Production process of sugar-free levocarnitine oral solution

Abstract

The invention relates to the technical field of pharmacy, and particularly discloses a production process of a sugar-free levocarnitine oral solution. A composite filter membrane and a titanium rod filter are adopted for multi-stage filtration, so that the physical stability and the appearance quality of a final product are remarkably improved, the risk of visible foreign matters is effectively reduced, the whole process design is coherent, and the production efficiency is high. A set of complete quality control closed loop is formed from preparation, filtering to filling and packaging amount adjustment, so that the consistency of the quality of products in different production batches can be guaranteed, and the stability and efficiency requirements of large-scale production can be met.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a production process for a sugar-free L-carnitine oral solution. Background Technology

[0002] L-carnitine plays a crucial role in human energy metabolism, acting as a carrier molecule to transport long-chain fatty acids into mitochondria for β-oxidation, thereby generating adenosine triphosphate (ATP), which provides energy for various tissues such as myocardium and skeletal muscle. Due to its important physiological functions, L-carnitine is widely used to treat primary or secondary L-carnitine deficiency, such as deficiency caused by dialysis in patients with chronic renal failure, certain metabolic diseases, and to improve symptoms of myocardial ischemia and heart failure. Therefore, the development of safe, effective, and stable oral formulations of L-carnitine is of significant clinical importance.

[0003] Currently, the production process of levocarnitine oral solution still has several aspects that urgently need improvement. Traditional preparation methods mostly rely on chemical synthesis routes, which, while meeting basic production needs, often face challenges such as complex process control, high production costs, and long production cycles in actual production. In the formulation stage, due to the strong hygroscopicity of levocarnitine itself, and the fact that its aqueous solution is easily affected by factors such as temperature, light, pH, and metal ions during storage, problems such as increased degradation products or decreased effective content may occur, affecting the product's shelf life and medication safety. Therefore, how to further improve the bioavailability of levocarnitine in formulations and ensure a high degree of uniformity and stability in product quality between different batches is also a direction that requires continuous optimization of existing production technologies. Summary of the Invention

[0004] To address the shortcomings of existing technologies, the present invention aims to provide a production process for a sugar-free L-carnitine oral solution.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] A manufacturing process for a sugar-free L-carnitine oral solution includes the following steps:

[0007] S1. Add purified water to the mixing tank, control the water temperature, and turn on the stirrer;

[0008] S2. Add sodium benzoate, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0009] S3. Add L-carnitine, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0010] S4. Add DL-malic acid, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0011] S5. Add sodium saccharin, rinse the container with purified water and add it to the mixing tank, then stir until the solution is clear;

[0012] S6. Adjust the pH of the solution to the target range with hydrochloric acid solution, continue stirring, and then take a concentrated solution to test the relative density.

[0013] S7. Add purified water to the total prepared volume according to the relative density of the concentrated solution. After circulating and stirring, filter the intermediate product through a composite filter membrane, take a sample and send it for testing to determine its appearance, color and clarity.

[0014] S8. After the intermediate product is qualified, it is filtered through a titanium rod filter and then the liquid medicine is transported to the filling and sealing production line. The filling volume is adjusted to meet the requirements and filling and sealing begins. Qualified products are selected, labeled and packaged to obtain the finished product.

[0015] In the technical solution disclosed in this invention, in step S1, the stirring frequency is 30-50Hz.

[0016] In the technical solution disclosed in this invention, in step S7, the composite filter membrane is a three-layer composite structure, wherein the first layer is a pre-filtration layer, which is made of polypropylene meltblown nonwoven fabric with a thickness of 5-8mm and is located on the liquid inlet side. Its core function is to intercept. When the liquid flows through this layer, the larger insoluble particles or accidental impurities introduced in the previous process that may exist in the liquid will be intercepted or adsorbed on the fiber surface by its tortuous pore structure.

[0017] In the technical solution disclosed in this invention, the second layer of the composite filter membrane is an adsorption layer with a thickness of 2-4 mm, which is composed of modified activated carbon particles and polyvinyl butyral.

[0018] In the technical solution disclosed in this invention, the preparation method of the modified activated carbon particles is as follows:

[0019] (1) Acryloyloxyethyltrimethylammonium chloride and hydroxyethyl acrylate were added to deionized water and stirred evenly. Then, isopropanol, a molecular weight regulator, was added and mixed evenly. Subsequently, an initiator was added, and the mixture was heated and stirred to react. After the reaction was completed, the copolymer was separated by ethanol extraction and vacuum dried.

[0020] (2) Activated carbon is dispersed in an aqueous ethanol solution, and then silane coupling agent KH560 is added to it. After stirring, it is filtered, washed and dried to obtain epoxy-grafted activated carbon.

[0021] (3) Epoxy-grafted activated carbon is dispersed in DMF, and then copolymer and triethylamine catalyst are added. The mixture is heated to react. After the reaction is completed, the modified activated carbon particles are obtained by filtration, washing, drying and grinding.

[0022] Specifically, in step (1), the mass ratio of acryloyloxyethyltrimethylammonium chloride, hydroxyethyl acrylate, isopropanol and initiator is 10-15:10-15:0.5-1:0.1-0.3.

[0023] More specifically, the initiator is selected from persulfates, such as ammonium persulfate, sodium persulfate, or potassium persulfate.

[0024] Specifically, in step (1), the temperature for heating and stirring the reaction is 60-80℃, for example, 60℃, 65℃, 70℃, 75℃, or 80℃ can be selected; the time for heating and stirring the reaction is 3-5h, for example, 3h, 3.5h, 4h, 4.5h, or 5h can be selected, but it is not limited to the listed values. Other unlisted values ​​within the range are also applicable.

[0025] Specifically, in step (2), the mass ratio of activated carbon to silane coupling agent KH560 is 10-15:0.3-0.5. For example, 10:0.3, 10:0.4, 10:0.5, 12:0.3, 12:0.4, 12:0.5, 15:0.3, and 15:0.4 can be selected, but it is not limited to the listed values. Other unlisted values ​​within the range are also applicable.

[0026] Specifically, in step (3), the mass ratio of epoxy-grafted activated carbon, copolymer and triethylamine is 10-15:4-8:1-3.

[0027] Specifically, in step (3), the temperature of the heating reaction is 50-70℃, for example, 50℃, 55℃, 60℃, 65℃, 70℃ can be selected; the heating reaction time is 2-4h, for example, 2h, 2.5h, 3h, 3.5h, 4h can be selected, but not limited to the listed values, other unlisted values ​​within the range are also applicable.

[0028] In the technical solution disclosed in this invention, the preparation method of the adsorption layer is as follows: polyvinyl butyral is dissolved in deionized water, then modified activated carbon particles are added to it, ultrasonically dispersed evenly, and cast into a film to obtain the adsorption layer.

[0029] The mass ratio of polyvinyl butyral to modified activated carbon particles is 8-12:1-2. For example, 8:1, 8:2, 10:1, 10:2, 12:1, and 12:2 can be selected, but are not limited to the listed values. Other unlisted values ​​within the range are also applicable.

[0030] In the technical solution disclosed in this invention, the adsorption layer is placed between the pre-filtration layer and the fine filtration layer, and its edge is tightly bonded to the inner and outer support layers by hot melting or ultrasonic welding, so that it is physically compressed and bound by the upper and lower layers inside, completely eliminating the risk of carbon powder migration and shedding that may exist in traditional particle-filled carbon layers.

[0031] The modified activated carbon particles provided by this invention are first obtained through a free radical copolymerization reaction to obtain a functional copolymer containing positively charged quaternary ammonium salt groups and strongly hydrophilic hydroxyethyl ester segments. Subsequently, the activated carbon is surface-treated with a silane coupling agent to introduce epoxy groups onto the surface of the activated carbon. Finally, under the action of a catalyst, the hydroxyl groups in the functional copolymer react with the epoxy groups on the surface of the activated carbon, and the copolymer is covalently grafted onto the surface of the activated carbon particles to form a polymer coating layer. The polymer coating layer encapsulates the activated carbon particles in a polymer network, solving the problem of easy detachment of activated carbon particles. At the same time, the coating layer is positively charged, which generates electrostatic repulsion against L-carnitine molecules, which are also positively charged in aqueous solution, effectively inhibiting the adsorption of L-carnitine molecules. For neutral or hydrophobic organic impurities and pigment molecules, they are adsorbed by the modified activated carbon particles, which can reduce white spots and white lumps that appear during storage, improve clarity, ensure the safety of medication, and maintain stable L-carnitine content during storage.

[0032] In the technical solution disclosed in this invention, the third layer of the composite filter membrane is a fine filter layer made of sulfonated polyethersulfone. The fine filter layer is located on the liquid outlet side. The fine filter layer further adsorbs extremely small particles that may penetrate from the adsorption layer, ensuring that the medicine liquid that finally flows into the filling pipeline reaches the qualified clarity.

[0033] In the technical solution disclosed in this invention, the composite filter membrane provided by this invention can be obtained through lamination composite technology.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] This invention provides a controllable and stable production process for L-carnitine oral solution. By employing multi-stage filtration with composite filtration membranes and titanium rod filters, the physical stability and appearance quality of the final product are significantly improved, and the risk of visible foreign matter is effectively reduced. The entire process is designed to be coherent, forming a complete quality control closed loop from preparation and filtration to filling and volume adjustment. This helps to ensure the consistency of product quality between different production batches and can meet the stability and efficiency requirements of large-scale production. Attached Figure Description

[0036] Figure 1 The detection chromatogram of the L-carnitine reference standard for content determination in the 6-month long-term stability test of this invention;

[0037] Figure 2 This is a chromatogram showing the content of the levocarnitine oral solution prepared in Example 1 of this invention after a 6-month long-term stability test.

[0038] Figure 3 This is a chromatogram showing the content of the levocarnitine oral solution prepared in Example 2 of the present invention after a 6-month long-term stability test.

[0039] Figure 4 This is a chromatogram showing the content of the levocarnitine oral solution prepared in Example 3 of this invention after a 6-month long-term stability test.

[0040] Figure 5 The content determination chromatogram of the L-carnitine oral solution prepared in Comparative Example 1 of this invention after 6 months of long-term stability test.

[0041] Figure 6 This is a chromatogram showing the content of the L-carnitine oral solution prepared in Comparative Example 2 of this invention after a 6-month long-term stability test.

[0042] Figure 7 The detection chromatogram of the L-carnitine reference standard for content determination in the 12-month long-term stability test of this invention;

[0043] Figure 8 This is a chromatogram showing the content of the L-carnitine oral solution prepared in Example 1 of this invention after 12 months of long-term stability testing.

[0044] Figure 9 This is a chromatogram showing the content of the L-carnitine oral solution prepared in Example 2 of the present invention after a 12-month long-term stability test.

[0045] Figure 10 This is a chromatogram showing the content of the levocarnitine oral solution prepared in Example 3 of this invention after a 12-month long-term stability test.

[0046] Figure 11 This is a chromatogram showing the content determination of the levocarnitine oral solution prepared in Comparative Example 1 of this invention during a 12-month long-term stability test.

[0047] Figure 12 This is a chromatogram showing the content of the L-carnitine oral solution prepared in Comparative Example 2 of this invention after 12 months of long-term stability testing.

[0048] Figure 13 The detection chromatogram of the L-carnitine reference standard for content determination in the 24-month long-term stability test of this invention;

[0049] Figure 14 This is a chromatogram showing the content of the L-carnitine oral solution prepared in Example 1 of this invention after a 24-month long-term stability test.

[0050] Figure 15 This is a chromatogram showing the content of the L-carnitine oral solution prepared in Example 2 of the present invention after a 24-month long-term stability test.

[0051] Figure 16 This is a chromatogram showing the content of the L-carnitine oral solution prepared in Example 3 of the present invention after a 24-month long-term stability test.

[0052] Figure 17 This is a chromatogram showing the content of the L-carnitine oral solution prepared in Comparative Example 1 of this invention after a 24-month long-term stability test.

[0053] Figure 18 This is a chromatogram showing the content of the L-carnitine oral solution prepared in Comparative Example 2 of this invention after 24 months of long-term stability testing.

[0054] Figure 19 A schematic diagram showing that a sample of L-carnitine oral solution has passed the light inspection.

[0055] Figure 20 This is a schematic diagram showing a sample of L-carnitine oral solution that failed the light inspection. Detailed Implementation

[0056] The present invention will be further described in detail below through specific preferred embodiments, but the present invention is not limited to the following embodiments.

[0057] It should be noted that, unless otherwise specified, all chemical reagents involved in this invention were purchased through commercial channels.

[0058] The L-carnitine oral solution prepared in this embodiment of the invention contains 100g of L-carnitine, 3.5g of DL-malic acid, 4.8g of sodium benzoate, and 0.5g of sodium saccharin per 1000mL of oral solution.

[0059] Example 1

[0060] A manufacturing process for a sugar-free L-carnitine oral solution includes the following steps:

[0061] S1. Add purified water to the mixing tank, control the water temperature at 20℃, turn on the stirrer, and stir at a frequency of 40Hz.

[0062] S2. Add sodium benzoate, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0063] S3. Add L-carnitine, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0064] S4. Add DL-malic acid, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0065] S5. Add sodium saccharin, rinse the container with purified water and add it to the mixing tank, then stir until the solution is clear;

[0066] S6. Adjust the pH of the solution to the target range with hydrochloric acid solution, continue stirring, and then take a concentrated solution to test the relative density.

[0067] S7. Add purified water to the total prepared volume according to the relative density of the concentrated solution. After circulating and stirring, filter the intermediate product through a composite filter membrane, take a sample and send it for testing to determine its appearance, color and clarity.

[0068] S8. After the intermediate product is qualified, it is filtered through a titanium rod filter and then the liquid medicine is transported to the filling and sealing production line. The filling volume is adjusted to meet the requirements and filling and sealing begins. Qualified products are selected, labeled and packaged to obtain the finished product.

[0069] The composite filter membrane has a three-layer composite structure and is prepared by lamination technology. The first layer is a pre-filtration layer made of polypropylene meltblown nonwoven fabric with a thickness of 6 mm. The second layer is an adsorption layer, which is prepared as follows: 10 g of polyvinyl butyral is dissolved in 100 mL of deionized water, and then 1.5 g of modified activated carbon particles are added. The mixture is ultrasonically dispersed and cast into a film to obtain the adsorption layer with a thickness of 3 mm. The third layer is a sulfonated polyethersulfone ultrafiltration membrane with a pore size of 0.22 μm.

[0070] The modified activated carbon particles are prepared as follows:

[0071] (1) Add 10g of acryloyloxyethyltrimethylammonium chloride and 10g of hydroxyethyl acrylate to 100mL of deionized water, stir evenly, then add 0.5g of molecular weight regulator isopropanol, mix evenly, then add 0.1g of initiator ammonium persulfate, heat and stir at 80℃ for 3h, after the reaction is completed, separate by ethanol extraction, and vacuum dry to obtain copolymer;

[0072] (2) Disperse 10g of activated carbon in 100mL of ethanol aqueous solution (volume ratio of ethanol to water is 4:1), then add 0.3g of silane coupling agent KH560, stir at room temperature for 2h, and then filter, wash and dry to obtain epoxy-grafted activated carbon.

[0073] (3) Disperse 10g of epoxy-grafted activated carbon in 100mL of DMF, then add 4g of copolymer and 1g of catalyst triethylamine, heat at 70℃ for 2h, and after the reaction is completed, filter, wash, dry and grind to obtain modified activated carbon particles.

[0074] Example 2

[0075] A manufacturing process for a sugar-free L-carnitine oral solution includes the following steps:

[0076] S1. Add purified water to the mixing tank, control the water temperature at 20℃, turn on the stirrer, and stir at a frequency of 40Hz.

[0077] S2. Add sodium benzoate, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0078] S3. Add L-carnitine, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0079] S4. Add DL-malic acid, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0080] S5. Add sodium saccharin, rinse the container with purified water and add it to the mixing tank, then stir until the solution is clear;

[0081] S6. Adjust the pH of the solution to the target range with hydrochloric acid solution, continue stirring, and then take a concentrated solution to test the relative density.

[0082] S7. Add purified water to the total prepared volume according to the relative density of the concentrated solution. After circulating and stirring, filter the intermediate product through a composite filter membrane, take a sample and send it for testing to determine its appearance, color and clarity.

[0083] S8. After the intermediate product is qualified, it is filtered through a titanium rod filter and then the liquid medicine is transported to the filling and sealing production line. The filling volume is adjusted to meet the requirements and filling and sealing begins. Qualified products are selected, labeled and packaged to obtain the finished product.

[0084] The composite membrane has a three-layer structure and is prepared by lamination technology. The first layer is a pre-filtration layer made of polypropylene meltblown nonwoven fabric with a thickness of 6 mm. The second layer is an adsorption layer, which is prepared as follows: 10 g of polyvinyl butyral is dissolved in 100 mL of deionized water, and then 1 g of modified activated carbon particles are added. The mixture is ultrasonically dispersed and cast into a film to obtain the adsorption layer with a thickness of 3 mm. The third layer is a sulfonated polyethersulfone ultrafiltration membrane with a pore size of 0.22 μm.

[0085] The modified activated carbon particles are prepared as follows:

[0086] (1) Add 10g of acryloyloxyethyltrimethylammonium chloride and 10g of hydroxyethyl acrylate to 100mL of deionized water, stir evenly, then add 0.5g of molecular weight regulator isopropanol, mix evenly, then add 0.1g of initiator ammonium persulfate, heat and stir at 80℃ for 3h, after the reaction is completed, separate by ethanol extraction, and vacuum dry to obtain copolymer;

[0087] (2) Disperse 10g of activated carbon in 100mL of ethanol aqueous solution (the volume ratio of ethanol to water is 4:1), then add 0.5g of silane coupling agent KH560, stir at room temperature for 2h, and then filter, wash and dry to obtain epoxy-grafted activated carbon.

[0088] (3) Disperse 10g of epoxy-grafted activated carbon in 100mL of DMF, then add 8g of copolymer and 3g of catalyst triethylamine, heat at 70℃ for 2h, and after the reaction is completed, filter, wash, dry and grind to obtain modified activated carbon particles.

[0089] Example 3

[0090] A manufacturing process for a sugar-free L-carnitine oral solution includes the following steps:

[0091] S1. Add purified water to the mixing tank, control the water temperature at 20℃, turn on the stirrer, and stir at a frequency of 40Hz.

[0092] S2. Add sodium benzoate, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0093] S3. Add L-carnitine, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0094] S4. Add DL-malic acid, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0095] S5. Add sodium saccharin, rinse the container with purified water and add it to the mixing tank, then stir until the solution is clear;

[0096] S6. Adjust the pH of the solution to the target range with hydrochloric acid solution, continue stirring, and then take a concentrated solution to test the relative density.

[0097] S7. Add purified water to the total prepared volume according to the relative density of the concentrated solution. After circulating and stirring, filter the intermediate product through a composite filter membrane, take a sample and send it for testing to determine its appearance, color and clarity.

[0098] S8. After the intermediate product is qualified, it is filtered through a titanium rod filter and then the liquid medicine is transported to the filling and sealing production line. The filling volume is adjusted to meet the requirements and filling and sealing begins. Qualified products are selected, labeled and packaged to obtain the finished product.

[0099] The composite membrane has a three-layer structure and is prepared by lamination technology. The first layer is a pre-filtration layer made of polypropylene meltblown nonwoven fabric with a thickness of 6 mm. The second layer is an adsorption layer, which is prepared as follows: 10 g of polyvinyl butyral is dissolved in 100 mL of deionized water, and then 2 g of modified activated carbon particles are added. The mixture is ultrasonically dispersed and cast into a film to obtain the adsorption layer with a thickness of 3 mm. The third layer is a sulfonated polyethersulfone ultrafiltration membrane with a pore size of 0.22 μm.

[0100] The modified activated carbon particles are prepared as follows:

[0101] (1) Add 10g of acryloyloxyethyltrimethylammonium chloride and 10g of hydroxyethyl acrylate to 100mL of deionized water, stir evenly, then add 0.5g of molecular weight regulator isopropanol, mix evenly, then add 0.1g of initiator ammonium persulfate, heat and stir at 80℃ for 3h, after the reaction is completed, separate by ethanol extraction, and vacuum dry to obtain copolymer;

[0102] (2) Disperse 10g of activated carbon in 100mL of ethanol aqueous solution (volume ratio of ethanol to water is 4:1), then add 0.3g of silane coupling agent KH560, stir at room temperature for 2h, and then filter, wash and dry to obtain epoxy-grafted activated carbon.

[0103] (3) Disperse 10g of epoxy-grafted activated carbon in 100mL of DMF, then add 6g of copolymer and 2g of catalyst triethylamine, heat at 70℃ for 2h, and after the reaction is completed, filter, wash, dry and grind to obtain modified activated carbon particles.

[0104] Comparative Example 1

[0105] A manufacturing process for a sugar-free L-carnitine oral solution includes the following steps:

[0106] S1. Add purified water to the mixing tank, control the water temperature at 20℃, turn on the stirrer, and stir at a frequency of 40Hz.

[0107] S2. Add sodium benzoate, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0108] S3. Add L-carnitine, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0109] S4. Add DL-malic acid, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0110] S5. Add sodium saccharin, rinse the container with purified water and add it to the mixing tank, then stir until the solution is clear;

[0111] S6. Adjust the pH of the solution to the target range with hydrochloric acid solution, continue stirring, and then take a concentrated solution to test the relative density.

[0112] S7. Add purified water to the total prepared volume according to the relative density of the concentrated solution. After circulating and stirring, filter the intermediate product through a composite filter membrane, take a sample and send it for testing to determine its appearance, color and clarity.

[0113] S8. After the intermediate product is qualified, it is filtered through a titanium rod filter and then the liquid medicine is transported to the filling and sealing production line. The filling volume is adjusted to meet the requirements and filling and sealing begins. Qualified products are selected, labeled and packaged to obtain the finished product.

[0114] Compared with Example 1, no composite filter membrane was used for filtration in Comparative Example 1.

[0115] Comparative Example 2

[0116] A manufacturing process for a sugar-free L-carnitine oral solution includes the following steps:

[0117] S1. Add purified water to the mixing tank, control the water temperature at 20℃, turn on the stirrer, and stir at a frequency of 40Hz.

[0118] S2. Add sodium benzoate, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0119] S3. Add L-carnitine, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0120] S4. Add DL-malic acid, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear;

[0121] S5. Add sodium saccharin, rinse the container with purified water and add it to the mixing tank, then stir until the solution is clear;

[0122] S6. Adjust the pH of the solution to the target range with hydrochloric acid solution, continue stirring, and then take a concentrated solution to test the relative density.

[0123] S7. Add purified water to the total prepared volume according to the relative density of the concentrated solution. After circulating and stirring, filter the intermediate product through a composite filter membrane, take a sample and send it for testing to determine its appearance, color and clarity.

[0124] S8. After the intermediate product is qualified, it is filtered through a titanium rod filter and then the liquid medicine is transported to the filling and sealing production line. The filling volume is adjusted to meet the requirements and filling and sealing begins. Qualified products are selected, labeled and packaged to obtain the finished product.

[0125] The composite filter membrane has a three-layer composite structure and is prepared by lamination technology. The first layer is a pre-filtration layer made of polypropylene meltblown nonwoven fabric with a thickness of 6 mm. The second layer is an adsorption layer, which is prepared as follows: 10 g of polyvinyl butyral is dissolved in 100 mL of deionized water, and then 1.5 g of activated carbon particles are added. The mixture is ultrasonically dispersed and cast into a film to obtain the adsorption layer with a thickness of 3 mm. The third layer is a sulfonated polyethersulfone ultrafiltration membrane with a pore size of 0.22 μm.

[0126] Compared with Example 1, no modification treatment was performed on the activated carbon in Comparative Example 2.

[0127] The L-carnitine oral solutions prepared in Examples 1-3 and Comparative Examples 1-2 were used to prepare 30 vials of each solution. Long-term stability tests were conducted according to the "Guidelines for Drug Stability". The test conditions were: temperature 30°C and humidity 65%. Samples were taken at 6, 12 and 24 months to examine the L-carnitine content in the samples and to perform light inspection.

[0128] The content determination method is as follows:

[0129] Determined by high performance liquid chromatography (General Chapter 0512, Part IV, Chinese Pharmacopoeia 2020 Edition).

[0130] Preparation of the test solution: Accurately measure 2 ml of this product, place it in a 200 ml volumetric flask, dilute with water to the mark, and shake well to obtain the solution.

[0131] Preparation of reference solution: Take an appropriate amount of L-carnitine reference standard, accurately weigh it, dissolve it in water and dilute it quantitatively to prepare a solution containing approximately 1 mg of L-carnitine per 1 ml.

[0132] Chromatographic conditions: Amide-bonded silica gel was used as the packing material (Welch Ultimate HILIC Amide 250mm x 4.6mm, 5μm or equivalent column); the mobile phase was 0.05mol / L phosphate buffer (6.81g of potassium dihydrogen phosphate was weighed, added to 1000ml of water, and the pH was adjusted to 4.7 with sodium hydroxide solution)-acetonitrile (35:65); the flow rate was 0.7ml / min; the column temperature was 30℃; the detection wavelength was 205nm; the run time was 25 minutes; and the injection volume was 20μl.

[0133] System applicability requirements: The theoretical plate number, calculated based on the levocarnitine peak, shall not be less than 2000.

[0134] For the assay, accurately measure the test solution and the reference solution, inject them separately into the liquid chromatograph, record the chromatograms, and calculate the results based on the peak area using the external standard method.

[0135] The content determination chromatogram of the levocarnitine oral solution sample after a 6-month long-term stability test is shown below. Figure 1-6As shown, the chromatogram of the content determination of the levocarnitine oral solution sample after 12 months of long-term stability test is as Figure 7-12 shown, and the chromatogram of the content determination of the levocarnitine oral solution sample after 24 months of long-term stability test is as Figure 13-18 shown.

[0136] Visual inspection mainly conducts foreign matter inspection. If there is no trace of foreign matter movement during inspection, it is considered qualified for visual inspection. The visual inspection result shows GOOD (as Figure 19 shown); otherwise, it is unqualified, that is, there is a trace of foreign matter movement during inspection, and the visual inspection result shows BAD (as Figure 20 shown).

[0137] Record the levocarnitine content and the qualified rate of visual inspection. The results are shown in Table 1.

[0138] Table 1 Results of long-term stability test

[0139] As can be seen from Table 1, in the long-term stability test, the qualified rate of visual inspection of the samples prepared in Examples 1-3 is relatively high, and the change in the qualified rate of visual inspection is very small during the test period (24 months), and the levocarnitine content is relatively stable with little change.

[0140] Finally, it should be noted that: the above embodiments do not limit the present invention in any form. For those skilled in the art, based on the present invention, some modifications and improvements can be made. Therefore, any modification or improvement made without departing from the spirit of the present invention falls within the scope of protection required by the present invention.

Claims

1. A manufacturing process for a sugar-free L-carnitine oral solution, characterized in that, Includes the following steps: S1. Add purified water to the mixing tank, control the water temperature, and turn on the stirrer; S2. Add sodium benzoate, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear; S3. Add L-carnitine, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear; S4. Add DL-malic acid, rinse the container with purified water and add it to the mixing tank, and stir until the solution is clear; S5. Add sodium saccharin, rinse the container with purified water and add it to the mixing tank, then stir until the solution is clear; S6. Adjust the pH of the solution to the target range with hydrochloric acid solution, continue stirring, and then take a concentrated solution to test the relative density. S7. Add purified water to the total prepared volume according to the relative density of the concentrated solution. After circulating and stirring, filter the intermediate product through a composite filter membrane, take a sample and send it for testing to determine its appearance, color and clarity. S8. After the intermediate product is qualified, it is filtered through a titanium rod filter and then the liquid medicine is transported to the filling and sealing production line. The filling volume is adjusted to meet the requirements and filling and sealing begins. Qualified products are selected, labeled and packaged to obtain the finished product.

2. The production process according to claim 1, characterized in that, In step S7, the composite filter membrane has a three-layer composite structure, wherein the first layer is a pre-filtration layer made of polypropylene meltblown nonwoven fabric; the second layer is an adsorption layer made of modified activated carbon particles and polyvinyl butyral; and the third layer is a fine filtration layer made of sulfonated polyethersulfone.

3. The production process according to claim 2, characterized in that, The modified activated carbon particles are prepared as follows: (1) Acryloyloxyethyltrimethylammonium chloride and hydroxyethyl acrylate were added to deionized water and stirred evenly. Then, isopropanol, a molecular weight regulator, was added and mixed evenly. Subsequently, ammonium persulfate, an initiator, was added and heated and stirred to react. After the reaction was completed, the copolymer was separated by ethanol extraction and vacuum dried. (2) Activated carbon is dispersed in an aqueous ethanol solution, and then silane coupling agent KH560 is added to it. After stirring, it is filtered, washed and dried to obtain epoxy-grafted activated carbon. (3) Epoxy-grafted activated carbon is dispersed in N,N-dimethylformamide, and then copolymer and triethylamine catalyst are added. The mixture is heated to react. After the reaction is completed, the modified activated carbon particles are obtained by filtration, washing, drying and grinding.

4. The production process according to claim 3, characterized in that, In step (1), the mass ratio of acryloyloxyethyltrimethylammonium chloride, hydroxyethyl acrylate, isopropanol and initiator ammonium persulfate is 10:10:0.5:0.

1.

5. The production process according to claim 3, characterized in that, In step (1), the temperature for heating and stirring the reaction is 60-80℃, and the time for heating and stirring the reaction is 3-5h.

6. The production process according to claim 3, characterized in that, In step (2), the mass ratio of activated carbon to silane coupling agent KH560 is 10:0.3-0.

5.

7. The production process according to claim 3, characterized in that, In step (3), the mass ratio of epoxy-grafted activated carbon, copolymer and triethylamine is 10:4-8:1-3.

8. The production process according to claim 3, characterized in that, In step (3), the temperature of the heating reaction is 50-70℃ and the heating reaction time is 2-4h.

9. The production process according to claim 2, characterized in that, The adsorption layer is prepared as follows: polyvinyl butyral is dissolved in deionized water, then modified activated carbon particles are added, ultrasonically dispersed evenly, and cast into a film to obtain the adsorption layer.

10. The production process according to claim 9, characterized in that, The mass ratio of polyvinyl butyral to modified activated carbon particles is 10:1-2.

Images