The influence of API concentration on the roller compaction process: modeling and prediction of the post compacted ribbon,granule and tablet properties using multivariate data analysis

Objective: While previous research has demonstrated roller compaction operating parameters strongly influence the properties of the final product, a greater emphasis might be placed on the raw material attributes of the formulation. There were two main objectives to this study. First, to assess the effects of different process variables on the properties of the obtained ribbons and downstream granules produced from the rolled compacted ribbons. Second, was to establish if models obtained with formulations of one active pharmaceutical ingredient (API) could predict the properties of similar formulations in terms of the excipients used, but with a different API.

Materials and methods: Tolmetin and acetaminophen, chosen for their different compaction properties, were roller compacted on Fitzpatrick roller compactor using the same formulation. Models created using tolmetin and tested using acetaminophen. The physical properties of the blends, ribbon, granule and tablet were characterized. Multivariate analysis using partial least squares was used to analyze all data.

Results: Multivariate models showed that the operating parameters and raw material attributes were essential in the prediction of ribbon porosity and post-milled particle size. The post compacted ribbon and granule attributes also significantly contributed to the prediction of the tablet tensile strength.

Conclusions: Models derived using tolmetin could reasonably predict the ribbon porosity of a second API. After further processing, the post-milled ribbon and granules properties, rather than the physical attributes of the formulation were needed to predict downstream tablet properties. An understanding of the percolation threshold of the formulation significantly improved the predictive ability of the models.     

改进垂直喂料式烟草切丝机压实系统

SQ31系列曲刃水平滚刀式切丝机将经过处理后的烟叶、烟梗切成符合制丝工艺规范求宽度的叶丝、梗丝,以满足后续生产加工求。由于垂直喂料式切丝机压实系统采用恒定转速运行,在此种工作方式下,当切丝机运行参数或生产牌号变更时,切丝机无法及时调节压实系统参数,储料仓内的烟叶压实程度不均匀,切后烟丝存在粗细条、碎角叶、跑片等现象,在后续加工过程中极易产生造碎,造成大量损耗。通过对原有压实系统进行改良,在PLC控制器与压实器之间加入压实变频器,实现压实器与切丝机系统变速联动控制,大幅提升垂直喂料式切丝机的生产适应能力,提高切丝过程均质性。     

Computational Analysis of the Oscillatory Mixed Convection Flow along a Horizontal Circular Cylinder in Thermally Stratified Medium

The present work emphasizes the significance of oscillatory mixed convection stratified fluid and heat transfer characteristics at different stations of non-conducting horizontally circular cylinder in the presence of thermally stratified medium. To remove the difficulties in illustrating the coupled PDE’s, the finite-difference scheme with efficient primitive-variable formulation is proposed to transform dimensionless equations. The numerical simulations of coupled non-dimensional equations are computed in terms velocity of fluid, temperature and magnetic field which are computed to examine the fluctuating components of skin friction, heat transfer and current density for various emerging parameters. The governing parameters namely, thermally stratification parameter     

Multiphase versus single pot granulation process: influence of process and granulation parameters on granules properties

High-shear wet granulation is widely used for the production of pharmaceutical dosage forms. Different equipment is available for high-shear granulation and drying. This review focuses on two main processes for granules production: multiphase consisting of high-shear granulation followed by drying in a separate apparatus, and single pot granulation/drying. At present, formulas are specifically developed with regard to the production equipment, which raises many problems when different industrial manufacturing equipment is used. Indeed, final granules properties are likely to depend on equipment design, process, and formulation parameters. Therefore, a good understanding of these parameters is essential to facilitate equipment changes.

The aim of this review is to present the influence of equipment, process, and formulation parameters on granules properties, considering both the granulation and the drying steps of multiphase and single pot processes.     

Multiphase versus Single Pot Granulation Process: Influence of Process and Granulation Parameters on Granules Properties

ABSTRACT

High-shear wet granulation is widely used for the production of pharmaceutical dosage forms. Different equipment is available for high-shear granulation and drying. This review focuses on two main processes for granules production: multiphase consisting of high-shear granulation followed by drying in a separate apparatus, and single pot granulation/drying. At present, formulas are specifically developed with regard to the production equipment, which raises many problems when different industrial manufacturing equipment is used. Indeed, final granules properties are likely to depend on equipment design, process, and formulation parameters. Therefore, a good understanding of these parameters is essential to facilitate equipment changes.

The aim of this review is to present the influence of equipment, process, and formulation parameters on granules properties, considering both the granulation and the drying steps of multiphase and single pot processes.     

An investigation into the impact of magnesium stearate on powder feeding during roller compaction

A systematic evaluation on the effect of magnesium stearate on the transmission of a placebo formulation from the hopper to the rolls during screw fed roller compaction has been carried out. It is demonstrated that, for a system with two 'knurled' rollers, addition of 0.5% w/w magnesium stearate can lead to a significant increase in ribbon mass throughput, with a consequential increase in roll gap, compared to an unlubricated formulation (manufactured at equivalent process conditions). However, this effect is reduced if one of the rollers is smooth. Roller compaction of a lubricated formulation using two smooth rollers was found to be ineffective due to a reduction in friction at the powder/roll interface, i.e. powder was not drawn through the rollers leading to a blockage in the feeding system. An increase in ribbon mass throughput could also be achieved if the equipment surfaces were pre-lubricated. However this increase was found to be temporary suggesting that the residual magnesium stearate layer was removed from the equipment surfaces. Powder sticking to the equipment surfaces, which is common during pharmaceutical manufacturing, was prevented if magnesium stearate was present either in the blend, or at the roll surface. It is further demonstrated that the influence of the hopper stirrer, which is primarily used to prevent bridge formation in the hopper and help draw powder more evenly into the auger chamber, can lead to further mixing of the formulation, and could therefore affect a change in the lubricity of the carefully blended input material.     

High-shear granulation of high-molecular weight hypromellose: effects of scale-up and process parameters on flow and compaction properties

Context: Knowledge of the effects of high-shear granulation process parameters and scale-up on the properties of the produced granules is essential for formulators who face challenges regarding poor flow and compaction during development of modified release tablets based on high-molecular weight hypromellose (hydroxypropylmethylcellulose (HPMC)) polymers. Almost none of the existing studies deal with realistic industrial formulation.

Objective: The aim was to investigate the effects of scale-up and critical process parameters (CPPs) of high-shear granulation on the quality attributes of the granules, particularly in terms of the flow and compaction, using a realistic industrial formulation based on HPMC K100M polymer.

Methods: The flow properties were determined using flow time, Carr index, tablet mass, and crushing strength variations. The compaction properties were quantified using the ‘out-of-die’ Heckel and modified Walker models, as well as the tensile strength profile and elastic recovery. High-shear granulation was performed at different scales: 4?L, 300?L, and 600?L.

Results and conclusion: The scale itself had larger effects on the granule properties than the CPPs, which demonstrated high robustness of formulation on the individual scale level. Nevertheless, to achieve the desired flow and compaction, the values of the CPPs need to be precisely selected to fine-tune the process conditions. The best flow was achieved at high volumes of water addition, where larger and more spherical granules were obtained. The CPPs showed negligible influence on the compaction with no practical implications, however, the volume of water addition volume was identified as having the largest effects on compaction.     

Is the adjustment of the impeller speed a reliable attempt to influence granule size in continuous dry granulation?

As the field of continuous manufacturing of solid pharmaceutics is developing, the interest in implementing continuous granulation methods is growing. Process analytical technology tools should be integrated to ensure the monitoring of the product quality and therefore enforce control strategies.Three single materials which are often used in dry granulation and additionally two formulations, one containing ibuprofen and the other acetaminophen were processed at various process parameters. They all differed in their compaction and fracture behavior. A statistical analysis of the influence of process parameters was executed, to work out which parameters could be used for a granule size control approach in continuous dry granulation. Thereby, the specific compaction force and the impeller speed were found to be significant factors in each design of experiment. However, the impeller speed was evaluated as the only suitable parameter to control granule size, as an impact on granule density is unlikely. Nevertheless, some restrictions such as an upper impeller speed limitation to avoid excessive fines and a lower speed limitation to impede a downturn of the throughput, have to be considered. Furthermore, a decreasing median granule size was observed at higher throughputs for plastically deforming materials and formulations.     

Features of Heat Transfer in the Granulation of Sulfur

The influence of the temperature regimes of the granulation of sulfur in an aqueous medium on the qualitative characteristics of the granules obtained has been experimentally investigated. The admissible range of change in the operating parameters of an apparatus for granulation of sulfur with the use of water has been determined and a dimensionless quantity defining this range has been derived. The influence of the heattransfer regimes on the formation of the internal structure of sulfur granules has been numerically investigated and the reasons for the dependence of the qualitative characteristics of the granules on the temperature conditions of their production have been revealed.     

多孔NiTi合金工艺参数与孔隙关系的神经网络研究

为了减少实验量,降低成本,利用人工神经网络的原理,选取温度、颗粒尺寸、压坯密度为输入量,产物的孔隙度为输出量,建立了反映自蔓延高温合成反应参数与产物孔隙特性内在关系的模型.研究表明,该模型可以对选定工艺条件下产物的孔隙度进行良好的预测,预测结果在合理的误差范围内.说明建立的反应参数与孔隙特性的关系模型是可靠的,可以通过此模型优化反应参数.     

Effect of convection heat transfer on the design of vapor-cooled current leads

A general optimization method for vapor-cooled current leads is presented with taking into account the effect of convection heat transfer and extended surfaces. This analytical work is considered as a unified design method, since one formulation calculates the minimum heat load and the corresponding optimal design condition for arbitrary heat transfer condition, spanning two limiting cases—the zero convection (or conduction-cooled leads) and the perfect heat transfer. It is clearly shown that the augmentation of the convective cooling can reduce the heat load to a certain extent, but the optimum lead parameter required to minimize the heat load for the finite heat transfer may not exist between the two limiting values. A new dimensionless parameter called the Ch number is introduced to conveniently incorporate the convection effect into the optimization. The present method is demonstrated for two specific lead designs that have been recently developed for 10 kA level of applications.     

Compaction behaviour of plaster of Paris dewatered- and air dried-Nigerian clay

The effects of compaction pressure on the green bulk density and porosity of Nigerian clay were examined over a range of pressure from 47-2 to 157-3 MPa. An exponential behaviour was found between pressed relative density and compaction pressure, the logarithm of relative density increasing with compaction pressure. An exponential behaviour was also found between compaction pressure and true porosity, the latter decreasing as the logarithm of compaction pressure increased. Finally, empirical equations relating to true porosity and compaction pressure and also the relationship between relative density and compaction pressure, are presented.     

Optimization of a Granulation Procedure for a Hydrophilic Matrix Tablet Using Experimental Design

An experimental design was used in order to optimize a granulation procedure in a high-shear mixer for a hydrophilic matrix tablet formulation. The parameters tested were the amount of water in the hydroalcoholic granulation liquid, the amount of granulation liquid, and the massing time. The amount of granulation liquid was the most important parameter, followed by the amount of water in the granulation liquid. The influence of the massing time was negligible. A granule with a friability below 20% was obtained.     

Limits of one-dimensional solutions for orthotropic annular fins under dehumidifying operating conditions

Thermal performance characteristics of orthotropic material annular fins subjected to dehumidifying operating conditions are studied using two-dimensional finite element method. The method accounts for non-linear temperature–humidity ratio psychrometric relationship under both partially and fully wet operating conditions. Limits of one-dimensional solutions for orthotropic material fins subject to dehumidifying conditions are investigated in somewhat more detail by introducing dimensionless parameters. The dry fin parameter that fully governs fin efficiency under a set of operating conditions is also defined. The optimum fin dimensions are also estimated for a set of operating conditions and fixed fin volume.     

Binder jetting of well-controlled powder agglomerates for breakage studies

Based on the similarity between the solidification process of the Additive Manufacturing (AM) binder jetting technique and wet granulation mechanisms, binder jetting is used to print powder granules with controlled geometry and strength. Powder granules with different strengths were achieved by changing the printing parameters, including the layer thickness and saturation level. The printed powder granules were then characterised for their structural properties such as their porosity and printing accuracy. Different parameter settings were found to have a significant influence on surface roughness. The strength of powder granules was improved by increasing the print saturation level, without compromising the printed geometry. A breakage study was carried out by compression tests of granules printed with different shapes and strengths. The relationship between print setting, structure and strength was established and discussed. This study demonstrates that AM powder granules with designed shapes and well-controlled strengths may act as ideal calibration particles for a range of industrial applications.     

Assessment of granulation technologies for an API with poor physical properties

Granulation technologies are widely used in solid oral dosage forms to improve the physical properties during manufacture. Wet, dry, and melt granulation techniques were assessed for Compound A, a BCS class II compound. Characterization techniques were used to quantify physical property limitations inherent for Compound A including hygroscopicity, low solubility and bulk density, and poor powder flowability. High shear aqueous wet granulation induced an undesirable water mediated phase transition of the solid form. A formulation and process for dry granulation by roller compaction was developed and scaled to 10 kg batch size. Roll force, and roll gap parameters were assessed. Porosity of compacted ribbons was analyzed by mercury intrusion porosimetry, and particle size distributions of milled ribbons by sieve analysis. A roll force of 15 kN/cm produced granules with higher density and improved flow properties compared to the pre-blend. Fines content (<75 µm) decreased from approximately 90% pre-granulation to 26% post-granulation. Cohesive properties of Compound A limited drug loading (API:excipient ratio) in roller compaction to 0.6:1 or less. Hot melt granulation by extrusion assessed with four polymers. A vast improvement in drug loading of 4:1 was achieved via melt processes using low molecular weight thermo-binders (glyceryl behenate and Polyethylene glycol 4000). Granules produced by melt processing contained less fines compared to wet and dry granulation. Both roller compaction and melt extrusion are viable granulation process alternatives for scale up to overcome the physical property limitations of Compound A.     

Mixed Convection of Water at 4 °C Along a Wedge with Variable Surface Temperature in a Porous Medium

In this study, the mixed convection of water at 4 °C along a wedge in a porous medium is investigated numerically using a finite difference method. To explore the effect of mixed convection, both forced and free convection-dominated regimes are considered. Non-similarity solutions are obtained for the variable walltemperature boundary condition. Velocity and temperature profiles as well as local dimensionless skin friction and the Nusselt number are obtained and compared with available numerical results for various values of different parameters. The wedge angle geometry parameter m and mixed convection parameter ξ ranged from 0 to 1 in both regimes, whereas different values of λ are considered for the purpose of comparison of heat transfer results.     

Dimensional changes during micropyretic synthesis

This article reports on the influence of the processing and material parameters, namely initial temperature, compaction pressure, particle size, diluent, and chemical composition on the dimensional changes of the product during micropyretic synthesis. The relationship between the porosity change and elongation is established. From a knowledge of this relationship it is possible to tailor the dimensions of a synthesized product for proper design in an engineering application. Conversely, from the noted dimensional changes it is possible to obtain the final porosity values and thus the mechanical properties.     

Mathematical modelling and numerical simulation of ordered porosity metal materials formation

Ordered porosity metal materials belong to a relatively new class of porous materials named gasars. This paper presents a mathematical model of the complex physical phenomena in the production of gasars. Analyses for heat transfer, solidification kinetics and gas diffusion were coupled to describe the formation of unique gasar structure. Several criterial functions were introduced to provide significant quantitative information about the relationship between the operating technological parameters and the final structure. The computational outcomes of the numerical simulation were compared with the characteristics of real gasar ingots. The model was applied to determine the boundary conditions that would provide approximately constant physical conditions on the solidification front. The structure sensitiveness of gasars with respect to the different technological parameters is discussed.     

Investigations at an industrial scale on granule and tablet attributes in high shear rapid mixer granulator

Particle agglomeration by granulation was a very ubiquitous operation that finds applications in various industries such as pharmaceutical, food, chemical, fertilizer, etc. Among many granulators, the high shear rapid mixer granulator (RMG) was a very commonly used wet granulator in pharmaceutical industry. The wet granulation process was sensitive to the process parameters and the input product variables. The flow pattern, fill ratio, cohesive forces, velocities, and the kinetic energy of the particles have impact on the granular and the tablet properties. In this work, solid dosage formulation integrated with the RMG process has been studied at an industrial scale. The total formulation of the tablet was kept constant and the impact of various critical operating and process parameters of RMG viz., impeller design, impeller speed, batch size, binder concentration, and binder type on granule and tablet attributes has been studied and analyzed. The optimal set of process parameters to achieve the desired granular and tablet attributes viz., bulk density, compressibility (Carr index) flow properties (Hausner ratio), particle size distribution, texture, tablet hardness, dissolution, and disintegration times were found in the study.