CN116178408A - Criborotate and crystal form, preparation method and application thereof - Google Patents

Criborotate and crystal form, preparation method and application thereof Download PDF

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CN116178408A
CN116178408A CN202310033870.8A CN202310033870A CN116178408A CN 116178408 A CN116178408 A CN 116178408A CN 202310033870 A CN202310033870 A CN 202310033870A CN 116178408 A CN116178408 A CN 116178408A
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salt
crystalline form
clenbuterol
piperazine
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葛晨灏
严波
盛晓霞
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Hangzhou Lingye Pharmaceutical Technology Co ltd
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    • C07F5/00Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02Boron compounds
    • C07F5/025Boronic and borinic acid compounds
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/06Antipsoriatics
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    • C07D295/02Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
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    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
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    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13Crystalline forms, e.g. polymorphs
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a clenbuterol piperazine salt and a crystal form thereof, a preparation method and application thereof. The clenbuterol piperazine salt and the crystal form thereof provided by the invention have the advantages of better stability, better solubility and the like, and are beneficial to improving the bioavailability of the medicine, thereby improving the efficacy of the medicine.

Description

Criborotate and crystal form, preparation method and application thereof
The application is a divisional application with the application date of 2022, 12 months and 30 days, the application number of CN202211732252.4, and the name of the patent is clenbuterol salt and crystal forms, preparation methods and application thereof.
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a clenbuterol piperazine salt and a crystal form, a preparation method and application thereof.
Background
In month 2016, the U.S. Food and Drug Administration (FDA) approved the use of the Anacor company's Crisabole ointment (trade name Eucrisa), a non-steroidal PDE-4 inhibitor, for the treatment of atopic dermatitis, having the formula:
Figure BDA0004048455980000011
disclosure of Invention
The invention provides a clenbuterol piperazine salt and a crystal form thereof, which have at least one of the following advantages: good solubility in water, good stability, good dissolution, high purity, low hygroscopicity and good fluidity, meets the requirements of medicine, can be stably stored, has simple preparation mode and high bioavailability, and is suitable for industrial production and the like.
In a first aspect of the present invention, there is provided a salt of cliboropiperazine having the structural formula (I),
Figure BDA0004048455980000012
a crystalline Form of a salt of cliboropiperazine of the first aspect of the present invention, the crystalline Form being Form I, having at least one characteristic diffraction peak selected from 10.42±0.2°, 13.77±0.2°, 14.22±0.2°, and 20.07±0.2° in an X-ray powder diffraction pattern (XRPD) expressed as diffraction angle 2θ; preferably at least three characteristic diffraction peaks.
Preferably, the crystal Form I further has at least one characteristic diffraction peak selected from the group consisting of 15.65±0.2°, 17.67±0.2°, 18.19±0.2° and 25.15±0.2° in an X-ray powder diffraction pattern expressed by a diffraction angle 2θ.
Preferably, the crystal Form I further has at least one characteristic diffraction peak selected from 16.47±0.2°, 22.25±0.2°, 26.09±0.2° and 26.55±0.2° in an X-ray powder diffraction pattern expressed by a diffraction angle 2θ.
Preferably, the X-ray powder diffraction data for Form I are shown in table 1.
Preferably, the Form I has an X-ray powder diffraction pattern substantially as shown in figure 1.
Preferably, the Form I is a Form I which is selected from 3255.96cm in Fourier IR spectroscopy -1 ±2cm -1 、3045.12cm -1 ±2cm -1 、2847.14cm -1 ±2cm -1 、2718.09cm -1 ±2cm -1 、1470.43cm -1 ±2cm -1 、1415.23cm -1 ±2cm -1 、1388.20cm -1 ±2cm -1 、1108.24cm -1 ±2cm -1 、1061.31cm -1 ±2cm -1 、1036.14cm -1 ±2cm -1 、833.31cm -1 ±2cm -1 、783.53cm -1 ±2cm -1 、710.01cm -1 ±2cm -1 Having a characteristic peak at least one of them.
Preferably, the Form I has a fourier infrared spectrum as shown in fig. 6.
Preferably, the Form I is anhydrate.
Preferably, the Form I has a TGA profile substantially as shown in figure 2.
Preferably, the Form I has a DSC profile substantially as shown in figure 3.
Preferably, the Form I has a DVS profile substantially as shown in figure 4.
In a second aspect of the present invention, there is provided a method for preparing a salt of clavulanic piperazine according to the first aspect, comprising the steps of: adding the clenbuterol and piperazine into a solvent to obtain a suspension, stirring until solid is separated out, separating, and drying to obtain the finished product; preferably, the solvent is an organic solvent.
The invention further provides a preparation method of the crystal Form I of the clenbuterol piperazine salt in the first aspect, which comprises the following steps:
adding the clenbuterol and piperazine into an organic solvent to obtain a suspension, carrying out crystal slurry, separating and drying to obtain the crystal form.
Preferably, the crystalline Form I of the salts of cliboropiperazine comprises the steps of: adding the clenbuterol and piperazine into an organic solvent to obtain a suspension, separating solids from crystal slurry which is more than or equal to 1h, and drying to obtain the crystal form.
Preferably, the crystal mush is more than or equal to 6 hours, more preferably, the crystal mush is more than or equal to 1 day; most preferably 2-5 days.
Preferably, the crystal slurry is room temperature crystal slurry.
Preferably, the solvent can be supplemented in the crystal slurry process.
Preferably, in the above preparation method, the organic solvent is one or a mixed solvent of ethers and esters; more preferably, the solvent is selected from tetrahydrofuran and ethyl acetate or a mixed solvent of both.
Preferably, in the preparation method, the mass-volume ratio (mg/mL) of the clenbuterol to the solvent is preferably more than or equal to 50:1, more preferably 60 to 120.
Preferably, in the preparation method, the molar ratio of the clenbuterol to the piperazine is 1-5:1, more preferably 1.5-3:1, and even more preferably 1.9-2.2:1;
preferably, in the above preparation method, the drying temperature is 40 to 70 ℃, still preferably 45 to 55 ℃, further preferably 48 to 52 ℃.
The clenbuterol piperazine salt and the crystal form thereof have the following beneficial effects:
1) The salt and the crystal form thereof have good stability. The crystal Form I is kept unchanged after being placed for 21 days under the conditions of long term and acceleration, so that the Form I bulk drug has good crystal Form stability and chemical stability.
2) The salt and the crystal form thereof have good water solubility, and are beneficial to improving the bioavailability of the clenbuterol medicine, thereby improving the patentability and the efficacy of the medicine; the dosage of the medicine is reduced while the curative effect of the medicine is ensured, thereby reducing the side effect of the medicine and improving the safety of the medicine.
3) The salt and the crystal form thereof hardly absorb moisture, do not need to strictly control humidity, and are more suitable for industrial production.
4) The salt and the crystal form thereof have almost no solvent residue and meet the medicinal requirements.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a salt of clavulanic piperazine according to the first aspect or/and a crystalline form thereof and at least one pharmaceutically acceptable carrier.
In the present invention, pharmaceutically acceptable carriers include diluents or excipients or other additives, examples of which include, but are not limited to, for example, wetting agents, disintegrants, lubricants, binders, surfactants, and the like. Examples of other additives include, but are not limited to, for example, shellac, gum arabic, talc, titanium oxide, sugar (e.g., sucrose), gelatin, water, polysaccharides such as lactose or glucose, paraffin (e.g., petroleum fractions), vegetable oils (e.g., peanut oil or sesame oil), and pharmaceutically acceptable organic solvents such as alcohols (e.g., ethanol or glycerol), natural mineral powders (e.g., kaolin, clay, talc, and chalk), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates), emulsifiers (e.g., lignin, sulfite solutions, methyl cellulose, starch, and polyvinylpyrrolidone), magnesium stearate, stearic acid, sodium lauryl sulfate, and the like.
The pharmaceutical composition of the present invention may be prepared in various dosage forms including, but not limited to, semi-solid pharmaceutical preparations suitable for topical skin administration, such as ointments, gels, creams, and the like, or pharmaceutical preparations suitable for oral administration, such as solid oral preparations including tablets, coatings, capsules, granules, powders, pills, powders, and the like, or liquid oral preparations including solutions, syrups, suspensions, emulsions, and the like; pharmaceutical preparations suitable for parenteral administration, for example intravenous drip preparations, intramuscular or subcutaneous preparations, suppositories for rectal administration, inhalant preparations for intranasal administration, or further transdermal patch forms for topical administration. In the preparation production, additional auxiliary materials can be further included, and preferably, the addition of the auxiliary materials does not cause the transformation of the crystal forms.
Preferably, the pharmaceutical composition of the present invention is an ointment.
In a fourth aspect of the invention, there is provided the use of a salt of clarithromycin and a crystalline form thereof according to the first aspect in the manufacture of a topical pharmaceutical formulation for the treatment of an inflammation-related disorder or condition including psoriasis and atopic dermatitis.
Preferably, the present invention provides the use of a salt of clarithromycin and a crystalline form thereof according to the first aspect in the manufacture of a medicament for the prevention or treatment of a phosphodiesterase 4 (PDE-4) related disease.
In a fifth aspect of the invention, there is provided a method for preventing or treating a disease comprising the step of administering to a subject in need thereof the salt of clavulanic piperazine as defined in the first aspect and its crystalline form or the pharmaceutical composition as defined in the third aspect, wherein the disease is a phosphodiesterase 4-related disease comprising psoriasis and an inflammatory-related disease of atopic dermatitis. Preferably, the pharmaceutical composition comprises a prophylactically and/or therapeutically effective amount of a salt of tolibupropium and crystalline forms thereof.
In a sixth aspect of the invention there is provided the use of a salt of clarithromycin according to the first aspect and a crystalline form thereof or a pharmaceutical composition according to the third aspect in combination with other pharmaceutically active ingredients.
Drawings
FIG. 1 is an XRPD pattern for Form I of a crystalline Form of creboropiperazine salt prepared according to example 1.
FIG. 2 is a TGA spectrum of crystalline Form I of the salt of toliprazine prepared according to example 1.
FIG. 3 is a DSC graph of Form I of the crystalline Form of the salt of tolibupropium prepared according to example 1.
Fig. 4 is a DVS spectrum of crystalline Form I of creboropiperazine salt prepared according to example 1.
Fig. 5 is a PLM spectrum of crystalline Form I of the salt of toliprazine prepared according to example 1.
Fig. 6 is a fourier infrared spectrum of crystalline Form I of the salt of creboropiperazine prepared according to example 1.
FIG. 7 is a single crystal PLM spectrum of Form I of the crystalline Form of the salts of creboropiperazine.
Fig. 8 is an XRPD pattern of crystalline Form I of creboropiperazine salt before and after placement under accelerated and prolonged conditions.
Detailed Description
Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In addition, for numerical ranges in the present invention, it is understood that the upper and lower limits of the ranges and each intermediate value therebetween are specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control. Unless otherwise indicated, "%" is percent by weight.
In the process according to the invention, the salts according to the invention and the crystalline forms thereof are generally prepared starting from Crisabelole, which is obtainable either from commercial products or from the process described in patent application WO2006/089067 by the company Anacor Pharmaceutical, and piperazine as starting material is obtainable from commercial products.
The term "subject" as used herein includes mammals. The mammal may be, for example, any mammal, e.g., human, primate, bird, mouse, rat, poultry, dog, cat, cow, horse, goat, camel, sheep, or pig. Preferably the mammal is a human.
The term "room temperature" as used herein generally refers to 10-30℃and preferably 20.+ -. 5 ℃.
In the present invention, the term "crystalline form" refers to a certain lattice configuration of a crystalline substance. It is known in the art that crystalline forms are related to stability, dissolution and mechanical properties in the manufacture of a medicament. Different crystal forms of the same substance typically have different lattices (e.g., unit cells) with different physical properties that are characteristic thereof. The different crystal forms may be characterized by methods known in the art. For example, it can be identified by solid state characterization methods, such as by X-ray powder diffraction (XRPD). Other characterization methods include Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor adsorption (DVS), solid state NMR, and the like. The crystalline form may be characterized using any of the methods described above, or by using two or more methods in combination.
Other experimental methods are known in the art, except for the specific description of the present invention, and reference is made to, for example, the pharmacopoeia of the people's republic of China. Wherein, the parameters for detection are set as follows:
specific conditions for XRPD (X-ray powder diffraction) measurement are: bruker D8, cu-K alpha radiation, detection range of 3-40 degrees 2 theta, step length of 0.02 degrees 2 theta and scanning speed of 0.2s.step-1.
Thermogravimetric analysis (TGA) data were taken from TA Instruments Q500TGA. The parameters are as follows:
scanning rate: at 10 ℃/min; protective gas: n (N) 2
Differential thermal analysis (DSC) data were taken from TA Instruments Q200 DSC. The parameters are as follows:
scanning rate: at 10 ℃/min; protective gas: n (N) 2
Dynamic moisture sorption analysis (DVS) data and isothermal sorption analysis data were taken from TA Instruments Q5000SA. The parameters are as follows:
temperature: 25 ℃; relative humidity range: 0% RH-80% RH.
Polarized Light Microscopy (PLM) spectra were taken from XP-500E polarized light microscopy. A small amount of powder sample is taken and placed on a glass slide, a small amount of mineral oil dispersion sample is dripped, a cover slip is covered, and the glass slide is placed on a stage for observation and photographing.
The test conditions for fourier infrared spectroscopy were: bruker tensor 27, ATR method, resolution 4cm -1
In the present invention, the terms "property" or "crystalline form property" or "pharmaceutical property" include physical and chemical properties thereof, and evaluation indexes include, but are not limited to, for example, melting point, water solubility, dissolution rate, mechanical properties, stability, pharmacokinetics or pharmacodynamics, hygroscopicity, flowability, compressibility, competitiveness, and the like.
The various reagents used in the examples were commercially available unless otherwise specified. Unless otherwise indicated, the examples were all run at room temperature.
Example 1
About 60.67mg of the clenbuterol and 10.76mg of piperazine are taken, 0.7mL of tetrahydrofuran is added, the mixture is stirred at room temperature to obtain white suspension, after stirring at room temperature for 2 days, a large amount of solids are separated out, 2mL of tetrahydrofuran solvent is added into the suspension, stirring at room temperature is continued for 1 day, centrifugal filtration is carried out, and the obtained solid is dried at 50 ℃ in vacuum for 1 hour to obtain the crystal Form I of the clenbuterol piperazine salt.
The sample of example 1 was taken for characterization, as follows.
1. XRPD pattern analysis
FIG. 1 is an XRPD pattern for Form I, and Table 1 shows the X-ray powder diffraction data for Form I.
Table 1: x-ray powder diffraction data for Form I
Figure BDA0004048455980000081
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Figure BDA0004048455980000091
2. TGA profile analysis
The TGA results are shown in figure 2. The weight loss step is arranged before 94 ℃, the weight loss rate is 0.5 percent, and the weight loss step is arranged between 94 ℃ and 150 ℃, and the weight loss rate is 10.2 percent.
3. DSC analysis of the spectrum
The result of the differential calorimetric scan analysis is shown in FIG. 3. Form I has a piperazine dissociation temperature of 102 ℃, melts at 213 ℃ and accompanies decomposition.
4. DVS profile analysis
The DVS analysis results are shown in fig. 4. Form I absorbs about 0.3% moisture at 80% rh, and exhibits little hygroscopicity.
5. PLM analysis
The Polarized Light Microscope (PLM) results are shown in fig. 5, which shows fine particles.
6. FT-IR analysis
The fourier infrared spectrum results are shown in fig. 6.
7. Single crystal PLM pattern
The single crystal cultivation method is as follows: 10mg of the sample prepared in example 1 was placed in a glass vial, dissolved with 3.4mL of ethyl acetate by sonication, and filtered using a syringe with a 0.45 μm filter head. And placing the obtained clear solution at room temperature for small pore volatilization to obtain a blocky crystal, and carrying out structural characterization on the obtained monocrystal. The single crystal pattern is shown in fig. 7, and the clenbuterol: piperazine = 2:1 and is coordinately and covalently bonded (n→b), which has the single crystal structure data of table 2.
TABLE 2 Single Crystal Structure information Table of Crystal Form I
Figure BDA0004048455980000101
Example 2
60.38mg of clenbuterol and 10.59mg of piperazine are taken, 0.9mL of ethyl acetate is added, the mixture is stirred at room temperature to obtain a white suspension, after stirring at room temperature for 2 days, a large amount of solids are separated out, 2mL of ethyl acetate solvent is added into the suspension, stirring at room temperature is continued for 1 day, centrifugal filtration is carried out, and the obtained solid is dried at 50 ℃ in vacuum for 1 hour to obtain clenbuterol piperazine salt Form I.
Example 3
Taking 5mg of Form I sample prepared in example 1, placing under acceleration (40 ℃,75% RH, open light shielding) and long term (25 ℃,60% RH, open light shielding) conditions respectively, and the results show that: form I remained unchanged for 21 days under accelerated and long term conditions, indicating that Form I was stable and the XRPD pattern of the sample stability test is shown in fig. 8.
While the invention has been described with reference to exemplary embodiments, it is to be understood that the invention is not limited to the disclosed exemplary embodiments. Various modifications or changes may be made to the exemplary embodiments of the present disclosure without departing from the scope or spirit of the invention. The scope of the claims is to be accorded the broadest interpretation so as to encompass all modifications and equivalent structures and functions.

Claims (10)

1. A clenbuterol piperazine salt with a structural formula shown as the following formula (I),
Figure FDA0004048455970000011
2. a crystalline form of a salt of clarithromycin according to claim 1, having at least one characteristic diffraction peak selected from the group consisting of 10.42±0.2°, 13.77±0.2°, 14.22±0.2° and 20.07±0.2° in an X-ray powder diffraction pattern expressed as diffraction angle 2Θ; preferably three characteristic diffraction peaks.
3. The crystalline form of claim 2, further having at least one characteristic diffraction peak selected from the group consisting of 15.65±0.2°, 17.67±0.2°, 18.19±0.2° and 25.15±0.2° in an X-ray powder diffraction pattern expressed as diffraction angle 2Θ; alternatively, the optical element further has at least one characteristic diffraction peak selected from 16.47 + -0.2 DEG, 22.25 + -0.2 DEG, 26.09 + -0.2 DEG, and 26.55 + -0.2 deg.
4. A crystalline form of clarithromycin salt as claimed in any one of claims 2-3 which is characterized by a composition selected from the group consisting of 3255.96cm in fourier infrared spectroscopy -1 ±2cm -1 、3045.12cm -1 ±2cm -1 、2847.14cm -1 ±2cm -1 、2718.09cm -1 ±2cm -1 、1470.43cm -1 ±2cm -1 、1415.23cm -1 ±2cm -1 、1388.20cm -1 ±2cm -1 、1108.24cm -1 ±2cm -1 、1061.31cm -1 ±2cm -1 、1036.14cm -1 ±2cm -1 、833.31cm -1 ±2cm -1 、783.53cm -1 ±2cm -1 、710.01cm -1 ±2cm -1 Having a characteristic peak at least one of them.
5. A process for the preparation of a salt of cliboropiperazine according to claim 1, characterized in that it comprises the steps of: adding the clenbuterol and piperazine into a solvent to obtain a suspension, stirring until solid is separated out, separating, and drying to obtain the finished product; preferably, the solvent is an organic solvent.
6. A process for the preparation of a crystalline form of a salt of clarithromycin according to any one of claims 2-4 comprising the steps of:
adding the clenbuterol and piperazine into an organic solvent to obtain a suspension, carrying out crystal slurry, separating and drying to obtain the crystal form.
7. The method according to claim 5 or 6, wherein the organic solvent is one or a mixed solvent of ethers and esters; preferably, the organic solvent is selected from tetrahydrofuran and ethyl acetate or a mixed solvent of the tetrahydrofuran and the ethyl acetate, preferably, the molar ratio of the clenbuterol to the piperazine is 1-5:1, preferably 1.5-3:1, and further preferably 1.9-2.2:1; preferably, the mass-to-volume ratio (mg/mL) of the clenbuterol to the solvent or the organic solvent is more than or equal to 50:1, more preferably 60-120; preferably, the drying temperature is 40-70 ℃, still preferably 45-55 ℃, still more preferably 48-52 ℃.
8. The method of claim 7, wherein the slurry is not less than 1h, more preferably not less than 6h, most preferably not less than 1-5 days.
9. A pharmaceutical composition comprising a salt of clarithromycin according to claim 1 or/and a crystalline form according to any one of claims 2-5 and at least one pharmaceutically acceptable carrier.
10. Use of the salts of clarithromycin according to claim 1 or of the crystalline form of any one of claims 2 to 5 in the manufacture of a topical pharmaceutical formulation for the treatment of an inflammation-related disease or disorder, wherein the inflammation-related disease or disorder includes psoriasis and atopic dermatitis; preferably, the use of a salt of clarithromycin according to claim 1 or/and a crystalline form according to any one of claims 2 to 5 or a pharmaceutical composition according to claim 9 in combination with other pharmaceutically active ingredients.
CN202310033870.8A 2021-12-31 2022-12-30 Criborotate and crystal form, preparation method and application thereof Pending CN116178408A (en)

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