Specific surface area of mannitol rather than particle size dominant the dissolution rate of poorly water-soluble drug tablets: A study of binary mixture

The dissolution behavior of tablets, particularly those containing poorly water-soluble drugs, is a critical factor in determining their absorption and therapeutic efficacy. Traditionally, the particle size of excipients has been considered a key property affecting tablet dissolution. However, lurasidone hydrochloride (LH) tablets prepared by similar particle size mannitol, namely M200 (D90 = 209.68 ± 1.42 μm) and 160C (D90 = 195.38 ± 6.87 μm), exhibiting significant differences in their dissolution behavior. In order to find the fundamental influential factors of mannitol influencing the dissolution of LH tablets, the properties (particle size, water content, true density, bulk density, tapped density, specific surface area, circularity, surface free energy, mechanical properties and flowability) of five grades mannitol including M200 and 160C were investigated.


  • The dissolution of lurasidone hydrochloride (LH) tablets containing different grades mannitol with similar particle size varied unexpectedly.
  • The key property of mannitol affecting tablet dissolving is specific surface area (SSA).
  • By affecting drug-drug bonding, SSA, rather than particle size, of mannitol affects the percolation threshold state of the tablet.
  • Increasing SSA of excipient: a promising strategy for development novel excipient grade aiming at improving drug dissolution functionality.

Principal component analysis (PCA) was used to establish a relationship between mannitol properties and the dissolution behavior of LH. The results demonstrated that specific surface area (SSA) emerged as the key property influencing the dissolution of LH tablets. Moreover, our investigation based on the percolation theory provided further insights that the SSA of mannitol influences the probability of LH-LH bonding and LH infinite cluster formation, resulting in the different percolation threshold states, then led to different dissolution behaviors.

Importantly, it is worth noting that these findings do not invalidate previous conclusions, as reducing particle size generally increases SSA, thereby affecting the percolation threshold and dissolution behavior of LH. Instead, this study provides a deeper understanding of the underlying role played by excipient SSA in the dissolution of drug tablets. This study provides valuable guidance for the development of novel excipients aimed at improving drug dissolution functionality.

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Five grades of mannitol i.e., Pearlitol 25C, 50C and 160C (Roquette, Lestrem, France), Parteck M100 and M200 (Merck, Darmstadt, Germany) were studied. 25C-5 (D50 = 5.97 ± 0.14 μm) was obtained by grinding 25C continuously in an air jet crusher (Jet mill lab, Noozle Fluid Technology Co., Ltd., Shanghai, China) 5 times. The purity of lurasidone hydrochloride (Changzhou Yinsheng Pharmacy Co., Ltd., Jiangsu, China) is 99.0 %. Magnesium stearate (Anhui Sunhere Pharmaceutical Excipients Co., Ltd..

Ke Zhang, Shuai Qian, Zhenjing Liu, Huina Liu, Zezhi Lin, Weili Heng, Yuan Gao, Jianjun Zhang, Yuanfen Wei,
Specific surface area of mannitol rather than particle size dominant the dissolution rate of poorly water-soluble drug tablets: A study of binary mixture, International Journal of Pharmaceutics, 2024, 124280, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124280.

Read also our introduction article on Mannitol here:

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