Factors influencing the stability of ranitidine in TPN mixtures

Clinical Nutrition (1995) 14:171-176 © Pearson Professional Ltd 1995

Factors influencing the stability of ranitidine in TPN mixtures M. C. ALLWOOD and H. MARTIN Medicines Research Unit, University of Derby, Mickleover, Derby DE3 5GX, UK (Correspondence to MCA) ABSTRACT--The stability of ranitidine in TPN mixtures has been widely studied with varying results. The evidence suggests that ranitidine is unstable and should be added within 24 h of administration, although other reports indicate ranitidine is stable for at least 14 days. The causes of ranitidine degradation in TPN mixtures were therefore studied in mixtures without fat emulsion using a stability-indicating HPLC method. The results indicated that the stability of ranitidine at 5°C depended on the commercial source of amino acid, additives and type of bag used. The principle mechanism of degradation was identified as oxidation. Ranitidine was more stable in EVA bags in the absence of the trace element additive, which appeared to accelerate ranitidine oxidation. Ranitidine was most stable in mixtures compounded in multi-layered bags. The results suggest TPN mixtures with ranitidine in multi-layered bags could be assigned shelf lives of at least 14 days at 5°C, depending on the amino acid infusion used in the regimen.

Introduction

Travasol as the amino acid infusion stored at room temperature. At least 90% remained after 24 h storage, although concentrations in some mixtures had fallen below 90% after 48 h. Cano et al (8) investigated the stability of ranitidine under similar conditions in complete All-in-One mixtures containing fat emulsion. The amino acid source was Nitrogeno PT. It was reported that ranitidine concentrations declined by approximately 10% in 12 h and 80% in 72 h at room temperature. In contrast, Andreu et al (12) reported that ranitidine was stable during 24 h storage in a similar mixture and under the same storage conditions. In a larger study comparing TPN mixtures with and without fat emulsion, Williams et al (7) investigated ranitidine stability of mixtures containing Travasol as the amino acid source, with glucose and electrolytes, but excluding trace elements or vitamins. Results indicated that ranitidine was relatively less stable in TPN mixtures with fat emulsion compared with mixtures not containing fat. Losses in All-in-One mixtures after 24 h storage at room temperature were in the range 3.3-6.3%, increasing to a maximum of 14.0% after 48 h. Degradation was reduced in mixtures stored at 4°C. In contrast, maximum losses in TPN mixtures without fat emulsion after 48 h storage amounted to 3.1% and 5.3% at 4°C and room temperature respectively. It was also reported that

The addition of H 2 receptor-blocking drugs such as cimetidine and ranitidine to TPN mixtures in Big Bags is common practice in many hospitals. The stability of these drugs has been widely studied, both in standard infusions such as normal saline or 5% glucose, and in various TPN mixtures. The outcomes of these various studies suggest that while both drugs are relatively stable in simple infusions, and cimetidine is stable for at least 7 days in amino acid infusions (1, 2), ranitidine is less stable in TPN mixtures and rates of degradation appear to depend on a variety of factors associated with differences between TPN mixtures. These include pH (3), glucose concentration (4), reducing agents (5), oxygen (6) and apparently the presence of fat emulsion, although this latter factor may be at least partiaily associated with the extraction method used in ranitidine analysis (7-9). Walker and Bayliff (10) determined the stability of ranitidine in a TPN mixture containing Freamine III, glucose infusion, electrolytes, vitamins and trace elements. They reported approximately 10% degradation after 48 h storage at 23°C. This was independent of ranitidine concentration. Bullock et al (11) also reported a study on the degradation of ranitidine in a range of TPN mixtures, similar in composition to those used by Walker and Bayliffe (10), but containing 171

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RANITIDINE STABILITY IN TPN

ranitidine was stable in 0.9% sodium chloride infusion for 48 h. Williams et al (7) suggest that the differences in their results compared with previous reports may be explained by pH differences between different TPN mixtures. These results were however questioned by Montoro and Pou (9), who suggested tqaat the analytical method, in particular the extraction procedure, may lead to erroneous results in Allin-One TPN mixtures. In a more recent study, the degradation of ranitidine in one TPN formulation with or without fat emulsion was investigated (3). The mixtures contained Aminoplasmol as the amino acid source, with glucose, electrolytes, trace elements and vitamins. The study was extended to 14 days storage at 4°C. Results showed that ranitidine losses amounted to 6.8% and 1.9% in mixtures with or without a fat emulsion, respectively. This data appears to indicate far greater stability for ranitidine in TPN mixtures than any of the previous reports. The authors suggest that this may be due to pH differences between the regimen used in their study and previous reports, since ranitidine has been reported to be most stable around pH 7. The mixture used was only weakly acid. However, it is also significant that the previous studies had been performed at room temperature and this would clearly result in accelerated degradation rates. Other as yet unidentified factors may also contribute to the accelerated degradation of ranitidine in TPN mixtures since the major mechanism of degradation is known to be oxidation (13). There is therefore considerable confusion in the literature regarding the stability of ranitidine in TPN mixtures, although it appears to be accepted that the drug can be safely added to any TPN mixture not more than 24 h prior to administration. The ability to add ranitidine to TPN mixtures prepared in the pharmacy with extended shelf lives remains controversial. Many factors influencing degradation rates have yet to be identified and quantified. It was the purpose of this investigation to identify formulation variables which influence the stability of ranitidine in TPN mixtures and indicate the potential for extending shelf lives of TPN mixtures containing ranitidine. Materials and methods

Materials Ranitidine injection 50 mg in 2 ml (Zantac) was obtained from Glaxo Laboratories Ltd, Ware, Herts, UK. Freamine III 8.5% was obtained from Fresenius Health Care Ltd, Runcorn, Cheshire, UK, Vamin 14 from Pharmacia Ltd, Milton Keynes, Beds, UK and Aminoplex 12 from Geistlich Pharma Ltd, Chester, UK. Glucose infusions (Viaflex) were obtained from

Baxter Healthcare Ltd, Thetford, Norfolk, UK. Multibionta from E. Merck Ltd, Alton, Hants, UK, contains, vitamin A, 10 000 i.u; thiamine hydrochloride, 50 mg; riboflavin sodium phosphate, 10 mg; pyridoxine hydrochloride, 15 mg; nicotinamide, 100 mg; pantothenyl alcohol, 25 mg; ascorbic acid, 500 mg; and alpha tocopherol acetate, 5 nag. Addamel, from Pharmacia Ltd, contains, as salts: calcium, 5 mmol; magnesium, 1.5 mmol; iron, 50 gmol; zinc, 20 gmol; manganese, 40 gmol; copper, 5 gmol; fluoride, 50 gmol; and iodide, 1 gmol (this product has now been withdrawn and replaced by Additrace, which contains a wider range of trace elements). Ethyl Vinyl Acetate (EVA, Mixeva) and Multi-layered (Ultrastab) TPN bags, 500 ml size, were obtained from Oxford Nutrition Ltd, Oxford, UK.

Analytical methods Ranitidine was analysed by a stability-indicating HPLC method, modified from the method reported by Williams et al (7) using an ODS 5 ~tm (Techsphere) column, 10 cm long, 0.4 cm I.D. The mobile phase was methanol:0.05 M disodium hydrogen phosphate pH 6.0 (30:70) with 24 mM diethylamine. The flow rate was 1 ml/min and detection was at 228 nm. The retention time for ranitidine was approximately 9.5 rain and showed complete separation from other compounds. Quantitation was by computerised integration of peak area, using the PC Integration Pack (Kontron Instrument Ltd, Wafford, Hefts, UK). The method was validated with the following results: linearity of response with concentration, four concentrations in the range 25-100 ~tg/ml in the experimental TPN mixture containing Aminoplex 12, injections (bracketed) in triplicate, r = 0.9995; coefficient of variation of repeated injections (100 ~tg/ml), 1.59% (n = 3); between days = 0.59% (n = 9). The method was shown to be stability-indicating for ranitidine samples treated by storage in solution containing sodium metabisulphite 0.05% w/v or hydrogen peroxide 1 volume/ ml for periods up to 48 h. Chromatograms showed substantial falls in the peak areas for ranitidine. All tests were performed using TPN mixtures stored in infusion bags. Although 500 ml capacity bags were used, mixtures were formulated to provide the equivalent of a 21 daily regimen (a 'Standard' regimen). The required volumes of each ingredient were injected into one bag for each test through the additive port commencing with the amino acid infusion (40 ml), followed by 20% glucose infusion (60ml), additives (Multibionta, 0.5 ml; Addamel, 0.5 ml) and finally ranitidine (Zantac, 0.4 ml, providing 100 ~tg/ml in the mixture). All transfers were performed using plastic syringes. All air was removed

CLINICALNUTRITION 173

from the bag at the completion of the filling process unless otherwise indicated. Bags were overwrapped in polythene and stored at 5°C (+ 2°C) protected from light, the recommended storage conditions for compounded TPN mixtures. Samples were withdrawn at the required intervals for analysis. Samples were analysed by direct injection onto the chromatograph. A new standard was prepared on each test occasion, by diluting 0.1 ml Zantac (from the same batch used in the experiment) to 25 ml in the Standard TPN formulation (containing Aminoplex 12 as amino acid source). All injections were performed in duplicate using the bracketting method. Each test was repeated. The major factors likely to be responsible for variations in the degradation rate of ranitidine in different TPN formulations (without fat emulsion) are the amino acid infusion source (which contain different reducing agents and also vary in both pH and buffering capacity), trace elements (which may catalyse oxidation) and the type of container (which vary with respect to oxygen barrier properties). These factors were investigated by monitoring the degradation of ranitidine in various TPN mixtures stored at 5°C.

and stored in either EVA bags or multilayerd bags is illustrated in Figures 1-3. In Figure 1, the amino acid used was Freamine III 8.5%, in Figure 2 it was Vamin 14 and in Figure 3 it was Aminoplex 12. Degradation, which was approximately linear with time, was observed in all mixtures. The rates of degradation were influenced by the amino acid source, the presence of additives and the type of bag used to store the TPN mixture. Degradation in Freamine III mixtures without additives in EVA bags amounted to approximately 20% loss after 28 days storage. The degradation rate was greater in mixtures containing Addamel and Multibionta, amounting to approximately 50% loss in the same period. In contrast, the same mixture stored in multilayered bags provided the most stable system, with losses amounting to approximately 8% after 28 days storage. A similar pattern was observed in mixtures formulated using either Vamin 14 or Aminoplex 12. Degradation was greatest in mixtures containing Addamel and Multibionta in EVA bags, and losses were least in the same TPN mixture stored in multilayered bags. The source of the amino acid infusion was also observed to have some influence on degradation, especially in mixtures containing the additives stored in EVA bags. Those mixtures containing Vamin 14 as the amino acid source were the least stable in EVA bags, showing losses of approximately 65% in 28 days. The results indicate that the degradation of ranitidine is influenced by the nature of the TPN mixture and the container. Degradation is greatest in mixtures containing additiv.es stored in EVA bags,

Results Effect o f commercial amino acid source on ranitidine stability

The degradation of ranitidine in amino acid-glucose mixtures without and with Addamel and Multibfonta

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Fig. 1. The degradation of ranitidine 100 gg/ml in standard TPN mixtures containing Freamine III 8.5% as amino acid infusion stored at 5°C, without additives in EVA bags (crosses), with Addamel and Multibionta in EVA bags (squares), with Addamel and Mulfibionta in multilayered bags (circles) (each point is the mean, n = 2, bar line indicates the range).

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RANITIDINESTABILITYIN TPN

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Fig. 3. The degradation of ranitidine 100 ].tg/ml in standard TPN mixtures containing Aminoplex 12 as amino acid infusion stored at 5°C without additives in EVA bags (crosses), with Addarnel and Multibionta in EVA bags (squares), with Addamel and Multibionta in multilayered bags (circles).

w h i c h is p e r m e a b l e to oxygen, and this degradation is substantially r e d u c e d if the s a m e mixtures are stored in multilayered bags. Therefore, c h e m i c a l oxidation i n v o l v i n g oxygen, catalysed by trace e l e m e n t s such as copper, is the m o s t likely m e c h a n i s m to account for these observations.

The influence of air in the bag on ranitidine degradation In order to c o n f i r m that o x y g e n (air) contributes to ranitidine degradation, and this reaction is accelerated by trace elements, degradation was c o m p a r e d in the

CLINICAL NUTRITION

Vamin-formulation (in which amino acid-formulation ranitidine was least stable in EVA bags) stored in multilayered bags with and without the inclusion in the bag of approximately 10 ml sterile air. Mixtures also contained Addamel. The results are shown in Figure 4. The presence of air caused substantially more rapid degradation of ranitidine in comparison to the bag without added air, indicating that the presence of air causes accelerated ranitidine breakdown. TPN mixtures with Multibionta alone or with Addamel and Multibionta stored in multilayered bags but with the addition of approximately 10 ml air showed ranitidine losses amounting to 17% and 24% degradation after 28 days storage respectively. Therefore, the drug was at least as stable as in the TPN mixture with Addamel alone but without added air in the bag, shown in Figure 4. These results support the theory that a major cause of ranifidine degradation in TPN mixtures is oxidation, catalysed by trace elements. Vitamin additives such as Multibionta protect ranitidine from this reaction by the preferential catalytic reduction of oxygen by ascorbic acid.(14).

commercial amino acid infusions, with and without vitamins and trace elements, some with fat emulsion and others excluding fat, and in EVA or PVC bags. Most studies were also performed at room temperature rather than under refrigeration. However, Grimble et al (3) provided data suggesting that ranitidine was stable for at least 14 days if stored at 4°C with an additional 42 h at room temperature in either Allin-One or non-fat containing TPN mixtures. Results also therefore suggested that ranitidine was stable for at least 42 h at room temperature. It was suggested that this greater stability, in comparison to previous studies, was due to differences in pH between mixtures. Since the regimens studied (3) all contained trace elements, our data would suggest accelerated degradation rates would be expected. Since this was not the case, the greater than expected stability may be due either to the container used (which was not specified in the paper), to some protective effect of the amino acid infusion or some other more obscure reason. The most significant observation in the present study is that ranitidine is more stable in mixtures stored in gas-impermeable (multi-layered) bags, rather than EVA containers. The chemical mechanism accounting for this difference is likely to be oxidation. Since oxidative reactions are commonly catalysed in TPN mixtures by trace elements, particularly copper ions (14), the greater degradation of ranitidine in

Discussion

Previous reports have suggested that ranitidine may be unstable in TPN mixtures (8-12). Most of these reports concerned mixtures containing a variety of

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Fig. 4. The degradationof ranitidine 100 ~tg/mlin Vamin-containingTPN mixtureswith Addamelin multilayeredbags, with (triangles) or without (circles) the inclusion of approximately10 ml air and stored at 5°C.

176 RAN1TIDINESTABILITYINTPN TPN mixtures containing trace elements would be expected. Multilayered bags substantially reduce oxygen transmission rates into the contents of the bag. Greater oxygen-transmission through EVA bag walls will also therefore influence rates of degradation during storage. Although the present results provide further evidence to explain differences in the degradation rates of ranitidine reported in previous studies, extrapolation of the current data to estimate shelf lives of TPN mixtures containing ranitidine must be treated with some caution. In particular, the surface areato-volume ratio will be substantially smaller for adult-sized 3 1 capacity bags compared to the 500 ml capacity bags used in this study. Stability is also influenced by the amino acid formulation, presumably due in part to the presence of reducing compounds. Freamine contains metabisulphite, while Vamin does not contain a specific reducing agent. This may partially at least explain why ranitidine degrades more rapidly in Vamin-containing mixtures containing additives, compared with Freamine formulations. Other factors such as pH may also influence ranitidine degradation i n TPN mixtures. The pH of Vamin mixtures was approximately 5.1, while Freamine and Aminoplex-containing"mixtures were approximately 6.4 and 6.8 respectively. In practice, this alone is unlikely to influence the different degradation rate s observed (13 ). In conclusion, this investigation has shown that ranitidine degradation in TPN mixtures depends on a number of factors. The major mechanism causing this variation appears to be oxidation. This reaction will depend on the amount of dissolved oxygen present, the amino acid source, the presence of trace elements and vitamins, and the type of bag used. Although these studies were undertaken in TPN mixtures without fat emulsion, the same mechanism of degradation would be expected to be observed in the presence of fat emulsion. M a x i m u m stability can be achieved by using a gas-impermeable container, with careful removal of all air after compounding, and storage under refrigeration. Extended shelf lives of up to 28 days may be possible, although this may depend on the amino acid source. The presence of vitamins can also enhance stability, due presumably to the reducing properties of ascorbic acid. It should be noted that Multibionta contains substantially more

ascorbic acid than is included in most other multivitaimin additives.

Acknowledgements We are gratefulto Dr Gil Hardy of Oxford NutritionLtd for the supply of TPN bags.

References 1. RosenbergH A, DoughertyJ T, MayronD, BaldinusJ G. Cimetidinecompatibility.I: Chemicalaspects and room temperature stabilityin intravenousinfusions.Am J Hosp Pharm 1980; 37: 390-392. 2. YnhasE M, Lotion F T, MayronD, BaldinusJ G, Rosenberg H A. Cimetidinehydrochloridecompatibility.II: Room temperature stabilityin intravenousinfusionfluids. Am J Hosp Pharm 1981; 38: 879-881. 3. GrimbleG K, HunjanM K, Payne-JamesJ J, Silk D B A. Long-termstabilityof ranitidinein total parenteralnutrition solutions:effects on lipid emulsionstability.Br J Int Care 1991; 1: 32-36. 4. GalanteL J, Stewart J T, WarrenF W, JohnsonS M, Duncan R. Stabifityof ranitidinehydrochlorideat dilute concentration in intravenousinfusionfluids at room temperatureAm J Hosp Pharm 1991; 47: 1580-1584. 5. AllwoodM C. Effect of reducingagents on the stabilityof ranitidinein TPN. Proceedings,BritishAssociationof Parenteral and EnteralNutrition, 1993. 6. McElroyB, WiggensD, Hardy G. Stabilityof ranitidinecontainingAll-In-One(A-I-O)parenteralnutritionmixtures. Clin Nutr 1991; 8(Suppl.): 88. 7. WilliamsM F, Hak L J, Dukes G. In vitro evaluationof the stabilityof ranitidinehydrochloridein total parenteralnutrient mixtures. Am J Hosp Pharm 1990;47: 1574-1579. 8. CanoS M, MontoroJ B, Pastor C, Pou L, SabinP. Stabilityof ranitidinehydrochloridein total nutrientadmixtures.Am J Hosp Pharm 1988;45: 1100-1102. 9. MontoroJ B, Pou L. Commenton the stabilityof ranitidine hydrochloride in total nutrientadmixtures.Am J Hosp Pharm 1991; 48: 2384. 10. Walker S E, BayliffC D. Stabilityof ranitidinehydrochloride in total parenteralnutrientsolutions.Am J Hosp Pharm 1985; 42: 590-593. 11. BullockL, parks R B, LampasonaV, MullindR E. Stabilityof ranitidinehydrochlorideand amino acids in parenteral nutritionsolutions.Am J Hosp Pharm 1985; 42: 2683-2687. 12. AndreuA, GarciaB, Pastor C, CardonaD, BonalJ. Studyof the in vitro stabilityof ranifidinein a total parenteralnutritional solutioncontaininglipids. Nutr Hosp 1988; 3: 50-55. 13. OgnallJ. Personalcommunication.GlaxoMedical Information,June 1992. 14. AllwoodM C. Factors influencingthe stabilityof ascorbic acid in total parenteralnutritioninfusions.J Clin Hosp Pharm 1984; 9: 75-85.

Submission date: 15 November 1994;Acceptance date: 27 January 1995