formulation development of insoluble drugs formulation

1

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

6

Classes of Problem Children

Non-ionized weak acids or weak bases

Lipophilicmolecules

Amphiphilicmolecules

Halogenated molecules

Brick dust

Macromolecules

7

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