Soft capsule is a kind of sealed capsule preparation, which is formed by encapsulating oily drug, drug solution or drug suspension with gelatin capsule shell. In this paper, the preparation process of soft capsule by pressing method and the matters needing attention were summarized.
The basic principle of the pressing method is as follows: the rubber sheet passes through the middle of a pair of cylindrical moulds, the feeding pump injects a fixed amount of liquid medicine through the spray body between the rubber sheet, and the mould moves towards each other to press the two rubber sheets together and cut them out of the rubber sheet, form a completely closed capsule. The main technological steps of the pressing method include four steps: chemical glue, liquid preparation, pill making and drying. In addition, in order to ensure product quality, production will also increase the pill-testing process, eliminate unqualified products.
(1) Gelatinization
① Feeding sequence
Usually, a certain proportion of gelatin, plasticizer, and water are added to a gelatinizing tank for heating and stirring. The gelatin absorbs water and dissolves to form a gel solution. The above materials can be added simultaneously, but it is recommended not to directly add gelatin to hot water. Otherwise, due to the dissolution of gelatin that comes into contact with hot water first, a dense gelatin layer will be formed, and the gelatin particles wrapped inside are difficult to dissolve. There will be many clumps in the obtained gel solution, which will affect normal production. In addition, pigments or shading agents such as titanium dioxide and iron oxide may also be added to gelatin. Colloidal grinding should be used to grind it together with some plasticizers and water. After sieving, it can be added to the gel solution to avoid the preparation of rubber with spots or pores.
② Glue temperature
It is generally advisable to control the temperature of the adhesive during production at 60-70 ℃. The main component of gelatin is a mixture of peptide molecules, and high temperatures can cause hydrolysis of peptide molecules, affecting the quality of the gelatin solution.
③ Vacuum degassing
There will be many bubbles in the newly melted glue, so vacuum degassing operation is necessary. Vacuum degassing generally requires a vacuum degree of -0.07~-0.08 MPa. At the beginning, a large number of bubbles will roll and release from the adhesive solution. Therefore, it is important to release the pressure in a timely manner to avoid pumping the adhesive solution into the vacuum pump and damaging the equipment. During the vacuum pumping process, attention should be paid to observing the state of the glue liquid until there are no obvious bubbles released on the surface, and the glue liquid flows in a honeycomb shape on the surface, indicating that the degassing is completed. The vacuum pumping operation can be stopped. The vacuum pumping time should not be too long, otherwise the glue liquid will lose a large amount of water, which will affect the subsequent shot pressing operation.
④ Glue insulation
The insulation temperature of the adhesive solution is generally controlled between 50-60 ℃. If the temperature of the adhesive solution is too low, it will lead to a decrease in the fluidity of the adhesive solution. Therefore, during the pelletizing stage, the adhesive solution still needs to be reheated, which takes a long time and may result in uneven properties of the adhesive solution.
The glue should not be used immediately after vacuum degassing is completed. It should be left to stand for more than 4 hours to fully discharge the bubbles in the glue. The upper limit of insulation time is evaluated based on specific projects, and the viscosity, freezing force, and moisture of the adhesive during the insulation process can be monitored to determine the stability of the adhesive quality during the insulation process.
(2) liquid preparation
The contents can be prepared according to the requirements of specific projects, according to the relevant solution, suspension, semi-solid preparation of the relevant technical requirements, to control the dispensing process. If the raw materials have light, heat, oxygen instability, can consider the light, cooling or nitrogen. The process of liquid preparation varies from one project to another, so it is not discussed in detail here.
(3) making pills
Pressing pills is the core work of the production of soft capsules. The prepared medicine liquid is added to the hopper, and the glue liquid is pressed and sent to the soft capsule machine through the conveying pipe, complete the preparation of rubber, content of quantitative filling, through the mold will be the rubber and content of the pressed into capsules. The main process parameters to be controlled are as follows:
① Rubber thickness
If it is a generic formulation, it is recommended to maintain the same thickness of the soft capsule shell as the reference formulation to ensure consistent disintegration time. A certain prescription can be used to apply wet rubber with different thicknesses, and after drying, the thickness of the dry rubber can be measured to determine the target rubber thickness range. In general, the thickness of rubber with a weight of 1g or more is controlled within 0.8-0.9mm, and the thickness of rubber with a weight of less than 1g is 0.7-0.8mm. Excessive thickness of the rubber may result in a higher spray temperature required, otherwise it may not have a good stitching effect. Thin rubber can affect the compressive strength of soft capsules, which is not conducive to storage and transportation. In addition, the thickness of the two pieces of rubber should be as consistent as possible, otherwise it will produce deformed pellets.
② Spray temperature
The spray temperature should be adjusted according to the condition of the rubber. If the moisture content of the rubber is too low or the rubber is too thick, the spray temperature should be appropriately increased. In addition, if the pressing speed of the shot is too high, it is also necessary to increase the spray temperature to ensure a better stitching effect. Usually, the temperature of the spray should be controlled between 35 ℃ and 40 ℃. If it is too low, it is difficult to sew, and if it is too high, it may cause the soft capsule suture line to twist and produce shaped pills.
③ Ball pressing speed
The increase in shot pressing speed may not only affect the spray temperature, but also affect the thickness of the rubber coating. A faster rotation speed can cause excessive stretching of the rubber during the shot pressing process, resulting in thinning of the rubber. Therefore, after adjusting the shot pressing speed, the thickness of the rubber should be monitored to ensure that it is within the target range.
④ Environmental temperature
The ambient temperature during the pressing process can also have an impact on the pressing effect. If the ambient temperature is too high, it may cause the pressed pellets to cool slowly and cause adhesion; If the ambient temperature is too low and the rubber is difficult to sew, it is necessary to increase the spray temperature appropriately.
⑤ Other
The soft capsule machine also has the temperature of the rubber conveying tube, the temperature of the rubber box, and the temperature of the cooling drum. The temperature of the rubber conveying tube and the temperature of the rubber box are generally 55-60 ℃ to ensure that the glue can flow smoothly and not cause blockage of the rubber conveying tube; The cooling drum is generally controlled below 20 ℃ to ensure that the rubber can be quickly cooled and formed.
In addition, attention should be paid to the type and amount of lubricating oil added during the pill making process, and corresponding quality standards should be established for the lubricating oil. There should be sufficient evidence to prove that the lubricating oil will not affect other components of the soft capsule. Commonly used lubricating oils include medicinal grade liquid paraffin and medium chain glycerides.
(4) Drying
The drying process is generally divided into two steps, namely fixed drying and static drying. The newly compressed soft capsules will be immediately transferred to a drying rotary cage for drying, reducing the moisture content to 25-30%. Under this moisture content, the shape of the soft capsules will be basically fixed. To improve production efficiency, transfer the shaped and dried soft capsules to a tray for further drying. To clean the lubricating oil on the surface of the soft capsule, an oil absorbing cloth can be added to the drying basket during the shaping and drying process.
Generally, the moisture content of soft capsule shells should be controlled between 8-12%. If the moisture content is too high, the finished capsule shell will be too soft and prone to mold; If the moisture is too low, the capsule shell will crack, which is not conducive to storage and transportation. The main factors affecting the drying effect of soft capsules are as follows:
① Environmental temperature and humidity
The study by Liu Hongyan et al. shows that changes in drying conditions have an impact on the drying rate of soft capsules, as shown in Figure 3. The temperature and sound of the drying environment are high, and the soft capsules dry quickly in the early stage of drying. However, in the later stage of drying, due to the surface drying and hardening of the capsule shell, it affects the internal water conduction and the drying rate decreases. As the environmental humidity decreases, the drying rate shows an accelerating trend. In general, the humidity in the environment should be controlled below 60%, otherwise it is extremely difficult for the capsules to dry.
② Dry wind speed
Increasing the wind speed in a dry environment can increase the water transfer rate and improve drying efficiency.
③ Drying time
Under strict control of environmental temperature and humidity, the moisture content of dried soft capsules depends on the length of drying time. During the process investigation stage, capsules with different drying times can be taken to measure the moisture content of the capsule shell, and a drying curve can be drawn to determine the drying endpoint.
(3) testing pills
The pill-checking process is to eliminate the unqualified products in the dry soft capsules, such as large and small pills, deflated pills, bubble pills, shaped pills and so on. The general way of taking pills is to put the soft capsules on the lamp table and pick them by hand.
In the process of soft capsule preparation, we need to evaluate the output material attributes of each process to ensure the output of qualified products.
In the chemical glue stage, the appearance, moisture, viscosity and freezing force of the glue are the general indexes. The appearance of the glue should be fine and smooth without fine bubbles, water should be controlled at 40% -50% , water is too low, in the process of pressing pills will be difficult to suture, too much water will lead to the formation of rubber; If the viscosity is too low, the soft capsule shell is easy to be saponified. The two indexes should be monitored in the course of heat preservation to prevent the quality of gelatin from decreasing too much.
In the pill-making stage, the appearance of the soft capsule, the amount of the soft capsule and the stitching condition, the appearance of the soft capsule, whether there are bubbles on the surface of the capsule, whether the stitching is even, the amount of the soft capsule must be cut open, after erasing the contents, the weight of the capsule was determined, and ether was recommended to clean the contents in the quality standard of preparation. The content is the difference between the total weight of the capsule and the weight of the capsule skin. The content should be determined immediately after the sample is taken out. If the waiting time is long, the accuracy of the content determination will be affected after the moisture of the soft capsule evaporates, the soft capsules shall be kept in an airtight container and placed at a low temperature to prevent the evaporation of water, and the stitching shall be observed under a microscope, determined by cutting the newly made soft capsules and cutting off the middle ring of rubber, under the microscope to observe the thickness of the rubber and the thickness of the seam, the microscope image as shown in figure 5, measuring and calculating the seam rate, the general suture rate should not be less than 30% .
Suture rate = seam thickness/capsule thickness * 100%
During the drying stage, the water content of the capsule should be monitored. The method of determination is to cut the soft capsule, wipe the contents of the capsule with oil-absorbent paper, and measure the water content of the capsule by the method of drying, until the moisture reaches the target range. If there is a proven method for monitoring moisture stability, it may also be used.
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