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Small Molecules: Process Intensification and Continuous Synthesis
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
A refocus to continuous flow-based equipment both in the pharma process chemistry laboratory and in the pilot plant results in some significant differences when compared to batch processing. The performance of the pilot plant reactor as compared to a round-bottom flask drives a large amount of experimentation due to the constraints of the plant vessel including limitations on stirring, temperature ranges, addition times, and challenges in controlling exotherms. In contrast, a continuous flow device is simply a tube reactor in which heating or cooling elements are applied, and the pumps become the main actors as they control the stoichiometry or the reaction and rate of material production. In the case of microreactors, mixing occurs essentially instantaneously under laminar flow conditions. In the case where reactant mixing is determined to be critical, a static mixer can be used just prior to the reactor or inserted into the reactor itself. Continuous flow tube reactors present advantages in terms of material production and ease of scaling. For example a very typical laboratory flow rate through a 1 mm microreactor would be 1 mL/min, which at a 10% concentration of product would correspond to production of 144 g over the course of a day, which is a large amount for a laboratory and could be increased without any action by the scientist other than ensuring the feed tanks were sufficiently stocked. As reactor diameter increases beyond 1 mm id, the production of expected product increases significantly and will outstrip the ability of a general purpose laboratory to manage the waste, cost, and product output.
Granulation of Poorly Water-Soluble Drugs
Published in Dilip M. Parikh, Handbook of Pharmaceutical Granulation Technology, 2021
Albert W. Brzeczko, Firas El Saleh, Hibreniguss Terefe
Nanoparticles produced by precipitation (or “bottom-up” processing), as the name suggests, involve a controlled build of the drug particle from a solution. In this technique, the drug is dissolved in a solvent, and the drug solution is added in a controlled manner to a drug antisolvent under high agitation. The drug precipitates rapidly and in a controlled manner in the presence of the antisolvent by generating a large number of nucleation sites and limiting the subsequent growth. Bottom-up processing has an advantage to top-down processing in that particle formation can be done with heterogeneous materials to form cocrystals or coprecipitates, which may further enhance the solubility of the poorly soluble drug compared with the homogeneous drug nanoparticles. Crystal size is controlled by thermodynamic principles, transport phenomena, and reaction kinetics. The key to this process is the presence of homogeneous nanoscale regions throughout the crystallization volume. The process can be as simple as using a static mixer for nanoparticle precipitation. However, results obtained in the R&D lab may not readily scale to larger containers where hydrodynamics, vessel volume to the surface, and turbulence are not readily reproduced. Alternatively, a jet stream homogenization technology using MCR has been reported to replicate the single confined impinging jet reactor scale experience by stacking multiple jet impinging reactor units to achieve the desired production rate [17]. In this process, a drug solution is jet impinged into an antisolvent for the drug. Carbamazepine crystals, manufactured by the jet impinging process, were 150 to 300 nm wide and 2 to 5 μm in length, whereas drug particles by conventional mixing were 1 to 2 μm wide and less than 20 μm in length. Zhou et al. [20] showed that danazol nanoparticles made in the MCR process significantly increased specific surface area (14.32 vs. 0.66 m2/g) and a dissolution rate in five minutes from 35% to 100% when compared with danazol particles “as received” [20].
Solid lipid nanoparticles by Venturi tube: preparation, characterization and optimization by Box–Behnken design
Published in Drug Development and Industrial Pharmacy, 2021
Gilberto García-Salazar, María de la Luz Zambrano-Zaragoza, Eduardo Serrano-Mora, Sandra Olimpia Mendoza-Díaz, Gerardo Leyva-Gomez, David Quintanar-Guerrero
Typical preparation of these dispersions has required a high-efficiency stirring tank, but this is not the only option, as, on some occasions, static devices are a better alternative for obtaining excellent mixing of the different fluids with no need for additional equipment because of their shape. Numerous industrial applications can be produced with static mixers, including homogenization, dispersion, emulsification, liquid/liquid contacting, and chemical reactions [8].
Development of a continuous reactor for emulsion-based microencapsulation of hexyl acetate with a polyuria shell
Published in Journal of Microencapsulation, 2019
Sven R. L. Gobert, Marleen Segers, Stijn Luca, Roberto F. A. Teixeira, Simon Kuhn, Leen Braeken, Leen C. J. Thomassen
Other means of creating liquid-liquid emulsions are active and passive mixers. Active mixers such as rotor stator mixers, colloidal mills and ultrasound transducers require an external energy source. These devices can mix large quantities (100–20,000 L/h), but have a CoV often exceeding 30% (Jeong et al.2016). Passive mixers induce mixing through the energy supplied by the feed pumps. Static mixers consist out of a fixed structure in the flow path that creates complex mixing patterns (Theron and Sauze 2011). The absence of moving parts leads to low energy costs and maintenance requirements (Theron et al.2010). A large variety of static mixers, discussed in detail by Thakur et al. (2003), have been engineered and used in emulsification processes (Thakur et al.2003). Extensively studied mixers are the Sulzer SMX and SMV (Legrand et al.2001, Meijer et al.2012, Das et al.2013), the Kenics® static mixer (Hobbs and Muzzio 1997, 1998) and the screen type mixer (Azizi and Al Taweel 2011a,b, Hweij and Azizi 2015). These studies focus on the generation of oil in water emulsions, whereby parameters such as hold-up (ratio of dispersed phase to total volume of emulsion), dispersed phase concentration ϕemulsion, viscosity of continuous and dispersed phase, and the number of static mixers are investigated (Das et al.2005, Fradette et al.2007, Theron et al.2010, Kiss et al.2011). In most studies of emulsification behaviour, the main focus is on deriving predictive correlations for droplet size. Often a model system, oil and water phase, without encapsulation application is used at low to intermediate dispersed phase concentrations (1–20 vol%) in order to avoid droplet coalescence (Paul et al.2004). In cases of microencapsulation, the curing is done in batch after the emulsion is collected. For industrial relevant applications, the dispersed phase concentration ratios are preferably above 20 vol% (Paul et al.2004) and would benefit from a continuous curing process. Theron (2012) addressed both issues in a study of the encapsulation of cyclohexane in a polyuria (PU) shell in a continuous reactor (Theron et al.2012). In their setup, gear pumps are used to recirculate the oil and water phases from a single holding tank. This means the two phases are in contact before they pass through a SMX static mixer in the recycle loop. In the reactor setup of the current paper, two separate feed streams of continuous and dispersed phase are implemented. First contact between the two phases occurs in the mixing zone. This design enables fully continuous production and avoids reagents like isocyanides (monomer for polyuria shell synthesis) to react too early with water from the continuous phase. After the emulsion is generated it is diverted into a residence time reactor where the polymerisation initiator is added and curing takes place at elevated temperature. The process was able to run with high dispersed phase concentrations of 25 vol% at a total flow rate of 163 mL/min (Theron et al.2012).