Finding Strategies for Controlling the Size of Paracetamol Crystals - Assignment Example

Name: Course: Tutor: Date: Finding Strategies for Controlling the Size of Paracetamol Crystals Introduction Crystallization Crystallization kinetics is the process of nucleation and crystal growth. For a crystal to be formed it has to undergo nucleation then growth to the desired levels (Jancic & Grootscholten 1984). Crystallization is the formation of an ordered structure from a solution or a melt (disordered structure phase). It is a representation of the mix between growth and nucleation. Crystallization is made possible by cooling down a semi crystalline polymer at specific temperatures or by adding solutions that reduce solubility and enhance crystallization. It begins from a discrete point, the nuclei, and progresses to spherulite formed from growth of the crystal around the nuclei. The process of crystallization is complete when all the spherulites meet other neighbouring spherulites (Brahmia 2006) Crystallization kinetics consists of primary nucleation and secondary nucleation just as has been noted. Primary nucleation involves a number fluctuation of particles formed at a nucleus size formed at high super saturations (cooling surfaces/boiling zones/ where generation of super saturation exceeds dissipation of super saturation). Secondary nucleation is a number fluctuation of a band of particles generated as a result of the presence of a parent crystal (Jancic & Grootscholten 1984). Formation of pharmaceutical compounds is mostly done by crystallization especially through cooling. Cooling crystallization ensures high yield and high purity of the products and can also be controlled to give a correct physical form of a product that dries and filters easily (Parsons et al 2003). Crystallization of paracetamol has two important principles which are nucleation and growth. The initial step in crystallization of paracetamol in ethanol is dissolution of the solvent and the solute at a specific temperature (60°c). This first solvent is saturated at 55°c then kept at 60°c for complete dissolution. The next step is cooling below the solubility level which is 50°c with an addition of a 1 gram crystal. The temperature is held constant then cooling done by a non-linear cooling ramp. After the cooling step, the temperature cycling step follows then addition of an anti-solvent. Water acts as anti-solvent in paracetamol crystallization and is added to decrease solubility hence crystallize paracetamol. The temperature and total mass profiles in the reactor are plotted. The program used for plotting such kind of data has to be selected (Worlitschek & De Buhr 2005). The crystallization kinetics and crystal population events determine the development of a population of crystals, in a vessel/reactor. Crystallization equipments assist in formation of desired crystals. They therefore have to be designed and operated in an efficient manner. For this to be done, the principles that control crystal formation have to be considered which are nucleation and crystal growth. Reactors Used in Crystallization Several reactors are used in crystallization and there are four types of reactors. These include; semi batch reactor, mixed flow reactor, batch reactor and plug flow reactor. Examples of reactors include automated lab reactors such as Auto Lab TM from Hertfordshire UK, LabMax R from Mettler-Tolledo, an Advantage Series TM from Argonaut Technologies in Red wood City, CA (Ekaterini & Andreas 2006). In an experiment on paracetamol crystallization, a semi-batch reactor known as HEL semi-batch reactor was used. Chemical Formula for the Paracetamol Crystallization Reaction. This product is obtained by crystallization of 4-Acetamino-phenol in ethanol (Worlitschek & Buhr 2005) which yields paracetamol of the structure shown. 4-Acetamino-phenol + ethanol (Crystallization) = Paracetamol. Paracetamol crystallization is a process similar to other pharmaceutical compounds’ crystallization. It begins with nucleation then crystals are grown. Its crystallization is done by cooling. The reactors therefore used in such a process are as have been mentioned, the Automated lab reactors. Automated lab reactors are used by so many pharmaceutical companies. Parsons and his colleagues of AstraZeneca, Macclesfield, Cheshire UK are an example of people and companies who have used this kind of reactor in an experiment used to determine the meta-stable zone of paracetamol (Parsons et al 2003). Crystallization Equations Crystallization involves growth rates of the crystals and conditions of crystal growth therefore have kinetic and thermodynamic equations. There is saturation ratio needed for forming solutions for growth and nucleation. Saturation ratio is calculated by S= c⁄c* (Nývlt et al 2002). The overall mass growth rate of a crystal is symbolized by RG and is given by this equation; RG =1⁄AC.dMc⁄dt. Another way of expressing growth rate is through face growth which is “the velocity of advance of the crystallographic face, measured perpendicular to the face and hence has the same dimension as velocity (Nývlt et al 2002: 14). Overall linear growth is another growth rate measurement and is calculated by GL=dL⁄dt. Growth rate expressions link growth rate to super saturation. The relation between overall concentration driving force and overall growth rate is as follows; RG= KG. (C∞-C*)g =KG.ΔCg . KG is the growth rate constant while g is the overall order of the growth process. C∞ is the intermediate driving force while C* is the equilibrium value (Nývlt et al 2002: 14). Some other equations involved in determination of crystal size distribution include M (L) =100 [1+Z+Z2/2+Z3/6]EXP(-Z) and dIn K/dT=ΔHѳ/RT2. There are several equations used in the crystallization process depending on the crystallizer and what is to be determined. (Word Count 855) Literature Review The HEL Batch Reactor and WinIso Program Tests or experiments done using Batch crystallisation are very important when conducted properly. They provide quick generation of data and are less demanding on operators and bulk material. This applies to those with scales of about 0.25-5litres. A semi batch process is where the addition of one or two reactants to the reactor is done continuously. The reactive Crystallization equation of such a process is as follows “A + B 􀃆 C↓ + D”. From the equation; A and B are reactants, C is a sparingle soluble solute while D forms a solute with high solubility (Louhi-Kultanen, 2008). HEL is a company that has several automated batch reactors which are used in crystallization. For a half-litre batch reactor, the process of adding the reagents to the reactors matters but the automated machine is just like a batch reactor. A batch reactor for example the Litre batch reactor should contain programmable re-circulating water bath, a jacketed glass vessel with a height/diameter ratio of approximately 1-2, a reflux condenser if only important, a glass lead to minimize evaporation, a thermometer or an immersed thermocouple, a multi blade axial flow impeller, a quarter to half a diameter above the vessel base, a sampling pot which helps prevent interruption of thermocouple, agitator or dip tube by withdrawing sample representatives from the slurry and an impeller with a diameter of one third or one half that of the diameter of the vessel (Korovessi & Linninger 2006). The HEL semi batch reactor belongs to the group of machines known as process scale-up auto-lab. This group has the capability of allowing parallel and multiple liquid and gases feeds. In addition, the reactors in this group allow control and measurement of temperature, agitation rates and pressure (HEL Product Overview 2009). A HEL auto lab reactor allows setting of cooling and heating profiles which are controlled by the temperature of the jacket or by the reactor itself and also allows control of concentration. Lowering of concentration for example is done by charging the solvent to the reactor. This auto lab reactor can be adapted to a turbidity meter and some other automation machines that support the process of crystallization. The turbidity meter is for the measurement of turbidity, but other components such as online monitoring tools have different functions (Parsons et al 2003). This auto lab reactor gives repeatable and precise control of the reaction variables like the temperature, pressure and many others. It automates the normal paracetamol crystallization procedures such as PH control, dosing and many others and allows very quick optimization of significant variables of the reaction for example dosing rate, solvent, catalyst, pressure and many others (Worlitschek & De Buhr 2005). The Auto lab from HEL can be combined with online monitoring tools to enable quick understanding of the effect of key parameters on the crystallization process (Worlitschek & De Buhr 2005) A program such as Win-Iso is important in the experiment of paracetamol crystallization as it enables data management therefore control of the process. Win-Iso is a software package that enables conversion of BIN to ISO. It has the capability of creating; extracting and editing ISO files directly, capability of making bootable CDs and is a BIN/ISO extractor, editor and converter. With these properties, this CD-ROM image utility file enables addition, renaming, deletion and even extraction of files in the image files during the crystallization process (WinIso 2005). Since measurement of crystallization thermodynamic processes and kinetic processes require standard measurements, Win-Iso is an appropriate tool as it allows conversion of image files to standard ISO formats which is important for analysis and control of the process especially during size determination. The systems operation requires Windows 98/98SE, Windows NT4, Windows 95, Windows Me, Windows XP or Windows 2000 (WinIso 2005). The Meta-stable Zone, Nucleus radius and Surface Tension of the crystal In a crystallization process meta-stable zone determination is important. The meta-stable zone is a region where crystals will grow due to favorable conditions but new crystals due to nucleation will not form (Parsons et al 2003). Rates of crystal growth and nucleation must be controlled for the formation of paracetamol. The aim of this control is to ensure formation of enough small crystals required for further growth of the crystals without further nucleation. For this kind of control to take place, knowledge about the conditions (concentrations and temperature) under which crystal growth and nucleation takes place has to be available (Parsons et al 2003). Crystal growth to final quality crystals is also affected by the surface tension of the solution. The surface tension driven convention is high when the natural conventions are reduced. This means that the there is a relationship between the crystal growth and surface tension of thermo capillary conventions. The meta-stable zone width affects the probability of formation of unwanted nucleation and the seeding applicability (Parson’s et al 2003). This means that the nucleus radius is important in crystal growth. The critical nucleus radius is that radius required for a seed that will be used for initiating crystal growth. Factors Affecting the Product Size Crystallizers meant for producing crystals are always expected to produce solids of a specific composition as well as solids of a certain size distribution. Size distribution determines the size of the crystal and is affected by several factors. These include friability, density, irregularity, particle shape and agglomeration (Nývlt et al 2002). The size of a crystal is measured based on the physical properties of the two phase flow of liquids and solids (for example optical and electrical conductivity) or on the mechanical separation techniques such as sieving and sedimentation (Nývlt et al 2002). How to Control Paracetamol Crystal Size Controlling the crystal size therefore is based on controlling the rate of crystal growth and other factors that affect crystal size. Growth rate can be controlled by knowledge of the ways of expressing growth rates. Growth rates of a population of crystals can be expressed in three ways, that is, the face growth rate symbolized by Vhki (the velocity of advance of the crystallographic face), the overall mass growth rate of a population of crystals and the overall linear growth rate. The overall mass growth rate is given by RG =1⁄AC.dMc⁄dt while the linear growth rate is given by GL=dL⁄dt. This is the rate of change of L of the crystal where L has to be defined by the crystal kinetic and thermodynamic characteristics. This linear growth rate can be used to control the size of the crystals in batch crystalisers as well as continuous crystalisers (Nyvlt et al 2002). One other way of controlling the crystal size is through the control of crystal size distribution. This can be done through in-situ control of the crystal distribution size where the meta-stable limit, the operation of concentration controlled by batch crystallization, and the solubility curve have to be determined. The solubility curve of paracetamol in water and the solution concentration can be determined by “chemometrics in combination with attenuated total reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy” (Briggeler et al 2005). Laser backscattering and attenuated total reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy can be used to determine the meta-stable zone width. This width determines the size of the crystals required among other factors. It is therefore important to control the batch crystalisers in a manner that can produce the desired size after determination of what width is appropriate for a specific size of crystal. Control of paracetamol crystal size requires control of super saturation within the meta-stable limit. This produces larger crystals with uniform size. This is done by use of the in-situ solution measurements obtained from the ATR-FTIR spectroscopy (Briggeler et al 2005). Effective control of the operating conditions for example the super saturation levels, operating pressure and temperature, type of solvent, type of concentrations, degree of geometry, degree of mixedness, seeding policies, the mode of operation of the crystallizer and the type of impurities, lead to desired paracetamol crystal product (Briggeler et al 2005). Problems Encountered by Workers in Paracetamol Crystallization This process is where workers in production of crystals experience problems. Controlling the crystal size distribution is always a problem (Dhanasekharan et al 2005). Kinetics determines the size of the crystal and not thermodynamics (Jancic, Paulus A. M. Grootscholten). Problems of industrial crystallization therefore include: matching design configuration and the operation conditions to the crystallizing system such that the crystallization kinetics and the population work out to produce the design specifications. Design specifications come from market demands and process requirements (Jancic &Grootscholten 1984). (Word Count 1422) Theory How to Find the Meta-stable Zone When developing crystallization process for pharmaceutical compounds it is appropriate to find the conditions under which the crystals will grow as well as its nucleation. In most cases of the processes such data is not always available, automated methods have since been developed to find out the metastable zone for crystallization growth and control. In order to measure a metastable zone the auto lab reactor has to be used with a turbidity meter (Parsons et al 2003) or with any device that assists in measurement of meta-stable zone. Turbidity is the amount of solid crystals in a solution. The process that utilizes an automated programme as follows is appropriate; the initial mixture is stirred at room temperature then heated to the boiling point of the solvent or the required temperature for complete solution, cooling then is done at a temperature that the solute is known to be out o the solution and a solvent is then added. Stirring and heating at a required temperature is done again. Turbidity is then measured. Measurement of turbidity is done by use of a turbidity meter and the gain of the meter has to be optimized before any measurements are taken. The probe is zeroed where the reactor is filled with the solvent at room temperature. The probe offset is adjusted to a level of zero output or approximately zero. Values around 10 are more appropriate as they allow for reduction in readings because of external factors for example background light and effects from temperature (Parsons et al 2003). The programme begins at the point where the solution’s initial concentration is charged to the reactor and the solvent made available to the pump feed. This process takes 48 hours after which data from the auto lab can be fed to the Excel or any chosen software for data analysis. Wincalc could be used as well as WinIso. These programmes help analyse data to obtain the cloud and the clear points. Cloud point is the first appearance of a solid crystal after the process of cooling in determination of super solubility. Clear point is the point obtained after heating the solvent and the solute until there is complete dissolution (Parsons et al 2003). The meta-stable zone can therefore be obtained from such data since the measurement of temperature, pressure and other variables are known at the cloud and clear points. The point between clear point and cloud point is the meta-stable zone. Requirements of this zone can easily be determined. If for example the auto lab out put indicates a turbidity of 100 as solution being cloudy and turbidity 7 as solution being clear, a reduction in turbidity fro 100 to 7 therefore gives the temperature and concentration of the solution at which the clear point is obtained or at which the crystals all dissolve. An increase in the same manner gives the temperature and concentrations at which crystals form from the solution (Parsons et al 2003). If extra steps in the crystalisation process are required, the auto lab programme can be changed. This is because the size and the shape of the crystals matter in most cases of pharmaceutical products. This process should ensure optimization of speed and type of agitator which in turn ensures suspension of all solids. The rate of heating and cooling determines the clear and cloud points (Parsons et al 2003). Nyvlt Equation and Van’t Hoff’s Equation and their Importance The sizes of the crystals have to be determined. This can be done by use of Nyvlt equation and Van’t Hoff’s equation. Nyvlt equation is used to measure the crystal size distribution and is written as M (L) =100 [1+Z+Z2/2+Z3/6] EXP(-Z). This Nyvlt equation is used to calculate the crystal size distribution at the end of each batch experiment (14th International Symposium on Industrial Crystallization 1999: 2). In the equation, Z=3 (L-LN)/(Lrz-LN). M(L0 is the weight fraction that is used to calculated z values that are determined by use of the z-L straight line (14th International Symposium on Industrial Crystallization 1999: 2) Paracetamol crystals have to be of a specific size, in the process therefore, their size have to be determined. The equation is used to measure the distribution of the crystals in the cooling batch crystallizer. This cumulative size distribution also helps in determination of specific required sizes of the crystals. The Van’t Hoff equation used in chemical dynamics is as follows. dIn K/dT=ΔHѳ/RT2. ΔHѳ is sometimes written as W and represents the quantity of heat evolved during a reaction. T is the absolute temperature. This equation is important in crystallization as it can be used to determine the molecular weight of dissolved substances (Van’t Hoff 1901: 9). Molecular weight equation and crystal size distribution determination equations are important as they help in determination of the conditions required during specific size crystal growth in batch crystallization processes. Other Methods of Calculating Crystal Size Distribution and Molecular Mass Another way of determining crystal size is the use of continuous crystalisers (MSMPR) that can also be used to describe particle size distribution in a batch cooling crystallizer (14th International Symposium on Industrial Crystallization 1999). The crystallizer mixes the solution with homogeneous conditions of temperature, pressure, velocity and other conditions necessary for crystallization. Super saturation is obtained by cooling and the nuclei of the crystals form and crystals grow. The slurry has a crystal size distribution so that the product has exactly the same composition as the vessel (Jones 2002). The crystallizer is modeled based on the rate expressions and the conservation equation. The conservation equation is as follows; “Input=Output +Accumulation-Net Generation” (Jones 2002: 66). The crystalisers determine the total crystal mass of solids formed through the equation Change in concentration (inlet-outlet) = Mass yield. Solid matter distribution within the crystallizer is determined by use of another equation of the population balance (Y=Mh (Ci-Co). Ci is the concentration inlet while Co is the concentration outlet. This equation calculates the overall mass balance. Crystallization kinetics and the crystallizer’s residence time predict the crystal size distribution (Jones 2002). The PAT Process In crystallization processes, there is a system that controls it known as PAT. PAT aims to control crystal size distribution, crystal purity, crystal morphology and polymorphism. By this it monitors and controls the crystallization process and scale-up batch crystallization process. PAT requires understanding of the process of crystallization which include fluid mechanics, overall super saturation profile, solid and liquid physical and chemical properties and interactive effects of mixing which are used in the crystal size distribution and scale-up control (Dhanasekharan et al 2005). According to information about PAT in control of the semi-batch crystallization process, the ATR-FTIR is important in the determination of concentrations of the solution used in paracetamol crystallization. In the above determination of crystal size for example, crystal size distribution is determined through in-situ control of crystal size distribution by use of with attenuated total reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy. This is important in determination of paracetamol solution concentration and the solubility curve of paracetamol in water. It is also noted that Laser backscattering and attenuated total reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy can be used to determine the meta-stable zone width (Briggeler et al 2005). Polymorphic compositions can be determined by use of Raman Spectroscopy in solid phase (Louhi-Kultanen). According to Dhanasekharan et al (2005), Computational Fluid Dynamics is important in studying the effect of non-ideal mixing and fluid mechanics. Computational Fluid Dynamics technology has the ability to predict mixing and fluid flow characteristics therefore very important in the crystallization process. It can enable different scale mixing and can be used to predict crystal size distribution with the availability of crystallization kinetics (Dhanasekharan et al 2005). (Word Count 1284) References Brahmia, N. Bourgin, P. Boutaous, M. and Garcia, D. 2006. ‘Numerical Simulation with “Comsol Multiphysics” of Crystallization Kinetics of Semi-Crystalline Polymer during Cooling: Application to Injection Moulding Process’. Excerpt from the Proceedings of the COMSOL Users Conference 2006 Paris. Dhanasekharan, Kumar., Tsai, Kuochen., and Terry Ring. 2005. ‘Using Computational Modeling to Control and Optimize the Crystallization Process’. Retrieved on 14th April 2009 from: http://www.ansys.com/assets/white-papers/wp107-crystallization.pdf IChemE. 1999. ‘14th International Symposium on Industrial Crystallization’. Institution of Chemical Engineers (IChemE), Institution of Chemical Engineers, Institution of Chemical Engineers (Great Britain), International Workshop on the Crystal Growth of Organic Materials, Symposium on Industrial Crystallization. Jancic, S. J. and Grootscholten, Paulus A. M.1984. ‘Industrial crystallization’. London: Springer. Jones. 2002. A. G. ‘Crystallization Process Systems’. Boston: Butterworth-Heinemann. Louhi-Kultanen, Docent Marjatta. ‘Applying PAT in Reactive Crystallizatio’. Department of Chemical Technology LAPPEENRANTA University of Technology. Retrieved on 14th April 2009 from: http://www.congreszon.fi/@Bin/1700815/Louhi-Kultanen_110608.pdf Nývlt, Jaroslav ., Garside, John . and Mersmann, Alfons . 2002. ‘Measurement of Crystal Growth and Nucleation Rates’. Institution of Chemical Engineers (IChemE). Institution of Chemical Engineers (Great Britain), Institution of Chemical Engineers, European Federation of Chemical Engineering. Working Party on Crystallization. Parsons, A. R. Black, S. N., and Colling, R. July 2003. ‘Automated Measurement of Metastable Zones for Pharmaceutical Compounds’. Trans IChemE. AstraZeneca, Macclesfield, Cheshire, UK, Vol 81. Retrieved on 14th April 2009 from: http://www.helgroup.net/home/articles/AutomatedMeasurementOfMetastableZones.pdf Process Screening, Process Optimization, Process Scale-up. ‘HEL Product Overview’. HEL. Retrieved on 14th April 2009 from: http://www.laborexport.hu/pdf/HEL%20Corporate%20Brochure.pdf Van’t Hoff, Ja c o b us h. 1901. ‘Osmotic Pressure and Chemical Equilibrium’. Nobel Lecture. Retrieved 15th April 2009 from: http://nobelprize.org/nobel_prizes/chemistry/laureates/1901/hoff-lecture.pdf WinIso. 2005. Retrieved on 14th April 2009 from: http://www.winiso.com/ Worlistcchek, Jorg and De Buhr, Jurgen. May 2005. ‘Crystalisation Studies with Focussed Beam Reflectance Measurement and MultiMax’. Mettler Toledo GmbH, AutoChem. Retrieved on 14th April 2009 from: Generic_1117648389578_files/Application_note_Crystallization_Studies_on_MultiMax_with_FBRM.pdf. Worlitschek, Jörg., Briggeler, Herbert., Barrett, Paul., O’Sullivan, Brian., Didierjea, Claude., Kowalchyk, Will. and Olivier Ubrich. November 1, 2005.’Supersaturation Monitoring with ATR-FTIR Relative Supersaturation Control for Optimization of a Cooling Crystallization’. American Association of Pharmaceutical Scientists (AAPS). Nashville, Tennessee. Retrieved on 12th April 2009 from: http://fr.mt.com/fr/fr/home/supportive_content/application_editorials.l2nVBNrLBNqVzNiVzNiVAg9Tzs9ZDxbWB3j0AxzLx2nVBNrLBNqVyxbWBgLJyxrPB25FzwrPDg9YAwfSCW--.z2vUzxjPy0vKAxrVCMLHBfbHCI4Znty4oq--.Supersaturation_monitoring_with_ATR-FTIR.MediaFileComponent.html/Supersaturation_II_web_01_06.pdf Read More