Poorly soluble drugs are the nemesis of formulation development scientists. Bruce Rehlaender the big issues and points out some approaches for dealing with these drugs and improving their bioavailability.

1. Poorly Soluble Drugs
Trials and Tribulations of the Modern Formulator
Bruce Rehlaender, Ph.D.
Principal, Formulation Development
PharmaDirections, Inc.
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2. The Problem of Insolubility
• Med Chemists are obsessed with affinity
and selectivity
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3. The Problem of Insolubility
• Med Chemists are obsessed with affinity
and selectivity
• Solubility can get left by the wayside
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4. The Problem of Insolubility
• Med Chemists are obsessed with affinity
and selectivity
• Solubility can get left by the wayside
• General tendency is that new drugs are
becoming more insoluble
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5. The Problem of Insolubility
• Med Chemists are obsessed with affinity
and selectivity
• Solubility can get left by the wayside
• General tendency is that new drugs are
becoming more insoluble
• And Formulators are
going crazier
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6. Classes of Problem Children
Non-ionized weak Halogenated
acids or weak bases molecules
Lipophilic Brick dust
molecules
Amphiphilic
molecules Macromolecules
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7. Two Big Issues with Insolubility:
• Cannot give particles IV
emboli
• Poor Bioavailability ng/mL
100
IV
50
Oral
0
0 3 6 9 12
hours
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8. Bioavailability Solutions
• Make drug particles
smaller
– ↑ Dissolution rate (kinetic)
*
– ↑ Solubility (thermodynamic)
• You can go to extremes and…
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9. Bioavailability Solutions
• Nanosize It
*Formerly known as colloid sciences
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10. Bioavailability Solutions
• Administer drug
in dissolved form
• Make drug form
more soluble
• Formulate with
a solubilizer
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11. Solubilized Liquid Formulations
• Injectables
– IV (bolus and infusion)
– SubQ (bolus and infusion)
– IM
• Inhalation
– Nasal sprays
– Nebulizer formulations
• Oral liquids
• Topicals
• Otics, ophthalmics, etc.
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12. Solubilizing Approaches
pH Adjustment Co-solvents Complexes
Micelles Emulsions Liposomes
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13. pH Adjustment
• Most drugs are weak acids or weak bases
• Solubility depends on ionization state
Solubility of Weak Base Solubility of Weak Acid
100 100
10 10
Solubility
Solubility
1 1
pKa pKa
0.1 0.1
0.01 0.01
0.001 0.001
pH pH
• Can get large solubility increase if pH still
reasonable 13

14. pH Adjustment
What pH is acceptable for injection?
• It depends…..
– Route of administration (central vein IV,
peripheral vein IV, SubQ, IM)
– Rate and duration of administration
– Buffer capacity of the formulation (D5W is in
spec at pH 2.5 due to lack of buffering)
– Indication (routine vs. critical, acute vs.
chronic)
• Problem is that you need buffer to assure
solubility, but buffering decreases range
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15. Pop Quiz
Which of these excipients are allowed for use
in injectable products?
– Polyethylene glycol?
– Ethanol?
– Bile salts?
– N-methyl-pyrrolidone (NMP)?
– Dimethyl-acetamide (DMA)?
– Polysorbates (Tweens)?
• All of the above are used in approved injectable
products
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16. Co-Solvent Formulations
• Adding a water-miscible solvent can
reduce polarity and increase solubility
• Most typical solvents are propylene
glycol, low MW PEGs, and ethanol.
– Problem: Typical Solubility Curve
you need a lot
– Can sometimes get
Solubility
formulation that is
metastable upon dilution 0 20 40 60
% Co-Solvent
80 100
in aqueous
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17. Co-Solvent Formulations
How much solvent is allowed?
• It depends…..
– Route of administration (central vein IV,
peripheral vein IV, SubQ, IM)
– Rate and duration of administration
– Indication (routine vs. critical, acute vs.
chronic)
• These formulations are very hypertonic, so
best for IV or dilute-for-use
• Example: several formulations with 40%
PG and 10% ethanol for IV and IM
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18. Complexes (Cyclodextrins)
• Cyclodextrins are “basket-like” molecules
with a hydrophobic pocket and hydrophilic
exterior
• Hydroxypropyl-β-CD and sulfobutyl ether- β-
CD used for injectables
• Need high concentration (>10%) since level
needs to be stoichiometric with drug
• Quite safe. Only significant issue is some
nephrotoxicity
• Licensing was a big issue in past
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19. Complexes (Cyclodextrins)
Hydrophobic
drug
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20. Micelles and Microemulsions
• Micelles are aggregates of surfactant
molecules that can solubilize drugs.
• Typically used surfactants are:
– Polysorbates (PEGylated sorbitan fatty acid esters)
– Cremophor (PEGylated castor oil)
– Pluronic F68 (PEG/PPG block copolymer)
– Solutol (PEGylated hydroxystearate)
• All can cause anaphylactic reactions
• Example: Taxol formulated in pure surfactant.
Diluted to metastable dispersion prior to infusing
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21. Micelles and Microemulsions
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22. Emulsions
• In contrast to micelles/microemulsions,
emulsions are thermodynamically unstable
• Prepared with high pressure homogenizer
• Oil droplet size typically >0.2 µm, so must be
heat (or radiation) sterilized
• Oil droplets similar to chylomicrons, so are
very safe
• Phospholipids used as emulsifier. Non-ionics
(Tweens, etc.) can be used for non-sterile
products but cannot take heat
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23. Emulsions
lipophile
am
ph
i ph
i le
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24. Liposomes
• Liposomes are small vesicles composed of
phospholipid bilayers
• Liposomes are also unstable and are
typically quite fussy and expensive
• Like emulsions, liposomes are very non-
toxic
• Unlike emulsions, liposomes can be sterile
filtered and lyophilized
• Special process equipment is required
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25. Liposomes
lipophile
am
ph
iph
ile
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26. Summary
Approach + -
Tight range for comfort
Adjust pH Simple, few excipients
and stability
Toxicity, osmolarity,
Co-solvent Simple process
precipitation on dilution
Complexes Low toxicity, dilutable, High cost, process can
lyophilizable be moderately complex
Anaphylaxis and other
Micelles Simple process, dilutable
toxicity issues
Non-toxic, isotonic, Complex process,
Emulsion generally dilutable no filter sterilization
Non-toxic, isotonic, Cost, complex process,
Liposomes filterable, lyophilizable poor physical stability
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27. Choosing a Formulation
Formulating poorly soluble drugs is like
voting….
There are seldom good options, just
least objectionable ones
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28. Choosing a Formulation
What system is right for you?
• It depends…..
– What solubilizes your drug (first and foremost)
– Stability considerations
– Route, rate, and duration of administration
– Factors specific to disease state
– IP considerations and, of course, marketing
• Step 1: Cast a broad net to identify your
options
• Step 2: Choose your poison
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29. The Dilemma of Druggability
Pharmacology Druggability
Receptor Affinity Solubility
very
Stability
Receptor Specificity
Disco
Hygroscopicity
Activity once bound Powder characteristics
(agonist or antagonist)
Polymorphism
Toxicity
Permeability/Absorption
Clearance/PK
The most active molecule isn’t always the best drug
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Often the two are at odds with each other, and

30. PharmaDirections, Inc.
Pharmaceutical Consulting and Project Management
Preclinical, CMC, Regulatory Affairs
www.PharmaDirections.com
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