Detecting absence of crystallinity in solid dosage forms with at-line terahertz process analytical technology

Amorphous solid dispersions (ASDs) enhance the solubility and bioavailability of drugs, yet their inherent instability and the risk of recrystallisation make the absence of crystallinity a critical quality attribute. Despite developments in non-destructive spectroscopic process analytical technologies (PAT), their applications to final amorphous dosage forms are relatively limited. This study establishes non-destructive terahertz time-domain spectroscopy (THz-TDS) as a simple, rapid and robust at-line PAT for determining the absence of crystallinity in solid dosage forms.

Two independent and physically interpretable approaches are established: (i) absence of characteristic phonon absorption peaks, and (ii) the ratio of absorption coefficients at a crystalline phonon frequency to a low-noise baseline frequency, which accounts for the vibrational density of states characteristic of disorder. Both simple methods unambiguously determined the absence of crystallinity in salbutamol ASD tablets, the model system used for evaluation. The methods are robust to scattering and excipient absorption, and are validated across multiple instruments and over long-term storage. These findings substantiate THz-TDS as a practical at-line PAT for amorphous solid dosages and as a feasible strategy for real-time release testing, as well as further extending its utility as a multi-attribute PAT. The potential of at-line THz-TDS PAT in predicting dissolution time of amorphous solid dosages shall be explored in future.

Introduction

Amorphous solid dispersion (ASD) represents a leading strategy to enhance the oral bioavailability of poorly soluble drug candidates, with nearly 50 ASD-containing drug products approved by the U.S. Food and Drug Administration (FDA) in the past decade. (Brouwers et al., 2009, Laitinen et al., 2013, Jain et al., 2015, Nyamba et al., 2024, Moseson et al., 2024, Shelke et al., 2024). By dispersing drug molecules in a high-energy, disordered state within a polymer matrix, ASDs can significantly improve dissolution rates, thereby enhancing bioavailability and absorption (Graeser et al., 2010, Grohganz et al., 2013, Laitinen et al., 2013, Williams et al., 2013, Schittny et al., 2020, Nambiar et al., 2022, Shi et al., 2022, Moseson et al., 2024, Kokott et al., 2024, Ueda et al., 2025, Taylor and Zografi, 2025, Ghosh et al., 2025). This thermodynamic advantage, however, is intrinsically linked to their greatest liability: physical instability. The amorphous state is metastable, creating a persistent thermodynamic driving force for recrystallisation. The emergence of even minor crystalline domains before the drug product is consumed can compromise product performance and safety, establishing the absence of crystallinity as a paramount critical quality attribute (CQA) for ensuring stability and performance in amorphous drug products (Ma and Williams, 2019, Schittny et al., 2020).

Conventional characterisation methods include differential scanning calorimetry (DSC), modulated DSC (MDSC), dynamic mechanical analysis (DMA) and powder X-ray diffraction (PXRD). DSC, MDSC and DMA are off-line, destructive, thermal techniques whose results are highly dependent upon the experimental parameters, such as heating rates. Moreover, heating may change the original ASD solid state or even lead to degradation, and residual solvents in the ASDs may compromise characterisation (Khanna, 1989, Baird and Taylor, 2012, Clas et al., 2012, Ma and Williams, 2019, Dedroog et al., 2020). Off-line, non-destructive PXRD has a limit of detection (LOD) of around 5 wt % crystallinity, which is less sensitive than MDSC (Aucamp and Milne, 2019, Ma and Williams, 2019, Iyer et al., 2021, Dedroog et al., 2020). PXRD cannot detect nanocrystallinity, different amorphous phases or amorphous–amorphous phase separation, thus using (M)DSC and PXRD in conjunction is recommended to unambiguously confirm the ASD solid state (Dedroog et al., 2020).

Alternatively, non-destructive small and wide angle X-ray scattering (SWAXS) can simultaneously identify possible crystallinity, nanoheterogeneity and discriminate between different amorphous structures in ASDs in about 5 min, but powdered samples are required, similar to PXRD. (Laggner and Mio, 1992, Laggner and Paudel, 2018, Dedroog et al., 2020, Kuchler et al., 2024). Whereas off-line, non-destructive transmission electron microscopy identifies crystallinity in ASDs at a greater sensitivity than DSC, PXRD and SWAXS, albeit at a much longer timescale (Ricarte et al., 2015, Liu et al., 2018, Ma and Williams, 2019, S’ari et al., 2021). Similarly, off-line, non-destructive solid-state nuclear magnetic resonance (ssNMR) quantifies the crystallinity in powder samples via relaxation times and via the deconvoluted integrated peak area (Paudel et al., 2014, Okada et al., 2019, Li et al., 2021, Jarrells and Munson, 2022, Katsumata et al., 2025). A LOD of around 1.7 wt % can be achieved and crystalline phase of less than 0.5 wt % can be quantified, but a long measurement time is required (Li et al., 2021, Jarrells and Munson, 2022). More niche approaches, such as isothermal microcalorimetry (Liu et al., 2002, Baird and Taylor, 2012), second order non-linear optical imaging of chiral crystals (Wanapun et al., 2010, Kissick et al., 2011, Baird and Taylor, 2012) and polarised light microscopy (PLM) as well as hot stage PLM (Liu et al., 2018, Ma and Williams, 2019), possess specific material requirements. These off-line characterisation techniques are time and resource-intensive, and remain challenging for at/on/in-line process monitoring.

Non-destructive process analytical technologies (PAT) have been developed to address these challenges. Near infrared (NIR) and Raman spectroscopy have been implemented in-line with principal component analysis (PCA) and partial least squares (PLS) regression calibration models (Saerens et al., 2012, Almeida et al., 2012, Saerens et al., 2014, Netchacovitch et al., 2017, Lim et al., 2021). However, non-transparent extrudates are required for reflectance NIR spectroscopy (Saerens et al., 2014). Low-frequency Raman spectroscopy is also explored in-line using a multivariate curve resolution model (Vivattanaseth et al., 2022). Fourier-transformed infrared spectroscopy (FTIR) yields mixed results. Amorphous and crystalline states can be identified off-line with PCA and artificial neural network (ANN) analysis methods when the ASDs are measured on their own (Kapourani et al., 2020), but not when the amorphous drug is mixed with a powder blend (Aucamp and Milne, 2019). In-line ultraviolet–visible spectroscopy demonstrates promise in early studies (Wesholowski et al., 2018), while mid-infrared spectroscopy is identified as suboptimal due to limited penetration depth and detection range (Hitzer et al., 2017). These non-destructive spectroscopic PATs mainly focused on the lack of crystallinity in ASD extrudates, a process intermediate, from hot melt extrusion (HME). To utilise these techniques, chemometric models are typically required, which can be far from straightforward, quantitative, and physically explainable. In contrast, there are fewer examples in the literature for successful sensing and real-time release testing (RTRT) of the final dosage forms. This leaves a gap for a simple, interpretable, and robust PAT to ensure the quality of amorphous drug products post-manufacture.

Terahertz time-domain spectroscopy (THz-TDS) is highly sensitive to solid-state structures, probing the vibrational density of states (VDOS) in amorphous solids, phonon modes in crystalline materials and dispersion forces in intermolecular interactions (Sibik and Zeitler, 2016, Hitzer et al., 2017). As a material transitions from the amorphous to the crystalline state, the VDOS, which dominates the baseline in the terahertz absorption spectra, decreases and converges into the characteristic low-frequency phonon modes at discrete frequencies that are characteristic of the crystal form (Sibik and Zeitler, 2016). Subtle amounts of crystallinity, as low as 1 wt%, can be detected in amorphous materials, often exceeding the sensitivity of Raman and PXRD (Taday et al., 2003, Strachan et al., 2005, Parrott et al., 2009a, Otsuka et al., 2012, Sibik and Zeitler, 2016). THz-TDS has been implemented offline to study solid state crystallisation kinetics (McIntosh et al., 2013, Sibik et al., 2014, Sibik and Zeitler, 2016, Zhang and Zeitler, 2025) and characterise novel formulations (Takebe et al., 2013, Ornik et al., 2020, Ornik et al., 2022, Heidrich et al., 2023b, Heidrich et al., 2023a, Heidrich et al., 2024). Separately, THz-TDS has more recently matured into a non-contact, non-destructive in/at-line multi-attribute PAT suitable for RTRT of pharmaceutical tablet mass, thickness, porosity, disintegration time and breaking force (Bawuah et al., 2023, Anuschek et al., 2023, Anuschek et al., 2024, Anuschek et al., 2025a, Anuschek et al., 2025b, Lee et al., 2025), and for monitoring polymer properties in HME (Krumbholz et al., 2009).

This study leverages the capabilities of THz-TDS and further establishes it as an at-line PAT for amorphous solid dosage forms within the RTRT framework. Two robust, distinct, simple and physically interpretable approaches to unequivocally confirm the absence of crystallinity in the final dosage forms are presented. Whilst salbutamol ASD pharmaceutical tablets are used as a model system, the methodology is broadly applicable across amorphous solid dosages given the universal response of the VDOS and the phonon modes. These demonstrate the robustness of at-line THz-TDS PAT in ensuring drug product quality, stability, and performance, and set the basis for predicting dissolution times of amorphous solid dosage forms in RTRT.

See the research paper as PDF: Detecting absence of crystallinity in solid dosage forms with at-line terahertz process analytical technology

or continue reading here

Chi Ki Leung, Lisa Kuchler, J. Axel Zeitler,
Detecting absence of crystallinity in solid dosage forms with at-line terahertz process analytical technology,
International Journal of Pharmaceutics, Volume 689, 2026, 126447, ISSN 0378-5173,
https://doi.org/10.1016/j.ijpharm.2025.126447.