The pharmaceutical industry is constantly developing new substances and drug delivery systems (DDS) which require ‘absolute’ protection in reference to humidity and oxygen. For these applications the barrier of thermoformed blisters made of high barrier plastics such as ACLAR- and COC-laminates is no longer sufficient. Self-evidently the blisters could be additionally packed in pouches. Nevertheless this would increase costs for production as well as for the packaging material used for the pharma company.
Laminate for blisters with aluminium as barrier layer (CFF; Panblok; alu-alu-blister) provide barrier from top and bottom. Products packed in CFF have the optimum protection against outer influences. The forming procedure is carried out with plugs and without thermo-forming techniques (no heating of laminate prior to forming) thus the blisters are 2.5 to three times larger than thermo-formed plastic blisters. Some machine manufacturers have accumulated a great deal of experience thus they manufacture formats for tools themselves and use existing tools for standard package dimensions (e.g. capsules), others do not have this experience and the result of cold formed result could be relatively an under performer.
Pharma companies also tend to have tool manufacturers ‘copy’ tools for existing products. This is the case in particular in Asia, and South America but is also no exception in Europe. The problem might arise in these cases is that the plug geometry is not identical with the original. If an existing cavity is measured the following data are still unknown:
- Exact dimension (steps and angles)
- Plug material,
- Forming depth,
- Space between plug – die.
In 99 per cent of these cases a new tool has to be calculated if pinholes and tears form with this tool. The cavity requires larger dimensions in order to achieve faultless forming results. This usually calls for new sealing tools, perforations, embossing station, larger folding cartons and eventually it translates to a higher cost. Due to the aforementioned reasons it is highly recommend to make use of the original machine producer or experienced tool maker for the parts as required during cold forming.
Whether or not the size of a cavity is correct can be roughly checked by dividing the width or diameter of the cavity by its height. The geometry of the filling good has also to be taken into account (Table 1).
| Table 1: Relation Height to width/ diameter (plug = Teflon) |
For rotary sealing the cavities have to fit exactly into the format of the transporting roller so that faultless transport of the formed laminate is safeguarded.
In order to safeguard faultless forming of the material these cavities are – in relation to the standards used for platen sealing – mostly larger. As this sealing technology for cold forming is still relatively new – with the exception of IMA – these statements are not yet statistically assured.
Application of different plug materials against the PVC sealing layer results in distinct forming ratios:
Caplet Teflon = 2.8 – 3.2
S-green = 2.9 – 3.4
POM = 3.4 – 3.5
The forming ratio changes due to the distinct coefficients of friction against the sealing layer. Increased friction results in insufficient material flow during forming. The material is mainly stretched in the first third – related to the radius of the die. In this area the laminate is extremely down-gauged, and thus pinholes form or the material might even tear (Drawing 1). The colour shades from yellow to red in the critical area of forming depicts the down-gauging of the material. At the same time the laminate is increasingly mono-axially stretched, the curve in the diagram moves increasingly to the y-axis.
| Drawing 1: Influence of plug material on forming properties |
Nevertheless this does not mean that other plug materials cannot be used. Tough more laminate is required for the forming process, the cavity – used for the same filling good – becomes larger and thus the requirement of packaging material increases. Three calculations from practical applications are provided below:
The coefficient of friction might change if distinct sealing layers are applied (Table 2).
| Table 2: Ratio of coefficient of friction of sealing layer – forming plug | ||
|
Plug material
|
PVC
|
HDPE
|
|
Teflon
|
1
|
1
|
|
UHMW-PE (S-green)
|
1.4
|
2.7
|
|
POM
|
2.2
|
1.3
|
|
Steel
|
3
|
1.3
|
The decision about the respective material is with the machine manufacturer and respectively the customer. This depends mainly on the capability of tool manufacturer to work with Teflon and handling of tool within the production area. If soft plug material is used the plug geometry might be altered due to inappropriate handling such as putting the plug on hard surfaces, scratches caused by finger nails or tools). Application of these faulty plugs has an impact on the stretch of CFF laminate during forming process; pinholes or tears might form.
| Atrovastatin (L x W x H; R = 12.3 x 6.5 x 4.9; 5, head space 0.3 mm) Cavity with Teflon 21.0 x 15.2 mm, Blister = 97 x 53 mm è100,000 Blisters = 514 m² Cavity with S-green 23.2 x 17.4 mm, Blister = 108 x 57.5 mm è100,000 Blisters = 621 m² Capsule Size 3 (Ø 5.8; Length 16.0 mm, head space 0.3 mm) Cavity with Teflon 27.6 x 17.4 mm, Blister = 108 x 66 mm è100,000 Blisters = 713 m² Cavity with S-green 30.0 x 19.8 mm, Blister = 120.5 x 71 mm è100,000 Blisters = 856 m² Capsule Size 0 (Ø 7.0; Length 21.5 mm, head space 0.4 mm) Cavity with Teflon 36.8 x 23.0 mm, Blister = 136 x 84.5 mm è100,000 Blisters = 1,149 m² Cavity with Steel 48.8 x 35.0 mm, Blister = 196 x 108.5 mm è100,000 Blisters = 2,127 m² |
A frequent question of users of CFF is always: how long the plug can be used before wearing out and how long before they have to be changed? There is no answer in general. If tooling is handled correctly (cleaned frequently and not damaged) six months with 24 hours production is possible. This is an example from praxis: blister for Pantoprazol with HDPE as sealing layer and Teflon as plug material.
Production environment has a big influence on the result of coldforming. As it was pointed out before, CoF between plug and sealing layer is mainly factor for the correct forming (no defects). If temperature is increasing in production the CoF will increase as well. Normal conditions are 22 – 25 degree C and 50 – 60 per cent r.h. If oPA is absorbing an excessive amount of humidity it becomes ‘soft’ and does not protect forming of aluminium. Results are pinholes and possible cracks.
| Product (mm) | Cavity (mm) | Blister (mm) | ||||||
| Ø | Height | Radius | Ø | Length | Width | Surface (cm²) | Ratio | |
| 5.0 | 16.1 | 101.5 | 43.0 | 43.6 | 92 | 53.4 | ||
| Olanzapine | 9.0 | 5.0 | 9.0 | 16.9 | 105.5 | 45.0 | 47.5 | 100 |
| 17.0 | 18.3 | 112.5 | 47.5 | 53.4 | 112 | |||
Check of CFF blisters
Processing of cold forming might result in formation of pinholes or material tears. The 100 per cent safe in-line check with a pinhole detector (info@hpf-elektronik.de; www.hpf-elektronik.de) detects these types of faults, and the faulty forming cycles are eliminated. Nevertheless this means increased costs and decreased productivity.
- The causes for pinholes/ tears:
- Laminate
- Tool geometry
- Centring of plugs
- Distance of plug – matrix
- Damaged plug
- Not correct processing
- Environment of production
- Environment of storage
| Product (mm) | Cavity (mm) | Blister (mm) | ||||||||
| Length | Width | Height | Radius | Length | Width | Length | Width | Surface (cm²) | Ratio | |
| 6.0 | 27.5 | 17.5 | 108.5 | 66.0 | 71.6 | 93 | ||||
| Mups | 18.25 | 8.25 | 5.5 | 12.0 | 28.4 | 18.4 | 113.0 | 68.0 | 76.8 | 100 |
| 18.0 | 29.3 | 19.3 | 117.5 | 69.5 | 81.7 | 106 | ||||
| design: edge to cavity: 4 mm, space cavity – cavity: 3 mm last tablet to end of blister (embossing of lot number, expiration date): 7 mm | ||||||||||
Influence of the filling good on the dimension of the cavity
Size and geometry of the filling good has a major influence on the dimension of the cavity, and thus on the requirement of packaging material. The decisive factor is the ratio of height to width. The smallest cavities are those of capsules. It would be ideal if also tablets would be produced in this shape. Whether or not a tablet or a capsule is used as DDS depends mainly on the mode of action of the active substances and the processability of the drug.
Nevertheless, the geometry of the tablets cannot exclusively be adjusted to the smallest cavity possible. Other features such as type of application, release of active substances within certain parts of the body, compressibility of the substances, and further conditioning factors have an influence on the form of the tablet.1
Ideal processing is freeze-drying of the product in the cavity. Using this process by Catalant (formerly RP Scherer) the size of the cavity is identical with the size of the thermoformed blister, if a special laminate is used. Nevertheless also normal tablets could be packed in smaller cavities after slight changes of their geometry.
Decreasing of the radius of round bi-convex tablets or oblong bi-convex tablets (Caplet) results in smaller cavities. We chose the round bi-convex tablet ‘Olanzapine’, and Caplet ‘Mups’ as examples.
Another possibility to decrease material requirement is achieved by decreasing the height of the product while maintaining the volume. This is depicted on the example of a round, flat tablet (10 x 4.2 mm, volume = 329.7 mm³) (Table 3).
| Table 3: Influence of the height of the product on the size of the cavity | ||||||
| Product | Cavity | Blister | ||||
| Ø | Height | Ø | Length | Width | Surface (cm²) | Ratio |
| 8.0 | 6.56 | 23.6 | 139.0 | 58.0 | 80.6 | 154 |
| 10.0 | 4.20 | 18.0 | 111.0 | 47.0 | 52.2 | 100 |
| 12.0 | 2.92 | 15.4 | 98.0 | 42.0 | 41.2 | 79 |
Apart from these mentioned possibilities for processing of ideal cavities there is also the opportunity to apply special Panblok material. The limit of formability with these laminates is > 35 per cent, the standard can be stretched 30 per cent 3 D.
By application of plastics as sealing layer with increased barrier properties against water vapour and oxygen, or significant decrease of foil gauge the diffusion through the edges of cut of the blister (land area) is achieved, and thus the shelf life of the active substances also increased.
1.W.A.Ritschel; A.Bauer-Brandl, „Die Tablette“, 2nd edition, published by: Editio Cantor Verlag Aulendorf, 2002