Optimal control of crystallization of alpha-lactose monohydrate

16 pagesInternational audienceWe present a mathematical model for solvated crystallization of alpha -lactose monohydrate in semi-batch mode. The process dynamics are governed by conservation laws including population, molar and energy balance equations. We present and discuss the model and then control the process with the goal to privilege the production of small particles in specific the range. We compare several specific and unspecific cost functions leading to optimal strategies with significantly different effects on product quality. Control inputs are temperature, feed rate, and the choice of an appropriate crystal seed

Crystallization diagram for antisolvent crystallization of lactose : using design of experiments to investigate continuous mixing- induced supersaturation

This study investigates the effects of key process parameters of continuous mixing-induced supersaturation on the antisolvent crystallization of lactose using D-optimal Design of Experiments (DoE). Aqueous solutions of lactose were mixed isothermally with antisolvents using a concentric capillary mixer. Process parameters investigated were the choice of antisolvent (acetone or isopropanol), concentration of lactose solution, total mass flow rate, and the ratio of mass flow rates of lactose solution and antisolvent. Using a D-optimal DoE a statistically significant sample set was chosen to explore and quantify the effects of these parameters. The responses measured were the solid state of the lactose crystallized, induction time, solid yield and particle size. Mixtures of α-lactose monohydrate and β-lactose were crystallized under most conditions with β-lactose content increasing with increasing amount of antisolvent. Pure α-lactose monohydrate was crystallized using acetone as the antisolvent, with mass flow ratios near 1:1, and near saturated solutions of lactose. A higher resolution DoE was adopted for acetone and was processed using multivariate methods to obtain a crystallization diagram of lactose. The model was used to create an optimized process to produce α-lactose monohydrate and predicted results agreed well with those obtained experimentally, validating the model. The solid state of lactose, induction time, and solid yield were accurately predicted

Laktoosi klasterdumine ja kristalliseerumine: Puhta laktoosi lahuse ja ricotta juustu vadaku eksperimentaaluuring

A Thesis for applying for degree of Doctor of Philosophy in Food ScienceCrystallisation is the main process in lactose production technology. It consists of several steps including formation of primary clusters of molecules, nucleation, growth of nuclei, and further formation of crystals. The aim of the current research work was to improve our knowledge about nucleation process and subsequent growth of lactose primary clusters depending on the temperature and concentration of the solution. The dependence of the lactose crystal final size and shape on the solution pH level and concentration, crystallization temperature and cooling profile were also investigated. The novelty of the present work was in the application of particularly sensitive optical technique (Zetasizer Nano ZS) to measure lactose particle size. This technique enables to measure the size of the smallest lactose particle and trace the growth of primary clusters without altering the original conditions of the sample. Investigation of clustering and crystallisation, using new techniques, will provide answers to numerous questions related to crystallisation of lactose and other sugars, as well as crystallography in general. The second aspect was that ricotta cheese whey was used as a raw material to explore the influence of environmental conditions on crystal shape and size. This raw material is rarely used in lactose production, but recently, stricter environmental requirements have increased interest to it. In Estonia, ricotta cheese whey was studied for the first time. The investigation and use of less traditional source of lactose will have a positive impact on the environment and provide substantial valorisation of these dairy by-products, and thus, have an added value for dairy production in generalLaktoosi tootmise tehnoloogiline põhiprotsess on kristalliseerimine. See sisaldab molekulidest esmaste kogumite ehk klastrite moodustumist, kristallituumade teket, kristallituumade suurenemist ja neist kristallide kujunemist. Käesoleva teadustöö põhieesmärk oli saada uusi teadmisi laktoosi kristalliseerimise algfaasist – laktoosimolekulide võimest moodustada esmaseid klastreid (kristallide algeid) sõltuvalt temperatuurist ja kontsentratsioonist. Samuti uuriti, kuidas mõjutavad laktoosikristallide kasvu ja lõppkuju lahuse pH ning kontsentratsioon, kristalliseerimise temperatuur ja temperatuuri alandamise kiirus. Käesoleva töö uudsus seisneb selles, et esmaste klastrite uurimiseks kasutati ülitäpseid mõõtmisi võimaldavat aparatuuri (Zetasizer Nano ZS), mille tõttu sai määrata üksiku laktoosimolekuli suurust ja jälgida lahusesse sekkumata laktoosiosakeste liitumisprotsessi. Selle protsessi uurimine uue meetodiga annab vastuseid paljudele kristalliseerimisprotsessiga seotud küsimustele nii suhkrute kristalliseerimise kui ka üldiselt kristallograafia alal. Teine aspekt on see, et analüüsides, mille abil uuriti lahuse parameetrite mõju laktoosi kristallide lõppkujule, kasutati toormaterjalina ricotta juustu vadakut, mida seni on laktoosi tööstuslikuks tootmiseks kasutatud suhteliselt harva. Viimastel aastakümnetel on huvi selle tooraine vastu suurenenud. Eestis ei ole seni ricotta vadaku kasutamise problemaatikaga tegeldud. Selle ebatraditsioonilise toormaterjali uurimine ja kasutamine aitab täiuslikumalt väärindada piimandussektoris tekkivaid kõrvalsaadusi ja vähendada keskkonnakoormust

Contrôle de la cristallisation du alpha-lactose monohydraté

National audienceLa cristallisation est une opération utilisée dans différents domaines industriels comme la pharmacie, l'agro-alimentaire ou la chimie fine. Ce processus consiste à isoler un produit en solution pour le récupérer sous forme solide dans l'objectif de conférer au solide synthétisé des spécifications voulues en vue de contrôler ses propriétés d'usage. Un grand intérêt est porté à l'étude du processus de cristallisation afin de le maîtriser, et donc d'améliorer les propriétés du produit final. Un modèle dynamique fiable décrivant les phénomènes mis en jeu est nécessaire pour l'étudier, et appliquer des stratégies de contrôle afin de produire des solides conformes aux cahiers des charges et aux exigences industrielles. Dans ce travail, nous nous intéressons à la cristallisation du α-lactose monohydraté en mode semi-continu avec ensemencement. Le lactose est un sucre réducteur présent dans le lait, qui existe sous deux formes anomériques α et β en solution (mutarotation). La modélisation mathématique de la cristallisation du α-lactose monohydraté comprend le bilan de population sur les cristaux de α-lactose monohydraté, les bilans de matières sur le α-lactose, le β-lactose et l'eau, avec prise en compte de la mutarotation et le bilan d'énergie. Cette étude présente le contrôle du processus de cristallisation selon deux objectifs d'optimisation : minimisation du taux de nucléation et minimisation du coefficient de variation de la distribution de taille en volume

A Process to Produce Lactose Phosphate from Dairy Byproducts And Used as an Alternative to Emulsifying Salts In Processed Cheese Food Manufacture

Lactose is the primary carbohydrate in most mammals\u27 milk, commonly known as milk sugar. Milk permeate is a by-product of whey protein manufacturing through membrane technologies. It is cost-effective, available, and an excellent source of lactose. Sugar phosphorylation is a technique used to alter sugar\u27s characteristics. It has numerous applications for developing dairy and food products. Lactose-6-phosphate (LP) is an organic compound that switches the hydrogen on lactose by monophosphate that has the potential to function as emulsifying salts (ES). ES, such as disodium phosphate (DSP) and trisodium citrate, have a critical effect on the emulsification characteristics of casein by sequestering the calcium from the calcium-paracaseinate phosphate complex in natural cheese during processed cheese (PC) manufacturing. PC is a dairy product manufactured by combining dairy and non-dairy components and heating the mixture with agitation to create a homogenous product with a long shelf life. The first objective of this study was to develop a method to phosphorylate α- lactose (LaP1), and milk permeate powder (LaP2) at specific concentrations that include pH, temperature, and time. A mass spectrometry (MS) was used to define LP in both treatments. Two samples were applied as controls. Control 1 and control 2 were used α-lactose monohydrate and milk permeate powder (MPP), respectively. The amount of lactose was lower in LaP1 (15.58%) and LaP2 (12.20%) compared to control 1 (69.32%) and control 2 (24.64%). However, the level of LP was increased in LaP1 (60.74%) and LaP2 (8.65%), which were 0.89 and 5.53% for control 1 and control 2, respectively. We conclude that lactose and milk permeate can be phosphorylated, and MS can be used to detect lactose and LP. The objective of the second study was to remove the dark color of LaP1 and LaP2 solutions. During the phosphorylation process, the color of the solutions turns dark. Activated carbon has been utilized for decades to remove the dark color and improve the appearance of solutions. The usage of activated carbon has been expanded to include decolorization, gas separation and polluted air treatment, heavy metal recovery, and food processing with no hazard. This methodology is cheap method and environmentally friendly. The compositional characteristics of the solutions, such as pH, total solids (TS), and color parameters (L*- lightness, a*- redness, and b*- yellowness) were examined at different stages (seven stages) of washing the solutions. Both solutions\u27 pH and TS decreased with increasing the number of washings with activated carbon. The L* of the initial solutions was lower than the final solutions. However, the a* and b* of the initial solutions were higher than the final solutions. The total color difference (ΔE) was calculated for both solutions. ΔE was decreased with increasing the number of washings with activated carbon in both solutions. The findings of this study indicate that activated carbon can be used to remove the dark color that results from the phosphorylation process. The objective of the third study was to produce processed cheese food (PCF) with LaP1 (52% TS) instead of DSP. PCF is a dairy product prepared by blending dairy ingredients with non-dairy ingredients and heating the blend with agitation to produce a homogeneous product with an extended shelf-life. The ingredients in the PCF formulations were Cheddar cheese, butter, water, milk permeate powder, and LaP1 (at a ratio of 2.0, 2.4, 2.8, 3.2, 4.0, 5.0, and 6.0%) were formulated to contain 17.0% protein, 25.0% fat, 44.0% moisture, and 2.0% salt. The LP concentrations in LaP1 solutions were ranged between 0.63 to 1.9%. The PCF made with 2.0% DSP was also produced as a control. The PCF was analyzed for moisture, pH, end apparent cooked viscosity, hardness, melted diameter, and melting temperature. The moisture of PCF ranged from 42.3 to 44.0%, with a pH of 5.6 to 5.8. The end apparent cooked viscosity increased from 818.0 to 2060.0 cP as the level of LaP1 solution raised from 2.0 to 6.0%, while it was 660.0 cP in control. The hardness of PCF made with LaP1 elevated from 61.9 to 110.1 g as the level of LaP1 increased; however, it was 85.6 g in control. The melted diameter decreased from 43 mm in control to 29 mm in 6% LaP1, while the melting temperature of PCF increased from 37.7°C in control to 59.0°C in 6% LaP1. We conclude that LaP1 can be utilized as a substitute for DSP in PCF manufacture. The objective of the final study was to produce PCF using LaP2 (70% TS). The amount of LP was 0.48%. The ingredients in the PCF formulations were Cheddar cheese, butter, water, MPP, and LaP2 (8.0%). Those ingredients were formulated to contain 17.0% protein, 25.0% fat, 43.0% moisture, and 2.0% salt. PCF with 2.5% DSP was also produced as a control. The experiment was repeated 5 times using five different batches of LaP2 solutions. The moisture of PCF ranged from 42.61 and 43.09%. The pH was 5.81 for PCF made with LaP2; however, it was 5.74 in control. The cooked viscosity of LaP2 was 2032.0 cP, while it was 1378.0 cP in control. The hardness of PCF made with LaP2 was 154.5 g and 91.6 g in control. The melted diameter decreased from 41.0 mm in control to 34.0 mm in LaP2, while the melting temperature of PCF increased from 43.2°C in control to 46.5°C in LaP2. We conclude that LaP2 can be utilized as a substitute for DSP in PCF manufacture

MECHANOCHEMICAL ACTIVATION OF PHARMACEUTICAL SUBSTANCES AS A FACTOR FOR MODIFICATION OF THEIR PHYSICAL, CHEMICAL AND BIOLOGICAL PROPERTIES

Objective: Study the influence of the mechanical preparation methods (grinding, fluidization) of solid pharmaceutical substances (PS) and herbal raw material on their physicochemical properties and biological activities. Methods: Test substances and solvents-Lactose monohydrate (DFE Pharma, Germany). Sodium chloride, bendazol hydrochloride (all Sigma-Aldrich, USA) and herbal raw material (Callisia fragrans). The dispersity and native structure of pharmaceutical substances were analyzed by several methods: optical microscopy–Altami BIO 2 microscope (Russia); low angle laser light scattering (LALLS) method (Malvern Instruments, UK); Spirotox method–Quasichemical kinetic of cell transition of cellular biosensor Spirostomum ambiguum; Fourier-transform infrared spectroscopy–the analysis in the middle IR region was carried out using an IR Cary 630 Fourier spectrometer (Agilent Technologies, USA). The analysis of dried leaves of C. fragrans before and after mechanical activation was performed using Shimadzu EDX-7000 X-ray fluorescence spectrophotometer without mineralization (Shimadzu, Japan). Results: It was established that the mechanical change, such as dispersion and drying, alters the biological activity of PS and herbal raw materials. The observed increase in the influence of the dispersed substance on the biosensor S. ambiguum is quantitatively estimated from the values of the activation energy (obsEa), which turns to be valued 1,5 (P≤0,05) times more than for the native form substance. In the study of the dependence of the availability of chemical elements K, Ca, Zn on the degree of dispersion of herbal raw materials was established a quantitative 4-fold (P≤0,05) increase in the concentration of elements in mechano-activated raw materials. Conclusion: By the example of the biological model of Spirotox (single-celled biosensor S. ambiguum) and herbal raw materials obtained from C. fragrans, the increase of biological activity of PS at the dispersion of initial preparations was proved

THE STUDY OF LOW-LACTOSE MILK WHEY STRUCTURE AND MODEL SYSTEMS ON ITS BASIS

This study developed a technology of low-lactose semi-finished products, based on fermented whey and pumpkin pulp puree, and offered a possibility of its use in the technology of structured culinary products. This research carried out the required substantiation of the methods of preliminary processing of raw materials, and studied the technological properties and structure of model compositions with their use. During the experiment, a number of studies were carried out, which substantiated the method and modes of condensation of whey, and provided a comparative analysis of the homogeneity of lactose-free and lactose-containing samples of whey under various modes of condensation. The study obtained the results of calculations of the equivalent diameter of the studied samples of lactose-containing and low-lactose whey, condensed by the contact method and in vacuum. It was found, that the structure is homogeneous at a number average crystal diameter of up to 5 μm. The restriction is valid for CLLWV with a calculated diameter of about 3.84 μm with a coefficient of variation of 1.35 % with an increase of 10,000 times. The study revealed the alternation of smooth and granular sections of the micron level (0.1 ... 5 μm) in the structure of the studied low-lactose semi-finished product with an increase of 300 times. It was determined, that the extremum of the differential curve of the particle size distribution of CLLWV corresponds to the number average crystal diameter of 3.84 μm. It was established, that the most homogeneous fractional composition is inherent in the studied sample of CLLWV, for which the values of fraction diameters are in the range from 1.46 μm to 4.96 μm. The optimal ratio of the components of the model CLLWV: FPPP system was determined as 70 % to 30 % respectively. With this composition, the model system is characterized by the formation of protein-pectin complexes, which is confirmed by microscopy with a magnification of 90 time

The Optimisation of Carrier Selection in Dry Powder Inhaler Formulation and the Role of Surface Energetics

This review examines the effects of particle properties on drug–carrier interactions in the preparation of a dry powder inhaler (DPI) formulation, including appropriate mixing technology. The interactive effects of carrier properties on DPI formulation performance make it difficult to establish a direct cause-and-effect relationship between any one carrier property and its effect on the performance of a DPI formulation. Alpha lactose monohydrate remains the most widely used carrier for DPI formulations. The physicochemical properties of α-lactose monohydrate particles, such as particle size, shape and solid form, are profoundly influenced by the method of production. Therefore, wide variations in these properties are inevitable. In this review, the role of surface energetics in the optimisation of dry powder inhaler formulations is considered in lactose carrier selection. Several useful lactose particle modification methods are discussed as well as the use of fine lactose and force control agents in formulation development. It is concluded that where these have been investigated, the empirical nature of the studies does not permit early formulation prediction of product performance, rather they only allow the evaluation of final formulation quality. The potential to leverage particle interaction dynamics through the use of an experimental design utilising quantifiable lactose particle properties and critical quality attributes, e.g., surface energetics, is explored, particularly with respect to when a Quality-by-Design approach has been used in optimisation

Advanced physical characterisation of milled pharmaceutical solids

Milling has been the key unit operation in controlling particle size of pharmaceutical powders at scale. The work carried out in this thesis is a comprehensive study of the stability of pharmaceutical solids post-milling and upon storage, from molecular level up to bulk handling scale. It is an attempt to fill key gaps in knowledge with regard to the anomalous behaviour and physical instability of milled powder through the development of advanced novel techniques. The physical instability of milled or amorphous pharmaceutical powders often manifest in changes in derived powder properties. Moisture induced dimensional changes of amorphous lactose compacts were monitored by in-situ environmental controlled optical profilometry. The complex volumetric behaviour involves glassy-rubbery phase transition followed by amorphous-crystalline transformation under the influence of water. These associated changes were not observed in physical aging of amorphous lactose compacts by measuring specific surface area. At the molecular level these physical changes are governed by relaxation processes. By operating within the linear viscoelastic region, low strain uni-axial indentation of small molecule organic glasses at a range of temperature generated master curves using WLF analysis. Viscoelastic behaviour of these materials were determined to be controlled by local β-relaxation around the glass transition rather than globally for polymers. At the bulk level, due to the non-equilibrium nature of milled and amorphous powders, their surface energies tends to be significantly higher than the equivalent crystalline forms. This can be detrimental as highly cohesive and poor flowing powders are difficult to process. The unconfined compression test was adapted to measure cohesion of small weak pharmaceutical powder compacts. More significantly, a positive relationship was confirmed between surface energetics and cohesion of modified D-mannitol. At the particle level, the mechanism(s) by which milling or micronisation creates low levels of amorphicity remains unclear. MOUDI fractionation of bulk micronised α-lactose monohydrate and characterisation of fine fractions has clearly demonstrated that micronisation as well as mechanical particle size reduction also generates low levels of highly amorphous ultrafine particles within bulk crystalline powder which will have a significant effect on powder physical stability post-milling and upon storage. In conclusion, using the novel techniques developed here, significant progress has been towards understanding the physical behaviour of milled and amorphous pharmaceutical solids

Freeze drying microscopy as a tool to study sublimation kinetics

Freeze-drying is the process of removal of water or organic solvent from a desired product by means of sublimation at a low temperature and low pressure. It is commonly employed for drying samples which are heat labile and require sensitive treatment, and is mainly used in the pharmaceutical and food industries. It is an expensive process, requiring vacuum, refrigeration and long cycle times, but does yield quality benefits due to the low temperatures involved and the porous nature of the product. Reducing drying times is important to manufacturers, and this depends on optimising rates of heat and mass transfer in the system without the sample losing its porous structure. However, freeze drying is difficult to study experimentally due to the low temperatures and pressures involved. The quality of the final product mainly depends on the sublimation rate and an optimum lyophilisation requires identification of the parameters which influence the process. The main aim of this study is to employ freeze drying microscopy (FDM) as a useful tool to identify these process parameters and help optimise primary drying phase of the freeze drying process for two systems: lactose (relevant to pharmaceuticals) and coffee (the most widely freeze-dried food product). This equipment allows the movement of sublimation fronts to be directly visualised in-situ under carefully controlled (and isothermal conditions), but has scarcely been used in the literature for this purpose. An image analysis method is developed to automatically track the movement of sublimation fronts, and the frontal data fitted to a simple mass transfer model employing surface and bulk resistances. Initial experiments with lactose solution show poor reproducibility in nucleation temperatures during the freezing step and thus primary drying rates. To improve reproducibility, a small amount of silver iodide (AgI) was added to samples which acts as a nucleating agent and increases the nucleation temperature. This addition of AgI also increases the mean ice crystal size in the samples and are easily visible under the freeze-drying microscope, and in many cases show a distinct orientation with respect to direction of sublimation front. Furthermore, the orientation greatly influences sublimation rates, being approximately factor of two faster when crystals are oriented in the direction of mass transfer. FDM experiments with coffee were less straightforward as nucleation temperatures could not be reliably controlled, even with AgI added. Nevertheless there was a clear decrease of bulk resistance with increasing nucleation temperature. An experimental programme was then undertaken to examine the impact of initial solid content, cooling rate, the addition of an annealing step, freeze drying temperature and aeration (for coffee samples). Frontal data were fitted to a simple mass transfer model comprising surface and bulk (per unit depth) resistances and good fits to data were obtained. FDM experiments with lactose and coffee clearly showed the presence of a surface resistance which could also be seen as a surface layer which was devoid of ice crystals (and hence not porous when sublimed). The edge resistance first increased and then decreased with solids content. The resistance per unit depth increased exponentially with solids content, so much so that there is an optimal solids content (around 10% solids) in relation of the rate of production of dried material. Cooling rates were mainly found to affect the surface resistance rather than bulk resistance and this may be due to different levels of surface drying when the samples are being cooled for different lengths of time. Annealing substantially changed the ice crystal sizes, and had a beneficial effect on freeze drying rates and had a similar effect to adding AgI. Freeze drying rates also increased with increasing temperature approximately in line with the saturated vapour pressure (SVP) of ice which is widely held to constitute the driving force for mass transfer. It was possible to make drying time calculations for conventional vial (lactose) and tray (coffee) drying using the frontal rate data obtained from FDM. For 10% lactose and 10% coffee (annealed) there was good agreement between the vial and tray data and predictions based on a microstructure oriented parallel to the direction of mass transfer. This was the only case where agreement was found, but also the only case where directionality was observed in FDM. The much faster drying times observed in the vial and tray experiments are thus attributed to directional solidification occurring in these systems, and this was borne out by SEM imaging. Aeration of the coffee samples was also found to substantially reduce drying times. The influence of microstructure on freeze drying rates is thus very clear