case studies in hazards during early process development and loss... · case studies in hazards...

SympoSium SerieS No. �54 © 2008 AstraZeneca

Case studies in Hazards during early ProCess develoPment

Alistair Boyd, paul Gillespie, mark Hoyle and ian mcConvey�

process engineering Group, AstraZeneca, Silk road Business park, macclesfield, SK�0 2NA

A number of examples of potentially hazardous situations are presented and the outcome of the subsequent evaluation of each of the safety challenges is discussed. The paper considers examples in the area of: solvent stability under reaction conditions, high pressure amination reaction in a hydrogenator, unexpected crystallisation at reflux, uncovering exothermicity of a scaled up reaction and the preparation of distillation residues for further experimental evaluation. in each case a general conclusion is reached that is helpful for: safety specialists, process developers and engineers.

1. introduCtionThe speed of process development to manufacture active pharmaceutical ingredients is increasing to ensure that the demands of patients for new medicines can be met. in fact speed to ‘First Time in man’ (FTim) is a critical benchmark for the industry. This bench-mark needs to be met whilst maintaining Safety, Health and environment requirements and Quality standards.

During the early phase of development the quantity of material required to carry out full hazard evaluation is not normally available. Therefore the avoidance and control of hazard can be improved by the vigilance of process technologists in identifying potentially unsafe or environmentally hazardous situations during early development.

production of intermediate and active pharmaceutical compounds for toxicological testing is generally carried out in large-scale laboratories (LSL) or kilo-labs. Typically these facilities operate with glass reactors (up to �00 litres in volume), which have low design pressures. Though most laboratories are also equipped with metallic pressure-rated reactors for use in hydrogenation reactions. The speed of delivery from the LSLs is of paramount importance, since toxicology testing of the active is a critical path activity.

This paper will present a number of Case Studies where potentially hazardous conditions were identified in early process development and remedial actions taken to avoid scale-up issues. examples will be given where the following underlying effects needed to be considered with Dimethyl Sulphoxide (DmSo) stability under reaction conditions, the use of ammonia in a high pressure batch reaction, crash crystallisation/precipitation from a solvent at reflux, the hazards of a reported thermo-neutral reaction,

�Address for correspondence: Dr i F mcConvey, AstraZeneca, process research and Development Silk road Business park, Charterway, macclesfield, Cheshire, SK�0 2NA, e-mail: [email protected]

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SympoSium SerieS No. �54 © 2008 Astra Zeneca

and ensuring that the correct composition of distillation residues was generated when a sample was generated under low temperature and low pressure conditions. it is expected that the lessons in this paper will raise the awareness of process developers and other safety experts to these potential issues and help to avoid potentially dangerous conditions in similar situations elsewhere.

2. dimetHyl sulPHoxide stability under reaCtion Conditionsin a proposed process, DmSo, amine intermediate and cesium carbonate were charged to a reactor and heated to 65°C. The results of Carius tube experiment indicated that this mixture would be free from self-heating and gas evolution up to at least �49°C on scale-up.

A bromo-ethoxyalkane was then added to this mixture and the batch held at 70°C overnight to complete reaction. A Carius tube experiment on this mixture resulted in a rapid exotherm and associated rapid pressure rise from �40°C, leading to bursting of the test container (Figure �). Assuming normal kinetics one would expect this exotherm to be seen from as low as 80°C in bulk. However, the rapidity of the exotherm and pressure rise indicated that the reaction/decomposition was probably autocatalytic in nature. in this type of reaction the sudden decomposition observed could occur after an induction period at a lower temperature. From the rate of reaction/decomposition noted from the experimental test it would be unventable and any vessel containing the mixture would probably rupture violently if it were to occur.

Figure 1. reaction mixture ramped at 2 K/min in glass Carius tube

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To determine if autocatalysis was occurring a Carius tube experiment was carried out with the oven set at ~�02°C. in the experiment the sample temperature remained at 95°C for about � hours at which point a sudden pressure and temperature rise occurred (Figure 2). This confirmed that the reaction/decomposition was autocatalytic. it should be noted that heat losses from the Carius tube under isothermal conditions are very high and the fact that an exotherm was observed indicates rapid and very energetic reaction/decom-position. in the context of the proposed process the results showed that holding the batch at 70°C overnight (this was required to complete the slow reaction) would almost certainly result in the batch decomposing with potential for over-pressurisation and rupture of the reactor. if the reaction were to be carried out at a lower temperature then a longer hold period would be required to complete reaction and again accessing the exotherm would probably still occur due to its’ autocatalytic nature.

A further ramped Carius tube experiment was carried out on the sample after the isothermal experiment was complete. in the experiment a large exotherm occurred from �2�°C (Figure �). This indicated that the decomposition exotherm was complex, i.e. possi-bly normal kinetics as well as an autocatalytic element was involved, and holding the sample at 95°C resulted in destabilisation of the reaction mixture – (as noted by the reduc-tion in onset temperature from �40°C to �2�°C).

From the small-scale experimental results it was concluded that the reaction stage could not be carried out safely on a pilot plant scale. The root of the problem was the

Figure 2. isothermal at 95°C – reaction mixture – exotherm noted after � hours

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instability of DmSo in the presence of bromide, which was generated in this reaction as cesium bromide.

DmSo is far from being an inert solvent and its’ decomposition can be catalysed by a range of reagents/impurities, including bromide. many incidents have previously been reported�.

After discussion of the experimental results with the process Chemist an alternative solvent was suggested (N-methylpyrrolidone (Nmp)). The results of Carius tube experi-ments showed that using this solvent would allow the batch reaction to be carried out up to at least �00°C without chemical reaction hazard (Figure 4). using Nmp was not without issues during the subsequent work-up and product isolation, however, these issues could be developed further without a major hazard potential.

3. HigH Pressure batCH reaCtion in a Hydrogenator using ammoniaA high pressure amination reaction needed to be accommodated in a large-scale labora-tory. (max �00 litre vessel volume). most kilo-labs or large-scale labs operate glass reac-tors and have low design pressures. Some are equipped with metal pressure-rated reactors, usually for hydrogenation reactions, and such a vessel was used in this case but with ammonia. The case study details the method by which it was ensured that the process could be accommodated safely in a hydrogenator pressure vessel.

Figure 3. ramped test at 2K/min after isothermal hold at 95°C for �7.5 hours

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The reaction to be accommodated was the amination of an organic chloride to form a primary amine by the following reaction:

r-Cl + NH� (aq) → r-NH2 + HCl(aq) [a]

r-NH2 + HCl(aq) → r-NH�+Cl-

(aq) [b]

NH�(aq) + HCl(aq) → NH4Cl(aq) [c]

The reaction was achieved using an overall stoichiometric mixture (two equiva-lents) of aqueous ammonia (�0.76% w/w) and the organic chloride, as shown in reactions [a] to [c] and heating to ��5°C. Thermal stability testing had not detected any thermal runaway or decomposition reactions in the reaction mixture. examination of the reaction conditions indicated that the process would need to be performed in a closed system to prevent excessive ammonia (and water) loss, thus a pressure rated hydrogenation vessel was chosen for the accommodation.

The hydrogenator vessel had a bursting disc with a minimum rupture pressure of �0.45 barg (at ��°C), and a jacket fed with heat transfer fluid up to 200°C. The maximum batch temperature alarm and trip were configured at �40°C to initiate crash cooling. it was therefore necessary to determine that the maximum developed pressure would not cause inadvertent activation of this bursting disc.

Figure 4. Same reaction mixture in Nmp ramped at 2 K/min

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The maximum developed pressure within the vessel was determined by summa-tion of:-

�. The inert compression of the head space (as the reactor was nitrogen purged after charging);

2. The vapour pressure of �0.76% w/w ammonia at �40°C;�. The vapour pressure of HCl (generated by reaction scheme).

The molecular weight of most pharmaceutical compounds is significantly large relative to solvents and other reagents, and it can be assumed that volatility and therefore vapour pressure due to the compound itself would be negligible.

in a closed reactor system any permanent gasses exert their partial pressure, and this will increase as both temperature increases and liquid density decreases. Knowing the liquid densities enables the vapour volume (V ) to be determined, and then partial pressure can simply be calculated using ideal gas laws:-

p p

V

V

T

T2 ��

2

2

�

=ÊËÁ

ˆ¯̃

ÊËÁ

ˆ¯̃

(�)

which in this case resulted in a pressure of

p bara2 � 0��

50

�6 �8

4��

27�2 �06= Ê

ËÁˆ¯̃

◊ ÊËÁ

ˆ¯̃

=. ..

.

(2)

The initial headspace volume was taken as being simply nitrogen, i.e. the partial pressure of aqueous ammonia was neglected, as errs to a safer result. in practice, nitrogen will inevitably dissolve in the solution to a low level.

The component and total vapour pressure of aqueous ammonia was readily obtained from literature sources, e.g. perry2. The data in perry was presented in table format and (for this example) was both interpolated and extrapolated, since the nearest available data was for 9.5 & �4.�% w/w ammonia up to �20°C.

it was assumed that the vapour pressure of aqueous ammonia followed the Antione equation, and the natural logarithm of the vapour pressure versus the reciprocal of the absolute temperature was plotted to yield straight lines. This confirmed the validity of the data. As the plot yielded straight lines, a linear interpolation to the required concentration was carried out and then extrapolated to the required temperature. The resultant vapour pressure of �0.76% w/w ammonia at �40°C was determined to be 7.28� bara.

The molar consumption of ammonia in the reaction is equal to the formation of hydrogen chloride. Therefore at the end of the reaction the hydrogen chloride concentra-tion would be equal to that of the initial ammonia charge. The total vapour pressure of aqueous ammonia solutions was far greater than those of aqueous hydrogen chloride, thus the highest vapour pressure would occur during the initial heating of the reactor. it is noted that for this reaction system, any HCl will react and form aqueous ammonium chloride,

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which will have negligible vapour pressure contribution. For this reaction, the sublimation of ammonium chloride can be regarded as insignificant under the reaction conditions.

The calculated maximum developed pressure was therefore 7.28� + 2.�06 = 9.�92 bara (8.�79 barg). This was below the minimum burst pressure of the relief device fitted on the proposed hydrogentator. Therefore it was concluded that a �0.79% w/w ammonia solution at �40°C would not cause the bursting disc to activate.

The calculated pressure was not exceeded in practice when the reaction was carried out (Figure 5).

4. CrasH Crystallisation/PreCiPitation at reFluxA semi-batch process was operated in the LSL with addition of the Bredereck’s reagent at reflux (batch boiling point, �00°C). However, after the addition was complete exothermic crystallization / precipitation of the product, due to unexpected self-seeding, occurred during reflux. This resulted in rapid boiling of the batch. if the condenser had liquid logged this could have resulted in over-pressurisation, or if the condenser had failed or been over-whelmed then it could have resulted in loss of solvent and potential thermal decomposition of the residue.

An attempt to measure the heat of crystallization directly was unsuccessful due to significant thickening of the batch during seeding. This heat can be estimated using the heat of fusion data, assuming no solvent interaction, in this measured as �06 J/g by DSC. From this, an adiabatic temperature rise of 22 K was calculated for the current process concentration which explains the rapid boiling observed during the crash crystallisation at reflux. To avoid the potential rapid boiling hazard a higher boiling solvent (bpt �5�°C) was incorporated whilst keeping the operating temperature at �00°C. This gave a 50 K temper-ature margin between operating temperature and the boiling point of the solvent, i.e. well above the maximum temperature the mixture could theoretically achieve (�22°C). However,

0

1

2

3

4

5

6

7

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150Temperature (°C)

P (b

ara)

Bx 1 Heat Up 10.76% w/w Regression

Figure 5. Theoretical total vapour pressure (including inert) versus batch � actual

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it was noted that some minor refluxing of a low boiling by-product generated during the reaction could still occur (but would be minor).

Although not a chemical reaction hazard per se, the potential for rapid boiling, condenser liquid logging, etc., exists for any process in which product supersaturation may occur. This includes reaction mixtures, as per the above case study, but also in operations where the reaction mixture is concentrated by distillation prior to a controlled cooling crystallization. information/observations from the development chemist, as to the potential for self-seeding, is then invaluable. one should also consider the consequences of over-distillation of the batch, which could increase the potential for crash crystallization, and its possible consequence as the heat sink would also be reduced.

5. tHe sCale-uP Hazard oF a rePorted tHermo-neutral reaCtionrapid process development and manufacture of bespoke molecules by Commercial manufacturing organisations (Cmo) is often crucial to meeting product delivery times for toxicology trials during drug development. A requirement to develop and manufacture an intermediate on a relative small scale was recently undertaken by a Cmo and they failed to manufacture the material. This required rapid development and manufacture of the intermediate within AstraZeneca to attempt to meet these stringent timelines.

information provided by the Cmo on their initial development of the process included a statement that ‘Stage 2 is thermo-neutral and therefore does not pose a hazard on scale-up’. However, the development chemist within AstraZeneca noted a nominal ‘creep’ in temperature and reported this to the Safety Group. The process developed by the Cmo was a batch reaction, i.e. all the reagents were charged to the vessel and heated to the reaction temperature. Such processing methods can potentially be unsafe if loss of control occurs during operation. Hence, this was investigated further.

Adiabatic Calorimetry is ideal for investigating batch reaction scenarios as it can directly simulate minimal heat losses associated with large-scale plant vessels. in an initial experiment the reagents were charged to the calorimeter and warmed to the start tempera-ture (�00°C) (Note: little reaction occurred below this temperature due to solubility effects and catalyst activation). on attaining the start temperature the reaction appeared to initiate and generated considerable heat (Figure 6). The temperature of the reaction mixture reached the boiling point of the solvent in approximately �9 minutes and some solvent was lost (~��% of the total solvent content). Calculation equated this to a heat of reaction of –�92.5 kJ mol-� (limiting reagent), when taking into account the heat capacity of the calorimeter and the vapourised solvent. The heat of reaction could theoretically give an adiabatic temperature rise of �66 K, assuming all the heat simply heated the reactants and none were lost to the containing vessel or surroundings, i.e. the worse case scenario. Hence, from the start temperature (�00°C) it could reach a theoretical maximum batch temperature of 266°C. This was well above the boiling point of solvent being used (bpt 202°C) and therefore solvent boil over could occur. Theoretically, vaporisation of ~40% of the total solvent charge could occur. in a practical case the reactor system will inevitably

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provide some heat sink but the contribution of this will become less with increase in scale. Therefore, the operation of the process developed by the Cmo at increased scale would pose some considerable hazard.

An attempt was made to operate the process in a semi-batch mode by controlling the rate of addition of one of the reagents. unfortunately, in the short amount of time available to develop this method it was chemically unsuccessful. Discussion between chemist, engi-neer and process safety assessor suggested that the best way forward for the chemistry to work would be to add the metal salt powder being used in a controlled manner. operationally this was considered the worst option with respect to powder handling and toxicity issues, but methods to avoid these issues were being worked on for later manufacturing campaigns.

Hence, the batch processing option was revisited and a method of making this inherently safer considered. The heat capacity of the batch was increased by addition of more solvent so as to safely accommodate the potential adiabatic temperature rise. Calculation showed that increase from 2 to 5 relative volumes of solvent would result in a temperature rise of ~80 K in the adiabatic calorimeter. repeating the experiment with the increased solvent level validated the calculation. The same temperature profile was noted as before with temperature rising rapidly from �00°C to �60°C and then a decrease in rate (Figure 7). The temperature drifted slowly upwards to �88°C during the 4.5 hours

Figure 6. initial experiment on ‘Batch process’ in adiabatic calorimeter – heat to start at �00°C.

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work-off. it was concluded that the calculated temperature rise was fairly accurate, albeit 8 K out over the whole experiment. This may be accounted for by some agitator power input, as the reaction mass was noted to be viscous, or possibly some minor variance in the heat capacity of the Calorimeter or reaction contents over this temperature range. Calculation using the measured temperature rise (88 K) suggested an adiabatic tempera-ture rise of ~��2 K would be the theoretical maximum. This would just take the batch temperature above the boiling point of the solvent (202°C). in reality the reactors in the plant have a significant heat capacity and it is considered that the Adiabatic Calorimeter essentially simulates a reactor vessel of at least �0 m�, and this scale was not being exceeded for this manufacture. (Note: the heat capacity of the Calorimeter was measured and the phi factor calculated to be �.� for the reaction mass used). if application of cool-ing to the reaction vessel were to fail at the worst possible moment, i.e. when the batch had just reached the start temperature, then the maximum temperature noted in the Calorimeter experiment would not be achieved at the scale being proposed.

The reaction mass was thermally stable to this maximum temperature (�88°C) when carried out in a separate test, with only nominal exothermic behaviour being noted at greater temperature, after allowance of an appropriate safety margin. Hence, the manufacture was carried out with confidence and indeed the maximum temperature rise was not achieved.

Figure 7. Time / Temperature profile from follow up experiment on batch reaction with increased solvent content

Time / minutes

Tem

per

atu

re /

°C

Sample Temperature

Oven Temperature(Note: this is directly below the sample temperature trace)

∆T = 88KWork off over280 minutes

Majority of reactionover in ~ 20 minutes

Heat to 100°C(heater on)

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in summary, the operation of a difficult chemical process was made inherently safer at the desired scale of operation by simply increasing the heat capacity of the batch, i.e. addition of extra solvent.

This is a good reminder that absence of temperature rise in a laboratory scale experiment does not necessarily mean that the reaction is thermo-neutral or thermally non-hazardous. it may simply be that the rate of heat loss from the laboratory vessel is greater than the rate of heat produced in the reaction, hence giving no apparent temperature rise at that scale.

6. distillation residue ComPosition: From a 2metHF/ Water/ metHanol mixtureDistillation processes can be potentially hazardous as over-distillation can leave residues prone to exothermic decomposition at the vessel service temperature. Therefore, an inves-tigation of the thermal stability of the residues is generally undertaken. To perform this investigation a sample is generated at low pressure and temperature to eliminate exposure to elevated temperatures and thus reduce the risk of thermal decomposition prior to ther-mal stability testing. unfortunately, in doing this the VLe boundaries/separatrices can change and it is possible that the residue could have a significantly different composition to that of an atmospheric distillation, in this particular instance that was the case.

A limited amount of physical properties data for this system is available in the literature and it is summarised below:

Normal boiling point Liq density (g/ml@20°C)

Water �00°C �methanol 65°C 0.79�2meTHF 79°C 0.855

Azeotropic composition 2meTHF/water� = 89.4/�0.6% wt Azeotropic boiling point 2meTHF/water� = 7� °C

2meTHF solubility in water is �4%w/w at 20°C�

Water solubility in 2meTHF is 4.4%w/w at 20�

The approximate composition of a reaction liquid phase, not including the reaction product(s), prior to the start of distillation was: 27.8%w/w methanol, 6�.9%w/w 2-methyl-tetrahydrofuran (2meTHF) and �0.�%w/w water.

The initial reaction sample was distilled down to a limited volume under reduced pressure (5 Torr) and resulted in a two-phase mixture (organic and aqueous phases). This was not the result of carrying out the distillation under atmospheric pressure whereby water was easily removed. it was obvious that the VLe boundary had changed under the reduced pressure conditions to favour concentration of water rather than removal.

SmSWin4 and propred5 were used to predictively model the ternary system using the uNiFAC method (universal Quasichemical Functional Group Activity Coefficient).

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The ternary diagram for the system including predicted LLe (liquid-liquid equilibria) is shown (Figure 8). For successful removal of water under 5 Torr pressure, it was shown to be necessary to add an appropriate amount of anhydrous 2meTHF to move the composi-tion into the region of the diagram where the 2meTHF was the stable node. This would ensure the effective removal of water from the system to below the specified target.

The two-phase LLe region is also shown on the ternary diagram (Figure 8). There was a lower level of confidence in the accuracy of this LLe region and if necessary a more detailed model would have had to be generated. However, the reduced distillation was attempted with the additional 2meTHF added and was shown to work by analysis of water level in the residue.

in summary, due account of the change in VLe/LLe equilibria when carrying out low temperature, low pressure, distillations to simulate atmospheric pressure distillation residues needs to be understood. it may require appropriate changes to the initial composition prior to the distillation to ensure the correct final composition is achieved in the final sample.

The pink lines shown are the separatrices (a separatix is an equation to determine the borders of a system). once within a region shown on the diagram it is not possible to cross these lines except by adding material from an external source.

Figure 8. predicted phase equilibria for water/2meTHF/methanol

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8. general ConClusions From tHese Case studiesDmSo STABiLiTy

l DmSo is a potentially reactive chemical and thermal instability can be induced by a range of chemicals/impurities.

l Alternative solvents should be investigated before choosing DmSo as a reaction solvent. Similarly, with other aprotic solvents such as dimethyl formamide (DmF), dichloromethane (DCm), etc.

l ideally, some form of thermal stability test of reaction mixtures using DmSo or other potentially reactive solvents should be carried out before use, particularly before heating.

ACCommoDATiNG HiGH preSSure reACTioNS iN LArGe SCALe LABorATory HyDroGeNATorS

l The accommodation of high pressure reactions should take account of the any inert compression of the head space (if the reactor is purged after charging), vapour pressure of the reaction mixture at the maximum vessel temperature, the vapour pressure of any generated volatile in the reaction, taking into account any gas evolution which may take place, in specifying maximum pressure achievable.

CrySTALLiSATioN oF mATeriAL AT reFLux

l Crash crystallization at or close to reflux, or during any process in which product supersaturation may occur, e.g. distillation, can be potentially hazardous. Chemists observations from small scale experiments are useful in determining the need for inves-tigation of such events, i.e. does it happen and, if so, then investigate heat of crystalliza-tion and potential consequence.

TemperATure oBSerVATioNS iN LABorATory experimeNTS

l observations from small-scale laboratory experiments can be very misleading. Be careful of taking verbatim the fact no temperature rise was noted in small-scale labora-tory experiments. This may simply be due to the scale of operation.

GeNerATioN oF repreSeNTATiVe DiSTiLLATioN reSiDueS AT LoW TemperATure AND preSSureThe change in VLe/LLe equilibria when carrying out low temperature, low pressure, distillations to simulate atmospheric pressure distillation residues needs to be understood. it may require appropriate changes to the initial composition prior to the distillation to ensure the correct final composition is achieved in the final sample.

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aCknoWledgementsThe help and expertise of the following people within AstraZeneca are acknowledged in producing this paper: Nigel Burke, Sue Burns, Steve Hallam, matthew Harrison, Sue Jenkinson, Darren maude, Julie mcmanus, Steve raw, paul Wilkinson and Stephen Whittingham.

reFerenCes�. Bretherick’s Handbook of reactive Chemical Hazards (6th edn. p��6)2. perry, r.H., Green, D., “Perry’s Chemical Engineers’ Handbook”, mcGraw-Hill.�. methyltetrahydrofuran (2004) peNN Specialty Chemicals www.pschem.com4. SmSWin is a software package which CApeC (Computer Aided process-product

engineering Center) maintain and are further developing for integration with iCAS. SmSWin has a database of compounds and their properties, a collection of property models for phase equilibrium calculations, which are especially suitable for solution properties involving solids. See also user Guide to Solvents, melts and Solutions by J W morrison. www.capec.kt.dtu.dk

5. propred - a toolbox for estimation of pure component properties of organic compounds (part of iCAS (integrated Computer Aided Systems) –see CApeC) www.capec.kt.dtu.dk

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