Formulation Development of Solid Dosage Forms Kansas City, MO Paul Skultety Senior Director, Pharmaceutics January 12, 2006

© 2005 Aptuit, Inc.

FPO

Prototype Formulation Development Assign Technical Lead Formulation Approach ƒ Excipient compatibility ƒ Develop 2 - 3 prototype formulations – Wet granulation – Direct compression – Roller compaction

Place on prototype stability ƒ Evaluate physical and chemical ƒ Evaluate pH dependency of release rate

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Prototype Formulation Development Evaluate Formulation ƒ ƒ ƒ ƒ ƒ ƒ ƒ ƒ

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API load Ratio of excipients API physical characteristics Flow properties Hardness vs. force Granulation particle size Friability Dissolution Profile

Tablet Formulation Development Outline Prototype Formulation (250 - 500 gm batch size) Scale up to pilot scale Process / Formulation DOE (15 kgs) Pivotal scale up (> 10% of commercial scale) Pivotal Bioequivalence and Registration Batch Manufacture Technology Transfer

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Prototype Formulation Development Prototype Formulation Approach High Dose >250 mg

Moderate Dose 50 - 250 mg

Low Dose > 1 gram

Solution

Freeze Dried Powder

Gamma irradiate

Asceptic Process

If insoluble develop co-solvent diluent

Terminally Sterilized

Asceptic Fill if unstable to terminal sterilization

Critical Factors: API: -Physical Characteristics

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Co-solvent solution

Terminally Sterilized

Aseptic

Critical Factors: API: -Physical Characteristics -Safety of co-solvent -Filter compatability for co-solvents

Late Phase Development of Parenterals Late Phase Development of Parenterals Late Phase Development Scale-Up Capabilities

Clinical Supplies Manufacturing

Utilize DOE Where Needed

Greater than 10 % of Full Scale

Generate Master Plan for Sterile Process Validation

Bracket Validated Sterile Processes Where Appropriate

Validate Sterile Processes Where Needed for Both Terminal and Sterile Filtered Processes

Validate Sterile Processes Where Needed Such as Media Fills for Aseptic Processes

Finalize Lyophilization Processes for Freeze Dried Products Support Regulatory Filings 13

Sustained Release Development General Approach Define Product Characteristics ƒ Estimation of Possible Doses – (Range is Important) – 1 to 10 mg’s – 100 to 500 mg’s

ƒ Define Most Desirable Dosage form – Tablets – Multiparticulate

ƒ Estimate Possible Drug Release Rate – 8 hour release – 24 hour release

ƒ Gather All Data on Bioavailability – Window of absorption – Absorbed at higher pH’s

ƒ Consider Amount of Drug Substance Available and Timing

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Sustained Release Development General Approach (cont’d) SR Development Overall Plan ƒ Develop Several Prototype Formulas – Evaluate stability – Evaluate pH effects on release – Evaluate getting complete release of compound

ƒ Test Several Formulas / Release Rates in Human Bioavailability Screen Study ƒ Select Target Formulation and Release Rate – Try to develop IV / IV correlation

ƒ Conduct Scale-up to at least 10% of Full Scale ƒ Test Target Formula and Two Additional Release Rates in Pivotal Bioavailability Study

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Sustained Release Development Prototype Formulas Prototype Formulations Approach High Dose (200-500 mg per Dosage Unit)

-Evaluate SR Beads Extrusion Spheronization -Evaluate SR Coating Polymer -Evaluate Filling into Capsules or Tablet Compression -Evaluate Release Rate at High and Low pH

-Evaluatate Matrix Tablet-Depends on Solubility and Maximum Dose -Hydrophilic Eroding Matrix Most Likely

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Moderate Dose (50-200 mg per Dosage Unit)

-SR Beads & Evaluation of SR Polymer -Hydrophilic Eroding Matrix -Wax Matrix is Possible -Evaluate Release Rate at High and Low pH

Low Dose (1-50 mg per Dosage Unit)

-Hydrophilic Eroding Matrix -Wax Matrix -SR Beads-Secondary Consideration -Evaluate Release Rate at High and Low pH

Sustained Release Development Scale-up Considerations Formula Selection -Consider Most Desirable Product Characteristics -Evaluate Variability in Bioavailability Data and Release Rates

Scale -Up of Target Formulation

SR Beads (More Difficult to Scale)

-Extrusion Spheronization Process (Difficult on a Large Scale) -Consistent Release from SR Beads can be Difficult

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Hydrophilic Matrix Tablet

Wax Matrix Tablet

-Particle Size of Drug Substance is Critical -Generally Requires Wet Granualtion or -Tablet Hardness has Significant Effect on Release Roller Compaction -Particle Size of Final Granulation can be Critical -Specifications of Release Controlling Excipients Critical

Sustained Release Development Selection of Prototype Formula for Bioscreen Study Type of Formulations ƒ If two Types of Formulas Result in Acceptable Release Rate Include two Formulas ƒ If only One Type of Formula is Acceptable – Consider Variations in Formula – Such as Drug Load

Target Release Rates ƒ ƒ ƒ ƒ

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Include a Minimum of Two Release Rates per Formula. Twice Daily Target 80% Release within 8 Hrs Once Daily Target 80% Release within 20 to 24 Hrs Include one Faster and one Slower Release Rate Compared to Target

Hydrophilic Eroding Matrix Tablets Release rate controlling excipients utilized ƒ Hydroxypropyl Methylcellulose (HPMC) – High Viscosity

ƒ Polyethylene oxide ƒ Carbomer / Polyethylene oxide ƒ Combination of above

Formulation Approach ƒ Screen Formulas based on dissolution profile and tablet properties ƒ Evaluate drug load ƒ Evaluate ratio of excipients ƒ Goal- Identify potential formulation with sustained release and total release by 12, 18 and 24 hour

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Hydrophilic Eroding Matrix Tablets (cont’d) Process considerations ƒ Usually require granulation – – – –

High Shear Fluid Bed Roller Compaction Possible Direct Compress - Depends on drug properties not possible with HPMC

Evaluation Process Characteristics ƒ Granulation Particle Size ƒ Final Blend Flow Properties ƒ Tablet Compression Properties – Hardness vs. Force

ƒ Tablet Physical Properties

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Wax Matrix Tablets Formulation Approach ƒ Screen formulas based on dissolution and tablet physical properties ƒ Evaluate drug load or ratio of drug to wax

Process Considerations ƒ Requires manufacture of Hot melt granulation ƒ Drug must be stable to temperatures up to 90°C ƒ Particle size of drug can have significant affect on dissolution

Evaluation Process Characteristics ƒ Granulation Particle Size ƒ Final Blend Flow Properties ƒ Tablet Compression Properties – Hardness vs. Force

ƒ Tablet Physical Properties 21

Sustained Release Beads Extrusion / Spheronization ƒ Drug loaded beads ƒ Can obtain high drug load depending on drug properties

Formulation / Process Development ƒ Experiments to determine range of acceptable drug load ƒ Primary factor in experiments is ability to make acceptable spherical bead – Shape – Size – Surface characteristics

ƒ Primary objective is acceptable processing of beads and bead with immediate release of drug

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Sustained Release Beads (cont’d) Sustained Release Coating ƒ Evaluate two Polymers – Eudragit® and Aquacoat®

ƒ Determine appropriate plasticizer level ƒ Determine appropriate cure time ƒ Determine effect of bead particle size on drug release from SR bead ƒ Fill sustained release beads into capsules ƒ Compress beads into tablets - requires additional excipients

SR Bead Development ƒ Requires more drug substance than matrix tablets ƒ SR beads allow more dose flexibility than matrix tablets

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