.' ..LM 1! .

    

      

                    

pkg}. 1.
111.1

1 .. F. .
. .. . 1. . .. “1. 1. ..NZ . .1. . I . .....11H11111.M.mw.1. . .
1.11%WHM1 K11111§H1¢§1§flm1 (H.141

 

         

 
      

     

         

.1 11111.11. 1 .11 . ..., J.\ 1
, u. 11.. . 1n11...r. 1. ......1. . 11.111.111.111...1 1.11m 111...... 111111111 . .
1.1.11 .1 .. $1.11.. . 11.. . 1 .1. .4. .111V11011fi111\ 1....“ 1111.11 1 . 11.
...UM1111M141 u..~.. “mug m:un.11h«wrmnw.1a.u1 .Igfimgwrfimn {suannmu . .
I . .1 w 11 111k. .... . ...1. 1.1111111"11 11.111.111.111h1111n1111}. . . “111.11.111‘1n11111fi1 . fthnfir‘i. 1... .11 . 1r .

. .1... 1| . 11111.. {1111113111149 ““1111. 1.11 1h“. . .111 111”“; .. . a. . 111.1"111...
. ,. .. ...r . 1P1H1Wn1mwmmmv+fldyn gsumhfirmhwflfiwg.d .1. firfiuflnmfiu . . 1. .1...
.....111 .. 1.1.F1ww1M1m. W11 . 11.. 11.1.11w1.... ..1...,.1.111....w111d1.1..1...H1nn11.111111fiw “11.441.111.141buflmflnnuWM11. RN11. . .

      

                           
       

1 4. . 1.1 . .
$111.11.. 1 11
11.1.1 L111 . wflf. flan—... 1.1. 1
hWrunfthfl.1|UuJflmWWufirl¢rq.u17. 1 1.3«hm1lu111. 1.1.”
. 1%. 1111”.” .1.1h~.v..11..111111.r11111ndll1.11n.v111 15wm4§.31%11 .
14 .xufiule‘mw./\.’I1 11511.11 ”wunmnrhflmbq .1..1...Iv1111.11.1. flaunt. 41‘...
11....11m....11111111\11m..1111.s1§ . 1 1.1. 111.13%... -

11,.

1 1.1
‘1. -:

‘31”.

3‘52

" v
A‘ ‘r 1
111., 1
A?

1

I

1

.1

1

1111.

{g

             

        
   

 

  

. .1... . .1 1.111... 111.111.} . 5115.11 1
11.. 1 1 ifigvflv 551111111 16.1. 13%.
.1 . . 211.1... 1 11. . . 1., 1H... ..111fl1... . . 1 1.1 1.11.1111 1.1.1.11. L1L1fl...u.wnm .nvflnwbénvuTfir hfiflggflvfin 1 1 .
h 1 . .131“ .kfiLnW.!.Pm1h . 1.1 gmmn. 1.11.1 :11. 1.3.11 1.111111111411311“... TlWWWWWMPNWvV.i1H¥JP111iJI .....11.11.1..1...I 11.11.111.11. lawmanui. .
...! 111111.111. 1.1 “14.1., .111 .11.1fl11n.11.lu.. 11.1....h11111h11..1. . “Bur; 11¢... 10:11... .ELWPSWA“\:{anginflrqnmflbqinmhmx .. .
1011P1J4u11m ..1.m1flm.u11m1wnlm1m1wa ,. 11uwn1ur1m1nlvhp111111111pfuhur. 1.1111Hw1 1.1nhHMWnWW1111N.I§In1\KWHHH§HNWHAH11 11.1.1.1 4111.11.11 1111u.um.h11l . .1... ,1. . . .
1. 1.le 11 .1111. ow. , 11 ..1 1111.. 1.111111 111.3 11.161- n111<1.u. 111.1111 11111. 11110111 11131101 .11I1um1111u 11110111111111
1 41111.1. 1.1...

11 1 I “1141Mfi. 1. .1..1.h1..11.l.11hh|. (Fla. 1.1... 1.. 11.111.111.11 #1111111...” 1111111 103a" 11. .
51¢.111M1V11vm1w11u. 1.11.1.1 . 8.11m .phhu1ux1101m1n1111u1urm1rvb £11.... “vii‘tgfiflmpfi Nu..1.1.11.11Wh.11r.4..1w111n ...1u..Hl..i1.1 11mm“. 11.11 1..”.
1 . I 1 . 1 “.1" -‘ I’ll-filrll II ’4'. .

. . . 1 1 .flhMfiumh‘JlAnHHVULNHQMHl . . . .1
L111 .1Jl.h1u11111nl1v111a1w1dh1h.1.¢kunlfl%1111 1
1LLHCAMWKW1WMIF. 11.
. 11.1..1 . 1
11MB. 1.."...th .

. . . 11 {Enhhhukwlhdn11131 11.1,

. 1 , . 1. .... Emirhul. 1%”4hgg1fi1mflffilfimmffifim

. 1 1.111.111.11. .U111T. uWimW 1...... 11N. .1. M..1m.11..11l1—01.11..1h11111..1.1171 1H1111".1.r.11 . .111”! ., . 11.11.111hfl11 .. I .
. L1111111. 1.14““. 1...! gfifiggvénfifld 111.111.1111....HH111mWW 111.111.111.111. .11h1111111111111111161 11.11.111.111“...

. [(AHMMHWJMJ «....11u111 .11; 1.111.114! .Auhg. 31.111u1unflflwu1um11111.111...4r1..111un1111111.111.1111uww- . .

611111.11,“ 1.91. £11.1Un11g1111111fl. r ..Wfiwflfi .11.”.11, 1%E1114Q1wfliwlh1fiu1115 . .

1." 1mm. 1.. 111.51% -....NLLiPJHMNmeflflw?“ 11thNMMWW1111nM.hW111111rrr1.111.11114
.1J(%1r....111111111 V111"; , . .111 .1111, 111.1

111.0. . ”111.11.111.1hlffl1mu111 fin...“
.1111!fo 11 . .

 
            

   

11'
t

     

  

 

5f...

                       
             

   

 

                     

    

           

«11'
1.1....
‘1
11

1
1
4
1

11.1111 1111\1

                  

11

n1. 1 . .. 4L111®m11111l1m1131hqr1fl1411hh4 «WOV'II

         

 

             

          

          
                    

 

‘11 ‘1. 1.3.111 1 I 1111. V1 £11!) $.11.
1.11.11.11.11. .- , J11... 1.111111111111u1111w1111 1111...... 1
_ .unhVVg. .. .1111. 111.11 . 11 11 ”fihWWJIWmW . . . . .. .1 1.... . .
.ME111MHW .. .. . 1 1 ......1/ 1 1111115.“.VH1Mvawmmfiflflifl. .. . .1 . n1”: Mflufimwiifirj 1111.111... 1
.. 1hr»? .1. . .1 . .. . ... . . 1. .. . 1 « 1W§1§1Qm111¥w11m1 1 . . . .1 1 1.1131111. ”filWEJ‘i .
... 1 ,1 .1 . . (111.. .l1u1...|1|11. “My“. 1nun111-M111uHU1111fl1u1111111Wn. 11 . . 1.51111.) 11.....MN 1|
. ... . “1%.” . .ggf. .111111111111...1.1,. 1H111\.i.l.r1h.11111ul111.1.11111 . .n RINK»... I411“...1111.nw. H1 . . W. .11 1,11 ..
1 1. .. . 1. 1. .. 1 . 1.1111... 1 1.11.111U11111.1.11\nl.111 11 1 n1... 1 1H11:§l.11 11. .11.. . “Nwflvnung 1.. 131111.»! 11.1 1 111111.111 .111»...
. .1 filmé . 1..”111 11H1..1.\.1.u1.l.111111. 1.?fimwuuflm1ww1flhflxnflvfilfiflqfiigitnqul1.1114...1 13.1%“11111 .h11H1 1111111211111
,. dwmy «mufl... inm. 1.1 1...”.511. .11L1mfium11wdflmhfl1Wh1MW3V1Jkamb1mwgzq 111.11%..111111111. .111. 111.14% “11.1“”. 111.
. . . .1 11112191 1 #111”H111.11...11N.111.H11.D111hfl.11.m41..11m14u1fil.4111111111111. 111.1ubfluu1.111.11111.1111n.11111l.11h4.111.111hl 111.1

111. “111.111.111.111. . 1.1..»1111h1M111MMM1P11nNW11111W111111W.1.1nwvnmn1m...1111111.11u1.1.1411
finrfi 1 “1111.11VIN411 11111 1.111111111111111111111111111111. 1.1.1 1111 . 1
11.1“”1 glfi’lrnrlnhfflkfififiw11110111191111.1111111111111.1111.1W111..1WH111111111.11.1 11.11.11.u1r11111.111m.GVN1 1.1. 1 .1

      

                   

    

11.1. . 1111111111mw11u1111v1111na 1.11.11.31.11.wa . ., 1 . . U111}...
$1 .1111“)! 1...“... 11. 1 ..1..... .. . .. .. . .... J1. g11qfl1Vtw1J1uu¢
. . 1 ...1..11..u0m1h11u11..§1

 

 

 

                 
            

   

111111 1Hfl11111111.1n111.1.1.-1w.1. 1..... 11$ 1..1 .. ,
. 1., .Hmmullzufimmflfi 1
13.11. Egg. 131“»): .111... .1
. 1.11.... m. 341... £11111“... “Long 1 .1 .
«1113... 11 111l11..d1¢.L.u111J\11111 $331.1. . 110111.
1111111111M111111111111NM311MWH1W1111W1 . “1.11.1.1... ..1L. . 1.1..
. . 1,1,...1.\11u.1.F1111m.n.11.11«.w1111h1 o... ..hmmnunuanuuw
{1111\qu 11ww11ndfl1uflfluumfl1 1.. \gfimw: 1111 . .1
.1

         

1.11.1111“. 1.1.1.113

. ....111 1111.11. .11 1.4.1uh111.1.1...11..fl).. 111.311.111.111.
. Jagfldfiggé
.1 1141. 1.111111. 1 .1111... 11 [111111.4U111111n1 1.1.
11a? 1111“.” 11.11MN111111111 . . will.
1.111111111111H1111111P. 1.1.1.111.
17.... 1. [Jul 191d§wh
11.111111“. . . 1... I1..11..1qn1.|111n1nll11111.\1111

. 1.111

 

                   
     

 

 

      

 

{”1131N11111." ““1111119111111111 .1h1111 11.1.1111. 141.16.. . 11.1...
...».Rflflflslghuflflaundfilmmnvfiwflm. .1 111%... .

                        

 

      

  

. .. . 11... 1 ER»...

.. .. 1.,1 i1.1%u% We...
.1.va 1.4.1u11w11Lw1
a§1mmummmmn

      

                             

  

11.141.111.11 {0.1111 .11 1.1.1111“ ..
. til. 111119111111? .1m1wl11c111 M111
1111 1 .. .J1.1VM“NTMVMWMWLN1PW§ 1%1n1fl11.
. ..tflqgflhlfimflfifirfl? 11H P101"? 1
. .1111. 11 11141911111111. filfiylfifiknfim1 .111. 11.1

1.1 1..-.
1.1.11 figw 1.11.
.1 1 . 1. 1 d. 1 v

 

        

                   

 

    
          

                                    

        

1.1....w111hudn1

hifimufi. - .11...) 1 .
1111.1..1m111vwwu 1.1.1111? .

        

 

.. N

       

1.1

             

          

  

   

11.1.1 .11... 11191111111?! . . 1w 11.1 111
111 1.. .. «1“»? 1 11111 . 1" 1 . '51.] 1‘ 1,11% 1511‘!!!
"11131“... 111.11. 1.1 1. .1. 4.11%“?! .1 11.1 111.1. 1.11 .. 1.111111 11..
..11..u.1«1111\1.1u.111111..(.u..11.11..) 1. ”#911511“: 4.1”}. . 1 . 1 11 1...... 1 111%” 1 .01..
. . ..1 . . 11. 11 .11 . 1. .1 1 H1111. ‘1.
1 1‘1 .1 113.11“)- .

       

      

1.11”}. . . . . 11. w 1. 1. .1 . . , . . .l 1%.... . M1 hvfi 11mm»!!! “a.
..I 11 . 1 . ,1. .1... 11.111”? .. ....111 . 11. .1 i1% 1 111.11 .1 1 L151 .iggflufi 1151111 in. . .
1.1%....111111111 $£thw1m1hr1wfin111lflvggHWhLNVHWH11m1flrlkhfidmbfl « {WHWEME .i. 1... EM... 1 1.1U.\ . 1. 1.
. . , nun g.kfififi1fi?flll‘fi 111K . . 1a... . .1011. 5311...!» 1 1111.

1113111. 3311111111 .. . RI... ..1. 1 . 13a... . . 1 .1 fill...

 

 

 

111n.11.1wm11 H311... ,. 11.1.1111... 11 .

. him” .11..§111111111. . 11 1%1nvwhmwxfihflnw1n1 . . .
11111111....» ....11111m%111w1111 11.111119

1-11.11.11.11 H1111. . Wgfihw 11h.

     

 

    

“31101.1
1.111711

1 1.
1%“inl11nn1 . “WW 1... 11.13.11.

        

1.111. 1m1uu111..w.11....1u1 "31.1.1.1 M.

. 1' . ‘1 . g. . .QII1H1I1'.H1 -111 .I h. 1
1111.!“ , . 1 1.11%.: 1.11.1.1. 111111.111w11mnn1hr1wku143? WW... 11...“.

, 11111111? .1

       

 

         

   
          

              

 

. . 1 l1 .. H1111. 11“”. . 11.111111. 111... 1.11.1“..1H1oH111
111. . . 1 1. Hm. 11.1111 .11 1.11111u111uv1 1.11. www.muhwupfivm. 111111.11 . n. . 1 ..11\.1 111111111 141%
1.111.119.1143 . . . . .

. 11 ... “MW; . . 1 11.. . 111108113 .Yfiflgx ..
1... 1 1 . , . . 1 . 1 .
111.1111m1...1v11w11 #1:..1W1, 1.1111; 11 .1111, «11.1.1 . .... 1 . Egg ..

1.1.1.]! 11.11.1111

 

     

1.1.1.1.. 1. .11. ....1..r11.. . ... . 1 1 . . .1 ...
11.11.! “I. 1.11 1 . 1.1 1 . . oa
11. 111131111. 1 1 11.4111. .. . . 1 1.1 1 ...1
4111 «11.1.11 1 1% 311.. 114M114. . .

111.111.111.1119111111M111-

 

            

13.

 

 

.13.! “B1”. I 1.1.1.”.«1 .11
Vuuliu‘ill L..- 511.1191:

1 1 .111 1111 2:! {1111111110

1 E11 1 ...

“1» 1.1...11.

 

 

 

 

 

 

ELHESIS
h.

LIBRARY

; Michigan State
University ‘

 

This is to certify that the
thesis entitled

THE DETERMINATION OF THE STABILITY OF
METAPROTERENOL SULFATE INHALENT
SUCCINYLCHOLINE CHLORIDE INJECTION, AND
THIAMYLAL SODIUM INJECTION IN PLASTIC SYRINGES AND
GLASS SYRINGES OR presentedby
VIALS

BARBARA LYNN FRITZ

has been accepted towards fulfillment
of the requirements for

PACKAGING

.7 c/ "'
I f D[ (TM—17L
Dr. ngh E. Lockhart

Major professor

degree in

yr

  

 

NOVEMBER 9, 198A
Date _ _ _ .________

0-7639 Msumn Acfimnr-‘u- A ' F, W “gamma"

 

 

1+

 

 

MSU

LIBRARIES
m

\'

 

 

RETURNING MATERIALS:
Piece in book drop to
remove this checkout from
your record. fifl§§_wi11
be charged If book Is
returned after the date
stamped beIow.

 

 

 

 

THE DETERMINATION OF THE STABILITY OF METAPROTERENOL SULFATE
INHALENT, SUCCINYLCHOLINE CHLORIDE INJECTION, AND
THIAMYLAL SODIUM INJECTION IN PLASTIC SYRINGES
AND GLASS SYRINGES OR VIALS

By

Barbara Lynn Fritz

A THESIS

Submitted to
Michigan State University
in partial fquiIIment of the requirements
for the degree of

MASTER OF SCIENCE
SchooI of Packaging

1984

ABSTRACT
THE DETERMINATION OF THE STABILITY OF METAPROTERENOL SULFATE
INHALENT, SUCCINYLCHOLINE CHLORIDE INJECTION, AND

THIAMYLAL SODIUM INJECTION IN PLASTIC SYRINGES
AND GLASS SYRINGES OR VIALS

By

Barbara Lynn Fritz

The stabiIity of SuccinyIchoIine ChIoride, Metaprotereno]
Sulfate, and ThiamyIaI Sodium was determined. Each drug was repackaged
into plastic syringes and gIass viaIs or syringes and stored for
periods from 30 to 70 days at 4°C, 22°C, and 37°C (ThiamyIaI was
stored onIy at 4°C). Drug degradation was foIIowed by monitoring
active ingredient concentration, pH, cIarity, coIor, weight change,
and steriIity.

It was determined that steriIity, cIarity, and originaI coIor
were maintained throughout the study (except MetaproterenoI--a yeIIow
tinge deveIoped within 45 days storage). Significant weight 1055 was
seen onIy in drug stored in pIastic syringes at 37°C. At 4°C storage,
SuccinyIchoIine maintained USP acceptabIe pH and concentration for
at Ieast 45 days, MetaproterenoI maintained concentration within
acceptabIe Boehringer IngeIheim Iimits for at Ieast 70 days, and
ThiamyIaI potency and pH remained within USP Iimits for at Ieast

I4 days.

This thesis is dedicated to my Ioving husband, Vincent,

in appreciation for his great patience and wisdom.

ii

ACKNOWLEDGMENTS

The generous guidance, patience, and support of Dr. Hugh
Lockhart are gratefully acknowledged. I would also like to thank
my other committee members, Drs. Jack Giacin and Bob Zustiak, for
their input and assistance. A special thank-you is extended to
Drs. Charles Cress and John Gill for their guidance in the
statistical design and analysis of this research.

Thank-you is also extended to Bob Faseske, Director of
Pharmacy at Ingham Medical Center, and Bill Adrian, Director of
Pharmacy at St. Lawrence Hospital, for their thoughts and material
support. I also acknowledge the cooperation and input of the
following companies: Boeringer Ingelheim; Parke, Davis and Co.;
and Abbott Laboratories.

Last, but not least, I would like to extend appreciation
to those whose assistance was of great value to me: Pat Derosa,

Vincent Fritz, Parvin (Heidi) Hoojjat, and Dr. Rick Brandenburg.

TABLE OF CONTENTS

Page
LIST OF TABLES .......................... v
LIST OF FIGURES ......................... vi
INTRODUCTION ........................... l
LITERATURE REVIEW ........................ 3
General Background ...................... 3
Stability Studies ...................... 5
MATERIALS AND METHODS ...................... ll
Materials .......................... ll
Repackaging Operation .................... l2
Storage Treatments ...................... l4
Stability Analysis ...................... 16
RESULTS AND DISCUSSION ...................... 28
SuccinyIchoIine Chloride ................... 28
Metaproterenol Squate .................... 37
Thiamylal Sodium ....................... 47
SUMMARY AND CONCLUSIONS ..................... 53
APPENDICES

A. ANALYSIS METHODS ..................... 57

B. COMPARISON OF THE RESPONSES OF THE ELECTRONIC

INTEGRATOR WITH THAT OF THE STRIP CHART RECORDER

IN CALCULATING METAPROTERENOL CONCENTRATION ....... 64
LIST OF REFERENCES ........................ 66

iv

Table

 

LIST OF TABLES

Desirable expiration dates for unit dose repackaged

pharmaceuticals .....................
Storage treatments--Succinylcholine Chloride ......
Storage treatments--Metaproterenol Sulfate .......
Storage treatments--Thiamylal Sodium . .........
Mean SuccinyIchoIine Chloride concentration (mg/ml) . . .
Mean SuccinyIchoIine Chloride pH values .........

ANOVA summary--Succinylcholine Chloride . . . . .....

Statistical significance of correlation coefficients

(r values) for concentration vs. storage length . . .

Theoretical effect of weight change (water loss)

on concentration ....................
Mean Metaproterenol Sulfate concentration (mg/ml) . .

Mean Metaproterenol Sulfate pH measurements .......

ANOVA summary—-Metaproterenol Sulfate .......

Mean weight (grams) of Thiamylal Sodium in package

Mean Thiamylal Sodium pH values .............
Mean Thiamylal Sodium concentration (mg/ml) .......

ANOVA summary--Thiamylal Sodium in plastic syringes .

Recommendations for storage at 4°C based on

concentration (mg/ml) .......... . . ......

Recommendations for storage at 4°C based on pH data . .

36

38
4O
41
42
48
48
49

54
55

Figure

l.

 

LIST OF FIGURES

SuccinyIcholine Chloride--4°C regression plots and

USP acceptable limits for concentration (mg/ml) . . . .

SuccinyIcholine Chloride--22°C regression plots and

USP acceptable limits for concentration (mg/ml) . . . .

SuccinyIcholine Chloride--37°C regression plots and

USP acceptable limits for concentration (mg/ml) . . . .

Metaproterenol Sulfate-—4°C regression plots and
Boehringer Ingelheim acceptable limits for

concentration (mg/ml) .................

Metaproterenol Sulfate—-22°C regression plots
and Boehringer Ingelheim acceptable limits for

concentration (mg/ml . ................

Metaproterenol Sulfate--37°C regression plots
and Boehringer Ingelheim acceptable limits for

concentration (mg/ml) .................

Thiamylal Sodium--4°C regression plots and USP

acceptable limits for concentration (mg/ml) ......

vi

Page

35

35

35

46

46

46

52

 

INTRODUCTION

Unit dose pharmaceutical packaging gives the hospital
pharmacist the greatest control over ”in-patient" drug therapy
(i.e., correct drug and dosage) and minimizes contamination risk.
Pharmaceutical manufacturers, however, market a limited selection
of types and concentrations of drugs in unit dose packaging; those
which are available are so at an increased cost to the pharmacy.

It is because of this limited availability and/or increased cost

that the hospital pharmacist must often repackage certain drugs into
unit dose form. After repackaging, the pharmacist does not know how
the new package affects drug stability and therefore what expiration
date should be assigned. A survey conducted earlier this year (Chaney
and Summerfield, l984) found that a broad assortment of arbitrarily
assigned expiration dates are being used when bulk drugs are repackaged
even though Current Good Manufacturing Practices (21 C.F.R. 2ll.l37),
the United States Pharmacopeia (USP, I980), and the American Society
of Hospital Pharmacists (ASHP, l977) recommended expiration dates
should ideally be supported by stability data.

The purpose of this thesis is to determine the stability of
three pharmaceuticals, Succinylcholine Chloride, Metaproterenol Sulfate,
and Thiamylal Sodium, in plastic unit dose syringes and to compare
these results to those obtained with the dispensing unit for these

drugs used presently by the hospital pharmacist. The stability

 

information gleaned from this study will aid the hospital pharmacist
in selecting the most cost effective unit dose repackaging system
which will adequately protect the product as well as in assigning

accurate expiration dates.

 

LITERATURE REVIEW

General Background

One definition for a unit dose package is “. . . one which
contains the particular dose of drug ordered for the patient” (ASHP,
I979). Innovative hospitals in the sixties initiated unit dose drug
distribution in pilot programs involving one ward at a time. This
system provided ”. . . improved safety, control, convenience, and
utilization of human resources; and more accurate dosage“ (Roulette,
I972); better utilization of human resources because pharmacists would
be used to their fullest capacity and nursing time, previously spent
on preparing drugs for patient administration, could now be spent on
delivering optimal nursing care (Latiolais, I970; S.G.K., I971). Some
of the benefits resulting from the introduction of unit dose packaging,
specifically for prefilled syringes, were cited by Elias and Apat
(I965): assured accurate dosage and sterility, elimination of a source
of serum hepatitis, less potential for allergic sensitization, better
utilization of nursing time, and less waste of drugs due to pilferage,
breakage, or incomplete use. Varnum (I974) characterizes the unit
dose system as a "comprehensive, well controlled, well managed drug
distribution mechanism” that does in fact reduce pharmacy costs.

Costs are reduced because improved inventory control decreases
acquisition costs and helps to eliminate waste or pilferage of

drugs (Varnum, I974; Hart and Marshall, I976).

 

General acceptance and usage of the unit dose system in
hospital pharmacies continues to increase. In I970, a questionnaire
(McDonald et al., I972) found that 94.4% of the I44 responding
hospitals were utilizing purchased prefilled syringes and I2% of
the respondents were filling their own syringes. This survey also
indicated that prefilled syringes for products not commercially
available in unit-of-use syringes was perceived as an important
function of the hospital pharmacist. This author goes on to cite
the disadvantages of nurses filling syringes: particulate matter
could go unnoticed due to poor lighting, contamination risk is
greater due to atmospheric air entering the vial being drawn from,
nurses generally fail to label syringes thereby increasing the
risk of mixup with other medication, and there is greater chance
of dosage calculation errors with nurses as compared to pharmacists.

Increased utilization of the unit dose system should continue,
as the Minimum Standards for Pharmacies in Institutions (I977) states
that all drugs should be dispensed in single-unit packages--". . . the
unit dose system of preparing and distributing drugs should be used”;
these Standards also say that drugs should be unit dose repackaged by
the pharmacist, when feasible, in cases where an item fulfilling a
need is not commercially available. Romberg (I979) states that the
use of unit dose systems in hospitals is increasing, 76% of hospitals
use the unit dose system to dispense more than 50% of their daily
doses, but that the trend is toward purchasing supplier produced unit
dose packaged drugs; these statements are based on a survey sent to

3,000 U.S. hospital chief pharmacists, with a l5% response rate.

 

Unit dose packaging may minimize contamination risks that
are present when using multi-use vials (multidose vials or MDV's)
or bottles on nursing wards, in respiratory therapy and in operating
rooms (Talley et al., I973). Microbially contaminated medications
are a potential source of nosocomial infection which can at best
complicate the hospitalized patients' recovery and at worst result
in death. Several studies indicate that while the contamination risk
in using MDV's is low, it has happened, and the potential indeed is
there (Highsmith et al., l982; Sanders et al., I970; Moffet and Allan,
I967; Alford et al., I966).

Unit dose packages have been shown to be a feasible alternative
to MDV's with respect to maintainence of sterility, stability, and
reducing costs. Talley et al. (I973) found that when seven inhalation
therapy drugs were repackaged into 2 ml glass cartridges, stability
and sterility were maintained throughout their six month study. Sheth
et al. (I983) found that a cost savings of 46% could be realized when
MDV's were replaced with unit dose alternatives; this author found
that when MDV‘s are used on nursing wards, 25% or less of the original

vial volume was used before the drug reached its expiration date.

Stability Studies

It is extremely important to determine the stability of unit
dose repackaged drugs so that an expiration date can be declared which
is accurate and insures that the drug is not wasted by being discarded
prematurely. Current Good Manufacturing Practice Regulations state

that stability testing should provide the basis for the expiration

date assigned to a packaged drug (2l CFR le.l37). The United States
Pharmacopeia (I980) defines stability as ". . . the extent to which a
product retains, within specified limits, and throughout its period
of storage and use, i.e., its shelf—life, the same properties and
characteristics that it possessed at the time of its manufacture."
The USP defines five types of stability:

l. Chemical--Iabeled potency is maintained;

2. Physical-~active ingredient maintains potency;

3. Microbiological--sterility is maintained;

4. Therapeutic--therapeutic effectiveness unchanged; and

5. Toxicological-~no significant toxicity increase.

The American Society of Hospital Pharmacies (ASHP) published
guidelines for unit dose drug packages in I977 which state: "drug
packages must fulfill four basic functions: (I) identify their
contents completely and precisely; (2) protect their contents from
deleterious environmental effects (e.g., photodecomposition); (3)
protect their contents from deterioration due to handling (e.g.,
breakage, contamination); (4) permit their contents to be used
quickly, easily, and safely.” These guidelines also assert that
the package material itself should not decompose over the shelf life
of its contents, should not absorb or adsorb or otherwise deleteriously
affect the drug they contain. The package should be easy to use and
open. The package should allow direct administration of the drug to

the patient or inhalation device.

In I983 an article by Nedich described a variety of packaging
materials available for injection drugs. Nedich states, "No container
or closure material is totally inert"--not glass or plastic. He goes
on to explain that glass is composed of a mixture of oxides, some
quite loosely bound and free to migrate and leach into the preparation.
These migrated or leached oxides may alter pH or act as a catalyst or
reactant. Plastics may contain a variety of additives, such as lubri-
cants and stabilizers, which can leach into the drug stored in contact
with the plastic. Rubber also has a variety of components which may
leach, such as reaction by-products, plastisizers, oils, and oxides.

After a thorough review of the literature it was determined
that no stability studies have been conducted on the three drugs
chosen for this study. As the research done on unit dose packaging
of other drugs is described in the following paragraphs, one must bear
in mind at all times that it can be inaccurate and misleading to equate
the results obtained with a particular drug in a given package to
either the same drug in a different package or a different drug in
the same package. This is because each drug and package are chemically
unique and the degradation of the drug in the package is affected by
the interaction of the two. In l972 Hicks et al. studied the stability
of Sodium Bicarbonate injection stored in two different brands (Becton-
Dickinson and Travenol) of polypropylene syringes stored at l2-l4°C,
22-23°C, and 37-38°C. Hicks found that the shelf life of this drug
is inversely related to storage temperature; while the rate of pH
change increased as temperature increased, there was no significant

difference in this rate of pH change or final pH‘s between the two

different syringes. Using spectrophotometric analysis, after the
packaged drugs had been stored for I45 days, the drugs packaged in
Becton-Dickinson syringes showed no evidence of chemical contamination
but the Travenol syringes did; the rubber plunger was the suggested
source of this observed contamination.

Kleinberg et al. (I980) used the Arrhenius Technique to
determine the stability of five liquid drugs in four different clear
or amber glass syringe-type (Hy-Pod, Ped-Pod, and Nebuject) packages.
Each drug was stored in a single type of glass package--there was no
attempt made to compare the stability of a given drug in different
packages.

In l982 Nolly et al. repackaged Thiamine Hydrochloride
injection into glass and plastic syringes and found that the solution
in both syringe types maintained at least l00% potency for 84 days
at 22-24°C. It was also determined that glass syringes have a lower
oxygen transmission rate than plastic syringes. Zvirblis and Ellin
(I982) compared the stability of an organophosphate antidote packaged
in glass and plastic cartridges (they failed to mention manufacture's
names and cartridge size) and found no significant difference in pH or
concentration between glass and plastic cartridges after four months
storage at 5°C. These authors estimate water loss to be approximately
I% per year for glass and 2% per year for plastic at 25°C.

Valproate Sodium syrup stability, when repackaged in three
different unit dose packages was compared when stored at 4, 25, and

60°C (Sartnurak and Christensen, I982). The three packages compared

 

were 5 ml amber polypropylene oral syringes, 3—4 ml clear glass oral
syringes and IS ml amber glass vials. No significant difference was
found between the two glass packages, but there was a significant
difference in concentration between the plastic package and the glass
packages--the glass vials and syringes maintained at least 95% of the
label claim after I80 days storage at 4°C and 25°C while in plastic
the concentration decreased to 88.5% of the label claim after 20 days
at 25°C but maintained 90% potency for at least 90 days at 4°C. This
increased loss of concentration seen in the plastic packages was
attributed to sorbtion of the drug into the polypropylene material.

Vancomycin repackaged into amber glass unit dose vials (Mallet
et al, I982, maintained USP recommended potency for at least 90 days
at 0 and 4°C; it was recommended that Vancomycin, repackaged in these
vials, not be stored at 25°C because a precipitate formed within 6 days
storage. A similar study was conducted to evaluate the stability of
Insulin repackaged in I ml polypropylene syringes (Zell and Paone,
I983) with the finding that this system was stable for at least
l4 days under ”refrigeration."

In I983 Christensen et al. found no significant difference
in the concentration of Furosemide and Cimetidine Hydrochloride
repackaged in either polypropylene oral syringes or glass vials
when stored at 4°C or 25°C. At higher temperatures (i.e., 44, 60,
and 76°C), the degradation rate increased for the drugs packaged in

the polypropylene syringes.

IO

To conclude, the above studies indicate what one would expect
to find, that drug degradation increases with increased storage
temperature and time. It can be further concluded that the stability
of any drug is unique to the system comprised of that drug and the
package it is stored in. Therefore, it is advisable to study the
stability of Succinylcholine Chloride injection, Metaproterenol
Sulfate inhalent, and Thiamylal Sodium injection in glass and

polypropylene packages.

 

MATERIALS AND METHODS

Materials

Three pharmaceuticals were chosen for unit dose stability
studies: Succinylcholine Chloride injection (a short—acting
depolarizing skeletal muscle relaxant), Metaproterenol Sulfate
inhalent (a bronchodilator), and Thiamylal Sodium injection (an
ultrashort-acting barbiturate). These drugs were identified by
Directors of Pharmacy of two Lansing hospitals as excellent candidates
for this study because all three are currently unit dose repackaged
and the effect the new package has on the drug's stability is unknown.
The Directors expressed interest in having documentation of the
stability of the pharmaceuticals in the unit dose package currently
used in their respective pharmacies, glass syringes or vials, as well
as in a less expensive plastic alternative. This information would
provide them with bases for both selecting the most economical unit
dose repackaging system and assigning accurate expiration dates.

Succinylcholine Chloride injection (Quelicin manufactured by
Abbott Laboratories--lot #55-607-DK) in 20 mg/ml concentration was
repackaged from the ID ml fliptop vials, received from the manu-
facturer, to 5 ml 80 glass (reorder number 5293) (current unit dose
package used at St. Lawrence Hospital pharmacy) and polypropylene
(reorder number 5603) syringes. These syringes were filled to capacity

at 5 ml and stoppered with BD rubber luer tip caps (reorder number

I2

834l). The specifics on the rubber and polypropylene formulations
were unavailable from the manufacturer.

Metaproterenol SDZfate inhalent (Alupent manufactured by
Boehringer Ingelheim Ltd.--lot #7I3OI3A) was repackaged from the
ID ml bottles received from the manufacturer into l0 ml Invenex glass
vials (number SV-5) (current unit dose package used at Ingham Medical
Center Pharmacy) and 6 ml Monoject polypropylene syringes (reorder
number 888I-5l69ll). Pharm-Aide Syringe Caps (Pharmaseal Laboratories
catalog number 7820), made from plastic, were used to seal the syringes.
The Metaproterenol Sulfate was diluted from 5% w/v concentration as
supplied by the manufacturer to the patient dosage--.45% w/v and
filled to 5 ml in each test package.

Thiamylal SOdium injection (Surital manufactured by Parke-
Davis--lot #03573P) was received from the manufacturer as IO grams
of powder in a 500 ml IV style bottle (Steri-vial l23) and was diluted
to a concentration of 2.5% w/v using sterile water for injection, USP
(Abbott Laboratories-~lot #49-505-DM-0I). The solution was tested in
this original vial (400 ml fill volume) as well as repackaged into
Monoject 20 ml polypropylene syringes (reorder number 888l-520046)
(20 ml fill volume) sealed with Pharm-Aide Syringe Caps (Pharmaseal

Laboratories catalog number 7820).

Repackaging Operation

 

All three pharmaceutical repackaging operations were handled
by the respective hospital pharmacy personnel in the manner normally

used by each to unit dose repackage these pharmaceuticals. In the

l3

case of Succinylcholine Chloride, a 20 ml syringe was filled from
two l0 ml vials and then 5 ml transferred to each 5 ml syringe and
capped. After repackaging, the glass syringes currently in use at
St. Lawrence are stored at 4°C and assigned a 30 day expiration date.

Metaproterenol Sulfate was prepared by transferring the total
quantity of undiluted drug needed from the manufacturer's bottles to
a sterile IV style glass bottle. To this IV bottle next was added
the total quantity of saline necessary to obtain patient dosage
concentration (.45% w/v). Syringes and vials are filled with 5 ml
of the diluted Metaproterenol Sulfate from this IV bottle. The
syringes were sealed with plastic caps. The vials are the current
repackaging system in use at Ingham Medical Center Pharmacy and are
stored at 4°C for 30 days maximum.

Finally, Thiamylal Sodium is diluted in the vial, as supplied
by the manufacturer, with 400 ml sterile water to 2.5% w/v. From this
vial, 20 ml of the drug were drawn into each 20 ml plastic syringe.

The syringes were sealed with plastic caps. Currently, Ingham Medical
Center Pharmacy supplies this drug to two different sources: in-patient
surgery and outpatient surgery. The pharmacy dispenses Thiamylal Sodium
to in-patient surgery in the manufacturer's vial each surgical day and
surgery stores the vials at 4°C. At the end of each surgical day, any
leftover drug is discarded.

In the case of out-patient surgery, the exact amount of
Thiamylal Sodium required for the number of patients scheduled on
a given surgical day is dispensed by pharmacy in 20 ml plastic syringes.

These syringes are stored by surgery, until needed, at 4°C.

 

I4

Storage Treatments

The pharmacy directors specified preferred lengths of storage
for each repackaged pharmaceutical on the basis that this amount of

time would offset the handling costs incurred with unit dose packaging.

These time lengths are given in Table I.

Table l. Desirable expiration dates for unit dose repackaged

 

 

pharmaceuticals
Minimum Length of Optimal Length of
Storage Preferred Storage Preferred
Pharmaceutical (Days) (Days)
Succinylcholine Chloride I4 30
Metaproterenol Sulfate 30 60
Thiamylal Sodium 6 30

 

It is these times listed in Table l which determined the length
of storage of each drug in the study as well as the time intervals
selected for stability analysis. These storage conditions and asso-
ciated lengths of storage are summarized in Tables 2, 3, and 4. Five
replicates of each sample were subjected to each treatment described
(storage period, package type, and temperature) with the exception of
the glass vial of Thiamylal Sodium. A single glass vial of Thiamylal
Sodium was subjected to each treatment. This was because of the
exceptionally high cost of the drug. The repackaged pharmaceuticals

were protected from direct exposure to light.

l5

Table 2. Storage treatments--Succinylcholine Chloride

 

Type of package Glass Syringe and Plastic Syringe

 

4°C, Ambient RH
Storage conditions 22°C, 50% RH
37°C, 85% RH

 

Storage periods (days) 0 5 30 45

 

Number of replicates 5 5 5 5

 

Table 3. Storage treatments--Metaproterenol Sulfate

 

Type Of package Glass Syringe and Plastic Syringe

 

4°C, Ambient RH

Storage conditions 22°C, 50% RH
37°C, 85% RH

 

Storage periods (days) 0 IS 30 45 60 70
Number of replicates 5 5 5 5 5 5

 

Table 4. Storage treatments--Thiamylal Sodium

 

 

 

Type of package Glass Syringe Plastic Syringe
Storage conditions 4°C, Ambient RH 4°C, Ambient RH
Storage periods (days) 0 6 I4 30 0 6 I4 30

 

Number of replicates l l l l 5 5 5 5

 

I6

0f the three conditions selected for storage of Succinylcholine

Chloride, 4°C is of most interest because this is the manufacturer's
recommended storage temperature. The 4°C and 22°C storage tempera-
tures for Metaproterenol Sulfate are of the most interest because the
manufacturer recommends storage at 25° C or below. The single storage
temperature, 4°C, for Thiamylal Sodium was chosen because the manu-
facturer recommends the reconstituted solution be discarded after six
days if "refrigerated" and 24 hours if kept at "room temperature"--
indicating that the solution is quite unstable at higher than refrig-
eration temperatures. The temperature 37°C was included in both the
Succinylcholine Chloride and Metaproterenol Sulfate studies because it

is common practice to collect storage data at accelerated conditions.

Stability Analysis

 

Clarity and color change. The clarity of a pharmaceutical

 

is very important because cloudiness may indicate formation of
particulate matter or microbial contamination. The consequences

of microbial contamination to a patient are both infection and possible
shock, while particulate matter can act as emboli in the case of
injectables or as an irritant in the case of inhalents.

The color change in a drug is also very important as it may
indicate either a breakdown of the active ingredient or some harmless
other change, such as a photochemical reaction with inert ingredients.
From a physician's or nurse's point of view, however, presence of any

unusual color in a pharmaceutical is undesirable. To these people, the

I7

unusual color signifies possible loss of efficacy or source of
potential harm to their patient, so such a drug would probably
be discarded.

Therefore in assessing each drug's stability, a careful
inspection was made to evaluate both clarity and color alteration.
First, each sample was transferred directly from a syringe (those
drugs stored in vials were first drawn into plastic syringes) to a
glass l0 ml beaker (4.0 ml Succinylcholine Chloride and Metaproterenol
Sulfate and 5.0 ml Thiamylal Sodium) and then individually inspected
visually against opaque white and black backgrounds while comparing
each sample to a freshly prepared control of the drug, identical to
the experimental sample in concentration, lot number, and volume,
also in a l0 ml beaker.

EH. Efficacy of a drug may be altered by a pH change.

For this reason, pH monitoring was part of each periodic stability
assessment. After evaluation for clarity and color change, the pH
was measured using a digital ionanalyzer (Orion Research model 50l)
equipped with a combination glass pH electrode (Orion number 9l-04).
The pH meter was calibrated with three commercially prepared buffers:
Mallinckrodt standard buffer solutions numbers 0029 and 0032 having
pH's of 4.0l and l0.00 respectively; and MCB standard buffer solution
number BXl635 having a pH of 7.00). The calibration was done using
the two buffers whose pH's bracket the pH of the drug being measured.
After rinsing the buffer from the electrode with distilled, deionized

water, the electrode then was placed sequentially into each l0 ml

I8

beaker containing drug. The meter was recalibrated after every five
samples. pH was measured to two decimal places.

Measuringgactive ingredient concentration. Drug efficacy
can be most directly related to active ingredient concentration.
The active ingredient concentration of each of the three study
pharmaceuticals was determined at the end of a storage period using
high performance liquid chromatography (HPLC) for Succinylcholine
Chloride and Metaproterenol Sulfate and gas liquid chromatography
(GLC) for Thiamylal Sodium.

succinylcholine Chloride active ingredient (C14H30CI2N204)
concentration was assayed in accordance with the procedure published
in the USP Supplement 3, found in Appendix A, with the following
sections changed to read:

. Standard preparation--Initial moisture content of the USP
Succinylcholine Chloride Standard (lot F) was 9% as determined
by USP personnel and communicated to me by telephone. The
standard was stored in its original vial within a glass weigh
bottle sealed with silicone sealing lubricant; the weigh bottle
was kept inside a glass desiccator filled with CaSO4 desiccant
and sealed with silicone sealing lubricant. To determine the
water loss the standard was experiencing as the study progressed,
a record was kept of the weight of the vial plus standard just
before the vial was returned to storage each time and the weight
of the same just before opening it again. The weight changes
noted over time were assumed to be due to water loss and from

this information, the percent moisture of the standard was

 

adjusted lower appropriately. The standard was prepared

for the analysis according to the published method.

Assay preparation--Succinylcholine Chloride samples and
controls were prepared for analysis in several steps. The

4.0 ml of sample was transferred from the ID ml glass beaker

to a l0 ml glass volumetric flask following pH measurement.
This transfer was accomplished by pouring the contents through
a glass funnel into the flask and then rinsing the beaker three
times with mobile phase (described in the published method) and
pouring each rinse through the funnel. Finally, mobile phase
was rinsed over the funnel into the flask. The l0 ml flask

was then brought to volume with additional mobil phase.
Chromatographic system--A Perkin-Elmer Series 3B Liquid
Chromatograph was equipped with a variable wavelength
Spectrophotometric Detector (LC75) set at 2l4 nm (UV) and

a .26 cm x 25 cm stainless steel column that was packed with
Silica-A (a porous silica-—I0 um). The flow rate was I.0 ml
per minute. A Spectra Physics SP4200 Computing Integrator was
used to record the response peaks and to calculate the corre-
sponding area ratios. To determine that the HPLC was responding
in a linear and otherwise acceptable fashion, first, a standard
curve was constructed by injecting in 2 ul, 4 ul, 6 ul, 8 ul,
and ID pl of standard prepared as described in the modified
procedure and plotting the respective area responses against

pl of injected sample. The resulting curve formed a straight

line indicating that the machine was responding in a linear

20

faShion over the range of expected concentrations to be
encountered in the study. Next, five l0 ul injections of
standard were made and found to differ from each other by
approximately l.4% which is within the acceptable l.5% limit
specified in the published method. The response peaks were
observed to be crisp with no discernible tailing.

o Procedure-~Separate l0 ul injections of standard and assay
preparations were made using a l0 ul Hamilton microsyringe.
The standard was injected initially and then again after
every five assay preparations were injected. The quantity
of CMH30CI2N204 in the samples and controls was calculated

using the equation (I):

Rsam x Cstd x 2.5

 

Csam = Rstd (I)
where:

Csam = concentration of C14H3OCIZN204 in each assay
preparation, mg/ml;

Cstd = concentration of C14H30Cl2N204 in standard
preparation, mg/ml;

Rsam = peak response of assay preparation, area units;

Rstd = average peak response of standard injections
bordering the respective assay preparation
injection, i.e., the average of two standard
injections, area units; and

2.5 = assay preparation dilution factor.

Metaproterenol sulfate active ingredient [(C11H17N03)2° H2804]

concentration was assayed using a method provided by Boehringer

2I

Ingelheim which is used in their quality control laboratory. This
method (found in Appendix A) was used with the following changes:

. Standard preparation--The standard (BIL/USA House Reference
Standard--BIL#0004 Code #4000I2) was initially dried, according
to manufacturer's directions, at I05°C for one hour and then
stored in a glass desiccator filled with CaSO4 desiccant.
Approximately l5 mg of standard were accurately weighed and
transferred to a 25 ml volumetric flask and dissolved in and
diluted to volume with the Mobile phase. Concentration of the
prepared standard was expressed as anhydrous, methanol and
isopropanol free metaproterenol sulfate by multiplying by a
factor of 99.8%. This factor was obtained from the manufac-
turer's statement of potency of the powdered standard as 99.8%
anhydrous by HPLC assay.

. Assay preparation--Metaproterenol samples and controls were
prepared as follows: 4.0 ml of sample was transferred from
the ID ml beaker to a 50 ml glass volumetric flask following
pH measurement. This transfer was accomplished as described
for Succinylcholine Chloride above.

. Chromatograph conditions--

Instrument--Perkin-Elmer Series 38 Liquid Chromatograph

as described above. The Spectra-Physics Computing Inte-
grator, also described above, was used to record peak
responses as well as to calculate respective area ratios
on all analysis days except for day 0 where a Perkin-Elmer

model 056-300l strip chart recorder was used and the peak

 

22

heights were measured manually in millimeters. A study

was done to compare calculated concentration based on the
electronic integrator response and the strip chart recorder
response. The procedure used for this may be found in
Appendix B. As a result of this study, a 0.ll6 mg/ml
correction term was subtracted from all day 0 calculated
concentrations.

Guard column--none used.

 

Column--.26 cm x 25 cm, stainless steel.

Stationary phase--HC ODS SIL-X (octadecylsilane chemically

 

bonded to porous silica--Perkin-Elmer).
To determine that the HPLC was responding in a linear manner,
a standard curve was constructed by plotting the area of the
respective peak heights corresponding to 2 pl, 4 pl, 6 pl,
8 pl, and I0 pl injections of the standard preparation. The
resulting curve formed a straight line indicating that the
HPLC was responding linearly over the concentration range
expected to be encountered in the study. The response peaks
showed very slight tailing-~the computing integrator does take
this tailing into consideration.
Procedure--Separate l0 pl injections of standard and assay
preparations were made using a IO pl microsyringe. The
standard was injected initially and then again after every
five assay preparations were injected. The quantity of
N0

(C11H - H 50 in the sample was calculated using

17 3)2 2 4
the following formula:

23

C d R
sthédsam x 50 (2)

Csam = 4

where:

Csam concentration of (C11H17N03)2: H2504 in each

assay preparation, mg/ml;

Cstd = concentration of (C11H17N03)2° H2304 in standard
preparation, mg/ml;

Rsam peak response of assay preparation, area units;

Rstd = average peak response of standard injections
bordering the respective assay preparation
injection, i.e., the average of two control
injections, area units; and

g9— assay preparation dilution factor.

Thiamylal Sodium (C12H17N2Na025) concentration was assayed in

accordance with a procedure supplied by Parke-Davis (found in Appendix

A), where it is used in their quality control laboratory. The following

modifications were made for use in this work.

Preparation of Phensuximide internal standard--approximately

28 mg of Phensuximide (provided by Parke-Davis Lot #583625)

was accurately weighed and transferred into a IOO ml volumetric
flask. The flask was then brought to volume with reagent
chloroform and thoroughly mixed (concentration = .28 mg/ml).
Preparation of Surital Acid standard solution--approximately

44 mg of Thiamylal Acid (Surital Acid provided by Parke-Davis
Lot #H726803) was accurately weighed and transferred into a

l00 ml volumetric flask. The flask was then brought to volume
with reagent chloroform and thoroughly mixed (concentration =

.44 mg/ml).

   

 

24

. Preparation of sample--A total volume of l9.0 ml of each

0

reconstituted 2.5% Thiamylal Sodium sample and control was
transferred to a IOO ml volumetric flask, brought to volume
with distilled, deionized water, and mixed. Of this l9.0 ml,
5.0 ml were transferred from the ID ml beaker following pH
determination. This transfer was accomplished by pouring the
contents of the beaker through a glass funnel into the flask
and then rinsing the beaker three times with distilled,
deionized water and pouring each rinse through the funnel.
Distilled, deionized water was then rinsed over the funnel
into the flask. The remaining l4.0 ml was transferred
directly from each respective 20 ml syringe into the I00 ml
flask. Continuation of the original method for sample
preparation followed.

Procedure--Initially a standard curve was constructed to
insure that the machine was responding in a linear manner.
Dilutions of Thiamylal Acid standard in PhenSUXimide were
made with resulting Thiamylal Acid concentrations ranging
from 9 mg/ml to 22 mg/ml giving corresponding area response
ratios of Thiamylal Acid to Phensuximide of .IO to .50
respectively. The standard curve obtained formed a straight
line, indicating that the machine was responding in a linear
fashion over the concentration range expected to be encountered
in this study. The response peaks were crisp with some slight
tailing (the electronic integrator considers this tailing in

its measurement). For each analysis, 2.0 ml each of prepared

 

25

sample or control or prepared Thiamylal Acid Standard and
prepared Phensuximide internal standard were pipetted into
a glass stoppered tube and mixed. Using a l0 pl Hamilton
microsyringe, 2.0 pl of the combined internal/external
standard solution were injected into the sample port of the
gas Chromatograph initially and then again after every five
2.0 pl prepared sample or control injections.
0 Technique notes--
Instrument--A Hewlett Packard Model 5830A Gas Chromatograph.
The peak response area ratios were calculated and recorded
using a Hewlett Packard Model l8850A Electronic Integrator.
Cglumnf-3 ft x I/4 in. 0.0. x 2 mm 1.0. glass column
packed with 3% SP-2250 on 80/l00 Supelcoport.

Carrier Gas--Helium at 52 ml per minute.

 

Temperature-~(a) column--l85°C isothermal

 

(b) injection port--l80°C
(c) detector--350°C

Sensitivity--Attenuation 6 millivolts on the electronic

 

integrator.

Retention time--Phensuximide = 2.2 minutes

 

Thiamylal = 4.5 minutes

Calculation--Quantitation of Thiamylal was calculated

 

using the following equation:

_ Bsztd IOO IOO
Csam - __—7T——_ x-T—— x 7E7 X I.086 (3)

26

where:

Csam = concentration of Thiamylal in each sample
or control, mg/ml;

Cstd = concentration of Thiamylal Acid standard,
mg/ml;

 

A _ area ratio Thiamylal Acid standard
area ratio Phensuximide standard
two standard injections bordering the respective
sample or control injection;

averaged for

area ratio Thiamylal sample or control

 

B = area ratio Phensuximide standard ’
IOO _ d' . .
TRT'- ilution of extracted sample,
l00

~T—— = dilution of sample; and

I.086 = manufacturer's factor to convert Thiamylal Acid
to Thiamylal Sodium.

Sterility. To determine that sterility was maintained
throughout the study, 4.0 ml of sterile trypticase soy broth (TSB)

(BBL Microbiology Systems #ll768) in glass tubes was inoculated with

a l.0 ml aliquot directly from the respective syringe of each drug
sample at each analysis interval. Each tube of TSB was then incubated
at 37°C, 85% RH and observed for evidence of growth after two days.
This is the standard procedure used at St. Lawrence Hospital in
Lansing, Michigan.

Water loss. Water loss from water based liquid pharmaceuticals
would result in an increase in concentration. If the pharmaceutical is
being stored, concentration increase, due to water loss, may mask con-
centration decrease due to degradation. It is of interest therefore to

quantitate the water lost by the three pharmaceuticals under test.

 

 

27

Water loss was quantitated for Succinylcholine Chloride and
Metaproterenol Sulfate packages in a separate study, in which packages
similar to those used in the original study were filled with distilled,
deionized water and put under identical storage conditions as in the
original study for 70 days. Each water filled package was weighed
on a Mettler balance at various intervals. These weights were recorded
to four decimal places. The change of weight seen over time was
attributed to water movement into or out of the package.

In the case of Thiamylal Sodium, the packages filled with the

drug were weighed on a Mettler balance concurrently with the other

 

 

monitoring procedures. Weight was recorded to four decimal places.
Care was taken to weigh the same packages at each period, i.e., the
packages which were to be held on test for the full 30 days. The
weight change observed over time was assumed to represent water

movement into or out of the package.

RESULTS AND DISCUSSION

Succinylcholine Chloride

 

Throughout the study sterility, colorlessness, and clarity
were maintained in every package. Further, there was no formation
of particulate matter observed.

The changes in concentration and pH associated with glass and
plastic packages over time at each storage temperature are presented
respectively in Tables 5 and 6. In not every case are the presented
data means based on five replicate samples; a few samples were lost
due to breakage or spillage and a few replications were not included
in the final analysis when they were clearly out of line with four
tightly clustered values. In fact, two values out of 99 for concen-
tration and two values out of 98 for pH were omitted in this manner.
Since the ANOVA contained 70 error degrees of freedom, the statistical
effect of these omissions is negligible. In these cases where repli-
cate values were obviously out of line, it was felt that inclusion of
these replicate values would have been a misrepresentation of the data.
An analysis of variance (ANOVA) was done to determine if there were
any statistically significant differences in pH or concentration due
to storage time, storage temperature, package type (glass or plastic),
or an interaction of any of these. The results of the ANOVA are pre-
sented in Table 7. Using the F values from this ANOVA it can be seen

that there was a three way interaction demonstrating significance at

28

29

Table 5. Mean Succinylcholine Chloride concentration (mg/ml)

 

4°C 22°C 37°C

 

 

 

Length of
Storage Glass Plastic Glass Plastic Glass Plastic
(Days) Control Syringe Syringe Syringe Syringe Syringe Syringe

 

0 19.8 21.0 20.9 -- -- -- --

5 20.0 20.7 20.5 20.7 20.5 20.5 20.7

30 l8.8 21.1 20.6a 19.8 20.9 18.5 19.5

45 20.1 20.2 20.3 20.1 20.3 18.3 17.6b
mean l9.7

 

 

: C
LSD(.01) 0.9

_ d
LSD(.O1) - 1.0

 

aOne replicate sample thrown out.

bOne replicate sample lost.

CUsed to compare treatment means; each with five replicates.

dUsed to compare treatment means; four with five replicates.

30

Table 6. Mean Succinylcholine Chloride pH values

 

4°C 22°C 37°C

 

 

Length of
Storage Glass Plastic Glass Plastic Glass Plastic

(Days) Control Syringe Syringe Syringe Syringe Syringe Syringe

 

 

o 3.55 3.57 3.57 -- ' -- -- --

5 3.58 3.59a 3.55 3.52a 3.55 3.55 3.57

30 3.54 3.58 3.53 3.55 3.52 3.31 3.30

45 3.52 3.53 3.51 3.48 3.45 3.20 3.21
mean 3.65
LSD(.01) = .01b

_ C
LSD(.01) _ .02

 

aOne replicate value thrown out.

bUsed to compare treatment means; each with five replicates.

CUsed to compare treatment means; four with five replicates.

 

3I

Table 7. ANOVA summary--Succinylcholine Chloride

 

 

 

 

 

pH Concentration
Source of Variation df ms F ms F
Time 2 .287 3836.924*** 8.468 26.908***
Temperature 2 .675 90l7.5l7*** I4 905 47.36l***
Package l .006 82.287*** .457 NS
Time x temperature 4 .063 834.990*** 4.593 l4.595***
Time x package 2 .003 34.382*** .980 3.ll5+
Temp. x pkg. 2 .002 24.347*** .508 NS
Time x temp. x pkg. 4 .00l 8.437*** I.025 3.256*
Error 70 .00007 .3l5
Significance levels: + = .lO
* = .05
*** = .00I
NS = non-significant.

32

the 5% level for concentration and at the .I% level (p==.00l) for pH
among the treatments, i.e., time, temperature, and package. When the
F values for the individual treatments are compared it can be seen
that the significance of the three way interactions is due mostly

to the two main effects, temperature and time. The F values for
temperature and time were very large while the F value for package
was non-significant in the case of concentration and much smaller
than the other two for pH.

The means for each package and between each package at each
temperature over time were tested for significant differences at the
I% level using the least significant difference (LSD) procedure (Steel
and Torrie, l980). The LSD's used for the comparisons are presented
in Tables 5 and 6. The following conclusions were drawn:

I. At 4°C there was no significant change of concentration over
time in either the glass or plastic packages; except in glass
from day 30 to day 45, the concentrations were statistically
significantly different. However, this difference (2l.l mg/ml
to 20.2 mg/ml) is not meaningful in a practical sense, since
both values are within the USP limit. There was also no
significant difference in concentration between glass and
plastic packaging over time. All means at 4°C remained within
the USP acceptable range (l8.6-2l.4 mg/ml).

2. There was a significant change in concentration over time in
glass at 22°C (decreased from 2l.0 mg/ml on day 0 to 20.l mg/ml
on day 45) and 37°C (decreased from 2l.0 mg/ml on day 0 to

l8.3 mg/ml on day 45). In plastic, there was no significant

 

33

change over time at 22°C; however, there was significant
degradation over time at 37°C. All concentration means at

22°C were within the USP acceptable range; at 37°C concentration
remained acceptable in glass through day 5 and in plastic
through day 30.

3. The LSD results for concentration showed that glass and plastic
syringes were not significantly different in the concentration
achieved at the various time intervals except on day 30 at both
22°C and 37°C.

4. There were statistically significant differences in pH through-

 

out the study at all temperatures, both between means in a
single package and between glass and plastic package means.
While these differences are statistically significant, they

are not meaningful since all pH means are within the acceptable

USP range (3.0-4.5 pH units).

The relationship between storage time and concentration in each
package, at each temperature is depicted in Figures l, 2, and 3. The
best straight line fit for the data was computed using regression. A
summary of the significance of the correlation coefficients is presented
in Table 8. With both glass and plastic the relationship between time
and concentration appears to become stronger as temperature increases.
In glass, there is no significant correlation between time and concen-
tration at 4°C but the correlation is significant at 22°C and 37°C.

In plastic, the correlation between time and concentration is non—

significant at 4°C and 22°C, but it is significant at 37°C. The

Figure I.

Figure 2.

Figure 3.

34

Succinylcholine Chloride--4°C regression plots and
USP acceptable limits for concentration (mg/ml).

Succinylcholine Chloride--22° regression plots and
USP acceptable limits for concentration (mg/ml).

Succinylcholine Chloride--37°C regression plots and
USP acceptable limits for concentration (mg/ml).

 

—i———'

35

glass u—o Y = 20.65 + (-.0028)X r: —.10
plastico-oo Y 320.46 +(-OOIS)X r: “.06

36609th. llmits----
22.0

 

21.0

20.0

Fig. I

19.0

 

18.0

couceumnou (mg/mil

 

17.0 )-
—r _ . . -
10 20 30 4O 50

STORAGE LENGTH (days)

glass ...—0 V: 20.53 + (-.Ol3l)X r = ‘.46
pingtico . . a Y 3 20.70 + i' 0076“ f 3 “.22

account». limits-no-
22.0

 

 

21.0

20.0 - -

 

Fig. 2

19.0 -

 

couceummou (mg/mil

18.0 -

 

”'an

10 20 30 do 50
STORAG! LEGTH (days)

glass o——o Y:20.80+(-.0630)X r=—.93
ptutico-«o Y=20.79+(-,osqo)x raras

mum. limits--
220 '

21.0
. 20.0
F1 9 . 3

19.0

 

18.0

.... t
d

coucemamou (mg/ml)

 

 

10 20 30 40 so
STORAGE LENGTH (days)

36

Table 8. Statistical significance of correlation coefficients
(r values) for concentration vs. storage length

 

 

 

r Value
Temperature

Package (°C) Succinylcholine Metaproterenol Thiamylal

4 NS NS NSa
Glass 22 -.46* -.54** ---a

37 -.93** -.77** --

4 NS -.68** NSa
Plastic 22 NS NS --

37 -.85** NS __a

 

aDrug not tested at these temperatures.

Significance levels: * .05

** = .OI

NS non-significant.

37

general conclusion here is that temperature appears to affect the
concentration of Succinylcholine over time and that this effect
appears at a lower temperature in glass syringes than in plastic
syringes.

Also considered was the effect on concentration of water loss
from the drug through each package. Theoretically, water loss could
cause an increase in concentration, and this might mask degradation.
The results of the study done to determine actual water loss by each
package is presented in Table 9. Here also the LSD value was used to
decide if a difference in the water lost/gained would significantly
affect concentration. Only at 37°C in plastic syringes would water
loss significantly increase concentration. However, this does not
affect the final outcome of the work because Succinylcholine Chloride

should never be stored at 37°C.

Metaproterenol Sulfate

 

All repackaged drug maintained sterility throughout this study.
The drug packaged in glass vials remained colorless throughout the
study at all temperatures. Metaproterenol stored in plastic syringes
also remained colorless throughout the study at 4°C and 22°C, but
a slight yellow tinge was noted on day 45 in drug stored at 37°C
(these did remain colorless through 30 days of storage). According
to Boehringer Ingelheim, this drug is very sensitive to oxidation
and such oxidation is almost immediately evidenced by such a yellow
hue. No particulate matter was noted in any packaged drug throughout

the study.

38

 

.mmmmcomu mmp00_0cw :mwm we xowp mommmpocw mmumuwuc

H+

.mmcw> mow> 0:0 mow commmcucw ou muem_ Ammop Loom: an emucommcamcv agave; Go mmoom

 

 

 

 

 

 

00N.+ 0.0_ 0.0 0.0 0.0 N._ 0opm 500_csm
0F_.+ “.0 0.0 0.0 m._ 0.0 0.00 0_ome_0
N_o.+ 0.0 0.0 0.0 m.~+ 0.0+ 050 Hum0ozoz
_E\0E mm...0md
000. N.o+ _._+ m.m+ 0.0+ 0.N+ 080m 0
000.+ N._ 0.0+ 0._+ 0._ N._+ 08NN _0_> mmuw>20
0pc. m.o+ N.N+ w.m+ o.m+ N.0+ 050
N0m.+ _.NP 0.0 N.m m.m N.o UONm 0
000.4 0.0_ 0.0_ 0.0 p.0 0.0 0000 UWSMMHMW00
mom.+ F.0F “.0 w.0 m.m 0.0 050 .
_e\0s 0...0md
mN0._+ 0.m~ 0.xm 0.N0 m.mm N.N_ moxm
000.+ N._ 0.? 0.. 0.0 0.0 0.00 0mmwflmm00
moo.+ 0.0 0.~ 0.. 0.0 F.o+ 080
ON 000 o» o Amancm____sv mczowcmasmh 000x000
00: 50c» mmoo mmcmcu v;m_mz m>mumpsszo mmmcoum
00003 0» 000
0000000 H0 0 0 0p N0 00 0. a
quwpmcomgh
mmmgoum mama
cowuwcucmozou co Ammo, cmamzv 000000 0:000; 40 uomwew quwumgomgp .0 anmp

39

Concentration and pH data are presented in Tables IO and II
respectively. In not every case are the presented data means based
on five replicate samples; a few samples were lost due to breakage
or spillage and a few replications were not included in the final
analysis when they were clearly out of line with four tightly
clustered values. In fact, two values out of I74 for concentration
and one value out of I77 for pH were omitted in this manner. Since
the ANOVA contained I34 error degrees of freedom for concentration
and I40 error degrees of freedom for pH, the statistical effect of
these omissions is negligible. The results of an ANOVA, used to
determine the significance of differences in pH or concentration
due to storage time, storage temperature, or package type (glass
vials or plastic syringes) can be found in Table I2. The ANOVA
showed a significant three way interaction among time, temperature,
and package at the .I% level (see F values).

The means for each package and between each package, at each
temperature, over time were tested for significant differences at the
I% level using LSD's. The LSD's used for the comparisons are presented
in Tables l0 and II. Several conclusions drawn from the LSD comparisons
follow:

I. The rate of concentration degradation at 4°C in plastic
appears greater than the rate in glass; glass vials show no
significant concentration loss over time, but a significant
loss of concentration occurs in plastic syringes after 30 days
of storage. There was no significant difference in concentra-

tion between glass and plastic packages. Every concentration

 

40

Table l0. Mean Metaproterenol Sulfate concentration (mg/ml)

 

 

 

 

 

 

4°C 22°C 37°C
Length of
Storage Glass Plastic Glass Plastic Glass Plastic
(Days) Control Vials Syringes Vials Syringes Vials Syringes
o 4.54 4.51 4.71a 4.47 4.55 4.53 4.57a
15 4.55 4.39a 4.42 4.32 4.30 4.44 4.41
30 4.14 4.40 4.50 4.33 4.45 4.40 4.13a
45 3.79 4.34b 4.27b 4.19 4.38 4.33 4.41
50 4.24 4.30 4.35 4.23 4.40 4.21 4.21
70 4.58 4.45 4.31a 4.21a 4.45 4.14 4.38
mean 4.30

 

- C
LSD(.0]) - .23
LSD(.O]) = .24

_ e
LSD(.0]) " .25

 

aOne replicate sample lost.

bOne replicate value thrown out.

CUsed to compare treatment means; each with five replicates.
dUsed to compare treatment means; four with five replicates.

eUsed to compare treatment means; four with four replicates.

4l

Table II. Mean metaproterenol Sulfate pH measurements

 

 

 

 

 

 

 

 

 

4°C 22°C 37°C
Length of
Storage Glass Plastic Glass Plastic Glass Plastic
(Days) Control Vials Syringes Vials Syringes Vials Syringes
0 3.83 3.85 3.76 3.85 3.74 3.85 3.74
15 3.80 3.81a 3.82 3.85 4.40b 3.87 5.51
30 3.85 3.84 3.85 3.85 5.72 3.92 6.98
45 3.79 3.84 3.89 3.87 6.44 3.89 7.08
60 3.69 3.74 3.87 3.79 6.47 3.84 7.05
70 3.74 3.82 3.94a 3.85a 5.58 3.88 7.09
mean 3.78
_ c
LSD(.0]) '" .10
LSD( 01) = .11d
aOne replicate sample lost.

bOne replicate value thrown out.

CUsed to compare treatment means; each with five replicates.

d

Used to compare treatment means; four with five replicates.

42

Table l2. ANOVA summary--Metaproterenol Sulfate

 

 

 

 

 

 

pH Concentration
Source of Variation df ms F df ms F
Time 5 5.326 I4l2.556*** 5 .254 7.807***
Temperature 2 26.093 69I9.8I7*** 2 .072 3.387*
Package l 93.732 .249E+05*** l .l48 6.025*
Time x temperature l0 l.464 388.I55*** ID .033 2.l82*
Time x package 5 5.I96 I377.885*** 5 .022 NS
Temp. x package 2 23.68l 6280.ll4*** 2 .058 3.l60*
Time x temp. x pkg. I0 I.393 369.327*** l0 .049 3.820***
Error I40 .004 I34 .0I5
Significance level: * = .05
*** = .OOI

NS non-significant.

 

43

mean at 4°C remained within acceptable limits (4.09-4.99 mg/ml—-
Boehringer Ingelheim, Personal Communication, MaureenWilson,
I984).

At 22°C there was a significant loss of concentration after

30 days of storage in glass vials and no significant change

in concentration throughout the study (70 days) in plastic
syringes. Glass and plastic packages were not significantly
different in concentration achieved at various time intervals
at 22°C except at 70 days of storage. All mean concentrations
remained within the acceptable range.

At 37°C, a significant loss of concentration occurred after

30 days of storage in glass vials and at days 30 and 60 in
plastic syringes. In spite of the increased concentration
loss seen at 37°C, all means were within acceptable limits.

At 4, 22, and 37°C there was no significant change in pH over
time using glass vials--except on day 60 at 4°C. It is believed
that this is an aberrant data point because it is an isolated
instance of pH decrease. When this drug is stored in plastic
syringes, the pH follows an upward trend; this trend becomes
stronger and increases in rate as temperature increases. In
plastic, there is a statistically significant increase in pH
after 30 days storage at 4°C, after l5 days storage at 22°C,
and at l5 days storage at 37°C. There is no clear answer as
to why pH increased when temperature was increased. Consul-
tation with Boehringer Ingelheim revealed that oxidation

normally results in a drop in pH and there was no mechanism

 

44

they knew of where temperature or oxidation alone caused this
drug's pH to rise. It seems that a possible explanation for
this observation is that there is an interaction between this
drug and the plastic syringes which is accelerated as temp-
erature increases; this conclusion is supported by the fact
that no such dramatic pH increase, associated with increasing
temperature, was observed in drug packaged in glass vials.
5. At 4°C there was no significant difference in pH between

glass and plastic packages until after 45 days of storage.
There is a significant difference in pH between glass and

plastic packages on all days at 22°C and 37°C.

The relationship between storage time and concentration of
the drug in glass vials and plastic syringes at each temperature is
shown in Figures 4, 5, and 6. Regression was used to find the best
fit line. A summary of the significance of the correlation coefficients
is presented in Table 8. In glass, the relationship between time and
concentration appears to become stronger as temperature increases;
plastic, however, shows no such consistent relationship, i.e., the
correlation coefficient shows no consistent downward and upward
trend. There does not appear to be any clear, reasonable explanation
for this. The correlation between time and concentration in glass is
non-significant at 4°C but is significant at 22°C and 37°C. In plastic,
there is a significant correlation between time and concentration at

4°C but not at 22°C and 37°C.

Figure 4.

Figure 5.

Figure 6.

45

Metaproterenol Sulfate--4°C regression plots
and Boehringer Ingelheim acceptable limits for
concentration (mg/ml).

Metaproterenol Sulfate--22°C regression plots
and Boehringer Ingelheim acceptable limits for
concentration (mg/ml).

Metaproterenol Sulfate-~37°C regression plots
and Boehringer Ingelheim acceptable limits for
concentration (mg/ml).

Fig. 4

Fig. 5

Fig. 6

couceumn sou (nu/ml)

CONCENTRATION (mg/ml)

 

46

 

 

 

 

 

 

 

 

 

 

 

 

 

*9
gm: —- Y= 4.3a.(-.oooo7)x ra-.oz
phonon-no Y:4.54+(-.oo4o) x r=-.sa
mm. limits-«—
5...., o
"s '00........... .
......‘..._‘A_A
v...” ..
c1'""--....'.°
. ‘0... ..
“I
f L ' ' ' .
15 30 45 60 7s
STORAGE LENGTH(days)
«a
glass — :4.43+(-.0037)X r:—.54
plastic and Y=4.38+ .OOOBX r: .11
MIN. limits-u-
15 30 45 so 75
STORAGE LENGTHld-ys)
5.0
. glass ...—... Y: 4.54+I-.0054Ix r:-.7‘7
:3 plastic o-uo Y: 4.39+I- .0014IX r:- .19
g! acceptable limits «mm
2
9 .
2
c:
1.-
z
u:
‘5’
Q 6 0t
4

 

.\

15 30 45 so 75
STORAGE LENGTH (days)

47

The effect of water loss on concentration was studied in the
same manner as for Succinylcholine Chloride (see Table 9 for data)
with similar conclusions; only at 37°C in plastic syringes would
water loss significantly increase concentration, and Metaproterenol

Sulfate should not be stored at 37°C.

Thiamylal Sodium

 

Thiamylal has a characteristic pale yellow color from
the moment it is reconstituted; all drug (in either glass vials
or plastic syringes) showed no perceivable deviation from this
initial color throughout the study. Sterility and clarity were
maintained throughout the study in both packages with no sign of
particulate formation.

Weight loss as well as the changes in pH and concentration
over time are presented in Tables l3, l4, and IS respectively. One
way ANOVA's were used to determine if there was any significant effect
of storage time on weight loss, pH, or concentration in plastic
syringes. The results of these ANOVA's are presented in Table I6.
Thiamylal stored in plastic syringes lost no significant amount of
water over time (as demonstrated by weight loss) and there was no
apparent weight loss seen over time in the glass vials. Storage time
did have a significant effect on pH (p==.00l) and on concentration
(p==.0l). An ANOVA was run a second time on the concentration data,
omitting day 0 results. This second ANOVA showed no significant
effect of storage time on concentration. It can be concluded that

in plastic there was a significant loss of concentration from day 0

 

48

Table I3. Mean weight (grams) of Thiamylal Sodium in package

 

 

Length of Storage Glass Plastic
(Days) Vial Syringe
0 722.2 34.8937
6 722.2 34.8940 8
LSD( 0l)='0916
I4 722.2 34.8943 '
30 722.2 34.8947

 

aUsed to compare plastic treatment means.

Table I4. Mean Thiamylal Sodium pH values

 

 

Length of Storage Glass Plastic
(Days) Control Vial Syringe
0 10.90 10.88 10.90
5 10.88 10.87 10 88 LSD(.O1)==.OO3a
14 10.93 10.91 10.91 LSD(.O])==.040b
30 10.90 l0.88 10.87
mean l0.90

 

aUsed to compare plastic treatment means.

b

Used to compare glass to plastic treatment means.

 

49

Table l5. Mean Thiamylal Socium concentration (mg/ml)

 

 

Length of Storage Glass Plastic
(Days) Control Vials Syringes
O 24.4 23.3 24.8
5 25.8 24.3 23.5 Lso(.0,) = 1.2a
14 25.2 24.3 23.4 LSD(.O]) = 2.0b
30 24.9 22.7 23.6
mean 25.3

 

aUsed to compare plastic treatment means.

b

Used to compare glass to plastic treatment means.

50

Table l6. ANOVA summary-~Thiamylal Sodium in plastic syringes

 

 

 

 

 

Source of
Variation df ms F
Total l9
pH Days 3 l3.733E-04 457.77***
Error I6 .003E-03
Total I9
Weight Days 3 .933E-06 NS
Error l6 .246E-02
Total I9
Concentration Days 3 2.288 5.72**
Error I6 .400
Total l4
Concentrationa Days 2 3.2345-02 NS
Error l2 3727.767E-04

 

aValues calculated after eliminating day 0 data.

Significance levels: ** = .Ol

*** = .001

NS non-significant.

5l

to day 6 but no significant loss after day 6. This conclusion was

reached by using the LSD calculated to compare means for plastic

syringes over time. LSD values are found in Tables l3, l4, and IS.

LSD values were also used to compare plastic pH means over time as

well as to compare pH and concentration means between glass and

plastic packages and these additional conclusions were drawn:

I.

each package is depicted in Figure 7.

the best straight line.

There was a significant difference among all plastic pH means
over time; however, this difference is not meaningful as the
greatest difference was .03 pH units and all pH means are
within USP acceptable limits.

Glass vials maintain an acceptable concentration (USP limits
are 23.2-26.8 mg/ml) through l4 days and plastic syringes
maintain acceptable potency through 30 days.

There was no statistically significant difference in
concentration or pH over time when the drug is stored

in either glass vials or plastic syringes.

The relationship between storage time and concentration in

glass vials and plastic syringes were found to be non-significant (see

Table 8) indicating that a consistent relationship between length of

storage time and concentration degradation is not evident.

Regression was used to calculate

The correlation coefficients computed for both

 

52

 

 

27.0 :__-_--__--_____ _
... glass o—o Y: 24.0+l-.03OIX r:—.5O
g plastico - 0 Y: 24.2+l-.030|X r.-.- .42
E, 26.0 nacceptable limits----
is 2505-
’2
E F’ ' o o o . .
E 2” \ ..........
(Z) O U ......... o o . . o . .?
o 23.0 "T "T: TTTTT "— =="""‘~—""
‘9 o
220
't: ,L 1 I
10 20 30
STORAGE LENGTH (days)
Figure 7. Thiamylal Sodium--4°C regression plots and USP

 

 

 

acceptable limits for concentration (mg/ml).

SUMMARY AND CONCLUSIONS

This study has determined the stability of Succinylcholine
Chloride, Metaproterenol Sulfate, and Thiamylal Sodium in glass and
plastic unit dose packages; also, differences between glass and
plastic packages in maintaining this stability have been established.
Recommendations for storage of each drug at 4°C are based on the
stability data collected and are presented in Tables I7 and IB. pH
and concentration considerations are given in these tables so that the
pharmacist can use these data to make a judgment on expiration dating
of the unit dose repackaged pharmaceuticals studied. From Tables l7
and IB, it can be seen that identical recommendations are made for
plastic and glass packages; this is because the data on all drugs
indicated that regardless of package, the drugs maintained acceptable
pH and concentration throughout the study--except in the case of
Thiamylal Sodium. Thiamylal Sodium maintained concentration within
the acceptable limits through 30 days storage in plastic syringes
but maintained acceptable potency only through l4 days of storage
in glass vials. This loss of potency on day l4 could be an aberrant
data point but to be safe, a l4 day maximum storage period was
recommended for storage of Thiamylal in glass and plastic. Study
of the tabulated data and the graphs reveal that the storage period
recommended for Thiamylal is approaching the limit. Any attempt to

extend these recommendations would require considerable additional

53

54

 

 

 

 

 

 

Table I7. Recommendations for storage at 4°C based on concentration
(mg/ml) data
Safe
Storage Beginning Ending Nominal Acceptable
Length [C] [C] % Loss [C] [C] Range
Drug/Package (Days) (mg/ml) (mg/ml) [C] (mg/ml) (mg/ml)
S.C./glass 2l.0 20.3 3.3 a
45 20.0 I8.6-2l.4
S.C./plastic 20.9 20.3 2.9
M.S./glass 4.5l 4.46 l.l b
70 4.54 4.09-4.99
M.S./plastic 4.7l 4.3l 8.5
T.S./glass 23.3 24.3 4.3C
14 25.0 23.2-25.86
T.S./plastic 24.8 23.4 5.6
aU.S.P.

bPersonal communication with Boehringer Ingelheim.

CGain.

S.C.

T.S.

Succinylcholine Chloride; M.S. = Metaproterenol Sulfate;

Thiamylal Sodium.

55

Table l8. Recommendations for storage at 4°C based on pH data

 

 

 

 

Safe
Storage
Length Beginning Ending Nominal Acceptable
Drug/Package (Days) pH pH pH pH Range
S.C./glass 3.67 3.63 a
45 3.65 3.0-4.5
S.C./plastic 3.67 3.6l
M.S./glass 3.85 3.82 b b
70 -- --
M.S./plastic 3.76 3.94
T.S./glass l0.88 I0.88 a
30 ll.l l0.7-ll.5
T.S./plastic lO.90 l0.87

 

aU.S.P.
bNot available.
S.C. = Succinylcholine Chloride; M.S. = Metaproterenol Sulfate;

T.S. = Thiamylal Sodium.

 

56

laboratory evaluation. It should be noted that while l4 days is the
recommended storage time for Thiamylal based on concentration, 30 days
is recommended based on pH--the data are presented and the pharmacist
must make his or her own decision on expiration dating.

Metaproterenol Sulfate is stable in glass vials at 22°C but
not in plastic syringes at 22°C, due to the dramatic pH increase.
Succinylcholine Chloride should not be stored at 22°C because the
manufacturer states that the drug must be stored at 4°C to 8°C.

Suggestions for future work on these drugs includes the

 

determination of kinetic degradation models for concentration and
possibly pH for any of these three drugs, analysis for absorption

of the drugs into the plastic packages, determination if migration

of syringe or vial components into the drugs occurs, and possible
quantitation of any migrating species. Determination of the per-
meability constants for water vapor and oxygen for the various plastic
syringes used in this study would provide valuable information which
could be applied to the packaging of many liquid pharmaceuricals.
Finally, kinetic models for drug degradation can be combined with
these permeability constants to develop models which can then be used
to select unit dose packaging systems that have maximum probability

of satisfactory results in stability testing.

 

APPENDICES

 

APPENDIX A

ANALYSIS METHODS

APPENDIX A

ANALYSIS METHODS

Third Supplement. USP-N F

solution having a known concentration of about 250 pg of USP
Spironolaetone RS per ml.

Assay preparation—Transfer about 25 mg of Spironolactone.
accurately weighed. to a IOO-ml volumetric Ilaslt. add a mixture of
acetonitnle and water (9. I) to volume. and mu.

Chromatographic system (see Chromatography (621 ))-The
liquid chromatograph 1s equipped with a 254-11m detector and a
4411111 x 11an column that contains packing L1. The flow rate
is about 1 ml per minute. Chromatograph six replicate 1njections
oftheStandardprepor-atlon. and record the peak responses asd1-
tuned undet’Prooeduru: therelativestandasddeviationisnosmoto

than I .591.

r ‘ ‘, injq: qua] volume (about 20 111) oftho
Standard preparation and the Assay preparation into the chro-
matograph by means of a suitable m1crosyr1nge or sampling valve.
recordthech andmeasutetheresponsesforthemajor
peaks. The retention time for spironolactone 1s about 5 m1nutes.
Calculate the quantity. in mg. 01 Cufl 330.5 1n the portion of Spi-
ronolactone taken by the formula 0. lC(rU/.r5) 1n which C it the
concentration. in as per ml. of USP Spironolactone R8 in the
Standard preparation. and ru and r: are the peak responses ob-
tained for spironolactone from the Assay preparation and the
Standa-d preparation. respectively. .,

 

f' loo-".1 -

Spironolactone Tablets

an. te roe.
Identification-— 'Mix a quantity of finely powdered Tablets.
equivalent to about 100 mg of spironolacsone. with 25 ml of mesh.
snot. and filter. On a su1table thin-layer chromatographic plate
(sea Chromatography (621 )1. coated with a 0. 25-mm layer of
chromatographic silica gel mixture. spat 10 ul of this solution and
10 pl of a solution of USP Spironolactone RS in methanol con-
taintng4 mgpu'ml. Developthechsomasognm 111s solventsystem
consisting ofchloroform. ethyl acetate. and methanol (2: 2: I) until
the solvens front has moved about three-fourths of the length of the
plate. Remove the plate from the developing chamber. mark the
solvent front. and allow the solvent to evaporate. Loate the spots
onthe plate viewing under short- wavelength ultrav1olet light:
the R, value 0 the principal spot obtained from the solution under
test corresponds to that obtained from the Standard solution. .”

at... to rent
Assay --

'Moln‘le phase. Standard preparation. and Chromatographic
system—Prepare as directed 1n the Assay under Spironolactona.

Assay preparation— Weigh and finely powder not less than 20
S actone Tablets. Transfer on accurately weighed portion

the powder. equivalent to about 25 mg of spironolactone. to a
lib-ml volumetric flask. add 10.0 ml of water. and swirl gently for
about IO minuta. Add 70 ml of acetonitrile. soniate for 30 min-
us. with occasional shaking to dissolve the soluble substation in
the mixture. dilute with acetotutrile to vdutne. and mix. Centrifuge
a portion of the mixtureat about 3000 rpm for 10 minutes. and use
the supernatant liquid.

Procedure—Proud as directed for Procedure in the Assay
under Sptronolactone. Calculate the quantity. in mg. of
Cal-113035 in the portion of Tablets taken by the formula
0.1C(ru/rs). 1n which C LI the concentration. in 11g per ml. ofUSP

R3 in the Standard preparation. and ru and r: are
the pnk ruponses obtained for spironolactone from the Assay
paparatton and the Standard preparation. respectively.”

Stannous Fluoride

a... to read
May for eta-o. ion—

'o.1.v Pomsnutn iodide-lodate—In a 1000-1111 volumetric flask.
dissolve 3. 567 g of potassium todate. previously dried at 110‘ to
onstant wetght.1n 200 ml of oxygen-tree water containmg l g of
asdium hydroxide and 10 g of potassium iodide. dilute with oxy-
pn-free water to volume. and mix. Standardize this solution by
titrating a solution prepared from an accurately weighed quantity

57

Official Monographs, USP XX / Succinylcholine 255

of reagent tin (Sn) and hydrochloric acid. Each ml of 0.] N Po-
tassium iodide-laden is equivalent to 5.935 mg of Sn.
Procedure— ”Transfer about 250 mg of Stannous Fluoride.
accurately weighed. 10 a SOD-ml conical flask. and add 300 ml of
hot. recently b011ed 3 1V hydrochloric acid. While passing a stream
of an oxygen-free inert gas over the surface of the liquid. sand the
flask to dissolve the Steam Fluoride. and cool to room tempera.
ture. Add 5 ml of potassium iodide TS. and titrate in an men at-
with ‘OJ Npotasst'tun iodide-laden. .3 adding 3 ml of
starch TSas theend-pointisspproached. Eachmlof '0. I Npo-
tassiunt iodide-lodateu is equivalent to 5.935 mg of Sn”.

Succinylcholine Chloride

Add the tun-esp

'Referance standard—USP S ucct'nylchollne Chloride Reference
Standard—Do not dry: determine the water content by Method
I before using for quantitative analyses...

Identification—

diagram?“ biz sametisweveleagtu
1onoitexh1tsmaximaoeiyatthe

111R?“ of a similar preparation of USP Succinylcholine Chloride

B!“ 'nieretention umeofthe majorpmkinthechtomatogram
of the Assay preparation is the same as that of the Standard
p tion obtained 1n the Assay. ...

'Dissolve a portion in water to obtain a solution containing
1 mg per ml. Spotting I-nl portions and using a solvent system
consistingofa mixtureofacetoneandl .V hydrochloncact'd (l : 1).
proceed as directed under Thin-layer Chmawgropht‘c Identtfi-
cation Test (201). Usethe following pundits-em Ioatethesposs:
Heat the platest 105' fu5mcookandspraym1h potassium
bismuth iodide TS. then heat again at 105' for 5 sonata...

'es

ale-p to not

Assay—'[Non—Since the Mobile phase etuployed in this pro-
cedure hasa fairly highconcustratioaofchlotideioaanda low pH.

it may be advisab. c to rinse the entire system with water following
the use of this Mobile phase.)

1 obile phase—Prepares l in lOsolutioeofl M aqueous tetra-
methylammonium chloride in methand. filter this solution
through a OAS-um membrane filter. and adjust with hydrochloric
acidtoa pH ofabou13.0

Standard preparation—Transfer about 88 mg of USP Succin-
ylcholine Chlonde RS. accurately weighed. to s 104111 volumetric
flask add 4 0 ml of water. and dilute with Mobile phase to volume
while mixing. Prepare the Standard prep'uion cottuuretuly with
the Assay preparation.

Assay preparation- Tramt‘er about 88 mg of Succinylcholine
Chloride. accurately we1ghed. to a lO-ml volume flask. add 4.0
ml of water. and dilute with Mobile phase to volume while
mixing.

Chromatographic system (see Chromatography (621 )l-The
liquid chmatograph is equipped with a 214-11111 detector and
4411111 x 254:1: column that contains packing L3. The flow rate
is about 0.75 ml per minute. Chromatograph five replicate injec-
tions of the Standard preparation. and record the peak responses
as directed under Procedure: the relative standard deviation 1: not

morethan l. 5%. and the tailing factor 1s not greater than- 7 .5

Procedure—Separately 1n1ect equal volume (about 10 1d) of the
Standard prepmtton and the Assay preparation mm the chro-
mstognph by means 01 a suitable microsynngeor sampling valve.
roundthechsunatogtammdmeasurethe ameliorated-mar
Eats. Calculate the quantity. 1n mg. of C11H10C11N~01 in the

ucunycholine Chloride taken by the lormula 10C lrU/rg) 1n which
C is the concentration. in mg per mL of anhydrous succtnylcholine
chloride 1n the Standard preparation. as determined from the
concentration of USP Succmylcholine Chloride RS canceled for
moisture content by a 11m metnc water determinauon. ru 1s the pak
response of the Assay preparation. and r; is the average pat re.
sponse of the Standard preparation. as

specttumofapotaasiutnbromide

58

256 Succinylcholine / Official Monographs. USP XX

Succinylcholine Chloride Injection

A“ h

'Relareaee stanhrd—USP S ucctnvlcholine Chloride Reference
Standard—Do not dry: determine the water content by Method
I before using for quantitative analyses.”

”let"
'A solution (1 in 20) responds to the tests for Chloride

(191 1..)
B: 'It responds to Identification tests 3 and C under Succin-
ylcholine Chloride. .3

I)

cu. to rent

Anny—'{NO‘rE-Since the Mobile phase employed in this pro-
cdure has a fairly high coricentration ofchloride ion and a low p.1-1
11 may be advisable to rinse the entire system with water following
the use of this Mobile phase. ]

Mobile phase and Chromatographic system—Prepare as di-
rectcd in the Assay under Succinylcholine Chloride.

Standard preparation—Transfer about 88 mg of USP Succin-
ylcholine Chloride RS. accurately weighed. to a IOoml volumetric
flask. add a volume of water to correspond to the solvent composition
of the Assay preparation. and dilute with Mobile phase to volume
while mixing. the Standard preparauon concurrently with
the Assay preparation.

ayrreparation—Transfer a volume of Succinylcholine
Chloride n.1ection equivalent to about 80 mg of anhydrous suc-
cinylcholine chloride. to a IO-ml volumetric flask. and dilute with
Mobile phase to volume while mixing.

Procedure—Proceed as directed for Procedure in the Assay
under Succinylcholine Chloride. Calculate the quantity. in mg.
of anhydrous succinylcholine chloride (Cid-l mClgNgO.) in each
ml of the Injection taken by the formula (10C/V)(ru/r3).1n which
V is the volume. in ml. of Injection taken."

Sterile Succinylcholine Chloride

see u» m
'Refm stunted—USP S ucctrrylcholine Chloride Reference
Standard—Do net dry: determine the water content by Method
1 before using for quantitative analyses.”

Sulfadiazine

Cherub“

Assay—-

'Mobile phase-Prepare a suitable. degassed solution of water.
acetonitrile. and glacial acetic acid (87:12: 1)

Internal standard solution— Dissolve USP Sulfamerazine RS
in methanol to obtain a solution having a concentration of about I
mg per ml.

Standard preparation—Transfer about 100 mg of USP Sulfa.
diazi’iie RS. amutately weighed. to 1 100-1111 volumetric flask. dilute
with 0.025 N sodium hydroxide to volume. and mix. Mix 5. 0 ml
of this solution with 5.0 ml of Internal standard solution

Assay preparation—Transfer about 100 mg of Sulfadiaa'ne.
accurately weighed. to a IOO-ml volumetric flask. dilute with 0.025
N sodium hydroxide to volume. and mix. Mix 5.0 ml of this solu-
tion with 5.0 ml of Internal standard solution.

Chromatographic system (see Chromatography (621 ))—The
liquid chromatograph is equipped w11h a 254-nm detector and a
441m X 30-cm column that contains packing L1. The flow rate
is about 2 ml per minute. Chromatograph five replicate injections
of the Standard preparation. and record the peak responses as di-
rooted under Procedure: the relative standard deflation is not more
than 2.0%. and the resolution factor between sulfadiazine and sul-
famerazine is not less than 2.0.

Procedure—Separately 1njec1 equal volumes (about I0 111) of the
Standard preparation and the Assay preparation into the chro-

 

Third Supplement. USP—NF

matographn record the chromatograrns. and measure the responses
for the mayor peaks The relative retention times are about 0 8 for
sulfadiazine and 1.0 for sulfamerazine. Calculate the quantity.
in mg. of C .oH.oN .035 in the portion of Sulfadiazine taken by the
formla 200C(Ru/R5) in which C is the concentration.1n mg per
ml. of USP Sulfadiazine RS in the Standard preparation. and Ru
and Rs are the peak response ratios of the sulfadiazineand internal
standard peaks obtained with the Assay preparation and the
Standard preparation. respectively. .3

Sulfadiazine Tablets

alt-sputum“:

Assay—

'Moblle phase. Internal standard solution. and Standard
preparation—Prepare as directed in the Assay under Sulfadia-
sine.

Assay preparation—Weigh and finely powder not less than 20
Sulfadiazine Tablets. Transfer an accurately weighed portion of

mm equivalent to about It!) mg of sulfadiazine. to a 100.1111
volumetric flask. add 75 ml of O. 025 N sodium hydroaide. shake for
30 minutes. dilute with 0. 025 N sodium hydroxide to volume. and
mix. Centrifuge a portion of this solution. and mix 5.0 ml of the
clear supernatant layer with 5.0 ml of the liner-rial standard solu-
tion.

Chromatographic system and Procedure—Proceed as directed
for Chromatographic system and for Proactive 1n the Assay under
Sui/adiozine. Calculate the quantity. in mg. of Cid-119M038 1n
the portion of the Tabletstaken inseam the formula ZNClRu/Rg).1n
which the terms are as therein

Sulfamerazine Tablets
pants 111s nut-h;
'Dh'mtegratiee (701 )1 30 minutes.”
has the m
'm (711)-
Medium: water: 900 ml.
Apparatus I: 100 rpm.

Time: 45 minutes.

Procedurr— Determine the amount of C . 1 1-1 .1N10§ dissolved
from ultraviolet ahaorbances at the wavelength of maximum ab-
sorbence at about 243 nm of filtered portions of the solution under
test. suitably diluted with Dissolution Medium. 1f nwessary. in

comparison with a Standard solution having a known concentration
of USP Sulfamerazine R5 in the same medium.

Tolerances—Not less than 75% (Q) of the labeled amount of
CuHuNa02s is dissolved ill ‘3 minutes...

Sulfamethizole

Minuet

HavymeflMethod '11.. (231): 0.002%.

Sulfamethoxazole

Charge to rent

Mela-grunge. 'Class I.) (741): between 168° and 172'.
Citation to rent

Seleni- (291 1: 0.003%. 'a ZOO-mg test specimen being

-Il

ALUPENT“
(brand of Metaproterenol Sulphate)
Solution for Inhalation

Essay - High Performance Liquid Chromatography

lUse special spe‘troouality solvents.)

Mobile phase - Dilute 10.0 ml of funnic acid {reagent grade) to
3000 nl vii th water”
Cn-4SO) or equivalent.

tandard preparation - Transfer about 30 mg of Metaproterenol.su]fate
Reference Standard, accurately weighed, into a SU—mfl volumetric
fTask, dissolve in, and dilute to volume with the Mobile phase,
Express the concentration as anhydrous, methanol ano isopropanol-free

metaproterenol sulfate.

Assay preparation - Test the solution obtained by pooling the
contents of 20 units. Transfer 5.0 of the sample into a SO-ml

volumetric flask, and dilute to volume with the figbile phase.

Chromatograph conditions - May be modified as needed to achieve
desired chromatographic response.

Instrument -
(or equivalent)
Guard column - Bondapah C13/Corasil
Column‘ : i - 3.9 mm x 30 cm, stainless steel
Stationary phase ' - u Bondapah C13 (Waters‘)
Mobile phase - {as defined above).
Flow rate . _ - 2.0 ml per minute
-Dete:tioh- - UV at 278 nm

INJECt 25 ul of the test solution into the Chromatograph which has
been suitably equilibrated. Calculate the resolution factor by the
fonpula 2(T2-T1)/(H1+H2) in which 11 and 12 are the

retention values (mm) of the peaks, and El and 32 are the widths
(mm) at the baseline,fobtained by extrapolation of the relatively
straight sides of the'peaks, for the Metaproterenol Sulfate and
tetaoroterenol Ketone Referen:e Standards, respectively. The
resolution is not less than 1.5. -

 

Procedure - Chromatograph two or more 25-el in;ectiC”$ ach of the
Standard and Assay preparations. H::::re the peel ’. c'ts and
me the Quantity. in msifof (C;::i17'-'C;-32 12804
in the 55;;1e l5 0 ml) taken by the icfi'ulc Et-(“u’:;) in which C
lS the CL'ZETL’EZTOD, ir 39 PE’ ”7. £5 ”?3:P'01‘7&“'7 5375519 '—
«eiecer'e Standard, Calcula‘ed as tie cnt§crous so. -n--.r:e £:li.
‘n _:5 _;,—-..; 5'? ;_7.: arc H. r d,i5 are the a —*c7°s o' the
ffli— j - . -:: F " rc :r :a’ ‘iors -- '. ‘3

Filter through a 0.4r-um membrane filter (Colman

 

Haters ALC 202 Liquid Chromatograph

6O

S.V. 122 Surital 543;
35-122

ASSAY SODIUM IAMYLAL GAS CHROMATOGRAPHY

Preparation of Phensuximide Internal Standard:

Transfer 300 mg. of Phensuximide accurately weighed into a
100 ml. volumetric flask. bring to volume with reagent

chloroform and mix (C . 3.0 mg./ml-).

Preparation of Surital Acid Standard Solution:

 

Accurately weigh 460 mg. of Surital Acid into a 100 ml.
volumetric flask. bring to volume with reagent chloroform

and mix (C u 4.6 mg./ml.).

Preparation of Working Standard:
Pipet 5 ml. each of Phensuximide Internal Standard (c a
3.0 mg./ml.) and Surital Acid Standard Solution (c a 4.6 mg.

ml.) into a glass stoppered tube and mix.

Preparation of Sample:
Carefully remove aluminum cap and rubber stopper from steri-
vial. Add 25 ml. of distilled water, swirl the contents of
the steri-vial until the powder is completely dissolved and
transfer solution to a 100 ml. volumetric flask. Rinse
steri-vial with small amounts of diStilled water and transfe

rinsings to the same flask. Bring to volume w1th distilled

 

6l

h

-.V. 122 Surital Sgg.
35'122

ASSAY (SODIUM THIAMYLALl {GAS CHROMATOGRAPHYL

water and mix. Pipet 10 ml. of this solution to a 125 ml.
separator. Add 25 ml. of distilled water and 5 ml. 1N HCl.
Mix contents of the separator and extraCt with 25.25.25.20 ml.
of chloroform passing extracts into a 100 ml. volumetric flask

Bring to volume and mix.

m=
Pipet 3 ml. of prepared sample and 5 ml. of Phensuximide
Internal Standard Solution (C = 3 mo./ml.) into a glass
stoppered tube and mix. Ingecc 2 -l of sample and working
Standard in: the Chromatograph using the outlined instrument

conditions. Calculate the area ratio of Phensuxinide/Surital

for the sample (A) and standard (a).

Q
I

Ca-culaticn:

 

g Sodium Thiamylal/Vial s d x C x 100 x £29 x 1.386
1000 to

a g x c x 1.086

C = concentration of Surizal ACid Standard mg./:l.

100 = dilution of sample

 

 

62

S.V. 122 Surital 5 9.
35-122

ASSAY (SODIUM THIAMYLAL) QGAS CHROMATOGRAPHY)

gggggigigation via Relative Retention Time:
The relative retention time of Surital/Phensuximide falls
within the limits shown.

Retention Time of Surital in Sample Preparation

Retention Time of Phensuximide in Sample Preparation °

Where:

 

RStd. Relative Retention Time a Ratent$°n TE?! Of Unknown
Retention Time or Internal Std.

RStd. is obtained from the chromatogram of the standard preparation.

 

 

 

 

63

35-122
TECHNIQUE NOTES

As a guideline for setting up a specific inscrument. the operating
conditions for the Hewlett Packard Model 5750 and H.P. Model 3370
Electronic Integrator are as follows. I

4 ft. x 2 mm. 1.0. packed with 3% ov-17 on Gas Chrom Q

(100-120 mesh).
335213 Size:

2 ul.
Carrier Gas:

Helium at 30 ml./min.
w:

a) Column - 170° isothermal

b) Injection Port - 180°. Do 223 exceed.

c) Detector - 190°
Sensitivity:

Range - l000

Attenuation - 2 mv on eleccronic integrator

Flame Ionization

hydrogen at 60 ml./min.

Air at 500 ml./min.
Retention Time:

Phensuximide = 2.0 minutes

Surital a 4.3 minutes

APPENDIX B

COMPARISON OF THE RESPONSES OF THE ELECTRONIC INTEGRATOR
WITH THAT OF THE STRIP CHART RECORDER IN CALCULATING
METAPROTERENOL CONCENTRATION

APPENDIX B
COMPARISON OF THE RESPONSES OF THE ELECTRONIC INTEGRATOR

WITH THAT OF THE STRIP CHART RECORDER IN CALCULATING
METAPROTERENOL CONCENTRATION

Five successive 10.0 p1 standard injections were made into the
HPLC fo11owed by five successive 10.0 p1 samp1e injections and the
response to each injection was recorded by the strip chart recorder
described in the Concentration Ana1ysis for Metaprotereno1 Su1fate in
the Materia1s and Methods section. Immediate1y fo110wing the above
injections, the HPLC was disconnected from the strip chart recorder and
connected to the e1ectronic integrater described in the same Materia1s
and Methods section. Again, five 10.0 p1 standard injections were made
into the HPLC fo11owed by five successive 10.0 p1 samp1e injections;
each response was recorded by the e1ectronic integrator. The five
standard rep1icate responses were averaged for each recording device.
Each averaged standard response and respective samp1e response was used
in equation 2 to ca1cu1ate five concentration va1ues for the samp1es
run with each recording device.

A two tai1ed Student's t test was used to compare the concen-
tration resu1ts obtained with the strip chart recorder with those from
the e1ectronic integrator. The ca1cu1ated t statistic was -3.4501 and
the critica1 t va1ue was 3.355 (p==.01); therefore, there was a statis-
tica11y significant difference between the concentrations ca1cu1ated

based on each of the two recording devices.

64

65

A term was ca1cu1ated to adjust the concentration data
c011ected on the strip chart recorder so that it wou1d be comparab1e
to the data accumu1ated on other days from the e1ectronic integrator.
This term, see equation 4, was subtracted from a11 concentrations
computed from the strip chart data. These corrected concentration

va1ues appear in Tab1e 10.

 

 

5.10 - 4.51 -
5.10 - .116 (4)
where:
5.10 = the average concentration--strip chart recorder;
4.51 = the average concentration--e1ectronic integrator; and

.116 conversion term.

LIST OF REFERENCES

LIST OF REFERENCES

A1ford, R. H., J. A. Kase1, P. J. Gerone, and V. Knight. 1966.
Human inf1uenza resu1ting from aeroso1 inha1ation. Proc.
Sco. Exp. Bio1. Med. 122:800-4.

American Society of Hospita1 Pharmacists. 1979. ASHP guide1ines
for repackaging ora1 so1ids and 1iquids in sing1e unit dose
and unit dose packages. Am. J. Hosp. Pharm. 36:223-4.

American Society of Hospita1 Pharmacists. 1977. ASHP guide1ines
for singIe unit and unit dose packages of drugs. Am. J.
Hosp. Pharm. 34:613-4.

Anon. 1977. Minimum standards for pharmacies in institutions.
Am. J. Hosp. Pharm. 34:1356-8.

Chaney, R. F., and M. R. Summerfie1d. 1984. Survey of expiration
dating po1icies for repackaged pharmaceutica1s. Am. J. Hosp.
Pharm. 41:1150-2.

Christensen, J. M., R. Y. Lee, and K. A. Parrott. 1983. Stabi1ity
of three ora1 1iquid drug products repackaged in unit dose
containers. Am. J. Hosp. Pharm. 40:612-5.

E1ias, w. F., and J. A. Apat. 1965. SingTe dose disposab1e syringes--
the tubex system. Bu11. Parentera1 Drug Assoc. 19:61.

Food and Drug Administration. Current good manufacturing practices.
21 C.F.R. 211.137.

Hart, R. J., and F. S. V. Marsha11. 1976. Wastage of pharmaceuticaIS.
Lancet 2:1239-40.

Hicks, C. I., J. P. B. Ga11ardo, and J. K. Gui11ory. 1972. Stabi1ity
of sodium bicarbonate injection stored in po1ypropy1ene syringes.
Am. J. Hosp. Pharm. 29:210-6.

Highsmith, A. K., G. P. Greenwood, and J. R. A11en. 1982. Microbia1
growth in parentera1 medications. J. C1in. Microbio1.
15:1024-8.

Hubert, Barbara. 1983. Ora1 communication. United States
Pharmacopeia—-Monograph Specia1ist.

66

67

K1einberg, M. L., G. L. Stauffer, and C. J. Latio1ais. 1980.
Stabi1ity of five 1iquid drug products after unit dose
repackaging. Am. J. Hosp. Pharm. 37:680-2.

LatioTais, C. J. 1970. A pharmacy coordinated unit dose dispensing
and drug administration system. Am. J. Hosp. Pharm. 27:886-9.

McDona1d, D. E., H. M. Prisco, and R. J. Parente. 1972. Prefi11ing
syringes in the hospita1 pharmacy. Am. J. Hosp. Pharm.
29:223-8.

Ma11et, L., G. P. Sesin, J. Ericson, and D. G. Fraser. 1982. Storage
of vancomycin ora1 so1ution. N. Eng. J. Med. 307:445.

Moffet, H. L., and D. A11an. 1967. Co1onization of infants exposed
to bacteria11y contaminated mists. Amer. J. Dis. Chi1d
114:21-5.

Nedich, R. L. 1983. Se1ection of containers and c1osure systems for
injectab1e products. Am. J. Hosp. Pharm. 40:1924-7.

N011y, R. J., P. E. Stach, C. J. Latio1ais, T. D. Soko1oski, and
M. C. Nahata. 1982. Stabi1ity of thiamine hydroch10ride
repackaged in disposab1e syringes. Am. J. Hosp. Pharm.
39:471-4.

Romberg, M. A. 1979. More unit dose products are forecast. Am. J.
Hosp. Pharm. 36:1728.

Rou1ette, A. w. 1972. An assessment of unit dose injectab1e systems.
Am. J. Hosp. Pharm. 29:60-2.

Sanders, C. V., Jr., w. G. Johanson, Jr., and J. P. Sanford. 1970.
Serratia marcescens infections from inha1ation therapy
medications: nosocomia1 outbreak. Ann. Intern. Med. 73:15-21.

Sartnurak, S., and J. M. Christensen. 1982. Stabi1ity of va1proate
sodium syrup in various unit dose containers. Am. J. Hosp.
Pharm. 39:627-9.

S. G. K. 1971. Unit-dose: wonderchi1d comes of age. Hospita1s
45:72-9.

Sheth, N. K., G. T. Post, T. R. Nisniewski, and B. V. Uttech. 1983.
Mu1tidose via1s versus sing1e-dose via1s: a study in steri1ity
and cost effectiveness. J. C1in. MicrobioI. 17:377-9.

Stee1, R. G. D., and J. H. Torrie. 1980. Princip1es and Procedures
of Statistics, A Biometric Approach. McGraw—Hi11 Book Company,
New York.

68

Talley, J. R., R. A. Magarian, and E. B. Sommers. 1973. Feasibility
of unit dose packaging of medications for inha1ation therapy.
Am. J. Hosp. Pharm. 30:526-30.

United States Pharmacopeia Convention. 1980. Stability considerations
in dispensing practice. United States Pharmacopeia XX. United
States Pharmacopeia Convention, Maryland.

United States Pharmacopeia Convention. 1982. Succinylcholine Chloride.
United States Pharmacopeia, Supplement 3. United States
Pharmacopeia Convention, Maryland.

Varnum, J. w. 1974. Administrator‘s view of unit-dose. Hospitals
48:108-112.

Wilson, Maureen. 1984. Oral communication. Research and development--
Boehringer Ingelheim.

Zell, M., and R. P. Paone. 1983. Stability of insulin in plastic
syringes. Am. J. Hosp. Pharm. 40:637-8.

Zvirblis, P., and R. I. Ellin. 1982. Kinetics and stability of a
multicomponent organophosphate antidote. J. Pharm. Sci.
71:321-5.

 

 

 

 

 

1|1111111911311111111111111111111111111