Planning Experiments Using an Instrumented Tablet Machine in Formulation

Abstract

For a few years, we have been in possession of a methodology for the formulation of tablets. It is based on an experimental planning design of rational development work using an instrumented tablet machine. On the other hand, it is possible to organize mathematically the scientific studies in various fields so that we can reach the best result as fast as possible, i.e. to carry out an optimal number of experiments giving the maximum amount of information: this is the application of the statistical experimental designs. The aim of this study is to associate these two concepts.

The major principle is to study the variations of well-chosen answers (tablet crushing strength…) according to the percentages of vehicles chosen as variables (diluent, disintegration agent…) while the methodology of mixing remains fixed. An experimental design is built, a well-defined number of experiments are carried out, and then we try to put into equation the responses as a polynomial function of the percentages of vehicles. The best mathematical models are statistically determined by multilinear regression and used to plot the response surfaces. This mathematical treatment associated with the objectives of the pharmacist allows us to determine the optimal formula. And so, carrying out the theoretical optimal experiment we can verify the accordance of the experiment with the model.

A first approach with wet granulation showed all the difficulties in fixing all the parameters. But it has already shown all the advantages of the experimental designs and that this technique can be very helpful in building the experimental planning design.

With direct compression, two experimental designs were built to determine the optimal formula as fast as possible: these were a Scheffe design and a Mac Lean and Anderson design.

When the constraints on vehicle percentages lead to a triangular experimental field, Scheffe designs are recommanded. For any other configuration Mac Lean and Anderson designs will be useful.

The responses were:

1. Y1/D, where Yl is the maximal pressure measured at the upper punch and D the crushing strength of the tablet.

2. (V10-V500), where V10 and V500 are the volumes of 100 grammes of the final mix of powder after 10 and 500 tamping taps given by a standardized apparatus. Their difference (V10 - V500) should not exceed 20 ml.

3. td, the disintegration time of tablets measured by way of the European Pharmacopea test.

In both cases, the results were excellent considering the differences between the response values given by the mathematical models and the corresponding experimental values.