A method for purifying hydrochlorothiazide
By heating and dissolving the hydrochlorothiazide under acidic conditions, followed by neutralization and cooling to induce crystallization, the problems of low purity and impure appearance of hydrochlorothiazide in existing technologies have been solved, and high-purity white hydrochlorothiazide has been prepared.
Patent Information
- Application Number
- CN202512034218.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2024-12-31
- Filing Date
- 2025-12-31
- Publication Date
- 2026-06-30
AI Technical Summary
In the prior art, when ethanol and water are used as recrystallization solvents for hydrochlorothiazide, the impurity C content of the finished hydrochlorothiazide product usually exceeds 0.15%, and existing methods are difficult to obtain white products that meet quality standards in appearance.
The purity of crude hydrochlorothiazide was improved by heating and dissolving it in a mixture containing acid and solvent, followed by neutralization and cooling to induce crystallization. The purification process was optimized by selecting appropriate solvents and acid-base conditions.
The purity of hydrochlorothiazide was significantly improved to over 99.9%, the impurity C content was reduced to below 0.10%, the product appearance was white, and the yield was also improved.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical and chemical engineering, and specifically relates to a method for purifying hydrochlorothiazide. Background Technology
[0002] Hydrochlorothiazide is a diuretic that primarily inhibits the inhibition of Na+ by the ascending limb cortex of the loop of Henle. + and Cl - The reabsorption of sodium chloride increases the excretion of sodium chloride by the kidneys, thus producing a diuretic effect. It can be used to treat edematous diseases, diabetes insipidus, and kidney stones. It also has an antihypertensive effect and can be used in combination with other antihypertensive drugs. Its structural formula is shown below:
[0003]
[0004] Impurities A, B, and C are common impurities in hydrochlorothiazide, and their structural formulas are shown below:
[0005]
[0006] Regarding the purification process of hydrochlorothiazide, the inventors discovered that:
[0007] 1) When ethanol and water are used as recrystallization solvents for hydrochlorothiazide, the impurity C content of the finished hydrochlorothiazide product usually exceeds 0.15%.
[0008] 2) Existing technologies report a purification method that involves first adding an alkaline solvent, then adjusting the acid, and finally cooling to crystallize. This method can obtain hydrochlorothiazide with a lower content of the above-mentioned impurities, but the product has a light yellow appearance. Even after adding activated carbon after dissolution, the appearance still does not meet the quality standards.
[0009] In view of the above-mentioned problems, it is necessary to develop a new purification method for high-purity hydrochlorothiazide. Summary of the Invention
[0010] This invention provides a method for purifying hydrochlorothiazide, comprising the following steps:
[0011] (1) Dissolve crude hydrochlorothiazide in a mixture containing acid and solvent under heating conditions;
[0012] (2) Cool down and add alkali to neutralize;
[0013] (3) Further cooling and crystallization, followed by filtration to obtain hydrochlorothiazide refined product.
[0014] In some embodiments, step (1) includes the following process: mixing the solvent with the acid to form a mixture; adding crude hydrochlorothiazide to the mixture after raising the temperature of the mixture and dissolving it, or adding crude hydrochlorothiazide to the mixture and then heating it to dissolve it.
[0015] In some embodiments, the crude hydrochlorothiazide is hydrochlorothiazide with an HPLC purity of less than 99.80%, more preferably hydrochlorothiazide with an impurity C content exceeding 0.10%, and even more preferably hydrochlorothiazide with an impurity C content exceeding 0.15%, wherein the structural formula of impurity C is shown below:
[0016]
[0017] In some embodiments, the crude hydrochlorothiazide is obtained by reacting sulfanilamide with formaldehyde or paraformaldehyde under heat and then separating the product. The structure of sulfanilamide is shown below:
[0018]
[0019] In some embodiments, the crude hydrochlorothiazide is obtained by heating and reacting sulfanilamide with formaldehyde or paraformaldehyde in an aqueous solution in the presence of ammonium chloride, followed by separation.
[0020] In some embodiments, the crude hydrochlorothiazide is obtained by heating sulfanilamide with formaldehyde or paraformaldehyde in an aqueous solution in the presence of ammonium chloride, followed by crystallization with ethanol after the reaction is complete.
[0021] In some embodiments, the solvent in step (1) is an organic solvent or a mixture of an organic solvent and water, preferably a mixture of an organic solvent and water. The organic solvent is preferably acetone, a C1-C3 alcohol, or a mixture thereof. There is no strict limitation on the amount of the organic solvent used, but it must be able to dissolve hydrochlorothiazide under reflux conditions. The C1-C3 alcohol is further preferably methanol or ethanol.
[0022] In some embodiments, the solvent in step (1) is a mixture of ethanol and water, wherein the volume ratio of ethanol to water is 10:1 to 1:5, preferably 5:1 to 1:5, and more preferably 3:1 to 1:3.
[0023] In some embodiments, the amount of solvent required per gram of the crude hydrochlorothiazide in step (1) is 10 to 30 mL, preferably 15 to 25 mL, and more preferably 18 to 23 mL.
[0024] In some embodiments, the acid is an organic acid or an inorganic acid, preferably hydrochloric acid, phosphoric acid, formic acid, acetic acid, oxalic acid, or citric acid, more preferably acetic acid or hydrochloric acid, and even more preferably hydrochloric acid.
[0025] In some embodiments, the pH of the mixture in step (1) is 2.5 to 4.5, more preferably 3.0 to 4.0, and even more preferably 4.0.
[0026] In some embodiments, the crude hydrochlorothiazide described in step (1) is dissolved at 55°C to solvent reflux temperature, preferably at solvent reflux temperature.
[0027] In some implementations, the cooling time in step (2) is about 2 hours or less.
[0028] In some embodiments, the temperature inside the system after cooling in step (2) is 30-50°C, more preferably 30-40°C.
[0029] In some embodiments, the base mentioned in step (2) is an organic base or an inorganic base, preferably sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, or triethylamine, more preferably triethylamine, sodium hydroxide, or potassium hydroxide, and even more preferably sodium hydroxide.
[0030] In some embodiments, the alkali in step (2) is added in the form of an inorganic alkali aqueous solution.
[0031] In some embodiments, after the alkali neutralization operation in step (2), the pH of the system is 4.5 to 6.0, more preferably 5.0 to 5.5, and even more preferably 5.0.
[0032] In some embodiments, the endpoint temperature of the crystallization operation in step (3) is 5 to 30°C, more preferably 5 to 25°C, and even more preferably 20°C.
[0033] In some embodiments, the crystallization time in step (3) is 4 to 12 hours, more preferably 6 to 10 hours.
[0034] In some embodiments, the filtration in step (3) is preferably vacuum filtration, and more preferably, the product is dried after filtration.
[0035] In some embodiments, the purified product obtained by the method according to the present invention has an HPLC purity of more than 99.9%, and the contents of impurities A, B and C are all less than 0.10%, and the product has a white appearance.
[0036] The purification method for hydrochlorothiazide provided by this invention, compared with direct recrystallization in a mixture of ethanol and water, produces a product with higher purity. The purity of the purified hydrochlorothiazide can be increased from 99.7%–99.8% to over 99.9%, the content of impurity C can be reduced from over 0.15% to below 0.10%, and the purification yield is further improved.
[0037] Terminology and Explanation:
[0038] In this invention, 95% ethanol refers to ethanol with a volume fraction of 95%.
[0039] In this invention, the purity of the product and the content of impurities are determined by HPLC using the peak area normalization method, and calculated using a correction factor. The specific HPLC detection conditions are as follows:
[0040]
[0041] Detailed Implementation
[0042] The present invention will be further described in detail below through specific embodiments. All raw materials used in the embodiments are commercially available.
[0043] Preparation Example
[0044]
[0045] 4200L of drinking water and 240kg of sulfanilamide were added to a reaction vessel. The temperature was raised to 90℃, and a mixed solution (prepared from 66kg of formaldehyde, 50kg of ammonium chloride, and 100L of drinking water) was added dropwise. After the dropwise addition was completed, the reaction was carried out at 90℃ for 2.5 hours. The temperature was then lowered to 70℃, and 3200L of ethanol was added. The temperature was raised to 80℃, stirred to dissolve, and then lowered to 20℃. The mixture was kept at this temperature for 8 hours to allow crystals to precipitate. The mixture was then filtered and dried for 8 hours to obtain 214.2kg of crude hydrochlorothiazide, with a total yield of 85.6% and a purity of 99.58%. Impurity A was not detected, impurity B content was 0.057%, and impurity C content was 0.160%.
[0046] Example 1
[0047] Add 3750L of purified water and 1800L of 95% ethanol to a refining dissolving vessel. Adjust the pH to 4.0 with purified hydrochloric acid (36wt%). Heat to 80℃, add 250kg of crude hydrochlorothiazide, stir to dissolve, and control the temperature to 30℃ over 2 hours. Add an aqueous solution of sodium hydroxide (0.3wt%) to adjust the pH to 5.0. Continue to cool to 20℃ and maintain the temperature for crystallization for 8 hours. Filter to obtain wet hydrochlorothiazide. Dry for 7 hours to obtain 238.4kg of refined hydrochlorothiazide, with a total yield of 95.4%. The color is white, and the purity is 99.92%. Impurity A was not detected, impurity B content was 0.013%, and impurity C content was 0.013%.
[0048] Example 2
[0049] Add 720 mL of purified water and 1440 mL of anhydrous ethanol to a round-bottom flask. Adjust the pH to 4.0 with purified hydrochloric acid (36 wt%). Heat to 80 °C, add 100 g of crude hydrochlorothiazide, stir to dissolve, and control the temperature for 2 hours. Cool down to 30 °C, add an aqueous solution of sodium hydroxide (0.3 wt%) to adjust the pH to 5.0, and continue cooling to 20 °C. Keep the temperature at this temperature for 8 hours to allow crystallization. Filter to obtain wet hydrochlorothiazide, dry for 7 hours to obtain 95.3 g of purified hydrochlorothiazide, with a total yield of 95.3%. The color is white, the purity is 99.93%, impurity A is not detected, impurity B content is 0.018%, and impurity C content is 0.016%.
[0050] Example 3
[0051] Add 720 mL of purified water and 1440 mL of anhydrous ethanol to a round-bottom flask. Adjust the pH to 4.0 with acetic acid. Heat to 80°C, add 100 g of crude hydrochlorothiazide, stir to dissolve, and control the temperature for 2 hours. Cool down to 30°C, add 0.3 wt% sodium hydroxide aqueous solution to adjust the pH to 5.0, and continue cooling to 20°C. Keep the temperature at this temperature for 8 hours to allow crystallization. Filter to obtain wet hydrochlorothiazide, dry for 7 hours to obtain 93.0 g of purified hydrochlorothiazide, with a total yield of 93.0%. The color is white, the purity is 99.92%, impurity A was not detected, impurity B content was 0.020%, and impurity C content was 0.023%.
[0052] Example 4
[0053] Add 720 mL of purified water and 1440 mL of anhydrous ethanol to a round-bottom flask. Adjust the pH to 4.0 with acetic acid, heat to 80 °C, add 100 g of crude hydrochlorothiazide, stir to dissolve, and control the temperature for 2 hours. Cool down to 30 °C, add triethylamine to adjust the pH to 5.0, and continue cooling to 20 °C. Keep warm for 8 hours to allow crystallization. Filter to obtain wet hydrochlorothiazide, dry for 7 hours to obtain 92.5 g of purified hydrochlorothiazide, with a total yield of 92.5%. The color is white, the purity is 99.92%, impurity A is not detected, impurity B content is 0.024%, and impurity C content is 0.023%.
[0054] Comparative Example 1
[0055] Add 600 mL of purified water and 1200 mL of anhydrous ethanol to a round-bottom flask, add 100 g of crude hydrochlorothiazide, heat to 80 °C and stir to dissolve, control the temperature for 4 hours, cool to 20 °C, keep warm to allow crystallization for 8 hours, filter to obtain wet hydrochlorothiazide, dry for 7 hours to obtain 89.5 g of purified hydrochlorothiazide, with a total yield of 89.5%, white color, and purity of 99.68%. Impurity A was not detected, impurity B content was 0.025%, and impurity C content was 0.159%.
[0056] Comparative Example 2
[0057] 875 L of purified water and 62.5 kg of sodium hydroxide were added to a refining dissolving vessel and stirred until dissolved. 250 kg of crude hydrochlorothiazide was then added, and the mixture was heated to 35 °C and stirred until dissolved. Hydrochloric acid was added to adjust the pH to 6.5. The mixture was filtered to obtain wet hydrochlorothiazide, which was dried for 7 hours to obtain 235.5 kg of refined hydrochlorothiazide, with a yield of 94.2% and a purity of 99.90%. Impurity A was not detected, impurity B was 0.010%, and impurity C was 0.011%. The obtained hydrochlorothiazide did not meet the appearance requirements; its color was pale yellow.
[0058] Comparative Example 3
[0059] Add 720 ml of purified water and 1400 ml of anhydrous ethanol to a round-bottom flask. Adjust the pH to 4.0 with purified hydrochloric acid (36 wt%). Heat to 80 °C, add 100 g of crude hydrochlorothiazide, stir to dissolve, and control the temperature for 4 hours. Cool down to 20 °C and maintain the temperature for 8 hours to allow crystallization. Filter to obtain wet hydrochlorothiazide. Dry for 7 hours to obtain 91.1 g of purified hydrochlorothiazide, with a total yield of 91.1%, purity of 99.84%, impurity A content of 0.042%, impurity B content of 0.022%, and impurity C purity of 0.016%.
Claims
1. A method for purifying hydrochlorothiazide, comprising the following steps: (1) Dissolve crude hydrochlorothiazide in a mixture containing acid and solvent under heating conditions; (2) Cool down and add alkali to neutralize; (3) Further cooling and crystallization, followed by filtration to obtain hydrochlorothiazide refined product.
2. The method of claim 1, wherein Step (1) includes the following process: mixing solvent and acid to form a mixture; adding crude hydrochlorothiazide after raising the temperature of the mixture and dissolving it, or adding crude hydrochlorothiazide to the mixture and then heating it to dissolve it.
3. The method of claim 1, wherein The solvent in step (1) is an organic solvent or a mixture of an organic solvent and water, preferably a mixture of an organic solvent and water. The organic solvent is preferably acetone, C1-C3 alcohol or a mixture thereof, and the C1-C3 alcohol is further preferably methanol or ethanol.
4. The method of claim 1, wherein The solvent in step (1) is a mixture of ethanol and water, and the volume ratio of ethanol to water is 10:1 to 1:5, preferably 5:1 to 1:5, and more preferably 3:1 to 1:
3.
5. The method of claim 1, wherein In step (1), the amount of solvent required per gram of crude hydrochlorothiazide is 10-30 mL, preferably 15-25 mL, and more preferably 18-23 mL.
6. The method of claim 1, wherein The acid is an organic acid or an inorganic acid, preferably hydrochloric acid, phosphoric acid, formic acid, acetic acid, oxalic acid, or citric acid, more preferably acetic acid or hydrochloric acid, and even more preferably hydrochloric acid.
7. The method of claim 1, wherein The pH of the mixture in step (1) is 2.5 to 4.5, more preferably 3.0 to 4.0, and even more preferably 4.
0.
8. The method of claim 1, wherein The temperature inside the system after cooling in step (2) is 30-50℃, more preferably 30-40℃.
9. The method of claim 1, wherein The alkali mentioned in step (2) is an organic or inorganic alkali, preferably sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, or triethylamine, more preferably triethylamine, sodium hydroxide, or potassium hydroxide, and even more preferably sodium hydroxide.
10. The method of claim 1, wherein After the alkali neutralization operation described in step (2), the pH of the system is 4.5 to 6.0, more preferably 5.0 to 5.5, and even more preferably 5.
0.
11. The method of claim 1, wherein The endpoint temperature of the crystallization operation in step (3) is 5 to 30°C, more preferably 5 to 25°C, and even more preferably 20°C.
12. The method according to any one of claims 1 to 11, characterized in that The purified product obtained in step (3) has a hydrochlorothiazide HPLC purity of over 99.9%, and the contents of impurities A, B and C are all below 0.10%, with a white appearance.