Ibuprofen-alpha-lipoic acid eutectic crystal as well as preparation method and application thereof

Abstract

The invention discloses an ibuprofen-alpha-lipoic acid eutectic crystal as well as a preparation method and application thereof, and belongs to the field of pharmaceutical chemistry and crystallization processes. The ibuprofen-alpha-lipoic acid eutectic crystal comprises ibuprofen and alpha-lipoic acid, and the molar ratio of the ibuprofen to the alpha-lipoic acid is (0.9 to 1.1): (0.9 to 1.1). The preparation method comprises the following steps: taking ibuprofen and alpha-lipoic acid as raw materials, and adopting a liquid-assisted grinding method to prepare the ibuprofen-alpha-lipoic acid compound. The ibuprofen-alpha-lipoic acid eutectic crystal has excellent water solubility and relatively high stability, and can effectively reduce production, storage and transportation costs.

Description

Technical Field

[0001] The present invention belongs to the fields of pharmaceutical chemistry and crystallization technology, and particularly relates to an ibuprofen-α-lipoic acid cocrystal, a preparation method thereof, and an application thereof. Background Art

[0002] Disclosing the information of this background art section is only intended to enhance the understanding of the overall background of the present invention, and it is not necessarily regarded as an admission or an implication in any form that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] Drug cocrystals are based on the theories of crystal engineering and supramolecular chemistry. Through non-covalent intermolecular interactions, in a way of molecular recognition and self-assembly, a drug active ingredient (API) that is solid at room temperature and a cocrystal former (CCF) are complexed in a fixed stoichiometric ratio to obtain a new crystal. By forming cocrystals, drugs can, on the one hand, improve their physicochemical properties and enhance their clinical therapeutic effects, and on the other hand, cocrystals can enrich their crystal forms. For chemically generic drugs, through the research of cocrystals, the patent protection of the original research drug companies can be broken, and the innovation and market competitiveness of drugs can be improved.

[0004] Ibuprofen, with the molecular formula of C 13 H 18 O 2 , and its molecular structural formula is shown as follows: Ibuprofen is a non-steroidal anti-inflammatory drug that reduces prostaglandin synthesis by inhibiting cyclooxygenase. It has relatively low toxicity and side effects, few adverse reactions, and significant clinical effects such as anti-inflammatory, analgesic, and antipyretic effects. Ibuprofen is widely used in the treatment of rheumatoid arthritis, rheumatoid arthritis, ankylosing spondylitis, etc. After its launch, it has been rapidly and widely used worldwide, and the market has been continuously expanding. In the late 1980s, many countries in Europe and America listed it as an over-the-counter drug, which accelerated its sales growth. It has now become one of the best-selling OTC drugs globally. In the early 1990s, the global sales of ibuprofen exceeded $1 billion, becoming the first antipyretic and analgesic drug to break through the $1 billion mark. Ibuprofen, paracetamol, aspirin, and diclofenac are among the four pillar products of antipyretic and analgesic drugs.

[0005] Ibuprofen belongs to the BCS class II compounds in the biopharmaceutics classification system. Its solubility in water is only 0.1 mg / ml. The low water solubility results in a low oral bioavailability, and at the same time limits its formulation types and clinical applications. Currently, the methods reported in the literature to improve the solubility of ibuprofen mainly include salt formation: Patent CN101190889B and CN102617330B disclose the preparation methods of arginine ibuprofen salt; Patent CN102180785A and CN101874794A disclose the preparation methods of lysine ibuprofen salt; Patent CN102557918B discloses the preparation method of ibuprofen sodium salt; Patent CN1897925A discloses the preparation method of ibuprofen potassium salt. In addition, the solubility of ibuprofen can also be improved by the drug cocrystal technology: Patent CN103304476B and CN106632024A disclose the preparation of ibuprofen-nicotinamide cocrystal; Patent CN114031515B reports the preparation of paracetamol-ibuprofen drug cocrystal and its preparation method; Patent CN110041325B reports the berberine hydrochloride-ibuprofen cocrystal and its preparation method. The above preparation of ibuprofen cocrystals uses the solvent evaporation method, which has a long time, large environmental pollution, and low product yield.

[0006] Lipoic acid (LA) has the molecular formula C 8 H 14 O 2 S 2 , and its molecular structural formula is shown as follows: Lipoic acid is a natural antioxidant, and lipoic acid in the human body can be synthesized in the liver and other tissues. As a unique strong inhibitor of redox bidirectional oxidative stress, lipoic acid can scavenge a variety of reactive oxygen free radicals in the human body; chelate metal ions; reduce the antioxidant system in the human body, prolong the lifespan of ordinary antioxidants or promote their regeneration. Oxidative stress exists throughout the process of life. It not only makes healthy organisms age, but also is a pathogenic link in many disease processes. Especially in the elderly with low immune function, it will induce and promote the occurrence and development of many diseases, such as atherosclerosis, stroke, coronary heart disease, hypertension, Alzheimer's disease, diabetes, Parkinson's disease, etc. With the increase of age, the antioxidant capacity of the human body continuously decreases, slowing down the process of human aging.

[0007] Lipoic acid is one of the most effective natural antioxidants known. Lipoic acid has dual (water-soluble / lipid-soluble) compatibility characteristics, is easily transported through cell membranes and the blood-brain barrier, reaches brain tissues, and exerts antioxidant functions. Currently, as a strong antioxidant stress preparation, lipoic acid is widely used in the prevention and adjuvant treatment of various heart diseases, diabetes, and neurodegenerative diseases of the brain such as Alzheimer's disease. Especially, it has beneficial effects in the treatment of various cerebrovascular and cardiovascular diseases.

[0008] Therefore, the synthesis of ibuprofen-lipoic acid cocrystal is not involved in the prior art, and the study of the synthesis of ibuprofen-lipoic acid cocrystal has important significance. SUMMARY OF THE INVENTION

[0009] In order to solve the deficiencies of the prior art, the object of the present invention is to provide an ibuprofen-α-lipoic acid cocrystal, its preparation method and application, which can significantly improve the solubility and bioavailability of ibuprofen, improve its medicinal value, and thus effectively reduce the production, storage and transportation costs.

[0010] In order to achieve the above object, the technical solution of the present invention is as follows:

[0011] In the first aspect, the present invention provides an ibuprofen-α-lipoic acid cocrystal, which includes ibuprofen and α-lipoic acid, and the molar ratio of ibuprofen to α-lipoic acid is (0.9 - 1.1):(0.9 - 1.1).

[0012] Preferably, the molar ratio of ibuprofen to α-lipoic acid is 1:1.

[0013] The ibuprofen is a pharmaceutically active ingredient, and the α-lipoic acid is a cocrystal precursor.

[0014] The structural formula of the ibuprofen-α-lipoic acid cocrystal is:

[0015]

[0016] In one or more embodiments, the X-ray powder diffraction (PXRD) pattern of the ibuprofen-α-lipoic acid cocrystal measured with Cu-Kα radiation has characteristic peaks at diffraction angles 2θ of approximately 6.12 ± 0.2°, 7.82 ± 0.2°, 12.23 ± 0.2°, 13.89 ± 0.2°, 16.61 ± 0.2°, 18.73 ± 0.2°, 19.06 ± 0.2°, 20.18 ± 0.2°, 22.34 ± 0.2°, 23.41 ± 0.2°, 24.03 ± 0.2°.

[0017] Preferably, the ibuprofen-α-lipoic acid eutectic has characteristic peaks in the PXRD pattern at 2θ angles of approximately 6.12±0.2°, 7.82±0.2°, 12.23±0.2°, 13.89±0.2°, 14.71±0.2°, 16.61±0.2°, 17.75±0.2°, 18.73±0.2°, 19.06±0.2°, 19.42±0.2°, 20.18±0.2°, 21.62±0.2°, 22.34±0.2°, 23.41±0.2°, 24.03±0.2°, 24.57±0.2°, 25.11±0.2°, 25.66±0.2°, 27.67±0.2°, 30.94±0.2°, 32.11±0.2°, 35.37±0.2°.

[0018] In a more specific embodiment, the eutectic has an X-ray diffraction pattern substantially as Figure 1 shown by "eutectic" in. Due to different measurement conditions, the 2θ angles and relative intensities of the peaks on the PXRD diffraction pattern will vary. Generally, the change in the 2θ angle is within ±0.2°, but it can also slightly exceed this range. Those skilled in the art should understand that the relative intensity of the diffraction can depend on, for example, the sample formulation or the equipment used.

[0019] In one or more embodiments, the ibuprofen-α-lipoic acid eutectic has a characteristic melting peak at approximately 51.5±1°C (onset temperature) in its differential scanning calorimetry (DSC) graph; further, its DSC graph has characteristics substantially as Figure 2 shown by "eutectic" in.

[0020] In one or more embodiments, the ibuprofen-α-lipoic acid eutectic has the following thermogravimetric analysis (TGA) performance: weight loss starts at 100±10°C and reaches 100% weight loss at 250±10°C; further, its TGA graph has weight loss characteristics substantially as Figure 3 shown by "eutectic" in.

[0021] In a second aspect, the present invention provides a method for preparing the above-mentioned ibuprofen-α-lipoic acid eutectic, comprising the following steps:

[0022] Using ibuprofen and α-lipoic acid as raw materials, it is prepared by a liquid-assisted grinding method.

[0023] In one or more embodiments, the liquid is an organic solvent, which is selected from one or more of ethanol, methanol, isopropanol, tetrahydrofuran, acetone, and acetonitrile, preferably ethanol. The liquid cannot be water.

[0024] In one or more embodiments, the liquid-assisted grinding method includes the following steps:

[0025] Ibuprofen and α-lipoic acid are ball-milled in a liquid to obtain ibuprofen-α-lipoic acid eutectic;

[0026] In one or more embodiments, the optimized process for the milling is as follows:

[0027] The milling can be achieved by a grinding jar or a ball mill. The steps are as follows: Put the ibuprofen and α-lipoic acid samples into the grinding jar, put in grinding balls (such as stainless steel grinding balls), drop a small amount of organic solvent into the grinding jar, or put the grinding jar into a ball mill (such as a planetary ball mill BM6pro used in some embodiments of the present invention). After the operation is over, remove the grinding jar, and scrape off the sample with a cleaning scraper to obtain the ibuprofen-α-lipoic acid eutectic of the present invention.

[0028] Preferably, the mass of the grinding balls is 2-10 times the amount of the samples (ibuprofen and α-lipoic acid), and more preferably 3-5 times.

[0029] Preferably, the set rotation speed of the ball mill is 100-1000 revolutions per minute, more preferably 200-300 revolutions per minute, and even more preferably 250 revolutions per minute; the milling method is: the milling time is 1-5 minutes, with an interval of 1-5 minutes, and the cycle is 1-5 times.

[0030] According to the research and determination of the present invention, in the above preparation method, the milling method can greatly shorten the time and reduce the cost, and has better industrial application prospects.

[0031] In one or more embodiments, the molar ratio of ibuprofen to α-lipoic acid is (0.9-1.1):(0.9-1.1), and the ratio of the mixture of ibuprofen and α-lipoic acid to the organic solvent is 1 g:(0.05-0.2) mL, preferably 1 g:(0.08-0.15) mL.

[0032] In a third aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned ibuprofen-α-lipoic acid eutectic and a pharmaceutically acceptable carrier or excipient.

[0033] The pharmaceutical composition of the present invention can be prepared according to known methods using well-known and easily obtainable components. When preparing the pharmaceutical composition of the present invention, the active ingredient is usually mixed with a carrier or excipient. The pharmaceutical composition can be prepared in solid, semi-solid or liquid forms, such as tablets, pills, powders, capsules, suspensions, etc., including preparations suitable for various administration modes, and the administration modes include but are not limited to inhalation, oral, workplace, parenteral (including subcutaneous, intradermal, intramuscular and intravenous), implantable and transdermal administrations. The most suitable administration route depends on the duration of the disease course of the subject, the required treatment time, the nature and severity of the disease to be treated, and the specific preparation used.

[0034] The above excipients generally have no pharmacological activity, but have various useful properties, such as improving the stability, sterility, bioavailability and formulation difficulty of the pharmaceutical composition. Some examples of suitable carriers or excipients are first required to be safe and compatible with the active pharmaceutical ingredient, and those skilled in the art can select from the conventional ingredients in the art, such as lactose, glucose, sucrose, sorbitol, mannitol, starch, gum, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylparaben and propylparaben, talc, magnesium stearate, polyethylene glycol, polyethylene glycol and mineral oil, etc. By formulating the pharmaceutical composition of the present invention, rapid release, sustained release or extended release of the active ingredient can be achieved after administration to a patient by methods well known in the art.

[0035] In a fourth aspect of the present invention, there is provided the use of the above ibuprofen-α-lipoic acid cocrystal and the above pharmaceutical composition in the preparation of drugs for treating arthritis, gout, primary dysmenorrhea, and in the preparation of drugs for relieving mild to moderate pain and high fever caused by common cold and influenza.

[0036] When the above pharmaceutical composition is used in the preparation of drugs for treating arthritis, gout, primary dysmenorrhea, and in the preparation of drugs for relieving mild to moderate pain and high fever caused by common cold and influenza, the ibuprofen-α-lipoic acid cocrystal or the pharmaceutical composition should be in an effective dose; the arthritis includes osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, etc.; the pain includes headache, joint pain, toothache, muscle pain, neuralgia, etc.

[0037] In a fifth aspect of the present invention, there is provided a method for using the above ibuprofen-α-lipoic acid cocrystal and / or the above pharmaceutical composition in the treatment of arthritis, gout, primary dysmenorrhea and in relieving mild to moderate pain and high fever caused by common cold and influenza, which comprises administering to a subject a therapeutically effective dose of the ibuprofen-α-lipoic acid cocrystal or the above pharmaceutical composition.

[0038] Wherein, the subject refers to an animal that has been or will be the subject of treatment, observation or experiment, such as a mammal (including humans).

[0039] The "therapeutically effective amount" refers to the amount of the compound of the present invention or the pharmaceutical composition containing the compound of the present invention, which is sufficient to effectively treat immune promoter-related diseases when administered to a subject. Such an amount will be sufficient to elicit a biological or medical response in the tissue system or patient sought by the researcher or clinician. The therapeutically effective amount generally varies depending on factors such as the compound and its biological activity, the pharmaceutical composition used for administration, the administration time, the administration route, the compound excretion rate, the treatment duration, the type and severity of the disease state or disorder being treated, the drugs used in combination with or simultaneously with the compound of the present invention, and the age, weight, general health, gender, and diet of the patient, etc. Such a therapeutically effective amount can be routinely determined by those skilled in the art considering their own knowledge, the prior art level, and the present disclosure.

[0040] One or some of the above technical solutions have the following advantages or beneficial effects:

[0041] The ibuprofen-α-lipoic acid cocrystal significantly improves the solubility and stability of ibuprofen, and can effectively reduce the production, storage, and transportation costs. The cocrystal is prepared by the grinding method, which is simple and easy to operate, low in cost, and convenient for large-scale promotion in industrial pharmacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] The specification drawings forming a part of the present invention are used to provide a further understanding of the present invention. The schematic embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention.

[0043] Figure 1 is the X-ray powder diffraction (PXRD) pattern of the ibuprofen-α-lipoic acid cocrystal prepared in Example 1 of the present invention;

[0044] Figure 2 is the differential scanning calorimetry (DSC) pattern of the ibuprofen-α-lipoic acid cocrystal prepared in Example 1 of the present invention;

[0045] Figure 3 is the thermogravimetric analysis (TGA) pattern of the ibuprofen-α-lipoic acid cocrystal prepared in Example 1 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0046] In order to enable those skilled in the art to more clearly understand the technical solutions of the present invention, the technical solutions of the present invention will be described in detail below with reference to specific embodiments.

[0047] Detection instruments and methods:

[0048] The instrument used for X-ray powder diffraction (PXRD) is a Bruker D8 Advance diffractometer, with Cu Kα radiation, a voltage of 40 kV, and a current of 40 mA. The instrument was calibrated for peak positions using the standard sample provided with the instrument before use. The acquisition software is Diffrac Plus XRD Commander, and the analysis software is MDI Jade 6.0. The samples were tested at room temperature, and the samples to be detected were placed on organic glass slides. The detailed detection conditions are as follows: 2θ angle range: 3 - 40°; step size: 0.02°; speed: 0.1 s / step. Unless otherwise specified, the samples were not ground before detection.

[0049] Differential scanning calorimetry (DSC) data were collected from a Mettler Toledo DSC1 differential scanning calorimeter, and both the instrument control software and the analysis software are the software provided with the instrument. The sample was heated from 30 °C to 150 °C at a heating rate of 10 °C / min, and the software recorded the heat change of the sample during the heating process.

[0050] Thermogravimetric analysis (TGA) data were collected from a Mettler Toledo DSC1 / TGA model, and both the instrument control software and the analysis software are the software provided with the instrument. The sample was heated from 60 °C to 400 °C at a heating rate of 10 °C / min under the protection of 20 mL / min dry nitrogen, and the software recorded the weight change of the sample during the heating process.

[0051] For the various analytical techniques and the resulting data as described in the present invention, the term "substantially" the same or similar means that within an acceptable scientific range, a specific set of analytical data is sufficiently similar to the data disclosed in the present invention such that a person skilled in the art can understand that the form of the compound is the same as that of the present invention. A person skilled in the art can understand that certain analytical techniques, such as PXRD and DSC, etc., do not produce exactly the same results every time due to instrument variations, sample preparation, scientific errors, etc. For example, although within the scope of recognized scientific principles, the form of the sample is the same, the PXRD results (i.e., the position, intensity, and / or the presence or absence of peaks) may vary slightly from sample to sample, which can be caused by, for example, the orientation direction or different solvent or water content. A person skilled in the art is fully capable of observing the data as a whole and understanding whether such differences indicate different forms, so as to determine whether it is substantially similar compared to the analytical data disclosed in the present invention. In this regard, as is usually done in the scientific community, it is not simply a literal comparison solely for the purpose of making a distinction. For example, whether each peak of the exemplary PXRD spectrum disclosed in the present invention is present in the comparison data, whether it is exactly in the same position and / or whether it has exactly the same intensity. Instead, as described above, a person skilled in the art will utilize recognized scientific principles to determine whether the data used for comparison and analysis is the same or a different form of the cocrystal of aspirin nicotinic acid disclosed in the present invention based on the integrity of the data.

[0052] The cocrystal of ibuprofen-α-lipoic acid according to the present invention, wherein the molar ratio of ibuprofen to α-lipoic acid is 1:1, and its X-ray powder diffraction (PXRD) pattern is as Figure 1 shown, and its differential scanning calorimetry (DSC) pattern is as Figure 2 shown, and its thermogravimetric analysis (TGA) pattern is as Figure 3 shown.

[0053] As Figure 1As shown, the PXRD patterns of ibuprofen-α-lipoic acid prepared in Example 1, the PXRD pattern of ibuprofen, and the PXRD pattern of α-lipoic acid; it can be seen from the PXRD pattern of the prepared ibuprofen-α-lipoic acid cocrystal that a series of characteristic peaks appear at 6.12 ± 0.2°, 7.82 ± 0.2°, 12.23 ± 0.2°, 13.89 ± 0.2°, 14.71 ± 0.2°, 16.61 ± 0.2°, 17.75 ± 0.2°, 18.73 ± 0.2°, 19.06 ± 0.2°, 19.42 ± 0.2°, 20.18 ± 0.2°, 21.62 ± 0.2°, 22.34 ± 0.2°, 23.41 ± 0.2°, 24.03 ± 0.2°, 24.57 ± 0.2°, 25.11 ± 0.2°, 25.66 ± 0.2°, 27.67 ± 0.2°, 30.94 ± 0.2°, 32.11 ± 0.2°, 35.37 ± 0.2°. The positions of these characteristic peaks are different from those of the API ibuprofen and the PXRD pattern of the precursor α-lipoic acid, proving the formation of a new phase.

[0054] As Figure 2 shown, the DSC patterns of the ibuprofen-α-lipoic acid cocrystal prepared in Example 1, the DSC pattern of ibuprofen, and the DSC pattern of α-lipoic acid; in the figure, the melting point of the ibuprofen-α-lipoic acid cocrystal is 51.5 ± 1 °C, the melting point of ibuprofen is 77.2 ± 1 °C, and the melting point of α-lipoic acid is 64.0 ± 1 °C. The melting point of the cocrystal is different from that of the API and the precursor, proving the formation of a new phase.

[0055] As Figure 3 shown, the TGA patterns of the ibuprofen-α-lipoic acid cocrystal prepared in Example 1, the TGA pattern of ibuprofen, and the TGA pattern of α-lipoic acid; under the test conditions of a nitrogen atmosphere, the thermogravimetric curve of the ibuprofen-α-lipoic acid cocrystal starts to lose weight at 100 °C and loses 100% at 250 °C. The thermogravimetric curve of the ibuprofen API starts to lose weight at 110 °C and loses 100% at 242 °C. It can also prove the formation of a new phase.

[0056] Specifically, the ibuprofen-α-lipoic acid cocrystal of the present invention can be prepared by the grinding method. The following Examples 1-5 are used as examples to illustrate the specific preparation method. The PXRD, DSC, and TGA patterns of the ibuprofen-α-lipoic acid cocrystal prepared in the following Preparation Examples are basically the same, as Figures 1 to 3 shown.

[0057] Example 1

[0058] Accurately weigh 1.03 g of ibuprofen and 1.03 g of α-lipoic acid respectively using an analytical balance into a 100 mL grinding jar. Add 0.2 mL of anhydrous ethanol using a micropipette and place 20 g of grinding balls. Put the grinding jar into a planetary ball mill BM6pro, set the rotation speed to 250 revolutions per minute, set the grinding time to 5 minutes, with an interval of 1 minute, and cycle 4 times. After the operation is completed, remove the grinding jar and scrape off the sample with a cleaning spatula to obtain the ibuprofen-α-lipoic acid co-crystal. In the ibuprofen-α-lipoic acid co-crystal, its X-ray powder diffraction (PXRD) pattern is as shown in Figure 1 shown, and its differential scanning calorimetry (DSC) pattern is as shown in Figure 2 shown, and its thermogravimetric analysis (TGA) pattern is as shown in Figure 3 shown.

[0059] Example 2

[0060] Accurately weigh 1.03 g of ibuprofen and 1.03 g of α-lipoic acid respectively using an analytical balance into a 100 mL grinding jar. Add 0.2 mL of tetrahydrofuran using a micropipette and place 25 g of grinding balls. Put the grinding jar into a planetary ball mill BM6pro, set the rotation speed to 300 revolutions per minute, set the grinding time to 4 minutes, with an interval of 2 minutes, and cycle 4 times. After the operation is completed, remove the grinding jar and scrape off the sample with a cleaning spatula to obtain the ibuprofen-α-lipoic acid co-crystal. It is verified that the PXRD, DSC, and TGA patterns of this co-crystal are basically the same as those in Example 1, confirming that the co-crystal structure is the same as that in Example 1.

[0061] Example 3

[0062] Accurately weigh 1.03 g of ibuprofen and 1.03 g of α-lipoic acid respectively using an analytical balance into a 100 mL grinding jar. Add 0.2 mL of methanol using a micropipette and place 18 g of grinding balls. Put the grinding jar into a planetary ball mill BM6pro, set the rotation speed to 300 revolutions per minute, set the grinding time to 4 minutes, with an interval of 2 minutes, and cycle 5 times. After the operation is completed, remove the grinding jar and scrape off the sample with a cleaning spatula to obtain the ibuprofen-α-lipoic acid co-crystal. It is verified that the PXRD, DSC, and TGA patterns of this co-crystal are basically the same as those in Example 1, confirming that the co-crystal structure is the same as that in Example 1.

[0063] Example 4

[0064] Accurately weigh 1.03 g of ibuprofen and 1.03 g of α-lipoic acid separately using an analytical balance into a 100 mL grinding jar. Add 0.2 mL of acetone using a micropipette and put in 28 g of grinding balls. Place the grinding jar into a planetary ball mill BM6pro, set the rotation speed to 250 revolutions per minute, set the grinding time to 5 minutes, with an interval of 1 minute, and cycle 4 times. After the operation is completed, remove the grinding jar and scrape off the sample with a cleaning spatula to obtain the ibuprofen-α-lipoic acid co-crystal. After verification, the PXRD, DSC, and TGA diagrams of this co-crystal are basically the same as those in Example 1, confirming that the co-crystal structure is the same as that in Example 1.

[0065] Example 5

[0066] Accurately weigh 1.03 g of ibuprofen and 1.03 g of α-lipoic acid separately using an analytical balance into a 100 mL grinding jar. Add 0.2 mL of isopropanol using a micropipette and put in 25 g of grinding balls. Place the grinding jar into a planetary ball mill BM6pro, set the rotation speed to 250 revolutions per minute, set the grinding time to 4 minutes, with an interval of 2 minutes, and cycle 4 times. After the operation is completed, remove the grinding jar and scrape off the sample with a cleaning spatula to obtain the ibuprofen-α-lipoic acid co-crystal. After verification, the PXRD, DSC, and TGA diagrams of this co-crystal are basically the same as those in Example 1, confirming that the co-crystal structure is the same as that in Example 1.

[0067] Comparative Example 1

[0068] Different from Example 1, when α-lipoic acid is replaced with other co-crystal ligands (such as benzoic acid, caffeic acid, saccharin, bipyridine), no co-crystal product can be formed.

[0069] Comparative Example 2

[0070] Different from Example 1, when α-lipoic acid is replaced with nicotinic acid, a co-crystal product can be formed, but the solubility is not improved and even slightly decreased. The specific solubility is shown in Table 1.

[0071] Comparative Example 3

[0072] Different from Example 1, when the solvent evaporation method is used, no ibuprofen-α-lipoic acid co-crystal is obtained.

[0073] Experimental Example

[0074] 1. Solubility determination:

[0075] Take 50 mg each of the ibuprofen-α-lipoic acid co-crystal obtained in Example 1 and the ibuprofen raw material, place them separately in different 100 ml beakers, add an appropriate amount of water, place them in a constant temperature heating magnetic stirrer at 25°C ± 2°C, stir for 30 min, let stand, filter, and take the subsequent filtrates as the test solution respectively.

[0076] Preparation of reference solution: Take an appropriate amount of aspirin reference substance, dissolve it with methanol and dilute to prepare a solution containing 0.5 mg of aspirin per 1 ml.

[0077] Conditions for high performance liquid chromatography detection: Use octadecylsilane chemically bonded silica gel as the filler; use sodium acetate buffer solution (take 6.13 g of sodium acetate, add 750 ml of water to dissolve it, adjust the pH value to 2.5 with glacial acetic acid)-acetonitrile (40:60) as the mobile phase; the flow rate is 1.0 mL / min; the column temperature is 30 °C; the detection wavelength is 263 nm; the injection volume is 20 μL.

[0078] Precisely measure the test solution and the reference solution, inject them into the high performance liquid chromatograph respectively, and perform detection according to the above high performance liquid chromatography detection conditions, and record the chromatogram. Calculate the ibuprofen content in the test sample by the external standard method based on the peak area. The solubility results are shown in Table 1.

[0079] Table 1 Solubility Results

[0080]

[0081]

[0082] As shown in the results of Table 1, the solubility of ibuprofen raw material in water is 0.041 mg / mL; the solubility of ibuprofen-α-lipoic acid cocrystal in water is 0.026 mg / mL, which is 3 times higher than the solubility of ibuprofen raw material in water.

[0083] 2. Stability determination

[0084] Determination of related substances: Take 100 mg each of the ibuprofen-α-lipoic acid cocrystal obtained in Example 1 and ibuprofen raw material, place them in different 20 ml volumetric flasks, place them in a stability incubator at a temperature of 60 °C and a humidity of 95% ± 5%, and take them out after 10 days.

[0085] Preparation of test solution: Take the above samples damaged by high temperature and high humidity, add 20 ml of acetonitrile respectively, ultrasonically dissolve them, dilute to the scale with 0.10 mol / L potassium dihydrogen phosphate solution (adjust the pH value to 3.0 with phosphoric acid), and shake well.

[0086] Preparation of control solution: Precisely measure 1 ml of the test solution, place it in a 200 ml volumetric flask, dilute to the scale with the mobile phase, and shake well.

[0087] Conditions for high performance liquid chromatography detection: Use octadecylsilane chemically bonded silica gel as the filler; use acetonitrile-0.10 mol / L potassium dihydrogen phosphate solution (adjust the pH value to 3.0 with phosphoric acid) as the mobile phase; the detection wavelength is 256 nm; the injection volume is 20 μl.

[0088] Precisely measure the test solution and the reference solution, and inject them into the high performance liquid chromatograph respectively. Detect according to the above high performance liquid chromatography detection conditions, and record the chromatogram. Calculate the content of impurities in the test sample by the self-reference method. The detection results of related substances are shown in Table 2.

[0089] Table 2 Detection Results of Related Substances

[0090]

[0091]

[0092] Among them, the impurity E and the impurity J respectively refer to:

[0093]

[0094] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. An ibuprofen-α-lipoic acid cocrystal, characterized in that: The invention comprises ibuprofen and alpha-lipoic acid, wherein the molar ratio of ibuprofen to alpha-lipoic acid is (0.9-1.1):(0.9-1.1); The ibuprofen-α-lipoic acid cocrystal has a characteristic peak in an X-ray powder diffraction pattern measured by Cu-Kα radiation at diffraction angles 2θ of approximately 6.12±0.2°, 7.82±0.2°, 12.23±0.2°, 13.89±0.2°, 16.61±0.2°, 18.73±0.2°, 19.06±0.2°, 20.18±0.2°, 22.34±0.2°, 23.41±0.2°, and 24.03±0.2°.

2. The ibuprofen-α-lipoic acid cocrystal according to claim 1, characterized in that The ibuprofen-α-lipoic acid cocrystal has a 2θ angle of approximately 6.12±0.2°, 7.82±0.2°, 12.23±0.2°, 13.89±0.2°, 14.71±0.2°, 16.61±0.2°, 17.75±0.2°, 18.73±0.2°, 19.06±0.2°, 19.42±0.2°, 2 There are characteristic peaks at 0.18±0.2°, 21.62±0.2°, 22.34±0.2°, 23.41±0.2°, 24.03±0.2°, 24.57±0.2°, 25.11±0.2°, 25.66±0.2°, 27.67±0.2°, 30.94±0.2°, 32.11±0.2°, and 35.37±0.2°; Preferably, the X-ray powder diffraction pattern of the ibuprofen-α-lipoic acid cocrystal is shown in FIG1 .

3. The ibuprofen-α-lipoic acid cocrystal according to claim 1, characterized in that In the differential scanning calorimetry analysis diagram of the ibuprofen-α-lipoic acid cocrystal, there is a characteristic melting peak at 51.5±1°C; Preferably, the differential scanning calorimetry analysis diagram of the ibuprofen-α-lipoic acid cocrystal is shown in FIG2 .

4. The ibuprofen-α-lipoic acid cocrystal according to claim 1, characterized in that The thermogravimetric analysis of the ibuprofen-α-lipoic acid cocrystal showed the following: it began to lose weight at 100±10°C and lost 100% of its weight at 250±10°C; Preferably, the thermogravimetric analysis graph of the ibuprofen-α-lipoic acid cocrystal is shown in FIG3 .

5. A method for preparing the ibuprofen-α-lipoic acid cocrystal according to any one of claims 1 to 4, characterized in that: The following steps are involved: It is prepared using ibuprofen and α-lipoic acid as raw materials by liquid-assisted grinding.

6. The preparation method according to claim 5, characterized in that: The liquid is an organic solvent, which is selected from one or more of ethanol, methanol, isopropanol, tetrahydrofuran, acetone and acetonitrile, preferably ethanol.

7. The preparation method according to claim 5, characterized in that: The liquid-assisted grinding method comprises the following steps: ibuprofen and α-lipoic acid are ball-milled in a liquid to obtain ibuprofen-α-lipoic acid cocrystals; Preferably, the mass of the grinding balls is 2-10 times, more preferably 3-5 times, the total mass of ibuprofen and α-lipoic acid; Preferably, the ball mill is set at a rotation speed of 100-1000 rpm, more preferably 200-300 rpm, and more preferably 250 rpm; the grinding method is: grinding time is 1-5 minutes, interval is 1-5 minutes, and cycle is 1-5 times.

8. The preparation method according to claim 5, characterized in that: The molar ratio of ibuprofen to α-lipoic acid is (0.9-1.1):(0.9-1.1), and the ratio of the mixture of ibuprofen and α-lipoic acid to the liquid is 1 g:(0.05-0.2) mL, preferably 1 g:(0.08-0.15) mL.

9. A pharmaceutical composition comprising the ibuprofen-α-lipoic acid cocrystal according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier or excipient.

10. Use of the ibuprofen-α-lipoic acid cocrystal according to any one of claims 1 to 4 and / or the pharmaceutical composition according to claim 9 in the preparation of drugs for treating arthritis, gout, primary dysmenorrhea, and drugs for relieving mild to moderate pain, common cold and high fever caused by influenza.

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