CN113956264A - Novel pranoprofen crystal form and preparation method thereof - Google Patents

Novel pranoprofen crystal form and preparation method thereof Download PDF

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CN113956264A
CN113956264A CN202111208951.4A CN202111208951A CN113956264A CN 113956264 A CN113956264 A CN 113956264A CN 202111208951 A CN202111208951 A CN 202111208951A CN 113956264 A CN113956264 A CN 113956264A
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pranoprofen
apoptotic cells
preparation example
crystal form
organic solvent
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刘向超
王浩然
黄冠彬
王成宇
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Zhongshan Wanhan Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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Abstract

The invention provides a pranoprofen crystal form, and the specific definition of the crystal form is shown in the specification. The in vitro AO/EB staining test result shows that the toxicity of the pranoprofen crystal form to human corneal epithelial cells (HCE cells) is lower than that of the pranoprofen crystal form in the prior art in terms of the number of non-apoptotic cells.

Description

Novel pranoprofen crystal form and preparation method thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel pranoprofen crystal form and a preparation method thereof.
Background
Pranoprofen is a nonsteroidal anti-inflammatory drug, and clinical medicinal preparations include eye drops and tablets. Yi-Han Li et al, Dose dependent cytotoxicity of pranoprofen in cultured human corneal endothelial cells by inducing apoptosis, noted in Dose dependent cytotoxicity of pranoprofen in cultured human corneal endothelial cells (discharge Chem Toxicol. 2015Jan; 38(1): 16-21.). Therefore, the safety of the composition for treating ophthalmic diseases is further improved.
The polymorphism of the drug can affect the properties of the drug such as chemical stability, melting point, dissolution rate, pharmacokinetics and the like, and the difference of different crystal forms in the aspect of pharmacological action/toxicity action is more and more concerned in recent years (see leilin et alSynthesis of tifen and preparation and characterization of crystal form A thereof [ J]The J.Chem.Chem.China 2020,30(07): 405-409). For example, the results of experiments disclosed in Liu's Master thesis "screening preparation, characterization and pharmacokinetic studies of tasimelteon polymorphs" indicate that the IC of tasimelteon in forms I and II on the C6 cell line50The values were 110 and 190. mu.g/mL, respectively, IC of both on U87 cells50The values were 131 and 191. mu.g/mL, respectively. Therefore, the crystal form with low cytotoxicity is searched for, and is a method for improving the safety of pranoprofen.
Disclosure of Invention
The invention aims to provide a novel pranoprofen crystal form and a preparation method thereof, wherein the crystal form can obviously reduce the cytotoxicity of pranoprofen.
In order to achieve the above object, the present invention provides a pranoprofen crystal form, wherein an X-ray diffraction pattern of the crystal form has a characteristic peak at a 2 θ ± 0.2 ° position, and the 2 θ is 8.2, 19.7, 26.1 and 13.0.
Preferably, the X-ray diffraction pattern of the crystal form of the invention has a characteristic peak at a 2 theta +/-0.2 DEG position, and the 2 theta is 8.2, 19.7, 26.1, 13.0, 12.0, 19.5, 16.4 and 18.5.
The invention also provides a pranoprofen crystal form, which is prepared by the following method:
step 1, adding a pranoprofen crude product into an organic solvent-water solution, and refluxing until the solution is clear.
And step 2, taking the solution obtained in the step 1, and carrying out gradient cooling to 5-0 ℃.
And 3, taking the product after gradient cooling, performing suction filtration, and leaching a filter cake by using an organic solvent-water solution.
In one aspect, the preparation method of the invention preferably comprises the following steps:
step 1, adding a pranoprofen crude product into a 70% -80% organic solvent-water solution, wherein the final concentration is 1.5-2.1 g/mL, refluxing to a clear solution, and stirring for 0-1.0 h under heat preservation.
And 2, taking the solution obtained in the step 1, sequentially carrying out gradient cooling until the temperature is reduced to 70-60 ℃, 50-40 ℃, 30-20 ℃ and 5-0 ℃, cooling for 30-45 minutes each time, and keeping the temperature for 0-3 hours after cooling each time.
And 3, taking the product after gradient cooling, performing suction filtration, and leaching the filter cake by using 70-80% of organic solvent-water solution at the temperature of 0-5 ℃.
In another aspect, the organic solvent of the present invention is preferably one selected from ethanol, methanol, isopropanol, N-dimethylformamide, tetrahydrofuran and acetonitrile.
In another aspect of the present invention there is provided a composition comprising a crystalline form of pranoprofen as hereinbefore described.
Preferably, the composition of the present invention can be prepared into eye drops.
In vitro test results show that the cellular toxicity of the pranoprofen crystal form on HCE cells is obviously lower than that of the pranoprofen crystal form prepared by the method of CN110372713A example 1
Drawings
FIG. 1 to 192 preparation examples 1 to 192 show cytotoxicity test results (AO/EB staining method) of pranoprofen crystal forms prepared in preparation examples 1 to 192 on HCE cells
FIG. 193 cytotoxicity test results (AO/EB staining) of pranoprofen crystal form prepared in example 1 of CN110372713A on HCE cells
FIG. 194, powder XRD patterns of pranoprofen crystal forms of preparation examples 7 and 12
Detailed Description
Crystal form preparation examples and screening test
Monolithic preparation method
To the solvent (for the organic solvent-water mixed solvent, the organic solvent concentration is set as the variable "C1"%) was added with pranoprofen crude product (final concentration set as variable" C) obtained from hanpu medicine ltd, guangzhou2"g/mL), refluxing to clear, and subsequent incubation stirring time set to the variable" t1"hours".
Step 2, taking the solution obtained in the step 1, and sequentially carrying out gradient cooling to the gradient temperature T1、T2、T3、T4At a temperature of each timeThe time length of the temperature reduction is set as a variable t2、t3、t4、t5Minutes, and the holding time after each temperature reduction is set as a variable t6、t7、t8、t9"hours".
And 3, taking the product after gradient cooling, performing suction filtration, leaching a filter cake by using a solvent at 0-5 ℃, and setting the concentration of the organic solvent as a variable C for the organic solvent-water mixed solvent3”％。
The upper, lower and intermediate values of each variable are shown in table 1.
Table 1 variable parameters
Variables of Unit of Upper limit of Lower limit of Median value Variables of Unit of Upper limit of Lower limit of Median value
C1 ％ 80 70 75 C2 g/mL 2.1 1.5 1.8
t1 Hour(s) 1 0 0.5 T1 ℃ 70 60 65
T2 ℃ 50 40 45 T3 ℃ 30 20 25
T4 ℃ 5 0 2.5 t2 Minute (min) 45 30 36
t3 Minute (min) 45 30 36 t4 Minute (min) 45 30 36
t5 Minute (min) 45 30 36 t6 Hour(s) 3 0 1.5
t7 Hour(s) 3 0 1.5 t8 Hour(s) 3 0 1.5
t9 Hour(s) 3 0 1.5 C3 ％ 80 70 75
Design of orthogonal experiments
Selecting alcohol-water as a solvent, sequentially selecting the upper limit and the lower limit of each variable for testing, and fixing other variables as intermediates thereof. The rate of HCE apoptosis induced by each crystal form after one hour treatment at a concentration of 10g/L was examined according to AO/EB staining method disclosed by Wuhong in its Master's thesis toxicity of resveratrol on mouse breast cancer 4T1 cells and transcriptomics study (see section 3.2.1), and the results are shown in Table 2 and FIGS. 1-12.
It is noted that apoptotic cells appear red and non-apoptotic cells appear green according to the principle of AO/EB staining. However, since the applicant could not express the above results by color in the application document, the applicant replaced a small number of cells with a blank as a comparison.
TABLE 2 examination results using ethanol-water solution as solvent
Figure BDA0003308108530000021
Figure BDA0003308108530000031
TABLE 3 examination results with acetonitrile-water solvent
Preparation example No Variables under investigation AO/EB staining results Blank meaning
Preparation example 33 C1 FIG. 33 Non-apoptotic cells
Preparation example 34 C1 FIG. 34 Non-apoptotic cells
Preparation example 35 C2 FIG. 35 is a schematic view of a Non-apoptotic cells
Preparation example 36 C2 FIG. 36 Non-apoptotic cells
Preparation example 37 t1 FIG. 37 Non-apoptotic cells
Preparation example 38 t1 FIG. 38 Non-apoptotic cells
Preparation example 39 T1 FIG. 39 shows Non-apoptotic cells
Preparation example 40 T1 FIG. 40 Non-apoptotic cells
Preparation example 41 T2 FIG. 41 Non-apoptotic cells
Preparation example 42 T2 FIG. 42 Non-apoptotic cells
Preparation example 43 T3 FIG. 43 Non-apoptotic cells
Preparation example 44 T3 FIG. 44 Non-apoptotic cells
Preparation example 45 T4 FIG. 45 Non-apoptotic cells
Preparation example 46 T4 FIG. 46 Non-apoptotic cells
Preparation example 47 t2 FIG. 47 Non-apoptotic cells
Preparation example 48 t2 FIG. 48 Non-apoptotic cells
Preparation example 49 t3 FIG. 49 Non-apoptotic cells
Preparation example 50 t3 FIG. 50 Non-apoptotic cells
Preparation example 51 t4 FIG. 51 Non-apoptotic cells
Preparation example 52 t4 FIG. 52 Non-apoptotic cells
Preparation example 53 t5 FIG. 53 Non-apoptotic cells
Preparation example 54 t5 FIG. 54 Non-apoptotic cells
Preparation example 55 t6 FIG. 55 Non-apoptotic cells
Preparation example 56 t6 FIG. 56 Non-apoptotic cells
Preparation example 57 t7 FIG. 57 Non-apoptotic cells
Preparation example 58 t7 FIG. 58 Non-apoptotic cells
Preparation example 59 t8 FIG. 59 Non-apoptotic cells
Preparation example 60 t8 FIG. 60 Non-apoptotic cells
Preparation example 61 t9 FIG. 61 Non-apoptotic cells
Preparation example 62 t9 FIG. 62 Non-apoptotic cells
Preparation example 63 C3 FIG. 63 Non-apoptotic cells
Preparation 64 C3 FIG. 64 Non-apoptotic cells
TABLE 4 examination results with methanol-water solvent
Figure BDA0003308108530000032
Figure BDA0003308108530000041
TABLE 5 examination of the results with isopropanol-water solvent
Figure BDA0003308108530000042
Figure BDA0003308108530000051
TABLE 6 examination results with N, N-dimethylformamide-water solvent
Preparation example No Variables under investigation AO/EB staining results Blank meaning
Preparation example 129 C1 FIG. 129 shows Non-apoptotic cells
Preparation example 130 C1 FIG. 130 Non-apoptotic cells
Preparation example 131 C2 FIG. 131 Non-apoptotic cells
Preparation 132 C2 FIG. 132 Non-apoptotic cells
Preparation example 133 t1 FIG. 133 Non-apoptotic cells
Preparation example 134 t1 FIG. 134 Non-apoptotic cells
Preparation example 135 T1 FIG. 135 Non-apoptotic cells
Preparation example 136 T1 FIG. 136 Non-apoptotic cells
Preparation example 137 T2 FIG. 137 Non-apoptotic cells
Preparation example 138 T2 FIG. 138 Non-apoptotic cells
Preparation example 139 T3 FIG. 139 Non-apoptotic cells
Preparation example 140 T3 FIG. 140 Non-apoptotic cells
Preparation example 141 T4 FIG. 141 Non-apoptotic cells
Preparation example 142 T4 FIG. 142 Non-apoptotic cells
Preparation example 143 t2 FIG. 143 Non-apoptotic cells
Preparation example 144 t2 FIG. 144 Non-apoptotic cells
Preparation example 145 t3 FIG. 145 Non-apoptotic cells
Preparation example 146 t3 FIG. 146 Non-apoptotic cells
Preparation example 147 t4 FIG. 147 Non-apoptotic cells
Preparation example 148 t4 FIG. 148 Non-apoptotic cells
Preparation example 149 t5 FIG. 149 Non-apoptotic cells
Preparation example 150 t5 Drawing 150 Non-apoptotic cells
Preparation example 151 t6 FIG. 151 Non-apoptotic cells
Preparation 152 t6 FIG. 152 Non-apoptotic cells
Preparation example 153 t7 FIG. 153 Non-apoptotic cells
Preparation example 154 t7 FIG. 154 Non-apoptotic cells
Preparation example 155 t8 FIG. 155 Non-apoptotic cells
Preparation example 156 t8 FIG. 156 Non-apoptotic cells
Preparation 157 t9 FIG. 157 Non-apoptotic cells
Preparation example 158 t9 FIG. 158 Non-apoptotic cells
Preparation example 159 C3 FIG. 159 Non-apoptotic cells
Preparation example 160 C3 FIG. 160 Non-apoptotic cells
TABLE 7 examination results with tetrahydrofuran-water solvent
Figure BDA0003308108530000052
Figure BDA0003308108530000061
The results of cytotoxicity of pranoprofen crystalline form prepared by the purification method of example 1 in CN110372713A on HCE cells are shown in fig. 193.
As shown in fig. 1 to 193, the pranoprofen crystal forms prepared in preparation examples 1 to 192 had significantly lower cytotoxicity to HCE cells than the pranoprofen crystal form prepared in CN 110372713A.
Powder XRD patterns of pranoprofen crystal forms of preparation examples 7 and 12 (conditions: Empyrean acute X-ray powder of PasnakeDiffractometer (PW3040/60, Dutch Pasnake Analyzer Co., Ltd.), Cu-Ka radiation, wavelength
Figure BDA0003308108530000062
Equipped with Bragg-Brentano High Definition. Incident light path: a divergence slit 1/8 degrees, a Soxhlet slit 0.04rad, a light shielding frame Mask 10mm degrees, and an anti-divergence slit 1/2 degrees; diffraction light path: an anti-scatter slit P7.5; an X-ray sample stage: a rotation mode; scanning the detector: PIXcel1D-Medipix 3; the voltage of the X-ray light pipe is 45kV, the current of the X-ray light pipe is 40mA, the scanning range is 2-40 degrees (2 theta), the step length is 0.026 degree, and the step length time is as follows: 36.465 s. Data Collector, Data viewer, HighScore Plus) are shown in fig. 194, 195, respectively.
Preparation examples of formulations
Dissolving 0.023g of methyl paraben and 0.011g of propyl paraben in boiling distilled water, dissolving 0.1g of pranoprofen crystal form prepared in preparation example 7 or 12 and sodium chloride in the solution at 60 ℃, filtering, adding distilled water to 100mL, filling, and sterilizing at 100 ℃ for 30 minutes to obtain the pranoprofen crystal form.

Claims (7)

1. A pranoprofen crystal form is characterized in that an X-ray diffraction pattern of the crystal form has a characteristic peak at a 2 theta +/-0.2 DEG position, and the 2 theta is 8.2, 19.7, 26.1 and 13.0.
2. The crystalline form according to claim 1, characterized in that said 2 Θ is 8.2, 19.7, 26.1, 13.0, 12.0, 19.5, 16.4 and 18.5.
3. The pranoprofen crystal form is characterized by being prepared by the following method:
step 1, adding a pranoprofen crude product into an organic solvent-water solution, and refluxing until the solution is clear;
step 2, taking the solution obtained in the step 1, and carrying out gradient cooling to 5-0 ℃;
and 3, taking the product after gradient cooling, performing suction filtration, and leaching a filter cake by using an organic solvent-water solution.
4. The crystalline form according to claim 3, characterized in that said preparation process comprises the following steps:
step 1, adding a pranoprofen crude product into a 70-80% organic solvent-water solution, wherein the final concentration is 1.5-2.1 g/mL, refluxing to a clear solution, and stirring for 0-1.0 h under heat preservation;
step 2, taking the solution obtained in the step 1, sequentially carrying out gradient cooling until the temperature is reduced to 70-60 ℃, 50-40 ℃, 30-20 ℃ and 5-0 ℃, cooling for 30-45 minutes each time, and keeping the temperature for 0-3 hours after cooling each time;
and 3, taking the product after gradient cooling, performing suction filtration, and leaching the filter cake by using 70-80% of organic solvent-water solution at the temperature of 0-5 ℃.
5. The crystalline form according to claim 3, characterized in that the organic solvent is one selected from the group consisting of ethanol, methanol, isopropanol, N-dimethylformamide, tetrahydrofuran and acetonitrile.
6. A composition comprising a crystalline form of pranoprofen according to claim 1 or 3.
7. The composition of claim 6, wherein said composition is in the form of an eye drop.
CN202111208951.4A 2021-12-06 2021-12-06 Novel pranoprofen crystal form and preparation method thereof Pending CN113956264A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110372713A (en) * 2019-08-15 2019-10-25 广州市汉普医药有限公司 A kind of polishing purification method of pranoprofen
CN211357820U (en) * 2019-12-13 2020-08-28 山东新鲁生物科技有限公司 Be used for synthetic integral type crystal separation device of using of pranoprofen

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110372713A (en) * 2019-08-15 2019-10-25 广州市汉普医药有限公司 A kind of polishing purification method of pranoprofen
CN211357820U (en) * 2019-12-13 2020-08-28 山东新鲁生物科技有限公司 Be used for synthetic integral type crystal separation device of using of pranoprofen

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MARIA RINCON ET AL.: "Development of Pranoprofen Loaded Nanostructured Lipid Carriers to Improve Its Release and Therapeutic Efficacy in Skin Inflammatory Disorders", 《NANOMATERIALS》, vol. 8, pages 1022 *
金荣庆等: "普拉洛芬的合成研究改进", 《精细化工中间体》, vol. 39, no. 3, pages 37 - 39 *

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