Quality of Coated Particles: Physical - Mechanical Characterization of Polymeric Film Coatings

(1)

Quality of Coated Particles

Physical - Mechanical Characterization

of Polymeric Film Coatings

Proefschrift

ter verkrijging van de graad van doctor

aan de Technische Universiteit Delft

op gezag van de Rector Magnificus,

Prof. ir. K.C.A.M. Luyben,

voorzitter van het College voor Promoties,

in het openbaar te verdedigen op

maandag 26 maart 2012 om 12.30 uur

door

Giacomo PERFETTI

Laurea Magistrale in Ingegneria Meccanica

Università Politecnica delle Marche

(2)

Dit proefschrift is goedgekeurd door de promotor:

Prof.dr. A. Schmidt-Ott

Copromotor: Dr.ir. G.M.H. Meesters

Samenstelling promotiecomissie:

Rector Magnificus

Voorzitter

Prof.dr. A. Schmidt-Ott Technische Universiteit Delft, promotor

Dr.ir. G.M.H. Meesters Technische Universiteit Delft

copromotor

Prof.dr. G-J Witkamp Technische Universiteit Delft

Prof.dr.ir. D. Poncelet Universiteit Nantes, Frankrijk

Prof.dr.ir. M.T. Kreutzer Technische Universiteit Delft

Dr.ir. P. van Hee

DSM

Dr.ir. F. Depypere

Barry Callebaut, België

Prof.dr.ir. S.J. Picken Technische Universiteit Delft, reserve

Copyright © 2011 by Giacomo Perfetti

Cover design by Giacomo Perfetti

ISBN 978 90 8666 251 7

All rights reserved. Parts of this thesis are published in scientific

journals and copyright is subject to different terms and

conditions.

(3)

Quality of Coated Particles

Physical - Mechanical Characterization

of Polymeric Film Coatings

Thesis

presented for the degree of doctor

at Delft University of Technology

under authority of the Vice-Chancellor,

Prof. ir. K.C.A.M. Luyben,

Chairman of the Board of Doctorates,

to be defended in public in the presence of a committee

on

monday 26 march 2012 at 12.30 o’clock

by

Giacomo PERFETTI

Degree in Mechanical Engineering

Università Politecnica delle Marche

(4)

This thesis is approved by the promotor:

Prof.dr. A. Schmidt-Ott

Copromotor: Dr.ir. G.M.H. Meesters

Composition of Examination Committee:

Rector Magnificus

Chairman

Prof.dr. A. Schmidt-Ott Delft University of Technology,

promotor

Dr.ir. G.M.H. Meesters Delft University of Technology

copromotor

Prof.dr. G-J Witkamp

Delft University of Technology

Prof.dr.ir. D. Poncelet Nantes University, France

Prof.dr.ir. M.T. Kreutzer Delft University of Technology

Dr.ir. P. van Hee

DSM

Dr.ir. F. Depypere

Barry Callebaut, Belgium

Prof.dr.ir. S.J. Picken Delft University of Technology, reserve

Copyright © 2010 by Giacomo Perfetti

Cover design by Giacomo Perfetti

ISBN 978 90 8666 251 7

All rights reserved. Parts of this thesis are published in scientific

journals and copyright is subject to different terms and

conditions.

(5)

(6)

ad Alessio

mi manchi cosi tanto…

I believe in you and me I’m coming to find you If it takes me all night Wrong until you make it right And I won’t forget you At least I’ll try And run, and run tonight Everything will be alright Everything will be alright …

(7)

(8)

1

Thermo-physical characterization of film formers Pharmacoat®_603,

Pharmacoat®_{615 and Mowiol}®_4-98 ₇

1.1 Introduction 7

1.2 Materials and Methods 8

1.2.1 Polymer film formers 8

1.2.2 X-Ray Diffraction, XRD 9

1.2.3 Thermogravimetry, TG 9

1.2.4 Dynamic Vapour Sorption Analysis 10

1.2.5 Differential Scanning Calorimetry, DSC 13

1.3 Results and Discussion 13

1.3.1 X-Ray Diffraction, XRD 14

1.3.2 Thermogravimetry, TG 14

1.3.3 Dynamic Vapour Sorption Analysis 15

1.3.4 Differential Scanning Calorimetry, DSC 23

1.3.4.1 Water content effect 23

1.4 Conclusions 26

1.5 References 27

2

Characterization of physical and viscoelastic properties of polymer films for coating applications under different temperature of drying and

storage 30

2.1 Introduction 31

2.2.1 Materials 32

2.2.2 Preparation of solutions 34

2.2.3 Viscosity of solutions 34

2.2.4 Film casting and sample preparation 35

2.2.5 Scanning electron microscopy, SEM 36

2.2.6 Thermo gravimetric analysis, TGA 36

2.2.7 Viscoelastic characterization: dynamic mechanical

thermal analysis, DMTA 37

(9)

2.3.1 Rheological characterization of solutions 38

2.3.2 Cast films 42

2.3.2.1 Effect of drying temperature: Morphological

characterization 42

2.3.2.2 Effect of drying temperature: mechanical

characterization 44

2.3.2.3 Effect of storage temperature: Morphological

characterization 49

2.3.2.4 Effect of storage temperature: mechanical

characterization 50

2.4 Conclusion 54

2.5 References 55

3

Investigation on resistance to attrition of coated particles by response

surface methodology 58

3.1 Introduction 59

3.2.1 Materials 62

3.2.2 Preparation of Solutions 62

3.2.3 Fluid Bed Coater and process variables 62

3.2.4 Repeated Impact Tester RIT 64

3.2.5 Experimental design 66

3.3 Results and discussion 68

3.3.1 Statistical analysis 68

3.3.2 Response surface 72

3.4 Conclusions 73

3.5 References 74

4

Influence of handling and storage conditions on morphological and mechanical properties of polymer-coated particles: characterization and

modelling 77

4.1 Introduction 78

4.2 Repeated Impact Testing 80

4.3.1 Materials 83

4.3.3 Particle coating 84

4.3.4 Scanning Electron Microscopy, SEM 84

4.3.5 Thermo Gravimetric Analysis, TGA 85

4.3.6 Repeated Impact Test, RIT 86

4.3.7 Accelerated Aging 86

(10)

4.4.1 Morphological characterization 87

4.4.2 Resistance to attrition 90

4.4.2.1 Thickness effect 90

4.4.2.2 Storage temperature effect 93

4.4.2.3 “Physical” Aging effect 96

4.5 Conclusion 104

4.6 References 105

5

Repeated impacts tests and nano-indentation as complementary tools for mechanical characterization of polymer-coated particle

109

5.1 Introduction 110

5.2 Repeated Impact Testing, RIT 111

5.3 Nano-indentation 117

5.4.1 Materials 116

5.4.2 Coating Procedure 116

5.4.2.1 Preparation of Solutions 116

5.4.2.2 Particle coating 117

5.4.4 Atomic Force Microcopy, AFM 118

5.4.6 Repeated Impact Test, RIT 119

5.4.7 Nano-indentation 120

5.4.7.1 Sample Preparation 120

5.4.7.2 Indentation Procedure 120

5.5.1 Morphological Characterization 121

5.5.3 Mechanical Characterization Using Repeated Impact

Testing 124

5.5.4 Mechanical Characterization Using

Nano-indentation 127

5.5.5 Comparison of RIT and nano-indentation 134

5.6 Conclusions 135

5.7 References 136

6

X-Ray micro tomography and image analysis as complementary methods for morphological characterization and coating thickness

measurement of coated particles 138

(11)

6.2.1 Materials 140 6.2.2 Preparation of Solutions and Particle Coating

141

6.2.4 X-Ray Micro Tomography 141

6.2.5 Coating thickness 143

6.2.5.1 Theoretical Experimental Thickness 144

6.2.5.2 Image Analysis Approach:

CT analyser 144

6.2.5.3 Matlab and DIPimage 146

6.2.6 Structural and morphological parameters of coating

shell 147

6.3.1 X-Ray Tomography 148

6.3.1.1 Reconstructed 2D images 148

6.3.1.2 Segmented-out 2D coating layers 152

6.3.1.3 3D model of coating shells 154

6.3.2 Coating Thickness 160

6.3.2.1 CT analyser 160

6.3.2.2 Matlab and DIPimage 163

6.3.3 Structural and morphological parameters

165

6.4 Conclusions 167

6.5 References 168

7

Relation between surface roughness of free films and process

parameters in spray coating 172

7.2.1 Material 173

7.2.3 Viscosity and dynamic surface tension of solutions 174 7.2.4 Spraying System and Sample Preparation 175

7.2.5 Design of experiments 176

7.2.6 Surface analysis: Scanning Electron Microscopy and

Atomic Force Microscopy 177

7.3 Results and discussion 178

7.3.1 Surface tension and viscosity 178

7.3.2 Influence ofP, Sp andD 180

7.3.3 Effect of process variables on surface roughness 181

(12)

7.3.4 Roughness response surface contour 185

7.3.5 Optimum Conditions 186

7.4 Proof of the Spray System: Comparison between spray coating,

film casting and particle coating 188

7.5 Conclusions 193

7.6 References 194

8

Attrition and abrasion resistance of particles coated with pre-mixed

polymer coating systems 197

8.2 Strength of coated particles 198

8.2.1 Abrasion 198

8.2.2 Attrition 199

8.3 Material and Methods 200

8.3.1 Core materials and their coatings 200

8.3.2 Particle coating 201

8.3.3 Repeated Impact Tester, RIT 202

8.3.4 Abrasion Tester 202

8.4 Results and Discussions 203

8.4.1 Attrition strength 203

8.4.1.1 Coefficient of restitution 203

8.4.1.2 Instacoat AQUA 204

8.4.1.3 Opadry® ₂₀₄

8.4.1.4 Kollicoat® IR 209

8.4.1.5 Comparison of the Coatings 211

8.4.2 Abrasion 214 8.5 Conclusions 224 8.6 References 225 General discussion 227 General Conclusion 233 Summary 235 Acknowledgments 236 Publications 240 Curriculum vitae 241

(13)

(14)

List of Figures

1.1 X-Ray diffraction patterns of bulk HPMC 603 (1a), HPMC 615 (1b) and PVA 4-98 (1c)

1.2 Thermo Gravimetric curves between 25 o_{C and 525} o_{C for the polymer}

HPMC 603 (dotted line), HPMC 615 (dashed line) and PVA 4-98 (solid line) at a heating rate of 10 °C min 1_.

1.3 Moisture sorption isotherms for HPMC 603, HPMC 615 and PVA 4-98 at room temperature, 25 o_{C (3a) and the fit of GAB (dashed line), BET}

(dotted line) and Park (solid line) equations for HPMC 603 and HPMC 615, and the fit of GAB (dashed line), BET (dotted line) andn-layerBET (solid line) equations for PVA 4-98 (3b).

1.4 Moisture sorption isotherms for HPMC 603 (4a), HPMC 615 (4b) and PVA 4-98 (4c) at 10 ( ), 25 ( ), 40 ( ), 55 ( ) and 70o_{C ( )}

1.5 Moisture sorption isotherms for PVA 4-98 at 10 ( ), 25 ( ), 40 ( ), 55 ( ), and 70o_{C ( )}

1.6 Water content effect on glass transition temperature of HPMC 603 (6a), HPMC 615 (6b) and PVA 4-98 (6c) and the fit of Linear ( ), Gordon-Taylor ( ), Fox ( ) andRoos ( ) equations. ( ) Experimental points 2.1 Shear Stress (full symbols) and Viscosity (empty symbols) of 3% HPMC

603 (1a) and HPMC 615 (1b) and PVA 4-98 (1c), solutions at varying Shear Rate measured at room temperature, RT ( ), 40 ( ), 55 ( ) and 70

o_{C ( )}

2.2 Temperature dependence of the viscosity of 3% w/w aqueous solutions of HPMC 603, HPMC 615 and PVA 4-98 solutions at a shear rate of 298 s-1

2.3 Reduced viscosity, red, function of concentration for aqueous solution for

HPMC 603 ( ), HPMC 615 [o] and PVA 4-98 ( ). Linear fitted lines: HPMC 603 dashed line, HPMC 615 solid line, PVA 4-98 dotted line. 2.4 Scanning Electron Microscope cross sections of HPMC 603 (1st_row),

HPMC 615 (2nd_{row) and PVA 4-98 (3}rd_{row) cast films dried at room}

temperature (RT), 40, 55 and 70o_C.

2.5 Plot of E’ and E’’ master curves with respect to reduced frequency (wred)

for HPMC 603 (5a), HPMC 615 (5b) and PVA 4-98 (5c) cast films dried at room temperature ( ), 40o_{C (}_*_{), 55}o_{C ( ) and 70}o_{C ( ). Note that no}

test-able sample for PVA 4-98 dried at 70o_{C could be obtained}

2.6 Shift factor (aT) function of temperature for HPMC 603 (a), HPMC 615 (b)

and PVA 4-98 (c) cast films dried at room temperature, 40 o_{C, 55}o_{C and}

70o_{C. For HPMC 603 and HPMC 615 the T}_ref_{= 150}o_{C while T}_ref_{= 50}o_C

for PVA 4-98.

2.7 Scanning Electron Microscope cross sections of HPMC 603 (1st_row),

HPMC 615 (2nd_{row) and PVA 4-98 (3}rd_{row) cast films dried at room}

(15)

2.8 Plot of E’ and E’’ master curves with respect to reduced frequency, wred

for HPMC 603 (a), HPMC 615 (b) and PVA 4-98 (c) cast films dried at room temperature and then stored at 40o_{C ( ), 55}o_{C ( ), and 70}o_{C ( ). A}

plot of Tan master curve is presented as inset.

2.9 Shift factor, aT, function of temperature for HPMC 603 (a), HPMC 615 (b)

and PVA 4-98 (c) cast films dried at room temperature and then stored at 40o_{C ( ), 55}o_{C ( ), and 70}o_{C ( ). The reference temperature, T}_ref_{is 150} o_{C for HPMC samples and 50}o_{C for PVA 4-98}

3.1 Projection of the chosen response surface model.

3.2 Significance of all the variables (single effects, interactions and second order effects) on the response variable (resistance to attrition). Pink bars: Positive effects. Red bars: negative effects.

3.3 Significance of the variables (single effects, interactions and second order effects) on the response variable (resistance to attrition) once the weak effect have been removed. Pink bars: positive effects. Red bars: negative effects

3.4 Main effects plots: 1st_{order effects of the coating thickness, h, and the}

coating formulation, Tg.

3.5 Interaction plots: 2nd_{order effects of combined factors.}

3.6 Response surface: the compilation of the main effects and interaction plots.

3.7 Contour plot of the response surface; Tg as function of the coating

quantity. The legend on the right displays the lines, corresponding to resistance to attrition.

4.1 Schematic drawing of the Repeated Impact Tester, RIT (1a) and attrition mechanisms as proposed by Beekman [45] (1b).

4.2 Scanning Electron Microscope cross sections images of Purox-S coated with PVA 4-98, HPMC 603 and HPMC 615, 1, 5 and 9% w/w coating percentage stored at room temperature.

4.3 Scanning Electron Microscope images of Purox-S coated with the three different coating agents PVA 4-98, HPMC 603 and HPMC 615, 1, 5 and 9% w/w coating percentage. 2a: coated particles stored at room temperature. 2b: coated particles stored at -18o_C.

4.4 RIT results for Purox-S coated with PVA 4-98, HPMC-603 and HPMC 615 for 1 – 5 – 9 % w/w coating thickness. RIT plot of uncoated Purox-S is included in the graphs for comparison (A = 3.8 cm, f = 40 Hz, vp= 7.04

m.s-1_{). Fig. 4.4a: coated particles stored at room temperature. Fig. 4.4b:}

coated particles stored at -18o_C

4.5 RIT results for Purox-S coated with 9% w/w PVA 4-98, HPMC-603 and HPMC 615 (A = 3.8 cm, f = 40 Hz, vp= 7.04 m.s-1)

4.6 SEM micrographs (magnification: 14x) comparison of Purox-S coated with 9% w/w PVA 4-98 (top row), HPMC 603 (middle row) and HPMC 615

(16)

(bottom row) at different RIT times (f = 40 Hz, A = 3.8 cm and vp= 7.04

m.s-1_{) and for different storage conditions, room temperature and -18}o_C.

4.7 Effect of aging time on the resistance to attrition of Purox-S coated with PVA 4-98 (7a), HPMC 603 (7b) and HPMC 615 (7c) and stored at ambient conditions (23o_{C, 55% RH), before aging and after 1, 4, 7 and 15 days of}

aging in vacuum oven at 65o_{C. The water content, w}_c_{(measured by TGA,}

see paragraph 2.5), after each aging period is mentioned in the legend. 4.8 Remaining mass, mm versus mass specific impact energy, Ei,m for

different values of mass specific fracture energy, Ef,m ( = 4 constant)

(8a). Remaining mass, mm versus mass specific impact energy, Ei,m for

different values of (Ef,m = 1970 j/kg, constant) (8b).

4.9 Effect of aging on the resistance to attrition of Purox coated with 9% w/w PVA 4-98 (9a), HPMC 603 (9b) and HPMC 615 (9c): experimental results (solid lines) fitted with the model (dot lines) described by Equation 9. 5.1 Schematic drawing of the Repeated Impact Tester, RIT (1a) and attrition

mechanisms as proposed by Beekman [16] (1b)

5.1 Scanning Electron Microscope micrographs of Purox-S coated with the three different coating agents PVA 4-98, HPMC 603 and HPMC 615 from the top to the bottom

5.3 AFM images of coating surfaces at a scan size of 40 µm x 40 µm

5.4 RIT results for Purox-S uncoated (-) and Purox-S coated with 9% w/w PVA 4-98 ( ), HPMC-603 ( ) and HPMC 615 ( ). (A = 3.8 cm, f = 40 Hz, vp= 7.04 m.s-1).

5.5 SEM micrographs (magnification: 14x) of Purox-S coated with PVA 4-98, HPMC 603 and HPMC 615 at different RIT times (f = 40 Hz, A = 3.8 cm and vp= 7.04 m.s-1)

5.6 Force-displacement datasets of quasi-static indentations for Purox coated with 9% w/w PVA 4-98 (6a), HPMC 603 (6b), and HPMC 615 (6c) for room temperature (dashed line) and -18o_{C (solid line).}

5.7 Dynamic indentation measurement performed on a HPMC 603 coated particles stored at room temperature

5.8 Averaged dynamic mechanical parameters (E’, E’’, tan ) for PVA 4-98, HPMC 603 and HPMC 615. Ten particles were averaged for each data point. On each particle 10 indentations were performed. The error bars correspond to the pooled standard deviation.

6.1 Projection image of the sample in the scanner (1a and 1b), and longitudinal, sagittal and transversal sections of X-Ray micro tomography 2D cross-sectional images (1c and 1d) for Purox-S (1a and 1c) and Cellets 1000 (1b and 1d) coated particles.

6.2 X-Ray micro tomography experimental protocol: reconstruction image (2a); reconstruction image once the Region of Interest has been identified and selected (2b); coating shell after thresholding and segmentation process (2c); 3D reconstructed model of the batch analysed (2d).

(17)

6.3 Reconstructed images of Purox-S (top part) and Cellets 1000 (bottom part) coated with PVA 4-98 (1st_{row), HPMC 603 (2}nd_{row) and HPMC 615}

(3rd_{row) for 1 (left column), 5 (centre column), 9% (right column) w/w}

coating after reconstruction and definition of Region of Interest, ROI. 6.4 Zoomed-in X-Ray micro tomography projection images of Purox-S coated

with 9% w/w PVA 4-98 (4a), HPMC 603 (4b), HPMC 615 (4c) and Cellets 1000 coated with 9% w/w PVA 4-98 (4d), HPMC 603 (4e) and HPMC 615 (4f).

6.5 X-Ray micro tomography images of HPMC 603, HOMC 615 and PVA 4-98 coated particles. Influence of core material (left: Cellets 1000, right: Purox-S) and coating fraction applied (1 - 5 – 9 %w/w from left to right per each set of images.

6.6 3D image reconstructions from X-Ray micro tomography of coating shells for all experiments performed.

6.7 Macroscale (>200 m), Microscle (<200 m) and cross section SEM micrographs of Purox-S coated with PVA 4-98, HPMC 603 and HPMC 615 from the left to the right, 1 - 5 - 9 % w/w coating level from the top to the bottom.

6.8 Macroscale (>200 m), Microscle (<200 m) and cross section SEM micrographs of Cellets 1000 coated with PVA 4-98, HPMC 603 and HPMC 615 from the left to the right, 1 - 5 - 9 % w/w coating level from the top to the bottom.

7.1 Variation of surface tension and viscosity of HPMC 615 (1a), HPMC 603 (1b) and PVA 4-98 (1c) aqueous solution at 3% w/w concentration with temperature

7.2 Estimated effects (95 % confidence level) of all factors (1st_{order, 2}nd_order,

and interactions) on surface roughness.

7.3 Adjusted model-fit for surface roughness after removal of all the in significant factors

7.4 Plots of the 1st_{order effects of the three main significant factors (a), and}

Interaction profiles of design factors (b) on response surface roughness. 7.5 Roughness response surface contour plot of the model for Sp = 30 % (a an

d), for P = 1.25 MPa (b and e) and for D = 15cm (c and f)

7.6 Scanning Electron Microscope micrographs (at low and high magnification) of PVA 4-98, HPMC 603 and HPMC 615 sprayed films (optimum configuration), and corresponding casting films (Perfetti et al., 2010_a) and particle coating layers (Perfetti et al., 2010_b), from the top to the bottom.

7.7 Atomic force microscopy images (2D and 3D) of PVA 4-98, HPMC 603 and HPMC 615 sprayed films (optimum configuration), and corresponding casting films (Perfetti et al., 2010_a) and particle coating layers (Perfetti et al., 2010_b), from the top to the bottom.

(18)

8.2 Schematic drawing of the Repeated Impact Tester, RIT (Fig 2a) and attrition mechanisms as proposed by Beekman [16] (Fig. 2b)

8.3 Remaining mass, mm, versus impact mass specific energy, Ei,m, for Purox-S uncoated (-) and Purox-S coated with 1 ( ), 5 ( ) and 9% w/w ( ) Instacoat AQUA and 1 ( ), 5 ( ) and 9% w/w ( ) pure HPMC 603 [12]. 8.4 SEM micrographs (magnification: 14x) of Purox-S coated with 1 (top row),

5 (central row) and 9% w/w (bottom row) Instacoat AQUA at different RIT times.

8. 5 Remaining mass, mm, versus impact mass specific energy, Ei,m, for Purox-S uncoated (-) and Purox-S coated with 1 ( ), 5 ( ) and 9% w/w ( ) Opadry®_{and 1 ( ), 5 ( ) and 9% w/w ( ) pure HPMC 603 [12].}

8.6 SEM micrographs (magnification: 14x) of Purox-S coated with 1 (top row), 5 (central row) and 9% w/w (bottom row) Opadry®_{at different RIT times.}

8.7 Remaining mass, mm, versus impact mass specific energy, Ei,m, for

Purox-S uncoated and Purox-S coated with 1 ( ), 5 ( ) and 9% w/w ( ) Kollicoat®_{IR and 1 ( ), 5 ( ) and 9% w/w ( ) pure PVA 4-98 [12] and}

PEG 2000/PEG 20000 ( ) [7].

8.8 SEM micrographs (magnification: 14x) of Purox-S coated with 1 (top row), 5 (central row) and 9% w/w (bottom row) Kollicoat®_{IR at different RIT}

times.

8.9 SEM images of Cellets 1000 coated with 1% Instacoat Aqua (top), 1% Opadry (centra) and 1% Kollicoat IR (bottom) before RIT tests (left) and after RIT (43 min corresponding toEm kinof 2100 kJ/kg).

8.10 Influence of Instacoat AQUA (a), Opadry®_{(b) and Kollicoat}®_{IR (c)}

coating thickness on Purox-S at different number of collisions during RIT. 8.11 SEM images of uncoated Cellets 1000 before Abrasion test (left) and after

Abrasion test (43 min,farm = 4.9 s-1andfbox = 9 s-1)

8.12 Remaining mass versus time as a function of the rotational frequency of the arm, farm, and the rotational frequency of the box, fbox, for uncoated

Purox-S

8.13 SEM micrographs of uncoated Purox-S after the abrasion test when t=43 min

8.14 The remaining mass as function of time for Purox-S coated with 1% w/w Instacoat AQUA (a), Opadry (b), Kollicoat IR (c) and the corresponding Purox-S in the attrition tester

8.15 SEM micrographs of Purox-S coated with 1% w/w Instacoat AQUA (top row), Opadry (central row), Kollicoat IR (bottom row) at t=0 min and t=43 min

8.16 The remaining mass as function of time for Purox-S coated with 5% w/w Instacoat AQUA (a), Opadry (b), Kollicoat IR (c) and the corresponding Purox-S in the attrition tester

8.17 Influence of Instacoat AQUA, Opadry®_{and Kollicoat}®_{IR coating}

(19)

List of Tables

1.1 Characteristic properties of Pharmacoat® 603 (HPMC 603),

Pharmacoat® 615

1.2 Water activity and temperatures of the satured salts solutions used to equilibrate the formulations (HPMC 615) and Mowiol® 4-98 (PVA 4-98) 1.3 Thermogravimetry parameters for HPMC 603, HPMC 615 and PVA 4-98 1.4 Parameters values derived from water sorption data at considered

temperatures from the GAB, BET, Park and n-layerBET equations for HPMC 603, HPMC 615 and PVA 4-98.

1.5 Computed values of Linear, Gordon Taylor, Fox and Roos parameters and RMSE (Eq. 2) obtained from the analysis of the relationship between water content and glass transition temperature of HPMC 603, HPMC 615 and PVA 4-98

2.1 Physic-chemical characteristics of the polymers used in the present work 2.2 Description of the drying – storage history of the tested samples

2.3 Arrhenius parameters for HPMC 603, HPMC 615 and PVA 4-98 at a shear rate of 298 s-1

2.4 Intrinsic viscosity, [ ], derived from reduced viscosity red for aqueous

solutions of HPMC 603, HPMC 615 and PVA 4-98 at 25o_C

2.5 Water content, Wc, for HPMC 603, HPMC 615 and PVA 4-98 cast films

dried at room temperature, 40o_{C, 55}o_{C, and 70}o_{C measured by TGA}

2.6 Effect of drying temperatures on Tg (both as max of Tan and inset of E’)

for HPMC 603, HPMC 615 and PVA 4-98 cast films dried at room temperature, 40o_{C, 55}o_{C, and 70}o_{C measured by DMTA}

2.7 Water content, Wc, for HPMC 603, HPMC 615 and PVA 4-98 cast films

dried at room temperature, 40o_{C, 55}o_{C, and 70}o_{C measured by TGA}

2.8 Effect of storage temperatures on Tg (both as max of Tan and inset of

E’) for HPMC 603, HPMC 615 and PVA 4-98 cast films dried at room temperature and then store (2 months) at 40 o_{C, 55} o_{C, and 70} o_C

measured by DMTA

3.1 Fluid Bed Coating process-related variables [16-17]. 3.2 Fluid Bed Coating product-related variables [16-17].

3.3 Characteristic properties of Pharmacoat® 603 (HPMC 603), Pharmacoat® 615 (HPMC 615) and Mowiol® 4-98 (PVA 4-98)

3.4 Process variables for fluidised bed coating experiments 3.5 Actual and coded values of the investigated process variables

(20)

4.1 Grade, degree of substitution, molecular weight, viscosity hydrolysis and polymerization degree of Pharmacoat®_{603 (HPMC 603), Pharmacoat}®₆₁₅

(HPMC 615) and Mowiol®_{4-98, PVA 4-98}

4.2 Process conditions and experimental values of all the performed spray-coating experiments.

4.3 Details on particle coatings.

4.4 Example of typical data gathered from Repeated Impact Testing using the preset setup described in Section 1.1 (coefficient of restitution, e = 0.59).

4.5 Water content (average value) of the samples aged in the oven (65o_{C) for}

1, 4, 7 and 15 days of aging prior performing repeated impact tests

5.1 Details on Pharmacoat®_{603 (HPMC 603), Pharmacoat}®_{615 (HPMC 615)}

and Mowiol®_{4-98, (PVA 4-98)}

5.2 Process variables for fluidised bed coating experiments 5.3 Details on particle coatings

5.4 Water content, average value and standard deviation, of the samples (by TGA) before performing RIT, quasistatic and dynamic nanoindentation 5.5 Example of typical data gathered from Repeated Impact Testing using

the preset setup described in Section 1.1 (coefficient of restitution, e = 0.59).

6.1 Coating thickness calculations for Purox-S and Cellets 1000 coated particles with PVA 4-98, HPMC 603 and HPMC 615 for 1, 5 and 9 %w/w coating level.

6.2 2D Cross-sectional Thickness obtained by cross-sectional image analysis, the standard deviation, and values for the smallest and biggest 2D Cross-sectional Thickness found in the series of all 2D slices

6.3 Measured thickness for a binary sphere of thickness 3 pixels with different outer radii by image analysis.

6.4 Coating Thicknesses and the corresponding statistics obtained by Image analysis using 2D and 3D approaches,

6.5 The ratio between the external surface and the volume of the coating shell ( ), the surface density ( ), the percent porosity ( ), the number of pores ( num), and the corresponding volume of pores ( vol) for Purox-S

and Cellets 1000 coated particles.

7.1 Details on Pharmacoat® 603 (HPMC 603), Pharmacoat® 615 (HPMC 615) and Mowiol® 4-98, (PVA 4-98)

7.2 Actual values of the investigated process variables: air pressure, P, rotational speed of the roll, Sp, and distance between the spray nozzle and

the roll, D.

(21)

7.4 Estimated effects for all factors (1st_{order, 2}nd_{order, and interactions)}

used in the model

7.5 Results for estimation of response roughness

7.6 Surface roughness optimum conditions of Spray Pressure, P, Rotational Speed, Sp, and Distance cylinder-nozzle, D for PVA 4-98, HPMC 603 and HPMC 615

7.7 The mean value (four measurements) and the standard deviation of the Average Roughness, Ra, and the RMS roughness, Rq, for HPMC 615,

HPMC 603 and PVA 4-98 sprayed films (optimum configuration), and corresponding cast films and coating layers.

7.8 Values of the Average, RA, the Peak-to-Peak Height, Ry, the Ten Point

Height, Rz, the Surface Skewness, Rsk and the Surface Kurtosis

coefficient, Rka, for HPMC 615, HPMC 603 and PVA 4-98 sprayed films

(optimum configuration), and corresponding cast films and coating layers. 8.1 Details on applied mixed polymers

8.2 Process variables for fluidised bed coating experiments 8.3 The coefficient of restitution of coated particles

8.4 Remaining Mass at 1500 kJ/kg for Purox-S coated with the three coating materials for 1, 5 and 9% w/w.

8.5 Comparison of 1 and 5 % w/w coatings when E = 6000 J/kg. [farm=3 s-1

(22)

Nomenclature

] Intrinsic viscosity. (mPas)

A Amplitude of the motion of the chamber. (m)

Ac Projected contact area. (mm2)

AL Concentration of specific sorption sites. (%)

AL Constant. (-)

aT Shift factor. (-)

Avg2D Coating thickness measured in each 2D slice as one average value. (mm)

aw Water activity. (%)

B Affinity constant of water. (-)

B Constant. (-)

b Parameter linked to the energy balance between the n-layer

binding energy and heat of evaporation. (-)

C Heat of adsorption of water. (kJ/mol)

c Polymer concentration. (%)

CBET BET constant. (-)

CGAB BET constant. (-)

D Damping coefficient. (-)

D Distance between the spray nozzle and the roll. (mm)

D*n Damage accumulated at the nth impact. (-)

DM Coating Solution Dry Matter Content. (%)

e Coefficient of restitution. (-)

E'' Loss modulus. (MPa)

E' Storage modulus. (MPa)

Ea Activation energy for viscous flow.

Ef,m Mass specific fracture energy. (kj/kg)

Ei,m Mass specific energy of impact. (j/kg)

Ek,m Mass specific kinetic energy. (kj/kg)

Ek,n Mass specific kinetic energy of the steel ball at the nth impact.

(j/kg)

En-1 Mass specific fracture energy of the particle after the (n-1)th

impact. (j/kg)

f Oscillation frequency of the flywheel. (Hz)

F0 Pre-set load amplitude.

farm Frequency of the arm of the abrasion tester. (Hz)

fbox Rotational frequency of the box of the abrasion tester. (Hz)

Fi Inlet air flow rate. (kg/h)

h Coating thickness. (%)

Ka Equilibrium constant. (-)

KH Constant. (-)

(23)

m Mass of the sensor. (g)

m0 Initial particle mass. (g)

mm Normalized remaining mass after experiment. (-)

N Average number of molecules in aggregates. (%)

n Number of data points. (-)

N Number of impacts. (-)

P Spray air pressure. (bar)

Pat Spraying pressure. (bar)

R Universal gas constant. (J/mol Kg)

Ra Average Roughness. (nm)

RA Mean height of all the pixels in the image. (nm)

rc Radius of core particle. (mm)

Rh Outlet Air Relative Humidity. (%)

RH Relative humidity. (%)

Rka Surface Kurtosis coefficient. (-)

rm Radius of the coated particles. (mm)

Rq Standard deviation of height average. (-)

Rsk Surface skewness coefficient. (-)

Rsol Coating solution spray rate. (g/min)

RT Room Temperature. (o_C)

Ry Peak-to-peak height. (nm)

Rz Ten Point Height. (nm)

S Spring stiffness. (N/m)

Sp Rotational speed of the roll. (%)

Ss Surface area of the solid object within the volume of interest.

(mm2₎

STD Standard deviation. (-)

Surf2D Coating thickness measured in each 2D slice as a function of the position on the coating. (mm)

Surf3D Coating thickness measured in the reconstructed volume as function of the coating surface. (mm)

T Temperature. (o_C)

t time. (s)

t Total duration of the RIT experiment. (s)

T1 Inlet air Temperature. (oC)

T2 Outlet air Temperature. (%)

tan Damping factor. (-)

Tbed Fluid bed temperature. (oC)

Tdeg Degradation Temperature. (oC)

Tg Glass Transition Temperature. (oC)

Tg_E' Glass Transition Temperature as inset of storage modulus, E’.

(o_C)

Tg_tan Glass Transition Temperature as Max of damping factor Tan .

(24)

Tg1 Glass Transition Temperature component 1. (oC)

Tg2 Glass Transition Temperature component 2. (oC)

Th Cross-sectional thickness. (mm)

Tref Reference temperature. (oC)

Ts Coating Solution Temperature. (oC)

V Volume of the object within the volume of interest. (mm3₎

Vi Inlet air velocity. (m/s)

vp Particle impact velocity. (m/s)

w Particles Coating Content. (%)

Wc Water content. (%)

wc Weight of the core material. (g)

Wcs Mass of Coating Solution. (g)

Wexp Experimental moisture content. (%)

Wi Initial mass of the sample. (g)

Wm Amount of water required to saturate the accessible binding

sites both on the surface and in the bulk material Wm (BET) BET constant. (-)

Wm (GAB) GAB constant. (-)

Wp Mass of core material. (g)

Wpred Predicted moisture content. (%)

wred Reduced frequency. (Hz)

Ws Mass of the dried sample. (g)

ws Weight of the coating material. (g)

X Displacement amplitude of the dynamic indentation. (nm)

Ratio solid surface-volume. (mm-1₎

Damage accumulation constant. (-)

tdr Drying time. (s)

tsp Spraying time. (s)

o Pre-exponential factor constant. (-)

red Reduced viscosity. (mPas)

rel Relative viscosity. (mPas)

sol Viscosity of the solvent. (mPas)

sp Specific viscosity. (mPas)

Surface density. (g/cm3₎

Percentage porosity. (%)

num Number of pores in the coating shell. (-)

vol Volume occupied by the pores present in the coating shell.

(25)

Abbreviations

AFM Atomic Force Microscopy

BET Braunauer-Emmett-Teller model

CLSM Confocal laser scanning microscopy

DMTA Dynamic mechanical thermal analysis

DoE Design of experiments

DSC Differential Scanning Calorimetry

GAB Guggenheim-Anderson-de Boer model

HPMC HydroxyPropyl MethylCellulose

LIBS Laser Induced Breakdown Spectroscopy

LM Light microscopy

MCC Micro-crystalline cellulose

Purox-S Sodium benzoate

PVA PolyVinyl Alcohol

RIT Repeated Impact Tester

RMSE Root mean square error

RMSEa Adjusted root mean square error

ROI Region of Interest

RSM Response surface methodology

TGA Thermogravimetry

UFLC Ultrafast Load Cell

VOI Volume of Interest

WLF Williams–Landel–Ferry equation

(26)

2

Outline

Can we climb this montain? I do not know higher now than ever before I know we can make it if we take it slow That’s takin’ easy, easy now, watch it go

When we were young, The Killers

Particulate products are generally coated to give the product specific functionalities in terms of enhancing resistance to mechanical and environmental stresses (Temperature, relative humidity, PH…), achieve desired drug release properties, modify the appearance and processability and, more in general, to improve the overall quality of the mother particles. In order to have this target achieved, we need to realize that, although to a different extent, all variables related to coating layer generation are playing an important role. Bulk raw material’s intrinsic properties, the coating process used to apply the coating agent onto the core particles, the morphology and the rheological-mechanical properties of the resulting coated layers are definitely the main aspects. All these parameters are strictly related and, in the end, responsible for breakage resistance of the coated particles. Inaccurate coating process rather that wrong selection of the coating agent or not properly designed coating morphology may lead to failure of the coated particle. Only by deeply understanding the effects of the above mentioned variables on the overall performance of the coating film layer, we can really have the right formulation and process development for a desired functional coating system. The final target is being able to generate a certain quality rather than control the quality at the end of the process.

Definition of the right coating formulation is of course of great importance. The coating agents should be chosen so that the resulting coating film is of uniform thickness (controlled release), homogenous, crack and defect free (breakage resistance and moisture barrier), well attached to the substrate and able to survive any type of mechanical and environmental stresses during production, handling and storage. However, in order for this to be accomplished, the following is necessary:

To understand the basic physical-chemical raw/bulk material properties and

To assess how the above mentioned basic properties vary as function of different and changing environmental conditions

(27)

3

Therefore, in the development of valuable and reliable coating systems, no matter what the end application is, it is important to accurately and usefully characterise their bulk properties to ensure optimisation of the coating design, and hence performance. Chapter 1 deals, in fact, with such basic characterization of the coating agents chosen as reference model coating materials with particular reference to their effect on the properties and performance of the final product. Hydroxypropylmethylcellulose, HPMC, and PolyVinyl Alcohol, PVA, which are extensively used in any type of coating industries, are chosen as reference coating agents for their appreciated good film-forming properties, their relatively small influence of processing parameters and their wide regulatory acceptance. Crystallinity and/or amorphousness of materials structure, thermal degradation, water adsorption/desorption and the glass transition temperature as function of relative humidity of the environment and water content, respectively, were accurately measured.

More and more particulate products are coated to enhance final performances and, more in general, to give the product specific functionalities. The rheological mechanical properties of the coating layers in form of polymeric films directly affect their performance and, even more important, are responsible for overall quality of the coated particles. It’s then clear that an accurate characterization of those polymeric films is definitely necessary. In Chapter 2, the coating agents chosen as reference materials and already investigated as bulk materials in Chapter 1, were investigated in the form of polymeric films. The viscosities as well as the shear stress as function of shear rate, temperature and polymer concentration of the aqueous solutions from which such polymers were obtained, were measured. The effect of the drying/storage temperature and relative humidity on the morphological structure of the cast films was evaluated by means of a scanning electron microscope, SEM. Dynamic mechanical thermal analysis, DMTA, was instead used to assess the viscoelastic properties over a wide temperature–frequency range. Moreover, thanks to the application of the time–temperature superposition principle, the determination of the shift factor, aT, and the composition of corresponding master curves was accomplished.

When a coating layer/system is applied onto a particle/particulate/agglomerate it should be strong enough to survive subsequent processing, conveying, handling and storage. Unexpected failures of the coating could lead to drastic wasting of the properties of the product and finally to breakage of the coated particles. Ensuring the desired level of quality and functionalities in the coating is not a trivial task. Despite being a common process in a wide range of industries coating processes are yet to be completely understood. Moreover the relationships between coating process variables and both quality of the obtained coating layer and their resistance to breakage still remain unclear. The purpose of Chapter 3 is to gain a better understanding of the influence of certain selected coating process variables (thickness, h, glass

(28)

4

transition of the chosen coating formulation,Tg, and the fluid bed temperature,

Tbed,) on the resistance to attrition (low magnitude forces in normal direction)

of coated Sodium Benzoate reference particles. The three reference coating agents studied so far have been sprayed by using top spray fluid bed coater. Resistance to attrition is measured by means of Repeated Impact Tester. Response surface methodology, RSM, has been used to design the experiments and evaluate both single effects of the three chosen coating process variables and the interactions between those on the resistance to attrition being selected as response variable.

The effects of attrition on the coated particles can be loss of valuable product, modification of the functionalities of the coating layer, i.e. controlled release ability, loss of flowability, environmental pollution due to a large quantity of dust (eventually inhaled by the operators) , and agglomeration and cacking during storage and/or shipment. Therefore it is of great importance that when applying the coating both the proper coating agent and the right coating thickness are selected. Similar attention should be paid to understand critical storage conditions (temperature and relative humidity) and physical aging effects on coated particles in order to be able to predict, and thus avoid, potentially negative conditions during handling and storage. These aspects are analysed in Chapter 4. The polymer-coated particles produced by top-spray fluid bed coater and morphologically assessed by Scanning Electron Microscope are tested by means of the Repeated Impact Tester. The resistance to attrition of those coated particles is put in relation to coating thickness, storage conditions and physical aging. This could be achieved by producing coated particles with different coating thickness, storing them at different temperatures and relative humidity and, finally, physically aging for a certain periods of time. The resulting morphology as well as the attrition mechanisms shown by the coated particles are extensively assessed and compared to previous studies. By using existing equations a new equation is developed which enables us to successfully model the experimental data and thus predict breakage failures of different coating materials and different coating thicknesses. This equation, in fact, takes into account the number of impacts, the velocity of the impacts, the coating thickness, the coefficient of restitution, e, of the coated particles and the mass specific fracture energy, Ef,m.

Although breakage of polymer-coated particles are mainly macroscopic-dominated phenomena, like the type of stress, direction and parameters, the core particle size, coating/core adhesion, the coating surface mechanical properties and its morphology are of great importance because most initial interactions occur at the surface. Specifically, the coating viscoelastic properties are of interest because in most of the cases coated particles are subjected to dynamic or cyclic loading/stresses. Nano indentation is generally recognized as a reliable and powerful technique for the investigation of nanoscale static and dynamic mechanical properties of many types of materials. Chapter 5 firstly presents experimental results of damage and

(29)

5

breakage caused to coated particles by repeated impacts. Then the viscoelastic properties (Displacement, storage modulus, E’, loss modulus, E’’, and damping factor, tan ), of the coating layer when applied onto the core particles are measured by using quasi-static and dynamic Nano Indentation technique. Macroscopic performance of the coated particles measured as resistance to attrition by RIT and microscopic response of the coating materials measured as viscoelastic properties by nano indentation are accurately measured for all three selected coating agents at different thickness level. The experimental data obtained by both techniques show the effect of the coating material and the type of stress on the damage caused to the particles. Then the resistance to attrition data correlated with viscoelastic properties to demonstrate the match between the Repeated Impact testing and the nano indentation technique. The scope of such correlation is to proof that an approximate estimation of resistance to attrition of standard coated particles can be determined and thus predicted based on measurement of intrinsic viscoelastic properties of the coating materials involved.

No matter the type of coating agent used or the coating process employed, a proper characterization method is required to assess the surface morphology, analyse the internal structure and measure the main characteristics of the of the coating film. Chapter 6 describes X-Ray Micro Tomography as a powerful tool for morphological characterization of coated particles and, in particular, of their coating layers. Such technique provides a. extremely high level of details at both micro and macro scale. Additionally to thickness characterization this technique is used for the determination of density, porosity, surface/volume ratio, and thickness of the coating layer. Image analysis, scanning electron microscopy and atomic force microscopy, AFM, are used as complementary and reference methods. Evaluation of the adhesion core/coating film together with comparison of different definitions of coating thickness and the generation of a 3D model of the analysed coating layers is the main focus of the chapter. Based on these images and quantitative data we can, first, evaluate the quality of the coating film (and predict its future performance) and, secondly, obtain a deep insight on coating process variables which enable us to tune them accordingly.

Coating of particles is well known to be an expensive and time consuming process. Similarly, as already mentioned, the characterization of the coating layer once this is applied onto the core particle requires quite complicated analysis and the use of specific equipments. In order to simplify that a technique which is able to generate free polymeric films having the same morphology and properties as those of the coated films when applied to core particle by fluid bed coating is developed. In Chapter 7 this novel spraying apparatus is presented. By using this reliable technique we could obtain reproducible free sprayed films from aqueous solutions of the three reference coating agents. The morphology of the sprayed films obtained using the optimum conditions are evaluated by means of Scanning Electron Microscopy,

(30)

6

SEM, and Atomic Force Microscopy, AFM, and then compared with those from corresponding cast films (Chapter 1) and coating films on particles (Chapter 4-6). Having the spraying air pressure, the cylinder rotation speed, and the cylinder-spray nozzle distance as chosen process variables, design of experiments, DoE, was used to find the optimum spraying process conditions for all three coating materials.

Coated particles have to survive not only attrition but many other types of stresses including compression, fragmentation, chipping and abrasion. Abrasion wear, defined as low magnitude force in tangential direction, is caused by rolling and/or sliding of the coated particles results in generation of fine particles (much smaller than the original particle) and more spherical mother particle. In Chapter 8 the resistance to attrition and abrasion of coated particles using three different pre-mixed polymer coating systems (Opadry®_,

Kollicoat®_{IR and Instacoat AQUA) is presented. Comparison of breakage}

resistance (attrition and abrasion) between reference coating systems presented in Chapters 3-6 and commercial pre-mixed polymer coating systems presented in this chapter is highlighted. Particular attention is devoted to the role of additives (plasticizers, colorant…) contained in the pre-mixed systems as well as the effect of different testing variables (rotational speed…) in the abrasion tester.

Finally overall discussion and general conclusions will be summarized in the last chapters of this thesis.

(31)

7

Chapter 1

Thermo-physical characterization of film formers

Pharmacoat

®

_{603, Pharmacoat}

®

_{615 and Mowiol}

®

_4-98

In the days before you were young We used to sit in the morning sun We used to turn the radio on And what happened Before you were young, Travis

HydroxyPropyl MethylCellulose, HPMC, and PolyVinyl Alcohol, PVA, are important polymers in pharmaceutical, food and other industries being largely used as encapsulation agents. The characterization of two reference grades of HPMC, and one reference grade of PVA, through X-Ray Diffraction, XRD, and Thermogravimetry, TG, is described. Specific analyses were performed by means of Dynamic Vapour Sorption Analysis of water adsorption/desorption from vapours at 10, 25, 40, 55, 70 o_C.

Guggenheim-Anderson-de Boer, GAB, Braunauer-Emmett-Teller, BET, Park and n-layer BET models were successfully used to fit the experimental data. The glass transition temperature as function of water content was measured by means of Differential Scanning Calorimetry, DSC. The experimental data were analysed according to Linear, Gordon-Taylor, Fox and Roos equations. XRD studies revealed amorphous structure for the HPMC’s and crystalline for PVA. Single and multi-step temperature degradation point was found for HPMC’s and PVA respectively. The water uptake is higher for HPMC’s than PVA. The influence of temperature on water uptake is opposite for the two types of polymers. GAB and n-layer BET were found to better model HPMC’s and PVA data respectively. The water makes the glass transition to decrease quite drastically. Gordon-Taylor fits better the experimental data both for HPMC’s and PVA.

The entire chapter has been published as: G. Perfetti, T. Alphazan, W. J. Wildeboer, G. Meesters. Thermo-physical characterization of Pharmacoat®_603,

Pharmacoat®_{615 and Mowiol}®_{4-98. Journal of Thermal Analysis and}

(32)

8 1.1 Introduction

Film formers such as the semi-synthetic derivative of cellulose HydroxyPropyl Methylcellulose, HPMC, and the water-soluble synthetic polymer Polyvinyl alcohol, PVA, are extensively used in the coating of tablets, pellet or granule as well as a binder in the formulation of sustained release dosage forms and oral controlled drug delivery systems as a swellable and hydrophilic polymer [1-4].

Moreover they are both appreciated for their good film-forming properties that enable the production of tough coats, protecting against degradation and moisture, preventing dust formation and breakage of the core particle, and formulation’s taste masking [5], their relatively small influence of processing parameters and simple manufacturing technology [6].

HydroxyPropyl methylcellulose, HPMC, which is propylene glycol ether of methylcellulose, is widely used as a thickening agent, filler, anti-clumping agent and emulsifier having non-toxic property, pretty ease handling [7] as well as high biodegradability, non-ionic property and high solubility [8]. The major application of Hydroxypropyl Methylcellulose, HPMC, is as a carrier material in the pharmaceutical industry. For the preparation of oral controlled drug delivery systems the hydrophilic material is very suitable because of its ability to let drugs slowly diffuse out of the system [9]. In food application, HPMC has many uses: as a thickening agent, filler, dietary fibre, anti-clumping agent and emulsifier. It is prepared from cellulose, but better soluble in water than cellulose. The substituent in its structure can be either a –CH3,

or a –CH2CH(CH3)OH group, or a hydrogen atom. The methoxy (–OCH3) group

content, hydroxypropoxy (–OCH2CH(CH3)OH) group content and the molecular

weight (MW) affect the physicochemical properties the most. Depending on the relative methoxy- and hydroxypropoxy content we can distinguish four types of polymer, namely HPMC 1828, HPMC 2208, HPMC 2906, and HPMC 2910. Variations of contents cause changes in product characteristics like, for instance, different rates of drug release in the final tablet [9].

Polyvinyl alcohol, PVA, which is a water-soluble synthetic polymer, is another well-known suitable material for fluid bed coating. It is frequently used as thickening agent in non-food products like shampoo and latex paint. As a water-soluble film it is very suitable for envelope glue and packaging. The Polyvinyl alcohol bases its high tensile strength, flexibility, as well as high oxygen and aroma barrier to its excellent film forming, emulsifying, and adhesive properties. It has very high grease, oil and solvent resistance together with odor-less and nontoxic properties. The chemical structure of this synthetic water-soluble polymer present a molecular formula which is (C2H4O)n. Vinyl

acetate is a starting monomer unit in PVA, in which most of the acetate parts are subsequently hydrolysed to alcohol units [10]. The basic properties of PVA

(33)

9

highly depend on the degree of hydrolysis (i.e. fully hydrolysed or partially hydrolysed grades) and viscosity [11].

HydroxyPropyl Methylcellulose, HPMC, and Polyvinyl alcohol, PVA, are humidity (water) dependant, having various strengths of interaction with water [12]. The mechanical properties such as tensile strength, elongation and tear strength as well as the thermal properties of polymers are drastically affected by polymer’s molecules-water interaction [13]. The plasticizing effect of the water enables formation of stable hydrogen bonding making the polymer to produce strong compacts [14]. Moreover, the analysis of the effect of water on bulk polymer properties is fundamental for many activities related to coating technology, like the prediction of glass transition temperature, Tg. The

correlation between water and Tg is fundamental for the evaluation of

agglomeration-stickiness ability of the coating agent, the design of drying methods as well as the selection of adequate storage conditions for the coated particles. In this context, the sorption isotherms are used as tool for measuring the water adsorption of the bulk coating agent and thus assess the relationship between water content, temperature and humidity.

The effect of temperature on the adsorption-desorption isotherm of HPMC and PVA results to be crucial when establishing the storage and processing conditions. Although few authors have reported on adsorption-desorption isotherms [15-16] and more in general about water interaction with bulk solids [17] for similar products, there is no data available for these specific formulations. Moreover the influence of temperature has not been studied yet. This work presents a basic thermo-physical characterization of the bulk properties of two reference grades of HPMC and one reference grade of PVA together with a review of the results already presented in literature. By studying the thermo-physical characteristics of the bulk coating agents represent the first fundamental step for a deep understanding of what makes the corresponding coating better. This work is part of a larger project focussing on the characterization and modelling of coating material properties. In the first part of the work, the amorphousness/crystallinity of the bulk materials and their behaviour over a certain temperature range are analysed. The paper examines the relationship between glass transition temperature,Tg, and water

content of the bulk materials as a function of humidity and temperature. We will first determine the experimental glass transition temperature of the three materials as a function of water content, and then compare the experimental data with Tg models predictions. All these equations are derived considering

the glass transition behaviour of amorphous solids as function of water content according to the polymer free volume theory [18]. Subsequently we measure the water up-take of the bulk materials as function of the humidity and the temperature and their interactions with water as powders. Similarly, the experimental data are compared to existing well-known models.

(34)

10

1.2.1 Polymer film formers

High substituted HydroxyPropyl Methylcellulose (HPMC) Pharmacoat® 603 and Pharmacoat® 615 (to be referred as HPMC 603, and HPMC 615 respectively further in this article) were supplied by Shin-Etsu Chemical Co., Japan. Polyvinyl Alcohol (PVA) Mowiol® 4-98 (to be referred as PVA 4-98 further in this article) was supplied by Sigma Aldrich GmbH, Germany. All the polymers were used as received. Table 1.1 summarizes the characteristic properties of each polymer.

Table 1.1: Characteristic properties of Pharmacoat® 603 (HPMC 603), Pharmacoat® 615 (HPMC 615) and Mowiol® 4-98 (PVA 4-98)

Degrees of substitution [% w /w] Polymer Grade

Methoxy Hydroxy_propoxyl

Mw Viscosity*_[mPa·s] _HydrolysisMol% Polymeri-_zation

Pharmacoat® 603 28.7 8.9 13000 4.5 - 5 Pharmacoat® 615 28.9 8.8 65000 29 - 31

Mowiol® 4-98 27000 4 – 4.5 98 -98.8 ~ 600 * 3 % solution in water at 25 °C.

1.2.2 X-Ray Diffraction, XRD

HPMC 603, HPMC 615 and PVA 4-98 bulk powder X-Ray Diffraction patterns were recorded employing a X-Ray diffractometer (XRD Bruker AXS D8 Advance) Ni-filtered Cu-K( ) radiation ( =1.54178 ), a voltage of 20 kV, a current of 20 mA from 2 =10 to 90 (2 : diffraction peak angle, scan rate 20 sec/step, step size: 0.01o_{) at room temperature. A divergence slit of 0.6 mm,}

anti-scatter slit of 0.6 mm and a detector slit of 0.2 mm were used. 1.2.3 Thermogravimetry, TG

Thermo Gravimetric Analyses using a TG 7 (Perkin Elmer Massachusetts, USA) with a dry nitrogen purge were performed to determine either the water content of HPMC 603, HPMC 615 and PVA 4-98 at equilibrium in the desiccators with satured salt solutions, and the thermal stability, the corresponding maximum temperature of thermal degradation and percentage of solid residue at 525o_{C of the bulk polymers. Alumel (152.17} o_C)

and Perkalloy (594.47 o_{C) were used to calibrate the temperature reading and}

the mass measurement was calibrated using reference materials according to the manufacturer’s instructions. Approximately 5 to 20 mg of bulk HPMC 603, HPMC 615 and PVA 4-98 stored in the satured salts solutions ambient were placed in alumina crucibles for TG and the water content as mass loss was

(35)

11

measured during heating from 25 °C to 150 °C at a heating rate of 10 °C/min followed by a isothermal step at 150 °C for 10 min. The difference between the initial and the final sample mass was used as a measure for the water content of the samples. All measurements were repeated at least twice.

1.2.4 Dynamic Vapour Sorption Analysis

Moisture sorption and desorption isotherms to relate polymer water content to relative humidity were generated at 10 - 25 - 40 - 55 – 70 °C using a high performance moisture sorption analyzer Q5000 SA (TA Instruments, Zellik, Belgium). The Q5000 SA is equipped with a sensitive symmetrical thermo balance (100 mg dynamic mass range), which monitored the sample mass at a specific relative humidity and an efficient humidity control chamber, for the accurate measurement of mass and relative humidity (RH). It includes a 10-position auto sampler with automated pan loading, automated humidity chamber movement, and 180 mL hemispherical metal-coated quartz boats. The instrument was calibrated using sodium chloride, NaCl (25 – 40 – 60 o_{C; 70 –}

77 % RH) and polyvinylpyrrolidone, PVP (25o_{C, 0 – 80 % RH). An average of 5}

– 10 mg of sample was used per each experiment. For HPMC’s samples the procedure consists in 5-10 % steps in RH from 0 to 85 % RH following an initial drying at experimental temperature for 120 minutes. During drying and adsorption-desorption, equilibrium was assumed to be established when there was a mass change less than 0.01% over a period of 2 minutes and a mass change less than 0.001 % over a period of 30 minutes respectively. For PVA 4-98 samples the procedure consists of 5-10 % steps in RH from 0 to 85 % RH following an initial drying at experimental temperature for 6 hours. PVA 4-98 samples were found much more difficult to dry. During drying and adsorption-desorption, equilibrium was assumed to be established when there was a mass change less than 0.01 % over a period of 2 minutes and a mass change less than 0.001 % over a period of 60 minutes respectively. 85 % RH was not included in the experiment method when testing samples at 70o_{C in order to minimize the}

risk of condensation of vapour and thus failure of the test. The systems studied were considered in equilibrium since temperature and pressure were constant during measurements and the desiccators were kept hermetically closed during storage.

A number of sorption models have been reported in the literature. In this paper Guggenheim-Anderson-de Boer, GAB [19-21], Braunauer-Emmett-Teller, BET [22], Park [23] and n-layer BET [24] models have been used to fit the experimental data and used to generally describe the water sorption behaviour between 0.1 and 0.9 of water activity. The quality of each model has been computed in terms of root mean square error, RMSE (Eq. 1), and adjusted root mean square error, RMSEa (Eq. 2), which are calculated as follows:

(36)

12

2 exp 1 ( ) n pred i w w RMSE n (1.1) exp 2 1 exp ( ) % n pred i w w w RMSEa n (1.2) whereWexp andWpred are respectively the experimental and predicted moisture

content, andn the number of data points. RMSEa measure the goodness of the model as percentage (%) of error between the experimental point and the predicted one.

It as been reported that the rigidity of both GAB and BET equations, in this work used to fit HPMC 603, HPMC 615 and PVA 4-98 experimental points, prevents an adequate goodness of fit between experimental and predicted data. In the range of aw = 0.9 – 1.0, GAB is perfectible [25] and BET seems to be

unsuitable to describe the sorption isotherm of amorphous polymer involving plastization and structural changes due the high amount of absorbed water aboveaw = 0.4 [26]. However, Tong et al. [27] have shown that BET equation

was adequate to model the water sorption of a dextran polymer (similar to HPMC) in the whole range of water activity. In Park’s model, which is only used to fit HPMC 603 and HPMC 615 experimental points, a different approach to moisture sorption is considered. GAB and BET models are based on a layer-by-layer condensation of water on adsorption surfaces (external as internal) whereas Park’s assumes an association of three mechanisms: a specific sorption (Langmuir’s law), a non specific sorption (Henry’s law) and a clustering mode (water aggregation) at high water activities. Park’s model is based on a 5 parameters equation. The Langmuir’s mode is characterized by AL, the concentration of specific sorption sites (polar groups, micro cavities or

porosities) andB, the affinity constant of water for these sites. Henry’s law is described by a constantKH, and the clustering mode is based on an equilibrium

constantKa and the average number of molecules in aggregatesn.

It is important to realize that GAB, BET and Park equations are empirical and based on theoretical assumptions.

1.2.5 Differential Scanning Calorimetry, DSC

Various water activities were considered from 0.8 to 0.03 by storing the powder formulations at eight different conditions. To obtain equilibrium moisture contents at constant temperatures standard saturated solutions of Ammonium Chloride, NH4Cl, Calcium Nitrate TetraHydrate, Ca(NO3)2 · 4H2O,

Magnesium acetate, (CH3COO)2Mg.4H2O, Calcium Chloride HexaHydrate,

(37)

13

were used to maintain constant vapour pressure. The powder formulations were also equilibrated at fixed ambient conditions (25 o_{C, 40-45 % RH). Glass}

desiccators containing the salt solutions were kept in temperature controlled rooms at 25o_{C. Samples of pure HPMC 603, HPMC 615 and PVA 4-98 powders}

were carefully weighed using a standard analytical balance (Model 204, Mettler, Toledo, Switzerland) and placed in each desiccators with the saturated salt solutions. At least triplicate samples of each formulation were stored inside each of the seven desiccators. Values for the water activity of the salt solutions at each temperature were experimentally measured using water activity apparatus (Novasina ms1, Novasina AG, Switzerland). The mass of the samples in the desiccators was measured periodically (PG8001-S, Mettler Toledo, Switzerland). When equilibrium (two successive readings were less than 1%) was reached (less than 2 months approximately) the moisture content of the samples were determined using thermogravimetry as described in Section 2.3. Table 1.2 reports the temperature and the water activity (at equilibrium) of the satured salts solutions used in this work.

Table 1.2: Water activity and temperatures of the satured salts solutions used to equilibrate the formulations

Salts - Equilibrium conditions Temperature [o_C] _{Water Activity, a}_w

Ammonium Chloride, NH4Cl 25 0.791

Calcium Nitrate TetraHydrate, Ca(NO3)2 · 4H2O 25 0.668

Magnesium acetate, (CH3COO)2Mg.4H2O 25 0.58

Calcium Chloride HexaHydrate, CaCl2· 6H2O 25.1 0.349

Lithium chloride, LiCl 25 0.2

Silica Gel 25 0.08

Phosphorus Pentoxide, P2O5 23 0.003

Differential Scanning Calorimetry studies of HPMC 603, HPMC 615 and PVA 4-98 were performed using a DSC 821e (Mettler Toledo AG, Giessen, Germany) equipped with an automatic refrigerated cooling accessory (RCS) and modulated capability, an auto-sampler tray (TSO 801R0 Mettler Toledo) and a thermal analysis data system. Nitrogen was used as the purge gas at a flow rate of 40 mL min-1_{. The calorimeter was automatically calibrated for}

baseline using no pans, for cell constant using indium (melting point 156.61 ºC, enthalpy of fusion 28.71 J g.1), and for temperature and heat capacity using Indium and Tin (St). After storage at conditions listed in Table 2 the samples were accurately weighed (5-15 mg) in aluminium light pans (Al SEIKO capsule, 20 l), covered with the lid, hermetically sealed, to prevent escape of vaporized moisture due to pressure build-up during heating cycle, and then loaded on an auto-sampler tray. The HPMC samples were heated from 25 °C to 225 °C,

(38)

14

stabilized at 225 °C for 5 minutes, quenched to 25 °C, stabilized at 25 °C for 5 minutes and then reheated to 225 °C always at a rate of 10 °C/min. The PVA samples were first chilled immediately to -20 °C and held at -20 °C for 5 min. Therefore they were up to 120 °C, stabilized at 120 °C for 5 minutes, quenched to -20 °C, stabilized at -20 °C for 5 minutes and then reheated to 120 °C always at a rate of 10 °C/min. Tg is reported as the midpoint of the glass transition

during both first and second heating. The samples pans were re-weighted after the test and the actual water content, wc, was calculated using Equation 1. The

measurements for each formulation at each RH condition were made at least in duplicate.

Several equations describe the influence of water on glass transition. Data fittings based on the linear model, Gordon-Taylor [18], Fox [28] and Roos [29] have been carried out in order to predict the glass transition temperature as function of water content, Fox and Roos equations. In the present study a value of -135 o_{C was taken as glass transition of the water while the glass}

transition of the product stored in Phosphorus Pentoxide, P2O5 was taken asTg

of solid dry polymer.

1.3 Results and Discussion

1.3.1 X-Ray Diffraction, XRD

X-Ray Diffraction was used to study the crystallinity-amorphous structure of the bulk powders of the HPMC 603, HPMC 615 and PVA 4-98. The three patterns are shown in Figure 1. The HPMC 603 and HPMC 615 showed two broad specific amorphous bands in the range 2 = 10-11 o_{and 2 =20-21} o

as evident in Fig. 1.1a and Fig. 1.1b [30-34].

Figure 1.1c shows the XRD pattern of PVA 4-98 bulk solid. PVA 4-98 is a crystalline polymer and the three typical diffractions peaks at 2 = 19.9 o_{, 23} o

and 40.7 o_{are evident in the plot [35-36]. The crystalline peak of PVA 4-98 is}

given by the interference of the polymer chains in the direction of the hydrogen bonds [37]. More PVA chains stuck together, larger the size of the crystallite and more intense the corresponding peak.

(39)

15

Fig. 1.1: X-Ray diffraction patterns of bulk HPMC 603 (a), HPMC 615 (b) and PVA 4-98 (c)

1.3.1 Thermogravimetry, TG

The thermal stability at a heating rate of 10 o_{C/min, under nitrogen,}

was investigated and the water content, the corresponding maximum temperature of thermal degradation and the percentage of solid residue at 525

(40)

16

Fig. 1.2: Thermo Gravimetric curves between 25o_{C and 525}o_{C for the polymer HPMC}

603 (dotted line), HPMC 615 (dashed line) and PVA 4-98 (solid line) at a heating rate of 10 °C min1_.

In Figure 1.2 the TG curves of HPMC 603, HPMC 615 and PVA 4-98 are shown. The maximum temperature of degradation, the percentage of mass loss in each stage of degradation and percentage of solid residue at 500 °C, are reported in Table 1.3.

Table 1.3: Thermogravimetry parameters for HPMC 603, HPMC 615 and PVA 4-98 Mass loss [%]

Polymer

25-70o_C _25-150o_C

Temperatures of

degradation [°C]. Residual mass at500 °C [%] HPMC 603 1.29 1.41 280-300 5.49 HPMC 615 1.54 1.73 280-300 8.02 PVA 4-98 0.41 4.03 280-300 11.29

The obtained curves show a rapid mass loss from ambient temperature to 70°C for HPMC 603 and HPMC 615 whereas, within the same temperature range, only a small mass loss has been detected for PVA 4-98. HPMC 603 and HPMC 615 had only one stage of degradation at Tdeg = 376.5 °C and Tdeg = 382.8 °C

respectively [38] measured in correspondence of 80% mass loss indicating that HPMC 603 is less thermally stable than HPMC 615. The quick loss in mass was attributed to evaporation of not-bounded moisture present on the surface of the solids. The PVA 4-98 had two main stages of degradation: the first one with Tdeg at 396 °C and 484 °C corresponding to 62.04% and 86.65% of mass