Ibuprofen-α-lipoic acid cocrystal and its preparation method and application

Abstract

The present invention discloses an ibuprofen-α-lipoic acid cocrystal and its preparation method and application, belonging to the field of pharmaceutical chemistry and crystallization technology. The ibuprofen-α-lipoic acid cocrystal comprises ibuprofen and α-lipoic acid, wherein the molar ratio of ibuprofen to α-lipoic acid is (0.9-1.1):(0.9-1.1). The preparation method comprises the following steps: using ibuprofen and α-lipoic acid as raw materials and preparing the cocrystal by liquid-assisted grinding. The ibuprofen-α-lipoic acid cocrystal has excellent water solubility and high stability, which can effectively reduce production, storage and transportation costs.

Description

Technical Field

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

[0002] The information disclosed in this background technology section is only intended to enhance understanding of the overall background of the invention and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to those skilled in the art.

[0003] Pharmaceutical cocrystals are based on the principles of crystal engineering and supramolecular chemistry. Through intermolecular non-covalent interactions, molecular recognition, and self-assembly, they combine a room-temperature solid active pharmaceutical ingredient (API) with a cocrystal former (CCF) in a fixed stoichiometric ratio to form new crystals. The formation of cocrystals can improve a drug's physicochemical properties and enhance its clinical therapeutic effects, while also enriching its crystalline forms. For generic drugs, the study of cocrystals can help overcome patent protection held by originator companies, enhancing their innovativeness and market competitiveness.

[0004] Ibuprofen, molecular formula C 13 H 18 O2, its molecular structure is as follows: Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase to reduce prostaglandin synthesis. It has minimal toxicity and adverse reactions, and demonstrates significant clinical efficacy in anti-inflammatory, analgesic, and antipyretic effects. Widely used in the treatment of rheumatoid arthritis, rheumatoid arthritis, and ankylosing spondylitis, ibuprofen quickly gained worldwide adoption after its launch, and its market continues to expand. In the late 1980s, it was listed as an over-the-counter drug in many countries, including Europe and the United States, accelerating its sales growth. It has now become one of the world's best-selling OTC medications. In the early 1990s, global sales of ibuprofen exceeded $1 billion, making it the first antipyretic and analgesic drug to do so. Ibuprofen, along with paracetamol, aspirin, and diclofenac, is one of the four pillars of the antipyretic and analgesic drug market.

[0005] Ibuprofen is a Class II compound in the Biopharmaceutics Classification System (BCS). Its solubility in water is only 0.1 mg / ml. This low water solubility results in low oral bioavailability, limiting its formulation options and clinical applications. Currently reported methods for improving ibuprofen solubility primarily involve salt preparation: Patents CN101190889B and CN102617330B disclose methods for preparing arginine ibuprofen salts; patents CN102180785A and CN101874794A disclose methods for preparing lysine ibuprofen salts; patent CN102557918B discloses a method for preparing sodium ibuprofen; and patent CN1897925A discloses a method for preparing potassium ibuprofen. In addition, ibuprofen solubility can be improved through pharmaceutical cocrystal technology: Patents CN103304476B and CN106632024A disclose the preparation of ibuprofen-nicotinamide cocrystals; Patent CN114031515B reports on acetaminophen-ibuprofen pharmaceutical cocrystals and their preparation methods; and Patent CN110041325B reports on berberine hydrochloride and ibuprofen cocrystals and their preparation methods. The preparation of these ibuprofen cocrystals utilizes a solvent evaporation method, which is time-consuming, environmentally hazardous, and results in low product yields.

[0006] The molecular formula of lipoic acid (LA) is C8H 14 O2S2, its molecular structure is as follows: Lipoic acid is a natural antioxidant that is synthesized in the liver and other tissues. As a unique and potent inhibitor of redox stress, lipoic acid can scavenge various reactive oxygen free radicals in the body, chelate metal ions, and restore the body's antioxidant system, thereby extending the lifespan or promoting the regeneration of conventional antioxidants. Oxidative stress occurs throughout life, not only contributing to the aging process in healthy individuals but also playing a causal role in many diseases. In particular, in immunocompromised elderly individuals, lipoic acid can induce and promote the development of numerous diseases, such as atherosclerosis, stroke, coronary heart disease, hypertension, Alzheimer's disease, diabetes, and Parkinson's disease. With aging, the body's antioxidant capacity decreases, accelerating the aging process.

[0007] Lipoic acid is one of the most potent known natural antioxidants. Its dual (water-soluble and fat-soluble) properties allow it to easily cross cell membranes and the blood-brain barrier, reaching brain tissue and exerting its antioxidant properties. Currently, as a potent antioxidant, lipoic acid is widely used in the prevention and adjunctive treatment of various heart diseases, diabetes, and neurodegenerative brain disorders such as Alzheimer's disease. It has a particularly beneficial effect in the treatment of various cerebrovascular and cardiovascular diseases.

[0008] Therefore, the prior art does not involve the synthesis of ibuprofen-lipoic acid cocrystals, and it is of great significance to study the synthesis of ibuprofen-lipoic acid cocrystals. Summary of the Invention

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

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

[0011] In a first aspect, the present invention provides an ibuprofen-α-lipoic acid cocrystal comprising ibuprofen and α-lipoic acid, wherein 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 ibuprofen-α-lipoic acid cocrystal has an X-ray powder diffraction (PXRD) pattern measured with 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°.

[0017] Preferably, 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° in the PXRD pattern. , 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°, and 35.37±0.2°, with characteristic peaks.

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

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

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

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

[0022] It is prepared from ibuprofen and α-lipoic acid using liquid-assisted grinding.

[0023] In one or more embodiments, the liquid is an organic solvent 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 comprises the following steps:

[0025] ibuprofen and α-lipoic acid were ball-milled in liquid to obtain ibuprofen-α-lipoic acid cocrystals;

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

[0027] The grinding can be achieved using a grinding jar or a ball mill, and the steps are as follows: placing ibuprofen and α-lipoic acid samples in a grinding jar, placing grinding balls (such as stainless steel grinding balls), and dropping a small amount of organic solvent into the grinding jar, or placing the grinding jar in a ball mill (such as a planetary ball mill BM6pro used in some embodiments of the present invention). After the run is completed, the grinding jar is removed and the sample is scraped off with a clean scraper to obtain the ibuprofen-α-lipoic acid cocrystal of the present invention.

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

[0029] Preferably, the ball mill is set to a 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 1-5 times.

[0030] According to the research and determination of the present invention, among the above preparation methods, the grinding method can greatly shorten the time and reduce the cost, and has a better industrial application prospect.

[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 cocrystal 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, readily available 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 into solid, semisolid or liquid forms, such as tablets, pills, powders, capsules, suspensions, etc., including preparations suitable for a variety of modes of administration, including but not limited to inhalation, oral, workplace, parenteral (including subcutaneous, intradermal, intramuscular and intravenous), implantable and transdermal administration. The most suitable route of administration depends on the duration of the subject's course of disease, the required treatment time, the nature and severity of the condition being treated, and the specific formulation used.

[0034] The above-mentioned excipients are usually not pharmaceutically active, but have a variety of useful properties, such as improving the stability, sterility, bioavailability and difficulty of formulation of the pharmaceutical composition. Some examples of suitable carriers or excipients are first required to be safe and compatible with the pharmaceutically active ingredient. Those skilled in the art can select from the ingredients routine in this area, such as lactose, glucose, sucrose, sorbitol, mannitol, starch, gum, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate and propylhydroxybenzoate, talc, magnesium stearate, polyethylene glycol, polyethylene glycol and mineral oil, etc. By preparing the pharmaceutical composition of the present invention, it is possible to achieve rapid release, sustained release or delayed release of the active ingredient after giving the patient by methods well known in the art.

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

[0036] When the above-mentioned 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, high fever caused by common cold and influenza, the ibuprofen-α-lipoic acid cocrystal or pharmaceutical composition should be an effective dose; the arthritis includes osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, etc.; the pain includes headache, joint pain, toothache, muscle pain, nerve pain, etc.

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

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

[0039] The "therapeutically effective amount" refers to the amount of the compound of the present invention or the amount of the pharmaceutical composition comprising the compound of the present invention, which, when administered to a subject, is sufficient to effectively treat an immunostimulatory agent-related disease. Such an amount will be sufficient to cause the biological or medical response of the tissue system or patient sought by the researcher or clinical staff. The therapeutically effective amount will generally vary according to the following factors, such as the compound and its biological activity, the pharmaceutical composition for administration, the time of administration, the route of administration, the compound excretion rate, the duration of treatment, the type of disease state or disorder treated and its severity, the drug used in combination with the compound of the present invention or used simultaneously, and the patient's age, weight, overall health, sex and diet, etc. Such a therapeutically effective amount can be routinely determined by those skilled in the art taking into account their own knowledge, the state of the art, and the disclosure.

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

[0041] Ibuprofen-α-lipoic acid cocrystals significantly improve the solubility and stability of ibuprofen, effectively reducing production, storage, and transportation costs. The cocrystals are prepared by a grinding method, which is simple, easy to operate, low-cost, and easy to promote on a large scale in industrial pharmaceuticals. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] The accompanying drawings, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0043] Figure 1 is an 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 a differential scanning calorimetry (DSC) chart of the ibuprofen-α-lipoic acid cocrystal prepared in Example 1 of the present invention;

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

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

[0047] Testing instruments and methods:

[0048] Powder X-ray diffraction (PXRD) was performed using a Bruker D8 Advance diffractometer, employing Cu-based Kα radiation at a voltage of 40 kV and a current of 40 mA. Peak positions were calibrated using the instrument's included standard samples before use. The acquisition software used was Diffrac Plus XRD Commander, and the analysis software used was MDI Jade 6.0. Samples were tested at room temperature, placed on a polystyrene slide. Detailed testing conditions were as follows: 2θ angle range: 3–40°; step size: 0.02°; speed: 0.1 s / step. Unless otherwise specified, samples were not ground prior to testing.

[0049] Differential scanning calorimetry (DSC) data were collected using a Mettler Toledo DSC1 differential scanning calorimeter. Both the instrument control and analysis software were built-in. The sample was heated from 30°C to 150°C at a rate of 10°C / min, while the software recorded the thermal changes during the heating process.

[0050] Thermogravimetric analysis (TGA) data were collected using a Mettler Toledo DSC1 / TGA instrument. Both the instrument control and analysis software were built-in. The sample was heated from 60°C to 400°C at a rate of 10°C / min under a 20 mL / min dry nitrogen atmosphere. The software simultaneously recorded the weight change during the heating process.

[0051] As with the various analytical techniques and data generated thereby, as described herein, the term "substantially" identical or similar means that a particular set of analytical data is sufficiently similar to the data disclosed herein, within acceptable scientific limits, to allow one skilled in the art to understand that the form of the compound is identical to the form of the present invention. Those skilled in the art will appreciate that certain analytical techniques, such as PXRD and DSC, do not always produce identical results due to instrumental variations, sample preparation, scientific errors, and the like. For example, even though the form of a sample is identical within generally accepted scientific principles, PXRD results (i.e., peak position, intensity, and / or presence of peaks) may vary slightly from sample to sample, due to, for example, orientation or different solvent or water content. Those skilled in the art are fully capable of examining the data as a whole to determine whether such differences indicate a different form, thereby determining whether the data is substantially similar to the analytical data disclosed herein. In this regard, as is commonly done in the scientific community, a literal comparison is not performed solely for the purpose of achieving differentiation, e.g., whether each peak of an exemplary PXRD spectrum disclosed herein is present in the compared data, in exactly the same position, and / or with exactly the same intensity. Rather, as described above, one skilled in the art will utilize generally recognized scientific principles to determine, based on the totality of the data, whether the data used for comparison and analysis represent the same or different forms of the co-crystals of aspirin and niacin disclosed herein.

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

[0053] like Figure 1As shown, the PXRD spectrum of ibuprofen-α-lipoic acid prepared in Example 1, the PXRD spectrum of ibuprofen and the PXRD spectrum of α-lipoic acid; from the PXRD spectrum of the prepared ibuprofen-α-lipoic acid cocrystal, it can be seen that the PXRD spectrum of the prepared ibuprofen-α-lipoic acid cocrystal is 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°, and 35.37±0.2°. The positions of these characteristic peaks are different from those of the PXRD spectra of both the raw material ibuprofen and the precursor α-lipoic acid, proving that a new phase has been generated.

[0054] like Figure 2 As shown, the DSC spectrum of the ibuprofen-α-lipoic acid cocrystal prepared in Example 1, the DSC spectrum of ibuprofen and the DSC spectrum of α-lipoic acid are shown; the melting point of the ibuprofen-α-lipoic acid cocrystal in the figure 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 the melting points of the raw material and the precursor, indicating that a new phase is generated.

[0055] like Figure 3 As shown, the TGA spectra of the ibuprofen-α-lipoic acid cocrystal prepared in Example 1, the TGA spectra of ibuprofen, and the TGA spectra of α-lipoic acid are shown. Under nitrogen atmosphere testing conditions, the thermogravimetric curve of the ibuprofen-α-lipoic acid cocrystal shows weight loss starting at 100°C and reaching 100% weight loss by 250°C. The thermogravimetric curve of the ibuprofen API shows weight loss starting at 110°C and reaching 100% weight loss by 242°C. This also demonstrates the formation of a new phase.

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

[0057] Example 1

[0058] Use an analytical balance to accurately weigh 1.03g of ibuprofen and 1.03g of α-lipoic acid in a 100mL grinding jar, add 0.2mL of anhydrous ethanol with a micropipette, and put in 20g of grinding balls. Place the grinding jar in a planetary ball mill BM6pro, set the speed to 250 rpm, set the grinding time to 5 minutes, with an interval of 1 minute, and cycle 4 times. After the run is completed, remove the grinding jar and scrape the sample with a clean scraper to obtain the ibuprofen-α-lipoic acid cocrystal. In the ibuprofen-α-lipoic acid cocrystal, its X-ray powder diffraction (PXRD) pattern is as follows Figure 1 Its differential scanning calorimetry (DSC) diagram is shown in Figure 2 As shown in the thermogravimetric analysis (TGA) diagram Figure 3 shown.

[0059] Example 2

[0060] Ibuprofen 1.03g and α-lipoic acid 1.03g were accurately weighed in a 100mL grinding jar using an analytical balance, and 0.2mL of tetrahydrofuran was added using a micropipette, followed by 25g of grinding balls. The grinding jar was placed in a planetary ball mill BM6pro, the speed was set to 300 rev / min, the grinding time was set to 4 minutes, the interval was 2 minutes, and the cycle was repeated 4 times. After the run was complete, the grinding jar was removed and the sample was scraped off with a cleaning scraper to obtain an ibuprofen-α-lipoic acid cocrystal. The results show that the eutectic PXRD, DSC, and TGA patterns are substantially consistent with those in Example 1, confirming that the eutectic structure is identical to that in Example 1.

[0061] Example 3

[0062] Ibuprofen 1.03g and α-lipoic acid 1.03g were accurately weighed in a 100mL grinding jar using an analytical balance, 0.2mL of methanol was added using a micropipette, and 18g of grinding balls were placed. The grinding jar was placed in a planetary ball mill BM6pro, the speed was set to 300 rpm, the grinding time was set to 4 minutes, the interval was 2 minutes, and the cycle was repeated 5 times. After the run was completed, the grinding jar was removed and the sample was scraped off with a cleaning scraper to obtain ibuprofen-α-lipoic acid cocrystal. It was verified that the PXRD, DSC, and TGA patterns of the cocrystal were substantially consistent with the spectra in Example 1, confirming that the cocrystal structure was identical to that in Example 1.

[0063] Example 4

[0064] Ibuprofen 1.03g and α-lipoic acid 1.03g were accurately weighed in a 100mL grinding jar using an analytical balance, 0.2mL of acetone was added using a micropipette, and 28g of grinding balls were placed. The grinding jar was placed in a planetary ball mill BM6pro, the speed was set to 250 rpm, the grinding time was set to 5 minutes, the interval was 1 minute, and the cycle was repeated 4 times. After the operation was completed, the grinding jar was removed and the sample was scraped off with a cleaning scraper to obtain ibuprofen-α-lipoic acid cocrystal. It was verified that the eutectic PXRD, DSC, and TGA patterns were substantially consistent with the spectra in Example 1, confirming that the eutectic structure was identical to that in Example 1.

[0065] Example 5

[0066] Ibuprofen 1.03g and α-lipoic acid 1.03g were accurately weighed in a 100mL grinding jar using an analytical balance, 0.2mL of isopropyl alcohol was added using a micropipette, and 25g of grinding balls were placed. The grinding jar was placed in a planetary ball mill BM6pro, the speed was set to 250 rpm, the grinding time was set to 4 minutes, the interval was 2 minutes, and the cycle was repeated 4 times. After the operation was completed, the grinding jar was removed and the sample was scraped off with a cleaning scraper to obtain ibuprofen-α-lipoic acid cocrystal. It was verified that the eutectic PXRD, DSC, and TGA patterns were substantially consistent with the spectra in Example 1, confirming that the eutectic structure was identical to that in Example 1.

[0067] Comparative Example 1

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

[0069] Comparative Example 2

[0070] Different from Example 1, α-lipoic acid was replaced with niacin, and a cocrystal product was formed, but the solubility was not improved, and was even slightly reduced. The specific solubility is shown in Table 1.

[0071] Comparative Example 3

[0072] Different from Example 1, no ibuprofen-α-lipoic acid cocrystal was obtained by the solvent evaporation method.

[0073] Experimental example

[0074] 1. Solubility determination:

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

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

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

[0078] Accurately measure the test sample solution and the reference sample solution, inject each solution into a HPLC instrument, and perform the HPLC analysis according to the above-described HPLC detection conditions. Record the chromatogram. Calculate the ibuprofen content in the test sample using the peak area using the external standard method. Solubility results are shown in Table 1.

[0079] Table 1 Solubility results

[0080]

[0081]

[0082] As shown in the results in 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: 100 mg of the ibuprofen-α-lipoic acid cocrystal obtained in Example 1 and 100 mg of the ibuprofen raw material were placed in different 20 ml volumetric flasks, placed in a stability incubator at 60° C. and 95%±5% humidity for 10 days and then taken out.

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

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

[0087] The conditions for HPLC detection were as follows: octadecylsilane bonded silica gel as the filler; acetonitrile-0.10 mol / L potassium dihydrogen phosphate solution (pH adjusted to 3.0 with phosphoric acid) as the mobile phase; detection wavelength of 256 nm; injection volume of 20 μl.

[0088] Accurately measure the test solution and control solution, inject each solution into a high-performance liquid chromatograph, and perform the test according to the above-mentioned HPLC test conditions. Record the chromatogram. Calculate the impurity content in the test sample using the self-control method. The test results for relevant substances are shown in Table 2.

[0089] Table 2 Test results of relevant substances

[0090]

[0091]

[0092] Wherein, the impurity E and impurity J refer to:

[0093]

[0094] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. An ibuprofen-α-lipoic acid cocrystal, characterized in that: The invention comprises ibuprofen and α-lipoic acid, wherein the molar ratio of ibuprofen to α-lipoic acid is (0.9-1.1):(0.9-1.1); The X-ray powder diffraction pattern of the ibuprofen-α-lipoic acid cocrystal measured by Cu-Kα ray is at a diffraction angle of 2 θ There are characteristic peaks at 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, wherein The ibuprofen-α-lipoic acid cocrystal has a PXRD pattern of 2 θ The angles are 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 There are characteristic peaks at .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°.

3. The ibuprofen-α-lipoic acid cocrystal according to claim 2, characterized in that The X-ray powder diffraction pattern of the ibuprofen-α-lipoic acid cocrystal is shown in FIG1 .

4. The ibuprofen-α-lipoic acid cocrystal according to claim 1, wherein The differential scanning calorimetry analysis chart of the ibuprofen-α-lipoic acid cocrystal shows a characteristic melting peak at 51.5±1°C.

5. The ibuprofen-α-lipoic acid cocrystal according to claim 4, characterized in that The differential scanning calorimetry analysis chart of the ibuprofen-α-lipoic acid cocrystal is shown in FIG2 .

6. The ibuprofen-α-lipoic acid cocrystal according to claim 1, wherein 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.

7. The ibuprofen-α-lipoic acid cocrystal according to claim 6, wherein The thermogravimetric analysis graph of the ibuprofen-α-lipoic acid co-crystal is shown in FIG3 .

8. A method for preparing the ibuprofen-α-lipoic acid cocrystal according to any one of claims 1 to 7, characterized in that: The following steps are involved: It is prepared using ibuprofen and α-lipoic acid as raw materials using liquid-assisted grinding; The liquid is an organic solvent selected from one or more of ethanol, methanol, isopropanol, tetrahydrofuran, acetone and acetonitrile; The liquid-assisted grinding method comprises the following steps: ibuprofen and α-lipoic acid were ball-milled in liquid to obtain ibuprofen-α-lipoic acid cocrystals; The mass of the grinding balls is 2-10 times the total mass of ibuprofen and α-lipoic acid; The ball mill is set to a speed of 100-1000 rpm; The grinding method is: grinding time is 1-5 minutes, interval is 1-5 minutes, and cycle is 1-5 times; 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.

9. The preparation method according to claim 8, characterized in that The organic solvent is ethanol.

10. The preparation method according to claim 8, characterized in that The mass of the grinding balls is 3-5 times the total mass of ibuprofen and α-lipoic acid.

11. The preparation method according to claim 8, characterized in that The ball mill is set to rotate at a speed of 200-300 rpm.

12. The preparation method according to claim 11, characterized in that The ball mill was set at a rotation speed of 250 rpm.

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

14. A pharmaceutical composition comprising the ibuprofen-α-lipoic acid cocrystal according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier or excipient.

15. Use of the ibuprofen-α-lipoic acid cocrystal according to any one of claims 1 to 7 and / or the pharmaceutical composition according to claim 14 in the preparation of a drug for treating arthritis, gout, primary dysmenorrhea, and a drug for relieving mild to moderate pain, common cold, and high fever caused by influenza.

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