Deconvoluting Amorphous Solid Dispersion Dissolution

Jonathan Booth

Formulation Science SectionAstraZenecaMacclesfield

PhysChem Forum 11 MeetingNottingham, September 21st

2011

Whats the Problem?

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Freq

uenc

y

logS (predicted using ALOGPS software)

~ 1300 marketed drugs

~ 40 % poorly soluble (logS < -4)

Solid Dispersions

Intimate mixture of drug and water soluble/swellable excipient(s) - usually amorphous polymers. Surfactants/plastisers may be added

Amorphous solid dispersions/solutions provide most potential for bioavailability enhancement due to solubility advantage of amorphous state

Commonly used polymers are PVP-based, Celluloses and Methacrylates

Key risks and challenges:

Amorphous SDs are normally thermodynamically unstable at practical drug loads –recrystallisation of amorphous drug generally reduces bioavailability

Analytical testing

Detecting low levels of crystallinity, etc

Poor biopharm. understanding

Sub-optimal dissolution methods and models

Dissolution Testing

A tool for performance verification and understandingBioavailability of oral dosage forms is dependant on release and solubilisation of drug, as only drug in solution can be absorbed

For drugs with poor solubility dissolution is likely to be a rate limiting step in drug absorption

Dissolution can therefore serve an indicator of product performance

dispersed drug

particles

solubilised drug

absorbeddrug

kdd

kid

kprecip kp

disintegration precipitation permeability

dissolution

Solid Dispersion Dissolution Wetting

Addition of hydrophilic carriers increases wettability of hydrophobic drugs leading to an improvement in dissolution performance

Karavas, E et al; Eur.J.Pharm.Biopharm. 2006, 63, 103-114.

θ

Example: Ketoconazole/PVP

Solid Dispersion DissolutionCarrier vs Drug Control

DRUG-CONTROLLEDCARRIER-CONTROLLED

Craig, D.Q.M. Int.J.Pharm. 2002, 231, 131-144

Drug

Solid Dispersion Dissolution Carrier vs Drug Control

For carrier-controlled systems the dissolution profiles of the drug and carrier are identical

Example: Mixtures of a poorly soluble drug and water soluble polymer

Physical mix

DRUG-CONTROLLED DISSOLUTION

Extruded amorphous solid solution

CARRIER-CONTROLLED DISSOLUTION

polymerdrug

polymerdrug

Solid Dispersion Dissolution Solubility Advantage of the Amorphous State

ΔGΔHTm

crystalline

amorphous

Scrystal

Samorphous

Solid Dispersion Dissolution Particle Formation

Solid dispersions typically yield (nano/micro) particles on dissolution

Particles can be pre-formed or precipitate during dissolution under super-saturated conditions formed within/adjacent to the dissolving matrix or in bulk solution

Particles may grow due to aggregation, ripening and crystal growth,or dissolve if the solution is under-saturated with respect to the solubility of the solid

Karavas, E et al. Eur. J. Pharm. Biopharm. 2007, 66, 334-347.

Example: Felodipine/PVP (90/10 w/w) : Dissolution in pH 6.5 / 2% Tween20 (37oC)

Solid Dispersion Dissolution Nucleation & Crystal Growth

[ ]20b

2

)/Sln(Ck

1 ekJ−

=J = Nucleation rate

(# supercritical nucleii / volume)k1, k2, = constantsCb = Monomer bulk concentrationS0 = Crystalline solubility

)(DV0

mbCS

RdtdR −

+=

λ -

dR/dt = Growth rateS0 = Crystalline solubilityD = Monomer diffusion coefficient Vm = Molar volumeλ = DVm/Ki withKi = Surface integration constant

Solid Dispersion DissolutionSolution Metastability

The amorphous state of the drug provides the spring. Suitable “inhibitor(s)” in the formulation act as a parachute to maintain super-saturation.

Brouwers, J et al; J. Pharm. Sci. 2009, 98 (8), 2549-2572.

Solid Dispersion Dissolution Solution Metastability

Excipient 1

Excipient 2

Excipient 3

Excipient 4

Excipient 5

Ability of excipients to maintain drug super-saturation : Excipient 5 ~4 > 3 > 2~1

Example: impact of various excipients on the precipitation of a poorly soluble drug

Spike 1

Spike 2Spike 3

Solid Dispersion Dissolution Solubilisation & Complexation

In solution solid dispersion carriers can solubilise / complex the drug substance – this can have an impact of dissolution performance. Interaction between drug and carrier can be assessed via the binding constant (K)

)1(01:1 SlopeS

SlopeK−

=

Slope

Balata, G et al; Asian Journal of Pharmaceutical Sciences 2010, 5(1), 1-12

Example: Ketoconazole/PVP

S0 = Crystalline solubility

Case StudyMaterials & Methods

N

O

O

O

O

Cl

Cl

CH

CH2N O

CH

CH2 O O

CH3 n

m

FelodipinePoorly soluble:BCS II compoundsS0 ~ 1ug/ml

Copovidone (VA64)Water soluble polymerMw ~ 30kDa

Small-scale fibre optic dissolutionSpray drier

Press MRI/ UV flow cell

Case StudyCharacterisation of Solid Dispersions

Spray dried solid dispersions of Felodipine and Copovidone are amorphous

2 theta (degrees)

Inte

nsity

(Cou

nts)

Case Study Dissolution of Pure Amorphous Felodipine

Dissolution of amorphous Felodipine only reaches theoretical amorphous solubility in the presence of a crystallisation inhibitor (Copovidone in this case) – acting as a “parachute”

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Felo

dipi

ne C

once

ntra

tion

(ug/

mL)

Time/ sec

Crystalline Felodipine - Mean

Amorphous Felodipine - Mean

Amorphous Felodipine + 2% Copovidone in media - Mean

Samorphous predicted

pH 6.537oC[Felodipine] total = 100ug/ml

Case StudyDissolution of Spray Dried Powder

Dissolution is very rapid especially at high polymer/drug - (transient) concentrations significantly greater than amorphous solubility can be achieved

Need greater than 50% w/w polymer (dry state )to achieve solution metastability for this system –corresponding to ratio of solution concentrations [polymer]/[drug] of 10 – 20 at the maxima (plateau) of the dissolution profiles for the 70, 85 and 95% w/w polymer formulations

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Polymer Content (% w/w)

Predicted amorphous solubility

5% Felodipine

15% Felodipine

30% Felodipine

50% Felodipine pH 6.537oC[Felodipine] total = 100ug/ml

Case StudyDissolution of Compacts

Dissolution of the compacts is relatively slow (compared to the corresponding powders)

Only reach theoretical amorphous solubility for the 5% Felodipine/95% Copovidone formulation

50% Felodipine formulation dissolution performance is comparable with a physical mix of crystalline drug and polymer

5% Felodipine

15% Felodipine

50% Felodipine

pH 6.537oC[Felodipine] total = 50 - 500ug/ml

Case StudyPowder vs Compact Dissolution Maximum Felodipine solution concentration is significantly lower for the compacts compared to the corresponding powders pointing to a difference in dissolution mechanism

Attribute high extent (and rapid) dissolution of Felodipine from powdered solid dispersion to rapid water uptake and dispersal of highly porous/ high surface area matrix – driven by conditions of relatively high convection

Attribute low extent (and slow) dissolution to lower porosity/surface area, slower water uptake and precipitation/crystallisation of Felodipineat/near the dissolving interface – driven by conditions of relatively low convection

Highlights the importance of compaction (and convection) on dissolution performance

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Fel

odip

ine

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cent

ratio

n (u

g/m

l)Felodipine Loading (% w/w)

Powder

Compact

Case StudyMRI Studies of Compact Dissolution

Fel-Copov MRI Sequences

• 5% (and 15%) Felodipine formulation steadily erodes erodes and dissolution proceeds to completion – 50% Felodipineformulation swells and remains intact

5 and 15% Felodipine formulations erode at the same rate (carrier-control) whereas the 50% formulation swells (drug-control)

Case StudyMRI Studies of Compact Dissolution

5% Felodipine / 15% Felodipine 50% Felodipine

long

long

short

short

Case Study Impact of Nucleation and Crystal Growth

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cent

ratio

n (u

g/m

l)

Time (h)

Measured solution concentrationTheoretical released due to erosion

Precipitated Drug

5% Felodipine/ 95% Copovidone

Case StudyProposed Dissolution Model for Compacts

D = k ([Fel] – SamFel)

G = G0 ([Fel]/ScrystFel – 1)

daminit, xam

dcrystinit, 1-xam

Case StudyProposed Dissolution Model for Compacts

Good fits of data from 5 and 15% formulations to model without need to include nucleation

5% Felodipine 15% Felodipine

xam 0.5 0.11

daminit 165nm 600nm

dcrystinit 165nm 600nm

0.0225 mm/min (MRI)

daminit, xam

dcrystinit, 1-xam

R2 = 0.99

R2 = 0.97

5% Felodipine/ 95% Copovidone

15% Felodipine/ 85% Copovidone

Case Study Summary & Conclusions

Dissolution behaviour of Felodipine from amorphous solid dispersions with Copovidone shows a strong dependence on drug/polymer ratio

Dissolution of spray dried solid dispersion powders is rapid and concentrations significantly in excess of the predicted/measured amorphous solubility were observed – especially in formulations with high polymer levels

Dissolution of Felodipine from compacted spray dried solid dispersions is much slower than from the corresponding uncompacted powders and for the 5 and 15% Felodipine formulations proceeds by linear erosion with identical rates –suggesting carrier control. At higher drug loadings the system becomes dominated by the drug and the system swells rather than erodes. Even at 5% drug load the effects of precipitation are significant

A dissolution model based on measured and fitted parameters was developed to accurately describe the observed dissolution profiles – key feature is the formation/release of amorphous and crystalline particles to act as a generator and sink for dissolved Felodipine

Future Work

Further validation/development of the dissolution model

Move towards more biorelevant media and hydrodynamics

Test further drug/carrier systems to study the impact of material properties on dissolution mechanism

Study the impact of different processing methods on dissolution mechanism and performance of solid dispersions

Acknowledgements

Felodipine Case Study Other Data/Slides

Zoe Langham Stephen Bush

Les Hughes Lennart Lindfors

Gavin Reynolds Kasia Nurzynska

Stephen Wren Ben Read

Kevin Treacher