CN116212639A - Method and system for removing organic solvent in liquid medicine - Google Patents
Method and system for removing organic solvent in liquid medicine Download PDFInfo
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- CN116212639A CN116212639A CN202310177126.5A CN202310177126A CN116212639A CN 116212639 A CN116212639 A CN 116212639A CN 202310177126 A CN202310177126 A CN 202310177126A CN 116212639 A CN116212639 A CN 116212639A
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/14—Ultrafiltration; Microfiltration
- B01D61/145—Ultrafiltration
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/14—Ultrafiltration; Microfiltration
- B01D61/18—Apparatus therefor
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/14—Ultrafiltration; Microfiltration
- B01D61/20—Accessories; Auxiliary operations
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Abstract
The invention provides a method for removing organic solvent in liquid medicine, which comprises the following steps: pumping the liquid medicine into an ultrafiltration membrane group for ultrafiltration dialysis to obtain liquid medicine with the organic solvent removed. The invention designs a method capable of actively separating water and small molecular organic solvent in nano suspension liquid medicine by adopting ultrafiltration dialysis technology through technical innovation. The method has the following advantages: 1. according to the method, the multiple of ultrafiltration dialysis can be freely selected according to the size of the product batch and the limit of the residual solvent, so that the liquid medicine meeting the process requirement of the limit of the residual solvent is obtained; 2. the ultrafiltration dialysis technology is used for removing the organic solvent, most of parameters are set before production, only monitoring is needed in the removal process, the degree of automation is high, and the risk of personnel misoperation is small; 3. the whole solvent removal process can be controlled to be carried out under the conditions of low temperature and normal temperature, and the high temperature is not needed, thereby being beneficial to the maintenance of main active ingredients of the product.
Description
Technical Field
The invention relates to the technical field, in particular to a method and a system for removing organic solvents in liquid medicine.
Background
The organic solvent is a kind of organic compound widely used in life and production, and exists in paint, adhesive, lacquer and cleaning agent, and is characterized by low molecular weight, liquid state at normal temperature and pressure, high volatility and no change in solute and solvent properties during dissolution.
In the field of medicine production, the organic solvent can dissolve some water-insoluble compounds, so as to achieve the purpose of carrying medicine in solution. The organic solvent has liposolubility, so that the organic solvent can be quickly absorbed through other parts of human body such as skin besides entering the inside and outside of the human body through respiratory tract and alimentary tract, and can act on nerves, blood systems, liver and kidney and other parenchymal organs rich in lipid substances after being absorbed into the human body, and meanwhile, the organic solvent has certain irritation to skin and mucous membrane. And the main target organ of the action and the intensity of the action of different organic solvents are different, which depends on the chemical structure, solubility, contact concentration and time of each organic solvent and the sensitivity of the organism, and when serious, the organic solvents can cause irreversible damage to the patient. The harm of residual solvent to human health and environment is thoroughly introduced in guidelines established by the international pharmaceutical registration technology association (ICH). Therefore, when the liquid medicine is produced, the organic solvent used in the preparation process of the product needs to be removed, so that the user is protected. Guidelines require that each organic solvent-containing product requires removal of the organic solvent and residue to an acceptable level. Therefore, when preparing the medicine which needs the auxiliary production of the organic solvent, the organic solvent used in the preparation process needs to be separated, so that the possible injury to personnel is reduced.
At present, the method for removing the mutually soluble organic solvent in the liquid mainly adopts a distillation method, the method requires that the organic solvent has volatility and is mutually soluble with water, the original components can not be destroyed along with the distillation of water vapor, the reaction with water does not occur, the liquid medicine has heat resistance, and the boiling point of the organic solvent in the liquid medicine component needs to be gradient, so that different components can be separated by adopting the distillation method. Because the boiling point of the organic solvent in the medicine component needs to be different from that of other substances, the requirements on the medicine component are strict; in addition, the mixed solution needs to be heated in the distillation process, the organic solvent is converted into gas to volatilize by using high temperature, and the effective components in part of the mixed solution are not heat-resistant and cannot adapt to the high temperature condition. Therefore, the existing method for removing the organic solvent from the solution has higher requirements on the property of the liquid medicine, and is not suitable for preparing and producing the heat-sensitive medicine.
In addition, the traditional distillation method needs more manual monitoring and operation, is easy to cause the condition that the liquid medicine is scrapped due to personnel errors, and is very unfavorable for the production of certain high-added-value products.
Disclosure of Invention
In view of the above, the present invention aims to provide a method and a system for removing organic solvents from a liquid medicine, which can be performed at normal temperature and has good removal effect.
The invention provides a method for removing organic solvent in liquid medicine, which comprises the following steps:
pumping the liquid medicine into an ultrafiltration membrane group for ultrafiltration dialysis to obtain liquid medicine with the organic solvent removed.
The method provided by the invention is suitable for removing the organic solvent in all liquid medicine systems, especially for some nano suspension products which are not suitable for distillation methods and have inconsistent boiling points of organic solvent components, and can actively separate water and small-molecule organic solvents in nano suspension liquid medicine.
The present invention is not particularly limited to the above-mentioned ultrafiltration membrane module, and may be a general commercially available ultrafiltration membrane module, and the present invention is preferably applied to an ultrafiltration membrane module which is a tangential flow ultrafiltration system.
According to the invention, by utilizing the tangential flow principle, the multiple of ultrafiltration dialysis can be freely selected according to the size of the product batch and the limit of the residual solvent, and the organic solvent is removed, so that the target compound is left, and the liquid medicine meeting the technological requirement and the limit of the residual solvent is obtained. Preferably, the membrane aperture of the ultrafiltration membrane group is 1/3-1/5 of the molecular weight of the organic solvent.
In the present invention, the organic solvent residue in the ultrafiltering and dialyzing medicinal liquid is reduced to below 0.05 wt%.
In some embodiments of the invention, the method is batch ultrafiltration dialysis, preferably comprising the steps of:
pumping the liquid medicine into an ultrafiltration membrane group for ultrafiltration dialysis concentration for 2-4 times, stopping ultrafiltration, adding water for injection into the liquid medicine to the initial weight, continuing ultrafiltration dialysis concentration for 2-4 times, repeating the operation for 3-5 times, and reducing the residual of the organic solvent in the liquid medicine to below 0.05wt%.
In some embodiments of the invention, the method is continuous ultrafiltration dialysis, preferably comprising the steps of:
pumping the liquid medicine into an ultrafiltration membrane group for ultrafiltration dialysis, adding injection water with the same quantity as the permeation quantity into the liquid medicine while removing the organic solvent by dialysis, stopping adding the injection water when the residual of the organic solvent in the liquid medicine is reduced to below 0.05wt%, and concentrating by 2-4 times by ultrafiltration dialysis to obtain the liquid medicine with the organic solvent removed.
Preferably, in the ultrafiltration dialysis, the inlet pressure is 0.5-1.8 bar, the permeate pressure is 0.2-0.8 bar, and the reflux pressure is 0-0.5 bar.
The invention provides a system for removing organic solvents in liquid medicine, which comprises a liquid medicine mixing tank, a pump, an ultrafiltration membrane group and a reflux valve which are connected in sequence.
Fig. 1 is a schematic structural diagram of a system for removing organic solvents in liquid medicine, which comprises a liquid medicine mixing tank 1, a pump 2, an ultrafiltration membrane group 3, a reflux valve 4, a manual regulation diaphragm valve 5 at a reflux end and a water inlet and exhaust valve 6.
The liquid medicine mixing tank 1 is used for placing liquid medicine and adding water for injection.
The pump 2 is used for providing power to enable the liquid medicine to pass through the ultrafiltration membrane group for ultrafiltration dialysis.
Preferably, the ultrafiltration membrane group is a tangential flow ultrafiltration device.
Compared with the prior art, the invention provides a method for removing organic solvent in liquid medicine, which comprises the following steps: pumping the liquid medicine into an ultrafiltration membrane group for ultrafiltration dialysis to obtain liquid medicine with the organic solvent removed. The invention designs a method capable of actively separating water and small molecular organic solvent in nano suspension liquid medicine by adopting ultrafiltration dialysis technology through technical innovation. The method has the following advantages:
1. according to the method, the multiple of ultrafiltration dialysis can be freely selected according to the size of the product batch and the limit of the residual solvent, so that the liquid medicine meeting the process requirement of the limit of the residual solvent is obtained;
2. the ultrafiltration dialysis technology is used for removing the organic solvent, most of parameters are set before production, only monitoring is needed in the removal process, the degree of automation is high, and the risk of personnel misoperation is small;
3. the whole solvent removal process can be controlled to be carried out under the conditions of low temperature and normal temperature, and the high temperature is not needed, thereby being beneficial to the maintenance of main active ingredients of the product.
Drawings
Fig. 1 is a schematic structural diagram of a system for removing an organic solvent in a liquid medicine according to the present invention.
Detailed Description
In order to further illustrate the present invention, the method and system for removing organic solvent from a medical solution according to the present invention will be described in detail with reference to the following examples.
The medicinal solutions used in the following examples and comparative examples were paclitaxel for injection (albumin-binding type), and the components thereof were detected by GC and contained 1% -3% of an organic solvent.
Example 1
Intermittent ultrafiltration dialysis:
the liquid medicine is transferred into a mixing tank ((1)), the liquid medicine is subjected to ultrafiltration dialysis concentration for 4 times by a liquid medicine pump ((2)) through a 20-piece parallel ultrafiltration membrane pack group ((3)) (membrane aperture 100 kd), ultrafiltration is stopped, injection water is added to the mixing tank ((1)) again to reach the initial weight, ultrafiltration dialysis concentration is carried out for 2 times, and the steps are repeated for 3 times, so that the treated liquid medicine is obtained. The inlet pressure is 0.6bar, the permeate pressure is 0.2bar and the reflux pressure is 0.1bar in the whole ultrafiltration dialysis process.
The content of the organic solvent in the medicinal liquid was measured by GC and found to be 0.04% (the content of the organic solvent before dialysis was 2.325%).
Example 2
Continuous ultrafiltration dialysis:
the drug solution was first transferred to a mixing tank (1), and the drug solution was subjected to ultrafiltration dialysis by a drug solution pump (2) through an ultrafiltration membrane pack (3) (membrane pore size 100 kd), and in the ultrafiltration concentration dialysis process, injection water having the same amount as the permeation amount was added to the mixing tank (1) while precipitating small organic solvent molecules. After the dialysis is maintained for a certain time, the injection water is stopped, and the liquid medicine in the mixing tank ((1)) is concentrated by ultrafiltration for 2 times. The inlet pressure is 0.5bar, the permeate pressure is 0.3bar and the reflux pressure is 0.1bar in the whole ultrafiltration dialysis process.
The content of the organic solvent in the medicinal liquid was measured by GC and found to be 0.04% by weight (2.329% by weight of the organic solvent before dialysis).
Comparative example 1
The dialysis procedure was as in example 1, and the parameters throughout the ultrafiltration dialysis are shown in Table 1.
The content of the organic solvent in the liquid medicine is detected by GC, the residual quantity is 0.2 percent, the residual level of the organic solvent exceeds the standard (the content of the organic solvent before dialysis is 2.319 percent), and the quality requirement of the product is not met.
Comparative example 2
The dialysis procedure was as in example 1, and the parameters throughout the ultrafiltration dialysis are shown in Table 1.
The content of the organic solvent in the liquid medicine is detected by GC, the residual quantity is 0.03%, but the level of sodium octoate and N-acetyl-L-tryptophan of the biological auxiliary material after ultrafiltration is lower than the quality standard (the content of the organic solvent before dialysis is 2.324%), and the quality requirement of the product is not met.
Comparative example 3
The dialysis procedure was as in example 2, and the parameters throughout the ultrafiltration dialysis are shown in Table 1.
The content of the organic solvent in the liquid medicine is detected by GC, the residual amount is 0.01 weight percent, but the content of the API after ultrafiltration is lower than the quality standard (the content of the organic solvent before dialysis is 2.328 percent), and the quality requirement of the product is not met.
Table 1 comparative examples 1 to 3 ultrafiltration dialysis parameters
The method for removing the organic solvent in the liquid medicine is suitable for various nanoparticle preparations for injection, and the residual organic solvent level meets the quality requirement by trial of 170 batches of products. Before the liquid medicine starts ultrafiltration, the organic solvent accounts for about 2.4%, after ultrafiltration elution by the first method or the second method, the residual proportion of the organic solvent is below 0.05%, and the trend is stable and never abnormal, which indicates that the technology has good effect on removing the organic solvents in various liquid medicines and completely accords with the regulations.
The above description of the embodiments is only for aiding in the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims.
Claims (9)
1. A method for removing organic solvent in a liquid medicine, comprising the following steps:
pumping the liquid medicine into an ultrafiltration membrane group for ultrafiltration dialysis to obtain liquid medicine with the organic solvent removed.
2. The method of claim 1, wherein the ultrafiltration membrane module is a tangential flow ultrafiltration system.
3. The method according to claim 1, wherein the membrane pore size of the ultrafiltration membrane group is 1/3 to 1/5 of the molecular weight of the organic solvent.
4. The method according to claim 1, wherein the ultrafiltration is performed until the residual organic solvent in the liquid medicine is reduced to less than 0.05 wt%.
5. The method according to claim 1, characterized in that it comprises in particular:
pumping the liquid medicine into an ultrafiltration membrane group for ultrafiltration dialysis concentration for 2-4 times, stopping ultrafiltration, adding water for injection into the liquid medicine to the initial weight, continuing ultrafiltration dialysis concentration for 2-4 times, repeating the operation for 3-5 times, and reducing the residual of the organic solvent in the liquid medicine to below 0.05wt%.
6. The method according to claim 1, characterized in that it comprises in particular:
pumping the liquid medicine into an ultrafiltration membrane group for ultrafiltration dialysis, adding injection water with the same quantity as the permeation quantity into the liquid medicine while removing the organic solvent by dialysis, stopping adding the injection water when the residual of the organic solvent in the liquid medicine is reduced to below 0.05wt%, and concentrating by 2-4 times by ultrafiltration dialysis to obtain the liquid medicine with the organic solvent removed.
7. The method according to claim 1, characterized in that in the ultrafiltration dialysis the inlet pressure is 0.5-1.8 bar, the permeate pressure is 0.2-0.8 bar and the return pressure is 0-0.5 bar.
8. A system for removing organic solvent in liquid medicine comprises a liquid medicine mixing tank, a pump, an ultrafiltration membrane group and a reflux valve which are connected in sequence.
9. The system of claim 8, wherein the ultrafiltration membrane module is a tangential flow ultrafiltration device.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310177126.5A CN116212639A (en) | 2023-02-28 | 2023-02-28 | Method and system for removing organic solvent in liquid medicine |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310177126.5A CN116212639A (en) | 2023-02-28 | 2023-02-28 | Method and system for removing organic solvent in liquid medicine |
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| CN116212639A true CN116212639A (en) | 2023-06-06 |
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| CN202310177126.5A Pending CN116212639A (en) | 2023-02-28 | 2023-02-28 | Method and system for removing organic solvent in liquid medicine |
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- 2023-02-28 CN CN202310177126.5A patent/CN116212639A/en active Pending
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