the moisture content of the crystal form I of the present invention is 15.47%, combined with TGA data, it shows that the crystal form I of the present invention is a monohydrate.
  • Another object of the present invention also is to provide a method for preparing the crystal form I, the method comprising the following steps:
  • step (1) the solution that step (1) obtains is mixed with alcoholic solvent
  • step (3) The mixture obtained in step (2) is added to a mixed solution of acetic acid and isopropanol with a volume ratio of 1:1 at -15°C to -10°C, seed crystals are added, and the mixture is stirred for 0.5 to 1 h;
  • the mass volume ratio of cycloserine and the ammonia solution is 1:5 ⁇ 10, and the unit is g/ml; the concentration of the ammonia solution is 1.8 ⁇ 2.2mol/L.
  • the alcohol solvent in step (2) is a mixture of isopropanol and ethanol, wherein the volume ratio of isopropanol and ethanol is 1:2 to 2:1; in the step (2), cycloserine and alcohols
  • the mass-volume ratio of the solvent is 1:20-40, and the unit is g/ml.
  • the mass-volume ratio of cycloserine in step (3) to the mixed solution of acetic acid and isopropanol with a volume ratio of 1:1 is 1:1.2-2.4, and the unit is g/ml.
  • Another object of the present invention is to provide a method for preparing the crystal form II of cycloserine (referred to as crystal form II in the present invention) with good fluidity, the method comprising vacuum drying the crystal form I at 35-40°C for 6- 8h, the vacuum degree is -0.08 ⁇ -0.095Mpa.
  • the X-ray powder diffraction pattern of the crystal form II of the present invention has characteristic peaks at the following diffraction angles 2 ⁇ : 9.64 ⁇ 0.2°, 18.78 ⁇ 0.2°, 19.44 ⁇ 0.2°, 20.88 ⁇ 0.2°, 22.12 ⁇ 0.2°, 23.50 ⁇ 0.2°, 29.44 ⁇ 0.2°, 31.68 ⁇ 0.2°, 33.16 ⁇ 0.2°, 33.50 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form II of the present invention has the 2 ⁇ value, the interplanar spacing d value and the relative intensity data as shown in Table 2 below:
  • Peak number 2 ⁇ (°) d(A) Relative Strength(%) 1 9.64 9.17 24.6 2 18.78 4.72 38.5 3 19.44 4.56 100 4 20.88 4.25 22.6 5 22.12 4.02 39.6 6 23.50 3.78 19.2 7 29.44 3.03 94.6 8 31.68 2.82 17.1 9 33.16 2.70 13.0 10 33.50 2.67 15.4
  • the X-ray powder diffraction pattern of Form II of the present invention is substantially as shown in FIG. 4 .
  • the differential scanning calorimetry (DSC) pattern of the crystal form II of the present invention has a decomposition peak with a Peak value of 156.2°C.
  • the crystal form II of the present invention has a DSC pattern as shown in FIG. 5 .
  • thermogravimetric analyzer (TGA) spectrum of the crystal form II of the present invention has a step.
  • the crystal form II of the present invention has a TGA pattern as shown in FIG. 6 .
  • the crystal form II of the present invention is anhydrous.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the crystal form I and/or crystal form II of the present invention, and one or more pharmaceutically acceptable carriers.
  • the present invention provides the application of crystal form I and/or crystal form II and the pharmaceutical composition thereof in the preparation of a medicine for treating drug-resistant tuberculosis infection.
  • the crystal form I prepared by the preparation method of the present invention is a cycloserine monohydrate crystal with good crystal habit, particle size and fluidity.
  • the crystal form I of the present invention has uniform particle size distribution and larger particle size, the crystal structure is similar to that of a single crystal, the aspect ratio is within 3:1, the fluidity is good, the particle size uniformity is good, it is easy to filter during production, and the solvent residue is low. It is beneficial to maintain good stability during storage.
  • the crystal I of the present invention has the advantages of simple process, convenient operation, little pollution and industrialized production.
  • the crystal form II obtained by the crystal form I of the present invention retains the crystal habit, particle size and good fluidity of the crystal form I.
  • the crystal form II of the invention has uniform particle size distribution and large particle size, the crystal structure is similar to that of a single crystal, the aspect ratio is within 3:1, the particle size uniformity is good, and the fluidity is good.
  • the crystallization process is cumbersome, the particles are small, and the particles are not uniform.
  • the crystallization process of the invention is simple, easy to operate, has little pollution, and has the advantages of realizing industrialized production.
  • the inventors have conducted a large number of experimental studies and found that after obtaining the crystal form I (monohydrate crystal) of cycloserine with good particle size and fluidity, the cycloserine crystal form I (monohydrate) is baked.
  • the cycloserine crystal II retains the good crystal habit, particle size and fluidity of the cycloserine crystal form I (monohydrate crystal), which solves the problem of the poor fluidity of the cycloserine API in the prior art. , difficult to unload, etc.
  • Fig. 1 is the X-ray powder diffraction pattern of the crystal form I obtained in Example 1;
  • Fig. 2 is the DSC spectrum of crystal form I obtained in Example 1;
  • Fig. 3 is the TGA spectrum of the crystal form I gained in Example 1;
  • Fig. 4 is the X-ray powder diffraction pattern of the crystal form II obtained in Example 4.
  • Fig. 5 is the DSC spectrum of crystal form II obtained in Example 4.
  • Fig. 6 is the TGA spectrum of the crystal form II obtained in Example 4.
  • Fig. 7 is the X-ray powder diffraction pattern of CN110183391A cycloserine
  • Fig. 8 is the X-ray powder diffraction pattern of CN105646385A cycloserine
  • Fig. 9 is the microscope photograph (10 ⁇ 10) of crystal form I obtained in Example 1;
  • Figure 10 is a microscope photograph (10 ⁇ 10) of the crystal form II obtained in Example 4.
  • Figure 11 is a microscope photo of CN110183391A cycloserine (10 ⁇ 10);
  • Figure 12 is a microscope photo of CN105646385A cycloserine (10 ⁇ 10);
  • Figure 13 is the particle size distribution diagram of crystal form I obtained in Example 1;
  • Figure 14 is the particle size distribution diagram of crystal form II obtained in Example 4.
  • the crude cycloserine used in the method of the present invention can be prepared according to Example 1 disclosed in Patent CN110183391A, including but not limited to the above sources.
  • the solvent used in the present invention is not particularly limited, and commercially available conventional solvents can be used.
  • stirring described in the method of the present invention may adopt conventional methods in the art, for example, stirring methods include magnetic stirring and mechanical stirring, and the stirring speed is 150-300 rpm/min.
  • the X-ray powder diffraction instrument involved in the present invention and the test conditions are: X-diffraction instrument model MiniFlex600Cu target; operation method: scanning speed 20°/min, scanning step width 0.02°.
  • the DSC test conditions involved in the present invention are: the model of the DSC detector is: NETZSCH DSC 214 Polyma; the operation method: the heating rate is 10°C/min, and the temperature range: 25-200°C.
  • the TGA test conditions involved in the present invention are: the model of the TGA detector is: METTLER TOLEDO TGA2; the operation method: the heating rate is 10°C/min, and the temperature range: 30-250°C.
  • the moisture test conditions involved in the present invention are as follows: the model of the moisture tester is: Mettler V20 moisture meter, which is tested by Karl Fischer titration.
  • the model of the particle size tester involved in the present invention is: BT-2001 laser particle size distribution analyzer.
  • the OLYMPUS microscope involved in the present invention is CX31 (10 ⁇ 10).
  • the specific rotation test conditions involved in the present invention are: the specific rotation tester model is: GE automatic polarimeter Autopol V; Operation method: take cycloserine, accurately weigh, add 2mol/L sodium hydroxide solution to dissolve and dilute to prepare Test into a solution containing about 50 mg per 1 ml.
  • the crystal seed involved in the present invention has no special requirements on its crystal habit and particle size, and can be a crude cycloserine product or a finished cycloserine product.
  • the seed crystals added in the embodiment of the present invention are all crude cycloserine products.
  • cycloserine crude product 500g was dissolved in 2.5L of 1.8mol/L ammonia solution, mixed with 10L of isopropanol and ethanol mixed solvent, the volume ratio of isopropanol to ethanol was 1:2, cooled to -15°C, added 6L of a mixed solution of acetic acid and isopropanol with a volume ratio of 1:1, add seed crystals, the seed crystal is crude cycloserine, stir for 0.5h, and continue to add dropwise a mixed solution of acetic acid and isopropanol with a volume ratio of 1:1 Adjust pH to 6. It was stirred for 1 h and filtered to obtain 490 g of crystals with a purity of 99.96%. It was confirmed to be crystal form I by measuring the X-ray powder diffraction pattern (XRD).
  • the particle size characteristic parameters of crystal form I are shown in Table 3, and the particle size distribution diagram of crystal form I is shown in Fig. 13 .
  • XRD X-ray powder diffraction pattern
  • Example 1 100g of the cycloserine crystal form I obtained in Example 1 was vacuum-dried at 35°C for 8h, and the vacuum degree was -0.08MPa.
  • the X-ray powder diffraction pattern (XRD) was measured to confirm that it was crystal form II, and 85.02g of crystals were obtained with a purity of 85.02g. is 99.96%.
  • the particle size characteristic parameters of the crystal form II are shown in Table 4, and the particle size distribution diagram of the crystal form II is shown in FIG. 14 .
  • Example 1 100 g of the cycloserine crystal form I obtained in Example 1 was vacuum-dried at 40° C. for 6 h, with a vacuum degree of -0.095 MPa, and 84.66 g of crystals were obtained by measuring the X-ray powder diffraction pattern (XRD), with a purity of 99.96%. Confirmed to be Form II.
  • XRD X-ray powder diffraction pattern
  • CN110183391A cycloserine sample was prepared according to the preparation method of Example 1 of CN110183391A.
  • CN105646385A cycloserine sample was prepared according to the preparation method in paragraphs [0040] to [0053] of CN105646385A.
  • the cycloserine of CN110183391A and CN105646385A are block-shaped and slender rod-shaped with smaller particles, respectively, and the length and width are relatively large, which is not easy to filter during production, which easily leads to high residual solvent, and the friction between particles is relatively high. Large, the material fluidity is small, which is not conducive to material storage and processing.
  • the crystal form I and crystal form II of the present invention have relatively uniform particles, small length-width ratio, within 3:1, good material fluidity, favorable for filtration during production, and less residual solvent in the obtained material, which is beneficial to the storage stability of the material sex and subsequent processing operations.
  • the cycloserine samples of CN110183391A and CN105646385A obtained from the crystal form I, crystal form II and preparation examples of the present invention were detected by a 50ml measuring cylinder, and the bulk density and solid density were tested, and the results were shown in Table 5; the angle of repose method was used to measure the angle of repose , the results are shown in Table 6.
  • the compressibility and the angle of repose of the crystal form I and the crystal form II of the present invention are basically the same, and both are lower than those of cycloserine of CN110183391A and CN105646385A.
  • Lower compressibility and lower angle of repose indicate better fluidity of the corresponding material. Therefore, the fluidity of the crystal form I and the crystal form II of the present invention is better than that of the cycloserine obtained according to the preparation methods of CN110183391A and CN105646385A.
  • the crystal form II of the present invention retains the good fluidity of the crystal form I.
  • the cycloserine of CN110183391A and CN105646385A begins to agglomerate when placed at 60°C for 3 days, while the crystal form II obtained by the present invention is still powdery; Under the condition of 25 ° C, the specific rotation and the decreasing speed of the purity of the cycloserine crystal form II obtained by the present invention are all smaller than the specific rotation and the decreasing speed of the purity of the cycloserine obtained by CN110183391A and CN105646385A.
  • the decreasing speed of the specific rotation and the purity of cycloserine is obviously greater than the decreasing speed of the specific rotation and the purity of the cycloserine crystal form II obtained by the present invention. It is shown that the stability of the crystal form II obtained by the present invention is better than that of the cycloserine obtained by CN110183391A and CN105646385A at 60°C and 25°C.

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Abstract

本发明涉及环丝氨酸的晶型I和II及它们的制备方法。所述晶型I及晶型II粒径分布均匀且粒度较大，晶体结构类似于单晶，长宽比在3:1以内，流动性好，在加工适应性方面均具有优异的性质，很好的解决了制剂过程中混样不均的问题。

Description

环丝氨酸晶型及其制备方法 技术领域
本发明涉及化学制药领域。更具体地说，本发明涉及环丝氨酸的晶型I和II以及所述晶型的制备方法，通过本发明的方法制备得到的环丝氨酸平均粒径较大，流动性好。
技术背景
D-环丝氨酸是一种由淡紫灰链霉菌(Streptomyces lavendulae)和兰花链霉菌(S.orchidaceus)产生或由化学合成的多肽类广谱抗生素。用于耐药性结核杆菌的感染。环丝氨酸的抗菌谱广，除结核杆菌外，对大多数革兰阳性与阴性细菌、立克次体以及某些原虫等也都有抑制作用，对链霉素、紫霉素、对氨基水杨酸、异烟肼、吡嗪酰胺等耐药的结核杆菌也有作用。因它是D-丙氨酸的结构类似物，可与D-丙氨酸竞争性地抑制肽聚糖合成过程中的两个重要酶——丙氨酸消旋酶和D-丙氨酰-D-丙氨酸合成酶。其抗结核分枝杆菌(Mycobacteriumtuberculosis)的能力弱，仅为链霉素的1/10～1/20。优点为对该菌的耐药株有效，且不易对它产生耐药性。本品可与其他抗结核药合用以治疗由耐药性结核分枝杆菌所引起的结核病。环丝氨酸的抗菌作用机制是抑制细菌细胞壁粘肽的合成，从而使细胞壁缺损。细菌细胞壁主要结构成分是胞壁粘肽，由N-乙酰葡萄糖胺(GNAc)和与五肽相连的N-乙酰胞壁酸(MNAc)重复交替联结而成。胞浆内粘肽前体的形成可被环丝氨酸所阻碍，环丝氨酸通过抑制D-丙氨酸的消旋酶和合成酶可阻碍N-乙酰胞壁酸五肽的形成。
环丝氨酸化学名为:D-4-氨基-3-异噁唑烷酮，其结构式如下所示:
Figure PCTCN2021117351-appb-000001
目前，口服给药仍占据人体给药途径的80％左右。其中，片剂是主要口服给药方式，现在国内片剂生产方法大多是湿法制粒工艺。一方面，对于遇湿和热易发生性质改变的药物，湿法制粒可能会影响药物质量；另一方面，制湿颗粒及干燥过程对工艺参数要求严格，工艺参数的稍微变化对最终产品质量有影响，大生产过程中较难把握，会给产品质量带来风险隐 患。
直混工艺来源于粉末直接压片法，而粉末直接压片法与湿法制粒压片法比较，显著的优势还在于其经济性，大大降低了生产及检测成本。直混工艺减少了制湿颗粒及干燥工序，提高了工艺适应性，降低产品质量风险的同时，缩短了生产周期，节约生产时间和能源，操作性强，批间差异小，连续生产有保证。
直混工艺的关键在于混合后物料是否具有压片所要求的的流动性和可压性。因此，对API的流动性要求较高，梁凤林等在期刊“直混工艺在口服制剂中的应用及影响因素分析”中描述:在直混工艺中，粒径约为300μm的粉末流动性好，压出的片子硬度高、药物均一度和溶解性都比较好，和湿法制粒片在脆碎度、溶出度和硬度方面都相似。
采用直混工艺制备环丝氨酸片剂，对环丝氨酸的晶习、颗粒度及流动性的要求较高。现有技术CN110183391A获得的环丝氨酸晶体颗粒小，流动性差，且收率低；CN105646385A精制时间长，且制备方法为静置-搅拌-静置-搅拌的重复过程，晶体容易结块、粘壁、粘桨，颗粒不均匀。目前，现有技术不能满足直混工艺对环丝氨酸API的要求。为此，有必要开发新的具有良好流动性的环丝氨酸晶型，以解决上述问题。
发明内容
因此，针对上述现有技术中存在的问题，本发明提供了流动性很好的环丝氨酸晶型I和II。
本发明所述的环丝氨酸的晶型I，在本发明中称作晶型I。本发明的晶型I的X-射线粉末衍射图谱在以下衍射角2θ处具有特征峰:11.88±0.2°、15.40±0.2°、17.08±0.2°、18.42±0.2°、23.72±0.2°、24.48±0.2°、27.66±0.2°、28.66±0.2°、34.40±0.2°。
更进一步地，本发明的晶型I的X-射线粉末衍射图谱具有如下表1所示的2θ值、晶面间距d值和相对强度数据:
表1
峰编号 2θ(°) d(A) 相对强度(％)
1 11.88 7.44 3.0
2 15.40 5.75 1.7
3 17.08 5.19 32.3
4 18.42 4.81 3.4
5 23.72 3.75 100.0
6 24.48 3.63 9.0
7 27.66 3.22 8.9
8 28.66 3.11 19.8
9 34.40 2.60 6.3
非限制性地，本发明的晶型I的X-射线粉末衍射图谱基本上如图1所示。
本发明所述晶型I的差示扫描量热(DSC)图谱存在一个吸热峰Peak值为70.8℃，一个分解峰Peak值为154.9℃。
非限制性地，本发明的晶型I具有如图2所示的DSC图谱。
本发明所述晶型I的热重分析仪(TGA)图谱存在两个台阶，第一台阶失重为15.44％。
非限制性地，本发明的晶型I具有如图3所示的TGA图谱。
本发明所述晶型I的水分含量为15.47％，结合TGA数据，表明本发明的晶型I为一水合物。
本发明的另一目的还在于提供制备所述晶型I的方法，该方法包括以下步骤:
(1)将环丝氨酸溶于氨水溶液中；
(2)步骤(1)得到的溶液与醇类溶剂混合；
(3)步骤(2)得到的混合物于-15℃～-10℃加入体积比为1：1的乙酸和异丙醇的混合溶液，加晶种，搅拌0.5～1h；
(4)继续滴加体积比为1：1的乙酸和异丙醇的混合溶液调节pH至6～8；
(5)搅拌1～2h，过滤，得晶型I。
优选地，其中，上述步骤(1)中环丝氨酸与氨水溶液的质量体积比为1:5～10，其单位为g/ml；所述氨水溶液的浓度为1.8～2.2mol/L。
优选地，步骤(2)中的醇类溶剂为异丙醇与乙醇的混合物，其中异丙醇与乙醇的体积比为1:2～2:1；所述步骤(2)中环丝氨酸与醇类溶剂的质量体积比为1:20～40，其单位为g/ml。
优选地，步骤(3)中的环丝氨酸与体积比为1：1的乙酸和异丙醇的混合溶液的质量体积比为1:1.2～2.4，其单位为g/ml。
本发明的另一目的还在于提供流动性良好的环丝氨酸的晶型II(在本发明中称作晶型II)的制备方法，该方法包括将晶型I在35～40℃真空干燥6～8h，真空度为-0.08～-0.095Mpa。
本发明的晶型II的X-射线粉末衍射图谱在以下衍射角2θ处具有特征峰:9.64±0.2°、18.78±0.2°、19.44±0.2°、20.88±0.2°、22.12±0.2°、23.50±0.2°、29.44±0.2°、31.68±0.2°、33.16±0.2°、33.50±0.2°。
更进一步地，本发明的晶型II的X-射线粉末衍射图谱具有如下表2所示的2θ值、晶面间距d值和相对强度数据:
表2
峰编号 2θ(°) d(A) 相对强度(％)
1 9.64 9.17 24.6
2 18.78 4.72 38.5
3 19.44 4.56 100
4 20.88 4.25 22.6
5 22.12 4.02 39.6
6 23.50 3.78 19.2
7 29.44 3.03 94.6
8 31.68 2.82 17.1
9 33.16 2.70 13.0
10 33.50 2.67 15.4
非限制性地，本发明的晶型II的X-射线粉末衍射图谱基本上如图4所示。
本发明所述晶型II的差示扫描量热(DSC)图谱存在一个分解峰Peak值为156.2℃。
非限制性地，本发明的晶型II具有如图5所示的DSC图谱。
本发明所述晶型II的热重分析仪(TGA)图谱存在一个台阶。
非限制性地，本发明的晶型II具有如图6所示的TGA图谱。
结合DSC及TGA数据，表明本发明的晶型II为无水物。
更进一步地，本发明提供一种药物组合物，所述药物组合物包括本发明的晶型I和/或晶型II，和一种或多种可药用的载体。
更进一步地，本发明提供晶型I和/或晶型II及其药物组合物在制备治疗耐药结核杆菌感染的药物中的应用。
采用本发明的制备方法制备得到的晶型I，其为具有良好的晶习、颗粒度和流动性的环丝氨酸一水合物晶体。本发明晶型I的粒径分布均匀且粒度较大，晶体结构类似于单晶，长宽比在3:1以内，流动性好，粒度均一性好，生产中容易过滤，溶剂残留低，有利于储存过程中保持良好的稳定性。本发明结晶I的工艺简单、便于操作、污染小、具有可实现工业化生产的优点。
通过本发明的晶型I获得的晶型II保留了晶型I的晶习、颗粒度及良好的流动性。本发明晶型II的粒径分布均匀且粒度较大，晶体结构类似于单晶，长宽比在3:1以内，粒度均一性好，流动性好，很好的解决了现有专利技术中结晶过程繁琐、颗粒小、颗粒不均匀等不足，在加工适应性方面均具有优异的性质，很好的解决了制剂过程中混样不均的问题。本发明的结晶工艺简单、便于操作、污染小、具有可实现工业化生产的优点。
综上，本发明人经过大量的实验研究，发现通过获得颗粒度、流动性良好的环丝氨酸的晶型I(一水合物晶体)后，对环丝氨酸晶型I(一水合物)进行烘料以获得药用的环丝氨酸晶体II，该环丝氨酸晶体II保留了环丝氨酸晶型I(一水合物晶体)良好晶习、颗粒度、流动性的特性，解决了现有技术中环丝氨酸API流动性差、难以下料等问题。
附图说明:
图1为实施例1所得晶型I的X-射线粉末衍射图谱；
图2为实施例1所得晶型I的DSC图谱；
图3为实施例1所得晶型I的TGA图谱；
图4为实施例4所得晶型II的X-射线粉末衍射图谱；
图5为实施例4所得晶型II的DSC图谱；
图6为实施例4所得晶型II的TGA图谱；
图7为CN110183391A环丝氨酸的X-射线粉末衍射图谱；
图8为CN105646385A环丝氨酸的X-射线粉末衍射图谱；
图9为实施例1所得晶型I的显微镜照片(10×10)；
图10为实施例4所得晶型II的显微镜照片(10×10)；
图11为CN110183391A环丝氨酸的显微镜照片(10×10)；
图12为CN105646385A环丝氨酸的显微镜照片(10×10)；
图13为实施例1所得晶型I的粒度分布图；
图14为实施例4所得晶型II的粒度分布图；
具体实施例
下列实施例是为了进一步解释说明本发明，而不是构成对本发明范围的限制或限定。
本发明方法中所使用的环丝氨酸粗品可按照专利CN110183391A公开的实施例1制备，包括但不限于上述来源。
本发明所使用的溶剂没有特别的限制，可采用商购的常规溶剂。
除非另有说明，本发明方法中所述的“搅拌”可以采用本领域的常规方法，例如搅拌方式包括磁力搅拌、机械搅拌，搅拌速度为150-300rpm/min。
本发明所涉及的X-射线粉末衍射仪器及测试条件为:X-衍射仪器型号MiniFlex600Cu靶；操作方法:扫描速度20°/min，扫描步宽0.02°。
本发明涉及的DSC测试条件为:DSC检测仪型号为:NETZSCH DSC 214 Polyma；；操作方法:升温速率10℃/min，温度范围:25-200℃。
本发明涉及的TGA测试条件为:TGA检测仪型号为:METTLER TOLEDO TGA2；操作方法:升温速率10℃/min，温度范围:30-250℃。
本发明涉及的水分测试条件为:水分测试仪型号为:梅特勒V20水分仪，采用卡尔费休滴定法测试。
本发明涉及的粒度测试仪型号为:BT-2001型激光粒度分布仪。
本发明涉及的OLYMPUS显微镜，型号为CX31(10×10)。
本发明涉及的比旋度测试条件为：比旋度测试仪型号为：GE全自动旋光仪Autopol V； 操作方法：取环丝氨酸，精密称定，加2mol/L氢氧化钠溶液溶解并稀释制成每1ml中约含有50mg的溶液测试。
本发明涉及的液相测试条件为：色谱柱为Shimapak clc-ODS C18，150×6.0mm，5μm；流动相：0.005mol/L辛烷磺酸钠和0.02mol/L磷酸二氢钾的水溶液(用磷酸调节pH值至2.6):甲醇＝80:20；检测波长：219nm；流速：1.0ml/min；进样量：10μl；柱温：30℃。
本发明涉及的晶种对其晶习及颗粒度无特别要求，可为环丝氨酸粗品、可为环丝氨酸成品，本发明实施例所加晶种均为环丝氨酸粗品。
应当强调的是，本发明技术方案中所涉及的数值或数值端点，其含义或意欲的保护范围并不局限于该数字本身，本领域技术人员能够理解，它们包含了那些已被本领域广为接受的可允许误差范围，例如实验误差、测量误差、统计误差和随机误差等等，而这些误差范围均包含在本发明的范围之内。
实施例1
将环丝氨酸粗品500g溶于2.5L 1.8mol/L的氨水溶液中，与10L异丙醇、乙醇的混合溶剂混合，异丙醇与乙醇的体积比为1:2，降温至-15℃，加入6L体积比为1：1的乙酸和异丙醇的混合溶液，加晶种，晶种为环丝氨酸粗品，搅拌0.5h，继续滴加体积比为1：1的乙酸和异丙醇的混合溶液调节pH至6。搅拌1h，过滤，得490g晶体，纯度为99.96％，经测X-射线粉末衍射图谱(XRD)，确认为晶型I。
该晶型的X-射线粉末衍射、DSC以及TGA谱图分别如图1-3所示，在本发明中将其命名为晶型I。
晶型I的粒度特征参数如表3所示，晶型I的粒度分布图如图13所示。
表3
长度平均径D(2,1):0.708μm 面积平均径D(3,2):48.02μm 体积平均径D(4,3):205.9μm
比表面积(SSA):40.3m 2/kg D10:78.59μm D50:172.4μm
D75:260.0μm D90:383.0μm D97:548.7μm
实施例2
将环丝氨酸粗品1g溶于10mL 2.2mol/L的氨水溶液中，与40mL异丙醇、乙醇的混合溶 液混合，异丙醇与乙醇的体积比为2:1，降温至-10℃，加入2.4ml体积比为1：1的乙酸和异丙醇的混合溶液，加晶种，搅拌1h，继续滴加体积比为1：1的乙酸和异丙醇的混合溶液调节pH至7。搅拌1h，过滤，得0.89g晶体，纯度为99.93％，经测X-射线粉末衍射图谱(XRD)，确认为晶型I。
实施例3
将环丝氨酸粗品1g溶于8mL 2mol/L的氨水溶液中，与30mL异丙醇、乙醇的混合溶液混合，异丙醇与乙醇的体积比为1:1，降温至-15℃，加入2.0ml体积比为1：1的乙酸和异丙醇的混合溶液，加晶种，搅拌1h，继续滴加体积比为1：1的乙酸和异丙醇的混合溶液调节pH至8。搅拌1h，过滤，得0.78g晶体，纯度为99.92％，经测X-射线粉末衍射图谱(XRD)，确认为晶型I。
实施例4
将实施例1获得的环丝氨酸晶型I 100g于35℃真空干燥8h，真空度为-0.08MPa，经测X-射线粉末衍射图谱(XRD)，确认为晶型II，获得85.02g晶体，纯度为99.96％。
该晶型的X-射线粉末衍射、DSC以及TGA谱图分别如图4-6所示，在本发明中将其命名为晶型II。
晶型II的粒度特征参数如表4所示，晶型II的粒度分布图如图14所示。
表4
长度平均径D(2,1):0.772μm 面积平均径D(3,2):43.32μm 体积平均径D(4,3):202.8μm
比表面积(SSA):44.67m 2/kg D10:75.90μm D50:169.6μm
D75:256.7μm D90:378.6μm D97:546.4μm
实施例5
将实施例1获得的环丝氨酸晶型I 100g于40℃真空干燥6h，真空度为-0.095MPa，经测X-射线粉末衍射图谱(XRD)，获得84.66g晶体，纯度为99.96％。确认为晶型II。
制备例：
CN110183391A环丝氨酸样品的制备：依照CN110183391A实施例1的制备方法制备得到CN110183391A环丝氨酸样品。
CN105646385A环丝氨酸样品的制备：依照CN105646385A的【0040】至【0053】段的 制备方法制备得到CN105646385A环丝氨酸样品。
取上述CN110183391A和CN105646385A环丝氨酸样品，经X-射线粉末衍射检测，CN110183391A环丝氨酸的X-射线粉末衍射图谱(XRD)如图7；CN105646385A环丝氨酸的X-射线粉末衍射图谱(XRD)如图8所示。
对比例1
本发明的实施例1所得晶型I、实施例4所得晶型II及制备例得到的CN110183391A和CN105646385A环丝氨酸样品，进行显微镜观察，结果分别见图9-12。
由图9-12可知，CN110183391A和CN105646385A的环丝氨酸分别为颗粒较小的块状及细长棒状，且长宽比较大，生产中不易过滤，容易导致残留溶剂高，而且颗粒之间摩擦力较大，物料流动性小，不利于物料存储及加工。本发明的晶型I及晶型II，颗粒较均匀，长宽比较小，在3：1以内，物料流动性好，生产中有利于过滤，获得的物料残留溶剂少，有利于物料的存储稳定性及后续加工等操作。
对比例2
本发明的晶型I、晶型II及制备例得到的CN110183391A和CN105646385A环丝氨酸样品，采用50ml的量筒检测，进行堆密度及实密度测试，结果如表5所示；采用休止角法测定休止角，结果如表6所示。
表5
Figure PCTCN2021117351-appb-000002
表6
样品 孔径(mm) 转速(rpm) 测试1 测试2 测试3 平均值
晶型I 6 0 34.3 33.8 34 34.0
晶型II 6 0 33.9 32.3 32.1 32.7
CN110183391A 6 1 47.8 46.1 45 46.3
CN105646385A 6 1 41.9 41.5 40.8 41.4
由表5及表6可知，本发明的晶型I及晶型II的可压缩性及休止角均基本相同，并且均低于CN110183391A和CN105646385A的环丝氨酸。可压缩性较低及休止角较小均说明对应物料的流动性较好。故本发明的晶型I及晶型II的流动性优于根据CN110183391A和CN105646385A制备方法获得的环丝氨酸。另外，由表5及表6可知，本发明的晶型II保留了晶型I的良好流动性。
对比例3
制备例得到的CN110183391A和CN105646385A环丝氨酸样品及本发明的实施例4得到的晶型II分别置于60℃条件下放置3天、5天，25℃放置1个月、3个月，比旋度及纯度测试结果如表7所示：
表7
Figure PCTCN2021117351-appb-000003
Figure PCTCN2021117351-appb-000004
由表7可知，CN110183391A和CN105646385A的环丝氨酸在60℃条件下放置3天时即开始有结块，而本发明获得的晶型II仍为粉末状；且由表7可知，在60℃条件下及25℃条件下，本发明获得的环丝氨酸晶型II的比旋度及纯度的下降速度均小于CN110183391A和CN105646385A获得的环丝氨酸的比旋度及纯度的下降速度，60℃时CN110183391A和CN105646385A获得的环丝氨酸的比旋度及纯度的下降速度均明显大于本发明获得的环丝氨酸晶型II的比旋度及纯度的下降速度。表明本发明获得的晶型II在60℃条件下及25℃条件下稳定性均优于CN110183391A和CN105646385A获得的环丝氨酸。

Claims (10)

  1. 一种结构式如下所示的环丝氨酸的晶型I，
    Figure PCTCN2021117351-appb-100001
    其特征在于，其X-射线粉末衍射图谱在以下衍射角2θ处具有特征峰:11.88±0.2°、15.40±0.2°、17.08±0.2°、18.42±0.2°、23.72±0.2°、24.48±0.2°、27.66±0.2°、28.66±0.2°、34.40±0.2°。
  2. 根据权利要求1所述的晶型I，其特征在于，其X-射线粉末衍射图谱基本上如图1所示。
  3. 一种制备权利要求1～2任一项所述的晶型I的方法，该方法包括以下步骤:
    (1)将环丝氨酸溶于氨水溶液中；
    (2)步骤(1)得到的溶液与醇类溶剂混合；
    (3)步骤(2)得到的混合物于-15℃～-10℃加入体积比为1：1的乙酸和异丙醇的混合溶液，加晶种，搅拌0.5～1h；
    (4)继续滴加体积比为1：1的乙酸和异丙醇的混合溶液调节pH至6～8；
    (5)搅拌1～2h，过滤，得晶型I。
  4. 根据权利要求3所述的方法，其特征在于，所述步骤(1)中环丝氨酸与氨水溶液的质量体积比为1:5～10，其单位为g/ml；优选地，所述氨水溶液的浓度为1.8～2.2mol/L。
  5. 根据权利要求3所述的方法，其中所述步骤(2)中的醇类溶剂为异丙醇与乙醇的混合物，其中异丙醇与乙醇的体积比为1:2～2:1；优选地，所述步骤(2)中环丝氨酸与醇类溶剂的质量体积比为1:20～40，其单位为g/ml。
  6. 根据权利要求3所述的方法，其中所述步骤(3)中的环丝氨酸与体积比为1：1的乙酸和异丙醇的混合溶液的质量体积比为1:1.2～2.4，其单位为g/ml。
  7. 一种结构式如下所示的环丝氨酸的晶型II，
    Figure PCTCN2021117351-appb-100002
    其特征在于，其X-射线粉末衍射图谱在以下衍射角2θ处具有特征峰:9.64±0.2°、18.78±0.2°、19.44±0.2°、20.88±0.2°、22.12±0.2°、23.50±0.2°、29.44±0.2°、31.68±0.2°、33.16±0.2°、33.50±0.2°。
  8. 一种制备权利要求7所述的环丝氨酸的晶型II的方法，该方法通过权利要求1或2所述的环丝氨酸的晶型I获得环丝氨酸的晶型II，其特征在于，该方法包括将权利要求1或2所述的环丝氨酸的晶型I在35～40℃真空干燥6～8h，真空度为-0.08～-0.095Mpa。
  9. 一种药物组合物，其特征在于，所述药物组合物包括如权利要求1或2所述的环丝氨酸的晶型I和/或如权利要求7所述的环丝氨酸的晶型II，和一种或多种可药用的载体。
  10. 一种权利要求1或2所述的环丝氨酸的晶型I和/或权利要求7所述的环丝氨酸的晶型II或者权利要求9所述的药物组合物在制备治疗耐药结核杆菌感染的药物中的应用。
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