Soft capsule refers to the dosage form made by sealing a certain amount of medicine or medicinal material extract with suitable auxiliary materials in a spherical or elliptical soft capsule material, which can be prepared by dropping method or compression method. Compared with other dosage forms, it has the advantages of high bioavailability, accurate content, good uniformity, masking the bad smell of the drug itself, improving the stability of the drug, and beautiful appearance. Wherein, the capsule material of the soft capsule is made of gelatin, glycerol or suitable medicinal materials.
With the advancement of technology, soft capsule dosage forms have developed rapidly. The contents of soft capsules can be drug solutions and suspensions, etc. Compared with traditional Chinese medicine pills and other dosage forms, they have the advantages of high bioavailability and quick curative effect. The advancement of traditional Chinese medicine extraction and separation technology has also greatly promoted the emergence of traditional Chinese medicine soft capsules. Some traditional Chinese medicines, such as Huoxiangzhengqi pills, have now been changed to Huoxiangzhengqi soft capsules, which are welcomed by patients and doctors. This article will discuss the main production process and equipment of traditional Chinese medicine soft capsules in detail based on our production experience.
1 Production process and production equipment
The production process of the soft capsule is shown in Figure 1.
According to the requirements of air cleanliness in the 2010 version of GMP, the traditional Chinese medicine production area of soft capsule dosage form should be in the D-level clean area, including the main production processes such as ingredients, sol, pill pressing, shaping, pill washing, drying, inner packaging (packaging), etc. . Then the outer packaging is located in the general production area.
1.1 Preparation of contents (ingredients)
Depending on the nature of the contents, the preparation process and equipment of soft capsules are slightly different. If the content is a solution, that is, the drug can be well dissolved in the solvent (usually oily), it is only necessary to accurately weigh the raw materials and auxiliary materials according to the pre-experimented production prescription, and dissolve them in the liquid dispensing tank. If necessary, it can be heated. to speed up the dissolution rate. If the content is a suspension, the medicinal materials or other ingredients and the liquid excipients in the prescription (such as soybean oil, etc.) need to be uniformly milled with a colloid mill, and the process conditions of the glue mill (such as the speed and time of the glue mill) are determined according to their properties. and times, etc.). A certain amount of suspending agent needs to be added to the suspension during preparation to ensure that the suspension cannot be delaminated within a certain period of time (such as 48-72 h, otherwise the uniformity of the drug will be affected. In addition, during the production process Pay attention to heat preservation to ensure the uniformity of the contents. Traditional Chinese medicine soft capsules are mostly mixed with extracts of traditional Chinese medicines and solvents or other auxiliary materials to make solutions or suspension contents. Some soft capsule technology researches in recent years mainly focus on the contents and solvent (or dispersant, etc.) on the formulation study.
The equipment for preparing the contents is mainly a liquid dispensing tank. The two-blade stirring paddle of the dosing tank (Figure 2) is driven by a series of cycloidal pinwheel reducers, and the tank body is polished. A colloid mill is required for suspension preparation (Figure 3).
1.2 Preparation of glue solution (sol)
The preparation of glue, commonly known as glue, is a key step to ensure the quality of soft capsules. The glue is generally composed of gelatin, glycerol and purified water. Among them, gelatin is the main component, which directly affects the quality of the glue. The 2010 edition of the Chinese Pharmacopoeia stipulates that gelatin is a product obtained by moderate hydrolysis (acid method, alkali method, acid-base mixing method or enzymatic method) of collagen in animal skin, bone, tendon and ligament, or it is different from the above. A mixture of gelatin products. The quality of gelatin mainly depends on the control of jelly concentration, pH, light transmittance, electrical conductivity, microbial limit and other indicators. 2 The main appearance characteristics of soft capsules are strong plasticity and high elasticity, and depend on the composition of the capsule material, that is, glue, The ratio of plasticizer and water. The glue used for soft capsules is basically gelatin, the plasticizer is glycerol, and the water is preferably deionized water or pure water. The hardness of soft capsules is directly related to the weight ratio between dry gelatin and plasticizer. If the ratio of glycerol:gelatin is 25:100, the obtained dried product (14% water content) is very hard, even harder and thicker than hard capsules; if glycerol:gelatin=60:100, the obtained dried product The resulting product (14% water content) is very soft, yet tangible, soft and elastic, and soft capsules can even be torn open with the fingers.
The pellet quality of soft capsules is also closely related to the weight ratio of dry gelatin to purified water. If the moisture is too low, the glue will be too viscous, the tape will be difficult to spread and form, and the pelletizing speed will be slow and abnormal. The product has poor appearance and leaks, and produces many non-adhesive pills and special-shaped pills.
The general feeding ratio is water: gelatin = 1:1, but different processes (temperature time, etc.) and different sol equipment, and even different products (such as transparent and shading products, etc.), must also make corresponding formulations and processes. Synchronization Adjustment. After studying the glue formula 3, it is concluded that the ratio of gelatin and water should be 1:1, which can be adjusted slightly. At the same time, titanium dioxide can be added as sunscreen and other auxiliary materials according to requirements. The sol equipment (Figure 4) is mainly composed of a glue tank and the like. In addition to the glue tank, water bath heating is required to provide a heat source of 90~100 ℃ to ensure the viscosity of the glue. Therefore, it is necessary to equip the coil type water heater at the same time. In the glue mixing process, in order to condense the glue liquid bubbles and water vapor in the glue tank when vacuuming, a coil condenser should be equipped at the same time, which has a certain protective effect on the vacuum pump.
The working principle of pill pressing: The rubber prepared by the rubber wheels on both sides of the main machine and the gelatin box enter into the gap of the roller mold relatively, and the liquid medicine is injected into the wedge-shaped spray body through the conduit through the feeding pump, and the liquid medicine and rubber are separated by the pressure of the feeding material. Press into the grooves of the two rolling molds. Due to the continuous rotation of the rolling molds, the two rubber sheets in the grooves are formed into two hemispheres, and the liquid medicine is encapsulated in the plastic film, and the remaining rubber sheets are cut and separated. The working principle of the rolling mode soft capsule machine and the soft capsule mold are shown in Figure 7 and Figure 8, respectively.
Before pressing, it is necessary to clean and check the relevant parts of the equipment to ensure the smooth flow of the liquid and the integrity of the sealing gasket. When pressing, attention should be paid to adjusting the injection time to prevent the problem of reducing the content of the capsule due to leakage during injection. During the pressing process, attention should also be paid to the control of the rubber temperature. If the temperature is too high, leakage will occur, and if the temperature is too low, the adhesive effect of the rubber will be poor. Generally, the temperature of the control spray body is 45~50 ℃, and the temperature of the plastic box is 55~60 ℃. If the thicknesses of the two rubber sheets are inconsistent, deformed pellets will appear during the pressing process. Therefore, the thickness of the rubber skin should be controlled, generally 0.7~0.8 mm. The uneven content of the content is also a problem that is easy to occur during the pressing process. There are two common reasons: one is that there are air bubbles in the capsule, which is due to the blockage of the spray body, It is caused by inaccurate injection time, loose rubber joints or poor sealing of rubber pads in the material pump; the second is the production of too large or too small rubber particles, which are mostly caused by the blockage of the spray body.
A considerable amount of mesh glue will be produced during the pressing process (Fig. 9). The recycling of mesh glue itself is an effective economic method for enterprises. The mesh glue recycling equipment is mesh glue crusher (Figure 10).
1.4 Washing pills
The production of soft capsules requires the use of paraffin oil, which can negatively affect the quality of the capsules and therefore requires cleaning of the formed capsules. The traditional process, which is commonly used at present, is to clean the capsule with alcohol and ether organic solvent, and wash off the paraffin oil sticking to the surface of the capsule. However, the solvent soaked and cleaned capsules will have residual solvent, which will pollute the capsules.
The rubber skin itself has natural tension. After soaking and cleaning in the solvent, the rubber skin will lose this tension, and the rubber skin will become dry and brittle, which will greatly shorten the shelf life of the capsule product. After solvent cleaning, adhesion between capsules will also occur. At the same time, explosion-proof requirements are also put forward for the cleaning operation room of organic solvents, and labor protection needs to be paid attention to in production.
1.5 Drying
Drying is an important link that affects the quality of soft capsules. At present, the drying of soft capsules on the market is mostly in two forms, one is the baking tray type, and the other is the rotating cage type.
The advantage of the tray dryer (Figure 11) is that it occupies a small area, but the disadvantage is that the drying time is long, and it needs to manually turn the tray many times to ensure the drying effect. In the traditional drying method, the shaped soft capsules are placed on a pallet truck and placed in a pill drying room to dry to the finished product. The pill drying room adopts horizontal laminar air supply, the temperature is controlled at 30~35 ℃, and the humidity is controlled below 25%. Each tray is placed with no more than two layers of soft capsules, and the pills are turned inside 4~5 times in the first 2 hours to ensure the soft capsule. The pill shape is good, the appearance is good, and the drying time can be completely dried within 12~16h.
Figure 11 Drying tray dryer
For rotary cage drying, attention should be paid to the control of indoor humidity and time. In the drying process, the main influencing factor is the indoor humidity. If the indoor humidity reaches 60%, it is very difficult to dry the soft capsule. Time is also an important factor. If the time is too short, the shape of the capsule is not good, and it is easy to deform due to extrusion; if the time is too long, the rubber will be too hard. Generally, the suitable drying time is 16-24 h. The drying equipment is shown in Figure 12.
Compared with other dosage forms, soft capsules have the characteristics of high bioavailability, good sealing, accurate content and beautiful appearance, and are a promising dosage form.
With the development of soft capsule dosage forms, more soft capsule dosage forms are bound to appear.
