!"  # $# #

!#   % !! &! #
&# !&!  #" ' (

      !"#$% &"'     

 
) ) 
*+ ,



(    ) *
-* . /''
11 .

(! 1 9


 1 ;

0
)  ) 1 =

1 )  2 1 1 M

1 03)
1 1 ..

1 
* )
)
1 .9

411   ) 5
) 
5
 65 
 *  *  )  7 *)
1
89/: ( ( .9
8949;:
411 7 *)
)
*  )0)
1 (( .:
89:
411/ 7 *)
*   0 )  )0)
1 (( .:
89<:
41141 ) 

 65 
*  )0)
( .;
89=:
41/ ) 
 *6 *
*  )0)
1 (( .<
8<9>:
41/11 0
) 9 * )   )3
1 (( .<

414   ) 5
) 
 )   *6 *  1 ( ( .=
8<9':
4141 * 1 (( .=
8<9=:
4141/ * 1 ( .>
? 8<9':
41414 * ) 8  :1 ( .M
8<9=9':
4141; ** * 8**:1 ( .M
8<:
4141 * @  @  8    :1 ( 8-

4141A @ *) 8*: ( 8-

8=:
4141< *) 8*: ( 8-
8;:
4141=  
  )   ) 1(( 88
8<9:
41; 
)  
)01 ( 88
8:
41;1   
  
 1 ( 89
89<:
41;1/ 03)
1 ( 89
89<:
41;14 
)  
)0   1 ( 89
 8:
41;1; 
)  
)0   B *+1 ( 8:
89<:
41;1  
 * 0    
)) 1 ( 8:

41;1A )*     

  )
89<:
 
1 ( 8<

1 * ) 7* ) 1 1 8M

;1 6*
9 ) 
9 )   *6   )
( ( 8M

;1/   2   )  ( ( 9.

;1/1  2   2  - )))1 ( 9.

;1/1/ )
))
  2  8! C D ': ( 9.

;1/14 *  )   )  ( 9.

;1/1; 
*   
 
) 
 *6 *
1
( 99

;14 
)0     ,

5
  65  ( 99

;141  
 
)0 ( ( 99

;141/ 

5
 -65 
+
 ) 

)01 ( 99

1 
)
1 9;

1  
  
0)
( ( 9;

1/ 
)  2 1 ( 9=

1/1  
 
)  )   
)  
) 

*61 ( 9=

14  2  )   *6       *  2

 * ,) 
5) 
( 9>

1 

2 1 :;

 

1 1 :=

  
1 :M

00B 5 1 ;.

7
1 ;9

%"+ , -. ( ;9
Dedicatoria A Dios Padre nuestro, por permitirme disfrutar de cada día y por todo lo que me
ha brindado. A mi padre Manuel y a la memoria de mi madre Olinda, por sus enseñanzas, su
confianza y todo el amor que me brindaron, los cuales son estímulo para alcanzar los objetivos
de mi vida. A mis queridos hermanos Manuel y Vladimir, por comprenderme, por sus ánimos,
y por sus ocurrencias que dan alegría a nuestras vidas.

/01 23""#$# 4 5
""67# #% &"  / .
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

8 /01 23""#$# 4 5
""67# #% &"  /
 (!

(!
A mi estimado Director de tesis
Dr. Bertran Santiago Trujillo por guiarme en el desarrollo de este trabajo, por su paciencia
ante mis dudas, y por apoyarme en hacer realidad este objetivo.
A mi Jurado Examinador y Calificador:
Dr. José Juárez Eyzaguirre (Presidente)
Dr. Alfredo Castillo Calle
Dr. Armando Rivero Laverde
Dr. Gustavo Bravo Orellana
Por su asesoramiento científico y estímulo para seguir creciendo intelectualmente.
A mis colegas y amigos:
Romell Trujillo, Fabiola Alva, Rosario Quintanilla y Gina Gonzales por su comprensión y
facilidades brindadas para la realización de esta tesis.

/01 23""#$# 4 5
""67# #% &"  / 9
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

: /01 23""#$# 4 5
""67# #% &"  /
 




El presente trabajo se realizó con el propósito de evaluar la influencia de cuatro tipos de
materiales de empaque que son empleados regularmente para tabletas, sobre una formulación de
lamivudina 150 mg tabletas recubiertas obtenida por compresión directa.
Para realizar este estudio se elaboró un lote piloto de lamivudina 150 mg tabletas
recubiertas, luego se acondicionó en cuatro tipos de materiales de empaque: PVC/Aluminio,
PVC/PVDC / Aluminio, Aclar / Aluminio y Alupol / Alupol, y fueron sometidos a un estudio de
estabilidad acelerada de seis meses, a condiciones de temperatura y humedad recomendadas para
el Perú según the United States Pharmacopeia 27 (USP 27). Para determinar el material de
empaque adecuado se realizaron los respectivos ensayos fisicoquímicos durante el estudio de
estabilidad. Al final del estudio, todos los materiales de empaque evaluados garantizaron la
calidad del producto. A continuación, se realizó el análisis económico de cada material de
empaque empleado, para establecer cuál permite ahorrar costos sin afectar la calidad de producto
final.
Finalmente considerando los aspectos de calidad, logísticos, costos y marketing, se concluye
que el PVC es el material de empaque mas adecuado para el producto de manera integral.
Palabras clave: Materiales de empaque, estabilidad acelerada, lamivudina.

/01 23""#$# 4 5
""67# #% &"  / ;
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

< /01 23""#$# 4 5

""67# #% &"  /
 0
)  )

0
)  )
The aim of this the present study was to evaluate the influence of four different primary package
materials that are used regularly for tablets, over a formulation by direct compression of
lamivudine 150 mg coated tablet.
The pilot-size batch was packed in the next primary package material used in this study:
PVC (polyvinyl chloride) / Aluminum, PVC/PVdC (polyvinylidene chloride) / Aluminum,
PVC/PCTFE (Polychlorotrifluoroethylene) / Aluminum and polyethylene aluminum foil
“Alupol/Alupol”. At last these product were include in an accelerated stability study during six
months to conditions of recommended temperature and humidity for Peru (zone IV) according to
the United States Pharmacopeia 27 (USP27). In order to determine the material of suitable
packing parameters test were developed during the stability study. At the end of the study, all the
evaluated materials of packing guarantee the quality of the product. Then the economic analysis
of each material of used packing was achieved, to establish which material allows to save costs
without affecting the quality of the product.
Finally considering the aspects of quality, logistic, cost and marketing, it is concluded that
the PVC is the material of suitable packaging but for the product of integral way.
Key words: Materials of packaging, accelerated stability, lamivudine.

/01 23""#$# 4 5
""67# #% &"  / =
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

> /01 23""#$# 4 5

""67# #% &"  /
 1 )  2

1 )  2

%  &?6& &" # >-@  1 67# "1"## !16? $6# " 1"$ &" "1A "
" 6%#$&"& 1"1"%" 61 " B$1 # "%  !3$66$C% &" % 1"&$61"%@
" 7 "# 6%#$&"& 61 " &" &"# &" & 6(
% "1A " D$1$E !16? $6 % &"3" $%"6  !#$6@ %$ A 1$61"%" 6%
 !1 6$C% &" 1%" A " % ""  6$&&@  "F  # 6%"%$& 1G# G &" #
1$"# "1$#$3"#(  "#3$$&& &" # & 6# !16? $6# "1$%&# &""%&"%
 % " &" !6"# 13$"%"#@ "# 61  "1" @  7 1"&& 2   F
13$"%H 2   "@ &" !6"# "6$%&# 6% " & 6@ "# 61@ #
$"&&"# A 1$6# 2 !#$6# &"  # #%6$ 6$I 2 &" # "+6$$"%"#@  !1
!16? $6@ " 6"# &" !3$66$C%@  % "F &" #$#"1 &" 6$"" &" "%I#" 2
# $"&&"# &" # 1"$"# &" "1A "(   6 @  ""66$C% &" "1A "
 "&" "%" % "!"6 ! %& #3"  "#3$$&& &" # & 6# !16? $6#(
  &@  #""66$C% &" 1"$ $& &"3" #" "$F& &" 6 "&  
$66$C% &" & 6@  "@  FC% 1G# $1%"  $%& 6$ " 3$#" 61
1"$ &" 6%&$6$%&@ ! " !"6"  # 6$"%"# % &#$# %$$(
% " "#"%" 3J #" "I C % !1 6$C% &" 1$I &$% .;- 10 3"#
"6 3$"# "% 6  $# &" 1"$"# &" "1A "@ # 6 "# #% "0 1"%"
"1"&#  "%I# 3"# "% 3$#" DKL 1$%$@ KLK
 L  1$%$@ 6 L
 1$%$ 2   L  E( #"$1"%" #" #1"$C  % "# &$ &" "#3$$&&
6""& &" #"$# 1"#"# 2 #" "$F% # "#"6$I# "%#2# !$#$6A 1$6# &"
#"6@ "# 1"&$@ &$1"%#$%"#@ & "F@ &"#$%"06$C%@ ?&$&  #"6&@

/01 23""#$# 4 5
""67# #% &"  / M
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

6%"%$& &" 0 @ $&"%$!$66$C%@ &#J"@ &$# 6$C%@ %$!1$&& &" &#$#@ $1 "F#
"# 2 1$" 1$63$%( &"1G#@  3#"I " 611$"% &" & 6 
6%&$6$%"# 13$"%"#@ #" "$F% &$67# "%#2#  # <9- &# &" 16"%1$"%
&" & 6  6%&$6$%"# 13$"%"#(
 6$&& &" & 6@ #" "I C &" 6 "&  # "# &# &" "# &$ &"
"#3$$&&@ 2 !$%1"%"  2  &"6$#$C% &" "#3"6" 6  "# " 1"$ &"
"1A " 1G# &"6 &  " & 6 &" 1%" $%"0@ #" 6%#$&"% #
#"6# &" 6##@ 0#$6# 2 &" 1N"$%0(

.- /01 23""#$# 4 5
""67# #% &"  /
 1 03)

1 03)

03) *  *

O
""1$% " 1"$ &" "1A " $1$ &"6 & "I %& # #"6# &"
6$&&@ 0#$6#@ 6## 2 &" 1N"$%0@  A " " & 6 1$I &$% .;- 10
3"# "6 3$"# 6 1 6% # # "#"6$!$66$%"# & %" # "$& &" I$0"%6$(

03)

* 5 

O I   I$6$C% "%  6$&& &" 1"&$61"%  I?# &" $"1 "% 6%&$6$%"#
&$#$%#  # 6%&$6$%"# &" 6%#"I6$C%  "## "% " "$A "&(
O ""66$% " 1"$ &" "1A " $1$ A " "1$ 6 1$ 6% # 6%&$6$%"#
&" 16"%1$"% &" & 6(

/01 23""#$# 4 5
""67# #% &"  / ..
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

.8 /01 23""#$# 4 5
""67# #% &"  /
 1 
* )
)

1 
* )
)

411   ) 5
) 
5
 65 

89/:
*  *  )  7 *)
1
# 3"# #% % !1 !16? $6 #C$&@ 6%"%$"%& $%6$$D#E 6$ID#E@ 2
"+6$$"%"#@ "&  61"#$C%( # 3"# 6% "6 3$" #$1" #""% %
"6  &" 1"$ # 3" "% 0 @ "# "6  #"" I"%J# 61 "%1#6 "
#3 2 (
1$I &$% "# % I 6$#$% 3%6 " $%&@ 6%6$& 13$?% 61 9 ( #
% %G0 &" % 6"C#$& #$%?$6 6% 6$I$&& 6% " I$ # &" $%1 %&"!$6$"%6$
7 1% DPK5.E 2 " I$ # &"  7"$$#  DPKE(

O C1  1"6 '  P   

> .. 9 9
O "# 1"6 ' 88M(8<
O ""#"%6$C% 6"% '

Q  :.(M. R
Q P :(>: R

/01 23""#$# 4 5
""67# #% &"  / .9
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

Q  .>(99 R
Q  8-(M: R
Q  .9(MM R

O  3$$&&' =- 10 L 1 0  D8- ,E

O "0 "? $6' %$I$
O # 6  1"6 '

8949;:
411 7 *)
)
*  )0)
1
&"1G# &" $%6$$ 6$I@ # 3"# #""% # # #%6$# $%""#@ &"%1$%&#
"+6$$"%"#( ## #"G% 6#$!$6&# &" 6 "&   A " &"#"1"S% "%  !1 6$C%
&"  3"(  $1" 0  #%  # #%6$# A " $1"% 66"#$6# #$#!6$#
&" 61"#$C% 2 1"J% " 6"# "%  !1 6$C%@ 61 #% # &$ 2"%"#@
0 $%%"#@ &"#$F%"# 2  3$6%"#(  #"0 %& 0  6$%% % 66"#$6
!#$6 "#"6$  61$1$&@ "%"1#' &"#$%"0%"#@ 6%"#@ #3$F%"#@
"& 6%"#@ 1"# &" $3"6$C% "&&@ "%" #(

89:
411/ 7 *)
*   0 )  )0)
1
 "6 3$" "# % 6 &"0& 2 %$!1"  3#" &" 1"# A " "# $6& #3"
% # #@ "% "#" 6#  3"(  0# &" % "6 3$" "0 1"%" "#G "%"

.: /01 23""#$# 4 5
""67# #% &"  /
 1 
* )
)

8- 2 .-- T1 D1$6#E( # 61%"%"# 61 %"# &" % # #"%#$C% &" "6 3$" #%'
" 1"@ #$!$6%"@ $01"% 6$!$6%" 2 " I"76 (
899A:
1 * 
1
 12 #% &"$I&# &" 6" #@ "# 61 ?#""# &" 6" #@  1"#
6$6# 2 61"#(
%" # $"&&"# &"#"3"#  # 1"# "#G # # 3$$&& "% % 1$
%0 &" #$#"1# &" #I"%"#@  # 1I"  !"+$3$$&& &"  !1 6$C%@ 
73$$&& &" & 6$ 6 3$"# A " #"% 6%I"%$"%"# $"&&"# 1"6G%$6# D! "F
"+"%#$3"@ "#$6$&&@ "%#$C%E 2  $& # 3$$&& "% ! $&# 0#$%"#$%"#
 A "  3$&$#%$3$$&& % #" I" 611"$&(
 "# 1"6  &" 1" $%! 2" #3" # $"&&"# &" #$#"1 &"
"6 3$"@ "# 61 I$#6#$&& &"  # 6$C%@ ! "F 1"6G%$6@ &7"#$I$&& 2
!"+$3$$&& &" !$1 "# %"(
899A:
01 *
) )
1
# #$!$6%"# #% # #%6$# #$1"# &" 3J "# 1"6 ( "J 
!"+$3$$&& &" !$1@ "& 6" " $"#0 &" # 1$1$"% 2 1"J # &7"#$C% 76$ "
# #(  "@ " #$!$6%" &"3" "%"  0& &" 61$3$$&& 6% " 1"
2 &"3" #" ""%$& &" 1%" "1%"%" "% " !$1( 1 "J"1# &" #$!$6%"#
"%"1# 0$6"$%@ $"%0$6@ $"$"%0$6@ $6"$% 2 $"$ 6$(
899A:
1  )
@ *  )
1
#" 0  &" 1"$"# #% 61B%1"%" "1"&# 61 " &" % !C1  &"
"6 3$"( # 6%"# #"  "&"% 6#$!$6 61'

O %"# # 3"# 0G%$6# 2 % "#@ #% 6 "1"&# A " "#"%%
6 "#3$$&& &" 6 2 1$06$C%(
O $01"%#  6#' $%6 2" # 6%"# $%0G%$6# D&$C+$& &" $%$@ C+$& &"
7$"' 1$@ J 2 %"0@ 2 6E A " "#"%% I"%J# 61 "#3$$&& &"
6(  # #"#  1%$6# &" # 6%"# 0G%$6#@ A " $"%"% % 1$ 01
&" 6"#(
89:
1
)
@ E5 
1
% # # #%6$# A " ! %6$%% 61 1"&$ &" %#" &" # 1"$"# &"
!$1 76$  # "!$6$" &"  3"( %" "# "%"1# " 0 @ 67"#@ 6"%#@
?#""#@ "%" #@ # 6 "#  "&"% "1"#" ##  "% 613$%6$C%( " "A $""
% 3 "% $%"66$C% "%" " #I"%" 2 " 1"  #"0  # $"&&"#
C$1# &" !$1@ 1"J # $"&&"# 1"6G%$6# &" 1" "# 61 # 67"#$C%
  3" 2 #"0  % &"#$6$C% 6%& &" 1" #3"  # "!$6$" &" 
3"(

89<:
41141 ) 

 65 
*  )0)

# 3"# #"  "&"% 66"$F  &"#6$3$  % %B1" &" "#"6$!$66$%"#( %"

/01 23""#$# 4 5
""67# #% &"  / .;
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

"## "%"1#' "# 1"&$@ &$1"%#$%"#@ &"#$%"06$C%@ & "F@ !$3$$&&@ &#J"@
&$# 6$C% 2 %$!1$&& &" 6%"%$&( # "#"6$!$66$%"# #"0 % A " # 3"#
U% I"%V "%" "# &" & 66$C%@ "# &"6$@ A " # I$6$%"# 1%$1# $%7""%"# 
6"# &" !3$66$C%@ % !"6%  6$&& &" & 6(
0 %# &" # 6%"# !$#$6A 1$6# 61 " #"6@ "# 1"&$@ !$3$$&&@
& "F@ $"1 &" &"#$%"06$C%@ 2 "% 6$"# 6##@  &$# 6$C%@ #" "I%  63 
&" "$F # J #"# %"6"#$# &" & 6  $%$6$ 2 & %" " 6"# &"
!3$66$C%(
""6%&  $"1 6 A $" G1" A " % #" "%6 "%" &"% &" #
"#"6$!$66$%"# "#3"6$&#(

41/ ) 
 *6 *
* 
89=:
)0)
1
6 1"%" 72 % 0% I$"&& &" 1"$"# &" "1A "' I$&$@ G#$6@ 01#@
"%" #@  " "%I#& &" &$I"## !1# !16? $6#@ "# 76" A " 
#$3$$&& &" $%"66$C% "%" # 61%"%"# &" 1"$ &" "1A " 2 #
$%0"&$"%"# &"  !1 6$C% #" I"% $%6"1"%&#(
 I$&$ ! " " 1"$ &" "1A " $1$ &" # "&1$%%" A " I""
"+6""%" "66$C% 6% " I &" 0  2 "1"3$$&& &" 0#"#@ " $"%" &#
$%6$"# &"#I"%J#' #  !0$$&& 2 # ""I& "#(
"3$&  "## #"6#
%"0$I#@ %$&  # $3 # #$$I# &" G#$6@ #$0%$!$6C  $%6 #$C% &" "1" &"
G#$6 61 1"$ &" "1A " !16? $6(
% G#$6  "&" &"!$%$#" 61 % 1"$ A " 6%$"%" 61 $%0"&$"%" "#"%6$
%  1# # #%6$# 0G%$6# $1?$6# &" "# 1"6  @ A " "# #C$& "% #
"#& !$% 2 "% % &""1$%& " "% # !3$66$C%  6"#@  "&" #" !1&
& %" " ! J &" # 6 # 63&# D#"0B% 7" 1"$6% 6$"2 ! "#$%0 %
"$#5 E(
# "1A "# &" G#$6 #% 1 2  "#  " "%I#& &" & 6#
!16? $6# 2 #" "3% &" &$!""%"# &"%#$&&"# 6&"   "#"6$!$66$C% A " #
& 6# "A $""%( % "#" 6#@  " "%I#& &" 3"#@ "%" # $%6$"#
!1# &" "1" "## G#$6#@ #" 6%#$&" # !#6# 2 # 3$#"(

8<9>:
41/11 0
) 9 * )   )3
1
# 3$#" !"6"% % 1$ 01 &" &$#"S# &" ! %6$%$&& 2 &" #"6@  "@
"+$#"% &$I"## $# &" 1"$"# &" "1A " A " #" &%  6$% %
3$#" 6% ! %6$%1$"% C$1( # 61%"%"# 3G#$6# &" 1"$ &" "1A "
3$#" #%'

O G1$%@ A " "#  6I$&& !1& A " ##$"%" " & 6(

.< /01 23""#$# 4 5

""67# #% &"  /
 1 
* )
)

O @ A " "# " 1"$ A " #"   6I$&& !1&(

"3$&   I$"&& &$#%$3" &" G1$%#  3$#"@  #""66$C% #" &"3" 3# #3"
" 0& &" "66$C% "A "$&(   &""%&" &" !6"# 61  #"0 $&& &"
3$#"@ " 0"%"1"%" #" "1" 6$%# &"  1$%$(
 FC% 1G# $1%"   6  #" $%& J  "6%0 &" "%I#& "% 3$#"
! " !"6"  # 6$"%"# &#$# $%&$I$& ( # 3$#" !"6"% 2 &  6$"%"  #"0 $
% ?0$1"% &" &#J"@ "66$C% &" 1"&$61"% & %" # $"1 &" I$& 2 #%
!G6$"# &" %#(
1& 6% # !#6#@ #% 6$%6 #"6# $1%"#  " 6  " 3$#" "#
6%#$&"& 61 % I"%J# 1"$ &" "1A "'

O (! # !F A " 6& 3" #" "%6 "% "% % 6I$&& A " 
"0" &" 1"&$ 13$"%"@  "6 $   &$#"%#6$C% &" &#$# %$$#@ %
"#"% 3"1# &" #" "5"%I#&# 3J 6%&$6$%"# 1#!?$6# %
6%&#(
O *!G # !F
""%&$"%& &" 1"$ "1"&  "66$C% 6% #
!6"# &" 1"&$ 13$"%" #" 61  1"$"# "1"&# "% !#6#(
O " # !F  %& % !#6 "# 3$"@ 6 A $" $%&$6$ &" 1%$ "
#"$ % "# "I$&"%6$&( $% "130 " 3$#" 6$% "66$C% $%&$I$& 
7# %"# &" # #(
O G  &# #  #F +$#"% &$#"S# &" "66$C% 6% "
"1" 66$&"% &" %$S#(
O
$G # F # ""# &" 1"&$66$C% "% 7#$"#  6 ## 61
6%! #$C% &" 1"&$61"%# #% 1"%"#(

414   ) 5
) 
 )   *6
*  1
 1"$ &" "1A " $1$ "# &"!$%$& 61 " "%I#" A " 6%$"%" "
1"&$61"% 2 "#G "% 6%6 &$"6 & %" &  I$& B$ &" "#"@   A "
6 A $" $%"66$C% !#$6  A 1$6 6% " 6%"%$&  "&" " # "%6$@  "F 2
6$&&(
 1"$ #&  !1  6I$&& &" 3$#" "# $61"%" % G#$6@ "%"
?## "%"1#'

8<9':
4141 * 1
3"I$  &" $6  &" I$%$@ & 6$&  $1"$F6$C% &" 1%C1" &"
6  &" I$%$(
/01 23""#$# 4 5
""67# #% &"  / .=
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

 K 0$& "# % 1"$ 6@  %A " $"%" 3J %#1$#$C% &" I &" 0 
DWK E@ 6$% 6 3" 6%  7 1"&&@ 2 #" "1" 6 %& " & 6
% "A $""  "66$C% "!$6F &"  7 1"&&(
"#"% "+6""%"# $"&&"# "1!13"#H 3 "% "#$#"%6$ A 1$6H 3J
"1"3$$&&  # 6"$"#@  # 0##@ 2  # #3$F%"#H &" 3J 6# 2 "# % &"
# 1"$"# 6% 12 66$&& &" &$$I6$C% 2 1G# !1 &@ A "  76"% %
1"$ 1 2 I"#G$  #$#!6" # "A "$1$"%# &" 1 67# $66$%"# "%
"%I#"#@  "J"1@ #" !1 &  3A " %0$ &"# &" %& $0"#
"#"6!$6#( ## 66"#$6# 76"% &" K 0$&@ " 1"$ &" "1A " &" 12
#(
 0# &" K #& #" &""1$%   ! %&$&& 2 " 1S &"  6I$&&
A " #" !1G( # G1$%# 61 %"# #&# "%  $%& #$ !16? $6 #" "+$"%&"%
&" =@;  ; 1$$ 0&# D.M-  9>- 1$6#E(

8<9=:
4141/ * 1
3"I$  &" $6  &" I$%$$&"%' 1" & 6$&   6$1"$F6$C% &"
1%C1" &" 6  &" I$%$$&"% DP8X8E 6% # 651%C1"# 61 " 6 
&" I$%$(

 %A " "#" & 6 "# &"%1$%& 61B%1"%" 61 K

@ "# $$F&
#$"1" 61 61" D"# % G1$% &%&" " K "#G 6 3$" 6% % "1 #$C%
&" 6  &" $I$%$$&"%E( $ 3$"%@ " I 1"% A " ""#"% "%  G1$% "#
"A "S@ " K
 &"#"1"S % " 6$6@ A "  "&" "& 6$  "1"3$$&& 
+0"% 2  I &" 0  "%" ;  .- I"6"#@ 61& 6%  G1$% &" K(

.> /01 23""#$# 4 5

""67# #% &"  /
 1 
* )
)

 K
 #" $6 "% % 6 2 0"%"1"%" #" 66 "% 6%6 6% "
& 6 2  1"$ &" #"&(
# !$1# &" KLK
 #% %#"%"#@ 3%&#@ ! ""#@ 6% "+6""%"#
$"&&"# &" 3"  +$0"% 2 # 0#"#@ 2 6% 1 2 3 "%# 66"#$6# &"
&7""%6$(
8 8
 6 &" K
 #" "#"6$!$6 "% 01  1 D0L1 E 2 #"  "&" "3 
6$% "66$C% 1"&$   6%  7 1"&&( # 6# #&# 61B%1"%"
8
"%  $%& #$ !16? $6 #% :-@ <-@ 2 M- 0L1 @ 2  "6  #" !"6" 6%  #$% %
6 1"&$ &" $"$"%(  $"$"% #" $$F  6 1G# "#&#@ "# 61 <-
8
2 M- 0L1 @  1"J # 66"#$6# &" "1!1& &"  6I$&& &" 3$#"(
1 )  )  2 * @ * 1
" &"#$ #3" " !$1'  0 &" 7$&C+$& &" #$ Y  0 &" $$&$%H   0
&" 1!$%( $  "66$C% "#"% % 66$C% %#"%"@ "# " & &" KH 2 #$
"#"% 6 1C%@ "# " & &" K
(

? 8<9':
41414 * ) 8  :1
# % G1$% "1G#$6 7"67 &" ! 1" $65$! "$"%(

 "6  &"   "# 1$%&  K  % 6 &7"#$I "%" " K 2 
"6  &"   D"# 6   &# 6#EH   % 6 &" $"$"% "%" " K 2
"   D"# 6  $"E(
# G1$%# KL  $"%"% 1G# 3J "1"3$$&&  I &" 0 @ A " #
G1$%# &" K 2 KLK
@ &""%&$"%& &"  6%$&& &"  @ #" 3$"%" %
3" 1"&$  "+"1 6% &"  7 1"&&( 1%&  "1"3$$&&  I
&" 0 @ &" % G1$% &" K 8;- 1$6#@ 2 % G1$% &" KL   D8--L.M
1$6#E@  #"0 %& G1$% "# .; I"6"# 1"%# "1"3"(

8<9=9':
4141; ** * 8**:1
 6 # &" # 1!0@ " $$"% #$I" 61 3 "% 3" 6%  7 1"&&
D"# 1G# 3J A " " K 2 "# 613"  KL K
E@ &"3$&  A " # "# 6 
"#!"$6@ 6" % 2"6$ &   A " # 1?6 # &" 0  I$"#"%(

/01 23""#$# 4 5
""67# #% &"  / .M
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

%" # &"#I"%J# &" # "1"@ "%"1# A " # "1" # "A "$&# 
" "1!1& 2 # #"$ "%!$1$"% &"3"% #" 6%&# 6% 3#%"
"+6$ &H "#"% $0$&"F 1G#  A " " KH 2 "# # #6"$3" &" 6%"#"  "0 &"
6"# &" "%I#&( &"1G#@ # G1$%# &"  "A $""% &"  1A $%$@ A "
#% &$!6$"# &" "1" "% % 1GA $% "#G%&  3$#" 2 % #"  "&"% 6"#
% G$&1"%" 61 " K( %#"6 "%"1"%"@ "  % "# $$F& 61B%1"%" "%
# ((@ " 6$% % "%$I "6%C1$6 2 #" $$F 6 "%   61
"%$I  K(  0# &" # G1$%# "#G "%" .-5.8 1$$ 0&# D8;-59--
1$6#E(

8<:
4141 * @  @  8    :1
#" 1"$ #" "1"  & 6# A " #% "+"1&1"%" 7$0#6C$6# 
#"%#$3"#    F( # % 3" "+"1 6%  7 1"&& 2 6%#$#" "% "# 6#'
K@  1$%$@ 2 %2%(

4141A @ *) 8*:

 $0  A " " %"$ "#" 1"$ #" "1"  & 6# A " #% "+"1&1"%"
7$0#6C$6#  #"%#$3"#    F(

8=:
4141< *) 8*:
%#$#" "% 6&"%# &" P8 2 #" !3$6  $ &" "$"%(  $"$"% &" 3J
&"%#$&& D
E "# % 1" &" 6&"% 1$!$6&( #" 1"$ "# 1# # I"@
!"+$3" 2 1# 6(  $"$"% &"  &"%#$&& D
E "# % 1" &" 6&"%
$%" % 1$!$6&( #" 1"$ "# & @ 1"%# !"+$3"@ 1"%# "1"3"  # 0#"#@
1# "#$#"%"  A 1$6#@ #I"%"# 2 0##( 13# $# #% 3&#   

 # "1" "% 1"&$61"%#(
%" 0 %# &" # $%6$"# &"#I"%J#@ 61 1"$ &" "1A "@ "%"1#'

O $"%"%  "1"3$$&&  # 7C0"%# $3"# D2&@ 6@ "6E 2  0 %# 6"$"#
 6"$"# &" "#"%6$#(
O   "&" #" "1"&  & 6# A " #% #"%#$3"#  +0"%(

% " 6 & , . 2 # 0G!$6# , . 2 , 8 #" $%&$6  616$C% &"  %#1$#$C% &"
I &" 0  2 +0"% "%" &$!""%"# 1"$"# &" "1A "(
13$?% "% " 6 & , 8 #" "#"% # G1"# 0"%""#  6%&$6$%
"% 3$#"@ &$67#  #  "&"% I$ &""%&$"%& &" $ 2 "#& &" # 1GA $%# 2
66"#$#(
89/94:
  D 1 *  2  ) 

2  *  B  75B 1

8- /01 23""#$# 4 5
""67# #% &"  /
 1 
* )
)

!# )!G  " !  ( )!G 

8H) : 4=J @ >' KE CI( / J
8(@/@/;L: 8@/@/;L1):
K D8;- 1$6#E 9(=8 ==(; Q .;;
KL K
 D8;- 1$6# L <- 0L18E -(:- .8(: Q .-<(M;
KL   D8;- 1$6# L .; -(9- .->(;
1$6#E
 L   - 5
KL  L  
 - 5

8(; 5 8(>. 1"&$ ==;-

-(> 1"&$ 8><>
 .(.; 898; Q 9>=;


' $"$"% &" 3J &"%#$&&@ 
' $"$"% &"  &"%#$&&@ '
$$"%


  
 
   
    

  

   
    

 

  

/01 23""#$# 4 5
""67# #% &"  / 8.
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (


  
   
 
  

8;:
4141=  
  )   ) 1

O " &"3" 16"% "% % 13$"%" 6%&@  % "1"  "%" .> , Q 88 ,

2 7 1"&& "$I "%" :- R 5 =- R(
O 16"% # 33$%# 6% # "1A " $0$%@ 2 A " " !$1  "&" " I$
13$"% D 66$C% ""6#G$6E 2 # 6 #(
O  #" &"3" 16"% %$ "+%" DB% "#%& "% # "%I#" $0$%E   66$C%
&$"6 &"  F #(
O I$ #1""  613$# 3 #6# &" "1" (
"J "1" # 33$%# 
"1"  13$"%"@   1"%# 8: 7# %"# &" # #(
O " 6%#"J "1" # !$1# &" KLK
 %"# &" # 8 S# 2 " K
1%G1$% 2 " KL  %"# &" # 9 S#(
O &# "## !$1# #% $%""#  6%&$6$%"# "#G%& &" "1"  2 "#$C% D8; ,
L.  E(  $"#0 &"  $0%$6$C% "# G6$61"%" % @ && A " " K $"%" %
"1"  &"   $0%$6$C% "% "# &" 12  :-- ,(

8<9:
41; 
)  
)01
#3$$&& #" &"!$%" 61 " 0& "% " 6  % & 6 6%#"I@ &"% &" # 1$"#
&" "#"6$!$66$C% 2  I?# &" "$& &" 16"%1$"% 2 #@ # 1$#1#
$"&&"# 2 66"#$6# A " "%  "0 &" # 1% !6 ( # G1"#
$%6 $&# #% "#3$$&& A 1$6@ !#$6@ 1$63$C0$6@ "? $6 2 % +$6C0$6(
& $%0"&$"%"  "&" !"6  "#3$$&& &" $%6$$ 6$I  !1 !16? $6(
%" # !6"# 13$"%"# $1$# A "  "&"% "& 6$  "#3$$&& #" $%6 2" 
"+#$6$C%  "1" # &I"##@  F@ 7 1"&&@ +0"% 2 &$C+$& &" 63%(
 C#$ &" "# &$ &" "#3$$&&@ "# 6$% "I$&"%6$ "% 6C1  6$&&
&" % # #%6$  &" % & 6 I 6% $"1@ 3J $%! "%6$ &" % I$"&& &"

88 /01 23""#$# 4 5
""67# #% &"  /
 1 
* )
)

!6"# 13$"%"# "# 61 "1" @ 7 1"&&@ 2  FH 2 "#3"6" % "& &"
 "5%G$#$#   # #%6$  % I$& B$  " & 6 2 # 6%&$6$%"# &"
16"%J" "61"%&&#(

8:
41;1   
  
 1
 "# &$ &" "#3$$&& 6""& 6$% % 1"&$  61 !1 6$%"#@
1"$"# &" "1A "@ 2L 6"## &" !3$66$C% "%$I# "% "+"$1"%#  6
& 6$C%( % % 61 #" "#3"F6  !1 6$C% 2 " 6"# &" !3$66$C%
&"!$%$$I#@ " !3$6%" "$F % #"$" &"  "3# &" "#3$$&& 6""& A "
"1$$G% "&"6$  "#3$$&& &" & 6@ " $"1 &" I$& 2 # 6%&$6$%"# &"
16"%1$"%(  1$#1 $"1 "%&G% A " 61"%F # "# &$# "% $"1 "@
 C#$# &"  6%!$16$C%(

89<:
41;1/ 03)
1

&M" )   

""66$% !1 6$%"# 6""&
"# &" %
&"6 &# D"#"6   & 6
"#3$$&&E 2 #$#"1# &"6 &#
&" 6$"" &" "%I#"(

""1$% " $"1 &" 6""& 2

"# &" %
6%#"I6$C% 2 # 6%&$6$%"# &" $"1 " & 6 2 "+"&$"%"
16"%1$"%( &" "0$#
13 " $"1 &" $"1 " +"&$"%" &" "0$#
6%#"I6$C% &"6&(
K"$!$6 A " % #" 7% & 6$& 6""& 2 #"0   6$&& "%
613$# "%  !1 6$C%  " $"1 " 0"%"@ $%6 # "
6"# &" !3$66$C% A "  "&% 6% &" 6$&&
"J &$6 "#3$$&& &" & 6

89<:
41;14 
)  
)0   1
% "# &$# &$#"S&# 6% " !$% &"  1"%  I"6$&& &" &"0&6$C% A 1$6 
"6$C% !#$6 &" % 1"&$61"%@ "1"%& 6%&$6$%"# "+"1# &"
16"%1$"%@ "% # "1A " $1$ &"!$%$$I( ## "# &$# $"%"% 61
C#$ &""1$% # G1"# 6$%?$6# &" # 6"## &" &"0&6$C% 2L
"&"6$ " "& &" I$&"F &" 1"&$61"%@ "% 6%&$6$%"# ""#  % "# &"
16"%1$"%( # "# &# &" "# &$# 6""&# &" "#3$$&& % #$"1"
"1$"% "&"6$  "I 6$C% &" # 613$# !#$6# "% " & 6 3J 6%&$6$%"#
% "# &" 16"%1$"%(

/01 23""#$# 4 5
""67# #% &"  / 89
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

" 6%#$&" A " 7 6 $& % 613$ #$0%$!$6$I'

O $ " "# & &"  I6$C% "I" % &$#1$% 6$C% &" ;R "% 616$C% 6% "
"# & $%$6$ &"  I6$C% &" % "(
O $ 6 A $" & 6 &" &"0&6$C% "#"6$!$6& #" 7 "#"%" "% 6%$&&"#
# "$"#  1$" &"  "#"6$!$66$C%(
O $ " P &" & 6 #" 7  ! " &" # 1$"# !$J&#(
O $ 2 % #" 6 1"% # 1$"# "#"6$!$6&#   &$# 6$C% &" .8 6G# # 
61$1$&#(
O $ 2 % #" 6 1"% # "#"6$!$66$%"# "% 6 %  #"6 2 # $"&&"#
!#$6# D6@ #"6$C% &" !#"#@ 0 $%6$C% 2 & "FE(

8:
41;1; 
)  
)0   B *+1
# 6%&$6$%"# "+"$1"%"# &" 16"%1$"% #"G% % "6$&#  #
6%&$6$%"# ""# &" 16"%1$"% "I$## "% " 1"6&@ 61 #" !6$3"( #
"# &$# "% $"1 " #" &"3"% 6%$%  7# " !$% &" $"1 &" 6%#"I6$C% 
6%!$1 " $"1 &" I$& &" & 6(

41;1  
 * 0    
)) 1
89<:
 &$#"S &" 01 &" "# &$ &" "#3$$&& &"3" 6%#$&" " 1"6& "I$# 2
# 6%&$6$%"# 6$1G$6# "%  F% "%  6  "% A " #" #G% # & 6#(  #
!$%"# &" "# &$ &" "#3$$&&@ #" &$#$%0 "% 6  F%# 6$1G$6#  %$I" 1 %&$'

O [% ' "1&(

O [% ' # 3$6@ #$3"1"%" 6% 7 1"&& ""I&(
O [% ' 6G$&L#"6(
O [% K' 6G$&L7B1"&(

  D '41  
,) 

F )

   0       
 )1

+   # !    # ## 

#N #&! #
\ R P \ R P
 .-(M =; .>(= :;
 .=(- =- 8.(. ;8
 8:(: 9M 8<(- ;:
K 8<(; == 8>(: =-

8: /01 23""#$# 4 5
""67# #% &"  /
 1 
* )
)

% I$# &" A " #% 1 2 6# # #"# $%6 $&# "%  F% 6$1G$6 @ "
!3$6%" A " ""%& 61"6$$F & 6# "% # 6$1# "1&# 7 3$"% "%
3# #  "3# &" "#3$$&& "% # 6%&$6$%"# A " "I"6"% "%  F% 6$1G$6
(  %& " 3J"$I #% #"# 6% 6$"# "0$%"# #$ &# "% # F%#   K@ 2
13$?% 6 %& #" ""%&" 61"6$$F "% & " 1 %&@ #" "61$"%& A " #
"# &$# &" "#3$$&& #" 3#"% "% # 6%&$6$%"# 6"#%&$"%"#   F% K(
&"1G# &" # F%# 6$1G$6#@  &""1$% # 6%&$6$%"# 6$1G$6# &"
 "3@ #" 6%#$&"  "1"    6  I  #" 6%#"I& " & 6 2 #$ "# %
1"$ #"1$"1"3"  $1"1"3"( "0B% #" " 6#@ "%"1# # #$0 $"%"#
6%&$6$%"# "61"%&&#   P(
1  (!#

  D ;1 
 B F  )
6
   
    

0)

   ) 

# I
.
0 F 8;\ ] 8\L<-R P ] ;R P  .8 1"#"#
9-\ ] 8\L<;R P ] ;R P
8
%"1"&$ 9-\ ] 8\L<;R P ] ;R P -< 1"#"#
6""& :-\ ] 8\L=;R P ] ;R P -< 1"#"#

.
" "1" 8; ] 8\L<-R P ] ;R P  F%  2 9-\ ] 8\L<;R P ] ;R P
 F%  2 K(
8
$ 6 " 613$ #$0%$!$6$I & %" # < 1"#"# &" "#3$$&& 6""&@ #"
"$FG % "%#2 &$6$% "% 6%&$6$%"# $%"1"&$#( +6"@ #$  6%&$6$C% &"
0 F "# 9-\ ] 8\L<;R P ] ;R P@ "%%6"# % "+$#" 6%&$6$C% $%"1"&$(
01  "  "  !&#1
 "## & 6#@  66$C% &" 7 1"&&  ?&$& &" #I"%" % "# %
"6 6$C% A " # "%I#"# $1"1"3"# 6$%% % 3" "1%"%" 
# &"  7 1"&&  0#"#( #@ # "# &$# &"  "#3$$&&  # & 6#
16"%&# "% "%I#"# $1"1"3"# #"  "&"% 6%& 6$ 3J 6 A $" 6%&$6$C% 
7 1"&&(
1  "  "  !&#1

  D 1  )
 


* 0

   ) 

# I
.
0 F 8;\ ] 8\L:-R P ] ;R P  .8 1"#"#
9-\ ] 8\L9;R P ] ;R P
8
%"1"&$ 9-\ ] 8\L<;R P ] ;R P -< 1"#"#
6""& :-\ ] 8\L % 12 &" 8;R P -< 1"#"#

/01 23""#$# 4 5
""67# #% &"  / 8;
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

.
" "1" 8; ] 8\L<-R P ] ;R P  F%  2 9-\ ] 8\L<;R P ] ;R P
 F%  2 K(
8
$6% # 1$#1# %6$%"# A " " 6# 0"%"( $ #C #" &""6 613$
#$0%$!$6$I "% " 6%"%$& &" 0 @ % "# %"6"#$ "$F # "# &$#  6%&$6$%"#
$%"1"&$#(

"3$&  A "  7 1"&& "$I "# &$!""%"@ #"  "&" "$F 6G6 # &" 6 "&
 # &# &" 6 & , <@ #$"1" "% 6 %& #" &"1 "#"  "6$C% $%" "%"
?&$& &" 0  2 " "$& &" 16"%1$"% "% # 6%&$6$%"# "+"$1"%"#(

E !#" E !#"    O!  ( ! 

#!" !$!   !!
<-R P 8;R P .(M
<-R P :-R P .(;
<;R P 9;R P .(M
=;R P 8;R P 9(-

1  %  "  !"!  &M  !!1

  D A1  
  ) *   )
6
 * )

   03
)* ) 
1

!"G )     ) 


!   # I
"!$0"& 0 F ; \ ] 9 \ .8 1"#"#
6""& 8; \ ] 8 \L <-R P ] -< 1"#"#
;R P
8
%0"& 0 F 58- \ ] ; \ -< 1"#"#

.
 # & 6# A " #" I%  6%#"I  % "1"  $%!"$  Q8- ,@ #
6%&$6$%"# &" "#3$$&& #" &"3"% &""1$% "% 6& 6#(
8
" "61$"%& "$F % "# &$  "1" # # "$"#   6%#"I6$C%
 "#@ #3" 6% " !$% &" &""1$% " "!"6  "#%6$# 6# ! " &" #
6%&$6$%"# &" 6%#"I6$C%(

41;1A )*     

  )
89<:
 
1
"0B%   @ " $"1 &" I$& &" & 6 #" &""1$% "% "6$C% 6% #
6%&$6$%"# &" 16"%1$"%( "  "&" "#3"6" % $"1 "$1$% &" 8: 1"#"#@
#$"1" 2 6 %&@ "%" # 6%&$6$%"#@ "#? 613&  "#3$$&& &" $%6$$
6$I D% #" &"0& 6% !6$$&&E(  # & 6# A " $"%"% $%6$$# 6$I#
1"%# "#3"#@ " $"1 &" I$& % "+6"&"G "% 1G# &" &3"  "$& A " 3A "%

8< /01 23""#$# 4 5

""67# #% &"  /
 1 
* )
)

# "# &$# "% $"1 "(

# 73" "I &  "#3$$&& &" & 6@ "%  "$A " #"  "&" $%#6$3$@ %
&" # #$0 $"%"# 6%&$6$%"# &" 16"%1$"%'
%?%0#" "% 6%&$6$%"# %1"# &" 16"%1$"%@ &"!$%$& 61 U13$"%"
#"6 2 I"%$&  "1" # &" .;  8; , @ "% &""1$%&# 6%&$6$%"# 6$1G$6#@
7# 9- ,(  #" 6"% "# "+S# %$ 6 A $"  $%&$6$ &" 6%1$%6$C%@ %$
 F $%"%#V(

O %?%0#" "%" 8 2 > , D"% "!$0"6$C% " #$% 6%0"E(

O %?%0#"  &"3J &" > , D"% "!$0"6$C%E(
O %?%0#" "%" 5; 2 58- , D"% % 6%0"&E(
O %?%0#"  &"3J &" 5.> , D"% % 6%0"& "%"E(

 61$? %"%6$% &" 1%$F6$C% 7 "3& % &6 1"% $%&""%&$"%" P

.' UI 6$C% &" # &# &" "#3$$&&V 2 61"1"%$   &$"6$F $%6$@ "%
" A " #" &"!$%" 6% 12 &"" " 6"&$1$"%  "#   "I 6$C% &" #
"# &# &" % "# &$ &" "#3$$&& 13$?% 76" 1"%6$C% &" $"1 &" I$& 
"#3"6"#" 2 # 6%&$6$%"# &" 16"%1$"%  "##  6& 6#(

/01 23""#$# 4 5
""67# #% &"  / 8=
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

8> /01 23""#$# 4 5

""67# #% &"  /
 1 * ) 7* )

1 * ) 7* )

;1 6*
9 ) 
9 )   *6
  )

O 
 

Q %F %$6 &I"% " P  .8-(

Q "F6& 6B3$6 ^"N )(1(3( P_ P. 9.:-.=;( 3""& %"#2 
..8.9<8(
Q 0$& W8- _5W_(
Q P10"%$F& 
9 #"$F"
Q 13 6%I"%6$% 

Q 13 "$#G$6 W  W(
Q $#" 6 58-- ) (
Q %6$%& 


/01 23""#$# 4 5
""67# #% &"  / 8M
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

O 
 `

Q %F %$6 +" P

Q %F "" "& 9-9
Q %F &" 7 1"&& "" "& * .<(
Q 1C0! A $& &"  "!1%6" 71 "6N(
Q
"#$%"0& P%#% "#"67 58.(
Q
C1" ^"N P 8>

Q A $ &$#  P%#% "#"67  <(
Q $3$$F& ^"N  8-(
Q $" &" "2 6% $%&$66$C% &$0$ $ 2 
5<V (
Q $ & _ $#7" $% >(

O  
 

Q  67%"# &" 6" $%+$&3" 2 # 7"+0%"#  "#&(

Q # &" 6" $%+$&3" , 8-@ , 9- 2 , ;-(

O  
 `

Q  1%  #7"  .>" 8;-11 + :11@ ; 1

Q "$ &" I$&$ 0& &
Q "13% !$%" &" -@:; 1 2 " ^1% a :.

O  
   DK"  & \ =E

Q $% K 6$# D8;- 1$6#E + .>8 11(

8
Q $% KL K
 6$# D8;- 1$6# L <-0L1 E + .>8 11(
Q $% KL   6$# D8;: 1$6# L .<1$6#E + .>8 11(
8 8
Q $%  L   D>; 0L1 L 99 0L1 E #$% $1"#$C% + .>;11(
8
Q $%   D<8 0L1 E #$% $1"#$C% + .=; 11(

O  K

Q 6" &" 1%$

Q `6$& 6?$6
Q "%
Q 0  &"#$&

9- /01 23""#$# 4 5
""67# #% &"  /
 1 * ) 7* )

Q  !!" !#! P =@:

O  `

 `

Q 1$I &$% "#G%& &" "!""%6$

;1/   2   ) 

;1/1  2   2  - )))1

 !1 6$C% &" % $ #" "$F "% 3#"  $%!16$C% &" # 66"#$6#
!$#$6A 1$6# &" $%6$$ 6$I 2 "+"$"%6$ 3"%$& &" & 6# #$1$"#( #
" "1$" "I  % #"$" &" !1 6$%"#@ 2 ""0$ A " A " 3"%0 #
1"J"# "# &# &" "#"6$!$66$%"# !$#$6A 1$6# 2 1$63$C0$6#@ ?## #"G%
"I &# 1"&$%" % "# &$ &" "#3$$&&@  &""1$% #@ #$  !1 6$C% "#
"#3" "% " $"1(   %@  ""0$  !C1  6 $56 %$$I A " I #"
#1"$&  "# &$ &" "#3$$&&@ #" "IB'

O  611$"% &"  !C1  "% " 6"# &" !3$66$C%@ "#"6$1"%" 3#"I
A " % "#"%" %$%0B% "%6$ $%6%I"%$"%" "%  !3$66$C%  0% "#6(
O  1$1$"% &" # "%#2# $%$6$"#@ $1&$1"%" # "%#2# 6$6# 61
&#J" 2 &$# 6$C%(

;1/1/ )
))
  2  8! C D ':
1$I &$%(
" # 1$66$#$%(
#61"# #C&$6(
#" &" 10%"#$(
P$&+$$1"$6" # .;6# 58M.-(

$C+$& &" $%$ (( ==>M(
$"$"%0$6 <---(
67 "$6 M<, L 0   $!$6&(

;1/14 *  )   ) 

 ' ( &# !&!

/01 23""#$# 4 5
""67# #% &"  / 9.
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

+   * 
2

 !"#$% $&'& %( )!&*%+&,

"1"  &" G"' 8; ] 8,
P 1"&& "$I &" G"' ;- ] ; R
 0 )    

 !"#$% %( )!&*%+& '% !%* -!./.%#$&,

"1"  &" G" 88 ] 8,
P 1"&& "$I &" G"' ;; ] ; R
 !"#$% %( )!&*%+& '% "*&#'.*.&#"'&,
"1"  &" G" 88 ] 8,
P 1"&& "$I &" G"' :. ] ; R

98 /01 23""#$# 4 5
""67# #% &"  /
 1 * ) 7* )

;1/1; 
*   
 
) 
 *6
*
1


 0    
     

b  1$ "#  3"I$6$C% $%0"# &" % 1$?#$1 &"  0&(

;14 
)0     ,

5
 
65 

;141  
 
)0
# 6%&$6$%"#  " "# &$ &" "#3$$&& 6""&@  # A " ! "% #1"$&# #
3"#@ "#G% &" 6 "&  # "A "$1$"%# &"  16" &" # #&# %$&#
D 8=E 2   %1$I "3&  " 1$? %"%6$% &" 1%$F6$C% "$I
 # "# &$# &" "#3$$&& &" 1"&$61"%# P . D8E( "1" ' :- , ] 8 ,
2 7 1"&& "$I' =; R ] ; R(

;141/ 

5
 -65 
+
 ) 

)01

/01 23""#$# 4 5
""67# #% &"  / 99
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

# 3"# #1"$&#  "#3$$&& 6""& ! "% %$F&# "% " $"1 $%$6$@ 9-
&#@ M- &# 2 .>- &#( # "%#2# "$F&# ! "% # #$0 $"%"#'

P )   N#

%$6$ ." 1"# 9" 1"# < 1"#
#"6 $ $ $ $
"# 1"&$ $ $ $ $

$1"%#$%"# $ $ $ $

"F $ $ $ $
$3$$&& $ $ $ $

"#$%"06$C% $ $ $ $
?&$&  #"6& DE $ $ $ $
%"%$& &" 0  D_ $#7"E $ $ $ $
&"%$!$66$C% 1$I &$% $ $ $ $

#J" 1$I &$% $ $ $ $

$# 6$C% $ $ $ $
%$!1$&& &" &#$# $   
1 "F# "# $ $ $ $
1$" 1$63$%b $   $

b #"6$!$66$%"# &" "6 "%  &" 7%0# #"0B%  8--9 c"%&$+ dK
e(

9: /01 23""#$# 4 5
""67# #% &"  /
 1 
)

1 
)

1  
  
0)


 , 


     
  1
2
 
   3%/)%!"$ !",45 6 
17 /%'"' !%("$.8", 09: 6 9:;

/01 23""#$# 4 5
""67# #% &"  / 9;
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (


 , 


     
  1 1 
<
 
   3%/)%!"$ !", 45
= 6  = 1 7 /%'"' !%("$.8", 09: 6 9:;


 >, 


     
  1  1 
<
 
   3%/)%!"$ !", 45
= 6  = 1 7 /%'"' !%("$.8", 09: 6 9:;


 4, 


     
 
 1 
 <
 
   3%/)%!"$ !", 45 = 6 
= 1 7 /%'"' !%("$.8", 09: 6 9:;


 9, 


    
 
<

9< /01 23""#$# 4 5

""67# #% &"  /
 1 
)

?>5 

1/ 
)  2 1

1/1  
 
)  )   
)  
) 

 *61


 ?,   

 
   ,
 1


 0,   

 
   ,
 1  1 

/01 23""#$# 4 5
""67# #% &"  / 9=
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (


 @,   

 
   ,
 1  1 


 A,   

 
   ,




 5,
     



14  2  )   *6 

9> /01 23""#$# 4 5
""67# #% &"  /
 1 
)

     *  2  * ,) 

5) 

 1 % &"6$#$C%@ !"6 "%"1"%" $1$6 "I  #$1 G%"1"%" #"6#
6 %$$I# 6% #"6# 6 $$I# % 1"%# 3"#(  # 6$C% 6%#$#" "% "#60"
# 6$"$# ""I%"#  "I   &"6$#$C%@  "0 &" "#3"6" % "#6 &"
6$!$66$C% 2 %# !6"# &" %&"6$C% &" # 6$"$# #""66$%&#(   %J"
%&"& &" # "%$I# &" # 6$C% "1$$G "#60"  1"J "%$I  
6%&$6$C% %$F&(
 2 " 6"# &" &"6$#$C%@ "% " 6  #" &"3" ""0$ D"%" 6 
"%$I#E " 1"$ &" "1A " &"6 &  " & 6@ #" #$0 $C  #$0 $"%"
1"&0'
.( &"%$!$6 # 6$"$# &" &"6$#$C%' 6$&&@ 0#$6#@ 6# 2 1N"$%0(
8( #$0% %&"6$C%  "## 6$"$#( ## &# #" 3 I$"% 1"&$%"
"%6 "##  "#%# &$"61"%" $%I 6&# 6% " 6$"$  "I (
9(  "#3"6"  %&"6$C% !$%@ #" 1"&$C # "# &#@ #"0B% #"
1 "# "% " 6 & , .8(
 #"6 0#$6 #" "I C #"0B% # &# 1"%6$%&# "% " 6 & , ..

  D F 
* )
B5
) 

!!I * * @* * @* ) * 

6"&"%6$ I""& 6 6 6 6 6
$"1 &" "#$6$C% .; .; <- .; .;
B1" &" 8 . . 8 8
I""&"#
"&$& 1%$1 DN0E ;-- .--- ;-- ;- ;-


 , 
   
 

/01 23""#$# 4 5
""67# #% &"  / 9M
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (


 >,    
   
 

    
   
 @5 

   ,    

  95 /B 
  
 
  

%""6$C% 0G!$6 , .' "0B% #" 3#"I@ # 3"# 6%&$6$%&# "% K
#% # A " "#"%% 12 "# & %"  "#3$$&& 6""&(  6%$ # 6"&"
6% # 3"# 6%&$6$%&# "%  

   ,    

  95 /B 
  
 
  

%""6$C% 0G!$6 , 8'  # 3"# 6%&$6$%&# "% K@ KLK
@
KL   & "F &$#1$% 2" & %"  "#3$$&& 6""&( # 3"#
6%&$6$%&# "%   % "#"%%  I$6$C%

   >,    C 

  
  95 /B
   
 
  

:- /01 23""#$# 4 5
""67# #% &"  /
 1 
)

%""6$C% 0G!$6 , 9'  # 3"# 6%&$6$%&# "% K@ KLK
@
KL  # "# &# &" ?&$&  #"6& #" $%6"1"%% & %" 
"#3$$&& 6""&(  A " % # 6"&" 6% # 3"# 6%&$6$%&# "%  (

   4,   

    95 /B
   
 
  

%""6$C% 0G!$6 , :'  # 3"# 6%&$6$%&# "% K@ KLK
@
KL  #" $%6"1"%% " 6%"%$& &" 0  & %"  "#3$$&& 6""&@
#$"%& "% 12 0&  " K( # 3"# 6%&$6$%&# "%   % "#"%%
 I$6$C%(

   9,    
D    95 /B 
  
 
  

%""6$C% 0G!$6 , ;' % # 6  6##@ # 3"# &$#1$% 2"% " I &"
&#J"  !$% &" "# &$ &" "#3$$&& 6""&( % %$%0 % &" # 6## "#
&$#1$% 6$C% "# 6$6(

   ?,    

     95 /B 
  
 
  

%""6$C% 0G!$6 , <' % # 6  6##@ # 3"# $%6"1"%% $0"1"%"
" I &" &$# 6$C%  !$% &" "# &$ &" "#3$$&& 6""&(

/01 23""#$# 4 5
""67# #% &"  / :.
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (


 4,
   
   

 
   3 @5 ;  
 
  3?>5
;

   0,
       
 
 3; 
 
 3 ;

%""6$C% 0G!$6 , =' # 3"# 6%&$6$%&# "% K #% # A "
"#"%% 12 "#  !$% &" # &# 6%&$6$%"#(  6%$ # 6"&" 6% #
3"# 6%&$6$%&# "%  @ # 6 "# "#"%% 1"% "#( &# # "## #"
"%6 "%% &"% &" "#"6$!$66$%"#(

   @,
   
D    3;

 
 3 ;

%""6$C% 0G!$6 , >' %&""%&$"%" &" 1"$ &" "1A "@ # 3"#  #
.>- &# &" "#3$$&& 6""&@ "#"%% 1"% &#J" 61& 6% " $"1
$%$6$( &# # "# &# #" "%6 "%% &"% &" %0 &" &#J" "#3"6$&(

:8 /01 23""#$# 4 5
""67# #% &"  /
 1 
)

   A,
    
   
 3; 
 
 3 ;

%""6$C% 0G!$6 , M' %&""%&$"%" &" 1"$ &" "1A " "I &@ "%
13# 6%&$6$%"# # "# &# &" &$# 6$C% #" I"% $0"1"%" $%6"1"%&#(

   5,
    E  
 3; 
 
 3 ;

%""6$C% 0G!$6 , .-' # 3"# 6%&$6$%&# "% K@ KLK

@ 2
KL  "#"%% &$#1$% 6$C% &"  & "F "% # &# 6%&$6$%"#( # 3"#
6%&$6$%&# "%  @ % "#"%% &$67 I$6$C% "%  & "F(

   ,
   
  
 
 3; 
 
 3 ;

%""6$C% 0G!$6 , ..'  # 3"# 6%&$6$%&# "% K@ KLK
 2
KL @ # "# &# &" ?&$&  #"6& #% 12"# "% " 6# &" 
"#3$$&& 6""&( # 3"# "%   "#"%% &$#1$% 6$C% "% " "# & &"
?&$&  #"6& "% 13# 6%&$6$%"#(

   ,
        
  3; 
 
 3 ;

%""6$C% 0G!$6 , .8'  &# # 1"$"# &" "1A "@ # "# &# &"

/01 23""#$# 4 5
""67# #% &"  / :9
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

&""1$%6$C% &" 0  #% 12"# "% " 6# &"  "#3$$&& 6""&( # 3"#
"%   "#"%% 1"% 66$C% &" 0  "% 13# "# &$#(

:: /01 23""#$# 4 5
""67# #% &"  /
 1 

2

1 

2

" 6 "&  # "# &# 3"%$&# & %" " "# &$ &" "#3$$&& 6""&@ #" 7
"#3"6$& A " # 3"# 6%&$6$%&# "% " 1"$ &" "1A " K L  1$%$
DK" 6 & , . 2 , =E@ "#"%% $%6"1"% "% " "# 1"&$ 2 "% #
&$1"%#$%"#H "# #" "%6 "% "% "6$C% &$"6 6% " $%6"1"% &" 6%"%$& &"
0  2 " "# & &"   "3 &" ?&$&  #"6&( #" $%6"1"% & #"
6 #&  0 %# "+6$$"%"# &"  !1 6$C% A " #% 1G# GI$&#   7 1"&&@
61  6" # 1$66$#$%( # 66$C% &" 7 1"&& $%! 2C   I"F "%  & "F
1"&$ &" # 3"#@ 3#"IG%&#" A " 7 &$#1$% $&  !$% &" "# &$(
" $0 
1%"@ "# 7 1"&& 6%$3 2C "%  "57 1"66$C% &" $%6$$ 6$I@  6  #"
I$ "!"J& "% " $%6"1"% &" 6"%J" &" &$# 6$C%(
# "# &# 3#"I&# "!"J%  66$&& &" %#1$#$C% &" I &" 0 
A " #"" " 1"$ $6  &" I$%$ DKE@ A " "# "6"$3" "%  7 1"&& A "
"#"% " & 6(
"#"6  # 3"# 6%&$6$%&# "% " 1"$ &" "1A " K
 L K DK"
6 & , 8 2 , =E@ % #" 3#"IC I$6$C% "% " #"6 &"  3"(  6%"%$& &"
0  2  "# & &"   "3 &" ?&$&  #"6& 13$?% #" I$"% $%6"1"%&#@
 A " $0$%C A " " "# 1"&$@ # 61 # &$1"%#$%"# #" "%6 "%"%
$%6"1"%&#H "@ "#"  1"% 1"% 61& 6% # 3"# 6%&$6$%&#
"% " 1"$ $6  &" I$%$( # #" "+$6   1"% 66$&& &" %#1$#$C%
&" I &" 0  A " #"" " $6  &" I$%$$&"%( $1$ "!"6 &" "# 7 1"&&
#" 3#"I "%  I$6$%"# 6%  & "F &" # 3"# A " #" I$C &$#1$% $& 2 "% 

/01 23""#$# 4 5
""67# #% &"  / :;
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

&$# 6$C% A " #" $%6"1"%C "% % -@;> R(

# 3"# 6%&$6$%&# "% 3$#" &"  LK L  1$%$ DK" 6 & , 9 2
, =E@ 13$?% "#"%% 613$# #$1$"# 61&# 6% # 1"$"# &"
"1A " %"$1"%" &"#6$#(  I$%" $%6$ #" "%6%C "% " 6
$%6"1"% &" 6%"%$& &" 0 H 61 6%#"6 "%6$@ " $%6"1"% &" "# 1"&$
! " 1"%@ 61&  # 1"$"# &" "1A " %"$1"%" &"#6$#( # &"3$&
 A " " 1"$ $6$! "$"% $"%" 1"% 66$&& &" %#1$#$C% &" I
&" 0  A " K 2 K
( # 7 1"&& 6& "# C "%" #$1$ "!"6 "% 
&$# 6$C%@  6  #" I$ $%6"1"%&(
# 3"# 6%&$6$%&# "% " 1"$ &" "1A "  DK" 6 & , : 2
, =E@ ! "% # A " "#"%% 1"% I$6$C% "% # G1"# !$#$6A 1$6# 2 #
611$"% ! " &$!""%"  # 1"$"# &" "1A " "I &# & %" " "# &$(
 6%"%$& &" 7 1"&& 2 " "# & &" ?&$&  #"6& #" "%6%3%
&$#1$% $&#  !$% &" "# &$@ 33"1"%"   "1"   A " ! "%
#1"$&# & %" " "$& &" "I 6$C% 2 # 66"#$6# &" 1"$ &"
"1A "H "#@  # I"F@ "#G $0&   &$#1$% 6$C% &" "# 1"&$ 2  6
I$6$C% &" # &$1"%#$%"# &" # 3"#(  &$#1$% 6$C% &" 6%"%$& &" 7 1"&&
A " "#"%3% # 3"# $1$6C A " # 3"# "#"%% % # $ $%6"1"% "%
# & "F(  &$#1$% 6$C% &" &#J" ! " 1"% A " # # 1"$"# &" "1A " 2
"# % !"6C  &$# 6$C%@  6  #" I$ $%6"1"%&  $0  A " # &"1G# 1"$"#
&" "1A "(

" 6 "&   &"#6$ %"$1"%"@ #"  "&" # 1$ A "  $%6$ I$6$C% "%
" "# &$ &" "#3$$&& 6""& &" & 6 "1$%&@ ! "  7 1"&&H &$67
&$!""%6$ "#G "6$%& 6%  66$&& &" %#1$#$C% &" 0  A " #"" 6&
1"$ &" "1A "H "%$"%& "% 6 "% A "  7 1"&& &" 1"&$ 13$"%" "# %
I$3" "+"%@ #" 3#"IC A "  $%6"1"% % !"63 # G1"# 6$6# &"
& 6 "1$%&(
&"1G#@ 6%#$&"%& # "# &# &" # 3"# "I &#  %&$6$%"#
13$"%"#@ &"1# "#3"6" A " # 613$# % #% % 6"% &#  #
 "3# &" ?&$&  #"6& 2
""1$%6$C% &" 0   _ $#7"@ 61 #$ 6 "
"%  #3$$&& 6""&(
  &@ "I %& # "# &$# &" 6## &" # 1"$"# &" "1A "@ #"
3#"I A " " K "# " 1"$ &" "1A " 1G# "6%C1$6@ " 6  0%$F 
6$&& &" & 6 # 61  "%3$$&&   61S(  !$%1"%"@ %#
21# "% % %G$#$# &" # #"6# A " 36 % & 6@ 61 #%  6$&&@
#"6# 0#$6#@ &" 6# 2 &" 1N"$%0 "% 3 #6 &" 1"$ &" "1A " A " #"
1G# &"6 &  " & 6 &" 1%" $%"0(

:< /01 23""#$# 4 5

""67# #% &"  /
  


 


.( # 1"$"# &" "1A " DK@ KLK

@ KL  2  E "I &#
& %" " "# &$ &" "#3$$&& 6""& 0%$F%  6$&& &" & 6 &"#6$(
8(  1"$ &" "1A " K L  1$%$ &"1#C #" "$I1"%" 1G#
"6%C1$6@ A " # &"1G# 1"$"# &" "1A " "1"&#(
9( % " "# &$ &" "#3$$&& 6""&@ " 1"$ &" "1A " K "#"%C
12 66$&& &" %#1$#$C% &" I &" 0 @  A " #" "I$&"%6$ "% " "# &
&" 6%"%$& &" 0  &"  3"(
:( % " "# &$ &" "#3$$&& 6""&@ " 1"$ &" "1A "  @ "#"%
1"% 66$&& &" %#1$#$C% &" I &" 0 (
;(% " "# &$ &" "#3$$&& 6""&@ # G1"# 6$6#@ 61 " &#J" 2 
&$# 6$C% % "#"%% 613$# 12"#  ;R(
<(  66$&& &" %#1$#$C% &" I &" 0 @ &" 1"$ K  6%&$6$%"#
13$"%"#@ #" 1$%$1$F "% 6  I"6"# 61& 6% " "# & "%  "#3$$&&
6""&(
=( %#$&"%& # #"6# &" 6$&&@ 0#$6#@ 6## 2 &" 1N"$%0@ "
1"$ K L  1$%$ "#  #" " 1G# 6%I"%$"%"  " & 6(

/01 23""#$# 4 5
""67# #% &"  / :=
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

:> /01 23""#$# 4 5

""67# #% &"  /
   

  

.( 1"1"% " "# &$ &" "#3$$&& 6""& 6% % "# &$  0 F 
&""1$% " $"1 &" I$& " &" & 6(
8( "$F % "# &$ &" "#3$$&& 6""& 6% K &" 12 0# 
1$%$1$F " $%6"1"% &" 6%"%$& &" 7 1"&&@  "%&" A "  & "F % #" I" %
!"6&(

/01 23""#$# 4 5
""67# #% &"  / :M
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

;- /01 23""#$# 4 5
""67# #% &"  /
 00B 5

00B 5

Gennaro AR., 2000. Remington: The Science and Practice of Pharmacy. Lippincott
Williams & Wilkins. 20th edition. Baltimore, Maryland. Págs. 690 – 1014.
The Merck Index- An encyclopedia of chemicals, drugs and biologicals. 2001,13th
edition. Merck and Co., New Jersey. Pág. 5367.
Liebermen H. A., Lachman L., Schwarts J.B., 1989. Pharmaceutical Dosage Forms.
Volume 1. Marcel Dekker, Inc. New York. Second edition, revised and expanded.
Págs. 91, 152, 169, 173, 174.
Gennaro AR., 1998. Problem solver and reference manual. Tablet ingredient. FMC
Corporation, Philadelphia. Sección 4, pag. 5,7,14
Graham C., Hogan J., Aulton M., 1995. Pharmaceutical Coating Technology. Taylor &
Francis Inc., Bristol. Págs. 7, 11, 12, 23, 27, 34 -37, 44.
Wade A.; Weller P.J., 1994. Handbook of Pharmaceutical excipients. American
Pharmaceutical Association, Washington. Págs. 126, 229, 355.
The United States Pharmacopeia Convention, Inc. United States Pharmacopeia (USP
28) / National Formulary (NF 23) <1146>,<1191>.
Jenkins W. A., Osborn K.R., 1993. Packaging Drugs and Pharmaceuticals. Technomic
Publishing Company Inc. Lancaster-Pensylvania. Págs. 104,116, 276-279.
R. Pilchik, “Pharmaceutical Blister Packaging, Part I: Rationale and Materials,”
Pharmaceutical Technology. 24 (11), Págs. 68–78 (2000).

/01 23""#$# 4 5
""67# #% &"  / ;.
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

Productos plásticos [en línea]. [Fecha de acceso Agosto-2003]. Disponible en

http://www.productosplasticos.com.
Tekni films [en línea]. [Fecha de acceso agosto-2003]. Disponible en
http://www.tekni-films.com/thermoforming_help.
Stibenz, B. Protección de las sustancias activas en blisters. En el Congreso y
Exposición de Tecnología Farmacéutica ETIF 2004. Buenos Aires; EVC
Films-Pharma Division; 2004.
Weeren R., Gibbeni D., Barrier packaging as an integral part of drug delivery. Drug
Delivery Technology [en línea]. 2003 [Fecha de acceso diciembre-2003]. Disponible
en http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=52.
Sessa G. J., Como emplear films PVC, PVC/PVDC, PVC/ACLAR en blisteras
farmacéuticas. En el Congreso y Exposición de Tecnología Farmacéutica ETIF 2004.
Buenos Aires; Klöckner Pentaplast; 2004.
World Health Organization (WHO), 1996. Technical Report Series, No. 863.
ICH Steering Committee, 2003. Stability Data Package for Registration Applications in
Climatic Zones III and IV - Q1F. Switzerland.
ICH Steering Committee, 2003. Stability Testing of New Drug Substances and Products
Q1A (R2) Switzerland.

;8 /01 23""#$# 4 5
""67# #% &"  /
 7

7

C D '
 $ #I  # ! *!

/01 23""#$# 4 5
""67# #% &"  / ;9
  !"  # $# # !#   % !! &! # &#
!&!  #" ' (

;: /01 23""#$# 4 5
""67# #% &"  /
 7

/01 23""#$# 4 5
""67# #% &"  / ;;