bioavailability enhancement utilizing spray drying technology · 2020. 6. 23. · intermediates...

Utilizing Spray Dried Dispersion Technology for Bioavailability EnhancementAaron Stewart | Senior ScientistAlyssa Ekdahl | Engineer

Webinar | Utilizing Spray Dried Dispersion Technology for Bioavailability Enhancement | 15 November 2018

2

Small molecule technologies

Feasibility Studies

ProductAnnuities

Drug Substance Intermediates

Drug substances Drug Product Intermediates

Drug Products

DesignSmall / Lab-Scale (non-GMP)

DevelopClinical Scale

ManufactureCommercial Scale

Flexible Model Across the Product Development Cycle


I. Introduction to bioavailability enhancement and spray drying fundamentals

II. Rationally selecting in vitro bioperformance tests to define rate limiting step to absorption

III. Case study (1) – Solubility-permeability limited absorption: Itraconazole

IV. Case study (2) – Dissolution rate limited absorption: belinostat

Agenda

3Webinar | Utilizing Spray Dried Dispersion Technology for Bioavailability Enhancement | 15 November 2018

Biopharmaceutical Classification System

2008;7:255–270

Approximately 80% of drugs in the pharmaceutical compounds pipeline exhibit low solubility and fall into the Biopharmaceutics Classification System (BCS) Class II or IV, according to a 2015 Market Study by Kline & Co.,1 with the majority of these compounds being Class II (poor solubility, high permeability).


5

Selecting the best for your specific molecule – API properties, dose, product conceptMany enabling technologies are available

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

• Polymorphs• Cocrystals• Salts

• Cosolvents• Surfactants• Cyclodextrins• Lipids:

• Oils• SEDDS/SMEDDS• Solid lipid pellets

AmorphousCrystal Form SolvationSize Reduction• Micronization• Sub-micron crystals (100 to

800 nm)• Nanocrystals (<100 nm)

• Solid dispersions• SDD• HME• Lyophiles• Drug/polymer

nanoparticles• Pure amorphous drug


INCR

EASI

NG

AQ

UEO

US

SOLU

BILI

TY

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


• Typical advantages for solid dispersions

• Broad applicability for diverse compound properties space

o Range of polymers and solvents for flexibility

o Fast quenching rates for kinetic stabilization of dispersion

• Well-tolerated at high dose for safety studies

• Applicable to many dosage form architectures

• Readily scalable

• Developing a solid dispersion formulation requires deep fundamental and technology experience

• Formulation strategies depending on rate-determining step for absorption

• Manufacturability to maintain stability, bioperformance and commercially relevant throughputs

Why spray dried solid dispersions?


Spray Drying Fundamentals


Spray dried dispersion process

SolventSo

lven

tExcipients API

SolventTank

SolutionTank

Process Heater Condenser

Filter

Cyclone

ProductCollection

Feed Pump

DryingChamber

Atomizer

Feed SolutionDroplet and Particle

FormationDownstream

Processing

Blending

Granulation

Compression

Dosage Form

Secondary Drying


10

Dryer equipment scale-up

Mini Spray Dryer25 mg → 1 g Lab Spray Dryer

BLD-350.5 g → 100 g

Pilot Scale BLD-150

50 g → 5 kgClinical and Commercial

PSD-2kg → tons

Pilot Scale and Clinical BLD-200 and NGD

50 g → 5 kg

< 35 kg/hr 75 - 150 kg/hr 75 - 200 kg/hr 450 - 750 kg/hrDrying Gas Flow Rates

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

Formulation IdentificationDiscovery


Development WorkSelect process conditions from operating spaceLab or pilot scale spray-drying

Define the Operating SpaceSDD Glass transition temperatureDryer scale process constraints Excipient maximum temperatureAtomization/droplet sizeThermodynamics Model

Transfer and Scale-UpInitial process defined and ready for further developmentClinical or commercial transfer Dryer scale-upIncorporate into a dosage form

Analyze Product PropertiesParticle size and morphologyBulk and tapped densityPowder flow and compressibilityPerformance and stability

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Designing a formulation and process

Define the FormulationAmorphous Solubility and Excipient Screening TestAPI Solubility ScreenSDD Stability Screen

Optimize Process and Product


Spray dried dispersion process

SolventSo

lven

tExcipients API

SolventTank

SolutionTank

Process Heater Condenser

Filter

Cyclone

ProductCollection

Feed Pump

DryingChamber

Atomizer

Feed SolutionDroplet and Particle

FormationDownstream

Processing

Blending

Granulation

Compression

Dosage Form

Secondary Drying


13

Atomization and droplet formation

Swirl Chamber

Film Formation

Droplet Breakup

Ligament Breakup

Swirl Insert

Orifice

Solution Feed RateNozzle Pressure

This image cannot currently be displayed.

Swirl Chamber

Film Formation

Droplet Breakup

Ligament Breakup

Swirl Insert

Orifice

Solution Feed RateNozzle PressureSwirl Insert

Orifice Insert

Nozzle Body / Cap

Swirl Channels

Self Cleaning Cone Face

Pressure Swirl Nozzle

I. Nozzle Operating Parameters• Nozzle Pressure• Solution Feed Rate

II. Solution Properties• Viscosity• Density• Surface Tension

III.Nozzle Geometry• Orifice Diameter• Swirl Channel Diameter• Number of Swirl Channels

𝐷𝐷 3,2 = 2.25𝜎𝜎0.25𝜇𝜇𝐿𝐿0.25�̇�𝑚𝐿𝐿0.25∆𝑃𝑃𝐿𝐿−0.5𝜌𝜌𝐴𝐴−0.25

Arthur Lefebvre, Atomization and Sprays (1989)

𝑀𝑀𝑀𝑀𝐷𝐷 = 2.47𝜎𝜎0.25𝜇𝜇𝐿𝐿0.16𝜇𝜇𝐺𝐺−0.04𝜌𝜌𝐿𝐿−0.22�̇�𝑚𝐿𝐿0.315∆𝑃𝑃𝐿𝐿−0.47 𝑙𝑙0

𝑑𝑑𝑜𝑜

0.03 𝐿𝐿𝑠𝑠𝐷𝐷𝑠𝑠

0.07 𝐴𝐴𝑠𝑠𝐷𝐷𝑠𝑠𝑑𝑑𝑜𝑜

−0.13 𝐷𝐷𝑠𝑠𝑑𝑑𝑜𝑜

0.21

Example Empirical Droplet Size Models:

Lefebvre:

Jones:

Nozzle Test Stand


14

Drying kinetics and thermodynamics

Solvent, Polymer and API

Solvent

Solvent

Solvent evaporates, concentrating the polymer

and API in the droplet

“Skinning” concentration ofthe polymer is exceeded at

the surface, forming a polymer shell at the viscous

gel point

Rest of solvent diffusesthrough film to evaporate,

leaving walled hollow particle

Droplet size determined by nozzle selection,

operating parameters and fluid properties

DropletFormation

Solvent Evaporation

FilmFormation

DriedParticle

Fast evaporation coupled with slow diffusion results in

higher concentration of solutes at the surface of

the droplet

Hollow SphereTparticle > Tboil

PparticleSolventVapor > PsprayDryer

Collapsed Hollow SphereTparticle < Tboil

PparticleSolventVapor < PsprayDryer


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Particle Attributes

• Particle morphology

• Particle wall thickness

• Particle size distribution

• Formulation

• Chemical stability

Downstream processing considerations

Bulk Powder Attributes

• Bulk and tapped density

• Powder flow

• Compressibility

• Tabletability

• Elasticity

Downstream Processing Risks

• Poor mixing/Segregation

• Poor die fill

• Content uniformity

• Friability/Chipping

• Strain Rate Sensitivity

• Pill burden/Tablet image

• Shelf life and packaging

Mean Particle Size (5-100µm)

Dryi

ng T

ime

A

B

C

DE

0

2

4

6

8

10

0.6 0.7 0.8 0.9 1.0

Tens

ile S

tren

gth

(MPa

)

Solid Fraction


16

SDD optimization for rational design of solid dosage formSpray dried dispersion and dosage form development

Powder Flow Bioperformance

Mechanical Properties

Physical State Stability

Chemical Stability

Throughput


Bioperformance In Vitro Test Selection Based On Rate-Limiting Step to Absorption


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In vitro & in silico tools can be used to assess the rate determining step(s) to absorption

HBD, HBA, PSAAcid/base/neutralpKa

LogP/LogDpH-solubilityTmProvisional BCS

ChemAxon Ltd

Basic property prediction

In vitro assessmentpH-solubilityLogP/LogDTm & TgMicelle partition coeff.Caco2 permeabilityPAMPA permeability

Dimensionless numbers/simple calculations

Dose NumberDissolution NumberPermeation Number

Simulations Plus, Inc.

Certera USA, Inc.

In silico modeling


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

𝐷𝐷𝐷𝐷 =�𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝑉𝑉𝐷𝐷𝑉𝑉

𝐶𝐶𝑠𝑠

Dose Number

𝑃𝑃𝑃𝑃 = 𝑘𝑘𝑎𝑎𝑎𝑎𝑠𝑠 � 𝑡𝑡𝑎𝑎𝑎𝑎𝑠𝑠

Permeation Number

Ref: Amidon, G.L., et al. Pharm Res. (1995), 12 (3), 413-420

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

Solubility-permeability limited

⁄𝑃𝑃𝑃𝑃 𝐷𝐷𝐷𝐷 < 𝐷𝐷𝑃𝑃 & 𝐷𝐷𝐷𝐷 > 1

𝑃𝑃𝑃𝑃 < 𝐷𝐷𝑃𝑃 & 𝐷𝐷𝐷𝐷 < 1

Permeability-limited

𝐷𝐷𝑃𝑃 = 𝑘𝑘𝑑𝑑𝑑𝑑𝑠𝑠𝑠𝑠 � 𝑡𝑡𝑎𝑎𝑎𝑎𝑠𝑠

Dissolution Number

𝐷𝐷𝑃𝑃 < 𝑃𝑃𝑃𝑃/𝐷𝐷𝐷𝐷

Dissolution-limited

BCS


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How do we select and design the appropriate formulation development tool?

Precipitation

Problem statement

Dissolution Rate Limited

Solubility-Permeability Limited

Formulation mechanism

Supersaturating formulations

pH driven supersaturation

Initial particle size

Dissolution rate changes over time

ABL limited

Epithelial limited

Predict in vivo problem statement

Select in vitro dissolution apparatus

Choose in vitro test parameters

In vitro toolkit

Controlled Transfer

Dissolution

Dissolution –permeation

Non-sinkpH shift

Sink single medium

Dissolution -permeation

SinkpH shift

Dissolution -permeation

Controlled Transfer

Dissolution

Non-sinkSingle medium

Non-sinksingle

medium

A/V, volume(s)

In vitro parameters

Fluid transfer rates

A/V,volume(s)Fluid

composition, volume

Fluid transfer rates

A/V,volume(s)

Fluid composition

Fluid composition,

volume

Physicochemical properties

API characterization

Existing in vitro/in vivo data

BCS/FaCS/MAD

Available data

Compound assessment


Case Study in Solubility-Permeability Limited Absorption- Understanding In Vivo Performance of Amorphous Dispersions of Itraconazole in Rats


22

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

+ItraconazoleBCS II basepKa = 3.7cLogP = 6.3

OH

H

CH2OR

H

ORH

OR HOH

HH

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

25% activeHydrophilic SDDAffinisol 716HP

25% activeHydrophobic SDDAffinisol 126HP

or

Stewart, A. M. et al. Impact of Drug-rich Colloids of Itraconazole and HPMCAS on Membrane Flux In Vitro and Oral Bioavailability in Rats. Mol. Pharm. (2017).

Key ITZ attributes:

• Itraconazole has exceedingly low aqueous solubility even in the amorphous state (ca. 0.1 µg/mL).

• High lipophilicity and neutral charge state at intestinal pH drives very low solubility but high lipid membrane permeability, resulting in aqueous boundary layer limited flux in vitro.


23



𝐶𝐶𝑠𝑠

Dose Number


Permeation Number








Dissolution Number


Dissolution-limited

BCS

ITZ SDDs in rats


24

Itraconazole is highly solubilized in micelles and colloids

25% ITZ:Affinisol 716 SDDpH 6.5, 27 mM bile salts

0

100

200

300

400

500

600

700

800

900

1000

~400 µg/ml

~580 µg/ml

Large undissolved

Solids (>10 µm)

Drug/Polymer Colloids (~200 nm)

Micelle-bound Drug

~20 µg/ml

Centrifugation

Unbound Drug~0.1 µg/ml


25

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

Stewart, A. M. et al. Development of a Biorelevant, Material-Sparing Membrane Flux Test for Rapid Screening of Bioavailability-Enhancing Drug Product Formulations. Mol. Pharm. (2017).

Resistances in series

• Dissolution limited

• ABL limited

• Membrane limited

Donor

Receiver

Membrane

Itraconazole = ABL Limited Flux


26

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

25% ITZ/75% HPMCAS SDD AFFINISOL 716HP

25% ITZ/75% HPMCAS SDD AFFINISOL 126HP

Sporanox® spray layered dispersion HPMC

All formulations have the same unbound (0.1 µg/mL) and micelle-bound (20 µg/mL) ITZ concentrations and only differ in the concentration of colloidal drug species. Difference in flux is driven by the nano-sized colloidal species.

0

100

200

300

400

500

600

700

800

9001000

0 30 60 90 120

Itrac

onaz

ole

App

aren

t C

once

ntra

tion

(µg/

ml)

Time (min)

Hydrophobic SDD

Hydrophilic SDD

Sporanox

Donor

0102030405060708090

100

0 30 60 90 120

Itrac

onaz

ole

Con

cent

ratio

n (µ

g/m

l)

Time (min)

Receiver


27

ABL limited diffusion in the membrane flux assay can by described by a steady state diffusion model

𝐷𝐷𝑒𝑒𝑒𝑒𝑒𝑒 = 𝐷𝐷𝑢𝑢 � 𝑓𝑓𝑢𝑢 + 𝐷𝐷𝑚𝑚 � 𝑓𝑓𝑚𝑚 + 𝐷𝐷𝑐𝑐 � 𝑓𝑓𝑐𝑐

Dc = 4 X 10-8 cm2/s(200 nm)

Dm = 1 X 10-6 cm2/s(7 nm)

Du = 5 X 10-6 cm2/s

Key assumptions• Psuedo-steady state• Du, Dm & Dc concentration independent• Drug that is unbound, micelle-bound, or in colloids

contribute to Deff based on size and abundance• Minimal transport due to convection• Well mixed solutions• Constant ABL thickness

Cu,m,c is the sum of all species:

𝑗𝑗 =𝐷𝐷𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝐴𝐴𝐴𝐴𝐿𝐿

𝑐𝑐𝑢𝑢,𝑚𝑚,𝑐𝑐

Hydrophobic SDDHydrophilic SDD

Sporanox

Model supports in vitromeasurements made in three different media: blank PBS buffer, 6.7 mM SIF, 27 mM SIF.

Dose for all flux measurements was 1000 µg/mL ITZ

0.0

0.5

1.0

1.5

0.0 0.5 1.0 1.5M

easu

red

Flux

(µg

min

-1cm

-2)

Calculated Flux (µg min-1 cm-2)


28

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

0

200

400

600

800

1000

1200

1400

0 20 40

Itrac

onaz

ole

Pla

sma

Con

cent

ratio

n (n

g/ m

l)

Time (h)

1

1.5

2

2.5

1 1.5 2 2.5

Rel

ativ

e M

ax. A

bs R

ate

In V

ivo

Relative Flux at 27 mM bile salts In Vitro

Hydrophilic SDD

Hydrophobic SDD

Sporanox

Absorption rate in vivo rank orders with in vitro

flux

Sporanox

Hydrophobic SDD

Hydrophilic SDD


29

Conclusions

• Identified unique drug speciation from ITZ:Affinisol SDDs compared to commercial formulation Sporanox

• Evaluated contributions of these species to in vitro flux based on ABL limited diffusion

• Described contributions of drug species mathematically

• Demonstrated the impact in vivo, showing absorption rate trends with in vitro flux.

Itraconazole Case Study


Dissolution Rate Limited Absorption -Mechanistic Understanding of Belinostat Oral Absorption in Beagle Dogs


31

Case study - SDDs of belinostat dosed to dogs

+Belinostat

BCS II/IV

pKa = ≥8 (acidic)

LogP < 2

HPMCAS (weakly acidic)25% activeHPMCAS-M SDD

Polyvinylpyrrolidone (neutral)

Polyvinylpyrrolidone Vinyl Acetate (neutral)

SDDs dosed to beagle dogs(n=4), fastedDose: 50 mgDosing vehicle: 0.5% MethocelA4M in H2O, 15 ml water rinse

25% activePVP K30 SDD

25% activePVP VA64 SDD

Key belinostat attributes:

• High amorphous solubility in biorelevant media (>500 µg/mL).

• Amorphous solubility is impacted by the presence of polymer.

• Dissolution rate is a key driver for absorption and differs depending on SDD formulation and testing method.

Stewart, A. et al. Mechanistic Study of Belinostat Oral Absorption from Spray Dried Dispersions. J. Pharm. Sci. (2018).


32

Belinostat apparent amorphous solubility depends upon dispersion polymer type

Belinostat

BCS II/IV

pKa = ≥8 (acidic)

LogP < 2

Ilevbare, G. A. & Taylor, L. S. Cryst. Growth Des. 13, 1497–1509 (2013).

Amorphous solubility is defined as the onset of amorphous liquid-liquid phase separation. Presence of polymer influences the LLPS concentration.

Blank Buffer (pH 2)6.7 mM SIF

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

Amor

phou

s Sol

ubili

ty (m

g/m

l)

Belinostat + HPMCAS-M

Belinostat+ PVP K30

Belinostat+ PVP VA64


33



𝐶𝐶𝑠𝑠

Dose Number


Permeation Number








Dissolution Number


Dissolution-limited

BCS

Belinostat SDDs in dogs


In vitro Gastric In vitro Intestinal In vitro Intestinal In vivo Gastric In vivo Intestinal

HPMCAS-M SDD 1.3 0.4 1.5 1.3 0.8

PVP K30 SDD 1.4 0.4 1.7 1.4 0.8

PVP VA64 SDD 3.3 1.0 4.0 3.3 2.0

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Evaluate belinostat dissolution performance using pH transfer test versus single medium test

Test design should be optimized towards the anticipated dose number and conditions in vivo.

Assumes:• Fasted state• 50 mL gastric volume• 50 mL intestinal volume

In vivo

pH 6.56.7 mM SIF

20 ml

Intestinal pH test(pH 6.5, 6.7 mM

SIF)

Gastric transfer test(pH 2 SGF 6.5, 6.7 mM SIF)

pH 2 SGF pH 6.56.7 mM SIF

AddConcentratedSIF solution att = 30 min

10 ml

20 ml

Dose/Volume/Solubility:

source: daviddarling.info

Non-sink Dose: 1000 µg/mL in SGF Non-sink Dose: 2000 µg/mL in SIF

In situ fiber optic detection


Relative extents of dissolution between SDDs depends upon dissolution medium composition

0.0

0.5

1.0

1.5

0 30 60 90Co

ncen

trat

ion

(mg/

mL)

Time (min)

0.0

0.5

1.0

1.5

0 30 60 90 120

Conc

entr

atio

n (m

g/m

l)

Time (min)

HPMCAS-M SDD

PVP K30 SDD

PVP VA64 SDD

HPMCAS-M SDD

PVP K30 SDD

PVP VA64 SDD

Intestinal pH test (pH 6.5, 7 mM SIF)M SDD > K30 SDD > VA64 SDD

Gastric transfer (pH 2 SGF 6.5, 7 mM SIF)K30 SDD > M SDD ≈ VA64 SDD

Dashed lines represent the apparent amorphous solubility measured in SGF and SIF from the amorphous solubility assay (slide 30)

Dose: 1000 µg/mL (SGF), 500 µg/mL (SIF) Dose: 2000 µg/mL


36

Gastric → intestinal transfer test better rank orders SDDs with respect to in vivo performance in dogs

Sequential exposure to SGF and SIF at a more relevant dose/volume/solubility (dose number) is a better indicator for rank-ordering in vivo exposure from each SDD.

0.0

0.5

1.0

1.5

0.0 0.5 1.0 1.5

In v

ivo

AUC

rela

tive

to P

VP K

30 S

DD

In vitro AUC relative to PVP K30 SDD

PVP VA64 SDD

HPMCAS-M SDD

PVP K30SDD

0.0

0.5

1.0

1.5

0.0 0.5 1.0 1.5

In v

ivo

AUC

rela

tive

to P

VP K

30 S

DD

In vitro AUC relative to PVP K30 SDD

PVP VA64 SDD

HPMCAS-M SDD

PVP K30 SDD

Gastric transfer (pH 2 pH 6.5, 7 mM SIF) Intestinal pH test (pH 6.5, 7 mM SIF)


37

Using amorphous solubility and dissolution data as key inputs to absorption model supports hypothesis of dissolution rate limited absorption Amorphous solubility Dissolution rate/extent

In vitro inputs to model

In silico predictions


38

Conclusions

• Amorphous solubility of belinostat depends on polymer type.

• SGF/SIF transfer test a better indicator of in vivo performance.

• Used in vitro inputs to describe blood plasma profiles via absorption modeling.

• Rate-determining step to absorption: dissolution rate and extent achieved in the stomach prior to transit down the GI tract.

Belinostat Case Study


39

• Amorphous spray dried dispersions are a widely applicable platform for bioavailability enhancement

• Solubility/dissolution rate over crystalline drug

• Scalability: from small scale feasibility to commercial scale

• Amenable to many dosage form architectures

• Physical stability of amorphous form

• Problem statement driven bioperformance studies and models elucidated the mechanism of action of SDDs of two compounds

• Itraconazole: solubility-permeability limited absorption

• Belinostat: dissolution rate limited absorption

Conclusions


40

Lonza: Dosage Form and Delivery Services• Dr. Michael Grass

• Timothy Brodeur

• Ian Yates

Lonza: Drug Product Development and Innovation• Dr. Deanna Mudie

• Dr. Michael Morgen

• John Baumann

• Dr. Aaron Goodwin (Current: Astex Pharmaceuticals)

• Dr. Dwayne Friesen

• Dr. David Vodak

Acknowledgements


41

Thank Youcontact: [email protected]


bioavailability enhancement utilizing spray drying technology · 2020. 6. 23. · intermediates...

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