Heterogeneous Primary Nucleation Research Articles

Quality-by-Design: An Integrated Process Analytical Technology Approach to Determine the Nucleation and Growth Mechanisms During a Dynamic Pharmaceutical Coprecipitation Process

The objective of this study was to demonstrate the feasibility of using an integrated process analytical technology (PAT) approach to determine nucleation and growth mechanisms of a dynamic naproxen (drug)-Eudragit L100 (polymer) coprecipitation process. The influence of several thermodynamically important formulation and process variables (drug/polymer ratio, alcohol, and water usages) on coprecipitation process characteristics was investigated via real-time in situ focused beam reflectance measurement (FBRM) monitoring and near real-time particle vision microscopy measurement. The final products were characterized by near-infrared (NIR) spectroscopy and NIR chemical imaging microscopy. The coprecipitation nucleation induction time (t(ind) ) was measured by both FBRM trend statistics and process trajectory method, respectively. Furthermore, nucleation kinetics was evaluated based on t(ind) measurement and corresponding supersaturation ratio (S) estimated. It was found that plots of ln(t(ind) ) versus (ln(2) S)(-1) consist of two linear segments and are consistent with classical primary nucleation mechanisms. Apparently, the coprecipitation process is governed by heterogeneous primary nucleation mechanism at low S (14 ≤ S ≤ 503) and by homogeneous primary nucleation mechanism at high S (1216 ≤ S ≤ 3649). Off-line characterizations collectively supported this statement. Therefore, it demonstrated that integration real-time PAT process monitoring with first-principles modeling and off-line product characterization could enhance understanding to coprecipitation process dynamics and nucleation/growth mechanisms, which is impossible via off-line techniques alone.

Primary nucleation of alpha-lactose monohydrate: The effect of supersaturation and temperature

Temperature and supersaturation are defined by classical nucleation theory as the key variables determining the rate of nucleation. These two variables were investigated, using turbidity to measure the induction time for the primary nucleation of alpha-lactose monohydrate. Absolute alpha-lactose supersaturations ranging from 8 to 32 (g per 100 g water) were investigated at temperatures of 25 °C, 40 °C, 50 °C and 60 °C. Using the results, the homogeneous and heterogeneous primary nucleation mechanisms were considered individually. When expressed as absolute supersaturation, temperature had an insignificant effect on the primary nucleation rate and the point at which homogeneous nucleation became the dominant mechanism. Classical nucleation theory can be used to show that at high supersaturation the temperature effect becomes negligible. This explains why conflicting observations on the effect of temperature on the nucleation rate of alpha-lactose monohydrate are given in the literature.

Inducing the stable polymorph using heterogeneous primary nucleation

Polymorphism plays an important role in crystallization of active pharmaceutical ingredients (APIs). At the earlier stage of development of a new API, a polymorph screening is performed to find out its different polymorphic forms. In particular, it is interesting to obtain the stable form. However, the form which nucleates spontaneously from solution is often a metastable form. This phenomenon corresponds to the so-called Ostwald rule of stages which is explained by the difference existing between the nucleation kinetics of the metastable and stable forms. The paper shows how a control of the heterogeneous primary nucleation can favour the nucleation of a more stable form. Several heterogeneous supports were tested with an API. The efficient supports did not act as templates but reduced the metastable zone widths and facilitated the primary nucleation of the different polymorphs. Optimising the operating conditions, i.e. mainly support concentration and supersaturation with respect to each polymorph modification, has allowed the preferential nucleation of the stable form. In the absence of heterogeneous support, a metastable form was systematically obtained. Since the interactions with the heterogeneous support do not need to be polymorph specific, the approach can a priori be used to perform the polymorph screening of any API, in addition to the usual in house screening methods.

Synthesis and characterization of microporous titanosilicate ETS-10 obtained with different Ti sources

Titanosilicate ETS-10 crystals were prepared by hydrothermal synthesis varying Ti source (TiCl 3 and commercial TiO 2-anatase), time in autoclave and seeding with previously prepared ETS-10 crystals. The crystalline powders were characterized by X-ray diffraction, N 2 adsorption, thermogravimetric analysis, and scanning and transmission electron microscopies. Control of the particle size of ETS-10 crystals ranging from 0.32 μm × 0.41 μm to 16.4 μm × 32.5 μm was successfully achieved varying the seeding and synthesis conditions. In particular, it was found that the use of TiO 2-anatase alone or together with TiCl 3 promotes heterogeneous primary nucleation. Transmission electron microscopy demonstrated that the largest crystals obtained here were twinned.

Bone-like apatite layer formation on the new resin-modified glass-ionomer cement

In this study, the apatite-forming ability of the new resin-modified glass-ionomer cement was evaluated by soaking the cement in the simulated body fluid. The Fourier Transform Infrared (FTIR) spectrometer and X-Ray Diffraction (XRD) patterns of the soaked cement pointed to the creation of poorly crystalline carbonated apatite. It was found that the releasing of calcium ions from the soaked cement will dominate the undesirable effect of polyacrylic acid on apatite formation. Consequently, the ionic activity products (IAPs) of the apatite in the surrounding medium increased which accelerated apatite nucleation induced by the presence of the Si-OH and COOH groups. Accordingly, the apatite nuclei started to form via primary heterogeneous nucleation and continued by secondary nucleation. Therefore, nucleation and growth occurs as in the layer-by-layer mode so that finite numbers of monolayers are produced. Subsequent formation of film occurs by formation of discrete nuclei (layer-plus-island or SK growth).

Fouling of roughened stainless steel surfaces during convective heat transfer to aqueous solutions

The deterioration of heat transfer performance due to fouling is the prime cause for higher energy consumption and inefficiency in many industrial heat exchangers such as those in power plants, refineries, food and dairy industries. Fouling is also a very complex process in which many geometrical, physical and operating parameters are involved with poorly understood interaction. Among them, the surface roughness is an important surface characteristic that would greatly influence crystallisation fouling mechanisms and hence deposition morphology and stickability to the surface. In this work, the effect of the surface roughness of AISI 304 BA stainless steel surfaces on fouling of an aqueous solution with inverse solubility behaviour has been investigated under convective heat transfer. Several experiments have been performed on roughened surfaces ranging from 0.18 to 1.55 μm for different bulk concentrations and heat fluxes. The EDTA titration method was used to measure the concentration of the calcium sulphate salt in order to maintain it at constant value during each fouling run. Experimental results show that the heat transfer coefficient of very rough surfaces (1.55 μm) decreases more rapidly than that of 0.54 μm. Several facts contribute to this behaviour notably (1) increased of primary heterogeneous nucleation rate on the surfaces; (2) reduction of local shear stress in the valleys and (3) reduced removal rate of the crystals from the surfaces where the roughness elements protrude out of the viscous sub-layer. The results also show linear and proportional variation of the fouling rate and heat flux within the range of operating conditions. In addition, the deposition process in terms of fouling rate could only be affected at lower surface contact angles. Such results would particularly be of interest for new surface treatment technologies which aim at altering the surface texture.

Crystallization kinetics of strontianite from Sr(HCO 3) 2 solutions

The kinetics of crystallization of strontium carbonate (strontianite) from strontium bicarbonate solutions were examined. CO 2 was stripped from a slightly acidic solution of Sr(HCO 3) 2 by stirring resulting in critical supersaturation and precipitation of strontianite. The reduction of the Sr 2+ concentration was recorded as a function of time by measuring the electrolytic conductivity and the pH value. Homogeneous primary nucleation is dominant at high supersaturations, whereas heterogeneous primary nucleation prevails at low supersaturations. The crystal growth rate increases with increasing supersaturation. This effect is less pronounced at higher supersaturations. The growth rate is mostly transport-controlled at high supersaturation. At lower supersaturation the crystal growth is mainly determined by integration of ions into the crystal lattice. These results may be used to explain the deposition of strontianite in natural systems.

Modelling the cyclic behaviour in a DTB crystallizer—a two-population balance model approach

A novel approach is introduced here to improve the description of the dynamic behaviour of industrial crystallizers using a two-population balance model to discriminate between primary and secondary nuclei. A heterogeneous primary nucleation model is implemented in a rigorous crystallizer model framework to explain the sustained oscillatory behaviour observed in industrial draft-tube baffle (DTB) crystallizers. The distinction between primary and secondary nuclei in the modelling framework is realized by using two different growth rates within the dispersed phase. The total crystal population is split up into two distinct and interacting populations, one representing the primary (no strain) population of crystals and the other the secondary (strained) population. Such a two-population balance model exhibits the sustained cyclic response for a 1100L DTB crystallizer, for an ammonium–sulphate water system. Including the degree of heterogeneity ( ψ ) and the two parameters; surface integration rate constant ( k r ) and condition for deformation ( Γ s ) from the growth model, the primary nucleation model framework has three unknown parameters which are fitted using measured transients from experiments performed on the pilot-plant crystallizers. The effect of the heterogeneity factor ( ψ ) on the dynamics of the process, suggests that the parameter ψ is very sensitive and hence, plays a very critical role in predicting the start-up and dynamics of the process. Validation of the model with the experimental data shows that the inclusion of a primary nucleation event definitely increases the descriptive capability of the model, thus justifying it's inclusion as a critical factor. The simulation results give a very good description of the start-up phase of the crystallizer operation, the dynamics of the process as well as the final steady-state values.

Nucleation and Morphology of Polyethylene Under Shear Flow

Effect of the shear flow (γ˙=0.5∼5 s−1) on the nucleation and on the morphology of polyethylene (PE) during crystallization from the melt was studied by means of polarizing optical microscopy and small angle X-ray scattering. In order to analyze the results by the nucleation theory, we observed the effect of shear flow on the equilibrium melting temperature The under shear flow and that under quiescent state are almost the same, Therefore, the shear flow does not affect the The “heterogeneous” primary nucleation rate (I) and the induction onset time of nucleation (τ onset) of the isolated crystals under shear flow are also almost the same as those under quiescent state. The heterogeneous primary nucleation means that isolated nuclei are sporadically generating from the melt with the aid of heterogeneities such as nucleating agents. After the generation of primary nuclei, the “shish” were generated independent of the primary nucleation. We found that the shish were formed by the chain elongation caused by the velocity difference between polymer chains and dust particles, etc. After that, we observed that the “kebabs” were formed on the shish. It was found that the nucleation from the melt after melting of the “shish-kebabs” (at melt annealing temperature T max=160°C for 5 min) was accelerated compared with the ordinary melt crystallization after melting of folded chain crystals. This indicates that the “solid memory effect” of the former solid is significant. This is because of the low entanglement density within the melt of shish kebabs.

Crystallization of Boric Acid through Reactive Dissolution of Oxalic Acid Crystals in Aqueous Borax Solution

AbstractIn the reaction between solid oxalic acid and aqueous borax solution, product boric acid precipitates in the solution phase after complete dissolution of oxalic acid crystals. This makes it possible to measure the dissolution and precipitation kinetics independently. The oxalic acid dissolution process was found to be diffusion controlled. Nucleation rates of product boric acid were influenced by heterogeneous primary nucleation and secondary nucleation, while growth rates were affected by both the bulk diffusion and surface integration processes. Dissolution of oxalic acid ctystals was described by a surface reaction model, and overall nucleation and growth rates were correlated in terms of the influencing process variables. Simulation analysis was carried out by linking the two processes of dissolution and precipitation in series. The trends of the predicted supersaturation profiles, number concentration, magma density and mean size of the product crystals are in good agreement with measured values.

Comparison Study of Mixing Effect on Batch Cooling Crystallization of 3-Nitro-1,2,4-triazol-5-one (NTO) Using Mechanical Stirrer and Ultrasound Irradiation

The insensitive explosive 3-nitro-1,2,4-triazol-5-one (NTO) has been recrystallized from water in an effort to prepare crystals with smaller size and narrower distribution in a batch cooling crystallizer. Two mixing devices, i.e., a mechanically stirred system with and without ultrasound in aqueous media were employed to compare the mixing effect on the crystallization. Under ultrasound irradiation, the metastable zone width was significantly reduced by more than 2 fold and the crystal size was shifted from 140∼160 μm to 50∼70 μm with a narrower CSD compared to the mechanically stirred system. However in the mechanical stirrer, the mixing effect on NTO crystallization was negligible if the impeller speed was sufficient to suspend all crystals in the crystallizer. It was found that the crystal growth was not influenced by mixing. We suggest that the NTO crystals were formed by primary heterogeneous nucleation that is common in batch cooling system. Finally, the population balance model (PBM), with the empirical nucleation and growth kinetic expressions, was solved numerically to predict the crystal size and the CSD with batch time, and the results were in good agreement with the experimental data.

Kinetics of Nucleation and Crystal Growth

This paper deals with homogeneous and heterogeneous primary nucleation and the atomistic model of heterogeneous primary and secondary nucleation. Three aspects of crystal growth mechanisms will be taken into account: growth by two-dimensional nucleation, the so-called birth and spread model, spiral growth without and with consideration of the influence of diffusion, and finally adhesive growth. An equation for the estimation of the growth rate of imperfect crystals including dislocations, published by Mersmann [1], is discussed. The influence of additives on nucleation and crystal growth, respectively, will be exemplarily explained for several model systems. The effect of growth rate dispersion (GRD) is described. Therefore, some experimental results concerning growth rates and different ways to influence growth are represented and discussed. Furthermore, a model explaining the effect of GRD is represented.

Composition of Tartrate Precipitates Deposited on Stainless Steel Tanks During the Cold Stabilization of Wines. Part II. Red Wines

The composition of potassium hydrogen tartrate (KHT) deposits formed on stainless steel surfaces during the cold stabilization of two red wines was determined and compared to those determined in white wines. Polysaccharides and polyphenols were associated with the tartrate crystals. They were present in higher amounts in red wines than in white wines, partly due to the presence of red wine tannins and anthocyanins. Tannins were the major wine components associated with the KHT crystals. Their mean degree of polymerization (DP) was twice the mean DP of wine tannins, which indicated a preferential association of the most hydrophobic molecules with the KHT crystals. Specificities evidenced in white wines with tartrate ester derivatives of phenolic acids and rhamnogalacturonans were confirmed in red wines. Yeast cells represented at least 20% of the tartrate deposits, as compared to 2% in white wines. Observations by scanning electron microscopy suggested that they adhered first on the stainless steel surfaces, where they may act as primary heterogeneous nucleation germs for the KHT crystals. Along with these differences in tartrate compositions, a strong evolution of crystal morphologies was noted between white and red wines.

Investigation of the unseeded nucleation of gibbsite, Al(OH) 3, from synthetic bayer liquors

This paper presents the novel application of multi-angle laser light scattering (MALLS) together with transmission electron microscopy (TEM), powder X-ray diffraction (XRD) and In-lens field emission scanning electron microscopy (IFESEM) for studying the unseeded nucleation of gibbsite from synthetic Bayer liquor (sodium aluminate). The effects of supersaturation in the absence or presence of a known inhibitor (sodium gluconate) were examined. In each series of experiments, both homogeneous and heterogeneous primary nucleation mechanisms were observed. For the unpoisoned liquor used in this work the nucleation appeared to be homogeneous for supersaturation ratios greater than 2.51±0.07 and heterogeneous for lower values. From the induction period measurements, the interfacial tension at 60°C was determined to be 45±6 mJ m −2, and used to predict the critical nucleus size of 1.2±0.1 nm. This was then compared to the measured particle sizes from samples examined by TEM (10–40 nm) and IFESEM (∼50 nm). A crystallite size was determined by XRD to be 22±6 nm. The presence of sodium gluconate inhibitor extended the region over which homogeneous nucleation is dominant, but did not affect the measured value of the interfacial tension and hence the critical nucleus size. This is consistent with the poison inhibiting processes on the solid phase and not the solution phase.

Modelling of crystalline layer growth using kinetic data obtained from suspension crystallization

The fouling of cooling surfaces of industrial crystallizers is a major problem which reduces the productivity of installations. This phenomenon is initiated by primary heterogeneous nucleation at the wall, followed by growth, leading to the formation of a crystalline layer which increases the thermal resistance of the system. An experimental device was designed to study the conditions of appearance and subsequent growth of the layer. The influence of the main parameters was studied. Thermal modelling of fouling in an annular exchanger was performed, using the experimental results. This led to an evolution of the thickness of the layer with time and position. It also enabled the supersaturation profile to be calculated at any time, thus making the link between the growth of the layer and the kinetics of crystallization in suspension. Although a simplifying hypothesis was used for modelling, good agreement was obtained concerning the initial mass flow of crystallization, using growth rates obtained in suspension crystallization to calculate the growth in thickness of the layer.

Experimental Study and Theoretical Approach of Cooling Surfaces Fouling in Industrial Crystallizers

Fouling of cooling surfaces of industrial crystallizers is a major problem which reduces the productivity of installations. This phenomenon, which results from the surface temperature being lower than that of the bulk so as to allow heat transfer, is essentially initiated by primary heterogeneous nucleation. The experimental setup has been designed to study the influence of different parameters such as suspension flow velocity, temperatures, the nature and the finish of the deposit surface, as well as the nature of the product which crystallizes. The conditions of the appearance of a crystalline layer and its subsequent growth are studied simultaneously by measuring the inlet and outlet temperatures of the two fluids which leads to calculation of the degradation of overall heat transfer coeffcient and, more directly, by physically measuring the evolution in time of the thickness profile.

Spherulite nucleation in blends of isotactic polypropylene with isotactic poly(butene‐1)

AbstractThe phase morphology and the influence of composition on the primary nucleation of isotactic polypropylene in isotactic polypropylene/isotactic poly(butene‐1) (iPP/iPB) blends were investigated by electron and light microscopy and small‐angle light scattering. It was found that iPP and iPB are miscible but the thermal treatment induces partial phase separation of components and the formation of iPP‐rich and iPB‐rich phases. The complete phase separation needs high temperatures and/or a long time of melt annealing. In samples crystallized isothermally at low undercooling the heterogeneous primary nucleation in blends is depressed as compared to plain iPP. In blends the less active heterogeneities lose their activity because of an increase of the energy barrier for critical size nucleus formation due to phase separation of blend components during crystallization. For the same reason the rate of homogeneous nucleation in blends decreases, as observed in samples crystallized at very high undercooling. At very high undercooling iPP and iPB are able to crystallize with similar rates, which results in the formation of a fraction of iPB spherulites in addition to iPP spherulites. Consequently the number of spherulites in the blend is larger than that in plain iPP, in spite of the decrease in the homogeneous nucleation rate of iPP in the blend. © 1994 John Wiley & Sons, Inc.

Crystallization and agglomeration kinetics during the batch drowning-out precipitation of potash alum with aqueous acetone

Kinetic processes occurring during the batch drowning-out precipitation of potash alum with aqueous acetone achieved by mixing aqueous saturated potash alum solutions with aqueous acetone at 25 °C over a range of supersaturation levels and under different stirring modes are reported. The induction period decreases significantly both with initial supersaturation and stirrer speed. Primary heterogeneous nucleation is predominant, with homogeneous nucleation becoming significant at S > 4.50. Weak secondary nucleation is also detected under the conditions studied. The degree of agglomeration has been assessed and found to be dependent on initial supersaturation.

Nucleation in polymer crystallization: A physical or a chemical mechanism?

AbstractPrimary nucleation is in general heterogeneous in polymer crystallization. In unseeded polymers, the crystallization originates from a very small concentration (<0.1 percent) of unknown submicroscopic heterogeneous nuclei. Only in three cases have the nucleation mechanisms been identified with precision. The first example is self‐nucleation, which relates to the nucleation of a polymer melt by fragments of its own crystals previously present in the melt. Another example of heterogeneous nucleation is represented by epitaxial nucleation of polymers on inorganic and organic substrates recently established by Lotz and Wittmann. More recently, it was discovered that finely divided organic salts added to reactive polymers do not behave as inert heterogeneous substrates but rather dissolve and cut molten macromolecules producing ionic chain ends which precipitate into the melt and form organized aggregates which are the true nucleating species. It is clearly shown that mechanisms of physical and chemical origin are involved in heterogeneous primary nucleation of polymer crystallization.

Heterogeneous primary nucleation of ice in water and aqueous solutions

The effect of the volume of the liquid sample, the degree of turbulence in the liquid, and the rate of cooling upon the probability of nucleation has been studied for water and aqueous solutions. Nucleation rates were measured for droplets nearly instantaneously cooled to a predetermined temperature. Also threshold temperatures for nucleation were determined in stirred externally cooled vessels. The liquids studied (tap water, distilled water, and orange juice) did not contain particles causing nucleation at supercoolings less than 6°C. Nucleation at smaller supercoolings is attributed to the nucleative action of surface irregularities of the vessel walls. Provided no air bubbles are dispersed in the liquid, the rate of stirring (degree of turbulence) appeared to have no influence upon the nucleation. The experimental results are inconsistent with the stochastic hypothesis of Bigg 7), the singular hypothesis of Langham and Mason 8) and the pseudo-singular hypothesis of Vali and Stansbury 10). They could, including those reported in literature 7, 8, 10) be explained by the assumption of three distinct probabilities of nucleation: namely, the probability per unit time that a particular particle can cause nucleation at equilibrium conditions; the probability per unit time that equilibrium is established; and the probability that a particle with characteristic properties is present in the sample.