7th Training School on Microencapsulation Strasbourg. Februar 2015 Textmasterformat in Mastervorlage eingeben

Transcription

1 7th Training School on Microencapsulation Strasbourg Februar

2 Dr. Anne Ettner, Glatt Pharmaceutical Services 2

3 Overview 1. Introduction 2. Fluid bed equipment 3. Basics of fluid bed Wurster technology 4. Characteristics of Bottom spray processes 5. Formulation and process parameters 6. Case Studies 3

4 1. Introduction: Pharmaceutical Pellets 4

5 1. Introduction: Pharmaceutical Pellets Spherical particles with smooth and uniform surface Particle size range: µm Narrow particle size distribution Layering of active pharmaceutical ingredients and coating (functional) excipients 5

6 1. Introduction: Pharmaceutical Pellets Formulation concepts for modified release preparations Matrix approach uniform and homogenous matrix Membrane approach multi-layer composition 6

7 1. Introduction: Pharmaceutical Pellets Formulation concepts for modified release preparations Coating of pellets required for: - Delayed release preparations - Extended release products - Taste masking 7

8 1. Introduction: Pharmaceutical Pellets Benefits - reduced variability in dosage (low intra- and inter- individual variability) - controlled onset time of drug release - delivery of API to distal sites within GI tract Pellets can be administered as capsules, tablets, sachets and oral suspensions 8

9 1. Introduction: State-of-the-art Pelletization Technologies Extrusion / Spheronization - Multitude of manufacturing steps Multitude of manufacturing equipment (mixing, wet granulation, extrusion, spheronization, drying, sieving, coating) - Particle size > 500 µm - Broad particle size distribution - Mostly particles not totally spherical 9

10 1. Introduction: State-of-the-art Pelletization Technologies Fluid Bed Layering (e.g. Wurster) - Drug layering onto starter material - Could be time consuming process for high drug loaded products - Narrower particle size distribution compared to extrusion/spheronization Direct pelletization: Rotor fluid bed granulator - Broad particle size distribution 10 10

11 1. Introduction: Fluid bed process for pellets manufacturing starting beads (drug layering liquid) coating liquid(s) application of liquid(s) on pellets no losses no agglomerates specified dissolution profile to be achieved 11 11

12 1. Introduction: Fluid bed process for pellets manufacturing Pellet drug layering and coating principle Starting beads + liquid to be processed 12 12

13 1. Introduction: The coating zone principle Spray drying Coalescence of droplets Spray nozzle Core Evaporation of solvent Penetration Contact / spreading 13 13

14 Overview 1. Introduction 2. Fluid bed equipment 3. Characteristics of Bottom spray processes 4. Formulation and process parameters 5. Case Studies 14 14

15 2. Fluid bed equipment: Fluid bed unit in bottom spray configuration Downbed Upbed Spray nozzle position: Bottom-spray ( Wurster ) 15 15

16 2. Fluid bed equipment: Fresh-air system vs. closed-loop system Fresh air system Water based systems Organic solvent based systems Closed-loop system with N 2 inertisation and organic solvent recovery system (SRS) Organic solvent based systems 16 16

17 2. Fluid bed equipment: Fresh-air system vs. closed-loop system Pellet surfaces Organic solution coating Aqueous dispersion (film condensation not completed) 17 17

18 Overview 1. Introduction 2. Fluid bed equipment 3. Characteristics of Bottom spray processes 4. Formulation and process parameters 5. Case Studies 18 18

19 3. Characteristics of Bottom spray processes Wurster partition HS nozzle Inlet air distribution plate HS collar 19 19

20 3. Characteristics of Bottom spray processes Wurster partition HS nozzle Inlet air distribution plate HS collar 20 20

21 3. Characteristics of Bottom spray processes: Inlet air distribution plate The air flow in the upbed zone is most important for the homogenous application of the film. The most feasible configuration is selected for each product quality (particle size of substrate). Downbed zone Upbed zone 21 21

22 3. Characteristics of Bottom spray processes: Inlet air distribution plate Upbed zone Downbed zone Plate type A B C D Inlet air volume in downbed 22 22

23 3. Characteristics of Bottom spray processes Wurster partition HS nozzle Inlet air distribution plate HS collar 23 23

24 3. Characteristics of Bottom spray processes: Wurster Partition h h downbed upbed downbed upbed 24 24

25 3. Characteristics of Bottom spray processes: High Speed ( HS ) nozzle system + Collar HS nozzle HS nozzle + collar 25 25

26 3. Characteristics of Bottom spray processes 26 26

27 Overview 1. Introduction 2. Fluid bed equipment 3. Characteristics of Bottom spray processes 4. Formulation and process parameters 5. Case Studies 27 27

28 4. Formulation and process parameters Formulation specified, no further optimisation possible Inlet air volume temperature and moisture adjustable Product: moisture temperature Atomization air pressure and spray rate adjustable Drying capacity Fluidization pattern Agglomeration or spray drying 28 28

29 4. Formulation and process parameters: hx diagram (Mollier diagram) For understanding the modifications in terms of HUMIDITY in the process air (inlet and outlet) and in the product, you may use the Mollier-Diagram = the psychrometric chart You can read relative and absolute values for: the inlet air humidity conditions and temperature the outlet air humidity conditions and temperature the product humidity conditions and temperature and you can predict the overwetting condition: when the product temperature reaches the 100 % relative humidity curve

30 4. Formulation and process parameters: hx diagram (Mollier diagram) Moisture can be present at different amounts in air, but the air becomes saturated at some point Air cannot contain more moisture than the saturated amount Hot air can contain more moisture than cold air before saturation is reached - air expands when heated The saturation point depends on the temperature of the air At saturation point, the Relative Humidity is 100% and the temperature is said to be the Dew Point % RH values show the % saturation of air at that temperature If the temperature of a sample of air is increased, its relative Humidity will decrease 30 30

31 Temperature [ C] Pellet Layering and Coating Processes 4. Formulation and process parameters: hx diagram (Mollier diagram) relativ humidity [%] The diagram shows the correlation of evaporation capacity relative humidity in exhaust air product temperature / moisture water content x [ g water / kg dry air] 31 31

32 4. Formulation and process parameters: hx diagram (Mollier diagram) Fluid Bed Layering and Coating in moderate climate conditions Ambient air : temperature 10 C relative humidity 40 % What is the dew point of the air? Heated to 55 C for processing, what will the inlet air relative humidity be? Passed through a bed of wet product, what will the product temperature be? 32 32

33 Temperature [ C] Pellet Layering and Coating Processes 4. Formulation and process parameters: hx diagram (Mollier diagram) B A C water content x [ g water / kg dry air] relativ humidity [%] Ambient conditions:10 C 40% rel. humidity: A x = 3 g / kg dry air heating to 55 C inlet inlet air temp.: A-B x = 3 g / kg dry air rel. hum.: 3,5 % by spraying the drug layering or coating liquid: a defined product moisture expressed as product / exhaust air temperature is achieved in the example: product temperature ~ 30 C rel. humidity ~ 45% stable process good product quality 33 33

34 Temperature [ C] Pellet Layering and Coating Processes 4. Formulation and process parameters: hx diagram (Mollier diagram) ! relative humidity [%] but: do not drive too fast!! Process speed is limited by specific qualities of coating formulations (temperature + moisture induced sticking)!! in the too fast example product temperature ~ 23 C rel. humidity ~ 80% catastrophe water content x [ g water / kg dry air]

35 4. Formulation and process parameters: hx diagram (Mollier diagram) Now what about drying in hot and humid summer times? 35 35

36 4. Formulation and process parameters: hx diagram (Mollier diagram) de-humidification by cooling (10 +/- 2 C) de-humidification +/- re-humidification absorption dryer with desiccants in combination with a de-humidifier + re-humidifier 36 36

37 Temperature [ C] Pellet Layering and Coating Processes 4. Formulation and process parameters: hx diagram (Mollier diagram) relativ humidity [%] A Dehumidification of inlet air Ambient conditions: 37 C, 90% rel. hum.: A 30 x = 38 g / kg dry air B Cooling to 6 C inlet air temp.: A-B rel. hum.: 100 % x = 6 g / kg dry air water content x [ g water / kg dry air]

38 4. Formulation and process parameters: hx diagram (Mollier diagram) 6 C / 100 % rh 6 g water/ kg dry air 37 C, 90% rh 38 g water/ kg dry air 38 6 = 32 [g water/kg dry air] 38 38

39 Overview 1. Introduction 2. Fluid bed equipment 3. Characteristics of Bottom spray processes 4. Formulation and process parameters 5. Case Studies 39 39

40 Summary and Conclusion The WURSTER fluid bed technology is a feasible process for highly efficient and reproducible pellet processing. It is a complex, but very logical and comprehensive process technology which provides stable conditions for particle coating (of pellets, micropellets, crystals ). The understanding of potential interactions of fluid bed equipment configuration and processing parameters is a prerequisite in order to achieve stable processes in development and industrial production. Development is ongoing in order to improve efficiency, stability and safety of processes PAT (Process Analytical Technology)

41 Thank you! Dr. Anne Ettner, Pharmacist Qualified Person Glatt GmbH 41 41