The impact of lactose type on disintegration: An integral study on porosity and polymorphism

Besides factors such as disintegrant and lubricant, the raw material properties of filler excipients can have an impact on the disintegration behavior of a tablet. The current research aims to model the impact of lactose properties on disintegration time. For the first time, the impact of lactose polymorphism, tablet tensile strength, and pore structure parameters on disintegration were evaluated in one study. Six different lactose qualities were compacted into tablets of different solid fractions in a formulation with 5 %w/w diclofenac sodium, 1 %w/w magnesium stearate and 2 %w/w croscarmellose sodium.

A linear model was built to identify which parameters impact the disintegration time, using as potential variables the polymorphic composition of the lactose, the porosity, pore size distribution and the tablet tensile strength. The model variables were derived from literature and calibrated with data. After optimization, the model shows a strong correlation (r² = 0.982) between measured and predicted disintegration times. Among all investigated variables, the polymorphic composition of lactose, and the pore size distribution have been identified to affect tablet disintegration most. A higher concentration of lactose monohydrate in tablets leads to faster tablet disintegration, explained by the slower dissolution rate of lactose monohydrate compared to anhydrous and amorphous lactose. Tablet tensile strength was not identified as a direct driver for disintegration. Instead, the pore size distribution is a mutual driver for both tablet tensile strength and disintegration.

The obtained insights provide guidance on the importance of quality attributes of filler binders for the prediction of tablet disintegration. This study can therefore be used as a starting point for quality-by-design formulation development and for the development of mechanistic models to predict tablet disintegration.

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Materials

Spray dried lactose (SuperTab® 50ODT, SuperTab® 11SD and SuperTab® 14SD), granulated lactose (SuperTab® 30GR), anhydrous lactose (SuperTab® 21AN) and granulated anhydrous lactose (SuperTab® 24AN) were obtained from DFE Pharma (Goch, Germany). Formulations were prepared in portions of 500 g by blending 92 % w/w lactose with 5 % w/w diclofenac sodium (Fagron, Rotterdam) and 2 % w/w croscarmellose sodium (DFE Pharma, Goch, Germany) in a Turbula blender (Turbula T2F, Willy A. Bachofen, Basel, Switzerland) at 90 rpm for 8 min. Lubrication was performed by adding 1 % w/w magnesium stearate (Sigma Aldrich, Missouri) and blending for another 2 min at 90 rpm in a Turbula blender.

Pauline H.M. Janssen, Alberto Berardi, Jurjen H. Kok, Anthony W. Thornton, Bastiaan H.J. Dickhoff, The impact of lactose type on disintegration: An integral study on porosity and polymorphism, European Journal of Pharmaceutics and Biopharmaceutics, Volume 180, 2022, Pages 251-259, ISSN 0939-6411,
https://doi.org/10.1016/j.ejpb.2022.10.012.