Abstract: Dry granulation is widely used in Chinese medicine solid preparations, and is an indispensable key operation link in the production process of many Chinese medicine solid preparations. Dry granulation technology has been widely used in recent years because it reduces the process, makes the process simple and properly controlled, and can effectively ensure the quality of traditional Chinese medicine. By reading the relevant references, this paper first briefly describes the development status of dry granulation technology; Then, the general process, advantages, classification and mechanism of dry granulation are described. Thirdly, the factors affecting dry granulation are analyzed, and the existing problems are pointed out. Finally, the dry granulation technology is summarized and prospected.
Keywords: dry granulation; Craft; heavy pressure method; Rolling method
1 Preface
Compared with wet granulation, dry granulation can save the process of making soft materials, drying and granulation, which can avoid the influence of moist heat on the chemical composition of medicine, simplify the process, reduce the amount of adhesive, high efficiency and energy saving. Dry granulation is a method of mixing drug extract with excipients evenly, extruding it into thin sheets by heavy pressure or an empress, and then grinding and sieving to make a predetermined size of granules. This method is to produce binding force between particles by compressive force, and its preparation methods include heavy pressure method and rolling method [1-2].
According to statistics, 85% of pharmaceutical companies in the foreign solid preparation industry use dry granulation [3]. At present, the granulation technology of traditional Chinese medicine in mainland China is mainly based on swing extrusion granulation and fluidization spray granulation, and the research on dry granulation is late, and there are limitations such as sticky wheel and low primary molding rate, which limit its development and application. In recent years, with the deepening of research, dry granulation technology has made certain progress in the field of proprietary Chinese medicine. In order to better promote the application of dry granulation, a green granulation technology, in the Chinese medicine industry, this paper reviews the research on dry granulation process of traditional Chinese medicine in recent years, in order to provide reference for the promotion of dry granulation process of traditional Chinese medicine.
2 Development status of dry granulation
Dry granulation technology originated at the end of the 19th century, and was applied and matured in the pharmaceutical food and chemical industries in Japan, the United States, Germany and other countries [4], but the research on dry granulation technology in the mainland started relatively late, starting from the 40s of the 20th century. At present, the technical level of dry granulation still needs to be improved, on the one hand, due to the high viscosity of Chinese medicine extract powder, it is easy to lead to the phenomenon of sticky wheels, which reduces production efficiency; On the other hand, the stability of domestic dry granulator equipment is poor compared with foreign equipment, and some have drawbacks such as powder leakage and low particle yield. Therefore, to a certain extent, the wide application and development of dry granulation technology is limited [5].
3 General process flow of dry granulation
Dry granulation refers to the method of directly pressing herbal powder, traditional Chinese medicine extract powder or mixed powder with auxiliary materials into large pieces or strip sheets under the condition of no or less liquid adhesive, and then crushing the whole grain into granules. Because there is no need to add solvent stirring to make soft materials, granulation, drying and other processes, compared with wet granulation, dry granulation has the characteristics of green and energy-saving, and its general process flow is shown in Figure 1 [6].
Figure 1 General process flow chart of dry granulation[6]
4Advantages of dry granulation[12]
Compared with wet granulation, dry granulation has less equipment, low maintenance cost and less floor space, so the production cost is low; The process is simple and there are few intermediate links, which can not only control the dust flying but also reduce powder waste, while there is no exhaust gas emission and reduce environmental pollution. The biggest advantage of dry granulation is low energy consumption, because dry granulation does not need to be humidified and then dried; Dry granulation without adding any binder; Some drugs (antibiotics, strong heat sensitivity) and traditional Chinese medicine extracts cannot meet the requirements, and can not add adhesives, must be completed by dry granulation process; After dry granulation, the finished product has uniform particle size, increased bulk density, improved fluidity and controllable disintegration, and is convenient for post-processing, storage and transportation.
5Classification and mechanism of dry granulation[6]
According to different pressing methods, dry granulation is divided into heavy pressure method (also known as large sheet method) and rolling method. The dry pressing process generally has 4 steps: 1) particle rearrangement, during which the air overflows, and the particles are further close to each other; 2) Particle deformation, under the further action of pressure, the particles are deformed, and the contact surface between the particles is further increased; 3) particle rupture, on the basis of deformation, particle rupture produces multiple new surface points and potential bonding points; 4) The particles are combined, the pressure is further increased, the particles undergo plastic deformation, relying on the mechanical force between the particles, the interaction force between molecules, such as van der Waals force and the action of the liquid surface film, the particles are bonded, forming large flakes [7-8].
5.1 Dry granulation by heavy pressure method
Heavy pressure dry granulation, also known as tablet pressing granulation, is to mix raw materials and auxiliary materials and press them into large pieces by the tablet press, and then crush and screen to obtain particles of the required size. A brief schematic of its preparation is shown in Figure 2. The heavy pressure dry tablet pressing process is divided into filling, compaction and film arrangement. The efficiency of this method is low and lubricants are generally required. The influencing factors of heavy pressure method are mainly heavy pressure pressure, crushing speed and granulation speed. If the pressure is too large, it will lead to high tablet hardness, incomplete crushing and low yield. At present, there are few related technologies for dry granulation by heavy pressure method. [5,9]
Fig.2 Brief flow chart of dry granulation by heavy pressure method[9]
5.2 Dry granulation by rolling method[5,9]
Dry granulation by rolling method is to mix the material powder evenly, use a roller to extrude into a strip sheet of suitable hardness, and then crush and screen to make the required size particles. A brief schematic of its preparation is shown in Figure 3. Compared with the heavy pressure method, the rolling method has the advantages of large production capacity and small amount of lubricant, so the rolling method is a commonly used method for dry granulation. According to the different feeding methods, the dry granulation by rolling method is divided into vertical feeding rolling method and horizontal feeding rolling method. The rolling method can control the mass of particles by adjusting parameters such as feeding speed, roller speed, and roller pressure.
Fig.3 Brief flow chart of dry granulation by rolling method[9]
The rolling dry granulation process is generally divided into feeding module, extrusion module and granulation module. The feeding system can use its own gravity for materials with good fluidity; Poor fluidity can be achieved by mechanical external forces, such as vacuum feeding. The extrusion module is the core module of the dry granulation process by rolling method by pressing the solid powder to form a sheet by extruding each other between the two rollers, of which the roller pressure and roller speed are the main factors affecting the quality. The design of the roller has differences in roller orientation, installation, configuration and pressurization system, such as roller configuration corresponding to vertical, horizontal and inclined three types, according to the nature of the material powder, the surface of the roller can also be changed accordingly, such as smooth type, wave type and groove type. The roller speed is mainly used to control the holding time of the roller to the material, in which the physical properties such as fluidity and plasticity of solid materials are the key parameters for selecting the roller speed.
6 influencing factors of dry granulation
6.1 Physical properties of preparation raw materials
The physical properties of the preparation raw materials have an important influence on the dry granulation. Some preparation raw materials use dry granulation effect is not good, or even dry granulation. For example, the active ingredients are polysaccharides and saponins of the preparation raw materials, which will adhere to the roller during the dry granulation process. The physical properties of the preparation raw materials directly determine whether the drug can be dry granulated and the quality of the prepared granules. The physical properties of the preparation raw materials mainly include particle size and particle size distribution, water content, fluidity, compressibility, viscosity and other properties [10].
6.2 Usage and ratio of auxiliary materials
The biggest defect of dry granulation is that the particle yield is not high, generally need to be extruded many times, the production efficiency is low, and the granules prepared have high hardness and long melting time. This greatly limits the scope of use of dry granulation. Studies have found that the addition of one excipients or a combination of excipients can achieve good results [11]. On the one hand, dry granulation requires good fluidity; On the other hand, it must be compressible and not easy to absorb moisture. It is manifested in: (1) magnesium stearate can be added before granulation when sticking the roller; If it absorbs moisture, you can add micronized silica gel and so on. (2) The combination of dextrin and lactose, in the same drug, the granulation is not smooth when dextrin is used alone, and the solubility and taste of the drug are poor; When lactose is used alone, the machine is easy to stick and cannot be granulated; Lactose and dextrin are used in a ratio of 2:3, the granulation is smooth, and the water solubility and taste of the prepared medicine are good [5].
6.3 Process parameters
Since the water content, fluidity, compressibility, viscosity, etc. of different raw materials are different, it is necessary to set appropriate process parameters according to the needs of materials. Setting the operating process parameters of the equipment has an important influence on whether the pellets can be produced and the quality of the pellets.
(1) Feeding speed. If the feeding speed is too fast, it will lead to the phenomenon of blockage of the feeding material. In the case of constant roller speed and roller pressure, the difference in feeding speed will also affect the particle yield. For example, Cao Hanhan et al. [10] under the condition that the rolling wheel speed and roller pressure remain unchanged, with the increase of horizontal feeding speed, the particle yield has an upward trend, and the particle brittleness has a downward trend.
(2) Roller speed. The speed of the roller is too slow, the longer the material stays in the rolling area, and the less air contained in the material is discharged. The roller speed is too large, the material pressure time is short, the plastic deformation of the powder particles is reduced, and the particle structure is loose, resulting in a decrease in particle yield [5].
(3) Roller pressure. The roller pressure has different effects on the hardness of the strip pressed by the Chinese medicine extract powder, the yield and brittleness of the particles. Different material characteristics require different roller pressure, therefore, by reasonably adjusting the pressure, the material is more stable and can effectively improve the dry granulation effect [1].
7Practical problems faced[5]
Due to the complexity of the properties of traditional Chinese medicine and the defects of dry granulation equipment, there are still some problems in actual production, such as: the yield of dry granulation is not high at one time, and there are more fine powders after crushing; Since most Chinese medicine extract powders have strong viscosity, the phenomenon of sticky wheels often occurs; Pressed strip layering; poor fluidity of powder; unstable pressure, etc.
8 Epilogue
The dry granulation process relies on the crystalline water of the material itself, and uses the principle of mechanical extrusion and crushing to directly granulate without adding adhesive. Dry granulation from equipment input to product output, whether it is cost, energy consumption is much lower than wet granulation, has an irreplaceable position [12]. In order to improve the level of dry granulation technology, it is necessary to deepen the understanding of the preparation process, strengthen process quality testing, and continuously optimize the process and equipment to ensure product quality. The dry granulation process is simple and easy to operate, and can fully realize the automation of production, but there are still many problems in the current dry granulation technology, we should fully learn from foreign dry granulation technology, continue to learn and absorb advanced experience to improve the level of domestic dry granulation technology of traditional Chinese medicine, and promote the rapid development of the modernization of traditional Chinese medicine preparations [5].
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