Forced Degradation Studies of Corticosteroids With an Alumina–Steroid–Ethanol Model for Predicting Chemical Stability and Degradation Products of Pressurized Metered-Dose Inhaler Formulations

doi:10.1002/jps.23111

Journal of Pharmaceutical Sciences

Volume 101, Issue 6, June 2012, Pages 2109-2122

https://doi.org/10.1002/jps.23111 Get rights and content

ABSTRACT

An alumina (Al₂O₃)–steroid–ethanol model is used for forced degradation testing of corticosteroids to predict chemical stability and degradation products in pressurized metered-dose inhaler (pMDI) solution formulations. The model involves an ethanolic solution of a test steroid with Al₂O₃, stressed at elevated temperatures to mimic the chemical interaction of drug, excipient, and packaging (an aluminum aerosol canister). The reactivity order of eight synthetic corticosteroids toward Al₂O₃-induced reactions is ranked with the stress model. The corticosteroids containing a C21-OH group possess the highest reactivity, suggesting that aluminum canisters with an inert interior coating are needed to stabilize their solution pMDIs. The Al₂O₃-induced degradation products and degradation pathways of a steroid containing C21-OH and triamcinolone acetonide are presented, and the role of Al₂O₃ in the degradation pathways is briefly discussed. A potential degradation profile of beclomethasone dipropionate (BDP) established with an Al₂O₃–BDP–ethanol stress model is the same as the actual degradation profile of the BDP pMDI product, indicating that the model indeed predicts the degradation products. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:2109–2122, 2012

Section snippets

INTRODUCTION

Forced degradation studies have been recognized as a part of the drug development strategy by both regulatory authorities and the pharmaceutical industry, and the studies can help assess intrinsic stability of drug substances, validate stability-indicating methodology, identify degradation products, and elucidate degradation pathways.1., 2., 3. Intentional forced degradation tests of a drug substance mainly include thermolysis, hydrolysis, oxidation, and photolysis.¹,² Ideally, those tests

Chemicals

Both budesonide 21-propionate (BUDP) and triamcinolone acetonide 21-propionate (TRAP) were synthesized in house. The remaining corticosteroids used in this study were purchased from Sigma–Aldrich (St Louis, Missouri), except for beclomethasone 17-propionate (17-BEP) and beclomethasone 21-propionate (21-BEP), which were purchased from Vinchem Inc. (Chatham, New Jersey). Al₂O₃ (activated, neutral, Brockmann I, 150 mesh), cupric acetate, pyridine, and propionic anhydride were purchased from

Chemical Stability of BUD in an Ethanol–Al₂O₃ Mixture and in a Solution pMDI

The intrinsic chemical stability of BUD in a solution pMDI was predicted with the forced degradation testing results using an Al₂O₃–BUD–ethanol model.¹⁸ Remaining percentages of BUD in ethanol with and without Al₂O₃ at 75°C were determined over time with HPLC method 1. In the presence of Al₂O₃, BUD is almost completely consumed in just 6 h, whereas the remaining percentage in ethanol without Al₂O₃ is as high as 95.5% even in 168 h (Fig. 2). The contrast observations indicate that Al₂O₃ indeed

CONCLUSIONS

In this paper, a novel stress system using an Al₂O₃–steroid–ethanol model to predict chemical stability and a degradation profile of an inhaled corticosteroid in a solution pMDI have been presented. The model reflects the chemical interaction of three components in a pMDI product, drug substance (a corticosteroid), excipient (ethanol), and packaging (an aluminum aerosol canister), and thus mimics the degradation reactions of a corticosteroid occurring in a solution pMDI. Case histories

ACKNOWLEDGEMENTS

The authors thank Gina Bui for laboratory assistance during the study and Dr. Thomas K. Chambers for his comparison of the HPLC chromatograms between BDP forced degradation mixtures and aged BDP MDI samples.

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Using thermal forced degradation approach for impurity profiling of budesonide solution-formulated metered dose inhalation with implementation of LC-QTOFMS and HPLC-UV
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Moreover, same report has proved that the reaction is dependent on trace-metal impurities, owing to the fact that the generation of steroid-glyoxal was totally blocked with the addition of disodium edetate. Furthermore, it has been postulated that the oxidation of triamcinolone acetonide with molecular oxygen occurs at the Al2O3 surface [4]. What should be notified is that both hydrocortisone and triamcinolone acetonide stated in the above investigations bear very close structures as BUD, i.e., similar corticosteroid structure skeleton and the same 20-keto-21-hydroxyl side chain at C-17.
The impurity profile of budesonide solution-formulated metered dose inhalation using thermal forced degradation approach was studied intensively in this article. The structural identification of 10 budesonide related impurities was conducted by LC-QTOFMS, and the impurity level in the formulations of different excipients and packing materials were compared using HPLC-UV. Based on our results, the impurities were classified into three groups: (Ⅰ) process impurities, including budesonide impurity A, C and F; (Ⅱ) degradation products, including budesonide impurity E, G, D, 17-carboxylate, and 17-ketone; (Ⅲ) not only process impurities but also degradation products, including budesonide impurity I and L. Budesonide impurity D, 17-carboxylate, 17-ketone and impurity L were found to be the major degradation products of budesonide, and the reaction pathways for the generation of these impurities were speculated. The generation of budesonide impurity D, 17-carboxylate and L was found to be an aerobic oxidation process induced by Al₂O₃ on the inner surface of aluminum canisters. Furthermore, an in-depth discussion on the proposed impact of the excipients on budesonide degradation, especially on the Al₂O₃-induced oxidation process, was provided in this article.
Topically used corticosteroids: What is the big picture of drug product degradation?
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For all in Fig. 1 mentioned corticosteroid groups a small selection of for topical application relevant degradation products is described in literature. For triamcinolone acetonide (TCA) (van Heugten et al., 2018a; Wu et al., 2012) and hydrocortisone (HC) (Hansen and Bundgaard, 1980; Zhang et al., 2016) a 17-carboxylic acid and 21-aldehyde have been reported and for desoximethasone (DS) only a 17-carboxylic acid (Srinivasu et al., 2012). Specifically for HC a 17-ketone and a 17-carboxylic acid and 21-aldehyde without the 17-hydroxide moiety have been described (Hansen and Bundgaard, 1980; Zhang et al., 2016).
Corticosteroids are widely used in topical formulations such as creams (aqueous) and ointments (non-aqueous). The generally used corticosteroids show large molecular resemblance, where especially the 20-keto-21-hydroxyl group bound to the 17 carbon is important for their chemical stability. Oxidation in both aqueous and non-aqueous environment occurs for triamcinolone acetonide (TCA), hydrocortisone (HC) and desoximethasone (DS). Besides the 20-keto-21-hydroxyl group, TCA, HC and DS have different other moieties attached to the same C17. These moieties are shown to influence not only the type of degradation product formed but also the degradation kinetics. Seven degradation products are found in total and a degradation mechanism is proposed. Furthermore the transesterfication of betamethasone-17-valerate to betamethasone-21-valerate is shown to occur both in aqueous and non-aqueous environment. Finally, a comprehensive scheme of degradation pathways is presented that is applicable for both aqueous and non-aqueous formulations.
Development and validation of a stability-indicating HPLC-UV method for the determination of triamcinolone acetonide and its degradation products in an ointment formulation
2018, Journal of Pharmaceutical and Biomedical Analysis
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The PG hemi-acetal is described in literature as a comparable degradation product of triamcinolone acetophenonide in the presence of PG [16]. The C17-glyoxilic acid has been described before for flurandrenolide in a cream formulation only, but not for TCA or other described corticosteroids [2,14,15,17]. For the PG ester of the C17-glyoxilic acid no prior report was found.
A stability indicating high performance liquid chromatography method has been developed for the determination of triamcinolone acetonide (TCA) and its main degradation products in ointment formulations. The method, based on extensive stress testing using metal salts, azobisisobutyronitrile, acid, base and peroxide, showed that TCA undergoes oxidative degradation. All degradation products were identified using HPLC mass spectrometry. Separation and quantification was achieved using an Altima C18 RP18 HP column (250 × 4.6 mm², with 5 μm particles) using a mobile phase consisting of acetonitrile and water buffered at pH 7 using 10 mM phosphate buffer. A gradient mode was operated at a flow rate of 1.5 ml/min and detection was at 241 nm. The method showed linearity for TCA and Impurity C in 0.02–125% of the workload, both square roots of the correlation coefficients were larger than 0.9999. Repeatability and intermediate precision were performed by six consecutive injections of both 1.25% and 125% of the work load for both TCA and Impurity C divided equally over two days. RSD were 0.6% and 0.7% for TCA and 0.5% and 0.1% for Impurity C respectively. Accuracy was determined as well, the average recoveries were 99.5% (±0.1%, n = 3) for TCA and 96.9% (±1.3%, n = 3) for impurity C respectively from spiked ointment samples. The robustness was also evaluated by variations of column (old vs new), mobile phase pH and filter retention. The applicability of the method was evaluated by analysis of a commercial ointment formulation. Interestingly, the extensive stress tests were able to predict all degradation products of TCA in a long term stability ointment sample.
Practical, regulatory and clinical considerations for development of inhalation drug products
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Having said that, the ethanol content in solution formulations must be balanced, as higher ethanol concentration can lead to decreased fine particle fraction, mainly due to the increase in initial atomized droplet size that subsequently affects solvent evaporation [9,10]. The chemical stability of drug could also be an issue for solution formulations [11,12]. In Atrovent, a solution formulation of ipratropium bromide, water and citric acid are added to improve the drug chemical stability.
The formulation and device collectively constitute an inhalation drug product. Development of inhaled drugs must consider the compatibility between formulation and device in order to achieve the intended pharmaceutical performance and usability of the product to improve patient compliance with treatment instruction. From the points of formulation, device and patient use, this article summarizes the inhalation drugs, including pressurized metered dose inhaler (pMDI), dry powder inhaler (DPI), and nebulizer that are currently available in the US and UK markets. It also discusses the practical considerations for the development of inhalers and provides an update on the corresponding regulations of the FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency).
The Role of Excipients in the Stability of Triamcinolone Acetonide in Ointments
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Pharmaceutics, Preformulation and Drug DeliveryForced Degradation Studies of Corticosteroids With an Alumina–Steroid–Ethanol Model for Predicting Chemical Stability and Degradation Products of Pressurized Metered-Dose Inhaler Formulations

ABSTRACT

Section snippets

INTRODUCTION

Chemicals

Chemical Stability of BUD in an Ethanol–Al2O3 Mixture and in a Solution pMDI

CONCLUSIONS

ACKNOWLEDGEMENTS

Adv Drug Del Rev

Int J Pharm

Adv Drug Del Rev

J Pharm Sci

Tetrahedron Lett

Guidance for industry Q1A (R2) stability testing of new drug substances and products

Federal Register

Available guidance and best practices for conducting forced degradation studies

Pharm Tech

Stress testing: A predictive tool. In Drugs and the pharmaceutical sciences

Transition to CFC-free metered dose inhalers—Into the new millennium