Formulation Development of Poorly Soluble Drugs

Poorly Soluble DrugsTrials and Tribulations of the Modern Formulator Bruce Rehlaender, Ph.D. Principal, Formulation Development PharmaDirections, Inc. 1

The Problem of Insolubility• Med Chemists are obsessed with affinity and selectivity 2

The Problem of Insolubility• Med Chemists are obsessed with affinity and selectivity• Solubility can get left by the wayside 3

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 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• And Formulators are going crazier 5

Classes of Problem Children Non-ionized weak Halogenated acids or weak bases moleculesLipophilic Brick dustmolecules Amphiphilic molecules Macromolecules 6

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 7

Bioavailability Solutions• Make drug particles smaller – ↑ Dissolution rate (kinetic) * – ↑ Solubility (thermodynamic)• You can go to extremes and… 8

Bioavailability Solutions• Nanosize It*Formerly known as colloid sciences 9

Bioavailability Solutions• Administer drug in dissolved form• Make drug form more soluble• Formulate with a solubilizer 10

Solubilized Liquid Formulations • Injectables – IV (bolus and infusion) – SubQ (bolus and infusion) – IM • Inhalation – Nasal sprays – Nebulizer formulations • Oral liquids • Topicals • Otics, ophthalmics, etc. 11

Solubilizing ApproachespH Adjustment Co-solvents ComplexesMicelles Emulsions Liposomes 12

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

pH AdjustmentWhat 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 14

Pop QuizWhich 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 15

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 16

Co-Solvent FormulationsHow 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 17

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 18

Complexes (Cyclodextrins) Hydrophobic drug 19

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 20

Micelles and Microemulsions 21

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 22

Emulsions lipophile am ph i ph i le 23

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 24

Liposomes lipophile am ph iph ile 25

SummaryApproach + - Tight range for comfortAdjust pH Simple, few excipients and stability Toxicity, osmolarity,Co-solvent Simple process precipitation on dilutionComplexes Low toxicity, dilutable, High cost, process can lyophilizable be moderately complex Anaphylaxis and otherMicelles 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 26

Choosing a Formulation Formulating poorly soluble drugs is like voting….There are seldom good options, just least objectionable ones 27

Choosing a FormulationWhat 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 28

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/PKThe most active molecule isn’t always the best drug 29 Often the two are at odds with each other, and

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

Formulation Development of Poorly Soluble Drugs

by InstantGMP on Feb 19, 2013

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