Pharma, the key to developing and producing vibrant multi-layered tablets
By Si-Hoon Lee. (Domestic Sales Manager) PTK Co. Ltd.
Dwell time, cross contamination, yield management, weight control..
Recently, as interest in fixed dose combination or combination drugs grows, the development of new drugs as well as the generics market is active.
Composites can be classified into monolithic FDC, which combines two or more components into a single tablet, Multi-layer FDC with multiple clear layered structures, and Core tablet-in tablet FDC, which wraps a more complex structure of core tablets. .
Active Pharmaceutical Ingredients (APIs) do not have compatibility with each other in many cases. Dissolution patterns are different and interfere with each other, affecting the efficacy or causing side effects.
This tricky nature led to the development of Multi-layer FDC, a technology that classifies and classifies each API into separate layers.
Composite and multilayer tablet production technology
Unlike a single tablet tablet press, a multi-layer tablet press requires two or more feeders to supply granules, several rollers for generating pressure, and several other parts.
Setting up a tablet press for multi-layer tablet production has been a complex task that takes much longer than single tablet presses and requires the know-how of an experienced operator. .
Considerations for the Production of Double-Layered Tablets
Dwell time, defined as the time required to maintain pressure due to contact between the punch head and the pressure roller, can cause capping and hardness problems if not sufficient.
D-type tooling (punch and die sets) has a long dwell time due to the large punch head area. Therefore, the two-layer tablet press can use the D-type tooling to ensure the most stable dwell time.
In addition, the dwell time is closely related to the turret rotation speed, so the production rate of the double-layer tablets is limited. Therefore, a large tablet machine with many stations is required for sufficient production capacity.
Laminating, Capping Phenomenon
Since the first layer is pressurized twice, it can't handle the pressure beyond the limit, and it breaks down. This can be avoided by setting to the minimum tableting pressure when pressurizing after primary layer filling.
Countermeasures for layer cross contamination
The two-bed tablet press adds a high performance suction nozzle and dust removal device to prevent intermixing to achieve a clear boundary line between each layer of the tablet.
A strong vacuum suction device is generally used to remove the granules remaining on the die table.
A dedicated scraper is set before and after the powder filling section to effectively remove powder residues that may remain on the die table where the die is mounted in the turret.
Layer incorporation is addressed by setting the feeder frame correctly to prevent leakage of granules and to provide adequate vacuum suction strength.
It is also important to minimize the clearance to the die table through die thickness control.
Tail over die scraper is made of non-metal material and fixed by spring tension on die table, which prevents the granules filled by centrifugal force from bouncing when die table is rotated to reduce weight deviation and powder loss.
Batch yield management
Production yield is an important consideration in the production of multilayer tablets.
Loss is generally managed within 2% to 3% in single tablets, but it is as high as 5% to 15% in poorly controlled double-layer tablets. The amount of powder lost in the suction nozzle to prevent layer mixing is the main cause.
Effective granulation of the particle size distribution of the granules and the gap between the feeder and turret table can reduce the loss due to overfilling of the granules.
In terms of the production of multilayer tablets, the flowability of granules is an important property in production efficiency. The appropriate amount of fines also serves to provide adequate filling as well as adhesion to form the tablet.
Of the functions of the tableting machine, the most important in the filling by the feeder is the properties of the granules and the amount of fines. Once the filling results are satisfied, the next important thing is the bulk density.
In the case of a double-column tablet press, it is common to define light-density granules as the primary layer because of the depth of filling of the secondary layer.
Minimizing the fines in the double-plum tableting machine minimizes the amount of fines that escape into the gap between the feeder and the turret, and also prevents cross contamination.
Blowing granules with too low a density require a larger filling depth and a larger preload depth. The preload of the primary layer plays an important role in creating a clear layer boundary. If the preload depth of the primary layer is low, the sufficient fill depth required for the desired secondary layer will not be obtained and the desired target weight will not be obtained. Therefore, the primary maximum preload depth is an important specification for multi-layer tablet presses.
Granules of the first and second layers are advantageously to have as close as possible physical properties, such as the amount of fines, density and properties of the granules.
Weight control by floor
For two-layer tablet production, tableting pressure measurement and statistical weight monitoring are important for in-line control.
If the pressure in the primary layer is too small, the load cell will not receive a clear signal. In this case, a dedicated small pressure roll for low pressure enables more accurate and stable tablet pressure measurement.
Another important point is the sampling function of the layer for weight check. The primary layer sample must be pressurized to release sufficient hardness to allow gravimetric measurement to be sampled during production. Otherwise, you will have to set up equipment for sampling, which will reduce productivity.
A common process control method is tableting pressure control, which uses a load cell to collect layered tamping pressures, processes the information, and sends a feedback signal to the tableting machine control. This information automatically weighs the granules filled inside the die via a weight control cam, resulting in maintaining the correct weight and tamping pressure of the layer.
Another method is to use a tablet sampling checker, which automatically takes samples of each layer from the tablet press, weighs the actual layer, and uses the information to operate the tablet press controller to control the weight as well as in-process control. There is an advantage to providing.
Equipment and process optimization
Proper tablet set up is important. The die table has a range of vertical run outs, so finding the highest point is important.
When setting the clearance of the feeder to the minimum, it is necessary to fit at this high point to minimize the granular loss.
Scraper blades should always be kept in the best condition to reduce mixing and the die table surface should be in the best condition.
An understanding of the operator's process and equipment must be preceded for optimal tablet press setup.
Multi-Layered Tablet Development Technology
The research compact tablet press used to develop new products in R & D operates with a limited number of punches at low speeds. Developing and going to a production scale without a pilot scale trial will increase the likelihood of unexpected problems.
Even research tablets use type D tooling and actual production is type B. In this case, since B has a less dwell time than D, a weaker tablet with less adhesive strength is obtained, and problems may occur in a subsequent coating or packaging process.
The research tablet press uses about eight toolings (up and down punches and die sets) and is compressed at low speeds, resulting in sufficient dwell time resulting in good hardness tablets while dozens of toolings rotate rapidly on production scales. Therefore, adhesion between layers is inevitably reduced as a result of insufficient dwell time.
Therefore, if possible, it is best to have a medium-sized tablet press with a pilot scale of about 20 stations.
Meanwhile, this article is based on the experience gained through troubleshooting based on the accumulated knowledge of PTK and the feedback of frontline pharmaceutical sites.
Posted on Tuesday 27th August 2019, in Latest News