Publications
169 results found
Guo M, Chang ZH, Liang E, et al., 2022, The effect of chain length and side chains on the solubility of peptides in water from 278.15 K to 313.15 K: a case study in glycine homopeptides and dipeptides, Journal of Molecular Liquids, Vol: 352, Pages: 1-14, ISSN: 0167-7322
The thermodynamic properties of peptides are significant in terms of the crystallization conditions of biomaterials. In this work, we seek to understand and explain the effect of side chains and chain length on the solubility of peptides. The amino acid residues of dipeptides investigated here were chosen based on their difference in side chain properties. The modified Apelblat equation was used to correlate the relationship between the solubility in water and temperature. In order to explore solute–solvent interactions, the solvation free energies of these peptides were calculated by Molecular Dynamic simulations. This work gives an indication of the effects of side chains and chain length on the solubility of amino acids and peptides in water under different temperatures, which not only provides the thermodynamic data for peptides, but is also critical in the prediction of peptide solubility using Statistical Associating Fluid Theory (SAFT).
Errington E, Guo M, Heng JYY, 2022, Environmental Impacts of Rice Husk-Derived Silica under Uncertainty: Is “Bio” better?, Computer Aided Chemical Engineering, Pages: 1615-1620
Millions of tonnes of rice husk (RH) are produced annually as an agricultural waste. One area of interest for RH valorisation is to use rice husk ash (RHA, a by-product of RH combustion) as a replacement for mineral-derived synthetic amorphous silica (M-SAS). However, little information is available on the environmental benefit of this approach. This study details the first evaluation of the environmental benefits of producing RH-derived synthetic amorphous silica (RH-SAS). This is done by describing the life cycle of RH-SAS in terms of stages for which existing life cycle inventories can be linked and aggregated in a modular way. It is then shown how the physical meaning of linkages between modules are governed by both the characteristics of the RH feedstock and efficiencies of processes across the life cycle. To provide more robust findings, the sensitivity of predictions to model uncertainty are also considered. Finally, a case is provided for the benefit of RH-SAS production within the Asia-Pacific (APAC) SAS market.
Velasco PQ, Karde V, Ito Y, et al., 2022, Rational synthesis of polymer coated inorganic nanoparticles-MWCNT hybrids via solvophobic effects, CARBON TRENDS, Vol: 6, ISSN: 2667-0569
Karde V, Jefferson AE, Hebbink GA, et al., 2022, Investigating sizing induced surface alterations in crystalline powders using surface energy heterogeneity determination, Powder Technology, Vol: 395, Pages: 645-651, ISSN: 0032-5910
Particle sizing is the most commonly employed and critical unit operation across powder processing industries. In this work, we show the surface energy changes prompted by the sizing operations like milling and sieving in α-lactose monohydrate powders using Finite Dilution Inverse gas chromatography (FD-IGC) analysis. Three separate sieved fractions of α-lactose monohydrate powder were divided into a top, middle and bottom fraction from the same starting material. Similarly, a custom grade α-lactose monohydrate was milled for a different duration to produce two milled samples with different median particle sizes. Sieved sample results showed that the bottom fraction exhibited higher heterogeneity with higher dispersive (γd) surface energy values ranging from 42.5 mJ/m2 to 45.9 mJ/m2 compared to the top and middle fractions. The finest fraction contains more cleaved surfaces that are exposed during the preparation process, i.e. milling, of the material resulting in different surface properties. Furthermore, the surface energy analysis of the milled samples revealed slight but vital differences in the γd heterogeneity profiles. The site-specific distribution of energies was obtained using the Boltzmann probability distribution model and revealed two distinct regions for crystalline α-lactose monohydrate. Thus, our work confirmed that sizing operations like milling and sieving affect the surface energy of the particulate solids due to the changes in properties like size, shape, exposure of internal cleavage planes, etc. and that the surface energy heterogeneity determination using FD-IGC helped in characterising these changes.
Li X, Heng JYY, 2021, Protein crystallisation facilitated by silica particles to compensate for the adverse impact from protein impurities, CrystEngComm, Vol: 23, Pages: 8386-8391, ISSN: 1466-8033
In this study, silica particles were used to improve target protein batch crystallisation from a binary protein mixture at a 5 mL scale. Lysozyme (40 mg mL−1) was used as the target protein and thaumatin (0.1–8 mg mL−1) was regarded as a protein impurity. It was demonstrated that even an impurity at the concentration as low as 0.1 mg mL−1 (0.25 w/w% of the target protein) would delay target protein crystallisation, predominantly by extending the induction time. When the silica particles were employed in the system to facilitate crystallisation, target protein crystallisation was significantly improved with a much shorter induction time and higher yield at the end of the experiment. It was also shown that the effectiveness of silica on target protein crystallisation depended on the impurity concentration and silica loading amount.
Guo M, Rosbottom I, Zhou L, et al., 2021, Triglycine (GGG) adopts a polyproline II (pPII) conformation in its hydrated crystal form: revealing the role of water in peptide crystallization, Journal of Physical Chemistry Letters, Vol: 12, Pages: 8416-8422, ISSN: 1948-7185
Polyproline II (pPII) is a left-handed 31-helix conformation, which has been observed to be the most abundant secondary structure in unfolded peptides and proteins compared to α-helix and β-sheet. Although pPII has been reported as the most stable conformation for several unfolded short chain peptides in aqueous solution, it is rarely observed in their solid state. Here, we show for the first time a glycine homopeptide (gly-gly-gly) adopting the pPII conformation in its crystalline dihydrate structure. The single crystal X-ray structure with molecular dynamic simulation suggests that a network of water and the charged carboxylate group is critical in stabilizing the pPII conformation in solid state, offering an insight into the structures of unfolded regions of proteins and the role of water in peptide crystallization.
Li X, Heng JYY, 2021, The critical role of agitation in moving from preliminary screening results to reproducible batch protein crystallisation, Chemical Engineering Research and Design, Vol: 173, Pages: 81-88, ISSN: 0263-8762
This study investigated the important role of agitation in obtaining consistent and reproducible results when moving from preliminary qualitative screenings for protein crystallisation to quantitative batch crystallisation experiments. Lysozyme-thaumatin binary protein mixture was used as the model protein system in this study. Poor reproducibility between batches were observed for non-agitated crystallisation conditions even if the same sampling timing and frequency applied. With agitation, from 0 to 200 rpm investigated in this study, improved reproducibility of protein crystallisation was observed with increased agitation. Additionally, agitation also had impacts on supersaturation exhaustion rate, yield and crystal size. Moreover, in agitated batch crystallisation, it was found that target protein crystallisation process was decelerated in the presence of protein impurity. In conclusion, we emphasised the essential role of agitation in protein crystallisation experiments else misleading conclusions with inconsistency might be drawn from non-agitated systems.
Chen W, Li X, Guo M, et al., 2021, Biopurification of monoclonal antibody (mAb) through crystallisation, Separation and Purification Technology, Vol: 263, Pages: 1-15, ISSN: 1383-5866
Therapeutics based on monoclonal antibody (mAb) represent the most advanced biopharmaceuticals, being able to treat a wide range of challenging diseases such as cancers and arthritis. As the scale of mAb production steadily increases with the demand for mAb-based therapeutics, the downstream biopurification continues to experience significant bottleneck due to the throughput limited nature of the current purification technology. Over the last decades, significant advances have been made in protein (and especially mAb) crystallisation as an alternative biopurification technology that offers high product stability and purity as well as scalability. This review starts with the discussion of general physicochemical properties of mAb before moving on to the in-depth discussion of the distinct phase behaviour of mAb in comparison with conventional globular proteins such as lysozyme. The final part of this review presents a summary of successful demonstrations of crystallisation scale-ups of mAb and discusses the critical factors (i.e. mixing and temperature control) to be considered.
Link FJ, Heng JYY, 2021, Enhancing the crystallisation of insulin using amino acids as soft-templates to control nucleation, CrystEngComm, Vol: 23, Pages: 3951-3960, ISSN: 1466-8033
Amino acids have been widely used in protein formulations to increase the protein's stability. In this study, amino acids have been introduced as soft-templates to control the nucleation of proteins. L-Arginine, L-glycine or L-leucine with concentrations between 0.01 M and 0.1 M were used in a hanging drop vapor diffusion set-up to investigate their role in the crystallisation of human insulin as a model protein at low supersaturation. All amino acids were in a dissolved state. Here we show that L-arginine and L-leucine clearly enhance the nucleation significantly. On the other hand, L-glycine does not enhance nucleation of human insulin at low supersaturation. We hypothesize that it is the intermolecular interaction between the protein's residues and the amino acid's residues that results in an enhancement in the formation of the initial protein nuclei. To prove that the enhanced nucleation is of a kinetic nature, the solubility of insulin in amino acid rich solution was also investigated. The solubility results show that amino acids increase insulin solubility. From that we derive that the enhancement in nucleation is not due to a change in the thermodynamic equilibrium between the crystalline and bulk-liquid phase. As this approach of using amino acids to enhance nucleation is based on a dissolved state in solution, we introduce here the concept of protein crystallisation by soft-templating.
Salehi H, Karde V, Hajmohammadi H, et al., 2021, Understanding flow properties of mannitol powder at a range of temperature and humidity, International Journal of Pharmaceutics, Vol: 596, ISSN: 0378-5173
Inadequate flowability of powders in industries during handling can cause many problems. For example, lack of flow from hoppers, poor tablet weight consistency, and low production rate in tableting. Many factors are known to commonly affect flow properties of powders, such as temperature, humidity and conditioning duration. In this paper, flow properties of a mannitol powder, which was conditioned between 24 and 72 h at various high relative humidities and temperature, were measured using a shear tester. A statistical model was developed to investigate the relative importance of these variables on the mannitol flow properties. The developed model showed all independent variables are significant in estimating bulk cohesion. Two separate approaches were used to evaluate inter-particle forces in the bulk, and how these changed with environmental conditions. First, inter-particle forces were inferred from the measured bulk properties using the Rumpf model approach. Secondly, inter-particle forces were predicted based on a model of moisture present on the particle surface using a combination of Kelvin model with the Laplace-Young (KLY) equation. The second approach also involved a new method to measure surface energy of mannitol powder based on measurements using Finite Dilution Inverse Gas Chromatography (FD-IGC). The surface energies of the mannitol powder were measured at high temperature (35 °C) and at different range of relative humidities. In spite of the fundamentally different approaches to the two ways of inferring inter-particles forces, these forces came out within less than 1.5:1 in magnitude. The Rumpf approach from bulk behaviour data obviously reflected the measured change in behaviour with humidity in particular, but this was not predicted from the KLY approach, however the likely reasons for this are postulated and recommendations for improvement are made.
Bian H, Ai L, Hellgardt K, et al., 2021, Phase behaviour of methane hydrates in confined media, Crystals, Vol: 11, Pages: 1-16, ISSN: 2073-4352
In a study designed to investigate the melting behaviour of natural gas hydrates which are usually formed in porous mineral sediments rather than in bulk, hydrate phase equilibria for binary methane and water mixtures were studied using high-pressure differential scanning calorimetry in mesoporous and macroporous silica particles having controlled pore sizes ranging from 8.5 nm to 195.7 nm. A dynamic oscillating temperature method was used to form methane hydrates reproducibly and then determine their decomposition behaviour—melting points and enthalpies of melting. Significant decreases in dissociation temperature were observed as the pore size decreased (over 6 K for 8.5 nm pores). This behaviour is consistent with the Gibbs–Thomson equation, which was used to determine hydrate–water interfacial energies. The melting data up to 50 MPa indicated a strong, essentially logarithmic, dependence on pressure, which here has been ascribed to the pressure dependence of the interfacial energy in the confined media. An empirical modification of the Gibbs–Thomson equation is proposed to include this effect.
Ouyang J, Chen J, Rosbottom I, et al., 2021, Supersaturation and solvent dependent nucleation of carbamazepine polymorphs during rapid cooling crystallization, CrystEngComm, Vol: 23, Pages: 813-823, ISSN: 1466-8033
Polymorphic nucleation behavior of carbamazepine (CBZ) was investigated in terms of supersaturation in several solvents: nitromethane, acetonitrile, acetone, ethanol, 2-propanol and toluene. The solubility was measured and the effects of interaction between the solvent and CBZ on solubility and polymorphic nucleation were discussed. It was found that the polymorphic forms of CBZ largely depended on the solvent type and supersaturation ratio. The carbonyl group in acetone blocked the NH⋯O interaction between the dimer in form II by mimicking the same interaction with CBZ, then favored the nucleation of form III. The aromatic–aromatic interaction between CBZ and the solvent like toluene decreased the solute–solute interaction and favored the formation of form II. The nucleation domains of CBZ polymorphs (forms II and III) were separated as a function of supersaturation ratio range in each solvent, and the effects of solvents and supersaturation ratios on the induction time and transformation process were also explored. The interfacial energies of forms II and III in different solvents were calculated, and it was found that, at all investigated supersaturation ratios, the interfacial energy of form II in all solvents except acetone was always lower than that of form III, indicating that nucleation kinetics preferably favored the formation of form II. However, at lower supersaturation ratios, thermodynamics was critical and form III was obtained.
Ouyang J, Chen J, Chen W, et al., 2021, Application of phenyl-functionalized porous silica for the selective crystallization of carbamazepine metastable form II, Industrial and Engineering Chemistry Research, Vol: 60, Pages: 939-946, ISSN: 0888-5885
Polymorphic nucleation of carbamazepine (CBZ) in several solvents (ethanol, 2-propanol, acetone, acetonitrile, toluene, and nitromethane) was investigated with different functionalized porous silica templates. It was found that the introduction of silica templates with different surface chemistries such as −OH, −NH2, and −phenyl affected the polymorphic outcomes. At a low supersaturation ratio, stable form III of CBZ was prone to nucleate as expected. However, the results in this work confirmed that a phenyl-functionalized porous silica template could crystallize and maintain metastable form II of CBZ at a low supersaturation ratio for a long time. In terms of the underlying mechanism, the aromatic–aromatic interaction between the surface of phenyl-functionalized silica and the CBZ molecule played an important role in stabilizing metastable form II. The influence of the amount of silica templates on the polymorph formation was also investigated. Our results will help to crystallize and maintain metastable materials, even at a low supersaturation ratio.
Chen W, Cheng TNH, Khaw LF, et al., 2021, Protein purification with nanoparticle-enhanced crystallisation, Separation and Purification Technology, Vol: 255, Pages: 1-7, ISSN: 1383-5866
In this study, silica nanoparticle was synthesised and used to promote lysozyme crystallisation effectively against high concentrations of protein impurity (bovine serum albumin (BSA); concentration = 25.0–50.0 mg/mL vs 5.0–25.0 mg/mL for lysozyme) at 1 mL scale, demonstrating that crystallisation is a viable and scalable protein purification technology with the aid of heterogeneous nucleants. The silica nanoparticle expedited the crystallisation of lysozyme through the enhancement of nucleation, significantly improving the process productivity. Furthermore, this study demonstrates the proper use of nanoparticle in terms of process time, as the improvement of product recovery by silica nanoparticle has a monomodal peak shape over time.
Ouyang J, Zhou L, Liu Z, et al., 2020, Biomass-derived activated carbons for the removal of pharmaceutical mircopollutants from wastewater: A review, Separation and Purification Technology, Vol: 253, Pages: 1-17, ISSN: 0950-4214
Biomass-derived activated carbons (biochars) have attracted great attention due to their excellent physicochemical properties such as high specific area, large pore volume, well-defined microporous structure and tunable surface chemistry. Although pharmaceuticals are an emerging class of micropollutants in wastewater through the sewerage disposal by pharmaceutical factories, hospitals and households, only a few recent studies have reviewed the adsorption and removal of pharmaceuticals from wastewater by biochars and they lack the systematic insights into total adsorption process from biochars preparation to adsorption mechanism. This paper aims to provide a comprehensive review on recent publications and to propose future research directions. The effects of lignocellulosic biomass as well as the pyrolysis, activation and modification conditions on the physicochemical properties of biochars and their adsorption capacities are discussed. The adsorption kinetics and isotherms of different pharmaceuticals onto various biochars are analyzed based on commonly used models. Finally, the potential adsorption mechanisms of pharmaceuticals by biochars are summarized.
Chen W, Karde V, Cheng TNH, et al., 2020, Surface hydrophobicity: effect of alkyl chain length and network homogeneity, Frontiers of Chemical Science and Engineering, Vol: 15, Pages: 90-98, ISSN: 2095-0179
Understanding the nature of hydrophobicity has fundamental importance in environmental applications. Using spherical silica nanoparticles (diameter = 369 ± 7 nm) as the model material, the current study investigates the relationship between the alkyl chain network and hydrophobicity. Two alkyl silanes with different chain length (triethoxymethylsilane (C1) vs trimethoxy(octyl)silane (C8)) were utilised separately for the functionalisation of the nanoparticles. Water contact angle and inverse gas chromatography results show that the alkyl chain length is essential for controlling hydrophobicity, as the octyl-functionalised nanoparticles were highly hydrophobic (water contact angle = 150.6 ± 6.6°), whereas the methyl-functionalised nanoparticles were hydrophilic (i.e. water contact angle = 0°, similar to the pristine nanoparticles). The homogeneity of the octyl-chain network also has significant effect on hydrophobicity, as the water contact angle was reduced significantly from 148.4 ± 3.5° to 30.5 ± 1.0° with a methyl-/octyl-silane mixture (ratio = 160 : 40 µL · g-1 nanoparticles).
Delmas LC, White AJP, Pugh D, et al., 2020, Stable metal-organic frameworks with low water affinity built from methyl-siloxane linkers, CHEMICAL COMMUNICATIONS, Vol: 56, Pages: 7905-7908, ISSN: 1359-7345
Li X, Chen W, Yang H, et al., 2020, Protein crystal occurrence domains in selective protein crystallisation for bio-separation, CrystEngComm, Vol: 22, Pages: 4566-4572, ISSN: 1466-8033
Bio-separation is a key bottleneck in the manufacture of biopharmaceuticals. In this work, we report experimental evidence of direct selective protein crystallisation from a binary protein mixture solution. Lysozyme–thaumatin mixtures with a wide protein composition range (0–100 mg mL−1, respectively) were tested under the same crystallisation cocktail conditions using the hanging-drop vapour-diffusion (HDVD) crystallisation method. This work demonstrates the selectivity of crystallisation from a model binary protein mixture and four crystal occurrence domains were determined as the operation windows of selective crystallisation of the target protein: 1) an unsaturated region with no crystal formation, 2 & 3) target regions with only a single type of protein crystals (lysozyme crystals only or thaumatin crystals only) and 4) a mixture region which have a mixture of both types of protein. This study demonstrates that protein crystallisation is not only applicable to high-purity protein solutions and emphasizes the vital impacts of the presence of protein impurities in the process of target protein crystallisation. The study concludes that protein crystallisation is a feasible approach to separate a target protein from a complex mixture environment which can be achieved by manipulating the crystallisation operation conditions such as mixture composition, precipitant concentration, and operation time.
Karde V, Guo M, Heng JYY, 2020, Influence of interparticle structuring on the surface energetics of a binary powder system, International Journal of Pharmaceutics, Vol: 581, ISSN: 0378-5173
The structuring of component particles in binary compositions affects the solid-solid interfacial properties. This work reports the effect of interparticle interactions in binary powder compositions of D-Mannitol and glass beads through the heterogeneity data obtained from Finite Dilution Inverse Gas Chromatography (FD-IGC). Three different scenarios viz. structured, random and segregated systems of the binary powder composition were considered for the analysis in the IGC column. Binary mixtures with large size disparity between the components produced structured mixtures exhibiting a guest-host type of interactions and energetic homogeneity irrespective of the energetics of the finer component. Random and segregated systems revealed a heterogeneous trend in the data indicating preferential probing of the active sites of the composition, particularly at the lower probe coverages. The results demonstrate that in the multicomponent binary systems the surface energetics is influenced by the solid-solid interfaces and structuring of the component particles within the mix i.e., the surface energy analysis could reveal a mixing behavior in powders. Furthermore, an adsorption energy distribution model based on Boltzmann statistics and simulation fitting approach was employed to deconvolute the distribution of the changing energy landscape of the binary mixtures.
Ngeow YW, Williams DR, Chapman A, et al., 2020, Surface energy mapping of modified silica using IGC technique at inite dilution, ACS Omega, Vol: 5, Pages: 10266-10275, ISSN: 2470-1343
The reinforcing silica filler, which can be more than 40% of an elastomer composite, plays a key role to achieve the desired mechanical properties in elastomer vulcanizates. However, the highly hydrophilic nature of silica surface causes silica particle aggregation. It remained a challenge for many tire manufacturers when using silica-filled elastomer compounds. Here, the silica surface energy changes when the surface is modified with coupling or noncoupling silanes; coupling silanes can covalently bond the silica to the elastomers. The surface energy of silica was determined using inverse gas chromatography (IGC) at finite dilution (FD-IGC) and found to be reduced by up to 50% when the silica surface was silanized. The spatial distribution of silica aggregates within the tire matrix is determined by transmission electron microscopy (TEM) and a direct correlation between aggregate size (silica microdispersion) and work of cohesion from IGC is reported, highlighting surface energy and work of cohesion being excellent indicators of the degree of dispersion of silica aggregates.
Roque ACA, Pina AS, Azevedo AM, et al., 2020, Anything but Conventional Chromatography Approaches in Bioseparation, Biotechnology Journal, Vol: 15, Pages: 1-8, ISSN: 1860-6768
While packed bed chromatography, known as conventional chromatography, has been serving the biopharmaceutical industry for decades as the bioseparation method of choice, alternative approaches are likely to take an increasing leading role in the next few years. The high number of new biological drugs under development, and the need to make biopharmaceuticals widely accessible, has been driving the academia and industry in the quest of anything but conventional chromatography approaches. In this perspective paper, these alternative approaches are discussed in view of current and future challenges in the downstream processing field.
Rosbottom I, Cheng TNH, Heng JYY, 2020, Computational analysis of the solid-state and solvation properties of carbamazepine in relation to its polymorphism, Chemical Engineering and Technology, Vol: 43, Pages: 1152-1159, ISSN: 0930-7516
The solvent‐dependent polymorphism of the active pharmaceutical ingredient (API) carbamazepine is interpreted from calculations of the solid‐state and API‐solvent intermolecular interactions. These simulations suggested that apolar solute‐solute interactions could be disrupted by apolar solvents. In contrast, the polar solute‐solute interactions were found to be easily disrupted by polar and protic solvents. This is consistent with experimental observations that the crystallization of the metastable form II is more dominant in apolar solvents. The Mercury program remains the gold standard in terms of usability; however, further expansion into more complex simulation techniques could make this package of even greater use in pharmaceutical manufacturing workflows.
Chen W, Park SJ, Kong F, et al., 2020, High protein-loading silica template for heterogeneous protein crystallization, Crystal Growth and Design, Vol: 20, Pages: 866-873, ISSN: 1528-7483
As a purification technology, crystallization is advantageous over chromatography and precipitation in terms of purity, cost, and scalability. In general, proteins have slow crystallization kinetics due to their complex configurations, but this problem can be overcome with heterogeneous nucleants. High protein-loading mesoporous silica is a promising nucleant due to its favorable interaction with protein. The current study employs such a template in the batch crystallization of lysozyme and thaumatin at 1 mL scale. Using lysozyme as the main model protein, the results show that the template had high protein loading (220–300 mg lysozyme/g silica) and induced significantly faster crystallization as compared to the unseeded samples over a wide range of initial protein concentration (10.0–47.5 mg/mL) at 25 °C with 0.5 M potassium sodium tartrate tetrahydrate (precipitant) concentration. It was found that the template had to be saturated with the target protein before the experiments to achieve faster kinetics, or else it could delay the crystallization process. These findings were reaffirmed by the crystallization experiments of thaumatin. The current study demonstrates the effectiveness of high protein-loading silica as a nucleant in protein crystallization and the importance of its pretreatment with the target protein.
Chen W, Yang H, Heng JYY, 2020, Continuous Protein Crystallization, HANDBOOK OF CONTINUOUS CRYSTALLIZATION, Editors: Yazdanpanah, Nagy, Publisher: ROYAL SOC CHEMISTRY, Pages: 372-392, ISBN: 978-1-78801-214-0
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Yang H, Huang L, Zhang F, et al., 2019, Gravity on crystallization of lysozyme: slower or faster?, Crystal Growth and Design, Vol: 19, Pages: 7402-7410, ISSN: 1528-7483
With the increase in applications of protein-based medicines approved and developed, downstream manufacturing of biopharmaceuticals has challenges of finding cost-effective and reliable routes. Biocrystallization and centrifugation have both been used to isolate and purify macromolecules, such as therapeutic protein and other functional proteins. However, the centrifugation cannot perfectly separate biomolecules, and the biocrystallization mainly focuses on structure determination on a scale of microliters or below. In this work, protein crystallization of lysozyme, with a concentration of 35–45 mg/mL, and sodium chloride, with a concentration of 45–55 mg/mL in the solution, on a scale of milliliters was performed under centrifugation. Different gravity levels of 1–20000g and centrifugation durations have been investigated during the nucleation and crystal growth process. There were no obvious influences of low gravity (<100g) and short duration (<5 min) of centrifugation on the crystallization process: i.e., on the changes in concentrations. With continuous centrifugation (>30 min), high gravity (>1000g) hindered the nucleation, i.e., it reduced the drop in concentration at the nucleation stage; however, it accelerated the crystal growth process, i.e. enhanced a drop in concentration at the crystal growth stage.
Parambil JV, Poornachary SK, Heng JYY, et al., 2019, Template-induced nucleation for controlling crystal polymorphism: from molecular mechanisms to applications in pharmaceutical processing, CrystEngComm, Vol: 21, Pages: 4122-4135, ISSN: 1466-8033
Over the last two decades, the use of template surfaces to induce heterogeneous crystal nucleation has been explored primarily to address two different goals: first, as an alternative to the conventional seeding technique used for polymorph control and, second, as a technique to promote the nucleation rate in novel crystallisation processes and formulations. The former need conceivably arises due to the risk of crystallising a new polymorph despite pre-seeding the solution with the desired crystal form. In this context, we review ongoing efforts in the research area of template-induced crystallisation, covering both experimental and simulation studies directed towards deeper understanding of the underpinning mechanisms. In addition, we report on the use of template-induced crystal nucleation as a process intensification technology for formulating drug substances and as a technique for enabling nucleation and polymorphic control during continuous manufacturing of active pharmaceutical ingredients.
Lapidot T, Matar OK, Heng JYY, 2019, Calcium sulphate crystallisation in the presence of mesoporous silica particles: experiments and population balance modelling, Chemical Engineering Science, Vol: 202, Pages: 238-249, ISSN: 0009-2509
A population balance model is used to investigate the effect of mesoporous silica particles on calcium sulphate crystallisation in a stirred batch crystalliser. The model accounts for nucleation, growth, agglomeration, breakage, and particle-assisted nucleation, and the model equations are solved numerically using the method of classes over a logarithmic, non-uniform mesh. The crystallisation process is characterized experimentally using electrical conductivity to track the ion concentration and laser diffraction to measure the steady-state crystal size distribution obtained at the end of the experiments. The experiments are carried out over a range of temperatures, initial supersaturations, particle pore diameters, and particle loadings. The model is first fitted to experimental data obtained in the absence of particles to determine kinetic parameters of the nucleation, growth, agglomeration, and breakage for pure calcium sulphate crystallisation. Varying pore diameter did not influence the catalytic effect of the particles, however, particle loading was found to significantly decrease the nucleation induction time. The model was extended to account for the presence of particles by fitting two additional mechanisms. The first proposed a particle-assisted nucleation where nuclei are produced via heterogeneous crystallisation, then detach by particle-particle collision that is second-order with respect to particle loading. The second proposed that the crystal breakage frequency increases linearly with particle loading. Good agreement with the experimental data is demonstrated over the range of conditions examined.
Ouyang J, Zhou L, Liu Z, et al., 2019, Solubility determination and modelling of benzamide in organic solvents at temperatures from 283.15 K and 323.15 K, and ternary phase diagrams of benzamide-benzoic acid cocrystals in ethanol at 298.15 K, Journal of Molecular Liquids, Vol: 286, ISSN: 0167-7322
In this paper, several common solvents including butyl acetate, methyl acetate, ethyl acetate, acetonitrile, 1-butanol, isobutanol, isopropanol, ethanol, 1-propanol, methanol, acetone, and water, were selected as solubility solvents for benzamide. The solubility of benzamide in all solvents increases with the increase of temperature from 283.15 K to 323.15 K, and generally depends on solvents in the following order: methanol > acetone > ethanol > 1-propanol > 1-butanol > isopropanol > isobutanol > methyl acetate > ethyl acetate > butyl acetate > acetonitrile > water. Solubility data in all solvents were well correlated with the temperature by using the NRTL, Wilson and modified Apelblat models. Furthermore, the dissolution thermodynamic properties, which include dissolution Gibbs energy, dissolution entropy and dissolution enthalpy, were also calculated. Based on the above results, ethanol was chosen as the solvent for preparing benzamide cocrystal with benzoic acid. The ternary phase diagram of benzamide-benzoic acid cocrystals in ethanol was constructed, and one stable cocrystal with a stoichiometry of 1:1 was determined and characterized.
Zou J, Wu J, Wang Y, et al., 2019, Synergistic effect of graphene oxide and different valence of cations on promoting catalase crystallization, Crystal Growth & Design, Vol: 19, Pages: 2838-2844, ISSN: 1528-7483
This study tests the effect of using the combination of graphene oxide (GO) with different valence cations as a heterogeneous nucleant on promoting catalase crystallization. By using GO and three types of salts with different valences, NaCl, MgCl2, and YCl3, the addition of GO with all three salts resulted in an increase in the percentage of crystal drops and a decrease in induction time. The experimental results further verified that there is a synergistic effect of GO and cations as the percentage of crystal drops was higher when GO with cations was added compared to control experiments where only GO or cations presented. It was also observed that the improvement in crystallization became more significant when cations with higher valence were utilized. It is believed that the enhancement in crystallization was due to the synergistic effect arising from the cation-π and electrostatic interactions between GO sheets and cations. These interactions subsequently contributed to the positively charged salt, which adsorbed and connected both negatively charged catalase molecules and the GO surfaces, increasing the local protein concentration and leading to crystallization. In addition, we compared LaCl3 and CeCl3 with YCl3 to verify the effect of the same valence salt on catalase crystallization and found that the higher the charge density, the more pronounced the promotion effect. This study provides a new protein crystallization methodology by exploiting GO with cations as heterogeneous nucleant to promote catalase crystallization and brings about a new model for investigating protein crystallization mechanisms.
Yang H, Belviso BD, Li X, et al., 2019, Optimization of vapor diffusion conditions for anti-CD20 crystallization and scale-up to meso batch, Crystals, Vol: 9, ISSN: 2073-4352
The crystal form is one of the preferred formulations for biotherapeutics, especially thanks to its ability to ensure high stability of the active ingredient. In addition, crystallization allows the recovery of a very pure drug, thus facilitating the manufacturing process. However, in many cases, crystallization is not trivial, and other formulations, such as the concentrate solution, represent the only choice. This is the case of anti-cluster of differentiation 20 (anti-CD20), which is one of the most sold antibodies for therapeutic uses. Here, we propose a set of optimized crystallization conditions for producing anti-CD20 needle-shaped crystals within 24 h in a very reproducible manner with high yield. High crystallization yield was obtained with high reproducibility using both hanging drop vapor diffusion and meso batch, which is a major step forward toward further scaling up the crystallization of anti-CD20. The influence of anti-CD20 storage conditions and the effect of different ions on the crystallization processes were also assessed. The crystal quality and the high yield allowed the first crystallographic investigation on anti-CD20, which positively confirmed the presence of the antibody in the crystals.
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