The world leader in serving science

An Innovative Approach to Solubility Enhancement – Quadrant 2®

Jason M Vaughn, PhD

Senior Director

2

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

3

Bioavailability: A Multi-Factorial Perspective

Bioavailability

Delivery Tools

• Solid dispersions

• Lipids (SEDD)

• Solubility enhancers

• (complexation, solutions)

• Excipients

• Nanoparticles / Micronization

• Particle engineering

API + Formulation

• API Solubility

• Particle size

• Crystal form

• Salt form

• Crystallinity

• GI activity

• Passive transport

• (trans/para cellular)

• Efflux substrates

• CYP substrates

Kinetics in GI

• Dispersion

• Dissolution

• Passive transport

• Active transport

• Efflux

• Metabolism

• Excretion

4

• Multi-factorial challenges

• No one solution works for all molecules

• Need to consider integrated solutions

• Solid-state properties

• Biopharmaceutics

• Physiological factors

• Formulation design and delivery system

• Time/cost sensitive

Bioavailability Enhancement

5

Solubilization• Solubility enhancers

• Complexation

• Lipids

• Surfactants

• Microenvironment

• Amorphous API

Solid Dispersion • Spray drying

• Hot melt extrusion

• Hot melt granulation

• Fluidbed layering

• Spinning disc

• Spray congealing

Size Reduction• Micronization

• High energy milling

• SEDD

• Microemulsions

Bioavailability Improvement Techniques

6

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

7

Novel Quadrant 2® Program Solves This Dilemma

API chemical structure

Physicochemical

properties

Business and

clinical objectives

Technology selection

Patheon’s exclusive

computational modeling

Technology selection

Excipient selection

8

Quadrant 2® Technology Selection Process

API chemical structure

Size reduction

Dispersion – Spray drying

Amorphous

Dispersion - HME

Dispersion – Coated beads

Lipids

Complexes

Patheon’s exclusive

computational modeling

API chemical structure

Physicochemical

properties

Business and

clinical objectivesPatheon’s exclusive

computational modeling

Excipient selection

Technology selection

9

Quadrant 2® Technology Selection Process

10

• Chemical structure • Melting Point

• Molecular Weight

• LogP or calculated ALogP

• Known or Calculated pKa

• Known or Calculated solubility

Inputs into Quadrant 2

11

Technology Assessment is Dose Dependent

12

Quadrant 2® Excipient Selection Process

API chemical structure

Physicochemical

properties

Business and

clinical objectives

Technology selection

Excipient selectionExcipient selection

Patheon’s exclusive

computational modeling

13

Quadrant 2® Excipient Selection Process: Amorphous Dispersion Example

Computer simulation of

drug 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 and

clinical objectives

Technology selection

Patheon’s exclusive

computational modeling

Excipient selection

14

Drug molecule – Run models & identify descriptors

15

Polymer Selection – Identify complementary descriptors

16

Molecular Dynamics Simulations

17

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

18

Example Drug Loading Assessment for Various Excipients in ASD

Polymer Predicted Maximum

Drug Loading (%)

Recommended Maximum

Drug Loading Range (%)

HPMC 36 35%-50%

PVP VA 64 40 35%-50%

Soluplus 49 40%-60%

HPMCAS-M 40 35%-50%

HPMCP-HP55 39 35%-50%

Eudragit L100-55 39 35%-50%

It should be noted that the predicted maximum drug loadings are based partially on

when the potential for drug-drug nucleation is observed.

19

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

20

Getting Started Is Quick And Easy

SME

consultation

Business and

clinical

objectives

SME review

Comprehensive

report with path

forward

2 weeks

Patheon’s exclusive

computational modeling

API chemical

structure

21

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 consult

and feasibility

proposal

Feasibility studies and animal PK

suppliesFirst in human development and manufacturing

Product life cycle

Formulation

services

22

Patheon Has the Capabilities to Address the Needs of Your Molecule

Addressing the overwhelming majority of solubility challenges

Amorphous DispersionsSoftgels

Liquid Hard Shell

Spray

Drying

Hot Melt

Extrusion

Coated

Beads

Size

Reduction

Lipids

Complexes

23

Case Study – Client X

24

In-Silico Selection of Polymers for Compound X

25

ASD formulations – Compound X:Polymer

26

Spray drying Amorphous Solid Dispersion Formulations

27

Compound X : PVAP in vivo data (dogs)

28

Compound X - Dosage Form Development and Scale-up

29

Phase 1 PK Study – Improved Bioavailability

30

Summary