Miniaturization of Powder Dissolution Measurement and Estimation of Particle Size

Abstract

The objective was to investigate the applicability and limitations of an approach for estimating particle size from powder dissolution measurement using as little as 50 microg of sample in 1 ml of buffer solutions. The powder dissolution profiles of five sparingly-soluble drugs (hydrochlorothiazide, phenazopyridine hydrochloride, 2-naphthoic acid, indomethacin, and dipyridamole) were evaluated with a novel biexponential spherical particle equation and also the Wang-Flanagan spherical particle non-sink equation. The results were compared to particle sizing based on measured specific surface area by the Brunauer-Emmett-Teller (BET) method, and also based on Coulter counting. With the exception of hydrochlorothiazide, the model compounds indicated some agglomeration in the dissolution media. The dry-state specific surface area was larger than expected from either the Coulter method or the powder-dissolution data, especially for phenazopyridine hydrochloride. The particle radii estimated by the powder dissolution method ranged from 10 to 68 microm, with equilibrium solubilities spanning from 5 microg/ml (dipyridamole) to 911 microg/ml (hydrochlorothiazide). Powder dissolution data collected with the miniaturized apparatus can be used to determine particle size, with estimated values agreeing reasonably with those measured by the Coulter counter method.

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.…”

Powder Dissolution Method for Estimating Rotating Disk Intrinsic Dissolution Rates of Low Solubility Drugs

“…Concentrations were determined by considering area-underthe-curve (AUC) in second derivative spectra, evaluated over a range of wavelengths. Interference due to background turbidity in powder measurements is minimized by this spectral method (11)(12)(13)(14).…”

“…This is because h app << h disk for very small particles (12,(15)(16)(17)(18). With rotating disks, the diffusion layer thickness, h disk , is time independent.…”

“…Thus, API-sparing methods are critical to early adoption of dissolution testing (11)(12)(13). Additionally, these methods need to be media-sparing as well, especially when simulated intestinal fluid or human intestinal fluid is used.…”

“…The miniaturized-apparatus disk IDR values were compared to those determined by traditional equipment (taken from several studies) yielding a correlation coefficient r 2 = 0.99 (n = 31) (11). The API concentrations in the miniaturized apparatus were monitored in real time by an in situ dip-probe fiber optic UV method (11)(12)(13)(14).…”