A review on key aspects of wet granulation process for continuous pharmaceutical manufacturing of solid dosage oral formulations

Wet granulation process is a major unit operation in production of pharmaceuticals as solid dosage oral formulation. Indeed, granulation is used to improve the formulation properties such as flowability, compressibility, and so on for pharmaceutical manufacturing. Different types of granulations can be used in pharmaceutical manufacturing in which the selection of proper process depends on the operational conditions as well as formulation properties. In current decades, twin-screw wet granulation has been of paramount interest owing to its superior properties. Pharmaceutical manufacturing industry are trying to move towards continuous mode by which the efficiency can be improved compared to the batch mode. Therefore, development of continuous granulation process is of great importance. In this review article, various processing units applicable for wet granulation of pharmaceutical formulations for solid dosage forms are reviewed and discussed. The advantages and disadvantages of the processes are discussed and listed along with modeling approaches for simulation of process. The governing models and numerical schemes applicable for design of wet granulation are also critically discussed. The main focus is on wet granulation as this method has attracted much attention in pharmaceutical processing.     

Numerical study of a stochastic particle algorithm solving a multidimensional population balance model for high shear granulation

This paper is concerned with computational aspects of a multidimensional population balance model of a wet granulation process. Wet granulation is a manufacturing method to form composite particles, granules, from small particles and binders. A detailed numerical study of a stochastic particle algorithm for the solution of a five-dimensional population balance model for wet granulation is presented. Each particle consists of two types of solids (containing pores) and of external and internal liquid (located in the pores). Several transformations of particles are considered, including coalescence, compaction and breakage. A convergence study is performed with respect to the parameter that determines the number of numerical particles. Averaged properties of the system are computed. In addition, the ensemble is subdivided into practically relevant size classes and analysed with respect to the amount of mass and the particle porosity in each class. These results illustrate the importance of the multidimensional approach. Finally, the kinetic equation corresponding to the stochastic model is discussed.     

Size-dependent coalescence kernel in fertilizer granulation-A comparative study

Granulation is a key process in several industries like pharmaceutical, food, fertilizer, agrochemicals, etc. Population balance modeling has been used extensively for modeling agglomeration in many systems such as crystallization, aerosols, pelletisation, etc. The key parameter is the coalescence kernel, β（ij） which dictates the overall rate of coalescence as well as the effect of granule size on coalescence rate. Adetayo, Litster, Pratsinis, and Ennis （1995） studied fertilizer granulation with a broad size distribution and modeled it with a two-stage kernel. A constant kernel can be applied to those granules which coalesce successfully. The coalescence model gives conditions for two types of coalescence, Type I and II. A twostage kernel, which is necessary to model granule size distribution over a wide size distribution, is applied in the present fluidized bed spray granulation process. The first stage is size-independent and non-inertial regime, and is followed by a size-dependent stage in which collisions between particles are non-random, i.e. inertial regime. The present work is focused on the second stage kernel where the feed particles of volume i and j collide and form final granule ij instead of i ＋j （Adetayo et al., 1995） which gives a wider particle size distribution of granules than proposed earlier.     

水淬渣-累托石颗粒吸附材料的制备及应用

研究了水淬渣-累托石颗粒吸附材料制备工艺条件、再生方法及其去除铜冶炼工业废水中重金属的条件.试验结果表明,累托石与水淬渣的比例为1∶1,另加入10%的添加剂(IS)和50%的水,焙烧温度为400℃时,制成的颗粒吸附材料体积密度为1.06kg/m3,显气孔率为62.29%,吸水率为58.82%,抗压强度为2.22Mpa,吸附效果好,散失率较低.在未调节铜冶炼工业废水pH值的条件下,颗粒吸附材料用量为0.05g/cm3,反应时间为40min,吸附温度为25℃(常温)时,Cu2 、Pb2 、Zn2 、Cd2 、Ni2 的去除率分别为98.2%、96.3%、78.6%、86.2%、64.2%,处理后的水符合国家污水综合排放标准(GB8978-1996)一级标准.颗粒吸附材料对Zn2 、Cu2 有很好的选择性.吸附饱和的颗粒吸附材料用1mol/L氯化钠溶液再生效果好.该颗粒吸附材料具有分离容易、可重复使用、处理效果好、应用前景广阔的优点.     

Near infrared spectroscopy in the study of polymorphic transformations

The potential of near infrared (NIR) spectroscopy for the characterization of polymorphs in the active principle of a commercial formulation prior to and after the manufacturing process was assessed. Polymorphism in active principles is extremely significant to the pharmaceutical industry. Polymorphic changes during the production of commercial pharmaceutical formulations can alter some properties of the resulting end-products. Multivariate curve resolution-alternating least squares (MCR-ALS) methodology was used to obtain the “pure” NIR spectrum for the active principle without the need to pretreat samples. This methodology exposed the polymorphic transformation of Dexketoprofen Trometamol (DKP) in both laboratory and production samples obtained by wet granulation. No polymorphic transformation, however, was observed in samples obtained by direct compaction. These results were confirmed using by X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC) measurements. Pure crystalline polymorphs of DKP were available in the laboratory but amorphous form was not, nevertheless the developed methodology allows the identification of amorphous and crystal forms in spite of the lack of pure DKP.     

单向S-粗集粗糙性的度量方法

根据单向S-粗集内(外)边界的定义,引入了外边界熵的概念,将外边界熵与知识粒度结合进来,提出了一种新的单向S-粗集粗糙性的度量方法,讨论了这一度量的特性。通过分析和实例可以看出,这一新的度量方法可以用来更合理、更精确地度量单向S-粗集的不确定性。     

Assessing mixing characteristics of particle-mixing and granulation devices

The mixing of particulates such as powders is an important process in many industries including pharmaceuticals, plastics, household products （such as detergents） and food processing. The quality of products depends on the degree of mixing of their constituent materials which in turn depends on both geometric design and operating conditions. Unfortunately, due to lack of understanding of the interaction between mixer geometry and the granular material, limited progress has been made in optimizing mixer design. The discrete element method （DEM） is a computational technique that allows particle systems to be simulated and mixing to be predicted. Simulation is an effective way of acquiring information on the performance of different mixers that is difficult and/or expensive to obtain using traditional experimental approaches. Here we demonstrate how DEM can be used to unravel flow dynamics and assess mixing in several different types of devices. These devices used for mixing and/or granulation of particulates, are classified broadly as gravity controlled, bladed and high shear. We also explore the role of particle shape in mixing performance and use DEM to test whether Froude number scaling is suitable for predicting scale performance of rotating mixers.     

Heat and mass transfer study in fluidized bed granulation-Prediction of entry length

Fluidized bed granulation is a process by which granules or coated particles are produced in a single piece of equipment by spraying a binder as solution, suspension, or melt on the fluidized powder bed. Heat and mass transfer correlation useful for designing a granulator has been derived based on the equivalence of evaporation rate of the liquid to the heat transferred from hot gas to particles: (m/A)Dp2λ/(Lmf(1- εmf)(Tg-Tl)Kg)=hDp/Kg . This equation is applied to data on granulation experiments by different workers to calculate Reynolds number and Nusselt number to obtain a relation between heat and mass transfer from gas to particles during granulation on a logarithmic scale from which the following empirical relation is obtained: Nu = 0.0205Re1.3876 which is comparable to Kothari's correlation Nu = 0.03Re1.3. By using the heat and mass transfer correlation obtained, the entry length, that is the length of granulator up to which effective heat transfer from gas to bed particles takes place, is estimated, which is also validated with experimental study. The correct estimation of entry length is useful in optimal design of a granulator.