CN114031611B - Preparation method of low-ethanol-residue small-granularity terazosin hydrochloride - Google Patents
Preparation method of low-ethanol-residue small-granularity terazosin hydrochloride Download PDFInfo
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- CN114031611B CN114031611B CN202111342833.2A CN202111342833A CN114031611B CN 114031611 B CN114031611 B CN 114031611B CN 202111342833 A CN202111342833 A CN 202111342833A CN 114031611 B CN114031611 B CN 114031611B
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- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 title claims abstract description 69
- 229960001909 terazosin hydrochloride Drugs 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 106
- 239000000047 product Substances 0.000 claims abstract description 56
- 239000013078 crystal Substances 0.000 claims abstract description 46
- 238000001816 cooling Methods 0.000 claims abstract description 37
- 239000002904 solvent Substances 0.000 claims abstract description 29
- 239000002245 particle Substances 0.000 claims abstract description 28
- 238000009826 distribution Methods 0.000 claims abstract description 20
- 238000005406 washing Methods 0.000 claims abstract description 18
- 238000001914 filtration Methods 0.000 claims abstract description 17
- 238000001035 drying Methods 0.000 claims abstract description 16
- 238000002425 crystallisation Methods 0.000 claims abstract description 15
- 230000008025 crystallization Effects 0.000 claims abstract description 15
- 239000012065 filter cake Substances 0.000 claims abstract description 13
- 239000000706 filtrate Substances 0.000 claims abstract description 12
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 64
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 22
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
- 239000007788 liquid Substances 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 239000012458 free base Substances 0.000 abstract description 12
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 abstract 2
- 238000009210 therapy by ultrasound Methods 0.000 description 19
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- 239000002253 acid Substances 0.000 description 9
- 239000002994 raw material Substances 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 238000005054 agglomeration Methods 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 150000004683 dihydrates Chemical class 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 238000010669 acid-base reaction Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 229960001693 terazosin Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to a preparation method of small-granularity terazosin hydrochloride with low ethanol residue. The technical scheme of the invention is as follows: firstly, adding terazosin hydrochloride free base into ethanol water solution, then adding hydrochloric acid water solution into a crystallizer, stopping adding the hydrochloric acid water solution when the pH value of the solution is between 2.3 and 2.8 at the flow rate of 0.1-2.0mL/min, decoloring and filtering. Transferring the filtrate into a crystallizer, preserving the temperature at 50-60 ℃, introducing ultrasonic wave to induce crystallization, reducing the temperature to 40-50 ℃ at the ultrasonic frequency of 25-40KHz, preserving the temperature and growing the crystals for 1-2 hours; and stopping ultrasonic, continuously cooling to 10-20 ℃, starting ultrasonic with the ultrasonic frequency of 20-33KHz, and growing the crystal for 2-4 hours. Filtering, washing the filter cake with a washing solvent, and finally drying the product to obtain the terazosin hydrochloride product with uniform particle size distribution.
Description
Technical Field
The invention belongs to the technical field of crystallization, and particularly relates to a preparation method of low-ethanol-residue small-granularity terazosin hydrochloride.
Background
Terazosin hydrochloride as long-acting selectivityα 1 Receptor blockers can be used for the treatment of benign prostatic hyperplasia and hypertension. The trazosin hydrochloride on the market is mainly prepared from tablets and capsules. The physicochemical properties of the raw materials have important influence on the curative effect, and the process of developing the preparation often needs to limit the indexes such as crystal form, particle size distribution and the like of the raw materials to ensure the stability of the preparation process. Patent WO9925715A1 reports that terazosin hydrochloride has four crystal forms of methanolic solvent compound, monohydrate, dihydrate, wherein the original preparation adopts the dihydrate crystal form of terazosin hydrochloride.
The preparation of the terazosin hydrochloride is mainly realized by the acid-base reaction of the terazosin free base and the hydrochloric acid, and the refining and purifying process mostly adopts the way of recrystallisation by an organic solvent. Because the terazosin hydrochloride is easily soluble in hot water and has poor solubility in alcohol solvents such as ethanol, isopropanol and the like, the crystallization process mainly adopts an ethanol solvent system to ensure the process yield. The conventional cooling crystallization process is difficult to directly obtain the terazosin hydrochloride product with the granularity meeting the preparation requirement, and the terazosin hydrochloride with the granularity of 80-100 meshes, which is obtained by the crystallization preparation process, often has ethanol residues in the product due to agglomeration of fine crystals, so that the ethanol soluble residue content is difficult to be less than or equal to 0.5% by using a common vacuum drying technology. Patent CN1563001A adopts 95% ethanol as a refined solvent system, and prepares terazosin hydrochloride by dissolving the solution at a high temperature of 60-65 ℃ and then rapidly cooling the solution in a refrigerator, wherein the granularity of the product can reach below 40 microns, but the ethanol solution residue of the product is about 1%. In addition, the method has a smaller application range, is only suitable for laboratory small-scale tests, and is not suitable for industrialized scale-up. The preparation method reported in patent US20070161791A1 is similar to this method, with only slightly different amounts of ethanol, and the resulting product still suffers from the drawbacks described above.
On the other hand, in addition to the crystal form, in order to ensure the clinical curative effect of the terazosin hydrochloride, the downstream preparation process often requires that the granularity of the terazosin hydrochloride is in a proper range, the too large or the too small granularity can cause uneven mixing of raw materials and auxiliary materials, and the too large granularity can cause slow dissolution. The terazosin hydrochloride is slightly soluble in water, and in order to obtain higher drug dissolution, the pharmaceutical preparation workers pulverize the terazosin hydrochloride API to D by adopting a mechanical pulverizing mode 90 The particle size is below 15 microns, and the production of the pharmaceutical preparation is convenient.
The method for solving the ethanol solvent residue in the current enterprises generally comprises the steps of preparing a large-granularity terazosin hydrochloride crystal product to avoid crystal agglomeration and occlusion of the ethanol solvent, and obtaining a small-granularity terazosin hydrochloride bulk drug required by a preparation manufacturer in a mechanical crushing mode. The method has the advantages of complex process procedures, low efficiency, high operation cost, high material loss, large dust pollution and poor reproducibility of particle size distribution among batches. Therefore, the preparation process of the terazosin hydrochloride with small granularity and low residual solvent is provided, which is beneficial to the industrial production of the terazosin hydrochloride pharmaceutical preparation.
Disclosure of Invention
Aiming at the problem of ethanol residue in the production process of the terazosin hydrochloride, the invention aims to provide a small-granularity terazosin hydrochloride preparation process with low ethanol solvent residue, so that the ethanol content in the terazosin hydrochloride is less than 0.5%, and meanwhile, the terazosin hydrochloride product can meet the requirements of a terazosin hydrochloride preparation without crushing.
In order to achieve the aim, the invention carries out systematic research on the preparation process of the terazosin hydrochloride, in particular to the crystallization process thereof, and finally obtains the small-granularity terazosin hydrochloride crystallization product with granularity distribution of 5-15 microns, the purity of the product is more than 99.95 percent, and the ethanol solvent residue is less than 0.5 percent.
Technical proposal
The technical scheme of the invention is as follows: the preparation process of the small-granularity terazosin hydrochloride with low ethanol solvent residue takes terazosin hydrochloride free alkali as a raw material, and obtains a terazosin hydrochloride crystal product after salifying, decoloring, filtering, induced crystallization and crystallization, and comprises the following steps:
and the first step, respectively adding ethanol aqueous solution and terazosin hydrochloride free alkali into a reaction kettle, uniformly stirring to obtain terazosin hydrochloride free alkali solution, wherein the solid-liquid ratio is 0.04-g/g-0.08-g/g, and continuously stirring for 30-60 minutes at 50-60 ℃.
And step two, adding the aqueous solution of the hydrochloric acid into the solution obtained in the step one, wherein the adding speed is 0.1-2.0mL/min, and stopping adding the aqueous solution of the hydrochloric acid when the pH value of the solution is 2.3-2.8. Then adding active carbon for decoloring and filtering. Transferring the filtrate into a crystallizer, preserving the temperature at 50-60 ℃, introducing ultrasonic wave to induce crystallization, reducing the temperature to 40-50 ℃ after the ultrasonic frequency is 25-40KHz, continuing to carry out ultrasonic treatment, and preserving the temperature and growing the crystals for 1-2 hours; stopping ultrasonic, continuously cooling to 10-20 ℃, starting ultrasonic with the ultrasonic frequency of 20-33KHz, and growing the crystal for 2-4 h.
And thirdly, filtering, washing a filter cake by using a washing solvent, and finally drying the product to obtain the terazosin hydrochloride product with uniform particle size distribution.
The ethanol water solution in the first step is 88% -92% ethanol water solution, and the percentage is mass percentage.
The molar concentration of the hydrochloric acid aqueous solution in the second step is 8-12 mol/L.
The cooling rate in the second step is 0.1-0.2 ℃/min.
The washing solvent in the third step is ethanol water solution, wherein the mass fraction of ethanol is 95-98%.
The drying condition in the third step is 40-60 ℃ and normal pressure, and the drying time is 8-12 hours.
The terazosin hydrochloride crystal obtained by the invention has complete crystal form, uniform and controllable granularity, easy filtration, washing and drying of crystal slurry and low labor intensity of process operation.
The beneficial effects are that:
the invention provides a preparation method of terazosin hydrochloride crystals with controllable granularity, the purity of the product is more than 99.95%, the residual ethanol solvent is less than 0.5%, the content of the crystals is lower than the specified value of pharmacopoeia, the crystals are not aggregated, the granularity is 5-15 microns, the granularity distribution is uniform, the single-pass molar yield in the crystallization process is more than 85%, and the method is suitable for industrial production.
The small-granularity terazosin hydrochloride crystals prepared by the technical scheme can be directly fed into a pharmaceutical preparation producer without crushing and other working procedures to prepare the terazosin hydrochloride.
Drawings
Fig. 1: example terazosin hydrochloride crystal morphology (100 x magnification);
fig. 2: example terazosin hydrochloride particle size distribution profile;
fig. 3: comparative example 4 particle size distribution plot.
Detailed Description
The terazosin hydrochloride free base used in the examples and comparative examples of the present invention was produced by Dijia pharmaceutical Co Ltd, D90 was 126.32 μm, ethanol solvent residue was 1.84%, and HPLC purity was 96.35%.
In the embodiment of the invention and the comparative example, the percentage of the ethanol solution is mass percentage.
Example 1
The terazosin hydrochloride free base was added to 90% ethanol at a solid-to-liquid ratio of 0.06g/g and stirred at 55℃for 60min. Then, 10mol/L hydrochloric acid was added dropwise at a rate of 0.1ml/min, and the acid addition was stopped when the pH of the solution reached 2.5. After the activated carbon is decolorized, the filtrate is transferred into a crystallizer, and the temperature is kept at 55 ℃. And carrying out ultrasonic treatment on the solution, wherein the ultrasonic frequency is 25KHz, then cooling the solution to 45 ℃, and continuing to carry out constant-temperature crystal growth under ultrasonic for 1h. Stopping ultrasonic treatment, cooling the solution to 15 ℃, and cooling at a speed of 0.1 ℃/min. Then continuing to carry out ultrasonic solution at the frequency of 20KHz, and growing crystals at constant temperature for 3h. Filtering, washing the filter cake with 95% ethanol, and drying at 50 ℃ and normal pressure for 10 hours to obtain the terazosin hydrochloride finished product. The product yield has uniform particle size distribution (shown in figure 1), the particle size distribution curve obtained by a Markov particle analyzer is normal unimodal, the D90 is 9.382 μm (shown in figure 2), the ethanol solvent residue is 0.32%, the HPLC purity is 99.96%, and the product yield is 89.7%.
Example 2
The terazosin hydrochloride free base was added to 92% ethanol with a solid-to-liquid ratio of 0.04, g/g and stirred for 30min at 50 ℃. Then, 12mol/L hydrochloric acid was added dropwise at a rate of 1.5ml/min, and the acid addition was stopped when the pH of the solution reached 2.3. After the activated carbon is decolorized, the filtrate is transferred into a crystallizer, and the temperature is kept at 50 ℃. And carrying out ultrasonic treatment on the solution, wherein the ultrasonic frequency is 40KHz, then cooling the solution to 40 ℃, and continuing to carry out constant-temperature crystal growth under ultrasonic for 1.5h. Stopping ultrasonic treatment, cooling the solution to 10 ℃, and cooling at a speed of 0.2 ℃/min. Then continuing to carry out ultrasonic solution at the frequency of 25KHz, and growing crystals at constant temperature for 2h. Filtering, washing the filter cake with 98% ethanol, and drying at 40 ℃ and normal pressure for 12 hours to obtain the terazosin hydrochloride finished product. The product yield has uniform particle size distribution, the particle size distribution curve obtained by a Markov particle analyzer is normal single peak, the D90 is 12.644 mu m, the ethanol solvent residue is 0.26%, the HPLC purity is 99.97%, and the product yield is 88.2%.
Example 3
The terazosin hydrochloride free base was added to 88% ethanol at a solid-to-liquid ratio of 0.08/g/g and stirred at 60℃for 40min. Then 8mol/L hydrochloric acid was added dropwise at a rate of 0.5ml/min, and the acid addition was stopped when the pH of the solution reached 2.8. After the activated carbon is decolorized, the filtrate is transferred into a crystallizer, and the temperature is kept at 60 ℃. And carrying out ultrasonic treatment on the solution, wherein the ultrasonic frequency is 30KHz, then cooling the solution to 50 ℃, and continuing to carry out constant-temperature crystal growth under ultrasonic for 1h. Stopping ultrasonic treatment, cooling the solution to 20 ℃, and cooling at a speed of 0.1 ℃/min. Then continuing to carry out ultrasonic solution at the frequency of 25KHz, and growing crystals at constant temperature for 4 hours. Filtering, washing the filter cake with 96% ethanol, and drying at 60 ℃ and normal pressure for 8 hours to obtain the terazosin hydrochloride finished product. The product yield has uniform particle size distribution, the particle size distribution curve obtained by a Markov particle analyzer is normal single peak, the D90 is 13.879 mu m, the ethanol solvent residue is 0.33%, the HPLC purity is 99.97%, and the product yield is 85.4%.
Example 4
The terazosin hydrochloride free base was added to 91% ethanol at a solid-to-liquid ratio of 0.05 g/g and stirred at 50℃for 40min. Then, 10mol/L hydrochloric acid was added dropwise at a rate of 1.0ml/min, and the acid addition was stopped when the pH of the solution reached 2.4. After the activated carbon is decolorized, the filtrate is transferred into a crystallizer, and the temperature is kept at 50 ℃. And carrying out ultrasonic treatment on the solution, wherein the ultrasonic frequency is 35KHz, then cooling the solution to 40 ℃, and continuing to carry out constant-temperature crystal growth under ultrasonic for 2 hours. Stopping ultrasonic treatment, cooling the solution to 10 ℃, and cooling at a speed of 0.1 ℃/min. Then continuing to carry out ultrasonic solution at the frequency of 33KHz, and growing crystals at constant temperature for 3h. Filtering, washing the filter cake with 98% ethanol, and drying at 50 ℃ and normal pressure for 10 hours to obtain the terazosin hydrochloride finished product. The product yield has uniform particle size distribution, the particle size distribution curve obtained by a Markov particle analyzer is normal single peak, the D90 is 7.686 mu m, the ethanol solvent residue is 0.42%, the HPLC purity is 99.96%, and the product yield is 86.5%.
Example 5
The terazosin hydrochloride free base was added to 90% ethanol with a solid-to-liquid ratio of 0.07, g/g and stirred at 60 ℃ for 60min. Then, 10mol/L hydrochloric acid was added dropwise at a rate of 2.0ml/min, and the acid addition was stopped when the pH of the solution reached 2.8. After the activated carbon is decolorized, the filtrate is transferred into a crystallizer, and the temperature is kept at 60 ℃. And carrying out ultrasonic treatment on the solution, wherein the ultrasonic frequency is 35KHz, then cooling the solution to 50 ℃, and continuing to carry out constant-temperature crystal growth under ultrasonic for 1.5h. Stopping ultrasonic treatment, cooling the solution to 20 ℃, and cooling at a speed of 0.2 ℃/min. Then continuing to carry out ultrasonic solution at the frequency of 30KHz, and growing crystals at constant temperature for 2h. Filtering, washing the filter cake with 95% ethanol, and drying at 60 ℃ and normal pressure for 8 hours to obtain the terazosin hydrochloride finished product. The product yield has uniform particle size distribution, the particle size distribution curve obtained by a Markov particle analyzer is normal single peak, the D90 is 5.742 mu m, the ethanol solvent residue is 0.35%, the HPLC purity is 99.96%, and the product yield is 87.1%.
Comparative example 1
The terazosin hydrochloride free base was added to 80% ethanol with a solid-to-liquid ratio of 0.04g/g and stirred at 60℃for 60min. Then, 10mol/L hydrochloric acid was added dropwise at a rate of 2.0ml/min, and the acid addition was stopped when the pH of the solution reached 2.8. After the activated carbon is decolorized, the filtrate is transferred into a crystallizer, and the temperature is kept at 60 ℃. And carrying out ultrasonic treatment on the solution, wherein the ultrasonic frequency is 25KHz, then cooling the solution to 40 ℃, and continuing to carry out constant-temperature crystal growth under ultrasonic for 1h. Stopping ultrasonic treatment, cooling the solution to 15 ℃, and cooling at a speed of 0.1 ℃/min. Then continuing to carry out ultrasonic solution at the frequency of 25KHz, and growing crystals at constant temperature for 3h. Filtering, washing the filter cake with 80% ethanol, and drying at 50 ℃ and normal pressure for 10 hours to obtain the terazosin hydrochloride finished product. The product particles D90 were 25.483 μm, ethanol solvent residue 0.45%, HPLC purity 99.04%, product yield 73.5%.
The concentration of the ethanol aqueous solution of the comparative example is 80 percent and is lower than 88 percent, and the granularity of the obtained terazosin hydrochloride product is larger because the supersaturation degree is lower and the crystal mainly grows. The HPLC purity is low, and the product yield is low, which are all caused by system reasons.
Comparative example 2
The terazosin hydrochloride free base was added to 90% ethanol at a solid-to-liquid ratio of 0.06g/g and stirred at 55℃for 60min. Then, 12mol/L hydrochloric acid was added dropwise at a rate of 6.0ml/min, and the acid addition was stopped when the pH of the solution reached 2.5. After the activated carbon is decolorized, the filtrate is transferred into a crystallizer, and the temperature is kept at 55 ℃. And carrying out ultrasonic treatment on the solution, wherein the ultrasonic frequency is 25KHz, then cooling the solution to 45 ℃, and continuing to carry out constant-temperature crystal growth under ultrasonic for 1h. Stopping ultrasonic treatment, cooling the solution to 15 ℃, and cooling at a speed of 0.2 ℃/min. Then continuing to carry out ultrasonic solution at the frequency of 20KHz, and growing crystals at constant temperature for 3h. Filtering, washing the filter cake with 95% ethanol, and drying at 50 ℃ and normal pressure for 10 hours to obtain the terazosin hydrochloride finished product. The product particles D90 were 15.556 μm, the ethanol solvent residue was 0.55%, the HPLC purity was 99.11%, and the product yield was 85.5%.
The speed of the hydrochloric acid solution is 6.0ml/min and is higher than 2.0ml/min, and the purity of the obtained terazosin hydrochloride product HPLC is lower. The reason is that the adding speed of the hydrochloric acid solution is too high, so that the supersaturation degree of the solution is too high, the product and the impurities are easy to be occluded, the purity of the product is reduced, and the solvent residue is increased.
Comparative example 3
The terazosin hydrochloride free base was added to 88% ethanol at a solid-to-liquid ratio of 0.08g/g and stirred at 60℃for 40min. Then 8mol/L hydrochloric acid was added dropwise at a rate of 0.5ml/min, and the acid addition was stopped when the pH of the solution reached 2.8. After the activated carbon is decolorized, the filtrate is transferred into a crystallizer, and the temperature is kept at 65 ℃. And carrying out ultrasonic treatment on the solution, wherein the ultrasonic frequency is 30KHz, then cooling the solution to 55 ℃, and continuing to carry out constant-temperature crystal growth under ultrasonic for 4 hours. Stopping ultrasonic treatment, cooling the solution to 20 ℃, and cooling at a speed of 0.1 ℃/min. Then continuing to carry out ultrasonic solution at the frequency of 25KHz, and growing crystals at constant temperature for 4 hours. Filtering, washing the filter cake with 96% ethanol, and drying at 60 ℃ and normal pressure for 8 hours to obtain the terazosin hydrochloride finished product. The product particles D90 were 33.276 μm, the ethanol solvent residue was 0.51%, the HPLC purity was 99.96%, and the product yield was 87.1%.
The primary ultrasonic crystallization temperature of the comparative example is 65 ℃ and higher than 60 ℃, and the granularity of the obtained terazosin hydrochloride product is larger because the crystallization temperature is too high, so that the growth speed of crystals is accelerated, the granularity of the crystals which are initially precipitated is larger, and further, the precipitation of crystals with larger granularity is induced.
Comparative example 4
The terazosin hydrochloride free base was added to 90% ethanol at a solid-to-liquid ratio of 0.06g/g and stirred at 55℃for 60min. Then, 10mol/L hydrochloric acid was added dropwise at a rate of 0.1ml/min, and the acid addition was stopped when the pH of the solution reached 2.5. After the activated carbon is decolorized, the filtrate is transferred into a crystallizer, and the temperature is kept at 55 ℃. And carrying out ultrasonic treatment on the solution, wherein the ultrasonic frequency is 25KHz, then cooling the solution to 45 ℃, and continuing to carry out constant-temperature crystal growth under ultrasonic for 1h. Stopping ultrasonic treatment, cooling the solution to 15 ℃, and cooling at a speed of 2.0 ℃/min. Then continuing to carry out ultrasonic solution at the frequency of 45KHz, and growing crystals at constant temperature for 3h. Filtering, washing the filter cake with 95% ethanol, and drying at 50 ℃ and normal pressure for 10 hours to obtain the terazosin hydrochloride finished product. The product particles D90 were 36.865 μm, the particle size distribution was not normal (as shown in FIG. 3), the ethanol solvent remained 1.10%, the HPLC purity was 98.90%, and the product yield was 86.4%.
The cooling speed of the comparative example is 2.0 ℃/min and is faster than 0.2 ℃/min, so that the supersaturation degree of the solution is larger in the cooling process, the explosion phenomenon is easy to occur in the crystallization process, the crystal product is easy to agglomerate, and the granularity of the product is enlarged. Meanwhile, impurities and solvent occlusion phenomenon can be caused during agglomeration, so that ethanol solvent residue is higher, and HPLC purity is lower. In addition, the secondary ultrasonic frequency of the comparative example is 45KHz and higher than 33KHz, most of crystal products are separated out during secondary ultrasonic, the ultrasonic mainly plays a role in ensuring the uniform dispersion degree of the crystals in the solution, the influence on the granularity of the products is small, and the increase of the ultrasonic frequency does not have a remarkable effect on the reduction of the granularity of the products.
The invention discloses and provides a preparation method of terazosin hydrochloride with low ethanol residue, which can be realized by a person skilled in the art by appropriately changing links such as raw materials, process parameters and the like by referring to the content of the text. While the methods and products of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and modifications can be applied to the methods and products described herein to practice the techniques of this invention without departing from the spirit or scope of the invention. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be included within the scope and content of the invention.
Claims (2)
1. The preparation method of the small-granularity terazosin hydrochloride with low ethanol solvent residue is characterized by comprising the following steps of:
respectively adding an ethanol aqueous solution and terazosin hydrochloride free alkali into a reaction kettle, stirring and dissolving, and continuously stirring for 30-60 minutes at 50-60 ℃, wherein the solid-to-liquid ratio of the obtained solution is 0.04-g/g-0.08-g/g, and the concentration of the ethanol aqueous solution is 88% -92%;
adding 8-12 mol/L hydrochloric acid aqueous solution into the solution obtained in the first step, wherein the adding speed of the added hydrochloric acid aqueous solution is 0.1-2.0mL/min, stopping adding the added hydrochloric acid aqueous solution when the pH value of the solution is 2.3-2.8, adding active carbon, filtering, transferring filtrate into a crystallizer, preserving heat at 50-60 ℃, introducing ultrasonic wave to induce crystallization, cooling to 40-50 ℃, continuing ultrasonic wave with the ultrasonic frequency of 25-40KHz, and preserving heat for 1-2 hours; stopping ultrasonic, continuously cooling to 10-20 ℃, wherein the cooling rate is 0.1-0.2 ℃/min, starting ultrasonic with the ultrasonic frequency of 20-33KHz, and growing the crystal for 2-4 hours;
and thirdly, filtering, washing a filter cake by using a washing solvent, and drying the filter cake to obtain the terazosin hydrochloride product with uniform particle size distribution, wherein the washing solvent is ethanol water solution, and the mass fraction of ethanol is 95-98%.
2. The method for preparing terazosin hydrochloride with small granularity and low ethanol solvent residue as claimed in claim 1, wherein the drying condition in the third step is 40-60 ℃ under normal pressure for 8-12 hours.
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| CA2150985A1 (en) * | 1995-06-05 | 1996-12-06 | Keshava Murthy | Process for the manufacture of terazosin hydrochloride dihydrate |
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| CN108623499A (en) * | 2018-06-15 | 2018-10-09 | 湖北航天化学技术研究所 | Prepare the method for crystallising and triamido guanidine nitrate crystal of the triamido guanidine nitrate crystal of narrow size distribution |
| CN113105439A (en) * | 2021-04-15 | 2021-07-13 | 迪嘉药业集团有限公司 | Method for preparing small-particle-size olmesartan medoxomil crystals |
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| CN108623499A (en) * | 2018-06-15 | 2018-10-09 | 湖北航天化学技术研究所 | Prepare the method for crystallising and triamido guanidine nitrate crystal of the triamido guanidine nitrate crystal of narrow size distribution |
| CN113105439A (en) * | 2021-04-15 | 2021-07-13 | 迪嘉药业集团有限公司 | Method for preparing small-particle-size olmesartan medoxomil crystals |
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Denomination of invention: A preparation method for small particle size terazosin hydrochloride with low ethanol residue Granted publication date: 20230912 Pledgee: Weihai Branch of Shanghai Pudong Development Bank Co.,Ltd. Pledgor: Dijia Pharmaceutical Group Co.,Ltd. Registration number: Y2024980004733 |
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