Tablet press qualification and mixing
Writer： admin Time：2021-02-01 18:11 Browse：℃
A test result is concluded in the following table. It can be seen that premixing and pressing are qualified but general mixing is not.
|
Batch No. |
Process |
Result |
RSD (%) |
Judgment |
|
1 |
Premixing (n=10) |
100.05%-104.39% |
1.65 |
Qualified |
|
General mixing (n=10) |
91.66%-113.24% |
6.98 |
Unqualified |
|
Pressing |
A+2.2S=3.88 |
|
Qualified |
But why premixing is qualified but general mixing is not? This question can be analyzed from the following aspects:
Powder has two properties, fluidity and segregation. We always pay more attention to its fluidity and ignore its segregation.
Segregation refers to the phenomenon that the granules with same properties including size, components, density, elasticity, static electricity and so on will gather and segregate in an equipment or during production. This phenomenon sometimes influences local concentration of API obviously, leading to non-uniformity.
Once powder moves, segregation occurs. For example:
1) During sampling, the powder close to the sampling area will also segregate as the sampling tool moves. The mixed material is powder containing API granules, lubricant and disintegrant. Therefore, the sampled material doesn’t always contain powder and granule in certain proportion. The sample sometimes contains more fine powder but sometimes more granules. Therefore, the sample result cannot represent the actual uniformity of the batch. Segregation caused by sampling is also the commonest error. It can lead to unqualified BU.
2) Material will be influenced by the external vibration and air flowing to segregate when it is discharged and transferred to another container.
Different from powder fluidity evaluation, there is still no good method to evaluate if segregation occurs. What can be done is to monitor fluidity, uniformity and some other indexes before, during and after every process to make sure that the material conforms to the requirements.
1. Before general mixing
For directly mixed powder, the physical properties of API and excipients should be well understood. Some properties include granularity (granule distribution), density, and shape (strip, sheet, granule or ball). If necessary, the material can be grounded. In this case, grinding machine type and screen mesh should also be considered.
Some material will be granulated. Its sensitivity to humidity and storing time should be inspected. Some material is likely to absorb moisture. If it is stored in unreasonable humidity for a long time, its fluidity might reduce. And as time goes by, the material will block and influence fluidity. Therefore, the best storing time and condition should be determined.
In addition, shape, moisture content and granule distribution of material after granulation will also influence fluidity and then cause to segregation. If segregation occurs, we can backcast to find out influencing factors, such as adhesive dosage, feeding way, drying time, drying temperature, screen mesh and so on.
2. During general mixing
For low-dosage drugs, their uniformity can be guaranteed before mixing. But general mixing can still cause non-uniform component distribution. Some common problem are insufficient mixing and over mixing. During mixing, the mixing parameters of the equipment, including rotating speed and mixing time, are pretty important. Generally speaking, the material with good fluidity can be mixed well at high speed but viscose material at low speed.
The mixing time should also be kept moderate. The material cannot be mixed uniformly in short mixing time and will segregate if the mixing time is too long. Besides, mixer type, shape and volume are also important. Common mixing equipment are V-blender, 3D mixer, high shear mixer and so on. In addition, the loading rate should be controlled. That too much material is loaded will make mixing more difficult.
3. During sampling
Sampling is somewhat challenging because all sampling tools have their own shortcomings. For instance, sampling during shutdown can bring about less sampling data, location deviation and segregation. Sampling frequency should be increased to reduce sampling error. In addition, electrostatic adsorption might occur in some material. Therefore, the material cannot be held by plastic bags. In this case, the container material (stainless or glass) should be appropriate to avoid its influence on drugs content.
4. During tablet press
During tablet press, segregation in hopper can be a possible factor for content uniformity. If it’s proved to be true, the hopper should be innovated to remove segregation.
If similar problems occur, it is recommended to consider from an overall perspective, take powder fluidity, segregation and some other possible factors into consideration and then adjust technical parameters. If the error is caused by sampling, check sampling quantity and method to reduce error. Otherwise the data make no sense.
Furthermore, the error caused by test method should also be considered. For example, is the solvent proper? Is the sampling amount moderate? Or is the test method scientific?
All in all, research is not as simple as data collection, methodical experiment and data analysis. Production is a practical application of research findings. If the errors cannot be solved in research, it will cost more to solve it in practical production. A good researcher should be able to analyze the problem deeply, develop themselves with keen observation and thinking ability, record abnormality during research and production and find out solutions through logical reasoning and comprehensive analysis.
