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Poorly Soluble DrugsTrials and Tribulations of the Modern
Formulator
Bruce Rehlaender, Ph.D.Director of Formulation Development
PharmaDirections, Inc.
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The Problem of Insolubility
• Med Chemists are obsessed with affinity and selectivity
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The Problem of Insolubility
• Med Chemists are obsessed with affinity and selectivity
• Solubility can get left by the wayside
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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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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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Classes of Problem Children
Non-ionized weak acids or weak bases
Lipophilicmolecules
Amphiphilicmolecules
Halogenated molecules
Brick dust
Macromolecules
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Two Big Issues with Insolubility:
• Cannot give particles IV
• Poor Bioavailability
emboli
0
50
100
0 3 6 9 12
hours
ng
/mL
IV
Oral
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Bioavailability Solutions
• Make drug particles smaller– ↑ Dissolution rate (kinetic)
– ↑ Solubility (thermodynamic)
• You can go to extremes and…
*
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Bioavailability Solutions
• Nanosize It
*Formerly known as colloid sciences
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Bioavailability Solutions
• Administer drug in dissolved form
• Make drug form more soluble
• Formulate with a solubilizer
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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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Solubilizing Approaches
pH Adjustment Co-solvents Complexes
Micelles Emulsions Liposomes
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pH Adjustment
• Most drugs are weak acids or weak bases• Solubility depends on ionization state
• Can get large solubility increase if pH still reasonable
Solubility of Weak Acid
0.001
0.01
0.1
1
10
100
pHS
olu
bil
ity
pKa
Solubility of Weak Base
0.001
0.01
0.1
1
10
100
pH
So
lub
ilit
y
pKa
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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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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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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.
Typical Solubility Curve
0 20 40 60 80 100
% Co-Solvent
So
lub
ilit
y
– Problem:you need a lot
– Can sometimes get formulation that is metastable upon dilution in aqueous
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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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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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Complexes (Cyclodextrins)
Hyd
rop
hob
icd
rug
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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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Micelles and Microemulsions
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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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Emulsions
lipophileamphiphile
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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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Liposomes
amphiphile
lipophile
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Summary
Approach + -
Adjust pH
Co-solvent
Complexes
Micelles
Emulsion
Liposomes
Simple, few excipientsTight range for comfort and stability
Simple processToxicity, osmolarity, precipitation on dilutionLow toxicity,
dilutable, lyophilizable
High cost, process can be moderately complex
Simple process, dilutableAnaphylaxis and other toxicity issues
Non-toxic, isotonic, generally dilutable
Complex process, no filter sterilizationNon-toxic, isotonic,
filterable, lyophilizable
Cost, complex process, poor physical stability
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Choosing a Formulation
There are seldom good options, just least objectionable ones
Formulating poorly soluble drugs is like voting….
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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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The Dilemma of Druggability
Pharmacology Druggability
Receptor Affinity
Receptor Specificity
Activity once bound(agonist or antagonist)
Clearance/PK
Solubility
Toxicity
Stability
Hygroscopicity
Powder characteristics
Permeability/Absorption
Polymorphism
Dis
covery
The most active molecule isn’t always the best drug
Often the two are at odds with each other, and