Could the Change of Excipient Content Improve the Stability of Gastroresistant Omeprazole Pellets?
Abstract
Omeprazole (OM), a temperature, pH, and moisture-sensitive drug, poses formulation challenges. This study delves into the complex development of OM pellets, focusing on the impact of buffering excipients on stability and release. Addressing the challenges of OM pellet stability requires a comprehensive compatibility and stress study involving key excipients. Binary mixtures of OM with dibasic sodium phosphate dihydrate (DSPD), mannitol, hypromellose (Hyp), and polysorbate underwent scrutiny for possible incompatibilities, subjected to 40°C stress and 75% relative humidity. DSC, TGA, and ATR-FTIR analyses were conducted, with quantitative monitoring of OM by HPLC. Formulations with varied proportions of DSPD and Hyp were also stress-tested. While all excipients exhibited compatibility with OM, thermal analysis suggested a potential incompatibility between OM and mannitol, disproven by HPLC. Stress tests on diverse formulations confirmed their adequacy, maintaining OM content and impurities within acceptable limits. Increased Hyp reduced impurities, and its combination with DSPD further enhanced stability. The study concludes that augmenting DSPD with Hyp offers effective protection for OM pellets, ensuring their stability.
Highlights
- Development of stable omeprazole pellets (OMP).
- Dibasic sodium phosphate dihydrate and hypromellose to protect OMP from degradation.
- Analytical techniques for testing the compatibility and stability of unstable drugs.
Introduction
The stability of pharmaceutical products refers to the ability of both the drug and formulation to maintain their original characteristics and biological properties over a specific period [1]. This stability is influenced not only by the physicochemical properties of the active pharmaceutical ingredient (API) but also by formulation characteristics and the production process [2].
In the context of formulations, typically comprising an API and pharmacologically inert excipients, it becomes imperative to investigate potential degradation mechanisms [2]. Many degradation reactions involving the interplay between the API and excipients remain poorly understood [3]. However, understanding possible physical and chemical incompatibilities is crucial during the pre-formulation phase for the rational development of pharmaceutical dosage forms [4].
The exposure of drugs and excipients to environmental variations, such as temperature, light, and humidity, aids in identifying potential degradation products and the conditions favoring their formation [5]. These stress factors contribute to investigating drug-excipient compatibility [4]. Pre-formulation studies, based on analytical methodologies like DSC and FT-IR, allow predictions about the formulation’s long-term chemical and physical stability [6,7]. While there is no universal protocol for assessing drug-excipient compatibility, researchers often employ analytical techniques alongside stress conditions recommended by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) [8-16]. Although DSC and FT-IR offer immediate results, combining them with classic chromatographic analyses provides more reliable information on the stability of the drug-excipient system [9, 15].
Omeprazole, frequently prescribed for gastrointestinal disorders, acts as a gastric proton pump inhibitor but is highly susceptible to degradation by acid, heat, humidity, light, and organic solvents [18]. The appearance of discoloration ranging from light beige to deep purple necessitates a well-designed pre-formulation study to prevent the formation of degradation products [19].
Enteric coating serves as a strategy for the modified release of drugs in orally administered dosage forms. Its primary objective is to ensure drug stability in harsh stomach conditions and controlled release in the digestive tract. This entails the dissolution of polymers in the intestine, releasing the drug appropriately [20-22]. Pellets, among solid dosage forms, are commonly used to enhance omeprazole stability, providing drug protection and controlled release for improved bioavailability, efficacy, and safety [23]. These drug pellets can be prepared by coating inert pellets with a drug solution/dispersion and various excipients. An insulating polymer layer may further coat the drug core, followed by a polyacrylic derivative [24,25]. Due to potential omeprazole-excipient interactions, a stress study during the pre-formulation phase becomes crucial to predict drug stability in the formulation.
Consequently, this study aimed to investigate the compatibility of omeprazole with specific excipients for the development of gastro-resistant omeprazole pellets. The formulation comprised three coating layers (drug coating, sealing coating, and gastro-resistant coating). The study evaluated the influence of the sodium phosphate buffer amount in the first layer (drug coating) and the presence of hypromellose in the intermediate layer (sealing coat).
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Materials
Omeprazole (purity > 98%; batch no. KOMO75) was procured from the United States Pharmacopeia (USP, North Bethesda, MD, USA). Inert sucrose pellets were obtained from Hanns G. Werner GmbH + Co. KG (Tornesch, Germany). Sodium phosphate dibasic dihydrate and mannitol were sourced from Plury Quimica and Ingredion Brasil (São Paulo, SP, Brazil), respectively. Polysorbate 80 was acquired from M Cassab (Sao Paulo, SP, Brazil). Hypromellose was purchased from IMCD Brasil Farma (Sao Paulo, SP, Brazil). Methacrylic acid copolymer (Eudragit® L-30 D55) was obtained from Evonik (Santos, SP, Brazil). Triethyl citrate was sourced from Vertellus Performance Materials Inc. (Indianapolis, IN, USA), and talc was acquired from Indukern (Maringa, PR, Brazil). All other chemicals were of analytical grade and used without further purification.
| Function | Component / characteristics | Formulation | ||
|---|---|---|---|---|
| F1 | F2 | F3 | ||
| Inert core | Sucrose sphere size 20-25 µm (inert pellets) | X | X | X |
| Omeprazole coating | ||||
| Drug | Omeprazole | X | X | X |
| Buffering | Dibasic sodium phosphate dihydrate | X | X | Increased by 100% |
| Diluent | Mannitol | X | X | X |
| Surfactant | Polysorbate 80 | X | X | X |
| Binder/coating polymer | Hypromellose 2910 (first cover) | X | X | X |
| Sealing coating | ||||
| Coating polymer | Hypromellose 2910 (second cover) | X | Increased by 18.5% | Increased by 18.5% |
| Gastro-resistant coating | ||||
| Functional polymer | Methacrylic acid copolymer (Eudragit®L30 D55) | X | X | X |
| Plasticizer | Triethyl citrate | X | X | X |
| Glidant | Talc | X | X | X |
Priscila Chiamulera Mantovani, Fernanda Belincanta Borghi-Pangoni, Monica Villa Nova, Vanderson Galan, Henrique dos Santos, Francielle Sato, Marcos Luciano Bruschi, Andréa Diniz, Could the Change of Excipient Content Improve the Stability of Gastroresistant Omeprazole Pellets?, BABT, Article – Engineering, Technology and Techniques, Vol.67: e24230850, 2024, Received: 11-Aug-2023; Accepted: 26-Feb-2024, https://doi.org/10.1590/1678-4324-2024230850, ISSN 1678-4324 Online Edition
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