Reports Ganciclovir sodium and amino acids

«MiIliporc GVWI' filter, Millipore, Bedford, M.A 017,A0, lot sodium in 5'!!. dextrose or 0.9'.';) sodium chloride i niections. Am
HINM 94283. I HospPluinn. 1986; 43:2810-2.
''Hypoxanthine, Sigma Chemical, St. Louis, MO 63178, lot Silvestri .-M', Mitrano FP, Baptista RJ. Stability and compatibility
69l'0231.
of ganciclovir sodium in S'Ki dextrose injection over 35 davs
'Millex GV filter, Millipore, lot HINM94494. Am I Hasp Pluirm. 1991; 48:2641-3.
iAnalytical-grade ganciclovir sodium, Svntex Laboratories, . 6. Parasrampuria J, Li LC, Stelmacb AH et al. Stabilitv of ganciclo­
Palo Alto, CA 94304, lot 680-103. '
vir'sodium in 5'!;. dextrose injection and in 6.9".," sodium
'~Pico Tag amino acid analysis system, Waters. chloride injection over 35 davs. Am / Horn Pharm 1992-
49:116-8. • " • •
References
Anon. Pico lag amino acid analvsis svstem operator's manual
1. Syntex l,aboratories. Inc. Ganciclovir package insert. Palo Alto Milford, MA: Waters: 1986.
CA; 1989 Jan. Wade CS, Lampasona \', Mullins RL et al. Stability of ceftazi­
2. Maksym Cj. Compatibility and administration of intravenous dime and amino acids in parenteral nutrient solutions. Am I
medications with parenteral nutrition solutions. Purcnh-uth Hasp PImnn. 1991; 48:1515-9.
1989; 7(5):l-8, Outman WR, Mitrano I P, Baptista RJ. Visual compatibility of

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3. Trissel LA. Handbook on injectable drugs. 6tb ed. lietbesda, ganciclovir sodium and total parenteral nutrient solution dur­
MD: American Society of Hospital Pharmacists; 1990:350. ing simulated Y-site injection, .liri / Hasp Pluirm 1991-
4. Visor GC, Lin LH, Jackson SL et al. Stability of ganciclovir 48:15.38-9. ' '

Stability of atenolol in an extemporaneously

compounded oral liquid
SANDRA S. GARNLR, DONALD B. WILSL, AND EDWARD R. RLVNOLDS, JR.

Abstract: The stability of and shaken immediately be­ chromatography. or 25 °C and shaken or at 5
atenolol in an oral liquid fore analysis, three were The concentration of or 25 =C and not shaken.
stored for 40 days under vari­ stored at room temperature atenolol remained above 96'H)
ous conditions was studied. (25 'O and shaken, three of the original concentration Index terms: Alcohols, eth­
A liquid preparation of were refrigerated and not . in each vial under each of the yl; Atenolol hydrochloride;
atenolol 2 mg/niL was pre­ shaken, and three were stored four sets of conditions. Mi­ Cardiac drugs; Compound­
pared by triturating 50-mg at room temperature and not crobial growth occurred in a ing; Diluents; Incompatibili­
atenolol tablets with a com­ shaken. One sample from few cultured samples, and pH ties: Polyethylene glycol
mercially available oral dilu­ each vial was assayed in du­ changed minimally. 8000; Saccharin; Solutions:
ent. Twelve 30-mL portions plicate on days 0, 15, 30, and Atenolol 2 mg/ml. in an Stability; Storage
in vials were prepared. Three 40 by stability-indicating oral liquid was stable for up Am J Hosp Pharm. 1994;
vials were refrigerated (5 'C) high-performance liquid to 40 days when stored at 5 51:508-11

B eta-adrenergic blocking agents are useful in the

prevention of supraventricular and ventricular
arrhythmias in pediatric patients. Even though
propranolol is most commonly used, atenolol offers the
advantages of a longer half-life, cardioselectivity, and
age form of atenolol is tablets in 25-, 50-, and lOG-mg
strengths. Because stability data for a liquid formulation
are lacking, pharmacists and parents must compound
each dose just before administration to infants and tod­
dlers. If the stability of atenolol in an e.xtemporaneously
lower lipid solubility. These properties may result in compounded liquid were known, a bulk supply could be
greater compliance, since the drug can be administered made and stored for an e.xtended period.
only once or twice daily, and fewer adverse effects.' "' This study was designed to determine the stability of
Currently, the only commercially available oral dos­ atenolol in a commercially available oral diluent over 40

SANDRA S. GARNKK, PHARM.D., is Assistant Professor of Clinical

University of South Carolina, 171 .-Ashlcv .Wenue, Charleston SC
Pharmacy and Instructor in Pediatrics and DONALD B. Wii.sr 29425.
PIIARM.D., is Associate Professor of Clinical Pharmacv and Instruc­
Presented at the American College of Clinical Pharmacv Annu­
tor In Pediatrics, Colleges of Pharmacv and Medicine, Medical al Meeting, Reno, NV, August 18, 1993.
University of South Carolina (MUSC), Charleston. LDWARD R.
RLYNOI.D.S, JR., IS a Pharm.D. degree candidate. College of Phar­
macy, MUSC. Copyright © 1994, American Society of Hospital Pharmacists,
Inc. All rights reserved. 0002-9289/94/0202-0508501.00.
Address reprint requests to Dr. Garner at CSB-219, Medical

508 Am J Hosp Pharm Vol 51 Feb 15 1994

 Atenolol Reports

days tinder various conditions. and discarded, and the organic layer was transferred to a
test tube and evaporated to dryness at 45 X under a
Methods stream of nitrogen. The residue was then dissolved in 200
Preparation of the liquid. .A liquid formulation of pL of 0.05 M sulfuric acid^ to prtxluce a theoretical
2-mg/mL atenolol was prepared by using a ceramic mor­ atenolol concentration of 2 pg/mL. The sample was
tar and pestle to triturate si.x 50-mg atenolol tablets' with mixed> for 15 seconds before a 30-pL volume was inject­
59 ml of flavored oral diluent containing 1% ethanol ed onto the column. The pH of the atenolol liquid was
and 0.05% saccharin in a cheny-flavored 33% polyethyl­ measured on days 0 and 40.
ene glycol 8000 base.'' The liquid was poured into a 250- Standard cairves were constructed by using analytical-
mL flask. The mortar and pestle were rinsed with two grade atenolol" at concentrations of 0.5, 1.0, 1.5,2.0, and
50-mL volumes of oral diluent, which were poured into 2.5 Pg/mL. Standards were assayed in duplicate just
before sample analysis, and the ratios of the peak areas

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the flask to yield a final volume of 150 ml. This proce­
dure was repeated three times. (An alternative method is for atenolol to those for the internal standard were
described in the appendix.) Each of the four flasks was analyzed by linear regression. The atenolol standard
placed on a mechanical wrist-action shakeb and agitated curves were linear over the concentrations investigated
for 15 minutes, at which time pH*^ was determined. Pjch (correlation coefficient, ^.99 for each test day). Stan­
flask was shaken again for three minutes, and three 30- dards were also assayed after sample analysis to ensure
mL samples were transferred into 2-oz amber glass vials.' reproducibility of results. The mean ± S.l"). between-day
The 12 vials were equally distributed to one of four and within-day coefficients of variation for the assay
storage conditions; (1) refrigerated (5 X) and shaken were 4.45 ± 2.39')ii and 2.15 ± 1.59'Hi, respectively.
immediately before sampling, (2) room temperature (25 To establish that the assay was stability indicating,
X) and shaken, (3) refrigerated and not shaken, and (4) samples of the atenolol reference standard were exjxised
room temperature and not shaken. One 500-pL sample to acidic and basic conditions, frozen, and heated. One
was removed from each vial and assayed in duplicate for milliliter of hydrochloric acid'' was added to a 30-mL
atenolol concentration on days 0,15,30, and 40 by high- sample of atenolol 2.5 pg/ml. to reduce the pH from 3.70
performance liquid chromatography. Vials stored under to 0.67. After storage for 2.5 hours at room temjx'rature,
conditions 1 and 2 were shaken for five minutes by the potassium hydroxide solution'" was added to increase
mechanical shaker just before sampling. the pH to 3.52. A second 30-mL sample of atenolol was
High-performance liquid chromatographic alkalinized to pH 12.03 with 1 ml, of fKitassium hydrox­
(HPLC) analysis. The HPLC assay was similar to that ide solution. After storage for 2.5 hours at nxnn tenqu'r-
described by Urech et al.^ The HPLC system included a ature, hvdrochloric acid was added to reduce the pH to
pump,' autosampler,"^ C,,, guard insert." C,^ cartridge (5.0 3.54. A third 1-mL sample of atenolol was stored in a
X 1(X) mm),' variable-wavelength ultraviolet light absor- freezer (-10 X) for 14 hours, while a fourth lO-ml,
bance detector' set at 226 nm with an absorbance-range sample was heated in an oven at UX) C for three hours.
setting of 0.02, and an integrator-chart-strip recorder.'' Five hundred microliters of each sample was then added
The mobile phase consisted of 10 mM phosphate to 500 pL of the internal standard. A 5(X)-pL sample of
buffer,' adjusted to pH 3.2 with 0.2 M phosphoric acid,"' atenolol reference standard 2.5 pg/ml was also com­
and HPLC-grade acetonitrile" (4:1 v/v) containing 3 mM bined with 500 pL of the internal standard to serve as a
1-octanesulfonic acid," The mobile phase was filtered control. The retention times for atenolol and the internal
and degassed by sonication under vacuum'' and deliv­ standard were 3.70 and 5.56 mimites, resjxxtively. The
ered at a flow rate of 1 niL/min, The extraction buffer was samples subjected to acidic and basic conditions pro­
a saturated solution of sodium tetraborate'' adjusted to duced extra peaks that were not obserx ed in the control,
pH 9 with hydrochloric acid.'The extraction solvent was heated, or frozen samples (Figure 1): therefore, the HPLt",
a mixture of HPLC-grade dichloromethane' and isopro- assay was stability indicating.
pyl alcohol' (3:1 v/v). The internal standard was analyti­ The initial concentrations of atenolol in the samples
cal-grade sotalol" 2.5 pg/mL. (day 0) were designated UXXlii. Concentrations measured
From each sample, 500 pL was diluted to 20 mL with on subsequent days were expressed as a percentage of the
HPLC-grade water' to yield a theoretical atenolol con­ initial concentration. .Stability was defined as the reten­
centration of 50 pg/mL, Then 800 pL was further diluted tion of at least 9(XHi of the original concentration.
to 10 mL to produce a final atenolol concentration of 4 Microbial analysis. To test for microbial growth, a
Pg/mL. Each sample was prepared by adding 100 pL (0.4 50-pL sample from each vial was plated onto chocolate
pg) of the final dilution with 100 pL of the internal agar medium" on days 0, 15, 30, and 40 and incubated
standard, 100 pL of the e.xtraction buffer, 500 pL of for 24 hours at 35.3 C in a 7.5"e carlmn dioxide
HPLC-grade water, and 5 mL of the extraction solvent to atmosphere."'
a glass test tube. Each sample was then agitated with a
mechanical shaker for five minutes and centrifuged" at Results
800,j for three minutes. The upper layer was aspirated The concentration of atenolol remained above 90"ti of

Vol 51 Feb 15 0594 Am I Hosp Pharm 509

 Reports Atenolol

the original concentration for each vial under each set of Although sediment formed in the vials, it seems
conditions (Table 1). The mean pH values for the four unlikely that this was due to precipitation of atenolol.
suspensions on day 0 were 3.99 (5 °C and not shaken), Atenolol has a solubility of 26.5 mg/mL in water at 37
4.21 (25 °C and not shaken), 4.16 (5 °C and shaken), and However, atenolol tablets contain insoluble excip-
3.99 (25 °C and shaken). The mean pH values on day 40 ients, including magnesium stearate, microcrystalline
were 4.23 (5 °C and not shaken), 4.30 (25 °C and not cellulose, povidone, and sodium starch glycolate.'-® This
shaken), 4.27 (5 °C and shaken), and 4.23 (25 °C and suggests that the atenolol 2-mg/mL liquid is actually an
shaken). Microbial growth was seen in a few of the atenolol solution and that the sediment consists of insol­
cultured samples (Table 2). Sediment formation was uble excipients; agitation before administration is proba­
observed in each vial. bly not necessary.
Discussion
Microbial growth was seen in some cultures of the
atenolol samples. Since the compounding took place

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In pediatric patients with a diagnosis of supraventric­ under conditions simulating a community pharmacy
ular tachycardia, 30-40% are diagnosed in the first few setting and not under sterile conditions, the microbial
weeks of life.® A liquid formulation of atenolol that has growth may have resulted from the preparer's technique.
an acceptable dosage volume is essential if atenolol is to Even though the correlation coefficient for the assay
be used as a therapeutic agent in this age group. Because and the between-day and within-day coefficients of vari­
a dosage of 1 mg/kg/day has been reported to be effec­ ation were acceptable, variability^ was evident in both the
tive in children with supraventricular tachycardia,^ a 2- initial and subsequent concentrations. Human error dur­
mg/mL atenolol liquid was formulated to allow a dosage ing the multiple dilutions involved in preparing samples
volume of 0.5-15 ml for patients weighing 1-30 kg. and during the extraction procedure probably contribut-

Flgure 1. Chromatograms of atenolol (peak 1) and sotalol internal standard (peak 2) initially (A), after exposure to pH 12 03 for 2 5 hours at 25 'C
(B), and after exposure to pH 0.67 for 2.5 hours at 25 °C (C).

a
s
0

s
c
1
s
.Q
<

Jli J
° 3 4 I a

Time (min)

Table 1.
Stability of Atenolol 2 mg/mL in Oral Liquid"

% Initial Concentration Remaining

Actual Initial Concentration
Storage Conditions (mg/mL) Day 15 Day 30 Day 40
5 °C, stiaken" 2.34 ± 0.15 97.5 ± 12.4
25 °C, shaken 99.4 ± 10.8 97.4 ± 6.5
2.06 ± 0.13 101.6 ±6.6 99.8 ± 3,0 108.8 ± 2.3
5 °C, not shaken 2.25 ± 0.03 96.7 ± 6.4
25 °C,not shaken 96.6 ± 3.2 101.2 ±3.5
2.32 ± 0.03 93.7 ± 0.6 92.7 ± 1.9 102.5 ± 2.8
® Values expressed as mean ± S.D. of three determinations.
® Shaken for five minutes immediately before sampling.

510 Am J Hosp Pharm Vol 51 Feb 15 1994

 Atenolol Reports

Table 2. son vacuum pump. Fisher Scientific. Fair Lawn.

Microbial Growth In Atenolol 2-mg/mL Oral Liquid iSodium tetraborate. Sigma, lot 81H0291.
'Flydrochloric acid. Fisher Scientific. Fair fjvvn. lot 862476.
No. Colonies per 50 ;iL of Suspension 'Methylene chloride. Chempure. Curtin Matheson Scientific
Inc.. Houston, T.K 77251. lot M088 KE5C.
Stoi^ge Day Day Day Day 'Isopropyl alcohol. HPLC grade. Chempure. Curtin Matheson
Concfitions 0 15 30 40 Scientific, lot Ml64 KEJG.
5 °C.shaken^ "Sotalol, Bristol-Myers Squibb, Princeton, NJ 08543. lot 017.
Vial 1 0 0 0 0 'Water. HPLC grade. Mallinckrodt Specialty Chemicals Co.,
Vial 2 0 0 0 1 Paris, KY 40361, lot 6795 KHAL.
Vial 3 0 0 0 0 "Dynac II centrifuge. Clay Adams Division of Becton Dickin­
25 °C. shaken son & Company, Parsippany. NJ 07054.
Vial 1 0 3 0 0 'Sulfuric acid 96%, Suprapur, EM Science. Curtin Matheson
Vial 2 0 1 0 0 Scientific, lot 31156.

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Vial 3 0 0 0 0 'MaxiMix II type 37600 mixer. Barnstead Fhermolyne. Du­
5 °C. not shaken buque, L-\ 52001.
Vial 1 0 0 0 0 'Atenolol powder. ICI Pharma. lot 111H0429.
Vial 2 0 0 0 0 "Flydrochloric acid. Fisher Scientific. Fair Lawn, lot 851469.
Vial 3 0 0 0 1 '•'Potassium hydroxide 1 iV solution. Fisher Scientific. Fair
25 °C. not shaken Lawn, lot 890326-24.
ViaJ 1 0 0 0 1 "BBL prepared medium Choc II, cat. no. 21169/21267, Becton
Vial 2 0 0 0 0 Dickinson Microbiology Svstems. Becton Dickinson. Cockes-sville,
Vial 3 - 0 0 0 0
MD 21030, lot L3RLLP.'
^ Shaken for five minutes Immediately before sampling. "•Model .3956. Forma Scientific, Nfallinckroslt Inc., Marietta.
OH 45750.

ed to the variability'. Because of this pratential variability References

in atenolol concentrations, close monitoring of the pa­ 1. Buck ML, Wiest D. Gillette PC et al. Pharmacokinetics and
pharmacodynamics of atenolol in children. C/i» Pluinniuvl
tient's clinical status is warranted. VICT. 1989;46:629-33.
2. Trippel DL. Gillette PC. .Atenolol in children with supraventric­
Conclusion ular tachycardia. .Im / C.irJiol. 1989: 64:233-6.
Atenolol 2 mg/mL in an oral liquid compounded from 3. Trippel DL, Gillette PC. Atenolol in children with ventricular
arrhythmias. .4m Heart/. 1990: 119:1312-6.
tablets was stable for up to 40 days when stored at 5 or 25 4. Case CL. Trippel DL. Gillette PC. New antiarrhythmic .igents in
"C and shaken or at 5 or 25 ''C and not shaken. pediatrics. PeJUitrClitt S'orth .4m. 1989: 36:1293-320.
5. Urech R. Chan L. Duffy P. Fligh-performance liquid chromato­
'Tenormin. ICI Pharma, Wilmington. DE 19897, lot AF659. graphic assay of sotalol: improved procedure and investigation
•"Diluent (flavored) for oral use, Roxane Laltoratories, Inc.. Co­ of peak broadening. / C/iromatogr. I960: 534:271-8.
lumbus, OH 43216-6532, lot 900929. 6. Till J.A. Shinebourne E.A. Supraventricular tachycardia: diagruv-
"Afodel 75 wrist-action shaker, Burrell Corporation. lYttsburgh. sis and current acute management. ,trc/i Dis ChiU. 1991:
PA 15219. 66:647-52.
'•.Accumet pH meter 915, Fisher Scientific, Pittsburgh, PA 7. AHFS drug information 93. McEvoy GK. ed. .Atenolol. Bethesda.
MD: American Society of Hospital Pharmacists: 1993:916.
15219.
'Owens-Brockway, Inc., Brocksvay, PA 15824. lot A0201. 8. ICl Pharma. Tenormin package insert. Wilmington. DE: 1991
'Model 510 solvent delivery svstem. Waters .Associates. Milford, Aug.
MA 01747.
«Model 712 WISP, Waters. Appendix—l>roc«dura for compounding atenolol
hNovapak C,g Guard-Pak. Waters. 2-mg/mL oral liquid
'Novapak C,j Radial-Pak cartridges, Waters. 1. Place five l(K)-mg atenolol tablets (Tenormin. ICI Pharma) in a
'Lambda Max model 481 LC spectrophotometer. Waters. mortar.
•"Nfodel 745 data module. Waters. 2. Crush and grind the tablets to a fine powder with a pestle.
'Potassium phosphate, Sigma Chemical Co., St. Louis. MO 3. Slowly add 50 ml. of oral diluent containing I'ki ethanol and
63178, lot 121H0372. 0.05'Ni saccharin in a cherry-tlavored 33'S' (Kilyethylene glycol
•"o-Phosphoric acid 85%, HPLC grade. Fisher Scientific. Fair 8000 base (diluent [tlavoredj for oral use. Roxane Laboratories)
Lawn. NJ 07410, lot 902543. and triturate the posvder to a fine paste.
"Acetonitrile, HPLC grade. Fisher Scientific, Fair Lasm, lot 4. .Add 200 ml. of the oral diluent to the mortar in three equal
903986. portions, thoroughly mixing after each dilution.
"l-Octanesulfonic acid, Sigma, lot 40HS614. 5. Pour 240 ml, of fhe 250 ml. into an 8-o/. prescription Ixittle and
PModel FS-14 ultrasonic equipment and model S/N 0490 Emer- label with an expiration date of not more than 40 days.

Vol 51 Feb 15 1994 Am J Hosp Phatm 511