Cariprazine and quercetin pharmaceutical co-crystal as well as preparation method and application thereof

Abstract

The invention relates to the technical field of pharmaceutical co-crystals, and particularly discloses a cariprazine and quercetin pharmaceutical co-crystal and a preparation method and application thereof.The cariprazine and quercetin pharmaceutical co-crystal is prepared by mixing cariprazine and quercetin according to the proportion, adding a good solvent n-propyl alcohol till complete dissolution, dropwise adding a poor solvent into the mixed solvent till the mixed solvent is in a supersaturated state to obtain a mixed solution, and then adding the mixed solution into a reaction kettle to obtain the cariprazine and quercetin pharmaceutical co-crystal. And volatilizing the solvent in the mixed solution by adopting a solvent evaporation crystallization method, so that the cariprazine and the quercetin form intermolecular hydrogen-bond interaction, and the cariprazine and quercetin pharmaceutical co-crystal is obtained. A powder dissolution experiment result of the cariprazine and quercetin eutectic crystal shows that the dissolution rate of the cariprazine is reduced compared with the release rate of a free drug under a neutral condition, and a potential slow release effect is shown, so that the cariprazine and quercetin pharmaceutical eutectic crystal can be prepared into a muscle injection, and the clinical application prospect is broad. The traditional Chinese medicine composition has the potential of treating schizophrenia for a long time and reducing muscle stimulation.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical cocrystals, and specifically to a cariprazine and quercetin pharmaceutical cocrystal, its preparation method and application. Background Art

[0002] Cariprazine is a novel atypical antipsychotic drug, belonging to a dopamine D2 / D3 receptor partial agonist and a 5-HT1A receptor partial agonist. It has a unique pharmacological mechanism of action, shows good efficacy for both positive and negative symptoms of schizophrenia, and has good tolerance, and has become a first-line drug for the treatment of schizophrenia.

[0003] Currently, cariprazine faces the common challenges in the treatment of mental diseases: patients with schizophrenia and bipolar disorder need to take medicine for a long time, but the compliance of short-acting formula drugs is poor, and frequent drug administration is required, which easily leads to recurrence of the disease. With the maturity of long-acting preparation technology, the clinical demand for a cariprazine long-acting preparation that can reduce the frequency of drug administration, improve patient compliance, and stabilize blood drug concentration is gradually increasing. Up to now, only Forest Laboratories has launched an oral cariprazine hydrochloride capsule, which needs to be administered daily to maintain its blood drug concentration; the high frequency of drug administration results in poor patient compliance and easy recurrence of the disease; therefore, a strategy for cariprazine with low adverse reactions and convenient long-term medication needs to be developed; for this purpose, a cariprazine and quercetin pharmaceutical cocrystal, its preparation method and application are provided. Summary of the Invention

[0004] The purpose of the present invention is to address the deficiencies of the prior art and provide a cariprazine and quercetin pharmaceutical cocrystal, its preparation method and application to solve the problems raised in the above background art.

[0005] To achieve the above purpose, the present invention provides the following technical solution: a cariprazine and quercetin pharmaceutical cocrystal.

[0006] As a preferred technical solution of the present invention, the cariprazine and quercetin pharmaceutical cocrystal is a triclinic system, and the space group is P-1, α = 69.3460(10)°, β = 84.9370(10)°, γ = 69.3460(10)°, The melting point of the cariprazine and quercetin pharmaceutical cocrystal is 135 - 160 °C.

[0007] A preparation method of the cariprazine and quercetin pharmaceutical cocrystal as described above, comprising the following steps:

[0008] Using cariprazine as the active drug and quercetin as the precursor, a good solvent was added to the mixture of cariprazine and quercetin and stirred until completely dissolved to obtain a clear solution. A poor solvent was added dropwise to the clear solution until it reached a supersaturated state to obtain a supersaturated mixture. Using the solvent evaporation crystallization method, the solvent in the supersaturated mixture was volatilized, and through intermolecular hydrogen bonding, a co-crystal of cariprazine and quercetin drugs was obtained.

[0009] As a preferred technical solution of the present invention, the good solvent is n-propanol; the poor solvent is n-heptane.

[0010] As a preferred technical solution of the present invention, the molar ratio of cariprazine to quercetin is 1:1 - 3.

[0011] As a preferred technical solution of the present invention, the dosage ratio of the mixture of cariprazine and quercetin to the good solvent is 1 mg:200 - 300 μL.

[0012] As a preferred technical solution of the present invention, the volume ratio of the good solvent to the poor solvent is 1:1 - 10.

[0013] As a preferred technical solution of the present invention, the temperature of dissolution is 20 - 70 °C.

[0014] As a preferred technical solution of the present invention, when the solvent is volatilized, the temperature is 5 - 35 °C and the relative humidity is 10% - 75%; the stirring is specifically heating to 40 - 65 °C and then stirring, and then filtering while it is hot. After adding the poor solvent dropwise until it reaches a supersaturated state, the filtrate is sealed with a film and left standing.

[0015] An application of a co-crystal of cariprazine and quercetin drugs as described above in the preparation of drugs for treating diseases or disorders such as schizophrenia, major depressive disorder, and bipolar disorder, characterized in that the drug is a long-acting injection containing the co-crystal of cariprazine and quercetin drugs.

[0016] Compared with the prior art, the beneficial effects of the present invention are:

[0017] In the present invention, a good solvent n-propanol was added to the mixture of cariprazine and quercetin and stirred until completely dissolved to obtain a clear solution. A poor solvent n-heptane was added dropwise to the clear solution until it reached a supersaturated state to obtain a supersaturated mixture. Using the solvent evaporation crystallization method, the solvent in the supersaturated mixture was volatilized, and through intermolecular hydrogen bonding, a co-crystal of cariprazine and quercetin drugs was obtained. The powder dissolution experiment of the co-crystal of cariprazine and quercetin drugs shows that the dissolution rate of cariprazine decreases compared with the release rate of the free drug under neutral conditions, showing a potential sustained-release effect. Therefore, by preparing the co-crystal of cariprazine and quercetin drugs into a muscle injection, there is the potential for long-term treatment of schizophrenia and reduction of muscle irritation. Brief Description of the Drawings

[0018] Figure 1 Powder X-ray diffraction patterns of cariprazine, quercetin, and the cariprazine and quercetin drug co-crystal of Example 1 of the present invention;

[0019] Figure 2 Differential scanning calorimetry diagrams of cariprazine, quercetin, and the cariprazine and quercetin drug co-crystal of Example 1 of the present invention;

[0020] Figure 3 Thermogravimetric analysis diagram of the cariprazine and quercetin drug co-crystal of Example 1 of the present invention;

[0021] Figure 4 Fourier transform infrared spectroscopy diagrams of cariprazine, quercetin, and the cariprazine and quercetin drug co-crystal of Example 1 of the present invention;

[0022] Figure 5 Molecular structure diagram of the cariprazine and quercetin drug co-crystal of Example 1 of the present invention;

[0023] Figure 6 Dissolution curves of cariprazine, the cariprazine and quercetin drug co-crystal of Example 1 of the present invention in a phosphate buffer solution at pH = 6.8;

[0024] Figure 7 Dissolution curves of cariprazine, the cariprazine and quercetin drug co-crystal of Example 1 of the present invention in a phosphate buffer solution at pH = 7.4. Detailed Description of the Invention

[0025] In order to enable those skilled in the art to better understand and implement the technical solutions of the present invention, the present invention will be further described below in conjunction with specific examples and drawings, but the examples given are not intended to limit the present invention. The following test methods and detection methods are all conventional methods unless otherwise specified; the reagents and raw materials are all commercially available unless otherwise specified.

[0026] A drug co-crystal refers to a crystalline material formed by the binding of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) through non-covalent interactions (such as hydrogen bonds, π-π stacking, etc.). As an emerging technology for improving the solid form of drugs, the drug co-crystal technology can adjust the physicochemical properties of drugs, such as solubility, dissolution rate, stability, bioavailability, etc., without changing the molecular structure of the drugs, thereby improving the efficacy and safety of drugs.

[0027] In view of the problems in the prior art that although the existing cariprazine pharmaceutical preparations can maintain the pharmacological activity of cariprazine, the poor compliance caused by the frequent dosing frequency and the easy recurrence of the disease, the present invention provides a cariprazine and quercetin drug cocrystal, its preparation method and application. Add a good solvent, n-propanol, to the mixture of cariprazine and quercetin and stir until completely dissolved to obtain a clear solution. Dropwise add a poor solvent, n-heptane, to the clear solution until it reaches a supersaturated state to obtain a supersaturated mixture. Using the solvent evaporation crystallization method, volatilize the solvent in the supersaturated mixture, and through intermolecular hydrogen bonding, obtain the cariprazine and quercetin drug cocrystal. While maintaining the pharmacological activity of cariprazine, its solubility and dissolution rate are reduced. Therefore, by preparing the cariprazine and quercetin drug cocrystal into a muscle injection, it has the potential for long-term treatment of schizophrenia and reducing muscle irritation.

[0028] The present invention uses cariprazine as the active substance and quercetin with antioxidant, anti-allergic and anti-inflammatory effects as the precursor. By means of drug cocrystals, the dissolution rate of cariprazine raw material drug is reduced, thereby prolonging the drug half-life, controlling the in-vivo blood drug concentration level and its fluctuation range, reducing the toxic and side effects after medication, and improving the medication compliance of patients.

[0029] The technical content of the present invention will be analyzed in detail below.

[0030] The present invention first provides a preparation method of a cariprazine and quercetin drug cocrystal, including the following steps: using cariprazine as the active drug and quercetin as the precursor, adding a good solvent, n-propanol, to the mixture of cariprazine and quercetin and stirring until completely dissolved to obtain a clear solution. Dropwise add a poor solvent, n-heptane, to the clear solution until it reaches a supersaturated state to obtain a supersaturated mixture. Using the solvent evaporation crystallization method, volatilize the solvent in the supersaturated mixture, and through intermolecular hydrogen bonding, obtain the cariprazine and quercetin drug cocrystal.

[0031] In order to obtain a cariprazine and quercetin drug cocrystal with higher yield and purity, the molar ratio of cariprazine to quercetin is 1:1 - 3. If it exceeds this value range, it is easy to precipitate single-drug crystals, thus affecting the cocrystal purity and yield.

[0032] To ensure the sufficient dissolution of cariprazine and quercetin and to enable the formation of co-crystals of cariprazine and quercetin as quickly as possible, the dosage ratio of the mixture of cariprazine and quercetin to n-propanol is 1 mg: 200 - 300 μL. If the dosage of n-propanol is less than 200 μL, cariprazine and quercetin cannot be sufficiently dissolved, so co-crystals cannot be formed; if the dosage of n-propanol is greater than 300 μL, the formation time of the co-crystals of cariprazine and quercetin is prolonged. The volume ratio of the good solvent to the poor solvent is 1:1 - 10. If it exceeds this range, single drug powder may precipitate, thus affecting the purity and yield of the co-crystals.

[0033] To ensure that the obtained co-crystals of cariprazine and quercetin drugs have a high yield and purity, the molar ratio of cariprazine to quercetin is 1:1, and the co-crystal yield and purity obtained at this molar ratio are the highest.

[0034] To further ensure the dissolution effect of the mixed drug of cariprazine and quercetin, the dissolution temperature is 20 - 70 °C. Temperatures below 20 °C or above 70 °C will affect the drug dissolution rate, thus unable to produce ideal drug co-crystals, and will also have a certain impact on the yield and purity of the produced drug co-crystals.

[0035] To obtain co-crystals of cariprazine and quercetin drugs in a shorter time, when the solvent evaporates, the temperature is 5 - 35 °C and the relative humidity is 10% - 75%. Too high or too low temperatures and humidity will affect the crystal precipitation rate.

[0036] To accelerate the dissolution of the mixed drug of cariprazine and quercetin, a stirring method is used for dissolution. Specifically, it is heated to 40 - 65 °C and stirred, then filtered while it is hot, and the poor solvent is added dropwise until it is supersaturated, and then the filtrate is sealed with a film and left standing.

[0037] The co-crystals of cariprazine and quercetin drugs prepared according to the preparation method provided above are triclinic,

[0038] the space group is P-1,

[0039] α = 69.3460(10)°, β = 84.9370(10)°,

[0040] γ = 69.3460(10)°, The technical effects of the present invention will be described below in combination with specific examples and comparative examples.

[0041] Example 1: A preparation method of cariprazine and quercetin drug cocrystal, comprising the following steps: using cariprazine as the active drug and quercetin as the precursor, mixing 427 mg of cariprazine (1 mmol) and 302 mg of quercetin (1 mmol) according to a molar ratio of 1:1 to obtain a mixture, adding 145.8 mL of n-propanol to the mixture and stirring according to a dosage ratio of 1 mg of the mixture of cariprazine and quercetin to 200 μL of n-propanol. The stirring is specifically heating to 40 °C and stirring, then filtering while it is hot, dropping a poor solvent until it is in a supersaturated state, then sealing the filtrate film and standing still. The solvent in the mixed solution is volatilized at 22 °C and 50% relative humidity, and a cariprazine and quercetin drug cocrystal is obtained through intermolecular hydrogen bonds.

[0042] Example 2: A preparation method of cariprazine and quercetin drug cocrystal, comprising the following steps: using cariprazine as the active drug and quercetin as the precursor, mixing 427 mg of cariprazine (1 mmol) and 453 mg of quercetin (1.5 mmol) according to a molar ratio of 1:1.5 to obtain a mixture, adding 176 mL of n-propanol to the mixture and stirring according to a dosage ratio of 1 mg of the mixture of cariprazine and quercetin to 200 μL of n-propanol. The stirring is specifically heating to 45 °C and stirring, then filtering while it is hot, dropping a poor solvent until it is in a supersaturated state, then sealing the filtrate film and standing still. The solvent in the mixed solution is volatilized at 25 °C and 65% relative humidity, and a cariprazine and quercetin drug cocrystal is obtained through intermolecular hydrogen bonds.

[0043] Example 3: A preparation method of cariprazine and quercetin drug cocrystal, comprising the following steps: using cariprazine as the active drug and quercetin as the precursor, mixing 427 mg of cariprazine (1 mmol) and 604 mg of quercetin (2 mmol) according to a molar ratio of 1:2 to obtain a mixture, adding 206.2 mL of n-propanol to the mixture and stirring according to a dosage ratio of 1 mg of the mixture of cariprazine and quercetin to 200 μL of n-propanol. The stirring is specifically heating to 50 °C and stirring, then filtering while it is hot, dropping a poor solvent until it is in a supersaturated state, then sealing the filtrate film and standing still. The solvent in the mixed solution is volatilized at 28 °C and 50% relative humidity, and a cariprazine and quercetin drug cocrystal is obtained through intermolecular hydrogen bonds.

[0044] Example 4: A preparation method of cariprazine and quercetin drug cocrystal, comprising the following steps: using cariprazine as the active drug and quercetin as the precursor, mixing 427 mg of cariprazine (1 mmol) and 755 mg of quercetin (2.5 mmol) according to a molar ratio of 1:2.5 to obtain a mixture, adding 236.4 mL of n-propanol to the mixture and stirring according to a dosage ratio of 1 mg of the mixture of cariprazine and quercetin to 200 μL of n-propanol. The stirring is specifically heating to 55 °C and stirring, then filtering while it is hot, dropping a poor solvent until it is supersaturated, sealing the filtrate film and standing still. The solvent in the mixed solution is volatilized at 26 °C and 70% relative humidity, and a cariprazine and quercetin drug cocrystal is obtained through intermolecular hydrogen bonds.

[0045] Example 5: A preparation method of cariprazine and quercetin drug cocrystal, comprising the following steps: using cariprazine as the active drug and quercetin as the precursor, mixing 427 mg of cariprazine (1 mmol) and 906 mg of quercetin (3 mmol) according to a molar ratio of 1:3 to obtain a mixture, adding 266.6 mL of n-propanol to the mixture and stirring according to a dosage ratio of 1 mg of the mixture of cariprazine and quercetin to 200 μL of n-propanol. The stirring is specifically heating to 65 °C and stirring, then filtering while it is hot, dropping a poor solvent until it is supersaturated, sealing the filtrate film and standing still. The solvent in the mixed solution is volatilized at 29 °C and 63% relative humidity, and a cariprazine and quercetin drug cocrystal is obtained through intermolecular hydrogen bonds. To further illustrate the technical effects of the present invention, a comparative example is also set in the present invention, which is specifically as follows:

[0046] Comparative Example 1: Compared with Example 1, only cariprazine is used.

[0047] Comparative Example 2: Compared with Example 1, only quercetin is used.

[0048] I. The solubility and stability of the cariprazine and quercetin drug cocrystals prepared in the above Examples 1-5, the cariprazine in Comparative Example 1, and the quercetin in Comparative Example 2 are tested, and the specific process is as follows:

[0049] 1. Solubility

[0050] Take equal amounts of cariprazine in Comparative Example 1, quercetin in Comparative Example 2, and the cariprazine and quercetin drug cocrystal in Example 1, respectively place them in 500 mL of dissolution medium, and place them in a constant temperature water bath at 37 ± 0.5 °C with a rotation speed of 100 rpm. After equilibration for 24 h, samples are taken at certain time points. After filtering with a 0.22 microporous filter membrane while keeping warm, it is determined according to the HPLC condition method for determining cariprazine. The results show that the solubility of cariprazine in the cariprazine and quercetin drug cocrystal decreases under different pH conditions.

[0051] 2. Stability

[0052] The stability of the cariprazine and quercetin drug cocrystal prepared in the examples of the present invention was salt-baked. The cariprazine / quercetin drug cocrystal was divided into three portions and placed in clean glass bottles, which were loosely sealed with plastic screw caps. Then the samples were placed on a tray and subjected to stress testing under the conditions of high temperature (60 °C), high humidity (92.5% RH), and strong light (4500 LX).

[0053] II. As Figure 1 shown, the X-ray powder diffraction patterns (PXRD) of the cariprazine and quercetin drug cocrystals prepared in the above Examples 1-5, cariprazine of Comparative Example 1, and quercetin of Comparative Example 2;

[0054] Characteristic peaks are present at diffraction angles of 10.72°, 12.96°, 15.14°, 15.85°, 17.02°, 18.36°, 19.45°, 20.40°, 21.08°, 22.48°, 23.52°, 24.61°, 25.65°, 26.01°, 27.18°, 28.25°, 29.69°, 30.72°, 31.58°, 32.65°, 33.54°, 35.32°, 36.45°, 39.4°, 46.29°. The peak positions of these characteristic peaks are different from the PXRD patterns of cariprazine and quercetin, proving the formation of a new crystal phase.

[0055] III. As Figure 2 shown, the differential scanning calorimetry (DSC) curves of the cariprazine and quercetin drug cocrystals prepared in the above Examples 1-5, cariprazine of Comparative Example 1, and quercetin of Comparative Example 2;

[0056] The melting points of the cariprazine and quercetin drug cocrystals are different from those of cariprazine and quercetin. The cocrystal formed by cariprazine and quercetin in n-propanol solvent has an endothermic peak at 149.7 °C, proving the formation of a new phase.

[0057] IV. As Figure 3 shown, the thermogravimetric analysis (TGA) curves of the cariprazine and quercetin drug cocrystals prepared in the above Examples 1-5, cariprazine of Comparative Example 1, and quercetin of Comparative Example 2;

[0058] The thermogravimetric curve of the cariprazine and quercetin drug cocrystal shows two weight loss steps. The first weight loss occurs at 53.6 °C, and the weight lost is 4.7%. This may be due to the rapid loss of about 1.5 water molecules by the cariprazine and quercetin cocrystal at around 53.6 °C. The second weight loss occurs at 151.2 °C, which is related to the degradation of the cocrystal framework composed of cariprazine molecules and quercetin molecules.

[0059] V. As shown in Figure 4 Figure 3, the infrared spectra (IR) of the cariprazine and quercetin drug co-crystals prepared in the above Examples 1-5, cariprazine of Comparative Example 1, and quercetin of Comparative Example 2;

[0060] The infrared spectra (IR) of the cariprazine and quercetin drug co-crystals prepared in the Examples of the present invention, cariprazine of Comparative Example 1, and quercetin of Comparative Example 2, as shown in Figure 4 Figure 4, due to intermolecular hydrogen bonding, groups such as C=O in cariprazine and OH in quercetin are shifted in the IR spectra of the cariprazine co-crystals.

[0061] VI. As shown in Figure 5 Figure 5, the structural spectra of the cariprazine and quercetin drug co-crystals prepared in the above Examples 1-5;

[0062] The molecular structure spectra of the cariprazine and quercetin drug co-crystals prepared in the Examples of the present invention, as shown in Figure 5 Figure 6, the cariprazine molecule, quercetin molecule, and water molecule are hydrogen-bonded in a ratio of 1:1:2.

[0063] VII. As shown in Figures 6-7 Figure 7, the dissolution rate curves of the cariprazine and quercetin drug co-crystals prepared in the above Examples 1-5 and cariprazine of Comparative Example 1;

[0064] The dissolution rate curves of the cariprazine and quercetin drug co-crystals prepared in the Examples of the present invention and cariprazine of Comparative Example 1 in a phosphate buffer solution at pH = 6.8; as shown in Figure 6 Figure 8, the solubility and dissolution rate of the cariprazine and quercetin drug co-crystals provided by the present invention in a phosphate buffer salt at pH = 6.8 and 37°C are lower than those of pure cariprazine.

[0065] The dissolution rate curves of the cariprazine and quercetin drug co-crystals prepared in the Examples of the present invention and cariprazine of Comparative Example 1 in a phosphate buffer solution at pH = 7.4, as shown in Figure 7 Figure 9, the solubility and dissolution rate of the cariprazine and quercetin drug co-crystals provided by the present invention in a phosphate buffer salt at pH = 7.4 and 37°C are lower than those of pure cariprazine.

[0066] The above examples only illustrate the implementation modes of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can be made, and these all fall within the protection scope of the present invention.

Claims

1. A cariprazine and quercetin drug cocrystal.

2. The cariprazine and quercetin pharmaceutical cocrystal according to claim 1, wherein, The cariprazine and quercetin drug co-crystal is triclinic with the space group P-1, α = 69.3460(10)°, β = 84.9370(10)°, γ = 69.3460(10)°, The melting point of the cariprazine and quercetin drug co-crystal is 135 - 160 °C.

3. A preparation method of the cariprazine and quercetin drug cocrystal according to any one of claims 1-2, characterized in that: It includes the following steps: Using cariprazine as the active drug and quercetin as the precursor, adding a good solvent to the mixture of cariprazine and quercetin and stirring until completely dissolved to obtain a clear solution, dropwise adding a poor solvent to the clear solution until it reaches a supersaturated state to obtain a supersaturated mixed solution. Using the solvent evaporation crystallization method, volatilize the solvent in the supersaturated mixed solution, and through intermolecular hydrogen bonding, obtain the cariprazine and quercetin drug cocrystal.

4. The preparation method of the cariprazine and quercetin drug cocrystal according to claim 3, wherein: The good solvent is n-propanol; the poor solvent is n-heptane.

5. The preparation method of the cariprazine and quercetin drug cocrystal according to claim 4, characterized in that: The molar ratio of cariprazine to quercetin is 1:1 - 3.

6. The preparation method of the cariprazine and quercetin drug cocrystal according to claim 5, characterized in that: The dosage ratio of the mixture of cariprazine and quercetin to the good solvent is 1 mg:200 - 300 μL.

7. The preparation method of the cariprazine and quercetin drug cocrystal according to claim 6, characterized in that: The volume ratio of the good solvent to the poor solvent is 1:1 - 10.

8. The preparation method of the cariprazine and quercetin drug co-crystal according to claim 3, characterized in that: The temperature of dissolution is 20 - 70 °C.

9. The preparation method of the cariprazine and quercetin drug co-crystal according to claim 3, wherein: When the solvent is volatilized, the temperature is 5 - 35 °C and the relative humidity is 10% - 75%; the stirring is specifically heating to 40 - 65 °C and then stirring, then filtering while it is hot, dropwise adding the poor solvent until it reaches a supersaturated state, and then sealing the filtrate film and standing still.

10. Use of the cariprazine and quercetin drug cocrystal according to any one of claims 1-2 in the preparation of a drug for treating a disease or disorder such as schizophrenia, major depressive disorder and bipolar disorder, characterized in that, The drug is a long-acting injection containing the cariprazine and quercetin drug cocrystal.

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