Controlling the performance of adhesive mixtures for inhalation using mixing energy.

A concept of mixing energy, ME, has been developed and applied to blending of adhesive mixtures for inhalation in a high shear blender. Six different systems were investigated, four of which included a coating agent. For blends containing a coating agent, it is shown that the applied ME is key to the control of two important functional mechanisms: i) coating of the carrier by the coating agent, and ii) the dispersibility of the active pharmaceutical ingredient (API). The mass of the carrier was identified to be the mass which is relevant to the forces acting during mixing. The dispersibility in terms of the fine particle fraction (FPF) can be expressed as the product of two exponentials which both are functions of ME. The first factor accounts for the initial increase in FPF, while the second accounts for the decrease observed at extensive mixing. For adhesive mixtures without a coating agent, a similar decrease in FPF is observed when high forces are applied during mixing. Mechanistic interpretation of the behavior is provided.

Quantification of surface composition and surface structure of inhalation powders using TOF-SIMS.

A multivariate TOF-SIMS methodology has been developed and applied to quantify surface composition and chemical distribution for dry powder blends. Surface properties are often critical to the behavior of powder formulations, especially in the case of dry powders for inhalation, as surface properties directly affect inter-particulate forces and, hence, the dispersibility of the formulation. The mass spectrum at each pixel was fit to a linear combination of reference spectra obtained by non-negatively constrained alternating least squares. From the pixel compositions, average surface coverage and a range of other image features were calculated. Two kinds of systems have been examined: 1) binary blends of lactose particles and coating agents, and 2) blends of different inhalation drugs with carrier lactose. For both kinds of systems, detailed insight into the surface composition and structure could be derived. For the former study, TOF-SIMS results were compared with a complementary surface analysis technique, XPS.

Comparison between integrated continuous direct compression line and batch processing - The effect of raw material properties.

There is a current trend in pharmaceutical manufacturing to shift from traditional batch manufacture to continuous manufacturing. The purpose of this study was to test the ability of an integrated continuous direct compression (CDC) line, in relation to batch processing, to achieve consistent tablet quality over long processing periods for formulations with poor flow properties or with a tendency to segregate. The study design included four industrially relevant formulations with different segregation indices and flow properties induced through different grades of the Active Pharmaceutical Ingredient (API), paracetamol, and major filler as well as varying the amount of API. The performance metrics investigated were content, uniformity of content, tablet weight, and tablet strength. The overall process stability over time was significantly improved with the CDC line as compared to the batch process. For all the formulations with a high API content, the CDC line provided better or equal uniformity of content and tablet weight as compared to batch. The CDC line was especially efficient in providing a stable content and tablet weight for poorly flowing formulations containing the standard, cohesive, grade of API. The only formulation that performed better in the batch process was the formulation with a low API content. Thus, for this formulation, the batch process achieved lower variation in tablet content since maintaining a low feed rate for the API proved challenging in the CDC line. In addition, some of the API became stuck in the CDC line between feeding and tableting, most likely at the funnel in the mixer inlet, highlighting the need for properly designed interfaces between units. The insensitivity of the CDC line towards poor flow indicates that one could use direct compression at high drug load compositions of poorly flowing powder blends that could not be processed via batch manufacturing.

Provoking an end-to-end continuous direct compression line with raw materials prone to segregation.

Continuous manufacturing of solid oral dosage forms is promising for increasing the efficiency and quality of pharmaceutical production and products. In this study a whole train continuous direct compression (CDC) line has been provoked using challenging formulations typically prone to segregation in batch powder processing. Industrial compositions including components with variable size, bulk density and cohesive nature were selected. An experimental design, including variables such as API/mannitol particle size, API amount, powder feed rate and mixer speed, enabled the output quality of the provoked process to be assessed. Contrary to previous studies, a broader range of finished tablet quality attributes were probed, including content, uniformity of content, tensile strength as well as release performance. Overall, the continuous direct compression line was found to be a capable and efficient manufacturing process for the challenging compositions studied and surprisingly tolerable to handle the materials susceptible to segregation in typical batch settings. As expected, and given the 'fixed' apparatus configuration used in this study, the particulate material properties were found to have the most significant impact on the finished tablet quality attributes. The results emphasize the importance for taking a holistic approach when developing the operational windows and the strategy for control, e.g. by integrating the appropriate material properties, the actual apparatus design, and the relevant formulation design. The CDC line's ability to handle cohesive materials also seem to be one of the key advantages, thus confirming the recent promising results from other continuous direct compression studies.

Achieving a robust drug release from extended release tablets using an integrated continuous mixing and direct compression line.

In the present work the viability of integrated continuous mixing and compression processes for manufacturing of extended release (ER) matrix tablets was investigated in terms of dissolution behavior. The purpose was also to evaluate the combined effect of processing variables and compositional variables on the release robustness. The continuous process was provoked by a challenging formulation design, including variable powder characteristics and compositions of high and low amount of poorly soluble and poorly flowing drug substance (ibuprofen). Additionally a relatively low amount of two different ER matrix former grades (standard granulation grade CR and direct compression grade DC2 of hydroxypropyl methylcellulose, HPMC) was used to challenge the system. Robust ibuprofen release was obtained faster when HPMC CR was used. However, robust release was also achieved when using HPMC DC2 at high ibuprofen content, even though it took slightly longer time to reach the steady state of the process. Due to its poor flow properties, HPMC CR would be very challenging to use in traditional direct compression. The results showed that by using continuous processing it is possible to manufacture and achieve robust performance of compositions that would not be possible with traditional batch processing due to for instance poorly flowability.

Continuous manufacturing of extended release tablets via powder mixing and direct compression.

The aim of the current work was to explore continuous dry powder mixing and direct compression for manufacturing of extended release (ER) matrix tablets. The study was span out with a challenging formulation design comprising ibuprofen compositions with varying particle size and a relatively low amount of the matrix former hydroxypropyl methylcellulose (HPMC). Standard grade HPMC (CR) was compared to a recently developed direct compressible grade (DC2). The work demonstrate that ER tablets with desired quality attributes could be manufactured via integrated continuous mixing and direct compression. The most robust tablet quality (weight, assay, tensile strength) was obtained using high mixer speed and large particle size ibuprofen and HPMC DC2 due to good powder flow. At low mixer speed it was more difficult to achieve high quality low dose tablets. Notably, with HPMC DC2 the processing conditions had a significant effect on drug release. Longer processing time and/or faster mixer speed was needed to achieve robust release with compositions containing DC2 compared with those containing CR. This work confirms the importance of balancing process parameters and material properties to find consistent product quality. Also, adaptive control is proven a pivotal means for control of continuous manufacturing systems.

Matrix Effects in Quantitative Assessment of Pharmaceutical Tablets Using Transmission Raman and Near-Infrared (NIR) Spectroscopy.

Raman spectroscopy can be an alternative to near-infrared spectroscopy (NIR) for nondestructive quantitative analysis of solid pharmaceutical formulations. Compared with NIR spectra, Raman spectra have much better selectivity, but subsampling was always an issue for quantitative assessment. Raman spectroscopy in transmission mode has reduced this issue, since a large volume of the sample is measured in transmission mode. The sample matrix, such as particle size of the drug substance in a tablet, may affect the Raman signal. In this work, matrix effects in transmission NIR and Raman spectroscopy were systematically investigated for a solid pharmaceutical formulation. Tablets were manufactured according to an experimental design, varying the factors particle size of the drug substance (DS), particle size of the filler, compression force, and content of drug substance. All factors were varied at two levels plus a center point, except the drug substance content, which was varied at five levels. Six tablets from each experimental point were measured with transmission NIR and Raman spectroscopy, and their concentration of DS was determined for a third of those tablets. Principal component analysis of NIR and Raman spectra showed that the drug substance content and particle size, the particle size of the filler, and the compression force affected both NIR and Raman spectra. For quantitative assessment, orthogonal partial least squares regression was applied. All factors varied in the experimental design influenced the prediction of the DS content to some extent, both for NIR and Raman spectroscopy, the particle size of the filler having the largest effect. When all matrix variations were included in the multivariate calibrations, however, good predictions of all types of tablets were obtained, both for NIR and Raman spectroscopy. The prediction error using transmission Raman spectroscopy was about 30% lower than that obtained with transmission NIR spectroscopy.

A quality by design approach to investigate the effect of mannitol and dicalcium phosphate qualities on roll compaction.

Roll compaction is a continuous process for solid dosage form manufacturing increasingly popular within pharmaceutical industry. Although roll compaction has become an established technique for dry granulation, the influence of material properties is still not fully understood. In this study, a quality by design (QbD) approach was utilized, not only to understand the influence of different qualities of mannitol and dicalcium phosphate (DCP), but also to predict critical quality attributes of the drug product based solely on the material properties of that filler. By describing each filler quality in terms of several representative physical properties, orthogonal projections to latent structures (OPLS) was used to understand and predict how those properties affected drug product intermediates as well as critical quality attributes of the final drug product. These models were then validated by predicting product attributes for filler qualities not used in the model construction. The results of this study confirmed that the tensile strength reduction, known to affect plastic materials when roll compacted, is not prominent when using brittle materials. Some qualities of these fillers actually demonstrated improved compactability following roll compaction. While direct compression qualities are frequently used for roll compacted drug products because of their excellent flowability and good compaction properties, this study revealed that granules from these qualities were more poor flowing than the corresponding powder blends, which was not seen for granules from traditional qualities. The QbD approach used in this study could be extended beyond fillers. Thus any new compound/ingredient would first be characterized and then suitable formulation characteristics could be determined in silico, without running any additional experiments.

Modeling dispersion of dry powders for inhalation. The concepts of total fines, cohesive energy and interaction parameters.

A range of carrier based dry powder formulations consisting of micronized drug, carrier lactose and, in some formulations, lactose fines were produced and tested for dispersibility, i.e. fine particle fraction (FPF). Two different drugs were used, budesonide (BUD) and beclomethasone dipropionate (BDP). A model based on the total amount of fines (TF) and the cohesive energy (CE) of the formulation is proposed, where TF is the sum of added drug, lactose fines and the fines inherent to the carrier. The expression for CE is derived from regular solutions theory and allows calculation of interparticle interaction parameters. The model was able to describe experimental data well, such as the decrease in FPF when the proportion of drug is increased at a constant TF level and the non-linear effects seen when a cohesive drug is added to carrier. BDP and BUD were found to be 5.3 times and 1.8 times more cohesive than lactose fines respectively. The model hence provides a link between the macroscopic behavior of a dry powder formulation and the interaction between the different species at the particulate level.

Combining experimental design and orthogonal projections to latent structures to study the influence of microcrystalline cellulose properties on roll compaction.

Roll compaction is gaining importance in pharmaceutical industry for the dry granulation of heat or moisture sensitive powder blends with poor flowing properties prior to tabletting. We studied the influence of microcrystalline cellulose (MCC) properties on the roll compaction process and the consecutive steps in tablet manufacturing. Four dissimilar MCC grades, selected by subjecting their physical characteristics to principal components analysis, and three speed ratios, i.e. the ratio of the feed screw speed and the roll speed of the roll compactor, were included in a full factorial design. Orthogonal projection to latent structures was then used to model the properties of the resulting roll compacted products (ribbons, granules and tablets) as a function of the physical MCC properties and the speed ratio. This modified version of partial least squares regression separates variation in the design correlated to the considered response from the variation orthogonal to that response. The contributions of the MCC properties and the speed ratio to the predictive and orthogonal components of the models were used to evaluate the effect of the design variation. The models indicated that several MCC properties, e.g. bulk density and compressibility, affected all granule and tablet properties, but only one studied ribbon property: porosity. After roll compaction, Ceolus KG 1000 resulted in tablets with obvious higher tensile strength and lower disintegration time compared to the other MCC grades. This study confirmed that the particle size increase caused by roll compaction is highly responsible for the tensile strength decrease of the tablets.

Real-Time assessment of granule and tablet properties using in-line data from a high-shear granulation process.

A method for real-time assessment of granule and tablet properties was investigated. A mixture of microcrystalline cellulose:mannitol:povidone (78.5:18.5:3) was used in the study and granulated with five different water amounts and two impeller speeds. This represents a full-factorial design with two factors, thus giving a causal structure to the variation between the experiments. Process data (power consumption, temperature and in-line near-infrared spectra) were collected during the granulations. In addition to the in-line process data, critical granule and tablet quality properties (such as particle size, porosity and tablet hardness) were measured in order to achieve in-depth process understanding. Neither power consumption nor temperature gave information that could be directly attributable to tablet properties, and these techniques were also heavily dependent on the speed of the impeller. In contrast, when using the first NIR overtone band for water (1460 nm), in-line real-time assessment of dry granule and tablet properties could be achieved.

On-line process control of gradient elution liquid chromatography.

The typical measure of the stability of analytical HPLC methods in the pharmaceutical laboratory is standards injected repeatedly throughout the sample sequence. To obtain improved control of the analysis and reduction of the number of standards and replicates, a novel approach to treat the analytical run as a process, where the chromatographic data is the product, is proposed. Thus, an alternative and continuous system suitability test procedure is described. This is obtained by continuous monitoring of several parameters of the chromatographic system such as pressure, temperature, and conductivity. The data are analyzed in real time with chemometrics to produce easily interpreted control charts. Gradient elution LC is extensively employed in pharmaceutical analysis. A gradient elution system is inherently dynamic due to the mobile-phase composition being changed during the chromatographic run. To handle the dynamics, suitable chemometric tools are needed. In this report, we extend the use of liquid chromatography process control (LCPC) to gradient elution LC by creating partial least-squares regression batch models of the data collected. The gradient elution LCPC system was evaluated by inducing disturbances, and it was shown to easily detect any real or simulated deviation.