Technical and regulatory perspective on acid stage dissolution assessed via optical coherence tomography (Part 1: Release Scenario)

Abstract

Enteric coating ensures a targeted release of active pharmaceutical ingredients (APIs) by protecting them from premature dissolution in the stomach. The effectiveness of such coating depends on its thickness and integrity, which are critical for achieving the desired acid protection. This study explores the use of Optical Coherence Tomography (OCT) as an innovative and non-destructive alternative to traditional acid stage dissolution testing performed by directly measuring the coating thickness. Three enteric coating materials (Acryl-Eze®, Aquarius™ Control ENA, and Nutrateric®) were tested in two manufacturing batches to evaluate operator variability. OCT was used to measure the coating thickness, which was correlated with the acid stage dissolution testing and established critical thicknesses of 68 µm for Acryl-Eze®, 69 µm for Aquarius™ Control ENA, and 65 µm for Nutrateric®. These specifications ensure compliance with the pharmacopeial performance criteria for acid protection and can be implemented into regulatory frameworks as part of product release protocols in the dossier. By demonstrating the agreement between the results of OCT-based thickness measurements and the pharmacopeial dissolution testing, this work underscores the potential of OCT to be recognized in regulatory contexts as a tool for enhanced production efficiency and quality assurance in manufacturing enteric-coated oral dosage forms.

Highlights

Demonstrates using OCT as a non-destructive method to predict acid resistance in enteric-coated tablets.

Provides a technical framework for correlating coating thickness with USP < 711 > acid stage dissolution compliance.

Explores the regulatory implications of OCT-based testing as an alternative to traditional dissolution methods.

Introduction

Pharmaceutical dosage forms must undergo rigorous testing to ensure the product’s quality, safety and effectiveness (FDA Office of Regulatory Affairs, 2017). The first five chapters of the USP Guidelines define the quality and performance tests that, although different with regard to the administration route, guarantee safety and efficacy of all drug products (USP42-NF37, 2020a, USP42-NF37, 2020b, USP42-NF37, 2020c, USP42-NF37, 2020d, USP43-NF38, 2022a). These tests generally have the same function and scope (USP42-NF37, 2020a, USP42-NF37, 2020b, USP42-NF37, 2020c, USP42-NF37, 2020d, USP43-NF38, 2021). Drug product quality tests assess such attributes as identification, strength (assay), impurities, dose content uniformity, pH, minimum fill, alcohol content, volatile content, and microbial content. Drug product performance tests are designed to assess the in vitro drug release of dosage forms, such as dissolution or drug release from oral, topical, mucosal and transdermal products (USP42-NF37, 2020b, USP42-NF37, 2020c, USP43-NF38, 2021).

Dissolution testing is one of the most relevant methods in pharmaceutical testing of oral dosage forms. It is generally accepted as the standard for approving new drugs and already approved formulations in cases of generics and post-approval changes in the process or formulation. The USP and the FDA have established a series of dissolution methods for approved products, which are used as a starting point for such tests (FDA Center for Drug Evaluation and Research, 2024, USP42-NF37, 2022). Many factors affect dissolution being a kinetic process. These factors could be related to the physicochemical and structural characteristics of the drug (e.g., salt type, particle size, polymorphism), formulation characteristics (e.g., lubricants, excipients, presence of surfactants) and process parameters (e.g., mixing and compaction force) (Pawar et al., 2016). Consequently, dissolution is a multifactorial response. While necessary for evaluating a drug product’s performance, tests can be time-consuming and expensive, depending on the product. Moreover, it can be difficult to predict the dissolution profile over time. Pharmaceutical research in process analytical technology (PAT) has been focused on predicting dissolution to eventually establish a real-time release testing (RTRT) approach (Pharmacopoeia, 2020, FDA Center for Drug Evaluation and Research, 1997, Godek et al., 2017, Gordon, 2019, Hernandez et al., 2016, Nagy et al., 2019, Pawar et al., 2016, USP42-NF37, 2022).

Within the established dissolution methodologies, the dissolution of enteric-coated pharmaceutical products is a critical process that ensures the targeted release of active pharmaceutical ingredients (APIs) in the gastrointestinal (GI) tract (USP42-NF37, 2022). Enteric coating is primarily designed to resist dissolution in the acidic environment of the stomach and to release the API in the more neutral to alkaline conditions of the small intestine (pH 5.5–7.5) (Maderuelo et al., 2019). This controlled-release mechanism is essential for protecting acid-sensitive drugs from degradation and for preventing irritation of the gastric mucosa by certain APIs (Maderuelo et al., 2019, Shokri and Adibki, 2013). This coating is typically composed of pH-sensitive polymers that dissolve when the environmental pH rises above a certain threshold (typically between 5.0 and 6.0), allowing for a timed release of the drug in the small intestine (Maderuelo et al., 2019).

The effectiveness of enteric coating in preventing premature drug release in the stomach while enabling a timely release in the intestine is influenced by several formulation and process variables (Al-Gousous et al., 2017). Clearly, the thickness and uniformity of the coating layer are key factors that directly affect the dissolution performance (Park et al., 2017, Radtke and Kleinebudde, 2020, Wolfgang et al., 2022). Insufficient coating thickness or coating defects, such as pores or cracks, can result in undesirable drug release in the stomach, compromising both the drug’s efficacy and patient safety (Thoma and Bechtold, 1999). Additionally, the integrity of the coating layer must be maintained throughout the manufacturing and storage processes to ensure consistent product performance. In contrast to the traditional approach, which requires additional separate dissolution testing to assess the integrity of the enteric coating in acidic media, recent advancements in non-destructive testing techniques (e.g., near-infrared spectroscopy (NIRS) (Sacré et al., 2021, Talwar et al., 2022, Vo et al., 2018), terahertz pulsed imaging (TPI) (Alves-Lima et al., 2020, Bawuah and Zeitler, 2021), and optical coherence tomography (OCT) (Lin et al., 2018, Lin et al., 2017, Wolfgang et al., 2022, 2019)) have enabled more precise characterization of the coating properties. There are also additional testing techniques such as broadband acoustic resonance dissolution spectroscopy (BARDS) (Alfarsi et al., 2018, O’Mahoney et al., 2021, O’Mahoney et al., 2020) which follow a destructive approach instead. These techniques offer the potential to link physical attributes of the coating, such as its thickness and uniformity, to its critical quality attributes (CQAs), such as the dissolution rate, contributing to the development of robust enteric-coated formulations that meet the stringent requirements of modern pharmaceutical products.

PAT tools that can enhance the overall product quality are highly appreciated by regulatory authorities (Gordon, 2019). However, a certain level of traditional compliance is still required for successful approval. For markets such as Europe and the United States, compliance with the existing local pharmacopeia monograph is mandatory. Failure to achieve compliance must be justified by demonstrating the criterion of equivalence or superiority to the test established in a specific monograph (FDA Center for Drug Evaluation and Research, 2015, McMath, 2015). This justification is subject to review by the health authority and may be either rejected or approved.

The present work aims to evaluate OCT as an analytical technique that can replace the required acid-stage dissolution test by understanding the relationship between the coating thickness and the overall integrity of enteric coatings and of how this variability affects the dissolution performance. Thus, we believe that the method is superior to existing tests. For this purpose, various sets of commercially available enteric coatings were assessed using a proton pump inhibitor prototype, which is as a typical example of a delayed-release product. In this work, the regulatory requirements and the Common Technical Document (CTD) presentation for a new submission were carefully considered.