Title: applications of reaction engineering in pharmaceutical process development

Introduction

I am writing this essay from the view of an undergraduate chemical engineering student that has spent 13 months located in an industry leading pilot plant, dedicated for the use of process development within a leading pharmaceutical company. With this I was exposed to process development first hand many undergraduate engineers do not get this opportunity and it has really helped me tie the theory that is learned in lectures at university to the practical aspects of chemical processing. During my placement I was introduced to many operations, technologies and people filling many different roles with in the development group. I hope to include a lot of my own experience into this essay. Chemical reaction engineering as a discipline started in the early 1950s by industrial chemical engineering researchers. Chemical reaction engineering encompasses two main fields reaction engineering and reactor engineering or design, it is a specialty mainly associated with chemical engineers. The Royal Society of Chemistry (RCI) describes Process development as the application of chemistry to the scale up of new synthetic processes from the laboratory, through pilot plant to full scale commercial manufacture and into life cycle management. It is an extremely broad discipline, crossing the boundaries between synthetic organic chemistry, process technology and chemical engineering. From this description of process development it is clear to see that reaction engineer will always play a vital role generally involving collaboration and inter disciplinary work between process chemists and chemical engineers. It is used heavily in the process industries for the development of new processes and the improvement of existing technologies and as such plays a vital role in the development of pharmaceutical processes. It is noted from literature and my own experience, as a general rule of thumb the ratio of between organic chemists and chemical engineers is in the region of approximately 0.1 to 0.2, in the chemists favour in the pharmaceutical industry. For example in the group I was part of not including myself or positions of management there was about 12 chemists and 2 chemical engineers. General due to time and resource constraints it is not heavily under taking in early stage process development of pharmaceutical compounds due to the large rates of attrition with generally only a small percentage of products making it to market. Vital topics for the understanding and study of chemical reaction engineering

1. Chemical Kinetics 2. Chemical Reaction Equilibria 3. Thermochemistry 4. Mole balances These are the key concepts of chemical reaction engineering that are built on and formulated into equations. Within chemistry there are many different types of reactions which are used in different areas with different advantages and limitations, for example, synthesis, decomposition, displacement, precipitation, isomerization, acid-base, redox or organic reactions. From my experience the choice of these are mostly the chemists role gaining knowledge from conducting chemistry in lab glass equipment. The chemists selection results in a reaction equation or equations which are generally more complicated than the example below. aA + bB cC + dD It is at this stage when the chemical engineer will become involved to firstly see if the process is reasonable to run on plant scale. This includes safety testing that I will talk about further on in this paper. Once it has been determined that the reaction/process is safe to operate, financially viable and does not cause a major source of pollution to the environment the process is moved to the next phase which is optimisation. This is where key chemical reaction engineering principles are applied to optimism the process for commercial production including selection of reactor type. The aim of chemical reaction engineering is to design a reactor such that the reaction proceeds with the highest efficiency towards the desired output, producing the highest yield and of product in the most cost effective way. Hence, the interactions of flow phenomena, mass transfer, heat transfer, and reaction kinetics are of prime importance in order to relate reactor performance to feed composition and operating conditions. Initial applied to the petroleum and petrochemical industries, the general ideas combining reaction chemistry and chemical engineering concepts allows to optimize a variety of systems where modelling or engineering of reactions is needed being heavily utilised in the pharmaceutical industry.

Taking a looking at some of the equations derived in reaction engineering shows us some of the ways chemical engineers can change processes to in order to optimise. Take the 2nd order rate equation r=kCaCb and the Arrhenius equation, a simple formula that represents how reaction rates change with temperature k=Ae-Ea/(RT) Where all the variable have their standard meanings. It can be seen that the rate constant k that is common in both equations is largely dependent on Ea the activation energy and T reaction temperature. These are bother variable that can be changed in process development. By either changing reaction conditions to achieve a higher temperature or introduce the use of a catalyst to reduce the activation energy. For a simple elementary second order reaction the rate of generation of products is proportional to the rate constant and the concentrations of reactants in this case A and B. It is there for shown that the clever design techniques can be used to achieve a desired rate by varying the concentration of one reactant in the reactor. There is a number of ways of doing this such as the staggered addition of B in flow reactors shown in the picture below.

Reasons for doing this could to control the rate of generation due to a large exotherm or even something more straight forward such as the production of an impurity by a side reaction if there is an excess of B in the reactor.

It is important to note that many reactions do not simply fit to the elementary rate equations (such as the one discussed in the previous section) and determining the parameters of the rate equation for a given process its highly time consuming and empirical process.

Health and safety

Safety in pharmaceutical manufacture is an important issue from the production floor right back to the research labs. This can in no way be skimmed over while redeveloping and/or optimizing a process. Before a process is run on pilot scale or as a rule of thumb, anything bigger than 1L in a lab environment, requires adequate safety testing to be conducted on the reaction prior to running. Before a process is run on full scale safety regulations require that all possible operational hazards have been determined, for example the presence and possible ignition of flammable atmospheres, and chemical reaction hazards are evaluated and that suitable parameters for safe operation are determined. Thermodynamics and also Kinetics play a major role in safety testing so therefore chemical engineers play a role at this step. Safety testing is an expensive and vital step for process development. For legal and unbiased testing it is generally completed by a third party and is always done so if a process is to go into operation. It is conducted and reviewed by experienced professionals as it is the key stone to the basis of safety when running a process at full scale. In a following section of this paper I will describe a recent development in automated lab technology that lets process development engineers and chemists conduct their own basic safety testing as a way to speed up process development.

The table above has been taken from the literature and describes five steps to well-rounded chemical reactivity screening. After receiving and understanding the problem the thermodynamic related work begins. Step two describes theoretical screening before even any experiments/reactions have been run. This includes a comprehensive review of literature such as chemical data (MSDS), compatibility tables, incident data and general reactivity data for the given type of reaction be it an oxidation, sulfonation or hydrogenation etc. The work then moves into the estimation of formation energies and reaction heats from tabulated date. This utilises basic thermodynamic principles of pure component properties and laws such as Hesss Law below. As Pharmaceutical compounds are complex uncommon molecules there is generally not very much tabulated data on them, estimates can be made from similar molecules and reactions.

Laboratory scale testing is into account under steps 3 and 4. From my experience this is achieved within three levels to achieve a degree of sensitivity. 1. Initial screening tests are conducted: These are capable of rapidly monitoring and characterising starting materials, reaction intermediates and reaction mixtures, final products and waste streams. One type of equipment used at this stage is Differential Scanning Calorimeters (DSC). One example of such a thermo physical analytical device is the MT DSC1 which like most other high-tech pieces of analytical instruments has a wide range of uses and thermal analysis techniques that you can add functionality to. Examples of thermal events and processes that can be determined by DSC

 Melting behaviour Curing Crystallization and nucleation Stability Polymorphism Miscibility Liquid-crystalline transitions Effects of plasticizers Phase diagrams and composition Thermal history Glass transitions Heat capacity and heat capacity changes Reactivity Reaction and transition enthalpies Reaction kinetics Purity

The initial screening is to clearly identify exothermic or endothermic activity and provides some guidance as to the magnitude of the exotherm. In addition some equipment is also able to detect the production of noncondensable gas and any vapour pressure effects associated with such phenomena occurring over the temperature range encountered during processing. This screening is only designed to provide an initial characterisation of the chemical or reaction system. If results from this type of equipment were taken as quantitative the heat loss relating to the sample and/or the sample container to the surroundings will introduce significant errors which render the data unacceptable for interpretation on the manufacturing scale, as the sample is only approximately 10g or less and not under typical reaction conditions. To quantify the errors in heat lose characteristics, the identification of the minimum temperature for a runaway reaction depends not only on the kinetics

of the reaction but also the rate of heat loss that will occur in the full scale reactor. Natural heat loss from a typical reactor vessel be it batch or semi-batch depends on a number of parameters such as the size of the vessel, the type of agitation and the heat input/removal system employed. I have found in literature quantified heat loss characteristics of a number of process vessels of varying size and insulation thickness. As you can see these larger scale vessels 10,000L are coming closer to adiabatic conditions Reactor Setup 100L reactor with 5 cm insulation 1000L reactor with 7.5 cm insulation 10,000L reactor with no insulation 10,000L reactor with 7.5 cm insulation Typical values of heat loss 0.146 W/L.K 0.074 W/L.K 0.025 W/L.K 0.011 W/L.K

As can be estimated from the above table the heat loss per unit volume per unit temperature has very different values from lab scale (commonly 1L or less in modern development labs) to plant scale. When laboratory scale testing is undertaken the natural heat loss characteristics of the test equipment has to be taken into consideration before providing data on self-heat rate and gas generation rates if that data is to be directly relevant to full scale manufacture. Normally, in the assessment of chemical reaction hazards, it is assumed that forced, plant cooling has failed. Experimental techniques to achieve test sensitivities appropriate to these plant heat loss values require accurate, stable temperature control with a high degree of sensor accuracy. 2. Isothermal reaction calorimetry: Is undertaken to assess the power output and accumulation characteristics of semi-batch processes. The principle of heat flow calorimetry is based on measuring the quantity of heat that flows across the reactor wall as an exothermic or endothermic process takes place. The total heat flow across the reactor wall is proportional to the temperature difference between the reaction mass contents and the reactor jacket. This can be written mathematically as: Qf = U.A.TLM Where: = Heat Flow (W) = Log mean temperature difference given by =((Tr-Tj1)-(Tr-Tj2)) / Ln((Tr-Tj1)/(Tr-Tj2)) and approximates to (Tr-Tj) Tr = Temperature of reaction mass (C) Tj = Temperature of the heat exchange medium (C) Qf TLM

U = Overall heat transfer coefficient (W.m-2.K-1) A = Heat exchange area (m2) (U.A.) is determined by electrical calibration of the reactor contents before and after the reaction. The heat released or absorbed by any reaction occurring in the reactor at any period in time can be directly determined by performing a heat balance across the system. The heat flow due to the reaction is made up of the measured heat flow across the reactor wall, the heat supplied or removed by dosing of reagents, the heat accumulated in the reaction mass and the heat lost to the surroundings. Qr = Qf + Qd + Qa + Ql Where: Qr = Reaction heat flow Qf = Measured heat flow Qd = Heat flow through dosing : This is the product of the rate of dosing of reagent, the specific heat capacity of the dosed reagent and the temperature difference between the reaction mass and the dosed reagent. Qa = Accumulated heat in the reaction mass: this is the product of the rate of change of reaction mass temperature, the mass of the reactor contents and the specific heat capacity of the contents. Ql = Heat losses By measuring Qf, Qd and Qa a figure for the enthalpy occurring in the calorimeter during the reaction can be determined. Ql, the change in heat transfer area and the environmental heat losses is accounted for by performing electrical calibrations both before and after the reaction. To experimentally determine the reaction enthalpy the expression below can be used

Where

is the initial number of moles of the limiting reagent.

3. Adiabatic calorimetry: is then undertaken to accurately quantify the magnitude of such effects under the low heat loss conditions normally associated with production scale manufacture as seen in table on previous page. Dhe adiabatic temperature rise for the reaction is defined as the temperature rise that would occur in the absence of any heat removal, dissipation or secondary reaction.

In order to study thermal runaway reactions under conditions normally associated with a low heat loss manufacturing environment, an Adiabatic Calorimeter is usually employed. The data determined from such laboratory equipment can be directly interpreted on the plant scale due to its unique low heat loss characteristics. There are two key areas from which heat losses can occur. Firstly, the vessel itself will consume energy generated by a reaction. Additionally, heat losses to the surroundings will occur. The former is overcome by utilising a calorimeter with low thermal mass and maintaining a high mass of reaction system in the calorimeter in proportion to its overall specific heat capacity. The latter, is overcome by employing an adiabatic shield to track the exothermic reaction as it occurs and minimise atmospheric heat flows. Adiabatic Dewar calorimeters such as the ones in the diagram below are employed to test for temperature and pressure data resulting from runaway chemical reactions and specifying plant protection measures, process failure scenarios and investigations into effects of chemical pumped additions. Such equipment is capable of operating under the highly adiabatic conditions required for such process simulation and consequently is able to examine directly thermal runaways and reaction conditions encountered in large vessels.

Current lab scale equipment

As an accepted industrial standard, reaction calorimetry is undertaken using the Mettler Toledo RC1 reaction calorimeter (diagram shown below). This is a highly sensitive, automated laboratory reactor equipped with calorimetric measuring facilities. Semi-batch processes with a very large range of operating pressures and temperatures, typically wider than that of a large scale plant reactor. The sensitivity of the equipment is exceptional, with heating rates accurate to about 0.2 W/kg. The equipment provides excellent data on the kinetics of a chemical process (including fully defined accumulation information) under isothermal or isoperibolic (constant cooling rate) conditions. Very capable of simulating the reaction conditions employed in large scale chemical processing.

Above is a sample graph from a reaction heat flow calorimetry experiment for the addition of two reagents to reactor operating under isothermal conditions at two different operating temperatures. The technique of step wise addition of species A is used here, this can be used to minimise the associated exotherm or also minimise the formation of impurities if it is the case that an excess of A will yield higher levels of impurities. The GREEN circle shows the second addition of species A and associated heat output from the reaction resulting in a small heat kick or temperature rise in the reaction mixture. The ORANGE circles on the graph show the reaction temperature rise and gas evolution from the reaction mixture after the addition of reagent B. In this case no significant gas generation was observed to be considered as an issue during plant operation. There are now small lab scale equipment packages available to do the same tasks as the very expensive RC1 equipment. The availability of these automated small scale equipment items such as the Mettler Telodo Optimax allows development labs to gather rich calorimetry that can be used to attain kinetic data on new reactive processes is a very powerful tool in the process development industry. Clever use of equipment enables labs to determine basic safety and kinetic data while in early stage development when the expensive work of independent safety testing laboratories is not available.

Process Analytical Technologies (PAT) used in kinetics analysis for the most part due to time constraints is sub optimal data is used to infer kinetic and model reactions IR traces, reaction calorimetry, HPLC data. It is possible to conduct inline analysis by tracking the concentration of a reactant over time with an FTIR probe in a reactor. But there are calls within the industry for more use of process analytical technologies to generate data for such applications as mechanistic inferences and possibly kinetic data collection in real time to drive models. One example I found in my research into this topic was the use of electrospray mass spectrometry such as the picture below. From my experience this type of setup could have a profound effect on process development time lines as generally this is done by taking a number of samples over time say every 20min during a reaction and then analysing the sample by HPLC this can take at the least a few days to get results back and can have large errors if analytical technique effects the species of interest or numerous other variable effect the sample.

Chemical reactor selection (Batch vs. Continuous)

Reactors are designed based on features like mode of operation, types of phases present and the geometry of reactors. They are thus called: Batch or Continuous depending on the mode of operation. Homogeneous or Heterogeneous depending upon the phases present. They may also be classified as one of a number of types depending upon the flow pattern and manner in which the phases make contact with each other below is a list of the main types. Stirred Tank Reactor Tubular Reactor Packed Bed Reactor Fluidized Bed Reactor As my industrial placement was in a development group with a keen interest and a secondary objective of demoing and introducing new and innovative technology I gained experience of all of these types of reactors but sadly not all being operational. One reactor operation that caught my eye while I was working on the design of a pilot plant batch hydrogenation unit was the Buss Loop Reactor pictured below which is another classification of reactor the slurry reactor where the solids are suspended mechanically.

During my work on the design of the pilot plant unit I had to learn from the ground up what a hydrogenation reaction was (liquid-solid gas type reaction), Processes the company had that involve hydrogenation and why(offers very selective synthesis which is beneficial for yields and purity), operating

conditions of these processes, full scale manufacturing vessels available in the companys global manufacturing network, critical process parameters involved with hydrogenation and scaling factors to name just a few topics I was tasked to look into during my work, this was the biggest project I was involved in during the year and I found it the most rewarding. As Hydrogenation is a heterogeneous catalytic reaction there are a lot more variables to be taken into account than your standard liquid phase batch reaction. As for instance transport effects of reagents to and from the catalyst surfaces bring about more steps in a reaction mechanism such as pore diffusion and surface adsorption and desorption. I was introduced to the buss loop reactor of which there was only the one full scale unit within the company and it was based on the Cork site. Advantages of such a reactor system Can be operated in batch or Continuous modes Flexibility in working volume with no drop in performance. Buss loop reactors may be operated between 30 and 110 % of the nominal capacity, still offering the same heat transfer area, the same mixing efficiency and therefore the same mass transfer rates. This is a welcome benefit for a multipurpose plant. Significant savings in catalyst cost up to 70 % can be achieved due to the high efficient mixing device combined with a high performance 3phase pump which works also when the liquid contains high gas volumes, which again has a positive effect on the life time of the catalyst. The selections of batch versus continuous process, Continuous has been utilised more in the fine chemicals and other bulk industries such as petrochemicals. Theoretically and realistically with the input of a capital fee to install a plant the product can be produced at faster rates than a batch plant for the most part.

The diagram above is what the inside of a pharmaceutical plant commonly looks like for the most part. In many cases the Centrifuge and Dryer units can be replaced by a Filter-dryer which serves both purposes cutting out a product handling operation but with some obvious trade-offs of filtration time and heat transfer performance. The use of integrated continuous operations is becoming more common in the pharmaceutical industry from my experience I came across the ideas and/or seen technologies such as liquid flow reactors, heterogeneous flow reactors, continuous crystallisation processes, continuous distillation (by wiped film evaporators),continuous separation (by centrifugal liquid-liquid separator) and high shear wet milling technology. Continuous technology has many advantages such as:

High Temperature and Pressure

Higher heat transfer areas per unit volume (A/V), for example a static mixer reactor on plant scale cant typically have 50 m2/m3 whereas plant batch reactors have between 2-6 m2/m3 Heating solvent above boiling point can provide dramatic rate acceleration. This higher A/V makes them more suited to highly exothermic processes They have an advantage of better mass transfer rates and mixing From a plant layout point of view they take up less space

 small scale minimize damage caused by reactor failure They can operate at higher pressures than standard batch reactors pre capital expenditure, giving rise to a wider range of possible chemistry. reactor has no headspace, uncontrolled pressure increases can be more easily mitigated They can be scaled up easier and manufactures are taking advantage of this in creating modular designs where you can use on module for lab work and then use up to 100s for full scale production, as shown by the Corning flow units in the image below.

Many other process industries use continuous equipment as standard but there are a number of reasons why this isnt the case in pharmaceuticals. Many products dont make it to market Batch reactors offer more flexibility and adaptable to many process and unit operations Volumes continuously change over lifetime of the product Tight regulations and GMP developed and demonstrated for batch operations

 Infrastructure already in place Continuous reactors are usually preferred for large scale production. They will normally give lower production costs as compared to batch production, but it faces the limitation of lacking the flexibility of batch production. They can also be more environmentally friendly processes. As during a process in reactants are fed to the reactor and the products, unreacted reactants and/or byproducts are withdrawn, it is possible in some cases to recycle the unreacted material if the process is designed in such a way that it can be separated easily and there is no accumulation of byproducts or impurities. There is also significant energy savings with the implementation of continuous processing.
Reactor design equations

Batch

CSTR

PFR

Above are the design equations for the 3 main types of reactors Batch, CSTR and PFR derived from component mole balances preformed on each type of reactor. in the above equations is the mean residence time which is a measure of the average time a molecule will spend in the flow reactor system this is generally experimentally determined by simple tracer experiments to characterize the vessel as they will all be slightly different and dont typical fit the idealised models available. Comparing the design equations from the three types of reactors you can see that to attain the desired conversion in a batch

reactor it is directly related the length of time the reaction is left running for. For a CSTR although the equation is a lot simpler, for a given flow rate which is defined by your desired rate of production we attain the reactor volume necessary to achieve the specified conversion. Similarly the plug flow reactor design equation also specifies a volume necessary to achieve conversion.

References
FOGLER, H. S. 2006. Elements of chemical reaction engineering PrenticeHall. LU, Q. & BOTHA, I. 2006. 'Process development: a theoretical framework', ,. International Journal Of Production Research. MCCONVILLE, F. X. 2007. The Pilot Plant Real Book. MICHAEL A.A. ONEILL, S. G. 2011. Application and use of isothermal calorimetry in pharmaceutical development. International Journal of Pharmaceutics, 83 93. RSC.ORG. 2013. RSC Conferences, chemistry events and training courses for the chemical sciences [Online]. Available: http://www.rsc.org/ConferencesAndEvents/conference/alldetails.cfm?evid=1148 74 [Accessed 27/10/13 2013].