Physical stability of salbutamol amorphous solid dispersion tablets measured by terahertz spectroscopy

Abstract

The physical stability of salbutamol amorphous solid dispersion (ASD) pharmaceutical tablets, manufactured via a novel strategy employing liquid drug feeding during hot-melt extrusion, was evaluated using terahertz time-domain spectroscopy (THz-TDS). A total of 41 salbutamol ASD pharmaceutical tablets were individually tracked for longitudinal assessment, and physical stability was demonstrated over 15 months with no detectable salbutamol crystals. The absorption coefficient spectra retained smooth, continuously increasing profiles, which match the vibrational density of states of amorphous solids. The absence of the crystalline salbutamol phonon mode at 0.98 THz was substantiated by first- and second-derivative spectral analyses. Temporal consistency in both absorption coefficient and refractive index spectra across all tablets further supported the lack of detectable crystallinity. These observations were equally demonstrated by the simpler, more straightforward and physically interpretable absorption coefficient ratio  of the salbutamol peak to the baseline. It was found that  is consistent over time and agrees with that of the salbutamol ASDs, whilst distinctively differentiating the pharmaceutical tablets from crystalline salbutamol. The direct, rapid, and non-destructive assessment of crystallinity, particularly via the simple, physically interpretable absorption coefficient ratio, makes THz-TDS advantageous for longitudinal stability studies and individual tracking of solid dosage forms during drug product development.

Introduction

Overcoming the limited solubility and bioavailability of Biopharmaceutics Classification System (BCS) class II drug candidates poses a persistent challenge in oral drug product development. Among the promising formulation strategies developed to address this challenge, amorphous solid dispersions (ASDs) have received increased interest over the past two decades (Moseson et al., 2024, Taylor and Zografi, 2025). ASDs are achieved by dispersing drug molecules in a polymer matrix. In ASDs, the drug molecules lack long-range order, have higher energy and greater mobility than in other solid forms. As a result, the drug molecules exhibit a greater tendency to dissolve readily in solution as they transition to a lower-energy, more stable state (Graeser et al., 2010, Grohganz et al., 2013, Laitinen et al., 2013, Taylor and Zografi, 2025). ASDs enhance drug solubility via supersaturation, and since the drug molecule is unaltered, the equilibrium solubility and permeability remain constant (Miller et al., 2012, Fine-Shamir and Dahan, 2024, Kawakami, 2019, Taylor and Zografi, 2025). A more optimal balance between solubility and permeability can thus be reached (Miller et al., 2012, Dahan et al., 2013, Dahan et al., 2016, Kawakami, 2019, Fine-Shamir and Dahan, 2024). This is in contrast to other methods such as cyclodextrins and micelles, where solubility enhancement is achieved but may compromise permeability (Miller et al., 2012, Kawakami, 2019, Fine-Shamir and Dahan, 2024).

Given the inherent metastable state of the drug’s amorphous solid form, ensuring the physical stability of ASDs in drug products is imperative. Physical stability of ASDs is defined by their ability to maintain an amorphous state in a single-phase, molecularly mixed dispersion (Newman et al., 2012, Bhujbal et al., 2021, Cools and Van den Mooter, 2025). A complex interplay of thermodynamic and kinetic factors, including drug–polymer miscibility, drug–polymer interactions, drug loading, glass forming ability (GFA), glass transition temperature, crystallisation tendency, temperature and humidity of the storage environment, contributes to physical stability (Cools and Van den Mooter, 2025).

Thermal, microscopic and spectroscopic techniques are commonly employed to characterise ASD physical stability (Baird and Taylor, 2012, Hitzer et al., 2017, Liu et al., 2018, Ma and Williams, 2019, Kawakami et al., 2025). Thermal methods such as differential scanning calorimetry (DSC) provide insights into crystallisation tendency yet often lack a direct correlation with physical stability in isothermal storage (Kawakami, 2019). Microscopic techniques such as scanning electron microscopy (SEM) and polarised light microscopy (PLM) offer high resolution for detecting incipient nucleation but are frequently limited by extensive sample preparation and/or specific material requirements (Tambe et al., 2022). Although powder X-ray diffraction (PXRD) is the primary method for identifying long-range order, it typically exhibits lower sensitivity than DSC in detecting trace crystallinity (Kawakami et al., 2025). Apart from dielectric spectroscopy, conventional spectroscopic tools, including Raman and infrared, may not be sufficient to directly probe the intermolecular interactions, specific relaxation and phonon modes associated with the amorphous to crystalline transition (Bhardwaj et al., 2014, Tambe et al., 2022).

The use of terahertz time-domain spectroscopy (THz-TDS) has been explored extensively in the pharmaceutical sciences (Zeitler, 2016), with a recent focus particularly on measuring porosity (Bawuah et al., 2023, Dong et al., 2024, Anuschek et al., 2025, Lee et al., 2025) and gaining mechanistic insights into tablet disintegration (Al-Sharabi et al., 2020, Ma et al., 2025). Despite this strong interest in using the technique for porosity and liquid transport measurements, it has long been established to provide exceptional sensitivity to probe solid-state transformations, from the vibrational density of states (VDOS) in amorphous systems to low-frequency phonon modes in crystalline materials (Taday et al., 2003, Strachan et al., 2005). With a limit of detection of around 1 wt% crystallinity, which often excels that of PXRD and Raman, THz-TDS is a robust characterisation technique for evaluating pharmaceutical formulations and kinetics of solid-state transitions (Zeitler et al., 2007, Parrott et al., 2009a, Otsuka et al., 2012, Takebe et al., 2013, McIntosh et al., 2013, Sibik et al., 2014, Sibik and Zeitler, 2016, Ornik et al., 2020, Ornik et al., 2022, Santitewagun et al., 2022, Heidrich et al., 2023b, Heidrich et al., 2023a, Heidrich et al., 2024, Zhang and Zeitler, 2025). Owing to THz-TDS’s ability to rapidly and non-destructively interrogate intact solid dosage forms without sample preparation, it has recently matured into an at-line process analytical technology (PAT) for confirming the absence of crystallinity in amorphous solid dosages (Leung et al., 2026). In particular, the absorption coefficient ratio has been demonstrated to provide a simple, calibration-free, and physically interpretable metric for assessing lack of crystallinity, offering an alternative to complex chemometric approaches (Leung et al., 2026).

A novel manufacturing strategy based on liquid drug feeding during hot melt extrusion (HME) has recently been developed for the production of salbutamol ASD pharmaceutical tablets (Kuchler et al., 2024, Kuchler et al., 2025). Given reports in the literature on the different physicochemical properties resulting from distinct amorphous preparation methods, it is essential to evaluate the physical stability of salbutamol ASD pharmaceutical tablets produced using this novel approach. In the present study, THz-TDS was employed to non-destructively and repeatedly interrogate the same 41 intact pharmaceutical tablets over 15 months, enabling direct longitudinal tracking of individual tablets without sample preparation or perturbing the amorphous solid dosage forms.

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2.1. Continuous manufacturing of ASD tablets

Pharmaceutical tablets containing the amorphous form of the active pharmaceutical ingredient (API) salbutamol free-base (Shenzhen Nexconn Pharmatechs Ltd, China) were produced on a continuous manufacturing line. The API was amorphised through HME.

This process was performed using a Coperion ZSK 18 extruder (Coperion GmbH, Germany), equipped with an 18 mm twin-screw and a 1.9 mm nozzle. Eudragit E PO (Evonik Industries AG, Germany) served as the polymeric matrix for embedding the API. The polymer was fed via a gravimetric K-Tron feeder (Coperion GmbH, Germany). The API, in the form of a suspension containing 30 wt % salbutamol free-base and 70 wt % water, was applied using a peristaltic pump (Ismatec SA Labortechnik Analytik, Switzerland). This suspension was side-fed into the extruder’s fourth barrel. Liquid side-feeding in HME is described in more detail by Kuchler et al. (2024). The polymer and solid API were combined in a 19:1 ratio, resulting in an API content of (5.00 ± 0.25) wt % in the extrudates. After the extruder, a conveyor belt (Geppert Band GmbH, Germany) was integrated into the production line. It was equipped with 10 pressurised air nozzles mounted along the belt on a custom-built structure to cool the extrudates. A PRIMO 60 E pelletiser (Maag GmbH, Germany) with a rotating knife cut the cooled extrudates into 1.9 mm diameter pellets of 1 mm to 2 mm length.

The pellets were transported onto the top of a direct compaction (DC) line by a Piovan S 50 vacuum transport device (Piovan S.p.A., Italy). The DC line comprised two gravimetric K-Tron KT 20 feeders (Coperion GmbH, Germany). Feeder 1, connected to the vacuum device, fed the pellets. Feeder 2 supplied an excipient blend consisting of 82.5 wt % Tablettose 70 (MEGGLE GmbH & Co. KG, Germany), 16.5 wt % Kollidon VA 64 fine (BTC Europe GmbH, Germany), which contains polyvinylpyrrolidone/vinyl acetate copolymer (PVPVA), and 1 wt % magnesium stearate (Merck KGaA, Germany). The pellets and excipient blend were combined at a 1:4 ratio in a Hosokawa Modulomix (Hosokawa Micron Powder Systems, Netherlands) blender set to 755 rpm. The mixture, with an API content of 1 wt %, was compressed into pharmaceutical tablets using a Fette 102 i tablet press (Fette Compacting GmbH, Germany) with a main compression force of 15 kN and a punch diameter of 8 mm. Kuchler et al. (2025) provide a detailed description of this continuous manufacturing process.

Chi Ki Leung, Lisa Kuchler, Andreas Kottlan, J. Axel Zeitler, Physical stability of salbutamol amorphous solid dispersion tablets measured by terahertz spectroscopy, International Journal of Pharmaceutics, Volume 697, 2026, 126903, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.126903.

Read also our introduction article on DC Excipients here: