A stable chloral hydrate syrup, its preparation method, quality control method and application

Abstract

The present invention discloses a stable chloral hydrate syrup, its preparation method, quality control method and application, belonging to the technical field of pharmaceuticals, and solves the problems in the prior art that chloral hydrate has poor stability, harsh storage conditions, short shelf life, and needs to be diluted during use. A stable chloral hydrate syrup of the present invention comprises chloral hydrate, sucrose and water, wherein the mass-volume concentration of chloral hydrate is 10%, and the pH value of the chloral hydrate syrup is 2.3 - 3.0. The chloral hydrate syrup of the present invention further comprises glycerol. The chloral hydrate syrup of the present invention adopts the specification with a chloral hydrate sugar concentration of 10% used clinically, does not need to be freshly prepared before use, has accurate dosage, is safe and controllable, and has stable properties.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceuticals, and particularly relates to a stable chloral hydrate syrup, a preparation method thereof, a quality control method thereof, and applications thereof. Background Art

[0002] At present, there is no sedative and hypnotic preparation approved by the National Medical Products Administration in China that can be produced by pharmaceutical enterprises and is applicable to pediatric examinations. In clinical practice, hospital preparations of chloral hydrate are generally used for pediatric examinations.

[0003] Chloral hydrate, also known as trichloroacetaldehyde monohydrate, has the chemical name of 2,2,2-trichloro-1,1-ethanediol and the molecular formula of C2H3Cl3O2, and has the effect of sedation and hypnosis. Through on-site investigations of many domestic hospitals, chloral hydrate oral solution or chloral hydrate syrup is the sedative and hypnotic drug with the longest application time, the widest application range, the most mature application, and the largest dosage in pediatric examinations in Chinese hospitals. It has become the first choice for sedation and hypnosis in clinical pediatric examinations in China, and there is no suitable alternative drug yet.

[0004] The quality standards of hospital preparations of chloral hydrate are generally lower than those of commercial products. According to literature reports, the stability of the said products is very poor. The 5% concentration product needs to be refrigerated and has a shelf life of only 30 days. The 10% concentration product is stored at room temperature (25°C) and has a shelf life of about 35 days. Literature reports that an attempt was made to add β-cyclodextrin to chloral hydrate oral solution to prepare an inclusion complex to improve stability. However, the shelf life of this product was only extended to 46.63 days (Song Yongxi, Li Liying, Li Qianmei. Preparation and stability prediction of chloral hydrate mucilage [J]. Tianjin Pharmacy, 2002, 14(2): 48-48), and there was no substantial improvement.

[0005] Patent CN201910111983.9 reported a preparation method of chloral hydrate oral solution. The mass concentration of chloral hydrate is 44%-80%, and the pH value of the chloral hydrate solution is 1.0-2.9. The long-term stability study results of 24 months for Examples 1-3 were disclosed in the specification: the pH value, the content of chloroform, and the content of trichloroacetic acid in the chloral hydrate solutions of Examples 1-3 did not change significantly, and its long-term stability was significantly better than that of existing hospital preparations. However, it should be noted that the pH values of the chloral hydrate prepared in Examples 1-3 were 1.64, 1.61, and 1.31. Therefore, the chloral hydrate solution prepared by this method has a low pH value and a high concentration, which will result in a poor taste of the product and certain irritation, and is not suitable for direct administration. Before taking the chloral hydrate solution of this invention, it needs to be diluted with simple syrup, water, or fruit juice, etc. as a diluent before taking. This dilution process not only brings inconvenience to clinical use but also easily leads to uncontrollable quality of the diluted oral liquid.

[0006] Zhao Lei, Tang Hui. Research on the production process of chloral hydrate syrup [J]. Research and Practice on Chinese Medicines, 2018, 28(4), 38 - 39, reported the prescription research of chloral hydrate syrup, and the pH value of the prepared chloral hydrate syrup was between 4.21 and 4.77. Since it is a hospital preparation, systematic impurity research has not been carried out, especially the research reports on the generated 5 - hydroxymethylfurfural and toxic chloroform.

[0007] Therefore, providing a chloral hydrate syrup that is suitable for direct administration and has stable properties has become an urgent problem to be solved by those skilled in the art. Summary of the Invention

[0008] One of the purposes of the present invention is to provide a stable chloral hydrate syrup that does not require refrigeration, is convenient to use, does not need to be freshly prepared before use, and solves the problems of poor stability of chloral hydrate, harsh storage conditions, short shelf life, and the need for dilution during use in the prior art.

[0009] Another purpose of the present invention is to provide a preparation method of the chloral hydrate syrup.

[0010] Another purpose of the present invention is to provide a quality control method of the chloral hydrate syrup.

[0011] Another purpose of the present invention is to provide an application of the chloral hydrate syrup.

[0012] To achieve the above - mentioned purposes, the technical solutions adopted by the present invention are as follows:

[0013] A stable chloral hydrate syrup described in the present invention includes chloral hydrate, sucrose and water, wherein the mass - volume concentration of chloral hydrate is 10%, when the mass is g and the volume is mL; the pH value of the chloral hydrate syrup is 2.3 - 3.0.

[0014] In some embodiments of the present invention, the pH value of the chloral hydrate syrup is 2.3 - 2.9, preferably 2.5 - 2.9, and more preferably 2.7.

[0015] The stability of chloral hydrate is very poor and it is greatly affected by temperature, light, and the acidity of the solution. Currently, for the chloral hydrate syrup in hospital preparations, no systematic impurity research has been conducted, especially regarding the research reports on the generated 5-hydroxymethylfurfural and toxic chloroform. The inventor conducted a systematic study on the prescription of chloral hydrate syrup and accidentally found that the stability of chloral hydrate increases with the increase in the acidity of the solution. Under higher pH conditions, chloral hydrate will generate toxic chloroform, while sucrose in the syrup will be converted into glucose at lower pH, and the latter will continue to generate toxic 5-hydroxymethylfurfural. Therefore, the control range of the pH of chloral hydrate syrup is the key to determining whether its quality is qualified. Through creative labor, the present invention found that when the pH value of chloral hydrate syrup is 2.3 - 3.0, its long-term stability is good, and both chloroform (limit 0.06%) and 5-hydroxymethylfurfural (limit 0.5%) can be controlled within the range permitted by the pharmacopoeia.

[0016] In some embodiments of the present invention, it further includes glycerol;

[0017] Preferably, in every 100 mL of chloral hydrate syrup, the content of glycerol is 2.5 - 30 g, more preferably 10 - 30 g, and most preferably 30 g;

[0018] Preferably, in every 100 mL of chloral hydrate syrup, the content of sucrose is 45 - 85 g, more preferably 45 - 60 g, and most preferably 50 g.

[0019] In chloral hydrate syrup, the lower the concentration of chloral hydrate, the less stable it is. The present invention unexpectedly found that glycerol has a great effect on the stability of chloral hydrate syrup. When the mass-volume concentration of chloral hydrate is 10%, adding glycerol can promote its stability and meet the medication requirements; and by adding glycerol, the generation of chloroform under high pH conditions can be effectively reduced.

[0020] In some embodiments of the present invention, it further includes a flavoring agent or / and a preservative;

[0021] Preferably, the flavoring agent includes steviol glycoside,

[0022] Preferably, the preservative includes sodium benzoate;

[0023] Preferably, the dosage of the flavoring agent in every 100 mL of chloral hydrate syrup is 0.1 - 0.2 g, more preferably 0.15 g;

[0024] Preferably, the dosage of the preservative in every 100 mL of chloral hydrate syrup is 0.2 - 0.5 g, more preferably 0.24 g.

[0025] The stable chloral hydrate syrup of the present invention contains 10 g of chloral hydrate, 50 g of sucrose, 30 g of glycerol, 0.15 g of steviol glycoside, and 0.24 g of sodium benzoate in every 100 mL of chloral hydrate syrup, and the pH value of the chloral hydrate syrup is 2.7.

[0026] In some embodiments of the present invention, a pharmaceutically acceptable acid is added to adjust the pH value of the chloral hydrate syrup. Preferably, the pharmaceutically acceptable acid is an inorganic acid or / and an organic acid; wherein the inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid and any combination thereof; the organic acid is selected from formic acid, acetic acid, acetic anhydride, acetoacetic acid, trifluoroacetic acid, propionic acid, pyruvic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, stearic acid, palmitic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, metatartaric acid, ascorbic acid, gallic acid, benzoic acid, salicylic acid, cinnamic acid, naphthoic acid, pamoic acid, nicotinic acid, orotic acid, phytic acid, methyl sulfuric acid, dodecyl sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 1,5-naphthalenedisulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, sulfamic acid, glutamic acid, aspartic acid, gluconic acid, glucuronic acid and any combination thereof; preferably, the pharmaceutically acceptable acid is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, malic acid, tartaric acid, fumaric acid.

[0027] The preparation method of the chloral hydrate syrup of the present invention comprises the following steps:

[0028] Step 1. Weigh the prescribed amount of chloral hydrate, dissolve it in a dilute acid solution to obtain a chloral hydrate solution.

[0029] Step 2. Weigh the prescribed amount of sucrose, add water, and heat to prepare a pure syrup.

[0030] Step 3. After cooling the pure syrup prepared in Step 2, add the chloral hydrate solution prepared in Step 1, mix well, adjust the pH value with an acid, make up the volume to the total amount, and mix evenly to obtain the product.

[0031] In some embodiments of the present invention, in Step 3, after cooling the pure syrup prepared in Step 2, first add the prescribed amount of glycerol, and then add the chloral hydrate solution prepared in Step 1.

[0032] In some embodiments of the present invention, the following steps are further included: Weigh the prescribed amounts of flavoring agent and preservative respectively, dissolve them in water to prepare a flavoring agent solution and a preservative solution; after adding glycerol to the cooled pure syrup, add the flavoring agent solution and the preservative solution, and finally add the chloral hydrate solution prepared in Step 1.

[0033] In some embodiments of the present invention, the dilute acid solution in step 1 is a dilute solution of a pharmaceutically acceptable acid; preferably, it is 0.05 - 0.2 M hydrochloric acid;

[0034] In some embodiments of the present invention, when the chloral hydrate solution is added to pure syrup, the temperature of the syrup is controlled to be less than 40°C, preferably 25 - 40°C.

[0035] The quality control method of the chloral hydrate syrup of the present invention includes examining the stability of the chloral hydrate syrup using 5 - hydroxymethylfurfural or / and chloroform as indicators;

[0036] Preferably, the mass content of 5 - hydroxymethylfurfural in the chloral hydrate syrup is less than or equal to 0.5% (mg / mg);

[0037] Preferably, the mass content of chloroform in the chloral hydrate syrup is less than or equal to 0.06% (mg / mg);

[0038] Preferably, the content of 5 - hydroxymethylfurfural in the chloral hydrate syrup is determined by high - performance liquid chromatography.

[0039] In some embodiments of the present invention, the method for determining the content of 5 - hydroxymethylfurfural in the chloral hydrate syrup by high - performance liquid chromatography,

[0040] Preferably, the chromatographic conditions are as follows: using octadecylsilane - bonded silica gel as the filler, a buffer solution with a pH of 3.8 - 4.2 as mobile phase A, and acetonitrile as mobile phase B, and performing gradient elution according to the regulations in the following table,

[0041] Table 1

[0042]

[0043] Preferably, the buffer solution is a 10 mmol / L potassium dihydrogen phosphate solution; preferably, the pH value is adjusted to 3.8 - 4.2 with phosphoric acid;

[0044] An ultraviolet detector is used, the detection wavelength is 284 nm, the column temperature of the chromatographic column is 30 - 35°C, and the flow rate of the mobile phase is 0.8 - 1.2 ml / min.

[0045] This method includes the following steps:

[0046] Preparation of the reference solution: Weigh accurately an appropriate amount of 5 - hydroxymethylfurfural reference substance, and dissolve it with a 10 mmol / L potassium dihydrogen phosphate solution (adjusted to a pH of 4.0 with phosphoric acid) - acetonitrile (85:15) to prepare a reference solution with a specified concentration. Preferably, the reference substance concentration is about 5.0 μg / ml;

[0047] Preparation of the test solution: Weigh an appropriate amount of chloral hydrate syrup test sample precisely, dissolve or dilute it with the mobile phase and make up the volume to obtain the test solution; preferably, the concentration of chloral hydrate in the test solution is about 1 mg / ml;

[0048] Take 10 μL each of the test solution and the reference solution, inject them into the liquid chromatograph respectively, and carry out the determination according to the said chromatographic conditions, record the chromatogram, and determine the content of 5-hydroxymethylfurfural in the test solution based on the chromatograms of the test solution and the reference solution.

[0049] The determination of the content of 5-hydroxymethylfurfural in the chloral hydrate syrup of the present invention has undergone systematic methodological verification, and the results of the methodological verification are shown in the following table, and all research items meet the requirements.

[0050] Table 2

[0051]

[0052] Use of the chloral hydrate syrup described in the present invention in the preparation of a drug used as a sedative and hypnotic preparation.

[0053] Compared with the prior art, the present invention has the following beneficial effects:

[0054] The present invention is scientifically designed and ingeniously conceived. The chloral hydrate syrup of the present invention adopts a specification with a chloral hydrate sugar concentration of 10% for clinical use, does not need to be freshly prepared before use, has accurate dosage, is safe and controllable, and has stable properties.

[0055] The present invention has made creative efforts and unexpectedly found that by adding glycerol and controlling the pH value of the syrup (2.5 - 2.9), the stability of chloral hydrate and sucrose in the chloral hydrate syrup is effectively improved, which is significantly better than hospital preparations and preparations under research and development. For example, the generation of degradation products chloroform and 5-hydroxymethylfurfural is reduced, and at the same time, the properties do not change after storage and no crystals precipitate. Description of the Drawings

[0056] Appendix Figure 1 It is a diagram showing the influence of different pH values in Example 2 on the generation amounts of chloroform and 5-hydroxymethylfurfural in the chloral hydrate syrup. Detailed Embodiments

[0057] The following further describes the specific implementation plan of the present invention in combination with specific embodiments, but it should not be understood that the scope of the present invention is limited to the following examples. According to the inventive concept and the full text content of the present invention, the various technical features in the following examples can be appropriately combined / replaced / adjusted / modified, etc., which is obvious to those skilled in the art and still falls within the scope of protection of the present invention. Unless otherwise specified, the various components used in the present invention can be obtained through market purchase.

[0058] In the embodiments of the present invention, the content of chloral hydrate refers to the percentage relative to the labeled amount (i.e., the theoretical content or the labeled content of chloral hydrate per preparation unit).

[0059] In the embodiments of the present invention, the method for determining the content of 5-hydroxymethylfurfural: High performance liquid chromatography is used, and the chromatographic conditions are as follows: Octadecylsilane chemically bonded silica gel is used as the filler, 10 mmol / L potassium dihydrogen phosphate solution (adjust the pH value with phosphoric acid) with a pH of 3.8 - 4.2 is used as mobile phase A, and acetonitrile is used as mobile phase B. Gradient elution is carried out according to the provisions in Table 3.

[0060] Table 3

[0061]

[0062] An ultraviolet detector is used, the detection wavelength is 284 nm, the column temperature of the chromatographic column is 30 - 35 °C, and the flow rate of the mobile phase is 1 ml / min.

[0063] This method includes the following steps:

[0064] Preparation of the reference solution: Weigh accurately an appropriate amount of 5-hydroxymethylfurfural reference substance, and dissolve it with 10 mmol / L potassium dihydrogen phosphate solution (adjust the pH value to 4.0 with phosphoric acid)-acetonitrile (85:15) to prepare a reference solution with a concentration of 5.0 μg / ml.

[0065] Preparation of the test solution: Take an appropriate amount of the chloral hydrate syrup test sample, weigh accurately, dissolve or dilute it with the mobile phase and make the volume constant to obtain a test solution with a chloral hydrate concentration of about 1 mg / ml.

[0066] Take 10 μL of the test solution and the reference solution respectively, inject them into the liquid chromatograph, and carry out the determination according to the above chromatographic conditions. Record the chromatogram, and determine the content of 5-hydroxymethylfurfural in the test solution based on the chromatograms of the test solution and the reference solution.

[0067] In the embodiments of the present invention, the method for determining the content of chloroform is determined with reference to the method for the determination of residual solvents (the second method in General Principles 0861 of the Chinese Pharmacopoeia 2020 Edition).

[0068] Accurately weigh an appropriate amount of this product (equivalent to about 200 mg of chloral hydrate), dilute it with 10 mmol / L citric acid solution (adjust the pH to 1.5 with phosphoric acid) to prepare a solution containing about 20 mg of chloral hydrate in 1 ml. Accurately transfer 2 ml and place it in a headspace vial, and seal it.

[0069] Reference solution Take an appropriate amount of chloroform, dilute it with N,N-dimethylformamide to prepare a stock solution containing about 150 μg / ml of chloroform per 1 ml; accurately measure an appropriate amount of the chloroform stock solution, dilute it with 10 mmol / L citric acid solution (adjust the pH to 1.5 with phosphoric acid) to prepare a solution containing about 6 μg / ml of chloroform per 1 ml. Accurately measure 2 ml and transfer it to a headspace vial, then seal it.

[0070] Chromatographic conditions Use a capillary column with (6%) cyanopropylphenyl-(94%) dimethylpolysiloxane (or similar polarity) as the stationary phase; the initial temperature is 40 °C, hold for 5 minutes, then increase the temperature at a rate of 15 °C per minute to 150 °C, and hold for 2 minutes; the inlet temperature is 150 °C; use a flame ionization detector (FID), and the detector temperature is 200 °C; the headspace vial equilibrium temperature is 50 °C, and the equilibrium time is 30 minutes.

[0071] Determination method Inject the reference solution and the test solution into the headspace sampler respectively, and record the chromatograms.

[0072] Limit Calculated by the external standard method based on the peak area, the content of chloroform should not exceed 0.06%. The determination of the chloroform content in the chloral hydrate syrup of the present invention has undergone systematic methodology verification, and the results of the methodology verification are shown in the following table. All research items meet the requirements.

[0073] Table 4

[0074]

[0075] Example 1

[0076] This example discloses the formulation and preparation method of the chloral hydrate syrup of the present invention. The formulation is as follows:

[0077]

[0078] Preparation method: Take the prescribed amounts of sodium benzoate and steviol glycoside respectively, add appropriate amounts of purified water to each, stir until dissolved, and prepare sodium benzoate solution and steviol glycoside solution. Weigh the prescribed amount of chloral hydrate, add an equal amount of 0.1 M hydrochloric acid solution, stir until completely dissolved, and prepare a chloral hydrate solution.

[0079] Preparation of syrup: Weigh 50 g of sucrose and 12 g of purified water in a beaker, heat and boil for 10 min, cool to about 50 °C, add the prescribed amounts of glycerol, steviol glycoside solution, and sodium benzoate solution, stir for 15 min, cool to about 25 °C, add the chloral hydrate solution, stir and mix, adjust the pH value to 2.0 with hydrochloric acid solution, make up the volume to the total amount, and mix well; fill the above solution into glass bottles at 10 ml per vial, crimp the caps, and seal.

[0080] Example 2

[0081] This example discloses the investigation of different pH values of chloral hydrate syrup. The preparation method of the chloral hydrate syrup described in this example is the same as that in Example 1, except that the finally adjusted pH value is different. The samples with different pH values prepared were placed at 60 °C for 30 days, and the degradation products chloroform and 5-hydroxymethylfurfural were used as indicators for stability investigation. The results are shown in the following table:

[0082] Table 5. Results of stability investigation of chloral hydrate syrup with different pH values (pH: 2.0 - 4.0)

[0083]

[0084] It can be seen from the detection results in Table 5 that within the range of pH value from 2.0 to pH 4.0, as the pH value increases, the content of chloroform, the degradation product of each numbered sample, gradually increases. According to the residual solvent limit requirements, the control limit of chloroform in chloral hydrate syrup is set at 0.06%; when pH ≥ 3.0, the toxic degradation impurity chloroform has exceeded the standard.

[0085] Within the range of pH value from 2.0 to pH 4.0, as the pH value increases, the degradation product 5-hydroxymethylfurfural of each numbered sample gradually decreases. According to the limit requirements of 5-hydroxymethylfurfural, the control limit of 5-hydroxymethylfurfural in chloral hydrate syrup is set at 0.5%. When pH ≤ 2.3, the toxic degradation impurity 5-hydroxymethylfurfural has exceeded the standard.

[0086] Therefore, it is optimal to control the pH value of chloral hydrate syrup at 2.3 - 3.0, which can not only control the toxic degradation impurity chloroform within the limit, but also control 5-hydroxymethylfurfural within the limit, thus ensuring the drug safety of chloral hydrate syrup.

[0087] Example 3

[0088] In order to further investigate the optimal pH value of chloral hydrate syrup, this example investigated the chloral hydrate syrup samples with pH values of 2.5, 2.7, and 2.9 respectively. The preparation method is the same as that in Example 1, except that the finally adjusted pH value is different. The samples with different pH values prepared were placed at 60 °C for 30 days, and the degradation products chloroform and 5-hydroxymethylfurfural were used as indicators for stability investigation. The results are shown in the following table:

[0089] Table 6. Results of stability investigation of chloral hydrate syrup with different pH values (pH: 2.5 - 2.9)

[0090]

[0091] As can be seen from the detection results in Table 6, in the range of pH 2.5 - 2.9, as the pH value increases, the chloroform in the degradation products of each numbered sample gradually increases. According to the requirements of the residual solvent limit, the control limit of chloroform in chloral hydrate syrup is set at 0.06%. When the pH is within 2.5 - 2.9, the toxic degradation impurity chloroform does not exceed the standard.

[0092] In the range of pH value from 2.5 to 2.9, as the pH value increases, the 5 - hydroxymethylfurfural in the degradation products of each numbered sample gradually decreases. According to the limit requirements of 5 - hydroxymethylfurfural, the control limit of 5 - hydroxymethylfurfural in chloral hydrate syrup is set at 0.5%. The toxic degradation impurity 5 - hydroxymethylfurfural does not exceed the standard.

[0093] Therefore, the pH value of the chloral hydrate syrup of the present invention is further 2.5 - 2.9, which can not only control the toxic degradation impurity chloroform within the limit, but also control 5 - hydroxymethylfurfural within the limit, thus ensuring the medication safety of chloral hydrate syrup.

[0094] Example 4

[0095] This example discloses the investigation of different glycerol dosages in chloral hydrate syrup. Each chloral hydrate syrup used in this example was prepared according to the method of Example 1, the difference being the different glycerol dosages, and the pH was adjusted to 2.7, with the other conditions being the same.

[0096] The syrup samples with different glycerol dosages were placed at 60 °C for 30 days for stability investigation. The chloroform content of the samples in each example was investigated.

[0097] Table 7, Stability investigation results of syrup samples with different glycerol dosages at 60 °C

[0098] Number 1 2 3 4 5 6 pH 2.7 2.7 2.7 2.7 2.7 2.7 Glycerol (per 100 ml syrup) 30g 20g 10g 5g 2.5g 0g Chloroform (%) on day 0 0.0005 0.0006 0.0006 0.0008 0.0011 0.0014 Chloroform (%) on day 30 0.0393 0.0495 0.0584 0.0624 0.0680 0.2030

[0099] As can be seen from the detection results in Table 7, as the glycerol in the syrup decreases and the water content increases, the chloroform in the degradation products of each comparative example gradually increases. The results show that glycerol plays an important role in the stability of the syrup, and the optimal effect is achieved when the glycerol dosage is 30 g.

[0100] Example 5

[0101] This example discloses the investigation of different liquid - preparation temperatures in chloral hydrate syrup. Different liquid - preparation temperatures will cause changes in the chloroform content in chloral hydrate.

[0102] The prescriptions of the chloral hydrate syrup of each number in this example are as follows:

[0103]

[0104] The preparation method is as follows: Weigh the prescribed amounts of sodium benzoate and steviol glycoside respectively, add appropriate amounts of purified water to each, stir until dissolved, and prepare a sodium benzoate solution and a steviol glycoside solution. Weigh the prescribed amount of chloral hydrate, add an equal amount of 0.1 M hydrochloric acid solution, stir until completely dissolved, and prepare a chloral hydrate solution.

[0105] Prepare syrup: Weigh 50 g of sucrose and 12 g of purified water in a beaker, heat to boiling for 10 min, when the temperature drops to about 50 °C, add the prescribed amounts of glycerol, steviol glycoside solution, and sodium benzoate solution, stir for 15 min, cool to about the specified temperature (i.e., the solution preparation temperatures shown in Table 8: 25 °C, 30 °C, 40 °C, 60 °C respectively), add the chloral hydrate solution, stir and mix, adjust the pH value to 2.7 with hydrochloric acid solution, make up the volume to the total amount, and mix well; fill the above solution into glass bottles at 10 ml per vial, crimp the caps, and seal.

[0106] Table 8 Results of investigation on different solution preparation temperatures

[0107] Number 1 2 3 4 Solution preparation temperature 25℃ 30℃ 40℃ 60℃ Chloroform (%) before solution preparation 0.0005 0.0007 0.0009 0.0009 Chloroform (%) after solution preparation 0.0009 0.0012 0.0018 0.0035

[0108] Note: The chloroform (%) before solution preparation in this table refers to the percentage content of chloroform in the chloral hydrate solution; the chloroform (%) after solution preparation refers to the percentage content of chloroform in the chloral hydrate syrup.

[0109] The results show that: If the solution preparation temperature is too high, it will lead to an increase in the residual amount of chloroform in the sample, and the solution temperature needs to be controlled at 25 - 40 °C appropriately.

[0110] Example 6

[0111] This example discloses a comparative experiment on the stability of the chloral hydrate syrup of the present invention and existing hospital preparations. Purchase two batches of commercially available chloral hydrate oral liquids: the hospital preparation of West China Second University Hospital and the hospital preparation of West China Hospital. Both the hospital preparation of West China Second University Hospital and the hospital preparation of West China Hospital are 10% chloral hydrate oral liquids. After testing, their pH values are 3.84 and 3.46 respectively.

[0112] Place the chloral hydrate syrup with a pH value of 2.7 prepared according to the method of Example 1 and the above two batches of commercially available samples at 60 °C for 30 days, and conduct a stability investigation with the degradation product chloroform as the index. The results are shown in the following table:

[0113] Table 9 Comparative results of the stability of the chloral hydrate syrup of the present invention and existing hospital preparations

[0114]

[0115] As can be seen from the above table, when the hospital preparations of West China Second University Hospital were accelerated at 60°C for 30 days, the content of chloroform, the degradation substance (0.56782%), far exceeded the ICH limit (0.06%). When the hospital preparations of West China Hospital were accelerated at 60°C for 30 days, the content of chloroform, the degradation substance (0.46685%), far exceeded the ICH limit (0.06%). However, for the chloral hydrate syrup of the present invention, the content of chloroform, the degradation substance, was far lower than the ICH limit (0.06%) when accelerated at 60°C for 30 days. This indicates that the stability of the chloral hydrate syrup of the present invention is far superior to that of the existing hospital preparations.

[0116] Comparative Example 1

[0117] This comparative example discloses a preparation method of a concentrated chloral hydrate solution, and its preparation formulation is as follows:

[0118]

[0119] The preparation method is as follows: Weigh 6.2 g of citric acid into a beaker, add 13.8 g of purified water, mix evenly, and prepare a citric acid solution with a pH value of 1.06. Then add 80 g of chloral hydrate, stir and mix to completely dissolve the chloral hydrate, and measure the volume; Dispense the above solution into 10-ml vials, crimp the caps, and seal them.

[0120] Comparative Example 2

[0121] This comparative example discloses a preparation method of a concentrated chloral hydrate solution, and its preparation formulation is as follows:

[0122]

[0123] The preparation method is as follows: Weigh 3.5 g of citric acid into a beaker, add 16.5 g of purified water, mix evenly, and prepare a citric acid solution with a pH value of 1.30. Then add 80 g of chloral hydrate, stir and mix to completely dissolve the chloral hydrate, and measure the volume; Dispense the above solution into 10-ml vials, crimp the caps, and seal them.

[0124] Comparative Example 3

[0125] This comparative example discloses a preparation method of a concentrated chloral hydrate solution, and its preparation formulation is as follows:

[0126]

[0127] The preparation method is as follows: Weigh 1.0 g of citric acid into a beaker, add 19.0 g of purified water, mix evenly, and prepare a citric acid solution with a pH value of 1.64. Then add 80 g of chloral hydrate, stir and mix to completely dissolve the chloral hydrate, and measure the volume; Dispense the above solution into 10-ml vials, crimp the caps, and seal them.

[0128] Example 7

[0129] This example discloses an experiment on the stability comparison between chloral hydrate syrup and chloral hydrate concentrated solution of the present invention.

[0130] The chloral hydrate syrup described in this example is the chloral hydrate syrup prepared by the method of Example 1 with a pH value of 2.7.

[0131] The chloral hydrate concentrated solution described in this example is the chloral hydrate concentrated solution prepared in Comparative Examples 1-3. Comparative Examples 1-3 are oral concentrated solutions with different pH values and containing 80% chloral hydrate.

[0132] The above four samples were respectively placed under the conditions of 40 °C and 60 °C to investigate their stability, and the results are shown in the following table:

[0133] Table 10, Results of the stability comparison between chloral hydrate syrup and chloral hydrate concentrated solution of the present invention

[0134]

[0135] As can be seen from the above table, when Comparative Examples 1-3 were accelerated at 40 °C for 30 days, the contents of the degradation substance chloroform also exceeded the ICH limit (0.06%), which were 0.8978%, 1.1963%, and 1.3315% respectively. When Comparative Examples 1-3 were accelerated at 60 °C for 30 days, the contents of the degradation substance chloroform also exceeded the ICH limit (0.06%), which were 1.3815%, 1.6267%, and 1.9869% respectively. However, the content of the degradation substance chloroform in the chloral hydrate syrup of the present invention at 40 °C and 60 °C acceleration for 30 days was far lower than the ICH limit (0.06%). Explanation: The stability of the chloral hydrate syrup of the present invention is superior to that of the chloral hydrate concentrated solution.

[0136] Examples 8-10

[0137] Examples 8-10 disclose the prescription and preparation method of the chloral hydrate syrup of the present invention. Compared with Example 1, the difference lies in the different amounts of sucrose, glycerol and water used, and the other conditions are the same.

[0138] Example 8

[0139] The prescription of the chloral hydrate syrup in this example is as follows:

[0140]

[0141] In the preparation method, when preparing the syrup, weigh 45 g of sucrose and 10.8 g of purified water in a beaker, heat to boiling for 10 min, and the other conditions are the same as in Example 1.

[0142] Example 9

[0143] The prescription of chloral hydrate syrup in this example is as follows:

[0144]

[0145] In the preparation method, when preparing the syrup, weigh 80 g of sucrose and 19.2 g of purified water in a beaker, heat to boiling and boil for 10 min, and the other conditions are the same as in Example 1.

[0146] Example 10

[0147] The prescription of chloral hydrate syrup in this example is as follows:

[0148]

[0149] In the preparation method, when preparing the syrup, weigh 60 g of sucrose and 14.4 g of purified water in a beaker, heat to boiling and boil for 10 min, and the other conditions are the same as in Example 1.

[0150] Finally, it should be noted that the above examples are only the preferred embodiments of the present invention to illustrate the technical solutions of the present invention, rather than to limit it, and certainly not to limit the patent scope of the present invention; although the present invention has been described in detail with reference to the foregoing examples, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing examples, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention; that is to say, any meaningless changes or refinements made in the main design concept and spirit of the present invention, and the technical problems solved by them are still the same as those of the present invention, should all be included in the protection scope of the present invention; in addition, directly or indirectly applying the technical solutions of the present invention to other related technical fields shall also be included in the patent protection scope of the present invention by the same token.

Claims

1. A stable chloral hydrate syrup, characterized in that, It includes chloral hydrate, sucrose, glycerol and water. The mass-volume concentration of chloral hydrate is 10%, where the mass is in g and the volume is in mL. The pH value of the chloral hydrate syrup is 2.5 - 2.9, and the content of glycerol in every 100 mL of chloral hydrate syrup is 10 - 30 g.

2. A stable chloral hydrate syrup according to claim 1, characterized in that, The pH value of the chloral hydrate syrup is 2.

7.

3. A stable chloral hydrate syrup according to claim 1, wherein, In every 100 mL of chloral hydrate syrup, the content of glycerol is 30 g.

4. A stable chloral hydrate syrup according to claim 1, characterized in that, In every 100 mL of chloral hydrate syrup, the content of sucrose is 45 - 85 g.

5. A stable chloral hydrate syrup according to claim 1, wherein, In every 100 mL of chloral hydrate syrup, the content of sucrose is 45 - 60 g.

6. A stable chloral hydrate syrup according to claim 1, wherein In every 100 mL of chloral hydrate syrup, the content of sucrose is 50 g.

7. A stable chloral hydrate syrup according to any one of claims 1 to 6, characterized in that, It also includes a flavoring agent or / and a preservative.

8. A stable chloral hydrate syrup according to claim 7, wherein The flavoring agent includes steviol glycoside.

9. A stable chloral hydrate syrup according to claim 7, characterized in that, The preservative includes sodium benzoate.

10. A stable chloral hydrate syrup according to claim 7, characterized in that, The dosage of the flavoring agent in every 100 mL of chloral hydrate syrup is 0.1 - 0.2 g.

11. A stable chloral hydrate syrup according to claim 7, characterized in that, The dosage of the flavoring agent in every 100 mL of chloral hydrate syrup is 0.15 g.

12. A stable chloral hydrate syrup according to claim 7, characterized in that, The dosage of the preservative in every 100 mL of chloral hydrate syrup is 0.2 - 0.5 g.

13. A stable chloral hydrate syrup according to claim 7, characterized in that, The dosage of the preservative in every 100 mL of chloral hydrate syrup is 0.24 g.

14. A stable chloral hydrate syrup according to claim 1, characterized in that, Every 100 mL of chloral hydrate syrup contains 10 g of chloral hydrate, 50 g of sucrose, 30 g of glycerol, 0.15 g of steviol glycoside, 0.24 g of sodium benzoate, and the pH value of the chloral hydrate syrup is 2.

7.

15. A stable chloral hydrate syrup according to any one of claims 1 to 6, characterized in that, The mass content of 5-hydroxymethylfurfural in the chloral hydrate syrup is less than or equal to 0.5%.

16. A stable chloral hydrate syrup according to any one of claims 1 to 6, characterized in that, The mass content of chloroform in the chloral hydrate syrup is less than or equal to 0.06%.

17. The preparation method of chloral hydrate syrup according to any one of claims 1 to 16, characterized in that, It includes the following steps: Step 1. Weigh the prescribed amount of chloral hydrate, dissolve it in a dilute acid solution to obtain a chloral hydrate solution. Step 2. Weigh the prescribed amount of sucrose, add water, and heat to prepare a pure syrup. Step 3. After cooling the pure syrup prepared in Step 2, first add the prescribed amount of glycerol, then add the chloral hydrate solution prepared in Step 1. After mixing evenly, adjust the pH value with acid, make up the volume to the total amount, and mix well to obtain the product.

18. The preparation method according to claim 17, characterized in that, It also includes the following steps: Weigh the prescribed amounts of the flavoring agent and the preservative respectively, dissolve them in water to prepare a flavoring agent solution and a preservative solution. After adding glycerol to the cooled pure syrup, then add the flavoring agent solution and the preservative solution, and finally add the chloral hydrate solution prepared in Step 1.

19. The method according to claim 17, wherein The dilute acid in Step 1 is 0.05 - 0.2 M hydrochloric acid.

20. The method according to claim 19, wherein When adding the chloral hydrate solution to the pure syrup, control the temperature of the syrup solution to be less than 40°C.

21. The method according to claim 19, characterized in that, When adding the chloral hydrate solution to the pure syrup, control the temperature of the syrup solution to be 25 - 40°C.

22. The method for detecting the stability of chloral hydrate syrup according to any one of claims 1 to 16, characterized in that, It includes using high performance liquid chromatography to determine the contents of 5-hydroxymethylfurfural and chloroform. The chromatographic parameters for determining 5-hydroxymethylfurfural include: using a buffer salt solution with a pH of 3.8 - 4.2 as mobile phase A, acetonitrile as mobile phase B, a detection wavelength of 284 nm, a column temperature of 30 - 35°C, and a mobile phase flow rate of 0.8 - 1.2 mL / min.

23. The detection method according to claim 22, wherein The mass content of 5-hydroxymethylfurfural in the chloral hydrate syrup is less than or equal to 0.5%.

24. The detection method according to claim 22, characterized in that, The mass content of chloroform in the chloral hydrate syrup is less than or equal to 0.06%.

25. Use of the chloral hydrate syrup according to any one of claims 1 to 16 in the preparation of a drug for use as a sedative and hypnotic preparation.

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