Soft capsule preparation process and precautions

Soft capsules refer to sealed capsule preparations formed by quantitatively encapsulating oily drugs, drug solutions or drug suspensions using a gelatin-based capsule shell. Common preparation methods include dripping and pressing. This article briefly describes the preparation process and precautions of the soft capsule compression method.

The basic principle of the pressing method is as follows: the rubber passes through the middle of a pair of cylindrical molds, the feed pump injects a certain amount of liquid into the rubber through the spray body, and the molds move toward each other to press the two pieces of rubber and cut them out from the rubber to form Completely closed capsule. The main process steps of the compression method include gelatinization, liquid preparation, pill making, and drying. In addition, in order to ensure product quality, a pill inspection process will be added during production to eliminate unqualified products.

(1) Glue

Feeding sequence

Usually, a certain proportion of gelatin, plasticizer and water is added to the glue tank, heated and stirred, and the gelatin absorbs water and melts to form a glue liquid. The above materials can be put in at the same time, but it is recommended not to put gelatin directly into hot water. Otherwise, after the gelatin that comes into contact with hot water first melts, a dense gelatin layer will be formed. The gelatin particles wrapped inside will be difficult to dissolve, and there will be some residue in the resulting glue. There are many clumps, which affects normal production. In addition, pigments or opacifiers, such as titanium dioxide, iron oxide, etc., may be added to the gelatin. Use a colloid mill to grind it together with some plasticizers and water, and then add it to the glue after sieving to avoid the rubber produced. Pits or holes.

Glue melting temperature

The temperature of chemical glue in production is generally controlled at 60~70℃. The main component of gelatin is a mixture of polypeptide molecules. Excessive temperature will cause the hydrolysis of the polypeptide molecules and affect the quality of the glue.

Vacuum degassing

There will be many bubbles in the newly melted glue, so vacuum degassing is required. Generally, the vacuum degree of vacuum degassing should reach -0.07~-0.08MPa. At the beginning, a large number of bubbles will be rolled and released from the glue. Therefore, pay attention to timely relief of pressure to avoid pumping the glue into the vacuum pump and damaging the equipment. During the vacuuming process, pay attention to the state of the glue until no obvious bubbles are released on the surface and the glue surface flows in a honeycomb shape, indicating that degassing is complete and the vacuuming operation can be stopped. The vacuuming time should not be too long, otherwise the glue will lose a lot of water, which will affect the subsequent pill pressing operation.

Glue liquid insulation

The insulation temperature of the glue solution is generally controlled between 50 and 60°C. If the temperature of the glue solution is too low, the fluidity of the glue solution will become poor, and the glue solution still needs to be reheated during the pill making stage, which takes a long time and The glue properties may be uneven.

The glue should not be used immediately after vacuum degassing is completed. It needs to be left for more than 4 hours to allow the bubbles in the glue to be fully discharged. The upper limit of the insulation time is inspected according to the specific project. The viscosity, freezing force and moisture of the glue during the insulation process can be monitored to ensure that the quality of the glue is stable during the insulation process.

(2) Liquid preparation

The contents can be prepared according to the requirements of specific projects, and the liquid preparation process can be controlled with reference to the relevant technical requirements for solutions, suspensions, and semi-solid preparations. If the raw materials are unstable to light, heat, or oxygen, consider avoiding light, cooling, or filling with nitrogen. The liquid preparation process varies depending on the specific project, so it will not be discussed in detail here.

(3) Pill making

Pill pressing is the core work of soft capsule production. Add the prepared medicinal liquid into the hopper, and send the glue liquid to the soft capsule machine through the hose to complete the rubber preparation, quantitative filling of the content, and the rubber and content through the mold. Pressed into capsules. The main process parameters that need to be controlled are as follows:

Rubber thickness

If it is a generic preparation, the thickness of the soft capsule shell is recommended to be consistent with that of the reference preparation to ensure consistent disintegration time. Wet rubber of different thicknesses can be laid with a determined prescription. After drying, the thickness of the dry rubber is measured to determine the target rubber thickness range. Under normal circumstances, the thickness of rubber with a weight of 1g and above is controlled at 0.8~0.9mm, and the thickness of rubber with a weight of less than 1g is controlled at 0.7~0.8mm. If the rubber is too thick, the required temperature of the spray body may be higher, otherwise the stitching effect will not be good. If the rubber is too thin, it will affect the pressure resistance of the soft capsule and is not conducive to storage and transportation. In addition, the thickness of the two pieces of rubber should be as consistent as possible, otherwise deformed pills will be produced.

Injector body temperature

The temperature of the spray body is 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 temperature of the spray body should be increased appropriately. In addition, if the shot speed is too high, the temperature of the spray body also needs to be increased to ensure a better stitching effect. Generally, the temperature of the spray body should be controlled at 35°C to 40°C. If it is too low, it will be difficult to suture. If it is too high, the suture line of the soft capsule may be distorted and abnormal pills may be produced.

Pellet pressing speed

Increasing the shot-pressing speed may not only affect the temperature of the spray body, but may also affect the thickness of the rubber. A faster rotational speed will overstretch the rubber during the pilling process, causing the rubber to become thinner. Therefore, after adjusting the pilling speed, the rubber thickness should be monitored to ensure that the rubber thickness is within the target range.

Ambient temperature

The ambient temperature during the pill pressing process will also affect the pill pressing effect. If the ambient temperature is too high, it may cause the pressed pills to cool slowly and cause adhesion. If the ambient temperature is too low, the rubber will be difficult to sew, and the temperature of the spray body needs to be increased appropriately. .

Others

The soft capsule machine also has the temperature of the rubber tube, the temperature of the plastic box, the temperature of the cooling drum, etc. The temperature of the rubber pipe and the glue box are generally 55~60℃ to ensure that the glue can flow smoothly without causing blockage of the rubber pipe; the cooling drum is generally controlled below 20℃ to ensure that the rubber can be quickly cooled and formed.

In addition, during the pill making process, attention should also be paid to the type and amount of lubricating oil added, and corresponding quality standards should be formulated 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 lubricants include pharmaceutical grade liquid paraffin and medium chain glyceryl esters.

(4) Drying

The drying process is generally divided into two steps, namely setting drying and standing drying. Shaping drying means that the freshly pressed soft capsules are immediately transferred to a drying cage for drying, so that the moisture content is reduced to 25~30%. At this moisture content, the shape of the soft capsules is basically finalized. In order to improve production efficiency, the shaped and dried soft capsules are transferred to a tray to continue drying. In order to clean the lubricating oil on the surface of the soft capsule, an oil-absorbing cloth can be added to the drying cage during the drying process.

Generally, the moisture content of soft capsule shells should be controlled between 8 and 12%. If the moisture content is too high, the finished capsule shell will be too soft and prone to mold; if the moisture content is too low, the capsule shell will become brittle, which is not conducive to storage and transportation. The factors that affect the drying effect of soft capsules mainly include the following three points:

Ambient temperature and humidity

Research by Liu Hongyan and others shows that the effect of changes in drying conditions on the drying rate of soft capsules is shown in Figure 3. The temperature of the drying environment is high, and the soft capsules dry faster in the early stage of drying. However, in the later stage of drying, due to drying and hardening of the capsule shell surface , affecting the internal moisture conduction, and the drying rate decreases. As the ambient humidity decreases, the drying rate shows an accelerated trend. Under normal circumstances, the ambient humidity should be controlled below 60%, otherwise the capsules will be extremely difficult to dry.

Drying wind speed

Increasing the wind speed in a dry environment can increase the moisture transfer rate and improve drying efficiency.

Drying time

Under strict control of ambient temperature and humidity, the moisture content of dry soft capsules depends on the length of drying time. During the process inspection stage, capsules with different drying times can be taken to measure the capsule shell moisture and a drying curve can be drawn to determine the drying end point.

(5) Check pills

The pill inspection process is to eliminate unqualified products in dry soft capsules, such as large and small pills, flat pills, bubble pills, special-shaped pills, etc. The general method of pill inspection is to place the soft capsules on a light inspection table and select them manually. The status of the soft capsule on the light examination table is shown in Figure 4.

In the soft capsule preparation process, we need to evaluate the output material properties of each process to ensure the output of qualified products.

In the gelling stage, the appearance, moisture, viscosity, and freezing force of the glue are generally used as inspection indicators. The appearance of the glue should be delicate and smooth without fine bubbles; the moisture should be controlled at 40%-50%. If the moisture is too low, it will be difficult to suture during the pill pressing process. If the moisture is too high, it will be difficult to form the rubber; the viscosity and freezing force are of the quality of gelatin. The main testing indicators are: if the viscosity is too low, the soft capsule shell is easy to saponify. These two indicators should be monitored during the glue insulation process to prevent the quality of the glue from declining too much.

In the pill-making stage, the main indicators of concern are the appearance, filling volume and stitching condition of the soft capsule. The appearance focuses on whether there are bubbles on the surface of the capsule and whether the seams are smooth.

To measure the filling volume, the soft capsule needs to be cut open, and the weight of the capsule skin is measured after wiping off the contents. , there are also preparation quality standards that recommend the use of ether to clean the contents. The filling capacity is the difference between the total weight of the capsule and the weight of the capsule skin. It should be measured immediately after the sample is taken out. If the waiting time is long, the evaporation of the water in the soft capsule will affect the accuracy of the filling capacity measurement result; if it cannot be measured immediately, Soft capsules need to be stored in an airtight container and placed in a low-temperature environment to prevent moisture from evaporating; the suture condition can be observed with a microscope.

The measurement method is to cross-cut the newly prepared soft capsule, cut off a circle of rubber in the middle, and observe the rubber under a microscope. The thickness and the thickness of the seam, the microscope mirror image is shown in Figure 5, measure and calculate the seam rate, generally the seam rate should not be less than 30%.

Suture rate = seam thickness/shell thickness*100%

During the drying stage, attention should be paid to monitoring the moisture content of the capsule shell. The measurement method is to cut the soft capsule, dry the contents in the capsule shell with oil-absorbing paper, and measure the moisture content of the capsule shell using the drying method. Generally, the measurement is performed once every 8 to 12 hours until the moisture content is reached. Reach the target range. If there is a proven method for monitoring moisture reliably, this may be used.