Method for removing residual solvents from fluorescein sodium
By adding water to sodium fluorescein or placing it in a high-humidity environment to replace residual solvent, combined with appropriate drying conditions, the problem of excessive solvent residue in sodium fluorescein was solved, and high-purity sodium fluorescein was prepared, meeting pharmaceutical-grade quality standards.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- ZHUHAI TRANEOT PHARMACEUTICAL CO LTD
- Filing Date
- 2023-10-26
- Publication Date
- 2026-05-22
AI Technical Summary
Existing technologies are insufficient to effectively remove residual solvents from sodium fluorescein, especially in high-purity pharmaceutical-grade sodium fluorescein where residual solvents exceed the limits, failing to meet the requirements of ICH Guideline Series Q3 Impurity Guideline.
The residual solvent is removed by adding water to sodium fluorescein or placing it in a high-humidity environment, and then drying it. Specific methods include using a weight ratio of sodium fluorescein to water of 1:0.3-1, a drying temperature of 70℃-90℃, a drying time of more than 6 hours, or placing it in a high-humidity environment for more than 0.5 hours, combined with vacuum or forced-air drying.
It achieves simple and low-cost removal of residual solvent from sodium fluorescein, improves product purity, meets pharmaceutical-grade quality requirements, and is easy to implement industrially.
Abstract
Description
Technical Field
[0001] This invention belongs to the field of chemical purification, and specifically relates to a method for removing residual solvent from sodium fluorescein. Background Technology
[0002] Sodium fluorescein, chemical formula C 20 H 10 Na2O5, the structural formula is shown below: Fluorescein sodium is readily soluble in water and slightly soluble in ethanol. It exhibits strong green fluorescence and is widely used in fluorescein angiography of iris vessels or in the diagnosis of fundus diseases. Therefore, the preparation of high-purity pharmaceutical-grade fluorescein sodium is crucial. Patent CN101628907A discloses a method for purifying fluorescein sodium, involving a method for preparing high-purity fluorescein sodium using reagent-grade fluorescein sodium as a raw material. This method involves first adding a polar solvent and activated carbon to reagent-grade fluorescein sodium for distillation and decolorization. After filtration, hydrochloric acid is added to the filtrate to obtain fluorescein, followed by cooling and crystallization. The crystals are then filtered again, washed with a polar solvent and pure water, and alkalized with sodium hydroxide or sodium carbonate. After further filtration, the filtrate is concentrated into a viscous substance and dried, which is believed to yield fluorescein sodium with a weight content of over 99.5%. Patent CN101792429A discloses a method for preparing high-purity fluorescein sodium, which involves further refining crude fluorescein sodium... Acetylation yields crude diacetyl fluorescein, which is then recrystallized to obtain a higher purity diacetyl fluorescein. Hydrolysis then yields fluorescein, and finally, alkalization yields high-purity sodium fluorescein. Patent CN101270124A discloses a new method for purifying and preparing high-purity fluorescein and fluorescein salts. This method involves reacting fluorescein or sodium fluorescein with an acetylation reagent in the presence of a polar solvent and pyridine compounds to generate diacetyl fluorescein. Utilizing the different chemical polarities of impurities and diacetyl fluorescein, impurities are separated using recrystallization or silica gel adsorption. The resulting solution undergoes saponification, acidification, and salt formation to obtain high-purity sodium fluorescein, with a believed weight content exceeding 99.2%. The above-mentioned methods for preparing sodium fluorescein all use organic solvents, which will leave solvent residues. Because sodium fluorescein readily forms solvent compounds with solvents, these residues are difficult to remove by high-temperature drying. High-purity pharmaceutical-grade sodium fluorescein needs to meet the requirements of ICH Guideline Series Q3 Impurity Guidelines: Class 1 solvents, i.e., solvents that can cause cancer or strong carcinogenicity in humans and are harmful to the environment, have a residual concentration limit of 2 ppm; Class 2 solvents, i.e. solvents that may cause irreversible toxicity, have a residual concentration limit of 3000 ppm; and Class 3 solvents, i.e. solvents with low potential toxicity to humans, have a residual concentration limit of 5000 ppm. Therefore, in order to meet the requirements of ICH Guideline Series Q3 Impurity Guidelines, it is crucial to effectively control the solvent residues in sodium fluorescein. Summary of the Invention
[0003] To address the aforementioned problems, this invention provides a method for removing residual solvent from sodium fluorescein. Specifically, this method involves adding water to sodium fluorescein containing residual solvent or using ambient moisture to replace the residual solvent before drying to remove the moisture.
[0004] This invention provides the following technical solution:
[0005] On the one hand, a method for removing residual solvent from sodium fluorescein is provided, the method comprising: mixing sodium fluorescein with water uniformly and then drying it, wherein the weight ratio of sodium fluorescein to water is 1:0.3-1.
[0006] It is understandable that sodium fluorescein contains a carboxyl group, which easily forms solvent compounds with solvent molecules. By adding water, the interaction forces between sodium fluorescein molecules and solvent molecules (such as hydrogen bonding forces) are disrupted, thereby reducing the binding degree of solvent molecules and making them easier to dry.
[0007] The weight ratio of sodium fluorescein to water is 1:0.3-1, for example, it can be 1:0.3, 1:0.5, 1:0.7, 1:0.8, 1:0.9 or 1:1, as well as specific values between the above values. Due to space limitations and for the sake of brevity, this invention will not exhaustively list the specific values included in the range.
[0008] It is understandable that adding too much water will make it difficult to dry after the sodium fluorescein solvent is removed, while adding too little water will result in incomplete replacement of the residual solvent.
[0009] In some embodiments, the drying method includes other suitable drying methods such as vacuum drying or forced-air drying.
[0010] In some embodiments, the drying temperature is 70°C-90°C and the drying time is greater than 6 hours.
[0011] The drying temperature is 70℃-90℃, for example, it can be 70℃, 73℃, 76℃, 80℃, 85℃, 80℃ or 90℃, as well as specific values between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values included in the range.
[0012] The drying time is greater than 6 hours, for example, it can be 6 hours, 6.5 hours, 7 hours, 7.8 hours, 8 hours, 10 hours or 12 hours, as long as the moisture is completely dried. As for the specific values between the above points, due to space limitations and for the sake of brevity, this invention will not exhaustively list the specific values included in the range.
[0013] On the other hand, another method for removing residual solvent from sodium fluorescein is provided, which includes: placing sodium fluorescein in a water-containing, high-humidity environment, using the moisture in the environment to replace the residual solvent, and then drying it, wherein the ambient humidity is 50%-100%.
[0014] The ambient humidity is 50%-100%, for example, it can be 50%, 60%, 70%, 80%, 90% or 100%, as well as specific values between the above points. Due to space limitations and for the sake of brevity, this invention will not exhaustively list the specific values included in the range.
[0015] The humidity referred to here is relative humidity, which is the percentage of water vapor pressure in the air to saturated water vapor pressure at the same temperature.
[0016] In some embodiments, the high-humidity environment can be obtained by placing a container containing sodium fluorescein in the same enclosed space as a container containing water, or by connecting containers containing sodium fluorescein and water together.
[0017] In other embodiments, the water temperature is 50°C-100°C.
[0018] In some embodiments, the sodium fluorescein is placed in a high humidity environment for more than 0.5 hours.
[0019] The water temperature is 50℃-100℃, for example, it can be 50℃, 55℃, 60℃, 70℃, 75℃, 80℃, 90℃ or 100℃, as well as specific values between the above points. Due to space limitations and for the sake of brevity, this invention will not exhaustively list the specific values included in the range.
[0020] The sodium fluorescein is placed in a high humidity environment for a period of more than 0.5 hours, for example, 0.5 hours, 1 hour, 1.6 hours, 2.8 hours, 3.5 hours, 5 hours, or 6 hours, as long as the sodium fluorescein absorbs enough water to replace the residual solvent. The specific values between the above-mentioned values are not exhaustively listed in this invention due to space limitations and for the sake of brevity.
[0021] In some embodiments, the drying method includes other suitable drying methods such as vacuum drying or forced-air drying.
[0022] In some embodiments, the vacuum drying temperature is 70°C-90°C and the time is greater than 8 hours.
[0023] The drying temperature is 70℃-90℃, for example, it can be 70℃, 73℃, 76℃, 80℃, 85℃, 80℃ or 90℃, as well as specific values between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values included in the range.
[0024] The drying time is greater than 8 hours, for example, it can be 8 hours, 8.5 hours, 9 hours, 9.8 hours, 10 hours, 11 hours or 12 hours, as long as the moisture is completely dried. As for the specific values between the above points, due to space limitations and for the sake of brevity, this invention will not exhaustively list the specific values included in the range.
[0025] In some embodiments, the residual solvent includes one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol, acetone, and dichloromethane.
[0026] In some implementations, the water refers to tap water.
[0027] In some embodiments, the water refers to purified water, which is more conducive to ensuring the purity of sodium fluorescein after removing residual solvents.
[0028] It is understandable that when the residual solvent in a product still fails to meet the requirements of ICH Guideline Series Q3 after trying various methods to remove residual solvent, it is often because the product and residual solvent have formed a solvate. A common method to remove residual solvent from solvates is to increase the drying temperature to break the intermolecular forces between the solvent and solute molecules. However, high-temperature drying is still ineffective in removing residual solvent from sodium fluorescein. Moreover, because sodium fluorescein is highly hygroscopic, it is not considered to add water to sodium fluorescein to displace the solvent.
[0029] The method provided by this invention has the following advantages:
[0030] 1. This method is simple to operate and easy to industrialize;
[0031] 2. This method uses water to displace the solvent, which is low-cost and environmentally friendly;
[0032] 3. This method can effectively improve the purity of sodium fluorescein and remove residual solvents, which facilitates quality control and compliance with regulatory requirements during drug preparation. Detailed Implementation
[0033] The present invention will now be described in detail through embodiments.
[0034] The sodium fluorescein in this invention is prepared according to the method disclosed in WO2023037158.
[0035] The method for detecting residual solvents is as follows: the residual solvent determination method (Chinese Pharmacopoeia 2020, Part IV, General Chapter 0861) shall be followed.
[0036] (1) Instruments:
[0037] Electronic balance, gas chromatograph.
[0038] (2) Chromatographic conditions:
[0039] Column: Capillary column (DB-SELECT624UI, 0.530mm×30m, 3.0μm) with 6% cyanopropylphenyl-94% dimethylpolysiloxane as stationary phase; Detector: Flame ionization detector (FID); Injector temperature: 220℃; Detector temperature: 250℃; Headspace vial equilibration temperature: 85℃; Split ratio: 10:1; GC equilibration time: 30min; Headspace vial equilibration time: 30min; Air flow rate: 400ml / min; Hydrogen flow rate: 30ml / min; Nitrogen flow rate: 25ml / min; Column flow rate: 3ml / min; Temperature program: Initial temperature 40℃, hold for 5min, increase to 180℃ at a rate of 10℃ / min, hold for 3min.
[0040] (3) Calculation formula:
[0041]
[0042] As---Peak area of each component in the test solution; Ar---Average peak area of each component in the reference solution; Ws--Sample weight of the test sample (mg); Wr---Sample weight of the reference sample (mg); Ds---Dilution factor of the test sample; Dr---Dilution factor of the reference sample; P---Purity of the reference sample.
[0043] Example 1
[0044] Add 0.8 ml of water to 2.00 g of sodium fluorescein (containing methanol), mix thoroughly in a petri dish, dry under reduced pressure at 80 °C for 6 h, and send a sample for GC analysis to determine the residual solvent.
[0045] Example 2
[0046] Add 1.2 ml of water to 2.00 g of sodium fluorescein (containing methanol), mix thoroughly in a petri dish, dry under reduced pressure at 80 °C for 6 h, and send a sample for GC analysis to determine the residual solvent.
[0047] Example 3
[0048] Place a petri dish containing 2.00g of sodium fluorescein (containing methanol) in a sealed oven. Add approximately 500ml of 90℃ hot water to another petri dish, seal and let stand for about 6 hours, replacing the 90℃ hot water every 3 hours. Remove the sample, dry under reduced pressure at 80℃ for 9 hours, and send the sample for GC analysis to determine the residual solvent.
[0049] Example 4
[0050] Place a petri dish containing 2.00g of sodium fluorescein (containing ethanol) in a sealed oven. Add approximately 500ml of 90℃ hot water to another petri dish, seal and let stand for about 6 hours, replacing the 90℃ hot water every 3 hours. Remove the sample, dry under reduced pressure at 80℃ for 9 hours, and send the sample for GC analysis to determine residual solvent.
[0051] Example 5
[0052] Place a petri dish containing 2.00g of sodium fluorescein (containing tert-butanol) in a sealed oven. Add approximately 500ml of 90℃ hot water to another petri dish, seal and let stand for about 6 hours, replacing the 90℃ hot water every 3 hours. Remove the sample, dry under reduced pressure at 80℃ for 9 hours, and send the sample for GC analysis to determine the residual solvent.
[0053] Comparative Example 1
[0054] 2.00 g of sodium fluorescein (containing methanol) was dried under reduced pressure at 100 °C for 30 h, and a sample was sent for GC analysis to determine the residual solvent.
[0055] Comparative Example 2
[0056] 2.00 g of sodium fluorescein (containing methanol) was dried under reduced pressure at 100 °C for 60 h, and a sample was sent for GC analysis to determine the residual solvent.
[0057] Example 6 Determination of Solvent Residue
[0058] The test results of the starting materials and solvent residues after drying are shown in Table 1 below:
[0059] Table 1. Detection results of solvent residues in starting materials and after drying.
[0060] ;
[0061] After solvent residue removal from crude sodium fluorescein using the methods of Examples 1-5, the methanol residue of the prepared sodium fluorescein was all below 3000 ppm, which meets the requirements of Q3 of the ICH Guideline Series. However, Comparative Examples 1 and 2 directly dried crude sodium fluorescein at high temperature, and the methanol residue of the prepared sodium fluorescein was much higher than 3000 ppm, which does not meet the requirements of Q3 of the ICH Guideline Series.
Claims
1. A method for removing residual solvent from sodium fluorescein, characterized in that, The method includes: mixing sodium fluorescein with water evenly and then drying it, wherein the weight ratio of sodium fluorescein to water is 1:0.3-1, the drying method includes vacuum drying or forced air drying, the drying temperature is 70-90℃, the drying time is greater than 6 hours, and the residual solvent includes one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol, acetone, and dichloromethane.
2. The method for removing residual solvent from sodium fluorescein according to claim 1, characterized in that, The water is tap water or purified water.