A minoxidil lactate crystal form and its preparation method and application

Abstract

The invention discloses a minoxidil lactate crystal form and a preparation method and application thereof, and relates to the technical field of drug crystal forms. The minoxidil lactate crystal form has XRPD characteristic peaks at diffraction angles 2θ=6.505°, 15.67°, 18.805°, 23.189°, 10.165°, 19.425°, 20.779°, 25.657° and 30.449°. The invention prepares minoxidil into a specific crystal form of minoxidil lactate, and the crystal form can significantly improve its water solubility, stability and permeability.

Description

Technical Field

[0001] The present invention relates to the technical field of drug crystal forms, and in particular to a minoxidil lactate crystal form and a preparation method and application thereof. Background Art

[0002] Modifying the crystal form of active drug ingredients through crystal engineering to obtain superior crystal forms that are more suitable for production, have better physicochemical properties, and better biological activity is a new "shortcut" for drug research and development. Drug salt formation is one of the ways to modify drug crystal forms. Compared with modification methods such as forming cocrystals or solvates, drug salt formation requires that each salt-forming reagent has an ionizable site and its ionic charges are different. The interaction strength of the ionic bonds formed is much greater than non-covalent interactions such as hydrogen bonds. It can be seen that drug salt formation can change the protonation state of active drug ingredients, have a huge impact on the spatial arrangement of drug molecules, and further change the physicochemical properties of drugs, such as solubility, stability, pharmacokinetics and other parameters, change the way drugs bind to targets, affect the intensity and selectivity of drug-target interactions, and significantly change the therapeutic effect.

[0003] The chemical name of minoxidil is 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide, and its molecular formula is C9H 15 N5O, the structural formula is as follows:

[0004] .

[0005] Minoxidil can be taken orally to treat hypertension, and can effectively treat hair loss when used externally. Minoxidil improves local blood circulation in the scalp and stimulates the proliferation and differentiation of hair follicle cells, thereby promoting hair growth. Minoxidil is a poorly water-soluble drug, which limits its application in water-soluble preparations. Most of the minoxidil topical preparations available on the market are tinctures, which usually have many side effects, such as allergies, itching, skin flushing, lower limb edema, and increased heart rate.

[0006] Chinese patent CN113336710A discloses a minoxidil-3-methoxybenzoate crystal form for treating hair loss and a preparation method thereof, wherein the minoxidil-3-methoxybenzoate crystal form is formed by combining two minoxidil cations and two 3-methoxybenzoic acid anions through ionic bond interactions; the crystal structure belongs to the monoclinic system, and the crystal form has powder diffraction peaks at diffraction angles 2θ=7.025°, 8.006°, 11.168°, 18.001°, 20.001°, 22.170°, and 22.780°. The therapeutic effect of the minoxidil crystal form is better than that of the original drug, and the solubility is also improved to a certain extent. However, during the preparation process, the irritation is greater when 3-methoxybenzoic acid is used.

[0007] At present, new crystal forms of minoxidil are still scarce. The present invention uses lactic acid to transform the crystal form of minoxidil. The structural formula of lactic acid is as follows:

[0008] .

[0009] The invention prepares minoxidil into a specific crystal form of minoxidil lactate, and the crystal form can significantly improve the water solubility, stability and permeability of the minoxidil lactate. Summary of the invention

[0010] The purpose of the present invention is to provide a minoxidil lactate crystal form and a preparation method and application thereof. The basic structural unit of the minoxidil lactate crystal form of the present invention is formed by combining a minoxidil cation and a lactate anion through ionic bond interaction, which can improve solubility and significantly improve solid stability, solution stability and permeability of aqueous solution.

[0011] To achieve the above-mentioned purpose of the invention, the technical solution of the present invention is as follows:

[0012] On the one hand, the present invention provides a minoxidil lactate crystalline form, having XRPD characteristic peaks at diffraction angles 2θ=6.505°, 15.67°, 18.805°, 23.189°, 10.165°, 19.425°, 20.779°, 25.657° and 30.449°, and the error range of the diffraction angle 2θ value is -0.30°~0.30°.

[0013] Preferably, the minoxidil lactate crystalline form has main peaks at diffraction angles of 2θ=6.505°, 15.67°, 18.805° and 23.189°, and the relative intensity of the main peaks is 30%-100%; there are secondary peaks at diffraction angles of 2θ=10.165°, 19.425°, 20.779°, 25.657° and 30.449°, and the relative intensity of the secondary peaks is 10%-30%.

[0014] Further preferably, the minoxidil lactate crystalline form also has at least one other diffraction peak selected from the group consisting of diffraction angles 2θ=12.88°, 15.013°, 16.923°, 20.275°, 26.839°, 27.606°, 31.496°, 32.305°, and 33.256°.

[0015] More preferably, the relative intensity of the other diffraction peaks is less than 10%.

[0016] More preferably, the minoxidil lactate crystalline form has XRPD characteristic peaks at diffraction angles 2θ=6.505°, 15.67°, 18.805°, 23.189°, 10.165°, 19.425°, 20.779°, 25.657°, 30.449°, 12.88°, 15.013°, 16.923°, 20.275°, 26.839°, 27.606°, 31.496°, 32.305° and 33.256°.

[0017] Preferably, the minoxidil lactate crystalline form has substantially Figure 2 Differential Scanning Calorimetry (DSC) graph shown.

[0018] Preferably, the minoxidil lactate crystalline form has substantially Figure 3 Thermogravimetric analysis (TGA) graph shown.

[0019] Preferably, the hydrogen nuclear magnetic resonance spectrum of the minoxidil lactate crystalline form is 1 H-NMR) has basically Figure 4 Chemical environment shown.

[0020] On the other hand, the present invention provides a method for preparing the above-mentioned minoxidil lactate crystalline form, comprising the following steps: mixing minoxidil, lactic acid and solvent 1 to dissolve the solid, adding solvent 2 to precipitate the solid, and separating the solid to obtain the minoxidil lactate crystalline form;

[0021] The solvent 1 is selected from at least one of acetone, ethanol, isopropanol, methanol, 1,4-dioxane, tetrahydrofuran, and N,N-dimethylamide, and the solvent 2 is at least one of ethyl acetate, isopropyl acetate, methyl tert-butyl ether, n-heptane, and acetonitrile.

[0022] Preferably, the molar ratio of minoxidil to lactic acid is 1:1-2.

[0023] Preferably, the temperature for dissolving the solid is 20-30°C, more preferably 25°C.

[0024] As a specific embodiment of the present invention, the preparation method of the minoxidil lactate crystalline form comprises the following steps: mixing minoxidil, lactic acid and solvent 1, ultrasonic treatment or magnetic stirring at 25°C to dissolve the solid, adding solvent 2 while stirring, magnetic stirring at room temperature for 1-2 hours or overnight to precipitate the solid, and separating the solid to obtain the minoxidil lactate crystalline form.

[0025] On the other hand, the present invention provides a method for preparing the above-mentioned minoxidil lactate crystalline form, comprising the following steps: mixing minoxidil, lactic acid and a solvent, reacting, precipitating a solid, and separating the solid to obtain the minoxidil lactate crystalline form;

[0026] Wherein, the solvent is selected from at least one of acetone, ethyl acetate, acetonitrile, isopropyl acetate and methyl ethyl ketone.

[0027] Preferably, the molar ratio of minoxidil to lactic acid is 1:1-2.

[0028] Finally, the present invention provides the use of the minoxidil lactate crystal form in the preparation of a drug for treating hair loss.

[0029] The beneficial effects of the present invention are:

[0030] The specific minoxidil lactate crystal form prepared by the present invention has improved solubility, significantly improved solid stability and solution stability, and also improved the permeability of the minoxidil lactate aqueous solution. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is the XRPD diagram of the minoxidil lactate crystalline form of Example 1 of the present invention.

[0032] Figure 2 This is the DSC spectrum of the minoxidil lactate crystalline form of Example 1 of the present invention.

[0033] Figure 3 This is the TGA spectrum of the minoxidil lactate crystalline form of Example 1 of the present invention.

[0034] Figure 4 The minoxidil lactate crystal form of Example 1 of the present invention 1 H-NMR results.

[0035] Figure 5 This is the XRPD pattern of minoxidil lactate crystal obtained by the method described in Experiment No. 1.

[0036] Figure 6 This is the XRPD pattern of the minoxidil lactate crystalline form obtained by the method described in Experiment No. 2.

[0037] Figure 7 This is the XRPD pattern of the minoxidil lactate crystalline form obtained by the method described in Experiment No. 3.

[0038] Figure 8 This is the XRPD pattern of the minoxidil lactate crystalline form obtained by the method described in Experiment No. 4.

[0039] Fig. 9 This is the XRPD pattern of the minoxidil lactate crystalline form obtained by the method described in Experiment No. 5.

[0040] Fig.10 This is the XRPD pattern of the minoxidil lactate crystalline form obtained by the method described in Experiment No. 6.

[0041] Fig.11 This is the XRPD pattern of the minoxidil lactate crystalline form obtained by the method described in Experiment No. 7.

[0042] Fig.12 This is an enlarged XRPD pattern of minoxidil lactate crystal.

[0043] Fig.13 This is a comparison chart of minoxidil lactate crystal forms and minoxidil pH-dependent solubility.

[0044] Fig.14 These are the crystal forms of minoxidil lactate and the results of minoxidil IVPT experiments. DETAILED DESCRIPTION

[0045] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, which should also fall within the scope of the present invention.

[0046] The present invention is further described below by way of specific examples. The various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are all weight contents. Unless otherwise specified, it is understood that the process is carried out at room temperature.

[0047] In the following embodiments,

[0048] Powder X-ray Diffraction (XRPD): Determine the powder X-ray diffraction pattern of the minoxidil lactate crystal form, and compare the patterns of the raw material minoxidil and the obtained crystal form to confirm the uniqueness of the crystal form. The equipment brand used is Bruker model D8ADVANCE.

[0049] Thermogravimetric analysis (TGA): The thermal stability of the crystal form was determined by thermogravimetric analysis. The equipment used was PerkinElmer TGA 4000.

[0050] Differential Scanning Calorimetry (DSC): The melting point and thermal behavior of the crystal form were determined by differential scanning calorimetry analysis. The equipment used was Perkin Elmer DSC 4000.

[0051] Nuclear Magnetic Resonance (NMR): Nuclear magnetic resonance hydrogen spectrum analysis was used to confirm the chemical environment changes of minoxidil lactate crystals. The equipment used was Bruker and the model was BioSpin GmbH.

[0052] Crystalline forms are most often characterized by XRPD. An XRPD pattern of diffraction (peaks) is often considered a fingerprint of a particular crystal form. The term "peak" refers to a reflection with a relative intensity of at least about 3% of the maximum peak intensity.

[0053] Temperature readings associated with DSC and TGA can vary by approximately ±4°C depending on the instrument, specific setup, sample preparation, etc.

[0054] Minoxidil was purchased from Qidongyue with batch number MN-202201501.

[0055] Example 1

[0056] Minoxidil lactate crystalline form was prepared according to the following method: 150 mg of minoxidil and 130 mg of lactic acid were weighed, 0.4 mL of acetone was added, and the solid was completely dissolved after ultrasonication for 1 min, 2 mL of ethyl acetate was added, and a white solid was precipitated after magnetic stirring for a period of time. The magnetic stirring was carried out at room temperature overnight, and the solid was separated by centrifugation.

[0057] The X-ray powder diffraction pattern with Cu Kα radiation is as follows Figure 1 As shown, the peak list is as follows:

[0058] Table 1.

[0059]

[0060] The DSC spectrum of the minoxidil lactate crystalline form is as follows Figure 2 As shown, there is endotherm at 105°C-140°C.

[0061] The TGA spectrum of the minoxidil lactate crystal form is as follows Figure 3 shown.

[0062] The minoxidil lactate crystalline form 1 The H-NMR results are as follows Figure 4 As shown in Figure 2, the molar ratio of minoxidil to lactic acid in minoxidil lactate is 1:1 as shown in Figure 2.

[0063] Example 2 Preparation of different minoxidil lactate crystal forms

[0064] 2.1 Reaction crystallization method

[0065] Weigh a certain amount of minoxidil and lactic acid, add an appropriate amount of solvent, and stir magnetically overnight at room temperature to allow minoxidil and lactic acid to react with each other. Separate the solid by centrifugation, and characterize the dried solid. The specific experimental conditions are as follows:

[0066] Table 2.

[0067]

[0068] The characterization results are as follows Figure 5-Figure 7 .

[0069] From the characterization results, Figure 5 , Figure 6 , Figure 7 The crystal form of minoxidil lactate shown in Figure 6 That is, the minoxidil lactate prepared in Experiment No. 2 has a stronger diffraction peak and a higher crystallinity.

[0070] 2.2 Antisolvent crystallization method

[0071] Weigh a certain amount of minoxidil and lactic acid, add an appropriate amount of solvent, dissolve the solid at room temperature, add an anti-solvent or add an anti-solvent (i.e., a solvent with lower solubility) after concentration to precipitate the solid, stir magnetically overnight at room temperature, separate the solid by centrifugation or filtration, and characterize the dried solid. The specific experimental conditions are as follows:

[0072] Table 3.

[0073]

[0074] The characterization results are as follows Figure 8-Figure 11 .

[0075] From the characterization results, we can see that: Figure 8-Figure 11 The crystal forms shown in are all the same crystal forms of minoxidil lactate. Figure 8 and Fig. 9 , Fig.10 , Fig.11 In comparison, there are two more diffraction peaks belonging to minoxidil at 16.64° and 19.80°, indicating that the reaction of No. 4 is incomplete.

[0076] Example 3 Amplification reaction

[0077] (1) Weigh 2000 mg of minoxidil, add 45 mL of methanol and ultrasonically dissolve it to obtain a methanol solution of minoxidil;

[0078] (2) Weigh 1.78g of lactic acid, dilute with 5mL of methanol to obtain a methanol solution of lactic acid, gradually add it dropwise to the methanol solution of minoxidil under stirring, stir evenly, then remove most of the methanol by rotary evaporation until the solution volume is 1-2mL, then add 20mL of ethyl acetate, stir magnetically at room temperature, and a white solid gradually precipitates after about 10 minutes. After overnight magnetic stirring, it becomes a white suspension. The solid is separated by suction filtration, and the filter cake is rinsed twice with 10mL of ethyl acetate to remove excess lactic acid. The filter cake is dried, and the obtained solid is the minoxidil lactate crystalline form. The characterization results are as follows: Fig.12 .

[0079] Test Case

[0080] 1. Solubility test

[0081] (1) Minoxidil solubility test method: Weigh 5 mg of minoxidil sample into each glass vial, add 50 μL of solvent each time at room temperature for shaking or ultrasound, and observe with the naked eye whether the solid is dissolved. When the solvent is added to about 1 mL, if there is still obvious solid remaining, you can choose to add 1 mL of solvent each time, and the maximum amount of solvent can be added is 5 mL. Record the minimum volume that makes the solid dissolve and the volume that cannot be dissolved in the previous time, and calculate the approximate solubility. The results are shown in the table below.

[0082] Table 4.

[0083]

[0084] The results showed that minoxidil was slightly soluble in methanol and ethanol, slightly soluble in isopropanol, and had a low solubility in other organic solvents.

[0085] (2) The solubility of the minoxidil lactate crystalline form in Example 3 and minoxidil at pH 2-pH 6 (24 h) was tested simultaneously. The test method was as follows: 500 mg of minoxidil and minoxidil lactate were weighed, and 5 mL of buffer solutions of pH = 2, pH = 3, pH = 4, pH = 5, and pH = 6 were added, respectively, and the phenomenon was observed. If there was any dissolution, minoxidil or minoxidil lactate was added to the buffer solution until the suspension was maintained. After shaking at room temperature for 24 h, the solubility was measured.

[0086] The results are as follows:

[0087] Table 5.

[0088]

[0089] It can be seen that the solubility of minoxidil lactate crystalline form is similar to that of minoxidil at pH=2 and pH=5; at pH=3 and pH=4, the solubility of minoxidil lactate crystalline form is significantly higher than that of minoxidil.

[0090] 2. Stability test

[0091] Test method: The minoxidil lactate in Example 3 and minoxidil were simultaneously tested for their solid and solution stability.

[0092] The stability at room temperature for 0 days, 40℃ for 1 week, 40℃ for 2 weeks, 60℃ for 1 week, and 60℃ for 2 weeks was investigated. The results are as follows:

[0093] Table 6.

[0094]

[0095] From the solid stability results, minoxidil lactate has lower total impurities and maximum single impurities than minoxidil.

[0096] The solution stability mainly examines the stability of pH = 4 and pH = 8 solutions in a 40% ethanol solvent system, as well as the stability of samples placed at 40°C and 60°C. The formulation and stability results are shown in Fig.13 and the table below:

[0097] Table 7.

[0098]

[0099] In the table, qs represents addition to 100%.

[0100] From the results of solution stability-related substances, by comparing Prescription 1 with Prescription 3, and Prescription 2 with Prescription 4, it can be seen that the stability of minoxidil lactate crystal form is better than that of minoxidil.

[0101] In summary, the solubility of minoxidil lactate at pH 3.0-pH 4.0 is greater than that of minoxidil, and its solid and solution stability are better than that of minoxidil.

[0102] 3. IVPT (in vitro permeation) experiment

[0103] (1) Preparation of experimental samples

[0104] Minoxidil and minoxidil lactate were separately prepared into 2 mg / mL (based on minoxidil) aqueous solutions.

[0105] (2) Test method:

[0106] The animal skin used for transdermal application was the abdominal and dorsal skin of 1-month-old male Panamanian miniature pigs, with an average thickness of 0.8 mm to 1 mm.

[0107] (1) Prepare the receiving solution (20% polyethylene glycol 400 + phosphate balanced buffer solution, pH = 7.4), and filter and degas before the test;

[0108] (2) Use a diffusion cell for penetration test. Fix the Bama Xiang pig skin between the receiving cell and the supply cell, with the stratum corneum facing the supply cell, and fix it with a spring clip. Add 8.3 mL of receiving solution preheated at 32°C to make the dermis and the receiving solution in close contact, expel bubbles, and balance for 30 minutes before dosing.

[0109] (3) Add 0.5 mL of sample to the supply side of the diffusion cell, place in a 32°C constant temperature water bath, and stir at a constant magnetic speed of 200 rpm / min;

[0110] (4) Accurately pipette 2 mL of receiving solution sample at 1, 2, 4, 8, and 24 h, then replenish with blank receiving solution of the same temperature and volume and remove any bubbles.

[0111] The results are as follows Fig.14 and the table below:

[0112] Table 8.

[0113]

[0114] The IVPT experimental results showed that the permeability of minoxidil lactate aqueous solution was significantly better than that of minoxidil aqueous solution.

Claims

1. A method for preparing a crystal form of minoxidil lactate, characterized in that: The method comprises the following steps: mixing minoxidil, lactic acid and a solvent, reacting, precipitating a solid, and separating the solid to obtain the minoxidil lactate crystal form; The molar ratio of minoxidil to lactic acid is 1:2, and the solvent is ethyl acetate; The XRPD pattern of the minoxidil lactate crystalline form is shown in Figure 6.

2. The preparation method according to claim 1, characterized in that: The minoxidil lactate crystalline form has main peaks at diffraction angles of 2θ=6.505°, 15.67°, 18.805° and 23.189°, and the relative intensity of the main peaks is 30%-100%; there are secondary peaks at diffraction angles of 2θ=10.165°, 19.425°, 20.779°, 25.657° and 30.449°, and the relative intensity of the secondary peaks is 10%-30%.

3. The preparation method according to claim 2, characterized in that: The minoxidil lactate crystalline form also has at least one other diffraction peak selected from diffraction angles 2θ=12.88°, 15.013°, 16.923°, 20.275°, 26.839°, 27.606°, 31.496°, 32.305°, and 33.256°.

4. The preparation method according to claim 3, characterized in that: The relative intensity of the other diffraction peaks is less than 10%.

5. The preparation method according to claim 4, characterized in that: The minoxidil lactate crystalline form has XRPD characteristic peaks at diffraction angles 2θ=6.505°, 15.67°, 18.805°, 23.189°, 10.165°, 19.425°, 20.779°, 25.657°, 30.449°, 12.88°, 15.013°, 16.923°, 20.275°, 26.839°, 27.606°, 31.496°, 32.305° and 33.256°.

6. Use of a minoxidil lactate crystal form in the preparation of a hair loss drug with improved permeability, characterized in that: The minoxidil lactate crystalline form has XRPD characteristic peaks at diffraction angles 2θ=6.505°, 15.67°, 18.805°, 23.189°, 10.165°, 19.425°, 20.779°, 25.657° and 30.449°, and the error range of the diffraction angle 2θ value is -0.30°~0.30°.

7. The use according to claim 6, characterized in that The minoxidil lactate crystalline form has main peaks at diffraction angles of 2θ=6.505°, 15.67°, 18.805° and 23.189°, and the relative intensity of the main peaks is 30%-100%; there are secondary peaks at diffraction angles of 2θ=10.165°, 19.425°, 20.779°, 25.657° and 30.449°, and the relative intensity of the secondary peaks is 10%-30%.

8. The use according to claim 6 or 7, characterized in that The minoxidil lactate crystalline form also has at least one other diffraction peak selected from diffraction angles 2θ=12.88°, 15.013°, 16.923°, 20.275°, 26.839°, 27.606°, 31.496°, 32.305°, and 33.256°.

9. The use according to claim 8, characterized in that The relative intensity of the other diffraction peaks is less than 10%.

10. The use according to claim 9, characterized in that The minoxidil lactate crystalline form has XRPD characteristic peaks at diffraction angles 2θ=6.505°, 15.67°, 18.805°, 23.189°, 10.165°, 19.425°, 20.779°, 25.657°, 30.449°, 12.88°, 15.013°, 16.923°, 20.275°, 26.839°, 27.606°, 31.496°, 32.305° and 33.256°.

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