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 Kollidon® 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.

Introduction

Recent data indicates that approximately 40 % of marketed drugs and nearly 90 % of new chemical entities in development fall under Classes II and IV of the Biopharmaceutics Classification System (BCS). These classes are characterised by poor solubility and variable permeability: Class II drugs exhibit good permeability but poor solubility, while Class IV drugs have both poor solubility and poor permeability (Kalepu and Nekkanti, 2015; Bhalani et al., 2022; Andreas et al., 2018; Rosenberger et al., 2018).

To address the growing number of poorly soluble drugs, amorphous solid dispersions (ASDs) have gathered significant interest in recent decades (Pandi et al., 2020; Moseson et al., 2024). ASDs consist of the drug dispersed at the molecular level within a hydrophilic polymer matrix. In the amorphous phase, drug molecules are disordered, leading to an increased dissolution rate (Lin et al., 2018; Démuth et al., 2015). This improved dissolution is further enhanced by increased wettability from the hydrophilic carrier and reduced drug agglomeration (Feng et al., 2018). The amorphous state can enhance solubility up to 1600-fold compared to the crystalline form (Lakshman et al., 2008). However, amorphous solid dispersions (ASDs) face stability challenges due to their disordered molecular structure and the higher free energy associated with the amorphous state (Vasconcelos et al., 2016). While the amorphization itself does not prevent recrystallization, the resulting steric hindrance and non-covalent bonding between the drug and polymer can mitigate this process (Li et al., 2015; Crowley et al., 2007). These interactions create a miscible one-phase system with a negative Gibbs free energy, promoting stability (Agrawal et al., 2013). Key factors affecting ASD stability include the glass transition temperature (Tg), molecular mobility, drug-polymer miscibility, drug molecular weight, recrystallization temperature, and storage conditions (Lin et al., 2018).

Itraconazole (ITZ) was selected as the model drug for this study, representing an extreme case of a BCS Class II drug due to its bioavailability being limited by its dissolution rate in the gastrointestinal tract (Verreck et al., 2003). ITZ is highly permeable, with a logP of 5.66 at pH 8.11, but has low solubility, less than 1 ng/mL at neutral pH in aqueous solution (Miller et al., 2008). As a weakly basic drug, its solubility is pH-dependent, increasing in acidic conditions due to ionization (Dinunzio et al., 2012; Sarode et al., 2013). ITZ is a synthetic, triazole-based, lipophilic, and hydrophobic compound (Miller et al., 2008). Despite its polar rings, which theoretically should interact with water, ITZ’s large molar mass (705.64 g/mol) and numerous non-polar Csingle bondH bonds contribute to its poor solubility (Reintjes, 2011).
Interestingly, ITZ also exhibits a unique morphology, forming multiple liquid crystal (LC) phases, particularly the thermotropic nematic and smectic A phases. These phases lie between crystalline and isotropic states, maintaining molecular order along specific axes (Atassi et al., 2013). The impact of this LC behavior, coupled with ITZ’s highly anisotropic, rod-like structure (Mugheirbi and Tajber, 2015), on ASD formation has not been extensively studied, adding complexity to ITZ product formulation.

Various strategies have been explored to enhance ITZ’s solubility, including co-crystals, cyclodextrin complexation, surfactant addition, mesoporous silica, self-emulsifying formulations, lipid nanoparticles, polymeric micelles, nanosuspensions, and solid dispersions (Anjum et al., 2024; Dhumal et al., 2024; Huang et al., 2022; Zhang et al., 2013). More advanced formulations include nanoparticles, ordered mesoporous silica, cyclodextrin nanosponges, laponite nanohybrids, and electrospun nanofibers (Engers et al., 2010).

Studies have shown that ITZ-polymer formulations, particularly those with Soluplus® (SOL), Kollidon® VA64 (KVA64), and HPMC, significantly increase ITZ solubility (Six et al., 2003b; Verreck et al., 2003; Zhang et al., 2013; Thiry et al., 2016; Davis et al., 2018). For example, Onmel®, a marketed ITZ melt extrusion product, contains 40 % ITZ and 60 % HPMC, offering a 2.3-fold increase in oral bioavailability compared to Sporanox® capsules (Repka et al., 2018).
Quality by Design (QbD) principles and data-driven models were used to track critical quality attributes (CQAs) in production. The integration of established PAT tools such as NIR, Raman, and UV–Vis spectroscopy in Hot Melt Extrusion (HME) has significantly improved pharmaceutical manufacturing efficiency, as documented in prior studies (e.g., Patel et al., 2023; Kumar and Singh, 2023; Almeida et al., 2020; Wesholowski et al., 2018; Schlindwein et al., 2018).

These tools allow real-time monitoring and immediate adjustments to critical process parameters, ensuring consistent product quality, reducing batch failures, and minimizing end-product testing. The integration of PAT directly into HME improves control over the extrudate’s composition, reduces waste, boosts production speed, and lowers quality control costs. Additionally, PAT supports regulatory compliance by providing detailed process documentation and traceability, essential for pharmaceutical safety. This approach not only ensures regulatory compliance but also fosters innovation, making HME processes more efficient and cost-effective (Smith and Robinson, 2024).

This study focuses on the application of real-time in-line Process Analytical Technology (PAT) to monitor product quality during the manufacturing of amorphous solid dispersions (ASDs) and explores the effects of low ITZ concentrations on UV–Vis spectral changes. These findings are supplemented by density functional theory (DFT) simulations and infra-red spectroscopy analysis. Furthermore, we investigate the effects of shear forces during extrusion on UV–Vis spectral outcomes, revealing previously unreported conformational changes within the ITZ-KVA64 ASD system. This approach not only enhances the understanding of the formulation but also contributes to the development of more robust manufacturing processes in pharmaceutical production.

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Materials

Itraconazole (ITZ), the active ingredient, was purchased from Wessex fine chemicals (Kent, UK). Kollidon® VA64 (KVA64) was donated by BASF (Germany). Onset melting, degradation and glass transition temperatures for ITZ are 166.6 °C, 200–220 °C and 59–65 °C (amorphous ITZ) respectively. KVA64 has a glass transition of around 105 °C.

Hetvi Triboandas, Mariana Bezerra, Juan Almeida, Matheus de Castro, Bianca Aloise Maneira Corrêa Santos, Walkiria Schlindwein, Optimizing extrusion processes and understanding conformational changes in itraconazole amorphous solid dispersions using in-line UV–Vis spectroscopy and QbD principles, International Journal of Pharmaceutics: X, Volume 8, 2024, 100308, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2024.100308.

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