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The world leader in serving science

Rational Selection of Excipients For Improving The Bioavailability of Poorly Soluble Drugs: A Case Study

Sanjay Konagurthu, PhDSenior Director, Global Science and Technologies

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Today’s Environment: Increasing Complexity, Increasing Risks

70 – 90%

Solubility and bioavailability

challenges

30%

Phase I

14%

Phase II

8 – 9%

Phase III / NDA

Source: http://www.fdareview.org/03_drug_development.php

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A Better Approach Exists to Being ‘Phase Ready’

Traditional Approach Quadrant 2®

Duration to get to Phase 1 CTM (14 to 19 months) Duration to get to Phase 1 CTM (8 to 9 months)

Phase ready Phase ready

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Novel Quadrant 2® Program Solves This Dilemma

API chemical structure

Physicochemical properties

Business andclinical objectives

Technology selection

Patheon’s exclusivecomputational modeling

Technology selection

Excipient selection

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Quadrant 2® Technology Selection Process

API chemical structureSize reduction

Dispersion – Spray drying

Amorphous

Dispersion - HME

Dispersion – Coated beads

Lipids

Complexes

Patheon’s exclusivecomputational modeling

API chemical structure

Physicochemical properties

Business andclinical objectives

Patheon’s exclusivecomputational modeling

Excipient selection

Technology selection

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Quadrant 2® Technology Selection Process

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Quadrant 2® Excipient Selection Process

API chemical structure

Physicochemical properties

Business andclinical objectives

Technology selection

Excipient selectionExcipient selection

Patheon’s exclusivecomputational modeling

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Quadrant 2® Excipient Selection Process: Amorphous Dispersion Example

Computer simulation ofdrug and excipient

Solid state

• Hydroxypropyl methylcellulose (HPMC)• Hydroxypropyl cellulose (HPC)• Carboxymethyl ethylcellulose (CMEC)• Cellulose acetate phthalate (CAP)• Hydroxypropyl methylcellulose phthalate (HPMCP)• Hydroxypropyl methylcellulose acetate succinate

(HPMCAS)

Cellulosic Polymers• Poly(butyl methacrylate, (2-dimethylaminoethyl)

methacrylate, methyl methacrylate) (Eudragit E)• Poly(methacrylic acid, methyl methacrylate)

(Eudragit L100)• Poly(methacrylic acid, ethyl acrylate (Eudragit

L100-55)• Poly(methacrylic acid, methyl methacrylate)

(Eudragit S100)

Polymethacrylate Polymers

• Surfactants• Plasticizers• Permeation enhancers

Additives

• Polyvinyl pyrrolidone (PVP)• Polyvinyl alcohol (PVA)• Polyvinylcaprolactam-polyvinyl acetate-PEG

graft copolymer (Soluplus®)• Polyvinyl acetate phthalate (PVAP)• Polyvinylpyrrolidone-polyvinyl acetate

(PVP-VA) copolymer

Polyvinyl Polymers

API chemical structure

Physicochemical properties

Business andclinical objectives

Technology selection

Patheon’s exclusivecomputational modeling

Excipient selection

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Drug molecule – Run models & identify descriptors

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Polymer Selection – Identify complementary descriptors

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Molecular Dynamics Simulations

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Dipyridamole loading in HPMCAS-M (Spray-dried Amorphous Dispersions)

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Selection of Excipients for Lipid-based Formulations - Example

• Predicted lipid-excipient solubility provides a guideline for the feasibility of a lipid-based formulation (e.g. soft-gel, LFHS).

Indomethacin

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Accuracy

Quadrant 2® Technology And Excipient Selection: Proven Accuracy

Calcitriol (Rocaltrol) – LipidsItraconazole (Sporanox) – Coated

Beads and (Onmel) - HME

Technology Selection

Excipient Selection

90%

80%

Validated with over 150 drug products

Posaconazole (Noxafil) – HME

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Getting Started Is Quick And Easy

SME consultation

Business and clinical

objectives

SME review

Comprehensive report with path

forward

2 weeks

Patheon’s exclusivecomputational modeling

API chemical structure

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PK results

Quadrant 2® Is Part of Overall Approach to Accelerate the Timeline to Clinic

Computational modeling(2 weeks)

Preclinical development(6 to 8 weeks)

Early clinical studies(4 to 6 months)

SME consultand feasibility

proposalFeasibility studies and PK supplies First in human development and manufacturing

Product life cycle

Formulation services

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Patheon Has the Capabilities to Address the Needs of Your Molecule

Addressing the overwhelming majority of solubility challenges

Amorphous DispersionsSoftgels

Liquid Hard Shell

SprayDrying

Hot Melt Extrusion

CoatedBeads

Size Reduction

Lipids

Complexes

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Quadrant 2® is Part of Integrated Process to Get Your Molecule to Clinic, Fast

Work smarter and faster, not harder

Exclusive computational model

Validated and highly accurate

Scientifically-based recommendations

Expert consultation

Broad formulation capabilities

Quick to clinic Global networkProven record of

approval

150+2 weeks

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10 Centers of Excellence, One Global Network

Whitby,Canada

Center of Excellence for Scale Up

Toronto,Canada

Center of Excellence for Highly PotentProducts

Cincinnati, OHUSA

Center of Excellence for Controlled Release & Controlled Substances

Bend, ORUSA

Center of Excellence for Solubility

Highpoint, NCUSA

Center of Excellence for SoftgelsEnhancement

Greenville, NCUSA

Center of Excellence for Sterile and Oral Solid Dose Development

Bourgoin,France

Center of Excellence for Mid & Late stage OSD Development

Ferentino,Italy

Center of Excellence for Sterile liquid and lyophilized product development

Tilburg, Netherlands

Center of Excellence for Softgels &Solubility Enhancement

Milton Park,UK

Center of Excellence for Early Development and Solubility Enhancement

75+ Markets

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Case Study – Client X

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In-Silico Selection of Polymers for Compound X

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ASD formulations – Compound X:Polymer

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Spray drying Amorphous Solid Dispersion Formulations

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Compound X : PVAP in vivo data (dogs)

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Compound X : Spray Drying Process Scale-up

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Thermodynamic Model – Spray Drying

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Compound X Spray Drying Scale-up

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Design of Experiments (DOE) around Spray-drying Process

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Dosage Form Design Space – Choice of Tableting Excipients

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Formulation and Process Considerations for a Tablet

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Excipient Selection for a Tablet – Mechanical Properties

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Tabletability – Different Excipients

Presster: Dwell time 27 mSec (+0.5% Mg Stearate)Tye, Sun, Amidon, J.Pharm.Sci. 94(3), 465-72 (2005)

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Compaction Simulation to Guide Excipient Selection

Heckel Analysis

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Compound X - Dosage Form Development and Scale-up

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200-250 mgA Tablet Formulation Compound X

Parameter Value

Tooling 3750'' x 7480''Weight (mg) 1031

Weight (%RSD) 1.9Thickness

(mm)7.94

Hardness (kP) 19.1Friability (%wt ) 0.11Disintegration

Time (min)~2.0

Material Trade Name Percentage

SDI 40% X: HPMCAS‐L 50%

Mannitol Parteck M 100 28.50%

MCC Avicel  PH101 13.50%

Croscarmellose Sodium Ac‐Di‐Sol 6%

Silicone Dioxide Cabo‐Sil M5P 1%

Magnesium Stearate (I.G.) Mg Stearate 0.50%

Magnesium Stearate (E.G.) Mg Stearate 0.50%

40% Cmpd X:HPMCAS‐L Tablet Formulation 

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Phase 1 PK Study – Improved Bioavailability

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Summary

• Quadrant 2® provides a streamlined approach for technology and excipient selection.

• Rational strategy for excipient selection Improved solubility/bioavailability.

• Formulation strategy for dosage forms based on excipient mechanical properties.

• Scale-up and process development is critical to a program’s success.

• Reduced experimentation saves time/costs to FIH clinical trials.

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Thank You