CN114113434B - Process evaluation method of traditional Chinese medicine formula granules containing volatile oil - Google Patents
Process evaluation method of traditional Chinese medicine formula granules containing volatile oil Download PDFInfo
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Abstract
The invention provides a process evaluation method of a traditional Chinese medicine formula granule containing volatile oil, which adopts S of evaluation index cqa Evaluating a product generated in any step of the preparation process of the traditional Chinese medicine formula granules; s of the evaluation index cqa S including at least a spectrum cqa Or S of a map cqa S in relation to the rate of transfer of essential oils cqa And the extract yield S cqa S indicating the transfer rate of component cqa At least one of (a); screening out S cqa The most numerous products with values closer to 1; s of the map cqa Is the peak area S in the map cqa The acquisition process comprises the following steps: respectively obtaining the spectrums of the standard decoction and the test sample, obtaining the peak areas of all characteristic peaks displayed in the spectrums, and then calculating the ratio of the peak areas of all corresponding characteristic peaks in the test sample and the standard decoction. The invention passes through S cqa The value can effectively evaluate the consistency between the material basis contained in the products prepared by different production process steps and the material basis contained in the standard decoction.
Description
Technical Field
The invention relates to the field of traditional Chinese medicine preparation, and in particular relates to a process evaluation method for traditional Chinese medicine formula granules containing volatile oil.
Background
The traditional Chinese medicine formula particle is a particle prepared by carrying out water extraction, separation, concentration, drying and granulation on traditional Chinese medicine decoction pieces, is taken by patients after being prepared according to a traditional Chinese medicine clinical prescription under the guidance of a traditional Chinese medicine theory, and has consistent clinical curative effect with the corresponding decoction pieces. The traditional Chinese medicine formula granules keep the material basis of the traditional decoction extraction by water, avoid the decoction link before clinical administration, and are an important practical way for the development of the traditional Chinese medicine decoction. The technical requirements for quality control and standard formulation of Chinese medicinal granules are definitely specified: the effective substances of the Chinese medicinal granule should be substantially identical to those of decoction pieces of Chinese medicinal materials.
At present, for most of traditional Chinese medicines, the preparation process of the traditional Chinese medicine formula granule has more sufficient extraction of effective components and higher utilization rate of medicinal materials compared with the traditional decoction. However, for some traditional Chinese medicines containing volatile components, the volatile components extracted by the conventional process are easy to lose, and for example, the traditional Chinese medicines for relieving exterior syndrome, inducing resuscitation and refreshing mind and the like mostly take the volatile oil as an effective component, so that the curative effect of the traditional Chinese medicines is influenced; therefore, the consistency of curative effect is always the focus and focus of the research on the traditional Chinese medicine formula granules. Although the research adopts beta-cyclodextrin inclusion technology to carry out inclusion preservation on the volatile loss components, and then the volatile loss components are returned to the process to prepare formula particles; however, the traditional Chinese medicine components are complex and various, and the content change is different after decoction, but the evaluation is usually carried out only by the volatile oil content in the prior art, so that the evaluation mode is too general and flaky, and the quality consistency of the formula granules and the standard decoction cannot be accurately evaluated.
Disclosure of Invention
Therefore, the technical problem to be solved by the present invention is to overcome the problems of the prior art for formulation granules containing volatile oil. The existing evaluation method cannot accurately evaluate the quality consistency of the standard decoction; thereby providing a process evaluation method of the Chinese medicinal formula granule containing volatile oil, which can ensure that the content of each component in the standard decoction is more consistent.
A method for evaluating Chinese medicinal granule containing volatile oil comprises:
key quality attribute similarity coefficient S adopting evaluation index cqa Evaluating a product generated in any step of the preparation process of the traditional Chinese medicine formula granules; s of the evaluation index cqa S including at least a spectrum cqa Or S of a map cqa S in relation to the rate of transfer of essential oils cqa And the extract yield S cqa S indicating the transfer rate of component cqa At least one of; screening out S cqa The process corresponding to the product with the maximum number and the value closer to 1;
wherein, S of the map cqa Is the peak area S in the map cqa The acquisition process comprises the following steps: respectively obtaining the standard decoction and the sample, wherein the sample is the product of any step in the process of preparing the Chinese medicinal granule, and the sample is obtained from the sampleCalculating peak area of each characteristic peak, and calculating the ratio of peak areas of each corresponding characteristic peak in the sample and the standard decoction, wherein the ratio is S of peak area in the chromatogram cqa ；
S of volatile oil transfer rate cqa The acquisition process comprises the following steps: respectively obtaining oil content transfer rate of the sample and standard decoction, and adopting S of volatile oil transfer rate cqa = calculating the oil content transfer rate of the test product/the oil content transfer rate of the standard decoction;
extract yield S cqa The acquisition process comprises the following steps: respectively obtaining extract yields of the test sample and the standard decoction, and adopting S of the extract yield cqa = calculating the yield of the test sample extract/the yield of the standard decoction extract;
s indicating the transfer rate of component cqa The acquisition process comprises the following steps: respectively obtaining index component transfer rates of the sample and standard decoction, and adopting S of index component transfer rate cqa = sample index component transfer rate/standard decoction index component transfer rate.
When the preparation process is an extraction step, S of evaluation index cqa S including at least the rate of transfer of essential oils cqa And the extract yield S cqa Or S of a map cqa 。
Wherein, the process for obtaining the oil content transfer rate comprises the following steps: obtaining the content of the volatile oil in the standard decoction or the test sample, obtaining the content of the volatile oil in the decoction pieces prepared into the standard decoction or the test sample, calculating the product of the content of the volatile oil in the standard decoction or the test sample and the extract yield of the corresponding process, and the ratio of the content of the volatile oil in the decoction pieces, wherein the ratio is the oil content transfer rate.
Namely, the content of the volatile oil = the content of the volatile oil in the quasi decoction or the test sample:theextract yield/the content of the volatile oil in the decoction pieces;
the method for measuring the content of the volatile oil comprises the following steps: transferring standard decoction or sample to round bottom flask, and detecting according to specification of 2204 volatile oil determination method in the fourth Provisions of 2020 edition of Chinese pharmacopoeia.
The obtaining process of the extract yield is as follows: obtaining standard decoction or test sample, concentrating at 50 deg.C or below until the material-liquid ratio is 1:1 or until the relative density is 1.05-1.10 (50 deg.C), lyophilizing to obtain the weight of dried material, and calculating the ratio of the weight of dried material to the material amount of corresponding decoction pieces, wherein the ratio is the extract yield.
S of evaluation index when the preparation process is a concentration step cqa At least including the concentration efficiency, the ratio of the peak area of each characteristic peak at different temperatures and different time to 0h, and the ratio closer to 1 is in the range of 1 +/-15%.
S of evaluation index when the preparation process is a drying step cqa S including at least a spectrum cqa S indicating the transfer rate of component cqa S of transfer rate of volatile oil cqa The method also comprises the step of evaluating a product generated in any step in the preparation process of the traditional Chinese medicine formula granules by adopting the evaluation index loss rate.
Loss rate% = (theoretical cream output of standard soup in the batch-actual cream output of process in the batch)/theoretical cream output of standard soup in the batch + 100%.
In the drying step, the addition amount of the volatile oil = effective utilization amount/inclusion rate of the volatile oil in the standard decoction of the same batch.
The effective utilization amount of the volatile oil in the standard decoction is that the standard decoction is transferred into a round-bottom flask, and the content of the volatile oil is read according to the specification of a 2204 volatile oil determination method in the fourth general rule of the fourth division of 2020 edition in Chinese pharmacopoeia, and the content is the effective utilization amount of the volatile oil in the standard decoction.
When the preparation process is a granulation step, S of evaluation index cqa S including at least a spectrum cqa S as an index of component transfer rate cqa S of volatile oil transfer rate cqa 。
S of a map closer to 1 cqa S of volatile oil transfer rate cqa And the extract yield S cqa S as an index of component transfer rate cqa The value of (b) is in the range of 1. + -. 30%.
S of a map closer to 1 cqa S of volatile oil transfer rate cqa And the extract yield S cqa S of index component content transfer rate cqa The value of (b) is in the range of 1. + -. 15%.
The standard decoction is prepared from the raw materials in the same batch as the traditional Chinese medicine formula granules.
The technical scheme of the invention has the following advantages:
1. the invention provides a process evaluation method of traditional Chinese medicine formula particles containing volatile oil, aiming at the traditional Chinese medicine based on small-polarity and volatile components as effective substances, when the formula particles are prepared, an inclusion technology is adopted to carry out inclusion preservation on the volatile small-polarity components, and when the volatile small-polarity components are quantitatively added into the formula particles, the effective substances and the curative effect of a finished product can be kept consistent with those of standard decoction; specifically, a key quality attribute similarity coefficient S is adopted cqa Evaluation method, clear as S cqa The value closest to the value 1 is the standard screening optimal process, the amplitude of material change in the process of process research is reduced, the difference condition between the material basis of products of different process steps and the material basis of standard decoction is comprehensively, accurately and effectively evaluated, and the formula particles and the material basis of the standard decoction are ensured to have higher consistency.
2. The invention takes the effective utilization amount of volatile oil in standard decoction of the raw materials of the same batch, the index component content of the standard decoction, the characteristics or the fingerprint as reference, controls the quantity value transmission of substances in the preparation process of the traditional Chinese medicine formula particles, avoids the blind pursuit of the concept of one-sided that the content of effective components is high, namely the medicine has good curative effect, realizes the root tracing from the finished product to the raw materials and the step reduction of each key process link, and realizes the individual evaluation of the finished product for the traditional Chinese medicine formula particles of different batches.
3. The standard decoction prepared from the same batch of raw materials is used as a follow-up contrast, and the quality parameters of the standard decoction are used for individually guiding the process research, so that the quantity transmission in the process of the process research of the formula granules of each batch can be ensured to accord with the quality parameters of the standard decoction of the same batch, and the purpose reduction of the standard for meeting the published standard range of the corresponding traditional Chinese medicine formula granules and further the waste of traditional Chinese medicine resources caused by the research of the high-quality raw materials can be avoided; the research cost of enterprise production verification can be reduced, and the traceability from finished products to raw materials is ensured.
Detailed Description
Example 1
A process evaluation method of a traditional Chinese medicine formula granule containing volatile oil is disclosed. Specifically, the present embodiment uses the key quality attribute similarity coefficient S cqa Sequentially evaluating products of the rhizoma atractylodis decoction pieces obtained by different process steps, wherein the process evaluation comprises the following steps:
1. determining the preparation process of standard decoction:
taking 100g of rhizoma atractylodis decoction pieces, putting the rhizoma atractylodis decoction pieces in a marmite, soaking for 30 minutes, adding water 9 times the amount of the decoction pieces in the first decoction, boiling with strong fire (500 w), then decocting with slow fire (200 w) for 30 minutes, adding water 7 times the amount of the decoction pieces in the second decoction, boiling with strong fire (500 w), then decocting with slow fire (200 w) for 20 minutes, filtering the liquid medicine with 150-mesh filter cloth while the liquid medicine is hot, and combining the filtrates to obtain the standard decoction.
2. The evaluation process of the process steps comprises:
2.1 detection method for obtaining evaluation indexes
2.1.1, the detection method of the extract yield comprises the following steps:
obtaining standard decoction or test sample, which is extractive solution under different process conditions, concentrating at 50 deg.C or below until the material-liquid ratio is about 1:1 or the relative density is 1.05-1.10 (50 deg.C), and lyophilizing to obtain dry powder. And (3) measuring 2 parts in parallel for each batch, and calculating according to a formula of extract yield = dry powder weight/corresponding decoction piece quantity multiplied by 100% ".
2.1.2, a detection method of the characteristic spectrum comprises the following steps:
in chromatographic condition and system applicability test, octadecylsilane chemically bonded silica is used as a filler, the length of the column is 10cm, the inner diameter of the column is 2.1mm, and the particle size is 1.8 mu m; acetonitrile is taken as a mobile phase A,0.1% formic acid is taken as a mobile phase B, and gradient elution is carried out according to the specification in the following table 1; the detection wavelength is 336nm and 250nm; the column temperature is 30 ℃; the flow rate is 0.4ml/min; the number of theoretical plates is not less than 5000 according to the peak of atractylodin.
TABLE 1 gradient elution Table
Preparing a test solution: taking a proper amount of the product, grinding the solid, taking 0.5g, placing into a conical flask with a plug, adding 20ml of 10% methanol, sealing the plug, carrying out ultrasonic treatment for 60min, taking out, cooling, shaking up, filtering, and taking out the subsequent filtrate.
The measuring method comprises precisely sucking 5 μ l of reference solution and sample solution respectively, injecting into liquid chromatograph, and measuring.
2.1.3, obtaining the oil content transfer rate:
obtaining standard decoction or a test sample, wherein the test sample is extracting solution under different process conditions, transferring the standard decoction or the test sample into a round-bottom flask, reading the content of volatile oil according to the specification of 2204 volatile oil determination method in the fourth Provisions of 2020 edition of Chinese pharmacopoeia, calculating the product of the content of the volatile oil in the standard decoction or the test sample and the extract yield of the corresponding process, and the ratio of the content of the volatile oil in the rhizoma atractylodis decoction pieces, namely the oil content transfer rate.
Namely, the oil content transfer rate = (the content of volatile oil in standard decoction or test sample = extract yield)/the content of volatile oil in rhizoma atractylodis decoction pieces;
transfer rate of volatile oil S cqa = oil content transfer rate of test sample/oil content transfer rate of standard decoction.
2.1.4, obtaining the loss rate according to the following calculation rule:
loss rate% = (theoretical cream output of standard soup in this batch-actual cream output of process in this batch)/theoretical cream output of standard soup in this batch 100%.
2.2 obtaining evaluation index of standard decoction
Performing process research on 08 batches of raw materials, and preparing and detecting the raw materials by adopting the preparation process of the standard decoction to obtain the batch of standard decoction, wherein the extract yield is 32.9%, the content transfer rate of atractylodin is 0.00594%, and the transfer rate of volatile oil is 1.60%; the relative peak area of each characteristic peak in the characteristic map is as follows: 1.34 (peak 1), 0.67 (peak 2), 2.79 (peak 3), 3.31 (peak 4), 5.02 (peak 5), 3.55 (peak 6), 1.80 (peak 7), 2.63 (peak 8), 2.54 (peak 9), 1.66 (peak 10), 1.22 (peak 11), 1.88 (peak 12), 0.86 (peak 13) and 1.00 (peak 14S), which all meet the standard decoction range.
2.3 evaluation of extraction Process parameters
Taking 08 batches of rhizoma atractylodis decoction pieces, putting 100g of the rhizoma atractylodis decoction pieces in a round-bottom flask, and passing through an orthogonal L 9 (3 4 ) The rhizoma atractylodis extraction technology is preferably selected in the experiment, the extraction frequency, the extraction time and the water addition amount are considered as factors, and the volatile oil is collected while the extraction is carried out. S with extract yield cqa And S of volatile oil transfer rate cqa The results are shown in Table 2, which is preferable for the purpose of examining the indices.
TABLE 2
Extract yield S cqa The analysis result shows that the yield of the extract of the experimental group 4 is S compared with that of the extract of the other experimental groups cqa The value is closer to 1; the transfer rate of the volatile oil in the nine tests is higher than that of the volatile oil in the same batch, which indicates that the nine tests can reach the target value of the volatile oil collection amount, and the extract yield S is combined cqa As a result, the experimental group 4 was more compatible with the standard decoction process than the rest of the processes. Therefore, the extraction process of the rhizoma atractylodis is determined as follows: decocting twice, extracting for 2 times, each time for 0.5 hr, and adding 10 times of water for each decoction.
2.4 evaluation of concentration Process parameters
Taking 100g of rhizoma atractylodis decoction pieces (08 batches), adding 9 times of water into the first decoction for 30 minutes and 7 times of water into the second decoction according to standard decoction conditions, decocting for 20 minutes, filtering by 150-mesh filter cloth, combining the filtrates, concentrating the filtrate and fixing the volume. Equally dividing the medicinal liquid into 21 parts, taking one part as 0h standard decoction solution, and heating the rest samples in water bath at 50 deg.C, 60 deg.C, 70 deg.C, and 80 deg.C for 0h standard decoction solution3h, 6h, 9h, 12h and 24h, concentrating, standing to room temperature, adding water to constant volume to the same scale, detecting according to characteristic spectrum method of 2.1.2, and determining peak area S in the spectrum cqa As an evaluation index, specifically, the variation condition of each characteristic peak in the characteristic spectrum under different temperatures and times is examined by taking +/-15% of the ratio of the peak area of each characteristic peak to the corresponding peak area of the 0h standard decoction solution as the evaluation index, and the result is shown in Table 3.
TABLE 3 ratio of different concentration temperatures-time-characteristic peak-to-peak areas
According to the result of the ratio of the peak area of each characteristic peak to the peak area of the sample of 0h, the value of the ratio of the corresponding characteristic peak to the peak area of 1 +/-30% is more in the characteristic map with the concentration temperature within 70 ℃ and the heating time within 12 h. And the peak area ratio is +/-15%, the ratio deviation is larger along with the increase of the heating temperature, particularly 70 ℃, and after 12h, the ratio deviation is larger. In order to ensure the integrity of material foundation in the concentration process and take production efficiency and energy consumption loss into consideration, the concentration process parameters of the rhizoma atractylodis are set as follows: concentrating at below 70 deg.C for no more than 12 hr.
2.5 evaluation of drying Condition
Adopting 08 batches of raw materials, extracting according to the optimal extraction process conditions of the rhizoma atractylodis, concentrating under reduced pressure at 50 ℃, collecting concentrated solution, mixing with the inclusion compound, and drying.
The inclusion compound is optimized by taking the yield and the inclusion rate of the inclusion compound as evaluation indexes, and specifically comprises the following steps: collecting 08 batches of the essential oil, passing through L 9 (3 4 ) Orthogonal test optimizes the inclusion process of volatile oil, takes beta-cyclodextrin, water addition and inclusion time as investigation factors, fixes the addition of volatile oil, and takes the yield and inclusion rate of the inclusion compound as evaluation indexesThe standard is optimized, and the results are shown in tables 4 and 5.
Inclusion rate of volatile oil = actual oil content of inclusion complex (ml)/[ input of volatile oil (ml) × blank recovery rate ] × 100% inclusion yield = inclusion weight (g)/[ beta-cyclodextrin amount (g) + input of volatile oil (ml) × relative density of volatile oil ] × 100%.
TABLE 4 orthogonal test Table
TABLE 5 results of comprehensive analysis of volatile oil inclusion orthogonal test-Design Expert software
Taking the yield and the inclusion rate of the inclusion compound as evaluation indexes, analyzing the inclusion orthogonal experiment result of the volatile oil by using software Design Expert 10, wherein according to the analysis result, the proportion of the volatile oil to the beta-cyclodextrin is 1:8, the water addition amount is 60 times of that of the volatile oil, and when the inclusion is carried out for 20min, the yield and the inclusion rate of the rhizoma atractylodis volatile oil inclusion compound are both high, and the result score is highest, so that the inclusion process is selected. The inclusion rate was determined to be about 91% and 93%.
And then according to the addition amount of the volatile oil = the effective utilization amount/inclusion rate of the volatile oil in the standard decoction of the same batch.
The process for obtaining the effective utilization amount of the volatile oil in the standard decoction comprises the following steps: transferring the standard decoction into a round-bottom flask, and reading the content of the volatile oil according to the specification of a volatile oil determination method 2204 in the fourth general rule of the 2020 edition of Chinese pharmacopoeia, wherein the content is the effective utilization amount of the volatile oil in the standard decoction.
According to calculation, the adding amount of the volatile oil in the batch is 0.05 percent of the amount of the decoction pieces.
Then, a single factor examination of spray drying of a mixture of the concentrated solution of atractylodes rhizome and the inclusion compound was performed as shown in table 6. And S based on loss rate of dried powder and atractylodin transfer rate cqa S of transfer rate of volatile oil cqa S of relative peak area in spectrum cqa Optimizing the process for evaluation index, wherein S is the relative peak area in the map cqa The results are shown in tables 6 and 7 below, with peak 14 being the S peak.
Loss rate% = (theoretical cream yield of standard soup in this batch-actual cream yield of process in this batch)/theoretical cream yield of standard soup in this batch = 100%
TABLE 6 results of spray drying
TABLE 7S of spray drying profiles cqa As a result, the
The results show that S of the experimental 5 groups of maps cqa Values near 1 are more numerous, with experimental groups 2 and 6 being ranked next to values near 1. Atractylodin transfer rate S cqa And S of volatile oil transfer rate cqa The results show that both are closer to 1 in the experiment 5 group. The loss rate result shows that the loss rate of the experimental group with the air inlet temperature of 170 ℃ is lower, the loss rate is lower when the density of the feed liquid is 1.15, and the loss rate is only reduced by 1.25 percent, which indicates that the influence of the addition of the auxiliary material on the loss rate is not significant, so that the auxiliary material is not added for drying. Comprehensively, when the temperature of the dry inlet air is 170 ℃, the components in the test sample are well preserved. Therefore, the density of the feed liquid is determined to be 1.15 by the rhizoma atractylodis spray drying process, no auxiliary materials are added, and the air inlet temperature is 170 ℃.
Example 2
The present example is used to verify the process condition parameters obtained in the mass production verification example 1, and specifically includes the following steps:
taking three batches of rhizoma atractylodis decoction pieces, carrying out production verification according to the selected process, collecting samples of each process link, and analyzing the transmission condition of quality indexes of each link.
1. The transmission of the extract yield and the detection results are shown in table 8.
TABLE 8 verification of quantity transmission in large-scale production of rhizoma Atractylodis formula granule-S of extract yield cqa
And (3) knotting: extract yield S cqa The result shows that in the production verification of 3 batches of the rhizoma atractylodis formula particles, the Scqa value of the extract yield of each key process link is closer to 1, and the result is in the range of standard decoction, which indicates that the 3 batches of verification results are better.
2. Volatile oil transfer Rate profiles
Calculating S of volatile oil transfer rate in key process link of production verification by taking standard decoction volatile oil transfer rate as reference cqa The results are shown in Table 9.
TABLE 9 production of rhizoma Atractylodis formula granule for verifying quantity transmission-S of transfer rate cqa
And (3) knotting: s of volatile oil transfer rate cqa The result shows that S of the volatile oil transfer rate in the key process link of the production of the rhizoma atractylodis formula granules cqa The values are all close to 1, the standard decoction range is met, the volatile oil is basically and completely transferred, and the verification result of 3 batches of production is better.
3. Transmission of atractylodin transfer rate
Taking the content transfer rate of atractylodin as a standard decoction as a reference, and comparing the production relation because the volatile oil is collected and included in the extraction process and is quantitatively added in the drying linkBond process link atractylodin transfer rate S cqa The results are shown in Table 10.
TABLE 10 Mass production of rhizoma Atractylodis formulation granule to verify magnitude transmission-S of transfer rate cqa
And (4) summarizing: s with atractylodin content transfer rate cqa The results show that the content of atractylodin is basically and completely transferred in the key process of the production of the rhizoma atractylodis formula granules, and the transfer rate S of atractylodin is determined in each key process link cqa The value was close to 1, the results were in the standard decoction range, indicating that 3 batches of the validation results were better.
4. Transfer condition of characteristic peak of characteristic map
TABLE 11 verification of the S of the atlas of each link in the large-scale production of rhizoma Atractylodis formula granule cqa
And (3) knotting: from the above results, it can be seen that the volatile oil was extracted and collected due to the extraction and concentration steps, and S of the characteristic peak 14 of atractylodin cqa A value of 0; after the volatile oil inclusion compound is added in a drying link, S of a characteristic peak 14 cqa A value of 1, indicating that atractylodin was stably transferred to the finished granules; the characteristic peaks of the characteristic spectrum of each key process link can be presented, and the S of the characteristic spectrum cqa The values show different degrees of variation within + -15%, the degree of variation is within the acceptable range, and the S of each characteristic peak cqa The transmission is more stable.
Example 3
A process evaluation method for Chinese medicinal granules containing volatile oil comprises preparing herba Schizonepetae granules. Specifically, the present embodiment uses the key quality attribute similarity coefficient S cqa Sequentially evaluating products of schizonepeta spike decoction pieces obtained by different process steps, wherein the process evaluation comprises the following steps of:
1. determining the preparation process of standard decoction:
taking schizonepeta spike decoction pieces, putting the schizonepeta spike decoction pieces into a marmite, decocting twice, adding water 14 times of the decoction pieces in the first decoction, soaking for 30 minutes, boiling with strong fire (500W), decocting with slow fire (200W) for 20 minutes, and filtering while the decoction pieces are hot; adding water 10 times the amount of decoction pieces, boiling with strong fire (500W), decocting with slow fire (200W) for 10 min, filtering, and mixing filtrates to obtain standard decoction.
2. The evaluation process of the process steps comprises:
2.1 detection method for obtaining evaluation indexes
2.1.1, and a detection method of extract yield:
obtaining standard decoction or test sample, which is extractive solution under different process conditions, concentrating at 50 deg.C or below until the material-liquid ratio is about 1:1 or the relative density is 1.05-1.10 (50 deg.C), and lyophilizing to obtain dry powder. And (3) measuring 2 parts of each batch in parallel, and calculating according to a formula of extract yield = dry powder weight/corresponding decoction piece amount multiplied by 100 percent to obtain the finished product.
2.1.2, a detection method of the characteristic spectrum comprises the following steps:
chromatographic conditions and system applicability test with octadecylsilane chemically bonded silica as filler (column length 100mm, inner diameter 2.1mm, particle size 1.6 μm); taking acetonitrile as a mobile phase A and 0.1% phosphoric acid solution as a mobile phase B, and carrying out gradient elution according to the following table; flow rate 0.4ml per minute; the column temperature was 35 ℃; the detection wavelength was 270nm. The number of theoretical plates should not be less than 3000 calculated according to caffeic acid peak.
TABLE 12 gradient elution Table
Preparation of reference solution A proper amount of caffeic acid, rosmarinic acid, and luteolin as reference substance is precisely weighed, and added with methanol to obtain solutions containing 0.1mg per 1ml as reference substance solutions.
Preparing a test solution, taking a proper amount of the product, grinding the solid, taking about 0.5g, putting the ground product into an erlenmeyer flask, adding 20ml of water, carrying out ultrasonic treatment (with the power of 250W and the frequency of 50 kHz) for 30 minutes, cooling the erlenmeyer flask, extracting the erlenmeyer flask twice by shaking with ethyl acetate, taking 30ml of ethyl acetate solution each time, combining the ethyl acetate solution, evaporating the ethyl acetate solution to dryness, adding 30% methanol into residues to dissolve the residues, fixing the volume to 10ml, shaking the mixture evenly, filtering the mixture, and taking subsequent filtrate to obtain the finished product.
The determination method comprises precisely sucking 2 μ l of reference solution and sample solution respectively, injecting into liquid chromatograph, and determining.
2.1.3, a method for detecting the content of the pulegone:
octadecylsilane chemically bonded silica is used as a filler in chromatographic conditions and system applicability tests; methanol-water (70: 30) is used as a mobile phase; the detection wavelength was 252nm. The number of theoretical plates should not be less than 3000 calculated from the pulegone peak.
Preparation of reference substance solution A proper amount of pulegone reference substance is precisely weighed, and methanol is added to prepare a solution containing 40 μ g of pulegone per 1 ml.
Preparation of test sample solution an appropriate amount of sample is taken, ground, about 0.5g is taken, precisely weighed, placed in a conical flask, precisely added with 25ml of 70% methanol, weighed, ultrasonically treated for 30 minutes, cooled, weighed again, complemented with 70% methanol, shaken up, filtered, and a subsequent filtrate is taken, thus obtaining the test sample solution.
The determination method comprises precisely sucking 10 μ l of each of the reference solution and the sample solution, injecting into liquid chromatograph, and determining.
2.1.4, obtaining the oil content transfer rate:
obtaining standard decoction or a test sample, wherein the test sample is extracting solution under different process conditions, transferring the standard decoction or the test sample into a round-bottomed flask, reading the content of volatile oil according to the specification of a 2204 volatile oil determination method in the fourth general rule of 2020 edition in Chinese pharmacopoeia, calculating the product of the content of the volatile oil in the standard decoction or the test sample and the extract yield of the corresponding process, and the ratio of the content of the volatile oil in schizonepeta spike decoction pieces, wherein the ratio is the oil content transfer rate.
2.1.5, obtaining the loss rate according to the following calculation rule:
loss rate% = (theoretical cream output of standard soup in this batch-actual cream output of process in this batch)/theoretical cream output of standard soup in this batch 100%.
2.2 obtaining evaluation index of standard decoction
Carrying out process research on the 3 rd batch of raw materials, preparing and detecting by adopting the preparation process of the standard decoction, wherein the extract yield of the obtained batch of standard decoction is 20.0%, the content transfer rate of pulegone is 6.9%, and the transfer rate of volatile oil is 3.9%; the chromatogram of the test sample should have 10 characteristic peaks, wherein 3 peaks should correspond to the retention time of the reference peak of the corresponding reference sample, the peak corresponding to the caffeic acid reference sample is the S peak, and the relative retention time of each characteristic peak and the S peak is calculated and should be within + -10% of the specified value. The specified values are: 0.41 (Peak 1), 0.43 (Peak 2), 0.58 (Peak 3), 0.61 (Peak 4), 0.65 (Peak 5), 3.09 (Peak 8), and 3.32 (Peak 9), all of which meet the standard decoction ranges.
2.3 evaluation of extraction Process parameters
Collecting batch 3 of herba Schizonepetae decoction pieces, 150g each, placing in round-bottom flask, passing through orthogonal L 9 (3 4 ) The rhizoma atractylodis extraction technology is preferably selected in the experiment, the extraction frequency, the extraction time and the water addition amount are considered as factors, and the volatile oil is collected while the extraction is carried out. S with extract yield cqa S of volatile oil transfer rate cqa S of map cqa Preferably, S of the map is used for examining indexes cqa S is relative peak area of each characteristic peak in the map cqa Wherein, S of the map cqa Calculated with peak 6 as the S peak. The results are shown in tables 13 and 14.
TABLE 13 yield of Quadrature extract and volatile oil transfer S cqa
TABLE 14 extraction of S of orthogonal feature maps cqa
By making into extractYield of S cqa The examination result shows that the extraction times have main influence on the extract yield, and the extraction time is short; when the schizonepeta spike is extracted for 2-3 times, the extract yield of the schizonepeta spike is high, and S cqa The values are closer to 1, where S for experimental groups 3, 5 cqa The value is closer to 1. Orthogonal experiment on transfer rates of nine groups of volatile oil cqa The results are all larger than 1, which indicates that the oil receiving amount of each experimental group can reach the standard frying target value. S of the map cqa The results show that S in the experimental groups 5, 8 and 9 cqa The data with the value close to 1 are more, and the S of the extract yield is considered cqa Preferably, experiment 5 groups are the schizonepeta spike extraction process, namely 2 times of extraction, 14 times of water for first decoction and 12 times of water for second decoction, and each decoction lasts for 60 minutes.
2.4 evaluation of concentration Process parameters
Taking 100g of schizonepeta spike decoction pieces (03 batches), adding 14 times of water into the first decoction and decocting for 20 minutes, adding 12 times of water into the second decoction and decocting for 10 minutes according to standard decoction conditions, filtering through 150-mesh filter cloth, combining filtrates, concentrating the filtrate and fixing the volume. Equally dividing the liquid medicine into 21 parts, taking one part as 0h standard decoction solution, heating the rest samples by a water bath kettle at 50 ℃, 60 ℃, 70 ℃ and 80 ℃ for 3h, 6h, 9h, 12h and 24h respectively, concentrating, standing to room temperature, then fixing the volume to the same scale by water, detecting according to the characteristic spectrum method of the schizonepeta spike in 2.1.2, taking the +/-30% ratio of the peak area of each characteristic peak to the corresponding peak area of the 0h standard decoction solution as an evaluation index, and inspecting the change condition of each characteristic peak in the characteristic spectrum at different temperatures and time. The results are shown in Table 15.
TABLE 15 ratio of different concentration temperatures-time-characteristic Peak-to-Peak areas
According to the results of the ratio of the peak area of each characteristic peak to the peak area of the sample of 0h, the numerical value that the ratio of the peak areas is close to 1 is more in the characteristic spectrum with the concentration temperature within 80 ℃ and the heating time within 9 h. And the peak area ratio is +/-15%, the ratio deviation is larger along with the increase of the heating temperature, particularly the numerical value of the ratio close to 1 is less after 80 ℃ and 9 h. In order to ensure the integrity of the material foundation in the concentration process and take production efficiency and energy consumption loss into consideration, the concentration process parameters of the schizonepeta spike are set as follows: concentrating at below 80 deg.C for no more than 9 hr.
2.5 evaluation of drying Condition
Adopting 03 batches of raw materials, extracting according to the optimal extraction process conditions of schizonepeta spike, concentrating under reduced pressure at 50 ℃, collecting concentrated solution, mixing with the inclusion compound, and drying.
The inclusion compound is optimized by taking the yield and the inclusion rate of the inclusion compound as evaluation indexes, and specifically comprises the following steps: collecting 03 batches of the essential oil, passing through L 9 (3 4 ) The orthogonal test optimizes the inclusion process of the volatile oil, takes the addition amount of beta-cyclodextrin and water and the inclusion time as the factors for investigation, fixes the addition amount of the volatile oil, takes the yield and the inclusion rate of the inclusion compound as evaluation indexes for optimization, and the results are shown in tables 16 and 17.
Inclusion rate of volatile oil = actual oil content of inclusion compound (ml)/[ input amount of volatile oil (ml) × blank recovery rate ] × 100% inclusion compound yield = inclusion compound weight (g)/[ beta-cyclodextrin amount (g) + input amount of volatile oil (ml) × relative density of volatile oil ] × 100%
TABLE 16 orthogonal test Table
TABLE 17 inclusion test results
According to the inspection result of inclusion experiments, the change of each experimental condition has little influence on the yield of the inclusion compound and has great influence on the inclusion rate of the volatile oil, so that an experimental group with higher inclusion rate of the volatile oil is preferred, namely the proportion of the volatile oil to the beta-cyclodextrin is 1:8, the addition proportion of the beta-cyclodextrin to the water is 1:3, and the inclusion process is selected because the yield and the inclusion rate of the schizonepeta spike volatile oil inclusion compound are higher when the volatile oil and the beta-cyclodextrin are included for 60 min. The inclusion rate is determined to be about 99.25%, and the inclusion rate is determined to be about 88.44%.
And then according to the addition amount of the volatile oil = the effective utilization amount/inclusion rate of the volatile oil in the standard decoction of the same batch.
The process for obtaining the effective utilization amount of the volatile oil in the standard decoction comprises the following steps: transferring the standard decoction into a round-bottom flask, and reading the content of the volatile oil according to the specification of a volatile oil determination method 2204 in the fourth general rule of the 2020 edition of Chinese pharmacopoeia, wherein the content is the effective utilization amount of the volatile oil in the standard decoction.
According to calculation, the adding amount of the volatile oil in the batch is 0.23 percent of the amount of the decoction pieces.
Then, a single factor investigation of spray drying of the mixture of the concentrate of schizonepeta spike and the inclusion compound was conducted, as shown in table 18. S in terms of loss rate and index component transfer rate cqa S of volatile oil transfer rate cqa S of map cqa Optimizing the process for evaluation index, the S of the map cqa Preferably S of relative peak area in the spectrum cqa Wherein peak 6 is calculated as the S peak, and the detection results are shown in tables 18 and 19 below.
Loss rate% = (theoretical cream yield of standard soup in this batch-actual cream yield of process in this batch)/theoretical cream yield of standard soup in this batch = 100%
TABLE 18 spray drying results
Table 19 results of Scqa of spray drying profiles
As can be seen from the results of examination of the drying pattern, the loss rates of spray drying and 80 ℃ reduced pressure drying were low, and S, which is the transfer rate of pulegone, in both groups of spray drying cqa And S of volatile oil transfer rate cqa Values closer to 1 are more indicative of thisThe two methods can obtain extract powder with better quality. S of the atlas cqa The results show the S of the two spray-dried spectra cqa The value is more close to 1, the existing production drying process of the schizonepeta spike is spray drying, the method is energy-saving and time-saving, and has strong operability, so the spray drying is selected as the drying method of the schizonepeta spike, the density is set to be 1.05 +/-0.03 (60 ℃), no auxiliary material is added, the air inlet temperature is 175 ℃, the concentrated schizonepeta spike liquid and the inclusion compound are dried, the loss rate and the spray drying state are better, the loss rate can be reduced to below 15 percent, and the spray drying is known to be suitable for the drying process of the schizonepeta spike formula particles.
Example 4
The present embodiment is used for verifying the process condition parameters obtained in the mass production verification embodiment 3, and specifically includes the following steps:
taking three batches of schizonepeta spike decoction pieces, carrying out production verification according to the selected process, collecting samples of each process link, and analyzing the transmission condition of quality indexes of each link.
1. The transmission of the extract yield and the detection results are shown in table 20.
TABLE 20 Large production verification of herba Schizonepetae granule magnitude transfer-S of extract yield cqa
And (3) knotting: s of extract yield cqa The result shows that S of the extract yield of each key process link in the production verification of 3 batches of schizonepeta spike formula particles cqa The values are all closer to 1, and the results are in the range of standard decoction, which indicates that the results of 3 batches of verification are better.
2. Volatile oil transfer Rate profiles
Calculating S of volatile oil transfer rate in key process link of production verification by taking standard decoction volatile oil transfer rate as reference cqa The results are shown in Table 21.
TABLE 21 bulk production of schizonepeta spike formula granules verifies quantity transfer-S of transfer rate cqa
And (3) knotting: s of volatile oil transfer rate cqa The results show that the volatile oil transfer rate in the extraction link is higher, which indicates that the volatile oil collected in the extraction link can reach the target value of standard decoction and the S of the volatile oil transfer rate of schizonepeta spike extract powder and formula particles cqa The values are all close to 1, the standard decoction range is met, the volatile oil is basically and completely transferred, and the verification result of 3 batches of production is better.
3. Transmission of the transfer Rate of pulegone
Taking the standard pulegone content transfer rate as reference, comparing the S of pulegone transfer rate in key production process because the volatile oil is collected and included in the extraction process and is quantitatively added in the drying process cqa The results are shown in Table 22.
TABLE 22S of confirmation of magnitude transmission-transfer rate in bulk production of schizonepeta spike formulation granules cqa
And (3) knotting: s from the rate of transfer of the content of pulegone cqa The results show that the content of the pulegone is basically and completely transferred in the key process of producing the schizonepeta spike formula particles, and the S of the pulegone transfer rate in each key process link cqa The value is close to 1, and the result is in the range of standard decoction, which indicates that the 3 batches of verification results are better.
4. Transfer condition of characteristic peak of characteristic map
TABLE 23S of herba Schizonepetae formula granule mass production verification link map cqa
And (4) summarizing: from the above results, the characteristic peaks of the characteristic spectrum of each key process link can be shown, and the S of the characteristic spectrum cqa The values show different degree changes, except that the characteristic peaks have larger fluctuation than the standard decoction after the peak 1, the peak 4 and the peak 9 are extracted for a long time in production, the change ranges of the other characteristic peaks are within +/-30 percent, the change degrees are within acceptable ranges, and the S of each characteristic peak cqa The transmission is more stable.
In conclusion, standard decoction is used as reference, and extract yield, volatile oil content transfer rate, index component content (or transfer rate), and S of characteristic peak of characteristic map are used cqa In order to examine indexes, the selected process parameters are reasonable, the quantity value transmission is stable, and the quality of the obtained product can be kept consistent with that of standard decoction.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. This need not be, nor should it be exhaustive of all embodiments. And obvious variations or modifications derived therefrom are intended to be within the scope of the invention.
Claims (9)
1. A process for evaluating the Chinese-medicinal particles containing volatile oil features that the similarity coefficient S of key quality attributes of the evaluation index is used cqa Evaluating a product generated in any step of the preparation process of the traditional Chinese medicine formula granules; s of the evaluation index cqa S comprising a map cqa S of volatile oil transfer rate cqa And the extract yield S cqa And S indicating the transfer rate of the component cqa (ii) a Screening out S cqa The most numerous processes with values closer to 1;
wherein, S of said map cqa S is the peak area of each characteristic peak in the map cqa Or relative peak area S cqa Wherein S is the relative peak area of each characteristic peak in the map cqa The acquisition process comprises the following steps: respectively obtaining the spectra of standard decoction and test sample, wherein the test sample is the product of any step in the process of preparing Chinese medicinal granule, obtaining peak area of each characteristic peak shown in the spectra, and calculating relative peak area of each characteristic peakThen, calculating the ratio of the relative peak areas of the corresponding characteristic peaks in the test sample and the standard decoction; s of peak area of each characteristic peak in atlas cqa The acquisition process comprises the following steps: respectively obtaining peak areas of the characteristic peaks of the product before and after treatment under the same reference condition, and calculating the ratio of the peak area of each characteristic peak of the treated product to the peak area of the corresponding characteristic peak of the product before treatment;
s of volatile oil transfer rate cqa The acquisition process comprises the following steps: respectively obtaining oil content transfer rate of the sample and standard decoction, and adopting S of volatile oil transfer rate cqa = calculating the oil content transfer rate of the test product/the oil content transfer rate of the standard decoction;
extract yield S cqa The acquisition process comprises the following steps: respectively obtaining extract yields of the test sample and the standard decoction, and adopting S of the extract yield cqa = calculating the extract yield of each process link/standard decoction extract yield;
s indicating the transfer rate of component cqa The acquisition process comprises the following steps: respectively obtaining index component transfer rates of the sample and standard decoction, and adopting S of index component transfer rate cqa = calculating the sample index component transfer rate/standard decoction index component transfer rate;
the process for obtaining the oil content transfer rate comprises the following steps: obtaining the content of the volatile oil in the standard decoction or the test sample, obtaining the content of the volatile oil in the decoction pieces prepared into the standard decoction or the test sample, calculating the product of the content of the volatile oil in the standard decoction or the test sample and the extract yield of the corresponding process, and the ratio of the content of the volatile oil in the decoction pieces, wherein the ratio is the oil content transfer rate.
2. The method for evaluating the process of a Chinese medicinal granule containing volatile oil of claim 1, wherein the preparation process is S as an evaluation index in the extraction step cqa Including volatile oil transfer rate cqa And the extract yield S cqa And S of the map cqa 。
3. The method as recited in claim 1The method for evaluating the process of the traditional Chinese medicine formula granules containing the volatile oil is characterized in that when the preparation process is a concentration step, the evaluation index at least comprises S of the peak area of each characteristic peak in a map cqa S of peak area of each characteristic peak in the map cqa The ratio of the peak area of each characteristic peak of the product under different concentration parameters to the peak area of the corresponding characteristic peak of the product under 0h concentration parameter is shown.
4. The method for evaluating the process of a granule of Chinese medicine containing volatile oil according to claim 1, wherein the preparation process is S as an evaluation index in the drying step cqa S including at least the transfer rate of the index component cqa S of map cqa S of volatile oil transfer rate cqa The method also comprises the step of evaluating a product generated in any step in the preparation process of the traditional Chinese medicine formula granules by adopting the evaluation index loss rate.
5. The method for evaluating the process of a Chinese medicinal granule containing volatile oil of claim 1, wherein the preparation process is S as an evaluation index in the granulation step cqa S including at least a spectrum cqa S as an index of component transfer rate cqa S of volatile oil transfer rate cqa 。
6. The method of any one of claims 1-5, wherein S is closer to 1 cqa The values were in the range of 1. + -. 30%.
7. The method of claim 6, wherein S is closer to 1 cqa The values were in the range of 1. + -. 15%.
8. The method for evaluating the process of a Chinese medicinal granule containing volatile oil according to any one of claims 1 to 5, wherein the standard decoction is prepared from the same batch of raw materials as the Chinese medicinal granule.
9. The method for evaluating the process of a granule of Chinese medicine containing volatile oil according to any of claims 1 to 5, wherein in the drying step, the added amount of volatile oil = effective utilization amount/inclusion rate of volatile oil in the same batch of standard decoction.
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