US 2019/0262453 Al  7  Aug. 29, 2019  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.  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.  [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  TABLE 2  TABLE 1  CFZ-HCl  (form B)  CFZ-2HC1  CFZ-Cl-2MeOH  chemical  C$_{27}$H$_{23}$Cl 3 N$_{4 }$ CnHn.16Cl3.76N4  C$_{29}$H 31 Cl 3 N$_{4}$ 0 2  formula  formula weight  509.84  537.46  573.93  T(K)  100  100  100  crystal system  triclinic  monoclinic  orthorhombic  space group  P-1  P2/c  Pbcn  a  (A)  8.754  12.073  14.151  b  (A)  12.178  15.270  13.796  C  (A)  12.589  14.612  28.103  a  (deg)  63.841  90  90  13 (deg)  80.740  111.04  90  y  (deg)  83.940  90  90  volume (A 3 )  1188.0  2514.20  5486.2  Dcalcd  (g cm- 3 )  1.425  1.420  1.390  z  2  4  8  R1  0.0331  0.0364  0.0319  wR$_{2 }$ 0.0760  0.0816  0.0823  GOF  1.074  1.052  1.040  Completeness  99.4%  99.8%  99.9%  Color  dark red  purple  red  Raloxifene  Doxorubicin  Solifenacin  (Vd in L/Kg unit)  2348  Irinotecan  15.2  Atorvastatin  5.4  682  Donepezil  14  Clozapine  5.4  671  Triarneterene  13.4  Buspirone  5.3  Hydroxychloroquine  525  Promethazine  13.4  Isotretinoin  5  Chloroquine  196.5 Citalopram  12.3 Verapamil  5  Loratadine  120  Sirolimus  12  Flecainide  4.9  Mitoxantrone  90  Posaconazole  11.9 Aripiprazole  4.9  Vinorelbine  76  Fluphenazine  11  Mirtazap ine  4.5  Amiodarone  66  Memantine  10.9 Cyclosporine  4.5  Tarnoxifen  55  Itraconazole  10.7 Diphenhydramine  4.5 