Mixing process of solid drug preparation process

For solid drugs, in addition to the active substances with therapeutic effects, there are also some pharmaceutical excipients. These excipients can help drug molding, facilitate market circulation, facilitate patient use, or make drug production possible, or reduce side effects and improve efficacy. In short, these excipients are also essential for the production of drugs.

The first step in drug production is often to mix the active substance with specific excipients evenly, so as to ensure that each drug has the same effect. The mixing process in the production of solid preparations often involves the mixing of two or more solid powders, which can also be called powders. At present, the excipients commonly used in the production of solid preparations are generally particles prepared by special processes, and the particle size is in the micron level. Because these particles have a large specific surface area, and many types of excipients have small holes on the surface or inside, they can further adsorb water, or adsorb smaller particles. These particles, together with the gas between them, form a powder. It is difficult for the powder particles to form a permanent connection unless under high pressure, which makes the powder have the same fluidity as the liquid, but the particles themselves do not have the thermal movement ability of liquid molecules, and can only move under the action of external forces.

The composition and properties of the powder are diverse, and the properties of the powder change with the composition. The uniform mixing of the powder is the key factor to ensure the uniform quality of the final preparation. In order to better select excipients, design processes, and accurately and comprehensively understand the powder mixing process, it is necessary for preparation researchers.

In the production of solid preparations, mixing is the most common operation, but in fact, many people think about what happens to the powder in the mixing process. As mentioned above, although the powder has fluidity at the macro level, it cannot move spontaneously at the micro level. The essence of mixing process is the process of redistribution of various components in the powder according to their own properties and environmental conditions under the action of external forces. If the force between particles is ignored, the external force of each component in the powder is distributed randomly.

The following describes the general powder mixing process with the simplest two-dimensional mixer. Add the components to be mixed into the mixing container, the container starts to rotate, the mixing starts, and the rotation stops, the mixing ends. During this period, mixing is divided into the following stages:

(1) Before mixing, the materials are added into the container, and the materials are deposited to form a powder bed due to gravity.

(2) When the instrument starts to operate, the movement of the container exerts a force on the particles in the powder. The force between particles is activated, and gaps are formed between particles. These gaps make it possible for particles of different components to interpenetrate and interweave.

(3) The instrument runs continuously, and the particles are continuously subjected to the mechanical force provided by the equipment, their own gravity and the pressure or shear force of other particles. Under the action of these forces, the particles continue to move. The movement of these powder particles generally has three forms, corresponding to three mixing mechanisms, namely the so-called convection, shear and diffusion. A certain particle moves in the form of particle clusters (convection). Due to the different movement rates of particles at the contact surfaces of different particle clusters, the particles produce relative sliding (shearing), thus causing the position exchange (diffusion) between adjacent particles. Generally speaking, in the initial stage of mixing, the movement of powder is dominated by convection, and shear is the main way to reduce particle aggregation, while diffusion is the microscopic mixing in the mixed system, which can achieve the most uniform mixing.

The mixing process of powder is different from that of solution mixing or dissolution, because the Brownian motion of the latter molecule can make the system move spontaneously in the direction of entropy increase, while the mixing process is the evolution of particle motion under the action of external force, and the mixing end point is the distribution of different particles in space, which is more controlled by "probability". Therefore, the motion of different particles can form a more uniform distribution in space, so these motion processes may also cause the particles to be distributed unevenly in space. The later stage of mixing is the balance between "uniform" and "uneven". However, behind this balance, there may also be other change trends brewing, such as the self aggregation of certain particles under shear or the adhesion to the container wall under strong pressure. These processes can cause the separation between different particles, leading to the decrease of homogeneity.

(4) When the equipment stops running, the additional mechanical force disappears, and the particles also stay still. The balance of various forces temporarily fixes the particles at a certain point in the instrument space. Perhaps a little external disturbance will cause the particle position to change again. How to maintain the achieved mixing state and prevent particle separation is also an important issue to be considered in the mixing process design.

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