UCL SCHOOL OF PHARMACY

PHAYG063  

Dry  Powder  Inhalers  

Learning  objec5ves  

•  To  describe  the  delivery  challenges  of  the  pulmonary  route  

•  To  know  the  types  of  inhaler  available  
•  To  understand  the  formula=on  principles  of  dry  powder  inhalers  
•  To  be  able  to  explain  the  role  of  surface  energy  in  DPI  performance  
•  To  know  why  physical  form  affects  DPI  performance  
Pulmonary  delivery  

•  Probably  the  most  popular  target  for  delivery  a@er  the  oral  route  

–  Pa=ent  compliance  and  convenience  

–  Large  surface  area  for  absorp=on  
–  Avoidance  of  first-­‐pass  metabolism  

•  Is  it  an  easy  route  of  delivery?  

–  No!  Device  is  cri=cal,  as  is  user  
–  Low  percentage  of  dose  delivered  
–  Effect  of  long-­‐term  exposure  of  lung  to  excipients  is  unclear  
Aerosols  

•  All  pulmonary  devices  generate  an  aerosol  which  is  inhaled  by  the  
pa=ent  
•  An  aerosol  is  a  suspension  of  solid  par=cles  or  liquid  droplets  in  a  gas  
•  Par=cle  or  droplet  size  is  a  cri=cal  factor  in  delivery  to  the  lower  lung  
 7 – 10 µm

2 – 7 µm

0.5 – 2 µm

Ideally, particles for inhalation < 5 µm

Pulmonary  delivery  strategies  

•  Three  main  devices  

–  Nebulisers  
•  Drug  in  solu=on  
•  Fine  mist  
–  pMDI  
•  Drug  in  suspension  
•  Device  generates  
aerosol  
–  DPI  
•  Drug  as  dry  powder  
•  Pa=ent  generates  
aerosol  
Dry  powder  inhalers  

•  The  main  device  for  pulmonary  delivery  because  

–  Formula=on  is  a  powder  blend  –  a  familiar  concept  for  
pharmaceu=cal  scien=sts  
–  Breath  actuated  –  cannot  be  anything  other  than  coordinated  with  
pa=ent  inspira=on  

•  How  to  formulate?  Simply  load  device  with  drug  par=cles  <  5μm?  
•  No!  Par=cles  of  this  size  are  difficult  to  manufacture  and  generally  
have  high  surface  energies  and  so  are  highly  cohesive  (clumping)  or  
adhesive  (s=ck  to  device)  
 
Manufacturing  par5cles  of  5  μm  diameter  

•  Not  easy,  because  this  is  a  very  small  diameter  

•  Only  op=ons  are;  
–  Controlled  crystallisa=on  up  to  5  μm  
–  Size  reduc=on  down  to  5  μm  

•  Usually,  size  reduc=on  is  used,  as  it  is  easier  to  control  
Par5cle  size  reduc5on  

•  A  mill  is  used,  so  the  process  is  referred  to  a  milling  (some=mes  
micronisa=on)  
•  Typical  designs  are  (i)  air-­‐jet  mill  or  (ii)  ball  mill  
•  Must  be  careful  when  milling,  as  physical  form  changes  can  occur  in  
addi=on  to  par=cle  size  reduc=on  

Macroscopic properties different

Crystalline Amorphous

•  Because  of  this,  manufacturers  must  demonstrate  to  the  FDA  the  
amorphous  content  of  powders  post-­‐milling  when  used  in  DPI  
products  
•  Usually  an  amorphous  content  of  >0.5%  w/w  can  exert  an  effect  
 Eur. Pharm. Rev. 1 (2009) 28-31
14 14

12 12
Particle size(micrometers)

%Amorphous content
10 10

8 8

6 6

4 4

2 2

0 0
0 10 20 30 40 50 60
Time(min)
DPI  formula5on  strategies  

•  Two  main  formula=on  principles  

–  Agglomerated  powder  systems  

Agglomeration Inspirational
Force

FPD/FPF

–  Performance  dependent  upon  force  of  cohesion  

•  Too  high  –  agglomerates  won’t  break  apart  
•  Too  low  –  agglomerates  won’t  form  
Agglomerated  powder  formula5ons  

•  Tend  to  be  used  for  high  dose  

products  
•  Bricanyl  Turbuhaler    
–  Terbutaline  sulphate  
•  Pulmicort  Turbuhaler  
–  Budesonide  

•  Both  products  are  free  of  

excipients  
DPI  formula5on  strategies  

•  Two  main  formula=on  principles  

–  Agglomerated  powder  systems  
–  Carrier-­‐based  systems  

Inspirational
Force

Coarse carrier usually lactose (> 50 µm) FPD or FPF

Carrier-­‐based  systems  

•  Tend  to  be  used  for  low  

dose  products  
•  Cyclohaler  and  Diskus  
systems  
•  Advair  –  flu=casone  
propionate  and  salmeterol  
DPI  products  

•  Device  can  either  meter  dose  from  a  reservoir,  or  use  single  doses  

Agglomerated
Carrier-based
powder

Metered Unit dose Metered

Single Multiple

Clickhaler Cyclohaler Diskus Turbuhaler

Interac5on  forces  

•  Both  these  designs  are  cri=cally  dependent  on  interac,on  forces  for  
their  in-­‐vivo  performance  
•  Since  solids  interact  through  their  surfaces,  then  surface  energy  is  a  
key  factor  
Cohesion

Adhesion
Interac5on  forces  

•  Both  these  designs  are  cri=cally  dependent  on  interac=on  forces  for  
their  in-­‐vivo  performance  
•  Since  solids  interact  through  their  surfaces,  then  surface  energy  is  a  
key  factor  
•  What  is  surface  energy?  
•  It  is  a  term  that  reflects  how  a  surface  can  interact  –  there  are  
numerous  types  of  molecular  interac=on  that  contribute  to  the  
surface  energy  of  a  material  
•  Is  equal  to  the  energy  required  to  form  the  surface  (or  the  energy  
required  to  break  intermolecular  bonds  when  a  surface  is  created)  
•  Units*  of  mJ  m-­‐2  
What  is  a  surface?  

•  Defined  mathema=cally  as  ‘the  extended  2-­‐D  outer  boundary  of  a  3-­‐D  
object  

•  Some=mes  surface  science  extends  this  defini=on  to  include  the  first  
100-­‐200  nm  below  the  surface  –  the  surface  layers  
Forma5on  of  a  surface  

•  Materials  will  always  act  to  minimise  surface  area  

–  Liquids  for  spheres  for  instance  because  that  is  the  geometry  with  
the  smallest  SA  to  volume  ra=o  
•  It  follows  that  surface  forma=on  must  be  unfavourable  (and  so  
requires  input  of  energy*)  

Energy (J)

*If cutting is done reversibly, energy of surface formed must be equal to energy
input to cut
Cohesion  

•  Energy  required  to  create  two  new  surfaces  by  dividing  one  material  

Energy (J)
b b

•  Mathema=cally  defined  as;  

Surface area of new face

Wc = 2Aγb
Adhesion  

•  Sample  principle  applies,  but  surfaces  are  formed  from  two  dis=nct  
materials  

Energy (J)

c b

 
•  And  so  the  mathema=cal  defini=on  is  

Wa = A(γb + γc - γbc)
Other  factors  -­‐  Electrosta5c  charges  

•  Forces  of  akrac=on  or  repulsion  between  charged  par=cles  

•  Par=cles  can  become  charged  during  milling,  by  fric=on  with  other  
par=cles  or  surfaces  (triboelectrifica=on)  
•  A  charged  par=cle  can  induce  an  image  charge  on  an  uncharged  
par=cle/surface  →  akrac=on  
•  Strength  of  these  forces  ↓  with  distance  
Capillary  forces  

•  At  high  rela=ve  humidi=es  (>50%)  water  condenses  on  par=cle  

surface  →  liquid  bridging:  
 
 
 
 
 
 
 
•  This  increase  adhesion,  due  to  the  surface  tension  of  the  water  
•  Dominant  force  above  65-­‐75%  RH  
Humidity  

•  High  humidity  makes  capillary  forces  more  likely  

•  But  humidity  also  allows  electrosta=c  forces  to  dissipate  
•  Humidity  also  induces  recrystallisa=on  of  amorphous  material,  which  
will  lower  surface  energy  of  a  milled  powder  

•  O@en,  a  milled  powder  will  be  ‘condi=oned’  by  exposing  it  to  
humidity  before  blending  
•  Humidity  will  dissipate  electrosta=c  charge  and  lower  surface  energy  
of  par=cles  
Morphology  

•  The  morphology  of  a  surface  can  have  a  massive  effect  on  the  
behaviour  of  the  material  
•  The  biggest  effect  is  on  adhesion,  because  of  contact  area  
 

Increasing contact area and hence force of adhesion

 Higher force of adhesion of SS to erythritol, and
DPI  performance   less aerosolisation

•  Performance  depends  upon  force  of  adhesion  or  cohesion*  

Carriers

*Traini et al., (2006). Eur. J. Pharm. Sci., 27:243

 *Tong et al., (2006). J Pharm Sci 95:228

Effect  of  polymorphism  

•  Different  polymorphs  will  have  different  surface  energies  

•  Salmeterol  xinafoate*   50

Fine particle fraction (%)

40

30
SX-I Stable
SX-II Metastable
20

10

0
SX-
I II
SX-
Summary  

•  DPI  formula=ons  typically  blended  powders  or  agglomerated  powders  

•  Small  sample  size  required  for  pulmonary  delivery  
•  Milling  will  increase  surface  energy,  and  so  affect  product  
performance  
•  Par=cularly  important  for  DPI  formula=ons  
•  Condi=oning  material  can  lead  to  a  more  stable  product