U"liza"on  of  Technology  Guidance  Maps  to  Address  Compound’s  Delivery  Challenges  

Ravi  Shanker  Senior  Research  Fellow  

Pharmaceu5cal  Science,  Worldwide  R&D  ravi.m.shanker@pfizer.com  

June  2nd  2013  Drug  Formula5on  &  Bioavailability  West,  San  Diego,    California    

   

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Acknowledgements

•  Pfizer  scien5sts  and  management  for  their  tremendous  intellectual  partnership,  hard  work  and  belief  in  the  advancement  of  solubiliza5on  &  drug  delivery  “systems”  

•  Mul5disciplinary  effort  –  Medicinal  Chemistry/Biology  –  Pharmacokine5cs  &  Drug  Metabolism  –  Drug  Safety  –  Clinical  Research    –  Pharmaceu5cal  Sciences  (API,  Analy5cal,  Drug  Product  Design,  Regulatory,  Quality  etc)  

•  External  partners  –  academic,  industry  (vendors,  CRO’s,  technology)  and  regulators  •  Literature  –  extensive  use  of  non-­‐pharmaceu5cal  &  pharmaceu5cal;  incessant  exchange  

of  scien5fic  thinking  and  debate  •  Organizers  of  this  symposium  

Poignant  Reminder  v Contents  of  presentation  –  personal  views  &  I  take  full  responsibility  v   Perspectives  from  a  novice  –  there  is  still  so  much  to  learn  

Outline of Presentation

•  Historical perspective: The foundations

•  Opportunities for bioavailability and modified release technology enabled drug products: Basic considerations

–  Dose –  Solubility –  Dissolution –  Crystallization –  Permeation

•  Development of guidance maps for selection of appropriate technology –  Thermodynamic and kinetic considerations –  Illustrative guidance maps –  Limitations of guidance maps

•  Future directions ---- cross industry collaboration?

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Thermodynamics: A tribute to two of the greatest whose contributions continue to influence development & understanding of solubilization and drug delivery technologies

J. Willard Gibbs

–  Theore7cal  physicist  /physical  chemist  at  Yale  

–  Developed  unique  graphical  display  of    phase  equilibria    

•  Van  der  Waals  during  his  Nobel  prize  acceptance  speech  acknowledged  Gibbs  

•  Max  Planck  declared  “not  only  in  America  but  in  the  whole  world  will  ever  be  reckoned  among  the  most  renowned  theore7cal  physicists  of  all  7mes”  

•  Albert  Einstein  stated  "the  greatest  mind  in  American  history“.  

•  created  sta7s7cal  mechanics  (a  term  that  he  coined),  explaining  the  laws  of  thermodynamics  as  consequences  of  the  sta7s7cal  proper7es  of  large  ensembles  of  par7cles  

Arnold Sommerfeld

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–  Theore7cal  physicist  in  Germany    

–  One  of  the  greatest  mentors  of  physicists  

•  7  PhD/  post  doc    students  won  Nobel  Prize  

–  Werner  Heisenberg,  Wolfgang  Pauli,  Peter  Debye,  and  Hans  Bethe    

–  Linus  Pauling,  Isidor  I.  Rabi  and  Max  von  Laue  

•  Nominated  81  7mes  for  the  Nobel  Prize!  

 “Thermodynamics  is  a  funny  subject.    

–  The  first  7me  you  go  through  it,  you  don't  understand  it  at  all.    

–  The  second  7me  you  go  through  it,  you  think  you  understand  it,  except  for  one  or  two  small  points.    

–  The  third  7me  you  go  through  it,  you  know  you  don't  understand  it,  but  by  that  7me  you  are  so  used  to  it,  so  it  doesn't  bother  you  any  more.”  

Kinetics: A tribute to two of the greatest whose contributions continue to influence development & understanding of solubilization and drug delivery technologies

Jacob Henricus van’t Hoff –  First Nobel Prize in Chemistry (1901) –  Discovery of the laws of chemical

kinetics and osmotic pressure of solutions

• 

Wilhelm Ostwald

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–  Nobel Prize in Chemistry (1909) Catalysis –  Coined the term 'Mole'

Ostwald dilution law Ostwald ripening Ostwald's rule Ostwald viscometer Ostwald–Freundlich equation

founded an influential scientific magazine named Zeitschrift für physikalische Chemie ("Journal of Physical Chemistry")

Ostwald, van 't Hoff and Svante Arrhenius are credited with being the modern founders of the field of physical chemistry

Insolubility & the Formulation “Tool Kit”

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H.D. Williams et al: Strategies to Address Low Drug Solubility in Discovery & Development. Pharmacol. Rev. 65: 315- 499 (2013)

Which tool? Which size? What to fix?

What are the biopharmaceutics considerations in evaluating solubilization & MR technologies?

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Dosage  Form  

Drug  in  Solu7on  

Drug  in  Systemic  circula7on  

Therapeu7c  &  Adverse  Effects  

Transit  of  compound  through  GI  

tract  

Compound  Permeability  (and  “flux”)  

Drug  release  and  dissolu7on  

Absorp7on  

Elimina7on  

Excre7on  and  Metabolism  

In  the  ever  expanding  world  of  insoluble  drugs:  how  much  improvement  in  solubility  and/or  dissolu7on  is  needed  for  a  specific  drug  to  achieve  op7mal  (maximal?)  frac7on  of  dose  absorbed?    Which  is  the  preferred  enabling  technology  &  why?  How  is  it  linked  to  achieving  desired  PK  characteris7cs  –  enhancement  of  oral  BA  and  CR    Is  it  possible  to  “dial-­‐a-­‐PK”  to  achieve  desired  balance  of  efficacy  &  safety?  What  is  the  role  of  drug  product  design?    

Selecting Enabling Technology for Enhancing Oral Bioavailability of Insoluble Compounds – Basis?

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BA  Enhancing  Delivery   Desired  Dose(s):  FIH  to  Commercial  

Technology  (excluding  MR)  

<  50  mg   50  to  150  mg   150  to  300  mg     >  300  mg  

Crystalline  (conventional)  

       

Salt/Co-­‐crystal          Particle  size  reduction          Soft  gel  (aqueous  miscible  or  non  aqueous)  

       

SEEDS/  SMEDDS  etc          Solid  Dispersion          Complexation          Nanoparticle          Nanoadsorbates  (mesoporous  silica  etc)  

       

§  Differentiate dose at which absorption is dissolution or solubility limited §  How much solubilization or dissolution enhancement is really necessary? §  Which is the preferred enabling technology for a particular compound of interest? §  Does the selection of preferred enabling technology have to be an iterative process? §  How to increase efficiency of optimal drug product design by balancing absorption, safety

& efficacy? § 

Progressing Low Solubility Drug Through Better Understanding of Factors Influencing Oral Absorption – Balancing Exposure with Safety & Efficacy : Estimating dissolution & solubility limiting regions

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Solution Fasted

Suspension Fasted

Suspension Fed

2nd Gen.Susp. Fasted

Susp. Standard Fed

Phase Diagrams/thermodynamic considerations for development of guidance maps

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Murdande,  S.;  Pikal,  M.;  Shanker,  R.;  Bogner,  R.  J  Pharm  Sci    (2010),    99(3),    1254-­‐1264  Murdande,  S.;  Pikal,  M.;  Shanker,  R.;  Bogner,  R..  Pharm  Research  (2010)  27,  2704-­‐2714  

Enthalpy  &  Free  Energy  of  Amorphous  Solid  is  always  greater  than  crystalline  form:    Could  this  be  the  universal  solubiliza7on  technology  if  the  amorphous  form  is  kine7cally  stable?  

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Favvas  EP,  Mitraplous  AC:  J.  Engg.  Scii.  Technol.  Rev.  1:  25-­‐27  (2008)  

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•  What  physicochemical  proper7es  of  organic  molecules  lead  to  insolubility?  •  Are  these  parameters  universally  relevant  for  solubility  and  solubiliza7on?  •  Insolubility  of  a  solute  is  an  outcome  of  a  solvent’s  insufficient  free  energy  to  disrupt  lahce  energy  and/or  its  

inability  to  solvate  solute  molecules  

log  P  

Tm  

•   Polar  •   Solva5on  energy  

•   High  lahce  energy    

•   Non-­‐polar  •   Solva5on  energy  

•   High  lahce  energy     Tg  

•   Polar  •   Solva5on  energy  

•   Low  lahce  energy    

•   Non-­‐Polar  •   Solva5on  energy  

•   Low  lahce  energy    

“Brick  Du

st”  

“Grease  Ball”  

Fundamental Reasons for Insolubility of Organic Molecules

Lahce  energy  of  a  crystal  represents  the  summa5on  of  all  intermolecular  forces  in  a  crystalline  solid  that  is  necessary  to  be  overcome  to  release  the  molecules  into  gaseous  state.  A    par5al  measure  of  lajce  energy    is  Tm    and  Hfusion    

Par77on  coefficient  of  a  solute  between  two  immiscible  solvents  represents  the  free  energy  necessary  to  cross  the  solvent  interface  .    In  the  case  of  drugs  the  octanol-­‐water  par55on  coefficient  (log  P)  represents  its  lipophilicity.    Higher  log  P  reflects  reduced  ability  of  the  drug  to  be  solvated  by  water.  

140  years  ago  Berthelot  and  Jungfleisch  published  a  predic5ve  theory  of  distribu5on  of  solutes  between  two  immiscible  liquids    In  1891  Nernst  published  that  par55on  coefficient  would  be  constant  only  if  a  single  molecular  species  was  considered  to  distribute  between  the  two  phases  Berthelot  &  Jungfleisch:    Ann.  Chim.  Phys.  4,  26  (1872)  W.  Nernst:  Z.  Phys.  Chem.  8,  110  (1891)  

120  Years  ago  I.  Schroder  published  the  rela5onship  for  the  “solubility  curve  of  a  non-­‐electrolyte”  by  considering  fusion,  dissolu5on  and  recrystalliza5on  

 I.  Schroder:  Z.Physik.  Chem.  Stoichiom.  Verwandscharl.  11,  449  (1893)    

⎟⎠

⎞⎜⎝

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11ln

TTRH

X f

Development of technology guidance maps

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Calcula7on  of  Maximum  Absorbable  Dose  (MAD)  for  development  of  guidance  maps  MAD(mg)  =  ka(min-­‐1)  *  7me(min)  *  solubility(mg/ml)  *  volume(ml)  

MAD  Solubility  

(ml)   =  0.2  *  250  *  200  =  10,000  ml  For  high  ka  

MAD  Solubility  

(ml)   =  0.001  *  250  *  200  =  50  ml  For  low  ka  

•  Posi7ve  slope  of  lines/curves  in  the  guidance  maps  are  due  to  following  considera7ons/assump7ons:            1)  Increase  in  ka  with  increasing  Log  P  

                                                 2)  Increase  in  micelle/aqueous  par55on  coefficient  with  Log  P                                                    3)  In-­‐vivo  observa5ons  with  a  large  number  of  proprietary  compounds  and  published  literature  

•  Guidance  maps  for  each  solubiliza5on  technology  addresses  the  probability  that  sufficient  absorp5on  (>50%  frac5on  absorbed)  can  be  achieved  for  the  drug  to  be  efficacious    

•  Other  aspects  of  applicability(processing,  stability)  are  not  addressed  –  separate  maps  developed  (not  shown)  •  Probability  that  acceptable  exposure  is  obtained  is  plowed  as  a  func5on  of  the  following  

•  The  dose(mg)  to  solubility(mg/ml)  ra5o  •  Log  P  •  Permeability  is  considered  as  an  important  factor  in  the  development  of  guidance  maps  

•  Guidance  maps  developed  for  •  Crystalline  Drug  (non-­‐ionizable  form)  •  Dispersions  (HME  and  SDDs)  •  Liquid-­‐Filled  Capsules  (water  miscible  and  immiscible  components)  -­‐  not  shown  •  Submicron  crystals(~200  nm)-­‐  not  shown  

Guidance map for delivery of crystalline (non-ionizable drugs)

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Guidance map for delivery of solid dispersions (spray dried or hot melt extrusion)

Thermodynamics and solubilization technology: Overall Technology Guidance Map

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1  =  Nanocrystals  2  =  Liquid  Fill  Capsules/  solvents  3  =Solid  Dispersions(Spray  Dried  

Dispersions  or  Hot  Melt  Extrusions)

Solubilization Technology Guidance Maps

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•  Equilibrium  solubility:  Na  salt  >>  arginine  salt  •  Dissolu7on  rate:  Na  salt  >>  arginine  salt  •  Forma7on  and  permeability  of  ion-­‐pairs:  only  with  arginine  salt  

Bioa

vailability      

in  Dogs  (%)  

0

20

40

60

80

100

FreeAcid

Sodiumsalt

Argininesalt

S

N

Cl

ON

O

OH

O

Example of Impact of Salt Form on Oral Bioavailability: Significant challenges for developing maps

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N

N N

O

O

F

N

O

O

•  Equilibrium  solubility  is  not  always  an  indicator  of  bio-­‐performance  of  polymorphs  

•  Polymorphism  can  significantly  affect  bioavailability  

0

100

200

300

400

500

Aq. Solubility(mcg/mL)

Bioavailabilityin Dogs (%)

Form BForm A

Bioa

vailability    

Aque

ous  S

olub

ility  

Mol Wt.: 482.6 Solubility (A and B): 396, 402 mg/mL (water, 25oC) (pH 6.34) Melting Point: 134,139oC (DSC)

Heat of Fusion: 5.4,6.0 Kcal/mol

Only  non-­‐sink  dissolu7on  tes7ng  revealed  forma7on  of  supersaturated  solu7on  by  Polymorph  B  

40  

20  

60  

80  100  

0  

Example of Impact of Polymorphic Form on Oral Bioavailability: Significant challenges for developing maps

CR Technology Applicability Map

1  

10  

100  

1000  

0.001   0.01   0.1   1   10   100   1000  

Solubility  (mg/mL)  

Daily  Dose  (m

g)  

Solubiliza7on  Needed  for  CR  (SDD,  etc.)  

Matrix  Tablets  

Asymmetric  Membrane  Tablet  -­‐  Osmo7c  

Mul7par7culates  

Swellable  Core    Tablets  -­‐Osmo7c  

GITS  -­‐  Osmo7c  

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•  Short  half-­‐life  •  Reduce  dosing  frequency  •  Reduce  Cmax    

Increase efficiency in utilization of scientific advances in individual disciplines for inter-disciplinary applications

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Enhanced understanding of the mechanisms of supersaturation & nucleation kinetics in the GI tract

ten  Wolde  &  P.R.  Frenkel:  Science  277,    1975-­‐1978  (1997)  

Cryo-­‐SEM  of  solu7ons  of  citric  acid  at  5,  20  &  40  wt%  in  water  K.  Ohgaki  et  al  Chem  Engg  Sci  47,  1819-­‐1823  (1992)  

Future Directions: Systems based Pharmaceutics (SbP) – A 2014 Cross-industry Partnership

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Objec7ve:  Create  a  modeling  and  simula7on  framework  that  would  provide  unprecedented  capability  of  considering  the  complete  train  of  effects  from  synthe7c  crystalliza7on  to  oral  absorp7on  in  the  design  of  medicines  to  assess  the  impact  of  local  perturba7on  of  arributes  on  performance  arributes  of  final  drug  product

API  Manufacturing  

Drug  Product  Manufacturing  

In-­‐vivo  pharmacokine5cs  

Polymorph,    Morphology,  Par5cle  Size  Distribu5on,  Purity,  etc  

Solvent  /Seed,  Unit  opera5ons  –  crystalliza5on,  

filtra5on,  drying,  etc  

Manufacturing  Process  Control:  Feedback/Feed-­‐

forward:  Content  uniformity,  Hardness,  Disintegra5on  etc  

Dosage  Form  –  tablet,  capsule  etc  Excipient:  Quality  Awributes  Unit  Opera5ons  -­‐  wet/dry    

granula5on/  direct  compression,  film  coa5ng  etc.  

BE:  Cmax,  AUC  

Dosage  Strengths  

In-­‐Vitro  Characteriza5on  e.g.  Dissolu7on  

Stability  

Analy5cal  Method    

Development  

Conclusions

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•  Company  specific  strategies  of  the  past  –  non  sustainable  (cost,  5me  and  resources)  v Guidance  maps  based  on  fundamental  considera7ons  can  be  extremely  useful  v Need  more  collabora7ve  and  integrated  and  mul7-­‐disciplinary  approaches  to  address  solubility  and  other  drug  delivery  challenges;  impera5ve  to  be  abreast  with  advances  in  fundamental  science  and  allied  disciplines    

v Advances  in  biology  and  chemistry  will    require  efficiency  in  inden5fica5on  of  effec5ve  drug  delivery  technologies  in  the  future  –  organ,  5ssue,  cell  specific  delivery  &  intra-­‐cellular  delivery  

v System  based  Pharmaceu7cs  a  necessity  for  risk  management  –  advanced  computa5onal  tools  to  link  local  perturba5on  in  awributes  to  ul5mate  quality  &  performance  of  product  

•  Emerging  Efforts:  innova5on  should  be  driven  through  science  &  collabora5on  via  global  v  Industrial  consor5a  for  pre-­‐compe55ve  partnerships  v Enhanced  partnerships  with  academic  ins5tu5ons    v Partnerships  across  Excipient,  CRO,  Biotech  &  Drug  Delivery  companies  v Strong  partnership  with  Regulatory  Agencies  

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Nature  Thermodynamics    

(independent  of  pathway)  

Ini7al  State   Final  State  

Kine7cs    (it  is  the  pathway!)        

Metastable  states  

• Thermodynamics is fundamental •  Kinetics influences outcomes

Knowledge of both is essential for optimizing the biopharmaceutics properties of a drug product through all stages of discovery & development

Biopharmaceu7cs:  A  Conundrum  Between  Thermodynamics  &  Kine7cs  ?  

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Comments, suggestions, questions, disagreements?

THANK YOU!

ravi.m.shanker@ pfizer.com