UCL SCHOOL OF PHARMACY

PHAYG062  Preformula2on  

Amorphous  materials  
 
Learning  objec2ves  

•  To  define  the  amorphous  state  

•  To  know  the  structure  of  amorphous  materials  
•  To  understand  how  amorphous  matrices  will  change  with  9me  
–  Relaxa9on  
•  To  discuss  the  changes  that  occur  at  the  glass  transi9on  temperature  
•  To  appreciate  which  processing  methods  can  produce  amorphous  
materials  
•  To  know  some  advantages  and  disadvantages  of  amorphous  forms  
The  amorphous  state  

•  Widely  studied,  poorly  understood  

•  Many  of  the  terms  used  originate  from  the  polymer  field  
•  Effect  of  amorphous  material  oDen  not  considered  
–  Misunderstanding  of  defini9on  
–  No  understanding  that  an  amorphous  (or  par9ally  amorphous)  
material  may  have  been  formed  

•  Generally,  amorphous  materials  only  characterised  when  product  is  

formulated  to  be  amorphous  
Defini2on  

•  Amorphous  (Gk,  lack  of  form)  

•  Easiest  conceptualisa9on  is  to  consider  a  material  with  the  molecular  
structure  of  a  liquid,  but  the  viscosity  of  a  solid  

Degree of disorder

Liquid Solid

Viscosity
Amorphous  materials  

•  Commonly  encountered  in  everyday  life  

Energy or volume
Glass Supercooled liquid Liquid

(i) Aging
(ii) (ii) Recovery
(i)

Temperature
TK Ta Tg mp
Forma2on  

•  Easily  formed  during  processing  and  manufacture  

•  Some  techniques  produce  almost  en9rely  amorphous  material  
–  Spray-­‐drying  
–  Freeze-­‐drying  
–  Quench-­‐cooling  

•  Others  produce  par9ally  amorphous  material  

–  Ball  or  air-­‐jet  milling  
–  Compac9on  
 Spray-­‐drying  

Hot air
Sample
inlet

Air outlet
Dry product
Freeze-­‐drying  

•  Based  on  triple-­‐point  of  water  

•  Sample  is  frozen,  placed  under  
vacuum  and  reheated  
•  Can  also  use  t-­‐butanol  as  a  
solvent  
Pressure (Pa) 105 2 1

Liquid

Vapour
Solid
610
Triple point
3 4

0.0075 Temperature (oC)

Both  amorphous  but…  

•  Note  that  while  both  materials  are  amorphous,  proper9es  likely  to  be  
significantly  different  (porosity,  stability,  dissolu9on  rate  etc).  
Uninten2onal  forma2on  

•  Any  technique  that  applies  a  force  to  a  sample  can  make  it  par9ally  
amorphous  
–  Localised  input  of  energy  can  disrupt  molecules  out  of  a  crystalline  
alignment  
–  Importantly,  because  force  is  usually  applied  at  the  surface,  while  
percent  amorphous  material  might  be  low,  the  effects  it  exerts  
might  be  significant  

Macroscopic properties different

For  example:  IGC  data  for  various  lactose  samples*  

Sample Surface Energy / mJ m-2

Amorphous lactose (spray dried) 37.1 ± 2.3

Crystalline lactose monohydrate 31.2 ± 1.1

Milled (ca. 1% w/w amorphous) 41.6 ± 1.4

Physical blend of crystalline and amorphous 31.5 ± 0.4

(99:1)

*Newell et al , Pharm Res 18 (2001) 662

Characteris2cs  of  amorphous  materials  

•  Glass  transi9on  temperature  

•  Below  Tg  material  is  termed  bri%le*  
•  Above  Tg  material  is  termed  rubbery*  
•  One  formalism  is  to  consider  molecules  as  being  in  structural  
equilibrium  with  temperature  above  Tg  but  not  below  
Energy or volume
Glass Supercooled liquid Liquid

(i) Aging
(ii) (ii) Recovery
(i)

Temperature
TK Ta Tg mp
Relaxa2on  

•  With  9me,  amorphous  materials  will  relax  

–  Essen9ally  all  the  molecules  begin  to  move  into  a  greater  
structural  alignment  
–  Excess  energy  is  lost,  so  system  tends  towards  supercooled  liquid  
state  
–  Eventually  crystallisa9on  will  occur  
–  Will  occur  faster  with  
•  Temperature    
•  and/or  addi9on  of  a  plas9ciser  
Advantages  of  amorphous  materials  

•  No  crystal  laXce  energy,  so  main  barrier  to  dissolu9on  overcome  

•  Therefore,  rapid  dissolu9on  leading  to  high  concentra9ons  

Crystalline and amorphous MOM*

*Sato  et  al,  Chem.  Pharm.  Bull.,  29:2675-­‐2682,  1981.  
Disadvantages  of  amorphous  materials  

•  However,  stability  can  oDen  be  

decreased  
–  Uptake  of  water  and/or  greater  
molecular  mobility  so  faster  
rate  of  reac9on  
•  Data  shows  temperature  stability  
of  cefotoxi9n  sodium*  
•  Crystalline  (top)  
•  Amorphous  (bofom)  
•  40oC  (r)  60oC  (£)  80oC  ()  

*Oberholtzer  et  al,  J.  Pharm.  Sci.,  68:863-­‐866,  1979  

Why  consider  amorphous  forms?  

•  Drivers  for  move  to  amorphous  formula9on  

–  Increasing  molecular  weight  of  ac9ve  

–  Use  of  deriva9sed  polymeric  ac9ves*  
–  Use  of  polymeric  excipients  
–  Increasing  number  of  BCS  class  II  ac9ves  as  lead  compound  
–  Formula9on  of  fast-­‐dissolving  oral  formula9ons  
–  Instability  in  solu9on,  but  IV  route  needed  
 

*For instance, PolyTherics Ltd

Amorphous  drug  products  

•  In  other  words,  choose  amorphous  formula9on  because  

 
–  Ac9ve  or  excipient  can’t  be  crystallised  
–  Increased  dissolu9on  rate  confers  a  solubility  advantage  
–  Ac9ve  is  too  unstable  in  solu9on,  but  must  be  administered  
intravenously    
Amorphous  drug  products  

•  Three  main  formula9on  types  

–  Solid  amorphous  dispersions  

–  Lyophilized  powders  
–  Oral  fast-­‐dissolving  tablets/films  
Solid  amorphous  dispersions  

•  Drug  is  dissolved  in  a  (usually  polymeric)  matrix  

–  Molecular  dispersion  -­‐  solid  solu9on  
–  Par9culate  dispersion  -­‐  solid  suspension  
 

2 component, 2 phase 2 component, 1 phase

Case  example:  SporanoxTM  (itraconazole)  

•  Itraconazole  has  very  poor  solubility  

•  During  manufacture  drug  and  HMPC  in  ethanol  and  dichloromethane  
are  sprayed  onto  sugar  core  
•  Solid  solu9on  formed  on  surface  
•  Granules  are  put  in  hard  capsules  

HPMC/itraconazole solid
solution

Sugar core
Oral  fast-­‐dissolving  tablets  

•  Generally  formulated  for  marke9ng  advantage  rather  than  

bioavailability  
•  ‘Melt’  in  mouth  with  no  need  for  added  water  
•  Freeze-­‐dried  tablet  
Case  example:  Nurofen  meltlets  

•  Mechanical  strength  of  freeze-­‐dried  ibuprofen  an  issue  

•  Co-­‐formulate  with  a  sugar  (mannitol)  for  strength  -­‐  a  ‘matrix  former’  
–  Also  helps  taste-­‐masking  
•  Also  add  a  collapse  protectant  (oDen  glycine)  
•  Freeze-­‐dry  solu9on  directly  in  blister  pack  
•  Suspension  formed  in  mouth  -­‐  easily  swallowed  
Lyophilized  powders  

•  Freeze-­‐dried  powder  in  sealed  vial  

•  Used  when  IV  solu9on  is  required  but  ac9ve  is  unstable  in  solu9on  
–  Drugs  that  hydrolyse  (penicillins)  
–  Biologics  (vaccines)  
•  Can’t  recons9tute  with  water  (not  isotonic  with  blood)  
•  Use  saline  BP  or  recons9tu9on  solu9on  
Summary  

•  Amorphous  state  is  a  non-­‐equilibrium  state  

•  Viscosity  of  a  solid,  structure  of  a  liquid  
•  Formed  by  various  processes  
–  Deliberate  formula9on  (high  content)  
–  Accidental  inclusion  (low  content)  
•  Can  have  desirable  quali9es  
–  Dissolu9on  rate  and  bioavailability  
•  But  also  undesirable  
–  Loss  of  physical  form  
–  Chemical  instability