Chinese herbal medicine oral liquids belong to traditional Chinese medicine liquid formulations. They are prepared by extracting the active ingredients from Chinese medicinal materials, improving upon traditional Chinese medicine decoctions and mixtures, and appropriately adding taste modifiers, preservatives, etc. These liquids are filled (sealed) under certain conditions to create an oral dosage form. In recent years, due to their advantages of small dosage, good therapeutic effect, rapid absorption, and suitability for the elderly and children, they have been widely accepted and recognized by patients. The development and production of Chinese herbal medicine oral liquids have also accounted for an increasing proportion in the development of traditional Chinese medicine formulations.
However, as Chinese herbal medicine oral liquids are often composed of complex prescriptions, their components are diverse. Active ingredients such as saponins, alkaloids, flavonoids, polysaccharides, and mucilage in the liquids can cause turbidity and low clarity, seriously affecting their quality. The pH value and relative density of Chinese herbal medicine oral liquids are closely related to clarity. Generally, when the pH value of the oral liquid is around 4.5, its appearance quality and taste are both good. The relative density of the oral liquid should mostly be between 1.03 and 1.20 (at 25°C). When it is greater than 1.20, the oral liquid tends to be thick and sticky, with obvious wall-clinging.
Apart from pH value and relative density, factors such as temperature, oxidation degree, solvent type, impurities in the oral liquid, metal ions, the instability of active ingredients, as well as the composition of the prescription and the preparation process, can also affect the clarity of Chinese herbal medicine oral liquids. Therefore, it is particularly important to select suitable purification processes for different Chinese herbal medicine oral liquids to improve their clarity.
Common Clarification Processes Used in Chinese Herbal Medicine Oral Liquids
1.Ethanol Sedimentation Process
Ethanol, as a commonly used clarifying agent, has advantages such as a wide range of solubility, economic availability, and safe usage. Moreover, ethanol can be mixed with water in any proportion, and in the production of formulations, it is often utilized to remove impurities through the use of different volume fractions of ethanol. The water-ethanol method is suitable for the refinement of Chinese herbal medicine concentrated liquids that contain high levels of ingredients such as sugars, polysaccharides, alkaloid salts, organic acid salts, tannins, pigments, gelatinized starch, proteins, mucilage, and resins. When the volume fraction of ethanol in the medicinal liquid reaches 50% to 60%, impurities such as starch can be removed. When the volume fraction of ethanol reaches 60%, inorganic salts in the medicinal liquid can be precipitated. And when the volume fraction of ethanol reaches 80%, besides tannins and water-soluble pigments, other impurities such as proteins, polysaccharides, and starches can also be removed.
In practical applications, due to the broad range of ethanol precipitation, it has poor selectivity for medicinal ingredients, often removing some active ingredients such as polysaccharides as impurities, thereby affecting the therapeutic effect. Therefore, selecting the appropriate volume fraction of ethanol and ethanol precipitation process parameters plays a crucial role in retaining active ingredients and achieving clarification effects in the medicinal liquid. To achieve both "purification" and retention of more active ingredients in the oral liquid, the following points should be noted for the ethanol precipitation process: ① Selection of ethanol concentration; ② Selection of the amount of ethanol used; ③ Adjustment of the relative density of the concentrated liquid, generally 1.20 to 1.25 g/mL is preferred; ④ During the ethanol precipitation operation, moderately concentrated ethanol should be added to the concentrated liquid cooled to room temperature, stirring continuously while adding, so that the ethanol content in the medicinal liquid gradually increases from low to high, and the medicinal liquid is fully and evenly "mixed" with ethanol.
2.Adsorption Clarification Process
The adsorption clarification method involves adding an adsorbent clarifying agent to traditional Chinese medicine decoctions or oral liquids. It removes macromolecular substances from the solution through adsorption while retaining most effective macromolecular substances such as polysaccharides, thus achieving the purpose of purification and improving the clarity of the preparation. Currently, commonly used adsorbent clarifying agents include ZTC1+1 natural clarifying agent, chitosan clarifying agent, gelatin, and 101 fruit juice clarifying agent.
① ZTC1+1 natural clarifying agent is a natural high-molecular-weight substance extracted from food, mainly composed of natural polysaccharides. It belongs to the category of adsorbent clarifying agents and consists of two components, A and B. Component A is a light yellow powder that is prepared into a solution with a mass concentration of 10 g·L-1 using deionized water. Component B is a light yellow or white powder that is prepared into a solution with a mass concentration of 10 g·L-1 using a 10 g·L-1 acetic acid solution. Adopting the "1+1" clarification technology, one component plays the main flocculating role, while the other component acts as an auxiliary flocculating agent through "bridging" to accelerate the clarification process. Research has shown that ZTC1+1 natural clarifying agent primarily removes impurities such as tannins, proteins, resins, and waxes from the medicinal liquid. Its first-step impurity removal rate is around 70%, and the second-step impurity removal rate exceeds 90%. Additionally, it has no impact on the active ingredients in traditional Chinese medicine, including flavonoids, alkaloids, glycosides, polysaccharides, amino acids, vitamins, and minerals.
② Chitosan clarifying agent and clarification process. Chitosan is a sugar or fiber isolated from the outer layer of crustacean skeletons such as crabs and shrimp. It is the only alkaline polysaccharide among natural polysaccharides. It forms crystalline regions through the interaction of numerous hydrogen bonds and amino groups on the molecular chain, resulting in excellent flocculation effects. It is non-toxic, tasteless, biodegradable, and has antibacterial properties. Additionally, chitosan, as an excellent clarifying agent, has the following advantages: It has a good clarification effect on traditional Chinese medicine oral liquids and can retain active ingredients in the oral liquids. Compared to other clarifying agents, chitosan has a shorter flocculation time, reducing the experimental duration, and has the significant advantage of adsorbing and assisting in the excretion of heavy metals from traditional Chinese medicine oral liquids.
③ Gelatin clarifying agent and clarification process. Gelatin clarifying agent is a water-soluble high-molecular-weight polymer with excellent flocculation properties. Its main characteristic is that in the glue solution, it can cause suspended substances to flocculate through charge neutralization and bridging adsorption, forming a clarifying agent with high molecular weight and ionic concentration in highly concentrated glue solutions. Research reports indicate that gelatin clarifying agent is not only used in the clarification process of medicinal liquids, but also in the production of products such as fruit juice, wine, and beer.
The clarification agent purification process has demonstrated promising applications in the clarification of traditional Chinese medicine oral liquids, and is expected to gradually replace the alcohol precipitation process and become a widely promoted purification process. However, current research on natural clarifying agents is not sufficient, and their application in traditional Chinese medicine oral liquids still has significant limitations. Additionally, factors such as the concentration ratio of traditional Chinese medicine liquid, the dosage of clarifying agent, flocculation temperature, stirring speed, and pH value have a significant impact on the effectiveness of the clarifying agent. Therefore, when applying the clarification agent purification process to remove impurities from oral liquids, it is necessary to optimize the process parameters through experiments.
3. Centrifugal Clarification Process
The centrifugal method utilizes a centrifuge as the primary equipment. By rapidly rotating the centrifuge, the centrifugal acceleration exceeds the gravitational acceleration by hundreds or even thousands of times, thereby increasing the sedimentation speed and accelerating the precipitation and removal of impurities in the medicinal liquid. The main types of centrifuges include sedimentation centrifuges, tubular centrifuges, disc centrifuges, filter centrifuges, pedestal centrifuges, horizontal scraper centrifuges, and piston pusher centrifuges. The application of the centrifugal method to oral liquids has gradually gained popularity due to its advantages such as continuous production, short process flow, low cost, minimal loss of active ingredients, complete impurity removal, and product stability. A comparison between the high-speed centrifugal method and the water precipitation method for preparing the heat-clearing and detoxifying oral liquid showed that the high-speed centrifugal method has a shorter process flow, lower cost, less loss of active ingredients, a deeper and clearer color of the finished product, and significantly higher flavonoid content compared to the water-alcohol method. However, due to the simplicity of the centrifugal method, it is not effective in removing components such as polysaccharides and mucilage. Additionally, factors like rotational speed, temperature, and centrifugation time need further investigation. Therefore, the use of the centrifugal method alone for impurity removal in the purification process of oral liquids is relatively rare, and it is more common to combine the centrifugal method with alcohol precipitation or clarification agent purification processes.
4. Membrane Separation Clarification Process
Membrane separation refers to a method of selective separation of mixtures of molecules with different particle sizes at the molecular level when passing through a semipermeable membrane. It utilizes a filter membrane as the filtering medium, relying on a certain pressure and flow rate at room temperature to allow the medicinal liquid to flow through the membrane surface, forcing low-molecular-weight substances to pass through the membrane while retaining high-molecular-weight impurities. The semipermeable membrane, also known as a separation membrane or filter membrane, is covered with small pores and can be classified into microfiltration membranes (MF), ultrafiltration membranes (UF), nanofiltration membranes (NF), reverse osmosis membranes (RO), etc., based on the pore size.
Although the application of membrane separation technology in the field of traditional Chinese medicine is still in its infancy, due to its advantages, more and more researchers in traditional Chinese medicine are dedicated to developing the application of membrane technology in the traditional Chinese medicine industry. Currently, in the traditional Chinese medicine oral liquid industry, with the proposal of China's strategy for modernizing traditional Chinese medicine, there are many reports on membrane separation technology, but few have been successfully applied to actual production. The main issues are the complex composition of traditional Chinese medicine oral liquids, which can easily lead to membrane clogging, low flux, significant loss of active ingredients, and short service life. Therefore, when applying membrane separation technology to the impurity removal process of traditional Chinese medicine oral liquids, a large number of parameters need to be considered. Firstly, the traditional Chinese medicine liquid must be pretreated before membrane separation. Secondly, an appropriate type of separation membrane should be selected. Thirdly, the membrane separation operating parameters, including operating pressure, feed flow rate, and medicinal liquid temperature, should be investigated. Finally, to avoid continuous decline in membrane flux during actual operation, the membrane should be cleaned in due time to extend its service life and improve membrane filtration efficiency. Compared with traditional impurity removal processes, the use of membrane separation technology can avoid issues such as large consumption of organic solvents, severe pollution, and low impurity removal rate. Therefore, the application of membrane separation technology to large-scale production of traditional Chinese medicine oral liquids has potential significance.
Clarity is an important quality control index for oral liquids, reflecting the stability of the product and posing a crucial issue in the preparation process of oral liquids. Oral liquids with good clarity generally have superior internal quality. To better control the quality of traditional Chinese medicine (TCM) oral liquids, it is necessary to improve the clarity during the preparation process. TCM oral liquids contain both fully dissolved small-molecule compounds with strong polarity and macromolecular compounds, as well as a large amount of lipid-soluble compounds with small polarity that are difficult to dissolve or insoluble in water. Additionally, they contain numerous molecular clusters and microparticles. Therefore, maintaining good clarity in oral liquids is not an easy task. Applying the aforementioned purification processes selectively to the preparation of TCM oral liquids can not only enhance the clarity and stability of the oral liquids, but also provide new research ideas and methods for maximizing the retention of active ingredients. Therefore, research on improving the clarity of TCM oral liquids is of significant practical importance for the rapid development of TCM oral liquids.
References
[1] Wang Feng, Li Kefan, Ding Wen, Li Xiaolan, Lian Yunlan, Pei Xiangping. Research progress on clarifying agents and clarifying processes for traditional Chinese medicine oral liquids [J]. Northwest Pharmaceutical Journal, 2022, 37 (05): 182-185
[2] Jin Guotai, Li Bo, Dai Long. Research progress on improving the clarity of traditional Chinese medicine oral liquids [J]. Journal of Liaoning University of Traditional Chinese Medicine, 2013, 15 (12): 245-247About the
About the Author
Xiaomichong, a pharmaceutical quality researcher, has been committed to pharmaceutical quality research and drug analysis method validation for a long time. Currently employed by a large domestic pharmaceutical research and development company, she is engaged in drug inspection and analysis as well as method validation.
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