Search for technological reasons to develop a capsule or a tablet formulation

The following work should be understood as an approval to the FDA’s new concept of quality assurance in the 21st century, i.e. to understand the process and the formulation, to build in and not to test in quality. There are a number of reasons from the economic and marketing point of view to prefer a capsule or a tablet formulation. The aim of this work, however, was to find specific technological reasons to develop a robust capsule or tablet formulation with special respect to physical properties of model drugs and excipients such as wettability, solubility as well as compressibility and compactibility. Formulations nowadays are usually developed under high-time pressure on the basis of “trial and error” experiments. They are complex, variable systems consisting not only of an active substance but also of a number of excipients. An in-depth and science based knowledge, whether to formulate a drug as a robust capsule or tablet formulation, would help to shorten the developing process and as a consequence, time and money could be saved. In early clinical trials for example when the dose is increased in order to find the optimal therapeutic effect with a minimum of side effects, the whole amount of drug should be released at the same time independently of the drug load. No decrease of the bioavailability has then to be expected from a technological point of view. In such a case, however, normally there is at first a capsule formulation because the developing time is in most cases not as complex as for a tablet formulation: a powder mixture can be filled directly into a capsule shell without a granulation and a compression process (Leuenberger et al., 2005). In the case of the well soluble and well wettable model drug caffeine such an approach would have been successful. The standard capsule formulation consisting of caffeine, lactose and magnesiumstearate turned out to be entirely robust in the dissolution test independently of the drug load. The poorly soluble and poorly wettable model drug proquazone, however, showed a dramatically prolonged release in the dissolution test when it was found in high concentrations. It became clear that proquazone needs to be formulated as a granulate or a tablet to achieve a robust formulation regarding dissolution. With the poorly soluble but well wettable model drug diclofenac sodium neither the capsule nor the corresponding tablet formulation turned out to be robust. It was therefore decided to introduce a novel excipient as all formulations mentioned above had all the same compositions. This excipient, UICEL, was developed at the University of Iowa. It is said to have excellent direct compressing properties, which could also be confirmed in this work. Furthermore it turned out to be a very good excipient in the capsule filling process leading to fast dissolution rates in combination with all model drugs because of its excellent wetting and disintegration properties. After a direct compression of all model drugs in combination with UICEL it also caused fast dissolution rates with the model drugs caffeine and proquazone. In combination with the model drug diclofenac sodium, however, no fast releases could be achieved. When the disintegration of all formulation was investigated, in the case of the model drug proquazone no correlation between dissolution behaviour and the disintegration time has been observed. When the different systems were evaluated from the point of view of sorption of water, which indicates the wettability behaviour of the different systems, a clear difference between the formulations could be observed having a correlation with the results found in the dissolution experiment. It is therefore strongly recommended for preformulation studies to include water sorption experiments, especially in the case of a high drug content. As a good compressibility and compactibility of different system are important in the production of tablet formulations in contrast to capsule formulations where the powder or granulate can be filled directly into the capsule shell without any compression, it was decided to find a fast but science based screening approach to discriminate between systems with poor compression properties that could be candidates for a capsule filling approach and systems with good compression properties that could be compressed to tablets. Therefore the physical model of powder compression proposed by Leuenberger (1980), which connects the parameters compressibility and compactibility, was chosen. In contrast to earlier studies, just five different compression forces for each sample were applied and the crushing strength was determined with a common tablet tester. This approach turned out to be very useful giving a clear discrimination between the different systems. It was found for a future continuation of this work that the wettability as a physical property for the decision whether to formulate a drug as a capsule or a tablet should be investigated in-depth and more specifically. Formulations with other excipients or other poorly wettable model drugs should be analysed at the same time than the sorption of water. The future compressibility or compactibility studies could be carried out with the PressterTM compaction simulator and with other model drugs having very poor compressibilities and compactibilities.