Detecting Blending End-Point Using Mean Squares Successive Difference Test and Near-Infrared Spectroscopy.

An algorithm based on mean squares successive difference test applied to near-infrared and principal component analysis scores was developed to monitor and determine the blending profile and to assess the end-point in the statistical stabile phase. Model formulations consisting of an active compound (acetylsalicylic acid), together with microcrystalline cellulose and two grades of calcium carbonate with dramatically different particle shapes, were prepared. The formulation comprising angular-shaped calcium carbonate reached blending end-point slower when compared with the formulation comprising equant-shaped calcium carbonate. Utilizing the ring shear test, this distinction in end-point could be related to the difference in flowability of the formulations. On the basis of the two model formulations, a design of experiments was conducted to characterize the blending process by studying the effect of CaCO3 grades and fill level of the bin on blending end-point. Calcium carbonate grades, fill level, and their interaction were shown to have a significant impact on the blending process.

Near-infrared chemical imaging (NIR-CI) as a process monitoring solution for a production line of roll compaction and tableting.

In the present study the application of near-infrared chemical imaging (NIR-CI) supported by chemometric modeling as non-destructive tool for monitoring and assessing the roller compaction and tableting processes was investigated. Based on preliminary risk-assessment, discussion with experts and current work from the literature the critical process parameter (roll pressure and roll speed) and critical quality attributes (ribbon porosity, granule size, amount of fines, tablet tensile strength) were identified and a design space was established. Five experimental runs with different process settings were carried out which revealed intermediates (ribbons, granules) and final products (tablets) with different properties. Principal component analysis (PCA) based model of NIR images was applied to map the ribbon porosity distribution. The ribbon porosity distribution gained from the PCA based NIR-CI was used to develop predictive models for granule size fractions. Predictive methods with acceptable R(2) values could be used to predict the granule particle size. Partial least squares regression (PLS-R) based model of the NIR-CI was used to map and predict the chemical distribution and content of active compound for both roller compacted ribbons and corresponding tablets. In order to select the optimal process, setting the standard deviation of tablet tensile strength and tablet weight for each tablet batch was considered. Strong linear correlation between tablet tensile strength and amount of fines and granule size was established, respectively. These approaches are considered to have a potentially large impact on quality monitoring and control of continuously operating manufacturing lines, such as roller compaction and tableting processes.

Impact of sodium dodecyl sulphate on the dissolution of poorly soluble drug into biorelevant medium from drug-surfactant discs.

The purpose was to elucidate the mechanism of action of sodium dodecyl sulphate (SDS) on drug dissolution from discs under physiologically relevant conditions. The effect of incorporating SDS (4-30%, w/w) and drug into discs on the dissolution constant and solubility were evaluated for the poorly soluble drugs griseofulvin and felodipine in a biorelevant dissolution medium (BDM). Dissolution constants from dissolution profiles of drug discs with and without SDS were measured using miniaturized rotating disc dissolution. Solid state changes were investigated by X-ray diffraction. Solubility was determined using HPLC-UV. The interaction between micelles in BDM and SDS was investigated by isothermal titration calorimetry and dynamic light scattering. Isothermal titration calorimetry showed that SDS formed mixed micelles with bile salt:phospholipid (BS:PC) micelles in BDM. Dynamic light scattering showed that the addition of SDS made the BS:PC micelles grow up to 2.5 times in volume. As a function of SDS addition, the dissolution constant showed an apparent exponential increase, while drug solubility showed a weak linear dependence. The pronounced effect on dissolution constant with SDS in the discs is not caused by an increased surface area as SDS dissolves, micelles in the bulk medium or changes in the solid state properties of the drugs. The proposed mechanism involves a high local concentration of SDS at the solid-liquid interface as SDS dissolves and this solubilizes the drug. The improved solubility at the solid-liquid interface provided a much steeper concentration gradient resulted in a faster dissolution. The total amount of SDS in the discs only gave a minor increase in total surfactant concentration in the dissolution medium and did therefore not to any large extent affect the drug solubility in the bulk.

Building quality into a coating process.

An effective approach towards optimal development strategy is to use the quality by design principle. However, this approach can first be implemented when possible risks impacting critical quality attributes are defined and interactions between those are fully understood. The objective of this study was to identify critical variables that affect the final modified release product performance using a risk management approach with supporting statistical tool. After risk ranking and filtering a full mixed factorial experimental design of coating experiments was performed. Experimental design clearly indicated that studied critical processes parameters have a great impact on coat integrity and hence on drug release.

Increasing process understanding by analyzing complex interactions in experimental data.

There is a recognized need for new approaches to understand unit operations with pharmaceutical relevance. A method for analyzing complex interactions in experimental data is introduced. Higher-order interactions do exist between process parameters, which complicate the interpretation of experimental results. In this study, experiments based on mixed factorial design of coating process were performed. Drug release was analyzed by traditional analysis of variance (ANOVA) and generalized multiplicative ANOVA (GEMANOVA). GEMANOVA modeling is introduced in this study as a new tool for increased understanding of a coating process. It was possible to model the response, that is, the amount of drug released, using both mentioned techniques. However, the ANOVA model was difficult to interpret as several interactions between process parameters existed. In contrast to ANOVA, GEMANOVA is especially suited for modeling complex interactions and making easily understandable models of these. GEMANOVA modeling allowed a simple visualization of the entire experimental space. Furthermore, information was obtained on how relative changes in the settings of process parameters influence the film quality and thereby drug release.

Helium pycnometry as a tool for assessment of sealing efficiency in microencapsulation.

There is a need for a fast and reliable method to evaluate the development in coating quality during coating, especially for fast dissolving coatings. In the present study, pycnometric density was evaluated as a tool for assessment of coating quality in terms of sealing efficiency for microspheres coated with polymeric aqueous solutions. Further, it was investigated if the method could be used to study effects of spray variables on the sealing efficiency of coated microspheres. The microcrystalline cellulose particles Ethispheres250 were coated with aqueous solutions of Hypromellose 5 and Povidone K-90F by Wurster bottom-spray technique. End products and samples drawn during coating were analysed in terms of pycnometric helium density and scanning electron microscopy (SEM). Experiments constituted a 2(3) factorial design with the following spray related variables: atomisation air flow, polymer type, and solution concentration/viscosity. Helium pycnometric density was seen to lower gradually during coating in all experiments and to follow a common pattern. The quantitative lowering in density was further seen to correlate to sealing of voids by gradual covering of the microsphere surface and thus the sealing efficiency. Hence, the present data suggests helium pycnometry as a tool for assessment of coating quality in terms of sealing efficiency. This goes particularly for testing of products coated with water-soluble coatings, where dissolution testing obviously is compromised. The specific data on sealing efficiency might also add to other analytical methods in the analysis of coating quality, in general. End point densities of coated microspheres were seen to reveal differences in sealing efficiency between polymers. Measured densities of final products were also generally seen to reflect differences in coating permeability caused by variations in spray conditions. Thus, the measurement of density is a potential a tool for evaluation of spray conditions with respect to sealing of microspheres and identification of critical spray conditions.

Acoustic monitoring of a fluidized bed coating process.

The aim of the study was to investigate the potential of acoustic monitoring of a production scale fluidized bed coating process. The correlation between sensor signals and the estimated amount of film applied and percentage release, respectively, were investigated in coating potassium chloride (KCl) crystals with ethylcellulose (EC). Vibrations were measured with two different types of accelerometers. Different positions for placing the accelerometers and two different product containers were included in the study. Top spray coating of KCl was chosen as a 'worst case' scenario from a coating point perspective. The acoustic monitoring has the potential of summarising the commonly used means to monitor the coating process. The best partial least squares (PLS) regressions, obtained by the high frequency accelerometer, showed for the release a correlation coefficient of 0.92 and a root mean square error of prediction (RMSEP) of 5.84% (31-82.8%), and for the estimated amount of film applied a correlation coefficient of 0.95 and RMSEP of 0.52% (0.6-6%). The results of the preliminary investigation are considered promising. There is however a need for further investigations on sampling procedures and product characterisation before a final conclusion on the applicability of acoustic monitoring can be made.

A new process control strategy for aqueous film coating of pellets in fluidised bed.

The parameters with effect on maximum spray rate and maximum relative outlet air humidity when coating pellets in a fluidised bed were investigated. The tested variables include type of water based modified release film coating (Eudragit NE 30D, Eudragit RS 30D, Aquacoat ECD) coating principle (top spray, bottom spray), inlet air humidity and type of pellets (sugar spheres, microcrystalline cellulose pellets). The maximum spray rate was not influenced by the coating principles. The highest spray rate was obtained for the film polymer with the lowest tackiness which is assumed to be the controlling factor. The type of pellets affected the maximum spray rate. A thermodynamic model for the coating process is employed throughout the process and not just during steady state. The thermodynamic model is incorporated into a new process control strategy. The process control strategy is based on in-process calculation of degree of utilisation of the potential evaporation energy (DUE) of the outlet air and the relative outlet air humidity (RH). The spray rate is maximised using set points of DUE and RH as control parameters. The product temperature is controlled simultaneously by regulating the inlet air temperature.

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.