Hydrodynamik und Lösungsgeschwindigkeit - Untersuchungen zum Einfluss der Hydrodynamik auf die Lösungsgeschwindigkeit schwer wasserlöslicher Arzneistoffe (rev. Fassung 2022) : Hydrodynamics and Dissolution - Influence of Hydrodynamics on Dissolution Rate of Poorly Soluble Drugs (rev. version 2022)

Abstract

The objectives of the present study were to (1) examine both the hydrodynamics of compendial in vitro dissolution test apparatus as well as the respective in vivo gastrointestinal hydrodynamics in dogs, (2) describe the influence of hydrodynamics on the dissolution rates of poorly soluble drugs and (3) to develop a hydrodynamic based model to a priori predict dissolution rates of poorly soluble compounds. Hydrodynamics of compendial dissolution test apparatus (paddle and basket) were directly characterized by means of an ultrasound pulse echo method. Fluid velocities within the dissolution vessels correlated well and in a linear manner with the rotational speed (rpm) of both the paddle and basket test apparatus, respectively. Thus, based on this correlation, it was possible to calculate 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. These fluid velocity data, determined empirically here for the first time in compendial dissolution vessels, are a prerequisite to forecast drug substance dissolution rates in vitro. In order to calculate such mass transfer rates the so called "Kombinations-Modell" was developed. This model is based on the convective diffusion theory by V.G. Levich. Here, we applied it on coarse and micronized felodipine powders as drug substance models as well as on oxygen as a model / vector to study hydrodynamics independent of chemical nature or state of aggregation. As a result, predicted dissolution rate data, calculated by means of the combination model, were found to correspond well with the respective dissolution rates determined by experiment. As expected, hydrodynamics did not discriminate between different states of aggregation of the two model compounds oxygen (gas) and felodipine (solid). Using the paddle method Reynolds numbers from Re=2292 to Re=31025 were calculated. In contrast, 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 to subsequently study gastric emptying and intestinal transit of caloric and non-caloric fluids in labradors. For orally administered solutions time needed for total gastric emptying (GE>95%) was found to depend on both volume and caloric content. GE>95% for 200 ml of 20 % aqueous glucose solution differed significantly (278 min.) from 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.). However, duodeno-jejunal transit itself was found not to correlate with gastric emptying. Gastro-intestinal flow rates (= flow influenced also by gastric emptying) were determined using an aspiration method. After administration of 200 ml of 20 % glucose solution gastro-intestinal flow rates reached (short time) maxima from 20 to 60 ml/min. (median: 8.3 ml/min.). In contrast, gastro-intestinal flow rates were found to be significantly higher following administration of 200 ml of 0.9 % sodium chloride solution, exhibiting (short lasting) maxima of up to 100 ml/min. (median: 35.0 ml/min.). Luminal dissolution rate of felodipine was found to be greater following coadministration of hypertonic (!) glucose than following coadministration of 0.9 % saline. This result correlated well with an increased intestinal fluid volume (collected 76 cm distal to the pylorus) following oral administration of 20 % glucose solution.