Tablets are currently one of the most widely used dosage forms, with the largest output and the most widely used. The traditional wet granulation process is still the mainstream process in the production of pharmaceuticals. It has mature production processes, good particle quality, high production efficiency, and compression molding. Good and other advantages, it is the most widely used in the pharmaceutical industry.
The manufacturing process of tablets can generally be divided into the processing of raw and auxiliary materials, weighing, granulating, drying, mixing, tableting, coating, etc. There is a saying in the industry: granulation is the leader, tableting is the core, and packaging is Phoenix tail, it can be seen that the granulation process plays a pivotal role in the entire tablet production, but how to make soft materials and obtain granules, so far there is only a very deep meaning in the textbooks “holding into a ball, touching and dispersing” , Has not been elaborated. Based on the author’s personal experience in actual production, this article analyzes several common factors affecting the stability of the tablet wet granulation process, and proposes relevant control measures to ensure the quality of drug production.
Pretreatment of raw materials
The raw and auxiliary materials generally need to be crushed and screened before wet mixing and granulation production. Some unqualified phenomena that often occur in the process of tableting, such as uneven mixing, splitting, sticking or dissolution, etc., are closely related to the insufficient pulverization fineness of the raw materials during pretreatment. If the raw materials are scaly or needle-shaped crystals, the possibility of the above deviations will be more obvious. The screen for pretreatment, crushing and sieving in the traditional process is generally 80 mesh or 100 mesh screen, but with the advancement of equipment and raw material technology, most of the raw materials that have been crushed through the 80 mesh screen in the traditional process can now exceed 100. The probability of the above phenomenon is greatly reduced for the fine powder that has been crushed through the 100-mesh sieve. Therefore, the fineness of the raw and auxiliary materials through the 100-mesh sieve is gradually replacing the 80-mesh sieving process.
Because the increase or decrease of the weight of each material will cause the subsequent changes in other process conditions, which will cause the instability of the particle quality, which may cause a series of problems such as tablet chipping, excessive friability, slow disintegration or reduced dissolution, so every time you feed The amount cannot be adjusted arbitrarily. In case of special circumstances, the weighing weight should be confirmed according to the process verification.
Preparation of particles
Nowadays, high-speed wet mixing granulator is the most commonly used equipment in granulation production. Compared with the traditional mixer and granulator, this kind of granulator is in fact because of the problem of variety prescription or the pursuit of high quality. Therefore, the granulator is not eliminated, and the high-speed wet mixing granulator is only used as a traditional mixer, and then more uniform granules are obtained through granulation. The process conditions that affect the quality of wet granules mainly include many factors such as the temperature, dosage, adding method of the binder, the stirring and cutting speed of the granulator, and the stirring and cutting time.
The temperature of the adhesive
The temperature of the adhesive is the most difficult index parameter to control in the scale-up production. It is almost impossible to accurately control the consistency of the temperature before adding the adhesive every time. Therefore, most varieties will not use temperature as the control index, but in actual production, it is found that the starch slurry temperature does have a greater impact on some special varieties. For these varieties, the temperature needs to be clearly required. Under normal circumstances, the temperature is higher. The higher the low adhesion, the lower the friability of the tablet; the higher the starch slurry temperature, the lower the adhesion, and the higher the dissolution of the tablet. Therefore, in some processes that use starch slurry as a binder, the temperature of the binder should be controlled to a certain extent.
The amount of adhesive
The amount of binder has the most obvious effect on wet particles, so its amount is also used as an important control parameter. Generally, the larger the amount of binder, the higher the particle density and hardness, but the amount of binder often varies with the batch of raw and auxiliary materials. There will also be slight changes in the differences between different varieties, which need to be accumulated in the long-term production process according to different varieties. For adjusting the tightness of soft materials, within a reasonable range, the method of increasing the amount of binder is better than the method of increasing the mixing time.
Concentration of adhesive
Generally, the greater the adhesive concentration, the greater the viscosity, which is inseparable from its dosage. Most manufacturers will not choose to adjust the concentration when obtaining the adhesive concentration after verification, but control the soft material by adjusting the amount of the adhesive, usually bonding The concentration of the agent will be written as a fixed value in the process specification and will not be used to adjust the quality of the wet particles, so I won’t repeat it here.
How to add adhesive
Use high-speed wet mixing granulation machine to granulate. Generally, there are two ways to add the binder. One is to stop the machine, open the cover of the granulator, and pour the binder directly. In this way, the binder is not easy to disperse, and the granulation is Sometimes it is easy to cause high local concentration and uneven particle tightness. The consequence is that the extruded tablets disintegrate or dissolve a large difference; the other is the non-stop state, using the binder feeding hopper, opening the feeding valve, and stirring. Adding in the process, this feeding method can avoid local unevenness and make the particles more uniform. However, due to the requirements for the type of binder, equipment design or operating habits, etc., it limits the use of the second slurrying method in production. use.
The choice of mixing speed and chopping speed
The formability of the soft material during granulation is directly related to the selection of the stirring and chopping speed of the high-speed mixing granulator, which has a greater impact on the quality of the pellets, and directly affects the quality of the extruded tablets. At present, the stirring motor of the high-speed wet mixing granulator has two speeds and variable frequency speed regulation. The double speed is divided into low speed and high speed. The frequency conversion speed control uses manual speed control, but manual speed control will affect the particles to a certain extent. Therefore, the high-speed mixing granulator with frequency conversion speed regulation generally sets the mixing speed and running time, and starts the automatic operation program to reduce the human difference. For individual varieties, the frequency conversion is actually still used as a two-speed, but for some special varieties, running the same time, you can increase the speed to obtain a moderate soft material, so as to avoid long-term mixing caused by the soft material too much tight.
The choice of mixing and shredding time
A process parameter that affects the quality of soft materials is the time of mixing and shredding. The setting of its parameters directly determines the success or failure of the granulation process. Although the mixing speed and shredding speed can be adjusted by frequency conversion, most of the process options are fixed In order to reduce the difference, in order to obtain a more suitable soft material, choose to obtain a suitable soft material by adjusting the time. Under normal circumstances, short mixing and shredding time will reduce the density, hardness, and uniformity of the particles, and cracks and unqualified uniformity during tableting; too long mixing and shredding time will cause the density and hardness of the particles If it is increased, the soft material may fail during tablet compression, the disintegration time of the tablet will be prolonged, and the dissolution rate will be unqualified.
Granulation equipment and granulation techniques
At present, the selection of granulating equipment for wet granulation is divided into multi-function granulator and swing granulator. The advantages of multi-function granulator are high efficiency and easy operation and use. The disadvantage is the difference in the amount and speed of feeding due to manual feeding. , The uniformity of the particles is slightly worse; the advantage of the swing type granulator is that the granules are relatively uniform, and the difference in the manual feeding amount and feeding speed is relatively small. The disadvantage is that the efficiency is low and the use of disposable screens is used for dismantling. Installation is relatively inconvenient. Uneven particle size can easily cause the difference to exceed the limit. The mesh number and speed of the whole particle screen can be controlled to improve. Generally, if the wet particles are tight, you can consider increasing the speed, choosing a larger screen, and reducing the amount of feed each time. If the particles are loose, you can consider reducing the speed, choosing a smaller screen, and increasing the amount of feed each time. In addition, in the selection of screens, there are often stainless steel screens and nylon screens to choose from. According to production experience and soft material properties, it is better to choose stainless steel screens for viscous soft materials, and dry soft materials. Nylon screen is more suitable, and the swing type granulator can also consider the tightness of the screen installation to adjust to obtain suitable particles.` `
The intuitive embodiment of the drying effect is the particle moisture. The particle moisture is an important evaluation factor for the quality of the particles. The reasonable control of this parameter directly affects the appearance and friability of the tablet during tableting. Under normal circumstances, the occurrence of chipping during tableting can be considered whether it is caused by low particle moisture, and if sticking occurs during tableting, it is necessary to consider whether it is caused by high particle moisture. The control index of particle moisture is generally determined initially through process verification, but the moisture is often difficult to reproduce, and it is necessary to collect data and formulate the moisture control range. Most of the traditional drying methods use boiling drying. The influencing factors include process parameters such as steam pressure, drying temperature, drying time, and the weight of dried particles. The moisture of the particles is controlled by a rapid moisture analyzer. A skilled operator can go through a long period of time. In production practice, the moisture content of each drying material is controlled within the ideal range, which can effectively improve production efficiency and can better control moisture. In addition to long-term experience, the core data source and drying time and dried materials temperature.
Whole granulation of dry granules
The same as wet granulation is that the process parameters that affect the quality of dry granules are generally the mesh number and speed of the whole granulation screen. In order to ensure the smooth production during tableting, obtain the most suitable particle size distribution. This is the last opportunity for adjustment. , By choosing different meshes and rotating speeds, it will have a significant impact on the dried particles. In general, when the particles are tight, choose a smaller screen, and when the particles are loose, choose a larger screen. However, under normal circumstances, this will not be a choice for a mature process. If you want to obtain better particles, you still need to study and improve the process of preparing soft materials.
The mixing process parameters that affect the particle quality are generally the amount of the mixture, the speed of the mixer, and the mixing time. The amount of the mixture is a fixed value after the process verification is confirmed. The speed of the mixer may be affected by the drift of the mixer speed due to the wear of the equipment. The uniformity of mixing requires equipment spot inspection and periodic confirmation of equipment before production. In order to ensure the uniformity of particle mixing to the greatest extent and obtain uniform quality products, it is necessary to obtain mixing time through process verification. Sufficient mixing time is an effective guarantee to ensure the degree of dispersion of the lubricant in the dry particles, otherwise the lubricant will form electrostatic adsorption groups during the mixing of the dry particles, which will affect the quality of the particles.
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Post time: Apr-20-2021