A release control method for concentrated liquid before alcohol precipitation

Abstract

The present invention discloses a release control method for a concentrate before alcohol precipitation. First, the quantitative relationship between the density and viscosity of the concentrate and the mixing situation of alcohol precipitation is determined, the threshold value of the mixing situation of alcohol precipitation is set, and the density value of the new batch of concentrate is detected; then, according to the density value of the new batch of concentrate, the quantitative relationship and the threshold value of the mixing situation of alcohol precipitation, the acceptable maximum value of the viscosity of the concentrate is calculated and determined; the viscosity value of the new batch of concentrate is measured again, and the acceptable maximum value and the viscosity value are compared to determine whether to release it for alcohol precipitation process. The present invention relates the viscosity and density of the concentrate to the mixing effect of alcohol precipitation, and gives the quantitative control limit of viscosity on the basis of density control, which can reflect the influence of the concentrate obtained from different batches of medicinal materials on the alcohol precipitation effect, and is conducive to relying on the alcohol precipitation process to improve the quality consistency of subsequent intermediates and finished products. This method has low cost, convenient industrial implementation, and good prospects for promotion and application in the traditional Chinese medicine industry.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines and relates to a release control method for a concentrate before alcohol precipitation. Background Art

[0002] In the 1950s, during the national dosage form reform, a number of modern dosage forms of Chinese medicine, such as tablets, capsules, injections, granules and mixtures, emerged. In order to meet the higher refining requirements of these dosage forms for the Chinese medicine system, the water extraction and alcohol precipitation process began to be widely used in Chinese medicine production. The alcohol precipitation process has many advantages such as simple operation, easy scale-up, and safe solvents. It can effectively remove highly polar molecules such as sugars, salts and proteins, which is conducive to reducing the dosage of medicines. Alcohol precipitation is often the first refining process after Chinese medicine extraction, or even the only refining process. The quality of its process has a significant impact on the difficulty of subsequent preparations and the quality of the final medicine. Chinese medicine injections have very high requirements for drug quality control. In production, multiple alcohol precipitations are often used to fully remove impurities; sometimes alkaline alcohol precipitation is used to remove tannins to further improve the safety of Chinese medicine injections.

[0003] One of the difficulties in implementing alcohol precipitation process in industry is to control the loss of coating in alcohol precipitation. Due to the large difference in density between the concentrate and ethanol and the high viscosity of the concentrate, it is difficult to fully mix the concentrate and ethanol. A large amount of precipitation produced in alcohol precipitation easily wraps part of the concentrate to form a coating phenomenon. The coating phenomenon causes the loss of active ingredients on the one hand, and reduces the consistency of the composition of the alcohol precipitation product on the other hand. Therefore, it is necessary to control the coating phenomenon at a lower level in alcohol precipitation.

[0004] Common methods to reduce the encapsulation phenomenon include: reducing the speed of ethanol addition, increasing the stirring speed, extending the stirring time, extending the standing time after alcohol precipitation, etc. However, due to various restrictions such as regulations, equipment and production efficiency, the above parameters are often difficult to adjust flexibly, so Chinese medicine companies prefer to fix a set of process parameters to process different batches of concentrates. Therefore, it is necessary to consider improving the quality control level of the concentrate to control the alcohol precipitation encapsulation phenomenon.

[0005] At present, the density range of the concentrate before alcohol precipitation is generally controlled in the production of traditional Chinese medicine. However, the density of the concentrate is mainly affected by the solid content, and it is difficult to reflect the difference in the solid composition of different batches of concentrates. Therefore, it is not enough to control the density range alone. In addition to being affected by the solid content, the viscosity of the concentrate is also affected by the content of high molecular weight substances, and high molecular weight substances are one of the major components that need to be precipitated and removed by alcohol precipitation. Therefore, after combining with the density, the characteristics of the solid component composition in the concentrate can be reflected. The inventor also found in the experiment that the concentrate of the same density has a higher viscosity and is more likely to be wrapped. Therefore, it is necessary to combine viscosity and density to control the quality of the concentrate before alcohol precipitation. Summary of the invention

[0006] The present invention provides a release control method for a concentrate before alcohol precipitation. The method firstly determines the quantitative relationship between the density and viscosity of the concentrate and the mixing condition of the alcohol precipitation as f, and then sets the threshold value of the mixing condition of the alcohol precipitation as E. T , and then detect the density value of the new batch of concentrate as ρ, and then according to the density value ρ of the new batch of concentrate, the quantitative relationship f and the threshold value E of the alcohol precipitation mixing situation T , calculate and determine the maximum acceptable value V of the concentrate viscosity M , and then determine the viscosity of the new batch of concentrate as V N , and finally compare V M and V N , if V N ≤V M , then the new batch of concentrate can be released for alcohol precipitation process; if V N >V M , the concentrate cannot be released.

[0007] This is achieved through the following steps:

[0008] The first step is to determine the quantitative relationship between the density of the concentrate, the viscosity of the concentrate and the mixing condition of the alcohol precipitation as f;

[0009] The second step is to set the threshold of alcohol precipitation mixing as E T ;

[0010] The third step is to detect the density of the new batch of concentrate as ρ N ;

[0011] The fourth step is to calculate the density of the new batch of concentrate according to its density value ρ. N , quantitative relationship f and threshold value E for alcohol precipitation mixing T , calculate and determine the maximum acceptable value V of the concentrate viscosity M ;

[0012] Step 5: Determine the viscosity value of the new batch of concentrate as V N ;

[0013] Step 6. Compare V M and V N , if V N ≤V M , then the new batch of concentrate can be released for alcohol precipitation process; if V N >V M , the concentrate cannot be released.

[0014] The density of the concentrated liquid described in the first step refers to the density measured when the temperature of the concentrated liquid is controlled at a temperature T1 between 15-80 degrees Celsius.

[0015] The viscosity of the concentrate described in the first step refers to the viscosity measured when the temperature of the concentrate is controlled at a certain temperature T2 between 15-80 degrees Celsius and the solid content of the concentrate is fixed at D2, and the D2 value is between 10%-70%.

[0016] The alcohol precipitation mixing condition described in the second step is represented by the mass ratio (WMR) of the concentrate fully mixed with the ethanol solution during the alcohol precipitation process. The WMR calculation formula is:

[0017]

[0018] Wherein: m0 is the amount of concentrated solution in alcohol precipitation, m1 is the amount of ethanol solution, m2 is the total mass of the obtained supernatant, S0 is the total solid mass content in the concentrated solution, C0 is the mass content of component A, S2 is the total solid content in the supernatant, and C2 is the mass content of component A in the supernatant.

[0019] The mathematical form of the quantitative relationship f described in the fourth step is:

[0020] Y=a0+a1ρ+a2V′+a3ρV′+a4ρ 2 +a5V′ 2

[0021] Where Y is the value obtained by square root arcsine transformation of WMR value, ρ is the density of the concentrate, V′ is the logarithm of the viscosity V of the concentrate, and a0-a5 are the partial regression coefficients obtained by fitting.

[0022] The threshold value of the alcohol precipitation mixing condition described in step 4 is E T , which ranges from 70%-100%.

[0023] The density of the new batch of concentrate described in step 4 is ρ N , detected at temperature T1.

[0024] The viscosity value V of the new batch of concentrate described in step 4 N , the solid content of the concentrate should be controlled to D2 and tested at temperature T2.

[0025] The accurate quantitative relationship f is the key to the smooth implementation of this method. The form of f is a polynomial equation, in which the first-order term represents the linear effect of the density and viscosity of the concentrate on the quality of the alcohol precipitation mixing; the second-order term represents the nonlinear effect of the density and viscosity of the concentrate on the quality of the alcohol precipitation mixing; the cross-term represents the interactive effect of the density and viscosity of the concentrate on the quality of the alcohol precipitation mixing. Considering that the WMR value describing the mixing situation is a rate data, its distribution is close to the normal distribution after the square root arcsine transformation, which will be more suitable for description by a polynomial equation. The viscosity of the concentrate will increase exponentially with the decrease of water content. Because the form of f is still close to a linear equation as a whole, the viscosity value was used in the modeling and its logarithm was used.

[0026] Another object of the present invention is to provide an application of the method in the quality control of the alcohol precipitation effect of the concentrated solution of traditional Chinese medicine before alcohol precipitation.

[0027] A key difficulty in the production of traditional Chinese medicine is to produce Chinese patent medicines with consistent quality using Chinese medicinal materials with significant quality differences between batches. This method introduces viscosity as another control index of the concentrate, and gives its quantitative control limit. When combined with density, it can reflect the difference in solid composition in the concentrate obtained from different batches of medicinal materials, which is conducive to improving the quality consistency of subsequent intermediates and finished products through alcohol precipitation process. For concentrates that cannot be released according to this method, it can be considered to increase the water content within the range permitted by regulations, or to mix batches to reduce viscosity. After the viscosity is reduced, this method can continue to be used to determine whether it is suitable for alcohol precipitation production. If it is already suitable, it can be considered for release. Compared with conventional concentrate quality control methods, this method requires the detection of concentrate viscosity. Considering that the price of online viscometers can be controlled below one thousand yuan, and the price of offline viscometers is even lower, the application of this method will not significantly increase production costs.

[0028] The present invention relates the viscosity and density of the concentrated solution to the alcohol precipitation mixing effect, provides a quantitative control limit of the viscosity based on the density control, can reflect the influence of the concentrated solution obtained from different batches of medicinal materials on the alcohol precipitation effect, and is conducive to improving the quality consistency of subsequent intermediates and finished products by relying on the alcohol precipitation process. The method has low cost, convenient industrial implementation, and good prospects for promotion and application in the traditional Chinese medicine industry. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 It is a schematic diagram of the implementation steps of the present invention. DETAILED DESCRIPTION

[0030] The present invention is further described in conjunction with the accompanying drawings and embodiments.

[0031] Example 1

[0032] See also Figure 1, taking Codonopsis pilosula concentrate as the research object, the density of the concentrate was measured at 45°C, and the viscosity of the concentrate was measured at 25°C and 45% solid content. After the membrane dispersion alcohol precipitation was carried out, the WMR value was measured, and after modeling, the quantitative relationship between the density, viscosity and mixing of the concentrate was determined as f = Y = -381.97 + 612.81ρ + 1.45V′ - 1.20ρV′ - 244.69ρ 2 +0.00153V′ 2 . Set the WMR threshold E according to production requirements T The density value ρ of the new batch of Codonopsis pilosula concentrate was tested at 45°C. N =1.196 g / mL. According to the density value of the new batch of concentrate ρ N , quantitative relationship f and threshold value E for alcohol precipitation mixing T The maximum acceptable value of the logarithm of the viscosity of the concentrate is 2.60, and the corresponding maximum acceptable viscosity V M =13.5mpa·s. The viscosity of the new batch of concentrate was measured at 25°C and 45% solid content as V N =4.08mpa·s. Because V N ≤V M , it is believed that the new batch of concentrate can be released for alcohol precipitation process. Another new batch of Codonopsis pilosula concentrate was tested at 45℃ and the density value was also ρ N =1.196g / mL; however, the viscosity of the concentrate measured at 25°C and 45% solid content is relatively high, at 15.4mpa·s. According to the conventional concentrate control method, only the density value of the concentrate is concerned, and it is believed that the two new concentrates have the same quality and can be put into production. However, according to the method of the present invention, it is believed that the viscosity of the latter is too high, which will make the proportion of the concentrate that can be fully mixed with ethanol lower than the threshold of 70%. Poor mixing conditions are more likely to cause fluctuations in drug quality, and it is judged that it is not suitable for direct production.

[0033] Example 2

[0034] See also Figure 1 , taking Codonopsis pilosula concentrate as the research object, the density of the concentrate was measured at 45°C, and the viscosity of the concentrate was measured at 25°C and 45% solid content. After the membrane dispersion alcohol precipitation was carried out, the WMR value was measured, and after modeling, the quantitative relationship between the density, viscosity and mixing of the concentrate was determined as f = Y = -381.97 + 612.81ρ + 1.45V′ - 1.20ρV′ - 244.69ρ 2 +0.00153V′ 2 . Set the WMR threshold E according to production requirements T The density value ρ of the new batch of Codonopsis pilosula concentrate was tested at 45°C. N =1.284 g / mL. According to the density value of the new batch of concentrate ρN , quantitative relationship f and threshold value E for alcohol precipitation mixing T The maximum acceptable value of the logarithm of the viscosity of the concentrate is 0.368, and the corresponding viscosity is V M =1.445mpa·s. The viscosity of the new batch of concentrate was measured at 25°C and 45% solid content as V N =2.94mpa·s. Because V N >V M , it is believed that the new batch of concentrate cannot be released, and it should be considered to be diluted or mixed with other batches of concentrate within the scope permitted by regulations, and then whether it can be released.

[0035] Example 3

[0036] See also Figure 1 , taking Astragalus concentrate as the research object, the density of the concentrate was measured at 15°C, and the viscosity of the concentrate was measured at 15°C after dilution to a solid content of 10%. After stirring and alcohol precipitation, the WMR value was measured, and after modeling, the quantitative relationship between the density and viscosity of the concentrate and the mixing condition of the alcohol precipitation was determined as f = Y = -206.09 + 327.39ρ + 0.7813V′ - 0.6252ρV′ - 129.38ρ 2 +0.008223V′ 2 . Set the WMR threshold E according to production requirements T The density value ρ of the new batch of Astragalus concentrate was tested at 15°C. N =1.230 g / mL. According to the density value of the new batch of concentrate ρ N , quantitative relationship f and threshold value E for alcohol precipitation mixing T The maximum acceptable value of the logarithm of the viscosity of the concentrate is 5.08, and the corresponding maximum acceptable viscosity V M =160.4mpa·s. The viscosity of the new batch of concentrate was measured at 15°C and 10% solid content as V N =2.52mpa·s. Because V N ≤V M , it is believed that the new batch of concentrate can be released for use in the alcohol precipitation process.

[0037] Example 4

[0038] See also Figure 1 , taking Astragalus concentrate as the research object, the density of the concentrate was measured at 80°C; after concentrating to 70% solid content, the viscosity of the concentrate was measured at 80°C. After stirring and alcohol precipitation, the WMR value was measured. After modeling, the quantitative relationship between the density and viscosity of the concentrate and the mixing condition of the alcohol precipitation was determined as f = Y = -223.6 + 359.7ρ + 0.8873V′ - 0.7128ρ V′ - 144.01ρ 2+0.0120V′ 2 . Set the WMR threshold E according to production requirements T The density value ρ of the new batch of Astragalus concentrate was tested at 80°C. N =1.247 g / mL. According to the density value of the new batch of concentrate ρ N , quantitative relationship f and threshold value E for alcohol precipitation mixing T The maximum acceptable value of the logarithm of the viscosity of the concentrate is 4.41, and the corresponding maximum acceptable viscosity V M =82.6mpa·s. The viscosity of the new batch of concentrate was measured at 80°C and 70% solid content as V N =103.8mpa·s. Because V N >V M , it is believed that the new batch of concentrate cannot be released, and it should be considered to be diluted or mixed with other batches of concentrate within the scope permitted by regulations, and then whether it can be released.

Claims

1. A method for controlling the release of a concentrate before alcohol precipitation, characterized in that: This is accomplished by following these steps: The first step is to determine the quantitative relationship between the density of the concentrate, the viscosity of the concentrate and the mixing condition of the alcohol precipitation as f; the density of the concentrate refers to the density measured when the temperature of the concentrate is controlled at a certain temperature T1 between 15-80 degrees Celsius; the viscosity of the concentrate refers to the viscosity measured when the temperature of the concentrate is controlled at a certain temperature T2 between 15-80 degrees Celsius and the solid content of the concentrate is fixed at D2, and the value of D2 is between 10% and 70%; The second step is to set the threshold of alcohol precipitation mixing as E T The alcohol precipitation mixing condition is represented by the mass ratio WMR of the concentrate fully mixed with the ethanol solution during the alcohol precipitation process. The WMR calculation formula is: Wherein: m0 is the amount of concentrate used in alcohol precipitation, m1 is the amount of ethanol solution used, m2 is the total mass of the obtained supernatant, S0 is the total solid mass content in the concentrate, C0 is the mass content of component A, S2 is the total solid content in the supernatant, and C2 is the mass content of component A in the supernatant; The third step is to detect the density of the new batch of concentrate as ρ N ; The fourth step is to calculate the density of the new batch of concentrate according to its density value ρ. N , quantitative relationship f and threshold value E for alcohol precipitation mixing T , calculate and determine the maximum acceptable value V of the concentrate viscosity M ; The mathematical form of the quantitative relationship f is: And=a0+a1ρ+a2V′+a3ρV′+a4ρ 2 +a5V′ 2 Where Y is the value obtained by square root arcsine transformation of WMR value, ρ is the density of the concentrate, V′ is the logarithm of the viscosity V of the concentrate, and a0-a5 are the partial regression coefficients obtained by fitting; The threshold value of the alcohol precipitation mixing condition is E T , which ranges from 70% to 100%; The density of the new batch of concentrate is ρ N , tested at temperature T1; Step 5: Determine the viscosity value of the new batch of concentrate as V N , the viscosity value V of the new batch of concentrate N , the solid content of the concentrate should be controlled to D2 and tested at temperature T2; Step 6. Compare V M and V N , if V N ≤V M , then the new batch of concentrate can be released for alcohol precipitation process; if V N >V M , the concentrate cannot be released.

2. The release control method of a concentrate before alcohol precipitation according to claim 1, characterized in that: The method is applied to the quality control of the alcohol precipitation effect of the concentrated solution of traditional Chinese medicine before alcohol precipitation.

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