If   you   would   recall,   only   unionized   drugs   are   allowed   to   pass   through   the  
semipermeable   membrane.   Generally,   ionized   drugs   CANNOT   pass   through   the  
semipermeable   membrane   (unless   you   have   ion-­‐pair   transport   existing   which   is  
rare).  
 

Slide  #32  
How   are   partially-­‐ionized   drugs   absorbed   or   pass   through   a   semipermeable  
membrane?  
Partially-­‐ionized   drugs   are   either   weak   acid   (e.g.   aspirin)   or   weak   bases   (e.g.  
paracetamol),  it  depends  on  their  pka.  
 

Slide  #33  
Let  us  review:  
 
 
pka  1-­‐-­‐strong  acid-­‐-­‐-­‐-­‐-­‐-­‐/-­‐-­‐weak  acid-­‐-­‐-­‐pka  7-­‐-­‐-­‐weak  base-­‐-­‐-­‐/-­‐-­‐-­‐strong  base—pka  14  
 
 
If  the  pka  is  below  7,  the  drug  is  likely  to  be  acidic,  if  the  pka  is  above  7  it  is  likely  to  
be  basic.  
 
Now,  if  the  pka  of  the  drug  lies  near  or  close  to  1,  it  becomes  a  strong  acid  and  if  the  
pka  lies  near  or  close  to  14,  it  becomes  a  strong  base.  
 
Strong  acid  and  strong  bases  are  ionized  (charged)  drugs.  
 
If  the  pka  of  the  drug  is  below  but  near  7  it  is  a  weak  acid,  and  if  its  pka  is  above  but  
near  7  it  is  a  weak  base.  
 
Weak  acid  and  weak  bases  are  partially-­‐ionized  drugs.  
 

Slide  #34  
Let’s  try  to  simplify.    
Partially-­‐ionized  drugs  can  either  exist  as  ionized  or  unionized.  As  to  how  many  will  
become   unionized   or   ionized   will   depend   on   their   pka   and   the   pH   of   the   medium  
where  they  are  in.  
 
You  could  say  partially-­‐ionized  drugs  are  indecisive  because  they  do  not  know  if  they  
will  exist  as  ionized  or  unionized  forms.  
 
As  to  how  many  of  the  partially-­‐ionized  drugs  will  be  in  the  ionized  form  or  in  the  
unionized  form  is  explained  by  the  Henderson-­‐Hasselbalch  equation.  

gntanodra  
  

 
Don’t   get   intimidated   by   the   equation   because   it   will   only   answer   your   question:  
How  much  of  the  drug  will  be  in  the  ionized  form  and  how  much  of  it  will  be  in  
the  unionized  form?  
According   to   the   Henderson-­‐Hasselbalch   equation,   the   number   of   ionized   and  
unionized  parts  of  a  drug  will  depend  on  the  pka  of  the  drug  and  pH  of  the  medium.  
 
The   pka   of   a   drug   is   fixed   while   the   pH   of   the   medium   changes   in   each   body  
compartment.   For   example,   the   pH   of   the   stomach   becomes   even   lower   (more  
acidic)   in   the   presence   of   food   due   to   secretion   of   HCl.   The   pH   of   the   blood   (pH   =  
7.4)   can   become   acidic   in   cases   when   a   patient   suffers   from   metabolic   acidosis   or  
basic  when  we  increase  the  bicarbonate  in  the  bloodstream.    
We  can  alter  the  pH  of  the  medium  but  the  pka  of  the  drug  will  depend  on  the  nature  
of  the  drug  itself.  
 
Take  note  of  the  equation  that  you’re  going  to  use  to  determine  the  amount  ionized  
&  unionized.  It  will  depend  if  a  drug  is  a  weak  acid  or  weak  base.  (pka)  
 
For  a  weak  acid:  
 
pH  =  pka  +  log  _  (ionized)__          or  if  you  will  remember:    pH  =  pka  +  log  (HCOO-­‐)  
         (unionized)                  HCOOH  
 
acid  is  a  H+  donor,  hence  it  becomes  (-­‐)charged  or  simply  ionized.    
Note   that   in   this   equation:   (ionized)   is   the   numerator   and   (unionized)   is   the  
denominator.  
 
For  a  weak  base:  
 
pH  =  pka  +  log  _  (unionized)___        or  if  you  will  remember:  pH  =  pka  +  log  _NH3__  
                 (ionized)                              (NH4+)  
 
Base  is  a  H+  acceptor,  hence  it  becomes  (+)  charged  or  again  simply  ionized.  
Note   that   in   this   equation:   (ionized)   is   the   denominator   and   (unionized)   is   the  
numerator.  
 

Slide  #35  
Let’s   apply   the   equation.   Notice   that   there   are   two   compartments   separated   by   a  
semipermeable  membrane  with  different  pH  levels.  The  stomach  is  acidic  (pH  =  1.2)  
and  the  blood  is  neutral  (pH  =  7.4).  
 
Imagine   your   anatomy.   The   stomach   is   perfused   by   a   rich   blood   supply   establishing  
the  relationship  of  the  two  compartments  (blood  &  stomach  side)  
 

gntanodra  
  

Slide  #36    
Focus  your  attention  on  the  left  side  compartment  (stomach).  
Let’s  say  you  took  the  aspirin  tablet  by  the  oral  route.  
So  now  the  aspirin  (with  a  pka  =  3)  is  in  the  stomach  (pH  =  1.2).  
Using  the  equation:  
  1.2  =  3  +  log  (ionized)/(unionized)  
  1.2  –  3  =  log  (ionized)/(unionized)  
  -­‐1.8  =  log  (ionized)/(unionized)  
 
Note  the  -­‐1.8  is  in  logarithm.  So  if  you  want  to  know  how  much  of  the  drug  is  ionized  
or  unionized  form,  get  the  antilogarithm  of  -­‐1.8.  
 
  0.0158  =  ___(ionized)___  
                   (unionized)  
 
0.0158   is   the   number   of   ionized   form   of   a   drug.   How   much   of   the   drug   is   in   the  
unionized  form?  It  is  1,  because  the  denominator  of  a  whole  number  is  always  1.    
 
  0.0158  =  ___(ionized)____  
           1                (unionized)  
 
The   0.0158   and   1   is   not   an   actual   number.   It   doesn’t   mean   that   you   have   0.0158   mg  
or   0.0158   mg/mL   in   the   compartment.   The   0.0158   &   1   only   gives   you   an   idea   of   the  
proportions  of  ionized  and  unionized  form  of  the  drug  in  the  compartment.  
 
We  could  also  say  that  1.58  of  the  drug  is  ionized  and  100  are  unionized.  
 
So  in  a  medium  with  a  pH  of  1.2  (acidic)  a  weak  acid  (pka  =  3)  is  predominantly  in  
the  unionized  form  (since  ionized:  1  >  unionized:  0.0158)  
 
What  is  the  percent  ionization  of  the  drug?  
 
  _________(ionized)_____________  x  100  =  %  ionization   OR  
               (ionized  +  unionized)  
 
  _________(ionized)_____________  x  100  =  %  ionization  
               (total  amount  of  drug)  
 
The  total  amount  of  drug  is  1.0158.    
Total  amount  of  drug  =  1  (unionized)  +  0.0158  (ionized)  =  1.0158  
 
%  ionization  =  (0.0158  /  1.0158)  x  100  =  1.58%  
 
How  many  %  is  unionized?  98.42%  

gntanodra  
  

 
%  unionized  =  (total  drug)  –  (%  ionized)  
%  unionized  =  100  –  1.58  =  98.42%  
 
So  in  an  acidic  medium  (pH  =  1.2),  aspirin  (pka  =  3)  is  1.58%  ionized  and  98.42%  
unionized.  
 
This   further   proves   the   theory   that   a   weakly   acidic   drug   in   an   acidic   medium   is  
predominantly  unionized  (98.42%)  
 
 
Moving  on………  
Now  what  will  happen  to  the  drug  in  the  left  compartment  after  it  has  separated  to  
its  ionized  (0.0158)  and  unionized  form  (1).  
 
The  principle  of  passive  diffusion  is  applied  (since  most  of  the  drugs  pass  through  
membranes  by  this  mechanism)  
 
The  0.0158  will  remain  in  the  compartment  (since  it  is  ionized)  while  the  1  (since  it  
is   unionized)   will   move   and   pass   through   the   membrane   to   reach   the  
bloodstream  side.  
 
Let’s  now  focus  on  the  right  compartment.  
Notice   that   upon   reaching   this   compartment,   the   pH   is   different   (7.4).   The   drug  
again  will  separate  into  different  proportions  of  ionized  and  unionized  form.  
 
Applying  again  the  equation.  It  is  still  aspirin  (pka  =  3)  so  we  apply  the  equation  of  a  
weak  acid.  
 
  pH  =  pka  +  log  (ionized)/(unionized)  
  7.4  =  3  +  log  (I)/(UI)  
  7.4  –  3  =  log  (I)/(UI)  
  4.4  =  log  (I)/(UI)  
   
Get   the   antilog   of   4.4   (SHIFT   LOG   4.4)   to   get   the   proportions   of   ionized   and  
unionized.  
  (ionized)/(unionized)  =  25,  119/1       or        25,119  ionized  is  to  1  ionized  
 
So   in   the   blood   (pH   =   7.4),   aspirin   is   25,100   ionized   and   1   unionized.   (or   in   the  
blood,  aspirin  is  99.9%  ionized  and  0.1%  unionized)  
 
So   will   the   25,  100   move   back   to   the   left   compartment   (stomach   side)?   No,   because  
it  is  ionized  (so  it  cannot  cross  the  membrane).  
Will   the   1   also   move   back   to   the   left   compartment?   No,   because   the   amount   of  
unionized  portions  on  both  sides  of  the  membrane  are  already  equal  so  there  is  no  
more  movement.  

gntanodra  
  

 So  what  you  see  now  (in  this  slide)  is  the  final  picture  after  the  drug  has  moved  in  
between  the  two  compartments.  
 
Where  is  the  drug  located?  It  is  found  in  the  right  compartment  (blood  side).  
 
So   how   does   this   translate?   Most   of   the   aspirin   is   predominantly   absorbed   in   the  
stomach  since  most  of  the  drug  in  the  stomach  (acidic  medium)  is  unionized.    
 
Notice   also   that   if   you   look   at   the   two   compartments,   where   would   you   find   most   of  
the   drug?   Most   of   the   drug   is   in   the   blood   side   (with   a   total   25,101   compared   to  
1.0158   in   the   stomach)   which   means   that   most   of   the   drug   is   already   absorbed   in  
this  area.    
 

Slide  #37-­‐41    
So   we’ve   discussed   the   pH-­‐partition   hypothesis.   Read   along   the   slides   since   this   is  
self-­‐explanatory.  
 

Slide  #42-­‐46  
As   we’ve   said   before,   the   pka   of   the   drug   does   not   change   but   the   pH   of   the   medium  
where  it  is  in  can  change.  
 
Focus   on   the   values   on   the   2nd   column;   a   weakly   acidic   drug   (pka   =   3)   is   put   in  
different  mediums  with  different  pH  levels.  
 
So  as  you  go  down  the  column,  the  pH  of  the  medium  becomes  more  acidic  and  as  
you  go  up  the  column,  the  pH  of  the  medium  becomes  more  basic.  
 
Notice  that  in  a  basic   medium  (topmost  part  of  the  column),  a  weak   acid  mostly  
exists   in   the   ionized   form  since  it  is  99.9%  ionized  (which  means  that  it  is  0.1%  
unionized).  
 
As  we  go  down  the  column,  the  medium  becomes  more  acidic  (pH  6  à  pH  5  à  pH  4  
à  pH  3.9  à  pH  3.8),  notice  again  that  the  %  ionization  of  the  weak  acid  decreases  
which  means  that  your  weak  acid  is  becoming  more  unionized.  
 
A   weakly   acidic   drug   in   an   acidic   medium   (bottommost   part   of   the   column)   is   more  
unionized.  
 
Now…….  
Focus  on  the  values  on  the  3rd  column;  a  weakly  basic  drug  (pka  =  9)  is  also  put  in  
different  mediums  with  different  pH  levels.  
 
 

gntanodra  
  

It   still   follows   that   as   you   go   down   the   column,   the   medium   becomes   more   acidic  
and  as  you  go  up  it  becomes  more  basic.  
 
Notice   that   in   a   basic   medium   (topmost   part   of   the   column),   the   weak   base   is  
predominantly  UNionized  (0.01%  ionized  meaning  it  is  99.9%  UNionized)  
 
As  you  go  down  again  (pH  13  à  pH  12  à  pH  11  à  pH  10  à  pH  9.9),  as  the  medium  
becomes  more  acidic,  the  weak  base  is  becoming  more  ionized.  
 
So  a  weakly  basic  drug  in  an  acidic  medium  is  predominantly  ionized.  
 

Slide  #47-­‐48  
This  just  summarizes  the  table  discussed  in  the  previous  slides.    
 
To  put  it  simply,  opposing  characteristic  of  the  pka  &  pH  (weakly  acidic  drug  in  a  
basic  medium  or  weakly  basic  drug  in  an  acidic  medium),  the  drug  is  predominantly  
>
IONIZED.  (ionized  form    unionized  form)  
 
Similar  characteristics  of  the  pka  &  pH  (weakly  acidic  drug  in  an  acidic  medium  or  
weakly  basic  drug  in  a  basic  medium),  the  drug  is  predominantly  UNIONIZED  

(unionized  form   >  ionized  form)  

 

Slide  #49  
To  solve,  take  note  that  the  drug  is  a  weak  base  (pka  8.5)  hence:  
 
  pH  =  pka  +  log  (unionized)/(ionized)  
 
Notice   that   the   unionized   portion   is   the   numerator   and   ionized   portion   is   the  
denominator.  
 
  2  =  8.5  +  log  (unionized)/(ionized)  
  2-­‐8.5  =  log  (UI)/(I)  
  -­‐6.5  =  log  (UI)/(I)  
  3.16  x  10-­‐7  =  (UI)/(I)       OR    
   
  3.16  x  10-­‐7/1  =  (unionized)/(ionized)  
 
In   a   medium   with   a   pH   of   2,   a   weakly   basic   drug   (pka   8.5)   exist   as   0.000000316  
unionized  &  1  ionized  
  %  ionization  =  1/(1.000000316)  =  99.99%  
  %  unionized  =  100  –  99.9%  =  0.1%  

gntanodra  
  

 
This   also   proves   that   a   weakly   basic   (pka   =   8.5)   drug   in   an   acidic   medium   (pH  
=  2)  is  predominantly  _______________________________  (99.9%).  
 

Slide  #50  
 
This  is  the  practical  application  of  the  Henderson-­‐Hasselbalch  equation.  
 
When   we   administer   sodium   bicarbonate   IV,   we   increase   the   pH   of   the   bloodstream  
making  it  more  basic.  
 
Take  note  that  the  drug  is  still  aspirin,  a  weakly  acidic  drug  (pka  3).  
 
In  a  blood  with  a  pH  of  7.4,  aspirin  is  25,100  ionized  and  1  unionized.  
 
Let’s  say  the  pH  of  the  blood  became  9  after  administering  Na  bicarbonate  IV.  
 
  9  =  3  +  log  (ionized)/(unionized)     remember  aspirin  is  a  weak  acid  
  9-­‐3  =  log  (I)/(UI)  
  6  =  log  (I)/(UI)  
  1,000,000/1  =  (ionized)/(unionized)  
 
Notice   that   when   we   increase   the   pH   of   the   blood,   the   number   of   ionized   form   of  
aspirin  increased  from  25,100  to  one  million.    
 
By   increasing   the   pH   of   the   medium   (after   giving   NaHCO3   IV),   we  
increase  the  amount  of  ionized  form  of  aspirin.  
 
Is   this   a   good   thing?   Yes,   because   there   will   be   less   chances   for   the   drug   to   cross  
biomembranes  because  we  increased  the  %  ionized  form  of  the  drug.  The  drug  will  
be  entrapped  in  the  bloodstream.  
 
Since  it  is  more  ionized,  the  kidneys  can  easily  excrete  the  drug  since  you  know  for  a  
fact  that  ionized  (polar,  charged)  forms  are  water-­‐soluble.  
 
By  giving  NaHCO3  IV  in  aspirin  toxicity/overdose,  we  enhance  the  
excretion   of   the   drug   by   converting   it   to   a   more   ionized/water-­‐
soluble  form  and  we  trapped  it  in  the  circulation.  
 
This  treatment  is  also  called  as  ION-­‐TRAPPING.  
 
 
 

gntanodra  
  

Slide  #51  
A   drug   existing   predominantly   in   an   IONIZED   form   tends   to   be   trapped   in   a  
compartment   where   it   is   in   and   is   less   likely   to   distribute   to   other   areas   of   the  
body.  
 
A  drug  existing  predominantly  in  a  UNIONIZED  form  tends  to  distribute   or   move  
to   other   areas/compartments  of  the  body  since  they  can   cross   biomembranes  
easily.  
 

Slide  #52-­‐57  
This   just   shows   how   a   drug   can   move   between   two   immiscible   liquids   (oil   and  
water).  
 
Picture  it  as  a  container  with  2  compartments  separated  by  a  membrane.  
 
 
 
  OIL   WATER  
 
 
 
 
Then   the   drug   is   put   in   the   water   compartment   (aqueous   phase   before  
equilibration)  and  then  it  is  allowed  to  equilibrate  between  the  two  compartments.  
 
After   equilibration   they   measure   the   drug   in   the   water   (aqueous   phase   after  
equilibration)  compartment  again  to  compute  for  the  apparent  lipid/water  partition  
coefficient.  
 
To  put  it  simply,  the  higher  the  lipid/water  coefficient  the  more  lipid  soluble  
the  drug  is  and  vice-­‐versa.  
 
 
This  ends  our  discussion.  I  do  hope  this  was  able  to  help  you.  

gntanodra