Purpose: It is desirable to predict the mechanical properties of the tablets based upon the knowledge of properties of individual components. This allows understanding of mechanical behavior of different formulation compositions without making the physical blends. Unfortunately, it is difficult to obtain intact tablet for the characterization of many drug compounds owing to their poor compressibility. Thus, it is challenging to generate a mechanical property development space for formulations of these drug candidates without physically preparing a large number of formulations. The objective of the present work was to a) extract the compactibility profile of a poorly compressible drug from the compactibility of a mixture containing the drug & a selection of other components and b) to use this extracted drug profile in predicting compactibility of various mixtures.
Methods: Tablet compaction was performed for acetaminophen mixtures and pure components at different porosities using an Instron Universal Testing System. A diametral compression test was used to measure the radial tensile strength of tablets. Tensile strength and porosity data were fitted to the Ryshkewitch-Duckworth equation to generate continuous compactibility profiles. The profiles of microcrystalline cellulose (MCC) and an acetaminophen-MCC (1:2) mixture were used for extraction of the acetaminophen compactibility profile using rearranged geometric mixing rule as shown below.
log σ_drug = (log σ_mixure - V_MCC x log σ_MCC)/V_drug
σ is tensile strength at given porosity
V is volume fraction of component in mixture
Extracted profile of acetaminophen was used as an input parameter in the geometric mixing rule equation to predict the tensile strength profiles of different compositions of acetaminophen-CombiLac®, acetaminophen-maltodextrin and acetaminophen-MCC-lactose mixtures.
Results: Figure 1(a) shows the extracted compactibility profile of acetaminophen using the rearranged geometric mixing rule. The extracted tensile strength over porosity range of 0.10 to 0.22 was predicted to be less than 0.6 MPa. This was consistent with its poor tableting behavior associated with this material and our experimental observation of inability to form intact tablets even at higher compression pressures up to 200 MPa.
Compactibility of other acetaminophen mixtures was predicted using the extracted acetaminophen profile. These predicted profiles were compared with the experimental profiles to assess the accuracy of the predictions. The figure 1(b) shows the overlay of experimental and predicted compactibility of the acetaminophen-maltodextrin (1:1) mixture.
Conclusion: It can be concluded from this investigation that the mechanical property extraction approach can be useful in obtaining the compactibility of difficult drug. This approach can enable the screening of different formulation compositions of such drugs without making physical blends.
Ira Buckner– Associate Professor, Duquesne University