Nicardipine hydrochloride Reports
`
`Stability of nicardipine hydrochloride
`in intravenous solutions
`
`D. MICHAEL BAASKE, ]OHN F. DEMAY, CANDACE A. LATONA, SHANTHA MIRMIRA, AND KEN W. SIGVARDSON
`
`Abstract: The stability of
`nicardipine hydrochloride in
`large-volume i.v. solutions
`was studied.
`Admixtures of nicardipine
`hydrochloride 0.05 and 0.5
`mg/mL were prepared in 5%
`dextrose and 0.45% sodium
`chloride injection, 5% dex(cid:173)
`trose and 0.90,1.> sodium chlo(cid:173)
`ride injection, 0.4SCYt> sodium
`chloride injection, 0.9oA> sodi(cid:173)
`um chloride injection, 5o/o
`dextrose and lactated Ringer's
`injection, St.llo dextrose injec(cid:173)
`tion, lactated Ringer's injec(cid:173)
`tion, 5% sodium bicarbonate
`injection, and 5% dextrose
`injection with potassium
`chloride 40 meq/L. Two glass
`and two polyvinyl chloride
`(PVC) containers of each so-
`
`lution were prepared and
`stored at ambient room tem(cid:173)
`perature under normal fluo(cid:173)
`rescent light. Samples were
`removed and tested for nicar(cid:173)
`dipine concentration by
`stability-indicating high(cid:173)
`performance liquid chroma(cid:173)
`tography at 0, 24, 48, and 72
`hours and seven days. Testing
`included visual checking and
`optical density measure(cid:173)
`ments.
`The admixtures remained
`clear and slightly yellow ex(cid:173)
`cept for nicardipine hydro(cid:173)
`chloride in sodium bicarbon(cid:173)
`ate injection, which showed
`immediate precipitation, and
`nicardipine hydrochloride in
`lactated Ringer's injection,
`which increased in optical
`
`density at 400 nm over time.
`There were no significant
`changes in nicardipine con(cid:173)
`centrations in glass contain(cid:173)
`ers. Admixtures stored in PVC
`containers showed a slow,
`constant decline in nicar(cid:173)
`dipine concentrations, some(cid:173)
`times to less than 85% of the
`initial drug concentration
`within 24 hours, except for
`nicardipine hydrochloride in
`lactated Ringer's injection or
`5% dextrose and lactated
`Ringer's injection, which
`showed an immediate and
`continuing rapid loss.
`Nicardipine hydrochloride
`0.5 and 0.05 mg/mL in eight
`i.v. solutions was stable in
`glass containers for up to sev(cid:173)
`en days. Drug concentrations
`
`slowly decreased in PVC con(cid:173)
`tainers. The drug was not sta(cid:173)
`ble in 5o/o sodium bicarbonate
`injection or in PVC bags con(cid:173)
`taining lactated Ringer's in(cid:173)
`jection or 5% dextrose and
`lactated Ringer's injection.
`
`Index terms: Additives;
`Cardiac drugs; Concentra(cid:173)
`tion; Containers; Dextrose;
`Diluents; Glass; Incompatibil(cid:173)
`ities; Injections; Nicardipine
`hydrochloride; Polyvinyl
`chloride; Precipitation; Ring(cid:173)
`er's injection lactated; Sodi(cid:173)
`um bicarbonate; Stability;
`Storage
`Am J Health-Syst Pharm.
`1996; 53:1701-5
`
`N icardipine hydrochloride is a calcium-channel
`
`antagonist indicated in the treatment of hyper(cid:173)
`tension. The drug is commercially available as a
`10-mL ampul containing nicardipine hydrochloride
`2.5 mg/mL in Water for Injection, USP, sorbitol (for
`tonicity), and a citrate buffer. The pH is adjusted, when
`necessary, with dilute citric acid or sodium hydroxide.
`The solution contains no preservatives. Before adminis(cid:173)
`tration, nicardipine hydrochloride should be diluted
`with an intravenous solution, yielding a concentration
`between 0.5 and 0.05 mg/mL.
`Although the physical compatibility of nicardipine
`hydrochloride with numerous pharmaceuticals has
`been established, 1'2 its stability in large-volume inject(cid:173)
`able solutions has not been documented to date. The
`purpose of this study was to determine the stability of
`nicardipine hydrochloride in commonly used large(cid:173)
`volume i.v. solutions.
`
`Methods
`Preparation and sampling of admixtures. A
`disposable syringea and needle were used to withdraw
`SO mL of solution from 250-mL containers of 5% dex(cid:173)
`trose injectionb and lactated Ringer's injectionc; 100 mL
`from 500-mL containers of 50AJ dextrose and 0.45CYcJ
`sodium chloride injection,C1 0.9<}1) sodium chloride
`injection, e 5% dextrose and lactated Ringer's injection/
`5% dextrose and 0.9% sodium chloride injection,g
`0.45% sodium chloride injection,11 lactated Ringer's
`injection/ 5% dextrose injectioni with potassium chlo(cid:173)
`ride 40 meq/L,k and 5% sodium bicarbonate injection1;
`and 200 mL from a 1000-mL container of 5% dextrose
`injection with potassium chloride 40 meq/L.m A vol(cid:173)
`ume of nicardipine hydrochloride 2.5 mg/mLn equiva(cid:173)
`lent to the volume of i.v. solution removed was then
`injected into the containers to produce 17 admixtures
`with a nicardipine hydrochloride concentration of ap-
`
`D. MICHAEL BAASKE, PH.D., is Senior Director, Research and Devel(cid:173)
`opment, Alpharma, Baltimore, MD; at the time of this study he
`was Section Head, Analytical Research and Development, DuPont
`jOHN F. DEMAY is Administrator,
`Critical Care, Waukegan, IL.
`Pharmaceutical Research and Development, DuPont Merck Phar(cid:173)
`maceutical Company. CANDACE A. LATONA is Associate Scientist,
`DuPont Critical Care. SHANTI-IA MIRMIRA is Scientist, Fujisawa USA,
`Melrose Park, IL. KEN W. SIGVARDSON, PH.D., is Associate Director,
`DuPont Merck Pharmaceutical Company.
`
`The assistance of Dale E. Herbranson, Helen Kesler, Earl
`Speicher, Lazondra Martin, julie Eichorst, and Ragu Srinivas is
`acknowledged.
`Address reprint requests to Dr. Baaske at Research and Devel(cid:173)
`opment, Alpharma, The Johns Hopkins Bayview Campus, 333
`Cassell Drive, Suite 3500, Baltimore, MD 21224.
`
`Copyright © 1996, American Society of Health-System Phar(cid:173)
`macists, Inc. All rights reserved. 1079-2082/96/0702-1701$06.00.
`
`Vol 53 Jul 15 1996 Am J Health-Syst Pharm 1701
`
`Sandoz Exhibit 1006 Page 1
`
`

`

`Reports Nicardipine hydrochloride
`
`proximately 0.5 mg/mL. A similar procedure was used
`to produce 17 admixtures of nicardipine hydrochloride
`0.05 mg/mL: 5 mL of i.v. solution was removed from
`the 250-mL containers and replaced with nicardipine
`hydrochloride injection; 10 mL from the 500-mL con(cid:173)
`tainers; and 20 mL from the 1000-mL containers. The
`containers were composed of glass or polyvinyl chlo(cid:173)
`ride (PVC). The solutions, prepared in duplicate, were
`thoroughly mixed and checked immediately for any
`visible changes. A 30-mL sample was taken from each
`container for initial testing.
`The containers were stored at atnbient room temper(cid:173)
`ature (18-28 °C) under laboratory fluorescent light.
`Samples (30 mL) were removed and tested after 24, 48,
`and 72 hours and seven days. If precipitation was noted
`in a container, testing of that solution was terminated.
`Optical density measurements and pH test(cid:173)
`ing. Optical density measurements at 400 and 600 nm
`were performed with a single-beam spectropho(cid:173)
`tometer. o These wavelengths were chosen to indicate
`any yellowing ( 400 nm) and cloudiness or opalescence
`(600 nm). The pH was determined with a pH meterP
`calibrated with two standards. Solution components
`were considered compatible when the admixture re(cid:173)
`mained virtually clear and unchanged in color with
`
`respect to a deionized water blank (these were aqueous
`admixtures) and showed no appreciable change in pH
`throughout the test period.
`Nicardipine assay. Nicardipine concentration was
`determined by high-performance liquid chromatogra(cid:173)
`phy (HPLC). A liquid.chromatographq equipped with an
`automatic sampler/ a variable-wavelength ultraviolet
`light detectors set at 237 nm, a 10-mV recorder,t and a
`data systemu were used to analyze the solutions. Quanti(cid:173)
`tation was by peak area, in duplicate. An octadecylsilane
`columnv was used with the mobile phase at a constant
`flow rate of 1.5 rnL/min. The injection volume was 20 JlL.
`The mobile phase consisted of a mixture of 0.02 M
`monobasic potassium phosphatew in water adjusted to
`pH 4.4-5.0 with phosphoric acid,X methanol,Y and
`acetonitrileY ( 40:10:50 v:v:v).
`Stock solutions of nicardipine hydrochloride refer(cid:173)
`ence standardz were prepared in mobile phase. Samples
`at 0.05 mg/mL were analyzed without further prepara(cid:173)
`tion. Samples at 0.5 mg/mL and stock standards were
`diluted with unbuffered mobile phase to a theoretical
`concentration of 0.05 mg/mL.
`The HPLC method was validated as stability indicat(cid:173)
`ing by stressing nicardipine hydrochloride and analyz(cid:173)
`ing the results. The stress conditions used were solu-
`
`Figure 1. Chromatogram of nicardipine hydrochloride after treatment with heat. Nicardipine eluted at 7.3 minutes. Peak 1 also appeared after
`nicardipine hydrochloride was treated with hydrogen peroxide; peaks 1-3 appeared after hydrochloride was treated with sodium hydroxide
`solution; peak 3 appeared after nicardipine hydrochloride was treated with hydrochloric acid; and peak 4 appeared after nicardipine hydrochlo(cid:173)
`ride was exposed to intense light. Peak 4 == pyridine analogue of nicardipine.
`
`I
`14
`
`11
`
`2
`
`Nicardipine
`
`2 3
`
`4
`
`1\
`
`1'o
`
`l
`
`6
`
`~
`8
`
`Time (min)
`
`2
`
`4
`
`120
`
`100-
`
`80-
`
`60-
`
`40-
`
`20
`
`s
`<(
`_§,
`
`(!)
`
`(,) c
`ctl
`..0
`0
`CJ)
`..0
`<C
`
`1702 Am] Health-Syst Pharm Vol 53 JullS 1996
`
`Sandoz Exhibit 1006 Page 2
`
`

`

`tions in 0.5 M hydrochloric acid or 0.1 M sodium
`hydroxide or 5o/o hydrogen peroxide, each heated to
`reflux for at least three hours; a solution in water stored
`at 75 oc for 10 weeks; and exposure to intense fluores(cid:173)
`cent light (1000-2000 foot-candles) for 10 weeks. Expo(cid:173)
`sure to these conditions resulted in a total of four major
`chromatographic peaks, all of which were resolved
`from the peak for the analyte (Figure 1). Exposure to
`intense light produced only one major degradation
`product, the pyridine analogue of nicardipine (peak 4
`in Figure 1; Figure 2). Exposure to hydrogen peroxide
`led to peak 1 in Figure 1; exposure to hydrochloric acid
`led to peak 3 and other, smaller peaks; exposure to
`sodium hydroxide resulted in peaks 1-3; and exposure
`to heat resulted in all four peaks.
`Linearity of the assay was demonstrated for five nicar(cid:173)
`dipine concentrations ranging from 0.025 to 0.075 mg/
`mL (correlation coefficient, >0.9999). Three analysts us-
`
`Figure 2. Structures of nicardipine hydrochloride (top) and 2,6-di(cid:173)
`methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2-
`[methyl-(phenylmethyl)amino]-ethyl ester, the pyridine analogue
`(bottom).
`
`Nicardipine hydrochloride Reports
`
`ing three separate chromatographic systems on three
`days achieved accuracies (recoveries) of >99o/o and rela(cid:173)
`tive standard deviations within days for a single analyst
`of <0.8o/o and overall (between days) of <1.2%.
`Stability was defined as the retention of at least 85o/o of
`the initial concentration of nicardipine hydrochloride.
`
`Results and discussion
`Precipitation occurred in the admixtures of nicar(cid:173)
`dipine hydrochloride in sodium bicarbonate injection
`immediately after their preparation. The other admix(cid:173)
`tures remained clear and slightly yellow throughout the
`study period, except for nicardipine hydrochloride in
`lactated Ringer's injection, which decreased in optical
`density at 400 nm over time. The pH of all the solutions
`remained unchanged (initial pH, 3.4-5.9, with 0.5-mg/
`mL solutions being 0.3-0.8 pH unit less than 0.05-mg/
`mL solutions).
`Absorbance readings were unchanged during the
`study (at 600 nm, absorbance was -1.2 and -0.2; at 400
`nm, 0).
`The HPLC results indicated that no significant
`change in nicardipine concentrations occurred in the
`glass containers (Table 1). Admixtures in PVC contain(cid:173)
`ers showed a slow, constant decline in nicardipine
`concentrations except for lactated Ringer's injection
`solutions, which showed a rapid decrease. No evidence
`of degradation was detected in any solution stored in a
`PVC container, suggesting that drug loss in some solu(cid:173)
`tions was due to adsorption of the drug to rvc.
`
`Conclusion
`Nicardipine hydrochloride 0.5 and 0.05 mg/mL in
`eight i.v. solutions was stable in glass containers for up
`to seven days under fluorescent light. Concentrations
`of nicardipine hydrochloride slowly decreased in PVC
`containers} sometimes to less than 85%> of the initial
`drug concentration within 24 hours. Nicardipine hy(cid:173)
`drochloride was not stable in 5% sodium bicarbonate
`injection or in PVC bags containing lactated Ringer's
`injection or 5% dextrose and lactated Ringer's injec(cid:173)
`tion.
`
`aB-D Plastipak, Becton Dickinson and Company, Rutherford,
`N].
`bMcGaw Laboratories, Irvine, CA, lot B6D06SC (glass), and
`Travenol Laboratories, Inc., Deerfield, IL, lot 9C016A8 (polyvinyl
`chloride [PVC]).
`'Travenol, lot C004085 (PVC).
`ciMcGaw, lot BSB083A (glass), and Travenol, lot OC020H3
`(PVC).
`cMcGaw, lot G761502 (glass), and Travenol,lot C026930 (PVC).
`fKendall-McGaw, lot ]7K002B (glass), and Travenol, lot
`9C018R8 (PVC).
`gKendall-McGaw, lot B6C009B (glass), and Travenol, lot
`C036590 (PVC).
`11Kendall-McGaw, lot BSD077 (glass), and Travenol, lot
`C033001 (PVC).
`iTravenol, lot G770289 (glass).
`iTravenol, lot G764829 (glass).
`
`Vol 53 Jul 15 1996 Am J Health-Syst Pharm 1703
`
`Sandoz Exhibit 1006 Page 3
`
`

`

`Reports Nicardipine hydrochloride
`
`Table I.
`Stability of Nicardipine Hydrochloride in Various I.V. Solutions in Glass and
`Polyvinyl Chloride (PVC) Containers
`
`Solution and
`Container Type
`
`5% Dextrose and
`0.45% sodium
`chloride injection
`Glass
`
`PVC
`
`5% Dextrose and
`0.9% sodium
`chloride injection
`Glass
`
`PVC
`
`0.45% Sodium
`chloride injection
`Glass
`
`PVC
`
`5% Dextrose and
`lactated Ringer's
`injection
`Glass
`
`PVC
`
`5% Dextrose injection
`Glass
`
`PVC
`
`0.9% Sodium chloride
`injection
`Glass
`
`PVC
`
`Lactated Ringer's
`injection
`Glass
`
`PVC
`
`5% Dextrose injection
`with potassium
`chloride 40 meq/L
`Glass
`
`PVC
`
`Initial Concentration (mg/ml)
`Actual a
`
`Nominal
`
`24 Hours
`
`% Initial Concentration Remaininga
`48 Hours
`
`72 Hours
`
`7 Days
`
`0.5
`0.05
`0.5
`0.05
`
`0.5
`0.05
`0.5
`0.05
`
`0.5
`0.05
`0.5
`0.05
`
`0.5
`0.05
`0.5
`0.05
`
`0.5
`0.05
`0.5
`0.05
`
`0.5
`0.05
`0.5
`0.05
`
`0.5
`0.05
`0.5
`0.05
`
`0.5
`0.05
`0.5
`0.05
`
`0.45, 0.44
`0.043, 0.043
`0.47, 0.44
`0.042b
`
`0.46, 0.46
`0.045, 0.046
`0.45, 0.45
`0.043, 0.043
`
`0.44, 0.45
`0.044, 0.044
`0.45, 0.45
`0.043, 0.043
`
`0.47, 0.50
`0.047, 0.045
`0.44, 0.43
`0.044, 0.043
`
`0.46, 0.46
`0.046, 0.047
`0.46, 0.46
`0.044, 0.048
`
`0.46, 0.47
`0.045, 0.046
`0.45, 0.44
`0.038, 0.043
`
`0.47, 0.47
`0.044, 0.044
`0.44, 0.45
`0.041, 0.040
`
`0.47, 0.47
`0.045, 0.046
`0.47, 0.48
`o.osb
`
`1 00.6, 101.2
`100.7, 100.6
`97.1, 99.2
`98.5, 99.5
`
`99,11 99,5
`1 00.1, 100.0
`94.9, 96.6
`97.2, 97.9
`
`96.5, 96.8
`99.5, 99.2
`91.2, 92.7
`95.5, 95.8
`
`100.2,101.6
`99.4, 98.8
`88.2, 100.9
`92.5, 93.0
`
`99.3, 99.5
`100.4, 99.6
`97.9, 98.8
`98.6, 97.4
`
`99.8, 100.1
`99.1 I 99,1
`98.11 98,1
`97.11 96.5
`
`99.3, 100.4
`99.0, 97.6
`98.2, 98.1
`95.5, 95.1
`
`99.5, 99.6
`99.6, 98.3
`96.5, 97.2
`94.0, 93.1
`
`99.3, 98.1
`99.8, 99.5
`98.1, 97.3
`90.8, 89.1
`
`100.9, 100.8
`100.3, 99.3
`99.2, 98.3
`87.5, 87.9
`
`10i.O, 100.5
`100.1, 99.3
`99.11 97.8
`86.0, 91.2
`
`100.5, 100.4
`99.1199,0
`97.4, 102.0
`81 .4, 84.1
`
`99.6, 96.8
`97.8, 100.2
`92.5, 93.0
`89.8, 88.2
`
`97.5, 96.9
`100.4, i00.8
`96.8, 97.6
`96.0, 86.6
`
`97.9, 93.3
`98,11 99.2
`88.4, 86.7
`82.9, 81.8
`
`99.0, 99.0
`i00.9, 100.3
`95.9, 95.7
`93.9, 85.6
`
`100.11 93.6
`96.7, 99.6
`85.8, 85.8
`78.4, 75.7
`
`97.9, 98.1
`100.9, 99.9
`95.1, 95.3
`92.6, 84.7
`
`99.4, 93.0
`96.5, 98.4
`76.6, 77.6
`65.8, 62.7
`
`98.3, 97.7
`100.2, 99.6
`93.7, 95.2
`90.0, 82.1
`
`97.4, 97.8
`101.1, 99.6
`98.9, 99.3
`1 1 0.8, 96.1
`
`98.9, 99.2
`99.7, 100.8
`97.2, 98.0
`108.5, 94.2
`
`97.4, 98.4
`1 00.2, 100.0
`97.4, 97.7
`107.3, 92.5
`
`98.7, 99.4
`100.4, 99.5
`96.2, 95.9
`102.0, 87.7
`
`100.3, 100.5
`98.4, 99.0
`85.5, 85.4
`58.1 I 58.5
`
`99.8, 99.7
`95.5, 96.8
`79.5, 79.9
`43.5, 42.8
`
`1 00.0, 99.4
`98.6, 99.1
`75.2, 74.3
`34.8, 35.7
`
`98.6, 98.3
`99.5, 100.0
`62.9, 62.1
`19.1, 19.8
`
`99.6, 100.2
`96.6, 100.9
`99.4, 95.4
`92.5, 93.1
`
`98.9, 99.5
`1 00.8, 101.4
`98.4, 93.6
`89.6, 87.5
`
`98.5, 98.9
`101.0,101.2
`97.0, 94.4
`90.2, 91.0
`
`98.3, 98.9
`99.4, 100.0
`96.4, 92.6
`87.4, 87.0
`
`8 Reported as individual values.
`bSecond value not obtained because of technical error. Alternate-container initial value used for calculation.
`
`k2 meq/mL, 30-mL vial, Elkins-Sinn Inc., Cherry Hill, NJ, lot
`065078.
`1Travenol, lot 764803 (glass).
`mTravenol,lot C032631 (PVC).
`ncardene, DuPont Merck Pharmaceutical Company, Wilming-
`ton, DE, lots 287-1-lB, 287-3-16, and Z86-3-S.
`0Spectronic 20, Bausch & Lomb, Rochester, NY.
`PModel 3560 digital pH meter, Beckman Instruments, Inc.1 Irv-
`ine1 CA.
`
`qSystem 2/2, Perkin-Elmer Corp., Norwalk, CT.
`rwiSP, Millipore Corp., Milford, MA.
`5LC 75 or LC 90, Perkin-Elmer.
`1Model 285/mm, Scientific Products, McGaw Park, IL.
`uMultichrom, VG Laboratory Systems, Ltd., Atrincham,
`Cheshire, England.
`vpartisil ODS-3, 5 J.Lm, 4.6 mm x 25 em, Whatman Inc., Clift-
`on, NJ.
`wMallinckrodt, Inc., St. Louis, MO.
`
`1704 Am] Health-Syst Pharm Vol 53 JullS 1996
`
`Sandoz Exhibit 1006 Page 4
`
`

`

`x;. T. Baker, Inc., Phillipsburg, NJ.
`YBurdick & jackson, Inc., Muskegon, MI.
`2Nicardipine hydrochloride, DuPont Critical Care, Waukegan,
`IL,lot W85-9-20.
`
`References
`I. Halpern NA, Colucci RD, Alicea Metal. The compatibility of
`
`nicardipine hydrochloride injection with various ICU medica(cid:173)
`tions during simulated Y-site injection. Int J Clin Pharmacal
`Ther Toxicol. 1989; 27:250-4.
`2. Halpern NA, Colucci RD, Alicea Metal. Visual compatibility of
`enalaprilat with commonly used critical care medications dur(cid:173)
`ing simulated Y-site injection. Int J Clin Pharmacal Ther Toxicol.
`1989; 27:294-7.
`
`Nicardipine hydrochloride Reports
`
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`therapy decisions.
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`or through parallel track protocols
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`answers Wast.
`Monographs are grouped by therapeutic use, so you can locate a drug-or com(cid:173)
`pare and evaluate information on an entire class of drugs-quickly and easily.
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`mon synonyms and classes of drugs.
`Advice *rom leading authorities provides the
`perspective you need.
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`mendations from leading health authorities such as the National Institutes of
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`price if you aren't completely satisfied with AHFS Drug Iriformation®.
`*Free shtppt11g within the U.S. and Ca11ada
`
`,--------------------------------------------~
`
`Order today!
`
`0 $125 Inside the U.S.
`0 $125 ** Canada
`0 $205 * Outside the U.S.
`and Canada
`•:•
`Includes $80 air delive!J• cbarge.
`':":'Does not include surcbargefor Canadian GST ami brokerage fee; call ASHP Customer
`Service for details.
`
`0 $70 Students
`0 $70 ** Canadian students
`0 $150 *Student Outside the U.S.
`and Canada
`
`Quantity discounts available. Master volume available without
`updates.
`
`For more information or to place your order, call ASHP Customer Service,
`301-657-4383.
`
`©1995 American Society ofHealth-System Pharmacists
`
`Code 220077
`
`Vol 53 Jul 15 1996 Am J Health-Syst Pharm 1705
`
`Sandoz Exhibit 1006 Page 5
`
`