Cariprazine and quercetin pharmaceutical co-crystal, and preparation method and application thereof
By preparing cocrystals of cariprazine and quercetin, the problem of frequent dosing of cariprazine was solved, enabling long-term treatment of schizophrenia and bipolar disorder, and improving patient compliance and safety.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- JIANGSU OCEAN UNIV
- Filing Date
- 2025-04-03
- Publication Date
- 2026-05-29
AI Technical Summary
Existing cariprazine medications require frequent administration, leading to poor patient compliance and frequent relapses. There is an urgent need for long-acting formulations.
Cariprazine and quercetin cocrystals were prepared by adding a good solvent, n-propanol, and a poor solvent, n-heptane, to form intermolecular hydrogen bonds, thereby reducing their solubility and dissolution rate, and preparing a long-acting injection.
It achieves long-term therapeutic effects of cariprasin, reduces the frequency of medication, improves patient compliance, reduces muscle stimulation, controls fluctuations in blood drug concentration, and reduces toxic side effects.
Smart Images
Figure CN120289405B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of drug cocrystallization technology, specifically to a drug cocrystallization of cariprazine and quercetin, its preparation method, and its application. Background Technology
[0002] Cariprazine is a novel atypical antipsychotic drug, belonging to the dopamine D2 / D3 receptor partial agonist and 5-HT1A receptor partial agonist classes. It possesses a unique pharmacological mechanism of action, demonstrating good efficacy against both positive and negative symptoms of schizophrenia, and is well-tolerated, making it a first-line treatment for schizophrenia.
[0003] Currently, caliprazine faces a common challenge in the treatment of mental illnesses: patients with schizophrenia and bipolar disorder require long-term medication, but short-acting formulations have poor adherence, requiring frequent dosing and easily leading to relapse. With the maturation of long-acting formulation technology, the clinical demand for long-acting caliprazine formulations that can reduce dosing frequency, improve patient adherence, and stabilize blood drug concentrations is gradually increasing. To date, only Forest Laboratories has marketed an oral caliprazine hydrochloride capsule, which requires daily dosing to maintain its blood drug concentration; this excessively high dosing frequency leads to poor patient adherence and a high risk of relapse. Therefore, there is a need to develop a strategy for caliprazine with low adverse reactions and convenient long-term use; this paper presents a caliprazine and quercetin cocrystal, its preparation method, and its application. Summary of the Invention
[0004] The purpose of this invention is to address the deficiencies of the prior art by providing a cocrystal of cariprazine and quercetin, its preparation method, and its application, thereby solving the problems raised in the background art.
[0005] To achieve the above objectives, the present invention provides the following technical solution: a cocrystal of cariprazine and quercetin.
[0006] In a preferred embodiment of the present invention, the caliracil and quercetin drug eutectic is triclinic with space group P-1. α=69.3460(10)°, β=84.9370(10)°, γ=69.3460(10)°, The melting point of the caliprazine and quercetin drug eutectic is 135-160℃.
[0007] A method for preparing a drug cocrystal of cariprazine and quercetin as described above includes the following steps:
[0008] Using cariprazine as the active drug and quercetin as the precursor, a good solvent was added to a mixture of cariprazine and quercetin and stirred until completely dissolved to obtain a clear solution. A poor solvent was then added dropwise to the clear solution until it reached a supersaturated state to obtain a supersaturated mixture. The solvent in the supersaturated mixture was evaporated by solvent evaporation crystallization, and a cocrystal of cariprazine and quercetin was obtained through intermolecular hydrogen bonding.
[0009] In a preferred embodiment of the present invention, the good solvent is n-propanol; the poor solvent is n-heptane.
[0010] As a preferred embodiment of the present invention, the molar ratio of cariprazine to quercetin is 1:1-3.
[0011] As a preferred embodiment of the present invention, the ratio of the mixture of cariprazine and quercetin to a good solvent is 1 mg: 200-300 μL.
[0012] As a preferred embodiment of the present invention, the volume ratio of the good solvent to the poor solvent is 1:1-10.
[0013] As a preferred embodiment of the present invention, the melting temperature is 20-70℃.
[0014] As a preferred technical solution of the present invention, the temperature is 5-35℃ and the relative humidity is 10%-75% when the solvent evaporates; the stirring is specifically carried out by heating to 40-65℃ and then stirring, then filtering while hot, adding undesirable solvent dropwise until supersaturation, and then sealing the filtrate and letting it stand.
[0015] The use of the cariprazine and quercetin cocrystal as described above in the preparation of a drug for treating schizophrenia, major depressive disorder and bipolar disorder, characterized in that the drug is a long-acting injectable containing the cariprazine and quercetin cocrystal.
[0016] Compared with the prior art, the beneficial effects of the present invention are:
[0017] This invention involves adding the good solvent n-propanol to a mixture of cariprazine and quercetin and stirring until completely dissolved to obtain a clear solution. Then, the unsuitable solvent n-heptane is added dropwise to the clear solution until supersaturation, resulting in a supersaturated mixture. The solvent in the supersaturated mixture is evaporated using a solvent evaporation crystallization method, and a cocrystal of cariprazine and quercetin is obtained through intermolecular hydrogen bonding. Powder dissolution experiments of the cariprazine and quercetin cocrystal show that the dissolution rate of cariprazine is lower than the release rate of the free drug under neutral conditions, exhibiting a potential sustained-release effect. Therefore, the cocrystal of cariprazine and quercetin can be prepared into an intramuscular injection with the potential for long-term treatment of schizophrenia and reduction of muscle stimulation. Attached Figure Description
[0018] Figure 1 Powder X-ray diffraction patterns of the drug cocrystals of cariprazine, quercetin, and cariprazine and quercetin of Example 1 of the present invention;
[0019] Figure 2 Differential scanning calorimetry (DSC) images of the cariprazine, quercetin, and the cariprazine and quercetin cocrystal of Example 1 of the present invention;
[0020] Figure 3 Thermogravimetric analysis diagram of the drug cocrystal of cariprazine and quercetin in Example 1 of the present invention;
[0021] Figure 4 Fourier transform infrared spectra of the drug cocrystals of cariprazine, quercetin, and cariprazine and quercetin of Example 1 of the present invention;
[0022] Figure 5 This is a molecular structure diagram of the drug cocrystal of cariprazine and quercetin in Example 1 of the present invention;
[0023] Figure 6 The dissolution curves of the cocrystal of caliprazine of the present invention, caliprazine of Example 1, and quercetin in a phosphate buffer solution at pH 6.8 are shown.
[0024] Figure 7 The dissolution curves of the cocrystal of cariprazine of the present invention, cariprazine of Example 1, and quercetin in phosphate buffer solution at pH 7.4 are shown. Detailed Implementation
[0025] To enable those skilled in the art to better understand and implement the technical solutions of this invention, the invention will be further described below with reference to specific embodiments and accompanying drawings. However, the embodiments described are not intended to limit the invention. Unless otherwise specified, the following test methods and detection methods are conventional methods; unless otherwise specified, the reagents and raw materials are commercially available.
[0026] Drug cocrystals refer to crystalline materials formed by the bonding of active pharmaceutical ingredient (API) and cocrystal form (CCF) through non-covalent interactions (such as hydrogen bonds, π-π stacking, etc.). As an emerging technology for improving the solid-state form of drugs, drug cocrystal technology can regulate the physicochemical properties of drugs, such as solubility, dissolution rate, stability, and bioavailability, without altering the drug's molecular structure, thereby improving the efficacy and safety of the drug.
[0027] To address the issues mentioned in the background art regarding existing caliprazine drug formulations, which, while maintaining the pharmacological activity of caliprazine, suffer from poor compliance and frequent relapses due to frequent dosing, this invention provides a caliprazine and quercetin cocrystal, its preparation method, and its application. The method involves adding the good solvent n-propanol to a mixture of caliprazine and quercetin and stirring until completely dissolved to obtain a clear solution. Then, the unsuitable solvent n-heptane is added dropwise to the clear solution until supersaturation, resulting in a supersaturated mixture. The solvent in the supersaturated mixture is evaporated using a solvent evaporation crystallization method, and the caliprazine and quercetin cocrystal is obtained through intermolecular hydrogen bonding. This method maintains the pharmacological activity of caliprazine while reducing its solubility and dissolution rate. Therefore, by preparing the caliprazine and quercetin cocrystal into an intramuscular injection, it has the potential for long-term treatment of schizophrenia and reduction of muscle stimulation.
[0028] This invention uses cariprazine as the active substance and quercetin, which has antioxidant, anti-allergic, and anti-inflammatory effects, as a precursor. By using drug co-crystallization, the dissolution rate of cariprazine raw material is reduced, thereby prolonging the drug half-life, controlling the blood drug concentration level and its fluctuation range in vivo, reducing the toxic side effects after medication, and improving patient medication compliance.
[0029] The technical content of the present invention will be analyzed in detail below.
[0030] This invention first provides a method for preparing a cocrystal of cariprazine and quercetin, comprising the following steps: using cariprazine as the active drug and quercetin as the precursor, adding the good solvent n-propanol to a mixture of cariprazine and quercetin and stirring until completely dissolved to obtain a clear solution; adding the poor solvent n-heptane dropwise to the clear solution until supersaturated to obtain a supersaturated mixture; and using a solvent evaporation crystallization method to evaporate the solvent in the supersaturated mixture, thereby obtaining the cocrystal of cariprazine and quercetin through intermolecular hydrogen bonding.
[0031] In order to obtain a cocrystal of cariprazine and quercetin with high yield and purity, the molar ratio of cariprazine to quercetin is 1:1-3. If it exceeds this range, single drug crystals are easily precipitated, which will affect the purity and yield of the cocrystal.
[0032] To ensure complete dissolution of cariprazine and quercetin and to facilitate the rapid formation of the co-crystal, the ratio of the cariprazine / quercetin mixture to n-propanol is 1 mg: 200-300 μL. If the amount of n-propanol is less than 200 μL, cariprazine and quercetin will not dissolve sufficiently, thus preventing co-crystal formation. If the amount of n-propanol is greater than 300 μL, the co-crystal formation time of cariprazine and quercetin will be prolonged. The volume ratio of the good solvent to the poor solvent is 1:1-10. Exceeding this range may result in the precipitation of single-drug powder, thus affecting the purity and yield of the co-crystal.
[0033] To ensure high yield and purity of the obtained cariprazine and quercetin cocrystal, the molar ratio of cariprazine to quercetin is 1:1, at which the cocrystal yield and purity are highest.
[0034] To further ensure the dissolution effect of the cariprazine and quercetin mixture, the dissolution temperature is 20-70℃. Temperatures below 20℃ or above 70℃ will affect the drug dissolution rate, thus failing to produce ideal drug cocrystals, and the yield and purity of the produced drug cocrystals will be affected to some extent.
[0035] To obtain cariprazine and quercetin cocrystals in a short time, the temperature during solvent evaporation should be 5-35℃ and the relative humidity 10%-75%. Excessively high or low temperatures and humidity will affect the crystal precipitation rate.
[0036] To accelerate the dissolution of the cariprazine and quercetin mixture, a stirring method was used. Specifically, the mixture was heated to 40-65°C and stirred, then filtered while hot. After adding a poor solvent until it reached supersaturation, the filtrate was sealed and allowed to stand.
[0037] The caliprazine and quercetin cocrystal prepared according to the above-described preparation method is a triclinic crystal.
[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 with reference to specific embodiments and comparative examples.
[0041] Example 1: A method for preparing a cocrystal of cariprazine and quercetin, comprising the following steps: using cariprazine as the active drug and quercetin as the precursor, 427 mg of cariprazine (1 mmol) and 302 mg of quercetin (1 mmol) are mixed in a 1:1 molar ratio to obtain a mixture. 145.8 mL of n-propanol is added to the mixture at a ratio of 1 mg:200 μL to the cariprazine and quercetin mixture and stirred. Specifically, the stirring is performed by heating to 40°C and stirring. The mixture is then filtered while hot, and a poor solvent is added dropwise until supersaturation is achieved. The filtrate is then sealed and allowed to stand. The solvent in the mixture is evaporated at 22°C and 50% relative humidity, and the cocrystal of cariprazine and quercetin is obtained through intermolecular hydrogen bonding.
[0042] Example 2: A method for preparing a cocrystal of cariprazine and quercetin, comprising the following steps: using cariprazine as the active drug and quercetin as the precursor, 427 mg of cariprazine (1 mmol) and 453 mg of quercetin (1.5 mmol) are mixed at a molar ratio of 1:1.5 to obtain a mixture. 176 mL of n-propanol is added to the mixture at a volume ratio of 1 mg:200 μL to n-propanol and stirred. Specifically, the stirring is performed by heating to 45°C and stirring. The mixture is then filtered while hot, and a poor solvent is added dropwise until supersaturation is achieved. The filtrate is then sealed and allowed to stand. The solvent in the mixture is evaporated at 25°C and 65% relative humidity, and the cocrystal of cariprazine and quercetin is obtained through intermolecular hydrogen bonding.
[0043] Example 3: A method for preparing a cocrystal of cariprazine and quercetin, comprising the following steps: using cariprazine as the active drug and quercetin as the precursor, 427 mg of cariprazine (1 mmol) and 604 mg of quercetin (2 mmol) are mixed in a molar ratio of 1:2 to obtain a mixture. 206.2 mL of n-propanol is added to the mixture at a ratio of 1 mg:200 μL to the cariprazine and quercetin mixture and stirred. Specifically, the stirring is performed by heating to 50°C and stirring. The mixture is then filtered while hot, and a poor solvent is added dropwise until supersaturation is achieved. The filtrate is then sealed and allowed to stand. The solvent in the mixture is evaporated at 28°C and 50% relative humidity, and the cocrystal of cariprazine and quercetin is obtained through intermolecular hydrogen bonding.
[0044] Example 4: A method for preparing a cocrystal of cariprazine and quercetin, comprising the following steps: using cariprazine as the active drug and quercetin as the precursor, 427 mg of cariprazine (1 mmol) and 755 mg of quercetin (2.5 mmol) are mixed at a molar ratio of 1:2.5 to obtain a mixture. 236.4 mL of n-propanol is added to the mixture at a volume ratio of 1 mg:200 μL to n-propanol and stirred. Specifically, the stirring is performed by heating to 55°C and stirring. The mixture is then filtered while hot, and a poor solvent is added dropwise until supersaturation is achieved. The filtrate is then sealed and allowed to stand. The solvent in the mixture is evaporated at 26°C and 70% relative humidity, and the cocrystal of cariprazine and quercetin is obtained through intermolecular hydrogen bonding.
[0045] Example 5: A method for preparing a cocrystal of caliprazine and quercetin, comprising the following steps: using caliprazine as the active drug and quercetin as the precursor, 427 mg of caliprazine (1 mmol) and 906 mg of quercetin (3 mmol) are mixed in a molar ratio of 1:3 to obtain a mixture. 266.6 mL of n-propanol is added to the mixture at a ratio of 1 mg:200 μL of the caliprazine and quercetin mixture to n-propanol, and the mixture is stirred while heated to 65°C. The mixture is then filtered while hot, and a poor solvent is added dropwise until supersaturation is achieved. The filtrate is then sealed and allowed to stand. The solvent in the mixture is evaporated at 29°C and 63% relative humidity, and the cocrystal of caliprazine and quercetin is obtained through intermolecular hydrogen bonding. To further illustrate the technical effects of the present invention, a comparative example is also provided, as follows:
[0046] Comparative Example 1: Compared with Example 1, only cariprazine was used.
[0047] Comparative Example 2: Compared with Example 1, only quercetin was used.
[0048] I. The solubility and stability of the cariprazine and quercetin cocrystals prepared in Examples 1-5 above, as well as cariprazine in Comparative Example 1 and quercetin in Comparative Example 2, were tested. The specific process is as follows:
[0049] 1. Solubility
[0050] Equal amounts of cariprazine (Comparative Example 1), quercetin (Comparative Example 2), and the cariprazine and quercetin cocrystal of Example 1 were placed in 500 mL of dissolution medium and placed in a constant temperature water bath at 37 ± 0.5 °C with a rotation speed of 100 rpm for 24 h. Samples were taken at certain time points, filtered through a 0.22 microporous membrane, and determined according to the HPLC method for determining cariprazine. The results showed that the solubility of cariprazine in the cariprazine and quercetin cocrystal decreased under different pH conditions.
[0051] 2. Stability
[0052] The stability of the cariprazine / quercetin cocrystal prepared in the embodiments of the present invention was tested by salt curing. The cariprazine / quercetin cocrystal was divided into three portions and placed in clean glass bottles. The glass bottles were loosely sealed with plastic screw caps. The samples were then placed on a tray and subjected to influence factor tests under high temperature (60°C), high humidity (92.5% RH) and strong light (4500 LX) conditions.
[0053] II. Figure 1 The X-ray powder diffraction (PXRD) patterns of the cocrystal of cariprazine and quercetin prepared in Examples 1-5 above, as well as cariprazine in Comparative Example 1 and quercetin in Comparative Example 2, are shown.
[0054] Characteristic peaks were observed 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°, and 46.29°. The elution positions of these characteristic peaks differed from those of carilarazine and quercetin in the PXRD spectra, indicating the formation of a new crystalline phase.
[0055] III. Figure 2 The differential thermal spectra (DSCs) of the cariprazine and quercetin drug cocrystals prepared in Examples 1-5 above, as well as cariprazine in Comparative Example 1 and quercetin in Comparative Example 2, are shown.
[0056] The melting point of the eutectic of cariprazine and quercetin is different from that of cariprazine and quercetin. The eutectic formed by cariprazine and quercetin in n-propanol solvent has an endothermic peak at 149.7℃, which proves that a new phase is formed.
[0057] IV. Figure 3 The thermogravimetric analysis (TGA) spectra of the cocrystals of cariprazine and quercetin prepared in Examples 1-5 above, and cariprazine in Comparative Example 1 and quercetin in Comparative Example 2 are shown.
[0058] The thermogravimetric curves of the caliprazine and quercetin cocrystals showed two weight loss steps. The first weight loss occurred at 53.6℃, with a weight loss of 4.7%, which may be due to the rapid loss of about 1.5 water molecules in the caliprazine and quercetin cocrystal at around 53.6℃. The second weight loss occurred at 151.2℃, which is related to the degradation of the cocrystal framework composed of caliprazine and quercetin molecules.
[0059] V. For example Figure 4 The infrared (IR) spectra of the cariprazine and quercetin drug cocrystals prepared in Examples 1-5 above, as well as cariprazine in Comparative Example 1 and quercetin in Comparative Example 2, are shown.
[0060] The infrared (IR) spectra of the cariprazine and quercetin cocrystals prepared in the embodiments of the present invention, and those of cariprazine in Comparative Example 1 and quercetin in Comparative Example 2, are as follows: Figure 4 As shown, due to intermolecular hydrogen bonding, the C=O groups in cariprazine and the OH groups in quercetin are shifted in the IR spectrum of the cariprazine eutectic.
[0061] VI. For example Figure 5 The image shows the structural diagrams of the cariprazine and quercetin drug cocrystals prepared in Examples 1-5 above.
[0062] The molecular structure spectrum of the cocrystal of cariprazine and quercetin prepared in the embodiments of the present invention is shown in the figure below. Figure 5 As shown, caliracil, quercetin, and water molecules are linked by hydrogen bonds in a 1:1:2 ratio.
[0063] VII. For example Figure 6-7 The dissolution rate curves of the cariprazine and quercetin drug cocrystals prepared in Examples 1-5 and the cariprazine in Comparative Example 1 are shown.
[0064] The dissolution rate curves of the caliprazine and quercetin cocrystal prepared in the embodiments of the present invention and the caliprazine of Comparative Example 1 in phosphate buffer solution at pH 6.8 are shown below. Figure 6 As shown, the solubility and dissolution rate of the cariprazine and quercetin cocrystal provided by this invention in a phosphate buffer at 37°C and pH 6.8 are lower than those of pure cariprazine.
[0065] The dissolution rate curves of the caliprazine and quercetin cocrystal prepared in the embodiments of the present invention and the caliprazine of Comparative Example 1 in phosphate buffer solution at pH 7.4 are shown below. Figure 7 As shown, the solubility and dissolution rate of the cariprazine and quercetin cocrystal provided by this invention in a phosphate buffer at 37°C and pH 7.4 are lower than those of pure cariprazine.
[0066] The above embodiments merely illustrate implementation methods of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention.
Claims
1. A drug cocrystal of cariprazine and quercetin, characterized in that: The caliracil and quercetin drug eutectic is triclinic, space group P-1, a=11.7290(2) Å, b=12.3179(2) Å, c=14.6894(2) Å, α=69.3460(10)°, β=84.9370(10)°, γ=69.3460(10)°, V=1862.37(6) Å 3 The melting point of the eutectic drug calcipocyanate and quercetin is 135-160 °C.
2. A method for preparing the drug cocrystal of cariprazine and quercetin as described in claim 1, characterized in that: Includes the following steps: Using cariprazine as the active drug and quercetin as the precursor, a good solvent was added to a mixture of cariprazine and quercetin and stirred until completely dissolved to obtain a clear solution. A poor solvent was then added dropwise to the clear solution until it reached a supersaturated state to obtain a supersaturated mixture. The solvent in the supersaturated mixture was evaporated by solvent evaporation crystallization, and a cocrystal of cariprazine and quercetin was obtained through intermolecular hydrogen bonding. The good solvent is n-propanol; the poor solvent is n-heptane; The molar ratio of cariprazine to quercetin is 1:1-3; The ratio of the mixture of cariprazine and quercetin to a good solvent is 1 mg: 200-300 µL; When the solvent evaporates, the temperature is 5-35 ℃ and the relative humidity is 10%-75%; the stirring is carried out by heating to 40-65 ℃ and then stirring, then filtering while hot, adding undesirable solvent dropwise until supersaturation, then sealing the filtrate and letting it stand.
3. The method for preparing the cariprazine and quercetin cocrystal according to claim 2, characterized in that: The volume ratio of the good solvent to the bad solvent is 1:1-10.
4. The method for preparing the cariprazine and quercetin cocrystal according to claim 2, characterized in that: The melting temperature is 20-70 ℃.
5. The use of the cariprazine and quercetin cocrystal as described in claim 1 in the preparation of a drug for treating schizophrenia, major depressive disorder, and bipolar disorder, characterized in that, The drug is a long-acting injectable formulation containing a cocrystal of cariprazine and quercetin.