UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE Pharmaceutica 2015

UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE Pharmaceutica 2015 Dubai 16th April 2015 Monitoring and inhibiting phase separation of amorphous solid dispersions Dr Min Zhao [email protected] Department of Pharmaceutics UCL School of Pharmacy, UK 1 UCL SCHOOL OF PHARMACY BRUNSWICK 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 2 UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE Poorly water soluble drugs More than 40% of newly discovered drugs have very low water solubility; More than 40% of newly discovered drugs have very low water solubility; 90% of drugs approved since 1995 have bioavailability issues. 90% of drugs approved since 1995 have bioavailability issues. Source: Connors, R.D. and Elder, E.J. Solubilization Solutions, www.drugdeliverytech.com 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 For most pharmaceutical companies many drugs in the pipeline fall into Class II of

the Biopharmaceutical Classification Systems (BCS). the Biopharmaceutical Classification Systems (BCS). 3 UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE Depending on the properties of the poorly soluble drugs different formulation strategies are applied Chemical modification: Chemical modification: Alteration of solvent Alteration of solvent system: system: pH adjustment pH adjustment Co-solvent

Co-solvent Pro drugs Pro drugs Salt formation Salt formation Carrier Carriersystems: systems: Solid Dispersions Solid Dispersions Complexation; Complexation; Liposomes Liposomes Emulsions Emulsions Cocrystals

Cocrystals Physical modification: Physical modification: Micronization Micronization Nanosizing Nanosizing Polymorph Polymorph Changing crystal habit Changing crystal habit 4 UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE 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 UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE Processing methods Melting/fusion---HME Solvent --- Spray Drying

Reference: Zhao et al. (2012) Eur. J. Pharm. Biopharm Hot Melt Extruder Hot Melt Extruder 6 UCL SCHOOL OF PHARMACY BRUNSWICK 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 PHARMACY BRUNSWICK SQUARE

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 UCL SCHOOL OF PHARMACY BRUNSWICK 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 PHARMACY BRUNSWICK 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 10

UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE 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 UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE 2) Heating the tip --- Localised Thermal Analysis (LTA)

Micro-TMA Derivative Micro-MDTA Sample Temperature Micro-TMA Derivative Micro-MDTA Sample Micro-TMA Temperature

Temperature Derivative Micro-MDTA Image acquired with AFM Location selected on surface Probe being heated with voltage profile applied Onset of phase transition detected as probe penetration Sample 12 UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE

x x x x x x x Deflection (V) Better understanding separated phases using LTA 9 8

7 6 5 4 3 2 1 0 -1 -2 20 40 60 80 100 120 140 160 180 o Temperature ( C)

13 UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE 3) Mapping --- Transition Temperature Microscopy (TTM) 14 UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE Phase distribution studied by TTM Crystal drug Drug/Polymer dispersions (Majority in Green: 90-110C)

API has a Tm at circa 150 C and Tg at 44.6 C; Polymer has a Tg at 120-125 C 15 UCL SCHOOL OF PHARMACY BRUNSWICK 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 PHARMACY BRUNSWICK 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. 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 UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE Methods Preparation: Binary system: Paracetamol + Plasdone.

Fully amorphous BUT sensitive to water!!! 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: 25C/53%RH over 3 months Characterization: MTDSC (Modulated Temperature Differential Scanning Calorimetry) TGA (Thermogravimetric Analysis) DVS (Dynamic Vapour Sorption) coupled with Microscope 18 UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE

DVS results Binary Ternary 19 UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE DVS microscope images over %RH scanning 20 UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE TGA results over 3 months 21

UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE MTDSC results after 3 weeks 0.10 0.08 Rev Heat Flow (W/g) 47.23C(I) 78.66C(I) 0.06 Binary system 80.98C(I) 0.04

Ternary system 0.02 0.00 Exo Up 0 50 100 Temperature (C) 150 200 Universal V4.5A TA Instruments

22 UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE Conclusions: Characterisation of physical structure of amorphous solid Characterisation of physical structure of amorphous solid dispersions, dispersions, especially especially phase phase separation separation may may require require novel novel techniques techniquessuch

suchas asAFM AFMbased basedLTA LTAand andTTM. TTM. Zein Zein may may be be aa potential potential stabilizer stabilizer for for inhibiting inhibiting moisture moisture induced inducedphase phaseseparation.

separation. 23 UCL SCHOOL OF PHARMACY BRUNSWICK SQUARE Acknowledgements: Dr Jonathan Moffat --- Oxford Instrument Celia Orive Surface Measurement Systems, UK Shire Pharmaceuticals UK 24

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