Hydrodynamics and Dissolution
Steffen Diebold, Ph.D.
University of Frankfurt, Germany

The objectives of the present study were to (1) examine the hydrodynamics of compendial in vitro dissolution test apparatuses and to examine the respective in vivo gastrointestinal hydrodynamics in dogs, (2) describe the influence of hydrodynamics on the dissolution rates of poorly soluble drugs, and, (3) develop a hydrodynamic based model to a priori predict the dissolution rates of poorly soluble compounds.

· Hydrodynamics of compendial dissolution test apparatuses (paddle and basket) were directly characterized by means of an ultrasound pulse echo method. The fluid velocities within the dissolution vessels correlated well and in a linear manner with the rotational speed (rpm) of the paddle and the basket. Therefore, on the basis of this correlation, it was possible to calculate the velocities of the dissolution media at any rotational speed. Fluid velocities were determined using the basket method to range between 0.3 and 5 cm/s (25 to 200 rpm) and for the paddle method to range between 1.8 and 37 cm/s. However, the empirical based knowledge of the fluid velocities enables the in vitro prediction of dissolution rates for pure drugs. To verify this hypothesis, mass transfer rates were calculated using a modified and adapted form of the convective diffusion theory by V.G. Levich, by the so called "Kombinations-Modell". The calculated dissolution rates for different felodipine powders and for oxygen were compared with the empirical dissolution rate data. The validity of the "Kombinations-Modell" was approved by excellent agreement between experimental and the predicted data. In this context oxygen was used as a vector for hydrodynamic purposes for the first time. In fact, the paddle hydrodynamics did not discriminate between the different states of aggregation of the two model compounds, namely oxygen (gas) and felodipine (solid). Using the paddle method Reynolds numbers between Re=2292 to Re=31025 were determined. In contrast however, Reynolds numbers determined using the basket apparatus ranged from Re=231 to Re=4541. With respect to changes in hydrodynamic conditions particles of coarse grade felodipine were found to be more sensitive than micronized material of the same chemical species.

· A scintigraphic method was established to modulate intestinal hydrodynamics and subsequently describe gastric emptying and intestinal transit of caloric and non-caloric fluids in labradors. For orally administered solutions the time needed for total gastric emptying (GE>95%) was found to depend on volume and caloric content. The GE>95% for 200 mL of 20 % aqueous glucose solution differed significantly (287 min.) from the GE>95% for the same volume of 0.9 % sodium chloride solution (97 min.). After administration of 20 % glucose solution the mean duodeno-jejunal transit rate (MTR) was determined to be 2.7 cm/min. This was significantly different from measured MTR after administration of the same volume of 0.9 % sodium chloride solution (1.1 cm/min.). Duodeno-jejunal transit was determined not to correlate with gastric emptying. Gastrointestinal flow rates were detemined using an aspiration method. After administration of 200 mL of 20 % glucose solution the intestinal flow rates ranged from 20 to 60 mL/min. with a median value of 8.3 mL/min.. Following 200 mL of 0.9 % sodium chloride solution the intestinal flow rate reached a maximum of approximately 100 mL/min. with a median value of 35.0 mL/min.. The luminal dissolution rate of felodipine was determined to be greater following co-administration with hypertonic glucose than with 0.9 % saline. This correlated well with an increased intestinal fluid volume following oral administration of 20% glucose solution.

Editor's note: For complimentary copies of Dr. DIebold's published thesis, Hydrodynamics and Dissolution - Influence of Hydrodynamics on Dissolution Rate of Poorly soluble Drugs, Shaker Verlag, ISBN# 3-8265-7403-6, Aachen, Germany, please contact:
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