Formulation

Development of
Solid Dosage Forms
FPO
Kansas City, MO

Paul Skultety
Senior Director, Pharmaceutics
January 12, 2006

2005 Aptuit, Inc.

 Prototype Formulation Development

Assign Technical Lead

Formulation Approach
Excipient compatibility
Develop 2 - 3 prototype formulations
Wet granulation
Direct compression
Roller compaction

Place on prototype stability

Evaluate physical and chemical
Evaluate pH dependency of release rate

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 Prototype Formulation Development

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

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 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 Moderate Dose Low Dose

>250 mg 50 - 250 mg <50 mg

Capsule: Capsule: Capsule:

-Bead -Bead -Bead
-Powder -Powder -Powder

Tablets: Tablets: Tablets:

-Roller Compaction -Direct Compression -Direct Compression
-Direct Compression -Wet Granulation -Wet Granulation
-Wet Granulation
-Spray Drying Critical Factors:
Critical Factors:
-API: -API:
-Physical characteristics -Physical characteristics
Critical Factors:
-Amount available -Solution stability
-API:
-Handling procedures
-Amount available
-Unit Dose Sampling
-Physical characteristics

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 Late Phase Formulation Development

Late Phase Development

Scale-Up Capabilities Clinical Supplies Manufacturing

Utilize Statistically Designed Experiments Greater than 10 % of Full Scale

Screening Designs: -Wet Granulation

-Identify Critical Process Parameters -Direct Compression
-Optimize Formulation -Fluid Bed Drying/Particle Coating
-Conduct Scale up at appropriate scale

Full Factorial Designs: -Compression & Encapsulation

-Characterize Magnitude of Effects -Film Coating

Response Surface Designs:

-Define Effect of Parameters on Critical Responses

Support Regulatory Filings

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 Process Design of Experiments Study

Objective:
Establish optimum manufacturing parameters
Minimize batch to batch variation
Provide scientific justification for processing
parameters / ranges

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Factors to be studied

High Shear Wet Granulation Blending

Spray rate Blend time
Granulating fluid used Blender
Impeller / chopper speed Compression
Fluid Bed Drying Feeder speed
Inlet temperature Press speed
Dew point Main compression force
Sizing Tamping
Feed rate Coating
Screen size Spray rate
Wet vs. dry Pan speed
Mill speed Tip / airhorn sizes
Inlet temperature
Airflow rate

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 Responses

Wet granule
Dry granule bulk and tap density
Granule size / shape distribution
Flow indicators (flow rate)
Granulation moisture content (LOD)
Tablet weight, thickness, hardness, disintegration, friability,
dissolution
Content uniformity

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 Oral Liquid Formulation Approach
Prototype Formulation Approach

Dose per unit volume

Soluble Insoluble

Stable Unstable Suspension Co-solvent system

Solution Reconstituted Stable Unstable Critical Factors:

Powder for Solution API:
-Physical characteristics
Taste/safety of co-solvent

Suspension Reconstituted
Critical Factors: Powder for Suspension
API:
-Physical Characteristics
including taste
-Preservation system Critical Factors:
API:
-Physical Characteristics
reduced taste factor
-Preservation system

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 Late Phase Development of
Oral Liquids
Late Phase Development
of Oral Liquids

Scale up Capabilities Clinical Supply Manufacturing

Utilize DOE Where Needed Greater than 10% of

Full Scale

Determine Compatability of Use Similar or Comparable

Product Contact Surface Manufacturing Equipment to intended
Commercial Manufacturing

Demonstrate Preservation Efficacy

for Multidose Products

Suspensions - Determine Limits of

API Particle Size

Mimic Commercial Manufacturing

Holding and Filling Times

Support Regulatory
Filings

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 Parenteral Formulation Approach
Parenteral Formulation Approach

Dose per unit volume

Soluble Insoluble

Stable Unstable Powder Fill Co-solvent solution

Dose >> 1 gram

Solution Freeze Dried Powder Gamma irradiate Terminally Sterilized Aseptic

Terminally Sterilized Asceptic Fill Asceptic Process If insoluble develop Critical Factors:
if unstable to co-solvent diluent API:
terminal sterilization -Physical Characteristics
-Safety of co-solvent
-Filter compatability for co-solvents
Critical Factors:
API:
-Physical Characteristics

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 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 Bracket Validated Sterile

Sterile Process Validation Processes Where Appropriate

Validate Sterile Processes Where Validate Sterile Processes

Needed for Both Terminal and Where Needed Such as Media Fills
Sterile Filtered Processes for Aseptic Processes

Finalize Lyophilization Processes for

Freeze Dried Products

Support Regulatory Filings

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Sustained Release Development
General Approach
Define Product Characteristics
Estimation of Possible Doses (Range is Important)
1 to 10 mgs
100 to 500 mgs
Define Most Desirable Dosage form
Tablets
Multiparticulate
Estimate Possible Drug Release Rate
8 hour release
24 hour release
Gather All Data on Bioavailability
Window of absorption
Absorbed at higher pHs
Consider Amount of Drug Substance Available and Timing

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 Sustained Release Development
General Approach (contd)
SR Development Overall Plan
Develop Several Prototype Formulas
Evaluate stability
Evaluate pH effects on release
Evaluate getting complete release of compound
Test Several Formulas / Release Rates in Human
Bioavailability Screen Study
Select Target Formulation and Release Rate
Try to develop IV / IV correlation
Conduct Scale-up to at least 10% of Full Scale
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 Moderate Dose Low Dose

(200-500 mg per Dosage Unit) (50-200 mg per Dosage Unit) (1-50 mg per Dosage Unit)

-Evaluate SR Beads Extrusion Spheronization -SR Beads & Evaluation of SR Polymer -Hydrophilic Eroding Matrix
-Evaluate SR Coating Polymer -Hydrophilic Eroding Matrix -Wax Matrix
-Evaluate Filling into Capsules or Tablet Compression -Wax Matrix is Possible -SR Beads-Secondary Consideration
-Evaluate Release Rate at High and Low pH -Evaluate Release Rate at High and Low pH -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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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 Hydrophilic Matrix Tablet Wax Matrix Tablet

(More Difficult to Scale)

-Extrusion Spheronization Process -Generally Requires Wet Granualtion or -Particle Size of Drug Substance is Critical
(Difficult on a Large Scale) Roller Compaction -Tablet Hardness has Significant Effect on Release
-Consistent Release from SR Beads can be Difficult -Particle Size of Final Granulation can be Critical
-Specifications of Release Controlling Excipients Critical

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Sustained Release Development Selection
of Prototype Formula for Bioscreen Study

Type of Formulations
If two Types of Formulas Result in Acceptable Release Rate
Include two Formulas
If only One Type of Formula is Acceptable Consider
Variations in Formula Such as Drug Load

Target Release Rates

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

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Hydrophilic Eroding Matrix Tablets

Release rate controlling excipients utilized

Hydroxypropyl Methylcellulose (HPMC)
High Viscosity
Polyethylene oxide
Carbomer / Polyethylene oxide
Combination of above
Formulation Approach
Screen Formulas based on dissolution profile and tablet
properties
Evaluate drug load
Evaluate ratio of excipients
Goal- Identify potential formulation with sustained
release and total release by 12, 18 and 24 hour

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Hydrophilic Eroding Matrix Tablets
(contd)
Process considerations
Usually require granulation
High Shear
Fluid Bed
Roller Compaction
Possible Direct Compress - Depends on drug properties
not possible with HPMC

Evaluation Process Characteristics

Granulation Particle Size
Final Blend Flow Properties
Tablet Compression Properties
Hardness vs. Force
Tablet Physical Properties

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Wax Matrix Tablets
Formulation Approach
Screen formulas based on dissolution and tablet physical
properties
Evaluate drug load or ratio of drug to wax
Process Considerations
Requires manufacture of Hot melt granulation
Drug must be stable to temperatures up to 90C
Particle size of drug can have significant affect on
dissolution
Evaluation Process Characteristics
Granulation Particle Size
Final Blend Flow Properties
Tablet Compression Properties
Hardness vs. Force
Tablet Physical Properties

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Sustained Release Beads

Extrusion / Spheronization
Drug loaded beads
Can obtain high drug load depending on drug properties
Formulation / Process Development
Experiments to determine range of acceptable drug load
Primary factor in experiments is ability to make acceptable
spherical bead
Shape
Size
Surface characteristics
Primary objective is acceptable processing of beads and
bead with immediate release of drug

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Sustained Release Beads (contd)
Sustained Release Coating
Evaluate two Polymers
Eudragit and Aquacoat
Determine appropriate plasticizer level
Determine appropriate cure time
Determine effect of bead particle size on drug release
from SR bead
Fill sustained release beads into capsules
Compress beads into tablets - requires additional
excipients
SR Bead Development
Requires more drug substance than matrix tablets
SR beads allow more dose flexibility than matrix
tablets

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