Inhoudsopgave
1 Agglomeration – granulation ................................................................................................... 5
1.1 Inleiding ................................................................................................................................ 5
1.2 Waarom granulatie? .............................................................................................................. 5
1.2.1 Voor- en nadelen van granulatie ....................................................................................... 5
1.2.2 Probleemgevallen ........................................................................................................... 5
1.3 Productiemethoden van granules ........................................................................................... 6
1.4 Wet granulation / natte granulatie ........................................................................................... 6
1.4.1 Deeltjesgroei ................................................................................................................... 7
1.4.2 Rol van bindmiddel .......................................................................................................... 8
1.4.3 Van vloeistofbruggen naar vaste bruggen .......................................................................... 9
1.4.4 High-shear granulatie .................................................................................................... 10
1.4.5 Low-shear granulatie ..................................................................................................... 10
1.4.6 Droogmethodes (high & low shear granulatie) ................................................................. 11
1.4.7 Fluid-bed granulation .................................................................................................... 11
1.4.8 Parameters die de granule-eigenschappen beïnvloeden.................................................. 13
1.4.9 Process monitoring / end point detection ....................................................................... 18
1.4.10 Voor- en nadelen van wet granulation ............................................................................. 18
1.5 Smeltgranulatie (melt granulation).........................................................................................19
1.6 Dry granulation .....................................................................................................................20
1.6.1 Deeltjesbinding in droge granulatie ................................................................................ 20
1.6.2 Compactie en vermaling ................................................................................................ 20
1.6.3 Voor- en nadelen ........................................................................................................... 22
1.7 Pellets .................................................................................................................................22
1.7.1 Sferische granules vs. onregelmatige granules................................................................ 22
1.7.2 Toepassingen ................................................................................................................ 22
1.7.3 Technieken ................................................................................................................... 23
1.8 Alternatieve granulatiemethoden...........................................................................................28
1.8.1 Spray drying .................................................................................................................. 28
1.8.2 Prilling .......................................................................................................................... 29
1.9 Kwaliteitscontrole van granules .............................................................................................30
2 Tablets ................................................................................................................................. 32
2.1 Inleiding ...............................................................................................................................32
2.2 Formulatie van tabletten .......................................................................................................33
2.2.1 Werkzame stof (API) ...................................................................................................... 33
2.2.2 Hulpstoffen ................................................................................................................... 35
2.3 Productieprocessen .............................................................................................................40
2.3.1 Directe compressie (DC)................................................................................................ 40
2.3.2 Granulatie ..................................................................................................................... 41
1
, 2.3.3 Tabletpers ..................................................................................................................... 41
2.4 Tabletsoorten en toepassingen .............................................................................................43
2.4.1 MUPS tabletten ............................................................................................................. 47
2.5 Compressie proces ..............................................................................................................48
2.5.1 Basisbegrippen ............................................................................................................. 48
2.5.2 Fysische veranderingen tijdens compressie .................................................................... 48
2.5.3 Mechanismen tijdens compressie .................................................................................. 48
2.5.4 Effect van compressiekracht.......................................................................................... 50
2.5.5 Effect van partikelgrootte ............................................................................................... 50
2.5.6 Effect van vocht & compressiesnelheid .......................................................................... 50
2.5.7 Rol van lubricantia (glijmiddelen) ................................................................................... 51
2.6 Kwaliteitscontrole van tabletten ............................................................................................51
3 Coated formulations ............................................................................................................. 54
3.1 Inleiding ...............................................................................................................................54
3.2 Types coatings......................................................................................................................55
3.2.1 Film coated tablets........................................................................................................ 55
3.2.2 Sugar coated tablets (dragees) ....................................................................................... 60
3.2.3 Gastro resistant coatings ............................................................................................... 62
3.3 Controles en kwaliteitsaspecten ...........................................................................................63
4 Controlled release ................................................................................................................ 64
4.1 Inleiding ...............................................................................................................................64
4.2 Soorten gecontroleerde afgifte ..............................................................................................64
4.3 Vereisten voor gecontroleerde afgifte.....................................................................................65
4.4 Mechanismen voor gecontroleerde afgifte .............................................................................66
4.5 Biofarmaceutische aspecten.................................................................................................74
4.5.1 Verschil single-unit vs. multi-unit systemen (MUPS) ........................................................ 74
4.5.2 Invloed maagdarmmotiliteit ........................................................................................... 74
5 Parenterals........................................................................................................................... 75
5.1 Inleiding ...............................................................................................................................75
5.2 Types en toedieningsroutes ...................................................................................................76
5.3 Hulpstoffen en additieven .....................................................................................................78
5.4 Verpakking en compatibiliteit ................................................................................................79
5.5 Productie .............................................................................................................................80
5.6 Toedieningssystemen ...........................................................................................................82
5.7 Speciale gevallen en toepassingen ........................................................................................83
5.8 Controles .............................................................................................................................87
2
,6 Freeze drying ........................................................................................................................ 88
6.1 Inleiding ...............................................................................................................................88
6.2 De 3 hoofdfasen van het proces ............................................................................................88
6.3 Apparatuur ...........................................................................................................................93
6.4 Verpakking en toebehoren.....................................................................................................94
6.5 Formulatieaspecten .............................................................................................................95
6.6 Evaluatie eindproduct ...........................................................................................................96
7 Inhalable formulations.......................................................................................................... 97
7.1 Inleiding ...............................................................................................................................97
7.2 Toedieningsvormen en devices..............................................................................................99
7.2.1 pMDI (pressurized metered dose inhalers) ...................................................................... 99
7.2.2 DPI (dry powder inhalers) ............................................................................................. 102
7.2.3 Nebulisatoren ............................................................................................................. 107
7.2.4 Soft mist inhalers (Respimat) ....................................................................................... 108
7.3 Depositie & farmacokinetiek ............................................................................................... 109
7.3.1 Depositie .................................................................................................................... 109
7.3.2 Aerodynamische diameter, MMAD, GSD....................................................................... 111
7.3.3 Optimale deeltjesgrootte i.f.v. de applicatie.................................................................. 112
7.4 Controle & kwaliteitsaspecten............................................................................................. 112
3
, Farmaceutische Technologie
General flow per dosage form:
* Formulation: API + excipients
* Technical aspects:
o Production process
o Effect of process variables on quality of the dosage form
* Biopharmaceutical aspects
o Effect on release
o Bioavailability
o Stability
o Production
* Controls: quality requirements
4
1 Agglomeration – granulation ................................................................................................... 5
1.1 Inleiding ................................................................................................................................ 5
1.2 Waarom granulatie? .............................................................................................................. 5
1.2.1 Voor- en nadelen van granulatie ....................................................................................... 5
1.2.2 Probleemgevallen ........................................................................................................... 5
1.3 Productiemethoden van granules ........................................................................................... 6
1.4 Wet granulation / natte granulatie ........................................................................................... 6
1.4.1 Deeltjesgroei ................................................................................................................... 7
1.4.2 Rol van bindmiddel .......................................................................................................... 8
1.4.3 Van vloeistofbruggen naar vaste bruggen .......................................................................... 9
1.4.4 High-shear granulatie .................................................................................................... 10
1.4.5 Low-shear granulatie ..................................................................................................... 10
1.4.6 Droogmethodes (high & low shear granulatie) ................................................................. 11
1.4.7 Fluid-bed granulation .................................................................................................... 11
1.4.8 Parameters die de granule-eigenschappen beïnvloeden.................................................. 13
1.4.9 Process monitoring / end point detection ....................................................................... 18
1.4.10 Voor- en nadelen van wet granulation ............................................................................. 18
1.5 Smeltgranulatie (melt granulation).........................................................................................19
1.6 Dry granulation .....................................................................................................................20
1.6.1 Deeltjesbinding in droge granulatie ................................................................................ 20
1.6.2 Compactie en vermaling ................................................................................................ 20
1.6.3 Voor- en nadelen ........................................................................................................... 22
1.7 Pellets .................................................................................................................................22
1.7.1 Sferische granules vs. onregelmatige granules................................................................ 22
1.7.2 Toepassingen ................................................................................................................ 22
1.7.3 Technieken ................................................................................................................... 23
1.8 Alternatieve granulatiemethoden...........................................................................................28
1.8.1 Spray drying .................................................................................................................. 28
1.8.2 Prilling .......................................................................................................................... 29
1.9 Kwaliteitscontrole van granules .............................................................................................30
2 Tablets ................................................................................................................................. 32
2.1 Inleiding ...............................................................................................................................32
2.2 Formulatie van tabletten .......................................................................................................33
2.2.1 Werkzame stof (API) ...................................................................................................... 33
2.2.2 Hulpstoffen ................................................................................................................... 35
2.3 Productieprocessen .............................................................................................................40
2.3.1 Directe compressie (DC)................................................................................................ 40
2.3.2 Granulatie ..................................................................................................................... 41
1
, 2.3.3 Tabletpers ..................................................................................................................... 41
2.4 Tabletsoorten en toepassingen .............................................................................................43
2.4.1 MUPS tabletten ............................................................................................................. 47
2.5 Compressie proces ..............................................................................................................48
2.5.1 Basisbegrippen ............................................................................................................. 48
2.5.2 Fysische veranderingen tijdens compressie .................................................................... 48
2.5.3 Mechanismen tijdens compressie .................................................................................. 48
2.5.4 Effect van compressiekracht.......................................................................................... 50
2.5.5 Effect van partikelgrootte ............................................................................................... 50
2.5.6 Effect van vocht & compressiesnelheid .......................................................................... 50
2.5.7 Rol van lubricantia (glijmiddelen) ................................................................................... 51
2.6 Kwaliteitscontrole van tabletten ............................................................................................51
3 Coated formulations ............................................................................................................. 54
3.1 Inleiding ...............................................................................................................................54
3.2 Types coatings......................................................................................................................55
3.2.1 Film coated tablets........................................................................................................ 55
3.2.2 Sugar coated tablets (dragees) ....................................................................................... 60
3.2.3 Gastro resistant coatings ............................................................................................... 62
3.3 Controles en kwaliteitsaspecten ...........................................................................................63
4 Controlled release ................................................................................................................ 64
4.1 Inleiding ...............................................................................................................................64
4.2 Soorten gecontroleerde afgifte ..............................................................................................64
4.3 Vereisten voor gecontroleerde afgifte.....................................................................................65
4.4 Mechanismen voor gecontroleerde afgifte .............................................................................66
4.5 Biofarmaceutische aspecten.................................................................................................74
4.5.1 Verschil single-unit vs. multi-unit systemen (MUPS) ........................................................ 74
4.5.2 Invloed maagdarmmotiliteit ........................................................................................... 74
5 Parenterals........................................................................................................................... 75
5.1 Inleiding ...............................................................................................................................75
5.2 Types en toedieningsroutes ...................................................................................................76
5.3 Hulpstoffen en additieven .....................................................................................................78
5.4 Verpakking en compatibiliteit ................................................................................................79
5.5 Productie .............................................................................................................................80
5.6 Toedieningssystemen ...........................................................................................................82
5.7 Speciale gevallen en toepassingen ........................................................................................83
5.8 Controles .............................................................................................................................87
2
,6 Freeze drying ........................................................................................................................ 88
6.1 Inleiding ...............................................................................................................................88
6.2 De 3 hoofdfasen van het proces ............................................................................................88
6.3 Apparatuur ...........................................................................................................................93
6.4 Verpakking en toebehoren.....................................................................................................94
6.5 Formulatieaspecten .............................................................................................................95
6.6 Evaluatie eindproduct ...........................................................................................................96
7 Inhalable formulations.......................................................................................................... 97
7.1 Inleiding ...............................................................................................................................97
7.2 Toedieningsvormen en devices..............................................................................................99
7.2.1 pMDI (pressurized metered dose inhalers) ...................................................................... 99
7.2.2 DPI (dry powder inhalers) ............................................................................................. 102
7.2.3 Nebulisatoren ............................................................................................................. 107
7.2.4 Soft mist inhalers (Respimat) ....................................................................................... 108
7.3 Depositie & farmacokinetiek ............................................................................................... 109
7.3.1 Depositie .................................................................................................................... 109
7.3.2 Aerodynamische diameter, MMAD, GSD....................................................................... 111
7.3.3 Optimale deeltjesgrootte i.f.v. de applicatie.................................................................. 112
7.4 Controle & kwaliteitsaspecten............................................................................................. 112
3
, Farmaceutische Technologie
General flow per dosage form:
* Formulation: API + excipients
* Technical aspects:
o Production process
o Effect of process variables on quality of the dosage form
* Biopharmaceutical aspects
o Effect on release
o Bioavailability
o Stability
o Production
* Controls: quality requirements
4
