Some formulations contain active ingredients that are not available as formulation substances. Then finished medicinal products are used. Our formulation expert Dr. Anna Berger.
Lately, we’ve had some inquiries from readers about making low-dose capsules for infants. The required active ingredient was not available as a prescription substance, so it had to be manufactured from a finished medicinal product.
Based on the following prescription, we would like to introduce you to the production of capsules from powdered finished drug tablets:
Aprovel® Capsules 15 mg 100 pieces
In infants: Capsules as divided powders
Many active ingredients for infants are prescribed in individual dosages by the doctor as a single-dose pharmaceutical form. In our example, the antihypertensive drug irbesartan is to be processed. It is manufactured from the finished medicinal product Aprovel® 150 mg film-coated tablets. For this purpose, powder trituration is usually produced from the FAM and a filler and this is packed in hard gelatine capsule shells as divided powders. In the case of children, the content for the application is understandably filled in and administered with food. In order to keep the amount of filler as small as possible, the smallest possible capsule size should be selected. However, the capsule filling machines usually available in pharmacies usually only allow sizes 0 (0.68 ml) and 1 (0.5 ml).
Use finished medicinal products in excess
1,500 mg of active ingredients are required to produce the desired number of capsules. This is contained in 10 tablets of the finished medicinal product. Due to a range of fluctuations in the content of the individual tablets in the double-digit percentage range, these always have to be processed in excess. Otherwise, the capsules produced can easily be underdosed. The exact size for determining this surplus does not exist. In its recipe information “Capsules for pediatric use”, the NRF recommends using at least a two-digit number of tablets. With the above recipe, it is advisable to use 20 FAM tablets to prepare the powder mixture. First, these tablets must all be weighed together and the average mass of a tablet determined from this, then these can be finely ground in a rough mortar.
Which filler is suitable?
In principle, when processing tablets into capsule formulations, an excipient that is already contained in the finished medicinal product should be used as a filler. As a result, other substances are not unnecessarily introduced into the powder mixture and compatibility can also be assumed. The exact ingredients of the finished product can be found in the information for professionals under point 6.1 “List of other ingredients”. The Aprovel® tablets contain, among other things, lactose monohydrate as an excipient, so this sugar can be used as a filler. In the case of lactose monohydrate, however, the flow properties are relatively poor if the particle size is small, but the addition of 0.5% highly disperse silicon dioxide as a flow regulator can help here.
Mass-based manufacturing is not possible
Mass-based production is now recommended, especially for low-dose capsule formulations. The active ingredient is mixed with the filler in a smooth stainless steel bowl without trituration. A prerequisite for this capsule manufacturing method is that the bulk density of the powder mixture is mainly determined by the filler and the standard filler made of mannitol 99.5% and silicon dioxide 0.5% according to NRF S.38. is used. It is therefore not possible to produce capsules from powdered finished medicinal product tablets using this method.
Volume supplementation method as an alternative
The hard gelatine capsules can be filled with powdered medicinal products according to the recipe using the well-known measuring cylinder method or using the volume-upfill method. In any case, a smooth shell must be used for both methods of production. In the volume supplementation method, the precisely weighed amount of powdered FAM is first mixed with some filler to form a concentrate. This concentrate is distributed as evenly as possible over the open capsule bases. The lower parts can then be filled with pure filler, and by carefully tapping on the capsule-filling device, they should even be slightly overfilled. This small addition of filler ensures that there is a sufficient amount of powder when the capsule is later filled. The filled bases are completely emptied, and the powder mixture is stirred in the bowl with a piece of card and then distributed evenly over the capsule bases.
Note on determining the use-by period
Raw materials for the production of medicines can be used for the production of formulations up to the last day of their shelf life, after which the use-by period for the patient follows as normal. This is because the starting materials must have the minimum content specified in the pharmacopeia until the end of their shelf life. This is different for finished medicinal products, where the specification already includes the permissible salary reduction. If a finished medicinal product is used in a recipe, the preparation made from it can never have a longer shelf life than the medicinal product used.