Preparation method and formula of diazepam oral solution

Abstract

The invention discloses a preparation method and a formula of a diazepam oral solution, relates to the field of chemical pharmacy, and solves the problem of poor solution stability in the prior art, and the preparation method of the diazepam oral solution is characterized by comprising the following steps: A, preparing a first solution, heating propylene glycol, and stirring to obtain a second solution; diazepam, anhydrous citric acid and polyethylene glycol 1000 are added and stirred until the materials are completely dissolved, and a first solution is obtained; b, preparing a second solution, adding sodium citrate, sorbitol and erythrosine into purified water, and stirring until sodium citrate, sorbitol and erythrosine are completely dissolved to obtain the second solution; c, mixing to a constant volume: mixing the second solution with the first solution, cooling, adding the juicy peach essence, supplementing the purified water to full dose, and uniformly stirring and mixing; and D, filtering: filtering the mixed liquid medicine through a filter element to obtain the diazepam oral solution. The purpose of improving the solution stability is achieved.

Description

Technical Field

[0001] The invention relates to the field of chemical pharmacy, and more specifically, to a preparation method and a formula of a diazepam oral solution. Background Art

[0002] Diazepam is a classic benzodiazepine Diazepam is a type of drug that is widely used in the treatment of anxiety, epilepsy, muscle spasms and other diseases. However, its inherent physical and chemical properties pose significant challenges to formulation development: diazepam has extremely low solubility in water and is easily degraded under light or alkaline conditions, resulting in traditional oral solid preparations (such as tablets and capsules) with slow absorption, large fluctuations in bioavailability, and poor compliance in patients with dysphagia. In order to meet the medication needs of special populations, liquid preparations have gradually become a research hotspot, but the development of diazepam oral solution in the prior art still faces multiple bottlenecks. First, most liquid preparations rely on high-concentration ethanol or propylene glycol as a single solvent. Although they can be solubilized for a short time, long-term use can easily cause oral mucosal irritation, and during storage, solvent volatilization can easily lead to drug precipitation or concentration deviation. Secondly, existing formulas often use thickeners such as sodium carboxymethyl cellulose to improve the taste, but their compatibility with diazepam is poor, and they are prone to form colloidal stratification after long-term storage, affecting dosage accuracy. Therefore, there is an urgent need to develop a diazepam oral solution formula that takes into account high solubility, long-term stability, suitable taste and low irritation, and to develop a robust preparation process to address the shortcomings of the existing technology and meet the clinical needs for precise drug delivery and patient-friendly preparations. Summary of the invention

[0003] In a first aspect, the present invention provides a method for preparing a diazepam oral solution, which achieves the purpose of improving dissolution efficiency and solution stability.

[0004] The above technical purpose of the present invention is achieved through the following technical scheme, a preparation method of diazepam oral solution, comprising the following steps: A, preparing a first solution, heating propylene glycol, adding diazepam, anhydrous citric acid and polyethylene glycol 1000, stirring until completely dissolved, to obtain a first solution; B, preparing a second solution, adding sodium citrate, sorbitol and erythrosine to purified water, stirring until completely dissolved, to obtain a second solution; C, mixing and fixing the volume, mixing the second solution with the first solution, adding peach essence after cooling, adding purified water to the full amount, stirring and mixing evenly; D, filtering, filtering the mixed liquid through a filter element to obtain a diazepam oral solution.

[0005] Further, in step A, the target temperature of heating propylene glycol is 60 to 80 degrees Celsius, the stirring speed is 190 to 300 rpm, and the stirring time is 60 to 90 minutes.

[0006] Further, in step B, the water consumption of the purified water is 12% - 16% of the total purified water consumption, the stirring speed is 190 - 300 revolutions per minute, and the stirring time is 60 - 90 minutes.

[0007] Further, in step C, the stirring and mixing time is 20 - 40 minutes, the stirring speed is 150 - 250 revolutions per minute, and the density of the liquid medicine after volume fixation is 1.13 ± 0.02 g / ml.

[0008] Further, the filter element is a 45μm stainless steel filter element, and the filtration pressure ≤ 0.25 MPa.

[0009] Further, it also includes the step of filling the diazepam oral solution:

[0010] E. Filling, filling the diazepam oral solution into high-density polyethylene bottles for oral liquid medicine; the filling volume is 101 - 106 ml / bottle; the time limit from the completion of preparation to the end of filling ≤ 96 hours; samples are taken before, during, and after filling respectively, and 4 bottles are sampled at each time node.

[0011] In the second aspect, the present invention provides a diazepam oral solution formula, which is used for the preparation method described in the first aspect; the formula contains the following components: diazepam, propylene glycol, anhydrous citric acid, sodium citrate, polyethylene glycol 1000, sorbitol, peach essence, erythrosine, purified water;

[0012] Among them, the formula dosage for each preparation of 100 ml of diazepam oral solution is as follows: diazepam 0.1 g, propylene glycol 40 - 55 g, anhydrous citric acid 0.1 - 0.15 g, sodium citrate 1.4 - 1.6 g, polyethylene glycol 1000 15 - 16 g, sorbitol 20 - 22 g, peach essence 0.05 - 0.15 g, erythrosine 0.04 - 0.06 g, and the balance is purified water.

[0013] Diazepam: The main drug component, which plays an anti-anxiety and sedative role.

[0014] Propylene glycol: The main solvent, accounting for 40 - 55%, solubilizes poorly soluble diazepam through hydrogen bonding, and reduces the irritation of a single solvent.

[0015] Anhydrous citric acid: Acidic pH regulator, forms a buffer system with sodium citrate to inhibit the alkaline hydrolysis of the drug.

[0016] Sodium citrate: Alkaline buffer component, stabilizes the pH, neutralizes bitterness, and improves the taste acceptance.

[0017] Polyethylene glycol 1000: Solubilizer and viscosity regulator, forms micelles synergistically with propylene glycol to improve the dissolution efficiency.

[0018] Sorbitol: A sweetening and stabilizing agent that masks bitterness and reduces water activity to inhibit microbial growth.

[0019] Peach essence: A flavoring agent that completely masks the odors of solvents and drugs, improving patient compliance.

[0020] Erythrosine: A red coloring agent that provides a visual identifier and indirectly indicates light protection for storage, extending stability.

[0021] Furthermore, the dosage of propylene glycol is 45 - 55 g, and the molar ratio of anhydrous citric acid to sodium citrate is 1:7 - 1:8.

[0022] Furthermore, for every 100 ml of diazepam oral solution prepared, the formulation dosages are as follows: diazepam 0.1 g, propylene glycol 55 g, anhydrous citric acid 0.15 g, sodium citrate 1.4 g, polyethylene glycol 1000 15 g, sorbitol 22 g, peach essence 0.05 g, erythrosine 0.04 g, with the balance being purified water.

[0023] Furthermore, for every 100 ml of diazepam oral solution prepared, the formulation dosages are as follows: diazepam 0.1 g, propylene glycol 50 g, anhydrous citric acid 0.116 g, sodium citrate 1.482 g, polyethylene glycol 1000 15.38 g, sorbitol 20.85 g, peach essence 0.1 g, erythrosine 0.05 g, with the balance being purified water.

[0024] In summary, the present invention has at least one of the following beneficial effects:

[0025] 1. By dissolving diazepam step by step with propylene glycol and polyethylene glycol 1000 under heating conditions, it avoids local supersaturation crystallization caused by the competitive dissolution of water-soluble excipients, significantly improving the dissolution rate of diazepam.

[0026] 2. Propylene glycol and polyethylene glycol 1000 form a composite solvent system, greatly enhancing the solubility of diazepam.

[0027] 3. The citric acid - sodium citrate buffer pair maintains the pH in an acidic environment, greatly extending the shelf life of diazepam. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 It is a flowchart of the preparation method of the diazepam oral solution in Example 1 DETAILED DESCRIPTION OF THE INVENTION

[0029] In order to make the technical problems, technical solutions, and beneficial effects to be solved by the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments.

[0030] The terms "first" and "second" are for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, features defined with "first" and "second" may explicitly or implicitly include one or more of such features. In the description of the present invention, "a plurality" means two or more, unless otherwise specifically defined.

[0031] Example 1

[0032] A method for preparing a diazepam oral solution, comprising the following steps:

[0033] A. Prepare the first solution. Add a measured amount of propylene glycol to mixing tank one, start stirring, set the stirring speed at 190 - 300 revolutions per minute, heat to 60 - 80 °C, and maintain the temperature between 60 - 80 °C. Sequentially add the formulated amounts of diazepam, anhydrous citric acid, and polyethylene glycol 1000, and stir for 60 - 90 minutes. Reasonably set the stirring speed to ensure that diazepam can be completely dissolved within 90 minutes to obtain the first solution. Propylene glycol serves as the main solvent, and its highly polar molecules effectively dissolve diazepam through hydrogen bonding and hydrophobic interactions. Increasing the temperature can reduce the liquid viscosity, accelerate molecular thermal motion, and shorten the diazepam dissolution time. The hydrophobic chain segments of polyethylene glycol 1000 wrap around diazepam molecules to form micelles, and the hydrophilic chain segments are compatible with propylene glycol, further improving the solubility. Preferably, heat propylene glycol to 70 °C and maintain the temperature between 65 - 70 °C to better reduce the decomposition rate of propylene glycol.

[0034] B. Prepare the second solution. Add 15% of the formulated volume of purified water to mixing tank two, start stirring, and sequentially add the formulated amounts of sodium citrate, sorbitol, and erythrosine. Select the stirring speed between 190 - 300 revolutions per minute according to the situation of the mixing tank to ensure that all components are completely dissolved after stirring for 60 - 90 minutes. Both sodium citrate and sorbitol are highly water-soluble excipients and preferentially dissolve in purified water to avoid solubility conflicts caused by direct contact with propylene glycol. Sodium citrate and the anhydrous citric acid in step A form a buffer pair (molar ratio 1:7 - 1:8), and after mixing, the pH of the medicinal liquid is stably acidic, and the hydrolysis rate of diazepam decreases by 90% compared to the neutral condition. Erythrosine is evenly dispersed in purified water to avoid aggregation when subsequently mixed with organic solvents, ensuring uniform color. Sorbitol is prone to caramelization at high temperatures, and dissolving at room temperature maintains its sweet taste characteristics and avoids the fading of the erythrosine color due to high temperatures.

[0035] C. Mix and make up to a fixed volume. Slowly add the second solution to the first solution in the preparation tank 1 and mix them. Rinse the preparation tank 2 with a small amount of water and transfer the rinsing liquid into the first solution. Stir and cool to room temperature. After cooling, add peach essence and make up to the full volume with purified water. Stir and mix evenly for 20 - 40 minutes at the same rotation speed as above. By gradually diluting the propylene glycol concentration, the risk of supersaturated crystallization of diazepam caused by the sudden change of solvent polarity is reduced. Peach essence contains volatile components, and high temperature will cause aroma loss. Adding it after cooling to room temperature can retain more than 95% of the active ingredients.

[0036] D. Filter. Filter the mixed liquid medicine through a filter element to obtain diazepam oral solution. Preferably, the filter element is a 45μm stainless steel filter element, and the filtration pressure ≤ 0.25 MPa. The 45μm stainless steel filter element has a pore size larger than the diazepam molecule and can intercept undissolved particles and fiber impurities introduced during the production process. The pressure ≤ 0.25 MPa can avoid the rupture of polyethylene glycol 1000 micelles or the desorption of diazepam molecules caused by high-pressure shearing.

[0037] E. Fill. Fill the diazepam oral solution into high-density polyethylene bottles for oral liquid medicine; the filling volume is 101 - 106 ml / bottle; the time limit from the completion of preparation to the end of filling ≤ 96 hours; samples are taken before, during, and after filling respectively, and 4 bottles are taken at each time point. Preferably, 3 - 6 L of the initial discharged liquid medicine is drained and the filling volume is adjusted during filling. The residual bubbles rinsed from the filter element and the initial liquid medicine in the pipeline are removed to ensure the consistency of filling concentration.

[0038] This embodiment has the following beneficial effects:

[0039] By raising the temperature, the viscosity of propylene glycol is reduced (the viscosity is reduced by about 40%), accelerating the diffusion of diazepam molecules and shortening the dissolution time; the upper temperature limit is controlled within 65 - 70 degrees Celsius. Compared with above 80 degrees Celsius, the oxidation decomposition rate of propylene glycol is greatly reduced. Dissolving the second solution at room temperature avoids the caramelization of sorbitol and the fading of erythrosine at high temperature. Adding peach essence at room temperature retains the volatile aroma components and avoids the loss of fragrance caused by high temperature.

[0040] The first solution preferentially dissolves hydrophobic components. Propylene glycol is used as the main solvent to first dissolve diazepam, the hydrophobic chain segment of PEG 1000, and anhydrous citric acid, avoiding competition for the dissolution space with water-soluble excipients. The second solution isolates the water / oil phase conflict. Water-soluble excipients such as sodium citrate and sorbitol are pre-dissolved in purified water to prevent the decrease in solubility caused by direct contact with propylene glycol.

[0041] Slowly add the second solution to the first solution to reduce the risk of sudden change in solvent polarity by gradual dilution. If the reverse operation is carried out, it may cause supersaturated crystallization of diazepam.

[0042] Example 2

[0043] This embodiment provides a formulation of diazepam oral solution, which contains the following components: diazepam, propylene glycol, anhydrous citric acid, sodium citrate, polyethylene glycol 1000, sorbitol, peach essence, erythrosine, and purified water.

[0044] The sources of raw materials are as follows:

[0045]

[0046]

[0047] The dosage for preparing every 100 ml of the diazepam oral solution formulation is as follows: diazepam 0.1 g, propylene glycol 40 - 55 g, anhydrous citric acid 0.1 - 0.15 g, sodium citrate 1.4 - 1.6 g, polyethylene glycol 1000 15 - 16 g, sorbitol 20 - 22 g, peach essence 0.05 - 0.15 g, erythrosine 0.04 - 0.06 g, and the balance is purified water. Applying this formulation to a method for preparing a diazepam oral solution provided in Example 1, a diazepam oral solution is obtained. During the preparation process, no new substances are generated by the reaction between the components, so the content of each component in the oral solution is basically the same as that in the formulation.

[0048] Optionally, the dosage of propylene glycol is 45 - 55 g, and the molar ratio of anhydrous citric acid to sodium citrate is 1:7 - 1:8.

[0049] Optionally, the dosage for preparing every 100 ml of the diazepam oral solution formulation is as follows: diazepam 0.1 g, propylene glycol 55 g, anhydrous citric acid 0.15 g, sodium citrate 1.4 g, polyethylene glycol 1000 15 g, sorbitol 22 g, peach essence 0.05 g, erythrosine 0.04 g, and the balance is purified water.

[0050] Preferably, the dosage for preparing every 100 ml of the diazepam oral solution formulation is as follows: diazepam 0.1 g, propylene glycol 50 g, anhydrous citric acid 0.116 g, sodium citrate 1.482 g, polyethylene glycol 1000 15.38 g, sorbitol 20.85 g, peach essence 0.1 g, erythrosine 0.05 g, and the balance is purified water.

[0051] Achieving Efficient Solubilization and Long-Term Stability through Multicomponent Synergistic Action: Propylene glycol serves as the main solvent and combines with polyethylene glycol 1000 to form micelles that encapsulate diazepam, significantly enhancing the solubility of the lipid-soluble drug to over 1.2 mg / mL; anhydrous citric acid and sodium citrate construct an acidic buffer system with a molar ratio of 1:6.1 to inhibit the hydrolysis of diazepam; sorbitol is dissolved at room temperature to avoid caramelization, and peach essence is added after cooling to retain >95% of the aroma components, while erythrosine is pre-dispersed to ensure uniform color; the stepwise dissolution and gradient dilution process of the excipients circumvents the risk of crystallization, and 45-μm low-pressure filtration protects the micelle structure, ultimately achieving multi-dimensional optimization of high drug loading, long shelf life, excellent taste, and industrial production feasibility.

[0052] Example 3

[0053] An oral solution of diazepam, the formula dosage for preparing every 100 ml of the oral solution of diazepam is as follows: 0.1 g of diazepam, 55 g of propylene glycol, 0.15 g of anhydrous citric acid, 1.4 g of sodium citrate, 15 g of polyethylene glycol 1000, 22 g of sorbitol, 0.05 g of peach essence, 0.04 g of erythrosine, and the balance is purified water. The preparation method is as follows:

[0054] Step 1: Add the measured amount of propylene glycol to Mixing Tank 1, start stirring, set the stirring speed at 190 revolutions per minute, and heat to 60-80 °C; sequentially add the formula amounts of diazepam, anhydrous citric acid, and polyethylene glycol 1000, and stir for 60-90 minutes to obtain the first solution.

[0055] Step 2: Add 15% of the purified water in terms of the preparation volume to Mixing Tank 2, start stirring, and sequentially add the formula amounts of sodium citrate, sorbitol, and erythrosine. Select the stirring speed between 190 revolutions per minute according to the situation of the mixing tank, and stir for 60-90 minutes until completely dissolved to obtain the second solution.

[0056] Step 3: Slowly add the second solution to Mixing Tank 1 to mix with the first solution, and use a small amount of water to rinse Mixing Tank 2. Transfer the rinsing liquid into the first solution together, stir and cool to room temperature. After cooling, add peach essence, make up the purified water to the total volume, stir and mix evenly, and stir for 20-40 minutes.

[0057] Step 4: Filter the mixed liquid medicine through a filter element to obtain the oral solution of diazepam. Take the prepared diazepam solution, observe the properties, and measure the content of each component.

[0058] Step 5: Fill the oral solution of diazepam into high-density polyethylene bottles for oral liquid medicine to obtain the filled finished product. Take the finished products stored for 6 months, 1 year, 1.5 years, and 2 years respectively, observe the properties, and measure the content of each component.

[0059] The diazepam oral solution prepared by this example presents a uniform, transparent, light red liquid state, without visible suspended matter or precipitation; the diazepam content is 0.098 - 0.102 g / 100 mL; the content errors of propylene glycol, polyethylene glycol 1000, and sorbitol within ±2% of the labeled amount in the formula meet the prescription requirements. When stored for 6 months, the properties and the contents of each component show no obvious changes; when stored for 1 year, the properties show no obvious changes, and the trace amount of diazepam decreases by 2 - 3% due to degradation; when stored for 1.5 years, a very small amount of flocculants appear and return to a uniform state after shaking, and the diazepam content decreases by 3 - 5%; when stored for 2 years, a small amount of flocculants appear, the clarity decreases, and the diazepam content decreases by 5 - 6%.

[0060] Example 4

[0061] A diazepam oral solution, the formula dosage for preparing every 100 ml of diazepam oral solution is as follows: diazepam 0.1 g, propylene glycol 50 g, anhydrous citric acid 0.116 g, sodium citrate 1.482 g, polyethylene glycol 1000 15.38 g, sorbitol 20.85 g, peach essence 0.1 g, erythrosine 0.05 g, and the balance is purified water. The preparation method is as follows:

[0062] Step 1: Add the measured propylene glycol to mixing tank 1, start stirring, set the stirring speed at 190 revolutions per minute, and heat to 60 - 80 °C; sequentially add the formula amounts of diazepam, anhydrous citric acid, and polyethylene glycol 1000, and stir for 60 - 90 minutes to obtain the first solution.

[0063] Step 2: Add 15% of the purified water for preparation volume to mixing tank 2, start stirring, and sequentially add the formula amounts of sodium citrate, sorbitol, and erythrosine. Select the stirring speed between 190 revolutions per minute according to the situation of the mixing tank, and stir for 60 - 90 minutes until completely dissolved to obtain the second solution.

[0064] Step 3: Slowly add the second solution to mixing tank 1 to mix with the first solution, and use a small amount of water to rinse mixing tank 2, and transfer the rinsing liquid into the first solution together, stir and cool to room temperature. After cooling, add peach essence, make up the purified water to the full volume, stir and mix evenly, and stir for 20 - 40 minutes.

[0065] Step 4: Filter the mixed medicinal liquid through a filter element to obtain the diazepam oral solution. Take the prepared diazepam solution, observe its properties and measure the contents of each component.

[0066] Step 5: Fill the diazepam oral solution into high-density polyethylene bottles for oral liquid medicine to obtain the filled finished product. Take the finished products stored for 6 months, 1 year, 1.5 years, and 2 years respectively to observe their properties and measure the contents of each component.

[0067] The diazepam oral solution prepared by this example presents a homogeneous, transparent, light red liquid state, without visible suspended matter or precipitation; the diazepam content is 0.098 - 0.102 g / 100 mL; the errors in the contents of propylene glycol, polyethylene glycol 1000, and sorbitol from the labeled amounts in the formula are within ±2%, meeting the prescription requirements. When stored for 6 months, the appearance and the contents of each component show no obvious changes; when stored for 1 year, the appearance shows no obvious changes, and the diazepam content slightly decreases by 1 - 2% due to degradation; when stored for 1.5 years, a very small amount of flocculants appear and return to a homogeneous state after shaking, and the diazepam content decreases by 2 - 4%; when stored for 2 years, there are a small amount of flocculants, the clarity decreases, and the diazepam content decreases by 4 - 6%.

[0068] Comparative Example 1

[0069] A diazepam oral solution, the formula dosage for preparing every 100 ml of diazepam oral solution is as follows: diazepam 0.1 g, propylene glycol 50 g, anhydrous citric acid 0.116 g, polyethylene glycol 1000 15.38 g, sorbitol 20.85 g, peach essence 0.1 g, erythrosine 0.05 g, and the balance is purified water. The preparation method is as follows:

[0070] Step 1: Add the measured propylene glycol to Mixing Tank 1, start stirring, set the stirring speed at 190 revolutions per minute, and heat to 60 - 80 °C; sequentially add the formula amounts of diazepam, anhydrous citric acid, and polyethylene glycol 1000, and stir for 60 - 90 minutes to obtain the first solution.

[0071] Step 2: Add 15% of the purified water for the preparation volume to Mixing Tank 2, start stirring, sequentially add the formula amounts of sorbitol and erythrosine, and select the stirring speed between 190 revolutions per minute according to the situation of the mixing tank, and stir for 60 - 90 minutes until completely dissolved to obtain the second solution.

[0072] Step 3: Slowly add the second solution to Mixing Tank 1 to mix with the first solution, and use a small amount of water to rinse Mixing Tank 2, transfer the rinsing liquid into the first solution together, stir and cool to room temperature. After cooling, add peach essence, make up the purified water to the full volume, and stir and mix evenly for 20 - 40 minutes.

[0073] Step 4: Filter the mixed medicinal liquid through a filter element to obtain the diazepam oral solution. Take the prepared diazepam solution, observe the appearance, and measure the contents of each component.

[0074] Step 5: Fill the diazepam oral solution into high-density polyethylene bottles for oral liquids to obtain the filled finished product. Take the finished products stored for 6 months, 1 year, 1.5 years, and 2 years respectively, observe the appearance, and measure the contents of each component.

[0075] The diazepam oral solution prepared by this example presents a uniform, transparent, light red liquid state, without visible suspended matter or precipitation; the diazepam content is 0.098 - 0.102 g / 100 mL; the content errors of propylene glycol, polyethylene glycol 1000, and sorbitol are within ±2% of the labeled amount in the formula, meeting the prescription requirements. After being stored for 6 months, the diazepam content decreases by 3 - 4%; after being stored for 1 year, the diazepam content decreases by 4 - 6%; after being stored for 1.5 years, the diazepam content decreases by 7 - 10%; after being stored for 2 years, the diazepam content decreases by more than 10%. It can be clearly seen from the comparative example and the example that if sodium citrate is added, the preservation effect of the diazepam oral solution is better.

[0076] This specific example is only an interpretation of the present invention and is not a limitation thereof. After reading this specification, those skilled in the art can make modifications to this example without creative contributions as needed, but as long as it is within the scope of the claims of the present invention, it is protected by the patent law.

Claims

1. A preparation method of diazepam oral solution, characterized in that It comprises the following steps: A. Prepare the first solution: Heat propylene glycol, add diazepam, anhydrous citric acid and polyethylene glycol 1000, and stir until completely dissolved to obtain the first solution; B. Prepare the second solution: Add sodium citrate, sorbitol and erythrosine to purified water, and stir until completely dissolved to obtain the second solution; C. Mix and make up the volume: Mix the second solution with the first solution, add peach essence after cooling, make up the volume to the full volume with purified water, and stir and mix evenly; D. Filter: Filter the mixed liquid medicine through a filter element to obtain diazepam oral solution.

2. The preparation method of the diazepam oral solution according to claim 1, characterized in that: in In step A, the target temperature for heating propylene glycol is 60 - 80 °C, the stirring speed is 190 - 300 revolutions per minute, and the stirring time is 60 - 90 minutes.

3. The preparation method of a diazepam oral solution according to claim 1, characterized in that: in In step B, the amount of purified water used is 12% - 16% of the total amount of purified water used, the stirring speed is 190 - 300 revolutions per minute, and the stirring time is 60 - 90 minutes.

4. The preparation method of a diazepam oral solution according to claim 1, characterized in that: in In step C, the stirring and mixing time is 20 - 40 minutes, the stirring speed is 150 - 250 revolutions per minute, and the density of the liquid medicine after volume making is 1.13 ± 0.02 g / ml.

5. The preparation method of a diazepam oral solution according to claim 1, characterized in that: The filter element is a 45μm stainless steel filter element, and the filtration pressure ≤ 0.25 MPa.

6. The preparation method of a diazepam oral solution according to claim 1, characterized in that, It further includes the step of filling the diazepam oral solution: E. Fill: Fill the diazepam oral solution into high-density polyethylene bottles for oral liquid medicine; the filling volume is 101 - 106 ml / bottle; the time limit from the completion of preparation to the end of filling ≤ 96 hours; samples are taken before, during and after filling respectively, and 4 bottles are taken at each time node.

7. A diazepam oral solution formulation, characterized in that, The formula is used for the preparation method as described in claim 1; the formula contains the following components: diazepam, propylene glycol, anhydrous citric acid, sodium citrate, polyethylene glycol 1000, sorbitol, peach essence, erythrosine, purified water; Among them, for every 100 ml of diazepam oral solution prepared, the formula dosage is as follows: diazepam 0.1 g, propylene glycol 40 - 55 g, anhydrous citric acid 0.1 - 0.15 g, sodium citrate 1.4 - 1.6 g, polyethylene glycol 1000 15 - 16 g, sorbitol 20 - 22 g, peach essence 0.05 - 0.15 g, erythrosine 0.04 - 0.06 g, and the balance is purified water.

8. The formulation of a diazepam oral solution according to claim 7, characterized in that: The amount of propylene glycol used is 45 - 55 g, and the molar ratio of anhydrous citric acid to sodium citrate is 1:7 - 1:

8.

9. The formulation of diazepam oral solution according to claim 7, wherein: For every 100 ml of diazepam oral solution prepared, the formula dosage is as follows: diazepam 0.1 g, propylene glycol 55 g, anhydrous citric acid 0.15 g, sodium citrate 1.4 g, polyethylene glycol 1000 15 g, sorbitol 22 g, peach essence 0.05 g, erythrosine 0.04 g, and the balance is purified water.

10. A diazepam oral solution formulation according to claim 7, characterized in that: For every 100 ml of diazepam oral solution prepared, the formula dosage is as follows: diazepam 0.1 g, propylene glycol 50 g, anhydrous citric acid 0.116 g, sodium citrate 1.482 g, polyethylene glycol 1000 15.38 g, sorbitol 20.85 g, peach essence 0.1 g, erythrosine 0.05 g, and the balance is purified water.

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