CN110903299A - Method for refining dorzolamide hydrochloride - Google Patents
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Abstract
A method for refining dorzolamide hydrochloride relates to the technical field of compound purification, and the dorzolamide hydrochloride is refined by mixing water and an organic solvent, so that compared with the prior art, the dorzolamide hydrochloride is higher in yield and purity; less waste treatment and simpler operation, and is economic and environment-friendly.
Description
Technical Field
The invention relates to the technical field of compound purification, and particularly relates to a method for refining dorzolamide hydrochloride.
Background
Dorzolamide hydrochloride (Dorzalamide hydrochloride), chemically (4S-trans) -4-ethylamino-5, 6-dihydro-6-methyl-4H-thieno [2,3-b ] thiopyran-2-sulfonamide-7, 7-dioxide monohydrochloride, having the formula:
dorzolamide hydrochloride, marketed under the name Trusopt, is an eye drop developed by the national mussoton pharmaceutical system (MSD) and suitable for treating ocular hypertension or ocular hypertension in open-angle glaucoma patients, and has been approved by the FDA for marketing in 1994.
In the prior art, detailed reports on the refinement method of dorzolamide hydrochloride are not provided, and only slight mention is made in the preparation method of dorzolamide hydrochloride. In the existing preparation method, dimethyl sulfoxide is usually adopted or water is directly adopted to crystallize dorzolamide hydrochloride. When dimethyl sulfoxide is adopted for refining, dimethyl sulfoxide is not easy to remove, and the purity of the product is greatly influenced; when water is adopted for refining, the material is sticky, and the condition of sticking to the wall is easy to occur during transfer, so that the loss of the material is caused.
Disclosure of Invention
The invention aims to provide a method for refining dorzolamide hydrochloride, which has the advantages of good refining effect, simple and convenient process, high yield, economy, environmental protection and suitability for large-scale industrial production.
The embodiment of the invention is realized by the following steps:
the embodiment of the invention provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
mixing the crude dorzolamide hydrochloride with water, heating to 85-95 ℃ to dissolve, and filtering to obtain a filtrate;
and adding an organic solvent into the filtrate, cooling, crystallizing, filtering and drying to obtain dorzolamide hydrochloride.
The embodiment of the invention has the beneficial effects that:
the embodiment of the invention provides a method for refining dorzolamide hydrochloride, which is characterized in that dorzolamide hydrochloride is refined by mixing water and an organic solvent, and compared with the prior art, the method has the advantages of higher yield and higher purity; less waste treatment and simpler operation, and is economic and environment-friendly.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is an HPLC chromatogram of dorzolamide hydrochloride obtained in example 1 of the present invention;
FIG. 2 is an HPLC chromatogram of dorzolamide hydrochloride obtained in example 3 of the present invention;
FIG. 3 is an HPLC chromatogram of dorzolamide hydrochloride obtained in example 6 of the present invention;
FIG. 4 is an HPLC chromatogram of dorzolamide hydrochloride obtained in example 8 of the present invention;
FIG. 5 is an HPLC chromatogram of dorzolamide hydrochloride obtained in example 10 of the present invention;
FIG. 6 is an HPLC chromatogram of dorzolamide hydrochloride obtained in example 11 of the present invention;
FIG. 7 is an HPLC chromatogram of dorzolamide hydrochloride obtained in example 13 of the present invention;
FIG. 8 is an HPLC chromatogram of dorzolamide hydrochloride obtained in example 17 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The method for purifying dorzolamide hydrochloride according to the embodiment of the present invention will be specifically described below.
The embodiment of the invention provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
mixing the crude dorzolamide hydrochloride with water, heating to 85-95 ℃ to dissolve, and filtering to obtain a filtrate;
and adding an organic solvent into the filtrate, cooling, crystallizing, filtering and drying to obtain dorzolamide hydrochloride.
In the prior art, detailed reports on the refinement method of dorzolamide hydrochloride are not provided, and only slight mention is made in the preparation method of dorzolamide hydrochloride. In the existing preparation method, dimethyl sulfoxide is usually adopted or water is directly adopted to crystallize dorzolamide hydrochloride. When dimethyl sulfoxide is adopted for refining, dimethyl sulfoxide is not easy to remove, and the purity of the product is greatly influenced; when water is adopted for refining, the material is sticky, and the condition of sticking to the wall is easy to occur during transfer, so that the loss of the material is caused.
In view of the above situation, the embodiment of the invention provides a method for refining dorzolamide hydrochloride, which adopts the mixture of water and an organic solvent to refine dorzolamide hydrochloride, and compared with the prior art, the method has the advantages of higher yield and higher purity; less waste treatment and simpler operation, and is economic and environment-friendly.
Further, when the crude dorzolamide hydrochloride is mixed with water, the mass ratio of the crude dorzolamide hydrochloride to the water is 1: 3 to 5. Preferably, the mass ratio of the crude dorzolamide hydrochloride to the water is 1: 3.8 to 4.2. If the amount of water is too small, the crude dorzolamide hydrochloride cannot be completely dissolved, and the purpose of purification cannot be achieved. If the amount of water is too large, the dorzolamide hydrochloride is difficult to separate out, and the yield of the product is reduced. The inventor finds out through creative work, that when the mass ratio of the crude dorzolamide hydrochloride product to the water is controlled within the proportion range, the water is used in an amount enough to dissolve the crude dorzolamide hydrochloride product, and the dorzolamide hydrochloride product can be obtained at a high yield.
Further, the mass ratio of the crude dorzolamide hydrochloride to the organic solvent is 1: 0.5 to 9. Preferably, the mass ratio of the crude dorzolamide hydrochloride to the organic solvent is 1: 0.9 to 1.2. The dosage of the organic solvent is particularly important for crystallization of dorzolamide hydrochloride, and if the dosage of the organic solvent is too small, the dorzolamide hydrochloride in the filtrate is difficult to be fully precipitated, so that the product yield is low. And the excessive use amount of the organic solvent can cause the crystallization rate to be too high, and the solvent or other impurities are included in the crystals, so that the purity of the product is low. The inventor finds that the dorzolamide hydrochloride product can be obtained with high yield and high purity by controlling the mass ratio of the dorzolamide hydrochloride crude product to the organic solvent within the proportion range.
The organic solvent adopted in the embodiment of the invention is a low-boiling-point organic solvent with a boiling point lower than 120 ℃. Comprises at least one of methanol, ethanol, isopropanol, n-butanol, acetonitrile, acetone, and tetrahydrofuran. The organic solvent with low boiling point is easier to remove in the treatment process, which is beneficial to obtaining the dorzolamide hydrochloride product with high purity. Preferably, the organic solvent comprises at least one of ethanol and acetone, more preferably, the organic solvent is ethanol. The inventor finds that the ethanol has good crystallization effect and can obtain dorzolamide hydrochloride products with high yield and high purity through creative work.
Further, when the organic solvent is added into the filtrate, the filtrate is cooled to 40-45 ℃, and then the organic solvent is added. On one hand, the temperature is reduced, so that the volatilization of the organic solvent can be reduced, and the accuracy of the addition amount of the organic solvent is ensured. On the other hand, crystals are more easily precipitated at a lower temperature, so that the monitoring of the addition amount of the organic solvent is facilitated, and the excessive addition of the organic solvent is avoided.
Further, after the organic solvent is added, cooling to 0-30 ℃ for crystallization, wherein the crystallization time is 2-4 h. Stirring can be carried out in the crystallization process, after crystallization is finished, crystals are filtered out by filtration, and after washing with a small amount of organic solvent, the crystals are dried for 6-10 hours at 50-60 ℃, so that the required dorzolamide hydrochloride product can be obtained.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
the crude dorzolamide hydrochloride (100g) is dissolved in water (400g) at 85-95 ℃. After filtration, ethanol (100g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 91.2g of dorzolamide hydrochloride was obtained in 91.2% yield. Purity 99.98%, single impurity less than 0.1% (HPLC see figure 1).
Example 2
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
the crude dorzolamide hydrochloride (100g) is dissolved in water (300g) at 85-95 ℃. After filtration, ethanol (300g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 25-30 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 75.5g of dorzolamide hydrochloride was obtained with a yield of 75.5%. The purity is 99.92 percent, and the single impurity is less than 0.1 percent.
Example 3
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
the crude dorzolamide hydrochloride (100g) is dissolved in water (400g) at 85-95 ℃. After filtration, ethanol (100g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 25-30 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 78.2g of dorzolamide hydrochloride was obtained in a yield of 78.2%. The purity is 99.95 percent, and the single impurity is less than 0.1 percent. (HPLC is shown in figure 2)
Example 4
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
crude dorzolamide hydrochloride (100g) was dissolved in water (500g) at 85-95 ℃. After filtration, ethanol (300g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 25-30 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 72.0g of dorzolamide hydrochloride was obtained in a yield of 72.0%. The purity is 99.93 percent, and the single impurity is less than 0.1 percent.
Example 5
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
the crude dorzolamide hydrochloride (100g) is dissolved in water (300g) at 85-95 ℃. After filtration, ethanol (900g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 84.9g of dorzolamide hydrochloride was obtained with a yield of 84.9%. The purity is 98.55%.
Example 6
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
the crude dorzolamide hydrochloride (100g) is dissolved in water (300g) at 85-95 ℃. After filtration, ethanol (300g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 85.1g of dorzolamide hydrochloride was obtained in 85.1% yield. Purity 99.95%, single impurity less than 0.1% (HPLC see figure 3).
Example 7
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
the crude dorzolamide hydrochloride (100g) is dissolved in water (400g) at 85-95 ℃. After filtration, ethanol (300g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 82.8g of dorzolamide hydrochloride was obtained with a yield of 82.8%. The purity is 99.93 percent, and the single impurity is less than 0.1 percent.
Example 8
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
the crude dorzolamide hydrochloride (100g) is dissolved in water (400g) at 85-95 ℃. After filtration, ethanol (200g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 85.8g of dorzolamide hydrochloride was obtained with a yield of 85.8%. Purity 99.95%, single impurity less than 0.1% (HPLC see figure 4).
Example 9
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
crude dorzolamide hydrochloride (100g) was dissolved in water (500g) at 85-95 ℃. After filtration, ethanol (300g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 76.3g of dorzolamide hydrochloride was obtained in 76.3% yield. The purity is 99.93 percent, and the single impurity is less than 0.1 percent.
Example 10
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
the crude dorzolamide hydrochloride (100g) is dissolved in water (300g) at 85-95 ℃. After filtration, ethanol (100g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. Obtained 87.5g of dorzolamide hydrochloride with a yield of 87.5%. Purity 99.96%, individual impurities less than 0.1% (HPLC see figure 5).
Example 11
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
the crude dorzolamide hydrochloride (100g) is dissolved in water (400g) at 85-95 ℃. After filtration, ethanol (150g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 86.8g of dorzolamide hydrochloride was obtained with a yield of 86.8%. Purity 99.95%, single impurity less than 0.1% (HPLC see figure 6).
Example 12
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
the crude dorzolamide hydrochloride (100g) is dissolved in water (400g) at 85-95 ℃. After filtration, ethanol (50g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 85.9g of dorzolamide hydrochloride was obtained with a yield of 85.9%. The purity is 99.80 percent, and the single impurity is less than 0.1 percent.
Example 13
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
the crude dorzolamide hydrochloride (100g) is dissolved in water (400g) at 85-95 ℃. After filtration, acetone (100g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 84.6g of dorzolamide hydrochloride was obtained with a yield of 84.6%. Purity 99.95%, single impurity less than 0.1% (HPLC see figure 7).
Example 14
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
the crude dorzolamide hydrochloride (100g) is dissolved in water (400g) at 85-95 ℃. After filtration, acetonitrile (100g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 85.7g of dorzolamide hydrochloride was obtained with a yield of 85.7%. The purity is 99.88%.
Example 15
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
the crude dorzolamide hydrochloride (100g) is dissolved in water (400g) at 85-95 ℃. After filtration, tetrahydrofuran (100g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 83.2g of dorzolamide hydrochloride was obtained in 83.2% yield. The purity is 99.82%.
Example 16
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
the crude dorzolamide hydrochloride (100g) is dissolved in water (400g) at 85-95 ℃. After filtration, methanol (100g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 84.4g of dorzolamide hydrochloride was obtained with a yield of 84.4%. The purity is 99.84%.
Example 17
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
the crude dorzolamide hydrochloride (100g) is dissolved in water (400g) at 85-95 ℃. After filtration, isopropanol (100g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 88.1g of dorzolamide hydrochloride was obtained in 88.1% yield. Purity 99.94%, single impurity less than 0.1% (HPLC see figure 8).
Example 18
The embodiment provides a method for refining dorzolamide hydrochloride, which comprises the following steps:
the crude dorzolamide hydrochloride (100g) is dissolved in water (400g) at 85-95 ℃. After filtration, n-butanol (100g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 86.1g of dorzolamide hydrochloride was obtained in 86.1% yield. The purity is 99.86 percent, and the single impurity is less than 0.1 percent.
Comparative example 1
The present comparative example provides a method for refining dorzolamide hydrochloride, comprising:
the crude dorzolamide hydrochloride (100g) is dissolved in water (300g) at 95-105 ℃. After filtering, cooling the water solution to 0-5 ℃, stirring for 3-5 hours at the temperature, washing a filter cake obtained by filtering with cold water, and drying for 4-8 hours at 55-60 ℃. 56.1g of dorzolamide hydrochloride was obtained in 56.1% yield. The purity is 98.43%.
Comparative example 2
The present comparative example provides a method for refining dorzolamide hydrochloride, comprising:
crude dorzolamide hydrochloride (100g) was dissolved in water (800g) at 85-95 ℃. After filtration, ethanol (100g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 48.3g of dorzolamide hydrochloride was obtained in 48.3% yield. The purity is 99.84%, and the single impurity is less than 0.1%.
Comparative example 3
The present comparative example provides a method for refining dorzolamide hydrochloride, comprising:
the crude dorzolamide hydrochloride (100g) is dissolved in water (400g) at 85-95 ℃. After filtration, ethanol (10g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 64.9g of dorzolamide hydrochloride was obtained in a yield of 64.9%. The purity is 99.87 percent, and the single impurity is less than 0.1 percent.
Comparative example 4
The present comparative example provides a method for refining dorzolamide hydrochloride, comprising:
the crude dorzolamide hydrochloride (100g) is dissolved in water (400g) at 85-95 ℃. After filtration, ethanol (1500g) was added dropwise to the aqueous solution at 40 to 45 ℃. Gradually cooling to 0-5 ℃, stirring for 2-4 hours at the temperature, washing a filter cake obtained by filtering with ethanol, and drying for 8 hours at 50 ℃. 94.3g of dorzolamide hydrochloride was obtained with a yield of 94.3%. The purity is 96.48%.
Test examples
Examples 1 to 18 and comparative examples 1 to 4 were compared, and the results are shown in Table 1.
TABLE 1 comparison of the refining results
As can be seen from table 1, except for example 4, the yield of the dorzolamide hydrochloride refining method of examples 1 to 18 of the present invention can reach more than 75%, and even up to 91.2%, and meanwhile, the purity can reach more than 99.8%, so as to achieve a better refining effect. In examples 2 to 4, the relatively high crystallization temperature is adopted, so that dorzolamide hydrochloride cannot be sufficiently separated out, and the yield is affected. In contrast, comparative example 1 is a method of crystallization using water in the prior art, and the yield is only 56.1%, the purity is only 98.73%, and the refining effect is poor. Comparative example 2 used an excess of water to dissolve the crude dorzolamide hydrochloride, resulting in difficulty in crystal precipitation, and although the purity was still high, the yield was only 48.3%. Comparative example 3 used a smaller amount of ethanol to precipitate crystals, which also resulted in insufficient precipitation of crystals, with a yield of only 64.9%. Comparative example 4 used more ethanol to precipitate crystals, which precipitated faster, and gave a yield of 94.3%, but the purity drop was significant, only 96.48%.
In summary, the embodiment of the present invention provides a method for refining dorzolamide hydrochloride, wherein dorzolamide hydrochloride is refined by mixing water and an organic solvent, and compared with the prior art, the method has the advantages of higher yield and higher purity; less waste treatment and simpler operation, and is economic and environment-friendly.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for refining dorzolamide hydrochloride is characterized by comprising the following steps:
mixing the crude dorzolamide hydrochloride with water, heating to 85-95 ℃ to dissolve, and filtering to obtain a filtrate;
and adding an organic solvent into the filtrate, cooling, crystallizing, filtering and drying to obtain the dorzolamide hydrochloride.
2. The refining method according to claim 1, wherein the organic solvent is a low-boiling-point organic solvent having a boiling point of less than 120 ℃.
3. The refining method according to claim 2, wherein the organic solvent includes at least one of methanol, ethanol, isopropanol, n-butanol, acetonitrile, acetone, and tetrahydrofuran.
4. The refining method according to claim 3, wherein the organic solvent includes at least one of ethanol and acetone, and preferably the organic solvent is ethanol.
5. The refining method of claim 1, wherein the mass ratio of the crude dorzolamide hydrochloride to the water is 1: 3 to 5.
6. The refining method of claim 5, wherein the mass ratio of the crude dorzolamide hydrochloride to the water is 1: 3.8 to 4.2.
7. The refining method of claim 1, wherein the mass ratio of the crude dorzolamide hydrochloride to the organic solvent is 1: 0.5 to 9.
8. The refining method of claim 7, wherein the mass ratio of the crude dorzolamide hydrochloride to the organic solvent is 1: 0.9 to 1.2.
9. The refining method according to claim 1, wherein the organic solvent is added after the filtrate is cooled to 40 to 45 ℃.
10. The refining method according to claim 9, wherein the organic solvent is added, and then the mixture is cooled to 0 to 30 ℃ for crystallization, wherein the crystallization time is 2 to 4 hours.
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| US20040198805A1 (en) * | 2003-04-07 | 2004-10-07 | Reddy Bandi Parthasaradhi | Novel crystalline form of dorzolamide hydrochloride |
| US20060155132A1 (en) * | 2005-01-06 | 2006-07-13 | Kovacs Laszlo Z | Method of making dorzolamide hydrochloride |
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| WO2018066004A1 (en) * | 2016-10-07 | 2018-04-12 | Indoco Remedies Limited | Process for the preparation of doraolzmide hydrochloride |
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2018
- 2018-09-17 CN CN201811083966.0A patent/CN110903299A/en active Pending
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| US20040198805A1 (en) * | 2003-04-07 | 2004-10-07 | Reddy Bandi Parthasaradhi | Novel crystalline form of dorzolamide hydrochloride |
| US20060155132A1 (en) * | 2005-01-06 | 2006-07-13 | Kovacs Laszlo Z | Method of making dorzolamide hydrochloride |
| CN101426795A (en) * | 2006-04-21 | 2009-05-06 | Zach系统股份公司 | Process for preparing dorzolamide |
| JP2009242368A (en) * | 2008-03-31 | 2009-10-22 | Nidek Co Ltd | Dorzolamide hydrochloride ophthalmic solution |
| WO2018066004A1 (en) * | 2016-10-07 | 2018-04-12 | Indoco Remedies Limited | Process for the preparation of doraolzmide hydrochloride |
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