Designing Amorphous Formulations and Manufacturing

Designing Amorphous Formulations and Manufacturing Processes for Challenging Compounds

Michael Grass | Principal Scientist, Lonza - Bend

Michael Grass | 8th American DDF Summit | 2018 SEP 11

• a

Michael Grass | 8th American DDF Summit | 2018 SEP 11 2

Flexible Model Across the Product Development Cycle

Small Molecule Technologies

DESIGNSmall / Lab-Scale (non-GMP)

DEVELOPClinical Scale

MANUFACTURECommercial Scale

Drug Substance Intermediates – early and GMP intermediates

Drug substances – full range of API inclusive of HPAPI, cytotoxic payloads for ADC’s

Drug Product Intermediates – multiparticulates (MP), micronized API, spray dried dispersions

Drug Products - tablets (IR and MR), encapsulated powder and MP, soft gels, liquid-fill hard caps

> 300Projects

> 200Products


Our Global Development & Manufacturing Network

3 Regions | 8 Sites

• Full Chemistry Capability

• Integrated Drug Product Development

APAC

Nansha, China

Europe

Edinburgh, UK

Ploermel, France

Molinazzo, Switzerland

Visp, Switzerland

North America

Bend, OR

Quakertown, PA

Tampa, FL

DPI and Drug Product

API


Bend, OR

Problem Statement Definition


Formulation Selection


Low Bioavailability Has Many Causes

Barriers to Absorption

P.B. Shekhawat, V.B. Pokharkar. Acta Pharmaceutica Sinica B, 2017, 7 (3), 260 - 280

• Solubility

• Dissolution rate

• Unstirred water layer (UWL) diffusion

• Epithelial membrane permeability

• Efflux

• Metabolism


70-80% of drugs in pharmaceutical pipeline are low solubility

Biopharmaceutical Classification System

2008;7:255–270

IIA Dissolution Rate

Limited

IIB Solubility Limited

Butler, J., Dressman, J. J. Pharm. Sci., 2010

500


Important Considerations for Pre-formulation Assessment

Solubility1. Crystalline Aqueous

2. Amorphous Aqueous3. Crystalline Organic

Aqueous Solubility Challenge1. Lipophilicity/Micelle partitioning

2. Melting point/Crystal lattice energy (i.e. “brick dust”)

Permeability1. Molecular Descriptors

(e.g. MW, rotatable bonds, charge state)

2. Caco-23. Perfusion

Metabolism/Efflux

Pharmacokinetics Absolute BA

1.BA dose dependence2.Food effect

3. Gastric pH effect

Target Product Profile1. Dose

2. Dosing Frequency3. In vivo model (e.g. rat,

dog, monkey, human, etc.)

Chemical Stability1. Labile functional groups

2. Forced degradation

Physical Stability1. Thermal Properties

(e.g. Tm, Tc, Tg)2. Water Uptake


Goal: efficiently arrive at product development with certainty of approach

Problem Statement Definition Guides Technology Choice

SDD

LIPIDIC

NXSTAL

Product Concept

Molecular Properties

Predictions

Technology & Formulation

In vitro, in silico, & in vivo testing

Problem Statement

HME


Many Enabling Technologies Are Available

H.D. Williams et al. “Strategies to Address Low Solubility in Discovery and Development,” Pharmacol. Rev., 65(2013)315-499

Amorphous

• Solid dispersions

• SDD

• HME

• Lyophiles

• Drug/polymer nanoparticles

• Pure amorphous drug

Size Reduction

•Micronization

• Sub-micron crystals (100 to 800 nm)

• Nanocrystals (<100 nm)

• Cosolvents

• Surfactants

• Cyclodextrins

• Lipids:

• Oils

• SEDDS/SMEDDS

• Lipid Multiparticulates

Solvation

• Polymorphs

• Cocrystals

• Salts

Crystal Form

•Molecular modification

• Pro-drugs

Molecular Design


Conceptual Guidance Map for Technology Selection Based on Molecular Properties and Dose

H.D. Williams et al. “Strategies to Address Low Solubility in Discovery and Development,” Pharmacol. Rev., 65(2013), 315-499

Historic focus on defining key parameters

impacting choice of technology in meeting target product

profiles

Thousands of compounds studied and modeled over 20+ years

Multiple reference maps developed for key API and formulation

parameters

Specialized in-vitro test methods developed

to characterize candidate compounds

Rapid technology selection methodologies reduce

empirical testing and API requirements

Solu

bili

ty (

mg

/mL)

LogP


Performance

ManufactureStability

Formulation Selection Criteria

Performance:• Prediction of in vivo performance• Can the technology achieve required PK

performance?• Dose, dosage form, etc.

Stability• Chemical stability• Physical/performance

stability• Stability risk (ability to

model with accelerated studies)

Manufacturability• Scale-up considerations• Cost of goods• Required batch size

Formulation Feasibility

Formulation Dev.

In-Vitro Tests

Stability Mapping

Identify

CQA and CPP Relationship

Fix Formulation

Formulation and Process History

RISK ASSESSMENTS

Scale-up

ID Commercial

Process

Define Commercial Operating

Space

Scale-Up

Knowledge

Pro

cess C

on

trol

Strategy

Co

mp

ou

nd

P

rop

erti

es

Small Scale Experiments

Predictive Models

(Performance, Stability,

manufacturing)


Spray Dried Amorphous Dispersions

Simplified Product Development Flow Chart

Animal Studies Clinical Studies

- Formulation Optimization

- Dose

- Dosage Form

Late Stage Clinical

- Commercial Quantity

- Commercial Image

- Business Drivers

- Cost of Goods

- Filing Strategy

Pre-Clinical Phase 1/2A Phase 2B/3 Commercial

- Biomodel

- Lead Compound ID

- Physical form

- Process Validation

- Process Monitoring

- Process Verification

Commercial Readiness

Spray Drying at Lonza - Bend


Spray Dryer Scales

Solv

ent

Excipients API

SolventTank

SolutionTank

Process Heater

Condenser

Baghouse / Police Filter

System Gas Blower

Cyclone

ProductCollection

System Gas Blower

Feed Pump

DryingChamber

Atomizer

Secondary Dryer

Closed Loop / Recycle Equipment

0 1 2 3 40%

1%

2%

3%

4%

Drying Time [hours]

Wt%

So

lve

nt

SolventPolymer

Active

Solution TankSolvent Tank

Feed Pump

Cyclone BaghouseDrying

Chamber

Process Heater

Condenser

Product

Collection

System Gas

Blower

System Gas

Blower

Atomization

Drying Kinetics


Spray-Dried Dispersion Equipment and Process Schematic

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=g98hYbPgvs2ukM&tbnid=oP-B8A4dDu0g_M:&ved=0CAUQjRw&url=http://www.pro-sonix.com/boilerFeedWaterHeatingInfo.asp?article=AP-90+Boiler+Feedwater+Heater&aid=35&id=14&ei=0-77UbrlGuH5igKkuYFI&bvm=bv.50165853,d.cGE&psig=AFQjCNF5lmOFGibdC5pS321JVdkT2a9L4A&ust=1375551556392780

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=g98hYbPgvs2ukM&tbnid=oP-B8A4dDu0g_M:&ved=0CAUQjRw&url=http://www.pro-sonix.com/boilerFeedWaterHeatingInfo.asp?article=AP-90+Boiler+Feedwater+Heater&aid=35&id=14&ei=0-77UbrlGuH5igKkuYFI&bvm=bv.50165853,d.cGE&psig=AFQjCNF5lmOFGibdC5pS321JVdkT2a9L4A&ust=1375551556392780


A Spray dryer is a spray dryer……

Spray Dryer Scalability – Why is it important?

• Feasibility and formulation screening dryers often have limited operating space (Small particles and fast drying)

• Ideally the manufacturability assessment happens as close to discovery as practical and may be strongly coupled with the formulation selection process• Understanding limitations early can reduce scale-up surprises later• Custom equipment designed for feasibility to keep properties in same ball park of future

clinical/commercial expectations• Offline tools and models for scale-up for larger scale spray dryers


Spray-Dried Dispersion (SDD): Equipment Scale Range

Late Stage Clinical/CommercialProcess DevelopmentToxicology and Early-Phase Clinical Supplies

FormulationIdentification

Mini Spray Dryer25 mg → 1 g

Lab Spray Dryer(<35 kg drying gas/hr)

0.5 g → 100 g

Lab to Pilot Scale (“PSD-1” <150 kg drying gas/hr)

5 g → 5 kg

Pilot to Commercial (“PSD-2” < 750 kg drying gas/hr)

kgs → tons

Pilot to Commercial (NGD <200 kg drying gas/hr)

kgs → tons

Confidential | 28 August 2018

High On-timeSmall Footprint

Continuous Solution Prep

Case Study #1


Amorphous Itraconazole Formulations: Room

for Improvement?


Amorphous Itraconazole (ITZ) is well absorbed relative to

crystalline ITZ

Amorphous RFP – Sporanox® (HPMC SLD)

Amorphous Dispersion (Soluplus HME)

Nanocrystals

Bulk Crystals

Is there room at the top?

Zhang et al. Eur J Pharmaceutics Biopharmaceutics (2013) 85 (3), 1285-1292

Itraconazole pH 6.5 Solubility (µg/mL)

Buffer FaSSIF

Crystalline < 10-3 0.07

Amorphous < 1 7 - 10

100x Amorphous Enhancement


Dimensionless numbers can predict impact of solubility, permeability or dissolution rate in vivo

FaCS Ref: Sugano, K., et al., J Pharm Sci. (2015), 104, 2777-2788

Solubility-permeability limited

Τ𝑃𝑛 𝐷𝑜 < 𝐷𝑛 & 𝐷𝑜 > 1

𝑃𝑛 < 𝐷𝑛 & 𝐷𝑜 < 1

Permeability-limited

𝐷𝑛 < 𝑃𝑛/𝐷𝑜

Dissolution-limited

Amorphous Itraconazole

ItraconazoleBCS II basepKa = 3.7cLogP = 6.3


Can a “better” amorphous dispersion be made via formation of nanoparticles?

Room at the Top?

Itraconazole pH 6.5 Solubility (µg/mL)

Buffer FaSSIF

Crystalline < 10-3 0.07

Amorphous < 1 7 - 10

100x Amorphous Enhancement

Mucus layer diffusion α r-1

100 nm

5 nm

1 nm

Dissolved drug


Amorphous spray dried dispersions (SDDs) of Itraconazole(ITZ) dosed to rats

+ItraconazoleBCS II basepKa = 3.7cLogP = 6.3

OH

H

CH2OR

H

ORH

OR H

OH

H

H

ORH

OR

CH2OR

H

O

O

n

R= -H-CH3-COCH3

-COCH2CH2CO2H-CH2CH(OH)CH3

-CH2CHCH3

OCOCH3

-CH2CHCH3

OCOCH2CH2CO2H

Hydroxypropyl MethylcelluloseAcetate Succinate (HPMCAS)

Formulations dosed to ratsSprague-Dawley (n=6), fastedDose: 50 mg/kgDosing vehicle: 0.5% Methocel A4Min H2ODosing route: oral gavage

Stewart, A.M., et al. Mol Pharmaceutics (2017), 14 (7), 2437-2449

25% activeHydrophilic SDDAffinisol 716HP

25% activeHydrophobic SDDAffinisol 126HP

or


Material sparing in vitro membrane flux test can assess solubility-permeability limited absorption

Accurel PP 1E membrane (55% porous, 100 µm thickness)

50 µL lipid (20% phospholipid in dodecane)

Feed Volume: 5 mLReceiver Volume: 10 mL

SA: 4.9 cm2

SA/V = 1.0 cm-1


Hydrophilic SDD has the highest flux in vitro

Flux (µg/min/cm2) Colloid (µg/ml)

1.18 602

0.85 150

0.53 0

No. Formulation Dispersion polymer

1 25% ITZ/75% HPMCAS SDD AFFINISOL 716HP

2 25% ITZ/75% HPMCAS SDD AFFINISOL 126HP

3 Sporanox® spray layered dispersion HPMC


Hydrophilic SDD shows the fastest absorption in rats – rank orders with in vitro performance

Case Study #2


Spray Drying Poly(methyl methacrylate-co-

methacrylic acid), PMMAMA [Eudragit L and S]Dr. Kim Shepard


Enabling improved physical stability and higher loading amorphous formulations

Eudragit L100: A high Tg enteric polymer

Improved Physical Stability Higher Loading, Improved Performance


Enteric Polymers with different properties and applications

PMMAMA HPMCAS

Structure

Trade Name(s)Eudragit® L100, S100, L100-55 (Evonik

Industries)

Affinisol® 912, 716, 126 (DOW)AQOAT® HPMCAS-L, M, H (Shin Etsu)

AquaSolve™ (Ashland)

Tg (°C) 190 115 – 120

Acid Substitution (mmol/g) 4.2 – 5.6 0.7 – 1.5

MW (kg/mol) 125 50

Comparison of PMMAMA and HPMCAS

OH

H

CH2OR

H

ORH

OR H

OH

H

H

ORH

OR

CH2OR

H

O

O

n

R= -H-CH3-COCH3

-COCH2CH2CO2H-CH2CH(OH)CH3

-CH2CHCH3

OCOCH3

-CH2CHCH3

OCOCH2CH2CO2H


Strings form during spray drying using typical spray drying conditions, leading to poor flow and powder properties

Spray Drying Eudragit L100 Using “Standard Conditions”

Lefebvre model for atomization

Sheets Filaments Droplets

◼ High MW ◼ High Tg

◼ “Skinning” occurs at a lower concentration than typical spray drying polymers

λL = 5-10 µm


Two characteristic times govern string formation

Model-based parameters to control string formation

Droplet skinning time

Solution concentration

Drying gas temperature

Solvent Volatility

Solution Temperature

Recycle (% RS)

Droplet break-up time

Atomization pressure

Nozzle geometry

Solution viscosity

Experimental “Handles”

Strings form when tskinning < tbreakup

Droplet skinning time

Droplet break-up time


Inlet Temperature & Solids Concentration

Adjusting String Formulation Through Process Handles

31

Increasing inlet temperature (BLD: 125, 160, 195°C)

Increasing solution concentration (NGD: 5, 7, 9%wt)


Qualitative & Quantitative Approach to Process Design

Inlet temperatureSolution concentration

Solvent volatilityDrying gas flow rateRecycle (wet) drying gasAtomization pressure (pressure swirl)

Solution temperatureAtomization pressure (2-fluid)*

*Depends on dryer scale

Strong effect

Weakeffect

𝐷𝑆𝑃 =

𝑇𝑖𝑛𝑙𝑒𝑡−𝑇𝑏𝑜𝑖𝑙𝑇𝑏𝑜𝑖𝑙

𝐶𝑠𝑘𝑖𝑛−𝐶𝑠𝑜𝑙𝑛𝐶𝑠𝑘𝑖𝑛

1.25 ∆𝐻𝑣𝑎𝑝

540

.75

Tinlet is the inlet temperature of the drying gas, in °C Tboil is the boiling point of the solvent, in °CCskin is the concentration of the Eudragit L100 solution, in wt%, at which skinning occurs (~15% for most solvents)Csoln is the concentration of the feed solution, in wt%ΔHvap is the standard enthalpy of vaporization, in J/g. It is normalized by 540 to bring its order of magnitude close to 1 and standardize its contribution to the other terms in the equation.

Empirical Dimensionless Solvent Parameter (DSP) to guide process selection

33

Process Space for Eudragit L100 Spray Drying on a PSD-1

Constant parameters: PSD-1, Methanol, 1850 g/min gas, SK80-16 nozzle, 400psi, single-pass

34

Secondary drying Eudragit L100 SDDs at 40°C/15% RH

Problem: • Drying of solvents other than MeOH is

unacceptably slow

Solutions: • Hotter/wetter drying (if chemical

stability is acceptable)• Methanol-assisted secondary drying

Q & A


Thank You

Documents

Designing Amorphous Formulations and Manufacturing