Stability of apomorphine in solutions containing selected antioxidant agents

Abstract

Apomorphine in solution undergoes rapid autoxidation, producing greenish colored solutions, making it difficult to formulate as a stable pharmaceutical solution. To identify the optimum antioxidant agent/combination for apomorphine solution, a high performance liquid chromatography assay was used to study the stability of 50 μg/mL apomorphine HCI in 0.1% L-ascorbic acid (AA), 0.1% sodium metabisulfite (SMB), 0.1% EDTA, and in selected combinations at 25°C, 32°C, and 37°C over a period of 14 days. The stability of apomorphine HCl (10 mg/mL) in 0.1% AA solution and in 0.1% EDTA solution at 25°C and 37°C was also evaluated. Apomorphine HCI solution (50 μg/mL) in 0.1% AA plus 0.1% SMB solution retained 99.7% (at 25°C) and 95.9% (at 37°C) of the initial concentration, as 0.1% AA plus SMB solution minimized the reactive oxygen content in solution which, in turn, reduced the oxidation rate of apomorphine HCl, and there was no green coloration perceptible. Conversely, apomorphine HCl solution (50 μg/mL) in 0.1% SMB solution was unstable as only 0.53% (at 25°C) and 0.06% (at 37°C) of the initial concentration was retained after 14 days. All 10 mg/mL apomorphine HCl samples were stable in both studies. The initial concentration of apomorphine HCl solution markedly affected its rate of oxidation and discoloration. The addition of 0.1% AA to a current formulation of apomorphine HCl injection (Apomine®), which contains SMB as an antioxidant, was recommended as providing the most stable solution.

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“…the solution was changed from colorless to be green−blue likely due to increased accumulation of oxidized APOoxoapomorphine. In fact, as the literature 39,40 has indicated, the presence of the oxidized APO (i.e., oxoapomorphine) likely caused this solution to be greenish. According to mass spectra of APO (MW 267 g/mol) samples before and after CV scanning (Figure 4), not only the peaks of m/z 266 (M−1) and 268 (M+1) but also one peak at m/z 264 (M+1) were shown.…”

“…According to mass spectra of APO (MW 267 g/mol) samples before and after CV scanning (Figure ), not only the peaks of m/z 266 (M–1) and 268 (M+1) but also one peak at m / z 264 (M+1) were shown. It was suspected that some content of oxoapomorphine (MW 263 g/mol) was formed due to electrochemical instability of APO. , Moreover, oxoapomorphine possessed more conjugated π electrons than APO; thereby, oxoapomorphine exhibited the more aromatic and the more ES characteristics as compared to its mother compound, APO. Thus, due to a trace amount of oxoapomorphine present in APO, the more significant intensity of the redox potential peak in the APO sample was evolved.…”

Effect of Formulation Factors and Oxygen Levels on the Stability of Aqueous Injectable Solution Containing Pemetrexed

“…Sacrificial reductants are compounds that are oxidized more readily than the drug. They effectively scavenge oxygen, while they are themselves consumed; hence, they inhibit the oxidation of the drug [17,21]. As shown in Figure 4a, the concentration of sulfite decreased while the concentration of sulfate increased over the storage period.…”

“…In general, following parameters can affect the stability of injectable drug solutions: temperature, exposure to light, pH of the solution, presence of additives, concentration of API, presence of oxygen, and duration of storage [10][11][12][13][14][15][16][17][18][19]. In order to stabilize the injectable drug solution, control strategies have been attempted after thorough understanding of the critical quality attributions (CQA), critical material attributes (CMA) and critical process parameters (CPP) in relation to the formulation and manufacturing process, and considering the quality of the intermediate and final products [20].…”

Development of a Liquid Chromatographic Method for Apomorphine Hydrochloride Quantitation in the Active Pharmaceutical Ingredients and in the Dosage Forms

“…Various analytical methods have been reported for analyzing the apomorphine HCl, including liquid chromatography-electrospray ionization mass spectrometry (Yang, 2006), proton nuclear magnetic resonance spectrometry (Tan, 2016) liquid chromatography . (Ang and Boddy and Liu and Sunderland, 2016), titrimetry (The United States Pharmacopeia; European Pharmacopoeia). These analytical methods (Liquid chromatographyelectrospray ionization mass spectrometry, proton nuclear magnetic resonance spectrometry) is more accurate and sensitive, however costly, therefore, limit their utility in the quality control of pharmaceutical formulations.…”