Modelling the Effect of Process Parameters on the Wet Extrusion and Spheronisation of High-Loaded Nicotinamide Pellets Using a Quality by Design Approach

Abstract

The aim of the present study was to develop an alternative process to spray granulation in order to prepare high loaded spherical nicotinamide (NAM) pellets by wet extrusion and spheronisation. Therefore, a quality by design approach was implemented to model the effect of the process parameters of the extrusion-spheronisation process on the roundness, roughness and useable yield of the obtained pellets. The obtained results were compared to spray granulated NAM particles regarding their characteristics and their release profile in vitro after the application of an ileocolon targeted shellac coating. The wet extrusion-spheronisation process was able to form highly loaded NAM pellets (80%) with a spherical shape and a high useable yield of about 90%. However, the water content range was rather narrow between 24.7% and 21.3%. The design of experiments (DoE), showed that the spheronisation conditions speed, time and load had a greater impact on the quality attributes of the pellets than the extrusion conditions screw design, screw speed and solid feed rate (hopper speed). The best results were obtained using a low load (15 g) combined with a high rotation speed (900 m/min) and a low time (3⁻3.5 min). In comparison to spray granulated NAM pellets, the extruded NAM pellets resulted in a higher roughness and a higher useable yield (63% vs. 92%). Finally, the coating and dissolution test showed that the extruded and spheronised pellets are also suitable for a protective coating with an ileocolonic release profile. Due to its lower specific surface area, the required shellac concentration could be reduced while maintaining the release profile.

Keywords: controlled release; design of experiment (DoE); niacin; quality by design; wet extrusion-spheronisation.

Figure 1

Configuration of the two different screw designs (L1 and L2) used in the present extrusion DoE. The red boxes highlight the differences between the L1 and L2 configurations.

Figure 2

NAM-MCC pellets (80%:20%) after extrusion and spheronisation (3 min, 15 g) with different solid feed rates (g/min): 5.3 (A), 5.5 (B), 5.6 (C), 6.2 (D), 6.4 (E), 6.6 (F), 6.7 (G), 7.4 (H), 7.9 (I). The granulating liquid was distilled water with a constant feed of 1.74 g/min.

Figure 3

Particle size distribution (%) after sieve analysis of NAM-MCC pellets (80%:20%) after extrusion and spheronisation (3 min, 15 g) with different solid feed rates (g/min). The granulating liquid was distilled water with a constant feed of 1.74 g/min.

Figure 4

(A) Effect of solid feed rate (g/min) on moisture content of wet extrudates (NAM: MCC; 80%:20%) and (B) the resulting shape of spheronised particles. The granulating liquid was distilled water with a constant feed of 1.74 g/min.

Figure 5

Interaction profiles of the extrusion process variables hopper speed and screw design on the responses roundness (A), roughness (B), useable yield (C), process yield SD (D) and moisture content (E).

Figure 6

SEM pictures of spheronised NAM: MCC-particles after DoE for extrusion process with screw design L1 (A) and L2 (B) with varying screw speed (y-axis) and hopper speed (x-axis).

Figure 7

Proposed extrusion configurations for a maximized desirability of all responses (CQAs) measured (useable yield, process yield SD, roughness, roundness, moisture content).

Figure 8

Interaction profiles of the spheronisation process variables rotation time, speed and load on the responses roundness (A), roughness (B), useable yield (C) and spheronisation yield (D).

Figure 9

SEM pictures of spheronised NAM: MCC-particles after DoE for spheronisation process with the highest spheroniser load (65 g) (A), midpoint of the spheroniser load (40 g) (B) and the lowest spheroniser load (15 g) (C) with varying spheronisation speed (y-axis) and time (x-axis).

Figure 10

Proposed spheronisation configurations for a maximized desirability of all responses.

Figure 11

SEM pictures of spheronised particles (NAM: MCC) of three different runs (A–C) with the same process parameter constellation. Extrusion: screw design L1, screw speed 200 rpm, hopper speed set to 270 (6.6 g/min); Spheronisation: speed 100%, load 15 g, time 3.5 min. Magnification: 50-times, 100-times and 1000-times from left to right.

Figure 12

Particle size distribution of spray granulated NAM pellets.

Figure 13

SEM pictures of NAM pellets produced by spray granulation.

Figure 14

Release rate of NAM from (A) uncoated spray granulated and extruded NAM and (B) from triple shellac coated spray granulated and extruded NAM pellets with a coating thickness of 3.7/4.9/6.2 mg/cm² and 3.6/4.6/6.0 mg/cm² and (C) from triple shellac coated extruded NAM pellets with a coating thickness of 5.8/7.6/10.0 mg/cm² at simulated gastrointestinal conditions (mean ± SD; n = 2).