Method for purifying adapalene bulk drug

Abstract

The invention provides a purification method of an adapalene raw material medicine, and belongs to the technical field of medicine purification, and the purification method comprises the following steps: firstly, carrying out hydrolysis reaction by using 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-methyl naphthoate (namely a compound I), sodium hydroxide, purified water and 1, 4-dioxane as raw materials to obtain an adapalene sodium salt crude product; then mixing with tetrahydrofuran, and sequentially carrying out first heating stirring and first hot filtration to remove a main impurity 3; 3, 3 '-diadamantyl-4, 4'-dimethoxybiphenyl (impurity 1 for short) is prepared into a first filter cake, then the first filter cake is mixed with purified water, second heating stirring and second hot filtering are sequentially carried out to remove the main impurity [2, 2 '-dinaphthalene]-6, 6'-dicarboxylic acid (impurity 2 for short), a second filter cake is obtained, then the second filter cake is mixed with purified water, acid is dropwise added to adjust the pH value, and a third filter cake is obtained; and converting the adapalene sodium salt into adapalene, and then sequentially filtering and washing to obtain the qualified adapalene bulk drug with high purity.

Description

Technical Field

[0001] The invention relates to the technical field of drug purification, in particular to a method for purifying an adapalene raw material drug. Background Art

[0002] Adapalene, chemical name is 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, molecular formula is C 28 H 28 O3, white or off-white powder at room temperature, insoluble in water or ethanol, slightly soluble in tetrahydrofuran. Adapalene is a dermatological drug, clinically suitable for the treatment of acne vulgaris with acne, papules and pustules as the main manifestations, and can also be used to treat acne on the face, chest and back.

[0003] According to most literature reports, the current method for preparing the precursor of this product (i.e., 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid methyl (or ethyl) ester, referred to as compound I) is mostly to undergo Negishi coupling of 2-(1-adamantyl)-4-bromoanisole and 6-bromo-2-naphthoic acid methyl ester, and then the coupling product is hydrolyzed and refined to obtain adapalene. Among them, Negishi coupling is the key step in the adapalene process, which has the greatest impact on the product quality, yield and cost of the entire preparation process. The main impurities in the crude adapalene are the bimolecular dehalogenation byproducts produced in the coupling step: 3,3'-diadamantyl-4,4'-dimethoxybiphenyl (referred to as impurity 1) and [2,2'-binaphthyl]-6,6'-dicarboxylic acid (referred to as impurity 2). Both are insoluble in most solvents, which brings great difficulties to purification.

[0004] Chinese patent CN 111333496 B discloses a novel preparation method of adapalene, and discloses a method for recrystallizing adapalene raw material medicine, namely: recrystallization with a mixed solvent of tetrahydrofuran and toluene, purity 99.9%, yield 87.3%, actual repetition effect is poor, the content of impurity 1 is 1.98%, and the content of impurity 2 is 1.51%. Chinese patent CN101033190 B also discloses a preparation method of adapalene, which mentions that the method for recrystallization of adapalene raw material medicine is: adapalene crude product is recrystallized with tetrahydrofuran, the yield is 95.1%, the actual repetition effect is poor, the content of impurity 1 is 3.01%, and the content of impurity 2 is 1.45%. It can be seen that the prior art uses tetrahydrofuran recrystallization or tetrahydrofuran / toluene recrystallization, which has the problems of large amount of recrystallization solvent, poor purification effect, and inability to effectively remove coupled impurities to obtain qualified adapalene. Summary of the invention

[0005] The object of the present invention is to provide a method for purifying an adapalene bulk drug. The method provided by the present invention has excellent purification effect and can effectively remove coupled impurities, thereby obtaining qualified adapalene with high purity.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a method for purifying an adapalene bulk drug, comprising the following steps:

[0008] S1, mixing 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid methyl ester (compound I), sodium hydroxide, purified water and 1,4-dioxane, and performing a hydrolysis reaction to obtain a crude product of adapalene sodium salt;

[0009] S2, mixing the crude adapalene sodium salt obtained in step S1 with tetrahydrofuran, and sequentially performing a first heating and stirring and a first hot filtration to obtain a first filter cake;

[0010] After mixing the first filter cake and purified water, sequentially performing a second heating and stirring and a second hot filtration to obtain a second filter cake;

[0011] S3. After mixing the second filter cake obtained in step S2 with purified water, acid is added dropwise to adjust the pH, and then filtering and washing are performed in sequence to obtain the adapalene bulk drug.

[0012] Preferably, in step S1, the molar ratio of compound I to sodium hydroxide is 1:(1-5); the mass ratio of compound I, purified water and 1,4-dioxane is 1:(0.5-5):(8-16).

[0013] Preferably, the temperature of the hydrolysis reaction in step S1 is 60-100° C., and the time of the hydrolysis reaction is 2-10 h.

[0014] Preferably, the hydrolysis reaction in step S1 is carried out until no compound I remains as detected by TLC.

[0015] Preferably, in step S2, the mass ratio of compound I, tetrahydrofuran and purified water is 1:(7-14):(8-16).

[0016] Preferably, the temperature of the first heating and stirring is 40-100° C., and the time of the first heating and stirring is 0.5-7 h.

[0017] Preferably, the temperature of the second heating and stirring is 40-110° C., and the time of the second heating and stirring is 0.5-7 h.

[0018] Preferably, in step S3, the mass ratio of compound I to purified water is 1:(10-20).

[0019] Preferably, in step S3, acid is added dropwise to adjust the pH value of the system to 1-4.

[0020] The invention provides a method for purifying an adapalene bulk drug. Firstly, a compound I, sodium hydroxide, purified water and 1,4-dioxane are used as raw materials for hydrolysis reaction to obtain a crude product of adapalene sodium salt, and then tetrahydrofuran is mixed, and a first heating stirring and a first hot filtration are sequentially performed to remove a main impurity 3,3'-diadamantyl-4,4'-dimethoxybiphenyl (referred to as impurity 1) to obtain a first filter cake, and then the first filter cake is mixed with purified water, and then a second heating stirring and a second hot filtration are sequentially performed to remove a main impurity [2,2'-binaphthyl]-6,6'-dicarboxylic acid (referred to as impurity 2) to obtain a second filter cake, and then the second filter cake is mixed with purified water, and acid is added dropwise to adjust pH to convert the adapalene sodium salt into adapalene, and then filtering and washing are sequentially performed to obtain a qualified adapalene bulk drug with high purity. The purification method of adapalene raw material provided by the present invention has a simple and easy-to-implement treatment process. Compared with other purification methods, less solvent is used, and the impurity removal effect is obvious. A high-purity qualified product can be obtained, and concentration and tetrahydrofuran recrystallization are not required. The safety is guaranteed, stable and continuous production can be achieved, and the reaction time is shortened, so that the yield per unit time is improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is a bar chart of the impurity content of the adapalene raw materials prepared in Examples 1 to 3 of the present invention and Comparative Examples 1 and 2. DETAILED DESCRIPTION

[0022] In the present invention, unless otherwise specified, the raw materials used are conventional commercial products in the art.

[0023] The present invention provides a method for purifying an adapalene bulk drug, comprising the following steps:

[0024] S1, mixing 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid methyl ester (compound I), sodium hydroxide, purified water and 1,4-dioxane, and performing a hydrolysis reaction to obtain a crude product of adapalene sodium salt;

[0025] S2, mixing the crude adapalene sodium salt obtained in step S1 with tetrahydrofuran, and sequentially performing a first heating and stirring and a first hot filtration to obtain a first filter cake;

[0026] After mixing the first filter cake and purified water, sequentially performing a second heating and stirring and a second hot filtration to obtain a second filter cake;

[0027] S3. After mixing the second filter cake obtained in step S2 with purified water, acid is added dropwise to adjust the pH, and then filtering and washing are performed in sequence to obtain the adapalene bulk drug.

[0028] The invention prepares a mixture of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid methyl ester, i.e., compound I, sodium hydroxide, purified water and 1,4-dioxane, and then performs a hydrolysis reaction to obtain a crude product of adapalene sodium salt.

[0029] In the present invention, the molar ratio of the compound I to sodium hydroxide is preferably 1:(1-5); the mass ratio of the compound I, purified water and 1,4-dioxane is preferably 1:(0.5-5):(8-16).

[0030] In the present invention, the temperature of the hydrolysis reaction is preferably 60-100° C., and the time of the hydrolysis reaction is preferably 2-10 hours. The temperature and time of the hydrolysis reaction are controlled within the above ranges to ensure that compound I is fully hydrolyzed without any residue.

[0031] In the present invention, the hydrolysis reaction is preferably carried out until no residue of compound I is detected by TLC. In the present invention, the developing solvent used for TLC detection is preferably composed of petroleum ether and dichloromethane in a volume ratio of 1:1.

[0032] After obtaining the crude product of adapalene sodium salt, the present invention mixes the crude product with tetrahydrofuran, and sequentially performs a first heating and stirring and a first hot filtration to obtain a first filter cake.

[0033] In the present invention, the mass of tetrahydrofuran is preferably 7 to 14 times that of compound I.

[0034] In the present invention, the temperature of the first heating and stirring is preferably 40-100° C., and the time of the first heating and stirring is preferably 0.5-7 hours. The present invention removes the main impurity 1 through the first heating and stirring.

[0035] The present invention has no special limitation on the first hot filtration method, and the solid-liquid separation can be achieved by adopting conventional technical solutions in the field.

[0036] After obtaining the first filter cake, the present invention mixes the first filter cake with purified water, and then sequentially performs a second heating and stirring and a second hot filtration to obtain a second filter cake.

[0037] In the present invention, the mass of the purified water is preferably 8 to 16 times that of compound I.

[0038] In the present invention, the temperature of the second heating and stirring is preferably 40-110° C., and the time of the first heating and stirring is preferably 0.5-7 hours. The present invention removes the main impurity 2 through the second heating and stirring.

[0039] The present invention has no special limitation on the second heat filtration method, and the solid-liquid separation can be achieved by adopting conventional technical solutions in the art.

[0040] After obtaining the second filter cake, the present invention mixes the second filter cake with purified water, drips acid to adjust the pH, and then sequentially filters and washes to obtain the adapalene bulk drug.

[0041] In the present invention, the mass of the purified water is preferably 10 to 20 times that of compound I.

[0042] In the present invention, the pH value of the system is preferably adjusted to 1 to 4 by dropping acid, and more preferably to 1 to 2 by dropping acid. In the present invention, the sodium salt of adapalene is converted into adapalene by dropping acid to adjust the pH. In the present invention, the acid is preferably concentrated hydrochloric acid.

[0043] The present invention has no particular limitation on the filtering and washing methods, and any technical solution known in the art may be used.

[0044] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0045] The raw materials used in the present invention were purchased through general commercial channels, and the manufacturers, models or CAS numbers of some raw materials and reagents are shown in Table 1 below.

[0046] Table 1 Information of some raw materials and reagents used in the present invention

[0047] Reagent name CAS Number Manufacturer Specification Sodium hydroxide 1310-73-2 Sinopharm Chemical Reagent Co., Ltd. AR 1,4-Dioxane 123-91-1 Sinopharm Chemical Reagent Co., Ltd. AR Tetrahydrofuran 109-99-9 Xilong Chemical Industry Co., Ltd. AR Concentrated hydrochloric acid 7647-01-0 Xilong Chemical Industry Co., Ltd. AR

[0048] The 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid methyl ester used in the present invention is homemade in the laboratory, and the preparation method is as follows:

[0049] (1) Add 90 g of acetic acid, 30 g of p-bromophenol, 26 g of 1-adamantanol, and 15 g of sulfuric acid to a reaction flask, stir and heat to 80° C. and keep warm for 8 h. After the reaction, there is a large amount of white solid in the flask. The temperature is lowered to 20-30° C., 150 g of purified water is added to the reaction flask, and stirred at 20° C. for 2 h. After stirring, the filter is filtered and the filter cake is rinsed with purified water until the pH of the filtrate is 6. After the filter cake is dried, 49.7 g of 2-(1-adamantyl)-p-bromophenol is obtained, with a yield of 93%.

[0050] (2) 150 g of acetone, 49.7 g of 2-(1-adamantyl)-p-bromophenol prepared in step (1), 29 g of potassium carbonate, and 31 g of dimethyl sulfate were added to a reaction flask at 20° C., and the mixture was stirred at 20° C. for 7 h. 250 g of purified water was added to the reaction flask, and the mixture was stirred for 1 h. The mixture was filtered, and the filter cake was washed with 50 g of purified water. Then, 600 g of the filter cake was dissolved in dichloromethane and washed three times with 150 g of purified water. The organic phase was concentrated in vacuo until there was no distillate. The concentrated product was slurried with 80 g of ethyl acetate, filtered, and dried to obtain 39 g of 2-(1-adamantyl)-4-bromoanisole, with a yield of 75%;

[0051] (3) 10 g of anhydrous tetrahydrofuran, 2 g of magnesium chips, and 2.4 g of 2-(1-adamantyl)-4-bromoanisole prepared in step (2) were added to the reaction flask, and the atmosphere was replaced with nitrogen three times; 0.7 g of 1,2-dibromoethane was added to the reaction flask, and the mixture was heated to reflux, and the temperature was raised to 40° C. to initiate the reaction. 100 g of a tetrahydrofuran solution of 21 g of 2-(1-adamantyl)-4-bromoanisole was slowly added dropwise to the reaction flask, and the mixture was refluxed and stirred for 2 h after the addition was complete. 150 g of a tetrahydrofuran solution of 14 g of anhydrous zinc chloride was added to the reaction flask, and the mixture was refluxed and stirred for 1 h after the addition was complete. 0.8 g of NiCl2 / DPPE was added to the reaction flask, and 13.5 g of 6-bromo-2-naphthoic acid methyl ester was added and refluxed for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo. After concentration, 500 g of the product was dissolved in dichloromethane and washed with 1N hydrochloric acid (100 g × 3). The organic phase was concentrated in vacuo to obtain a crude product. The crude product was refluxed and slurried with 200 g of ethyl acetate for 2 hours, cooled to room temperature and filtered, washed with 50 g of ethyl acetate, and dried to obtain 14.3 g of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid methyl ester, i.e., compound I, with a yield of 65%.

[0052] In the present invention, the impurity 1 is 3,3'-diadamantyl-4,4'-dimethoxybiphenyl, and its structural formula is shown in Formula 1 below; the impurity 2 is [2,2'-binaphthyl]-6,6'-dicarboxylic acid, and its structural formula is shown in Formula 2 below.

[0053]

[0054] Example 1

[0055] Method for purifying adapalene raw material, steps:

[0056] S1. Add 10 g of compound I, 2.80 g of sodium hydroxide, 20 g of purified water, and 120 g of 1,4-dioxane into reaction flask A and stir. Heat the reaction temperature to 90° C. and stir for hydrolysis reaction for 5 h to obtain a crude product of adapalene sodium salt.

[0057] S2, adding 100 g of tetrahydrofuran into the reaction flask A containing the crude product of adapalene sodium salt obtained in step S1, heating and stirring at 110° C. for 0.5 h, and performing first hot filtration with heat preservation to obtain a first filter cake;

[0058] The first filter cake was added into reaction flask B, and 120 g of purified water was added into reaction flask B for a second heating and stirring at 110° C. for 0.5 h, followed by a second hot filtration with heat preservation to obtain a second filter cake;

[0059] S3. The second filter cake obtained in step S2 is transferred to reaction flask C, 120 g of purified water is added to the reaction flask C and stirred at room temperature, concentrated hydrochloric acid is added dropwise to the reaction flask C until the pH value of the system is 2, and the mixture is filtered and washed in sequence to obtain a white solid adapalene bulk drug with a yield of 86% and a purity of 99.78%.

[0060] Example 2

[0061] Method for purifying adapalene raw material, steps:

[0062] S1, 10 g of compound I, 1.0 g of sodium hydroxide, 5 g of purified water and 80 g of 1,4-dioxane were added to reaction flask A and stirred. The reaction temperature was heated to 60° C. and stirred for hydrolysis reaction for 10 h to obtain a crude product.

[0063] S2, adding 140 g of tetrahydrofuran into the reaction flask A containing the crude product obtained in step S1, heating and stirring at 90° C. for 2 h, and performing a first hot filtration with heat preservation to obtain a first filter cake;

[0064] The first filter cake was added into reaction flask B, and 160 g of purified water was added into reaction flask B for a second heating and stirring at 90° C. for 2 h, followed by a second hot filtration with heat preservation to obtain a second filter cake;

[0065] S3. The second filter cake obtained in step S2 is transferred to another reaction bottle C. 160 g of purified water is added to the reaction bottle C and stirred at room temperature. Concentrated hydrochloric acid is added dropwise to the reaction bottle C until the pH value is 1 and filtered to obtain a white solid with a yield of 85.6% and a purity of 99.73%.

[0066] Example 3

[0067] Method for purifying adapalene raw material, steps:

[0068] S1. Add 10 g of methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate, 4.70 g of sodium hydroxide, 50 g of purified water and 160 g of 1,4-dioxane into reaction flask A and stir. Heat the reaction temperature to 80° C. and stir for hydrolysis reaction for 7 h to obtain a crude product.

[0069] S2, adding 70 g of tetrahydrofuran into the reaction flask A containing the crude product obtained in step S1, heating and stirring at 70° C. for 5 h, and performing a first hot filtration with heat preservation to obtain a first filter cake;

[0070] The first filter cake was added into reaction flask B, and 80 g of purified water was added into reaction flask B for a second heating and stirring at 70° C. for 5 h, followed by a second hot filtration with heat preservation to obtain a second filter cake;

[0071] S3. Transfer the second filter cake obtained in step S2 to another reaction flask C, add 80 g of purified water into the reaction flask C and stir at room temperature, add concentrated hydrochloric acid dropwise into the reaction flask C until the pH is 1 and filter to obtain white solid adapalene bulk drug with a yield of 85% and a purity of 99.85%.

[0072] Comparative Example 1

[0073] In a three-necked flask, 10.00 g of methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate and 3.75 g of sodium hydroxide were added, followed by 40 g of water and 35 mL of tetrahydrofuran. The mixture was heated and refluxed for 5 hours. The reaction solution was cooled to 0 degrees, the pH value was adjusted to weak acidity with 10% hydrochloric acid, solids were precipitated, and the white solids were collected by filtration and recrystallized with a mixed solvent of tetrahydrofuran and toluene to obtain 7.94 g of adapalene bulk drug with a yield of 82% and a purity of 95.95%.

[0074] Comparative Example 2

[0075] To a three-necked flask, add 180 g of a tetrahydrofuran solution of 10.00 g of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid methyl ester, and then add 200 g of a potassium hydroxide solution with a mass concentration of 4%, and reflux for 3 hours. After the reaction is complete, evaporate the tetrahydrofuran, add 250 g of water to the residue, filter out the solid, wash with water until neutral, add the solid to 300 g of water, acidify with concentrated hydrochloric acid to pH 1, stir for 2 hours, filter out the crude product, and recrystallize the crude product with tetrahydrofuran to obtain 7.74 g of adapalene raw material drug product with a yield of 80% and a purity of 95.06%.

[0076] The purity and impurity content of the adapalene raw materials prepared in Examples 1 to 3 and Comparative Examples 1 and 2 were respectively detected by high performance liquid chromatography and are shown in Tables 2 and 3. Figure 1 shown.

[0077] Table 2 Comparison of purity and impurity content of adapalene raw materials prepared in Examples 1 to 3 and Comparative Examples 1 and 2

[0078] sample Impurity 1 Impurity 2 purity Comparative Example 1 1.98％ 1.51％ 95.95％ Comparative Example 2 3.01％ 1.45％ 95.06％ Example 1 0.03％ 0.08％ 99.78％ Example 2 0.05％ 0.07％ 99.73％ Example 3 0.02％ 0.07％ 99.85％

[0079] Figure 1This is a bar chart of the impurity content of the adapalene raw materials prepared in Examples 1 to 3 and Comparative Examples 1 and 2.

[0080] The specific conditions for the above-mentioned high performance liquid chromatography test for purity and impurity content are as follows:

[0081] Chromatographic conditions: phenylsilane bonded silica gel was used as filler; glacial acetic acid-water (0.1:100) was used as mobile phase A, acetonitrile-tetrahydrofuran (65:35) was used as mobile phase B, and gradient elution was performed according to Table 3 below; the flow rate was 1.2 mL per minute; the detection wavelength was 270 nm; and the column temperature was 30°C.

[0082] Table 3 Mobile phase parameters for gradient elution of HPLC

[0083]

[0084]

[0085] In summary, compared with Comparative Examples 1 and 2, the purification method of adapalene raw materials in Examples 1 to 3 of the present invention has a simple and easy processing process, a small amount of solvent is used, and the impurity removal effect is obvious, and a high-purity qualified product can be obtained. There is no need for concentration and tetrahydrofuran recrystallization, and the safety is guaranteed. Stable and continuous production can be achieved. In addition, the reaction time is shortened, so that the yield per unit time is improved.

[0086] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for purifying adapalene bulk drug, characterized in that: The following steps are involved: S1, mixing 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid methyl ester (compound I), sodium hydroxide, purified water and 1,4-dioxane, and performing a hydrolysis reaction to obtain a crude product of adapalene sodium salt; S2, mixing the crude adapalene sodium salt obtained in step S1 with tetrahydrofuran, and sequentially performing a first heating and stirring and a first hot filtration to obtain a first filter cake; After mixing the first filter cake and purified water, sequentially performing a second heating and stirring and a second hot filtration to obtain a second filter cake; S3. After mixing the second filter cake obtained in step S2 with purified water, acid is added dropwise to adjust the pH, and then filtering and washing are performed in sequence to obtain the adapalene bulk drug.

2. The method for purifying the adapalene bulk drug according to claim 1, wherein In the step S1, the molar ratio of compound I to sodium hydroxide is 1:(1-5); the mass ratio of compound I, purified water and 1,4-dioxane is 1:(0.5-5):(8-16).

3. The method for purifying the adapalene bulk drug according to claim 1, wherein: The temperature of the hydrolysis reaction in step S1 is 60-100° C., and the time of the hydrolysis reaction is 2-10 hours.

4. The method for purifying the adapalene bulk drug according to claim 1, wherein: In the step S1, the hydrolysis reaction is carried out until no compound I remains as detected by TLC.

5. The method for purifying the adapalene bulk drug according to claim 1, characterized in that: In step S2, the mass ratio of compound I, tetrahydrofuran and purified water is 1:(7-14):(8-16).

6. The method for purifying the adapalene bulk drug according to claim 1, characterized in that: The temperature of the first heating and stirring in step S2 is 40-100° C., and the time of the first heating and stirring is 0.5-7 hours.

7. The method for purifying the adapalene bulk drug according to claim 1, characterized in that: The temperature of the second heating and stirring in step S2 is 40-110° C., and the time of the first heating and stirring is 0.5-7 h.

8. The method for purifying the adapalene bulk drug according to claim 1, characterized in that: In the step S3, the mass ratio of the compound I to purified water is 1:(10-20).

9. The method for purifying the adapalene bulk drug according to claim 1, characterized in that: In step S3, acid is added dropwise to adjust the pH value of the system to 1-4.

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