Refining method of medicinal chlorocresol

Abstract

The invention provides a refining method of medicinal chlorocresol, and relates to the field of pharmacy. The method comprises the following steps: mixing an industrial-grade chlorocresol crude product with a mixed solvent, heating, adding a decolorizing agent, stirring and refining to obtain a crude product refined solution; the mixed solvent comprises an alcohol organic solvent and an alkane organic solvent; and carrying out sterilization and first solid-liquid separation on the crude product refined liquid, continuously cooling to a first temperature and a second temperature in a stirring state, crystallizing, carrying out second solid-liquid separation, and drying to obtain the medicinal chlorocresol. According to the refining method of the medicinal chlorocresol, provided by the invention, specific impurities such as phenol and m-cresol in the crude chlorocresol product are refined, so that the crude chlorocresol product is almost free of residues after being refined, the purity of the product is effectively improved, the medicinal requirement is met, and the problem that commercially available industrial chlorocresol related substances such as m-cresol and the like do not meet the medicinal requirement is solved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceuticals, and in particular relates to a method for refining pharmaceutical-grade chlorocresol. Background Art

[0002] In addition to being used as a pharmaceutical excipient, chlorocresol is used as an antibacterial agent in pharmaceutical formulations. Its concentration in various preparations, except for oral preparations, can reach 0.2%. Chlorocresol is effective against bacteria, spores, molds and yeasts, and its activity is greatest in acidic media. Its antibacterial effect is reduced in the presence of certain excipients, especially non-ionic surfactants. At higher concentrations, chlorocresol is an effective disinfectant.

[0003] The structural formula of chlorocresol is as follows:

[0004]

[0005] Industrial-grade chlorocresol is mainly obtained by chlorinating m-cresol under the action of a catalyst. The specific reaction equation is as follows:

[0006]

[0007] Since the raw material m-cresol has a strong adhesion, the crude chlorocresol produced from industrial products contains more impurities such as m-cresol.

[0008] Chlorocresol is a pharmaceutical excipient and has strict requirements on related impurities. Among them, the pharmaceutical-grade finished product needs to control m-cresol Not more than 0.5% phenol The industrial-grade and cosmetic-grade chlorocresol available on the market are difficult to meet the pharmaceutical-grade requirements.

[0009] Therefore, it is urgent to develop an effective chlorocresol refining and purification process to obtain a pharmaceutical grade chlorocresol product with low content of impurities meta-cresol and phenol, high product purity and pharmaceutical requirements.

[0010] In view of this, the present invention is proposed. Summary of the invention

[0011] The object of the present invention is to provide a method for refining pharmaceutical grade chlorocresol to solve the above problems.

[0012] In order to achieve the above objectives, the present invention particularly adopts the following technical solutions:

[0013] A method for refining pharmaceutical-grade chlorocresol, comprising:

[0014] The industrial grade chlorocresol crude product is mixed with a mixed solvent, heated, a decolorizing agent is added, and stirred and refined to obtain a crude product refined liquid; the mixed solvent includes an alcohol organic solvent and an alkane organic solvent;

[0015] The crude refined liquid is sterilized and subjected to a first solid-liquid separation, and then continuously cooled to a first temperature and a second temperature for crystallization while stirring, followed by a second solid-liquid separation and drying to obtain the pharmaceutical-grade chlorocresol.

[0016] Preferably, the mixed solvent is a mixture of ethanol and n-heptane and / or n-hexane.

[0017] The mixed solvent here can be a mixture of ethanol and n-heptane, a mixture of ethanol and n-hexane, or a mixture of ethanol, n-heptane, and n-hexane.

[0018] Preferably, the volume-to-mass ratio of the mixed solvent to the crude industrial-grade chlorocresol is (2 - 8):1, preferably 3:1.

[0019] Optionally, the volume-to-mass ratio of the mixed solvent to the crude industrial-grade chlorocresol can be 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or any value between (2 - 8):1.

[0020] Preferably, the mass ratio of ethanol to the crude industrial-grade chlorocresol is (0.005 - 0.1):1, preferably 0.02:1.

[0021] Optionally, the mass ratio of ethanol to the crude industrial-grade chlorocresol can be 0.005:1, 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.1:1, or any value between (0.005 - 0.1):1.

[0022] The role of ethanol is to weaken the adhesion of the main impurity m-cresol and increase the solubility of the impurity m-cresol, thereby achieving the purpose of refining m-cresol. The amount of ethanol cannot be too much because chlorocresol is highly soluble in ethanol. Therefore, choosing ethanol and an appropriate amount of ethanol is very crucial.

[0023] Preferably, the temperature of the stirring and refining is 40 - 70°C.

[0024] Optionally, the temperature of the stirring and refining can be 40°C, 50°C, 60°C, 70°C, or any value between 40 - 70°C.

[0025] Preferably, the decolorizing agent includes one or more of activated carbon, silica powder, and activated clay.

[0026] The activated carbon specialized for oil products has the best effect and can produce the maximum refining and decolorizing effect on the red pigment of the product itself.

[0027] Preferably, the first solid-liquid separation is carried out by precision filtration, and the pore size of the filter element for precision filtration is 0.22 - 0.45 μm.

[0028] Optionally, the pore size of the filter element for precision filtration can be 0.22 μm, 0.25 μm, 0.30 μm, 0.35 μm, 0.40 μm, 0.45 μm or any value between 0.22 - 0.45 μm.

[0029] Preferably, the first temperature is 15 - 35 °C and the second temperature is 0 - 5 °C.

[0030] Under the conditions of programmed crystallization, first let the refined liquid generate crystal buds of a specific crystal form, and then through further crystal growth, a product crystal form structure with the best medicinal effect can be obtained.

[0031] Optionally, the first temperature can be 15 °C, 20 °C, 25 °C, 30 °C, 35 °C or any value between 15 - 35 °C, and the second temperature can be 0 °C, 1 °C, 2 °C, 3 °C, 4 °C, 5 °C or any value between 0 - 5 °C.

[0032] Preferably, the crystallization time under the second temperature condition is 1 - 12 h.

[0033] Optionally, the crystallization time under the second temperature condition can be 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h or any value between 1 - 12 h.

[0034] Preferably, the liquid obtained from the second solid-liquid separation is concentrated, then complexed with urea, refined and decomplexed to recover m-cresol.

[0035] Advantages of the present invention:

[0036] The refining method of medicinal grade chlorocresol provided by this application uses industrial grade chlorocresol as raw material, and through solvent refining treatment, azeotropic impurities such as m-cresol are removed to obtain medicinal grade high-purity chlorocresol. This method can refine impurities such as m-cresol and phenol in the crude industrial grade chlorocresol to almost undetected levels, and obtain a finished product of chlorocresol with a specific crystal form and high medicinal activity. This method effectively improves the product purity, meets the medicinal requirements, and solves the problem of excessive impurities in commercially available industrial grade chlorocresol. Description of the drawings

[0037] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the specific embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0038] Figure 1 XRD pattern of the crude chlorocresol used as the raw material for the example;

[0039] Figure 2 1H NMR spectrum of the pharmaceutical-grade chlorocresol obtained in Example 1;

[0040] Figure 3 XRD pattern of the pharmaceutical-grade chlorocresol obtained in Example 1;

[0041] Figure 4 1H NMR spectrum of m-cresol obtained in Example 2. Specific embodiments

[0042] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the scope of protection of the present invention.

[0043] First, the quality requirements for chlorocresol will be described. As a pharmaceutical excipient, chlorocresol is mainly included in the pharmacopoeias of the United States, Europe, and China. Among them, the quality requirements in the fourth part of the Chinese Pharmacopoeia 2020 are shown in Table 1.

[0044] Table 1 Quality standards for m-cresol

[0045]

[0046] The information and sources of the raw materials used in the following specific examples are shown in Table 2:

[0047] Table 2 Raw material table

[0048]

[0049]

[0050] Example 1

[0051] This example provides a refining method for pharmaceutical-grade chlorocresol, including the following steps:

[0052] 100 g of crude chlorocresol (purity 97.47%, m-cresol 2.15%, phenol 0.11%, X-ray diffraction pattern as Figure 1 shown) was added to a three-necked flask, 700 ml of n-hexane and 2 g of ethanol were added, the temperature was controlled to 50 °C, 0.5 g of special activated carbon for grease (JH-312 type) and 0.5 g of 200-mesh silica gel powder were added, stirred for 30 min, filtered through a 0.22-μm filter element while hot, the filtrate was cooled to 20 °C, and crystallized at this temperature for 1 h; then cooled to 0 - 5 °C and stirred for crystallization for 2 h, filtered, and the wet product was dried in vacuo at 45 °C to obtain 87.3 g of refined pharmaceutical-grade chlorocresol. The refined product was white. The tested purity was 99.81%, m-cresol was not detected, and phenol was 0.002%. The product met the quality requirements of the Chinese Pharmacopoeia 2020 Edition. The finished product was subjected to NMR and powder diffraction tests, as shown in Figure 2 and 3 .

[0053] Example 2

[0054] This example provides a method for refining pharmaceutical-grade chlorocresol, which includes the following steps:

[0055] 100 g of crude chlorocresol (purity 97.47%, m-cresol 2.15%, phenol 0.11%) was added to a three-necked flask, 300 ml of n-heptane and 2 g of ethanol were added, the temperature was controlled to 50 °C, 1.0 g of special activated carbon for grease was added, stirred for 30 min, filtered through a 0.22-μm filter element while hot, the filtrate was cooled to 25 °C, and crystallized at this temperature for 2 h; then cooled to 0 - 5 °C and stirred for crystallization for 1 h, filtered, and the wet product was dried in vacuo at 45 °C to obtain 89.4 g of refined pharmaceutical-grade chlorocresol. The refined product was white. The tested purity was 99.92%, m-cresol was not detected, and phenol was 0.003%. The product met the quality requirements of the Chinese Pharmacopoeia 2020 Edition.

[0056] The mother liquor was concentrated, and the recovered m-cresol was complexed with urea and subjected to NMR test, as shown in Figure 4 .

[0057] Example 3

[0058] This example provides a method for refining pharmaceutical-grade chlorocresol, which includes the following steps:

[0059] 100 g of crude chlorocresol (purity 97.47%, m-cresol 2.15%, phenol 0.11%) was added to a three-necked flask, 500 ml of n-heptane and 2 g of ethanol were added, the temperature was controlled at 50 °C, 2.0 g of activated clay was added, and the mixture was stirred for 30 min. Then it was filtered through a 0.22-μm filter while hot. The filtrate was cooled to 27 °C and crystallized for 2 h while maintaining the temperature. Then it was cooled to 0 - 5 °C and stirred for crystallization for 1 h, and then filtered. The wet product was dried in vacuo at 45 °C to obtain 87.9 g of refined pharmaceutical-grade chlorocresol. The refined product was white. The tested purity was 99.52%, m-cresol was 0.05%, and phenol was 0.004%. The product met the quality requirements of the Chinese Pharmacopoeia 2020 Edition.

[0060] In summary, the purity of the refined products obtained in Examples 1 - 3 was significantly and effectively improved, the maximum single impurity was reduced, the product color became lighter, and the obtained products were high-purity pharmaceutical-grade chlorocresol meeting the pharmaceutical requirements.

[0061] Furthermore, in this application, to determine the experiment on the dosage of the key reagent ethanol, in order to exclude the influence of the crystallization process on its quality, the crystallization solution was directly cooled to 0 - 5 °C. Except for the change in the amount of ethanol used, the other components and process conditions remained unchanged. The experimental scheme was designed as follows (Test Examples 4 - 9):

[0062] Feed ratio:

[0063] 100 g of industrial-grade chlorocresol and 0.5 g of activated carbon;

[0064] 400 ml of n-heptane;

[0065] Dosage of ethanol: 0.5 g, 1.0 g, 2.0 g, 3.0 g, 4.0 g, 5.0 g;

[0066] Detailed operation steps:

[0067] 100 g of crude chlorocresol (purity 96.26%, m-cresol 3.5%, phenol 0.14%) was added to a three-necked flask, 400 ml of n-heptane and ethanol (0.5 g, 1.0 g, 2.0 g, 3.0 g, 4.0 g, 5.0 g) were added, the temperature was controlled at 60 °C, 0.5 g of activated carbon was added, and the mixture was stirred for 30 min. Then it was filtered through a 0.22-μm filter while hot. It was cooled to 0 - 5 °C and stirred for crystallization for 2 h, and then filtered. The wet product was dried in vacuo at 45 °C to obtain refined pharmaceutical-grade chlorocresol. The yield was calculated and a preliminary quality inspection was carried out in accordance with Part IV of the Chinese Pharmacopoeia 2020 Edition. The test results are shown in Table 3:

[0068] Table 3 Optimization experiment on the dosage of ethanol

[0069] Case Experiment on Ethanol Dosage Phenol m-Cresol Yield Test Example 4 0.5g 0.005％ 0.43％ 93.68％ Test Example 5 1.0g 0.003％ 0.24％ 91.45％ Test Example 6 2.0g 0.002％ 0.12％ 87.62％ Test Example 7 3.0g 0.002％ 0.10％ 81.65％ Test Example 8 4.0g 0.001％ 0.09％ 72.51％ Test Example 9 5.0g 0.001％ 0.06％ 53.24％

[0070] In summary, as can be seen from Table 3, the amount of ethanol has an obvious effect on the purification of m-cresol impurities. Selecting 0.05 w / w, although the purification effect is very good, the product yield is very low. Excessive ethanol increases the solubility of parachlorophenol in the entire purified liquid system. However, when the amount of ethanol is greater than 2.0 g, the purification effect on m-cresol decreases. Therefore, an ethanol amount of 0.02 w / w is preferably selected.

[0071] Furthermore, in order to determine the influence of key factors on the crystallization conditions in this application, except for the changes in the crystallization conditions, the other components and process conditions remain unchanged. The experimental scheme is designed as follows (Test Examples 10-14):

[0072] Feed ratio:

[0073] 100 g of industrial-grade parachlorophenol and 0.5 g of activated carbon.

[0074] 400 ml of n-heptane;

[0075] Amount of ethanol used: 2.0 g;

[0076] Detailed operation steps:

[0077] Add 100 g of crude parachlorophenol (purity 96.26%, m-cresol 3.5%, phenol 0.14%) to a three-necked flask, add 400 ml of n-heptane and 2.0 g of ethanol, control the temperature to 60 °C, add 0.5 g of activated carbon, stir for 30 min, filter while hot through a 0.22-μm filter element, cool down through different crystallization conditions, crystallize, filter, and vacuum dry the wet product at 45 °C to obtain purified pharmaceutical-grade parachlorophenol. Calculate the yield and conduct a preliminary quality inspection in accordance with the fourth part of the Chinese Pharmacopoeia 2020 Edition. The inspection results are shown in Table 4:

[0078] Table 4 Optimization experiment on the amount of crystallization conditions

[0079]

[0080]

[0081] In summary, as can be seen from Table 4, programmed crystallization has a greater impact on the impurity removal effect, and the crystallization temperature has a greater impact. The lower the crystallization temperature, the more m-cresol impurities remain, and the longer the total crystallization time, the higher the yield.

[0082] Comparative Example 1

[0083] Based on the above cases, to investigate the influence of alcohol solvents on the purification effect, the amount of alcohol solvent used is selected as 0.02% w / w of the parachlorophenol feed amount. The results are shown in Examples 16-18

[0084] Table 5 Influence of alcohol solvents on the purification effect

[0085] Case Solvent Phenol m-Cresol Yield Test Example 16 Methanol 0.002％ 0.09％ 17.4％ Test Example 17 Ethanol 0.003％ 0.11％ 87.15％ Test Example 18 n-Propanol 0.008％ 0.86％ 86.19％ Test Example 19 n-Butanol 0.015％ 0.96％ 87.57％

[0086] The yield of methanol, another alcohol solvent, is very low, and the refining cost is high; the refining effects of n-butanol and n-propanol on m-cresol are limited.

[0087] In summary, starting from industrial-grade chlorocresol, through a specific refining system and crystallization conditions, the present invention has successfully refined a high-purity pharmaceutical-grade chlorocresol product with few impurities of m-cresol, high purity, light product color, and meeting pharmaceutical requirements; moreover, this refining method has a simple process, rationally utilizes resources, and has strong market competitiveness.

[0088] Please note that the technical features of the above embodiments can be combined arbitrarily. For the sake of concise description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope described in this specification. The above embodiments only express several implementation manners of the present application, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the invention patent. It should be pointed out that for those of ordinary skill in the art, without departing from the concept of the present application, several deformations and improvements can still be made, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application should be subject to the appended claims.

Claims

1. A refining method of medicinal grade parachlorometacresol, characterized in that, Comprising: Mix the crude industrial chlorocresol with a mixed solvent, add a decolorizing agent after heating, and stir and refine to obtain a refined crude liquid; the mixed solvent includes an alcohol organic solvent and an alkane organic solvent; Perform sterilization and first solid-liquid separation on the refined crude liquid, then continuously cool it to a first temperature and a second temperature under stirring for crystallization, and then perform second solid-liquid separation and drying to obtain the pharmaceutical-grade chlorocresol.

2. The refining method of medicinal grade chlorocresol according to claim 1, characterized in that, The mixed solvent is ethanol and a mixture of n-heptane and / or n-hexane.

3. The refining method of medicinal grade chlorocresol according to claim 2, characterized in that, The volume-mass ratio of the mixed solvent to the crude industrial chlorocresol is (2-8):

1.

4. The refining method of medicinal grade chlorocresol according to claim 3, characterized in that, The mass ratio of the ethanol to the crude industrial chlorocresol is (0.005-0.1):

1.

5. The refining method of medicinal grade chlorocresol according to claim 1, characterized in that, The temperature of the stirring and refining is 40-70 °C.

6. The refining method of medicinal grade chlorocresol according to claim 1, characterized in that, The decolorizing agent includes one or more of activated carbon, silica powder, and activated clay.

7. The refining method of medicinal grade chlorocresol according to claim 1, characterized in that, The first solid-liquid separation is carried out by precision filtration, and the pore size of the filter element for the precision filtration is 0.22-0.45 μm.

8. The refining method of medicinal grade chlorocresol according to claim 1, characterized in that, The first temperature is 15 - 35 °C, 所述第 二 温度为 0-5 ℃ .

9. The refining method of medicinal grade chlorocresol according to claim 1, characterized in that, The crystallization time under the second temperature condition is 1-12 h.

10. The refining method of medicinal grade chlorocresol according to any one of claims 1-9, characterized in that, The liquid obtained by the second solid-liquid separation is concentrated, then complexed with urea, refined, and decomplexed to recover m-cresol.

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