左卡尼汀配伍稳定性
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Peer Reviewed
Stability of Acetyl-l-carnitine in 5% Dextrose Using a High-performance Liquid Chromatography-Mass Spwenku.baidu.comctrometry Times 2 Method
Yang Zhang, MS Hongliang Jiang, PhD Paul Hutson, PharmD
Introduction
Acetyl-l-carnitine is an endogenous ester of the trimethylated amino acid, l-carnitine and is quantitatively and functionally the most important ester in the mammalian carnitine pool for longchain fatty acid oxidation and cellular energy production.1 Acetyl-lcarnitine may provide benefits in certain neurological disorders such as mild to moderate Alzheimer’s, depression, and neuropathic pain caused by diabetes or chemotherapy.2-3 In its oral form, acetyl-l-carnitine is being tested in a cooperative group trial for the prevention of peripheral neuropathy secondary to neurotoxic chemotherapy. The hydrolysis product of acetyl-l-carnitine, l-carnitine, is indicated as an intravenous (IV) formulation for carnitine deficiency in pre-term infants or in patients undergoing hemodialysis.3 The stability and compatibility has been well established for l-carnitine in various intravenous solutions.4 The oral bioavailability following a typical oral dose of carnitine supplements is reported to be only 14% to 18%, owing to the charged quaternary amine moiety.1,5 Rapid renal excretion after oral administration of acetyl-l-carnitine mandates frequent dosing and risks poor adherence.1 In light of these challenges, development of IV acetyl-l-carnitine with established stability in solution may provide an alternative for research in clinic or inpatient settings. IV acetyl-l-carnitine has been evaluated in European studies and has demonstrated clinical benefits in circulatory shock, spastic paraparesis, Alzheimer’s dementia, hepatic encephalopathy, and chemotherapy-induced peripheral neuropathy.5-10 Daily IV doses ranging from 0.2 g to 4 g at concentrations up to 10 mg/mL were used in these studies for up to 10 days without reported side effects. Acetyl-l-carnitine is hydrolyzed to l-carnitine via acid/base catalysis in commonly used aqueous solutions for infusion or injection. Conversion to l-carnitine may lead to loss of function unique to the acetyl ester. No stability data has been reported for IV acetyl-lcarnitine to date. Analytical methods have been developed to quantify endogenous and exogenous levels of acetyl-l-carnitine in biological fluids.11-15 These methods are limited by issues of sample preparation, chemical derivatization, long run time, or are not stability indicating. The purpose of this study was therefore to develop and validate a simple stability-indicating method, and use it to establish the stability of acetyl-l-carnitine in water (D5W) under clinical conditions.
Yang Zhang, a Doctor of Pharmacy student, and Paul Hutson, an associate professor, are affiliated with the University of Wisconsin-Madison, School of Pharmacy, Madison, Wisconsin. Hongliang Jiang is a professor at the Huazhong University of Science & Technology, Tongji School of Pharmacy, Wuhan, Hubei Province, China.
170
International Journal of Pharmaceutical Compounding Vol. 16 No. 2 | March/April 2012
www.ijpc.com
Peer Reviewed
Method
High-performance Liquid Chromatography-Mass Spectrometry Times 2 Method
Abstract
A stability-indicating high-performance liquid chromatography-mass spectrometry times 2 method was developed to establish the stability of acetyl-l-carnitine dissolved in 5% dextrose in water; quantitation of acetyl-l-carnitine and its hydrolysis product l-carnitine was performed using this method. Acetyl-lcarnitine dissolved in water was stress-degraded at a pH range of 3 to 12, and conversion to l-carnitine was quantified over 18 hours. The method was further validated by stressing the acetyl-l-carnitine solution at 68°C, 82°C, and 90°C for up to 10 days, yielding a temperature-dependent hydrolysis rate constant. Acetyl-l-carnitine solutions were stored at 25°C and 4°C to 8°C for 33 days to validate the kinetics prediction. The liquid chromatography-mass spectrometry times 2 method was sensitive and specific, allowing rapid separation and simultaneous quantitation of acetyl-l-carnitine and l-carnitine. Acetyl-l-carnitine dissolved in aqueous solutions is stable at neutral to acidic pH, but unstable at pH>9. After 1 hour storage at room temperature, only 72.6% of acetyl-l-carnitine was left at pH 11 and 4.2% left at pH 12. The kinetics relationship between temperature and rate constant was ln(k) = -8650.1 /T + 20.344 (r2= 0.9851) at pH 5.2. The time required to degrade 15% of acetyl-lcarnitine was estimated to be 38 days at 25°C or 234 days at 8°C, and was confirmed with actual storage stability testing. Acetyl-l-carnitine dissolved in water (pH 5.2) at concentrations of 1 and 10 mg/mL was found stable at room temperature or refrigerated for at least 33 days using the established stabilityindicating method. Acetyl-l-carnitine solutions are not stable at basic pH. When reconstituted in water, acetyl-l-carnitine is stable for over 30 days at room temperature or under refrigeration.
Stability of Acetyl-l-carnitine in 5% Dextrose Using a High-performance Liquid Chromatography-Mass Spwenku.baidu.comctrometry Times 2 Method
Yang Zhang, MS Hongliang Jiang, PhD Paul Hutson, PharmD
Introduction
Acetyl-l-carnitine is an endogenous ester of the trimethylated amino acid, l-carnitine and is quantitatively and functionally the most important ester in the mammalian carnitine pool for longchain fatty acid oxidation and cellular energy production.1 Acetyl-lcarnitine may provide benefits in certain neurological disorders such as mild to moderate Alzheimer’s, depression, and neuropathic pain caused by diabetes or chemotherapy.2-3 In its oral form, acetyl-l-carnitine is being tested in a cooperative group trial for the prevention of peripheral neuropathy secondary to neurotoxic chemotherapy. The hydrolysis product of acetyl-l-carnitine, l-carnitine, is indicated as an intravenous (IV) formulation for carnitine deficiency in pre-term infants or in patients undergoing hemodialysis.3 The stability and compatibility has been well established for l-carnitine in various intravenous solutions.4 The oral bioavailability following a typical oral dose of carnitine supplements is reported to be only 14% to 18%, owing to the charged quaternary amine moiety.1,5 Rapid renal excretion after oral administration of acetyl-l-carnitine mandates frequent dosing and risks poor adherence.1 In light of these challenges, development of IV acetyl-l-carnitine with established stability in solution may provide an alternative for research in clinic or inpatient settings. IV acetyl-l-carnitine has been evaluated in European studies and has demonstrated clinical benefits in circulatory shock, spastic paraparesis, Alzheimer’s dementia, hepatic encephalopathy, and chemotherapy-induced peripheral neuropathy.5-10 Daily IV doses ranging from 0.2 g to 4 g at concentrations up to 10 mg/mL were used in these studies for up to 10 days without reported side effects. Acetyl-l-carnitine is hydrolyzed to l-carnitine via acid/base catalysis in commonly used aqueous solutions for infusion or injection. Conversion to l-carnitine may lead to loss of function unique to the acetyl ester. No stability data has been reported for IV acetyl-lcarnitine to date. Analytical methods have been developed to quantify endogenous and exogenous levels of acetyl-l-carnitine in biological fluids.11-15 These methods are limited by issues of sample preparation, chemical derivatization, long run time, or are not stability indicating. The purpose of this study was therefore to develop and validate a simple stability-indicating method, and use it to establish the stability of acetyl-l-carnitine in water (D5W) under clinical conditions.
Yang Zhang, a Doctor of Pharmacy student, and Paul Hutson, an associate professor, are affiliated with the University of Wisconsin-Madison, School of Pharmacy, Madison, Wisconsin. Hongliang Jiang is a professor at the Huazhong University of Science & Technology, Tongji School of Pharmacy, Wuhan, Hubei Province, China.
170
International Journal of Pharmaceutical Compounding Vol. 16 No. 2 | March/April 2012
www.ijpc.com
Peer Reviewed
Method
High-performance Liquid Chromatography-Mass Spectrometry Times 2 Method
Abstract
A stability-indicating high-performance liquid chromatography-mass spectrometry times 2 method was developed to establish the stability of acetyl-l-carnitine dissolved in 5% dextrose in water; quantitation of acetyl-l-carnitine and its hydrolysis product l-carnitine was performed using this method. Acetyl-lcarnitine dissolved in water was stress-degraded at a pH range of 3 to 12, and conversion to l-carnitine was quantified over 18 hours. The method was further validated by stressing the acetyl-l-carnitine solution at 68°C, 82°C, and 90°C for up to 10 days, yielding a temperature-dependent hydrolysis rate constant. Acetyl-l-carnitine solutions were stored at 25°C and 4°C to 8°C for 33 days to validate the kinetics prediction. The liquid chromatography-mass spectrometry times 2 method was sensitive and specific, allowing rapid separation and simultaneous quantitation of acetyl-l-carnitine and l-carnitine. Acetyl-l-carnitine dissolved in aqueous solutions is stable at neutral to acidic pH, but unstable at pH>9. After 1 hour storage at room temperature, only 72.6% of acetyl-l-carnitine was left at pH 11 and 4.2% left at pH 12. The kinetics relationship between temperature and rate constant was ln(k) = -8650.1 /T + 20.344 (r2= 0.9851) at pH 5.2. The time required to degrade 15% of acetyl-lcarnitine was estimated to be 38 days at 25°C or 234 days at 8°C, and was confirmed with actual storage stability testing. Acetyl-l-carnitine dissolved in water (pH 5.2) at concentrations of 1 and 10 mg/mL was found stable at room temperature or refrigerated for at least 33 days using the established stabilityindicating method. Acetyl-l-carnitine solutions are not stable at basic pH. When reconstituted in water, acetyl-l-carnitine is stable for over 30 days at room temperature or under refrigeration.