New crystal form of quinidine sulfate and preparation method thereof
The problem of quinidine sulfate crystal form preparation was solved by heating and stirring in an organic solvent and then cooling to precipitate quinidine sulfate crystals. This method achieves a drug crystal form with high purity and good dissolution rate, which is suitable for industrial production and the preparation of various drug formulations.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-24
- Publication Date
- 2026-03-27
AI Technical Summary
Existing technologies do not disclose the crystal form and preparation method of quinidine sulfate, making it difficult to meet the needs of industrial production. Furthermore, early quality control methods were cumbersome and prone to errors, making it difficult to guarantee the efficacy and safety of the drug.
A novel crystalline form of quinidine sulfate and its preparation method are provided. Crystals are precipitated by heating and stirring in an organic solvent and water, followed by cooling. Crystal forms 1 and 2 of quinidine sulfate with high purity and good flowability are prepared, which are suitable for industrial production.
The prepared quinidine sulfate crystal form has high purity and good dissolution, making it suitable for preparing various drug formulations to meet clinical needs. The operation is simple and suitable for industrial production.
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Figure CN121735939A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical technology and relates to a new crystal form of quinidine sulfate and its preparation method. Background Technology
[0002] Quinidine sulfate tablets, a classic Class Ia antiarrhythmic drug, were initially developed due to the high incidence of cardiovascular disease and the urgent need for effective treatments. Clinically, atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia are common cardiovascular emergencies, often presenting patients with symptoms such as palpitations, chest tightness, and dizziness. In severe cases, these can lead to complications such as heart failure and thromboembolism, even endangering life. Traditional treatments (such as electrical cardioversion and pharmacological cardioversion) can temporarily correct arrhythmias, but they have high recurrence rates and lack effective drugs for long-term maintenance therapy. Quinidine sulfate, through mechanisms such as inhibiting sodium channels in myocardial cell membranes, prolonging the effective refractory period, and reducing automaticity, can effectively control ectopic rhythms and prevent arrhythmia recurrence, making it an indispensable treatment option in clinical practice. With the increasing aging of the population (the proportion of people aged 60 and over has reached 13% globally, and as high as 18.7% in China), the number of cardiovascular disease patients continues to grow (the number of cardiovascular disease patients in China has exceeded 300 million).
[0003] Early production of quinidine sulfate relied on natural extraction from cinchona bark, but this method had many limitations: limited raw material sources (cinchona trees mainly grow in South America, with harsh climate and soil conditions), low extraction efficiency (quinidine content of only about 0.5%-1%), and high cost (the extraction cost per kilogram of quinidine can reach hundreds of US dollars). With the development of organic chemistry and pharmaceutical synthesis technology, the chemical synthesis of quinidine (using quinine as a raw material, obtained through a series of reactions) was achieved, which not only solved the raw material shortage problem but also significantly increased the yield (about 200 kilograms of quinidine can be synthesized from one ton of quinine) and purity (reaching over 99%). Based on this, the preparation process of quinidine sulfate was further optimized: by controlling the molar ratio of sulfuric acid to quinidine (usually 1:1.1-1.2), reaction temperature (25-30℃), and pH value (4.5-5.5), the complete salt formation reaction was ensured, avoiding the residue of free alkali or excess sulfuric acid. These process upgrades significantly improved the quality stability of quinidine sulfate, laying the foundation for its large-scale production and clinical application.
[0004] Quinidine sulfate has a narrow therapeutic window (effective blood concentration of 3-6 mg / L, with serious adverse reactions easily occurring above 8 mg / L), and there are significant individual differences (elderly patients and those with impaired liver function have slower metabolism, making blood concentrations more likely to rise). Therefore, quality control is a core aspect of its research and development. Early quality control mainly relied on chemical titration, which was cumbersome and prone to large errors (relative error can reach ±10%), making it difficult to meet clinical needs. With the advancement of analytical technology, methods such as high-performance liquid chromatography (HPLC) and ultraviolet spectrophotometry (UV) have been introduced, achieving precise quantification of quinidine sulfate (detection limit down to 0.1 μg / mL, relative error ≤ ±2%). Meanwhile, the pharmacopoeia is continuously raising its quality standards: the 2025 edition of the Chinese Pharmacopoeia stipulates that the content uniformity of quinidine sulfate tablets must meet the requirement of A+1.80S≤15.0, the dissolution rate (paddle method, 50 rpm, pH 6.8 phosphate buffer) must be ≥70% after 30 minutes, and the related substances (such as deacetylquinidine and quinidine glucuronide) must be ≤0.5%. These strict standards effectively ensure the efficacy and safety of quinidine sulfate tablets.
[0005] National policy support for the pharmaceutical industry has created a favorable environment for the research and development of quinidine sulfate tablets. For example, the "Pharmaceutical Industry Development Plan" explicitly proposes to "strengthen the research and development of innovative drugs, with a focus on supporting innovative drugs urgently needed in clinical practice," and lists cardiovascular disease drugs as one of the key areas. Furthermore, improved medical insurance policies (such as including quinidine sulfate tablets in the national medical insurance catalog) have reduced the cost of medication for patients (reimbursement rates can reach 70%-80%), improved drug accessibility, and further stimulated market demand. At the same time, market competition has also driven research and development innovation: domestic companies (such as Jiangsu Hengrui and Shanghai Hyundai) have reduced costs and improved quality through technological innovation, gradually breaking the monopoly of imported brands (such as Pfizer and Sanofi); foreign companies, on the other hand, have seized the high-end market by developing new formulations (such as sustained-release tablets). These factors have collectively promoted the technological progress in the research and development of quinidine sulfate tablets.
[0006] The molecular formula of quinidine sulfate is (C 20 H 24 N2O6·H2SO4·2H2O, with a molecular weight of 782.96, has the following chemical structural formula: .
[0007] Quinidine, a classic antiarrhythmic drug, has a history of extraction and clinical application dating back to 1918, when its antiarrhythmic effects were discovered by German scientists. Quinidine sulfate was first approved for marketing in the United States in the 1850s. In China, quinidine sulfate tablets were first approved for marketing by Beijing Shuanghe Pharmaceutical Co., Ltd. on August 10, 2010, with the approval number H11020970.
[0008] To date, no official documents or patents have disclosed the crystal form and preparation method of quinidine sulfate. In order to promote the diversified development of quinidine sulfate pharmaceutical formulations and meet the needs of industrial production, it is necessary to develop a stable and high-yield crystal form preparation method.
[0009] To address this issue, a new crystal form of quinidine sulfate and its preparation method were designed to overcome the aforementioned problems. Summary of the Invention
[0010] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a new crystalline form of quinidine sulfate and its preparation method. The crystalline product prepared by the method of this invention has high purity, good fluidity, and good solubility, making it suitable for industrial production.
[0011] This invention is achieved through the following technical solution: a novel crystal form of quinidine sulfate, characterized in that the crystal form is either quinidine sulfate crystal form 1 or quinidine sulfate crystal form 2, and confirmed by X-ray diffraction, the 2θ angles on the XRPD diffraction pattern of quinidine sulfate crystal form 1 are 6.597°±0.2°, 8.142°±0.2°, 9.286°±0.2°, and 13.293°±0.2°. Characteristic peaks are observed at 0.2°, 16.679°±0.2°, 18.757°±0.2°, 21.488°±0.2°, and 23.234°±0.2° in the XRPD diffraction pattern of quinidine sulfate crystal form 2 at 2θ angles of 8.669°±0.2°, 9.245°±0.2°, 16.149°±0.2°, and 18.719°±0.2°.
[0012] A method for preparing a new crystalline form of quinidine sulfate, comprising the following steps: 1) Add quinidine sulfate to one or more solutions of organic solvent, mixed solvent, or pure water, and heat and stir. 2) After quinidine sulfate has completely dissolved, filter the solution and cool and stir the filtrate. 3) After crystal precipitation, filter and dry to obtain quinidine sulfate new crystal form 1 or quinidine sulfate new crystal form 2.
[0013] Preferably, the organic solvent is selected from methanol, ethanol, and isopropanol.
[0014] Preferably, the mixed solvent is methanol / water.
[0015] Preferably, the concentration of methanol / water is 10% to 90%.
[0016] Preferably, the heating and stirring temperature is 40~90℃.
[0017] Preferably, the cooling and stirring method is either rapid cooling or slow cooling.
[0018] Preferably, the slow cooling method involves placing the container in water at 50-90°C and stirring for more than 4 hours until it reaches room temperature; while the rapid cooling method involves placing the container in water at approximately room temperature and stirring continuously until it reaches room temperature.
[0019] Preferably, the drying temperature is 20~90℃.
[0020] A pharmaceutical composition comprising quinidine sulfate crystal form 1 and / or quinidine sulfate crystal form 2, wherein quinidine sulfate crystal form 1 and quinidine sulfate crystal form 2 are prepared by the method described above.
[0021] The beneficial effects of this invention are as follows: The novel quinidine sulfate crystal form provided by this invention is not documented in the literature. The quinidine sulfate crystal form product prepared by this method has high purity, good dissolution, and good flowability, meeting the conditions for further preparation into formulations such as injections and solid dosage forms, preferably solid dosage forms, such as capsules and tablets. Furthermore, the formulation may contain at least one of the following excipient categories: diluent, binder, disintegrant, or lubricant. The process of this invention is simple to operate, with mild reaction conditions, suitable for industrial production. It provides a new crystal form option for the development of quinidine sulfate pharmaceutical formulations, promotes innovation in pharmaceutical formulation technology, and has profound significance for drug development. Attached Figure Description
[0022] Figure 1 This is the XPRD pattern of quinidine sulfate crystal form 1 in this invention; Figure 2 This is the XPRD pattern of quinidine sulfate crystal form 2 in this invention. Detailed Implementation
[0023] To enable those skilled in the art to more clearly understand the purpose, technical solution, and advantages of the present invention, the present invention will be further described below in conjunction with the accompanying drawings and embodiments.
[0024] The invention will now be described in detail with reference to the accompanying drawings: A new crystal form of quinidine sulfate, characterized in that the crystal form is either quinidine sulfate crystal form 1 or quinidine sulfate crystal form 2, confirmed by X-ray diffraction, wherein the 2θ angle on the XRPD diffraction pattern of quinidine sulfate crystal form 1 is 6.597°±0.2°, 8.142°±0.2°, 9.286°±0.2°, and 13.293°±0.2°. Characteristic peaks are observed at 0.2°, 16.679°±0.2°, 18.757°±0.2°, 21.488°±0.2°, and 23.234°±0.2° in the XRPD diffraction pattern of quinidine sulfate crystal form 2, at 2θ angles of 8.669°±0.2°, 9.245°±0.2°, 16.149°±0.2°, and 18.719°±0.2°. Figure 1 The image shows the XPRD pattern of quinidine sulfate crystal form 1. Figure 2 The image shows the XPRD pattern of quinidine sulfate crystal form 2.
[0025] A method for preparing a new crystalline form of quinidine sulfate, comprising the following steps: 1) Add quinidine sulfate to one or more solutions of organic solvent, mixed solvent, or pure water, and heat and stir. 2) After quinidine sulfate has completely dissolved, filter the solution and cool and stir the filtrate. 3) After crystal precipitation, filter and dry to obtain quinidine sulfate new crystal form 1 or quinidine sulfate new crystal form 2.
[0026] The organic solvent is selected from methanol, ethanol, and isopropanol.
[0027] The mixed solvent is methanol / water.
[0028] The concentration of methanol / water is 10% to 90%.
[0029] The heating and stirring temperature is 40~90℃.
[0030] The cooling and stirring method is selected from either rapid cooling or slow cooling.
[0031] The slow cooling method involves immersing the item in water at 50-90°C and stirring for at least 4 hours until it reaches room temperature. The rapid cooling method involves immersing the item in water at approximately room temperature and stirring continuously until it reaches room temperature. The drying temperature is 20-90°C.
[0032] A pharmaceutical composition comprising quinidine sulfate crystal form 1 and / or quinidine sulfate crystal form 2, wherein quinidine sulfate crystal form 1 and quinidine sulfate crystal form 2 are prepared by the method described above.
[0033] Examples 1-8 are methods for preparing quinidine sulfate crystal form 1, and Examples 9-15 are methods for preparing quinidine sulfate crystal form 2.
[0034] Example 1 The preparation method of quinidine sulfate crystal form 1 is as follows: 5.5 g of quinidine sulfate was added to 26.5 ml of isopropanol, and heated to 65 °C while stirring. After the quinidine sulfate was completely dissolved, the solution was filtered. The filtrate was then placed in 65 °C water and stirred, and slowly cooled to 26 °C. Crystals precipitated were collected by filtration and dried overnight at 85 °C in a drying oven to obtain quinidine sulfate crystals with a yield of 95%. The XRPD test results are attached. Figure 1 As shown, this is crystal form 1.
[0035] Example 2 The preparation method of quinidine sulfate crystal form 1 is as follows: 5.2 g of quinidine sulfate was added to 156 ml of water and heated to 84 °C while stirring. After the quinidine sulfate was completely dissolved, the solution was filtered. The filtrate was then placed in water at 84 °C and stirred. The solution was slowly cooled to 27 °C, and the precipitated crystals were collected by filtration. The crystals were then dried overnight at 25 °C for 3 days to obtain quinidine sulfate crystals with a yield of 94%. The XRPD test result showed crystal form 1.
[0036] Example 3 The preparation method of quinidine sulfate crystal form 1 is as follows: 5.4 g of quinidine sulfate was added to a mixed solution of methanol (13 ml) and water (117 ml). The solution was heated to 70°C while stirring. After the quinidine sulfate was completely dissolved, the solution was filtered. The filtrate was then placed in 70°C water and stirred. The solution was slowly cooled to 27°C, and crystals precipitated. These crystals were collected by filtration and dried overnight at 45°C in a drying oven to obtain quinidine sulfate crystals with a yield of 92%. XRPD analysis showed crystal form 1.
[0037] Example 4 The preparation method of quinidine sulfate crystal form 1 is as follows: Take 5.2g of quinidine sulfate, add 156ml of water, and heat to 85℃ while stirring. After the quinidine sulfate is completely dissolved, filter. Put the filtrate into water at 22℃ and stir. Cool rapidly to precipitate crystals, collect them by filtration, and dry them overnight at 85℃ in a drying oven to obtain quinidine sulfate crystals with a yield of 90%. Its XRPD test result is crystal form 1.
[0038] Example 5 The preparation method of quinidine sulfate crystal form 1 is as follows: 5.4 g of quinidine sulfate was added to a mixed solution of methanol (13 ml) and water (117 ml). The solution was heated to 70 °C while stirring. After the quinidine sulfate was completely dissolved, the solution was filtered. The filtrate was then placed in water at 22 °C and stirred. The solution was rapidly cooled, and crystals precipitated. These crystals were collected by filtration and dried overnight at 45 °C in a drying oven to obtain quinidine sulfate crystals with a yield of 92%. XRPD analysis showed crystal form 1.
[0039] Example 6 The preparation method of quinidine sulfate crystal form 1 is as follows: Take 5.3 g of quinidine sulfate and add it to a mixed solution of methanol (16 ml) and water (64 ml). Heat the solution to 70 °C while stirring. After the quinidine sulfate is completely dissolved, filter the solution. Place the filtrate in water at 22 °C and stir. Cool rapidly to precipitate crystals, collect the crystals through filtration, and dry them overnight at 85 °C in a drying oven to obtain quinidine sulfate crystals with a yield of 92%. The XRPD test result shows crystal form 1.
[0040] Example 7 The preparation method of quinidine sulfate crystal form 1 is as follows: Take 6.2g of quinidine sulfate, add 15.5ml of anhydrous ethanol, heat to 65℃ while stirring, and after the quinidine sulfate is completely dissolved, filter. Put the filtrate into 22℃ water and stir, then rapidly cool. After crystals precipitate, collect them by filtration and place them in a drying oven at 85℃ overnight to obtain quinidine sulfate crystals with a yield of 90%. Its XRPD test result is crystal form 1.
[0041] Example 8 The preparation method of quinidine sulfate crystal form 1 is as follows: Take 5.4g of quinidine sulfate, add 18.5ml of isopropanol, and heat to 75℃ while stirring. After the quinidine sulfate is completely dissolved, filter. Put the filtrate into 22℃ water and stir. Cool rapidly and precipitate crystals. Collect the precipitate by filtration and dry it overnight at 85℃ in a drying oven to obtain quinidine sulfate crystals with a yield of 90%. Its XRPD test result is crystal form 1.
[0042] Example 9 The preparation method of quinidine sulfate crystal form 2 is as follows: 5.4 g of quinidine sulfate was added to a mixed solution of methanol (15.5 ml) and water (36.2 ml). The solution was heated to 70°C while stirring. After the quinidine sulfate was completely dissolved, the solution was filtered. The filtrate was then placed in 70°C water and stirred. The solution was slowly cooled to 27°C, and crystals precipitated. These crystals were collected by filtration and dried overnight at 85°C in a drying oven to obtain quinidine sulfate crystals with a yield of 92%. The XRPD test results are attached. Figure 2 As shown, this is crystal form 2.
[0043] Example 10 The preparation method of quinidine sulfate crystal form 2 is as follows: Take 5.4 g of quinidine sulfate and add it to a mixed solution of methanol (16 ml) and water (64 ml). Heat the solution to 70 °C while stirring. After the quinidine sulfate is completely dissolved, filter the solution. Place the filtrate in water at 70 °C and stir. Slowly cool the solution to 27 °C. After crystals precipitate, collect the precipitate by filtration and dry it overnight at 85 °C in a drying oven to obtain quinidine sulfate crystals with a yield of 92%. The XRPD test result shows crystal form 2.
[0044] Example 11 The preparation method of quinidine sulfate crystal form 2 is as follows: Take 5.2g of quinidine sulfate, add 18ml of methanol, and heat to 58℃ while stirring. After the quinidine sulfate is completely dissolved, filter. Put the filtrate into water at 58℃ and stir. Slowly cool to 27℃ to precipitate crystals. Collect the precipitate by filtration and dry it overnight at 25℃ in a drying oven to obtain quinidine sulfate crystals with a yield of 91%. Its XRPD test result is crystal form 2.
[0045] Example 12 The preparation method of quinidine sulfate crystal form 2 is as follows: Take 5.6g of quinidine sulfate, add 18ml of anhydrous ethanol, and heat to 60℃ while stirring. After the quinidine sulfate is completely dissolved, filter. Put the filtrate into 60℃ water and stir. Slowly cool to 27℃, and collect the precipitated crystals by filtration. Place the crystals in a drying oven at 45℃ overnight to obtain quinidine sulfate crystals with a yield of 90%. Its XRPD test result is crystal form 2.
[0046] Example 13 The preparation method of quinidine sulfate crystal form 2 is as follows: Take 5.1 g of quinidine sulfate and add it to 51 ml of a mixed solution of methanol and water (methanol / water volume ratio of 3:7). Heat to 70 °C while stirring. After the quinidine sulfate is completely dissolved, filter the solution. Place the filtrate in water at 22 °C and stir. Cool rapidly to precipitate crystals, collect the crystals through filtration, and dry them overnight at 45 °C in a drying oven to obtain quinidine sulfate crystals with a yield of 95%. Its XRPD test result is crystal form 2.
[0047] Example 14 The preparation method of quinidine sulfate crystal form 2 is as follows: Take 6.4 g of quinidine sulfate, add 19.2 ml of methanol, and heat to 60 °C while stirring. After the quinidine sulfate is completely dissolved, filter, put the filtrate into 22 °C water and stir, then rapidly cool to precipitate crystals. Collect the precipitated crystals by filtration, and dry them overnight at 85 °C in a drying oven to obtain quinidine sulfate crystals with a yield of 92%. Its XRPD test result is crystal form 2.
[0048] Example 15 The preparation method of quinidine sulfate crystal form 2 is as follows: Take 5.2 g of quinidine sulfate and add it to 23.2 ml of a mixed solution of methanol and water (methanol / water volume ratio of 9:1). Heat to 65 °C while stirring. After the quinidine sulfate is completely dissolved, filter the solution. Place the filtrate in water at 22 °C and stir. Cool rapidly to precipitate crystals, collect the precipitate through filtration, and dry it overnight at 85 °C in a drying oven to obtain quinidine sulfate crystals with a yield of 90%. Its XRPD test result is crystal form 2.
[0049] As can be seen from the above embodiments, this invention discloses for the first time a new crystal form of quinidine sulfate and its preparation method. The crystals obtained by this preparation method have high purity and good fluidity, and the process is simple and suitable for industrial production, which has profound significance for the development and utilization of drugs.
[0050] The specific embodiments described herein are merely illustrative of the principles and effects of the invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in this invention should still be covered by the claims of this invention.
Claims
1. A novel crystalline form of quinidine sulfate, characterized in that, The crystal form is either quinidine sulfate crystal form 1 or quinidine sulfate crystal form 2. X-ray diffraction confirmed that the XRPD diffraction pattern of quinidine sulfate crystal form 1 showed characteristic peaks at 2θ angles of 6.597°±0.2°, 8.142°±0.2°, 9.286°±0.2°, 13.293°±0.2°, 16.679°±0.2°, 18.757°±0.2°, 21.488°±0.2°, and 23.234°±0.2°, while the XRPD diffraction pattern of quinidine sulfate crystal form 2 showed characteristic peaks at 2θ angles of 8.669°±0.2°, 9.245°±0.2°, 16.149°±0.2°, and 18.719°±0.2°.
2. The method for preparing the new crystal form of quinidine sulfate according to claim 1, characterized in that, Includes the following steps: 1) Add quinidine sulfate to one or more solutions of organic solvent, mixed solvent, or pure water, and heat and stir. 2) After quinidine sulfate has completely dissolved, filter the solution and cool and stir the filtrate. 3) After crystal precipitation, filter and dry to obtain quinidine sulfate new crystal form 1 or quinidine sulfate new crystal form 2.
3. The method for preparing the new crystal form of quinidine sulfate according to claim 2, characterized in that, The organic solvent is selected from methanol, ethanol, and isopropanol.
4. The method for preparing the new crystal form of quinidine sulfate according to claim 2, characterized in that, The mixed solvent is methanol / water.
5. The method for preparing the new crystal form of quinidine sulfate according to claim 4, characterized in that, The concentration of methanol / water is 10% to 90%.
6. The method for preparing the new crystal form of quinidine sulfate according to claim 2, characterized in that, The heating and stirring temperature is 40~90℃.
7. The method for preparing the new crystal form of quinidine sulfate according to claim 2, characterized in that, The cooling and stirring method is selected from either rapid cooling or slow cooling.
8. The method for preparing the new crystal form of quinidine sulfate according to claim 7, characterized in that, The specific method for slow cooling is to place the container in water at 50-90°C and stir for more than 4 hours until it cools to room temperature; while the method for rapid cooling is to place the container in water at approximately room temperature and stir continuously until it cools to room temperature.
9. The method for preparing the new crystal form of quinidine sulfate according to claim 2, characterized in that, The drying temperature is 20~90℃.
10. A pharmaceutical composition, characterized in that, The composition comprises quinidine sulfate crystal form 1 and / or quinidine sulfate crystal form 2, wherein quinidine sulfate crystal form 1 and quinidine sulfate crystal form 2 are prepared by any one of claims 2-9.