- Email: [email protected]
Stability of premixed syringes of diamorphine and hyperbaric bupivacaine
International Journal of Obstetric Anesthesia (2005) 14, 284–287 Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ijoa.2005.03.004
ORIGINAL ARTICLE
Stability of premixed syringes of diamorphine and hyperbaric bupivacaine S. J. Hudson, M. F. Jones, S. Nolan, H. Ellis, R. Duncombe, J. M. Alexander-Williams Departments of Anaesthesia and Pharmacy, Broomfield Hospital, Chelmsford and Quality Control North West, Stepping Hill Hospital, Stockport, UK Background: It is common clinical practice to add diamorphine to heavy bupivacaine when performing spinal anaesthesia for either obstetric or general surgical procedures. If pre-filled syringes were available potential problems arising due to the wrong mixture being administered could be reduced, whilst also providing greater assurances of sterility and accuracy of dosage. It is therefore necessary to establish whether diamorphine 100 lg/mL is stable in solution with 0.5% hyperbaric bupivacaine, to allow production of pre-filled syringes for use in spinal anaesthesia. Method: Diamorphine hydrochloride was dissolved in water for injection, and added to hyperbaric bupivacaine then stored in 5-mL plastic syringes. Eleven syringes were stored at 40°C/75% relative humidity, 25°C/ 60% relative humidity and 7°C for 90 days. Samples were taken at five time points for measurement of diamorphine and bupivacaine concentrations using high performance liquid chromatography. Results: Diamorphine concentrations fell over the study period. No significant changes were observed the bupivacaine content of the samples. There was 10% degradation of diamorphine after 4 days at 40°C, after 7 days at 25°C, and after 26 days at 7°C. Conclusion: Diamorphine is stable in hyperbaric bupivacaine at 7°C for long enough to allow preparation of pre-filled syringes in advance (by hospital pharmacy aseptic units) for use in spinal anaesthesia. Ó 2005 Elsevier Ltd. All rights reserved. Keywords: Anaesthetic techniques, spinal; Anaesthetics local, bupivacaine; Anaesthetics opioid, diamorphine
opioid derived from morphine. It is supplied as the hydrochloride salt, which decomposes more slowly than the diamorphine base when added to water. It hydrolyses to 6-O-acetylmorphine and acetic acid, then to morphine. The rate of degradation is affected by heat, light and pH; the most stable pH range is between 4 and 5.3 The smallest available ampoule of diamorphine contains 5 mg of freeze-dried diamorphine hydrochloride. In vivo, diamorphine hydrolyses to 6-O-acetylmorphine rapidly then to morphine at a slower rate. High concentrations of 6-O-acetylmorphine appear rapidly in the central nervous system after intrathecal injection.4 Hyperbaric bupivacaine is formulated in 8% dextrose to produce a hyperbaric solution for intrathecal injection with a specific gravity of 1.026 at 20°C. Bupivacaine is an amide local anaesthetic with a pKa of 8.1, it is extensively bound to plasma proteins (95%) and exhibits a high degree of lipid solubility. These factors contribute to its prolonged duration of action. It is marketed in glass ampoules containing 4 mL 0.5% w/v bupivacaine
INTRODUCTION In the UK it is common practice to add diamorphine to hyperbaric bupivacaine when performing spinal anaesthesia for either obstetric or general surgical procedures.1,2 Data on the stability of such solutions have not been available up until now. Diamorphine (3,6 diacetylmorphine) is a highly lipid-soluble semi-synthetic Accepted March 2005 This work was presented to the Anaesthetic Research Society in July 2004 and has been published in abstract in the British Journal of Anaesthesia, October 2004. S.J. Hudson, J.M. Alexander-Williams, Department of Anaesthesia, Broomfield Hospital, Chelmsford, CM1 7ET, UK, H. Ellis, R. Duncombe, Pharmacy Department, Broomfield Hospital, Chelmsford, CM1 7ET, UK, M.F. Jones, S. Nolan, Quality Control North West, Stepping Hill Hospital, Stockport, UK. Correspondence to: Dr. S.J. Hudson, Broomfield Hospital, Chelmsford, Essex, CM1 7ET, UK, Tel.: +44 1245 514080. E-mail: [email protected] 284
Stability of diamorphine and hyperbaric bupivacaine 285 hydrochloride with 80 mg/mL of dextrose monohydrate. The ampoule also contains sodium hydroxide and water for injection.5 Opioids have been added to local anaesthetics for intrathecal injection for over 20 years, and recent work suggests that use of intrathecal diamorphine leads to a lower postoperative requirement for systemic opioids than when intrathecal fentanyl is used.1 Because of its fast onset but prolonged postoperative effects, diamorphine is frequently used in the UK in preference to combinations of fentanyl and morphine, which are commonly used in countries where diamorphine is not available. Diamorphine in doses up to 500 lg has been reported to be safe when administered intrathecally.6 Currently many anaesthetists mix their own solution by dissolving diamorphine hydrochloride in water, then drawing off a small volume to add to the hyperbaric bupivacaine. This preparation within the operating room environment involves a number of individual manipulations during which microbial contamination could occur. Furthermore, the more manipulations and measurements involved the greater the risk of errors; the patient may receive either a sub-therapeutic dose or an overdose. It is therefore important to establish the stability of diamorphine in hyperbaric bupivacaine to allow prefilled syringes to be produced in hospital pharmacy aseptic units and stored ready for intrathecal use. In this study we used a concentration of 100 lg in 1 mL of diamorphine, although at present the optimum intrathecal dose is still being debated.7
METHODS Diamorphine hydrochloride 10 mg (Evans Vaccines Ltd., Gaskill Road, Speke, Liverpool, L24 9GR: Lot 765438) was dissolved in water for injections (20 mL) then added to 80 mL of a stirred solution of hyperbaric bupivacaine (bupivacaine hydrochloride, Societa Italiana Medicinali Scandicci, 5006 Leggello, Firenze: Batch 40669) to give a final mixture of diamorphine 100 lg/mL and bupivacaine 0.4%. The mixture was then filtered through a 0.45-lm nylon filter and used to fill thirty-three 5-mL Becton-Dickinson (B-D) plastic syringes fitted with Baxter Luer-lock caps. Eleven syringes were stored at each of the following conditions: 7°C, 25°C/60% relative humidity and 40°C/75% relative humidity. These conditions were chosen to conform to International Conference on Harmonisation guidelines for sterility testing.8 One-millilitre samples were removed from the syringes at five time points up to 91 days. The concentrations of diamorphine and bupivacaine were measured after diluting 1 mL to 100 mL in 0.02M phosphate buffer at pH 8, using high performance liquid chromatography on a 10-cm column of Partisil
ODS3 (5 lm). The eluent consisted of water (70 mL), acetonitrile (30 mL) and 0.4% w/v orthophosphoric acid adjusted to pH 5 with sodium hydroxide. At a flow rate of 1 mL/min, retention times were 2.5 min for diamorphine and 4.45 min for bupivacaine. UV detection was at 206 nm. Stock standard solutions of diamorphine hydrochloride (10 mg in 100 mL) and bupivacaine hydrochloride (40 mg in 10 mL) were prepared in water, and 1-mL aliquots were combined and further diluted to 100 mL in a diluent corresponding to the chromatographic eluent omitting the acetonitrile. The standard and sample solutions were analysed in replicate and peak areas and component concentrations calculated using chromatographic data handling software (EZChrom Elite Ver. 2.61, Aston Scientific Ltd., Stoke Mandeville, England). The method was shown to indicate stability by demonstrating separation of peaks due to morphine and to 6O-acetylmorphine, (the decomposition products of diamorphine), and 2,6-dimethylaniline (xylidine), the only known decomposition product of bupivacaine, from each other and from the peaks produced by diamorphine and bupivacaine. Shelf lives were calculated using the confidence bound or maximum rate method.9 In this, the slope of the least squares linear regression of the natural logarithm of the concentration of diamorphine vs. time represents the first order rate constant of the decomposition. The maximum rate method uses the calculated upper 95% confidence bound of this decomposition rate, which thus corresponds to the maximum rate of decomposition represented by the analytical data. A validated Excele spreadsheet was used to calculate shelf lives, based on an acceptable loss of 10% of the initial diamorphine dose.
RESULTS Table 1 shows the quantitative validation parameters evaluated for the analytical method. Bupivacaine degradation was not demonstrated during the study period. Diamorphine degraded over time as demonstrated in Table 2, which shows the degradaTable 1. Analytical method validation Diamorphine Standard repeatability (RSD) Sample repeatability (RSD) Intermediate precision (RSD) Linearity
Bupivacaine
0.75% (n = 6)
0.24% (n = 6)
0.26% (n = 6)
0.91% (n = 6)
1.07% (n = 12)
0.8% (n = 12)
R = 0.9998 between (21–109 lg/mL)
R = 0.9999 between (0.9–4.4 lg/mL)
RSD = Relative Standard Deviation.
286 International Journal of Obstetric Anesthesia Table 2. Degradation of diamorphine at different temperatures 40°C/75% RH
25°C/60% RH
7°C
Time (days)
pH
[diamorphine] lg/mL
Time (days)
pH
[diamorphine] lg/mL
Time (days)
pH
[diamorphine] lg/mL
0 0 21 21 49 49 70 70 91 91
4.98
100.5 99.55 68.8 66.7 35.6 33.6 26.15 24.75 18.6 14.0
0 0 21 21 49 70 70 91 91
4.98
100.5 99.55 91.2 92.2 64.15 47.4 54.4 41.1 39.3
0 0 21 21 49 49 70 70 91 91
4.98
100.5 99.55 100.3 99.5 86.3 85.5 76.5 75.9 75.4 78.4
4.61 4.79 4.52 4.45 4.39 4.38 4.72 4.74
4.87 4.89 4.87 4.72 4.78 4.79 4.85
5.34 5.28 5.38 5.26 5.38 5.26 5.14 5.14
RH: relative humidity.
logn [diamorphine] [µg/ml]
4. 85
data points 90% line regression line lower limit upper limit
4. 75 4. 65 4. 55 4. 45 4. 35 4. 25 4. 15
0
20
40
60
80
Days at 7 oC
logn [diamorphine] [µg/ml]
4.80 4.60 4.40 4.20 4.00 3.80 3.60
Days at 25 oC /60% RH
logn [diamorpine] [µg/ml]
4.60
4.10
3.60
3.10
2.60 0
20
40 o
60
80
Days at 40 C / 75%RH Fig. 1 Graphs showing degradation of diamorphine over study period for samples stored at 7°C, 25°C/60%RH, and 40°C/75%RH.
Stability of diamorphine and hyperbaric bupivacaine 287 tion of diamorphine samples based on linear regression analysis. The data were log transformed and presented graphically to show linear regression. Fig. 1 represents the kinetic data for storage at 7°C, 25°C/60% relative humidity, and 40°C/75% relative humidity respectively. On comparing the three groups, it was clear that diamorphine degraded at a faster rate at higher storage temperatures; 10% degradation had occurred by 26 days at 7°C and by 7 days at 25°C, but by only 4 days at 40°C. pH changes in the samples did not differ significantly over the test period in any of the groups except for a slight decrease from 4.98 to 4.74 over 13 weeks storage at 40°C/75% relative humidity. This probably represents the increase in production of acetic acid due to the faster diamorphine decomposition at this temperature.
The preparation of syringes for intrathecal use made under Grade A conditions (Rules and guidance for pharmaceutical manufacturers and distributors 2002) will result in a significantly reduced risk of microbial contamination entering the syringe system, as these conditions have on-going microbiological monitoring and the environments should be free from bacteria and particles. Staff working in these units have validated and approved aseptic techniques and the preparation would follow strict guidelines. It has to be accepted that aseptic preparation will give a lower level of sterility assurance than a terminally sterilised product, but given the heat sensitivity of solutions of diamorphine, other methods of sterilisation would need to be considered.
ACKNOWLEDGEMENT
DISCUSSION In this study, diamorphine behaved much as it did in previous studies using other aqueous solutions.10,11 Degradation was faster in warmer conditions. As expected the bupivacaine concentration was not affected by the addition of diamorphine. The shelf life of 26 days at 7°C confirms that it would be possible to manufacture and store pre-filled syringes at this temperature for intrathecal use. The metabolites, morphine and 6-O-acetylmorphine are both active and will continue to provide analgesia, but their pharmacokinetics are quite different from those of diamorphine as they are considerably less lipid soluble. This means their duration of intrathecal action is prolonged but their onset of action delayed when compared to diamorphine. Further studies into the longerterm stability of these metabolites may be of interest as they significantly add to the opioid analgesic effects. In the UK diamorphine is a schedule-2 controlled drug and therefore subject to requirements for safe storage and handling. Given the need for the prepared syringes to be refrigerated, the refrigerator will need to conform to local regulations for a controlled drugs cupboard. The complexity of the preparation of these syringes (given the number of individual manipulations involved), and the potentially serious consequences if microbial contamination entered the system, indicate that these syringes should be prepared within the controlled environment of a pharmacy department.
We are grateful to the committee of the Chelmsford Medical Education and Research Trust for providing funding for this study.
REFERENCES 1. Cowan C M, Kendall J B, Barclay P M, Wilkes R G. Comparison of intrathecal fentanyl and diamorphine in addition to bupivacaine for Caesarean section under spinal anaesthesia. Br J Anaesth 2002; 89: 452–458. 2. Abuzaid H, Prys-Roberts C, Wilkins D G, Terry D M. The influence of diamorphine on spinal anaesthesia induced with isobaric 0.5% bupivacaine. Anaesthesia 1993; 48: 492–495. 3. Payne H A S, Tempest S M. The chemistry and pharmacy of diamorphine. In: Scott D B, ed. Diamorphine. Cambridge: Woodhead-Faulker, 1988: 1–14. 4. Stevens L A, Wooton C M. The pharmacokinetic properties of diamorphine. In: Scott D B, ed. Diamorphine. Cambridge: Woodhead-Faulkner, 1988: 15–43. 5. AstraZeneca. Marcain Heavy 0.5% Datasheet. May 2002. 6. Kelly M C, Carabine U A, Mirakhur R K. Intrathecal diamorphine for analgesia after caesarean section. A dose finding study and assessment of side effects. Anaesthesia 1998; 53: 231–237. 7. Saravanan S, Robinson A P, Qayoum Dar A, Columb M O, Lyons G R. Minimum dose of intrathecal diamorphine required to prevent intraoperative supplementation of spinal anaesthesia for Caesarean section. Br J Anaesth 2003; 91: 368–372. 8. ICH Harmonised Tripartite Guideline. Stability testing of new substances and products, Q1A(R2). Federal Register Nov 2003 68: 65717–65718. 9. Norwood T E. Statistical analysis of pharmaceutical stability data. Drug Dev Ind Pharm 1986; 12: 553–560. 10. Sanchez del Aguila M J, Jones M F, Vohra A. Premixed solutions of diamorphine in ropivacaine for epidural anaesthesia: a study on their long-term stability. Br J Anaesth 2003; 90: 179–182. 11. Omar O A, Hoskin P J, Johnston A, Hanks G W, Turner P. Diamorphine stability in aqueous solution for subcutaneous infusion. J Pharm Pharmacol 1989; 41: 275–277.
ORIGINAL ARTICLE
Stability of premixed syringes of diamorphine and hyperbaric bupivacaine S. J. Hudson, M. F. Jones, S. Nolan, H. Ellis, R. Duncombe, J. M. Alexander-Williams Departments of Anaesthesia and Pharmacy, Broomfield Hospital, Chelmsford and Quality Control North West, Stepping Hill Hospital, Stockport, UK Background: It is common clinical practice to add diamorphine to heavy bupivacaine when performing spinal anaesthesia for either obstetric or general surgical procedures. If pre-filled syringes were available potential problems arising due to the wrong mixture being administered could be reduced, whilst also providing greater assurances of sterility and accuracy of dosage. It is therefore necessary to establish whether diamorphine 100 lg/mL is stable in solution with 0.5% hyperbaric bupivacaine, to allow production of pre-filled syringes for use in spinal anaesthesia. Method: Diamorphine hydrochloride was dissolved in water for injection, and added to hyperbaric bupivacaine then stored in 5-mL plastic syringes. Eleven syringes were stored at 40°C/75% relative humidity, 25°C/ 60% relative humidity and 7°C for 90 days. Samples were taken at five time points for measurement of diamorphine and bupivacaine concentrations using high performance liquid chromatography. Results: Diamorphine concentrations fell over the study period. No significant changes were observed the bupivacaine content of the samples. There was 10% degradation of diamorphine after 4 days at 40°C, after 7 days at 25°C, and after 26 days at 7°C. Conclusion: Diamorphine is stable in hyperbaric bupivacaine at 7°C for long enough to allow preparation of pre-filled syringes in advance (by hospital pharmacy aseptic units) for use in spinal anaesthesia. Ó 2005 Elsevier Ltd. All rights reserved. Keywords: Anaesthetic techniques, spinal; Anaesthetics local, bupivacaine; Anaesthetics opioid, diamorphine
opioid derived from morphine. It is supplied as the hydrochloride salt, which decomposes more slowly than the diamorphine base when added to water. It hydrolyses to 6-O-acetylmorphine and acetic acid, then to morphine. The rate of degradation is affected by heat, light and pH; the most stable pH range is between 4 and 5.3 The smallest available ampoule of diamorphine contains 5 mg of freeze-dried diamorphine hydrochloride. In vivo, diamorphine hydrolyses to 6-O-acetylmorphine rapidly then to morphine at a slower rate. High concentrations of 6-O-acetylmorphine appear rapidly in the central nervous system after intrathecal injection.4 Hyperbaric bupivacaine is formulated in 8% dextrose to produce a hyperbaric solution for intrathecal injection with a specific gravity of 1.026 at 20°C. Bupivacaine is an amide local anaesthetic with a pKa of 8.1, it is extensively bound to plasma proteins (95%) and exhibits a high degree of lipid solubility. These factors contribute to its prolonged duration of action. It is marketed in glass ampoules containing 4 mL 0.5% w/v bupivacaine
INTRODUCTION In the UK it is common practice to add diamorphine to hyperbaric bupivacaine when performing spinal anaesthesia for either obstetric or general surgical procedures.1,2 Data on the stability of such solutions have not been available up until now. Diamorphine (3,6 diacetylmorphine) is a highly lipid-soluble semi-synthetic Accepted March 2005 This work was presented to the Anaesthetic Research Society in July 2004 and has been published in abstract in the British Journal of Anaesthesia, October 2004. S.J. Hudson, J.M. Alexander-Williams, Department of Anaesthesia, Broomfield Hospital, Chelmsford, CM1 7ET, UK, H. Ellis, R. Duncombe, Pharmacy Department, Broomfield Hospital, Chelmsford, CM1 7ET, UK, M.F. Jones, S. Nolan, Quality Control North West, Stepping Hill Hospital, Stockport, UK. Correspondence to: Dr. S.J. Hudson, Broomfield Hospital, Chelmsford, Essex, CM1 7ET, UK, Tel.: +44 1245 514080. E-mail: [email protected] 284
Stability of diamorphine and hyperbaric bupivacaine 285 hydrochloride with 80 mg/mL of dextrose monohydrate. The ampoule also contains sodium hydroxide and water for injection.5 Opioids have been added to local anaesthetics for intrathecal injection for over 20 years, and recent work suggests that use of intrathecal diamorphine leads to a lower postoperative requirement for systemic opioids than when intrathecal fentanyl is used.1 Because of its fast onset but prolonged postoperative effects, diamorphine is frequently used in the UK in preference to combinations of fentanyl and morphine, which are commonly used in countries where diamorphine is not available. Diamorphine in doses up to 500 lg has been reported to be safe when administered intrathecally.6 Currently many anaesthetists mix their own solution by dissolving diamorphine hydrochloride in water, then drawing off a small volume to add to the hyperbaric bupivacaine. This preparation within the operating room environment involves a number of individual manipulations during which microbial contamination could occur. Furthermore, the more manipulations and measurements involved the greater the risk of errors; the patient may receive either a sub-therapeutic dose or an overdose. It is therefore important to establish the stability of diamorphine in hyperbaric bupivacaine to allow prefilled syringes to be produced in hospital pharmacy aseptic units and stored ready for intrathecal use. In this study we used a concentration of 100 lg in 1 mL of diamorphine, although at present the optimum intrathecal dose is still being debated.7
METHODS Diamorphine hydrochloride 10 mg (Evans Vaccines Ltd., Gaskill Road, Speke, Liverpool, L24 9GR: Lot 765438) was dissolved in water for injections (20 mL) then added to 80 mL of a stirred solution of hyperbaric bupivacaine (bupivacaine hydrochloride, Societa Italiana Medicinali Scandicci, 5006 Leggello, Firenze: Batch 40669) to give a final mixture of diamorphine 100 lg/mL and bupivacaine 0.4%. The mixture was then filtered through a 0.45-lm nylon filter and used to fill thirty-three 5-mL Becton-Dickinson (B-D) plastic syringes fitted with Baxter Luer-lock caps. Eleven syringes were stored at each of the following conditions: 7°C, 25°C/60% relative humidity and 40°C/75% relative humidity. These conditions were chosen to conform to International Conference on Harmonisation guidelines for sterility testing.8 One-millilitre samples were removed from the syringes at five time points up to 91 days. The concentrations of diamorphine and bupivacaine were measured after diluting 1 mL to 100 mL in 0.02M phosphate buffer at pH 8, using high performance liquid chromatography on a 10-cm column of Partisil
ODS3 (5 lm). The eluent consisted of water (70 mL), acetonitrile (30 mL) and 0.4% w/v orthophosphoric acid adjusted to pH 5 with sodium hydroxide. At a flow rate of 1 mL/min, retention times were 2.5 min for diamorphine and 4.45 min for bupivacaine. UV detection was at 206 nm. Stock standard solutions of diamorphine hydrochloride (10 mg in 100 mL) and bupivacaine hydrochloride (40 mg in 10 mL) were prepared in water, and 1-mL aliquots were combined and further diluted to 100 mL in a diluent corresponding to the chromatographic eluent omitting the acetonitrile. The standard and sample solutions were analysed in replicate and peak areas and component concentrations calculated using chromatographic data handling software (EZChrom Elite Ver. 2.61, Aston Scientific Ltd., Stoke Mandeville, England). The method was shown to indicate stability by demonstrating separation of peaks due to morphine and to 6O-acetylmorphine, (the decomposition products of diamorphine), and 2,6-dimethylaniline (xylidine), the only known decomposition product of bupivacaine, from each other and from the peaks produced by diamorphine and bupivacaine. Shelf lives were calculated using the confidence bound or maximum rate method.9 In this, the slope of the least squares linear regression of the natural logarithm of the concentration of diamorphine vs. time represents the first order rate constant of the decomposition. The maximum rate method uses the calculated upper 95% confidence bound of this decomposition rate, which thus corresponds to the maximum rate of decomposition represented by the analytical data. A validated Excele spreadsheet was used to calculate shelf lives, based on an acceptable loss of 10% of the initial diamorphine dose.
RESULTS Table 1 shows the quantitative validation parameters evaluated for the analytical method. Bupivacaine degradation was not demonstrated during the study period. Diamorphine degraded over time as demonstrated in Table 2, which shows the degradaTable 1. Analytical method validation Diamorphine Standard repeatability (RSD) Sample repeatability (RSD) Intermediate precision (RSD) Linearity
Bupivacaine
0.75% (n = 6)
0.24% (n = 6)
0.26% (n = 6)
0.91% (n = 6)
1.07% (n = 12)
0.8% (n = 12)
R = 0.9998 between (21–109 lg/mL)
R = 0.9999 between (0.9–4.4 lg/mL)
RSD = Relative Standard Deviation.
286 International Journal of Obstetric Anesthesia Table 2. Degradation of diamorphine at different temperatures 40°C/75% RH
25°C/60% RH
7°C
Time (days)
pH
[diamorphine] lg/mL
Time (days)
pH
[diamorphine] lg/mL
Time (days)
pH
[diamorphine] lg/mL
0 0 21 21 49 49 70 70 91 91
4.98
100.5 99.55 68.8 66.7 35.6 33.6 26.15 24.75 18.6 14.0
0 0 21 21 49 70 70 91 91
4.98
100.5 99.55 91.2 92.2 64.15 47.4 54.4 41.1 39.3
0 0 21 21 49 49 70 70 91 91
4.98
100.5 99.55 100.3 99.5 86.3 85.5 76.5 75.9 75.4 78.4
4.61 4.79 4.52 4.45 4.39 4.38 4.72 4.74
4.87 4.89 4.87 4.72 4.78 4.79 4.85
5.34 5.28 5.38 5.26 5.38 5.26 5.14 5.14
RH: relative humidity.
logn [diamorphine] [µg/ml]
4. 85
data points 90% line regression line lower limit upper limit
4. 75 4. 65 4. 55 4. 45 4. 35 4. 25 4. 15
0
20
40
60
80
Days at 7 oC
logn [diamorphine] [µg/ml]
4.80 4.60 4.40 4.20 4.00 3.80 3.60
Days at 25 oC /60% RH
logn [diamorpine] [µg/ml]
4.60
4.10
3.60
3.10
2.60 0
20
40 o
60
80
Days at 40 C / 75%RH Fig. 1 Graphs showing degradation of diamorphine over study period for samples stored at 7°C, 25°C/60%RH, and 40°C/75%RH.
Stability of diamorphine and hyperbaric bupivacaine 287 tion of diamorphine samples based on linear regression analysis. The data were log transformed and presented graphically to show linear regression. Fig. 1 represents the kinetic data for storage at 7°C, 25°C/60% relative humidity, and 40°C/75% relative humidity respectively. On comparing the three groups, it was clear that diamorphine degraded at a faster rate at higher storage temperatures; 10% degradation had occurred by 26 days at 7°C and by 7 days at 25°C, but by only 4 days at 40°C. pH changes in the samples did not differ significantly over the test period in any of the groups except for a slight decrease from 4.98 to 4.74 over 13 weeks storage at 40°C/75% relative humidity. This probably represents the increase in production of acetic acid due to the faster diamorphine decomposition at this temperature.
The preparation of syringes for intrathecal use made under Grade A conditions (Rules and guidance for pharmaceutical manufacturers and distributors 2002) will result in a significantly reduced risk of microbial contamination entering the syringe system, as these conditions have on-going microbiological monitoring and the environments should be free from bacteria and particles. Staff working in these units have validated and approved aseptic techniques and the preparation would follow strict guidelines. It has to be accepted that aseptic preparation will give a lower level of sterility assurance than a terminally sterilised product, but given the heat sensitivity of solutions of diamorphine, other methods of sterilisation would need to be considered.
ACKNOWLEDGEMENT
DISCUSSION In this study, diamorphine behaved much as it did in previous studies using other aqueous solutions.10,11 Degradation was faster in warmer conditions. As expected the bupivacaine concentration was not affected by the addition of diamorphine. The shelf life of 26 days at 7°C confirms that it would be possible to manufacture and store pre-filled syringes at this temperature for intrathecal use. The metabolites, morphine and 6-O-acetylmorphine are both active and will continue to provide analgesia, but their pharmacokinetics are quite different from those of diamorphine as they are considerably less lipid soluble. This means their duration of intrathecal action is prolonged but their onset of action delayed when compared to diamorphine. Further studies into the longerterm stability of these metabolites may be of interest as they significantly add to the opioid analgesic effects. In the UK diamorphine is a schedule-2 controlled drug and therefore subject to requirements for safe storage and handling. Given the need for the prepared syringes to be refrigerated, the refrigerator will need to conform to local regulations for a controlled drugs cupboard. The complexity of the preparation of these syringes (given the number of individual manipulations involved), and the potentially serious consequences if microbial contamination entered the system, indicate that these syringes should be prepared within the controlled environment of a pharmacy department.
We are grateful to the committee of the Chelmsford Medical Education and Research Trust for providing funding for this study.
REFERENCES 1. Cowan C M, Kendall J B, Barclay P M, Wilkes R G. Comparison of intrathecal fentanyl and diamorphine in addition to bupivacaine for Caesarean section under spinal anaesthesia. Br J Anaesth 2002; 89: 452–458. 2. Abuzaid H, Prys-Roberts C, Wilkins D G, Terry D M. The influence of diamorphine on spinal anaesthesia induced with isobaric 0.5% bupivacaine. Anaesthesia 1993; 48: 492–495. 3. Payne H A S, Tempest S M. The chemistry and pharmacy of diamorphine. In: Scott D B, ed. Diamorphine. Cambridge: Woodhead-Faulker, 1988: 1–14. 4. Stevens L A, Wooton C M. The pharmacokinetic properties of diamorphine. In: Scott D B, ed. Diamorphine. Cambridge: Woodhead-Faulkner, 1988: 15–43. 5. AstraZeneca. Marcain Heavy 0.5% Datasheet. May 2002. 6. Kelly M C, Carabine U A, Mirakhur R K. Intrathecal diamorphine for analgesia after caesarean section. A dose finding study and assessment of side effects. Anaesthesia 1998; 53: 231–237. 7. Saravanan S, Robinson A P, Qayoum Dar A, Columb M O, Lyons G R. Minimum dose of intrathecal diamorphine required to prevent intraoperative supplementation of spinal anaesthesia for Caesarean section. Br J Anaesth 2003; 91: 368–372. 8. ICH Harmonised Tripartite Guideline. Stability testing of new substances and products, Q1A(R2). Federal Register Nov 2003 68: 65717–65718. 9. Norwood T E. Statistical analysis of pharmaceutical stability data. Drug Dev Ind Pharm 1986; 12: 553–560. 10. Sanchez del Aguila M J, Jones M F, Vohra A. Premixed solutions of diamorphine in ropivacaine for epidural anaesthesia: a study on their long-term stability. Br J Anaesth 2003; 90: 179–182. 11. Omar O A, Hoskin P J, Johnston A, Hanks G W, Turner P. Diamorphine stability in aqueous solution for subcutaneous infusion. J Pharm Pharmacol 1989; 41: 275–277.