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`
`the effect of a
`
`COMPOUND
`on
`POLYVINYL
`CHLORIDE
`in medical practice
`
`a preliminary report
`
`by W. L. GUESS, L. F. WORRELL,- AND J. AUTIAN
`
`• FOR THE PAST SEVERAL YEARS OUR LABORATORY HAS
`been investigating problems associated with the use of
`plastics in pharmaceutical and medical practice. Results
`from our studies, as well as reports from other sources,
`have indicated that drug-plastic interactions may and
`do occur which may not be evident to those using the
`particular plastic device.
`
`Nicolaides and Autian''* have summarized two po­
`tential consequences in the use of plastics in medical
`practice. These may be stated as follows:
`
`W. L. GUESS, Ph.D.j is Associate Professor of Phar­
`macy, L. F. WORRELL, Ph.D., is Professor of Pharma­
`ceutical Chemistry, and J. AUTIAN is Associate Professor
`of Pharmacy at The University of Texas, Austin.
`
`Presented at the AAAS, Denver Meeting, December 1961.
`Acknowledgment is given to Mr. John Prescott for tech­
`nical assistance throughout this study.
`
`the Drug-Plastic Research Laboratory, College of
`From
`Pharmacy, The University of Texas, Austin, Texas. This
`research project was conducted under a grant from The
`University Research Institute, The University of Texas.
`
`Direct Consequence. Many plastic substances may have
`direct contact with the patient for a very short time or an
`extremely long time. For example, a surgical implant might
`well last for the lifetime of the patient while a drainage
`catheter may remain for a very short period. In both
`instances, the polymer or other ingredient in the plastic might
`cause a tissue sensitivity or toxic response.
`
`Indirect Consequence. Plastic administration devices, such
`as syringes and tubings, may react with the drug or nutri­
`tional product and either (1) release a constituent from the
`plastic to the solution which will then be injected into the
`patient, or (2) the plastic device may bind or adsorb a
`significant quantity of the active ingredient, thus reducing
`the potency of the drug product to be administered to the
`patient.
`
`Since at the present time there are no standards
`for safety of plastics to be used in medical practice,
`a great responsibility rests upon those who purchase,
`distribute, and use these devices. The hospital phar­
`macist, of course, is very much involved with these
`devices and should be continually alert to practice his
`professional judgment in the selection of plastic de­
`vices to be used in his own hospital. A guide to the
`hospital pharmacist in the evaluation of plastic devices
`has already been published.'"
`
`370
`
`Opiant Exhibit 2321
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 1
`
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`

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`
`Method of Analysis of Benzalkonium Chloride
`
`The benzalkonium chloride content was determined
`by using the following volumetric technique:
`One ml. samples were accurately withdrawn from the
`samples and transferred to 100 ml. glass stoppered
`cylindrical graduates. To this was added 30 ml. dis­
`tilled water, 5 ml. of dilute sulfuric acid, 1 ml. of a
`0.01 percent W/V solution of methyl yellow and 20
`ml. of chloroform. After thorough agitation, the benzal­
`konium chloride was titrated with a 0.012 percent
`solution of standardized sodium lauryl sulfate from
`a semi-micro burette. This assay follows the proce­
`dure as outlined by Carkhuff and Boyd.^'' Proper blank
`controls were used during each scries of analysis.
`
`Effect of Concentration on Uptake
`
`Previously washed arid dried strips of polyvinyl
`chloride (PVC) sheets (approximately 20 gram sam­
`ples) were accurately weighed and transferred into
`specially constructed glass stoppered tubes containing
`exactly 150 ml. of benzalkonium chloride solutions
`at four different concentrations. Each tube was then
`sealed with a silicone-grease coated, ground glass stop­
`per and further secured by the use of rubber bands.
`These prepared tubes were placed in a constant tem­
`perature water bath adjusted to 49° ±: 0.5° C. At
`certain time intervals 1 ml. aliquofs of solution were
`withdrawn and assayed according to the procedure
`previously outlined. The data obtained were calculated
`
`Fig.I.-EFFECT OF CONCENTRATION ON UPTAKE OF
`BENZALKONIUM CHLORIDE BY P.V.C.
`
`D G4 mg/ml
`
`I 28mg /ml.
`
`1.92 mg./ml.
`
`2.56 mg./ml.
`
`3.20 mg./ml.
`
`120
`
`206
`ISO
`TIME IN HOURS
`
`240
`
`280
`
`320
`
`371
`
`In an endeavor to keep the hospital pharmacists
`well-informed on plastics, another problem is brought
`into view. This concerns polyvinyl chloride (PVC)
`used in medical practice. Most of the flexible tubings
`used in cannulas, feeding tubes, administration tubes,
`etc., are probably manufactured from one or more
`polyvinyl chloride formulas. Even though the generic
`name "vinyl" or "polyvinyl chloride" is assigned to
`this material, other ingredients are added to the poly­
`mer which gives to the final material flexibility as well
`as other desired properties. Often the other additives in
`the formula amount to as much as 40 percent by
`weight of the total weight of the plastic.
`The very high proportion of other ingredients added
`to the basic polymer, polyvinyl chloride, increases the
`opportunity of one or more of the additives to migrate
`into a solution having contact with the plastic. For
`example, previous studies have shown that polyvinyl
`chloride tubings used for medical purposes would
`leach a constituent to various alcohols and that certain
`of these tubings would react with a parenteral drug
`product.
`A year or so ago, our laboratory received reports
`that certain hospitals were resterilizing disposable tub­
`ings by a "cold" method using benzalkonium chloride.
`This directed our attention to other polyvinyl chloride
`materials which might also conceivably be sterilized
`by the use of a specific agent. In particular, we be­
`came interested in polyvinyl chloride sheets which are
`used for various and sundry purposes in a hospital.
`This particular paper deals with a preliminary re­
`port on the observations made after benzalkonium
`chloride solution was kept in contact with a particular
`brand of PVC sheets which are now being used in
`certain hospitals. The results reported in this paper
`have also been been noted for commercially obtained
`PVC tubings used in medical practice. The informa­
`tion in this preliminary report should once again em­
`phasize the seriousness of the "misuse" of plastics and
`alert the hospital pharmacists and others to test or
`have tested the plastic device for safety until proper
`standards are formulated and followed in the manu­
`facture, distribution, and use of a plastic item to be
`used by the medical profession.
`
`EXPERIMENTAL
`
`Materials Polyvinyl Chloride Sheet (4 mils)
`Benzalkonium Chloride (as Zcphiran® Chloride
`Solution)
`Sodium Lauryl Sulfate Solution 0.0129f
`Alcohol, Absolute
`Propylene Glycol, U.S.P.
`Glycerin, A. R.
`Polyethylene Glycol 400, U. S. P.
`
`Apparatus Leeds & Northrup pH meter
`Semi-micro Burette
`200 ml. Glass Stoppered Pyrex Tubes
`
`American Journal of Hospital Pharmacy Vol 19 AUG 1962
`
`Opiant Exhibit 2321
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
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`Page 2
`
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`
`as total uptake of benzalkonium chloride by the par­
`ticular sample of PVC and then adjusted to an
`equivalent uptake per unit weight of plastic. From
`these figures, percent uptake was calculated and related
`to time of contact as shown in Figure 1. All experiments
`here and which follow were conducted in duplicate.^
`
`Effect of pH on Uptake
`
`on the
`In order to determine the influence of
`uptake of benzalkonium chloride by PVC, weighed strips
`of PVC film were placed in 150 ml. of solution con­
`taining 1.28 mg. of benzalkonium chloride per ml. and
`adjusted to various j!;H's by the addition of sulfuric
`acid-ammonium sulfate solutions for acidic pWs and'
`sodium hydroxide-ammonium sulfate solutions for the
`basic
`s. These buffer systems were chosen because it
`has been reported^" that acids, other than sulfuric acid,
`interfere with the assay. The procedure for the ex­
`periment was exactly as previously described except
`initial pH and final pH values were determined. These,
`experiments were run for a period of 312 hours. At the
`end of the experiment, the pU of the original solution
`having a pU of 7.0 had dropped to 5.7 and the pH
`of the solution at 9.0 had dropped to 6.2. The results
`of this study are shown in graphic form (uptake in
`mg./Gm. vs pH) in Figure 2 and (uptake vs time) in
`Figure 3.
`
`Effect of Solvents on Uptake
`
`In order to determine the effect various solvents
`may have on the uptake of benzalkonium chloride by
`PVC, a study was conducted using various concen­
`trations of glycerin, propylene glycol, alcohol and poly­
`ethylene glycol 400. Weighed strips of PVC film were
`placed in the glass tubes and exactly 150 ml. of a
`solution containing 1.28 mg. of. benzalkonium cloride
`per ml. with the required amount of test solvent was
`added. The tubes were scaled as before and placed in
`the water bath set at 49° + 0.5° C. At certain time
`intervals, aliquots were withdrawn and assayed as
`outlined. 1 he results arc presented graphically in Fig­
`ures 4 to 7.
`
`Desorption of Benzalkonium Chloride
`
`Previous experiments had shown that some of the
`benzalkonium chloride which had been absorbed by the
`PVC would be leached back out of the plastic if the
`plastic were exposed to distilled water. Therefore,
`
`* In all experiments which contained benzalkonium chlor­
`ide, the PVC released a constituent to the solution as evi­
`denced by the original, clear solution becoming progressively
`cloudy. Atternpts were made
`to isolate and identify the
`leached constituent but this was soon relegated for future
`studies. The leached constituents did not materially alter the
`assay results.
`Partition coefficient experiments were also conducted but
`the results could not properly be interpreted because of the
`leaching.
`
`Kig.2.-EFFECT OF pH ON UPTAKE OF
`BENZALKONIUM CHLORIDE BY P.V.C.
`
`Fig.3-EFFECT OF pH ON UPTAKE OF
`BENZALKONIUM CHLORIDE BY P.V.C.
`
`120
`
`200
`160
`TIME IN HOURS
`
`240
`
`280
`
`320
`
`Fig. 4 -EFFECT OF ,ETHYL ALCOHOL ON UPTAKE OF
`BENZALKONIUM CHLORIDE BY P.V.C.
`
`120
`
`200
`ISO
`TIME IN HOURS
`
`240
`
`280
`
`320
`
`372
`
`Opiant Exhibit 2321
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 3
`
`

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`Downloaded from https://academic.oup.com/ajhp/article-abstract/19/8/370/5232276 by Reprints Desk user on 06 March 2020
`
`Fig.5.-EFFECT OF PROPYLENE GLYCOL ON UPTAKE OF
`BENZALKONIUM CHLORIDE BY RV.C.
`
`120
`
`200
`160
`TIME IN HOURS
`
`240
`
`280
`
`320
`
`FIg.G.-EFFECT OF GLYCERIN ON UPTAKE OF
`BENZALKONIUM CHLORIDE BY P.V.C.
`
`120
`
`200
`160
`TIME IN HOURS
`
`240
`
`280
`
`320
`
`FIg.T.-EFFECT OF POLYETHYLENE GLYCOL 400 ON UPTAKE OF
`BENZALKONIUM CHLORIDE BY P.V.C.
`
`120
`
`200
`160
`TIME IN HOURS
`
`240
`
`280
`
`320
`
`373
`
`samples of PVC which had been exposed to benzal-
`konium chloride solution buffered at pH 7.0 and had
`taken up known amounts of benzalkonium chloride
`were exposed to 75 ml. of distilled water in the special­
`ly constructed tubes and stored over a period of
`time in a water bath adjusted to 49° ± 0.5°C. Before
`exposure to the distilled water, the PVC samples were
`rinsed three times in distilled water to remove any
`surface solution of benzalkonium chloride adhering to
`the plastic. The surface moisture was then air-dried so
`that the exact volume of added distilled water would be
`known. At the end of 222 hours from 24 to 30 percent
`of the absorbed benzalkonium chloride was released
`back to water.
`
`DISCUSSION
`
`7 he results found in the various experiments clearly
`indicate that a reaction will take place between a solu­
`tion of benzalkonium chloride and flexible PVC. Even
`though cold sterilization is usually carried out at a much
`lower temperature and for much shorter periods of
`time, than employed in the experiments reported here,
`the more severe conditions were used to accentuate the
`reaction and to permit the collection of useful infor­
`mation in a much shorter period of time.
`
`Effect of Concentration
`
`It may be surprising to note that large quantities of
`benzalkonium chloride were removed from the various
`aqueous solutions in contact with the PVC, as may be
`noted in Figure 1. The uptake of the agent can occur
`at either the surface of the plastic (ac?sorption) or the
`benzalkonium chloride can penetrate
`the plastic
`(absorption). Even though aclsorption is probably tak­
`ing place, this could not account for the large amounts
`of uptake. Surface adsorption on plastics is usually
`instantaneous and thus a state of equilibrium would
`be reached within a very short time, but as the data
`indicates, many hours were needed before an apparent
`equilibrium was approached. This would suggest that
`the main route of uptake was by absorption.
`The question still to be answered, however, is the
`mechanism of interaction. There is no theoretical rea­
`son to indicate that a quaternary ammonium compound
`is interacting with the polyvinyl chloride since this
`polymer is relatively a non-polar molecule with no real
`sites to attract large amounts of an ionic compound
`such as benzalkonium chloride. The compound must
`be interacting with one or more of the additives, or
`partitioning itself between the solvent and the plastic.
`Delineation of one from another was not possible since
`the ingredients in the final PVC sheet were not made
`known to us and since the partition coefficient experi­
`ments were continually being marred by the leaching
`of an
`ingredient
`into
`the aqueous phase. The
`large amount of desorption into pure water, however.
`
`American Journal of Hospital Pharmacy Vol 19 AUG 1962
`
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`
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`
`supports the contention that partition was operating-
`hut to what degree was still another matter which
`could not be answered.
`In general an increase in concentration of a solute
`will reflect an increase in uptake of that solute by a
`plastic material, but when this is calculated as percent
`uptake as depicted in Figure 1 the relationship reverses
`and must be interpreted as meaning that dilute solu­
`tions will loose more of the solute to the plastic as per­
`cent than a more concentrated solution. Since benzal-
`konium chloride is often used in dilute solutions
`(1:1000 to 1 : 10.000) much of the original solute may
`be removed from a solution, thereby reducing the ef­
`fective bacteriostatic or bacteriocidal activity of
`the.
`agent. Kundsin and Walter^ " and Myers and Lcfebvce^""
`have emphasized the importance of this point.
`In the experiments conducted, apparent equilibrium
`was approached but true equilibriurn was probably
`never attained since leaching from the plastic would
`keep altering the equilibrium. For this reason the
`quantitizing of the concentration data by the usual
`Frcundlich or Langmuir adsorption isotherms was not
`possible.
`
`Effect ©f pH
`
`The effect of pH on the uptake of benzalkohium
`chloride presents an interesting result in that the up­
`take at pH 1.0 'is very high, decreasing at pH 3.0
`and then rising at pH 5.0 and beyond. The very low
`pH (1.0) apparently alters the PVC to a greater
`extent than the other /;H's, permitting greater uptake
`of the benzalkonium chloride. Figure 3 illustrates the
`leaching tendency of one or more of the additives
`which are of an acidic nature since the buffer capacity
`is broken at the higher /;H values (7.0 and 9.0) and
`the pH reduced to within an acid range.
`
`Effect of Solvents
`
`Reducing the dipolar characteristic of the solvent
`system by replacing the water with less polar solvents
`tends to decrease the uptake by the PVC. In two
`cases, (alcohol and propylene glycol) the decrease in
`uptake of benzalkonium chloride by the plastic was
`observed for all, three percentages of solvent added
`while in the case of polyethylene glycol 400 and gly-
`. cerin, the decrease in uptake was not noted except at a
`solvent concentration of 2 percent or more. The ex­
`planation for these observed effects is difficult to eluci­
`date within the experimental framework employed in
`the study.
`
`Summary and Conclusion
`
`Since flexible polyvinyl chloride and tubings and
`sheets ^are being used in medical practice for one rea­
`son or another, it was thought judicious to investigate
`
`374
`
`one particular PVC sheet as to its resistance to a
`commonly employed chemical sterilizing agent such as
`benzalkonium chloride. The resultsTndicated that the
`agent would be absorbed by the PVC and that the
`total uptake would be influenced by concentration, pH
`and solvents. Even though it is known that benzalkon­
`ium chloride will be bound by certain substrates,
`no such information appears to have been reported
`for PVC. The implications of uptake and leaching
`should caution those in the medical field employing
`PVC sheets and tubings to test their own particular
`PVC item prior to actual use to ensure safety. The
`results of this study once again emphasize the need
`for standards for plastics to be used in medical practice
`if better and safer patient care is to be achieved.
`Further work on this problem is continuing and will
`be reported at a later date.
`-
`
`References
`
`1. Autian, J.: The Effect of Plastics on Parenteral Pro­
`ducts. BM//. Parenteral Drug Assoc. 11:25 (1957).
`2. .\utian, J. and Brewer, J. H.: The Effect on Parenteral
`Products of Disposable Needles Having a Plastic Hub, Am,
`J. Hasp. Pharm. 75:313, (1958).
`3. Autian, J.; Leaching and Sorption of Plastics Used for
`Parcnterals, Bull. Parenteral Drug A.ssoc. 72:17 (1958).
`4. Autian, J. and Dhoi da, C. N.: Evaluation of Dispos­
`able Plastic Syringes as to Physical Incompatibilities with
`Parenteral Products, Am. J. Hasp. Pharm. 75:176 (1959).
`5. Marcus, E., Kim, H. K., and .Autian, J.: Bindings of
`Drugs by Plastics I. Interaction of Bacteriostatic Agents with
`Plastic Syringes, /. Am. Pharm. Assoc., Sci. Ed. 48:457
`(1959).
`6. Kim, H. K. and .Autian, J.: Binding of Drugs by Plastics
`II. Interaction of Weak Organic .Acids with Plastic Syringes,
`ibid, 49:227 (I960).
`7. Autian, J. and Shaikh, Z. I.: Binding of Drugs by
`Plastics III. Potential Value of Drug-Plastic Interaction with
`Respect to Packaging Materials, Drug Standards, 28:103
`(1960).
`8. Autian, J. and Kapadia, A. J.: A Note on the Leaching
`of a Constituent from Medical Grade Plastic Tubings, ibid,
`28:101 (I960).
`in Parenteral Packaging, Bull.
`9. Autian, J.: Plastics
`Parenteral Drug Assoc., 14:10 (1960).
`10. Autian, J.: Plastics—Uses and Problems in Pharmacy
`and Medicine, Am. J. Hosp. Pharm., 18:529 (1961).
`11. Richards, J. M. and Whittet, T. D.: Nylon Syringes
`Under Test, Chemist and Druggist, 170:16 (1958).
`12. Fagard, J.: Stabilite du Chlorhydrate de Neosyne-
`phrine en Fonction de la Nature du Conditionnement, /.
`Pharm. Belg. 76:128 (1961).
`13. Dcnoel, A et Fagard, J.: Comportement de Quelques
`Matieres Plastiques vis-a-vis Agents Physiques et Chimiques
`et son Incidence sur les Application Pharmaceutiques, ibid,
`75:384 (1960).
`14. Hartop, W. L.: The Influence of Packaging on the
`Quality of Liquid Dosage Forms, presented at the A.Ph.A.
`(Industrial Section), Chicago meeting, April 1961.
`15. Nicolaide.s, H. J. and Autian, J.: Plastics—A Potential
`Problem in Hospitals, Hospitals, 35:63 (1961).
`16. Carkhuff, E. D. and Boyd, W. F.: J. Am. Pharm.
`Assoc., Sci. Ed. 43:240 (1954).
`17. Kundsin, R. S. and Walter, C. W.: Investigations on
`Adsorption of Benzalkonium Chloride, U. S. P. by Skin,
`Gloves and Sponges, Arch. Surg., 75:1036 (1957).
`18. Myers, G. E. and Lefebvre, C.: Antibacterial Activity
`of Benzalkonium Chloride in the Presence of Cotton and
`Nylon Fibres, Canadian Pharm. J., 94:55 (1961).
`
`Opiant Exhibit 2321
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 5
`
`