Optimizing extrusion processes and understanding conformational changes in itraconazole amorphous solid dispersions using in-line UV-Vis spectroscopy and QbD principles

Abstract

This paper presents a comprehensive investigation of the manufacturing of itraconazole (ITZ) amorphous solid dispersions (ASDs) with Kolllidon® VA64 (KVA64) using hot-melt extrusion (HME) and in-line process monitoring, employing a Quality by Design (QbD) approach. A sequential Design of Experiments (DoE) strategy was utilized to optimize the manufacturing process, with in-line UV-Vis spectroscopy providing real-time monitoring. The first DoE used a fractional factorial screening design to evaluate critical process parameters (CPPs), revealing that ITZ concentration had the most significant impact on the product quality attributes. The second DoE, employing a central composite design, explored the interactions between feed rate and screw speed, using torque and absorbance at 370 nm as responses to develop a design space. Validation studies confirmed process robustness across multiple days, with stable in-line UV-Vis spectra and consistent product quality using 30 % ITZ, 300 rpm, 150 °C and 7 g/min as the optimized process conditions. Theoretical and experimental analyses indicated that shifts in UV-Vis spectra at different ITZ concentrations were due to conformational changes in ITZ, which were confirmed through density functional theory (DFT) calculations and infrared spectroscopy. This work offers novel insights into the production and monitoring of ITZ-KVA64-ASDs, demonstrating that in-line UV-Vis spectroscopy is a powerful tool for real-time process monitoring and/or control.

Keywords: Amorphous Solid Dispersion (ASD); Density Functional Theory (DFT); Design of Experiments (DoE); Hot-Melt Extrusion (HME); Itraconazole (ITZ); Quality by Design (QbD), In-line UV–Vis spectroscopy.

Graphical abstract

Fig. 1

a) Absorbance spectra for 11 runs of DoE 1: b) Baseline shift 1 for absorption values at 380 nm as a function of concentration of ITZ, c) L* values as a function of concentration of ITZ.

Fig. 2

PC1 (a) and PC2 (b) loadings for DoE 1.

Fig. 3

a) Score plot of the PCA, b) UV-Vis spectra for DoE 1. Four factors investigated (ITZ %, Temperature, Screw speed and Feed rate).

Fig. 4

Prediction profiler plots showing the relationship between the 3 responses (L*, Abs at 390 and 370 nm) and 4 factors investigated (ITZ %, Temperature, Screw speed and Feed rate).

Fig. 5

Absorbance results for DoE 2: a) Full Spectra with the 10 samples, b) runs at 5 g/min, c) runs at 7 g/min and d) runs at 9 g/min.

Fig. 6

PC1 (a) and PC2 (b) loadings for DoE 2.

Fig. 7

Plots for DoE 2. a) Score plot of the PCA. b) Prediction profiler showing the effect of screw speed and feed rate on the responses average torque and absorption at 370 nm. Interaction profile of the factors with respect to c) the average torque response and d) absorption at 370 nm responses.

Fig. 8

a) Design space obtained by modelling the abs at 370 nm and the average torque values for each run; verification points marked in the white borderline areas within the DS region (300 rpm and 7 g/min, 300 rpm and 6 g/min, 380 rpm and 7.5 g/min and 360 rpm and 8.5 g/min). b) UV-Vis spectra for the 4 verification samples. c) Validation runs performed at 3 different days within 4 to 6-month interval.

Fig. 9

In-line UV-Vis results for the low (full lines) and high (dotted lines, from DoE 1) concentration ITZ-KVA64-ASDs.

Fig. 10

a) Score plot for the low concentration samples (0.01 to 1 %) showing the FPC1 versus FPC2 scores, b) Eigenvalues for the FPCA, c) FPC1 and FPC2 versus wavelength.

Fig. 11

a) ITZ molecules with torsion points (highlighted in yellow and orange dotted circles) where rotamers were obtained, b) rotamer M0373, c) rotamer M0019, and d) alignment of six low-energy rotamers generated as listed in Table S3. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 12

Infrared spectra generated for the minimum energy (a) M0373 and (b) M0019 rotamers.

Fig. 13

FTIR spectra of 100 % pure ITZ, 20 % ITZ-KOL-ASD and 1 % ITZ-KOL-ASD. The shaded areas show the differences between high (20 %) and low (1 %) concentrations compared to 100 % ITZ.

Fig. 14

In-line and at-line UV-Vis spectra for 1 % and 20 % ITZ-KVA64-ASDs prepared with shear (HME) and without shear (vacuum compression molding – MeltPrep disc).