Insights into the Mechanism of Enhanced Dissolution in Solid Crystalline Formulations

Abstract

Solid dispersions are a promising approach to enhance the dissolution of poorly water-soluble drugs. Solid crystalline formulations show a fast drug dissolution and a high thermodynamic stability. To understand the mechanisms leading to the faster dissolution of solid crystalline formulations, physical mixtures of the poorly soluble drugs celecoxib, naproxen and phenytoin were investigated in the flow through cell (apparatus 4). The effect of drug load, hydrodynamics in the flow through cell and particle size reduction in co-milled physical mixtures were studied. A carrier- and drug-enabled dissolution could be distinguished. Below a certain drug load, the limit of drug load, carrier-enabled dissolution occurred, and above this value, the drug defined the dissolution rate. For a carrier-enabled behavior, the dissolution kinetics can be divided into a first fast phase, a second slow phase and a transition phase in between. This study contributes to the understanding of the dissolution mechanism in solid crystalline formulations and is thereby valuable for the process and formulation development.

Keywords: dissolution; dissolution enhancement; dissolution mechanism; flow through cell; formulation strategy.

Figure 1

Chemical structures of celecoxib (left), naproxen (middle) and phenytoin (right).

Figure 2

In vitro dissolution profiles of physical mixtures with different drug loads (w) and pure xylitol (orange plane) (av ± min/max; n = 3).

Figure 3

In vitro dissolution profiles of physical mixtures with a drug load of w = 0.5 wt.% with different Reynolds numbers (Re) in the flow through cell (apparatus 4) (av ± min/max; n = 3).

Figure 4

K_HC of the first dissolution phase (0–1 min) and the second phase (5–10 min) as a function of the Reynolds number (Re) in the flow through cell for physical mixtures of different drug loads w (av ± min/max; n = 3).

Figure 5

Ratio of the mean dissolution time (MDT_PM) of the physical mixture with drug content w and the MDT of pure xylitol (MDT_XYL) over the Reynolds number (Re) in the flow through cell (av ± min/max; n = 3).

Figure 6

Particle size distribution of drug particles co-milled with xylitol in a planetary ball mill for different milling times.

Figure 7

Thermograms of pure xylitol, pure drug, physical mixtures of celecoxib and naproxen unmilled and co-milled, and phenytoin unmilled and milled.

Figure 8

In vitro dissolution profiles of co-milled physical mixture, unmilled physical mixture (PM), and pure drug at a flow rate of 16 mL/min and a drug load of w = 1 wt.% (av ± min/max; n = 3).

Figure 9

K_HC in the first phase of drug dissolution, over the Sauter mean diameter of the drug particles of pure drug powder, unmilled and co-milled physical mixtures (av ± min/max; n = 3).

Figure 10

Schematic of the drug dissolution from solid crystalline formulations.