Method for preparing nadroparin calcium and dalteparin sodium

Abstract

The invention belongs to the field of preparation of low-molecular-weight heparin, and relates to a method for preparing nadroparin calcium and dalteparin sodium. Specifically, the invention relates to a method for preparing low-molecular-weight heparin, which comprises the steps of heparin sodium cracking, reduction, neutralization and ultrafiltration in a microchannel reactor, and the low-molecular-weight heparin is selected from nadroparin calcium and dalteparin sodium. According to the method, the selectivity of heparin sodium cracking reaction is improved, and the probability of repeated cracking is reduced, so that the increase of micromolecular heparin is avoided, the load of later ultrafiltration molecular weight screening is reduced, and the yield of the product is improved.

Description

technical field

[0001] The invention belongs to the field of low molecular weight heparin preparation and relates to a method for preparing nadroparin calcium and dalteparin sodium. Background technique

[0002] Heparin is a sulfated glycosaminoglycan compound extracted from mammalian tissues. Its molecular structure is extremely complex and its molecular weight ranges from 3kd to 30kd. Currently, only heparin derived from pig small intestinal mucosa can be used for clinical treatment. Heparin drugs are mainly used for the prevention and treatment of deep vein thrombosis, hemodialysis anticoagulation, as well as anticoagulation in surgical operations, acute coronary syndrome, ischemic cerebral thrombosis, etc. Department of oncology, burns, etc.

[0003] Compared with unfractionated heparin, low-molecular-weight heparin has a higher anti-FXa / anti-FⅡa potency ratio, so it can greatly reduce the bleeding tendency caused by antithrombotic process, and is currently more widely ...

Examples

Embodiment 1

[0039] The preparation of embodiment one nadroparin calcium

[0040] Weigh 1 kg of heparin sodium, add 3.5 kg of water to dissolve, adjust the pH to 3.0 with 2% dilute hydrochloric acid, and obtain solution A;

[0041] Weigh 24g of sodium nitrite, add 0.6kg of water to dissolve, and obtain solution B;

[0042] Add solutions A and B to the microchannel reactor from two pipelines, mix well at the inlet of the reactor, control the flow rate of solution A to 60mL / min, the flow rate of solution B to 10mL / min, and control the temperature of the reactor to 20 °C, the time for the feed liquid to flow through the reactor and carry out the cracking reaction is 30 minutes;

[0043]Collect the reaction liquid with a receiving tank at the outlet of the microchannel reactor, add sodium hydroxide solution, and maintain the pH of the receiving tank at 7.0-7.5. After receiving, add 15g of sodium borohydride and stir for 15h;

[0044] The above feed solution was adjusted to pH 3.8 with 2% di...

Embodiment 2

[0048] The preparation of embodiment dinadroparin calcium

[0049] Weigh 1 kg of heparin sodium, add 6 kg of water to dissolve, adjust the pH to 1.5 with 15% dilute hydrochloric acid, and obtain solution A;

[0050] Weigh 35g of sodium nitrite, add 0.46kg of water to dissolve, and obtain solution B;

[0051] Add solutions A and B to the microchannel reactor from two pipelines, mix well at the inlet of the reactor, control the flow rate of solution A to 650mL / min, the flow rate of solution B to 50mL / min, and control the temperature of the reactor to 45 °C, the time for the feed liquid to flow through the reactor and carry out the cracking reaction is 3 minutes;

[0052] Collect the reaction liquid with a receiving tank at the outlet of the microchannel reactor, add sodium hydroxide solution, and maintain the pH of the receiving tank at 8.0-8.5. After receiving, add 25g of sodium borohydride and stir for 20h;

[0053] The above feed solution was adjusted to pH 2.0 with 15% di...

Embodiment 3

[0057] The preparation of embodiment Sandalparin Sodium

[0058] Weigh 1 kg of heparin sodium, add 5.4 kg of water to dissolve, adjust the pH to 2.8 with 8% dilute nitric acid, and obtain solution A;

[0059] Weigh 15g of sodium nitrite, add 0.9kg of water to dissolve, and obtain solution B;

[0060] Add solutions A and B to the microchannel reactor from two pipelines, mix well at the inlet of the reactor, control the flow rate of solution A to 60mL / min, the flow rate of solution B to 10mL / min, and control the temperature of the reactor to 15 °C, the time for the feed liquid to flow through the reactor and carry out the cracking reaction is 30 minutes;

[0061] Collect the reaction liquid with a receiving tank at the outlet of the microchannel reactor, and add sodium hydroxide solution to maintain the pH of the receiving tank at about 7.5-8.0. After receiving, add 10g of sodium borohydride and stir for 10h;

[0062] Add 8% dilute nitric acid to the above feed solution to ad...

technical field

[0001] The invention belongs to the field of low molecular weight heparin preparation and relates to a method for preparing nadroparin calcium and dalteparin sodium. Background technique

[0002] Heparin is a sulfated glycosaminoglycan compound extracted from mammalian tissues. Its molecular structure is extremely complex and its molecular weight ranges from 3kd to 30kd. Currently, only heparin derived from pig small intestinal mucosa can be used for clinical treatment. Heparin drugs are mainly used for the prevention and treatment of deep vein thrombosis, hemodialysis anticoagulation, as well as anticoagulation in surgical operations, acute coronary syndrome, ischemic cerebral thrombosis, etc. Department of oncology, burns, etc.

[0003] Compared with unfractionated heparin, low-molecular-weight heparin has a higher anti-FXa / anti-FⅡa potency ratio, so it can greatly reduce the bleeding tendency caused by antithrombotic process, and is currently more widely ...

Examples

Embodiment 1

[0039] The preparation of embodiment one nadroparin calcium

[0040] Weigh 1 kg of heparin sodium, add 3.5 kg of water to dissolve, adjust the pH to 3.0 with 2% dilute hydrochloric acid, and obtain solution A;

[0041] Weigh 24g of sodium nitrite, add 0.6kg of water to dissolve, and obtain solution B;

[0042] Add solutions A and B to the microchannel reactor from two pipelines, mix well at the inlet of the reactor, control the flow rate of solution A to 60mL / min, the flow rate of solution B to 10mL / min, and control the temperature of the reactor to 20 °C, the time for the feed liquid to flow through the reactor and carry out the cracking reaction is 30 minutes;

[0043]Collect the reaction liquid with a receiving tank at the outlet of the microchannel reactor, add sodium hydroxide solution, and maintain the pH of the receiving tank at 7.0-7.5. After receiving, add 15g of sodium borohydride and stir for 15h;

[0044] The above feed solution was adjusted to pH 3.8 with 2% di...

Embodiment 2

[0048] The preparation of embodiment dinadroparin calcium

[0049] Weigh 1 kg of heparin sodium, add 6 kg of water to dissolve, adjust the pH to 1.5 with 15% dilute hydrochloric acid, and obtain solution A;

[0050] Weigh 35g of sodium nitrite, add 0.46kg of water to dissolve, and obtain solution B;

[0051] Add solutions A and B to the microchannel reactor from two pipelines, mix well at the inlet of the reactor, control the flow rate of solution A to 650mL / min, the flow rate of solution B to 50mL / min, and control the temperature of the reactor to 45 °C, the time for the feed liquid to flow through the reactor and carry out the cracking reaction is 3 minutes;

[0052] Collect the reaction liquid with a receiving tank at the outlet of the microchannel reactor, add sodium hydroxide solution, and maintain the pH of the receiving tank at 8.0-8.5. After receiving, add 25g of sodium borohydride and stir for 20h;

[0053] The above feed solution was adjusted to pH 2.0 with 15% di...

Embodiment 3

[0057] The preparation of embodiment Sandalparin Sodium

[0058] Weigh 1 kg of heparin sodium, add 5.4 kg of water to dissolve, adjust the pH to 2.8 with 8% dilute nitric acid, and obtain solution A;

[0059] Weigh 15g of sodium nitrite, add 0.9kg of water to dissolve, and obtain solution B;

[0060] Add solutions A and B to the microchannel reactor from two pipelines, mix well at the inlet of the reactor, control the flow rate of solution A to 60mL / min, the flow rate of solution B to 10mL / min, and control the temperature of the reactor to 15 °C, the time for the feed liquid to flow through the reactor and carry out the cracking reaction is 30 minutes;

[0061] Collect the reaction liquid with a receiving tank at the outlet of the microchannel reactor, and add sodium hydroxide solution to maintain the pH of the receiving tank at about 7.5-8.0. After receiving, add 10g of sodium borohydride and stir for 10h;

[0062] Add 8% dilute nitric acid to the above feed solution to ad...

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