Nifedipine lysine co-crystal, preparation method and application

Abstract

The present application relates to a nifedipine lysine co-crystal, a preparation method and application, and belongs to the technical field of drug co-crystals. The present application relates to a preparation method of a nifedipine (1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicarboxylic acid dimethyl ester) and L-lysine drug co-crystal. The nifedipine lysine co-crystal can reduce the photodegradation rate of nifedipine and improve the light stability, and has important value for further improving the medicinal economy of nifedipine.

Description

Technical Field

[0001] This invention belongs to the field of drug cocrystallization technology, and relates to a nifedipine lysine cocrystallization, its preparation method and application. Background Technology

[0002] Nifedipine (NFD), with the structure of Formula I, has the CAS number 21829-25-4 and a molecular weight of 346.34. It is a typical 1,4-dihydropyridine calcium channel blocker used to treat hypertension and angina pectoris, and is one of the essential medicines of the World Health Organization.

[0003]

[0004] Nifedipine belongs to the dihydropyridine class of compounds. The dihydropyridine ring is particularly prone to oxidation to a pyridine ring upon exposure to light, and the resulting impurities have certain toxic side effects. The photo-oxidation reaction of nifedipine is an intramolecular redox process. Drug cocrystals refer to crystalline compositions with a certain stoichiometric ratio formed by drug molecules and cocrystal formations under the influence of non-covalent bonds such as hydrogen bonds. They are often used to improve the solubility, stability, and other physicochemical properties of drug molecules. Chinese patent CN108794383A reports a cocrystal of nifedipine and isonicotinamide, which can improve the photostability of nifedipine to some extent.

[0005] This invention selects pharmacologically inactive L-lysine as a co-crystal form and prepares a nifedipine-L-lysine co-crystal by co-crystallizing nifedipine and L-lysine using crystal engineering techniques. This process slows down the photodegradation rate of nifedipine and improves its photostability. L-lysine is an important component of proteins, beneficial to the human body, and cannot be synthesized by the body itself; it is known as the "first essential amino acid." Furthermore, the preparation method of this co-crystal is simple, easy to perform, and highly reproducible, providing a practical means to improve the photostability of nifedipine. Summary of the Invention

[0006] The purpose of this invention is to provide a nifedipine lysine cocrystal, its preparation method, and its application, wherein the obtained cocrystal has better light stability.

[0007] The objective of this invention can be achieved through the following technical solutions:

[0008] A nifedipine-lysine cocrystal, wherein the cocrystal comprises nifedipine and L-lysine, characterized in that the X-ray powder diffraction pattern of the nifedipine-L-lysine cocrystal exhibits characteristic peaks at 2θ(°)±0.2°: 5.6°, 10.7°, 11.2°, 16.8°, 17.2°, 18.2°, 19.1°, 19.8°, 20.1°, 22.5°, 24.2°, 24.8°, 25.2°, 25.8°, 26.6°, and 27.8°.

[0009] Furthermore, characterization techniques used to verify the eutectic include XRPD and DSC.

[0010] In existing crystallization techniques, there are many types of solvents that can be used for crystallization, and there are countless mixed solvents of different types and proportions. However, it is impossible to predict the crystal form that will be crystallized before the crystallization experiment, especially for the formation of drug cocrystals. Through long-term experimental research on nifedipine, this invention has discovered a solvent for preparing cocrystals and its preparation method.

[0011] Furthermore, the first method for preparing the nifedipine L-lysine co-crystal is as follows:

[0012] S1: Add nifedipine and L-lysine to an organic solvent at a molar ratio of 2:1, stir, and heat to 30-80℃ until the solution is clear;

[0013] S2: Cool the above clarified solution to 5-35℃ and continue stirring;

[0014] S3: Stir, filter, and dry the filter cake at 30-80℃ to obtain eutectic.

[0015] Furthermore, the organic solvent is one or more of water, ethanol, methanol, isopropanol, acetone, butanone, and ethyl acetate; the ratio of the total mass of nifedipine and L-lysine to the amount of solvent is 1 g:(5-25) mL; the cooling rate of the clarified liquid is 5-30 °C / h; and the stirring time in S3 is 1-48 hours.

[0016] Furthermore, the second method for preparing the nifedipine-lysine co-crystal is as follows: Nifedipine and L-lysine are mixed at a molar ratio of 2:1, an auxiliary solvent is added, and the mixture is mechanically ground in a ball mill to obtain a nifedipine-L-lysine co-crystal.

[0017] Furthermore, the auxiliary solvent is one or more of water, ethanol, methanol, isopropanol, acetone, butanone, and ethyl acetate; the ratio of the total mass of nifedipine and L-lysine to the amount of solvent is 1 g:(50-500) μL, and the mechanical grinding time is 10-120 min.

[0018] An application of a nifedipine lysine cocrystal, characterized in that the cocrystal has better stability than nifedipine and is used in the preparation of drugs for treating hypertension.

[0019] As a preferred technical solution of the present invention,

[0020] The beneficial effects of this invention are:

[0021] The co-crystal form of nifedipine and lysine provided by this invention has the following advantages: high purity and good stability. The co-crystal of nifedipine and L-lysine greatly slows down the photodegradation rate of nifedipine under light conditions, which can improve its photostability and is of great value for the future optimization and development of this drug.

[0022] The co-crystal form of nifedipine and lysine of the present invention has broad application prospects in the preparation of drugs for the prevention or treatment of hypertension. Attached Figure Description

[0023] To facilitate understanding by those skilled in the art, the present invention will be further described below with reference to the accompanying drawings.

[0024] Figure 1 X-ray powder diffraction pattern of the eutectic form of nifedipine L-lysine;

[0025] Figure 2 DSC diagram of the co-crystal form of nifedipine L-lysine;

[0026] Figure 3 TGA image of the co-crystal form of nifedipine L-lysine;

[0027] Figure 4 The image shows the remaining content of the active pharmaceutical ingredient in the light stability test of the cocrystal of nifedipine L-lysine. Detailed Implementation

[0028] To further illustrate the technical means and effects of the present invention in achieving its intended purpose, the following detailed description of the specific implementation methods, structures, features, and effects of the present invention, in conjunction with the accompanying drawings and preferred embodiments, is provided.

[0029] Testing instruments and methods:

[0030] X-ray powder diffraction (XRPD) was performed using Cu with Kα rays at a voltage of 40 kV and a current of 40 mA. The instrument was calibrated for peak positions using its standard sample before use. Samples were tested at room temperature, placed on an organic glass slide. Detailed testing conditions were as follows: 2θ angle range: 5–30°; step size: 0.02°; speed: 0.1 sec / step. Unless otherwise specified, samples were not ground before testing.

[0031] Differential thermal analysis (DSC) was used to heat the sample from room temperature to 200°C at a heating rate of 10°C / min under the protection of dry nitrogen at a rate of 50 mL / min. At the same time, TA software recorded the heat change of the sample during the heating process.

[0032] The following embodiments further illustrate the present invention, but they do not constitute a limitation or restriction on the scope of the present invention.

[0033] Example 1

[0034] S1: Disperse 346g of nifedipine and 73g of L-lysine in 2L of methanol at a molar ratio of 2:1 to form a supersaturated solution. Stir for 48h and heat to 50℃. The solution is clear.

[0035] S2: Cool the above clear solution to 30°C and continue stirring;

[0036] S3: Stir, filter, and dry the filter cake at 30℃ for 2 hours to obtain 298g of light yellow solid, which is the eutectic of nifedipine L-lysine. The XRD pattern is consistent with... Figure 1 Consistent; such as Figure 2 As shown, its differential scanning calorimetry curve has a characteristic absorption peak at 177±5℃.

[0037] Example 2

[0038] S1: Disperse 34.6g nifedipine and 7.3g L-lysine in 200mL acetone at a molar ratio of 2:1, stir for 48h, heat to 45℃, and the solution is clear;

[0039] S2: Cool the above clarified solution to 25°C and continue stirring;

[0040] S3: Stir, filter, and dry the filter cake at 30℃ for 2 hours to obtain 32g of light yellow solid, which is the cocrystal of nifedipine L-lysine. The XRD pattern is consistent with... Figure 1 Consistent; such as Figure 2 As shown, its differential scanning calorimetry curve has a characteristic absorption peak at 177±5℃.

[0041] Example 3

[0042] 346 mg of nifedipine and 73 mg of L-lysine were placed in the adapter of a ball mill at a molar ratio of 2:1, followed by 60 μL of methanol and zirconia grinding balls. The mixture was thoroughly ground and mixed using a ball mill for 1.5 hours, yielding a light yellow solid, which was the cocrystal of nifedipine and L-lysine. The XRD pattern was consistent with... Figure 1 Consistent; such as Figure 2 As shown, its differential scanning calorimetry curve has a characteristic absorption peak at 177±5℃.

[0043] The co-crystal forms of nifedipine and lysine were obtained through different methods in the above embodiments. The photostability of the co-crystals of the present invention was then studied.

[0044] Light stability test: Approximately 15 mg of each sample was weighed after grinding the nifedipine-lysine cocrystal and the nifedipine active pharmaceutical ingredient powder. The samples were spread evenly on a glass plate and gently pressed with weighing paper to flatten them. The plates were then placed in a high-intensity light irradiation chamber. The samples were positioned approximately 20 cm from the light source, and samples were taken after a period of light exposure. The residual sample content at each sampling point was detected using high-performance liquid chromatography (HPLC). The light stability curves of the nifedipine-lysine cocrystal and the nifedipine active pharmaceutical ingredient were finally obtained.

[0045] The lighting conditions are as follows:

[0046] Instrument: High-intensity light irradiation test chamber for pharmaceuticals; light intensity: 4000 lux; light temperature: 25℃; sampling time: 0h, 2h, 4h, 6h, 8h, 10h.

[0047] High performance liquid chromatography (HPLC) conditions: ODS column (5 μm, 4.6 mm × 250 mm); methanol-water (60:40, V:V) as mobile phase; detection wavelength 235 nm; column temperature 30 ℃; injection volume 20 μL.

[0048] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A nifedipine L-lysine crystal, said crystal being composed of nifedipine and L-lysine, characterized in that, The X-ray powder diffraction patterns of the crystal forms of nifedipine and L-lysine show characteristic peaks at 2θ(°)±0.2°: 5.6°, 10.7°, 11.2°, 16.8°, 17.2°, 18.2°, 19.1°, 19.8°, 20.1°, 22.5°, 24.2°, 24.8°, 25.2°, 25.8°, 26.6°, and 27.8°. The method for preparing the nifedipine L-lysine crystals is selected from one of the following methods: (1) Method 1: Nifedipine and L-lysine are added to an organic solvent at a molar ratio of 2:1, stirred, heated to 30-80°C, and the solution is clear. The clear solution is cooled to 5-35°C, stirred, filtered, and the filter cake is dried at 30-80°C to obtain the nifedipine L-lysine crystals. The organic solvent is one or more of ethanol, methanol, isopropanol, acetone, butanone, and ethyl acetate; the ratio of the total mass of nifedipine and L-lysine to the amount of the organic solvent is 1 g:(5-25) mL; the cooling rate of the clarified liquid is 5-30 °C / h. (2) Method 2: Nifedipine and L-lysine are mixed at a molar ratio of 2:1, an auxiliary solvent is added, and mechanical grinding is carried out in a ball mill to obtain the nifedipine L-lysine crystals; The auxiliary solvent is one or more of water, ethanol, methanol, isopropanol, acetone, butanone, and ethyl acetate; the ratio of the total mass of nifedipine and L-lysine to the amount of the auxiliary solvent is 1 g:(50-500) μL, and the mechanical grinding time is 10-120 min.

2. The nifedipine L-lysine crystal according to claim 1, characterized in that, The characterization methods used to verify the crystal are XRPD and DSC.

3. The use of the nifedipine L-lysine crystal as described in claim 1 in the preparation of a medicament for treating hypertension.

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