1. Research Achievement Winner Lecture AAPS Annual Meeting 2010
Abu T. M. Serajuddin, Ph.D.
St. John’s University, Queens, New York
Phone:
Formulation of Poorly Water-Soluble Drugs:
Drug Delivery Strategies 1

2. Two-thirds (?): Insoluble or Practically Insoluble
Recent Trends in New Molecule Solubility
Two-thirds (?): Insoluble or Practically Insoluble
Very slightly soluble or soluble
New
Generation
<10µg/mL
10-100µg/mL
>100µg/mL
Solubility < 1 μg/mL (0.001 mg/mL) is common 2
Source: Personal experience, literature data and anecdotal information

3. Dosage Form Development Strategies
97MAY08 EC
A few common strategies to overcome impacts of low solubility on product development:
Particle size reduction
Milling
Nanosizing
Salt formation
Solubilization
Solid dispersion
Lipid-based drug delivery
To save time and resources in product development, relatively simpler approaches should be tried first.

4. Salt Formation 4

5. How Does Salt Formation Increase Dissolution Rate?
97MAY08 EC
Diffusion Layer Model DA h
(Cs - C )
J = = dM dt
Stagnant
Diffusion
Layer
Bulk Liquid
Phase
(Dissolution Medium)
Cs, h=0 >>
Cs, bulk medium
…. by changing
microenvironmental
pH and solubility
Solid
(salt)
Saturate
Supersaturate,
and/or
Fine precipitate C h 5 5

6. Effect of Salt Formation on Drug Solubility
30 mg/mL
Line: fitted by equation
Mesylate
HCl
Phosphate
2.5 µg/mL
Mesylate > HCl > Phosphate
Ref: S. Li, S.M. Wong, S. Sethia, H. Almoazen, Y.M. Joshi and A.T.M. Serajuddin. Investigation of Solubility and Dissolution of a Free Base and Two Different Salt Forms as a Function of pH. Pharm. Res. 22: (2005)

7. Dissolution Profiles of a Free Base
Solubility is practically zero under intestinal pH conditions (5 and higher)
Ref: S. Li, S.M. Wong, S. Sethia, H. Almoazen, Y.M. Joshi and A.T.M. Serajuddin. Investigation of Solubility and Dissolution of a Free Base and Two Different Salt Forms as a Function of pH. Pharm. Res. 22: (2005)

8. Dissolution Rates of Salt Forms of a Basic Compound
Ref: S. Li, S.M. Wong, S. Sethia, H. Almoazen, Y.M. Joshi and A.T.M. Serajuddin. Investigation of Solubility and Dissolution of a Free Base and Two Different Salt Forms as a Function of pH. Pharm. Res. 22: (2005)

9. Limitation of Salt Formation9

10. X X Diffusion Layer Model
Limitation of Salt Formation for the New Generation of Poorly Water-soluble Drugs
97MAY08 EC
Diffusion Layer Model
When the intrinsic solubility is very low, the precipitated free base coats the dissolving surface, preventing further dissolution of salt.
Stagnant
Diffusion
Layer
Bulk Liquid
Phase
(Dissolution Medium)
Cs, h=0 >> X
Cs, bulk medium
Solid
(salt) X
Please note: Precipitation at the surface, not in the bulk medium. No increase in surface area.
Precipitated Free Base C h 10 10

11. High-energy Solid

12. High-energy amorphous
Structure of High-energy Solids
liquid
High-energy amorphous
solid
Super-cooled liquid
Glass
Heat content
(enthalpy, H)
Crystal
Low-energy
crystalline solid
Temperature 2

13. Solid Dispersion

14. Advantage of Solid Dispersion: Better Stability than Purely Amorphous System
Storage temperature
Drug only
Tg (mixture)
Drug - polymer
miscible blend
Super-cooled liquid
Heat content
(enthalpy, H)
Elevated Tg
Glassy state
Tg (drug)
Temperature 2

15. What is Solid Dispersion ?
“the dispersion of one or more active ingredients in an inert carrier or matrix, where the active ingredients could exist in finely crystalline, solubilized or amorphous state” - Chiou and Riegelman, J Pharm Sci 1971, 60,
Drug
(crystalline)
Carrier
(amorphous) +
Partial miscibility
Complete miscibility
No miscibility

16. Advantage of Solid Dispersion: Higher Dissolution Rate
96JUN10
KF/JH
Poorly Water-Soluble Drug
Solid Dispersion
Tablet/Capsule
Dosage Form
Disintegration
Matrix Dissolves
Large Solid Particles (Usually microns)
Drug in G.I. Tract
Colloidal Drug Particles/Globules
Lower Dissolution Rate
Higher Dissolution Rate
Absorption into Body Systems
Ref: Serajuddin, J. Pharm. Sci. 1999, 88, 1058

17. Surfactant-based
Solid Dispersions

18. Solid Dispersion by Melt-Filling: Advantage of Surfactant
96OCT14
KF/JAM
Aqueous Dispersion of Solid Plug
Solid dispersion
Disintegration of capsule shell
Solid Plug with Layer
Solid Plug
Non-Surface active vehicle
Forms drug-rich surface layer
Retards/prevents dissolution of drug
Surface active vehicle
Disperses/emulsifies drug
Rapid dissolution rate

19. Composition of Solid Dispersion Prepared
Development of Solid Dispersion: Compound A
97MAY28
VG/EC
Composition of Solid Dispersion Prepared
Compound A (LAB687) 20 mg
Polysorbate mg
PEG mg
Total Weight 500 mg
Capsule size # 0
Ref: Dannenfelser et al., J. Pharm. Sci. 93: (2004) 19 19

20. Composition of Solid Dispersion
Solid Dispersion Selected for Clinical Study: Compound A
97MAY28
VG/EC
Composition of Solid Dispersion
Compound A 20 mg
Polysorbate mg
PEG mg
Capsule size # 0
Ref: Dannenfelser et al., J. Pharm. Sci. 93: (2004)

21. Bioavailability in Dogs from Solid Dispersion: Compound A
97MAY28
VG/EC
Formulation AUC (0-48h) Relative
(ng.h/mL) Bioavailability
Solid dispersion
Solubilized system
Capsule (mic. Powder)
Ref: Dannenfelser et al., J. Pharm. Sci. 93: (2004)

22. Solid Dispersion by
Melt Extrusion

23. Solid Dispersion by Melt Extrusion Technology
Melt extrusion is a single-step process ideally suitable to manufacture solid dispersion
Homogeneous mixture of active, polymer
plasticizer, surfactant
Reality TV / Easier to discuss what wouldn’t work rather than what would
Now one must deal with different cultures: European, South American, Chinese
As well as the language of these foreign commercial launch centers. This is not unique to Foreign Based Pharma Companies but also domestic ones
Global economy has changed the landscape completely. Not that long ago dev centers & manufacturing plants were across the street from each other now the global economy has changed this completely
Who controls the Batch manufacture at the launch site the Dev QA group, Local QA?
All hurdles for failure.
But I will not focus on this rather I'd like to focus on what has worked well for Novartis.
Ref: Adapted from J. Kowalski (Novartis) presentation

24. Lower Temperature Melt Extrusion – A Novel Strategy
Crystalline drug subs.
High
temperature
melt extrusion
Drug
degradation +
Polymer
Amorph. extrudate
Amorphous drug subs.
Lower temperature
melt extrusion +
Stable product
Polymer
Ref: Lakshman et al., Molecular Pharmaceutics, 5: , 2008

25. Microemulsion 25 25

26. What is Microemulsion? -‘Cyclosporine A’ Example
20 – 150 nm ( < 200 nm)
Microemulsion (o/w)
Without dilution
Cyclosporin A
Sandimmune® Neoral®
Dilution with water
Ref:A. Meinzer et al,
BT Gattefosse 88 :21-26, 1995

27. Systematic Screening of Lipids for Microemulsion Formation

28. Structures of Lipids
C8 Chain fatty acid Glyceryl Caprylate/Caprate (Capmul MCM; ABITEC Co.) Glyceryl Dicaprylate (ABITEC Co.) Glyceryl Tricaprylate (Captex 8000; ABITEC Co.)

29. Ternary System for Monoglyceride (Glyceryl Caprylate/Caprate), Cremophor EL and Water
Oil : Surfactant
9:1
7:3
5:5
3:7
2:8
1:9 70
4815
7865
1215
2481 28 15 80
7126
3859
1532
1265 18 12 90
1609
3242
743
473 99
2978
1173
578
430 14
Particle Size, nm
Gel

30. Ternary System for Diglyceride( Glyceryl Dicaprylate), Cremophor EL and Water
Oil : Surfactant
9:1
7:3
5:5
3:7
2:8
1:9 70
2788
492 90 17 80 32
2007
286 55 20 77 14
1844
222 35 18 19 99
1903
153 16
Particle Size, nm

31. Ternary System for Triglyceride (Caprylate/ Caprate Triglyceride), Cremophor EL and Water
Oil : Surfactant
9:1
7:3
5:5
3:7
2:8
1:9 70
1580
619
1296
533
867
116 80
1794
463
634
390
685 39 90
2136
380
383
334
402 22 99
3851
291
218
172
154 20
Particle Size, nm

32. Pseudo-Ternary System using 1:1-Tri- + Mono-Glycerides, Cremophor EL and Water
Oil : Surfactant
9:1
7:3
6:4
5:5
4:6
3:7
2:8
1:9 70
3353
1105
115 43 22 20 18 24 80
5303
395
153 21 17 15 14 33 90
875
546 44 16 99
338 41 30 25
Particle Size, nm

33. Pseudo-Ternary System using 1:1-Di- + Mono-Glycerides, Cremophor EL and Water
Oil : Surfactant
7:3
5:5
3:7
2:8
1:9 70
1029
1079
150 82 80
1063
442 22 18 17 90
870
252 16 99 50 78 20
Particle Size, nm

34. Solid Microemulsion Preconcentrate - A Novel Solid Dispersion

35. Solid Microemulsion Preconcentrate
Solid dispersion
Solid preconcenrate
Liquid preconcentrate
Component
Solid Microemulsion Preconcentrate
Compound A (%w/w) 4 8
Capmul PG8 (%w/w)
28.8
27.6
Cremophor EL (%w/w)
PEG 3350 (%)
38.4
36.8
Compound A
Ref: Li et al., J. Pharm. Sci., 98: , 2009

36. Formulation of Poorly Water-Soluble Drugs
96JUN05 KF
Concluding Remarks
Almost one-third of compounds synthesized by discovery scientists is extremely water-insoluble (solubility in water: <10 µg/mL)
Conventional formulation techniques may no longer be applicable to most, if not all, of them.
Special formulation approaches are necessary to enable development of such compounds.
Formulation strategies must be selected based on dose, solubility and other physicochemical properties of NCEs. 36 36