by Xiaoyue Xu, Holger Grohganz and Thomas Rades from the Department of Pharmacy, University of Copenhagen
Water is generally regarded as a universal plasticizer of amorphous drugs or amorphous drug containing systems. A decrease in glass transition temperature (Tg) is considered the general result of this plasticizing effect. A recent study however, exhibited that water can increase the Tg of amorphous prilocaine (PRL) and thus shows an anti-plasticizing effect.1 The structurally similar drug lidocaine (LID) might show similar interactions with water, and thus an anti-plasticizing effect of water is hypothesized to also occur for amorphous LID. However, the influence of water on the Tg of LID cannot be determined directly due to the very low stability of LID in the amorphous form. The aim of this study was to investigate, if water acts as an anti-plasticizer for LID. It is possible to extrapolate the Tg of LID from co-amorphous systems of PRL-LID using the Gordon-Taylor equation. The Tg of hydrated LID can be predicted upon addition of water to co-amorphous PRL-LID systems. Overall, an anti-plasticizing effect of water on LID would be expected if the Tg of hydrated LID was higher than that of water-free amorphous LID.
Conventional and modified Gordon-Taylor equations
The conventional Gordon-Taylor equation is commonly used to estimate the Tg of the binary systems without consideration of additional interactions
A modified version can also be applied to co-amorphous systems with interactions.2 Here it is hypothesized that an excess amorphous component is ideally molecularly dispersed in the optimal co-amorphous system.
Prediction of the Tg of LID
Due to the high crystallization tendency of LID, co-amorphous mixtures were limited to the compositions containing a molar ratio of PRL of 0.3 and above. Figure 1A shows a fitting of the experimental Tgs of PRL-LID according to the conventional Gordon-Taylor equation. A particularly large deviation was observed from the fitting data. Therefore, strong hydrogen bonds might be possible between PRL and LID, resulting in a deviation from the theoretical Tg line.
For predictive purposes, using the modified Gordon-Taylor equation, the optimal co-amorphous system and the excess amorphous drug are assumed to be the two components to predict the Tg of LID. The optimal co-amorphous PRL-LID system was estimated to be at a molar ratio of PRL of 0.6. As shown in Figure 1B, the experimental Tgs followed the new theoretical Tgs. The Tg of LID was found to be 209.8±0.5 K.
Figure 1. Comparison between the experimental Tgs and the theoretical Tgs based on the conventional (A) and modified (B) Gordon-Taylor equations.
Prediction of the Tg of hydrated LID
Water was estimated to interact with PRL and LID molecularly evenly. The optimal hydrated co-amorphous PRL-LID system was estimated to be at a molar ratio of PRL of 0.7. The experimental Tgs of hydrated PRL-LID with a molar ratio of PRL below 0.7 were used to extrapolate the Tg of hydrated LID. The Tg of hydrated LID was found to be 210.7±0.5 K (Figure 2, red dots).
Figure 2. Comparison between the experimental Tgs and the theoretical Tgs of PRL-LID and hydrated PRL-LID based on the modified Gordon-Taylor equation.
The Tg of fully hydrated LID was found to have increased by 0.9±0.7 K compared with the Tg of anhydrous LID. It could be shown that water exhibited a small anti-plasticizing effect on LID.
The full version of this article can be consulted at: https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.2c00339
Xiaoyue Xu acknowledges the China Scholarship Council (Grant 202008420212) for financial support.
 Ruiz, G. N.; Romanini, M.; Hauptmann, A.; Loerting, T.; Shalaev, E.; Tamarit, J. L.; Pardo, L. C.; Macovez, R. Genuine antiplasticizing effect of water on a glass-former drug. Sci. Rep. 2017, 7 (1), 7470-7470. DOI: 10.1038/s41598-017-07643-5.
 Jensen, K. T.; Larsen, F. H.; Lobmann, K.; Rades, T.; Grohganz, H. Influence of variation in molar ratio on co-amorphous drug-amino acid systems. Eur. J. Pharm. Biopharm. 2016, 107, 32-39. DOI: 10.1016/j.ejpb.2016.06.020.