CN111675669A - Linezolid crystal form, preparation method and pharmaceutical composition thereof - Google Patents
Linezolid crystal form, preparation method and pharmaceutical composition thereof Download PDFInfo
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- CN111675669A CN111675669A CN202010412403.2A CN202010412403A CN111675669A CN 111675669 A CN111675669 A CN 111675669A CN 202010412403 A CN202010412403 A CN 202010412403A CN 111675669 A CN111675669 A CN 111675669A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
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- 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
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- 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
Abstract
The application discloses a linezolid crystalline form, a method for its preparation and a pharmaceutical composition. The linezolid crystalline form having a diffraction peak at least one of diffraction angles 2 theta ± 0.1 ° of 9.4 °, 13.9 °, 14.2 °, 16.7 °, 19.8 °, 21.5 °, 22.3 °, 23.5 ° and 25.2 ° in a diffraction pattern of powder X-ray diffraction of the crystalline form using CuK α radiation at the angle 2 theta; also, the linezolid crystalline form has a particle size Dv90 in the range of 37 μ ι η to 41 μ ι η; moreover, the crystalline form is substantially native. The linezolid crystal form of the invention has high product purity and high solubility.
Description
Technical Field
The present invention relates to the pharmaceutical technology, in particular to a linezolid crystalline form, a process for its preparation and a pharmaceutical composition.
Background
The structure of linezolid is shown as formula (I):
linezolid, chemically known as (S) -N- {3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -2-oxo-5-oxazolidinyl } methyl acetamide, is the first novel class of oxazolidinone antibacterial drugs synthesized and was first synthesized in 1996. Linezolid entered the market in 2000 under the trade name swo (Zyvox). FDA approval in the united states was obtained in 2000 for the treatment of infections caused by gram positive (G +) cocci, including suspected or confirmed Hospital Acquired Pneumonia (HAP), Community Acquired Pneumonia (CAP), complex skin or Skin Soft Tissue Infections (SSTI), and vancomycin-resistant enterococci (VRE) infections caused by MRSA.
Disclosure of Invention
The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of protection.
The present application provides a crystalline form of linezolid having a diffraction peak at least one of diffraction angles 2 θ ± 0.1 ° of 9.4 °, 13.9 °, 14.2 °, 16.7 °, 19.8 °, 21.5 °, 22.3 °, 23.5 ° and 25.2 ° in a diffraction pattern of powder X-ray diffraction of the crystalline form using CuK α radiation at 2 θ angles; furthermore, the linezolid crystalline form has a particle size Dv90 in the range of 35 μm to 41 μm.
In another aspect, the present application provides a method for preparing a crystalline form of linezolid, comprising the steps of:
adding linezolid raw material into ethyl acetate, stirring, heating to 60-80 ℃ and keeping for a period of time; then, cooling to 40-55 ℃ for a period of time; and finally, cooling to room temperature, carrying out suction filtration and drying to obtain the linezolid crystal form.
In a third aspect, the present application provides a pharmaceutical composition comprising the aforementioned crystalline form of linezolid.
In some embodiments herein, there is provided a crystalline form of linezolid having diffraction peaks at least two of diffraction angles 2 Θ ± 0.1 ° of 9.4 °, 13.9 °, 14.2 °, 16.7 °, 19.8 °, 21.5 °, 22.3 °, 23.5 °, and 25.2 ° in a diffraction pattern of powder X-ray diffraction of the crystalline form using CuK α radiation at angles 2 Θ; furthermore, the linezolid crystalline form has a particle size Dv90 in the range of 35 μm to 41 μm.
In some embodiments herein, the present application provides a crystalline form of linezolid having diffraction peaks at diffraction angles 2 θ ± 0.1 ° of 9.4 °, 13.9 °, 14.2 °, 16.7 °, 19.8 °, 21.5 °, 22.3 °, 23.5 ° and 25.2 ° in a diffraction pattern of powder X-ray diffraction of the crystalline form using CuK α radiation at the angle 2 θ.
In some embodiments herein, the present application provides a crystalline form of linezolid having a powder X-ray diffraction pattern using CuK α radiation expressed in degrees 2 θ substantially as shown in figure 1.
In some embodiments herein, provided is a crystalline form of linezolid having a particle size Dv90 in the range from 37 μ ι η to 41 μ ι η, in the range from 38 μ ι η to 41 μ ι η, in the range from 39 μ ι η to 41 μ ι η, or in the range from 40 μ ι η to 41 μ ι η.
In some embodiments of the application, the linezolid crystalline form has a particle size Dv90 of 37.1 μm, 37.2 μm, 37.3 μm, 37.4 μm, 37.5 μm, 37.6 μm, 37.7 μm, 37.8 μm, 37.9 μm, 38.0 μm, 38.1 μm, 38.2 μm, 38.3 μm, 38.4 μm, 38.5 μm, 38.6 μm, 38.7 μm, 38.8 μm, 38.9 μm, 39.0 μm, 39.1 μm, 39.2 μm, 39.3 μm, 39.4 μm, 39.5 μm, 39.6 μm, 39.7 μm, 39.8 μm, 39.9 μm, 40.1 μm, 40.2 μm, 40.3 μm, 40.4 μm, 40.5 μm, 40.6 μm, 40.8 μm, or 8 μm.
In some embodiments of the present application, the linezolid crystalline form further comprises a particle size Dv50 in the range of 3 μm to 15 μm, and may be in the range of 3 μm to 10 μm, 3 μm to 9 μm, 3 μm to 8 μm,4 μm to 10 μm,4 μm to 9 μm, or 4 μm to 8 μm, and the like.
In some embodiments of the present application, the linezolid crystalline form further comprises a particle size Dv10 in the range of 1 μm to 5 μm, may be in the range of 1 μm to 4 μm, 1 μm to 3 μm, or 1 μm to 2 μm, and the like.
In some embodiments of the present application, the mean particle size of the linezolid crystalline form is 2 μm x 12 μm x 40 μm, optionally, a micrograph of the linezolid crystalline form is shown in figure 4.
In embodiments of the present application, the linezolid crystalline form is native, i.e. obtained by direct crystallization without a comminution process.
In another aspect, the present application provides a method for preparing the above-mentioned crystalline form of linezolid, comprising the steps of:
adding linezolid raw material into ethyl acetate, stirring, heating to 60-80 ℃ and keeping for a period of time; then, cooling to 40-55 ℃ for a period of time; finally, cooling to room temperature, and carrying out suction filtration and drying to obtain the linezolid crystal form; here, the period of time is 0.2h to 5 h.
In some embodiments, provided herein are methods of preparing the aforementioned crystalline forms of linezolid, wherein the weight to volume ratio of linezolid starting material to ethyl acetate is from 1:15 to 1:25 in g/ml, alternatively from 1:16 to 1:25, 1:17 to 1:25, 1:18 to 1:25, 1:19 to 1:25, 1:20 to 1:25, 1:15 to 1:21, 1:17 to 1:21, 1:18 to 1:21, 1:19 to 1:21, or 1: 20.
In some embodiments of the present application, the present application provides a method for preparing the above linezolid crystalline form, wherein the temperature of the heating may be 70 ℃ to 80 ℃, 71 ℃ to 80 ℃, 72 ℃ to 80 ℃, 73 ℃ to 80 ℃, 74 ℃ to 80 ℃, 75 ℃ to 80 ℃, 76 ℃ to 80 ℃, 70 ℃ to 77 ℃, 71 ℃ to 77 ℃, 72 ℃ to 77 ℃, 73 ℃ to 77 ℃, 74 ℃ to 77 ℃, 75 ℃ to 77 ℃, or the temperature at which the ethyl acetate is refluxed.
In some embodiments of the present application, there is provided a method for preparing the above linezolid crystalline form, wherein the temperature of the cooling is from 41 ℃ to 55 ℃, from 42 ℃ to 55 ℃, from 43 ℃ to 55 ℃, from 44 ℃ to 55 ℃, from 45 ℃ to 55 ℃, from 46 ℃ to 55 ℃, from 47 ℃ to 55 ℃, from 48 ℃ to 55 ℃, from 49 ℃ to 55 ℃, or from 50 ℃ to 55 ℃.
In some embodiments of the present application, there is provided a method for preparing the above linezolid crystalline form, wherein the heating is for a time period of 0.2h to 2h, 0.3h to 2h, 0.4h to 2h, 0.2h to 1h, 0.3h to 1h, 0.4h to 1h, 0.2h to 0.6h, 0.3h to 0.6h, 0.4h to 0.6h, 0.5h to 0.6h, or 0.5 h.
In some embodiments, the present application provides methods of preparing the aforementioned crystalline forms of linezolid, wherein the post-cooling time is 0.5h to 5h, 0.6h to 5h, 0.7h to 5h, 0.8h to 5h, 0.9h to 5h, 1h to 5h, 1.1h to 5h, 1.2h to 5h, 1.3h to 5h, 1.4h to 5h, 1.5h to 5h, 1.6h to 5h, 1.7h to 5h, 1.8h to 5h, 1h to 4h, 1.1h to 3h, 1.2h to 3h, 1.3h to 3h, 1.4h to 2.5h, 1.5h to 2.5h, 1.6h to 2.5h, 1.7h to 2.5h, 1.8h to 2.5h, or 2 h.
In a third aspect, the present application provides a pharmaceutical composition comprising the crystalline form of linezolid described above and a pharmaceutically acceptable excipient. Here, the pharmaceutical composition is a tablet, a capsule, a solid granule or a dry suspension, optionally a tablet or a dry suspension. When the pharmaceutical composition is a tablet, the pharmaceutically acceptable excipients include corn starch, microcrystalline cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, magnesium stearate, and carnauba wax; optionally, the pharmaceutical composition comprises the crystalline form of linezolid 400.0mg, corn starch 36.0-44.0mg, microcrystalline cellulose 70.5-86.2mg, hydroxypropyl cellulose 7.2-8.8mg, sodium carboxymethyl starch 25.2-30.8mg, magnesium stearate 5.04-6.16mg, carnauba wax 0-0.0224mg, and may further comprise a coating agent such as opadry 11.2-22.4 mg; alternatively, the pharmaceutical composition comprises crystalline form of linezolid 600.0mg, corn starch 54-66mg, microcrystalline cellulose 105.84-129.36mg, hydroxypropyl cellulose 10.8-13.2mg, sodium carboxymethyl starch 37.8-46.2mg, magnesium stearate 7.56-9.24mg, carnauba wax 0-0.0336mg, and may further comprise a coating agent such as opadry 16.8-33.6 mg; when the pharmaceutical composition is a dry suspension, the pharmaceutically acceptable excipients are sucrose, sodium citrate, citric acid, microcrystalline cellulose, sodium carboxymethylcellulose, aspartame, xanthan gum, mannitol, sodium benzoate, colloidal silicon dioxide, sodium chloride and flavoring agents.
The invention has the beneficial effects that:
1. the linezolid crystal form of the invention has uniform and smaller granularity, and the obtained product has higher purity and special removal effect on impurities F which are easily wrapped by raw material medicines.
2. The linezolid bulk drug belongs to BCS four-class drugs, is of a low-solubility hypotonic type, and the linezolid crystal form has smaller granularity, thereby being beneficial to improving the solubility and reducing the dissolution time.
3. The linezolid crystal form solves the problems that solid raw material medicines are fluffy and easy to agglomerate, poor in flowability, difficult to disperse in a dispersion medium and easy to foam after being stirred.
Additional features and advantages of the application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the application. Other advantages of the present application may be realized and attained by the instrumentalities and combinations particularly pointed out in the specification and the drawings.
Drawings
The accompanying drawings are included to provide an understanding of the present disclosure and are incorporated in and constitute a part of this specification, illustrate embodiments of the disclosure and together with the examples serve to explain the principles of the disclosure and not to limit the disclosure.
FIG. 1 shows the powder diffraction pattern of the crystalline form of linezolid obtained in example 1 of the present invention;
FIG. 2 shows a powder diffraction pattern of the drug substance of the product batch LNZE0010816 linezolid;
FIG. 3 shows the powder diffraction pattern of the linezolid product obtained in comparative example 1 according to the present invention;
FIG. 4 shows a micrograph of the crystalline form of linezolid obtained in example 1 according to the invention;
FIG. 5 shows a micrograph of linezolid starting material batch No. LNZE 0010816;
figure 6 shows a micrograph of the crystalline form of linezolid obtained from comparative example 1 according to the invention.
Detailed Description
Hereinafter, embodiments of the present invention will be described in detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.
In the examples of the present application, the reagents used were all commercially available.
In the examples of the present application, the crude Linezolid starting materials used are all those which have been prepared by the Applicant according to the document KondaaiahSeku et al, "A Novel Method for Preparation of Linezolid, (S) -N- ((3- (3-Fluoro-4-Morpholinophenyl) -2-Oxo-5-Oxazolidinyl) Methyl) Acetamide", Letters in organic chemistry,14(1), pp 56-60; 2017, batch number LN 18101001-CPLB.
Wherein the HPLC detection result of the crude linezolid raw material of the batch is as follows:
in the examples of the present application, the particle size was determined using the instrument model of the particle size analyzer: malvern MS3000
Setting instrument parameters:
dispersing air pressure: 2.0bar
Sample introduction rate: 60 percent of
Slit width: 1.0mm
Refractive index: 0.5 to 10 percent
Sample introduction amount: 0.4g
In the examples of the present application, the HPLC assay was performed using the instrument type: agilent 1260
The detection conditions of HPLC are as follows:
a chromatographic column: welch voltimate XB-C18(3 μm,4.6 mm. times.250 mm);
a detector: the UV light is emitted from the UV light source,
detection wavelength: 254 nm;
column temperature: 40 ℃;
flow rate: 0.8 mL/min;
sample introduction amount: 10 μ L.
Mobile phase: 0.1mol/L aqueous trifluoroacetic acid solution: 0.1mol/L trifluoroacetic acid acetonitrile solution
In the examples of the present application, the powder X-ray diffraction instrument used was:
piinilyticil, Netherlands (original Philips Analyzer Co.) X' Pert PRO MPD X-ray diffractometer;
the conditions are as follows: cuk alpha radiation; 0.15418nm tube pressure: 40 kV; pipe flow: 40 mA; a Ni filter.
Example 1
To a 50L reactor, 2.12kg of crude linezolid (batch: LN18101001-CPLB) and 42.5L of ethyl acetate were added. Starting stirring, heating, controlling the temperature of the pulping system to be 75 +/-2 ℃, keeping the temperature and stirring for 2h, stopping heating, keeping the temperature at 50 +/-2 ℃ for 2h, and naturally cooling to room temperature. And (4) carrying out suction filtration, collecting a filter cake and drying. Off-white powder 1.61kg was obtained, molar yield: 75.94 percent. Mass spectrum m +1/z 337.35, HPLC purity 99.88%. The batch number is denoted LN 18101001. The micrograph of the above-mentioned white-like powder is shown in FIG. 4.
The X-ray powder diffraction pattern of the white-like powder is shown in figure 1, and the specific data are as follows:
example 2
To a 500mL three-necked flask were added 10g of crude linezolid (batch # LN18101001-CPLB) and 200mL of ethyl acetate. Starting stirring, heating, controlling the temperature of the pulping system to be 75 +/-2 ℃, keeping the temperature and stirring for 2h, stopping heating, keeping the temperature at 50 +/-2 ℃ for 2h, and naturally cooling to room temperature. And (4) carrying out suction filtration, collecting a filter cake and drying. Off-white powder 7.73g was obtained, molar yield: 77.3 percent. Mass spectrum m +1/z 337.35, HPLC purity 99.81%, batch LN 19061703-JP. The X-ray powder diffraction pattern of the white-like powder described above in this example is substantially as shown in FIG. 1.
Example 3
To a 1L three-necked flask were added 20.5g of crude linezolid (batch: LN18101001-CPLB) and 410ml of ethyl acetate. Starting stirring, heating, controlling the temperature of the pulping system to be 75 +/-2 ℃, keeping the temperature and stirring for 2h, stopping heating, keeping the temperature at 50 +/-2 ℃ for 2h, and naturally cooling to room temperature. And (4) carrying out suction filtration, collecting a filter cake and drying. Off-white powder 17.8g was obtained, molar yield: 86.83 percent. Mass spectrum m +1/z 337.35, HPLC purity 99.70%. Batch number is LN 19061704-JP. The X-ray powder diffraction pattern of the white-like powder described above in this example is substantially as shown in FIG. 1.
Comparative example 1
To a 500mL three-necked flask, 10.1g of crude linezolid (batch number: LN18101001-CPLB, the same applies hereinafter) and 80mL of ethanol were added. Starting stirring, heating to 80 +/-2 ℃, stopping heating after the system is completely dissolved, and naturally cooling to room temperature. And (4) carrying out suction filtration, collecting a filter cake and drying. Off-white powder 8.5g was obtained, molar yield: 84.16 percent. Mass spectrum m +1/z 337.35, HPLC purity 99.38%, batch LN 19061701-JP. The X-ray powder diffraction pattern of the white-like powder is shown in figure 3.
Comparative example 2
To a 500mL three-necked flask were added 10.08g of crude linezolid (batch number: LN18101001-CPLB, the same below) and 110mL of ethanol. Starting stirring, heating to 80 +/-2 ℃, stopping heating after the system is completely dissolved, and naturally cooling to room temperature. And (4) carrying out suction filtration, collecting a filter cake and drying. Off-white powder 8.3g was obtained, molar yield: 82.34 percent. Mass spectrum m +1/z 337.35, HPLC purity 99.49%, batch LN 19061702-JP. The basic X-ray powder diffraction pattern of the white-like powder is shown in FIG. 3.
Comparative test
(1) Influence of raw material particle size control and purity
Four batches of linezolid drug substance were used in the present invention, in which the impurity removal was compared between the two batches of drug substance of comparative examples 1 and 2 (batch No.: LN19061701-JP, LN19061702-JP), and the two batches of drug substance of example 2 and example 3 (batch No.: LN19061703-JP, LN 19061704-JP). Wherein the structure of linezolid impurity F is shown as formula (II):
the above comparison results show that the linezolid crystalline form of the present invention is significantly superior to the comparative examples in terms of both impurity number and content.
(2) Comparison investigation of whether raw material granularity is controlled or not
In a study using linezolid as a starting material to prepare linezolid tablets (formulation and preparation as in example 2 CN 01806469A), the dissolution profiles of the formulations were compared using commercially available Indian feedstock (Indian Symed Labs Limited, lot: LNZE0010816, with an X-ray powder diffraction pattern as shown in FIG. 2 and a micrograph as shown in FIG. 5) with the linezolid crystalline forms of the examples of the present application and the starting materials of the comparative examples (lot: LN18101001 and LN 19061701-JP). The results of the particle size measurements of the linezolid crystalline form of the present application, the comparative example and the indian feedstock are shown in the following table.
As can be seen from the comparison of the above tables, when the above three raw materials are used for particle size measurement, the average value of the particle size data Dv90 of lot number LN18101001 is about 38.9 μm, the particle size is smaller and the distribution is uniform as shown in the micrograph, which is shown in FIG. 4; bulk Indian crude drug batch No. LNZE0010816, as shown in FIG. 5, has no advantage in dissolution time; the average value of the particle size data Dv90 of batch LN19061701-JP is about 179.0. mu.m, and the appearance of the particles is as thin and long as flocculent filaments as shown in FIG. 6, which is not favorable for a series of processes such as tabletting of the preparation. The three raw materials are used for preparing samples by using hot water (the temperature is 70-80 ℃) and the test process and the results are shown in the following table.
The comparison of the above table shows that, under the condition that the particle size difference of the raw materials is large, the time difference of the complete dissolution of the raw materials is large when the hot water is used for preparing the liquid, which indicates that, in the preparation process of the linezolid raw material, when the hot water is used for preparing the liquid, the application of the linezolid crystal form of the application can ensure that the linezolid crystal form is completely dissolved in a short time, and simultaneously, the risk caused by the uncontrolled particle size is reduced.
In addition, although in production, in order to ensure that different batches of raw materials can be completely dissolved in liquid preparation, the raw materials can be crushed according to the principle of minimizing risks, and the particle size distribution Dv90 is controlled to be not more than 40.7 μm, so that the raw materials can be rapidly and completely dissolved, and the content of each batch of samples meets the requirement of quality standard, the crystal form of the application is primary, the crystal form can be maintained, the particle size is uniform, and the crushing treatment process is reduced.
(3) Comparative investigation of powder diffraction patterns of XRD of different feedstock particle sizes
When measured by powder diffraction by XRD using the above three starting materials, the diffractogram of the crystalline form of batch LN18101001 of example 1 is shown in FIG. 1, the diffractogram of the crystalline form of batch LNZE0010816 of Indian raw material is shown in FIG. 2, and the diffractogram of the crystalline form of batch LN19061701-JP of comparative example 1 is shown in FIG. 3.
The XRD powder diffraction patterns of the above LNZE0010816 and LN19061701-JP raw materials before and after pulverization to a particle size of about 80 μm in Dv90 were compared, and the results showed that the XRD diffraction results were not affected before and after pulverization in the same lot number. In the present application, the crystalline form of batch No. LN18101001 of example 1 (FIG. 1) has absorption peaks at 21.5 and 22.3 degrees at diffraction angles 2 theta + -0.1 degrees, which are significantly different from those at the same positions of the raw material batch No. LNZE0010816 (FIG. 2) of India (Symed Labs Limited) and comparative example 1 batch No. LNZE 19061701-JP (FIG. 3), and the bulk drug of Indian LNZE0010816 and comparative example 1 batch No. LN19061701-JP are not significantly different.
The present application describes embodiments, but the description is illustrative rather than limiting and it will be apparent to those of ordinary skill in the art that many more embodiments and implementations are possible within the scope of the embodiments described herein.
Claims (10)
1. A crystalline form of linezolid having a diffraction peak at least one of diffraction angles 2 Θ ± 0.1 ° of 9.4 °, 13.9 °, 14.2 °, 16.7 °, 19.8 °, 21.5 °, 22.3 °, 23.5 ° and 25.2 ° in a diffractogram of the crystalline form by powder X-ray diffraction using CuK α radiation at the angle 2 Θ; furthermore, the linezolid crystalline form has a particle size Dv90 in the range of 37 μm to 41 μm.
2. The crystalline form of linezolid according to claim 1, wherein the crystalline form of linezolid has diffraction peaks at diffraction angles 2 Θ ± 0.1 ° of 9.4 °, 13.9 °, 14.2 °, 16.7 °, 19.8 °, 21.5 °, 22.3 °, 23.5 ° and 25.2 ° in its powder X-ray diffraction pattern using CuK α radiation at 2 Θ angles.
3. The crystalline form of linezolid according to claim 2, wherein the crystalline form of linezolid has a powder X-ray diffraction pattern expressed in degrees 2 Θ using cuka radiation substantially as shown in figure 1.
4. The crystalline form of linezolid according to any one of claims 1 to 3, wherein the particle size Dv90 of the crystalline form of linezolid is in the range of 37 to 41 μ ι η, in the range of 38 to 41 μ ι η, in the range of 39 to 41 μ ι η, or in the range of 40 to 41 μ ι η.
5. The crystalline form of linezolid according to claim 4, wherein the mean particle size of the crystalline form of linezolid is 2 μ ι η x 12 μ ι η x 40 μ ι η, optionally, a micrograph of the crystalline form of linezolid is shown in figure 4.
6. A method of preparing the crystalline form of linezolid according to any one of claims 1 to 5, comprising the steps of:
adding linezolid raw material into ethyl acetate, stirring, heating to 60-80 ℃ and keeping for a period of time; then, cooling to 40-55 ℃ for a period of time; finally, cooling to room temperature, and carrying out suction filtration and drying to obtain the linezolid crystal form; here, the period of time is 0.2h to 5 h.
7. The preparation method of claim 6, wherein the weight to volume ratio of linezolid starting material to ethyl acetate is from 1:15 to 1:25 in g/ml, optionally from 1:16 to 1:25, 1:17 to 1:25, 1:18 to 1:25, 1:19 to 1:25, 1:20 to 1:25, 1:15 to 1:21, 1:17 to 1:21, 1:18 to 1:21, 1:19 to 1:21, or 1: 20.
8. The preparation method according to claim 6, wherein the temperature of the heating temperature rise may be 70 ℃ to 80 ℃, 71 ℃ to 80 ℃, 72 ℃ to 80 ℃, 73 ℃ to 80 ℃, 74 ℃ to 80 ℃, 75 ℃ to 80 ℃, 76 ℃ to 80 ℃, 70 ℃ to 77 ℃, 71 ℃ to 77 ℃, 72 ℃ to 77 ℃, 73 ℃ to 77 ℃, 74 ℃ to 77 ℃, 75 ℃ to 77 ℃, or a temperature at which ethyl acetate is refluxed;
optionally, the temperature of the cooling is from 41 ℃ to 55 ℃, from 42 ℃ to 55 ℃, from 43 ℃ to 55 ℃, from 44 ℃ to 55 ℃, from 45 ℃ to 55 ℃, from 46 ℃ to 55 ℃, from 47 ℃ to 55 ℃, from 48 ℃ to 55 ℃, from 49 ℃ to 55 ℃, or from 50 ℃ to 55 ℃.
9. The production method according to any one of claims 6 to 8, wherein the time duration after the temperature rise by heating is 0.2 to 2 hours, 0.3 to 2 hours, 0.4 to 2 hours, 0.2 to 1 hour, 0.3 to 1 hour, 0.4 to 1 hour, 0.2 to 0.6 hour, 0.3 to 0.6 hour, 0.4 to 0.6 hour, 0.5 to 0.6 hour, or 0.5 hour;
optionally, the time duration after cooling is 0.5h to 5h, 0.6h to 5h, 0.7h to 5h, 0.8h to 5h, 0.9h to 5h, 1h to 5h, 1.1h to 5h, 1.2h to 5h, 1.3h to 5h, 1.4h to 5h, 1.5h to 5h, 1.6h to 5h, 1.7h to 5h, 1.8h to 5h, 1h to 4h, 1.1h to 3h, 1.2h to 3h, 1.3h to 3h, 1.4h to 2.5h, 1.5h to 2.5h, 1.6h to 2.5h, 1.7h to 2.5h, 1.8h to 2.5h, or 2 h.
10. A pharmaceutical composition comprising the crystalline form of linezolid according to any one of claims 1 to 5.
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| CN (1) | CN111675669A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20010051621A1 (en) * | 2000-02-02 | 2001-12-13 | Bergren Michael S. | Linezolid-crystal form II |
| CN101262853A (en) * | 2005-07-20 | 2008-09-10 | 特瓦制药工业有限公司 | Stable pharmaceutical composition comprising linezolid form IV |
| CN102399200A (en) * | 2011-12-14 | 2012-04-04 | 浙江新东港药业股份有限公司 | Suspension crystallization method for preparing crystal form I of linezolid |
| CN102850290A (en) * | 2012-10-10 | 2013-01-02 | 天津市炜杰科技有限公司 | Preparation method of crystal form I linezolid |
| CN104370846A (en) * | 2013-08-15 | 2015-02-25 | 杭州华东医药集团生物工程研究所有限公司 | Method for preparing linezolid IV crystal form |
| CN104370847A (en) * | 2013-08-16 | 2015-02-25 | 浙江医药股份有限公司新昌制药厂 | Preparation method of crystal form I of linezolid |
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2020
- 2020-05-15 CN CN202010412403.2A patent/CN111675669A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20010051621A1 (en) * | 2000-02-02 | 2001-12-13 | Bergren Michael S. | Linezolid-crystal form II |
| CN101262853A (en) * | 2005-07-20 | 2008-09-10 | 特瓦制药工业有限公司 | Stable pharmaceutical composition comprising linezolid form IV |
| CN102399200A (en) * | 2011-12-14 | 2012-04-04 | 浙江新东港药业股份有限公司 | Suspension crystallization method for preparing crystal form I of linezolid |
| CN102850290A (en) * | 2012-10-10 | 2013-01-02 | 天津市炜杰科技有限公司 | Preparation method of crystal form I linezolid |
| CN104370846A (en) * | 2013-08-15 | 2015-02-25 | 杭州华东医药集团生物工程研究所有限公司 | Method for preparing linezolid IV crystal form |
| CN104370847A (en) * | 2013-08-16 | 2015-02-25 | 浙江医药股份有限公司新昌制药厂 | Preparation method of crystal form I of linezolid |
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