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Since the introduction of combinatorial chemistry and high-throughput screening in drug discovery in the early 1990s, the solubility of new chemical entities (NCE) decreased drastically while their lipophilicities increased greatly. Characterizing physicochemical properties of low soluble molecules can be especially challenging, since such molecules can undergo complicated reactions in aqueous solution, such as forming precipitates or complexes with buffer species or undergoing self-aggregation (dimer, trimer, etc.) or micelle formations. Most drugs are ionizable. Foremost to the rational interpretation of solution behavior of ionizable drugs in a physiologically-relevant pH domain requires an accurate aqueous pKa, determined by a suitable method. In a pH-dependent measurement of a property (e.g. solubility-, lipophilicity-, permeability-pH), when the apparent pKa value is different from the true aqueous pKa value, it may be an early clue that nonideal solution behavior may be taking place. In pharmaceutical research, it may seem cost-effective to use calculated pKa instead of measured values, but paradoxically, such preference can lead to inaccurate rationalization of the pH-dependent behavior of the drug molecule. For simple molecules, calculated values can be useful, but for today’s new drugs or for molecules prone to complicated solution behavior, the use of calculated pKas can substantially wrench the interpretation of solution properties. Clofazimine (CFZ), although discovered about 66 years ago, and used therapeutically for nearly 40 years, exhibits some of the properties of relatively recent drug molecules by being extremely water insoluble and having variable pKa values reported. We have recently combined potentiometric titrations and UV/Vis spectrophotometry in methanol-water cosolvent media, accompanied by DFT calculations, to assess the hypothesis of CFZ free base dimerization. We reasoned that a soluble dimer might form from drug-drug adhesion along the

Methods for drug solubilization have become important part of modern drug discovery and development due to increasing number of extremely insoluble drugs and drug candidates. One of such methods is acid-base supersolubilization (ABS) [1]. Clofazimine (CFZ) is weakly basic antibiotic and anti-inflammatory drug, most notably used in the treatment of leprosy and tuberculosis, with recently proven inhibitory activity against several coronaviruses [2]. We have recently unraveled its aqueous pKa value and its unique cosolvent dependence [3]. The aim of the present study was to investigate CFZ solubilization using the ABS approach. Eight small organic acids were tested for the ABS effect (glutaric, malic, tartaric, citric, malonic, maleic, succinic, adipic) but only glutaric (GA), malic (MA), and tartaric (TA) acids showed some solubilization effect. The effect of their concentration (and the solution pH value) was further tested. The solubility of CFZ was determined in GA, MA, and TA solutions in wide concentration (1.0×10-2 – 5.0 M) and pH range (~0.2 – 4.8). Equilibration time was 24 hours (6 h of stirring + 18 h of sedimentation). Phases were separated by filtration. The CFZ concentration in supernatant was determined by HPLC-UV/VIS. Results show that CFZ solubility increases as acid concentration increases: from 3.04×10-3 to 10.68 mg/mL (in GA), from 9.06×10-3 to 1.23 mg/mL (in MA) and from 4.76×10-3 to 0.32 mg/mL (in TA). The effect of CFZ solubilization is much more pronounced when the acid concentration is raised above 2 M. These results can be used as the basis for further CFZ formulation optimization. Furthermore, our ongoing research is focused on the type of interactions and other possible factors that can influence CFZ and other prectically insoluble drugs, embracing (super)solubilization as a general methodology in drug design and development.

Since the introduction of combinatorial chemistry and high-throughput screening in drug discovery in the early 1990s, the solubility of new chemical entities (NCE) decreased drastically while their lipophilicities increased greatly. Characterizing physicochemical properties of low soluble molecules can be especially challenging, since such molecules can undergo complicated reactions in aqueous solution, such as forming precipitates or complexes with buffer species or undergoing self-aggregation (dimer, trimer, etc.)1,2 or micelle formations. Most drugs are ionizable. Foremost to the rational interpretation of solution behavior of ionizable drugs in a physiologically-relevant pH domain requires an accurate aqueous pKa, determined by a suitable method. In a pH-dependent measurement of a property (e.g. solubility-, lipophilicity-, permeability-pH), when the apparent pKa value is different from the true aqueous pKa value, it may be an early clue that nonideal solution behavior may be taking place. In pharmaceutical research, it may seem cost-effective to use calculated pKa instead of measured values, but paradoxically, such preference can lead to inaccurate rationalization of the pH-dependent behavior of the drug molecule. For simple molecules, calculated values can be useful, but for today’s new drugs or for molecules prone to complicated solution behavior, the use of calculated pKas can substantially wrench the interpretation of solution properties. Clofazimine (CFZ), although discovered about 66 years ago, and used therapeutically for nearly 40 years, exhibits some of the properties of relatively recent drug molecules by being extremely water insoluble and having variable pKa values reported. We have recently combined potentiometric titrations and UV/Vis spectrophotometry in methanol-water cosolvent media, accompanied by DFT calculations, to assess the hypothesis of CFZ free base dimerization. We reasoned that a soluble dimer might form from drug-drug adhesion along

The in-person workshop “Drug Dissolution in Oral Drug Absorption” was held on May 23–24, 2023, in Baltimore, MD, USA. The workshop was organized into lectures and breakout sessions. Three common topics that were re-visited by various lecturers were amorphous solid dispersions (ASDs), dissolution/permeation interplay, and in vitro methods to predict in vivo biopharmaceutics performance and risk. Topics that repeatedly surfaced across breakout sessions were the following: (1) meaning and assessment of “dissolved drug,” particularly of poorly water soluble drug in colloidal environments (e.g., fed conditions, ASDs); (2) potential limitations of a test that employs sink conditions for a poorly water soluble drug; (3) non-compendial methods (e.g., two-stage or multi-stage method, dissolution/permeation methods); (4) non-compendial conditions (e.g., apex vessels, non-sink conditions); and (5) potential benefit of having both a quality control method for batch release and a biopredictive/biorelevant method for biowaiver or bridging scenarios. An identified obstacle to non-compendial methods is the uncertainty of global regulatory acceptance of such methods.

The solubility of a model basic drug, nortriptyline (Nor), was investigated as a function of pH in phosphate and/or a chloride-containing aqueous suspension using experimental practices recommended in the previously published “white paper” (Avdeef et al., 2016). The pH-Ramp Shake-Flask (pHRSF) method, introduced in our earlier work (Marković et al., 2019), was applied. An improved and more detailed experimental design of the Nor solubility measurement allowed us to exploit the full capacity of the pH-RSF method. Complex equilibria in the aqueous phase (cationic and anionic complex formation between Nor and the phosphate) and solid-phase transformations (Nor free base, 1:1 Nor hydrochloride salt, 1:1 and 1:2 Nor phosphate salts) were characterized by a detailed analysis of the solubility measurements using the computer program pDISOL-X. The solid phases were characterized by thermogravimetric analysis, differential scanning calorimetry, powder X-ray diffraction, and elemental analyses. The results of the present investigation illustrate the influence of competing counterions, such as buffering agents, complexing agents, salt coformers, tonicity adjusters, and so forth, on the aqueous solubility of drugs and interconversion of salts. Careful attention given to these factors can be helpful in the formulation of drug products.

The solubility of a model basic drug, nortriptyline (Nor), was investigated as a function of pH in phosphate and/or a chloride-containing aqueous suspension using experimental practices recommended in the previously published “white paper” (Avdeef et al., 2016). The pH-Ramp Shake-Flask (pHRSF) method, introduced in our earlier work (Marković et al.,2019), was applied. An improved and more detailed experimentaldesign of the Nor solubility measurement allowed us to exploit thefull capacity of the pH-RSF method. Complex equilibria in theaqueous phase (cationic and anionic complex formation betweenNor and the phosphate) and solid-phase transformations (Nor freebase, 1:1 Nor hydrochloride salt, 1:1 and 1:2 Nor phosphate salts)were characterized by a detailed analysis of the solubilitymeasurements using the computer program pDISOL-X. The solid phases were characterized by thermogravimetric analysis,differential scanning calorimetry, powder X-ray diffraction, and elemental analyses. The results of the present investigation illustratethe influence of competing counterions, such as buffering agents, complexing agents, salt coformers, tonicity adjusters, and so forth,on the aqueous solubility of drugs and interconversion of salts. Careful attention given to these factors can be helpful in theformulation of drug products.