UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE Monitoring and inhibiting phase separation of amorphous solid dispersions Dr Min Zhao [email protected] Department

UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE

Monitoring and inhibiting phase separation of amorphous solid dispersions

Dr Min [email protected]

Department of Pharmaceutics

UCL School of Pharmacy, UK

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Pharmaceutica 2015 Dubai 16th April 2015


Content

Rationale of amorphous solid dispersion used for poorly

water soluble drugs

Stability issues with amorphous solid dispersions

Analytical tools for monitoring phase separation

A promising approach to inhibiting moisture induced phase separation

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Poorly water soluble drugs

• More than 40% of newly discovered drugs have very low water solubility; • 90% of drugs approved since 1995 have bioavailability issues.

Source: Connors, R.D. and Elder, E.J. Solubilization Solutions, www.drugdeliverytech.com

• More than 40% of newly discovered drugs have very low water solubility; • 90% of drugs approved since 1995 have bioavailability issues.

Source: Connors, R.D. and Elder, E.J. Solubilization Solutions, www.drugdeliverytech.com

• For most pharmaceutical companies many drugs in the pipeline fall into Class II of the Biopharmaceutical Classification Systems (BCS).

• For most pharmaceutical companies many drugs in the pipeline fall into Class II of the Biopharmaceutical Classification Systems (BCS).

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Depending on the properties of the poorly soluble drugs different formulation strategies are applied

Carrier systems: Solid Dispersions• Complexation;• Liposomes• Emulsions• Cocrystals

Carrier systems: Solid Dispersions• Complexation;• Liposomes• Emulsions• Cocrystals

Alteration of solvent system: • pH adjustment• Co-solvent

Alteration of solvent system: • pH adjustment• Co-solvent

Chemical modification:• Pro drugs• Salt formation

Chemical modification:• Pro drugs• Salt formation

Physical modification:• Micronization• Nanosizing• Polymorph• Changing crystal habit

Physical modification:• Micronization• Nanosizing• Polymorph• Changing crystal habit

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Why amorphous solid dispersions?

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• Decrease in crystallinity – amorhous material has high solubility due to disordered structure

• Reduction of drug particle size to molecular level (increased surface area of the drug)

• Reduced or absence of aggregation and agglomeration due to the presence of polymer

• Improved wettability due to intiminate contact with hydrophilic polymers


老年痴呆治疗药Solvent --- Spray Drying

Melting/fusion---HME

Hot Melt Extruder Hot Melt Extruder Reference: Zhao et al. (2012) Eur. J. Pharm. Biopharm

Processing methods

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Content Rationale of amorphous solid dispersion used for poorly water

soluble drugs




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– Will recrystallise - amorphous materials undergo nucleation and growth

– Will relax – amorphous materials are very dynamic and will undergo relaxation towards equilibrium state

– Tendency to absorb water

Stability issues – amorphous solid dispersions

All may cause phase separation!!!


Content Rationale of amorphous solid dispersion used for poorly

water soluble drugs




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1) Acquiring the imaging -- Atomic Force Microscopy (AFM)

• Laser onto probe

• Reflection to photodetector

• Probe engaged on surface

• Closed feedback loop

• Probe deflection held at constant deflection

• Sample or probe adjusted

• Topographic/deflection information

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Corresponding AFM topography images

HPMC AS LF/API (70/30) strand granule Extrudate studied by SEM

How to determine what the phases are??? – Local Thermal Analysis (LTA)

Phase 1

Phase 2

Identifying phase separation of HME systems using AFM

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2) Heating the tip --- Localised Thermal Analysis (LTA)

• Image acquired with AFM

• Location selected on surface

• Probe being heated with voltage profile applied

• Onset of phase transition detected as probe penetration

Sample

Sample

Sample

Temperature

Mic

ro-T

MA

TemperatureM

icro

-TM

A

Temperature

Mic

ro-T

MA

De

riva

tive

Mic

ro-M

DT

AD

eriv

ativ

eM

icro

-MD

TA

De

riva

tive

Mic

ro-M

DT

A

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Better understanding separated phases using LTA

xx

xx

x

x

x

20 40 60 80 100 120 140 160 180

-2

-1

0

1

2

3

4

5

6

7

8

9

Defl

ectio

n (V

)

Temperature (oC)

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3) Mapping --- Transition Temperature Microscopy (TTM)

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API has a Tm at circa 150 ºC and Tg at 44.6 ºC; Polymer has a Tg at 120-125 ºC

Drug/Polymer dispersions

(Majority in Green: 90-110C)

Phase distribution studied by TTM

Crystal drug

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Content Rationale of amorphous solid dispersion used for poorly

water soluble drugs




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Aim of the study

• Aim: to investigate the stabilizing effect of “zein” on preventing moisture induced phase separation of amorphous dispersions prepared by spray drying.

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Zein:•major storage protein of corn •with a wide application in food industry and more recently in the pharmaceutical arena •a versatile excipient due to its low toxicity, sustainable production source and biodegradable nature•has been used to form hydrophobic coatings


• Binary system: Paracetamol + Plasdone.1% w/v total solids (30:70 w/w drug/polymer). Solvent: distilled water.

• Ternary system: Paracetamol + Plasdone + Zein.

1% w/v total solids (30:70:10 w/w drug/polymer/zein). Solvent 50:50 distilled water/ethanol.

Methods

Preparation:

Characterization:

• MTDSC (Modulated Temperature Differential Scanning Calorimetry)

• TGA (Thermogravimetric Analysis)

• DVS (Dynamic Vapour Sorption) coupled with Microscope18

Fully amorphous BUT sensitive to water!!!

Storage condistion:

• 25ºC/53%RH over 3 months


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DVS results

Binary

Ternary


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DVS microscope images over %RH scanning


TGA results over 3 months 21


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47.23°C(I)

78.66°C(I)

80.98°C(I)

0.00

0.02

0.04

0.06

0.08

0.10

Re

v H

ea

t F

low

(W

/g)

0 50 100 150 200

Temperature (°C)Exo Up Universal V4.5A TA Instruments

MTDSC results after 3 weeks

Binary system

Ternary system


Conclusions:

Characterisation of physical structure of amorphous solid dispersions, especially phase separation may require novel techniques such as AFM based LTA and TTM.

Zein may be a potential stabilizer for inhibiting moisture induced phase separation.

Characterisation of physical structure of amorphous solid dispersions, especially phase separation may require novel techniques such as AFM based LTA and TTM.

Zein may be a potential stabilizer for inhibiting moisture induced phase separation.

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Acknowledgements:

Dr Jonathan Moffat --- Oxford Instrument

Celia Orive

Surface Measurement Systems, UK

Shire Pharmaceuticals UK

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Documents

UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE Monitoring and inhibiting phase separation of amorphous solid dispersions Dr Min Zhao [email protected] Department