Effect of drug particle co-processing on tablet microenvironment and protection against pH induced degradation

Abstract

The shelf life of pharmaceutical products depends on the stability of active pharmaceutical ingredients in the presence of other formulation components and environmental factors. Degradation processes can be suppressed by the addition of protective excipients. The present work is concerned with understanding the role of spatial arrangement of drug and protectant particles at the tablet microstructure level on the effectiveness of protection against pH induced degradation. Atorvastatin – a major cardiovascular drug – was chosen as a case to investigate the possibility to suppress lactone impurity formation by modifying the tablet pH microenvironment. The effect of the quantity added, particle size, and process route on the protective effect of Na₂CO₃ as a protective agent has been systematically investigated by accelerated stress tests under 30% and 75% relative humidity at 60 °C. The addition of Na₂CO₃ into the tablet formulation in the range from 2.5-20.0 wt.% relative to atorvastatin was found to be effective in suppressing degradation but the efficacy was strongly dependent on the process route and the particle size. The direct compression route was found to be equally or more effective than wet granulation. Scanning electron microscopy analysis with elemental mapping revealed that the use of fine Na₂CO₃ particles resulted in a uniform mixing with atorvastatin particles, whereas coarse particles were too few and far between to provide effective pH protection. Based on these results, a general framework for determining the appropriate particle size, quantity and route of addition of protective excipients into pharmaceutical tablet formulations has been proposed.

Introduction

The chemical degradation of active pharmaceutical ingredients (API) in drug products is an undesired phenomenon that limits the shelf life. Degradation not only reduces the quantity of API in the drug product and therefore its efficacy, but some impurities produced by degradation can also be toxic, which would pose a risk of side effects to patients. Degradation can also cause changes in the product visual appearance, such as discoloration. While this may not directly affect the drug efficacy or safety, it can reduce patient trust in the medication and lead to non-adherence. Therefore, the presence of degradation impurities in drug products is tightly regulated and it is essential to understand the mechanisms of API degradation and to master strategies for its prevention (Melo et al., 2014, Alsante et al., 2007).

Chemical degradation can be categorized based on different initiating factors, such as temperature and humidity, pH, light, and oxidation (Gabrič et al., 2022, Waterman and Adami, 2005). These may come from the outside environment or from excipients present in the formulation. The chemical structure of the drug molecule primarily determines its susceptibility to specific degradation pathways (Bhangare et al., 2022, Comanescu and Racovita, 2024). The International Conference on Harmonization (ICH) provides comprehensive guidelines for stability testing during drug development (ICH Q1A–Q1F and ICH Q3A–Q3E), which are widely adopted across regulatory regions including the European Union, the United States, and Japan. According to these guidelines, one key stability requirement is that the level of impurities in a medicinal product must not exceed a defined threshold after two years of storage under standard conditions of 25 °C and 60% relative humidity (RH) (European Medicines Agency, 2003). To facilitate the drug product development process, accelerated stability testing is conducted under more extreme conditions (40 °C/75% RH) for a duration of six months. Additionally, stress studies are conducted under more severe conditions, usually lasting two weeks, to rapidly assess the type and extent of degradation the product may experience (Bhangare et al., 2022, Blessy et al., 2014).

Protecting the API from degradation can be achieved by incorporating a stabilizing agent into the formulation (Crowley, 1999, Du and Hoag, 2001). The protectant can be introduced into the formulation either by simple physical mixing or through co-processing techniques, such as dry particle coating, fluid bed granulation (Fayed et al., 2022, Koleilat et al., 2025), wet granulation (Eremin et al., 2024, Arndt et al., 2018) or hot melt granulation (Guimarães et al., 2017, Ng et al., 2022). When the stabilizer is simply mixed with the formulation, it comes into partial contact with the API particles and is mainly effective against external environmental factors. However, if degradation is caused by interactions between individual components within the formulation itself (Vranić, 2004), a different strategy is necessary to ensure effective protection of API particles at the microstructure level. Additional processing steps may be required in that case (Wu et al., 2011). One approach could be drug particle coating, which creates a protective barrier around each individual API particle. This barrier prevents direct contact with reactive impurities within the formulation as well as various external degradation factors. Another approach is granulation, which can enhance API stability by promoting a more intimate contact with the protective excipient at the level of API particle clusters or granules (Arndt et al., 2018, Wang et al., 2022) and reduce the frequency of contacts between API particles and any formulation components that might be a source of reactive initiating factors.

The present work is concerned with understanding the role of spatial distribution of stabilizing excipient within the tablet microenvironment on the efficacy with which it protects the API from degradation. Atorvastatin has been chosen as a model API for the present study due to its industrial relevance and well described degradation pathways. In this study, atorvastatin calcium trihydrate, the commercially used salt form, was employed as the drug substance. A member of the statin drug class, atorvastatin is widely used for the treatment of dyslipidemia and the prevention of cardiovascular diseases (McIver and Siddique, 2025). It was first introduced to the market in 1997 by Warner-Lambert Co. under the trade name Lipitor (Hájková et al., 2008). Today, it remains one of the most widely prescribed medications, reaching over 115 million prescriptions issued in the USA in 2023 (Kane, 2025). Atorvastatin is commercially available as oral tablets in strengths of 10, 20, 40, and 80 mg, as well as an oral suspension containing 20 mg per 5 mL (McIver and Siddique, 2025). Atorvastatin is prone to the formation of Impurity H (lactone), and the degradation reaction is pH-dependent (Hoffmann and Nowosielski, 2008). In acidic pH the equilibrium shifts towards the formation of the impurity and in alkaline environment, the equilibrium shifts back towards atorvastatin (Fig. 1). Therefore, the stability of atorvastatin tablets can be improved by the addition of an alkaliser to the formulation. In the present work, Na₂CO₃ is used as the protective agent added to the formulation.

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Materials

Sodium carbonate (Na₂CO₃, 99%, CAS 497-19-8) and ammonium dihydrogen phosphate (98%, CAS 7722-76-1) were obtained from Sigma-Aldrich (St. Louis, MO, USA). Magnesium chloride hexahydrate (98%, CAS 7791-18-6) was obtained from Fluka Analytical. Ortho-phosphoric acid (85%, CAS 7664-38-2) was purchased from Penta (Prague, Czech Republic). Methanol (MeOH, CAS 67-56-1) and acetonitrile (ACN, CAS 75-05-8), both of HPLC grade, were purchased from J. T. Baker (Radnor, PA, USA). Hydroxypropyl methylcellulose (Methocel E5, CAS 9004-65-3), atorvastatin calcium trihydrate (CAS 134523-03-8, batch no. M114042, manufactured by Centrient Pharmaceuticals India Pvt), microcrystalline cellulose (Avicel PH 101, CAS 9004-34-6), lactose monohydrate (CAS 10039-26-6), low-substituted hydroxypropyl cellulose (CAS 9004-64-2), Povidone K30 (CAS 9003-39-8), colloidal anhydrous silica (CAS 7631-86-9), and magnesium stearate (CAS 557-04-0) were kindly provided by Zentiva, k.s.

Zuzana Hlavačková, Jakub Petřík, Dita Spálovská, Martin Balouch, Radovan Budoš, František Štěpánek, Effect of drug particle co-processing on tablet microenvironment and protection against pH induced degradation, Chemical Engineering Research and Design, 2026, ISSN 0263-8762, https://doi.org/10.1016/j.cherd.2026.04.028.

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