Fundamental understanding of the drug absorption phenomena coupled with firm knowledge of physicochemical and solid-state properties of drug molecules are necessary for successful development and application of enabling formulation technologies that address drug development challenges. These concepts and a toolbox of enabling pharmaceutical technologies are explored. High-level overview of strategies for preclinical formulation development and form selection are also presented.
Early Development Webinar Shimanovich Seventh St Development Group 4-2017.pdf
1. Enabling Role of Pharmaceutical
Sciences in Early Stages of Drug
Development
Roman Shimanovich, Ph.D.
Amgen
2. 2
Objectives
1. Fundamentals of drug absorption
2. Solid state and physicochemical properties
3. Enabling pharmaceutical technologies
4. Preclinical formulation and form selection
strategies
3. 3
Drug Development Challenges
• Compound attrition in development
Hay et al., Nature Biotechnology, 2014, 32, 40-51
All drugs in clinical development between 2003 and 2011 (n=4451)
a: Probability of successful advance to the next phase
b: Likelihood of successful FDA approval
4. 4
Drug Development Challenges
• Poor physicochemical properties
Meanwell, Chem. Res. Toxicol. 2011, 24, 1420-1456
Median ClogP for Compounds
Published in J. Med. Chem.
Mean ClogP for Drugs Launched
Waters et al., J. med. Chem. 2011, 54, 6405-6416
5. 5
Drug Development Challenges
• Pharmaceutical sciences and technologies can successfully mitigate
poor physicochemical properties of current drug candidates
Kola and Landis, Nature Rev. Drug Discovery, 2004, 3, 711-715
Arrowsmith, Nature Rev. Drug Discovery, 2011, 10, 328-329
11%
2008-2010
40%
6. 6
Drug Development Challenges
• Pharmaceutical sciences and technologies can successfully mitigate
poor physicochemical properties of current drug candidates
7. 7
Recent Progress in Pharmaceutics
Fundamental
Understanding
of Drug
Absorption
Fundamental
Understanding of
Physicochemical and
Solid State Properties
Development
and
Application of
Enabling
Technologies
For a broader picture see: Rowland, et al,
“Impact of the Pharmaceutical Sciences on
Health Care: A Reflection over the Past 50
Years” J. Pharm. Sci. 2012, 101, 4075-4099
8. 8
Objectives
1. Fundamentals of drug absorption
2. Solid state and physicochemical properties
3. Enabling pharmaceutical technologies
4. Preclinical formulation and form selection
strategies
9. 9
Fundamentals of Drug Absorption
GI tract is a dynamic system with chemical, pH and surface area gradients
Stomach
pH 1 - 3
Colon
pH 7 - 7.4
Surface
Area
0.053 m2
200 m2
0.35 m2
Duodenum
pH ~6.5
Jejunum
pH ~7.2
Ileum
pH 6.5 – 8
Transit
Time
~ 0.5 h
3 - 4 h
~ 24 h
GI
Epithelium
10. 10
Fundamentals of Drug Absorption
• Drug absorption is a dynamic solution-mediated process, dependent
on physiology and physicochemical properties
• Dissolution Flux – a function of
Solubility and Dissolution Rate
• Absorption Flux – a function of
Solubility and Permeability
s
diss
DC
r
t
2
2
0
C
P
J eff
res
t
A
dAdt
C
P
t
M
0
)
(
Drug In Solution
in GI Lumen
Solid Drug Particles
Absorbed Drug
in GI Epithelium
Amidon, et al., Pharm. Res. 1995, 12, 413-420
• P – GI permeability
• C – concentration of drug in lumen
• A – surface area of the GI tract
• M – amount of drug absorbed
• tres – GI residence time
• tdiss – dissolution time
• Cs – drug solubility
• D – diffusion coefficient
• r – particle radius
• – particle density
• J – drug flux
across GI wall
• Peff – effective GI
permeability
• C – concentration
of drug in lumen
11. 11
Fundamentals of Drug Absorption
• Key drivers of drug absorption
• Free drug hypothesis
• Solubility
• Dissolution
• Permeability
• Maximum Absorbable Dose model
If drug needs time to
dissolve in GI tract,
then values of tres and
Cs will be smaller
• Ka – intestinal absorption rate
• C – solubility of drug
• V – intestinal volume
• tres – intestinal residence time
V
K
t
C
MAD a
res
Assumed
4 hr
Assumed
250 mL
Extrapolated from
cellular permeability
Extrapolated from
solubility in simulated
intestinal fluid
Johnson and Swindell, Pharm. Res. 1996, 13, 1795-1798
12. 12
Fundamentals of Drug Absorption
• pH dependence of drug absorption – neutral/unionizable drug
Stomach
pH 1 - 3
Colon
pH 7 - 7.4
Surface
Area
0.053 m2
200 m2
0.35 m2
Duodenum
pH ~6.5
Jejunum
pH ~7.2
Ileum
pH 6.5 – 8
Transit
Time
~ 0.5 h
3 - 4 h
~ 24 h
GI
Epithelium
Solubility
low high
13. 13
Fundamentals of Drug Absorption
• pH dependence of drug absorption – weakly basic drug
Stomach
pH 1 - 3
Colon
pH 7 - 7.4
Surface
Area
0.053 m2
200 m2
0.35 m2
Duodenum
pH ~6.5
Jejunum
pH ~7.2
Ileum
pH 6.5 – 8
Transit
Time
~ 0.5 h
3 - 4 h
~ 24 h
GI
Epithelium
Solubility
low high
14. 14
Fundamentals of Drug Absorption
• pH dependence of drug absorption – weakly acidic drug
Stomach
pH 1 - 3
Colon
pH 7 - 7.4
Surface
Area
0.053 m2
200 m2
0.35 m2
Duodenum
pH ~6.5
Jejunum
pH ~7.2
Ileum
pH 6.5 – 8
Transit
Time
~ 0.5 h
3 - 4 h
~ 24 h
GI
Epithelium
Solubility
low high
15. 15
Fundamentals of Drug Absorption
• Key takeaways:
• Drug absorption is a dynamic, solution-mediated process
• Key absorption parameters to consider
• Solubility
• Dissolution
• Permeability
• (pKa)
• (Precipitation)
16. 16
Objectives
1. Fundamentals of drug absorption
2. Solid state and physicochemical properties
3. Enabling pharmaceutical technologies
4. Preclinical formulation and form selection
strategies
17. 17
Solid State and Physicochemical
Properties
• Solid state forms of pharmaceuticals
Amorphous
Crystalline
Salt Cocrystal
Neutral
Polymorphs, Solvates, Hydrates
Polymorph
Salt form
Solvate
Hydrate
Co-crystal
= solvent
= water
= excipient/ligand/coformer
= counter-ion
Multicomponent
Stahly, Cryst. Growth Des. 2007, 7, 1007-1026
18. 18
Solid State and Physicochemical
Properties
• Solid state forms and their energetics: crystalline versus amorphous
• Crystal: a solid material whose constituent atoms, molecules, or ions are arranged
in an orderly repeating pattern extending in all three spatial dimensions
• Amorphous: a solid that lacks long-range molecular order
• Amorphous solids possess higher molecular energy and mobility
Crystalline
stable
E Amorphous
minutes, hours, days
unstable
19. 19
Solid State and Physicochemical
Properties
• Solid state forms and their energetics: crystalline versus amorphous
• Traditionally, pharmaceuticals are developed as crystalline solids
Property Amorphous Crystalline
Solubility1
Dissolution2
Physical Form Stability3
Chemical Stability4
Hygroscopicity5
1 – Hancock and Parks, Pharm. Res. 2000, 17, 397-404
2 – Langham et al., J. Pharm. Sci, 2012, 101, 2798-2810
3 – Karmwar et al., Int. J. Pharm. 2011, 417, 94-100
4 – Grooff et al., J. Pharm. Sci. 2013, 102, 1883-1894
5 – Newman et al., J. Pharm. Sci. 2008, 97, 1047-1059
20. 20
Solid State and Physicochemical
Properties
• Solid state forms and their energetics: Polymorphs
• Definitions:
• Polymorph: same chemical composition but different crystalline arrangement
• Prevalent among pharmaceuticals
• Bonding
• Ionic/Dipole
• Hydrogen bonding
• Van der Waals
• Electronic effects, p-stacking
• Energetics and Stability
Temperature
Energy
Monotropic Enantiotropic
Form I
Form II
Liquid
Form I
Form II
Liquid
Stahly, Cryst. Growth Des. 2007, 7, 1007-1026
Higher energy translates into higher
solubility, but also into higher propensity
to convert to a more stable form
21. 21
Solid State and Physicochemical
Properties
• Effect of form change on solubility
Pudipeddi and Serajuddin, J. Pharm. Sci. 2005, 94, 929-939
Hancock and Parks, Pharm. Res. 2000, 17, 397 – 404
Average solubility ratio is ~2 –
rare examples of extreme
solubility difference
Polymorphs
Amorphous to crystalline
Anhydrous to hydrate
Average solubility ratio is ~8.5
Average solubility ratio is ~4
22. 22
Solid State and Physicochemical
Properties
• Solid state forms: Salts
Paulekhn et al., J. Med. Chem. 2007, 50, 6665-6672
0 2 4 6 8 10
0
2
4
6
pH
Solubility
Ksp
pKa=6.5
in situ salt
[BH+]=[B](1+10(pKa-pH))
Henderson-Hasselbalch
pHmax
23. 23
Solid State and Physicochemical
Properties
• Solid state forms: Cocrystals
• Multicomponent phase
• Coformer (aka ligand) is defined as substance that cocrystallizes with drug and
exists as a solid at room temperature
• Fixed ratio of drug and coformer
• Can exhibit polymorphism
• Can exist as salts, solvates, hydrates
• In case of highly water-soluble coformers, the solubility of cocrystal (Ksp) can be
higher than of pure drug
• As cocrystal dissolves, the initial concentration of the drug can exceed its
equilibrium solubility
Thakuria et al., Int. J. Pharm. 2013, 101-125
Good and Rodriguez-Hornedo, Cryst. Growth Des. 2009, 9, 2252-2264
Stahly, Cryst. Growth Des. 2007, 7, 1007-1026
Coformersoln
Drugsolid Coformersolid
Cocrystalsolid
Sdrug Scoformer
Ksp = [Drug]×[Coformer]
Drugsoln +
24. 24
Solid State and Physicochemical
Properties
• Solid state forms: Salts and Cocrystals
Form
Concentration
Form
Spring
Spring + Parachute
Form
Time
Free form
How to get the most out of a
disproportionating salt or
cocrystal?
First understand what the form
gives you…
…then determine if formulation
can give you more.
25. 25
Solid State and Physicochemical
Properties
• Solubility
Enthalpy
(Gain / Loss)
Entropy
(Gain / Loss)
Crystal Lattice Breaking
Solvent Rearrangement and Mixing
Breaking of
crystal lattice
(melting) requires
energy input
Solvent-solvent
interactions need
to be overcome
to create space
for solute
molecules
Favorable
solvent-solute
interactions are
created when
drug dissolves
Entropy
increases when
crystal lattice is
broken
Entropy
decreases when
an ordered
solvation shell is
created around
drug molecules
Entropy
increases when a
mixed solution
phase is created
High M.P. High LogP
drug solvent
26. 26
Solid State and Physicochemical
Properties
• Poorly water-soluble drugs that have high melting point and heat of
fusion can be solubilized:
• By generating amorphous form, or, by pre-dissolving the drug to reduce this
enthalpic loss
• By using salts and cocrystals with water-soluble counterions and coformers to
increase energy gain from solvent-solute interactions
• Poorly water-soluble drugs that have high logP can be solubilized:
• By using solvents and surfactants that will reduce solid-liquid surface tension (i.e.
poor wetting), or, by pre-dissolving the drug, to reduce this entropic loss
27. 27
Solid State and Physicochemical
Properties
• Dissolution
h
C
C
DA
dt
dM b
s
• Solubility – concentration of a saturated drug solution at the surface of the solid particle ,Cs,
provides the driving force for drug dissolution
• A local increase in drug solubility at the surface can be achieved using salt forms, pH modifiers and solubilzing
excipients that are incorporated into drug particles, modifying their microenvironment, without altering drug
solubility in the bulk solution
• An increase in drug solubility will produce a proportional increase in dissolution rate as long as sink conditions
are maintained (permeability is not rate limiting)
• Surface Area – total surface area of drug particles is directly proportional to the dissolution rate
• Reduction of drug particle size results in a proportional increase in total surface area , thereby increasing
dissolution rate; reduction of particle size from 10 mm (typical suspension) to 100 nm (nanosuspension) will
produce a 100x increase in total surface area and dissolution rate
• Diffusion Layer – stationary layer of solvent (GI fluids) in which a drug concentration gradient
exists, its thickness depends on particle size and fluid hydrodynamics; the diffusion coefficient of a
drug depends largely on its molecular size, fluid viscosity and temperature
• Cs – drug solubility
• Cb – drug concentration in bulk solution
• A – total surface area of solid
• D – diffusion coefficient of drug molecule
• h – diffusion layer thickness
• M – amount of drug dissolved
28. 28
Solid State and Physicochemical
Properties
• Precipitation
• Nucleation Flux
• Crystal Growth Rate
• Approaches to mitigate precipitation
• Reduce degree of supersaturation by increasing equilibrium solubility
• Increase viscosity
• Increase cluster-liquid interfacial energy
• Change adsorption layer at crystal-medium interface, electrostatic or steric barriers to nucleation
• Change solvation at crystal-liquid interface, improve solvation of dissolved molecules
Brouwers et al., J. Pharm. Sci. 2009, 98, 2549-2572
• N0 – number of molecules in a unit volume
• v – frequency of transport at nucleus-liquid
interface
• kb – Boltzmann’s constant
• T – temperature
• u – molecular volume of crystallizing solute
• gns – interfacial energy per unit area
• S – supersaturation, i.e., ratio of bulk
concentration and equilibrium solubility
• D – diffusion coefficient
• k+ - surface integration factor
• NA – Avogadro’s number
• r – particle radius
• (C – Ceq) – difference between bulk
concentration and concentration at particle
surface
29. 29
Solid State and Physicochemical
Properties
• Permeability
• Partition coefficient – ratio of drug concentration in membrane interior and at its
surface at equilibrium, can be approximated by Kow (or LogP), depends on relative
hydrophobicity of the drug and the membrane
• Diffusion coefficient – diffusivity of a drug depends on its molecular size,
membrane viscosity, and temperature
• Excipients can have profound effect on drug membrane permeability,
diffusivity, and membrane properties
m
m
m
m
h
K
D
P
• Pm – membrane permeability
• Dm – membrane diffusion coefficient
• Km – membrane/aqueous partition coefficient
• hm – membrane thickness
Walter and Gutknecht, J. Membrabe Biol. 1986, 90, 207-217
Andenberg et al., J. Pharm. Sci. 1992, 81, 879-887
Takizawa,et al., Int. J. Pharm. 2013, 453, 363-370
30. 30
Solid State and Physicochemical
Properties
• Solubility-permeability interplay
• Increased apparent solubility of a drug does not necessarily lead to a greater
absorption flux!
C
P
J eff
Dahan et al., J. Pharm. Sci. 2010, 99, 2739−2749
Miller et al., Mol. Pharmaceutics 2011, 8, 1848−1856
Miller et al., Int. J. Pharm. 2012, 430, 388−391
Miller et al., Mol. Pharmaceutics 2012, 9, 581−590
m
m
m
m
h
K
D
P
aq
aq
aq
h
D
P
• Paq – permeability through unstirred water layer
• Daq – diffusion coefficient of unstirred water layer
• haq – thickness of unstirred water layer
• Saq – intrinsic aqueous solubility of drug
• Sm – apparent membrane solubility of drug
m
aq
eff
P
P
P
1
1
1
Beig et al., Eur. J. Pharm. Biopharm. 2012, 81, 386−391
Dahan et al., AAPS J. 2012, 14, 244−251
Miller et al., Mol. Pharmaceutics 2012, 9, 2009-2016
Yalkowsky, J. Pharm. Sci. 2012, 101, 3047-3050
aq
m
m
S
S
K
• Unstirred water layer is defined as the
distance from the membrane surface to the
point at which drug concentration in the
aqueous medium becomes constant and
equal to bulk
UWL
GI Lumen
Enterocyte
Cdrug
31. 31
Solid State and Physicochemical
Properties
• Solubility-permeability interplay: Cosolvent Effect
Dahan et al., AAPS J. 2012, 14, 244−251
• Increase in intrinsic aqueous drug solubility results in decreased partition coefficient, Km
• However, supersaturation (as when an amorphous drug is dosed), does not affect Km
32. 32
Solid State and Physicochemical
Properties
• Solubility-permeability interplay: Free Drug Effect
Dahan et al., AAPS J. 2012, 14, 244−251
• Only free, dissolved drug is able to permeate membrane through passive diffusion process
• When complexation (cyclodextrins) or micelle formation (lipids/surfactants) is used to
solubilize the drug, most dissolved drug is bound and small fraction of the drug remains free
33. 33
Solid State and Physicochemical
Properties
• Key takeaways:
• Energetics of solid forms define their solubility properties
• Properties of solid forms can be exploited
• Solubility, dissolution, and precipitation can be manipulated
• Understanding solubility-permeability interplay is essential
34. 34
Objectives
1. Fundamentals of drug absorption
2. Solid state and physicochemical properties
3. Enabling pharmaceutical technologies
4. Preclinical formulation and form selection strategies
35. 35
Enabling Pharmaceutical Technologies
• Pharmaceutics Toolbox
Complex
Simple
Short Long
Time to develop
Nanoparticles
Salts and Cocrystals
ASD
pH / in situ Salts
Surfactants
Cyclodextrins
Cosolvents
Lipids
Microspheres and
Liposomes
A little A Lot
Resources
Technology
Science
(Micro/Nano)
Emulsions
36. 36
Enabling Pharmaceutical Technologies
• Preclinical Pharmaceutics Toolbox - selection inputs
pH
Osmolality
Solution or Suspension
Dose Volume
pKa
LogP
Crystallinity
Target Validation
Lead Optimization
Clinical
Behavioral
Diabetes
Liver/Renal
Impairment
Sterility
Toxicology
Hit-to-lead
Acute
or Chronic
Stability
Solubility
Clearance
AUC
Transporters
Papp
Metabolism
Cmax/Tmax
API
Properties
Project
Stage
Dosing
Route
In Vivo
Model
ADME Properties
Preclinical
38. 38
Enabling Pharmaceutical Technologies
• Overview of “Salts and Cocrystals”
Advantages
Key Technological
Challenges
Typical Feasibility Data
• Alternate crystal forms of the API
with different physicochemical,
solid-state, material properties
• Improved solubility and dissolution
rate; driving force due to highly
water-soluble counterion or
coformer
• Formation cannot be predicted with
certainty
• Requires empirical screening
across counterions or coformers
and formation conditions
• Counterions and coformers must be
pharmaceutically-acceptable
• Must provide a significant and
durable improvement in solubility
and/or dissolution rate in GI fluids
• Must be sufficiently physically and
chemically stable in dosing vehicle
and GI fluids
• Can be reproducibly scaled up
39. 39
Enabling Pharmaceutical Technologies
• Overview of “Surfactants, Cosolvents, and Complexing Agents”
Advantages
Key Technological
Challenges
Typical Feasibility Data
• Significantly increase apparent
solubility of hydrophobic APIs
• Avoid rate-limiting dissolution by
pre-dissolving crystalline API or
reducing interfacial tension
• Effectiveness of complexing agents
limited to shape-specific APIs
• Temporal solubility enhancement
limited due to dilution effect in GI
• Choice of excipients and their
amounts can be limited due to
toxicity or side effects
• Must remain in solution and be
chemically stable during storage
• Must maintain API in solubilized
state upon contact with GI fluids for
sufficient length of time
• For parenteral dosing, show
minimal precipitation risk
40. 40
Enabling Pharmaceutical Technologies
• Overview of “Lipid-based Systems”: Emulsions, microemulsions, self-
emulsifying systems, liposomes
Advantages
Key Technological
Challenges
Typical Feasibility Data
• Significantly increase apparent
solubility of hydrophobic APIs
• Avoid rate-limiting dissolution by
pre-dissolving crystalline API
• Enhanced absorption through
lymphatic and paracellular
pathways
• Limited to lipophilic compounds with
high logP, low melting point, and
high solubility in lipids
• Requires oil/surfactant/cosolvent
phase diagrams
• Sufficiently high API loading and
scalable preparation process
• Must remain physically and
chemically stable during storage
• Must maintain API in solubilized
state upon contact with GI fluids for
sufficient length of time
• Can be reproducibly scaled up
41. 41
Enabling Pharmaceutical Technologies
• Overview of “Amorphous Solid Dispersion”
Advantages
Key Technological
Challenges
Typical Feasibility Data
• Enhancement of solubility and
dissolution rate through disruption
of crystal lattice of API
• Can be relatively easily translated
to clinical formulations and dosage
form
• High-energy amorphous state is
prone to chemical instability, higher
hygroscopicity, phase separation
and crystallization,
• Empirical screening of excipients
• Detection and quantitation of
crystalline phase
• Polymer matrix and solvent system
to give single amorphous phase
• Must remain amorphous during
storage and in dosing vehicle
• Must provide a significant and
durable improvement in solubility
and/or dissolution rate in GI fluids
42. 42
Enabling Pharmaceutical Technologies
• Overview of “Nanocrystalline particles”
Advantages
Key Technological
Challenges
Typical Feasibility Data
• Reduction of particle size to <1 mm
(typically 100-500 nm) provides
significant increase in total surface
area and dissolution rate over
• Allows for parenteral dosing of
poorly-soluble compounds
• Specialized and small-scale
equipment and optimization of
process parameters for top-down
(particle size attrition) and for
bottom-up (nanoparticle formation)
approaches
• Empirical screening of stabilizers
• Process parameters for production
of nanoparticles of consistent size
• Polymer and/or surfactant additives
to sufficiently stabilize particle
growth and agglomeration
• Dissolution rate significant enough
to increase dissolution flux
43. 43
Enabling Pharmaceutical Technologies
• Key takeaways:
• No “one size fits all” approach
• Understand fundamental physicochemical properties of compound
• Keep study goals in mind (tool vs lead compound)
44. 44
Objectives
1. Fundamentals of drug absorption
2. Solid state and physicochemical properties
3. Enabling pharmaceutical technologies
4. Preclinical formulation and form selection
strategies
45. 45
Preclinical Formulation Strategies
• Branchu S, Rogueda PG, Plumb AP, Cook WG, “A decision-support tool for the formulation of
orally active, poorly soluble compounds” Eur. J. Pharm. Sci. 2007, 32, 128-139
• Li P, Zhao L, “Developing early formulations: practice and principle” Int. J. Pharm. 2007, 341, 1–19
• Mackie C, Lampo A, Brewster M, “Formulation for Toxicology Studies: Current Challenges and
Future Prospectives” presented at Improving Solubility -2008, London, UK, 2008
• Palucki M, Higgins JD, Kwong E, Templeton AC, “Strategies at the Interface of Drug Discovery and
Development: Early Optimization of the Solid State Phase and Preclinical Toxicology Formulation
for Potential Drug Candidates” J. Med. Chem. 2010, 53, 5897-5905
• Gopinathan S, Nouraldeen A, Wilson AGE, “Development and application of a high-throughput
formulation screening strategy for oral administration in drug discovery” Future Med. Chem. 2010,
2, 1391–1398
Decision
Trees
Practice Intuition
46. 46
Form Selection Strategies
• Bastin RJ, Bowker MJ, Slater BJ, “Salt selection and optimization procedures for pharmaceutical
new chemical entities” Org. Process Res. Dev. 2000, 4, 427-435
• Huang L-F and Tong W-Q, “Impact of solid state properties on developability assessment of drug
candidates” Adv. Drug. Dev. Rev. 2004, 56, 321-334
• Saxena V, Panicucci R, Joshi Y, Garad S, “Developability Assessment in Pharmaceutical Industry:
An Integrated Group Approach for Selecting Developable Candidates” J. Pharm. Sci. 2009, 98,
1962-1979
• Ding X, Rose JP, Van Gelder J, “Developability assessment of clinical drug products with maximum
absorbable doses” Int. J. Pharm. 2012, 427, 260-269
• Korn C, Balbach S, “Compound selection for development – Is salt formation the ultimate answer?
Experiences with an extended concept of the ‘‘100 mg approach’’” Eur. J. Pharm. Sci. 2013
Decision
Trees
Practice Intuition
47. 47
Preclinical Formulation Strategies
• Accelerating timelines, two approaches:
• Invest upfront, right-the-first-time
• Fit-for-purpose formulation, optimize later
• Risk assessment
• Generate, understand and use Preformulation data
Good
Fast
Pick
Any
Two
Cheap
• Bergström CAS et al., “Early pharmaceutical profiling to predict oral drug absorption: Current
status and unmet needs” Eur. J. Pharm. Sci. 2013, http://dx.doi.org/10.1016/j.ejps.2013.10.015
48. 48
Summary
1. Fundamentals of drug absorption
2. Solid state and physicochemical properties
3. Enabling pharmaceutical technologies
4. Preclinical formulation and form selection strategies
Williams HD et al., “Strategies to Address Low Drug Solubility in
Discovery and Development” Pharmacol. Rev. 2013, 65, 315-499