Part 2: Interfacing strategies

(1)

Automated

chemical

synthesis.

Part

2:

Interfacing strategies

Daniel

F. Chodosh,

Francis

E. Wdzieckowski,

Julius Schainbaum

and Charles

E. Berkoff

Smith Kline

&

FrenchLaboratories,

Inc.,

PreclinicalResearch

&

Development, 1500 Spring Garden

Street,

Philadelphia, Pennsylvania 19101, USA.

Researchfocusedlargelyondevelopingnew, highly automated

tools for theprocessdevelopment laboratoryiscarried out in the

authors’ laboratory. The abilityto evaluate, characterize and

optimizesynthetic routes, bothquicklyandcomprehensively,is

especially important in the pharmaceuticalprocessdevelopment

laboratory, where typically in a complex synthetic sequence

manyreactionparametersmustbeexamined.Furthermore,the

rapidelucidation ofprocess routes details and idiosyncrasies

will allowthe synthesis ofnewmaterialsintendedforextensive preclinical and clinicaltesting toproceed by ’final. chemistry’, whereevenslightchangesinprocessconditionscanaffecttrace

impurity profiles. Increasing attention is being given to the

opportunities generated by computers to enhance the

pro-ductivity of these laboratories

[1-2].

On the pilot and production scale, batch-reaction auto-mation instrumentation and technology employing fully and semi-distributedcontrol schemes arewidelyavailable

[3-6].

On

the laboratory scale, however,most researchers havepursued

automation of continuous-flow techniques

[7-9].

The automated chemical synthesis project described here entails

designing and constructingacomputer-controlled,bench-scale

batch-typereactor, whichiscapableofself-directing

experimen-tation andoptimization

[9-15].

Such a systemwould permit extensive, and often tedious, examination of chemical reactions in quiteearlystages of theirdevelopment. Experimentationon the bench-scale in batch-type reactors will allow chemical reactionandprocesscontrol data tobe obtained,subsequently

this willbe directly applicabletothepilotand production scales.

Further, byminimizing the size of the vessel, scarce

develop-mental quantities of chemical intermediatescanbeconservedas automation technologyis appliedatthe veryearlieststagesof

processdevelopment programmes.

A

prototype unitwas constructed topermita close

evalu-ation of various automation parameters: reactor design,

temperature control, reagent delivery, chemical analysis.and

computer interfacing. The unit consisted of a 100ml glass

(jacketed) vessel with ports for a condenser, stirrer bearing,

temperaturesensor,reagentinlet,reactionsampling andadrain.

Reagent

and solventwereintroduced intothe vesselbypositive

displacement pumps; temperaturewascontrolled by mixinghot

andcoldfluidsandcirculatingthe mixturethrough the vessel jacket; sampleswereremoved and diluted (usingaTechnicon AutoAnalyser pumpingsystem)forsubsequenton-line analysis

by HPLC.

A

timesharecomputing system

(a

Digital Equipment

Corporation

PDP11/34 RSTS)was

usedtocalculatethe various operational parameters (stoichiometry, temperature, reaction

time)accordingto asimplex experimental design. The chemical

analysis results were reported back to the RSTS resident

programwhichthen calculatednewreaction parameters.

For

a

detailed description of these systems the readerisreferred to the

preceding paperin this series

[-16].

Throughthispreliminary effort the projectwasshown to be

suitably viable andasystem-by-systemevaluation and redesign wasinitiated.Instrumentreliabilitywasofparticularconcern;

self-checking and fail-safe features also became fundamental

considerations in the redesign efforts.

To

achieve greater reliability andmoreprecise"control the transfer of information

betweenthecomputationalsystem and theautosynthesis system

wasalso scrutinized

[17-19].

Theprototypeunitemploysa timesharedcomputerto

calcu-late reaction operating parameters. TheRSTSresidentprogram

(in this case, a simplex optimization algorithm

[10

and

14])

communicatesvia asingleseriallink

(modem)

tothelaboratory

(see

figure

1).

This timeshare environmentdoesnotsupport

real-time functions, so it is not possible to place time-dependent

instrument-controldemands on the computing system. Once

reaction parameters(time, temperatureset-point,stoichiometry)

are calculated they are passed to local digital controllers for

execution.Theflowof informationisunidirectional,fromRSTS

tothe controller. Each controller must be ’hardwired’ toaccepta

parameter and independently actuate the requisite control

function.For example,thereagent deliverycontrolleracceptsa serial string ofASCIIcharacterscorrespondingtothe number of

required pumprevolutions. Thecontroller then activates the

indicatedpumpuntilahardwiredfeedback loopcounts off the

appropriatenumber ofpumprevolutions.The controllerthen

deactivates the pump. The delivery rate of the pump, once

manually set, remains fixed throughout the course of the

experimental run. The computer system does not access

in-formation regarding the overall integrity of the synthesis

apparatus

(for

example, reagentreservoirdepletion,line fatigue

or rupture, viscosity

effects),

or the completion status ofthe

operation itself.

In

each casethe instrument-controlalgorithmis fixed by the electronic design of the controller device. Each controller must be designed to communicate, albeit

unidirec-tionally,with thecomputerinthe identicalmanner(viaserial

modem),

regardless ofitscontrol function or signalcomplement.

Whilemoresophisticatedlocal controllers can beconstructed,

CPU PDP11 RSTS

Figure

1. system. O C e Temperature control unit Pump controlunit Sensor *-Actuator LCdetector controlunit Sensor *-Actuator Sensor Modem

Analogue information transfer Digital informationtransfer

Prototype

unit:

_interface

totimeshare computer

(2)

D.F. Chodoshetal.Automatedchemicalsynthesis.Part2

this timeshare automation approach constrains the overall

system bylimiting the computer-synthesis systems to strictly non-timecriticalordependentinteractionsandtoamodestdata

collection.

By

abandoning timesharingfor real-timecomputing,

signifi-cantadvantagescanbe realized both in instrumentdesignand

performance.

In

recent years well-packaged

microprocessor-based systems, complete with signal-acquisition interfaces

(analogue-to-digital, digital-to-analogue, parallel

I/O, etc.),

have become available at reasonable cost. The capability to

directly coupledata signals between the synthesisapparatusand

the computing system,through appropriate interfaces, totally

redefines theautomation problem

(see

figure

2).

Whereas,formerly,elementsofdecision-makingwere

hard-wired inthevariouscontrollers

(for

example,

P

versus

PI

versus

PID

temperature

control),

decision-makingcan nowbe software

resident. Changes to automation-control strategies can be implementedthroughfacilesoftwaremodification,asopposed

tohardware modifications

and/or

redesignoftheautosynthesis

electronics.

However,

semi-distributedcontrol elements arenot necessarily avoided--indeed, certainaspectsof thetemperature

control and fail-saferecoveryautomation in this systemrelyon semi-distributed control functionality. Rather, various auto-synthesis systems can be selectively engineered through the

range ofnon-distributed to semi-distributed--dictatedonly by

thespecificcontrolproblemathand.

In

this computing environment, substantially greater

numbers of signalsareavailableto themicroprocessorfordata

collectionandinstrumentcontrol. With suitablemass-storage

devices, the dedicated microcomputer is capable of extensive

data collection whichisinaccessibletothe time-share environ-ment.Thusdata become available forarange of administrative and scientific tasks: for example, report writing, instrument activity logs, kinetic modelling studies, response surface mapping, cost analysis and impurity profiling.

By

choosinga real-time computing environment precise instrument control

withauto-calibratingauto-correcting featuresisachievable. The

experimentation can be self-directing, where the chemical

analysis results of experimentNareused to calculate theN

₊

setof experimental conditions to be evaluated.Further, by

real-timemonitoringofthe autosynthesis,electromechanical

hard-ware system integrity can be assured allowing unattended

operation;thisprovidesbetteruseofstaff and costsavings.

Parallel interface

Decoder Actuator Actuator Sensor

Decod;r

Sensor

Fail-saferecoveryprocedureswereof fundamentalconcern

throughout the re-evaluation. Assuming that the requisite

automation hardware is present, verification of proper

operation can bedesigned into theautomation software. For

example signals from flow monitors can be used to verify

pump/syringeoperations.Powerfailuresand computer

drop-outsituationspresentadditionalchallengestothedesigner. To

avoid a catastrophe in the laboratory the apparatus should

defaultto aquiescentstateuntil either automatic(i.e. computer)

ormanual recovery stepscanbe executed.

A

general-purpose

interfacewasconstructed to providefail-safeprotections.

A

Digital Equipment Corporation MINC LSI

11/2

com-puter and associated interfaces were selected for the authors’

application. Thesystemconfigurationincludesadualharddisc

storage system

(RLO 1),

floppydiscs

(RXO2),

aVT105 graphics

CRT andaline-printer

(shown

infigure

3).

TheMINCinterfaces

provide excellent signal-handling capabilities:

A/D

(12

bit,

successiveapproximation),

D/A

(12

bit, uni-and bipolar), digital

input andoutput (16-bitregisters) andaprogrammableclock. Thereal-time

foreground/background

operatingsystem

(RTll

V4

F/B)

providesreal-timecomputing capacityand accesstoa

setofcomprehensivescientific programlibraries.

Instrument-control anddata-acquisitionsoftwareiswritten inFortranwith real-time extensions

(REAL-11/MNC).

To utilize the digital

input andoutputinterfaces itwasnecessaryto augmenttheir functions. To protect the computer system from electrical anomalies(induction effects, sparking)thesesignallinesmustbe optically decoupled from the synthesis apparatus. The

TTL

signals availablethrough the digital output interfaces

(2

x16

bits),whilecapableof interfacing to semiconductor logic, cannot

directlycoupletodevicessuch as motorsorsolenoids. The

opto-LA120 Line-printer I/

plotter

DEC LSI 11/2 MINC 64 Kb RTII F/B Synthesis system

Figure

3. Dedicated

real-time computer

configuration.

CPU Analogue-to-digital interface

Oecoderl

Sensor Sensor LS1 11/2 RT11 Digital interface

-t-nalguell

Decder Serial interface

RsTs

Actuator Actuator

Analogue informationtransfer Digital informationtransfer

Figure 2.

Autosynthesis

system:

_interface

to

dedicated

computer system. TTLinput CPU Figure

4. diagram.

Auto Manual H/L switch Voltage ADd TTL VAC VDC HI _TTL _HI

ILO

_TTL_LO HI

[

12o VAC 0 VAC HI

[

O-28VDC 0 VDC

Opto-isolator

_interface:

single channel block

(3)

isolator interface wasdesignedtoaddnewfunctions to these

I/O

interfacesandprovidemany of thedefaultsafeguards required.

As

shown infigure4,theopto-isolatorinterface accepts

TTL

signalsfroma 16-bitparalleloutput interface. Eachsignal line

(i.e.

bit)

is electrically decoupled via an opto-isolator

semi-conductor and propagated through the interface

simul-taneously, making available three signals for the synthesis

apparatus:

TTL,

VACandVDC.When the

TTL

inputislow the

outputsonthe indicatedchannelareall low:

TTL

low, O VAC

and OVDC.

A TTL

input high produceshigh outputstates:

TTL

high, 120VACandVDC.The d.c.voltagelevel in thehigh

stateismanually selected by adjustingapotentiometeroneach

channel.

(The

interfacehas a panelmeter for voltage

adjust-ments.)

To operatea24VDCsolenoidtheusersetsthe indicated

interface channel to 24

VDC;

when the computer system generatesa

TTL

high signaltheoutput oftheselectedchannel

changes from 0 to 24 VDC driving the solenoid. Thevoltage

range,0-28

VDC,

allowsawide variety of direct current devices

tobe interfaced easily and quickly. The individual channels have

AUTO/MANUAL

switches that select the channel input

source.

In

the AUTO mode, the computer-generated signal

drives the channel and determines the output state.

In

the

MANUAL

mode atoggle switchon each channel allows the

user toselecttheoutputstate; with thisarrangementsomeof the

channels can be driven by the computer while others are

manually operated--thisisusefulduringthetesting and

devel-opmentof the automationsoftware.To address the problemof

computer drop-out, a ’sense line’ couples the interface to a

computer-generated

TTL

source.

As

long as the ’sense line’

remainshightheopto-isolatorinterfaceoperatesas described

above. Should the ’senseline’ go low, the

AUTO/MANUAL

switch isoverriddenandtheoutputsare setbythepositionofthe

toggleswitches.Thisprovidessubstantialdefaultprotections for

the system. For example, the power-supplies for the heater systemsaredrivenviathe 120VAC outputsof the interface. The

operator leaves the appropriate toggle switches in the OFF

position and selects the AUTO mode for normal computer

operation.Should thecomputer dropout(i.e.the’senseline’go

low),

the interface defaults to turn off thepower-supplieswhich

in turn prevents uncontrolled heating.

In

a similar fashion,

defaultsettings for thevalves,motors andsolenoidsprotectsthe

synthesis apparatus from catastrophe.

An

additional 16-bit

parallel output register is optically isolated and propagated

(TTL

output),as is a 16-bitparallelinput

register

(signalsfrom

the apparatus to the computer system) making available

additional 16

TTL

input and 16

TTL

outputsignals. Finally,a

true-positivetrue-negative switch forlogic polarityinversionis

provided to assuregeneral compatibilitywithother computer

systems.

A

schematic diagram of one channel is shown as

figure 5.

This computer environment and the interfaces described

have sufficient signal- and data-handling capabilities for the automationexperiment.Withthe addition of theopto-isolator

interface, sufficient safeguards can be engineered into the

laboratory apparatustopermitreliableunattendedoperation.

Thedesignof the synthesisapparatusitself, its interfaces to the

computer and the automation software, will be described in future papers. 0/1 manual toggle Auto Manual MNCDO Data in (TTL) MNCDOPIN13 Senseline (TTL} r

Switch CPU drop-out

debouncer sensor

+

Manual

+

220

14N25

220

+q

SN74279 SN74157 Polarity select SN74157

1 +

Toother channels To meter switch LM550

--TOswitchmeter

-.__

adjust SSR

---’ON’

LED

’OFF’

LED DVMselect TTLout O-28VDC 50out 120VAC out

(4)

D.F.Chodoshetal.Automatedchemicalsynthesis.Part2

References

11. 12. 13.

1. WALSER,P.E.andBARTELS, H.A.,AmericanLaboratory(1982), 113.

2. FRAZER,J.W., Accounts

of

ChemicalResearch, 7(1974),141. 3. BRODMANN,M. T.andSMITH,C. L.,Chemical Engineering, 83

(1976), 191.

4. KENNEDY, J. P.,Chemical EngineeringProgress,77(1981),33. 5. MERRITT, R.,Inst.Cont.Sys. (1981),34.

6. GARTON,R.D.,Chemical EngineeringProgress,77,(1981),44. 7. NAGY, G., FEHER, Z.andPUNGOR,E.,Analytica ChimicaActa,52

(1970),47.

8. SPELLMAN, R. A. and QUINN, J. B., AIChE Workshop in IndustrialProcessControl,Tampa,Florida(November 1974). 9. FRAZER, J.W., RIGDON, L. P., BRAND, H. R.andPOMERNACKI,

C.L.,Analytical Chemistry,51(1979), 1739.

10. DEAN, W. K., HEALD, K.J. andDEMNG,S.N.,Science,189(1975), 805.

DEMING,S.N.,AmericanLaboratory(1981),42. Box, G. E.P.,Biometrics, 10(1964),16.

FRAZER,J.W., KRAY, A. M., SELIG, W.and LIM, R.,Analytical Chemistry47 1975), 869.

14. DEMrNG, S.N. and MORGAN, S. L., Analytical Chemistry, 45 (1973),278A.

15. WATSON,M.W.andCARR, P.W.,AnalyticalChemistry,51(1979), 1835.

16. WrNICOV, H., SCHAINBAUM, J.,BUCKLEY,JR.,J.T.,LONGINO,G., HILL, J.andBERKOFF, C.E.,AnalyticaChimicaActa,103(’1978), 469.

17. CHODOSH, D. F., WINICOV, H.,BUCKLEY,JR.,J. T. and BERKOFF, C.E., Computers

at’the

bench (BelgianPharmaceuticalSociety International Conference on Computers in Pharmaceutical Research,Namur,Belgium, November 1979).

18. CHODOSH, D. F.,1979FallD.E.C.U.S. Symposium, Workshop onLaboratoryAutomation,SanFrancisco(November 1978). 19. CHODOSH, D. F., BUCKLEY, JR., J. T., LONGINO, G.,

SCHAINBAUM, J., WDZIECZKOWSKI, F. E., WINICOV, H. and BERKOFF, C.E.,MINC interfacing(1981 D.E.C.U.S.Symposium, Los Angeles,December1981).

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