1. Pharmaceutica 2015 Dubai 16th April 2015
Monitoring and inhibiting phase separation of amorphous solid dispersions
Dr Min Zhao
Department of Pharmaceutics
UCL School of Pharmacy, UK 1

2. 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 2

3. 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,
For most pharmaceutical companies many drugs in the pipeline fall into Class II of the Biopharmaceutical Classification Systems (BCS). 3

4. Depending on the properties of the poorly soluble drugs different formulation strategies are applied
Chemical modification:
Pro drugs
Salt formation
Alteration of solvent system:
pH adjustment
Co-solvent
Carrier systems:
Solid Dispersions
Complexation;
Liposomes
Emulsions
Cocrystals
Physical modification:
Micronization
Nanosizing
Polymorph
Changing crystal habit 4

5. Why amorphous solid dispersions?
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 5

6. Melting/fusion---HME Solvent --- Spray Drying
Processing methods
Melting/fusion---HME
Solvent --- Spray Drying
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Scheme of a hme
Reference: Zhao et al. (2012) Eur. J. Pharm. Biopharm
Hot Melt Extruder 6

7. 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

8. Stability issues – amorphous solid dispersions
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
Rate dependent upon temperature, degree of plasticisation
All may cause phase separation!!! 8

9. 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

10. 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
used to characterize surfaces at extremely high resolution 10

11. Identifying phase separation of HME systems using AFM
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) 11

12. 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
Temperature
Micro-TMA
Derivative Micro-MDTA 12

13. Better understanding separated phases using LTAx 13

14. 3) Mapping --- Transition Temperature Microscopy (TTM)14

15. Phase distribution studied by TTM
Crystal drug
Drug/Polymer dispersions
(Majority in Green: C)
API has a Tm at circa 150 ºC and Tg at 44.6 ºC; Polymer has a Tg at ºC 15

16. 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

17. 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.
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
The binary system is composed of molecular dispersions of paracetamol via co-spray drying with a hydrophilic polymer, as Plasdone. The big issue with this system is that it is quite sensitive to water. In order to solve this problem, the addition of “zein” in the system is going to be studied. 17

18. Methods Preparation: Storage condistion: Characterization:
Fully amorphous
BUT sensitive to water!!!
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.
Storage condistion:
25ºC/53%RH over 3 months
Characterization:
MTDSC (Modulated Temperature Differential Scanning Calorimetry)
TGA (Thermogravimetric Analysis)
DVS (Dynamic Vapour Sorption) coupled with Microscope 18

19. DVS results
Binary
Ternary 19

20. DVS microscope images over %RH scanning20

21. TGA results over 3 months21

22. MTDSC results after 3 weeks
Binary system
Ternary system 22

23. 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. 23

24. Acknowledgements: Dr Jonathan Moffat --- Oxford Instrument Celia Orive
Surface Measurement Systems, UK
Shire Pharmaceuticals UK 24