Esmolol hydrochloride Reports
`
`Stability of esmolol hydrochloride
`in intravenous solutions
`
`D. MICHAEL BAASKE, STEVEN D. DYKSTRA, DIETMAR M. WAGENKNECHT, AND NANCY N. KARNATZ
`
`Abstract: The stability of es-
`molol hydrochloride in a va-
`riety of i.v. solutions was
`studied.
`
`Solutions of esmolol hydro-
`chloride 10 mg/mL were pre-
`pared separately in 0.45% so-
`dium chloride injection, 0.9%
`sodium chloride injection,
`5% dextrose injection, 5%
`dextrose and 0.45% sodium
`
`chloride injection, 5% dex-
`trose and 0.9% sodium chlo-
`
`ride injection, 5% dextrose
`with lactated Ringer's injec-
`tion, lactated Ringer's injec-
`tion, 5% sodium bicarbonate
`
`injection, and 5% dextrose
`injection with potassium
`chloride 40 meq/L. One glass
`and one polyvinyl chloride
`container of each solution
`
`(except glass only in the case
`of the solution in 5% sodium
`
`bicarbonate injection) were
`stored in the dark at 5 °C, un-
`der ambient room light at
`23-27 °C, in the dark at 40 °C,
`and under intense light at
`25-30 ‘C. At storage intervals
`up to 168 hours, samples
`were tested for esmolol hy-
`drochloride concentration by
`high-performance liquid
`
`chromatography. Optical
`density and pH were also
`measured.
`
`Esmolol hydrochloride was
`stable in the various i.v. flu-
`ids for at least 168 hours
`when stored at 5 °C or 23—Z7
`°C, for at least 24 hours when
`stored under intense light,
`and, with one exception, for
`at least 48 hours when stored
`at 40 ‘’C. When mixed with
`5% sodium bicarbonate injec-
`tion, the drug was stable for
`only about 24 hours at 40 °C.
`There were no substantial
`
`changes in optical density or
`
`pH. The type of container
`had no effect on stability.
`With one exception, es-
`molol hydrochloride was
`stable in all the i.v. solu-
`tions under all the condi-
`tions tested.
`
`Index terms: Additives;
`Cardiac drugs; Containers; Es-
`molol hydrochloride; Glass;
`Incompatibilities; Polyvinyl
`chloride; Sodium bicarbon-
`ate; Stability; Storage; Tem-
`perature; Vehicles
`Am J Hosp Pharm. 1994;
`5l:2693-6
`
`smolol hydrochloride injection has been report-
`ed to be visually compatible” and chemically
`stable” when mixed with various drugs, but
`data on the stability of esmolol hydrochloride in i.v.
`solutions have not appeared in the scientific literature.
`We describe here a series of studies that provide those
`data. These studies are the basis of information includ-
`
`ed in the package insert for esmolol hydrochloridef‘
`
`Methods
`
`Preparation and storage of solutions. A dis-
`posable syringe“ and needle” were used to withdraw 20
`mL of solution from 500-mL containers of the follow-
`
`ing i.v. fluids: 0.45% sodium chloride injectionf 0.9%
`sodium chloride injection,“ 5% dextrose injections
`5% dextrose and 0.45% sodium chloride injection,‘ 5%
`dextrose and 0.9% sodium chloride injection,8 5%
`dextrose with lactated Ringer's injection,“ lactated
`Ringer's injection,‘ and 5% sodium bicarbonate
`injection? Twenty milliliters of esmolol hydrochloride
`injection“ 250 mg/mL (from ampuls) was then injected
`
`into the containers to produce solutions with an es-
`molol hydrochloride concentration of approximately
`10 mg/mL.
`A slightly different procedure was used to prepare
`another solution. Twenty milliliters of fluid was with-
`drawn from 500-mL containers of 5% dextrose
`
`injection,"- and 10 mL of potassium chloride injection‘
`2 meq/mL was added and mixed in. Twenty milliliters
`of esmolol hydrochloride injectionk 250 mg/mL was
`then injected into the containers to produce solutions
`with an esmolol hydrochloride concentration of ap-
`proximately 10 mg/mL and a potassium chloride con-
`centration of approximately 40 meq/L.
`With one exception, eight admixtures of each solu-
`tion were prepared—four in glass containers and four
`in polyvinyl chloride (PVC) containers. Four admix-
`tures of esmolol hydrochloride in 5% sodium bicar-
`bonate injection were prepared in glass containers.
`All
`the solutions were mixed thoroughly and
`checked immediately for visual changes. Samples were
`taken from each container for initial testing. One glass
`
`D. MICHAEL BAASKE, Pl-I.D., is Senior Director, Analytical Research
`and Development, A.L. Laboratories, Baltimore, MD; at the time
`of these studies he was Section Head, Analytical Research and
`Development, American Critical Care (ACC), McGaw Park,
`IL.
`STEVEN D. DYKSTRA is Manufacturing Manager, MGI Pharma,
`Minnetonka, MN; at the time of these studies he was Research
`Associate, Product Development, ACC. DIETMAR M. WAGEN—
`KNECHT, M.B.A.,
`is Vice President, Pharmaceutical Sciences,
`Fujisawa USA, lnc., Deerfield, IL; at the time of these studies he
`was Section Head, Product Development, ACC. NANCY N. KARNATZ
`is Quality Control Manager, Technical Operations and Quality
`
`Assurance Department, Lorex Pharmaceuticals, Skokie, IL; at the
`time of these studies she was Research Associate, Analytical Re-
`search and Development, ACC.
`Address reprints to Dr. Baaske at A.L. Laboratories, lnc., 333
`Cassell Drive, Suite 3500, Baltimore, MD 21224.
`The contributions of Earl R. Speicher and Lisa P. Cahill are
`acknowledged.
`
`Copyright © 1994, American Society of Hospital Pharmacists,
`Inc. All rights reserved. 0002-9289/94/1101-2693$01.00.
`
`Vol 51 Nov 1 1994 Am] Hosp Pharm 2693
`MYLAN ET AL. - EXHIBIT 1014
`
`MYLAN ET AL. - EXHIBIT 1014
`
`

`
`at 400 and 600 nm with a double-beam spectropho-
`tometer” or a single-beam photodiode array.“ These
`wavelengths were chosen to detect yellowing (400 nm)
`and cloudiness or opalescence (600 nm). Readings
`were compared with those for deionized water. Solu-
`tion pH was determined with a pH meter° that had
`been calibrated with two standards. Optical density
`and pH were measured immediately after the admix-
`tures were prepared and after 168 hours for the solu-
`tions stored at 5 °C and 23-27 °C, after 48 hours for
`the solutions stored at 40 °C, and after 24 hours for the
`solutions stored under intense light.
`Esmolol assay. A high-pressure liquid chromato-
`graphic procedure9 was adapted to measure the es-
`molol hydrochloride concentration. The system
`consisted of a liquid chromatograph,P an ultraviolet
`light-absorption photometer‘! set at 214 nm, and a 10-
`mV recorder.‘ A 3.9-mm x 30—cm columns was operated
`at a constant flow rate of 2.0 mL/min, which produced
`a head pressure of 2000 psi.
`The mobile phase consisted of 0.005 M monobasic
`potassium phosphate‘ in water (65%), methanol“
`(20%), and acetonitrile” (15%). An autosamplerV in-
`jected 100-uL samples into the system.
`The following stock solutions were prepared: es-
`molol hydrochloride“ 200 jig/IIIL, 3-[4-[2-hydroxy—3-
`(isopropylamino)propoxy]phenyl]propionic acid (the
`free-acid degradation product of esmolol9) 20 ug/mL,
`and 0-chlorobenzyl alcohol“ (the internal standard)
`200 ug/mL. The free—acid degradation product was
`made from esmolol by base hydrolysis, acidification,
`extraction into chloroform, and reduction to dryness.
`Five—rnilliliter samples of admixture solutions were
`diluted to 25 mL with distilled water, and, after thor-
`ough mixing, 5-mL portions were further diluted to 50
`mL. Then, 10—mL portions of each diluted sample, the
`esmolol hydrochloride standard, the free—acid degrada-
`tion product, and the internal standard were diluted
`separately to 50 mL with distilled water to obtain
`working concentrations. Esmolol hydrochloride con-
`centrations in the admixtures were determined from
`
`peak height ratios; the single-point standard was es-
`molol hydrochloride 40 jig/IIIL. All determinations
`were done in duplicate.
`Chromatography, as described above, was per-
`formed for each of the infusion solutions without es-
`
`molol hydrochloride; there were no interfering peaks.
`The stability—indicating nature of the assay has been
`demonstrated?
`
`2694 Am] Hosp Pharm Vol 51 Nov 1 1994
`
`Results
`
`No changes were visible in any of the admixtures
`throughout the storage periods. All optical density
`readings were negligible (absorbance, $0.01). The pH
`remained within 0.3 unit of the initial Value for the
`sodium bicarbonate solutions and within 0.1 unit for
`
`_
`all the other solutions.
`Esmolol hydrochloride was stable in the various i.v.
`fluids for at least 168 hours when stored at 5 °C or
`23-27 °C, for at least 24 hours when stored under
`
`intense light, and with one exception, for at least 48
`hours when stored at 40 °C (Table 1). When mixed
`with 5% sodium bicarbonate injection, the drug was
`stable for only about 24 hours at 40 °C,
`The type of container used had no effect on stability.
`
`Discussion
`
`Esmolol hydrochloride was stable in all the solu-
`tions tested for at least 168 hours when kept at typical
`storage temperatures (5 °C or 23-27 °C). The drug was
`also stable after 24 hours under intense light, a condi-
`tion chosen to simulate short-term storage directly in
`indoor or window light. At 40 °C——a high but conceiv-
`able storage temperature—all the admixtures were sta-
`ble for at least 48 hours except for the one prepared
`with 5% sodium bicarbonate injection, which was sta-
`ble for only about half that time.
`Basic solutions tend to promote ester hydrolysis.
`Thus, the stability of esmolol hydrochloride, an ester,
`is influenced by both pH and temperature. The initial
`pH (at room temperature) of the esmolol hydrochlo-
`ride-sodium bicarbonate admixtures was 8.1-8.2, but
`USP specifications allow the pH of sodium bicarbonate
`injection to be as high as 8.5,“) and storage tempera-
`tures for admixtures could easily approach 40 °C.
`Thus, it would be difficult to predict the stability of
`esmolol hydrochloride in 5% sodium bicarbonate in-
`jection under all likely storage conditions. The pack-
`age insert for esmolol hydrochloride takes the
`conservative position that the drug is not compatible
`with 5% sodium bicarbonate injection.“ Our data sug-
`gest that if an admixture of esmolol hydrochloride in
`5% sodium bicarbonate injection is required, it should
`be used within 24 hours or, if possible, immediately.
`Esmolol hydrochloride is available in ampuls (2.5 g/
`10 mL), which were used in these studies, and vials
`(100 mg/ 10 mL).’3 The ampuls contain propylene gly-
`col and alcohol, which the vials do not. We do not
`
`

`
`Table 1.
`Stability of Esmolol Hydrochloride in Various |.V. Solutions
`
`Esmolol hydrochloride Reports
`
`Solution and
`Container Type
`
`0.45% Sodium chloride injection
`Glass
`
`PVC“
`
`0.9% Sodium chloride injection
`Glass
`
`5% Dextrose injection
`Glass
`
`Storage
`Conditiona
`
`5 °C
`23-27 °C
`40 °C
`Intense light
`5 “C
`23-27 °C
`40 °C
`Intense light
`
`5 °C
`23-27 °C
`40 °C
`Intense light
`5 °C
`23-27 °C
`40 °C
`Intense light
`
`Lactated Ringer's injection
`Glass
`
`I
`I
`I E
`‘t’
`I
`|_?)',('jE:oCfi|rgr°idC:e
`Concentration
`(mg/mL)b~°
`
`.
`.
`.
`.
`.
`O
`/0 Mean Initial Concentration Remaining“
`
`24 hr
`
`48 hr
`
`72 hr
`
`168 hr
`
`m
`
`.m
`
`P3105150
`
`@@@@@@Q©mmwmmmow—oj—m_L_LW@@@@@@*@%mmbmmwmmmmmm
`
`9.
`10.23, 10.19
`10.73, 10.85
`1025, 10.21
`.
`.
`.
`.
`.
`.
`.
`.
`
`_|.__A..._L._L
`
`.
`.
`.
`.
`.
`
`.
`
`.
`.
`.
`.
`
`—kLOLOmmmmo
`
`, 10.29
`, 10.17
`0 , 10.03
`, 9.96
`.
`, 9.96
`.
`. 1, 10.16
`9.97, 10.00
`10.00, 9.94
`
`1
`
`10.47, 10.44
`10.43, 10.45
`10.32, 10.39
`10.30, 10.35
`9.91, 9.92
`9.87, 9.95
`9.80, 9.79
`10.05, 9.93
`
`10.11, 10.11
`10.15, 10.18
`10.17, 9.98
`1034, 10.33
`
`(0(D
`
`.so
`
`
`
`
`
`m@@mmoomSew(OUTCOQDTUCD$03wagmwmmg:©fl
`
`102.6, 99.2
`98.4, 97.4
`99.1, 98.3
`100.4, 100.1
`98.8, 97.3
`97.6, 98.3
`99.5, 99.1
`98.2, 98.3
`
`100.2, 100.0
`97.9, 98.8
`100.9, 101.3
`99.9, 99.9
`. 100.1, 100.4
`99.4, 99.1
`98.8, 98.1
`97.3, 99.9
`
`99.7, 99.9
`100.1, 100.0
`101.0, 100.7
`100.0, 100.4
`100.6, 100.5
`99.2. 99.6
`100.6, 101.0
`100.1, 99.8
`
`100.3, 99.3
`99.8, 100.4
`100.1, 101.1
`100.7, 100.6
`99.8, 100.9
`100.4, 100.6
`100.99
`100.9, 100.5
`
`100.4, 101.1
`100.5, 100.0
`99.8, 100.0
`100.7, 100.2
`101.9, 99.5
`100.4, 99.9
`101.4, 100.3
`99.7, 99.7
`
`99.4, 100.3
`99.9, 99.6
`100.0,101.1
`99.9, 98.2
`100.6, 99.6
`99.9, 98.9
`101.8,102.0
`99.99
`
`106.2, 103.4
`96.5, 99.3
`96.9, 99.3
`96.99
`101.1, 99.9
`98.8, 99.9
`101.6, 100.2
`100.9, 98.1
`
`.
`.
`.
`
`.
`.
`.
`
`100.8, 100.7
`99.7, 97.1
`98.2, 98.8
`
`100.8, 100.1
`99.2, 98.4
`...
`
`100.9, 100.8
`98.3, 98.4
`...
`
`99.9, 99.9
`98.8 98.8
`
`4
`, 98.4
`8.
`97.2
`7
`.2,
`
`9
`9
`
`.. .
`98.5, 98.5
`98.4, 98.4
`...
`
`0
`, 99.0
`100.
`99.3
`98.6,
`..
`.. .
`98.8, 100.2
`98.8, 98.7
`...
`
`99.5, 98.4
`96.8, 96.7
`98.9, 96.8
`
`98.6, 98.5
`97.7, 96.7
`99.5, 98.3
`...
`98.9, 97.6
`98.1, 98.4
`97.2, 96.8
`.
`.
`.
`
`99.6, 98.8
`99.8, 98.8
`99.7, 100.0
`
`100.3, 99.8
`99.3, 99.2
`99.3, 99.5
`.
`.
`.
`
`99.8, 100.0
`100.0, 100.7
`100.3, 99.8
`
`100.3, 98.2
`99.7, 99.8
`101.2, 100.6
`.
`.
`.
`
`100.1, 100.4
`100.7, 95.8
`101.2, 99.4
`. ..
`100.3, 100.3
`100.5, 99.6
`100.2, 100.8
`.
`.
`.
`
`100.5, 99.9
`100.3, 100.0
`101.0, 101.4
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`,
`...
`
`...
`
`...
`
`99.9, 99.5
`99.6, 100.3
`
`101.0, 100.7
`99.6, 100.2
`...
`
`100.2, 100.2
`100.5, 99.9
`
`100.4, 100.6
`98.5, 99.4
`
`100.7, 100.0
`100.2, 100.0
`
`100.6, 100.3
`99.7, 98.4
`
`99.1, 98.1
`97.6, 99.5
`
`.
`.
`
`.
`.
`
`99.2, 98.9
`99.0, 98.6
`
`98.8, 98.7
`99.3, 98.7
`
`102.5, 102.0
`99.7, 98.7
`99.1, 99.1
`.
`.
`.
`100.9, 101.1
`99.5, 99.7
`95.8, 99.2
`...
`
`101.1, 100.0
`98.0, 98.3
`81.3, 84.5
`.
`.
`.
`
`103.1, 103.8
`100.4, 99.8
`...
`.
`.
`.
`102.0, 102.0
`100.9, 101.0
`...
`
`102.5, 102.2
`98.7, 98.4
`...
`.
`.
`.
`100.6, 100.6
`99.4, 100.3
`...
`
`100.9, 100.4
`95.2, 96.6
`.
`
`94.3, 95.1
`92.3, 92.4
`...
`
`Continued on next page
`
`Vol 51 Nov 1 1994 Am] Hosp Pharm 2695
`
`5 °C
`23-27 °C
`40 °C
`Intense light
`5 °C
`23-27 °C
`40 °C
`Intense light
`5% Dextrose and 0.45% sodium chloride injection
`Glass
`5 °C
`23-27 “C
`40 °C
`Intense light
`5 °C
`23-27 “C
`40 “C
`Intense light
`5% Dextrose and 0.9% sodium chloride injection
`Glass
`5 °C
`23-27 °C
`40 ‘’C
`Intense light
`5 °C
`23-27 °C
`40 °C
`Intense light
`5% Dextrose and lactated Ringer's injection
`Glass
`5 “C
`23-27 °C
`40 °C
`Intense light
`5 °C
`23-27 °C
`40°C
`Intense light
`5 °C
`23-27 °C
`40 °C
`Intense light
`5 °C
`23-27 °C
`40 °C
`Intense light
`
`5% Sodium bicarbonate injection
`Glass
`
`5 °C
`23-27 °C
`40 °C
`Intense light
`
`10.12, 9.93
`10.34, 10.27
`10.02, 10.19
`10.38, 10.42
`
`

`
`103.4,‘ 97.6
`98.8. 100.0
`
`7
`99.9,‘ 8.
`.6
`96.8, 7
`
`99
`
`1032, 10.35
`
`Intense light
`5 °C
`23-27 °C
`40 “C
`Intense light
`
`97.3, 98.7
`99.7, 100.1
`101.2, 100.7
`99.4, 97.5
`
`99.2, 98.2
`101.1. 99.5
`101.8, 101.6
`
`3 Solutions stored at 5 °C and 40 °C were protected from light. Solutions stored at 23-27 °C were kept under ambient room light. Intense light = 1400~
`2000 foot—cand|es, normally 25-30 °C.
`9 Theoretical concentration = 10 mg/mL.
`C Duplicate values.
`9 PVC = polyvinyl chloride.
`5 Duplicate value not obtained because of instrument failure.
`
`know whether using the vials in our studies would
`have produced different results, but the ampuls are
`intended for use in preparing solutions for infusion,
`whereas the vials are intended for direct i.v. injection.
`Thus, we used the more appropriate formulation for
`our investigations.
`
`‘Fisher Scientific, Pittsburgh, PA.
`“Burdick and Jackson, Muskegon, M1; or J. T. Baker, Inc.,
`Phillipsburg, NJ.
`VWISP, Waters.
`WGaines Chemicals, lnc., Carlstadt, NJ, lot 907-32.
`‘Aldrich Chemical Co., Milwaukee, WI.
`
`Conclusion
`
`References
`
`With one exception, esmolol hydrochloride was sta-
`ble in a variety of i.V. solutions under a broad range of
`conditions. In 5% sodium bicarbonate injection, the
`drug was stable for only about 24 hours at 40 °C.
`
`lot B3D111A (glass), and Travenol,
`
`lot 8C90755
`
`lot 4C916H5
`
`lot B3DO81B (glass), and Travenol,
`
`lot 4C925F5
`
`lot B2PO53A (glass), and Travenol,
`
`lot 7C864W2
`
`3B-D Plastipak, Becton-Dickinson and Co., Franklin Lakes, NJ.
`I718 gauge, Becton-Dickinson.
`°McGaw Laboratories, Inc., Irvine, CA, lot B2N134B (glass),
`and Travenol Laboratories, Inc., Deerfield, IL, lot 4C93111O (poly-
`Vinyl chloride [PVC]).
`“McGaw,
`lot B3AO98B (glass), and Travenol,
`(PVC).
`°McGaw,
`(PVC).
`‘McGaw,
`(PVC).
`3McGaw, lotJ9PO83B (glass), and Travenol, lot 9C925 L3 (PVC).
`“McGaw,
`lot B2N096C (glass), and Travenol,
`lot, 6C928L6
`(PVC).
`‘McGaw,
`(PVC).
`lMcGaw, lot 6668OW7A (glass).
`“Brevibloc, American Critical Care, Aguadilla, PR, lots 767-49,
`803-31, and 5DA101.
`'Elkins-Sinn Inc., Cherry Hill, NJ, lot 082131.
`"‘Acta CIII, Beckman Instruments, Inc., Irvine, CA.
`“Model 8450A, Hewlett-Packard Co., Avondale, PA.
`°Model 130 or 145, Corning Glass Works, Inc., Corning, NY.
`PSystem 2/2, Perkin-Elmer Corp., Norwalk, CT.
`‘ILC-55A, Perkin-Elmer, or LC-160, Beckman.
`‘Model 285/mm, Scientific Products, McGaw Park, IL.
`5pBondapak C18, Waters Associates, Milford, MA.
`
`1. Colucci RD, Cobuzzi LE, Halpern NA. Visual compatibility of
`esmolol hydrochloride and various injectable drugs during
`simulated Y-site injection. Am I Hosp Phrznn. 1988; 45:630-2.
`. Halpern NA, Colucci RD, Alicea M et al. Visual compatibility
`of enalaprilat with commonly used critical care medication
`during simulated Y-site injection. Int I Clin Pharmacol Ther
`Toxicol. 1989; 27:294-7.
`. Halpern NA, Colucci RD, Alicea M et al. The compatibility of
`nicardipine hydrochloride injection with various ICU medi-
`cations during simulated Y-site injection. Int I Clin Phanmzcol
`Ther Toxical. 1989; 27:250-4.
`. Savitsky ME. Visual compatibility of neuromuscular blocking
`agents with various injectable drugs during simulated Y-site
`injection. Am [Hosp Pharm. 1990; 47:820-1.
`. Karnatz NN, Wong J, Kesler H et al. Compatibility of esmolol
`hydrochloride with morphine sulfate and fentanyl citrate
`during simulated Y-site administration. Am I Hosp Pharm.
`1988; 45368-71.
`. Karnatz NN, Wong J, Baaske DM et al. Stability of esmolol
`hydrochloride and sodium nitroprusside in intravenous ad-
`mixtures. Am IHOsp Pharm. 1989; 46:101-4.
`. Schaaf L], Robinson DH, Vogel G] et al. Stability of esmolol
`hydrochloride in the presence of aminophylline, bretylium
`tosylate, heparin sodium, and procainamide hydrochloride.
`AmIHOsp Pharm. 1990; 47:1567-71.
`. Anaquest Inc. Brevibloc package insert. Liberty Corner, NJ;
`1993 May.
`. Karnatz NN, Baaske DM, Herbranson DE et al. High-perfor-
`mance liquid chromatographic (HPLC) method for the deter-
`mination of esmolol hydrochloride in solutions and
`parenteral formulations. I Chromatogr. 1985; 330:420-4.
`. The United States pharmacopeia, 22nd rev., and The national
`formulary, 17th ed. Rockville, MD: The United States Pharma-
`copeial Convention; 1989:1254.
`
`2696 Am] Hosp Pharm Vol 51 Nov 1 1994