Continuous Flow Precipitation Research Articles

MLAPI: A framework for developing machine learning-guided drug particle syntheses in automated continuous flow platforms

Recently, machine learning (ML) models are increasingly being used in process analytical technology (PAT) frameworks for pharmaceutical manufacturing. Yet, the applications of ML-integrated PAT frameworks are limited by big data requirements. This work introduces a computational framework to develop data-efficient ML models to guide drug particle synthesis in an automated continuous flow precipitation platform. The framework incorporates classification algorithms to identify feasible (fouling-free) operating regions of the precipitation platform, a multiple-output Gaussian process (GP) regression model to relate key process parameters to the drug particle size, and active learning to optimally generate new data for training and validation of the GP model. The usefulness of the proposed framework is demonstrated on the synthesis of ibuprofen microparticles in an automated flow precipitation platform. We envision that properly trained GP models developed using the proposed framework can be employed to fine tune the drug particle size, targeting desired particle bioavailability and processability.

Antisolvent based ultrasound-assisted batch and continuous flow precipitation of metformin hydrochloride particles

Small sized particles of the antidiabetic drug metformin hydrochloride (MET.HCl) were produced by antisolvent based precipitation using an ultrasound assisted inverted jet reactor (IJR). This novel approach was implemented as a small passive mixer in which intensified turbulent mixing of the solution and the antisolvent occurred under controlled conditions. The optimized conditions for antisolvent precipitation (ASP) were investigated by studying the effect of solute concentration, antisolvent to solvent ratio and antisolvent temperature in batch systems. The optimized batch precipitation conditions were successfully translated into continuous flow process for the ultrasound assisted inverted jet reactor. The ability of the proposed clogging free inverted jet reactor approach can provide a scaled up alternative pathway to micro and millifluidic devices for manufacturing of small sized API particles, such as, MET.HCl for the formulations and encapsulations on an industrial scale.

Lab‐scale atmospheric CO2 absorption for calcium carbonate precipitation in sand

AbstractThe microbial‐induced calcite precipitation (MICP) process for ground improvement uses microorganisms to hydrolyze urea, producing carbonate ions to induce in situ calcium carbonate (CaCO3) precipitation in soil to improve its strength. This paper proposes using the hydroxide‐based absorption of CO2 instead to provide the carbonate ion source. This study utilizes direct air capture (DAC) to absorb atmospheric CO2 using potassium hydroxide (KOH) in a semi‐batch bubble absorption column. Potassium carbonate (K2CO3) was then injected into sand with calcium hydroxide (Ca(OH)2 as a calcium source to precipitate CaCO3 and regenerate KOH. Batch and continuous flow precipitation methods produced a poor distribution of CaCO3, with more CaCO3 precipitated on top, resulting in unconfined compressive strength (UCS) of 6.9 to 19.6 kPa. Sand pre‐mixed with Ca(OH)2 gave well distributed CaCO3, precipitated throughout the sample with 7.56 wt% and 6.87 wt% CaCO3 content and UCS of 39.2 and 35.3 kPa before failing for batch and continuous flow precipitation respectively. This differs from MICP strength improvement of 1000 kPa with 5.3 wt% CaCO3 due to poor binding of sand with the precipitated CaCO3 crystals. However, this application provides a stable sequestration source for atmospheric CO2 in soil. © 2019 Society of Chemical Industry and John Wiley & Sons, Ltd.

Reverse osmosis brine for phosphorus recovery from source separated urine

Phosphorus (P) recovery from waste streams has recently been recognized as a key step in the sustainable supply of this indispensable and non-renewable resource. The feasibility of using brine from a reverse osmosis (RO) membrane unit treating cooling water as a precipitant for P recovery from source separated urine was evaluated in the present study. P removal efficiency, process parameters and precipitate properties were investigated in batch and continuous flow experiments. More than 90% of P removal was obtained from both undiluted fresh and hydrolyzed urines by mixing with RO brine (1:1, v/v) at a pH over 9.0. Around 2.58 and 1.24 Kg of precipitates could be recovered from 1 m3 hydrolyzed and fresh urine, respectively, and the precipitated solids contain 8.1–19.0% of P, 10.3–15.2% of Ca, 3.7–5.0% of Mg and 0.1–3.5% of ammonium nitrogen. Satisfactory P removal performance was also achieved in a continuous flow precipitation reactor with a hydraulic retention time of 3–6 h. RO brine could be considered as urinal and toilet flush water despite of a marginally higher precipitation tendency than tap water. This study provides a widely available, low - cost and efficient precipitant for P recovery in urban areas, which will make P recovery from urine more economically attractive.

Continuous-flow precipitation as a route to prepare highly controlled nanohydroxyapatite: in vitro mineralization and biological evaluation

This work reports the biological evaluation of nanosized hydroxyapatite (HAp) previously synthesized by continuous-flow precipitation in a scaled-up meso oscillatory flow reactor (meso-OFR). Physico-chemical characterization of the synthesized HAp suggests high surface reactivity namely because of its high specific surface area and low crystallinity. On the other hand, in vitro biomineralization assays demonstrated the apatite-forming activity of the prepared HAp and their higher surface reactivity when compared to a commercial HAp. Furthermore, human osteoblastic-like (Saos-2) cells culture evidenced that the synthesized HAp stimulated cell proliferation, especially when applied at lower concentrations (30 and 50 μg ml−1), although its cellular uptake behavior. Therefore, the prepared HAp shows immense potential as biomedical material, as well as drug and gene delivery vehicle. The results are also very promising regarding further scaling up of the process, as the designed methodology allow for the preparation in a continuous mode of nanosized HAp with controlled physico-chemical properties.

Sirolimus formulation with improved pharmacokinetic properties produced by a continuous flow method

The oral bioavailability of Sirolimus is limited by poor dissolution of the compound in the gastrointestinal tract resulting in a low bioavailability and large inter-individual differences in blood levels. Several different formulation approaches were applied to overcome these disadvantageous pharmacokinetic properties including the marketed oral solution and a tablet form containing wet milled nanocrystals. These approaches deliver improved pharmacokinetics, yet, they share the characteristics of complex production method and composition. We have developed a nanostructured Sirolimus formulation prepared by the controlled continuous flow precipitation of the compound from its solution in the presence of stabilizers. We have shown that contrary to the batch production the process could be easily intensified and scaled up; apparently the uniformity of the precipitation is heavily dependent on the production parameters, most likely the mixing of the solvent and antisolvent. We compared the physicochemical and pharmacokinetic properties of the nanostructured formula with the marketed nanoformula. We found that our method produces particles in the size range of less than 100nm. The solid form redispersed instantaneously in water and in biorelevant media. Both the solid form and the redispersed colloid solution showed excellent stability even in accelerated test conditions. The oral administration of the nanostructured formula resulted in faster absorption, higher exposure and higher trough concentrations when compared to the marked form. These advantageous properties could allow the development of solid oral Sirolimus formulae with lower strength and gel based topical delivery systems.

Novel continuous flow technology for the development of a nanostructured Aprepitant formulation with improved pharmacokinetic properties

The oral bioavailability of Aprepitant is limited by poor dissolution of the compound in the gastrointestinal tract which is more prominent in the fasted state resulting in significant positive food effect. Due to the low aqueous solubility of the active substance the product development has been focused on decreasing the particle size of the active compound down to the submicron range in order to overcome this disadvantageous pharmacokinetic property. The marketed drug consisting of wet-milled nanocrystals exhibits significantly higher oral bioavailability in the fasted state and reduced food effect when compared to the unformulated compound. We have developed a novel process for the production of a nanostructured Aprepitant formulation in which the generation of the nanosized particles takes place at molecular level. The process relies on controlled continuous flow precipitation of the compound from its solution in the presence of stabilizers. The precise control of the production parameters (mixing geometry, flow rates, temperature, etc.) allows to tailor the physicochemical properties and biological performance of the active compound. We have prepared a novel nanostructured Aprepitant formulation using this method and compared its physicochemical and pharmacokinetic properties with the reference compound and the marketed nanoformula. We found that our method produces a stable amorphous solid form comprising novel nanostructured particles having a particle size of less than 100nm with instantaneous redispersibility characteristics and improved apparent solubility and permeability. In vivo beagle dog pharmacokinetic studies showed that the novel formula exhibited greatly improved pharmacokinetic characteristics when compared to the reference compound, while serum blood concentrations for the nanostructured formula and the wet-milled formula were similar. The marked food effect observed for the reference compound was practically eliminated by our formulation method. These results indicate that the novel continuous flow precipitation technology is a suitable tool to prepare nanostructured formulations with similar, or even superior in vitro and in vivo characteristics when compared to the industrial standard milling technology.

Continuous-Flow Precipitation of Hydroxyapatite at 37 °C in a Meso Oscillatory Flow Reactor

Continuous-flow precipitation of hydroxyapatite (HAp) was investigated in a meso oscillatory flow reactor (meso-OFR) and in a scaled-up meso-OFR, obtained by associating in series eight vertical meso-ORFs. Experiments were carried out under near-physiological conditions of temperature and pH, using fixed frequency (f = 0.83 Hz) and amplitude (x0 = 4.5 mm), and varying the residence time from 0.4 to 6.7 min. It has been shown that the mean particle size and the aggregation degree of the prepared HAp particles decrease with decreasing residence time. HAp nanoparticles with a mean size (d50) of 77 nm, narrow size distribution, and uniform morphology were obtained at the lowest residence times, τ = 0.4 and 3.3 min in the meso-OFR and the scaled-up meso-OFR, respectively. These results show the capability of the meso-OFR and the scaled-up meso-OFR for continuous production of uniform HAp nanoparticles, while also confirming the possibility of OFR scale-up by in series association of individual OFRs.

Process intensification and optimization for hydroxyapatite nanoparticles production

Precipitation processes are widely used in industry for the production of particulate solids. Efficient mixing of the reagents is of major importance for the chemical and physical nature of the synthesized particles. Recently, microreactors have been studied to overcome homogeneity problems found when using stirred tank batch reactors. The present work investigated an ultrasonic tubular microreactor for the continuous-flow precipitation of hydroxyapatite (HAp), both in single-phase flow (SPF) and in gas–liquid flow (GLF). HAp nanoparticles were yielded for both configurations under near-physiological conditions of pH and temperature. The as-prepared particles, especially those that were prepared under GLF, show improved characteristics compared to commercial powder or powder obtained in a stirred tank batch reactor. Primary particles are smaller, particle shape is more homogeneous, and the aggregation degree of the particles is lower.

Continuous-flow precipitation of hydroxyapatite in ultrasonic microsystems

This paper describes the continuous-flow precipitation of hydroxyapatite Ca5(PO4)3OH (HAp) in two ultrasonic microreactors using diluted aqueous solutions of calcium and phosphate at 37°C. Precipitation of HAp was first carried out in a tubular microreactor immersed in an ultrasonic bath, where single-phase (laminar) flow and segmented gas–liquid flow were both evaluated. The single-phase flow study was then conducted in a novel microfluidic device developed at MIT. It consists of a Teflon stack microreactor with an integrated piezoelectric element (Teflon microreactor), thereby allowing the direct transmission of ultrasound to the reactor. Both microsystems produce single-phased calcium-deficient carbonated HAp under near-physiological conditions of temperature and pH. In addition, particle aggregation and primary particle size were significantly reduced in the segmented-flow tubular microreactor and in the Teflon microreactor. The as-prepared particles mostly consisted of rod-like shape nanoparticles with dimensions below 100nm in length and around 20nm in width. Further, the microreactors used yielded HAp particles with improved characteristics, namely higher crystallinity and less carbonate contamination, when compared to the HAp particles produced in a stirred tank batch reactor.

Modeling the effect of anti-scalant on CaCO3 precipitation in continuous flow

Scale inhibition by anti-scalants is known to involve blockage of active growth sites by adsorbed inhibitor molecules, but there is virtually no quantitative information on the kinetics of anti-scalant retarded precipitation. This paper presents a model integrating the process of anti-scalant adsorption on precipitated CaCO3 particles with the kinetics of the ensuing retarded precipitation. Adsorption is analyzed according to the Langmuir, Freundlich and Langmuir-Freundlich models, and CaCO3 precipitation is described by the commonly used surface reaction controlled model. The proposed model is validated by experimental data measured in a continuous flow precipitation system over a wide range of conditions.

P‐125: Small Particle Size Lanthanum Cerium Terbium Phosphate (LAP) and Yttrium Europium Oxide (YEO) Phosphors for CCFL Backlight Units in LCD Displays

AbstractSmall particle, green‐emitting lanthanum cerium terbium phosphate (LAP) and red‐emitting yttrium europium oxide (YEO) phosphors have been synthesized by a scalable continuous flow precipitation method for incorporation into white triblend phosphors for high brightness, sub‐miniature CCFLs for LCD backlight units, and the emission properties have been investigated.

Continuous flow precipitation

The effect of flow conditions on the nature of the precipitation curve is analyzed by applying population model concepts, under the assumption that agglomeration of precipitated particles is absent. Generalized non-dimensional precipitation curves reveal that plug flow conditions provide higher conversions of solute to precipitate, as compared to mixed flow conditions, except for the region of relatively low residence times. The enhancement of precipitation under mixed flow conditions at relatively low residence times is due to the shorter induction period occurring under mixed flow conditions. When the induction period is not taken into account, plug flow conditions are shown to provide more rapid precipitation at practically all conversion levels. A result of considerable practical significance is the prediction that the product of induction time and initial precipitation rate is a constant. Its magnitude depends solely on the measurement method for detecting the induction period and is independent of initial supersaturated solution conditions. Literature data on CaCO 3 precipitation at different temperatures are shown to support this theoretical prediction. In water treatment and desalination practice, inhibitors are added in order to extend the induction period and reduce the precipitation and scale formation rates. One of the difficulties in interpreting results of laboratory tests comparing the relative effectiveness of different inhibitors is the absence of fundamentally derived parameters to quantify the significant inhibition properties. Since the theoretically predicted expression, relating induction period to initial precipitation rate, can provide such fundamentally based characterizing parameters, further experiments were carried out to test the validity of the predicted relationship for the case of CaCO 3 precipitation in the presence of additives. Results of these tests, extending over a rather wide range of conditions, confirm the validity of the theoretical prediction and indicate the possibility of developing a fundamentally based standardized test method for characterizing important scale inhibition properties of additives.

The kinetics of protein salting-out: precipitation of yeast enzymes by ammonium sulfate.

Protein solubility can be adequately represented by the classical Cohn equation for the salting-out of alcohol dehydrogenase and fumarase from clarified yeast homogenate with ammonium sulfate. However, the constant beta in this equation is a function of the contacting procedure employed. The kinetics of continuous salting-out were similar for alcohol dehydrogenase and fumarase. The overall rate equation for precipitation had a variable order which was high initially, up to 3.1, but approached unity on completion of precipitation. This was followed by a partial resolution stage which was first order with respect to the concentration driving force. Precipitate particle size was estimated as 0.5 to 5 mum with continuous flow precipitation producing the largest particles.