Application of new technology in pretreatment of traditional Chinese medicine preparation

All the processes from the processing of traditional Chinese medicine to the first stage of preparation can be collectively called the pre-preparation process. Pre-preparation technology includes the steps of crushing, extraction, separation, purification, concentration and drying, which has a great influence on the comprehensive production cost and product quality of finished drugs. Therefore, when evaluating the potential value of a new drug research result, we should not only examine its curative effect and dosage form, but also demonstrate and analyze its preparation technology. In recent years, the application research of new technology in preparation pretreatment has been deepened gradually, which has played an increasingly important role in reducing production cost, reducing toxic and side effects, improving curative effect and increasing preparation stability. This paper summarizes several new technologies that are active in research and application at present.

First, ultra-fine grinding technology

The dissolution rate of effective components of traditional Chinese medicine is related to the degree of pulverization and bioavailability of drugs in vivo. The dissolution test of Panax notoginseng with different pulverization degrees in vitro was carried out. The results showed that within 45 minutes, the dissolution amount of Panax Notoginseng and total saponins of Panax Notoginseng were as follows: micropowder > micropowder; Fine powder > coarse powder > granules. In order to improve the crushing degree of traditional Chinese medicine, in recent years, the application of ultrafine grinding technology in traditional Chinese medicine crushing is increasing. With the application of modern ultra-micro processing technologies such as ultrasonic pulverization and ultra-low temperature pulverization, the central particle size of the original medicinal materials can be increased from 150 ~ 200 mesh powder (below 75 micron) to 5 ~ 10 micron. Under this fineness condition, the cell wall-breaking rate of general medicinal materials is ≥ 95%. The adoption of this new technology is not only suitable for all kinds of medicinal materials with different textures, but also can directly expose the effective components, so that the dissolution and action of medicinal materials are rapid and thorough.

There is no local overheating in the crushing process, and the crushing speed is fast, which retains the bioactive substances and various nutritional components in Chinese herbal medicines to a certain extent and improves the drug effect. For the crushing of some special medicinal materials, choose the appropriate method according to their service points. According to the different sources and properties of traditional Chinese medicine, the grinding methods can be used: single grinding, mixed grinding, dry grinding, wet grinding and so on. For some medicinal materials rich in sugar and with certain fluidity, traditional crushing methods such as cross-material method can be used; For medicinal materials with more fatty oil, the oil-stringing method can be used; For pearls, cinnabar, etc. , "water flying method" can be; For thermoplastic materials, methods such as low-temperature crushing can be used.

Second, the extraction technology

With the progress of science and technology, some new extraction methods, such as semi-bionic extraction, ultrasonic extraction, supercritical fluid extraction, cyclone extraction, pressurized countercurrent extraction, enzymatic extraction and microwave extraction, have been continuously applied to improve the quality of traditional Chinese medicine preparations.

Semi-bionic extraction method: From the perspective of biopharmaceutics, a new extraction process of traditional Chinese medicine preparation through gastrointestinal tract was designed by combining the whole drug research method with the molecular drug research method to simulate the environment of drug transportation after oral administration. That is to say, the powder is first extracted with acidic water with a certain pH value, and then extracted with alkaline water with a certain pH value. By combining one or more effective components with the main pharmacological indexes, the selection of technological parameters such as pH value of extracted water can be optimized by proportional division method. Taking paeoniflorin and glycyrrhetinic acid as indicators, the extraction rate of Shaogan Zhitong Granules by semi-bionic extraction method was compared with that by traditional decoction method. The results showed that the semi-bionic extraction method was better than the traditional decoction method. With berberine, baicalin and geniposide as indexes, four extraction methods of Hantongdingpao Tengchong agent were investigated. Results semi-bionic extraction method >: semi-bionic extraction and alcohol precipitation method >: water extraction method >: water extraction and alcohol precipitation method. The semi-bionic extraction method is generally only suitable for the extraction of water-soluble and polar effective components.

Ultrasonic extraction method: it is a kind of extraction method which uses ultrasonic wave to increase the movement frequency and speed of substance molecules, increase the penetration of solvents, improve the dissolution speed and times of drugs and shorten the extraction time. Baicalin was extracted from jujube by ultrasonic extraction, which improved the yield of baicalin. Ultrasonic wave is a kind of high-frequency mechanical wave. Ultrasonic waves with the frequency range of 15 ~ 60 kHz are often used to strengthen the process and initiate chemical reactions. The ultrasonic field mainly provides energy for the system through ultrasonic cavitation, and instantaneous cavitation can realize high temperature of 5000℃ and local high pressure of 50 MPa. Ultrasonic wave has been used to degrade organic matter and extract effective components from natural substances. Ultrasonic extraction is fast, and the yield may be much higher than Soxhlet extraction, which is selected as the method of sample processing in many Chinese medicine analysis processes. However, ultrasonic wave may have a certain destructive effect on the extract.

Supercritical fluid extraction (SFE) is a method to extract and separate the effective components of Chinese herbal medicine from liquid or solid by supercritical fluid. Supercritical CO2 extraction (SFE-CO2) is usually used. Its advantages are that the pressure range is 8-30 MPa and the temperature is 35-80℃. By adjusting the pressure and temperature, the density of supercritical CO2 can be changed, thus its solubility in substances can be changed, and some components in traditional Chinese medicine can be selectively extracted, so that the extraction and separation can be completed in one step. It can be extracted at room temperature and is suitable for the extraction of heat-sensitive components. Supercritical fluid has both high diffusivity of gas and good solubility of low viscosity liquid, which can prevent various components from escaping and oxidizing, and has the advantages of high efficiency and high speed. Supercritical extraction is usually carried out at a temperature slightly higher than the critical temperature of extractant. It is very simple and safe to separate products under reduced pressure. Volatile components or physiologically active substances in traditional Chinese medicine are rarely lost or destroyed, and there is no solvent residue, so the product quality is high. Supercritical fluid has been widely used in the production of spices and oils, and people have begun to pay attention to its application in drug extraction, such as the extraction of ginkgo flavonoids. SFE carbon dioxide technology also has some limitations. Generally speaking, it is more suitable for the extraction of lipophilic substances with small molecular weight. For glycosides, polysaccharides and other substances with large polarity and large molecular weight, it is difficult to industrialize by adding entrainers under high pressure.

Cyclone extraction method: using PT- 1 tissue mixer to stir, the stirring speed is 8000 rpm, and the raw materials need not be crushed in advance. The extraction water temperature is 20℃ and 100℃ respectively, and the treatment time is 20 ~ 30 minutes. A cyclone method (8000 rpm) was used to extract Adonis amurensis, and the flavonoids, saponins and organic acids in the extract were analyzed. The results showed that the extraction efficiency of cyclone method was improved.

Pressurized countercurrent extraction method: this method is a method that several extraction devices are connected in series, and the solvent and medicinal materials pass in countercurrent and keep a certain contact time. This method can increase the concentration of Rabdosia rubescens extract by 19 times, and reduce the solvent consumption and heat energy consumption by 40% and 57% respectively.

Enzymatic extraction: The impurities in traditional Chinese medicine preparations include starch, pectin, protein, etc. And corresponding enzymes can be selected to decompose and remove them. In view of the fact that the root contains many fat-soluble, water-insoluble or water-insoluble components, the fat-soluble or water-insoluble or water-insoluble effective components are converted into water-soluble glycosides by adding starch partial hydrolysate and grapefruit glucosidase or transglycosidase. Enzymatic reaction gently decomposes plant tissues, which can greatly improve efficiency. In China, Shanghai Chinese Medicine Factory successfully prepared Shengmaiyin oral liquid by enzymatic method.

Microwave extraction (MAE): Microwave is a kind of non-ionizing electromagnetic radiation, and polar molecules of irradiated substances quickly turn to directional arrangement in the microwave electromagnetic field, thus causing tearing and mutual friction to generate heat, and at the same time ensuring the rapid transfer and full utilization of energy. The study of microwave-assisted extraction shows that microwave radiation-induced extraction technology has the characteristics of high selectivity, short operation time, low solvent consumption and high yield of effective components, and has been applied to the extraction of organic pollutants, natural compounds and bioactive components. Pare et al. applied for the patent of microwave-assisted extraction of organic matter from materials. Using microwave transparent medium as coolant, the proposed organic matter can be quickly cooled and transferred to the main phase, so as to improve the extraction rate and reduce thermal damage. They extracted volatile oil from mint and onion in this way. Microwave can degrade some compounds to some extent, but some scholars think that microwave extraction time is very short, and its destructive effect may even be less than that of ordinary methods. Microwave extraction has been applied to the extraction of tanshinone, orange peel pectin and Paris polyphylla saponin.

Third, separation and purification technology

The separation and purification process includes selecting corresponding separation methods and conditions according to the properties of the crude extract to obtain the drug extract. Remove invalid and harmful components, and try to keep effective components or effective parts. Various purification, purification and refining methods can be adopted to provide qualified raw materials or semi-finished products for different types of new drugs and dosage forms, and provide indicators and basis for the formula of purified substances. In recent years, several new separation and purification methods have appeared, such as flocculation and precipitation, ultrafiltration, high-speed centrifugation, macroporous resin adsorption, molecular distillation and so on.

Flocculation precipitation method: It is a new technology to add flocculation precipitation agent to the suspended Chinese medicine extract or concentrated extract, and make it interact with protein pectin through adsorption bridging and electric neutralization, so as to make it settle and remove coarse particles in the solution, thus achieving the purpose of refining and improving the quality of finished products. There are many kinds of flocculants, such as tannin, gelatin, egg white, 10 1 juice clarifier, ZTC clarifier, chitosan and so on. The water extract of children's antiphlogistic and antipyretic agent was refined with tannic acid and gelatin. The finished product has good stability and clarity, and its clinical effect is better than that of the original decoction. Adding egg white flocculant to settle colloidal particles and macromolecular substances in medicinal liquor can reduce the appearance of sediment in medicinal liquor, thus improving the clarity of medicinal liquor. Yupingfeng oral liquid was clarified by 10 1 fruit juice clarifier. Compared with alcohol precipitation method, the total solid content of amino acids, polysaccharides and astragaloside IV is better than that of alcohol precipitation method, which reduces the production cost and cycle. ZTC clarifier was used in the preparation of Bazhen oral liquid, and compared with alcohol precipitation method. The results showed that the clarifier could well retain the index components of Chinese herbal medicine.

Ultrafiltration: It is a membrane separation technology. According to the size and properties of molecules in the system, separation can be carried out at the molecular level through membrane screening. Substances with molecular weight of 65,438+0,000 ~ 65,438+0,000,000 daltons can be separated and used for separation, purification, concentration or desalination. It is mainly used to produce injections with high clarity and high component purity, and can be used to filter out bacteria, particles and salts. Ultrafiltration is a simple process for preparing traditional Chinese medicine injections, which has the characteristics of improving the clarity of traditional Chinese medicine injections, removing impurities and pyrogens, retaining more effective components and partially decolorizing. The preparation processes of Acanthopanax senticosus injection, Salvia miltiorrhiza injection and Xiangdan injection can all be ultrafiltered.

High-speed centrifugation: it is a method that the centrifuge is the main equipment, and through the high-speed operation of the centrifuge, the centrifugal acceleration exceeds hundreds of times the gravitational acceleration, thus improving the settling speed and accelerating the precipitation and removal of impurities in the liquid medicine. Sedimentation centrifuge is time-saving and labor-saving, which has the characteristics of complete recovery of liquid medicine, high content of effective components and high clarity, and is more suitable for separating suspensions containing fine particles or flocs that are difficult to settle and filter. Compared with the water-alcohol method, the content of flavonoids in oral liquid was detected by high-speed centrifugation. The results show that the high-speed centrifugation method has the advantages of short process, low cost and less loss of effective components, and the content of flavonoids is obviously higher than that of water-alcohol method.

Molecular distillation method: In the separation process, the material is in a high vacuum and relatively low temperature environment, with short residence time and small loss. Therefore, molecular distillation technology is especially suitable for materials with high boiling point and low heat sensitivity, especially for separating natural products whose active ingredients are extremely sensitive to temperature, such as rose oil, agastache oil, eucalyptus oil and litsea cubeba oil.

Macroporous resin adsorption method: it is an organic polymer adsorbent developed in recent years, and the content of ginkgo flavone is more than 26%. In addition, macroporous adsorption resin can also be used for pre-separation of samples before content determination.

In the process of extraction and refining, more than two processes can be used together to achieve better results. After the liquid medicine was treated by ZTC clarifier, it was adsorbed and eluted by macroporous adsorption resin, and the Ginkgo biloba extract with stable quality was obtained, and the contents of flavonoids and lactones reached above 26% and 6% respectively. The macroporous resin adsorption combined with ultrafiltration technology was used to refine Liuwei Dihuang pills. The weight of the extract is only 46% of the original medicinal materials, while 98% of paeonol and 86% of loganin are retained. The preparation of Acorus calamus Yizhi oral liquid by adsorption clarification-high-speed centrifugation-microfiltration method can better remove impurities and selectively retain effective components, in which ginsenoside Rg 1 and total polysaccharide are improved compared with the alcohol precipitation process, which shortens the process cycle and realizes the continuous alcohol-free production of traditional Chinese medicine oral liquid.

Fourthly, concentration and drying technology.

Concentration and drying should optimize the methods and conditions according to the properties of materials and the factors affecting the concentration and drying effect, so as to achieve a certain relative density or water content. The rationality and feasibility of this process should be evaluated by the yield of concentration and drying and the content of index components. Spray drying: it is a method of drying liquid materials by fluidization technology. Because it is instantaneous drying, it is especially suitable for heat-sensitive materials. The obtained product has good quality, maintains the original color and fragrance, and is easy to dissolve. The preparation of microcapsules by spray drying is under way. Suspend the core material in the clothing solution and spray it into the hot air with a centrifugal sprayer. The obtained product is microcapsule wrapped in clothes. This microcapsule powder can not be directly pressed, but it can also be made into capsules, syrups or suspensions.

Freeze-drying: it is a method of freezing dry liquid materials into solids, and dehydrating the materials at low temperature under the condition of low temperature and reduced pressure by using the sublimation characteristics of water. Because the material is dried under high vacuum and low temperature, it is very suitable for drying some extremely heat-resistant articles. Wang Dalin reported a new technology of spray ventilation freeze-drying: using cold air or nitrogen as medium, making it flow quickly through frozen substances and sublime water. The product prepared by spray freeze-drying has the advantages of small particles, fast drying, short time, uniformity, good fluidity and good instant solubility. In recent years, great progress has been made in the study of drying paste materials and viscous materials. On this basis, fluidization technology, jet technology and inert carrier technology are developed. Rotary flash dryer, thermal jet air dryer and inert carrier dryer are all suitable for drying heat-sensitive materials and paste-like materials.