Extended release of theophylline

from ethylcellulose coated pellets:

preparation and characterization

M. Margherita Cafaro

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UNIVERSITÀ DEGLI STUDI DI SALERNO

Facoltà di Ingegneria Dipartimento di Ingegneria Industriale

Corso di Laurea Magistrale in Ingegneria Chimica

Extended release of theophylline from ethylcellulose coated pellets: preparation and characterization

Master’s Thesis in Chemical Engineering

Relatori: Candidata:

Prof. Gaetano Lamberti Maria Margherita Cafaro

Prof. Anna Angela Barba Matricola: 0622200160

Prof. Anette Larsson

Anno Accademico 2014/2015

The experimental part of this thesis work has been performed during the Erasmus project at Chalmers University of Technology, Göteborg, Sweden. It has been developed at the Department of Chemistry and Chemical Engineering, in the Pharmaceutical Technology, under the supervision of Prof. Anette Larsson and Dr. Jurgita Kazlauske.

La parte sperimentale di questo lavoro di tesi è stata svolta nell’ambito del progetto Erasmus presso Chalmers University of Technology, Göteborg, Svezia, al Dipartimento di Chimica ed Ingegneria Chimica, in Tecnologie Farmaceutiche sotto la supervisione della Prof.ssa Anette Larsson e della Dott.ssa Jurgita Kazlauske.

To my crazy family

Questo testo è stato stampato in proprio, in Times New Roman La data prevista per la discussione della tesi è il 10 Giugno 2015 Fisciano, 1 Giugno 2015

Contents

Contents ........................................................................... I

List of Figures ................................................................. V

List of Tables ................................................................ IX

Sommario ...................................................................... XI

Abstract ..................................................................... XIII

Introduction ..................................................................... 1

1.1 Introduction ............................................................... 2

1.1.1 Controlled release formulations _____________________ 2

1.1.2 Film formation from aqueous based polymeric dispersions ______________________________________ 3

1.2 State of the art ........................................................... 4

1.2.1 Importance of the starter core on aqueous based coatings 4

1.2.2 Importance of the coating level and type of plasticizer on aqueous based coatings __________________________ 9

1.3 Aims ......................................................................... 15

Materials and Methods ................................................. 17

[I]

II Extended release of theophylline from coated pellets M. Margherita Cafaro

2.1 Materials ................................................................. 18

2.1.1 Microcrystalline cellulose pellets __________________ 18

2.1.2 Theophylline __________________________________ 19

2.1.3 Surelease _____________________________________ 19

2.2 Methods ................................................................... 21

2.2.1 Free standing film ______________________________ 21

2.2.1.1 Preparation of Surelease free film ________________ 21

2.2.1.2 Film morphology _____________________________ 22

2.2.1.2.1 Leaching of the films 22

2.2.1.2.2 Scanning electron microscopy 22

2.2.1.3 Permeability study ____________________________ 23

2.2.1.3.1 Theory 23

2.2.1.3.2 Experimental part 25

2.2.1.4 Mechanical testing ____________________________ 26

2.2.2 Coated pellets _________________________________ 26

2.2.2.1 Preparation of coated pellets ____________________ 26

2.2.2.2 Pellet morphology ____________________________ 29

2.2.2.2.1 Leaching of the pellets 29

2.2.2.2.2 Pellets’ average coating thickness 29

2.2.2.2.3 Scanning electron microscopy 30

2.2.2.3 Drug release from a whole dose __________________ 30

2.2.2.4 Sensitivity to the osmolality of the release medium __ 31

2.2.2.5 Single pellet release ___________________________ 31

2.2.2.6 Swelling test ________________________________ 31

Results and Discussion ................................................. 33

3.1 Free film .................................................................. 34

3.1.1 Film morphology _______________________________ 34

3.1.2 Determination of permeability coefficient ___________ 35

III

3.1.3 Tensile testing _________________________________ 41

3.2 Coated pellets ........................................................... 42

3.2.1 Pellets morphology _____________________________ 42

3.2.1.1 Morphology of pellets with coating thickness 20 μm 43

3.2.1.2 Morphology of pellets with coating thickness 30 μm 44

3.2.1.3 Morphology of pellets with coating thickness 60 μm 45

3.2.2 Real coating thickness ___________________________ 46

3.2.3 Dose release ___________________________________ 49

3.2.3.1 Release from a whole dose of pellets with coating thickness 20 µm50

3.2.3.2 Release from a whole dose of pellets with coating thickness 30 µm51

3.2.3.3 Release from a whole dose of pellets with coating thickness 60 µm52

3.2.3.4 Dose release: comparison different thicknesses 53

3.2.4 Sensitivity to the osmolality of the release medium ____ 54

3.2.5 Single pellet release _____________________________ 59

3.2.5.1 Release from single pellets with coating thickness 20 µm 61

3.2.5.2 Release from single pellets with coating thickness 30 µm 66

3.2.5.3 Release from single pellets with coating thickness 60 µm 70

3.2.5.4 Single pellets release and whole dose release 73

3.2.6 Swelling behaviour _____________________________ 74

Conclusions .................................................................... 79

4.1 Conclusions .............................................................. 80

4.2 Perspectives .............................................................. 81

Appendix ........................................................................ 83

A.1 UV-Vis Calibration curves ..................................... 84

A.1.1 Theophylline in phosphate buffer ph 6.8(Cary 60 UV-Vis, Agilent Technologies) ________________________ 85

A.1.2 Theophylline in Milli-Q water (Cary 60 UV-Vis, Agilent Technologies) ____________________________ 86

IV Extended release of theophylline from coated pellets M. Margherita Cafaro

A.1.3 Theophylline in phosphate buffer ph 6.8(SpectraMax M2, Molecular Devices) __________________________ 87

References ..................................................................... 89

Acknowledgments ......................................................... 91

V

List of Figures

Figure 1. Blood drug concentration in the time; Green line: intravenous injection; Blue line: oral administration (quick response); Black line: oral administration; Yellow line: multiple administrations; Pink line: optimal administration (controlled release system) ....................................................... 2

Figure 2. Major steps in film formation from an aqueous polymeric dispersion. (A)Atomization of fine droplets and impingement onto the substrate surface; (B) water evaporation causes close packing of polymer spheres; (C) further water evaporation causes polymer deformation and coalescence to form the film [6] 4

Figure 3. Importance of the type of starter core (indicated in the figure) on diltiazem HCl release from pellets coated with ethylcellulose:PVA-PEG graft copolymer 90:10 in 0.1 N HCl (coating level: 25%)[11] .................................. 5

Figure 4. Effects of the coating level (indicated in the figures) on drug release from ethylcellulose: PVA-PEG graft copolymer 90:10 coated diltiazem HCl layered: (A) MCC cores and (B) sealed sugar cores in 0.1 N HCl[11] .............. 6

Figure 5. Impact of the osmolality of the release medium (indicated in the figures) on drug release from different types of diltiazem HCl layered starter cores coated with ethylcellulose: PVA-PEG graft copolymer 90:10. The release media are shown at the top, the type of cores is indicated on the left (coating level: 25%, the stars indicate non-physiological conditions)[11] ...................... 7

Figure 6. Drug release from single pellets coated with ethylcellulose: PVA-PEG graft copolymer 90:10 in 0.1 N HCl, containing: (a) sugar cores, (b) MCC cores, (c) sealed sugar cores (coating level: 25%). For reasons of comparison also drug release from ensembles of pellets is shown[11] ................................................ 8

Figure 7. Effects of the coating level and curing conditions on drug release from diltiazem HCl-layered sugar cores coated with aqueous ethylcellulose dispersion plasticized with TEC (symbols and thin curves: experiments; thick curves: theory)[12] .................................................................................................... 10

Figure 8. Effects of the coating level and curing conditions on drug release from diltiazem HCl-layered sugar cores coated with aqueous ethylcellulose dispersion plasticized with DBS (symbols and thin curves: experiments; thick curves: theory)[12] .................................................................................................... 11

VI Extended release of theophylline from coated pellets M. Margherita Cafaro

Figure 9. Effects of the coating level and curing conditions on drug release from diltiazem HCl-layered sugar cores coated with aqueous ethylcellulose dispersion plasticized with Myvacet (symbols and thin curves: experiments; thick curves: theory)[12]..................................................................................................... 12

Figure 10. Effects of the type of plasticizer on diltiazem HCl release from pellets coated with aqueous ethylcellulose dispersion. The coating level and curing conditions are indicated in the figure[12] ............................................ 13

Figure 11. Schematic diagram of coated pellets.............................................. 15

Figure 12. Cellets® 500 ................................................................................. 18

Figure 13. Theophylline chemical structure.................................................... 19

Figure 14. Schematic representation of the equipment Gandalf 2 [14] ............ 21

Figure 15. Diffusion cells used for permeability testing ................................. 25

Figure 16 Gandalf 0 equipment [15] .............................................................. 27

Figure 17. SEM pictures of free standing film cross-section: non-leached (a,b); leached (c,d) .................................................................................................. 34

Figure 18. Determination of water permeability for Surelease free standing film (sample 1). Donor compartment: pure water .................................................. 35

Figure 19. Determination of water permeability for Surelease free standing film (sample 2). Donor compartment: pure water .................................................. 36

Figure 20. Determination of water permeability for Surelease free standing film (sample 3). Donor compartment: pure water .................................................. 36

Figure 21. Determination of water permeability for Surelease free standing film (sample 1). Donor compartment: solution of theophylline in water ................ 37

Figure 22. Determination of Theophylline permeability for Surelease free standing film (sample 1) ................................................................................ 38

Figure 23. Determination of water permeability for Surelease free standing film (sample 2). Donor compartment: solution of theophylline in water ................ 38

Figure 24. Determination of Theophylline permeability for Surelease free standing film (sample 2) ................................................................................ 39

Figure 25. Determination of water permeability for Surelease free standing film (sample 3). Donor compartment: solution of theophylline in water ................ 39

Figure 26. Determination of Theophylline permeability for Surelease free standing film (sample 3) ................................................................................ 40

Figure 27. Free film Stress-Strain results ....................................................... 41

Figure 28. SEM pictures of Cellets® 500 (a,b,c) and Theophylline-HPMC (90:10) pellets (d,e,f) ..................................................................................... 43

Figure 29. SEM pictures of theophylline-HPMC pellets coated with Surelease (coating thickness=20 μm): before leaching (a,b,c); after leaching (d,e,f) ....... 44

VII

Figure 30. SEM pictures of theophylline-HPMC pellets coated with Surelease (coating thickness=30 μm): before leaching (a,b,c); after leaching (d,e,f) ....... 45

Figure 31. SEM pictures of theophylline-HPMC pellets coated with Surelease (coating thickness=60 μm): before leaching (a,b,c); after leaching (d,e,f) ....... 46

Figure 32. Cross-section of cut pellet with coating thickness 20 µm .............. 47

Figure 33 Cross-section of cut pellet with coating thickness 30 µm ............... 48

Figure 34 Cross-section of cut pellet with coating thickness 60 µm ............... 49

Figure 35. Theophylline release over time from a whole dose of pellets without ethylcellulose coating .................................................................................... 50

Figure 36. Theophylline release over time from a whole dose of pellets with coating thickness 20 µm ................................................................................ 51

Figure 37.Theophylline release over time from a whole dose of pellets with coating thickness 30 µm ................................................................................ 52

Figure 38. Theophylline release over time from a whole dose of pellets with coating thickness 60 µm ................................................................................ 53

Figure 39. Theophylline release over time from a whole dose of pellets: comparison different coating thicknesses ....................................................... 54

Figure 40. Effect of the osmotic pressures in the release media on theophylline release rate from a whole dose of coated pellets (coating thickness 30 µm) .... 55

Figure 41. Impact of the osmolality of phosphate buffer pH 7.4 on the release diltiazem HCl from MCC pellets coated with EC dispersion, containing 10% (w/w) PVA-PEG graft copolymer, stabilized by TEC (coating level 25%). The original picture is shown at page 7 ................................................................. 55

Figure 42. Linear fitting of theopylline release curves at different osmotic pressure in the release medium (Figure 40) .................................................... 56

Figure 43. Linear fitting of diltiazem HCl release curves at different osmotic pressure in the release medium (Figure 41) .................................................... 57

Figure 44. Slope of theophylline release curves at different osmolality of the release medium .............................................................................................. 58

Figure 45. Slope of the diltiazem HCl release curves at different osmolality of the release medium ........................................................................................ 59

Figure 46. Single pellets release: pellets without ethylcellulose coating (n=24)60

Figure 47. Average curve of single pellet release from uncoated pellets ......... 60

Figure 48. Comparison between single pellet release average curve and release curve from a whole dose for uncoated pellets................................................. 61

Figure 49. Single pellets release: coating thickness 20 µm (n=48).................. 62

Figure 50. Single pellets release: coating thickness 20 µm (group 1) .............. 63

Figure 51. Single pellets release: coating thickness 20 µm (group 2) .............. 63

VIII Extended release of theophylline from coated pellets M. Margherita Cafaro

Figure 52. Single pellets release: coating thickness 20 µm (group 3) .............. 64

Figure 53. Single pellets release: coating thickness 20 µm (group 4) .............. 65

Figure 54. Single pellets release: coating thickness 20 µm (group 5) .............. 66

Figure 55. Single pellets release: coating thickness 30 µm(n=48) ................... 67

Figure 56. Single pellets release: coating thickness 30 µm (group 1) .............. 67

Figure 57. Single pellets release: coating thickness 30 µm (group 2) .............. 68

Figure 58. Single pellets release: coating thickness 30 µm (group 3) .............. 69

Figure 59. Single pellets release: coating thickness 30 µm (group 4) .............. 70

Figure 60. Single pellets release: coating thickness 60 µm (n=48) .................. 70

Figure 61. Single pellets release: coating thickness 60 µm (group 1) .............. 71

Figure 62. Single pellets release: coating thickness 60 µm (group 2) .............. 72

Figure 63. Single pellets release: coating thickness 60 µm (group 3) .............. 72

Figure 64. Single pellets release: average curves ............................................ 73

Figure 65. Comparison between single pellet release average curves and release curves from a whole dose............................................................................... 74

Figure 66. Example of the method used to monitor pellets swelling by optical microscopy .................................................................................................... 75

Figure 67. Swelling behaviour of pellets with coating thickness 20 µm ......... 76

Figure 68. Swelling behaviour of pellets with coating thickness 30 µm ......... 77

Figure 69. Swelling behaviour of pellets with coating thickness 60 µm ......... 77

Figure 70. Comparison of swelling behaviour for different coating thicknesses ...................................................................................................................... 78

Figure 71. Calibration curve of theophylline in phosphate buffer pH 6.8 (Cary 60 UV-Vis, Agilent Technologies) ................................................................. 85

Figure 72. Calibration curve of theophylline in Milli-Q water (Cary 60 UV-Vis, Agilent Technologies) .................................................................................... 86

Figure 73. Calibration curve of theophylline in phosphate buffer pH 6.8 (SpectraMax M2, Molecular Devices)............................................................ 87

IX

List of Tables

Table 1. Characteristics of Cellets® 500 ........................................................ 18

Table 2. Theophylline properties ................................................................... 19

Table 3. Surelease 20 composition ................................................................. 20

Table 4. Conditions used to spray Surelease free film .................................... 22

Table 5. Conditions of coating step I.............................................................. 28

Table 6. Conditions of coating step II ............................................................ 29

Table 7. Water and theophylline permeability coefficients ............................. 40

Table 8. Results of free film tensile testing .................................................... 41

Table 9. Coating thickness measurements ...................................................... 49

Table 10. Fitting parameters of the release curves in Figure 42 ...................... 57

Table 11. Fitting parameters of the release curves in Figure 43 ...................... 58

Table 12. Measurements of pellets diameter over time after the exposure to phosphate buffer pH 6.8 ................................................................................ 76

Table 13. Comparison of swelling behaviour for different coating thicknesses.78

X Extended release of theophylline from coated pellets M. Margherita Cafaro

XI

Sommario

Una parte ricerca farmacologica è da anni dedicata allo studio di forme farmaceutiche a rilascio controllato. Uno dei metodi di preparazione di questi sistemi è quello dell’uso di un rivestimento prevalentemente di natura polimerica, involucro che per le forme farmaceutiche destinate alla via orale può avere anche altre funzioni, come ad esempio il camuffamento del cattivo sapore degli ingredienti della formulazione. Per anni sono state utilizzate, per produrre i rivestimenti, soluzioni organiche con polimeri opportunamente selezionati; attualmente la ricerca scientifica è sempre più orientata all’uso di rivestimenti ottenibili da dispersioni acquose per ragioni ambientali, di sicurezza e tossicità. Questo nuovo approccio formulativo è campo di sfida poiché molti studi preparativi e di caratterizzazione non sono stati ancora pienamente sviluppati e approfonditi. Lo scopo di questo lavoro di tesi è stato valutare le cinetiche ed i meccanismi di rilascio di principio attivo da una forma farmaceutica solida rivestita con una dispersione acquosa di etilcellulosa commerciale, il Surelease. Allo scopo di ottenere un rilascio controllato del farmaco, il Surelease è stato utilizzato per ricoprire una piattaforma di dosaggio micrometrica (pellet) strutturata a geometria sferica e costituita da tre strati: un core inerte di cellulosa microcristallina, uno strato di principio attivo composto da un farmaco modello, la Teofillina, e un polimero utilizzato come plastificante, l’ idrossipropil metilcellulosa (HPMC), ed in superficie il rivestimento polimerico di etilcellulosa. Le sferette ricoperte sono state preparate utilizzando un letto fluido. La preparazione, in particolare, è stata suddivisa in due fasi differenti: durante la prima fase il core inerte è irrorato con la soluzione di Teofillina e HPMC; durante la seconda fase ha luogo il rivestimento di etilcellulosa, sempre adoperando la stessa apparecchiatura. Allo scopo di investigare l’influenza dello

XII Extended release of theophylline from coated pellets M. Margherita Cafaro

spessore di ricoprimento sulla cinetica di rilascio del principio attivo, sono stati prodotti tre diverse tipologie di lotti di sferette ricoperte; lo spessore è stato modificato variando la quantità di dispersione di etilcellulosa impiegata durante la seconda fase di preparazione, ottenendo ricoprimenti di 20, 30 e 60 µm. Le sferette micrometriche sono state caratterizzate con diversi metodi. La microscopia elettronica a scansione (SEM) è stata utilizzata per studiare la morfologia e per misurare lo spessore effettivo dello strato di ricopertura in Surelease. Le proprietà di rilascio di sistemi di dosaggio approntati sono state investigate ponendo in immersione in tampone fosfato a pH 6.8, a 37°C e sotto agitazione controllata, sia lotti di microsferette ricoperte che microsferette singole. I test di rilascio condotti sui lotti di microsferette sono stati condotti per avere informazioni sulla cinetica di rilascio complessiva; i test di rilascio da microsferette singole sono stati effettuati per investigare il comportamento “non di massa” e l’eventuale presenza di fenomeni di lag time. Per i lotti di microsferette prodotte con spessore pari a 30 µm (ricoprimento con spessore di valore intermedio) sono stati condotti test di rilascio variando anche l’osmolalità del mezzo di rilascio, attraverso la solubilizzazione di NaCl, al fine di valutare l’influenza della pressione osmotica sulla cinetica di rilascio. Test di rigonfiamento (swelling) di lotti di microsferette sono stati effettuati per investigare l’effetto dell’espansione dello strato polimerico di HPMC sul film di Surelease di ricopertura, in particolare, per osservare la possibile formazione di fratture. Parallelamente alla preparazione delle microsferette ricoperte, sono stati condotti studi di resistenza a trazione meccanica e di permeabilità ad acqua e teofillina di film di Surelease ottenuti mediante lo spray di dispersioni su supporto inerte posizionato su un tamburo rotante. I risultati sperimentali mostrano che il metodo utilizzato per la preparazione delle microsferette ricoperte finalizzate al rilascio controllato del farmaco fornisce buoni risultati: la ricopertura di etilcellulosa ritarda significativamente il rilascio del farmaco e, variando lo spessore del ricoprimento, è possibile variare il tempo necessario affinché tutto il farmaco inizialmente caricato nella formulazione passi nel bulk di dissoluzione. Il meccanismo di rilascio predominante per la formulazione preparata e caratterizzata sembra essere diffusivo, poiché il film di etilcellulosa appare intatto dopo l’esposizione al mezzo di rilascio.

XIII

Abstract

A section of pharmaceutical research is dedicated to the study of controlled release formulations. One technique adopted to prepare this remedies consist of using a polymeric coating, in case of oral administrations the coating can have more functions, for example it can be used for taste masking applications. For many years coatings were produced using organic solutions of the chosen polymer, but nowadays the research is switching on coating based on aqueous dispersions because of the environment, safety and toxicity. Aqueous based coatings are a new challenge for many reasons and they have to be studied and characterized. The aim of this thesis work is to understand the mechanism of the active substance release from a solid formulation coated with a commercial aqueous dispersion of ethylcellulose, called Surelease®. In order to design a controlled release formulation, Surelease® was used to coat a spherical micrometric formulation (pellet) made of three layers: an inert core of microcrystalline cellulose, a layer of active substance made by a model drug, theophylline, and polymer used as plasticizer, hydroxypropyl methylcellulose (HPMC), and a polymeric layer of ethylcellulose. Pellets were prepared using a fluid bed coater equipment. The preparation was divided in two steps: during the first step the inert core was sprayed with a solution of theophylline and HPMC and during the second one the drug layered pellets were coated with the aqueous dispersion of ethylcellulose. Three different batches were made with three different coating thicknesses in order to understand the influence of coating thickness on the release rate of theophylline; the thickness of the coating was changed modifying the amount of dispersion used during the second phase of preparation, the values of thicknesses investigated are 20, 30 and 60 µm. Pellets were characterized with different methods. Scanning electron microscopy

XIV Extended release of theophylline from coated pellets M. Margherita Cafaro

was used on whole pellets to study them morphology and it was used on pellets cross-section to evaluate the real coating thickness. Drug release experiments from a whole dose of pellets and from single pellets were performed using phosphate buffer pH 6.8, at 37°C, under stirring. Whole dose release tests were used to evaluate the drug release curve. Single pellets release tests were used to understand if every pellet has the same release behaviour; this test was also used to check if the system is characterized by lag time. Drug release experiments from a whole dose of the batch with coating thickness 30 µm were performed, changing the osmolality of the release medium to understand the influence of it on the release rate. Pellets swelling behavior was investigated to check the formation of eventual cracks and fracture in the film. In order to characterize the only layer of coating, Surelease® free standing film was prepared, with a modified fluid bed equipment, spraying the ethylcellulose dispersion onto a rotating drum. Free film cross-section was investigated by scanning electron microscopy. Mechanical properties were determined by tensile testing. Several permeability studies were performed to determine water and drug permeability coefficients. It can be concluded, from the experimental data, that the technique used to prepare coated pellets intended for controlled release applications provided satisfying results: drug release rate over time is significantly delayed by the ethylcellulose layer; using different thickness of the coating the time needed to release the whole amount of drug in the formulation can be changed. The release mechanism predominant in this system seems to be drug diffusion.

88 Extended release of theophylline from coated pellets M. Margherita Cafaro

References

1. K. E. Uhrich, S. M. Cannizzaro, R. S. Langer, K. M. Shakesheff. Polymeric systems for controlled drug release. Chemical reviews. 1999,99(11) 3181-98

2. E. Kaunisto, M. Marucci, P. Borgquista, A. Axelssona, Mechanistic modelling of drug release from polymer-coated and swelling and dissolving polymer matrix systems, International Journal of Pharmaceutics 418 (2011) 54– 77

3. M. Marucci, G. Ragnarsson, U. Nyman, A. Axelsson, Mechanistic model for drug release during the lag phase from pellets coated with a semi-permeable membrane, Journal of Controlled Release 127 (2008) 31–40

4. M. Marucci, G. Ragnarsson, C. von Corswant, A. Welinder, A. Jarkeb, F. Iselaub, A. Axelssona, Polymer leaching from film coating: Effects on the coating transport properties, International Journal of Pharmaceutics 411 (2011) 43–48

5. F. Lecomte, J. Siepmann, M. Walther, R. J. MacRae, R. Bodmeier, Polymer Blends Used for the Coating of Multiparticulates: Comparison of Aqueous and Organic Coating Techniques, Pharmaceutical Research, 21 (2004) 882–890

6. L.A. Felton, Mechanisms of polymeric film formation, International Journal of Pharmaceutics 457 (2013) 423– 427

7. J. Siepmann, F. Siepmann, Stability of aqueous polymeric controlled release film coatings, International Journal of Pharmaceutics 457 (2013) 437– 445

8. F. Siepmann, J. Siepmann, M. Walther, R.J. MacRae, R. Bodmeier, Polymer blends for controlled release coatings, Journal of Controlled Release 125 (2008) 1–15

9. J. Hjaertstam, T. Hjertberg, 1999. Studies of the water permeability and mechanical properties of a film made of an ethyl cellulose–ethanol–water ternary mixture. Journal of Applied Polymer Science 74, 2056–2062.

[89]

90 Extended release of theophylline from coated pellets M. Margherita Cafaro

10. Y. Cuppok, S. Muschert, M. Marucci, J. Hjaertstam, F. Siepmann, A. Axelsson, J. Siepmann, Drug release mechanisms from Kollicoat SR:Eudragit NE coated pellets, International Journal of Pharmaceutics 409 (2011) 30–37

11. S. Muschert, F. Siepmann, B. Leclercq, B. Carlin, J. Siepmann, Prediction of drug release from ethylcellulose coated pellets, Journal of Controlled Release 135 (2009) 71–79

12. Q.W. Yang, M.P. Flament, F. Siepmann, V. Busignies, B. Leclerc, C. Herry, P. Tchoreloff, J. Siepmann, Curing of aqueous polymeric film coatings: Importance of the coating level and type of plasticizer, European Journal of Pharmaceutics and Biopharmaceutics 74 (2010) 362–370

13. M. Marucci, H. Andersson, J. Hjärtstam, G. Stevenson, J. Baderstedt, M. Stading, A. Larsson, C. Von Vorswant, New insights on how to adjust the release profile from coated pellets by varing the molecular weight of ethyl cellulose in the coating film, International Journal of Pharmaceutics 458 (2013) 218-223

14. M. Marucci, J. Arnehed, A. Jarke, H. Matic, M. Nicholas, C. Boissier, C. Von Vorswant, Effect of the manufacturing conditions on the structure and permeability of polymer films intended for coating undergoing phase separation, European Journal of Pharmaceutics and Biopharmaceutics 83 (2013) 301–306

15. U. M. Heckötter, A. Larsson, P. Sriamornsak, M. Kumpugdee-Vollrath, Effect of annealing time and addition of lactose on release of a model substance from Eudragit® RS coated pellets produced by a fluidized bed coater, Chemical Engineering Research and Design 89 (2011) 697–705

16. B. Brodin, B. Steffansen, C. U. Nielsen, Passive diffusion of drug substances: the concepts of flux and permeability. ULLA Pharmacy Series. (2010) 135-51

17. F. Siepmann, A. Hoffmann, B. Leclercq, B. Carlin, J. Siepmann, How to adjust desired drug release patterns from ethylcellulose-coated dosage forms, Journal of Controlled Release 119 (2007) 182–189

Acknowledgments

I really want to express my gratitude to prof. Anette Larsson for making this experience possible and wonderful, for all the help and the advices and for all the laughs; I am really pleased I have met such a nice person and professor. I am grateful to prof. Gaetano Lamberti and prof. Anna Angela Barba that also gave me the chance to live this experience and the support I needed during all the steps of this work. My sincere thanks to Dr. Jurgita Kazlauske for her availability, suggestions and aid during my experience in Chalmers and for her friendship. I am thankful to Dr. Mariagrazia Marucci from AstraZeneca, Mölndal, Sweden, for her skillful contribution and encouragement. I would like to acknowledge Dr Barbara Mikolaszek from the Medical University of Gdansk, Poland, for her valuable help and for inspiring ideas. I am obliged to Dr Diego Caccavo for his precious aid, (huge) patience and friendly encouragement. A very big thank to my family that everyday has to deal with the worst part of me. I would like to show my gratitude to all the people I met during my Erasmus experience: all the people of the Department of Pharmaceutical & Technology at Chalmers for the daily little helps, the guys in the master students’ room for all the fun and laughs, my amazing kitchen mates in Kjellmansgatan for their friendship and last, but not the least my fika group for all the crazy adventures. I am thankful to the group of Transport Phenomena & Processes at University of Salerno and to my class mates for all the daily support.

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