RESUMEN
Improvement in drug solubility is a major challenge for developing pharmaceutical products. It was demonstrated earlier that aqueous solubilities of weakly basic drugs could be increased greatly by interaction with weak acids that would not form salts with the drugs, and the highly concentrated solutions thus produced converted to amorphous solids upon drying. The technique was called acid-base supersolubilization (ABS). The current investigation explored whether the ABS principle could also be applied to weakly acidic drugs. By taking flurbiprofen (pKa 4.09; free acid solubility 0.011 mg/mL) as the model weakly acidic drug and tromethamine, lysine, meglumine, and NaOH as bases, it was studied which of the bases would result in ABS. While in the presence of NaOH and tromethamine, flurbiprofen converted to salts having aqueous solubility of 11-19 mg/mL, the solubility increased to > 399 mg/mL with lysine and > 358 mg/mL with meglumine, producing supersolubilization. However, crystallization of lysine salt was observed with time, followed by some decrease in solubility after reaching maximum solubility with lysine. In contrast, the supersolubilization was maintained with meglumine, and no crystallization of meglumine salt was observed. Upon drying, flurbiprofen-meglumine solutions produced amorphous materials that dissolved rapidly and produced high drug concentrations in aqueous media. Thus, the ABS principle also applies to acidic drugs depending on the weak base used.
RESUMEN
BACKGROUND: Pharmaceutical salts of poorly soluble drugs typically dissolve faster than their corresponding free acid or base, resulting in supersaturation under some circumstances. The key questions relevant to drug bioavailability "does the salt invoke the supersaturated state?" and, if so, "does precipitation occur?" remain. To answer these questions, different types of dissolution equipment are often used at different stages of the development process. AIM: To compare the dissolution behaviour of ibuprofen and its sodium and lysine salts in the USP 2 apparatus and the µDISS Profiler™ apparatus. The dissolution, supersaturation of the salt forms and precipitation to the free acid of ibuprofen were characterized along with the dissolution of the free acid form. METHODS: Media containing different concentrations of the salt-forming counterions - sodium and lysine - were used to investigate the influence of the type of dissolution apparatus used for the study on dissolution, supersaturation and precipitation behaviour. KEY RESULTS: Supersaturation was observed for both the sodium and lysinate salts of ibuprofen in all USP 2 apparatus and µDISS Profiler™ experiments. However, precipitation tended to be far greater in the µDISS Profiler™ than in the USP 2 apparatus. The difference was most pronounced in pH 4.5 acetate buffer, in which precipitation was observed exclusively in experiments with the µDISS Profiler™. CONCLUSION: Choice of dissolution apparatus can affect the dissolution/supersaturation/precipitation characteristics of pharmaceutical salts. This has to be carefully taken into account when investigating salts over different stages of pharmaceutical research and development.