Quantification of microparticle coating quality by confocal laser scanning microscopy (CLSM)

In this work, a novel protocol was developed for determining film coating thickness and coating quality of microparticles, based on the use of confocal laser scanning microscopy (CLSM). CLSM was found to be an adequate non-destructive technique for the quantification of the coating thickness and coating quality of individual thin-coated small particles. Combined with image analysis, it was possible to derive with high accuracy the coating thickness distribution of a representative number of microparticles. The performance of the novel methodology was assessed by the quantification of the coating thickness and coating quality of protein-coated microparticles produced by fluidized bed coating. It was found that the CLSM data on coating layer thickness were generally in good agreement with the results from chemical analysis, down to a thickness of 1–1.5 μm. Using CLSM the importance of setting up the appropriate distance between the coating nozzle and the powder bed with respect to microparticle coating quality in fluidized bed processing was illustrated. Coating quality was found to decrease with increasing distance the coating droplets have to travel before impinging onto the core particles as a result of spray-drying of the coating droplets. Also, coating quality decreased with increasing viscosity of the coating droplets, resulting in reduced spreading on the cores.     

Evaluating the effect of coating equipment on tablet film quality using terahertz pulsed imaging

In this study, terahertz pulsed imaging (TPI) was employed to investigate the effect of the coating equipment (fluid bed and drum coater) on the structure of the applied film coating and subsequent dissolution behaviour. Six tablets from every batch coated with the same delayed release coating formulation under recommended process conditions (provided by the coating polymer supplier) were mapped individually to evaluate the effect of coating device on critical coating characteristics (coating thickness, surface morphology and density). Although the traditional coating quality parameter (weight gain) indicated no differences between both batches, TPI analysis revealed a lower mean coating thickness (CT) for tablets coated in the drum coater compared to fluid bed coated tablets (p < 0.05). Moreover, drum coated tablets showed a more pronounced CT variation between the two sides and the centre band of the biconvex tablets, with the CT around the centre band being 22.5% thinner than the top and bottom sides for the drum coated tablets and 12.5% thinner for fluid bed coated tablets. The TPI analysis suggested a denser coating for the drum coated tablets. Dissolution testing confirmed that the film coating density was the drug release governing factor, with faster drug release for tablets coated in the fluid bed coater (98 ± 4% after 6 h) compared to drum coated tablets (72 ± 6% after 6 h). Overall, TPI investigation revealed substantial differences in the applied film coating quality between tablets coated in the two coaters, which in turn correlated with the subsequent dissolution performance.     

Suppression of agglomeration in fluidized bed coating. IV. Effects of sodium citrate concentration on the suppression of particle agglomeration and the physical properties of HPMC film

We previously reported that sodium citrate (Na citrate), which is a high order salt in the Hofmeister's series, greatly suppressed particle agglomeration in fluidized bed coating (Pharm. Res., 16 (1999), 1616-1620). In this paper, we studied the effects of Na citrate concentration on the particle agglomeration in fluidized bed coating and on the structure of coated film on the particles. Spherical granules made of crystalline cellulose (Celphere) containing phenacetin were coated in a fluidized bed with the aqueous coating solution of hydroxypropylmethyl cellulose (HPMC) containing Na citrate at various concentrations. The particle diameter and drug release profile of coated particles, and the physical properties, i.e. tensile strength, elongation percentage at break, porosity and pore size distribution, of the HPMC cast film were investigated. The particle agglomeration was suppressed with the increasing Na citrate concentration. It is considered that the increase in the suppression effect was caused by the salting-out effect of the increased Na citrate. In the HPMC cast film system, the tensile strength and elongation percentage decreased and the porosity and cumulative pore volume increased with an increase in Na citrate concentration. It is considered that the increase in the porosity by adding Na citrate resulted from a phase separation due to the salting-out during the film forming process. The drug release rate from coated particles also increased with the increasing Na citrate concentration. It can be concluded that the increase in the release rate was due to the increase in porosity of the HPMC coated film caused by the increased Na citrate concentration.     

Validation of an image analysis method for estimating coating thickness on pellets.

A digital image analysis method for the estimation of mean pellet size and coating thickness employing optical microscopy was evaluated. The coating thickness was expressed as the difference in mean projected area radius of the uncoated and the coated pellets. The repeatability, the intermediate precision and the robustness of the image analysis method were investigated. The repeatability and the intermediate precision of the image analysis method was excellent with a low degree of scatter between the measurements. The robustness investigation on the image analysis method illustrated the importance of controlling and monitoring the illumination technique utilised. Calibration of the image analysis equipment was of the highest importance. Using pellets with a high degree of sphericity and narrow size distribution, it was sufficient to use 1000 pellets to estimate the mean pellet size and the coating thickness with an accuracy of +/-1.2 microm. An equation is presented for an approximation of the number of pellets necessary to achieve a given accuracy in the estimation of mean pellet size and coating thickness.     

Determination of Tablet Coating Distribution by Deconvolution of Uncoated and Coated Tablet Weight Distributions

Purpose. The purpose of this research is to obtain the tablet coating distribution from weight distributions of uncoated and coated tablets. Methods. The method of deconvolution with digital smoothing was used to calculate the distribution of coating applied to a tablet population from separate random measurements of individual uncoated and coated tablets. Results. It was demonstrated that the calculated coating weight distribution agrees well with the measured distribution. The effect of the smoothing factor on the solution is illustrated. Conclusions. This method can be used during development to facilitate process scale-up/optimization. In routine production, the method can assess the reproducibility and consistency of a coating process.     

Design of sustained release fine particles using two-step mechanical powder processing: Particle shape modification of drug crystals and dry particle coating with polymer nanoparticle agglomerate

We attempted to prepare sustained release fine particles using a two-step mechanical powder processing method; particle-shape modification and dry particle coating. First, particle shape of bulk drug was modified by mechanical treatment to yield drug crystals suitable for the coating process. Drug crystals became more rounded with increasing rotation speed, which demonstrates that powerful mechanical stress yields spherical drug crystals with narrow size distribution. This process is the result of destruction, granulation and refinement of drug crystals. Second, the modified drug particles and polymer coating powder were mechanically treated to prepare composite particles. Polymer nanoparticle agglomerate obtained by drying poly(meth)acrylate aqueous dispersion was used as a coating powder. The porous nanoparticle agglomerate has superior coating performance, because it is completely deagglomerated under mechanical stress to form fine fragments that act as guest particles. As a result, spherical drug crystals treated with porous agglomerate were effectively coated by poly(meth)acrylate powder, showing sustained release after curing. From these findings, particle-shape modification of drug crystals and dry particle coating with nanoparticle agglomerate using a mechanical powder processor is expected as an innovative technique for preparing controlled-release coated particles having high drug content and size smaller than 100 μm.     

Development and Characterization of Microencapsulated Microspheres

A process for the coating of polymer microspheres with the same or different polymers and the characterization of these particles is described. Coated microspheres were manufactured from degradable and non-degradable polymers. Several physicochemical methods were used to establish that the particles were fully coated. Polarized light microscopy revealed strong birefringence of coated microspheres resulting in the appearance of Maltese Crosses on coated microspheres. After staining the core and the coating of particles using different fluorescent dyes, the uneven distribution of the dyes in the core and on the surface allows one to verify the coating success. After cutting microspheres using a cryomicrotome we were able to assess the microstructure of the coated microspheres. Electron Spectroscopy for Chemical Analysis (ESCA) was used to determine the surface composition of coated microspheres. Determining the carbon and oxygen content of samples we were able to verify the completeness of the coating procedure. To examine the benefit of coating microspheres, the effect of coating on the release of tetanus toxoid from polylactide microspheres was studied as a possible pharmaceutical application.     

Terahertz In-Line Sensor for Direct Coating Thickness Measurement of Individual Tablets During Film Coating in Real-Time

We present a new in-line measurement technique to determine the coating thickness of individual pharmaceutical tablets during film coating in a pan coating unit using pulsed terahertz technology. Results of these real-time terahertz measurements acquired during a production scale coating run are validated using both off-line high-resolution terahertz pulsed imaging of the whole dosage form as well as weight-gain measurements made on sample tablets removed at discrete time intervals during the process run. The terahertz measurements provide a direct method of determining the coating thickness, and no chemometric calibration models are required for the quantification. The results, and their repeatability, demonstrate that real-time monitoring of pharmaceutical tablet coating is not only possible but also provides substantially more information of the coating quality than the standard quality control method. Rather than providing the average coating thickness of a large number of tablets, the terahertz sensor provides the thickness of up to 100 individual tablet coatings per minute. Using this information, the operator can get additional information about the thickness distribution in the coating pan and adjust the process accordingly. At present, a minimum coating thickness of 40 μm is required to determine the coating thickness. The technique is applicable for coatings up to 1 mm in thickness. Within that range, it provides thickness measurements of sub-micron resolution. Terahertz in-line coating process measurements show considerable potential for applications in real-time release, process analytical technology and quality by design.     

Use of Modified Ethylcellulose Lattices for Microporous Coating of Osmotic Tablets

Commercially available lattices are often used to coat nonpareils or beads. Drug release occurs via diffusion through the polymer coating. Adequate release rates may be achieved with small particles because the surface area is large. However, tablets coated with unmodified lattices have exceedingly slow release rates. Therefore, a pore-forming agent, urea, was added to a commercially available ethyl cellulose latex, Aquacoat, to increase the release rate of drugs from coated osmotic tablets. Modified lattices were used to coat KC1 and diltiazem · HC1 tablets. Release of KC1 and diltiazem into water or buffer solutions was determined in a standard U.S.P. dissolution apparatus. Rates varying from 1 to 100% release in 12 hr were obtained by varying the coating thickness, pore-former level, and plasticizer type and concentration. Scanning electron microscopy (SEM) showed that the urea was eluted from the coat in aqueous solution leaving a porous coating. Coat burst strengths were dependent on the coat thickness and the concentrations of pore former and plasticizer. Hence, modified lattices hold potential for use as coatings for controlled release osmotic formulations.     

Dynamic Calibration for the In-Line NIR Monitoring of Film Thickness of Pharmaceutical Tablets Processed in a Fluid-Bed Coater

NIR spectroscopy has been extensively employed for the in-line monitoring of pharmaceutical processes as one of the key PAT implementation tools. Nevertheless, pharmaceutical processes such as fluid-bed coating have not fully made the most of the NIR in-line monitoring primarily due to a difficulty in handling random in-line spectra. In this study, novel approaches to develop a reasonable dynamic calibration model were proposed; averaging and clustering. Pharmaceutical test tablets were coated with HPMC-based materials using a fluid-bed processor. During the 160 min coating process under tangential spraying mode, 10 tablets were sampled out at every 10 min mark for actual coating thickness measurements. NIR spectra at and near each 10 min mark were treated and processed by the averaging and clustering operations. Averaging of 21 spectra resulted in a reasonably good dynamic calibration model whose determination coefficient was estimated as high as 0.9916. The PCA-based clustering turned out to be substantially helpful especially when a large number of NIR spectra were averaged. A prediction experiment verified that our dynamic calibration model can control the coating thickness in-line as good as 3% deviated from the actual thickness, which can offer a reasonable end-point for the fluid-bed coating process. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:325–335, 2010     

Physical Characterization of Pharmaceutical Solids

A general review of the methods available for the physical characterization of pharmaceutical solids is presented. The techniques are classified as being on the molecular level (properties capable of being detected in an ensemble of individual molecules), the particulate level (properties which can be detected through the analysis of an ensemble of particles), and the bulk level (properties which can be measured only using a relatively large amount of material). The molecular-level properties discussed are infrared spectroscopy and nuclear magnetic resonance spectrometry, the particulate-level properties discussed are particle morphology, particle size distribution, powder X-ray diffraction, and thermal methods of analysis, and the bulk-level properties discussed are surface area, porosity and pore size distribution, and powder flow characteristics. Full physical characterization of three modifications of lactose (hydrous, anhydrous, and Fast-Flo) is presented to illustrate the type of information which can be obtained using each of the techniques discussed.     

Formulation and process considerations affecting the stability of solid dosage forms formulated with methacrylate copolymers.

General considerations concerning the stability of coated dosage forms are discussed, in order to avoid predictable interactions which may cause long-term stability problems. As polymers themselves maintain a high chemical stability and a low reactivity, instability phenomena mainly have to be explained by interactions of low molecular weight substances or physical changes. Possible interactions of functional groups can be predicted easily and insulating subcoates are proper countermeasures. Impurities, remaining in the polymeric material from the manufacturing process, may accelerate the hydrolysis of sensitive drugs. Instabilities of coated dosage forms are mainly based on physical interactions, caused by improper formulations of coating suspensions (i.e. plasticizers or pigments) or the film coating process. Residual moisture or solvents, probably enclosed in the core and migrating over time, may increase the permeability of coatings, due to plasticizing effects. The functionality of coatings from aqueous dispersions is linked to coalescence of latex particles. Thus any incomplete film formation, caused by too high or too low coating temperatures, may result in high permeable coatings. During storage, preferably under stress conditions this process will continue and thus change the release profile. Therefore bed temperatures of 10-20 degrees C above MFT must ensure the formation of homogeneous polymer layers during the coating process. Stability test procedures and packaging materials also need to be adapted to the physicochemical properties of the dosage form, in order to get meaningful results in stability tests.     

Real-time imaging as an emerging process analytical technology tool for monitoring of fluid bed coating process

Abstract

A direct imaging system (Eyecon^TM) was used as a Process Analytical Technology (PAT) tool to monitor fluid bed coating process. Eyecon^TM generated real-time onscreen images, particle size and shape information of two identically manufactured laboratory-scale batches. Eyecon^TM has accuracy of measuring the particle size increase of ±1?μm on particles in the size range of 50–3000?μm.

Eyecon^TM captured data every 2?s during the entire process. The moving average of D90 particle size values recorded by Eyecon^TM were calculated for every 30?min to calculate the radial coating thickness of coated particles. After the completion of coating process, the radial coating thickness was found to be 11.3 and 9.11?μm, with a standard deviation of?±0.68 and 1.8?μm for Batch 1 and Batch 2, respectively. The coating thickness was also correlated with percent weight build-up by gel permeation chromatography (GPC) and dissolution. GPC indicated weight build-up of 10.6% and 9.27% for Batch 1 and Batch 2, respectively.

In conclusion, weight build-up of 10% can also be correlated with 10?±?2?μm increase in the coating thickness of pellets, indicating the potential applicability of real-time imaging as an endpoint determination tool for fluid bed coating process.     

Computational Fluid Dynamics-Discrete Element Method Modeling of an Industrial-Scale Wurster Coater

Large-scale fluid bed coating operations using Wurster coaters are common in the pharmaceutical industry. Experimental measurements of the coating thickness are usually analyzed for just few particles. To better predict the coating uniformity of the entire batch, computational techniques can be applied for process understanding of the key process parameters that influence the quality attributes. Recent advances in computational hardware, such as graphics processing unit, have enabled simulations of large industrial-scale systems. In this work, we perform coupled computational fluid dynamics-discrete element method simulations of a large-scale coater that model the actual particle sizes. The influence of process parameters, inlet air flow rate, atomizing air flow rate, bead size distribution, and Wurster gap height is studied. The focus of this study is to characterize the flow inside the coater; eventually, this information will be used to predict the coating uniformity of the beads. We report the residence time distribution of the beads inside the Wurster column, that is, the active coating zone, which serves as a proxy for the amount of coating received by the beads per pass. The residence time provides qualitative and quantitative measurements of the particle-coating uniformity. We find that inlet air flow rate has the largest impact on the flow behavior and, hence, the coating uniformity.     

Osseointegration of titanium with an antimicrobial nanostructured noble metal coating

Nanometer scale surface features on implants and prostheses can potentially be used to enhance osseointegration and may also add further functionalities, such as infection resistance, to the implant. In this study, a nanostructured noble metal coating consisting of palladium, gold and silver, never previously used in bone applications, was applied to machined titanium screws to evaluate osseointegration after 6 and 12 weeks in rabbit tibiae and femurs. Infection resistance was confirmed by in vitro adhesion test. A qualitatively and quantitatively similar in vivo bone response was observed for the coated and uncoated control screws, using histology, histomorphometry and electron microscopy. The bone-implant interface analysis revealed an extensive bone formation and direct bone-implant contact. These results demonstrate that the nanostructured noble metal coating with antimicrobial properties promotes osseointegration and may therefore be used to add extra implant functionality in the form of increased resistance to infection without the use of antibiotics.From the Clinical EditorThe authors of this paper demonstrate that nanostructured noble metal coating of implants and prostheses used in orthopedic procedures promotes osseointegration and may be used to add extra implant functionality in the form of increased resistance to infection without the use of antibiotics.     

Analysis of coating structures and interfaces in solid oral dosage forms by three dimensional terahertz pulsed imaging

Three dimensional terahertz pulsed imaging (TPI) was evaluated as a novel tool for the nondestructive characterization of different solid oral dosage forms. The time-domain reflection signal of coherent pulsed light in the far infrared was used to investigate film-coated tablets, sugar-coated tablets, multilayered controlled release tablets, and soft gelatin capsules. It is possible to determine the spatial and statistical distribution of coating thickness in single and multiple coated products using 3D TPI. The measurements are nondestructive even for layers buried underneath other coating structures. The internal structure of coating materials can be analyzed. As the terahertz signal penetrates up to 3 mm into the dosage form interfaces between layers in multilayered tablets can be investigated. In soft gelatin capsules it is possible to measure the thickness of the gelatin layer and to characterize the seal between the gelatin layers for quality control. TPI is a unique approach for the nondestructive characterization and quality control of solid dosage forms. The measurements are fast and fully automated with the potential for much wider application of the technique in the process analytical technology scheme.     

Liposome coated with low molecular weight chitosan and its potential use in ocular drug delivery

In this study liposome coated with low molecular weight chitosan (LCH) was proposed and investigated its in vitro and in vivo properties, and its potential use in ocular drug delivery was evaluated. LCH with a molecular weight of 8 kDa was prepared and coated on liposome loaded with diclofenac sodium. The LCH coating changed the liposome surface charge and slightly increased its particle size, while the drug encapsulation was not affected. After coating, the liposome displayed a prolonged in vitro drug release profile. LCH coated liposome also demonstrated an improved physicochemical stability at 25 °C in a 30-day storage period. The ocular bioadhesion property was evaluated by rabbit in vivo precorneal retention, and LCH coated liposome achieved a significantly prolonged retention compared with non-coated liposome or drug solution. The LCH coating also displayed a potential penetration enhancing effect for transcorneal delivery of the drug. In the ocular tolerance study, no irritation or toxicity was caused by continual administration of LCH coated liposome in a total period of 7 days. In conclusion, the LCH coating significantly modified the properties of liposome and brought a series of notable advantages for ocular drug delivery.     

Characterization of a Hot-Melt Fluid Bed Coating Process for Fine Granules

The equipment modifications and process changes necessary to perform hot-melt particle coating in a fluid bed granulator are reviewed. A specific case is presented in which partially hydrogenated cottonseed oil is coated onto fine granules (mean particle size, 77 µm; range, 10–150 µm; one standard deviation is 10 µm) composed of a hydrophobic drug and sucrose. The major variables were product bed temperature, temperature of the wax, spray rate, and atomization air pressure. The product bed temperature was selected to give the optimum congealing rate, and the latter three variables were varied in a statistically designed experiment. The physical properties of wax-coated granules fabricated using combinations of process variables were examined. Response surface analysis was used to determine the optimum process settings in terms of dissolution, particle size, and density of the coated product. This system proved quite adequate for the production of uniformly coated granules, with the best product being obtained at the optimized conditions using 120°C atomization air and molten coating temperature, 30 g/min as the spray rate, and an atomization air pressure of 5 bar.     

Porous fibres with encapsulated functional materials and tunable release

A novel sequential processing approach to fabricate versatile fibres containing encapsulated materials is presented. It is based on developing highly porous fibres, to be filled with functional materials and coated with protective layers. Applicability of the approach to develop porous poly(methyl methacrylate) (PMMA) fibres with encapsulated antibacterial salts within a coating is demonstrated. The salt was introduced to the fibre via a sacrificial solvent. Desired solvent properties to ensure successful filling was discussed. The salt was encapsulated via spray coating. The coating characteristics were tuned via vapour treatment to facilitate controllable radial salt release. Large volume axial release was also achieved due to the axial pore connectivity. Compared to state-of-the-art methods to produce fibres with functional material inclusions such as emulsion electrospinning, the method presented herein, due to its sequential processing nature, offers greater freedom in material selection and thus broad applications of the fibres.     

The Measurement of Spray Quality for Pan Coating Processes

In this study, we describe the use of an innovative imaging system to measure and control the effect of nozzle operating parameters on the characteristics of a spray. These characteristics, including spray pattern, droplet size distribution, and droplet velocity, define the quality of the spray. They can have significant impact on the efficiency of the pan coating process and the quality of the coat. Suspensions of different composition were used in this study, and the authors demonstrated that the spray characteristics can be controlled with this approach. The main conclusions from this study were: