1 Department of Anaesthesia, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. 2 Quality Control North West, Stepping Hill Hospital, Stockport, UK
Corresponding author. E-mail: avohra@compuserve.com
Accepted for publication: October 2, 2002
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Abstract |
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Methods. In our study, diamorphine was added to ropivacaine 0.2% 200-ml polybags to give a concentration of 25 µg ml1 and to ropivacaine 1% 50-ml syringes to give a concentration of 45 µg ml1. The polybags and syringes were stored at 40°C, 21°C and 4°C for up to 120 days. Samples were taken during this period for measurement of diamorphine and ropivacaine content and pH of the solutions.
Results. We found that the storage temperature and the initial concentration influenced the rate of degradation of diamorphine in both the polybags and the syringes. In the syringes, 10% degradation of diamorphine [T (0.9)] was: 6 days at 40°C, 16 days at 21°C and 30 days at 4°C. In the polybags, diamorphine T (0.9) was 6 days at 40°C, 28 days at 21°C and 70 days at 4°C.
Conclusions. It is feasible to manufacture such solutions in pharmacy aseptic units and to store them for up to 1 month for routine use in epidural infusions.
Br J Anaesth 2003; 90: 17982
Keywords: anaesthetic techniques, epidural; anaesthetics local, ropivacaine; anaesthetics opioid, diamorphine; analgesic techniques, infusion
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Introduction |
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Ropivacaine is a long-acting amide local anaesthetic licensed for epidural/perineural injection and epidural infusion in surgical anaesthesia and acute pain management. It is marketed as polyamps with ropivacaine at 0.2%, 0.75% and 1% concentrations, and 100 ml and 200 ml polybags of ropivacaine 0.2%. The solution also contains sodium chloride, sodium hydroxide, hydrochloric acid and water for injections.3
The addition of opioids to local anaesthetic solutions has been common practice for many years.4 Local anaesthetic and opioid mixtures as single doses or as infusions are often used to provide spinal and/or epidural anaesthesia/analgesia during the perioperative period and may be used for many days after surgery. The use of low-concentration local anaesthetic solutions combined with an opioid generates a faster onset and more profound analgesia with little motor block. Thus, pain relief lasts longer than after either drug alone.5
It is important to establish the stability of these mixtures if we are to use them in such a manner. Furthermore, it would be helpful if such combinations could be provided as ready-made mixtures in order to give greater assurance of sterility6 and availability, as well as to reduce the incidence of drug administration errors.7 Conventionally, the infusions have been provided in the form of big bags (100500 ml) or premixed 50 ml syringes. However, the stability of diamorphine in ropivacaine solution has not been ascertained. This study has been designed to evaluate the stability of diamorphine (25 µg ml1) in 100 ml Polybags of ropivacaine 0.2%, and diamorphine 45 µg ml1 in a 50 ml syringe of ropivacaine 1%.
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Methods |
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Two polybags and three syringes were immediately stored at three different conditions of temperature and humidity for periods of up to 126 days: 40°C with 75% relative humidity, 21°C at ambient humidity, and at 4°C.
Two-millilitre samples were removed from the syringes at four time points up to 126 days, and from the polybags at three time points up to 120 days. The pH values were measured using the Corning 120 meter (Scientific and Medical Products Ltd, Manchester, UK) standardized over the range 4.09.0.
Diamorphine and ropivacaine contents were measured after dilution of 0.5 ml samples of ropivacaine 1% to 50 ml, or 1.0 ml samples of ropivacaine 0.2% to 25 ml in 0.02 M phosphate buffer at pH 8. High performance liquid chromatography (HPLC) assay of replicate samples was carried out on a 15 cm column of Partisil ODS3 (5 µm) (Whatman Labsales Ltd, Over, Cambs, UK). The eluant system consisted of water (700 ml), acetonitrile (300 ml) and orthophosphoric acid (4 ml) adjusted to apparent pH 5.0 with 5 M sodium hydroxide solution. At a flow rate of 1 ml min1 retention times were 5.3 min and 6.3 min for diamorphine and ropivacaine, respectively. UV detection was at 206 nm. The HPLC system was demonstrated to adequately separate the decomposition products of diamorphine (monoacetylmorphine and morphine) from the other peaks in the chromatogram.
The precision (repeatability) as % relative standard deviation of the method in the determination of diamorphine and ropivacaine was found to be 3.23 and 3.09, respectively, for the polybags, and 2.54 and 2.48 for the syringes (n=6 in all cases). The method was found to be linear for diamorphine concentration over the range 1035 µg ml1 (r=0.9985) and for ropivacaine over the range 13 mg ml1 (r=0.9985).
Peak areas were converted to concentration terms by external standardization with diamorphine hydrochloride (Hillcross Pharmaceuticals, Burnley, UK; Batch 23373) and ropivacaine hydrochloride (Astra Pharmaceuticals Ltd, Kings Langley, Herts, UK; Batch 201/94) solutions.
Linear regression of timeconcentration data allowed the first-order rate constants, 95% confidence limits of the regressions, and storage life [calculated as the time to lose 10% of the initial concentration, T (0.9)] to be calculated by the maximum rate method.8
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Results |
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Table 1 shows the results of the diamorphine changes. The rate of degradation of diamorphine in both the polybags and the syringes appeared to be influenced by two factors: storage temperature and initial concentration. Failure of two time-point assays for syringe 3 led to its abandonment because of insufficient data points.
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The data were log transformed to show linear degradation (Fig. 1). When comparing the slopes we found that, at 4°C, the rate of diamorphine degradation was higher in the containers containing 45 µg ml1 diamorphine than in those with 25 µg ml1 (X=0.0013 vs 0.0003). This phenomenon seems to decrease as the storage temperature rises, and at 40°C the slopes of the curves were similar (45 µg ml1 X=0.0060; 25 µg ml1 X=0.0056).
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Discussion |
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The reason for the higher initial pH in the stored polybags is unclear, and it would be expected that this value would result in a significantly higher rate of decomposition than in the stored syringes. In practice, the initial decomposition swiftly brings the pH value close to that of the syringe solutions, the result of acetic acid production, and the potentially higher rate of decomposition is undetectable. The syringes did not show a consistent decrease in pH. Furthermore, some syringes showed a slight increase. We dont know the reason for this but it might imply some leaching of a constituent of the syringe assembly that masks the production of acetic acid from the diamorphine decomposition.
The stability of diamorphine and ropivacaine solutions means that they can be manufactured by hospital pharmacy services. These preparations require strict aseptic formulation before storage, and refrigeration is required to minimize bacterial growth.11 A shelf life of 1 month at 4°C can be applied to both presentations. Our results support the view that diamorphine will be stable at room temperature and even at 40°C when used in the postoperative period.
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Acknowledgements |
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References |
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