Roller compaction of theophylline

1. Summary
Direct compaction requires a very good flowability and compressibility of the materials. Those parameters become even more critical if the formulation contains large amount of active substance. To overcome these problems, several alternatives have been used. Roller compaction is a very attractive technology in the pharmaceutical industry. It is a fast and efficient way of producing granules, especially suitable for moisture sensitive materials. The intention of this work was to understand the effect of roller compaction on the tablet properties. In the literature it is often shown that after roller compaction a material tend to loose mechanical strength. This phenomenon is affected by deformation behavior of the materials exposed to roller compaction. Plastic deformable materials are particularly sensitive because of the limiting binding potential which may be consumed in the first compression step by increasing particle size and decreasing specific surface area. However, materials which undergo fragmentation under pressure showed less or even no loss of tabletability after roller compaction. The loosing of mechanical strength is called loss of reworkability or loss of tabletability. To diminish or even eliminate loss of reworkability the crucial moment is the development of a correct and robust formulation. If excipients with adequate properties, regarding an active material, are chosen it is possible to hold mechanical strength of the tablets. Another problem that could take place during roller compaction is disruption of crystal lattice and changing of polymorphic form of the material. Polymorphic transformation may occur as a result of applied pressure during roller compaction or even due to double compaction after tableting. Due to the fact that Theophylline exists as two polymorphic forms of anhydrate and as monohydrate, it was used as a model drug. Two grade of Theophylline anhydrate: Theophylline anhydrate powder (THAP) and Theophylline anhydrate fine powder (THAFP) were employed in order to check if there is difference in compactibility and tablet properties produced from the same material with different particle size distribution. There is the risk that during the compaction cycle hydrate looses water and transforms to anhydrate, therefore Theophylline monohydrate (THMO) was compacted. Microcrystalline cellulose (MCC) was chosen as a material to combine with THAP, THAFP and THMO because it is
widely used pharmaceutical excipient and its mechanical properties are well
understood.
Due to the importance of active material and excipientes properties on the process
parameters of roller compaction the materials were characterized in detail.
Differential scanning calorimetry (DSC) and X-Ray analysis confirmed that roller
compaction, milling and tableting did not influence polymorphic / pseudoplymorphic
forms of THAP, THAFP and THMO. It is well known that various materials have a
different behavior under compression pressure. In order to see effect of roller
compaction on compressibility and compactibility of the materials after roller
compaction various mathematical equation were applied. The most used equations
for checking the compressibility of a material are Heckel and modified Heckel
equation. Compactibility of the materials with and without roller compaction was
determined by measuring the tensile strength of the tablets produced from the
granules and the original materials. Leuenberger equation, which connects
compressibility and compactibility parameters and this equation, was also applied in
this study.
According to the equations which are responsible for compressibility measuring,
THAP, THAFP, THMO and MCC belong to the same group and showed plastic
behavior when they were exposed to pressure. However, when tensile strength of
tablets produced by direct compaction and roller compaction was measured,
differences in behavior were occurred. Tensile strength of MCC tablets after roller
compaction was extremely decreased, while THAP, THAFP and THMO tablets
showed slightly decreased tensile strength. The phenomenon of loosing tableting
properties during roller compaction is characteristic for plastic materials and since the
tablets produced from THAP, THAFP and THMO showed almost the same tensile
strength after roller compaction led to the conclusion that these materials showed
significantly less plastic behavior than MCC. Tablets composed of the mixture of 10%
Theophylline and 90% MCC showed the best compressibility and compactibility
properties.
In order to check the influence of roller compaction on disintegration and dissolution
rate, tablets with the same properties were produced from the original materials and
granules produced by roller compaction at pressure of 20 and 30 bars. Tablets of
THAP, THAFP and THMO produced by direct compaction and roller compaction
showed very slow disintegration because these materials do not show any
disintegrant properties and tablets were more dissolvable. Adding MCC to the tablets
formulation extremely improved disintegration, especially if tablets were produced by
roller compaction. During the dissolution process anhydrate underwent
transformation to monohydrate. However, during the dissolution process THAP and
THAFP were transformed to monohydrate and showed slightly higher dissolution rate
than THMO. This could be explained by different particles shape and surface area of
THMO and hydrate which was obtained from initially anhydrate surface. Due to the
faster disintegration rate of the tablets produced by roller compaction, dissolution rate
of these tablets was higher as well. As it was demonstrated that roller compaction
improves disintegration time and dissolution rate of the tablets it could be proposed
as a method of choice for immediate release tablets.