A statistical design to evaluate the influence of manufacturing factors on the material properties and functionalities of microcrystalline cellulose

The aim of this study is to statistically evaluate the effects of manufacturing factors on the material properties and functionalities of microcrystalline cellulose (MCC) products. How the material properties of MCC products dominate their functionalities was further explored. Results demonstrate that the desired material properties and functionalities of MCC products can be obtained by manipulation of the manufacturing factors using proper polynomial equations, and the key manufacturing factor is temperature. On the other hand, the functionalities can be quantitatively predicted by material properties. Meanwhile, the key material property is molecular mass in controlling MCC functionalities. The particle morphologies may also serve as important material properties. In conclusion, the careful control of temperature during the manufacture of MCC might minimize inter-batch variation. The correlation of the material properties of MCC products with their functionalities might help the formulation designer rationally select proper MCC products. The universal harmonization of MCC products might be achieved by the regulation of their molecular mass, surface roughness, and roundness.     

A comparative study of the influence of alpha-lactose monohydrate particle morphology on granule and tablet properties after roll compaction/dry granulation

The influence of particle morphology and size of alpha-lactose monohydrate on dry granules and tablets was studied. Four different morphologies were investigated: Two grades of primary crystals, which differed in their particle size and structure (compact crystals vs. agglomerates). The materials were roll compacted at different specific compaction forces and changes in the particle size distribution and the specific surface area were measured. Afterwards, two fractions of granules were pressed to tablets and the tensile strength was compared to that from tablets compressed from the raw materials. The specific surface area was increased induced by roll compaction/dry granulation for all materials. At increased specific compaction forces, the materials showed sufficient size enlargement. The morphology of lactose determined the strength of direct compressed tablets. In contrast, the strength of granule tablets was leveled by the previous compression step during roll compaction/dry granulation. Thus, the tensile strength of tablets compressed directly from the powder mixtures determined whether materials exhibited a loss in tabletability after roll compaction/dry granulation or not. The granule size had only a slight influence on the strength of produced tablets. In some cases, the fraction of smaller granules showed a higher tensile strength compared to the larger fraction.     

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 R² 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.     

Influence of the roll compactor parameter settings and the compression pressure on the buccal bio-adhesive tablet properties

Miconazole buccal tablets were prepared via a dry granulation process. By applying a factorial design (2⁴), the roll compactor parameters (compaction force, gap between the rolls, type of the rolls (smooth, ribbed) and the sieve aperture) were optimised for the tablet strength. The compaction force and the roll type significantly affected the tablet strength. Afterwards, a quarter fractional factorial design (2^5-2) was applied, consisting of the four compactor parameters and additionally the compression pressure, in order to optimise these parameters for the dissolution profile and the buccal bio-adhesion characteristics (bio-adhesive force and energy). In order to evaluate the dissolution profiles properly, the similarity factor between sample and a zero-order release reference profile was used. The compression pressure and the roll type significantly affected the dissolution profile. The sieve aperture had a significant effect on the buccal adhesion properties and the compaction force had a significant effect on the dissolution profile and the bio-adhesive energy. The gap between the rolls affected the bio-adhesive force significantly.     

Understanding the effect of lactose particle size on the properties of DPI formulations using experimental design

Medicines for delivering therapeutic agents to the lung as dry powders primarily consist of a carrier and a micronised active pharmaceutical ingredient (API). The performance of an inhaled formulation will depend on a number of factors amongst which the particle size distribution (PSD) plays a key role. It is suggested that increasing the number of fine particles in the carrier can improve the aerosolisation of the API. In addition the effect of PSD upon a bulk powder is also broadly understood in terms of powder flow. Other aspects of functionality that different size fractions of the carrier affect are not clearly understood; for example, it is not yet clearly known how different size fractions contribute to the different functionalities of the carrier. It is the purpose of this investigation to examine the effects of different lactose size fractions on fine particle dose, formulation stability and the ability to process and fill the material in the preferred device. In order to understand the true impact of the size fractions of lactose on the performance of dry powder inhaled (DPI) products, a statistically designed study has been conducted. The study comprised various DPI blend formulations prepared using lactose monohydrate carrier systems consisting of mixtures of four size fractions. Interactive mixtures were prepared containing 1% (w/w) salbutamol sulphate. The experimental design enabled the evaluation of the effect of lactose size fractions on processing and performance attributes of the formulation. Furthermore, the results of the study demonstrate that an experimental design approach can be used successfully to support dry powder formulation development.     

An investigation of the influence of process and formulation variables on mechanical properties of high shear granules using design of experiment

Being able to predict the properties of granules from the knowledge of the process and formulation variables is what most industries are striving for. This research uses experimental design to investigate the effect of process variables and formulation variables on mechanical properties of pharmaceutical granules manufactured from a classical blend of lactose and starch using hydroxypropyl cellulose (HPC) as the binder. The process parameters investigated were granulation time and impeller speed whilst the formulation variables were starch-to-lactose ratio and HPC concentration. The granule properties investigated include granule packing coefficient and granule strength. The effect of some components of the formulation on mechanical properties would also depend on the process variables used in granulation process. This implies that by subjecting the same formulation to different process conditions results in products with different properties.     

Metabolomics study on the therapeutic effect of traditional Chinese medicine Xue-Fu-Zhu-Yu decoction in coronary heart disease based on LC-Q-TOF/MS and GC-MS analysis

The present study aims is to investigate the metabolic mechanism of Xue-Fu-Zhu-Yu decoction (XFZYD) in the treatment of blood-stasis syndrome in Coronary Heart Disease (CHD). To that end, 30 CHD patients with Blood-Stasis Syndrome (BSS) and 20 healthy subjects were enrolled. LC-Q-TOF/MS analysis determined that in comparison between CHD with BSS patients (Group A) and healthy subjects (Group C), 59 significantly differential metabolites in the positive mode and 18 significantly differential metabolites in the negative mode. The metabolite constituents in the plasma of 30 CHD with BSS patients before (group A) and after 30 days of treatment (Group B), and 20 healthy subjects (Group C) were analyzed using LC-Q-TOF/MS and GC-MS. Based on multivariate statistical analysis (PCA, PLS-DA and OPLS-DA), we determined 69 differential metabolites. The levels of hemorheology indexes were significantly down-regulated after treatment. Metabolic pathway attribution analysis showed that lipid metabolism, amino acid metabolism and bile acid metabolism pathways are involved. Our study identifies the metabolic networks of CHD and demonstrates the efficacy of this metabolomics approach to systematically study the therapeutic effect of XFZYC on CHD.