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to equal the dose-dependent rates by which proton and chloride ions get sequestered by CFZ. This allowed the model to determine a) the effect of introducing a proton and chloride sequestering drug into the lysosome on lysosomal pH, chloride, and membrane potential; and b) the accom› modative capability of the lysosome of hydrochloride drug salt by monitoring the changes in the lysosomal pH, chlo› ride, and membrane potential from their respective physi› ological values. As such, other drug candidates can be similarly characterized for their accumulation rates, inhib› ited state accumulation as well as overall macrophage› driven stability. 

[0080] In some embodiments, candidate drug salts are screened for stability by constructing a pH dependent solu› bility profile in aqueous media. Such a study was first established by Kramer and Flynn in 1972 to help charac› terize the relationship between the stabilization of free base versus salt form of a given drug molecule and the environ› mental pH. In some embodiments, in order to characterize the stabilizing role of macrophages on synthetic formula› tions in vivo, in vivo experiments are performed. In some embodiments, using mice as an experimental model, animals are treated with liposomal formulations of clodronate to selectively kill different macrophage populations, or with liposomal formulations of phosphate-buffered saline, to serve as a control. Following the depletion of macrophages, mice are treated with various synthetic drugs salts through a variety of routes of administration (intraperitoneal, intrave› nous, inhalation, etc.) depending on the specifics of the formulation. Following treatment with the synthetic formu› lations, the role of macrophages in stabilizing these formu› lations is established through the use of microscopic imag› ing and biochemical analysis of tissues. Using microscopic analysis, the presence of the physiologically insoluble drug aggregate in the tissues or macrophage populations is detected and quantified via fluorescence microscopy. Bio› chemically, the stabilizing role of macrophages on formu› lations is quantified by determining the concentration of drug found within various organs (liver, spleen, lung), as well as systemically by measuring the concentration of drug within the blood. Other drug candidates are similarly studied also via absorbance spectroscopy or HPLC analysis. 

[0081] In some embodiments, in order to characterize the stabilizing role of macrophages on synthetic formulations ex vivo, different macrophages are collected from mice, such as peritoneal, alveolar, and Kupffer cells of the liver. Once collected, the stabilizing role of the macrophage is deter› mined through the use of various pharmacological agents which interfere with cellular acidification processes, or which kill the cell itself. The proton-pump Vacuolar-type proton-ATPase (V-ATPase) is inhibited through treatment 

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with bafilomycin Al, resulting in a more alkaline endo› lysosomal environment. Cells are killed by treatment with staurosporine, which induces apoptosis within the cell. Fol› lowing treatment with the pharmacologic agent, macro› phages are exposed to the various synthetic formulations and the stability of the formulations within the cellular environ› ment is monitored. The internalization and stabilization is qualitatively monitored using microscopy, and can be quan› tified by measuring the total soluble drug released into the extracellular media at various time points throughout the experiment. 

[0082] In some embodiments, various drug polymorph formulations are tested for their response in an inflammatory environment in small animal models (rodents). Examples include, but are not limited to, carrageenan-induced footpad or joint inflannnation, monosodium urate-induced inflam› mation in the joints, lipopolysaccharide-induced inflamma› tion in the lungs, airpouch models to study local inflamma› tion responses etc. The full spectra of characterization on inflammatory response and treatment can be performed via common biomarkers analysis via immunohistochemistry (for cellular proliferation density and cell-types), western blots (for modification of common proteins and phosphory› lation events) and ELISAs (for cytokine/chemokine analysis such as TNFa, IL-1~ and IL-IRA). Drug stability can be measured via lH-NMR or HPLC of local tissue digests in these environments. 

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