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Journal of Clinical Pharmacy and Therapeutics (1998) 23, 311314

Determination of compatibility and stability of drugs

used in palliative careD. Schrijvers 1 MD, C. Tai-Apin 2, M. C. De Smet2, P. Cornil 3 MD, J. B. Vermorken 1 MD,PhD and P. Bruyneel 21Department of Medical Oncology, and 2Department of Pharmacy, University Hospital Antwerp, Wilrijkstraat 10,B-2650 Edegem, Belgium, and 3Ispahan, Palliative Home Care Organization, Turnhout, Belgium

SUMMARY INTRODUCTION

Background: Drugs for symptom control in the ter-When gastrointestinal obstruction, nausea or vomiting

minal phase of palliative patients may be used inprevents oral drug administration, drugs are oftenpump systems.given by thesubcutaneousroute. Drugs used for symp-

Objective: To investigate the compatibility and sta-tomatic control in palliative patients include opiates

bility of solutions of morphine hydrochloride, hal-(e.g. morphine hydrochloride, hydromorphone), cor-

operidol, metoclopramide hydrochloride, atropineticosteroids (e.g. dexamethasone, methylprednis-

sulphate, butylhyoscine bromide and ranitidine olone), anti-emetics (e.g. metoclopramide hydro-hydrochloride, which may be used together under chloride, haloperidol), anticholinergic drugs (e.g.such circumstances. butylhyoscine bromide, atropine sulphate, sco- Method: Solutions of the drugs were exposed to polamine) and muscle relaxants (e.g. midazolam).ambient light at a temperature of 20 5 C and 31 C Thestability of some of theseproducts, used assinglefor 24 h and 7 days and the solutions studied by agents in syringe driver pumps, has been describedultraviolet spectrophotometry. previously ( 1, 2). Morphine hydrochloride in con-Results: The combination of haloperidol or me- centrations of 150 mg/ml is stable for at least 31 daystoclopramide hydrochloride with different con- at room temperature ( 1); hydromorphone solutionscentrations of morphine hydrochloride seemed to be from 150 mg/ml are stable for at least 42 days ( 2).compatible and stable. The concentration of atropine Data on the compatibility and stability of com-sulphate or butylhyoscine bromide could not be binations of drugs used in the treatment of terminallydetermined by the study method, but morphine ill patients are rare. When dexamethasone was com-hydrochloride seemed to be stable. The combination bined with diphenhydramine, metoclopramide hydro-of ranitidine hydrochloride and morphine hydrochloride and lorazepam at room (23 C) or body (30 C)chloride showed a change in colour after 7 days. temperature,only therst threedrugs were found to beConclusion: The results suggest that the combination stable after 1 and 7 days, while there was an importantof different concentrations of morphine hydro- decrease in concentration of lorazepam after 24 h ( 3).chloride with haloperidol, metoclopramide hydro-

Information on other combinations is not reportedchloride, atropine sulphate, butylhyoscine bromide in the literature. Therefore, we tested the compatibilityor ranitidine hydrochloride do not affect their sta- and stability of several drugs which are currently oftenbility when stored for 7 days up to 30 C under the used in combination for symptom control in palliativeinuence of ambient light. However, more robust care.stability-indicating methods are required to conrmthese results. The proposed method is more usefulfor identifying combinations that are clearly in- MATERIALS AND METHODScompatible than to identify those that arecompatible.

The compatibility and stability of solutions of mor-phine hydrochloride, haloperidol, metoclopramidehydrochloride, atropine sulphate, butylhyoscine brom-Correspondence: Dirk Schrijvers, MD. Tel. + 32 3821 5306; fax:

+ 32 3825 1592; e-mail: [email protected] ide and ranitidine hydrochloride were tested.

1998 Blackwell Science Ltd 311


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312 D. Schrijvers et al.

Table 1. Degradation of different drugs in combination with morphine hydrochloride. Figures are % of remaining drug(VC= visual changes)

Time

0 24 h 7 days

Temperature ( C) 23 31 23 31

(a) Haloperidol 5 mg/ml in combination with different concentrations of morphine hydrochloride (HCl) (analysis in water).pH = 445 and VC= none in all cases Morphine HCl 5 mg/mlHaloperidol 977 932 921 934

Morphine HCl 10 mg/mlMorphine HCl 983 973Haloperidol 1001 954 932 991 916 Morphine HCl 20 mg/mlMorphine HCl 915 938 934 902 895Haloperidol 979 972 939 964 929 Morphine HCl 30 mg/mlMorphine HCl 989 947 955 921 925Haloperidol 979 938 937 940 905

(b) Metoclopramide hydrochloride (HCl) 10 mg/2 ml in combination withdifferent concentrations of morphine hydrochloride (analysis in water).pH = 55, VC= none in all cases. Morphine HCl 5 mg/mlMetoclopramide HCl 1013 1035 988 966 Morphine HCl 10 mg/mlMetoclopramide HCl 1035 1046 983 1004 Morphine HCl 20 mg/mlMetoclopramide HCl 1053 1051 971 973 Morphine HCl 30 mg/mlMorphine HCl 1009 1005 1005 1013 1008Metoclopramide HCl 958 974 999 983 997

(c) Atropine sulphate 1 mg/ml in combination with differentconcentrations of morphine hydrochloride (HCl) (analysis in

water).pH = 56, VC= none in all cases Morphine HCl 5 mg/mlMorphine HCl 975 1041 981 1057 Morphine HCL 10 mg/mlMorphine HCl 1005 1001 1019 1021 Morphine HCl 20 mg/mlMorphine HCL 976 971 985 997 Morphine HCl 30 mg/mlMorphine HCl 967 966 965 1001

contd

1998 Blackwell Science Ltd, Journal of Clinical Pharmacy and Therapeutics, 23, 311314


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Compatibility of drugs 313

Table 1. contd

Time

0 24 h 7 days

Temperature ( C) 23 31 23 31

(d) Butylhyoscine bromide 20 mg/ml in combination with different concentrations of morphine hydrochloride (HCl) (analysis in 01 N H2SO4).pH = 4555 and VC= none in all cases. Morphine HCl 5 mg/mlMorphine HCl 1015 1041 Morphine HCl 10 mg/ml

Morphine HCl 996 1012 Morphine HCl 20 mg/mlMorphine HCl 1034 1023 1054 1036 Morphine HCl 30 mg/mlMorphine HCl 1028 1035 1069 1021

(e) Ranitidine hydrochloride (HCl) 50 mg/2 ml in combination with differentconcentrations of morphine hydrochloride (analysis in water).pH = 75, VC= none in all cases, except VC= yellow Morphine HCl 5 mg/mlRanitidine HCl 984 967 996 1032 1003 Morphine HCl 10 mg/mlRanitidine HCl 1025 1009 1023 1059 1041 Morphine HCl 20 mg/mlRanitidine HCl 1024 983 989 1021 1013 Morphine HCl 30 mg/mlRanitidine HCl 966 978 998 1036 1019

Incompatibility of the drugs was dened as the hydrochloride was added to 1 ml of haloperidol, 2 mlof metoclopramide hydrochloride, 1 ml of atropinedevelopment of a deposit, a change of colour or a

clouding of the solution. Instability of the solution was sulphate, 1 ml of butylhyoscine bromide or 2 ml of ranitidine hydrochloride in a glass container. The so-dened as an irreversible chemical reaction, with the

development of inactive or toxic metabolites. This may lutions were mixed and divided in two 5-ml glass

vials. They were stored under ambient light at a tem-occur without noticeable changes of the solution.The concentrations tested were morphine hydro- perature of 20 5 C and 31 C.The wave-length ( ) of maximal absorption of eachchloride 5 mg/ml, 10 mg/ml (Sterop lot 98 A15),

20 mg/ml (Sterop lot 98B25) and 30 mg/ml (Federa single agent was determined by ultraviolet spec-trophotometry (Perkin Elmer UV/VIS Lambda Bio).lot 96K25), haloperidol 5 mg/ml (Janssens Cilag N.V.

lot97/11/501),metoclopramide hydrochloride 10 mg/ In the range of an absorption between 015 and 09,there was a linear relationship between absorbance2 ml (Synthelabo lot 98 A29/1180041), atropine sul-

phate 1 mg/ml (Federa lot 95/19), butylhyoscine and concentration for each drug tested. To obtainconcentrations in this absorption range, a dilution was bromide 20 mg/ml (Boehringer Ingelheim KG 97 J22)

and ranitidine hydrochloride 50 mg/2 ml (Glaxo Well- made using distilled water or 01 N H 2SO4.The absorption of a solution at a given wave-lengthcome lot 97K24).

The solutions tested are given in Table 1. One is given by the sum of the absorbance of all theabsorbing agents present in the solution. If the molarmillilitre of different concentrations of morphine



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314 D. Schrijvers et al.

change in colour seemed to be related to the con-Table 2. Wave-length of maximum absorption used forcentration of morphine hydrochloride, as the col-the determination of the concentration of the tested drugsoration was more intense with increasing concentra-

tions of morphine hydrochloride. However, the con-Maximal wave-lengthcentration of ranitidine hydrochloride remained stableDrug ( max) (nm)during the observation period. The concentration of morphine hydrochloride could not be determined be-

Haloperidol 245 cause of the dilution used to determine ranitidineMorphine hydrochloride 285 hydrochloride.Metoclopramide hydrochloride 309Atropine sulphate Butylhyoscine bromide 263 CONCLUSIONRanitidine hydrochloride 314

The results suggest that the combinations of differentconcentrations of morphine hydrochloride with ha-loperidol, metoclopramide hydrochloride, atropinesulphate, butylhyoscine bromide or ranitidine hydro-chloride are stable when stored for 7 days at differentabsorbances ( x, x, y, y) are known for the singletemperatures under the inuence of ambient light andagentsat wave-lengths ( , ), it is possible to calculatethat these drugs may be combined to treat patients inthe concentrations of both drugs (X and Y) using thea palliative care setting.method and formula given by Morton & Stubbs ( 4):

However, several problems related to the method-A= x.[X]+ y.[Y] and A= x .[X]+ y .[Y] ology should be noted. The method used can only be

seen as a screening procedure. With this method, itFor each drug, a concentrationabsorbance standardwas not possible to determine breakdown products,was constructed at different wave-lengths and the because their wave-lengths of absorbance were notmolar absorption coefcients were determined.

known. For atropine sulphate and ranitidine hydro-For both morphine hydrochloride and the drug chloride, the dilution factor used made it impossibletested in combination, the wave-length of maximalto determine their concentrations in the combinationabsorption was determined and was used to measuresolutions. The use of more specic and sensitivethe concentration (Table 2). Measurements were per-methods such as high performance liquid chromato-formed after 24 h and 7 days.graphy is required to test the compatibility and stability of these combinations in a more robust manner.

RESULTS

REFERENCESThe results for the combinations tested are shown inTable 1. The combination of haloperidol with different 1. Stiles L, Tu YH, Allen L. (1989) Stability of morphineconcentrations of morphine hydrochloride seemed to

sulphate in portable pump reservoirs during storage and be compatible and stable at different temperatures and simulated administration. American Journal of Hospitalduring the study period of 7 days. This was also the Pharmacy, 46, 14041407.

2. Walker S, CoonsC, Matte D, et al. (1988) Hydromorphonecase for metoclopramide hydrochloride.and morphine stability in portable infusion pump cas-The concentration of atropine sulphate could notsettesand minibags. Canadian Journalof Hospital Pharmacy, be determined by the study method, so no denite41, 177182.conclusion can be drawn for this drug. However, the

3. Stiles L, Allen L, Prince S, Holland J. (1994) Stabilityconcentrations of morphine hydrochloride seemed toof dexamethasone sodium phosphate, diphenhydramine

be stable when combined with atropine sulphate. This chloride, lorazepam and metoclopramide hydrochloridewas also the case for butylhyoscine bromide. in portable infusion pump reservoirs. American Journal

The combination of ranitidine hydrochloride and of Hospital Pharmacy, 51, 514517.morphine hydrochloride showed a change in colour 4. Clarke EGC. (1969) Isolation and Identication of Drugs.

The Pharmaceutical Press, London.after 7 days, indicating a possible incompatibility. This


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