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. 2018 Feb 13;8:2934. doi: 10.1038/s41598-018-21271-7

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© The Author(s) 2018

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Chemical characterization of CFZ. (a) Chemical structure of clofazimine (CFZ) with its two protonation sites and corresponding predicted (chemi-informatic) pK_a values (pK_a,1 = 2.31 and pK_a,2 = 9.29). (b) CFZ-H⁺Cl⁻ solubility-pH study revealed the solution pH dependence of the stabilization of the free base versus salt form of the drug with respect to its solubility parameters; which include the intrinsic free base solubility (S_o), apparent pK_a,2 (pK_a’), and pH_max. (c) Illustration showing the cellular and subcellular accumulation of free base CFZ, its subsequent protonation (CFZH⁺), and ion-ion interaction of CFZH⁺ and cellular Cl⁻ to form CFZ-H⁺Cl⁻. This phenomenon depends on the drug’s intrinsic solubility properties as well as the cellular pH and Cl⁻ levels, which are primarily regulated by membrane proteins: proton-pump known as V-ATPase and Cl⁻/H⁺ antiporter known as CLC7. (d) Stability of CLDIs, CFZ-H⁺Cl⁻, and free base CFZ in PBS (pH 7.4), lysosomal buffer without sodium chloride (LB−, pH 4.5), and lysosomal buffer with 100 mM sodium chloride (LB+, pH 4.5) was monitored via brightfield and fluorescence microscopy.