UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE Monitoring and inhibiting phase separation of amorphous...
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Transcript of UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE Monitoring and inhibiting phase separation of amorphous...
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
UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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
UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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
7
UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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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!!!
UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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
9
UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
3) Mapping --- Transition Temperature Microscopy (TTM)
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UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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
16
UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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
UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
• 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
UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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DVS results
Binary
Ternary
UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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DVS microscope images over %RH scanning
UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
TGA results over 3 months 21
UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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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
UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACYBRUNSWICK SQUARE
Acknowledgements:
Dr Jonathan Moffat --- Oxford Instrument
Celia Orive
Surface Measurement Systems, UK
Shire Pharmaceuticals UK
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