Dissolution Rate and Apparent Solubility of Poorly Soluble Drugs in Biorelevant Dissolution Media

Abstract

A series of poorly soluble BCS class II compounds with "grease ball" characteristics were assessed for solubility and dissolution rate in biorelevant dissolution media (BDM) with the purpose of investigating which molecular structures gain most in solubility when dissolved under physiologically relevant conditions. The compounds were studied in four media (simulated intestinal fluid in fasted (FaSSIF pH 6.5) and fed state (FeSSIF pH 5.0), and their corresponding blank buffers (FaSSIF(blk) and FeSSIF(blk))) at a temperature of 37 °C. The experimental results were used to analyze which molecular characteristics are of importance for the solubility in BDM and for in silico modeling using multivariate data analysis. It was revealed that a majority of the compounds exhibited a higher dissolution rate and higher solubility in the FaSSIF and FeSSIF than in their corresponding blank buffers. Compounds which were neutral or carried a positive charge were more soluble in FeSSIF than FaSSIF. The acidic compounds displayed clear pH dependency, although the higher concentration of solubilizing agents in FeSSIF than FaSSIF also improved the solubility. Five of the ten compounds were upgraded to BCS class I when dissolved in FaSSIF or FeSSIF, i.e., the maximum dose of these compounds given orally was soluble in 250 mL of these BDMs. Lipophilicity as described by the log D(oct) value was identified as a good predictor of the solubilization ratio (R(2) = 0.74), and computed molecular descriptors were also shown to successfully predict the solubilities in BDM for this data set. To conclude, the physiological solubility of "grease ball" molecules may be largely underestimated in in vitro solubility assays unless BDM is used. Moreover, the results herein indicate that the improvement obtained in BDM may be possible to predict from chemical features alone.

Phosphate Precipitates and Water-Soluble Aggregates in Re-analyzed Solubility-pH Data of Twenty-five Basic Drugs

“…The analysis of the Bergström log S -pH data tested for the presence of solid species B(s), BH•Cl(s), BHB•Cl(s), BH•H 2 PO 4 (s), (BH) 2 •HPO 4 (s), BHB•H 2 PO 4 (s), (BHB) 2 •HPO 4 (s), (BH) 3 •H 2 PO 4 •HPO 4 (s), as well as water soluble cationic aggregates (BH) n and (BHB) n , n = 1-6, and the uncharged aggregate B 2 . Up to three different solids could be tested in a single calculation.…”

“…Perhaps as a result, the need for such analyses had not been widely appreciated. Yet, quantitative analysis of such complex reactions clearly would have beneficial impact in early drug development in terms of clearer interpretations of mechanistic dissolution studies involving salts of sparingly soluble drugs in complex media with which the drugs can directly interact (e.g., such as simulated intestinal fluids) [1][2][3][4][5]. Since salt solubility is a conditional constant, depending on the drug and the specific counterion concentrations, the determination of the thermodynamic solubility product allows for scalability of salt effects across a wide range of concentrations of substituents in formulation research.…”

Mathematical Models to Explore Potential Effects of Supersaturation and Precipitation on Oral Bioavailability of Poorly Soluble Drugs

“…The in vitro peak drug concentration and peak duration produced by supersaturating dosage forms are highly dependent on the drug, drug form, formulation components, and solution composition (5,(28)(29)(30)(31)(32)(33)38,39,(48)(49)(50). To bracket a range of bioavailability that could be reasonably expected from supersaturating dosage forms, two alternative assumptions were used: either (a) the duration of the peak drug concentration in vivo corresponds to the in vitro data or b) the drug concentration in vivo reaches the peak concentration observed during in vitro dissolution.…”

Suggested Improvements for Measurement of Equilibrium Solubility-pH of Ionizable Drugs

“…However, the miniaturized-volume dissolution apparatus, µDISS Profiler (Pion Inc.), uses 1.0 mL working volumes and makes it practical to determine solubility (Avdeef et al [69]; Avdeef and Tsinman [70]; Tsinman et al [71]; Avdeef et al [72]; Fagerberg et al [73]). Since the instrument uses in situ fiber optic UV (diode array) detection, the progression of dissolution may be followed in real time, making it possible to characterize the (transient) solubility of different polymorphs/solvates, over periods of days, if necessary.…”