Crystal form of free alkali of econazole as well as preparation method and application of crystal form

Abstract

The invention relates to a pharmaceutical composition of econazole free alkali and a crystal form of the econazole free alkali. The crystal form has characteristic diffraction peaks in a powder X-ray diffraction pattern at the 2 theta angle of 9.36 degrees + / -0.2 degrees and at the 2 theta angle of 23.15 degrees + / -0.2 degrees. The crystalline econazole free alkali provided by the invention has the advantages that the solubility of econazole in a matrix can be remarkably improved, the diffusion velocity and permeability of a medicine can be improved, the phenomenon that the econazole is separated out in a crystal form in a pharmaceutical composition can be avoided, so that the influence on the absorption and curative effect of the medicine is reduced, and the like, and also has the advantages of simple purification method, low cost and the like. The production cost is low, and a high-purity product is easy to obtain.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a crystal form of econazole free base, a preparation method thereof, and an application thereof. Background Art

[0002] Econazole is an imidazole compound with antifungal activity. Currently, it is mainly used as a drug in the form of nitrate in the market and is widely used to treat fungal infectious diseases such as tinea pedis, tinea cruris, and tinea versicolor. The common dosage forms are creams and ointments, and the content is usually 1%. There are no reports in domestic and foreign literatures on pharmaceutical compositions of econazole free base.

[0003]

[0004] However, econazole nitrate has some significant disadvantages. It has a relatively large polarity and cannot be completely dissolved in creams and ointments. Physical phase separation often occurs during the preparation of pharmaceutical preparations due to salting-out effects, which affects the product quality. In addition, econazole nitrate has a relatively high melting point (163°C - 167°C) and is prone to precipitate in the form of crystals in pharmaceutical preparations, making it difficult to be absorbed by the skin and resulting in the drug being unable to effectively exert its therapeutic effect. Studies have shown that approximately 90% of econazole nitrate (as a cream) remains on the skin surface and cannot exert its therapeutic effect. Therefore, the concentration of its preparations is usually low, generally 1%. The low-concentration econazole nitrate preparations not only limit the concentration of the drug at the action site, reduce the penetration rate, but also seriously affect the exertion of the curative effect. Usually, it needs to be used continuously for several weeks (twice a day) to eliminate the signs and symptoms of skin infections. At the same time, econazole nitrate also has certain irritation, and about 1 - 4% of patients will experience side effects such as irritation, redness, burning, or itching.

[0005] For some special diseases, such as onychomycosis (commonly known as ringworm of the nail), it is particularly difficult to deliver the drug to the action site. Onychomycosis is a fungal infection of the fingernails or toenails caused by fungi. The fungi are hidden under the nail plate of the fingernails or toenails, and it is difficult for the drug to reach the action site through local treatment and penetrate through the nail plate. Although in recent years, there have been studies attempting to enhance the penetration of antifungal drugs by preparing new drug delivery systems such as nanoparticles, colloidal particles, and vesicle carriers, their applications in actual products are relatively few. Commonly used physical or chemical methods to enhance permeability, such as softening or thinning the nail plate of the nail, or adding chemical substances such as urea or thioglycolic acid to change the nail plate structure, but these methods cause greater damage to the nail plate and it is difficult to restore the firm and smooth shape of the nail plate. Summary of the Invention

[0006] An object of the present invention is to address the deficiencies in the prior art. On the one hand, a pharmaceutical composition is provided, which is characterized by containing econazole free base shown in structural formula I or its physiologically acceptable solvate, preferably the solvent-free free base.

[0007] The econazole solvent compound provided by the present invention includes, but is not limited to, solvents such as water of crystallization and crystalline ethanol.

[0008] The econazole free base provided by the present invention can be amorphous or crystalline, and the crystalline form is preferred.

[0009] Preferably, the pharmaceutical composition is a topical pharmaceutical composition, and its dosage form is selected from at least one of ointment, cream, gel, solution, suppository, nail polish, nail lacquer, mucosal adhesive film, or mucosal adhesive tablet.

[0010] The pharmaceutical composition provided by the present invention includes at least one pharmaceutically acceptable carrier.

[0011] Preferably, the pharmaceutically acceptable carrier is selected from at least one of ethyl lactate, n-propyl lactate, isopropyl lactate, n-butyl lactate, 2-ethylhexyl lactate, C10-C20 fatty alcohol lactates, diethyl adipate, di-n-propyl adipate, diisopropyl adipate, di-n-butyl adipate, diisobutyl adipate, diethyl azelate, di-n-propyl azelate, diisopropyl azelate, decamethylcyclopentasiloxane cyclomethicone or dodecamethylcyclohexasiloxane cyclomethicone.

[0012] The advantages of the pharmaceutical composition of the present invention are that it can significantly improve the solubility of econazole in the matrix, can increase the diffusion rate and permeability of the drug, and avoid the problem of precipitation in crystal form due to its low melting point (86°C - 90°C), thereby reducing the impact on drug absorption and efficacy.

[0013] The second aspect of the present invention is to provide an application of the pharmaceutical composition as described above in the preparation of a drug for treating fungal infections.

[0014] Preferably, the fungal infection is a superficial fungal infection, which is selected from at least one of skin fungal infections, fingernail / toenail fungal infections, oral fungal infections, or vaginal fungal infections.

[0015] The third aspect of the present invention provides a crystal form of econazole free base, its preparation method and application.

[0016] To achieve the above object, the technical solution adopted by the present invention is:

[0017] 1. Provide a crystal form of econazole free base, which has characteristic diffraction peaks at 2θ angles of 9.36° ± 0.2° and 23.15° ± 0.2° in the powder X-ray diffraction pattern.

[0018] Preferably, the crystal form has characteristic diffraction peaks at 2θ angles of 9.36° ± 0.2°, 16.14° ± 0.2°, 23.15° ± 0.2°, 24.28° ± 0.2°, 25.87° ± 0.2°, and 34.89° ± 0.2° in the powder X-ray diffraction pattern.

[0019] Furthermore, the powder X-ray diffraction pattern of the crystal form is as Figure 1 shown.

[0020] Table 1 Powder X-ray diffraction data of crystalline econazole

[0021]

[0022]

[0023] Preferably, the crystal form has a single endothermic peak in the differential scanning calorimetry pattern, with an initial endothermic temperature of 87°C - 89°C and a peak endothermic temperature of 89°C - 91°C.

[0024] 2. Provide a preparation method of the crystal form as described above, the steps include:

[0025] React econazole nitrate with a base in a first solvent to generate the free base of econazole;

[0026] Recrystallize the free base of econazole in a second solvent to obtain the crystal form of the free base of econazole as described above;

[0027] Wherein, the second solvent is an ether solvent or an ester solvent, the dissolution temperature for recrystallization is from room temperature to the reflux temperature, the crystallization temperature is from room temperature to -20°C, preferably 0°C to -15°C, and the crystallization duration is 1 - 12 hours, preferably 2 - 6 hours.

[0028] Preferably, the base is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate.

[0029] Preferably, the first solvent is selected from at least one of water, ethanol, ether, ester, dichloromethane, or chloroform.

[0030] Preferably, the second solvent is selected from at least one of n-propyl ether, isopropyl ether, n-butyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, isopropyl acetate, n-butyl acetate, ethyl propionate, n-propyl propionate, isopropyl propionate, n-butyl propionate, ethyl butyrate, n-propyl butyrate, isopropyl butyrate, or n-butyl butyrate.

[0031] 3. Provide a pharmaceutical composition comprising: the free base of econazole in the crystalline form as described above or a physiologically acceptable solvate thereof, and at least one pharmaceutically acceptable carrier.

[0032] Preferably, the pharmaceutical composition is a topical pharmaceutical composition, and its dosage form is selected from at least one of: ointment, cream, gel, solution, suppository, nail polish, nail lacquer, mucoadhesive film, or mucoadhesive tablet.

[0033] Preferably, the pharmaceutically acceptable carrier is selected from at least one of: ethyl lactate, n-propyl lactate, isopropyl lactate, n-butyl lactate, 2-ethylhexyl lactate, C10-C20 fatty alcohol lactates, diethyl adipate, di-n-propyl adipate, diisopropyl adipate, di-n-butyl adipate, diisobutyl adipate, diethyl azelate, di-n-propyl azelate, diisopropyl azelate, decamethylcyclopentasiloxane cyclomethicone or dodecamethylcyclohexasiloxane cyclomethicone.

[0034] 4. Provide an application of the pharmaceutical composition as described above in the preparation of a drug for treating fungal infections.

[0035] Preferably, the fungal infection is a superficial fungal infection, which is selected from at least one of: cutaneous fungal infection, fingernail / toenail fungal infection, oral fungal infection, or vaginal fungal infection.

[0036] The present invention adopts the above technical solutions, and compared with the prior art, has the following technical effects:

[0037] The crystalline free base of econazole provided by the present invention, in addition to being able to significantly improve the solubility of econazole in the matrix, can improve the diffusion rate and permeability of the drug, and can avoid precipitation in the form of crystals in the pharmaceutical composition, thereby reducing the impact on drug absorption and efficacy, etc., also has the unique advantages of simple purification method, low production cost, and easy access to high-purity products. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 It is the powder X-ray diffraction pattern of the free base of econazole in the present invention;

[0039] Figure 2 It is the differential scanning calorimetry analysis pattern of the free base of econazole in the present invention;

[0040] Figure 3 It is the nail penetration test result graph of the free base of econazole in the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0041] The following will describe the specific embodiments of the present invention in detail.

[0042] Unless otherwise defined, technical terms or scientific terms used in the claims and the specification shall have the ordinary meanings as understood by those of ordinary skill in the technical field to which the present invention pertains.

[0043] The term "comprising" or similar terms used in the specification and claims of this patent application for invention means that the elements appearing before "comprising" cover the elements or their equivalents listed after "comprising", and do not exclude other elements.

[0044] The numerical values mentioned in the present invention include all numerical values increasing unit by unit from low to high, assuming that there is an interval of at least two units between any lower value and higher value. For example, if it is stated that a component amount or a physical quantity ranges from 1 to 100, more preferably from 10 to 90, and most preferably from 20 to 80, it is intended to express that numerical values such as 5 to 95, 14 to 76, 23 to 67, 32 to 58, 41 to 49, etc. are clearly listed in this specification; for numerical values less than 1, 0.0001, 0.001, 0.01 or 0.1 is considered a suitable unit. The foregoing examples are for illustrative purposes only. In fact, all numerical combinations between the lowest value and the highest value listed are considered to be clearly listed in this specification in a similar manner.

[0045] Example 1

[0046] This example provides a free base of amorphous econazole, and its preparation steps include:

[0047] 20 g of solid econazole nitrate and 60 g of 95% ethanol are stirred and mixed, and an aqueous solution of 50 mL of sodium hydroxide (1.9 g) is added dropwise. After stirring for 0.5 hour after the addition is complete, 100 mL of water is added, and then stirring is continued for 0.5 hour. The solid obtained by suction filtration is the free base of econazole (14.2 g).

[0048] Example 2

[0049] This example provides a free base of amorphous econazole, and its preparation steps include:

[0050] 20 g of solid econazole nitrate, 120 g of water, and 160 mL of dichloromethane are stirred and mixed, and an aqueous solution of 40 mL of anhydrous sodium carbonate (4.77 g) is added dropwise. After stirring for 0.5 hour, the aqueous phase is separated. The obtained organic phase is successively washed with 120 mL of 20% brine, 120 mL of water, dried over anhydrous magnesium sulfate, and the magnesium sulfate is filtered off. The obtained filtrate is concentrated under reduced pressure to obtain the free base of econazole (17 g).

[0051] Example 3

[0052] This embodiment provides a crystalline free base of econazole, and its preparation steps include:

[0053] Stir 10 g of the free base of econazole with 50 mL of isopropyl ether, heat to reflux until all solids are dissolved; after cooling to room temperature, crystallize at -15 °C for 4 hours, and the solid obtained by suction filtration is the crystalline free base of econazole.

[0054] Example 4

[0055] This embodiment provides a crystalline free base of econazole, and its preparation steps include:

[0056] Stir 10 g of the free base of econazole with 40 mL of n-butyl ether, heat to reflux until all solids are dissolved; after cooling to room temperature, crystallize at -15 °C for 4 hours, and the solid obtained by suction filtration is the crystalline free base of econazole.

[0057] Example 5

[0058] This embodiment provides a crystalline free base of econazole, and its preparation steps include:

[0059] Stir 10 g of the free base of econazole with 30 mL of n-butyl acetate, heat to reflux until all solids are dissolved; after cooling to room temperature, recrystallize at -15 °C for 4 hours, and the solid obtained by suction filtration is the free base of econazole.

[0060] Detection Example

[0061] 1. Perform powder X-ray diffraction measurement on the free base of econazole:

[0062] Instrument model: D8 Advance powder X-ray diffractometer;

[0063] Detector type: LynxEye array detector;

[0064] Test conditions:

[0065] X-ray type: Cu K α radiation, wavelength is 0.15418 nm;

[0066] X-ray tube working voltage: 40 kV, working current: 40 mA;

[0067] Optical path system: The radius of the goniometer is 217.5 mm, the divergence slit is 1.0 mm, the anti-scattering slit is 8.0 mm, the receiving slit is 12.57 mm, both Soller slits are 2.5°, using a Ni filter, without a monochromator;

[0068] Test parameters: The scanning range is 5° - 50°, the scanning mode is continuous scanning, the step size is 0.02°, and the scanning time for each step is 0.1S.

[0069] The obtained powder X-ray diffraction pattern is as Figure 1 shown, and the specific data is shown in Table 1.

[0070] 2. Differential scanning calorimetry analysis was performed on the free base of econazole:

[0071] Instrument model: Diamond differential scanning calorimeter;

[0072] Test conditions: Nitrogen, flow rate: 15 mL / min;

[0073] Temperature program: The starting temperature is 30°C, the ending temperature is 150°C, and the heating rate is 10°C / min.

[0074] The obtained differential scanning calorimetry analysis pattern is as Figure 2 shown.

[0075] 3. Melting point determination was performed on the free base of econazole:

[0076] Instrument model: YRT-3 melting point determinator (TianDa TianFa Technology Co., Ltd.);

[0077] It was determined by the melting point determination method (Appendix VI 0612, Method 1, Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0078] The melting point of econazole nitrate is 164°C - 166°C, and the melting point of the free base of econazole is 86°C - 88°C.

[0079] 4. Solubility determination was performed on the free base of econazole:

[0080] 1 g of the free base of econazole was added to 10 g of the matrix, and a clear solution was obtained after shaking;

[0081] 0.1 g of econazole nitrate was added to 10 g of the matrix, and the solid was not completely dissolved after shaking;

[0082] Among them, the matrix is composed of the components in Table 2:

[0083] Table 2 Composition of the matrix

[0084]

[0085]

[0086] Application examples

[0087] Take the nail plates of the index finger, middle finger, and ring finger. After thawing at room temperature (25°C ± 2°C), rinse them with deionized water to remove attached tissues, then rinse with DPBS, and then soak them in 70% ethanol for disinfection. After that, dry them with lint-free wiping paper, and require that there are no cracks visually, the weights are similar, and the average thickness is 0.7 mm ± 0.15 mm;

[0088] Soak the nail plates in an aqueous solution of 10% (w / v) mercaptoacetic acid and an aqueous solution of 10% (w / v) PEG400 for overnight incubation, take them out and dry for later use;

[0089] Prepare a saturated solution of the free base of econazole with the matrix described in Table 2, filter it through a 0.45 μm membrane, and the resulting filtrate is the test solution;

[0090] Prepare a saturated solution of econazole nitrate with the matrix described in Table 2, filter it through a 0.45 μm membrane, and the resulting filtrate is the control solution;

[0091] Clamp the nail plate with a nail adapter and fix it on a modified vertical Franz diffusion cell with an effective exchange area of 0.2 cm 2 . The receptor chamber is filled with 5 mL of DPBS buffer with a pH of 7.4, which contains 30% (v / v) ethanol, keep it warm at 37°C, and stir at a speed of 600 rpm. Apply 200 μL of the test solution and 200 μL of the control solution respectively to the exposed part of the back surface of the nail plate installed on the adapter. At the time points of 0 h, 12 h, 24 h, 36 h, and 48 h, collect 300 μL of samples from the sampling arm of the Franz cell, and then sample every 24 h until the 7th day. After each sampling, supplement an equal volume of fresh receptor medium.

[0092] The results are as Figure 3 shown. The abscissa in the figure is the sampling time point (h), and the ordinate is the amount of econazole permeating through the nail plate (μg / cm 2 ), and the amount of the free base of econazole permeating through the nail plate is much higher than that of econazole nitrate permeating through the nail plate.

[0093] In summary, the crystalline free base of econazole provided by the present invention, in addition to being able to significantly improve the solubility of econazole in the matrix, can improve the diffusion rate and permeability of the drug, can avoid precipitation in the form of crystals in the pharmaceutical composition, thereby reducing the impact on drug absorption and efficacy, etc., also has the unique advantages of simple purification method, low production cost, and easy access to high-purity products.

[0094] The above are only the preferred embodiments of the present invention, and do not limit the implementation manners and protection scope of the present invention. For those skilled in the art, it should be realized that all the solutions obtained by equivalent substitution and obvious changes made by using the description and illustrations of the present invention should be included within the protection scope of the present invention.

Claims

1. A crystalline form of econazole free base, characterized in that, The crystalline form has characteristic diffraction peaks at 2θ angles of 9.36° ± 0.2° and 23.15° ± 0.2° in the powder X-ray diffraction pattern.

2. The crystalline form according to claim 1, wherein, The crystalline form has characteristic diffraction peaks at 2θ angles of 9.36° ± 0.2°, 16.14° ± 0.2°, 23.15° ± 0.2°, 24.28° ± 0.2°, 25.87° ± 0.2°, and 34.89° ± 0.2° in the powder X-ray diffraction pattern.

3. The crystalline form according to claim 1, characterized in that, The crystalline form has a single endothermic peak in the differential scanning calorimetry pattern, with an initial endothermic temperature of 87°C - 89°C and a peak endothermic temperature of 89°C - 91°C.

4. A method for preparing a crystal form as described in any one of claims 1-3, characterized in that the steps Comprising: Reacting econazole nitrate with a base in a first solvent to form the free base of econazole; Recrystallizing the free base of econazole in a second solvent to obtain the crystalline form of the free base of econazole as described in any one of claims 1 - 3; Wherein, the second solvent is an ether solvent or an ester solvent, the dissolution temperature for recrystallization is from room temperature to the reflux temperature, the crystallization temperature is from room temperature to -20°C, and the crystallization duration is 1 - 12 hours.

5. A pharmaceutical composition, characterized in that, Comprising: The free base of econazole or its physiologically acceptable solvate, and at least one pharmacologically acceptable carrier.

6. A pharmaceutical composition, characterized in that, Comprising: The free base of econazole in the crystalline form as described in any one of claims 1 - 3 or its physiologically acceptable solvate, and at least one pharmacologically acceptable carrier.

7. The pharmaceutical composition according to claim 5 or 6, characterized in that, The dosage form of the pharmaceutical composition is selected from at least one of: ointment, cream, gel, solution, suppository, nail polish, nail lacquer, mucosal adhesive film, or mucosal adhesive tablet.

8. The pharmaceutical composition according to claim 5 or 6, characterized in that, The pharmacologically acceptable carrier is selected from at least one of: ethyl lactate, n-propyl lactate, isopropyl lactate, n-butyl lactate, 2-ethylhexyl lactate, C10 - C20 fatty alcohol lactate, diethyl adipate, di-n-propyl adipate, diisopropyl adipate, di-n-butyl adipate, diisobutyl adipate, diethyl azelate, di-n-propyl azelate, diisopropyl azelate, decamethylcyclopentasiloxane cyclomethicone, or dodecamethylcyclohexasiloxane cyclomethicone.

9. Use of a pharmaceutical composition as described in any one of claims 5 - 8 in the preparation of a medicament for treating fungal infections.

10. The application according to claim 9, wherein The fungal infections are selected from at least one of: cutaneous fungal infections, fingernail / toenail fungal infections, oral fungal infections, or vaginal fungal infections.

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