Real-time monitoring and characterization of thin film drug delivery systems using optical coherence tomography

Abstract

The development of drug delivery systems demands close attention to product quality and consistency of quality attributes to guarantee reproducibility in fabrication, performance and therapeutic effectiveness. While some methods exist for monitoring in-line manufacturing, these methods are limited in terms of spatial resolution or depth penetration, which can lead to inconsistent characterization. Furthermore, conventional static characterization methods often lack the ability to monitor time-dependent changes within drug delivery systems. This limits their effectiveness in capturing dynamic processes such as swelling, disintegration, and drug release, underscoring the need for advanced techniques that offer reliable, high-resolution, and depth-specific insights into these mechanisms over time. Optical coherence tomography (OCT) is a non-invasive, high-resolution imaging technique which shows promise for comprehensive characterization of structural and dynamic characterization of drug delivery systems. In this study, we explore applications of OCT to structural and dynamic characterization of thin film drug delivery systems. We demonstrate that OCT can be used to non-destructively monitor the spatial variation of the refractive index and thickness of thin films, providing crucial feedback for quality control and ensuring standardized doses in individual film units. Further, we demonstrate that OCT can be used to monitor the dissolution dynamics, enabling characterization of time-controlled release mechanisms. These results suggest that OCT has the potential to enhance thin-film characterization by enabling more precise monitoring of critical quality attributes, which can contribute to improved manufacturing consistency and better control over the uniformity of the dose in each film unit.

Introduction

The development of drug delivery systems requires careful control of product quality and consistency to ensure reproducible performance and reliable therapeutic outcomes. Understanding the characteristics of a drug delivery system offers valuable insights during the early screening stages, helping to accelerate and improve the reliability of the development process. In continuous manufacturing, real-time monitoring of critical quality attributes and process parameters is essential for making controlled modifications to the process parameters during production (Su, 2019). Particularly in the context of thin films, characterization is critical for ensuring their functional performance.

As the demand for high-throughput, real-time quality control increases, especially in industrial environments, there is a growing need for non-destructive and versatile measurement techniques. Characterization methods can be broadly classified based on their mode of implementation — namely in-line (integrated into the production line), at-line (near-line with rapid feedback), and off-line (laboratory-based analysis), —as well as their impact on the sample, i.e., destructive or non-destructive. While traditional methods such as scanning electron microscopy (Sarecka-Hujar, 2017), transmission electron microscopy (Inkson, 2016, Eddleston et al., 2010), and secondary ion mass spectrometry (Gillen and Roberson, 1998) offer both spatial and chemical resolution, they are often inherently destructive and time-consuming (Laity et al., 2010, Zeitler and Gladden, 2009). In contrast, non-destructive techniques such as terahertz time-domain spectroscopy (THz-TDS) (Naftaly et al., 2019), ultraviolet (Østergaard, 2018) and near-infrared spectroscopy (NIRS) (Wargo and Drennen, 1996, Van Eerdenbrugh and Taylor, 2011), and Raman techniques (Johansson et al., 2007), provide robust alternatives that preserve sample integrity while enabling rapid, non-contact analysis. THz-TDS, for instance, allows for precise thickness measurement and defect detection in multilayer structures (Naftaly et al., 2019), whereas NIRS is particularly suited for in-line monitoring of chemical composition and physical properties (Gorachinov, 2025). These advancements are facilitating more efficient, automated, and non-invasive quality control in the manufacturing of thin films.

Nevertheless, the existing static characterization methods often fall short in capturing transient or dynamic changes within drug delivery systems, highlighting the need for techniques capable of providing high-resolution, depth-specific insights into the mechanisms of drug release and distribution over time. Non-invasive methods for studying drug delivery processes, such as degradation of the drug delivery system and drug dissolution are crucial for gaining a deeper understanding of their underlying mechanisms. While traditional bulk measurements provide valuable information, they often fail to capture the complex interactions occurring at the surface and within the delivery system. Techniques that allow for real-time, in situ visualization, such as Raman spectroscopy in dissolution setups, offer insights into these processes at the molecular level (Fussell et al., 2013). In the context of thin films, characterizing them as drug delivery systems is critical due to their distinct advantages over traditional tablets. Thin films are designed to dissolve rapidly, enabling a quicker onset of action, and are particularly beneficial for patients who have trouble swallowing, such as pediatric or geriatric populations (Nair, 2023).

Additionally, buccal films, as a type of thin film, offer enhanced precision in dosing compared to oral tablets. Their controlled release profile allows for more consistent and predictable absorption of the active pharmaceutical ingredient (API) through the buccal mucosa, bypassing the gastrointestinal tract and first-pass metabolism. This leads to more efficient and reliable systemic drug delivery (Alqahtani et al., 2021, Shipp et al., 2022). Unlike tablets, which can be subject to variability due to gastrointestinal factors like pH, transit time, and food intake, buccal films deliver a precise dose directly to the oral mucosa, ensuring more accurate drug delivery (Sako et al., 1996, Abuhelwa et al., 2016). Furthermore, buccal films are typically smaller and more discreet, making them easier to administer and improving patient compliance, ultimately contributing to more consistent dosing and better therapeutic outcomes (Jacob, S. et al. An Updated Overview of the Emerging Role of Patch and Film-Based Buccal Delivery Systems. Pharmaceutics, 2021). These properties, combined with their potential for innovative drug delivery applications, such as buccal or sublingual administration, necessitate specialized evaluation techniques. To ensure product quality and performance, several critical quality attributes of thin films, including film thickness, mechanical properties, disintegration time, and drug release profile must be systematically monitored.

Optical coherence tomography (OCT) is a non-invasive imaging technique designed for label free, micro-scale cross-sectional and volumetric visualization of biological systems (Fujimoto et al., 2015). Utilizing low-coherence interferometry, OCT generates images by capturing optical scattering from microstructures within tissues, similar to ultrasonic pulse-echo imaging. This technique provides high spatial resolution on the order of a few micrometers and can detect reflected signals as faint as approximately 10-10 of the incident optical power, i.e., the sensitivity of OCT systems is typically around 100 dB (Huang, 1991). Compared with ultrasonic imaging, OCT offers superior resolution while maintaining depth information up to 1–2 mm in biological tissues depending on the optical scattering properties (Hajar, 2019). The ability to obtain real-time, detailed, and non-invasive information about samples in situ has positioned OCT as a clinical standard in several fields including ophthalmology and dermatology (Sattler et al., 2013).

Beyond medical diagnostics, OCT has shown promise for non-destructive testing of both biological and non-biological materials, including applications to in-line monitoring for manufacturing of various materials (Duncan, et al., 1998, Mason et al., 2004). In the pharmaceutical industry, OCT can be utilized for inline monitoring of fabrication processes in the development of drug delivery systems and could allow visualization of drug release without altering the system. This means that OCT can offer valuable insights into the drug delivery process, complementing traditional methods and enhancing the optimization of drug formulations. Previously, OCT was used for monitoring pharmaceutical coating processes, utilizing polyethylene terephthalate films as a model system to validate the accuracy of OCT (Wolfgang, 2019).The OCT results were compared with other measurement techniques, including micrometer gauges, X-ray micro-CT, terahertz pulsed imaging, and light microscopy. The findings demonstrated that OCT results closely matched light microscopy measurements of coating thickness, revealing significant intra- and inter-tablet variations in coating. OCT shows promise for advancing thin-film drug delivery characterization by enabling non-destructive, high-resolution imaging of surface morphology, microstructure, and thickness uniformity. It may also aid in detecting manufacturing defects, monitoring disintegration and swelling under various conditions, and potentially assessing API release. These capabilities position OCT as a valuable tool for evaluating critical parameters that influence drug performance and development. A recent review has comprehensively highlighted the emerging applications of OCT in pharmaceutical drug delivery, highlighting its potential as a non-destructive imaging tool for monitoring structural and dynamic changes in drug delivery systems (Aglyamov and Larin, 2025).

This study proposes the application of OCT for comprehensive characterization of thin films used for buccal drug delivery. Static experiments were conducted to evaluate the sensitivity of the system in determining drug and excipient concentrations, detecting defects, and assessing the optical properties of the formulations. Dynamic experiments simulating physiological conditions were performed to investigate disintegration mechanics. Ultimately, this research aims to establish OCT as a valuable tool for characterizing drug delivery systems, improving manufacturing efficiency, reproducibility of production, and quality control.

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2. Materials & methods

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