Towards desired crystalline product properties: In-situ monitoring of batch crystallization

The objective of industrial crystallization is to obtain a crystalline product which has the desired crystal size distribution, mean crystal size, crystal shape, purity, polymorphic and pseudopolymorphic form. Effective control of the product quality requires an understanding of the thermodynamics of the crystallizing system and the effects of operation parameters on the crystalline product properties. Therefore, obtaining reliable in-line information about crystal properties and supersaturation, which is the driving force of crystallization, would be very advantageous. Advanced techniques, such asRaman spectroscopy, attenuated total reflection Fourier transform infrared (ATR FTIR) spectroscopy, and in-line imaging techniques, offer great potential for obtaining reliable information during crystallization, and thus giving a better understanding of the fundamental mechanisms (nucleation and crystal growth) involved. In the present work, the relative stability of anhydrate and dihydrate carbamazepine in mixed solvents containing water and ethanol were investigated. The kinetics of the solvent mediated phase transformation of the anhydrate to hydrate in the mixed solvents was studied using an in-line Raman immersion probe. The effects of the operation parameters in terms of solvent composition, temperature and the use of certain additives on the phase transformation kineticswere explored. Comparison of the off-line measured solute concentration and the solid-phase composition measured by in-line Raman spectroscopy allowedthe identification of the fundamental processes during the phase transformation. The effects of thermodynamic and kinetic factors on the anhydrate/hydrate phase of carbamazepine crystals during cooling crystallization were also investigated. The effect of certain additives on the batch cooling crystallization of potassium dihydrogen phosphate (KDP) wasinvestigated. The crystal growth rate of a certain crystal face was determined from images taken with an in-line video microscope. An in-line image processing method was developed to characterize the size and shape of thecrystals. An ATR FTIR and a laser reflection particle size analyzer were used to study the effects of cooling modes and seeding parameters onthe final crystal size distribution of an organic compound C15. Based on the obtained results, an operation condition was proposed which gives improved product property in terms of increased mean crystal size and narrowersize distribution.

Monitoring of crystallization processes by using infrared spectroscopy and multivariate methods

Väitöstutkimuksessa on tarkasteltuinfrapunaspektroskopian ja monimuuttujaisten aineistonkäsittelymenetelmien soveltamista kiteytysprosessin monitoroinnissa ja kidemäisen tuotteen analysoinnissa. Parhaillaan kiteytysprosessitutkimuksessa maailmanlaajuisesti tutkitaan intensiivisesti erilaisten mittausmenetelmien soveltamista kiteytysprosessin ilmiöidenjatkuvaan mittaamiseen niin nestefaasista kuin syntyvistä kiteistäkin. Lisäksi tuotteen karakterisointi on välttämätöntä tuotteen laadun varmistamiseksi. Erityisesti lääkeaineiden valmistuksessa kiinnostusta tämäntyyppiseen tutkimukseen edistää Yhdysvaltain elintarvike- ja lääkeaineviraston (FDA) prosessianalyyttisiintekniikoihin (PAT) liittyvä ohjeistus, jossa määritellään laajasti vaatimukset lääkeaineiden valmistuksessa ja tuotteen karakterisoinnissa tarvittaville mittauksille turvallisten valmistusprosessien takaamiseksi. Jäähdytyskiteytyson erityisesti lääketeollisuudessa paljon käytetty erotusmenetelmä kiinteän raakatuotteen puhdistuksessa. Menetelmässä puhdistettava kiinteä raaka-aine liuotetaan sopivaan liuottimeen suhteellisen korkeassa lämpötilassa. Puhdistettavan aineen liukoisuus käytettävään liuottimeen laskee lämpötilan laskiessa, joten systeemiä jäähdytettäessä liuenneen aineen konsentraatio prosessissa ylittää liukoisuuskonsentraation. Tällaiseen ylikylläiseen systeemiin pyrkii muodostumaan uusia kiteitä tai olemassa olevat kiteet kasvavat. Ylikylläisyys on yksi tärkeimmistä kidetuotteen laatuun vaikuttavista tekijöistä. Jäähdytyskiteytyksessä syntyvän tuotteen ominaisuuksiin voidaan vaikuttaa mm. liuottimen valinnalla, jäähdytyprofiililla ja sekoituksella. Lisäksi kiteytysprosessin käynnistymisvaihe eli ensimmäisten kiteiden muodostumishetki vaikuttaa tuotteen ominaisuuksiin. Kidemäisen tuotteen laatu määritellään kiteiden keskimääräisen koon, koko- ja muotojakaumansekä puhtauden perusteella. Lääketeollisuudessa on usein vaatimuksena, että tuote edustaa tiettyä polymorfimuotoa, mikä tarkoittaa molekyylien kykyä järjestäytyä kidehilassa usealla eri tavalla. Edellä mainitut ominaisuudet vaikuttavat tuotteen jatkokäsiteltävyyteen, kuten mm. suodattuvuuteen, jauhautuvuuteen ja tabletoitavuuteen. Lisäksi polymorfiamuodolla on vaikutusta moniin tuotteen käytettävyysominaisuuksiin, kuten esim. lääkeaineen liukenemisnopeuteen elimistössä. Väitöstyössä on tutkittu sulfatiatsolin jäähdytyskiteytystä käyttäen useita eri liuotinseoksia ja jäähdytysprofiileja sekä tarkasteltu näiden tekijöiden vaikutustatuotteen laatuominaisuuksiin. Infrapunaspektroskopia on laajalti kemian alan tutkimuksissa sovellettava menetelmä. Siinä mitataan tutkittavan näytteenmolekyylien värähtelyjen aiheuttamia spektrimuutoksia IR alueella. Tutkimuksessa prosessinaikaiset mittaukset toteutettiin in-situ reaktoriin sijoitettavalla uppoanturilla käyttäen vaimennettuun kokonaisheijastukseen (ATR) perustuvaa Fourier muunnettua infrapuna (FTIR) spektroskopiaa. Jauhemaiset näytteet mitattiin off-line diffuusioheijastukseen (DRIFT) perustuvalla FTIR spektroskopialla. Monimuuttujamenetelmillä (kemometria) voidaan useita satoja, jopa tuhansia muuttujia käsittävä spektridata jalostaa kvalitatiiviseksi (laadulliseksi) tai kvantitatiiviseksi (määrälliseksi) prosessia kuvaavaksi informaatioksi. Väitöstyössä tarkasteltiin laajasti erilaisten monimuuttujamenetelmien soveltamista mahdollisimman monipuolisen prosessia kuvaavan informaation saamiseksi mitatusta spektriaineistosta. Väitöstyön tuloksena on ehdotettu kalibrointirutiini liuenneen aineen konsentraation ja edelleen ylikylläisyystason mittaamiseksi kiteytysprosessin aikana. Kalibrointirutiinin kehittämiseen kuuluivat aineiston hyvyyden tarkastelumenetelmät, aineiston esikäsittelymenetelmät, varsinainen kalibrointimallinnus sekä mallin validointi. Näin saadaan reaaliaikaista informaatiota kiteytysprosessin ajavasta voimasta, mikä edelleen parantaa kyseisen prosessin tuntemusta ja hallittavuutta. Ylikylläisyystason vaikutuksia syntyvän kidetuotteen laatuun seurattiin usein kiteytyskokein. Työssä on esitetty myös monimuuttujaiseen tilastolliseen prosessinseurantaan perustuva menetelmä, jolla voidaan ennustaa spontaania primääristä ytimenmuodostumishetkeä mitatusta spektriaineistosta sekä mahdollisesti päätellä ydintymisessä syntyvä polymorfimuoto. Ehdotettua menetelmää hyödyntäen voidaan paitsi ennakoida kideytimien muodostumista myös havaita mahdolliset häiriötilanteet kiteytysprosessin alkuhetkillä. Syntyvää polymorfimuotoa ennustamalla voidaan havaita ei-toivotun polymorfin ydintyminen,ja mahdollisesti muuttaa kiteytyksen ohjausta halutun polymorfimuodon saavuttamiseksi. Monimuuttujamenetelmiä sovellettiin myös kiteytyspanosten välisen vaihtelun määrittämiseen mitatusta spektriaineistosta. Tämäntyyppisestä analyysistä saatua informaatiota voidaan hyödyntää kiteytysprosessien suunnittelussa ja optimoinnissa. Väitöstyössä testattiin IR spektroskopian ja erilaisten monimuuttujamenetelmien soveltuvuutta kidetuotteen polymorfikoostumuksen nopeaan määritykseen. Jauhemaisten näytteiden luokittelu eri polymorfeja sisältäviin näytteisiin voitiin tehdä käyttäen tarkoitukseen soveltuvia monimuuttujaisia luokittelumenetelmiä. Tämä tarjoaa nopean menetelmän jauhemaisen näytteen polymorfikoostumuksen karkeaan arviointiin, eli siihen mitä yksittäistä polymorfia kyseinen näyte pääasiassa sisältää. Varsinainen kvantitatiivinen analyysi, eli sen selvittäminen paljonko esim. painoprosentteina näyte sisältää eri polymorfeja, vaatii kaikki polymorfit kattavan fysikaalisen kalibrointisarjan, mikä voi olla puhtaiden polymorfien huonon saatavuuden takia hankalaa.

The influence of crystallization conditions on the filtration characteristics of sulphathiazole suspensions

Cooling crystallization is one of the most important purification and separation techniques in the chemical and pharmaceutical industry. The product of the cooling crystallization process is always a suspension that contains both the mother liquor and the product crystals, and therefore the first process step following crystallization is usually solid-liquid separation. The properties of the produced crystals, such as their size and shape, can be affected by modifying the conditions during the crystallization process. The filtration characteristics of solid/liquid suspensions, on the other hand, are strongly influenced by the particle properties, as well as the properties of the liquid phase. It is thus obvious that the effect of the changes made to the crystallization parameters can also be seen in the course of the filtration process. Although the relationship between crystallization and filtration is widely recognized, the number of publications where these unit operations have been considered in the same context seems to be surprisingly small. This thesis explores the influence of different crystallization parameters in an unseeded batch cooling crystallization process on the external appearance of the product crystals and on the pressure filtration characteristics of the obtained product suspensions. Crystallization experiments are performed by crystallizing sulphathiazole (C9H9N3O2S2), which is a wellknown antibiotic agent, from different mixtures of water and n-propanol in an unseeded batch crystallizer. The different crystallization parameters that are studied are the composition of the solvent, the cooling rate during the crystallization experiments carried out by using a constant cooling rate throughout the whole batch, the cooling profile, as well as the mixing intensity during the batch. The obtained crystals are characterized by using an automated image analyzer and the crystals are separated from the solvent through constant pressure batch filtration experiments. Separation characteristics of the suspensions are described by means of average specific cake resistance and average filter cake porosity, and the compressibilities of the cakes are also determined. The results show that fairly large differences can be observed between the size and shape of the crystals, and it is also shown experimentally that the changes in the crystal size and shape have a direct impact on the pressure filtration characteristics of the crystal suspensions. The experimental results are utilized to create a procedure that can be used for estimating the filtration characteristics of solid-liquid suspensions according to the particle size and shape data obtained by image analysis. Multilinear partial least squares regression (N-PLS) models are created between the filtration parameters and the particle size and shape data, and the results presented in this thesis show that relatively obvious correlations can be detected with the obtained models.

Supersaturation-controlled crystallization

Identification of product requirements and quality, together with the management of production are key issues in chemical engineering. Quality control of crystalline products is part of the quality of many industrially manufactured products like paper, paintings, medicines and fertilizers. In most crystallization cases, quality is described with the size, polymorph, shape and purity of the crystal. The chemical composition, hydrodynamics and driving force, together with the operating temperature are in a key position when the properties of a crystalline product are controlled with the crystallization process. This study concentrates on managing the identified properties of a crystalline product with the control of a driving force. The controlling of the driving force can be based on the change of solubility or the change of concentration. Solubility can be changed with temperature, pressure and an antisolvent. The concentration of crystallizing compound, the solute can be changed with the evaporation of the solvent and with the addition of a reagent. The present study focuses on reagent addition and temperature change as methods of changing the level of the driving force. Three control structures for direct control of supersaturation are built, one for cooling crystallization and two for reactive crystallization. Closed loop feedback control structures are based on the measurement of the solute concentration with attenuated total reflection - Fourier transform infrared spectrometer. The details of the reagent feed are analyzed with experimental studies and with results of computational fluid dynamic simulations of the inert particle pulse in the premixer and inert particle injection to the mixing tank. Nucleation in conditions of controlled reactive crystallization is analyzed with Nielsen’s equation of homogeneous nucleation. The resulting control systems, based on regulation of supersaturation, can be used to produce the desired polymorph of an organic product. The polymorph composition of product crystals is controlled repeatably with the decision of a set value of supersaturation level.

Effect of hydrodynamics on modelling, monitoring and control of crystallization

Crystallization is a purification method used to obtain crystalline product of a certain crystal size. It is one of the oldest industrial unit processes and commonly used in modern industry due to its good purification capability from rather impure solutions with reasonably low energy consumption. However, the process is extremely challenging to model and control because it involves inhomogeneous mixing and many simultaneous phenomena such as nucleation, crystal growth and agglomeration. All these phenomena are dependent on supersaturation, i.e. the difference between actual liquid phase concentration and solubility. Homogeneous mass and heat transfer in the crystallizer would greatly simplify modelling and control of crystallization processes, such conditions are, however, not the reality, especially in industrial scale processes. Consequently, the hydrodynamics of crystallizers, i.e. the combination of mixing, feed and product removal flows, and recycling of the suspension, needs to be thoroughly investigated. Understanding of hydrodynamics is important in crystallization, especially inlargerscale equipment where uniform flow conditions are difficult to attain. It is also important to understand different size scales of mixing; micro-, meso- and macromixing. Fast processes, like nucleation and chemical reactions, are typically highly dependent on micro- and mesomixing but macromixing, which equalizes the concentrations of all the species within the entire crystallizer, cannot be disregarded. This study investigates the influence of hydrodynamics on crystallization processes. Modelling of crystallizers with the mixed suspension mixed product removal (MSMPR) theory (ideal mixing), computational fluid dynamics (CFD), and a compartmental multiblock model is compared. The importance of proper verification of CFD and multiblock models is demonstrated. In addition, the influence of different hydrodynamic conditions on reactive crystallization process control is studied. Finally, the effect of extreme local supersaturation is studied using power ultrasound to initiate nucleation. The present work shows that mixing and chemical feeding conditions clearly affect induction time and cluster formation, nucleation, growth kinetics, and agglomeration. Consequently, the properties of crystalline end products, e.g. crystal size and crystal habit, can be influenced by management of mixing and feeding conditions. Impurities may have varying impacts on crystallization processes. As an example, manganese ions were shown to replace magnesium ions in the crystal lattice of magnesium sulphate heptahydrate, increasing the crystal growth rate significantly, whereas sodium ions showed no interaction at all. Modelling of continuous crystallization based on MSMPR theory showed that the model is feasible in a small laboratoryscale crystallizer, whereas in larger pilot- and industrial-scale crystallizers hydrodynamic effects should be taken into account. For that reason, CFD and multiblock modelling are shown to be effective tools for modelling crystallization with inhomogeneous mixing. The present work shows also that selection of the measurement point, or points in the case of multiprobe systems, is crucial when process analytical technology (PAT) is used to control larger scale crystallization. The thesis concludes by describing how control of local supersaturation by highly localized ultrasound was successfully applied to induce nucleation and to control polymorphism in reactive crystallization of L-glutamic acid.

Influence of multi-phase phenomena on semibatch crystallization processes of aqueous solutions

Crystal properties, product quality and particle size are determined by the operating conditions in the crystallization process. Thus, in order to obtain desired end-products, the crystallization process should be effectively controlled based on reliable kinetic information, which can be provided by powerful analytical tools such as Raman spectrometry and thermal analysis. The present research work studied various crystallization processes such as reactive crystallization, precipitation with anti-solvent and evaporation crystallization. The goal of the work was to understand more comprehensively the fundamentals, phenomena and utilizations of crystallization, and establish proper methods to control particle size distribution, especially for three phase gas-liquid-solid crystallization systems. As a part of the solid-liquid equilibrium studies in this work, prediction of KCl solubility in a MgCl2-KCl-H2O system was studied theoretically. Additionally, a solubility prediction model by Pitzer thermodynamic model was investigated based on solubility measurements of potassium dihydrogen phosphate with the presence of non-electronic organic substances in aqueous solutions. The prediction model helps to extend literature data and offers an easy and economical way to choose solvent for anti-solvent precipitation. Using experimental and modern analytical methods, precipitation kinetics and mass transfer in reactive crystallization of magnesium carbonate hydrates with magnesium hydroxide slurry and CO2 gas were systematically investigated. The obtained results gave deeper insight into gas-liquid-solid interactions and the mechanisms of this heterogeneous crystallization process. The research approach developed can provide theoretical guidance and act as a useful reference to promote development of gas-liquid reactive crystallization. Gas-liquid mass transfer of absorption in the presence of solid particles in a stirred tank was investigated in order to gain understanding of how different-sized particles interact with gas bubbles. Based on obtained volumetric mass transfer coefficient values, it was found that the influence of the presence of small particles on gas-liquid mass transfer cannot be ignored since there are interactions between bubbles and particles. Raman spectrometry was successfully applied for liquid and solids analysis in semi-batch anti-solvent precipitation and evaporation crystallization. Real-time information such as supersaturation, formation of precipitates and identification of crystal polymorphs could be obtained by Raman spectrometry. The solubility prediction models, monitoring methods for precipitation and empirical model for absorption developed in this study together with the methodologies used gives valuable information for aspects of industrial crystallization. Furthermore, Raman analysis was seen to be a potential controlling method for various crystallization processes.

On the Properties and Cosmology of Q-balls

The properties and cosmological importance of a class of non-topological solitons, Q-balls, are studied. Aspects of Q-ball solutions and Q-ball cosmology discussed in the literature are reviewed. Q-balls are particularly considered in the Minimal Supersymmetric Standard Model with supersymmetry broken by a hidden sector mechanism mediated by either gravity or gauge interactions. Q-ball profiles, charge-energy relations and evaporation rates for realistic Q-ball profiles are calculated for general polynomial potentials and for the gravity mediated scenario. In all of the cases, the evaporation rates are found to increase with decreasing charge. Q-ball collisions are studied by numerical means in the two supersymmetry breaking scenarios. It is noted that the collision processes can be divided into three types: fusion, charge transfer and elastic scattering. Cross-sections are calculated for the different types of processes in the different scenarios. The formation of Q-balls from the fragmentation of the Aflieck-Dine -condensate is studied by numerical and analytical means. The charge distribution is found to depend strongly on the initial energy-charge ratio of the condensate. The final state is typically noted to consist of Q- and anti-Q-balls in a state of maximum entropy. By studying the relaxation of excited Q-balls the rate at which excess energy can be emitted is calculated in the gravity mediated scenario. The Q-ball is also found to withstand excess energy well without significant charge loss. The possible cosmological consequences of these Q-ball properties are discussed.

Properties of slow-release phosphorus fertilizers with special references to their use on drained peatland forests : A review

Tiivistelmä: Hidasliukoisten fosforilannoitteiden ominaisuudet ja käyttökelpoisuus suometsien lannoituksessa. Kirjallisuuteen perustuva tarkastelu

Effects of composite casein and [beta]-lactoglobulin genotypes on renneting properties and composition of bovine milk by assuming an animal model

Selostus: Kaseiinien yhdistelmägenotyyppien ja [beta]-laktoglobuliinin genotyyppien vaikutus maidon juoksettumisominaisuuksiin ja koostumukseen

The functional and biological properties of whey proteins : prospects for the development of functional foods

Selostus: Heraproteiinit terveysvaikutteisten elintarvikkeiden kehittämisessä

Properties of top soil and the relationship between soil and trees in a boreal Scots pine stand

Summary