Monitoring and inhibiting phase separation of amorphous solid dispersions

1. Pharmaceutica 2015 Dubai 16th April 2015 Monitoring and inhibiting phase separation of amorphous solid dispersions Dr Min Zhao Min.zhao@ucl.ac.uk 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, www.drugdeliverytech.com • 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 strategiesare 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. Processing methods Melting/fusion---HME Solvent --- Spray Drying 老年痴呆治疗药 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 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 10

11. Identifying phase separation of HME systems using AFM Phase 2 Phase 1 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. DerivativeMicro-MDTA Micro-TMA Sample Temperature DerivativeMicro-MDTA Micro-TMA Sample Temperature Sample DerivativeMicro-MDTA Micro-TMA Temperature 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 12

13. Better understanding separated phases using LTA x x x x x x x 13

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

15. Phase distribution studied by TTM Crystal drug Drug/Polymer dispersions (Majority in Green: 90-110C) API has a Tm at circa 150 ºC and Tg at 44.6 ºC; Polymer has a Tg at 120-125 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 17

18. Methods Preparation: 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 scanning 20

21. TGA results over 3 months 21

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