Study of coat quality of tablets coated by an on-line supercell coater

The aim of this study was to investigate the nature of Supercell coating, an on-line tablet coater that employed a unique pattern of airflow. Tablets coated at different spray rates (4, 6, 8, 10, and 12 mL/min) were analyzed to investigate the influence of different wetting conditions on the quality of coats formed. Scanning electron micrographs showed that tablet coats formed at a spray rate of 4 mL/min consisted of spray-dried droplets that did not coalesce. At a spray rate of 6 mL/min, surface roughness was found to be lower than at the other spray rates, and the coat appeared smoothest, whereby droplets seemed fused together. At higher spray rates, the droplets appeared as branching arms and scale-like structures. This was attributed to the spread of spray droplets by the processing air and mass transfer of wet coating materials between tablets. Further tests showed that coats formed at higher spray rates had higher drug yield, drug uniformity, color uniformity, and density. However, the variability in coat thickness was increased due to the mass transfer of coats and dissolution of tablet core surfaces by the coating material. Since coats of different characteristics can be formed in Supercell coating, the choice of wetting conditions would depend on the type of coat required and the coating materials used. Published: August 10, 2007     

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.     

Quantitative analysis of film coating in a pan coater based on in-line sensor measurements

A method was developed that enables in-line analysis of film coating thickness on tablets during a pan coating operation. Real-time measurements were made using a diffusereflectance near-infrared (NIR) probe positioned inside the pan during the coating operation. Real-time spectra of replicate batches were used for modeling film growth. Univariate analysis provided a simple method for in-line monitoring of the coating process using NIR data. An empirical geometric 2-vector volumetric growth model was developed, which accounts for differential growth on the face and band regions of biconvex tablets. The thickness of the film coat was determined by monitoring the decrease of absorption bands characteristic of a component of the tablet core and monitoring the increase of bands characteristic of a component in the coating material. There was good correlation between values estimated from the NIR data and the measured tablet volumetric growth. In-line measurements allow the coating process to be stopped when a predetermined tablet coating thickness is achieved. Published: September 20, 2005     

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.     

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.     

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.     

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.     

Soluble Itraconazole in Tablet Form Using Disordered Drug Delivery Approach: Critical Scale-up Considerations and Bio-equivalence Studies

The present research work explores formulation design, critical scale-up considerations and bio-equivalence studies of soluble itraconazole (ITZ) in a tablet form using disordered drug delivery approach. Disordered system of ITZ with a lower viscosity grade of hydroxypropyl methyl cellulose (Pharmacoat 603) was developed for the first time and extensively characterised at three different stages, namely development of glass system, pellet coating and tablet compression using advanced analytical techniques. Complete molecular embedment of ITZ resulting in amorphisation was observed and found to be sustained until end of the real-time and accelerated stability studies. Developed formulation exhibited comparative in vitro dissolution profile (similarity factor >70) with reference product (Sporanox, Janssen Pharmaceutica) in simulated gastric fluid without enzymes. Formulation was scaled up in three batches (50,000 tablets/batch) with detailed validation of critical process parameters using process capability index method. Critical scale-up considerations like control of residual solvent content, effect of pellet size on dissolution, process variables in pellet coating, compressibility of coated pellets and cushioning effect required for desired compressibility were thoroughly discussed. Bioequivalence study of single dose of test and reference product in seven healthy human volunteers under fed condition exhibited significant bioequivalence with results (AUC_last and AUC_∞) lying between 90% confidence interval. With increase in number of subjects to 24, a significant effect on pharmacokinetic parameters of both reference as well as developed ITZ tablets was observed.     

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.     

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.     

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     

Chitosan and Enteric Polymer Based Once Daily Sustained Release Tablets of Aceclofenac: <Emphasis Type="BoldItalic">In Vitro</Emphasis> and <Emphasis Type="BoldItalic">In Vivo</Emphasis> Studies

The purpose of this study was to develop a once daily sustained release tablet of aceclofenac using chitosan and an enteric coating polymer (hydroxypropyl methylcellulose phthalate or cellulose acetate phthalate). Overall sustained release for 24 h was achieved by preparing a double-layer tablet in which the immediate release layer was formulated for a prompt release of the drug and the sustained release layer was designed to achieve a prolonged release of drug. The preformulation studies like IR spectroscopic and differential scanning calorimetry showed the absence of drug–excipient interactions. The tablets were found within the permissible limits for various physicochemical parameters. Scanning electron microscopy was used to visualize the surface morphology of the tablets and to confirm drug release mechanisms. Good equivalence in the drug release profile was observed when drug release pattern of the tablet containing chitosan and hydroxypropyl methylcellulose phthalate (M-7) was compared with that of marketed tablet. The optimized tablets were stable at accelerated storage conditions for 6 months with respect to drug content and physical appearance. The results of pharmacokinetic studies in human volunteers showed that the optimized tablet (M-7) exhibited no difference in the in vivo drug release in comparison with marketed tablet. No significant difference between the values of pharmacokinetic parameters of M-7 and marketed tablets was observed (p > 0.05; 95% confidence intervals). However the clinical studies in large scale and, long term and extensive stability studies at different conditions are required to confirm these results.     

Optimization of an Aqueous Tablet-Coating Process Containing Carboxymethylated Cassia fistula Gum

The present investigation was aimed at developing and optimizing a simple aqueous tablet-coating formulation and its process. 5-Fluorouracil (5-FU) was used to ascertain the relative lipophilic/hydrophilic behavior of the coating system. Optimization was performed by evaluating the adhesive force strength and cohesive force strength of the tablet coat using a texture analyzer. The in vitro release of 5-FU was found to decrease with an increase in (tablet surface-coat) adhesive force strength. The (tablet-tablet) cohesive force strength was reduced by the addition of magnesium silicate to the coating solution. The addition of magnesium silicate (0.2% w/v) to the carboxymethyl Cassia fistula gum-chitosan (CCG-CH) coating surface significantly inhibited the release of 5-FU possibly due to an increase in the hydrophobic character of the coated tablet surface. This was possible by coating cohesive force strength reduction coating compositions (CCG-CH (70:30) and 0.3% magnesium silicate). Further, the FTIR-ATR and DSC analyses suggested the pivotal role of magnesium silicate in modifying the release of 5-FU from CCG-CH-coated tablets due to hydrogen bonding of its Si-O-Si or Mg-O groups with -OH moieties of CCG-CH.     

Application of Quality by Design (QbD) Approach to Ultrasonic Atomization Spray Coating of Drug-Eluting Stents

The drug coating process for coated drug-eluting stents (DES) has been identified as a key source of inter- and intra-batch variability in drug elution rates. Quality-by-design (QbD) principles were applied to gain an understanding of the ultrasonic spray coating process of DES. Statistically based design of experiments (DOE) were used to understand the relationship between ultrasonic atomization spray coating parameters and dependent variables such as coating mass ratio, roughness, drug solid state composite microstructure, and elution kinetics. Defect-free DES coatings composed of 70% 85:15 poly(dl-lactide-co-glycolide) and 30% everolimus were fabricated with a constant coating mass. The drug elution profile was characterized by a mathematical model describing biphasic release kinetics. Model coefficients were analyzed as a DOE response. Changes in ultrasonic coating processing conditions resulted in substantial changes in roughness and elution kinetics. Based on the outcome from the DOE study, a design space was defined in terms of the critical coating process parameters resulting in optimum coating roughness and drug elution. This QbD methodology can be useful to enhance the quality of coated DES.KEY WORDS: biodegradable polymers, coating, drug-eluting stents, processing, quality by design     

Chitosan and Enteric Polymer Based Once Daily Sustained Release Tablets of Aceclofenac: In Vitro and In Vivo Studies

The purpose of this study was to develop a once daily sustained release tablet of aceclofenac using chitosan and an enteric coating polymer (hydroxypropyl methylcellulose phthalate or cellulose acetate phthalate). Overall sustained release for 24 h was achieved by preparing a double-layer tablet in which the immediate release layer was formulated for a prompt release of the drug and the sustained release layer was designed to achieve a prolonged release of drug. The preformulation studies like IR spectroscopic and differential scanning calorimetry showed the absence of drug–excipient interactions. The tablets were found within the permissible limits for various physicochemical parameters. Scanning electron microscopy was used to visualize the surface morphology of the tablets and to confirm drug release mechanisms. Good equivalence in the drug release profile was observed when drug release pattern of the tablet containing chitosan and hydroxypropyl methylcellulose phthalate (M-7) was compared with that of marketed tablet. The optimized tablets were stable at accelerated storage conditions for 6 months with respect to drug content and physical appearance. The results of pharmacokinetic studies in human volunteers showed that the optimized tablet (M-7) exhibited no difference in the in vivo drug release in comparison with marketed tablet. No significant difference between the values of pharmacokinetic parameters of M-7 and marketed tablets was observed (p > 0.05; 95% confidence intervals). However the clinical studies in large scale and, long term and extensive stability studies at different conditions are required to confirm these results.Key words: aceclofenac, chitosan, matrix tablet, pharmacokinetics, sustained release     

Buccal Drug Delivery of Pravastatin Sodium

The purpose of this study was to develop and optimize formulations of mucoadhesive bilayered buccal tablets of pravastatin sodium using carrageenan gum as the base matrix. The tablets were prepared by direct compression method. Polyvinyl pyrrolidone (PVP) K 30, Pluronic® F 127, and magnesium oxide were used to improve tablet properties. Magnesium stearate, talc, and lactose were used to aid the compression of tablets. The tablets were found to have good appearance, uniform thickness, diameter, weight, pH, and drug content. A 2³ full factorial design was employed to study the effect of independent variables viz. levels of carrageenan gum, Pluronic F 127 and PVP K30, which significantly influenced characteristics like in vitro mucoadhesive strength, in vitro drug release, swelling index, and in vitro residence time. The tablet was coated with an impermeable backing layer of ethyl cellulose to ensure unidirectional drug release. Different penetration enhancers were tried to improve the permeation of pravastatin sodium through buccal mucosa. Formulation containing 1% sodium lauryl sulfate showed good permeation of pravastatin sodium through mucosa. Histopathological studies revealed no buccal mucosal damage. It can be concluded that buccal route can be one of the alternatives available for the administration of pravastatin sodium.     

Scale-up of a pan-coating process

The purpose of this work was to develop a practical scale-up model for a solvent-based pan-coating process. Practical scale-up rules to determine the key parameters (pan load, pan speed, spray rate, air flow) required to control the process are proposed. The proposed scale-up rules are based on a macroscopic evaluation of the coating process. Implementation of these rules does not require complex experimentation or prediction of model parameters. The proposed scale-up rules were tested by conducting coating scale-up and scale-down experiments on 24-inch and 52-inch Vector Hi-coaters. The data demonstrate that using these rules led to similar cumulative drug release profiles (f2≫50; and P Analysis of Variance [P _ANOVA]≫0.05 for cumulative percentage of drug released after 12 hours [Cum 12] from tablets made at 24- and 52-inch scales. Membrane characteristics such as opacity and roughness were also similar across the 2 scales. The effects of the key process variables on coat weight uniformity and membrane characteristics were also studied. Pan speed was found to be the most significant factor related to coating uniformity. Spray droplet size was found to affect the membrane roughness significantly, whereas opacity was affected by the drying capacity.     

Evaluation of the Performance Characteristics of Bilayer Tablets: Part II. Impact of Environmental Conditions on the Strength of Bilayer Tablets

Ambient air humidity and temperature are known to influence the mechanical strength of tablets. The objective of this work is to understand the influence of processing parameters and environmental conditions (humidity and temperature) on the strength of bilayer tablets. As part of this study, bilayer tablets were compressed with different layer ratios, dwell times, layer sequences, material properties (plastic and brittle), first and second layer forces, and lubricant concentrations. Compressed tablets were stored in stability chambers controlled at predetermined conditions (40C/45%RH, 40C/75%RH) for 1, 3, and 5 days. The axial strength of the stored tablets was measured and a statistical model was developed to determine the effects of the aforementioned factors on the strength of bilayer tablets. As part of this endeavor, a full 3 × 2⁴ factorial design was executed. Responses of the experiments were analyzed using PROC GLM of SAS (SAS Institute Inc, Cary, North Carolina, USA). A model was fit using all the responses to determine the significant interactions (p < 0.05). Results of this study indicated that storage conditions and storage time have significant impact on the strength of bilayer tablets. For Avicel–lactose and lactose–Avicel tablets, tablet strength decreased with the increasing humidity and storage time. But for lactose–lactose tablets, due to the formation of solid bridges upon storage, an increase in tablet strength was observed. Significant interactions were observed between processing parameters and storage conditions on the strength of bilayer tablets.

Electronic supplementary material

The online version of this article (doi:10.1208/s12249-012-9846-8) contains supplementary material, which is available to authorized users.KEY WORDS: axial tester, bilayer tablet, design of experiments, storage conditions, tablet strength     

Optimization and <Emphasis Type="Italic">In vivo</Emphasis> Pharmacokinetic Study of a Novel Controlled Release Venlafaxine Hydrochloride Three-Layer Tablet

Several matrix tablet formulations (hydrophilic-based, wax-based, and three-layer tablets) were designed for controlling the release of the highly water soluble drug, venlafaxine hydrochloride (VenHCl) for once-daily administration. The three-layer tablets consist of non-swellable, compritol-based middle layers containing the drug to which hydrophilic top and bottom barrier layers were applied. A 2³ full-factorial design was employed for optimization and to explore the effect of different variables on the release rate of the drug from the three-layer tablets. The optimized levels of each independent variable were based on the criterion of desirability. The calculated values of f ₁ and f ₂ were 4.131 and 79.356, respectively; indicating that the release profile of the optimized PEO layered tablet formulation is comparable to that of the target release model. The pharmacokinetic parameters of VenHCl from the optimized three-layer tablet was compared to the marketed extended release capsule as a reference in healthy human subjects using a randomized crossover design. In this study, the 90% confidence interval for AUC_0–24 and AUC_0−∞ are within (0.8–1.25), which satisfied the bioequivalence criteria. It could be concluded that a promising once-daily extended-release three-layer tablet of the highly water soluble drug, VenHCl, was successfully designed.