Premixed solutions of diamorphine in ropivacaine for epidural anaesthesia: a study on their long-term stability

M. J. Sánchez del Águila1, M. F. Jones2 and A. Vohra*,1

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


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Local anaesthetics and opioid mixtures are commonly used to provide anaesthesia or analgesia during the perioperative period. In order to facilitate their preparation and storage it is necessary to establish the stability of such solutions.

Methods. In our study, diamorphine was added to ropivacaine 0.2% 200-ml polybags to give a concentration of 25 µg ml–1 and to ropivacaine 1% 50-ml syringes to give a concentration of 45 µg ml–1. 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: 179–82

Keywords: anaesthetic techniques, epidural; anaesthetics local, ropivacaine; anaesthetics opioid, diamorphine; analgesic techniques, infusion


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Diamorphine is an opioid derivative synthesized from morphine by the addition of two acetyl groups, making the molecule highly lipid soluble. Its salt, diamorphine hydrochloride, decomposes more slowly than diamorphine base in the presence of water. The initial degradation products are 6-O-acetylmorphine (after hydrolysis of the 3-acetyl group) and acetic acid. The 6-acetyl group also hydrolyses slowly to give morphine. Daylight, heat and acidic and alkaline pH will accelerate decomposition. The most stable pH range is 4–5.1 Diamorphine is presented in tablets and in 5 mg, 30 mg, 100 mg and 500 mg ampoules of freeze-dried diamorphine. In the body, diamorphine is rapidly hydrolysed to 6-O-acetylmorphine and then more slowly to morphine. The former rapidly enters the central nervous system where it achieves very high concentrations and is subsequently metabolized more slowly to morphine.2

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’ (100–500 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 ml–1) in 100 ml Polybags of ropivacaine 0.2%, and diamorphine 45 µg ml–1 in a 50 ml syringe of ropivacaine 1%.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Diamorphine hydrochloride was added to 100 ml Polybags of ropivacaine 0.2% to give a nominal diamorphine concentration of 25 µg ml–1 (n=6) and to ropivacaine 1.0% solution to give a nominal concentration of 45 µg ml–1, which was stored in 50 ml B–D syringes sealed with luerlock blind hubs (n=9).

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 4.0–9.0.

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 min–1 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 10–35 µg ml–1 (r=0.9985) and for ropivacaine over the range 1–3 mg ml–1 (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 time–concentration 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


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Degradation of ropivacaine was not found at any time under the test conditions. The HPLC method would not of course detect changes in enantiomeric purity of the ropivacaine, but a study of ropivacaine stability when stored in polybags and syringes at up to 32°C has previously shown that such changes were absent.9

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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Table 1 Degradation of diamorphine samples based on linear regression analysis. Degradation rate constant, 95% confidence intervals, and time to reduce to 90% of starting concentration [T (0.9)].
 
When comparing the rates of degradation in the two groups it becomes evident that diamorphine degradation is faster in the containers stored at higher temperature than in those stored at room temperature or 4°C. At 40°C 10% degradation occurred at 7–9 days in both the syringes and the polybags; 75% of the initial concentration had been lost by 80–125 days. At 21°C, 10% degradation occurred at 16–18 days in syringes and 28–37 days in polybags. At 4°C, 10% degradation occurred at approximately 30 days in the syringe and 30% of the initial concentration had been lost by 128 days, whereas 9% degradation was found in the Polybags at 70 days.

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 ml–1 diamorphine than in those with 25 µg ml–1 (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 ml–1 X=0.0060; 25 µg ml–1 X=0.0056).



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Fig 1 Logarithmic representation of the changes in concentration of diamorphine. Two groups of curves represent the different initial concentrations.

 
The initial pH measurements were higher in the Polybags (5.92–6.25) than in the syringes (5.03). In subsequent measurements, the polybags showed a consistent decrease in pH, whereas the syringes did not, or even showed a slightly increased pH (5.35) (Table 1).


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The behaviour of diamorphine in ropivacaine solutions is not very different to that in other aqueous solutions. When comparing degradation of diamorphine, the rate of diamorphine decomposition was approximately 2.2 times higher in the syringes than in the polybags stored under equivalent conditions, which may reflect the difference in initial concentration. It is important to note that the 70-day shelf life of the polybags stored at 4°C (Table 1) makes it feasible to manufacture and store such solutions in pharmacy aseptic units for routine use in epidural infusions. If solutions of ropivacaine without 0.9% saline were available, higher shelf lives would be likely because the very strong accelerating effect of ionic strength on the decomposition of diamorphine would be eliminated.10

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 don’t 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.


    Acknowledgements
 
We are grateful to Astra Pharmaceuticals (now AstraZeneca Ltd) for the gift of the Naropin (ropivacaine) products, and also to Mr A. Holmes for invaluable technical assistance.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Payne HAS, Tempest SM. The chemistry and pharmacy of diamorphine. In: Scott DB, ed. Diamorphine. Cambridge: Woodhead-Faulkner, 1988; 1–14

2 Stevens LA, Wooton CM. The pharmacokinetic properties of diamorphine. In: Scott DB, ed. Diamorphine. Cambridge: Woodhead-Faulkner, 1988; 15–43

3 Astra. Naropin Datasheet. May 1996

4 Behar M, Olswang D, Magora F, Davidson JT. Epidural morphine in the treatment of pain. Lancet 1979; 1: 527[ISI][Medline]

5 Dailland P, Chaussis P, Michel D. Opiates for epidural analgesia: for or against? Cah Anesthesiol 1994; 42: 275–85[Medline]

6 McIntosh D, Spaven J, Hagen NA. How long do prepared epidural solutions remain sterile? J Pain Symptom Manage 1999; 18: 137–9[CrossRef][ISI][Medline]

7 Kulka PJ, Stratesteffen I, Grunewald R, Wielback A. Inadvertent potassium chloride infusion in an epidural catheter. Anaesthesist 1999; 48: 896–9[CrossRef][ISI][Medline]

8 Norwood TE. Statistical analysis of pharmaceutical stability data. Drug Dev Ind Pharm 1986; 12: 553–60[ISI]

9 Oster, K. (Astra) Internal Report No. 802-ILU-0332, July 1997

10 Beaumont IM. A stability study of aqueous solutions of diamorphine and morphine using high performance liquid chromatography. Anal Proc 1982; 19: 128–31

11 Sevarino FB, Pizarro CW, Sinatra R. Sterility of epidural solutions recommendations for cost-effective use. Reg Anesth Pain Med 2000; 25: 368–71[CrossRef][ISI][Medline]





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