In-line monitoring and analysis of fluid-bed pellet ...€¦ · Coating is one of the most commonly...
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D. Kitak 1 , G. Podrekar 1 , C. Funaro 2 , G. Mondelli 2 , G. Bertuzzi 2 , B. Likar 1,3 , D. Tomaževič 1,3 1 Sensum, Computer Vision Systems, Tehnološki park 21, 1000 Ljubljana, Slovenia 2 IMA S.p.A. Active Division, Via I Maggio 14, 40064 Ozzano Emilia, Bologna, Italy 3 Laboratory of Imaging Technologies, Faculty of Electrical Engineering, University of Ljubljana, Tržaška cesta 25, 1000 Ljubljana, Slovenia In-line monitoring and analysis of fluid-bed pellet coating processes using PATVIS APA AIM The aim of this study was to evaluate the performance of PATVIS APA (Sensum, Slovenia), a visual inspection system designed for in-line monitoring and analysis of pellet coating processes, on a fluid-bed coater. In particular, the pellet size was measured in real-time, from which the pellet coating thickness was estimated and compared to the final coating thickness determined by batch weight gain as a reference method. CONCLUSION Results show the potential of PATVIS APA as a process analytical technology (PAT) tool for more in-depth understanding, controlling and optimisation of pellet coating processes. PATVIS APA revealed process footprints in the form of pellet size and the underlying size distribution, enabling effective process end-point detection and intervention. MATERIALS The coating formulation was composed of hydroxypropyl methylcellulose (9.36%), polyethylene glycol (0.29%), riboflavin (0.13%) and deionized water (90.22%). The sugar pellet cores had a size distribution in the range of 850-1000 µm. PATVIS APA shows good correlation and minimum discrepancy with reference to the batch weight gain method, even for very thin film coatings (Table 2). METHODS COATING Five coating processes were performed in the pilot- scale fluid-bed coater ARIA 120 (IMA, Italy) in the bottom-spray configuration (Table 1). MONITORING The image acquisition was performed through an observation window of the coater. Images were MATERIALS AND METHODS RESULTS AND DISCUSSION INTRODUCTION Coating is one of the most commonly employed processes within manufacturing of solid oral dosage forms [1]. Fluid-bed coating with a draft tube insert is the preferred method for coating pellets [2]. The main parameter that characterizes both the state of the coating process and the product is the coating thickness. It is especially important in active and functional coatings [3] and represents one of the most important critical quality attributes that should be routinely monitored [4]. 1. Porter SC. Coating of tablets and multiparticulates. In: Aulton, ME (Ed), Aulton’s Pharmaceutics: The Design and Manufacture of Medicines. London: Churchill Livingstone; 2013. p. 912. 2. Teunou E, Poncelet D. Batch and continuous fluid bed coating – review and state of the art. J Food Eng. 2002 Aug;53(4):325–40. 3. Knop K, Kleinebudde P. PAT-tools for process control in pharmaceutical film coating applications. Int J Pharm. 2013 Dec 5;457(2):527–36. 4. Kucheryavski S, Esbensen KH, Bogomolov A. Monitoring of pellet coating process with image analysis—a feasibility study. J Chemom. 2010 Jul 1;24(7-8):472–80. 5. Luštrik M, Dreu R, Šibanc R, Srčič S. Comparative study of the uniformity of coating thickness of pellets coated with a conventional Wurster chamber and a swirl generator-equipped Wurster chamber. Pharm Dev Technol. 2012 Jun 1;17(3):268–76. Table 2: Final coating thickness estimation Coating thickness [µm] Difference [µm] Batch PATVIS APA Weight gain PATVIS APA-Weight gain 1 15.0 14.5 0.5 2 7.6 7.6 0.0 3 7.6 7.1 0.5 4 5.8 6.0 -0.2 5 9.0 8.4 0.6 Root mean square (RMS) 0.42 Coefficient of determination (R 2 ) 0.99 Table 1: Process parameters (Tin, Qin = Temperature and quantity of the fluidizing air; SR = Spray rate; AP = Atomization pressure; CD = Column distance; WG = Theoretical weight gain) Batch Size [kg] T in [°C] Q in [m 3 /h] SR [ml/min] AP [bar] CD [mm] WG [%] 1 50 70 800 80 2 28 10 2 25 70 800 150 3 28 5 3 50 55 800 150 2 35 5 4 50 70 500 80 3 35 5 5 25 55 500 80 2 28 5 Figure 3: Size distribution of pellets at coating-start and coating-end time points for batch 1 Broadening of the pellet size distribution is evident throughout the coating process in addition to an expected distribution shift (Figure 3). 10th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology acquired at 100 frames per second, giving a 200 000 pellets sample size in a two minute sampling interval. COATING THICKNESS ESTIMATION The coating thickness was estimated from the difference between the medians (d 50 ) of the measured pellet size distributions at coating- start and coating-end time points. A clear trend in pellet growth throughout the coating process is evident for all the observed percentiles of the size distribution (Figure 1). Figure 1: Progress of the pellet coating process for batch 1 Time [min] Pellet Size [µm] 890 970 910 d 90 d 75 d 50 d 25 d 10 990 930 1010 950 1030 0 340 680 170 510 The evolution of the coating thickness gains (Figure 2) indicates that smaller pellets receive a lesser amount of coating material, which is consistent with previous findings [5]. Figure 2: Evolution of the coating thickness gains for batch 1 Percentile Coaating Thickness [µm] 0 8 2 t 5 = 680 min t 4 = 510 min t 3 = 340 min t 2 = 170 min t 1 = 0 min 10 4 12 6 14 16 18 d 10 d 25 d 50 d 75 d 90 Pellet Size [µm] Coating-start σ = 49.0 Coating-end σ = 52.5 800 850 900 950 1000 1050 1100 1150 1200 2016-03-25 Sensum poster 841 × 1189 mm FINAL.indd 1 25.3.2016 12:59:18
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D. Kitak1, G. Podrekar1, C. Funaro2, G. Mondelli2, G. Bertuzzi2, B. Likar1,3, D. Tomaževič1,3
1 Sensum, Computer Vision Systems, Tehnološki park 21, 1000 Ljubljana, Slovenia2 IMA S.p.A. Active Division, Via I Maggio 14, 40064 Ozzano Emilia, Bologna, Italy3 Laboratory of Imaging Technologies, Faculty of Electrical Engineering, University of Ljubljana, Tržaška cesta 25, 1000 Ljubljana, Slovenia
In-line monitoring and analysis of fluid-bed pellet coating processes using PATVIS APA
AIMThe aim of this study was to evaluate the performance of PATVIS APA (Sensum, Slovenia), a visual inspection system designed for in-line monitoring and analysis of pellet coating processes, on a fluid-bed coater. In particular, the pellet size was measured in real-time, from which the pellet coating thickness was estimated and compared to the final coating thickness determined by batch weight gain as a reference method.
CONCLUSIONResults show the potential of PATVIS APA as a process analytical technology (PAT) tool for more in-depth understanding, controlling and optimisation of pellet coating processes.PATVIS APA revealed process footprints in the form of pellet size and the underlying size distribution, enabling effective process end-point detection and intervention.
MATERIALSThe coating formulation was composed of hydroxypropyl methylcellulose (9.36%), polyethylene glycol (0.29%), riboflavin (0.13%) and deionized water (90.22%). The sugar pellet cores had a size distribution in the range of 850-1000 µm.
PATVIS APA shows good correlation and minimum discrepancy with reference to the batch weight gain method, even for very thin film coatings (Table 2).
METHODSCOATINGFive coating processes were performed in the pilot-scale fluid- bed coater ARIA 120 (IMA, Italy) in the bottom-spray configuration (Table 1).
MONITORINGThe image acquisition was performed through an observation window of the coater. Images were
MATERIALS AND METHODS
RESULTS AND DISCUSSION
INTRODUCTIONCoating is one of the most commonly employed processes within manufacturing of solid oral dosage forms [1]. Fluid-bed coating with a draft tube insert is the preferred method for coating pellets [2]. The main parameter that characterizes both the state of the coating process and the product is the coating thickness. It is especially important in active and functional coatings [3] and represents one of the most important critical quality attributes that should be routinely monitored [4].
1. Porter SC. Coating of tablets and multiparticulates. In: Aulton, ME (Ed), Aulton’s Pharmaceutics: The Design and Manufacture of Medicines. London: Churchill Livingstone; 2013. p. 912. 2. Teunou E, Poncelet D. Batch and continuous fluid bed coating – review and state of the art. J Food Eng. 2002 Aug;53(4):325–40. 3. Knop K, Kleinebudde P. PAT-tools for process control in pharmaceutical film coating applications. Int J Pharm. 2013 Dec 5;457(2):527–36. 4. Kucheryavski S, Esbensen KH, Bogomolov A. Monitoring of pellet coating process with image analysis—a feasibility study. J Chemom. 2010 Jul 1;24(7-8):472–80. 5. Luštrik M, Dreu R, Šibanc R, Srčič S. Comparative study of the uniformity of coating thickness of pellets coated with a conventional Wurster chamber and a swirl generator-equipped Wurster chamber. Pharm Dev Technol. 2012 Jun 1;17(3):268–76.
Table 2: Final coating thickness estimation
Coating thickness [µm] Difference [µm]Batch PATVIS APA Weight gain PATVIS APA-Weight gain
1 15.0 14.5 0.52 7.6 7.6 0.03 7.6 7.1 0.54 5.8 6.0 -0.25 9.0 8.4 0.6
Root mean square (RMS) 0.42Coefficient of determination (R2) 0.99
Table 1: Process parameters (Tin, Qin = Temperature and quantity of the fluidizing air; SR = Spray rate; AP = Atomization pressure; CD = Column distance; WG = Theoretical weight gain)
Batch Size [kg] Tin [°C] Qin [m3/h] SR [ml/min] AP [bar] CD [mm] WG [%]1 50 70 800 80 2 28 102 25 70 800 150 3 28 53 50 55 800 150 2 35 54 50 70 500 80 3 35 55 25 55 500 80 2 28 5
Figure 3: Size distribution of pellets at coating-start and coating-end time points for batch 1
Broadening of the pellet size distribution is evident throughout the coating process in addition to an expected distribution shift (Figure 3).
10th World Meeting on Pharmaceutics,
Biopharmaceutics and Pharmaceutical Technology
acquired at 100 frames per second, giving a 200 000 pellets sample size in a two minute sampling interval.
COATING THICKNESS ESTIMATIONThe coating thickness was estimated from the difference between the medians (d50) of the measured pellet size distributions at coating-start and coating-end time points.
A clear trend in pellet growth throughout the coating process is evident for all the observed percentiles of the size distribution (Figure 1).
Figure 1: Progress of the pellet coating process for batch 1
Time [min]
Pel
let
Size
[µm
]
890
970
910
d90
d75
d50
d25
d10
990
930
1010
950
1030
0 340 680170 510
The evolution of the coating thickness gains (Figure 2) indicates that smaller pellets receive a lesser amount of coating material, which is consistent with previous findings [5].
Figure 2: Evolution of the coating thickness gains for batch 1
Percentile
Coaa
ting
Thi
ckne
ss [
µm]
0
8
2
t5 = 680 min
t4 = 510 min
t3 = 340 min
t2 = 170 min
t1 = 0 min
10
4
12
6
14
16
18
d10 d25 d50 d75 d90
Pellet Size [µm]
Coating-startσ = 49.0
Coating-endσ = 52.5
800 850 900 950 1000 1050 1100 1150 1200
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