Prediction of Tablet Film-coating Thickness Using a Rotating Plate Coating System and NIR Spectroscopy

The purpose of this research was to create a calibration model based on near-infrared (NIR) spectroscopy data obtained during a small-scale coating process to predict in-line the coating layer thickness of tablets coated in a side-vented drum coater. The developed setup for the small-scale coating process consisted of a rotating plate with 20 tablets molds that pass a spraying unit, a heating unit, and an in-line NIR spectroscopy probe during one rotation. High-density polyethylene (HDPE) was compressed to flat-faced tablets, and these were coated with a sustained release coating suspension containing Kollicoat IR and Kollicoat SR 30D. The film thickness of these tablets was determined for each tablet individually with a digital micrometer. A calibration model of predicted film thickness versus real-film thickness using PLS regression was developed. This model was tested against in-line NIR data obtained from a coating drum process, in which biconvex HDPE tablets were film-coated with the same film-coating suspension. The model predicted a final coating thickness of 240 μm, while the measured average thickness (n = 100 tablets) was 210 μm. Taking into account the use of a different setup and differently shaped tablets, it was possible to predict the coating thickness with accuracy comparable to the one of the digital micrometer. Thus, the small-scale rotating plate system was found to be an efficient means of preparing calibration model for a tablet-coating drum process.     

A Study on In-Line Tablet Coating—the Influence of Compaction and Coating on Tablet Dimensional Changes

Prior to coating, tablets are usually stored for a definite period to enable complete strain recovery and prevent subsequent volumetric expansion-related coating defects. In-line coating is defined as the coating of tablets immediately after compaction. In-line coating will be expected to improve manufacturing efficiencies. In this study, the possibility of in-line coating was studied by evaluating the influence of compaction and coating on tablet dimensional changes. The use of tapered dies for compaction was also evaluated. Two types of tablet coaters which presented different coating environments, namely the Supercell™ coater and pan coater, were employed for coating. The extent of tablet dimensional changes was studied in real time using optical laser sensors in a controlled environment. After compaction, tablet dimensional changes were found to be anisotropic. In contrast, coating resulted in isotropic volume expansion in both the axial and radial directions. Pan coating resulted in significantly greater tablet dimensional changes compared to Supercell™ coating. There was no significant difference in dimensional changes of tablets coated in line or after complete viscoelastic strain recovery for Supercell™ coating. However, significantly different dimensional changes were observed for pan coating. The use of tapered dies during compaction was found to result in more rapid viscoelastic strain recovery and also significantly reduced tablet dimensional changes when tablets were immediately coated after compaction using the pan coater. In conclusion, the Supercell™ coater appeared to be more suitable for in-line tablet coating, while tapered dies were beneficial in reducing tablet dimensional changes when the pan coater was employed for in-line coating.KEY WORDS: continuous manufacturing, in-line coating, tablet coating, tapered dies, viscoelastic strain recovery     

Monitoring tablet surface roughness during the film coating process

The purpose of this study was to evaluate the change of surface roughness and the development of the film during the film coating process using laser profilometer roughness measurements, SEM imaging, and energy dispersive X-ray (EDX) analysis. Surface roughness and texture changes developing during the process of film coating tablets were studied by noncontact laser profilometry and scanning electron microscopy (SEM). An EDX analysis was used to monitor the magnesium stearate and titanium dioxide of the tablets. The tablet cores were film coated with aqueous hydroxypropyl methylcellulose, and the film coating was performed using an instrumented pilot-scale side-vented drum coater. The SEM images of the film-coated tablets showed that within the first 30 minutes, the surface of the tablet cores was completely covered with a thin film. The magnesium signal that was monitored by SEM-EDX disappeared after ∼15 to 30 minutes, indicating that the tablet surface was homogeneously covered with film coating. The surface roughness started to increase from the beginning of the coating process, and the increase in the roughness broke off after 30 minutes of spraying. The results clearly showed that the surface roughness of the tablets increased until the film coating covered the whole surface area of the tablets, corresponding to a coating time period of 15 to 30 minutes (from the beginning of the spraying phase). Thereafter, the film only became thicker. The methods used in this study were applicable in the visualization of the changes caused by the film coating on the tablet surfaces.     

Improvement of tablet coating uniformity using a quality by design approach

A combination of analytical and statistical methods is used to improve a tablet coating process guided by quality by design (QbD) principles. A solid dosage form product was found to intermittently exhibit bad taste. A suspected cause was the variability in coating thickness which could lead to the subject tasting the active ingredient in some tablets. A number of samples were analyzed using a laser-induced breakdown spectroscopy (LIBS)-based analytical method, and it was found that the main variability component was the tablet-to-tablet variability within a lot. Hence, it was inferred that the coating process (performed in a perforated rotating pan) required optimization. A set of designed experiments along with response surface modeling and kriging method were used to arrive at an optimal set of operating conditions. Effects of the amount of coating imparted, spray rate, pan rotation speed, and spray temperature were characterized. The results were quantified in terms of the relative standard deviation of tablet-averaged LIBS score and a coating variability index which was the ratio of the standard deviation of the tablet-averaged LIBS score and the weight gain of the tablets. The data-driven models developed based on the designed experiments predicted that the minimum value of this index would be obtained for a 6% weight gain for a pan operating at the highest speed at the maximum fill level while using the lowest spraying rate and temperature from the chosen parametric space. This systematic application of the QbD-based method resulted in an enhanced process understanding and reducing the coating variability by more than half.     

Process Optimization of a Novel Immediate Release Film Coating System using QbD Principles

This work describes a quality-by-design (QbD) approach to determine the optimal coating process conditions and robust process operating space for an immediate release aqueous film coating system (Opadry® 200). Critical quality attributes (CQAs) or associated performance indicators of the coated tablets were measured while coating process parameters such as percent solids of the coating dispersion, coating spray rate, inlet air temperature, airflow rate and pan speed were varied, using a design of experiment protocol. The optimized process parameters were then confirmed by independent coating trials. Disintegration time of coated tablets was not affected by the coating process conditions used in this study, while tablet appearance, as determined by measurement of tablet color, coating defects and gloss was determined to be a CQA. Tablet gloss increased when low spray rate and low percent solids were used, as well as with increased coating pan speed. The study used QbD principles and experimental design models to provide a basis to identify ranges of coating process conditions which afford acceptable product quality. High productivity, color uniformity, and very low defect levels were obtained with Opadry 200 even when using a broad range of coating process conditions.     

Development of an automation system for a tablet coater

An instrumentation and automation system for a side-vented pan coater with a novel air-flow rate measurement system for monitoring the film-coating process of tablets was designed and tested. The instrumented coating system was tested and validated by film-coating over 20 pilot-scale batches of tablets with aqueous-based hydroxypropyl methylcellulose (HPMC). Thirteen different process parameters were continuously measured and monitored, and the most significant ones were logged for analysis. Laser profilometry was used to measure the surface roughness of the coated tablets. The instrumentation system provided comprehensive and quantitative information on the process parameters monitored. The measured process parameters and the responses of the film-coated tablet batches showed that the coating process is reproducible. The inlet air-flow rate influenced the coating process and the subsequent quality of the coated tablets. Increasing the inlet flow rate accelerated the drying of the tablet surface. At high inlet flow rate, obvious film-coating defects (ie, unacceptable surface roughness of the coated tablets) were observed and the loss of coating material increased. The instrumented and automated pancoating system described, including historical data storage capability and a novel air-flow measurement system, is a useful tool for controlling and characterizing the tablet film-coating process. Monitoring of critical process parameters increases the overall coating process efficiency and predictability.     

Characterization of tablet film coatings using a laser-induced breakdown spectroscopic technique

Laser-induced breakdown spectroscopy (LIBS) was evaluated as an early phase process analytical technology (PAT) tool for the rapid characterization of pharmaceutical tablet coatings. Measurement of coating thickness, uniformity, and photodegradation-predictive potential of the technique were evaluated. Model formulation tablets were coated with varying amounts (2%-4% wt/wt) of red and yellow Opadry II, and a pulsed laser was used to sample at multiple sites across the tablet face. LIBS was able to successfully detect the emissions of Fe and Ti in the coated samples, and a proportional increase in signal with coating thickness was observed. Batch-to-batch variability in the coating procedure was also easily monitored by LIBS. The coating thickness was non-uniform across the tablet surface with higher thickness at the edges, likely due to the concave shape of the tablet. Film coating levels and color of the film had been subjected to photostability studies according to the International Conference on Harmonisation (ICH) guideline to determine effectiveness of the film coats. LIBS measurements of coating thickness provided a good correlation (R (2) > 0.99) to photodegradation as measured by high-performance liquid chromatography (HPLC). Last, the concentration of Fe in the coating was varied and monitored by LIBS. Increasing photostability was observed with increasing levels of ferric oxide, providing a new understanding of the photoprotection mechanism in the coated formulation. Determination of levels of ferric oxide and coating thickness by LIBS demonstrated its utility as a good PAT tool for the determination of photoprotection of the drug, thereby enabling facile optimization of the coating process.     

In-Line Film Coating Thickness Estimation of Minitablets in a Fluid-Bed Coating Equipment

Film coating thickness of minitablets was estimated in-line during coating in a fluid-bed equipment by means of visual imaging. An existing, commercially available image acquisition system was used for image acquisition, while dedicated image analysis and data analysis methods were developed for this purpose. The methods were first tested against simulated minitablet’s images and after that examined on a laboratory-scale fluid-bed Wurster coating process. An observation window cleaning mechanism was developed for this purpose. Six batches of minitablets were coated in total, using two different dispersions, where for the second dispersion coating endpoint was determined based on the in-line measurement. Coating thickness estimates were calculated from the increasing size distributions of the minitablet’s major and minor lengths, assessed from the acquired images. Information on both the minitablet’s average band and average cap coating thicknesses was obtained. The in-line coating thickness estimates were compared to the coating thickness weight gain calculations and the optical microscope measurements as a reference method. Average band coating thickness estimate was found the most accurate in comparison to microscope measurements, with root mean square error of 1.30 μm. The window cleaning mechanism was crucial for the accuracy of the in-line measurements as was evident from the corresponding decrease of the root mean square error (9.52 μm, band coating thickness). The presented visual imaging approach exhibits accuracy of at least 2 μm and is not susceptible to coating formulation or color variations. It presents a promising alternative to other existing techniques for the in-line coating thickness estimation.     

A novel method for analyzing thick tablets by near infrared spectroscopy

A near-infrared (NIR) spectroscopic method to determine content uniformily of a large, thick tablet using an approach that could facilitate future validations has been developed. A CT ibuprofen 800-mg tablet weighs about 1150 mg and is about 18.6 mm wide and 7.6 mm thick. The FT NIR spectrometer was optimized for transmission spectra of the tablets by moving it to the sample compartment and placing it immediately behind the tablet. In spite of this dedicated setup, the transmission spectra obtained were very poor, indicating that the NIR radiation was not reaching the detector. The spectra of the tablet improved with use of a simple preparation in which a flat-face die applies pressure of 20 000 psi to the tablet, this reduced the thickness of the tablet from 7.6 mm to 3.6 mm. A calibration model was developed for tablets with drug content ranging from 70% to 130% of label. The calibration model was tested using a validation set of tablets with a drug content of 752, 800, and 848 mg. The results obtained were within 1.5% of the known drug content of the validation set, tablets. Even with the sample preparation, the content uniformity results of 10 tablets could be determined using this method in less than 1 hour. The approach described in this article could also be used to validate NIR content uniformity methods for orther formulations. Published: July 12, 2001.     

Rapid Assessment of Tablet Film Coating Quality by Multispectral UV Imaging

Chemical imaging techniques are beneficial for control of tablet coating layer quality as they provide spectral and spatial information and allow characterization of various types of coating defects. The purpose of this study was to assess the applicability of multispectral UV imaging for assessment of the coating layer quality of tablets. UV images were used to detect, characterize, and localize coating layer defects such as chipped parts, inhomogeneities, and cracks, as well as to evaluate the coating surface texture. Acetylsalicylic acid tablets were prepared on a rotary tablet press and coated with a polyvinyl alcohol-polyethylene glycol graft copolymer using a pan coater. It was demonstrated that the coating intactness can be assessed accurately and fast by UV imaging. The different types of coating defects could be differentiated and localized based on multivariate image analysis and Soft Independent Modeling by Class Analogy applied to the UV images. Tablets with inhomogeneous texture of the coating could be identified and distinguished from those with a homogeneous surface texture. Consequently, UV imaging was shown to be well-suited for monitoring of the tablet coating layer quality. UV imaging is a promising technique for fast quality control of the tablet coating because of the high data acquisition speed and its nondestructive analytical nature.     

Investigation of the Variability of NIR In-line Monitoring of Roller Compaction Process by Using Fast Fourier Transform (FFT) Analysis

The purpose of this research was to investigate the variability of the roller compaction process while monitoring in-line with near-infrared (NIR) spectroscopy. In this paper, a pragmatic method in determining this variability of in-line NIR monitoring roller compaction process was developed and the variability limits were established. Fast Fourier Transform (FFT) analysis was used to study the source of the systematic fluctuations of the NIR spectra. An off-line variability analysis method was developed as well to simulate the in-line monitoring process in order to determine the variability limits of the roller compaction process. For this study, a binary formulation was prepared composed of acetaminophen and microcrystalline cellulose. Different roller compaction parameters such as roll speed and feeding rates were investigated to understand the variability of the process. The best-fit line slope of NIR spectra exhibited frequency dependence only on the roll speed regardless of the feeding rates. The eccentricity of the rolling motion of rollers was identified as the major source of variability and correlated with the fluctuations of the slopes of NIR spectra. The off-line static and dynamic analyses of the compacts defined two different variability of the roller compaction; the variability limits were established. These findings were proved critical in the optimization of the experimental setup of the roller compaction process by minimizing the variability of NIR in-line monitoring.     

Polymorph Transformation in Paracetamol Monitored by In-line NIR Spectroscopy During a Cooling Crystallization Process

The reliable in-line monitoring of pharmaceutical processes has been regarded as a key tool toward the full implementation of process analytical technology. In this study, near-infrared (NIR) spectroscopy was examined for use as an in-line monitoring method of the paracetamol cooling crystallization process. The drug powder was dissolved in ethanol-based cosolvent at 60°C and was cooled by 1°C/min for crystallization. NIR spectra acquired by in-line measurement were interpreted by principal component analysis combined with off-line characterizations via X-ray diffraction, optical microscopy, and transmission electron microscopy. The whole crystallization process appeared to take place in three steps. A metastable form II polymorph of paracetamol was formed and transformed into the stable form I polymorph on the way to the growth of pure form I by cooling crystallization. These observations are consistent with a previous focused beam reflectance method-based study (Barthe et al., Cryst Growth Des 8:3316–3322, 2008).     

A novel approach in the assessment of polymeric film formation and film adhesion on different pharmaceutical solid substrates

The purpose of this study was to evaluate the nature of film formation on tablets with different compositions, using confocal laser scanning microscopy (CLSM), and to measure film adhesion via the application of a novel “magnet probe test”. Three excipients, microcrystalline cellulose (MCC), spray-dried lactose monohydrate, and dibasic calcium phosphate dihydrate, were individually blended with 0.5% magnesium stearate, as a lubricant, and 2.5% tetracycline HCl, as a fluorescent marker, and were compressed using a Carver press. Tablets were coated with a solution consisting of 7% hydroxypropyl methylcellulose (HPMC) phthalate (HP-55), and 0.5% cetyl alcohl in acetone and isopropanol (11:9). The nature of polymer interaction with the tablets and coating was evaluated using CLSM and a designed magnet probe test. CLSM images clearly showed coating efficiency, thickness, and uniformity of film formation, and the extent of drug migration into the film at the coating interfaces of tablets. Among the excipients, MCC demonstrated the best interface for both film formation and uniformity in thickness relative to lactose monohydrate and dibasic calcium phosphate dihydrate. The detachment force of the coating layers from the tablet surfaces, as measured with the developed magnet probe test, was in the order of MCC>lactose monohydrate>dibasic calcium phosphate dihydrate. It was also shown that the designed magnet probe test provides reliable and reproducible results when used for measurement of film adhesion and bonding strength.     

API Determination by NIR Spectroscopy Across Pharmaceutical Production Process

The purpose of this research was to demonstrate the ability of reflectance near-infrared (NIR) spectroscopy for quantitative analysis of an active ingredient in different production steps of a solid formulation. The drug is quantified at two different steps of a pharmaceutical process: after granulation and after tablet coating. Calibration samples were prepared by mixing pure drug, excipients, and batch samples (75–120 mg/g active ingredient) using a simple methodology that can be easily carried out in a laboratory. Partial least squares calibration models were calculated in second-derivative mode using the wavelength range 1,134–1,798 nm. The error of prediction for granulated samples was 1.01% and 1.63% for tablets. The results prove that NIR spectroscopy is a good alternative to other, more time-consuming means of analysis for pharmaceutical process monitoring.     

Influence of Process Parameters on Tablet Bed Microenvironmental Factors During Pan Coating

Recent studies have shown the importance of monitoring microenvironmental conditions (temperature, relative humidity) experienced by the tablet bed during a pan coating process, thereby necessitating the need to understand how various process parameters influence these microenvironmental conditions. The process parameters studied in this work include exhaust air temperature, spray rate, inlet airflow rate, gun-to-bed distance, coating suspension percent solids, and atomization and pattern air pressure. Each of these process parameters was found to have an impact on the tablet bed relative humidity (RH), as measured using PyroButton data logging devices. A higher tablet bed RH was obtained with an increase in spray rate and atomization air pressure and with a decrease in exhaust air temperature, inlet airflow rate, gun-to-bed distance, suspension percent solids, and pattern air pressure. Based on this work, it can be concluded that the tablet bed thermodynamic conditions are a cumulative effect of the various process conditions. A strong correlation between the tablet bed RH and the frequency of tablet coating defect (logo bridging) was established, with increasing RH resulting in a higher percent of logo bridging events.     

Quantitation of drug content in a low dosage formulation by transmission near infrared spectroscopy

A transmission near infrared (NIR) spectroscopic method has been developed for the nondestructive determination of drug content in tablets with less than 1% weight of active ingredient per weight of formulation (m/m) drug content. Tablets were manufactured with drug concentrations of ∼0.5%, 0.7%, and 1.0% (m/m) and ranging in drug content from 0.71 to 2.51 mg per tablet. Transmission NIR spectra were obtained for 110 tablets that constituted the training set for the calibration model developed with partial least squares regression. The reference method for the calibration model was a validated UV spectrophotometric method. Several data preprocessing methods were used to reduce the effect of scattering on the NIR spectra and base the calibration model on spectral changes related to the drug concentration changes. The final calibration model included the spectral range from 11 216 to 8662 cm⁻¹ the standard normal variate (SNV), and first derivative spectral pretreatments. This model was used to predict an independent set of 48 tablets with a root mean standard error of prediction (RMSEP) of 0.14 mg, and a bias of only −0.05 mg per tablet. The study showed that transmission NIR spectroscopy is a viable alternative for nondestructive testing of low drug content tablets, available for the analysis of large numbers of tablets during process development and as a tool to detect drug agglomeration and evaluate process improvement efforts. Published: March 24, 2006     

Optimization of Process Parameters for a Quasi-Continuous Tablet Coating System Using Design of Experiments

The aim of this study was to identify and optimize the critical process parameters of the newly developed Supercell quasi-continuous coater for optimal tablet coat quality. Design of experiments, aided by multivariate analysis techniques, was used to quantify the effects of various coating process conditions and their interactions on the quality of film-coated tablets. The process parameters varied included batch size, inlet temperature, atomizing pressure, plenum pressure, spray rate and coating level. An initial screening stage was carried out using a 2^6−1(IV) fractional factorial design. Following these preliminary experiments, optimization study was carried out using the Box–Behnken design. Main response variables measured included drug-loading efficiency, coat thickness variation, and the extent of tablet damage. Apparent optimum conditions were determined by using response surface plots. The process parameters exerted various effects on the different response variables. Hence, trade-offs between individual optima were necessary to obtain the best compromised set of conditions. The adequacy of the optimized process conditions in meeting the combined goals for all responses was indicated by the composite desirability value. By using response surface methodology and optimization, coating conditions which produced coated tablets of high drug-loading efficiency, low incidences of tablet damage and low coat thickness variation were defined. Optimal conditions were found to vary over a large spectrum when different responses were considered. Changes in processing parameters across the design space did not result in drastic changes to coat quality, thereby demonstrating robustness in the Supercell coating process.     

Process analysis of fluidized bed granulation

This study assesses the fluidized bed granulation process for the optimization of a model formulation using in-line near-infrared (NIR) spectroscopy for moisture determination. The granulation process was analyzed using an automated granulator and optimization of the verapamil hydrochloride formulation was performed using a mixture design. The NIR setup with a fixed wavelength detector was applied for moisture measurement. Information from other process measurements, temperature difference between process inlet air and granules (T_diff), and water content of process air (AH), was also analyzed. The application of in-line NIR provided information related to the amount of water throughout the whole granulation process. This information combined with trend charts of T_diff and AH enabled the analysis of the different process phases. By this means, we can obtain in-line documentation from all the steps of the processing. The choice of the excipient affected the nature of the solid-water interactions; this resulted in varying process times. NIR moisture measurement combined with temperature and humidity measurements provides a tool for the control of water during fluid bed granulation.     

Monitoring Granulation Rate Processes Using Three PAT Tools in a Pilot-Scale Fluidized Bed

The purpose of this research was to analyze and compare the responses of three Process Analytical Technology (PAT) techniques applied simultaneously to monitor a pilot-scale fluidized bed granulation process. Real-time measurements using focused beam reflectance measurement (Lasentec FBRM) and near-infra red spectroscopy (Bruker NIR) were taken by inserting in-line probes into the fluidized bed. Non-intrusive acoustic emission measurements (Physical Acoustic AE) were performed by attaching piezoelectric sensors on the external wall of the fluidized bed. Powder samples were collected at regular intervals during the granulation process and characterized offline using laser diffraction, scanning electron microscopy, stereo-optical microscopy and loss on drying method. PAT data comprising chord length distribution and chord count (from FBRM), absorption spectra (from NIR) and average signal levels and counts (from AE) were compared with the particle properties measured using offline samples. All three PAT techniques were able to detect the three granulation regimes or rate processes (wetting and nucleation, consolidation and growth, breakage) to varying degrees of sensitivity. Being dependent on optical signals, the sensitivities of the FBRM and NIR techniques were susceptible to fouling on probe windows. The AE technique was sensitive to background fluidizing air flows and external interferences. The sensitivity, strengths and weaknesses of the PAT techniques examined may facilitate the selection of suitable PAT tools for process development and scale-up studies.     

Modeling weight variability in a pan coating process using Monte Carlo simulations

The primary objective of the current study was to investigate process variables affecting weight gain mass coating variability (CV _m) in pan coating devices using novel video-imaging techniques and Monte Carlo simulations. Experimental information such as the tablet location, circulation time distribution, velocity distribution, projected surface area, and spray dynamics was the main input to the simulations. The data on the dynamics of tablet movement were obtained using novel video-imaging methods. The effects of pan speed, pan loading, tablet size, coating time, spray flux distribution, and spray area and shape were investigated. CV _m was found to be inversely proportional to the square root of coating time. The spray shape was not found to affect the CV _m of the process significantly, but an increase in the spray area led to lower CV _ms. Coating experiments were conducted to verify the predictions from the Monte Carlo simulations, and the trends predicted from the model were in good agreement. It was observed that the Monte Carlo simulations underpredicted CV _ms in comparison to the experiments. The model developed can provide a basis for adjustments in process parameters required during scale-up operations and can be useful in predicting the process changes that are needed to achieve the same CV _m when a variable is altered.