Document 1QKD312kOmOpzDOVern2YYmXd

Interactions between Drugs and Polyvinyl Chloride Infusion Bags Elizabelh A. Kowaluk, Michael S. Roberta, Harvey 0. Blackburn, and Alan E. Polack Forty six injectable drug priniucta, many of which are admin istered by i.v. infusion, were studied for loss from aqueous solu tions stored in polyvinyl chloride infusion bans for various peri ods of time. The polyvinyl bags were stored in the dark at room tempera ture for up to three months. Drugs stored in glass vials served as controls. The solutions were assayed spectrophotumetrically at regular intervals. The effects of drug concentration and pH on the loss of drug from solution were studied. Oclanol-waler par tition coefficients were used as a gauge of lipid solubility of the drugs. Five of the drug products--clomethiaiole edisylate, diaze pam. hydralazine hydrochloride, thiopental sodium, and war farin sodium--were fnund to be lost to a substantial extent after one week. For all drugs studied, the effect of the initial concen tration on drug loss varied. The amount ofdrug loet over a given time was a function of the pH of the solution. The main physico chemical determinants controlling drug sorption appeared to be the extent of ionization and the lipid solubility of the drug. For most of the drugs studied, minimal losses from the aqua- ous solutions were observed over short periods of storage time. Disappearance was slow and time dependent, indicating a diffu- ' *. s sion-controlled sorption process. The losses of domethiazols edisylate. thiopental sodium, and diazepam may be clinically important. Index terms: Absorption; Anesthetics; Anticoagulants; Clomethiazole edisylate; Concentration; Containers; Diazepam; Diffusion; Hydralazine hydrochloride; Hydrogen ion concentra tion; Hypotensive agents; Injections; Ionization; Plastics; Poly vinyl chloride; Sedatives and hypnotics; Solubility, Stability; Storage: Thiopental sodium; Warfarin sodium Previous studies1-6 have reported the loss of certain drugs from aqueous solutions stored in plastic infusion bags for various periods of time. Generally, these losses have been attributed to interaction between the drug and the plastic infusion bag. Such interaction may result in reduced drug delivery to the patient and, in some cases, diminished ther apeutic response. Documentation of the compatibility of substances cur rently administered by intravenous administration sets, with the plastic infusion bags used in certain systems, is lim ited.1-3'^7 The most detailed evaluation of drug sorption by plastic infusion bags is in the study of Moorhatch and Elizabeth A. Kowaluk, Michael S. Roberta,PhJD., Harvey D. Blackburn, M5, and Alan E. Polack, Ph.D., are associated with the School of Pharmacy. University of Tasmania. Address reprint requests to Ms Kowaluk, School of Pharmacy, University of Tasmania, Box 2S2C, GPO, Hobart, 7001. Tasmania, Australia. The donations ofTraveno! Laboratories and other pharmaceutical man- ufacturers in Australia are acknowledged. The assistance of the hospital pharmacy departments of Flinders Medical Center in Adelaide, Royal Hobart Hospital in Hobart, ard'Alfred Hospital in Melbourne, is acknowledged. Supported by a grant from the National Health and Medical Research Council, Australia. -* Presented at the Pharmaceutical Sciences Section of the Australian and New Zealand Association for the Advancement of Science meeting, Adelaide, May 1980. Copyright 1981, American Society of Hospital Pharmacists, Inc. All right* reserved. Chiou,4 which reported on the sorption of 17 drugs. Although only limited information is available on the compatibility of drugs with polyvinyl chloride (the main resin in com mercially available plastic infusion bags), the sorptinn of drugs by nylon and polyethylene has been evaluated ex tensively.8-12 As the availability of medication through the intravenous route is of critical importance in patient therapy, it is essential to know not only which substances may be lost during intravenous infusion, but also which drugs may be safely administered using plastic intravenous delivery sys tems. The present study was undertaken with the following intentions; , 1. To survey a range of drugs, including those presently being administered by intravenous infusion, for possible inter actions with plastic infusion bags, 2. To establish some of the physicochemical variables that control the rate, extent, and mechanism ofsuch interactions to enable the subsequent development of criteria that may be used to predict their occurrence, and 3. To assess the possible clinical implications, ifany, ofthose interactions that were found to occur. b The study consisted of several parts, the first being a preliminary survey of a range of drugs to identify the drugs that are lost from aqueous solution during storage in plastic infusion bags. The main goal of the survey was to evaluate the compatibility of medicaments routinely used in infusions by various Australian hospitals. The compatibility ofanti neoplastic medications with plastic infusion bags was not examined in this survey because of their restricted avail ability and cost. ` In the second part of the study, the relative losses ofsome selected drugs in unbuffered aqueous solutions were com pared with the losses in solutions buffered at pH 7.4. This study was undertaken because in situ pharmacologic studies are usually performed with drug solutions maintained at a pH of 7.4.13 Methods Table 1 lists the drug products used in the preliminary survey. The drugs norepinephrine bitartrate* and isopro terenol hydrochloride1* were examined; however, they were found to be unstable on storage and were not considered further. Studies of the loss of all but two of the drugs from aqueous solution during storage in plastic infusion bags were con ducted using 0.9% sodium chloride injection as the solvent. The study of the loss of sodium nitroprusside was performed with 5% dextrose injection as the solvent, and the study with clomethiazole edisylate used the infusion solution supplied by the manufacturer. The preliminary survey was conducted using Viaflej (polyvinyl chloride) infusion bags' containing 500 mi of 0.9$ sodium chloride injection or 500 ml of 5% dextrose injection in the case of sodium nitroprusside. Each drug was prepared in an appropriate concentratior so that when a practical volume (50 ml or less) was injectec . 21133001 130S American Journal of Hospital Pttarmacy Vol 38 Sap 1981 BFG10702 0002-9289/81/6901-1308S0I.50 0)ug* tod poiftloyl ehlorkte Motion bogs drug was determined (Table 1). Blank solutions containing all components except the drug were used for adjustment of zero absorbance. In all cases, the drug solutions followed Beer's law over the concentration range studied. Samples of the following drug solutions were diluted immediately before assay: (1) acetazolamide sodium solutions were di luted 1:1 with phosphate buffer pH 8.1; (2) ampicillin tri- hydrate solutions were diluted 1:1 with phosphate buffer pH 7.4; (3) amoxicillin trihydrate and metronidazole solutions were diluted 1:1 with 0.2 N hydrochloric acid; (4) diazepam and dopamine hydrochloride solutions were diluted 1:1 with 0.2 iV sulfuric acid; and (5) clomethiazole edisylate solutions were diluted 1:200 with distilled water. The aminoglycoside antibiotics, gentamicin sulfate, ka- namycin sulfate, and tobramycin sulfate, were assayed using the chemical derivatization procedure of Csiba.14-15 This procedure involved the preparation of the dihydrolutidine derivative of the aminoglycoside and its subsequent spec- trophotoraetric determination. In this study absorbance was measured at 336 nm rather than at 356 nm as suggested by Csiba.14 Samples of all other drug solutions were assayed undi luted. ,, The difference, ifany, between the amount of drug in so lution in the Viaflex bag and.the amount in solution in the glass vial at any specific time was taken to be the amount of drug lost from solution during storage in the plastic infusion bag. Each result reported is the mean of the assays of at least two containers. The coefficient ofvariation for the assays was less than 10%. Effect of pH on Loss. The effect of the pH of the drug solution in the plastic infusion bag on loss of drug from so lution was studied for a number of selected drugs by buf fering the solutions to a pH of 7.4 with a final phosphate buffer concentration of 0.02 M. The experimental procedure was the same as the one used for the preliminary survey except that 50 ml of 0.9% sodium chloride injection from the Viaflex bags and 10 ml of 0.9% sodium chloride injection from the glass vials were replaced by an equivalent volume of a concentrated solution of the phosphate buffer (0.2 Af). The initial concentrations were the same as in the preliminary survey. Effect of Initial Concentration on Loss. The effect of varying the initial concentration ofa drug solution on the loss of the drug was studied for a selection of drugs that showed losses of greater than 10% either from solutions buffered to pH 7.4 or from unbuffered solutions after storage for one week in plastic infusion bags. These drugs were clomethiazole edisylate, hydralazine hydrochloride, thiopental sodium, and warfarin sodium in unbuffered solutions and chlorpromazine hydrochloride, promazine hydrochloride, and promethazine hydrochloride in buffered solutions. -- Octanoi- Water Partition Coefficients. Literature values for octanol-water partition coefficients have been used for all drugs studied where possible. When these values were not available for given compounds, partition coefficients were determined experimentally as follows. An aliquot of each drug solution was added to an aliquot of 0-0010001" (ana lytical grade), which had been saturated with the particular diluent being used, in a glass bottle. (The proportions of aqueous phase to octanoi phase were varied from 1:1 to 250:1 according to the affinity of a given drug for octanoi.) Each bottle was sealed and agitated periodically during its storage in the dark at room temperature. Two aliquots of the drug solution were also placed into separate 50-ml glass bottles to act as controls. The aqueous phase was analyzed at weekly intervals until equilibrium was achieved. To prepare the solutions for assay, the content of the sample bottles was centrifuged at 3000 rpm for 10 minutes to achieve as com plete as possible separation of aqueous and octanoi phases. The octanoi was aspirated off together with about 1 ml of the aqueous phase. The remainder of the aqueous phase was assayed spectrophotometrically (Table 1) and compared with the absorbance of the drug solutions from the control bottles. r;' The apparent octanol-water partition coefficients were determined for each drug according to the following equa tion: K - [(Awi-- Awf)/AwfJ (V/V->1 where K is the appar dent, Awi is the initial. lution, Awf i the the fir solution, Vw is the volun the volume of the octanoi The apparent octanol-u ofi the drugs were adjuste infusion solutions using the ^ --non: PIni'll* * PWf (1 AIaIu) " P,pp(l inlu)/(l Q|pp) (2) where P|nfu is the apparent octanol-water partition coeffi cient for a drug in a given infusion solution, Pcorr is the true octanol-water partition coefficient (i.e., octanol-water par tition coefficient of the unionized drug), P,pp is the experi mentally determined octanol-water partition coefficient, and end or.pp are the degree of ionization of drug in the infusion solution and aqueous solution used for partition coefficient determination, respectively. Results and Discussion Preliminary Survey. Only five of the 46 drug products examined showed substantial loss after storage in plastic infusion bags for one week--clomethiazole edisylate, di azepam, hydralazine hydrochloride, thiopental sodium, and warfarin sodium (Table 1). Except for the phenothiazines, quinine sulfate, quinidinesulfate, and prednisolone, all drugs showing negligible loss from solution, had apparent octa nol-water partition coefficients less than 5. The majority of drugs appeared to be relatively stable in aqueous solutions stored in glass containers. After one week of storage, only methicillin sodium and cephalothin sodium showed any change in absorbance. In both cases an increase in absorbance was observed. 1310 American Journal of Hospital Pharmacy Vol36 Sep 1961 BFG10704