CN113620982A - Crystal form of Crisabiole solvate and preparation method and application thereof - Google Patents

Crystal form of Crisabiole solvate and preparation method and application thereof Download PDF

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CN113620982A
CN113620982A CN202111060407.XA CN202111060407A CN113620982A CN 113620982 A CN113620982 A CN 113620982A CN 202111060407 A CN202111060407 A CN 202111060407A CN 113620982 A CN113620982 A CN 113620982A
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crisabiole
solvate
crystalline form
pyridine
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盛晓红
盛晓霞
吴涛
吕康乐
胡晨阳
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Hangzhou Lingye Pharmaceutical Technology Co ltd
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    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
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Abstract

The invention discloses a crystal form of Crisabiole solvate and a preparation method and application thereof. The crystal form provided by the invention has better water solubility, and the obviously improved water solubility is beneficial to improving the bioavailability of the medicine, so that the patent medicine property and the medicine effect of the medicine are improved. In addition, the preparation obtained by the crystal form has better stability, and particularly has high crystal form stability in a pharmaceutical preparation taking pyridine or 1, 3-propylene glycol as an auxiliary material.

Description

Crystal form of Crisabiole solvate and preparation method and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical crystals, in particular to a crystal form of a solvate of clitoriron (sometimes referred to as Crisabiole or Crisabione) and a preparation method and application thereof.
Background
Among the diseases associated with skin inflammation, psoriasis and Atopic Dermatitis (AD), particularly atopic dermatitis, have a familial tendency to easily suffer from asthma, allergic rhinitis, eczema, and are allergic to foreign proteins, and eosinophilia in blood, and are chronic and recurrent inflammatory dermatoses, and some patients often have other atopic diseases such as allergic asthma, allergic rhinitis, and allergic conjunctivitis. In recent years, despite numerous breakthrough advances in clinical treatment, the development of related drugs still faces many challenges.
In 2016, 12 months, the ointment of Crisabiole (trade name Eucrisa) approved by the United states Food and Drug Administration (FDA) company, Anacor, was marketed and became the first new molecular entity approved by the FDA for the treatment of AD in the last 15 years. The medicine is a phosphodiesterase 4(PDE-4) inhibitor, which has antiinflammatory effect by inhibiting phosphodiesterase 4(PDE4), and can be used for treating atopic dermatitis, and has the following structural formula:
Figure BDA0003255668830000011
meanwhile, several reports related to Crisabiole crystal forms are disclosed in the prior art, for example, CN108884111A discloses Crisabiole hydrate and anhydrate crystal forms, wherein the anhydrate crystal forms have hygroscopicity.
For another example, WO2017203514a1 discloses crisaboole ethanolate and a process for its preparation, and IN201941003851A discloses n-butanolate and a process for its preparation, although the solvent residues IN the above-described processes for the preparation of the crystalline forms exceed ICH requirements.
At present, a new crystal form is still required to be developed to solve the problems of low water solubility, low stability and the like of the Crisabiole solvate in the preparation of a pharmaceutical preparation. In addition, the crystal form properties of the crisabaroll solvate and the preparation of high purity crystal forms still need to be further improved.
The information in this background is only for the purpose of illustrating the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art that is known to a person skilled in the art.
Disclosure of Invention
In order to solve at least part of the technical problems in the prior art, the invention provides a specific crystal form of a crisabaroll solvate, which has excellent properties more suitable for preparing a pharmaceutical preparation. For example, higher water solubility, formulation stability, and higher bioavailability. Specifically, the present invention includes the following.
In a first aspect of the invention, there is provided a crystalline form of a pyridine solvate of Crisabiole having the formula (I),
Figure BDA0003255668830000021
has at least three characteristic diffraction peaks selected from the group consisting of 5.33 + -0.2 DEG, 14.58 + -0.2 DEG, 16.47 + -0.2 DEG and 23.23 + -0.2 DEG in an X-ray powder diffraction pattern expressed by a diffraction angle 2 theta.
The crystalline crisabanole pyridine solvate form according to the first aspect of the present invention preferably further has at least one characteristic diffraction peak selected from 18.76 ± 0.2 °, 23.77 ± 0.2 °, 25.71 ± 0.2 ° and 27.99 ± 0.2 ° in an X-ray powder diffraction pattern expressed by diffraction angle 2 θ.
The crystalline crisabanole pyridine solvate form according to the first aspect of the present invention preferably further has at least one characteristic diffraction peak selected from the group consisting of 19.31 ± 0.2 °, 21.21 ± 0.2 °, 22.21 ± 0.2 ° and 22.87 ± 0.2 ° in an X-ray powder diffraction pattern expressed by diffraction angle 2 θ.
Preferably, the X-ray powder diffraction data of the crystalline form according to the first aspect of the invention is shown in table 1.
Preferably, the crystalline form according to the first aspect of the invention has an X-ray powder diffraction pattern substantially as shown in figure 1.
The crystalline form of Crisabiole pyridine solvate according to the first aspect of the invention preferably has a characteristic peak in Fourier infrared spectroscopy at least one selected from 2228.14 + -2 cm-1, 1425.72 + -2 cm-1, 1360.35 + -2 cm-1 and 1164.51 + -2 cm-1.
The crystalline form of Crisabiole pyridine solvate according to the first aspect of the invention preferably further has a characteristic peak in Fourier infrared spectroscopy at least one selected from 3382.93 + -2 cm-1, 1592.10 + -2 cm-1, 1442.40 + -2 cm-1, 1238.26 + -2 cm-1, 1052.51 + -2 cm-1, 982.57 + -2 cm-1, 852.96 + -2 cm-1 and 699.19 + -2 cm-1.
The crystalline form of crisabaroll pyridine solvate according to the first aspect of the present invention, preferably, has a fourier transform infrared spectrum as shown in figure 5.
The crystalline crisabaroll pyridine solvate form according to the first aspect of the present invention, preferably the crystalline form is FB-2, wherein the content of pyridine in the crisabaroll solvate is 23.96%, which has a weight loss step before showing 75 ℃ in TGA profile, with a weight loss not higher than 12%.
The crystalline form of crisabaroll pyridine solvate according to the first aspect of the present invention, preferably, said crystalline form exhibits a melting point in the DSC diagram of 66 ± 2 ℃.
The crystalline form of Crisabiole pyridine solvate according to the first aspect of the invention, which crystalline form of Crisabiole solvate has a TGA profile substantially as shown in figure 2.
The crystalline form of crisabaroll pyridine solvate according to the first aspect of the present invention, preferably, the crystalline form of crisabaroll pyridine solvate has a DSC profile substantially as shown in figure 3.
In a second aspect of the invention, there is provided a crystalline form of a Crisabiole semi-1, 3-propanediol solvate of formula (II),
Figure BDA0003255668830000041
has at least three characteristic diffraction peaks selected from 10.39 + -0.2 DEG, 12.40 + -0.2 DEG, 19.23 + -0.2 DEG and 22.53 + -0.2 DEG in an X-ray powder diffraction pattern expressed by a diffraction angle 2 theta.
The crystalline crisabanole semi-1, 3-propanediol solvate form according to the second aspect of the present invention preferably further has at least one characteristic diffraction peak selected from 15.97 ± 0.2 °, 21.15 ± 0.2 °, 23.09 ± 0.2 ° and 23.89 ± 0.2 ° in an X-ray powder diffraction pattern expressed by a diffraction angle 2 θ.
The crystalline crisabanole semi-1, 3-propanediol solvate form according to the second aspect of the present invention preferably further has at least one characteristic diffraction peak selected from 16.91 ± 0.2 °, 17.81 ± 0.2 °, 20.31 ± 0.2 ° and 27.43 ± 0.2 ° in an X-ray powder diffraction pattern expressed by diffraction angle 2 θ.
Preferably, the X-ray powder diffraction data of the crystalline form according to the second aspect of the invention is shown in table 2.
Preferably, the crystalline form of the second aspect of the invention has an X-ray powder diffraction pattern substantially as shown in figure 7.
The crystalline form of the Crisabiole semi-1, 3-propanediol solvate according to the second aspect of the invention preferably has a characteristic peak in Fourier infrared spectroscopy at least one selected from 2232.00 + -2 cm-1, 1618.12 + -2 cm-1, 1596.57 + -2 cm-1 and 1240.11 + -2 cm-1.
The crystalline form of Crisabiole semi-1, 3-propanediol solvate according to the second aspect of the invention preferably further has a characteristic peak in Fourier infrared spectroscopy at least one selected from 1492.74 + -2 cm-1, 1371.03 + -2 cm-1, 1171.75 + -2 cm-1, 1112.92 + -2 cm-1, 1011.36 + -2 cm-1, 938.40 + -2 cm-1, 839.58 + -2 cm-1 and 639.79 + -2 cm-1.
The crystalline form of the crisabaroll semi-1, 3-propanediol solvate according to the second aspect of the present invention preferably has a fourier transform infrared spectrum as shown in figure 11.
The crystalline form of the crisabaroll solvate according to the second aspect of the present invention, preferably the crisabaroll half 1, 3-propanediol solvate crystalline form is FB-3, wherein the content of 1, 3-propanediol in the crisabaroll half 1, 3-propanediol solvate is 13.16%, which shows a weight loss in TGA profile of not more than 15% before 150 ℃.
The crystalline crisabaroll half 1, 3-propanediol solvate form according to the second aspect of the present invention having a TGA profile substantially as shown in figure 8.
The crystalline form of a crisabaroll solvate according to the second aspect of the present invention, preferably the crystalline form of a crisabaroll hemi-1, 3-propanediol solvate, has a DSC profile substantially as shown in figure 9.
The crystal form of the Crisabiole solvate has the following technical effects:
1) the crystal form provided by the invention has better water solubility. Compared with the prior art, the water solubility of the crystal form in biological media is remarkably improved. The water solubility of the crystal form is obviously improved, so that the bioavailability of the medicine is improved, and the medicine performance and the medicine effect of the medicine are improved; the dosage of the medicine is reduced while the curative effect of the medicine is ensured, so that the side effect of the medicine is reduced and the safety of the medicine is improved.
2) The crystal form of the invention has better stability. In particular, the crystalline form of 1, 3-propanediol solvate has a high degree of crystalline stability in pharmaceutical formulations (e.g., ointments) in the presence of alcoholic solvents. As the most critical active ingredient in pharmaceuticals, it is crucial that the crystalline form has good physical and chemical stability. The crystal form has good physical stability, and ensures that the raw material medicine is not easily converted into other crystal forms in the process of storage and preparation processes, thereby ensuring that the quality of a sample is consistent and controllable. The crystal form has good chemical stability, the purity is basically unchanged in the storage process, and the crystal form has important significance for ensuring the curative effect and safety of the medicament and preventing the occurrence of adverse reaction of the medicament. In addition, the stable crystal form is more controllable in the crystallization process, impurities and mixed crystals are not easy to appear, and especially, less solvent residues are generated, so that the method is beneficial to industrial production.
In a third aspect of the invention, a preparation method of the crisabaroll pyridine solvate crystal form of the first aspect is provided.
The production method according to the third aspect of the present invention, preferably, includes any one of the following methods:
a method (1) comprising mixing a solvent with a pyridine clear solution of Crisabiole until a solid precipitates to obtain a crystalline form of a Crisabiole solvate;
the method (2) comprises the steps of dissolving Crisabiole in a mixed solvent of a solvent and pyridine, and carrying out temperature change treatment until a solid is precipitated to obtain a crystal form of a Crisabiole solvate.
According to the preparation method of the third aspect of the present invention, preferably, the solvent is water, or a solution of water and a solvent selected from polyacrylic acid, polyethylene glycol, polyethylene oxide, and povidone.
According to the production process of the third aspect of the present invention, preferably, in the process (1), the ratio of Crisabiole to the pyridine compound is 50 to 70:1, and further preferably 55 to 65: 1. Further preferred is 58-62: 1;
according to the preparation method of the third aspect of the present invention, the volume ratio of pyridine to water is preferably 1:1 to 4. Still more preferably 1:1.5-3.5, still more preferably 1: 2.5-3.3.
According to the production method of the third aspect of the present invention, preferably, the supernatant solution is obtained by raising the temperature to 55 to 70 ℃, preferably 58 to 65 ℃, and further preferably 59 to 62 ℃.
According to the preparation method of the third aspect of the present invention, preferably, the temperature-changing treatment refers to a process of sequentially raising the temperature, preserving the temperature and lowering the temperature after the dissolution, and further preferably raising the temperature to 40-60 ℃ and lowering the temperature to 4-30 ℃.
According to the preparation method of the third aspect of the present invention, preferably, in the method (2), the concentration of Crisabiole in the solution is 25 to 40mg/mL, more preferably 26 to 35mg/mL, and still more preferably 30 to 34 mg/mL.
According to the preparation method of the third aspect of the present invention, preferably, the concentration of the polyacrylic acid, the polyethylene glycol, the polyethylene oxide, and the povidone in the solvent solution is 0 to 10mg/mL, more preferably 0 to 8mg/mL, and still more preferably 0 to 7 mg/mL.
In a fourth aspect of the invention, there is provided a process for preparing a crystalline form of a crisabarol semi-1, 3-propanediol solvate according to the second aspect.
The production method according to the fourth aspect of the present invention, preferably, it comprises the following method (1) or (2):
the method (1) comprises the steps of adding 1, 3-propylene glycol into Crisabiole, stirring for 12-36h at a first temperature, then stirring for 12-36h at a second temperature, and then stirring for 12-36h at a third temperature to obtain the crystal form;
and (2) adding 1, 3-propylene glycol into Crisabiole, adding the crystal form seed crystal obtained in the method (1), and stirring at room temperature for over 36 hours to obtain the crystal form.
According to the preparation method of the fourth aspect of the present invention, the concentration of Crisabiole in the 1, 3-propanediol solution is preferably 0.1-0.5g/mL, more preferably 0.15-0.45mg/mL, and still more preferably 0.18-0.35 mg/mL.
According to the preparation method of the fourth aspect of the present invention, preferably, the first temperature refers to a temperature condition of 8-15 ℃, preferably a temperature of 9-12 ℃; the second temperature is 20-30 ℃, preferably 22-28 ℃; the third temperature is a temperature condition of 32-40 ℃, preferably 35-38 ℃.
In a fifth aspect of the present invention, there is provided a pharmaceutical composition comprising the crystalline form of the cristabolite pyridine solvate according to the first aspect, or the crystalline form of the cristabolite 1, 3-propanediol solvate according to the second aspect, or the crystalline form obtained according to the preparation method of the third aspect, or the crystalline form obtained according to the preparation method of the fourth aspect, or any combination of these crystalline forms, and at least one pharmaceutically acceptable carrier.
The pharmaceutically acceptable carrier in the present invention includes a diluent or excipient 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, sugars (e.g., sucrose), gelatin, water, polysaccharides such as lactose or glucose, paraffin (e.g., petroleum fractions), vegetable oils (e.g., peanut 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, methylcellulose, 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, for example, semisolid pharmaceutical preparations suitable for topical skin administration such as ointments, gels, etc., or pharmaceutical preparations suitable for oral administration such as solid oral preparations including tablets, coatings, capsules, granules, powders, pills, powders, etc., or liquid oral preparations including solutions, syrups, suspensions, emulsions, etc.; pharmaceutical preparations suitable for parenteral administration, for example in the form of intravenous drip preparations, intramuscular or subcutaneous injection preparations, suppositories for rectal administration, inhalant preparations for intranasal administration, or else transdermal patches for topical administration. In the production of the preparation, the preparation can also comprise additional auxiliary materials, and preferably, the addition of the auxiliary materials does not cause the transformation of crystal forms.
In a sixth aspect of the invention, there is provided the use of the crystalline form of a crisaboole pyridine solvate according to the first aspect, or the crystalline form of a crisaboole 1, 3-propanediol solvate according to the second aspect, or the crystalline form obtained by the process according to the third aspect, or the crystalline form obtained by the process according to the fourth aspect, or any combination of these crystalline forms, in the manufacture of a topical pharmaceutical formulation for the treatment of a disease or condition associated with inflammation, including psoriasis and atopic dermatitis.
Preferably, the present invention provides the use of said crystalline form in the manufacture of a medicament for the prevention or treatment of a phosphodiesterase 4(PDE-4) associated disease.
In a seventh 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 crystalline form of crisaboole pyridine solvate according to the first aspect, or the crystalline form of crisaboole 1, 3-propanediol solvate according to the second aspect, or the crystalline form obtained by the process for preparation according to the third aspect, or the crystalline form obtained by the process for preparation according to the fourth aspect, or any combination of these crystalline forms, or the pharmaceutical composition according to the fifth aspect, wherein the disease is a phosphodiesterase 4 related disease comprising psoriasis and inflammatory related diseases of atopic dermatitis. Preferably, the pharmaceutical composition comprises a prophylactically and/or therapeutically effective amount of the crystalline form.
In an eighth aspect of the present invention, there is provided a crystalline form of a pyridine solvate according to the first aspect, or a crystalline form of a solvate 1, 3-propanediol solvate according to the second aspect, or a crystalline form obtained by the preparation method according to the third aspect, or a crystalline form obtained by the preparation method according to the fourth aspect, or any combination of these crystalline forms, or a pharmaceutical composition according to the fifth aspect, for use in combination with other pharmaceutically active ingredients (examples of other pharmaceutically active ingredients are provided below).
Drawings
Figure 1 is an XRPD pattern of crisabaroll solvate form FB-2 prepared according to example 1.
Figure 2 is a TGA profile of crisabaroll solvate crystalline form FB-2 prepared according to example 1.
Figure 3 is a DSC profile of crisabaroll solvate crystalline form FB-2 prepared according to example 1.
Figure 4 is a PLM map of crisabaroll solvate form FB-2 prepared according to example 1.
Figure 5 is a fourier transform infrared spectrum of crisabaroll solvate form FB-2 prepared according to example 1.
Figure 6 is a 1HNMR map of crisabaroll solvate form FB-2 prepared according to example 1.
Figure 7 is an XRPD pattern of crisabaroll solvate form FB-3 prepared according to example 4.
Figure 8 is a TGA profile of crisabaroll solvate crystalline form FB-3 prepared according to example 4.
Figure 9 is a DSC profile of crisabaroll solvate crystalline form FB-3 prepared according to example 4.
Figure 10 is a PLM map of crisabaroll solvate form FB-3 prepared according to example 4.
Figure 11 is a fourier transform infrared spectrum of crisabaroll solvate form FB-3 prepared according to example 4.
Figure 12 is a 1HNMR map of crisabaroll solvate crystalline form FB-3 prepared according to example 4.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description 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. Further, for numerical ranges in this disclosure, it is understood that the upper and lower limits of the range, and each intervening value therebetween, is specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in a stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, 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 herein 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 method, the crystal form I of Crisabiole is generally used as a starting material for preparing the crystal form I of the invention, and other compounds and salts in any form of Crisabiole can also be used as the starting material, and the Crisabiole crystal form I as the starting material can be obtained from a commercially available product or prepared by the method mentioned in WO2017/193917A1 or CN 108884111A.
The term "subject" as used herein includes mammals. The mammal can be, for example, any mammal, e.g., a human, primate, bird, mouse, rat, poultry, dog, cat, cow, horse, goat, camel, sheep, or pig. Preferably, the mammal is a human.
As used herein, the term "room temperature" generally means 10-30 deg.C, preferably 20. + -. 5 deg.C.
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 involved in stability, dissolution and mechanicalness in pharmaceutical formulations. Different crystalline forms of the same substance typically have different crystal lattices (e.g., unit cells) with different physical properties characteristic thereof. The different crystalline forms can be characterized by methods known in the art. For example, identification can be by solid state characterization methods, such as by X-ray powder diffraction (XRPD). Other methods of characterization include Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), Dynamic Vapor Sorption (DVS), solid state NMR, and the like. The crystalline form may be characterized using any of the methods described above, or 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 may be made to, for example, "pharmacopoeia of the people's republic of china" or the like. The parameters for detection are set as follows:
the specific conditions for XRPD (X-ray powder diffraction) measurements were: bruker D8, Cu-Kalpha radiation, detection range of 3-40 degrees 2 theta, step size of 0.02 degrees 2 theta, scanning speed of 0.2s.step-1, current voltage of 40mA and 40 KV.
TGA (thermogravimetric analysis) test conditions were: placing 1-15mg of sample in a platinum crucible, and adopting a segmented high-resolution detection mode, wherein the temperature is 10.00 ℃/min from room temperature to 350 ℃; for the TGA plot, the temperature points and loss of weight values were retained.
The test conditions for differential scanning calorimetry analysis were: placing 1-10mg of sample in a perforated platinum crucible, balancing at 0 deg.C, and heating to 300 deg.C at 10 deg.C/min; for the DSC plots, the temperature points and enthalpy values were retained.
The dynamic water adsorption analysis and detection method comprises the following steps: 1-10mg of the sample is placed in a platinum crucible, and the weight change of the sample in the process of changing the relative humidity from 0% to 80% to 0% is detected.
A Polarized Light Microscope (PLM) map was taken from XP-500E polarized light microscope. And (3) placing a small amount of powder sample on a glass slide, dropwise adding a small amount of mineral oil dispersed sample, covering the glass slide, placing on an objective table for observation and taking a picture.
The test conditions of the Fourier infrared spectrum are as follows: bruker tenor 27, ATR method, acquisition range 600cm-1-4000cm-1, resolution 4 cm-1.
In the present invention, the terms "performance" or "crystalline form performance" or "property" or "pharmaceutical property" include physical and chemical properties thereof, and the evaluation index includes, but is 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 are commercially available unless otherwise specified. The examples were run at room temperature unless otherwise indicated.
Example 1
Taking about 90mg of Crisabiole crystal form, adding 1.5mg of pyridine, and heating to 60 ℃ to obtain a solution 1; adding 4.5mL of water-soluble clear solution into about 6mg of polyethylene glycol to obtain a solution 2; and dropwise adding the solution 2 into the solution 1 to separate out a solid, continuously stirring overnight, and centrifuging to obtain FB-2.
The sample of example 1 was taken for characterization as follows.
1. XRPD pattern analysis
FIG. 1 is an XRPD pattern for FB-2, with Table 1 showing X-ray powder diffraction data for FB-2.
Table 1: x-ray powder diffraction data of FB-2
Figure BDA0003255668830000151
Figure BDA0003255668830000161
2. TGA profile analysis
The TGA (thermogravimetric analysis) results are shown in FIG. 2. The product has a weight loss step before 75 ℃, the weight loss rate is 11.3 percent, and the decomposition temperature is 273 ℃.
3. DSC profile analysis
The differential scanning calorimetry analysis results are shown in FIG. 3. Form FB-2 has a melting point at 66 ℃.
4. PLM analysis
The results of Polarized Light Microscopy (PLM) are shown in FIG. 4. Shown as fine particles.
6. FT-IR analysis
The Fourier infrared spectrum results are shown in FIG. 5. The crystal form FB-2 has the following characteristic peaks:
characteristic diffraction peaks exist at 2228.14 +/-2 cm-1, 1425.72 +/-2 cm-1, 1360.35 +/-2 cm-1 and 1164.51 +/-2 cm-1 of the FB-2 crystal form; in addition, there are characteristic diffraction peaks at 3382.93 + -2 cm-1, 1592.10 + -2 cm-1, 1442.40 + -2 cm-1, 1238.26 + -2 cm-1, 1052.51 + -2 cm-1, 982.57 + -2 cm-1, 852.96 + -2 cm-1, and 699.19 + -2 cm-1. Considering the variation of wave number under different conditions, it is generally considered acceptable to be within a range of ± 2.
The 1HNMR map of the crystal form FB-2 is shown in figure 6.
Example 2
About 30mg of Crisabiole is taken, 0.5mL of pyridine is added, the temperature is raised to 60 ℃ for dissolving, 1.5mL of water is added dropwise to precipitate solid, and the mixture is continuously stirred overnight to obtain FB-2.
Example 3
Taking about 90mg of Crisabiole, adding 0.8mL of pyridine and 2mL of water, dissolving at 60 ℃, filtering, keeping the temperature of the filtrate for 20min, then placing the filtrate at 4 ℃, stirring overnight, and precipitating a solid to obtain FB-2.
Example 4
Adding 5mL of 1, 3-propylene glycol into about 1.3 g of Crisabiole, and stirring at 10 ℃ for 24 h; transferring the system in the step 1 to 25 ℃ and stirring for 24 h; and transferring the system in the previous step to 37 ℃ and stirring for 24h to obtain a large amount of white solid, thus obtaining FB-3.
The sample of example 4 was taken for characterization as follows.
1. XRPD pattern analysis
FIG. 7 is an XRPD pattern for FB-3, with X-ray powder diffraction data for FB-3 shown in Table 2.
Table 2: x-ray powder diffraction data of FB-3
Figure BDA0003255668830000171
Figure BDA0003255668830000181
2. TGA profile analysis
The TGA (thermogravimetric analysis) results are shown in FIG. 8. The weight loss before 150 ℃ is 14.1%, and the decomposition temperature is 265 ℃.
3. DSC profile analysis
The results of the differential scanning calorimetry are shown in FIG. 9. Form FB-3 has a melting point at 58 ℃.
4. PLM analysis
The results of Polarized Light Microscopy (PLM) are shown in FIG. 10. Shown as fine particles.
6. FT-IR analysis
The Fourier infrared spectrum results are shown in FIG. 11. The crystal form FB-3 has the following characteristic peaks:
the FB-3 crystal form has characteristic diffraction peaks at 2232.00 + -2 cm-1, 1618.12 + -2 cm-1, 1596.57 + -2 cm-1 and 1240.11 + -2 cm-1; in addition, there are characteristic diffraction peaks at 1492.74 + -2 cm-1, 1371.03 + -2 cm-1, 1171.75 + -2 cm-1, 1112.92 + -2 cm-1, 1011.36 + -2 cm-1, 938.40 + -2 cm-1, 839.58 + -2 cm-1, and 636.79 + -2 cm-1. Considering the variation of wave number under different conditions, it is generally considered acceptable to be within a range of ± 2.
The 1HNMR map of the crystal form FB-3 is shown in figure 12.
Example 5
And (3) adding 5mL of 1, 3-propylene glycol into 1.5g of Crisabiole, adding a proper amount of crystal form seed crystals obtained in the example 4, and stirring at room temperature for 2 days to obtain FB-3.
While the present 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. Many modifications and variations may be made to the exemplary embodiments of the present description without departing from the scope or spirit of the present 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 Crisabiole pyridine solvate crystal form with a structural formula shown as a formula (I),
Figure FDA0003255668820000011
characterized by having at least three characteristic diffraction peaks selected from the group consisting of 5.33. + -. 0.2 DEG, 14.58. + -. 0.2 DEG, 16.47. + -. 0.2 DEG and 23.23. + -. 0.2 DEG in an X-ray powder diffraction pattern expressed by a diffraction angle 2 theta.
2. The crystalline crisabarol e pyridine solvate form according to claim 1, characterized by further having at least one characteristic diffraction peak selected from 18.76 ± 0.2 °, 23.77 ± 0.2 °, 25.71 ± 0.2 ° and 27.99 ± 0.2 ° in an X-ray powder diffraction pattern expressed in diffraction angle 2 Θ.
3. The crystalline crisabarol e pyridine solvate form according to claim 1 or 2, characterized by further having at least one characteristic diffraction peak selected from 19.31 ± 0.2 °, 21.21 ± 0.2 °, 22.21 ± 0.2 ° and 22.87 ± 0.2 ° in an X-ray powder diffraction pattern expressed in diffraction angle 2 Θ.
4. A process for preparing a crystalline form of a crisabonole pyridine solvate according to any of claims 1 to 3, characterized in that it is selected from any one of the following processes:
a method (1) comprising mixing a solvent with a pyridine clear solution of Crisabiole until a solid precipitates to obtain a crystalline form of a Crisabiole solvate;
the method (2) comprises the steps of dissolving Crisabiole in a mixed solvent of a solvent and pyridine, and carrying out temperature change treatment until a solid is precipitated to obtain a crystal form of a Crisabiole solvate.
5. A crystal form of Crisabiole semi-1, 3-propanediol solvate with a structural formula shown as the following formula (II),
Figure FDA0003255668820000021
characterized by having at least three characteristic diffraction peaks selected from 10.39 + -0.2 DEG, 12.40 + -0.2 DEG, 19.23 + -0.2 DEG and 22.53 + -0.2 DEG in an X-ray powder diffraction pattern expressed by a diffraction angle 2 theta.
6. The crystalline form of Crisabiole hemi 1, 3-propanediol solvate according to claim 5, further having at least one characteristic diffraction peak selected from 15.97 ± 0.2 °, 21.15 ± 0.2 °, 23.09 ± 0.2 ° and 23.89 ± 0.2 ° in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 θ.
7. The crystalline form of Crisabiole hemi 1, 3-propanediol solvate according to claim 5 or 6, characterized by further having at least one characteristic diffraction peak selected from the group consisting of 16.91 ± 0.2 °, 17.81 ± 0.2 °, 20.31 ± 0.2 ° and 27.43 ± 0.2 ° in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 θ.
8. A process for preparing a crystalline form of a crisabaroll hemi-1, 3-propanediol solvate according to any one of claims 5 to 7, characterized in that it is selected from any one of the following processes:
the method (1) comprises the steps of adding 1, 3-propylene glycol into Crisabiole, stirring for 12-36h at a first temperature, then stirring for 12-36h at a second temperature, and then stirring for 12-36h at a third temperature to obtain the crystal form;
and (2) adding 1, 3-propylene glycol into Crisabiole, adding the crystal form seed crystal obtained in the method (1), and stirring at room temperature for over 36 hours to obtain the crystal form.
9. A pharmaceutical composition comprising the crystalline form of crisaboole pyridine solvate according to any one of claims 1 to 3, or the crystalline form of crisaboole 1, 3-propanediol solvate according to any one of claims 5 to 7, and at least one pharmaceutically acceptable carrier.
10. Use of the crystalline form of a crisabolite pyridine solvate according to any one of claims 1 to 3, or the crystalline form of a crisabolite 1, 3-propanediol solvate according to any one of claims 5 to 7, or a combination of these crystalline forms, in the manufacture of a topical pharmaceutical formulation for the treatment of an inflammation-related disease or disorder, including psoriasis and atopic dermatitis.
CN202111060407.XA 2021-09-10 2021-09-10 Crystal form of Crisabiole solvate and preparation method and application thereof Pending CN113620982A (en)

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