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.     

Design of pseudo-simulated moving bed process with multi-objective optimization for the separation of a ternary mixture: Linear isotherms

Pseudo-SMB, often called “J-O process”, is a modified SMB process to completely separate a ternary mixture with two discrete steps per one cycle. For improved separation, two new design parameters, the position of step 1 (χ_S1) and the number of port switches during step 2 (n_SMB), were introduced. A multi-objective optimization method was used to optimize the operating conditions of the pseudo-SMB process with four average zone flow-rate ratios for one cycle. Nadolol isomers were selected for the model solutes and the global objective for the design of the pseudo-SMB was to collect 99% of the intermediate retained solute. The separation was optimized for 8-column pseudo-SMB system with three column lengths (2.5, 5.0, and 10 cm) and three feed composition ratios (1/1/1, 1/2/1, and 2/1/2). The simulation results showed that productivity was increased 4.3 times (n_SMB = 20, χ_S1 = 0.5, 1/1/1) and desorbent to feed ratio D/F was decreased 45% (n_SMB = 16, χ_S1 = 0.5, 1/1/1) compared to normal operation (n_SMB = 8, χ_S1 = 0.5, 1/1/1). Productivity and D/F were significantly improved when short columns were used in the pseudo-SMB process. The pseudo-SMB was compared with recycle chromatography and SMB cascades for the same total amount of adsorbent. Recycle chromatography and 8-column SMB cascades using 20 cm and 40 cm of total column lengths were not able to separate the intermediate component with the target purity and the same feed rate of the pseudo-SMB process.     

Porous electrospun polycaprolactone fibers: Effect of process parameters

The effect of electrospinning process parameters (solution flow rate, applied voltage, spinning distance) on the size and surface morphology of porous electrospun poly(ε‐caprolactone) was investigated in this study. Response surface methodology was implemented for the design and conduction of electrospinning experiments. The feed solution was a 12.5% w/v poly(ε‐caprolactone) (PCL) solution in a binary solvent mixture of 90%v/v chloroform/dimethyl sulfoxide. Spinning distance of 10–25 cm, applied voltage of 10–25 kV and feed flow rate of 0.5–5 mL/h were the range of limiting values of the independent variables used for the development of a central composite design. Second‐order polynomial equations, correlating electrospinning process parameters to relative pore coverage, and fiber average diameter were developed and validated. An increase in any of the investigated parameters (solution flow rate, applied voltage, spinning distance) resulted in the increase of both, pore formation on electrospun fibers, and produced fiber average diameter. Under the experimental conditions investigated, the relative pore surface coverage was 15.8–31.9% and the average fiber diameter was in the range of 1.6–3.3 μm. Applied voltage was proven to be the parameter with the strongest impact on both, fiber diameter and surface morphology. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2016 , 54, 1878–1888     

Coagulation and ultrafiltration: Understanding of the key parameters of the hybrid process

A hybrid coagulation–ultrafiltration process has been investigated to understand membrane performance. Coagulation prior to ultrafiltration is suspected to reduce fouling by decreasing cake resistance, limiting pore blockage and increasing backwash efficiency. Coagulation followed by tangential ultrafiltration should gather the beneficial effects of particle growth and cross-flow velocity. Our study aims at determining the key parameters to improve membrane performance, by describing floc behaviour during the hollow fibre ultrafiltration process. Flocs encounter a wide range of shear stresses that are reproduced through the utilization of different coagulation reactors. Performing a Jar-test enables the formation of flocs under soft conditions, whereas Taylor-Couette reactors can create the same shear stresses occurring in the hollow fibres or in the pump. Synthetic raw water was made by adding bentonite into tap water. Five organic coagulants (cationic polyelectrolytes) and ferric chloride were selected. Floc growth was thoroughly monitored in the different reactors by laser granulometry. Coagulation–ultrafiltration experiments revealed different process performance. The effect on the permeate flux depended on the coagulant used: some coagulants have no influence on permeate flux, another enables a 20% increase in permeate flux whereas another coagulant leads to a decrease of 50%. Flocs formed with ferric chloride do not resist shear stress and consequently have no influence on permeate flux. These results show the necessity to create large flocs, but the size is not sufficient to explain membrane performance. Even if flocs show a good resistance to shear stress, a high compactness (D_f = 3) will lead to a dramatic decrease of permeate flux by increasing the mass transfer resistance of the cake. On the contrary, flocs less resistant to shear stress, then smaller and also more open have no effect on permeate flux. An optimum was quantified for large flocs, resistant enough to shear stress facilitating flow between aggregates.     

Low-gradient magnetic separation of magnetic nanoparticles under continuous flow: Experimental study,transport mechanism and mathematical modelling

Low-gradient magnetic separation (LGMS) of magnetic nanoparticles (MNPs) has been proven as one of the techniques with great potential for biomedical and environmental applications. Recently, the underlying principle of particle capture by LGMS, through a process known as magnetophoresis, under the influence of hydrodynamic effect has been widely studied and illustrated. Even though the hydrodynamic effect is very substantial for batch processes, its impact on LGMS operated at continuous flow (CF) condition remained largely unknown. Hence, in this study, the dynamical behaviour of LGMS process operated under CF was being studied. First, the LGMS experiments using poly(sodium 4-styrenesulfonate)-functionalized-MNP as modelled particle system were performed through batchwise (BW) and CF modes at different operating conditions. Here BW operation was used as a comparative study to elucidate the transport mechanism of MNP under the similar environment of CF-LGMS process, and it was found out that the convection induced by magnetophoresis (timescale effective is ∼1200 s) is only significant at far-from-magnet region. Hence, it can be deduced that forced convection is more dominant on influencing the transport behaviour of CF-LGMS (with resident time ≤240 s). Moreover, we found that the separation efficiency of CF-LGMS process can be boosted by the higher number of magnets, the higher MNP concentration and the lower flowrate of MNP solution. To better illustrate the underlying dynamical behaviour of LGMS process, a mathematical model was developed to predict its kinetic profile and separation efficiency (with average error of ∼2.6% compared to the experimental results).     

Window consensus PCA for multiblock statistical process control: adaption to small and time‐dependent normal operating condition regions,illustrated by online high performance liquid chromatography of a three‐stage continuous process

A method for multiblock statistical process control is described, involving the computation of Q and D statistics both for individual blocks and for the overall process using window consensus principal components analysis (WCPCA). The approach overcomes two common problems. The first is a small normal operating conditions (NOC) region, which is done by determining the Q‐statistic limits and D statistics using leave‐one‐out (LOO) residuals and scores, rather than employing the residuals and scores of a single training set model obtained from the entire NOC region. The second overcomes the problem of temporal drift of the process and/or measurement technique by updating the NOC covariance matrix to adapt to normal process changes. The unifying multiblock statistical process control and relevant statistics are adapted to cope with these issues and are illustrated in this paper using CPCA as applied to online high performance liquid chromatography (HPLC) of a three‐stage continuous process. Copyright © 2010 John Wiley & Sons, Ltd.     

Direct borohydride fuel cells: A selected review of their reaction mechanisms,electrocatalysts, and influence of operating parameters on their performance

Direct borohydride fuel cells (DBFC) oxidize an easily-stored energy-dense borohydride fuel (sodium borohydride: NaBH₄), that in theory reacts ca. 400 mV below H₂ and produces 8 electrons per BH₄^- anion. However, the borohydride oxidation reaction (BOR) does not fully meet these promises in practice: the electrocatalyst nature, structure and state-of-surface, and the operating conditions (pH, BH₄^- concentration, temperature, fluxes) noticeably influence the BOR kinetics and mechanism. Nickel and platinum-based catalysts both have assets for the BOR. DBFCs can only yield decent performance if their separator combines high ion-conductivity and efficient separation of the reactants; cation-exchange membranes, anion-exchange membranes, bipolar membranes and porous separators all have their own advantages and drawbacks. Besides the anode, the choice of separator must consider the DBFC cathode reaction, where oxygen (usually from air) or hydrogen peroxide are reduced, provided adapted catalysts are used. All these aspects drive the DBFC performance and stability/durability.     

EXAFS study of zirconium alkoxides as precursors in the sol-gel process: II. The influence of the chemical modification

EXAFS studies of primary zirconium alkoxides Zr(OR)₄ with OR = n-propoxide and n-butoxide, dissolved in their corresponding alcohols and chemically modified with acetylacetone (Hacac) and acetic acid (HOAc) in different molal ratios, are presented. The EXAFS-spectroscopic results, supported by FT-IR-studies, indicate a different chemical behavior of the complexing agents. In contrast to acetylacetone, the addition of acetic acid does not change the oligomeric structure of the zirconium alkoxides. Amazingly, the modification with acetic acid leads, in comparison to the pure compounds, to a shortened metal centre distance, whereas in the reaction with acetylacetone the Zr-Zr distance is not changed. With the determined distances and a rough quantitative inclusion of the coordination numbers it was possible to deduce detailed structure models.     

Development of a strategy and process parameters for a green process in counter-current chromatography: purification of tanshinone IIA and cryptotanshinone from Salvia miltiorrhiza Bunge as a case study

A strategy for the development of a green process using counter-current chromatography technology is presented in this paper. The strategy began with solvent system selection, followed by linear scale-up from an analytical to a preparative process with optimized operating parameters. A two-stage separation using a multi-injection method was performed with a solvent system of hexane-dichloromethane-methanol-water (4:0.75:4:1) for the 1st stage and a hexane-ethanol-water (4:2:2) for the 2nd stage. A 191.8 mg of tanshinone IIA was purified, with a 97% purity and 34.4% recovery and a 276.7 mg of cryptotanshinone was separated, with a 95% purity and 31.8% recovery from 2.1g of crude extract. Process parameters (throughput, efficiency, environmental risk factor and general process evaluation) and mass factors (mass intensity, separation mass efficiency and greenness) of a target were developed for monitoring of the counter-current chromatography process.     

Catalytic reduction of hazardous acid orange 10 dye by BiVO4/TiO2 nanocrystalline heterojunction and influence of aeration,FeSO4, H2O2 and FeCl3 on removal efficiency: A novel and environmentally friendly process

Bismuth vanadate in combination with titanium dioxide were synthesized by hydrothermal method and its photocatalytic activity was investigated under visible light irradiation for acid orange 10 (AO10) dye removal. The 10% BiVO₄/TiO₂ showed the highest catalytic activity in comparison with 20, 30, 40 and 50% BiVO₄/TiO₂ ratios. The removal of AO10 azo dye in aqueous solutions was studied in laboratory-scale experiments using 25 removal processes and their removal efficiencieswere evaluated, separately. The results showed that the amount of de-colorization for each oxidation process is completely different. The order of the investigated processes in removing the dye after 90 min is as follows: LED < TiO₂ < BiVO₄ < 10% BT/without LED < BiVO₄/ LED < 50% BT < 40% BT < 30% BT < 20% BT < UV/H₂O₂ < 10% BT < 5a-10 %BT < 5F-10 %BT < 10a-10 %BT < 50F-10 %BT < 20a-10 %BT < 10F-10 %BT < 20F-10 %BT < 20H_-10 %BT < 40H-10 %BT < 50H_-10 %BT < 20a-20F-10 %BT < 20a-20F-50H_-10 %BT. Among the above processes, 20a-20F-50H-10 %BT had the best removal performance and can be suggested for using in real conditions. Coagulation/precipitation process was done using 5 mg/L of FeCl₃ as post-treatment reaching efficiency of 100% in the studied system.