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

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

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

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

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

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

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

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

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

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

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

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

Better understanding separated phases using LTA x 13

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

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

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

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

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

DVS results Binary Ternary 19

DVS microscope images over %RH scanning 20

TGA results over 3 months 21

MTDSC results after 3 weeks Binary system Ternary system 22

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

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