A method for separating a phenobarbital impurity

Abstract

The application discloses a method for separating a phenobarbital impurity, which comprises the following steps: dissolving phenobarbital raw medicine in a separation solvent to obtain a to-be-separated solution; dispersing the to-be-separated solution on a silica gel plate, and then performing development and elution by using a developing agent and an eluent; collecting a solution eluted out, and concentrating and crystallizing to obtain an impurity product; and the silica gel plate is prepared from carbon-based silica gel, and raw materials of the carbon-based silica gel include silica gel and activated carbon. In the application, the carbon-based silica gel containing activated carbon is used as an adsorption material, the adsorption effect is good in the elution process, and the elution can be completed as soon as possible when the eluent is used for elution, so that the method is suitable for separation of a small amount of phenobarbital impurity.

Description

Technical Field

[0001] This application relates to a method for separating phenobarbital impurities. Background Technology

[0002] Phenobarbital is a barbiturate sedative and hypnotic. It is primarily used for sedation, hypnosis, anticonvulsant, antiepileptic, pre-anesthetic administration, and in combination with antipyretics and analgesics to enhance their effects, as well as for the treatment of neonatal hyperbilirubinemia. During the synthesis of phenobarbital, various types of impurities are generated. Some are byproducts inevitably produced during the synthesis, while others are impurities resulting from the synthetic route. For the latter, GC-MS and similar methods are generally used for detection and analysis. However, this is only suitable for impurities obtained through known synthetic routes. For impurities with unknown routes, it is necessary to obtain the substance itself and then use methods such as ¹H NMR to obtain its precise structure before analyzing the synthetic route of the product. Summary of the Invention

[0003] To address the aforementioned problems, this application proposes a method for separating phenobarbital impurities, comprising the following steps: dissolving phenobarbital raw material in a separation solvent to obtain a solution to be separated; dispersing the solution to be separated onto a silica gel plate, then using a developing agent and an eluent for development and elution, collecting the dissolved effluent, concentrating and crystallizing to obtain the impurity product; wherein the silica gel plate is prepared from carbon-based silica gel, and the raw materials of the carbon-based silica gel include silica gel and activated carbon. This application uses carbon-based silica gel containing activated carbon as the adsorbent material, which exhibits good adsorption effect during elution, and when using an eluent for elution, it can complete elution quickly, making it suitable for the separation of small amounts of phenobarbital impurities.

[0004] Preferably, the developing agent is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 70:30; the eluent is petroleum ether-acetone, and the volume ratio of petroleum ether to acetone is 60:40.

[0005] Preferably, the carbon-based silica gel is prepared in the following manner:

[0006] Add glucose solution to sodium silicate solution and stir thoroughly to obtain a preliminary mixture;

[0007] Sulfuric acid was added to the initial mixture to obtain a gel.

[0008] The gel is granulated with a particle size of 100-500 μm, and then heated to 70-80℃ and maintained for 2-4 hours.

[0009] Then, the silica gel is washed with water and heated to carbonize, yielding carbon-based silica gel. The carbon group in this application's carbon-based silica gel is derived from glucose, which is thoroughly mixed with the silica gel. This mixing process achieves the effect of carbonization to adjust the properties of the silica gel, and the preparation process is also very convenient.

[0010] Preferably, the heating and carbonization is achieved in the following manner:

[0011] First, set the heating and carbonization atmosphere to nitrogen or argon, and raise the temperature from room temperature to 400-500℃ at a heating rate of 5-8℃ / min.

[0012] Maintain at 400-500℃ for 15-30 minutes;

[0013] Then, the temperature is lowered to room temperature at a rate of 2-4℃ / min. This application employs controlled heating and cooling to avoid cracking during carbonization, ensuring the shape integrity and performance of the obtained silica gel particles.

[0014] Preferably, the concentration of the glucose solution is 15-20 wt%; the concentration of the sodium silicate solution is 15-20 wt%; and the concentration of the sulfuric acid is 10-15 wt%.

[0015] Preferably, the mass ratio of the sodium silicate solution to the glucose solution is 5-8:1.

[0016] Preferably, the separation solvent is ethanol.

[0017] Preferably, the length of the silicone sheet is 40-50cm, the width of the silicone sheet is 10-20cm, and the thickness of the silicone sheet is 1-2cm.

[0018] Preferably, the silicone plate is obtained according to the following method:

[0019] A coating material is obtained by adding a binder to carbon-based silicone.

[0020] The coating material is applied to the substrate using a coating machine, and then placed in an oven for heating and drying.

[0021] Preferably, the binder is hydroxymethyl cellulose, and the amount added is 1.5-2 wt% of the carbon-based silica gel.

[0022] The heating and drying process is carried out as follows: dry at 70-80℃ for 2-3 hours;

[0023] Then raise the temperature to 110-115℃ and maintain it for 0.5-1 hour, and then lower it to room temperature to obtain a silicone plate.

[0024] This application can bring the following beneficial effects:

[0025] 1. This application uses carbon-based silica gel containing activated carbon as the adsorbent material, which has a good adsorption effect during the elution process, and can complete the elution quickly when using an eluent, making it suitable for the separation of small amounts of phenobarbital impurities.

[0026] 2. The carbon-based silica gel of this application has a carbon group derived from glucose, which is thoroughly mixed with silica gel. After mixing, it can achieve the effect of carbonization to adjust the performance of silica gel, and the preparation process is also very convenient.

[0027] 3. This application uses controlled heating and cooling to avoid cracking during carbonization and ensure the shape integrity and performance of the obtained silica gel particles. Detailed Implementation

[0028] To clearly illustrate the technical features of this solution, the following detailed description of specific implementation methods will be provided.

[0029] This application is actually divided into two steps: the first step is the synthesis of carbon-based silica gel, and the second step is the separation of phenobarbital impurities.

[0030] The carbon-based silica gel synthesis process includes the following steps:

[0031] S11: Add glucose solution to sodium silicate solution and stir thoroughly to obtain a preliminary mixture;

[0032] The concentration of the glucose solution is 15-20 wt%; the concentration of the sodium silicate solution is 15-20 wt%.

[0033] The mass ratio of the sodium silicate solution to the glucose solution is 5-8:1.

[0034] S12 is obtained by adding sulfuric acid to the initial mixture to form a gel;

[0035] The sulfuric acid concentration is 10-15 wt%.

[0036] S13 is used to granulate the gel, with the particle size controlled at 100-500μm, and then the temperature is raised to 70-80℃ and maintained for 2-4h.

[0037] S14 is then washed with water and heated to carbonize, yielding carbon-based silica gel.

[0038] The heating and carbonization is achieved as follows:

[0039] First, set the heating and carbonization atmosphere to nitrogen or argon, and raise the temperature from room temperature to 400-500℃ at a heating rate of 5-8℃ / min.

[0040] Maintain at 400-500℃ for 15-30 minutes;

[0041] Then cool down to room temperature at a cooling rate of 2-4℃ / min.

[0042] S15 uses carbon-based silicone as a raw material to prepare silicone sheets.

[0043] The silicone sheet has a length of 40-50cm, a width of 10-20cm, and a thickness of 1-2cm.

[0044] The silicone plate is obtained according to the following method:

[0045] A coating material is obtained by adding binder and water to carbon-based silicone.

[0046] The coating material is applied to the substrate using a coating machine, and then placed in an oven for heating and drying.

[0047] The binder is hydroxymethyl cellulose, and the amount added is 1.5-2 wt% of the mass of carbon-based silicone.

[0048] The heating and drying process is carried out as follows: dry at 70-80℃ for 2-3 hours;

[0049] Then raise the temperature to 110-115℃ and maintain it for 0.5-1 hour, and then lower it to room temperature to obtain a silicone plate.

[0050] Examples of methods for preparing silicone sheets are provided below:

[0051] Silicone plate Example 1:

[0052] The carbon-based silica gel synthesis process includes the following steps:

[0053] S1011: Add glucose solution to sodium silicate solution and stir thoroughly to obtain a preliminary mixture;

[0054] The concentration of the glucose solution is 15 wt%; the concentration of the sodium silicate solution is 15 wt%.

[0055] The mass ratio of the sodium silicate solution to the glucose solution is 5:1.

[0056] S1012 is obtained by adding sulfuric acid to the initial mixture to form a gel;

[0057] The sulfuric acid concentration is 10 wt%.

[0058] S1013 is used to granulate the gel, with the particle size controlled at 100-500μm, and then the temperature is raised to 70℃ and maintained for 4h.

[0059] S1014 is then washed with water and heated to carbonize, yielding carbon-based silica gel.

[0060] The heating and carbonization is achieved as follows:

[0061] First, the heating and carbonization atmosphere was set to nitrogen, and the temperature was increased from room temperature to 400°C at a heating rate of 5°C / min.

[0062] Maintain at 400℃ for 30 minutes;

[0063] Then, the temperature is reduced to room temperature at a cooling rate of 2℃ / min.

[0064] S1015 uses carbon-based silicone as a raw material to prepare silicone sheets.

[0065] The silicone sheet is 40cm long, 10cm wide, and 1cm thick.

[0066] The silicone plate is obtained according to the following method:

[0067] A coating material is obtained by adding binder and water to carbon-based silicone.

[0068] The coating material is applied to the substrate using a coating machine, and then placed in an oven for heating and drying.

[0069] The binder is hydroxymethyl cellulose, and the amount added is 1.5 wt% of the carbon-based silicone.

[0070] The heating and drying process is carried out as follows: drying at 70°C for 3 hours;

[0071] Then raise the temperature to 110℃ and maintain it for 1 hour, and then lower it to room temperature to obtain silicone plate No. 1.

[0072] Silicone plate Example 2:

[0073] The carbon-based silica gel synthesis process includes the following steps:

[0074] S2011 involves adding glucose solution to sodium silicate solution and stirring thoroughly to obtain a preliminary mixture;

[0075] The concentration of the glucose solution is 20 wt%; the concentration of the sodium silicate solution is 20 wt%.

[0076] The mass ratio of the sodium silicate solution to the glucose solution is 8:1.

[0077] S2012 is obtained by adding sulfuric acid to the initial mixture to form a gel;

[0078] The sulfuric acid concentration is 15 wt%.

[0079] S2013 was used to granulate the gel, with the particle size controlled at 100-500 μm, and then the temperature was raised to 80℃ and maintained for 2 hours.

[0080] S2014 is then washed with water and heated to carbonize, yielding carbon-based silica gel.

[0081] The heating and carbonization is achieved as follows:

[0082] First, the heating and carbonization atmosphere is set to nitrogen or argon, and the temperature is increased from room temperature to 500°C at a heating rate of 8°C / min.

[0083] Maintain at 500℃ for 15 minutes;

[0084] Then, the temperature is reduced to room temperature at a cooling rate of 4℃ / min.

[0085] S2015 uses carbon-based silicone as a raw material to prepare silicone sheets.

[0086] The silicone sheet is 50cm long, 20cm wide, and 2cm thick.

[0087] The silicone plate is obtained according to the following method:

[0088] A coating material is obtained by adding binder and water to carbon-based silicone.

[0089] The coating material is applied to the substrate using a coating machine, and then placed in an oven for heating and drying.

[0090] The binder is hydroxymethyl cellulose, and the amount added is 2 wt% of the carbon-based silicone.

[0091] The heating and drying process is carried out as follows: drying at 80℃ for 2 hours;

[0092] Then raise the temperature to 115℃ and maintain it for 0.5 hours, and then lower it to room temperature to obtain silicone plate No. 2.

[0093] The separation of phenobarbital impurities includes the following steps:

[0094] S21 Dissolve phenobarbital raw material (selected from the same batch of self-produced drugs with high impurity content) in ethanol to obtain the solution to be separated;

[0095] S22 disperses the liquid to be separated onto a silica gel plate, then uses a developing agent and an eluent to develop and elute, collects the dissolved and effluent solution, concentrates and crystallizes it to obtain the impurity product;

[0096] The developing solvent is petroleum ether-ethyl acetate, with a volume ratio of 70:30; the eluent is petroleum ether-acetone, with a volume ratio of 60:40.

[0097] In a specific embodiment, phenobarbital raw material containing impurities was selected for impurity separation. 100g of phenobarbital raw material was placed on a silica gel plate for separation.

[0098] Example 1 of phenobarbital isolation:

[0099] S1021 Dissolve 100g of phenobarbital raw material in ethanol to obtain the solution to be separated;

[0100] S1022 disperses the liquid to be separated onto silica gel plate No. 1, and then develops and elutes it using petroleum ether-ethyl acetate (volume ratio 70:30) and petroleum ether-acetone (volume ratio 60:40). The dissolved effluent is collected, concentrated, and crystallized to obtain the impurity product. Finally, after elution at a constant flow rate for 15 minutes, the elution is completed, and the impurity product is weighed to obtain 0.124 g.

[0101] Example 2 of phenobarbital isolation:

[0102] S2021 Dissolve 100g of phenobarbital raw material in ethanol to obtain the separation solution;

[0103] S2022 dispersed the liquid to be separated onto silica gel plate No. 2, and then developed and eluted using petroleum ether-ethyl acetate (volume ratio 70:30) and petroleum ether-acetone (volume ratio 60:40). The dissolved effluent was collected, concentrated, and crystallized to obtain the impurity product. Finally, after elution at a constant flow rate for 13 minutes, the elution was completed, and the impurity product was weighed to obtain 0.115g.

[0104] Phenobarbital Isolation Comparative Example 1:

[0105] S3021 Dissolve 100g of phenobarbital raw material in ethanol to obtain the solution to be separated;

[0106] S3022 disperses the liquid to be separated onto a commercially available silica gel plate, and then uses petroleum ether-ethyl acetate (volume ratio 70:30) and petroleum ether-acetone (volume ratio 60:40) for development and elution. The dissolved effluent is collected, concentrated, and crystallized to obtain the impurity product. Finally, after elution at a constant flow rate for 25 minutes, the elution is completed, and the impurity product is weighed to obtain 0.071g.

[0107] The above are merely embodiments of this application and are not intended to limit the scope of this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the scope of the claims of this application.

Claims

1. A method for separating phenobarbital impurities, characterized in that: Includes the following steps: Phenobarbital raw material is dissolved in a separation solvent to obtain the solution to be separated; The liquid to be separated is dispersed on a silica gel plate, and then developed and eluted using a developing solvent and an eluent. The dissolved and effluent solution is collected, concentrated, and crystallized to obtain the impurity product. The silicone plate is prepared from carbon-based silicone, and the raw materials of the carbon-based silicone include silicone and activated carbon. The developing solvent is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 70:30; the eluent is petroleum ether-acetone, and the volume ratio of petroleum ether to acetone is 60:

40. The carbon-based silica gel is prepared in the following manner: Add glucose solution to sodium silicate solution and stir thoroughly to obtain a preliminary mixture; Sulfuric acid was added to the initial mixture to obtain a gel. The gel is granulated with a particle size of 100-500 μm, and then heated to 70-80℃ and maintained for 2-4 hours. Then, the mixture is washed with water and heated to carbonize, yielding carbon-based silica gel. The concentration of the glucose solution is 15-20 wt%; the concentration of the sodium silicate solution is 15-20 wt%; and the concentration of the sulfuric acid is 10-15 wt%. The mass ratio of the sodium silicate solution to the glucose solution is 5-8:

1.

2. The method for separating phenobarbital impurities according to claim 1, characterized in that: The heating and carbonization is achieved as follows: First, set the heating and carbonization atmosphere to nitrogen or argon, and raise the temperature from room temperature to 400-500℃ at a heating rate of 5-8℃ / min. Maintain at 400-500℃ for 15-30 minutes; Then cool down to room temperature at a cooling rate of 2-4℃ / min.

3. The method for separating phenobarbital impurities according to claim 1, characterized in that: The separation solvent is ethanol.

4. The method for separating phenobarbital impurities according to claim 1, characterized in that: The silicone sheet has a length of 40-50cm, a width of 10-20cm, and a thickness of 1-2cm.

5. The method for separating phenobarbital impurities according to claim 4, characterized in that: The silicone plate is obtained according to the following method: A coating material is obtained by adding a binder to carbon-based silicone. The coating material is applied to the substrate using a coating machine, and then placed in an oven for heating and drying.

6. The method for separating phenobarbital impurities according to claim 5, characterized in that: The binder is hydroxymethyl cellulose, and the amount added is 1.5-2 wt% of the carbon-based silica gel. The heating and drying process is carried out as follows: dry at 70-80℃ for 2-3 hours; Then raise the temperature to 110-115℃ and maintain it for 0.5-1 hour, and then lower it to room temperature to obtain a silicone plate.