Pharmaceutical industry drying technology development process
I. Overview
1. Drying methods for various types of medicines
Drugs can be broadly divided into Western medicines and pharmaceuticals, including sterile drugs and non-sterile drugs. Another Chinese medicine, biological agents and so on. The raw material medicine is the basic raw material of the medicine, most of which are crystalline type. The wet material is a crystalline powdery granular solid that is filtered or separated. According to the characteristics and requirements of the material, an appropriate drying method is used to obtain a dried product. In the early days, more and more dry boxes were used. In the past 20 years, they have gradually been replaced by various kinds of more advanced drying devices. The most widely used ones are double cone rotary dryers, vacuum vibrating dryers, multi-functional dryers, and some direct ones. Heated drying equipment. The other part of the drug substance is an aqueous solution, and the dry product is directly obtained by spray drying, such as streptomycin, gentamycin and the like. An aqueous solution requiring low temperature drying is freeze-dried.
Formulation drugs are finished drugs. One is the bulk drug made of injections, is a sterile drug. The other is that raw material medicines and auxiliary materials are mixed into capsules or mixed into small granules and then compressed into tablets. The oral medicine is usually a sterile medicine. Granulation is an important process in the production of pharmaceuticals. Early operations are accomplished by mixing, kneading, granulating, and drying multiple units of equipment. In recent years, boiling granulation, spray granulation, and other methods have been used. Primary and auxiliary materials can be mixed and granulated at one time. Drying, also known as one-step granulation drying.
Traditional Chinese medicines are usually blocky, flaked, or made from decoction pieces. Special performance, such as particles (pieces, tablets, pills) large, containing sugar, viscosity, heat, etc., and some also require temperature change process, to determine the drying process and equipment selection difficulties. At present, more fluidized drying and improved vibrated fluidized bed, spray drying, etc. are used.
Biological products have strict temperature limits, and most require instantaneous drying, such as microwave drying, fluidized drying, and freeze drying.
2. Requirements for drying equipment in the pharmaceutical industry
Pharmaceutical drying equipment not only has to meet the requirements of chemical equipment strength, precision, surface roughness and operational reliability, but also needs to be detachable from the structural considerations, easy to clean, no dead ends, to avoid contaminants infiltration. Designed to eliminate difficult to clean and check the site, using a reliable seal. The inner surface of the device is manufactured with a high degree of finish, there is no recess structure, and all corners have a smooth transition. A qualified drying equipment not only meets the drying operation requirements, but also meets the GMP (Pharmaceutical Hygienic Quality Management) requirements, and has the functions of in-situ cleaning (CIP) and in-situ sterilization (SIP), so that the equipment does not need to be moved. And disassembly can be effectively cleaned and cleaned after sterilization.
Second, the development of drying equipment used in the pharmaceutical industry
1. Dry box
Box drying is the oldest and simplest drying method. Heating pipes are arranged on both sides of the box, and the trays are placed on shelves in the boxes, or directly on the racks made of steam exhaust pipes. Vent holes are provided at the top or exhaust fans are used to discharge moisture. The vacuum drying box connects the box with the condenser and the vacuum pump. The system is sealed and the discharged solvent vapor is withdrawn through the condenser.
In 1978, the original Jiangsu Wujin Drying Equipment Factory first manufactured a hot air circulation drying oven. The horizontally flowing hot air conducts heat to the material, and the hot air circulation is driven by the fan and replenish fresh air and exhaust gas. In 2001, Changzhou Fanqun Drying Equipment Factory manufactured a special oven for medicines, improved the structure of the old oven, and added a filter in the hot air circulation system to make the hot air entering the box reach the required cleanliness.
The drying oven has a wide applicability and is generally applicable to flammable, fragile, viscous, thixotropic or creamy materials. The disadvantage is that because the material is standing, the drying time is long, the efficiency is low, the manual loading and the drying process need to be turned several times, the dust is large, the pollution is easy, the labor intensity is high, the energy consumption is large, and the thermal energy utilization rate is not more than 40%. .
2. Air dryer
The air dryer is a high-speed hot air flow that fully mixes and disperses the wet material to make it instantaneously dry. The drying time is only a few seconds to several seconds. The process flow is shown in Figure 1. In order to improve the efficiency, the drying tube is made into a pulse tube of unequal diameter, which is called pulse air drying. A cyclone dryer was added to the process to extend the residence time of the material, and the cyclone airflow was dried. Viscous or massive materials can be installed in front of the gas flow tube to install a crushing device, and the material can be broken while drying. The air drying equipment has a simple structure, can operate continuously, has a high drying efficiency, and has a dispersing effect on loose bulk materials, but is not suitable for products requiring crystal integrity.
Airflow drying was used earlier. In the sixties and seventies, it was used for the drying of drugs such as oxytetracycline, chloramphenicol, and pyrazolone. However, there was no specification equipment available, and most of them were technological transformation achievements of various pharmaceutical companies. In recent years, the production of drugs has grown to a large scale, and intermittent batch operations of small batches have been unable to meet production needs. In addition, the perfection of ancillary equipment to ensure the air drying environment requirements, this direct heating of the drying method is simple and efficient and continuous production, and re-emphasized.
3. Spray drying
The study of spray drying began in the early 19th century. By the middle of the 1930s, the spray drying technology and spray dryer design had matured. Spray drying is to atomize the raw liquid, drying the droplets with hot air, and obtaining the solid product directly from the liquid. Non-crystalline or high viscosity solution commonly used this method, divided into centrifugal type, pressure type and air flow type. Compared with the drying after dehydration, spray drying consumes more energy, the equipment has a larger volume, and the cost is high. However, solid products can be obtained directly from the liquid, which simplifies the process, prevents contamination in the intermediate process, and is widely used in pharmaceutical production.
In the mid-1950s, China introduced the former Soviet Union's streptomycin aseptic spray drying device. In 1977, a sterile spray drying device developed and manufactured by itself was put into operation at the Second Pharmaceutical Factory in Wuxi and used for gentamycin drying. Domestically, in the 1980s, drying equipment plants such as Wuxi Linzhou and Wuxi Angyida have been serialized. In recent years, closed-circuit circulation drying systems have also been developed.
4. Fluidized drying
When the particles of the material are stacked on the porous distribution plate of the bed, the hot gas passes through the material layer from the bottom upwards. When the flow rate reaches a certain value, the particles will be suspended in the gas and become boiling, with the fluid characteristics, which is called boiling dry or fluid state. Drying. The fluidized bed has vertical and horizontal type and can be operated intermittently or continuously. Material residence time can be arbitrarily adjusted, suitable for high humidity, large particles or products that require maintaining crystal form. There have been applications in China in the 1950s and 1960s. In the early days, it was mostly used for drying of Chinese herbs and drying of granules after wet granulation. In 1964, the 11th Shanghai Pharmaceutical Factory produced a continuous horizontal multi-chamber fluidized bed.
Because the horizontal fluidized bed can continuously operate without destroying the crystal form, it can realize automatic control with the interface between the upper and lower processes, and it is widely used in foreign pharmaceutical production. Its closed circuit circulation system can adopt nitrogen gas protection and recovery solvent. Intermittent closed-circuit circulating fluidized drying system has applications in the domestic chemical industry, and continuous operation is suitable for large-scale production of drugs. For example, an annual output of 30,000 tons in a pharmaceutical plant requires 8 sets of 5,000 L double-cone rotary dryers. After tests verify that only one 1.5m2 horizontal fluidized bed is used for closed-circuit circulating fluidized drying, and the entire installation covers an area. Small, automatic control can be achieved with the upper and lower process interfaces. 5. Vibrating fluidized bed and multilayer horizontal circular motion vibrating dryer
(1) Vibrating fluidized bed In order to improve the defect that the common fluidized bed is easy to form in the ditch and dead zone, a vibration source is installed in the lower part of the bed, and the vibration force continuously throws up the material to facilitate fluidization and reduce the minimum flow. The gas velocity, forming the ideal plug flow is shown in Figure 2. In 1976, Shanghai Pharmaceutical Factory No. 6 applied self-made vibrating fluidized bed to dry sodium saccharin. In 1983, Tieling Seiko Co., Ltd. established a test device, followed by the introduction of foreign equipment to develop a series of industrial vibrating fluidized bed dryers, and domestic research institutes carried out theoretical research in this area, and they have been widely used in a few short years.
(2) The main body of the multi-layer horizontal circular motion dryer dryer is a multi-layer annular body with multi-layer annular orifice plates stacked on one another. The lower part adopts two vibrating motors mounted in phase to generate circular vibration, and the material is along the annular hole. The plate moves in a circular motion and passes through each layer of disks from top to bottom. The hot air flows from the bottom to the top (or from top to bottom) through the drip and the surface of the powder in order to make them adhere to each other and grow into granules and be worn. Hot air drying over the material layer. Spray boiling granulation drying is to put a small amount of powder in the bed for seeding. The liquid material is pumped to the nozzle atomized and evenly sprayed onto the boiling bed so that the seed crystal gradually grows up to the required particle size and is Dry to the required moisture content.
Boiling granulation drying and spray boiling granulation drying were used for dye drying in the late 1970s and in the domestic pharmaceutical industry in the 1990s. Now the traditional multi-unit drying device has been completely replaced by various one-step granulation dryers that meet the GMP requirements, and all are produced domestically. China's granulation drying technology and equipment are close to the international level.
6. Other drying methods
(1) Vacuum freeze-drying After drying, the finished product has a small volume and is loose and brittle. Used in thermal, easy oxidation, antibacterial drugs, biological drugs and so on.
(2) Infrared Drying Since water molecules have a good ability to absorb infrared rays, the drying process is extremely rapid, and the drying rate is increased several times to several dozen times. The research and application of infrared radiation drying have begun in foreign countries in the 30's. In the 1970s, infrared drying was listed as an energy conservation promotion project in China. Currently there are few applications in the pharmaceutical industry.
(3) Microwave drying Microwaves have the property of penetrating non-metal, reflecting by metal, and being absorbed by water or water-containing substances. The microwave energy is directly radiated into the interior of the material layer, so that the internal temperature of the material layer rises, and the production pressure causes moisture to evaporate to the surface and be carried away by the hot gas. The drying time is shortened by 2/3 and disinfection is also available. Microwave drying is mainly used for the drying of traditional Chinese medicines. There are not many applications in the drying of raw materials and the prospects are promising.
(4) Heat Pump Drying Heat pump drying consists of two cycles: a drying system and a refrigeration system. Its characteristic is that the mechanical energy works on the system and can transfer heat from low temperature to high temperature. Save energy and enable the material to dry at low temperatures. In today's increasingly tense energy, this kind of energy-saving low-temperature drying method is of great value for development and application.
1. Drying methods for various types of medicines
Drugs can be broadly divided into Western medicines and pharmaceuticals, including sterile drugs and non-sterile drugs. Another Chinese medicine, biological agents and so on. The raw material medicine is the basic raw material of the medicine, most of which are crystalline type. The wet material is a crystalline powdery granular solid that is filtered or separated. According to the characteristics and requirements of the material, an appropriate drying method is used to obtain a dried product. In the early days, more and more dry boxes were used. In the past 20 years, they have gradually been replaced by various kinds of more advanced drying devices. The most widely used ones are double cone rotary dryers, vacuum vibrating dryers, multi-functional dryers, and some direct ones. Heated drying equipment. The other part of the drug substance is an aqueous solution, and the dry product is directly obtained by spray drying, such as streptomycin, gentamycin and the like. An aqueous solution requiring low temperature drying is freeze-dried.
Formulation drugs are finished drugs. One is the bulk drug made of injections, is a sterile drug. The other is that raw material medicines and auxiliary materials are mixed into capsules or mixed into small granules and then compressed into tablets. The oral medicine is usually a sterile medicine. Granulation is an important process in the production of pharmaceuticals. Early operations are accomplished by mixing, kneading, granulating, and drying multiple units of equipment. In recent years, boiling granulation, spray granulation, and other methods have been used. Primary and auxiliary materials can be mixed and granulated at one time. Drying, also known as one-step granulation drying.
Traditional Chinese medicines are usually blocky, flaked, or made from decoction pieces. Special performance, such as particles (pieces, tablets, pills) large, containing sugar, viscosity, heat, etc., and some also require temperature change process, to determine the drying process and equipment selection difficulties. At present, more fluidized drying and improved vibrated fluidized bed, spray drying, etc. are used.
Biological products have strict temperature limits, and most require instantaneous drying, such as microwave drying, fluidized drying, and freeze drying.
2. Requirements for drying equipment in the pharmaceutical industry
Pharmaceutical drying equipment not only has to meet the requirements of chemical equipment strength, precision, surface roughness and operational reliability, but also needs to be detachable from the structural considerations, easy to clean, no dead ends, to avoid contaminants infiltration. Designed to eliminate difficult to clean and check the site, using a reliable seal. The inner surface of the device is manufactured with a high degree of finish, there is no recess structure, and all corners have a smooth transition. A qualified drying equipment not only meets the drying operation requirements, but also meets the GMP (Pharmaceutical Hygienic Quality Management) requirements, and has the functions of in-situ cleaning (CIP) and in-situ sterilization (SIP), so that the equipment does not need to be moved. And disassembly can be effectively cleaned and cleaned after sterilization.
Second, the development of drying equipment used in the pharmaceutical industry
1. Dry box
Box drying is the oldest and simplest drying method. Heating pipes are arranged on both sides of the box, and the trays are placed on shelves in the boxes, or directly on the racks made of steam exhaust pipes. Vent holes are provided at the top or exhaust fans are used to discharge moisture. The vacuum drying box connects the box with the condenser and the vacuum pump. The system is sealed and the discharged solvent vapor is withdrawn through the condenser.
In 1978, the original Jiangsu Wujin Drying Equipment Factory first manufactured a hot air circulation drying oven. The horizontally flowing hot air conducts heat to the material, and the hot air circulation is driven by the fan and replenish fresh air and exhaust gas. In 2001, Changzhou Fanqun Drying Equipment Factory manufactured a special oven for medicines, improved the structure of the old oven, and added a filter in the hot air circulation system to make the hot air entering the box reach the required cleanliness.
The drying oven has a wide applicability and is generally applicable to flammable, fragile, viscous, thixotropic or creamy materials. The disadvantage is that because the material is standing, the drying time is long, the efficiency is low, the manual loading and the drying process need to be turned several times, the dust is large, the pollution is easy, the labor intensity is high, the energy consumption is large, and the thermal energy utilization rate is not more than 40%. .
2. Air dryer
The air dryer is a high-speed hot air flow that fully mixes and disperses the wet material to make it instantaneously dry. The drying time is only a few seconds to several seconds. The process flow is shown in Figure 1. In order to improve the efficiency, the drying tube is made into a pulse tube of unequal diameter, which is called pulse air drying. A cyclone dryer was added to the process to extend the residence time of the material, and the cyclone airflow was dried. Viscous or massive materials can be installed in front of the gas flow tube to install a crushing device, and the material can be broken while drying. The air drying equipment has a simple structure, can operate continuously, has a high drying efficiency, and has a dispersing effect on loose bulk materials, but is not suitable for products requiring crystal integrity.
Airflow drying was used earlier. In the sixties and seventies, it was used for the drying of drugs such as oxytetracycline, chloramphenicol, and pyrazolone. However, there was no specification equipment available, and most of them were technological transformation achievements of various pharmaceutical companies. In recent years, the production of drugs has grown to a large scale, and intermittent batch operations of small batches have been unable to meet production needs. In addition, the perfection of ancillary equipment to ensure the air drying environment requirements, this direct heating of the drying method is simple and efficient and continuous production, and re-emphasized.
3. Spray drying
The study of spray drying began in the early 19th century. By the middle of the 1930s, the spray drying technology and spray dryer design had matured. Spray drying is to atomize the raw liquid, drying the droplets with hot air, and obtaining the solid product directly from the liquid. Non-crystalline or high viscosity solution commonly used this method, divided into centrifugal type, pressure type and air flow type. Compared with the drying after dehydration, spray drying consumes more energy, the equipment has a larger volume, and the cost is high. However, solid products can be obtained directly from the liquid, which simplifies the process, prevents contamination in the intermediate process, and is widely used in pharmaceutical production.
In the mid-1950s, China introduced the former Soviet Union's streptomycin aseptic spray drying device. In 1977, a sterile spray drying device developed and manufactured by itself was put into operation at the Second Pharmaceutical Factory in Wuxi and used for gentamycin drying. Domestically, in the 1980s, drying equipment plants such as Wuxi Linzhou and Wuxi Angyida have been serialized. In recent years, closed-circuit circulation drying systems have also been developed.
4. Fluidized drying
When the particles of the material are stacked on the porous distribution plate of the bed, the hot gas passes through the material layer from the bottom upwards. When the flow rate reaches a certain value, the particles will be suspended in the gas and become boiling, with the fluid characteristics, which is called boiling dry or fluid state. Drying. The fluidized bed has vertical and horizontal type and can be operated intermittently or continuously. Material residence time can be arbitrarily adjusted, suitable for high humidity, large particles or products that require maintaining crystal form. There have been applications in China in the 1950s and 1960s. In the early days, it was mostly used for drying of Chinese herbs and drying of granules after wet granulation. In 1964, the 11th Shanghai Pharmaceutical Factory produced a continuous horizontal multi-chamber fluidized bed.
Because the horizontal fluidized bed can continuously operate without destroying the crystal form, it can realize automatic control with the interface between the upper and lower processes, and it is widely used in foreign pharmaceutical production. Its closed circuit circulation system can adopt nitrogen gas protection and recovery solvent. Intermittent closed-circuit circulating fluidized drying system has applications in the domestic chemical industry, and continuous operation is suitable for large-scale production of drugs. For example, an annual output of 30,000 tons in a pharmaceutical plant requires 8 sets of 5,000 L double-cone rotary dryers. After tests verify that only one 1.5m2 horizontal fluidized bed is used for closed-circuit circulating fluidized drying, and the entire installation covers an area. Small, automatic control can be achieved with the upper and lower process interfaces. 5. Vibrating fluidized bed and multilayer horizontal circular motion vibrating dryer
(1) Vibrating fluidized bed In order to improve the defect that the common fluidized bed is easy to form in the ditch and dead zone, a vibration source is installed in the lower part of the bed, and the vibration force continuously throws up the material to facilitate fluidization and reduce the minimum flow. The gas velocity, forming the ideal plug flow is shown in Figure 2. In 1976, Shanghai Pharmaceutical Factory No. 6 applied self-made vibrating fluidized bed to dry sodium saccharin. In 1983, Tieling Seiko Co., Ltd. established a test device, followed by the introduction of foreign equipment to develop a series of industrial vibrating fluidized bed dryers, and domestic research institutes carried out theoretical research in this area, and they have been widely used in a few short years.
(2) The main body of the multi-layer horizontal circular motion dryer dryer is a multi-layer annular body with multi-layer annular orifice plates stacked on one another. The lower part adopts two vibrating motors mounted in phase to generate circular vibration, and the material is along the annular hole. The plate moves in a circular motion and passes through each layer of disks from top to bottom. The hot air flows from the bottom to the top (or from top to bottom) through the drip and the surface of the powder in order to make them adhere to each other and grow into granules and be worn. Hot air drying over the material layer. Spray boiling granulation drying is to put a small amount of powder in the bed for seeding. The liquid material is pumped to the nozzle atomized and evenly sprayed onto the boiling bed so that the seed crystal gradually grows up to the required particle size and is Dry to the required moisture content.
Boiling granulation drying and spray boiling granulation drying were used for dye drying in the late 1970s and in the domestic pharmaceutical industry in the 1990s. Now the traditional multi-unit drying device has been completely replaced by various one-step granulation dryers that meet the GMP requirements, and all are produced domestically. China's granulation drying technology and equipment are close to the international level.
6. Other drying methods
(1) Vacuum freeze-drying After drying, the finished product has a small volume and is loose and brittle. Used in thermal, easy oxidation, antibacterial drugs, biological drugs and so on.
(2) Infrared Drying Since water molecules have a good ability to absorb infrared rays, the drying process is extremely rapid, and the drying rate is increased several times to several dozen times. The research and application of infrared radiation drying have begun in foreign countries in the 30's. In the 1970s, infrared drying was listed as an energy conservation promotion project in China. Currently there are few applications in the pharmaceutical industry.
(3) Microwave drying Microwaves have the property of penetrating non-metal, reflecting by metal, and being absorbed by water or water-containing substances. The microwave energy is directly radiated into the interior of the material layer, so that the internal temperature of the material layer rises, and the production pressure causes moisture to evaporate to the surface and be carried away by the hot gas. The drying time is shortened by 2/3 and disinfection is also available. Microwave drying is mainly used for the drying of traditional Chinese medicines. There are not many applications in the drying of raw materials and the prospects are promising.
(4) Heat Pump Drying Heat pump drying consists of two cycles: a drying system and a refrigeration system. Its characteristic is that the mechanical energy works on the system and can transfer heat from low temperature to high temperature. Save energy and enable the material to dry at low temperatures. In today's increasingly tense energy, this kind of energy-saving low-temperature drying method is of great value for development and application.
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