New crystal form of milrinone lactate and preparation method and application thereof
By preparing a new crystal form of lactated milrinone, the problem of poor stability of the injection was solved, and the stability and efficacy were improved under high temperature, high humidity and light conditions.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- BEIJING HUIKANG BOYUAN PHARM TECH CO LTD
- Filing Date
- 2026-03-20
- Publication Date
- 2026-05-08
AI Technical Summary
Milrinone lactate injection has poor stability and is prone to degradation and the increase of related substances, which affects efficacy and storage stability.
A novel crystalline form of lactic acid milrinone was prepared by dissolving it in lactic acid at high temperature, followed by adding a ketone solvent and an ether antisolvent at low temperature, resulting in the precipitation of a white solid and forming a chemically stable novel crystalline form.
It improved the chemical stability of lactated milrinone, enhanced its storage stability under high temperature, high humidity and light conditions, and improved its efficacy and bioavailability.
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Abstract
Description
Technical Field
[0001] This application relates to the technical field of pharmaceutical chemical crystallization, specifically to a novel crystal form of lactic acid milrinone, its preparation method, and its application. Background Technology
[0002] Milrinone lactate is a novel non-cardiac glycoside, non-catecholamine inotropic drug developed by Sterling Pharmaceuticals in the United States as a treatment for congestive heart failure. It was first approved by the FDA in 1987 and officially launched in the United States in 1992, subsequently becoming available in the United Kingdom, France, Germany, the Netherlands, and Belgium. The chemical name of milrinone lactate is 2-methyl-6-oxo-1,6-dihydro-3,4-bispyridine-5-carboxynitrile lactate. It is a phosphodiesterase inhibitor, a drug in the same class as amrinone, with the same mechanism of action. It is effective both orally and intravenously, possessing both positive inotropic and vasodilatory effects, and its potency is 10-30 times stronger than amrinone. It plays a role in the treatment of congestive heart failure and peripheral vasodilation.
[0003] Milrinone lactate is mainly used for short-term intravenous administration of congestive heart failure. Studies have shown that milrinone can also be used for low cardiac output syndrome in cardiac surgery cardiopulmonary bypass, to relieve spasm of bypass grafts, improve cardiac function and anti-inflammatory response in orthotopic heart transplant recipients, and improve visceral blood perfusion. The cardiovascular effects of milrinone are dose-related. At low doses, it mainly exhibits a gray positive inotropic effect. As the dose increases, it gradually reaches the steady-state maximum positive inotropic effect. Its vasodilatory effect also gradually increases with the increase of dose. Milrinone is relatively safe for patients with conduction block. Clinically, it is suitable for acute and chronic refractory congestive heart failure caused by various reasons that are ineffective or have poor effects on digitalis, diuretics, and vasodilators.
[0004] Studies show that milrinone lactate injections have poor stability and are prone to degradation and the accumulation of related substances. Therefore, providing new crystalline forms of milrinone lactate with high stability is of great significance, as it is easier to store and can offer a new solution for developing safe and stable formulations. Summary of the Invention
[0005] To address the aforementioned technical problems, this application provides a novel crystal form of lactic acid milrinone, its preparation method, and its application.
[0006] In a first aspect, this application provides a novel crystalline form of lactic acid milrinone, the X-ray powder diffraction pattern of which contains characteristic diffraction peaks at diffraction angle 2θ at 10.48±0.2, 11.25±0.2, 16.39±0.2, 17.861±0.2, 24.88±0.2, and 26.07±0.2; wherein the X-ray powder diffraction is generated using CuKα1 rays.
[0007] In the process of studying the crystal form of lactic acid milrinone, this application prepared a novel crystal form that is chemically stable and easy to preserve.
[0008] Milrinone lactate has the chemical name 6-methyl-1-2-oxo-5-(pyridin-4-yl)-1,2-dihydropyridine-3-cyano lactate and has the chemical structure shown in formula (1).
[0009] Equation (1).
[0010] Specifically, the X-ray powder diffraction pattern of the new crystal form of lactic acid milrinone has an intensity greater than 50% at a diffraction angle of 2θ.
[0011] Preferably, the X-ray powder diffraction pattern of the new crystalline form of lactic acid milrinone contains characteristic diffraction peaks at diffraction angle 2θ located at 10.48±0.2, 11.25±0.2, 12.36±0.2, 12.99±0.2, 13.83±0.2, 14.76±0.2, 15.83±0.2, 16.39±0.2, 16.67±0.2, 17.861±0.2, 18.99±0.2, 20.85±0.2, 21.36±0.2, 22.37±0.2, 23.45±0.2, 24.88±0.2, 26.07±0.2, and 28.23±0.2.
[0012] Specifically, the X-ray powder diffraction pattern of the new crystal form of lactic acid milrinone has an intensity greater than 10% at a diffraction angle of 2θ.
[0013] Secondly, this application provides a lactated milrinone with a novel crystal form, wherein the lactated milrinone has the aforementioned novel crystal form.
[0014] Thirdly, this application provides a method for preparing the novel crystal form of lactic acid milrinone, specifically comprising the following steps in sequence: (1) Dissolve milrinone in lactic acid and heat to dissolve; (2) Cool the solution to -10 to 25°C, add a ketone solvent to the solution, and a white solid will precipitate; (3) Add an ether-based antisolvent to the solution to ensure complete crystallization; (4) Filter the solution, collect the solid after crystallization, and dry it at 10-50℃ to obtain the final product.
[0015] Preferably, in step (1), the weight ratio of milrinone to lactic acid is 1:2 to 10; and the heating temperature is 80 to 150°C.
[0016] Further, in step (1), the weight ratio of milrinone to lactic acid is 1:3 to 5; the heating temperature is 100 to 130°C.
[0017] Preferably, in step (2), the solution is cooled to a temperature of -10 to 0°C, and the ketone solvent is selected from one or more of acetone, butanone, and tetramethyldipentanone; the amount of the ketone solvent used is 3 to 5 times the weight of milrinone.
[0018] In one specific implementation, the solution can be cooled to -10°C, 5°C, or 0°C.
[0019] Preferably, in step (3), the ether antisolvent is selected from one or more of diethyl ether, isopropyl ether, methyl tert-butyl ether, and petroleum ether; the amount of the ether antisolvent is 7 to 9 times the weight of milrinone.
[0020] Preferably, in step (4), the drying temperature is 20 to 50°C.
[0021] Furthermore, in step (4), the drying temperature is 20–30°C.
[0022] This application discloses a novel crystalline form of milrinone lactate and its preparation method. The method involves dissolving lactic acid and milrinone at high temperature, then crystallizing at low temperature, followed by the addition of an antisolvent to precipitate the solid and obtain the novel crystalline form. This novel crystalline form exhibits good stability under high temperature, high humidity, and light conditions. Compared with existing technologies, it has higher solubility, which is significant for improving drug efficacy and bioavailability, and can be used to treat heart failure-related diseases.
[0023] Fourthly, this application provides a pharmaceutical composition comprising the novel crystalline form or milrinone lactate having the novel crystalline form.
[0024] Fifthly, this application provides the use of the novel crystalline form, or the lactated milrinone having the novel crystalline form, or the pharmaceutical composition thereof, in the preparation of a cardiotonic drug.
[0025] In summary, the technical solution of this application has the following effects: This application provides a new crystal form of lactic acid milrinone and its preparation method. The new crystal form of lactic acid milrinone prepared is defined as crystal form A. This crystal form has stable chemical properties, is easy to store, and significantly increases the stability of the product. Attached Figure Description
[0026] Figure 1 The X-ray powder diffraction pattern is the new crystal form of lactic acid milrinone in Example 1. Detailed Implementation
[0027] The present application will be further described in detail below with reference to embodiments, comparative examples and performance test results. These embodiments should not be construed as limiting the scope of protection claimed in this application.
[0028] Unless otherwise specified, the experimental methods described in the following examples are conventional methods.
[0029] The X-ray powder diffraction (XPRD) spectra in this application were obtained using a Bruker D2 X-ray powder diffractometer.
[0030] Example
[0031] Example 1
[0032] Example 1 provides a new crystal form of lactic acid milrinone and its preparation method.
[0033] The specific method for preparing the new crystal form of lactic acid milrinone in Example 1 is shown below.
[0034] (1) Dissolve 20g of Milrinone in 80g of lactic acid and heat to 110℃ to dissolve.
[0035] (2) Cool the solution to -10℃, add 80g of acetone to the solution, stir for 2h, and a white solid will precipitate.
[0036] (3) At room temperature, add 160g of isopropyl ether, an ether-based antisolvent, to the solution and stir for 1 hour to allow complete crystallization.
[0037] (4) The solution was filtered, the solid after crystallization was collected, and dried at 25°C for 3 hours to obtain a white crystalline solid milrinone lactate. The yield of the target product of the new crystal form of milrinone lactate (defined as crystal form A) was 92.5%.
[0038] (5) Detection: such as Figure 1 The image shows the X-ray powder diffraction pattern of the new crystal form of lactic acid milrinone in this embodiment. Table 1 shows the relevant data of the 2θ angle of X-ray powder diffraction for the new crystal form of lactic acid milrinone in this embodiment; it can be seen that the 2θ angle includes characteristic diffraction peaks located at 10.48±0.2, 11.25±0.2, 12.36±0.2, 12.99±0.2, 13.83±0.2, 14.76±0.2, 15.83±0.2, 16.39±0.2, 16.67±0.2, 17.861±0.2, 18.99±0.2, 20.85±0.2, 21.36±0.2, 22.37±0.2, 23.45±0.2, 24.88±0.2, 26.07±0.2, and 28.23±0.2 (diffraction intensities below 10% are ignored).
[0039] Table 1. Relevant data on the diffraction angle 2θ of the new crystal form of milrinone lactate in Example 1 using X-ray powder diffraction.
[0040] Experimental Example 1 Stability: The new crystalline form of lactic acid milrinone in Example 1 was tested for stability data under the following conditions, including appearance, loss on drying, related impurities (single impurity represents the content of the largest single impurity, and total impurities represent the sum of all impurities; the detection methods for related impurities of milrinone in the Chinese Pharmacopoeia were used for detection), and content.
[0041] (1) Condition 1: Constant temperature and humidity chamber, set temperature 25℃±2℃, relative humidity RH60%±5% for 24 months long-term stability. Test results: as shown in Table 2.
[0042] (2) Condition 2: Constant temperature and humidity chamber, set temperature 30℃±2℃, relative humidity RH 65%±5% for 24 months for long-term stability. Test results: as shown in Table 3.
[0043] (3) Condition 3: Constant temperature and humidity chamber, set temperature 40℃±2℃, relative humidity RH75%±5% for 6 months long-term stability. Test results: as shown in Table 4.
[0044] (4) Condition 4: Stability data for 30 days at a set temperature of 60℃, relative humidity of 92.5%, and illuminance of 4500±500 Lux. Test results: as shown in Table 5.
[0045] Table 2. Stability test results of the new crystalline form of lactic acid milrinone in Example 1 under condition 1.
[0046] Table 3. Stability test results of the new crystalline form of lactic acid milrinone in Example 1 under condition 2.
[0047] Table 4. Stability test results of the new crystalline form of lactic acid milrinone in Example 1 under condition 3.
[0048] Table 5. Stability test results of the new crystalline form of lactic acid milrinone in Example 1 under condition 4.
[0049] As can be seen from the test results in Tables 2-5 above, the new crystal form of lactic acid milrinone prepared using the technical solution provided in Example 1 has good stability and can remain stable under high temperature, high humidity and strong light.
[0050] Examples 2-4 Examples 2-4 provide a new crystal form of lactic acid milrinone and its preparation method, respectively.
[0051] The difference between the above embodiment and embodiment 1 is that the cooling temperature in step (2) is different; as shown below.
[0052] In Example 2: The solution was cooled to -0°C, 80g of acetone was added, and the mixture was stirred for 2 hours, resulting in the precipitation of a white solid. The yield of the target product in this example was 92.0%.
[0053] In Example 3: The solution was cooled to 10°C, 80g of acetone was added, and the mixture was stirred for 2 hours, resulting in the precipitation of a white solid. The yield of the target product in this example was 91.5%.
[0054] In Example 4: The solution was cooled to 25°C, 80g of acetone was added, and the mixture was stirred for 2 hours, resulting in the precipitation of a white solid. The yield of the target product in this example was 89.3%.
[0055] All other process parameters in the above embodiments are the same as those in Embodiment 1.
[0056] Examples 5-7 Examples 5-7 respectively provide a new crystal form of lactic acid milrinone and its preparation method.
[0057] The specific differences between the above embodiments and Embodiment 1 are as follows: the types or amounts of ether antisolvents are different, as detailed below.
[0058] In Example 5, 160g of diethyl ether was used as the ether antisolvent. The yield of the target product in this example was 90.5%.
[0059] In Example 6, 160 g of methyl tert-butyl ether was used as the ether antisolvent. The yield of the target product in this example was 91.7%.
[0060] In Example 7, 160g of petroleum ether was used as the ether antisolvent. The yield of the target product in this example was 91.2%.
[0061] All other process parameters in the above embodiments are the same as those in Embodiment 1.
[0062] Comparative Example Comparative Examples 1-3 Comparative Examples 1-3 provide a new crystal form of lactic acid milrinone and its preparation method, respectively.
[0063] The difference between the above comparative example and Example 1 is as follows:
[0064] In Comparative Example 1: In step (2), an equal amount of ethanol was used instead of acetone. The yield of the target product in this comparative example was 82.7%.
[0065] In Comparative Example 2: In step (3), an equal amount of ethanol was used instead of diethyl ether. The yield of the target product in this comparative example was 83.5%.
[0066] In Comparative Example 3: In step (4), the drying temperature was 60°C. The yield of the target product in this comparative example was 86.7%.
[0067] All other process parameters in the above comparative examples are the same as those in Example 1.
[0068] Experimental Example 2 Stability: Based on Test Example 1, stability data for the new crystal forms of lactic acid milrinone in Examples 2-7 were tested, including appearance, loss on drying, related impurities, and content.
[0069] Test results are shown in Table 6.
[0070] Table 6. Stability test results of the new crystal forms of lactic acid milrinone in Examples 2-7
[0071] As can be seen from the test results in Table 6 above, the new crystal form of lactic acid milrinone prepared using the technical solutions provided in Examples 2-7 of this application has good stability and can remain stable under high temperature, high humidity and strong light.
[0072] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.
Claims
1. A novel crystalline form of milrinone lactate, characterized in that, The X-ray powder diffraction pattern of the new crystal form of lactic acid milrinone contains characteristic diffraction peaks at diffraction angle 2θ at 10.48±0.2, 11.25±0.2, 16.39±0.2, 17.861±0.2, 24.88±0.2, and 26.07±0.2; wherein the X-ray powder diffraction is generated using CuKα1 rays.
2. The novel crystalline form of lactic acid milrinone according to claim 1, characterized in that, The X-ray powder diffraction pattern of the new crystalline form of lactic acid milrinone contains characteristic diffraction peaks at diffraction angle 2θ at 10.48±0.2, 11.25±0.2, 12.36±0.2, 12.99±0.2, 13.83±0.2, 14.76±0.2, 15.83±0.2, 16.39±0.2, 16.67±0.2, 17.861±0.2, 18.99±0.2, 20.85±0.2, 21.36±0.2, 22.37±0.2, 23.45±0.2, 24.88±0.2, 26.07±0.2, and 28.23±0.
2.
3. A lactic acid milrinone with a novel crystal form, characterized in that, Milrinone lactate has the novel crystal form as described in any one of claims 1-2.
4. A method for preparing a novel crystalline form of lactic acid milrinone as described in any one of claims 1-2, characterized in that, Specifically, the following steps are performed sequentially: (1) Dissolve milrinone in lactic acid and heat to dissolve; (2) Cool the solution to -10 to 25°C, add a ketone solvent to the solution, and a white solid will precipitate; (3) Add an ether-based antisolvent to the solution to ensure complete crystallization; (4) Filter the solution, collect the solid after crystallization, and dry it at 10-50℃ to obtain the final product.
5. The method for preparing the new crystalline form of lactic acid milrinone according to claim 4, characterized in that, In step (1), the weight ratio of milrinone to lactic acid is 1:2 to 10; the heating temperature is 80 to 150°C.
6. The method for preparing the new crystalline form of lactic acid milrinone according to claim 4, characterized in that, In step (2), the solution is cooled to a temperature of -10 to 0°C, and the ketone solvent is selected from one or more of acetone, butanone, and tetramethyldipentanone; the amount of the ketone solvent used is 3 to 5 times the weight of milrinone.
7. The method for preparing the new crystalline form of lactic acid milrinone according to claim 4, characterized in that, In step (3), the ether antisolvent is selected from one or more of diethyl ether, isopropyl ether, methyl tert-butyl ether, and petroleum ether; the amount of the ether antisolvent used is 7 to 9 times the weight of milrinone.
8. The method for preparing the new crystal form of lactic acid milrinone according to claim 4, characterized in that, In step (4), the drying temperature is 20-50℃.
9. A pharmaceutical composition, characterized in that, It includes the new crystal form as described in any one of claims 1-2 or the lactic acid milrinone having the new crystal form as described in claim 3.
10. Use of the novel crystalline form as described in any one of claims 1-2, or of the lactic acid milrinone having the novel crystalline form as described in claim 3, or of the pharmaceutical composition as described in claim 9, in the preparation of a cardiotonic drug.