An Alternate Coating Method for Tablets: Wurster Technology

Transcription

1 An Alternate Coating Method for Tablets: Wurster Technology Stamato, Howard 1 ; Levins, Christopher 1 ; Martin, Kyle 1 ; Keluskar, Rekha 1 ; Pafiakis, Steve 1 ; Jayawickrama, Dimuthu 1 ; Fiske, John 1 ; Chen, Wei 1 ; Lin, Shujie 1, Tejwani, Ravi 1 ; Timmins, Peter 1 ; Godek,Ed 2 ; Ahearn, James 2 1 Bristol-Myers Squibb 2 Glatt Air Techniques AIChE Annual Meeting November

2 Background Tablets are routinely coated for appearance, controlled release and in some cases with active ingredients. Pan coating is an older process which has been updated through the use of perforated pan technology to meet the needs of modern pharmaceutical processing. Air suspension coating, such as that accomplished in a Wurster device, has rarely been applied. The mechanical forces which a tablet could experience are the most often cited cause for discounting the Wurster process for tablets. 2

3 Background The proper selection/setup of equipment and design of tablet properties can assure a successful coating process. Although the basic coating technology - applying an atomized liquid to moving tablets - is the same in both processes; the airflow, tablet flow, and contact with the atomized liquid is different and can actually impart some advantages for the Wurster For example, in the Wurster the contact between liquid and tablet occurs when the tablets are spatially separated in lean phase pneumatic transport upwards in the central column rather than tumbling against each other in a pan. 3

4 Background In another example, the droplet flight to the tablet is typically shorter in a Wurster which can reduce the amount of spray dried coating generated during the process. Experiments have shown that small scale Wurster devices can be used to prepare samples of product quickly, allowing rapid screening of prototypes in early development while consuming a minimal amount of material (ref. 1). Some reports indicate tablet coating in a Wurster can be achieved with good uniformity and a rapid batch time (ref. 2 & 3). 4

5 Objectives Laboratory Scale : Feasibility Determine how Wurster technology can be used to produced prototypes with the minimum amount of material. Pilot Scale Feasibility: Evaluate the ability to coat tablets at pilot scale (50kg) using a Wurster device Pilot Scale Performance Explore how coating uniformity develops in a Wurster device compared to a perforated pan coater 5

6 Fluidized Bed in Wurster Configuration Tablets are in a dense bed in the annulus between the outer wall and inner partition While still air suspended the motion of tablets in the dense phase is downward Airflow is preferentially directed under the partition drawing tablets from the dense bed into the partition Tablets are pneumatically conveyed up the partition where they contact the cloud of spray from the nozzle mounted at the base of the partition. Figure courtesy Glatt Air techniques Ramsey, New Jersey

7 Tablets Coated in the Wurster for Sustained Release Figures courtesy Glatt Air techniques Ramsey, New Jersey

8 Laboratory Scale: Feasibility Reasons to pursue coating tablets in a Wurster: Limited amount of sample Realistic process conditions compared to a benchtop handmade sample Shorter run times, and better equipment availability help meet tight timelines Resource sparing predictive approach ~ 10 mm Note tablet identifiers blinded for presentation Range of Substrate Tablets ~1200 mg to 154 mg Range of Tablet Hardness 24 to 33 SCU depending on parameters and size Coating a commercial Polyvinyl Alcohol based coating suspension in white and butterscotch colors 8

9 Lab Scale - Typical Coating Parameters Strea mm nozzle Inlet temp: 58 C Exhaust temp: 48 C Airflow: adjusted to maintain fluidization Typical batch: g Tablets Spray rate: ~ 2 g/min Process efficiency a function of: Tablet shape / batch size Spray rate (wetter is best) Run as a spouted bed with no partition due to batch size Batch (g) Spray rate (g/min) Photo: 9 Atomization (bar) Process efficiency % % %

10 Larger Batches at Lab Scale Glatt GPCG-1 ~1.2 g tablets ~1 kg batch size Wurster partition in place Bottom plate designed for pellets High atomization air (~4 bar) helps fluidization A few tablets stuck in the corner and were not coated perhaps due to the small processor size compared to the tablet size A tablet coating bottom plate may improve flow Modifications to wall configuration may assist tablet flow (ref. 2) 10

11 Pilot Scale- Feasibility with Pellet Coating Design Niro S2-3 with Precision Coater ~ 1.2 g oblong convex tablets kg batch size explored Changed partition height, center ring, swirl air, and fluidization air in order adjust tablet motion Larger center ring (2 ) and standard partition at ~2 height, with swirl air on gives the most rapid and smooth tablet motion Product Temperature held at ~42 C Air Volume cfm Spray rates ranged from g/min Results Tablets were intact but did show some edge erosion ssor/ 11

12 Pilot Scale Feasibility and Performance with Tablet Coating Design Photo courtesy Glatt Air Techniques Ramsey NJ Glatt GPCG 60 with MacroWurster Insert Round SC ~450 mg tablet used Batch Sized Tested kg Changed partition height, and fluidization air in order adjust tablet motion Metformin Hydrochloride was used as a tracer in some experiments 50 kg and 100 kg batch sizes had analytical testing Product Temperature ~42 C Spray rate up to 350 g/min Air volume ~ cfm 12

13 MacroWurster Features to assist tablet flow Photos courtesy Glatt Air Techniques Ramsey NJ 13

14 Observations Pilot Scale Tablet Wurster Partition Height Adjusted to ~3 Lower partition heights reduced tablet flow into the partition Airflow Set near the lower limit of fluidizing tablets upward through the partition Rapid tablet motion with a dense plume of tablets achieved at minimum fluidization % Filter A tablet retention screen was used rather than a standard filter Tablets did contact the screen incurred damage as a result A larger screen with more room for the tablets to decelerate is available and should be used on future trials Tablet Cycle Time Ranged from 8-15 seconds for batches of kg at various conditions Tablet mixing was tested by layering 50 kg of white tablets on 50 kg of butterscotch colored tablets and initiating fluidization Backmixing was observed with a homogeneous distribution of tablets after approximately four cycles of the tablets around the inner partition Tablet Quality Tablets intact but after a time some edge erosion observed Higher spray rates adequately covered tablet edges and eliminated erosion Tablets from a 50 kg and 100 kg batch were analyzed for uniformity by determining the relative standard deviation of a tracer (%RSD) 14

15 NIR Method - Determination of %RSD An offline Near Infrared (NIR) method was used to determine Metformin amount coated on tablets. Tablets samples were collected as a function of coating time and presented to the NIR with 40 mm window size. NIR spectral data were recorded in the reflectance mode and the Metformin amounts were calculated using a multivariate calibration model (partial least square, PLS) and NIR spectral data. Three tablet samples were collected at each time point and five NIR measurements were performed per sample (~ 40 tablets/sample). Tablets were well mixed in between each measurement to randomize the sample. The metformin values were determined near-real time as fluid bed coating process occurred. 15

16 UV Method - Determination of %RSD 30 tablets were analyzed; HPLC measurements were performed in triplicate and averaged. Solution preparation Extraction solvent: M KH 2 PO 4 Diluent: 20:80 acetonitrile / water Buffer: 0.05% (w/v) sodium 1-heptanesulfonate, 0.05% (w/v) NaCl, to ph 3.85 with 0.4% phosphoric acid Mobile phase: 10:90 acetonitrile / buffer HPLC conditions Column: C 18, 4.6 mm 150 mm, 3 μm particle size Column temperature: 30 C Sample temperature: ambient Detector wavelength: 218 nm Injection volume: 10 microliters Running conditions: 1.0 ml/min mobile phase, 25 minutes (isocratic) Sample preparation One tablet added to a volumetric flask (100 ml). 25 ml extraction solvent was added; suspension mixed (shaker) for 10 min. ~ 50 ml of diluent added to suspension; flask sonicated for 5 minutes. Volumetric flask filled to mark with diluent. Flask was inverted, then the suspension was stirred using a magnetic stirbar. ~ 2 ml of suspension was transferred by pipette into microcentrifuge tube. The tube was centrifuged at rpm for 10 minutes. Supernatant transferred to HPLC vial and analyzed. 16

17 Comparison to Pan Coating Normalized by Number of Cycles at All 3 Scales Similar Performance HPLC results show more variation than NIR Number of cycles estimated from visual observation of tablets in the Wurster Pilot Wurster Batch 50 kg 100 kg NIR HPLC Figure adapted from reference 5 17

18 Comparison to Pan Coating - Temporal at Pilot Scale Similar Results Product Container about 50% full for 50 kg batch Product Container near capacity for 100 kg batch Results show uniformity achieved at least as fast as pan coater NIR results show uniform tablets in a shorter time Pilot Wurster Batch 50 kg 100 kg NIR HPLC Figure adapted from reference 5 18

19 Scale up is Linear The 32 and 46 Wursters are a multiple of the 18 Wurster Figures courtesy Glatt Air techniques Ramsey, New Jersey

20 Comparison to Pan Coating - Temporal at Commercial Scale Improved Performance Linear projection based on Wurster scale up characteristics Estimation shows significantly reduces batch time Figure adapted from reference 5 Pilot Wurster Batch 50 kg 100 kg NIR HPLC 20

21 Computational Fluid Dynamics A composite CFD-Dem model is in progress to understand the tablet flow. From the model predictions and a mechanistic mathematical model prediction of the %RSD can be correlated with the experimental results. This model may be able to compare pan and Wurster performance in silico by also running a previously developed model for pan coating (ref. 4) with similar assumptions 21

22 CFD Model Wurster Fluidized Bed Coating 23.8 (GPCG-60) Fluidized bed Geometry Particle Velocity Tracking Fluid Velocity Contour

23 Conclusions A fluidized bed Wurster device can be used to coat tablets Tablets must be designed for coating A lab scale device may be used for rapid prototyping At pilot scale uniformity is achieved as fast or faster than a pan coater 23

24 Future Work Coating: Pan coaters scale non-linearly as the volume of the coater increases faster than the spray nozzles (ref. 5) Wurster devices scale more linearly as the nozzle and partition is replicated in the larger device It may be possible to achieve uniform coatings with a four fold to six fold reduction in batch time on a production scale Wurster compared to a similarly sized production scale pan 24

25 Future Work Coating: Expand the understanding of performance as a function of settings (e.g. filter type, partition height) and operating parameters (e.g. batch size, air volume) Methods: Determine why there is an offset between the NIR and HPLC data Explore the use of NIR for online use for assay determination 25

26 References 1. Tablet Coating Methods for Very Small Batches and Their Suitability for Scaling Up; W.Bueb G. Warnke, K.H. Bauer; Drug Development and Industrial Pharmacy, 20(9), p ; Identification and characterization of factors controlling tablet coating uniformity in a Wurster coating process; S. Shelukar, J. Ho, J. Zega, E. Roland, N. Yeh, D. Quiran, A Nole, A. Katdare, S. Reynolds; Powder Technology; vol. 110 pp , Process Improvement: a Study to Compare Coating Uniformity of Tablet Coating by Bottom Spray Fluid Bed Process; D. Jones and O. Rubino; Poster Presentation at AAPS Annual meeting,new Orleans, November, Modeling of Pan Coating Processes: Prediction of Tablet Content Uniformity and Determination of Critical Process Parameters; W. Chen, S-Y. Chiang, S Kiang, A. Marchut, O. Lyngberg, J. Wang, V. Rao, D. Desai, H. Stamato, W. Early; J. Pharm. Sci., vol. 99(7), July Scale-down Experiments in a New Type of Pan Coater; R. Muller and P. Klienebudde; Pharm. Ind., vol.67(8) pp ,