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 chemist’s 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 Hess’s 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 non-

condensable 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 Typical values of heat loss

100L reactor with 5 cm insulation 0.146 W/L.K

1000L reactor with 7.5 cm insulation 0.074 W/L.K

10,000L reactor with no insulation 0.025 W/L.K

10,000L reactor with 7.5 cm insulation 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: Qf = Heat Flow (W)

∆TLM = 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)

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

company’s 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 3-

phase 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 100’s 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 isn’t the case in pharmaceuticals.

Many products don’t 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 don’t 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 Prentice-

Hall.

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. O’NEILL, 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].