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ISSN 1720-4003ANNO 15 - NUMERO 1/2 2016

Editorial Committee

January/February 2016 - anno 15 - N. 1-2

CONTENTS

PharmaChem is abstracted in: Chemical Abstracts Service, Chemistry Citation Index, BiotechnologyCitation Index, Derwent Biotechnology Abstracts, The British Library Document Supply Center,Hessler - Hancock info services, Abstracts in Biocommerce, SRDS, Infotrieve.

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In the next issue

MARCH - APRILFine & specialtychemicals

Outsourcing

Pharmaceuticals

Generics

Biotech

Drug Discovery & Delivery

FINE & SPECIALTY CHEMICALS

2 Dithiobutylamine. An improved reagent for reducing disulfide bondsMuhammed Majeed, Smitha Thazhathidath, Priti Vaidyanathan, Hemantha P. Hosahalli

14 Nature’s strategies for photosynthetic light-harvestingKouichi Urata

TECHNOLOGY

4 Thin-cake filtration technology to meet full containment for air-sensitive and toxic chemical and pharmaceutical productionBarry A. Perlmutter

10 Spray drying and screening of foods, pharmaceuticals,nutraceuticalsHenry Alamzad

PEPTIDES

12 Crossing cell membranes with (bi)cyclic peptidesPepscan

BARRY A. PERLMUTTER

BHS-Sonthofen Inc.14300 South Lakes DriveCharlotte, NC 28273-6794, USA

Tel +1 704.845.1190Fax+1 704.845.1902

barry.perlmutter@bhs-filtration.comwww.bhs-filtration.com

TECHNOLOGY

4 TECHNOLOGYJANUARY/FEBRUARY 2016

Thin-cake filtrationtechnology to meetfull containment forair-sensitive and toxic chemical andpharmaceuticalproduction

IMPORTANCE OF THIN-CAKEFILTRATION

T hin-cake solid-liquid separation can bedefined as the formation of a cake inthe 2-20 mm thickness range. In thisrange, cake compressibility becomes

less important in the cake building stage of aseparation process. Compressible cakes canbe better handled at thinner cake depths andhigher pressures. For example, an amorphouscrystal that does not centrifuge well can befiltered at 45 psig (3.1 barg) with a cakethickness of 2-3 mm. Thin-cakes also lendthemselves to more effective washing anddrying as there is less of a chance ofchanneling and the mechanism of “plug-flow”of liquids or gases is enhanced.

THEORY OF THIN-CAKE FILTRATION

FiltrationDuring the initial mechanism of cake formingin the filtration step, the filter cloth acts just toinitiate filtration by capturing the first particles.These first particles form bridges over thepores of the cloth (bridging). During this initialphase, smaller particles may pass through thefilter cloth leading to turbid liquid (filtrate). Assoon as a first layer of particles hasaccumulated on the filter medium, this cakewill then act as the actual filter medium.

When plotting the amount of filtrateobtained at constant filtration pressure versusthe filtration time, a filtration curve isdeveloped, which represents a root function,VF = Constant * tF0.5, as shown in Figure 1.

ABSTRACT & INTRODUCTIONIn many chemical and pharmaceutical processes, solid-liquid separation, cake washing anddrying steps directly impact the effectiveness of the production operation. Furthercomplicating these operations is the nature of the process and especially if the process isair-sensitive or toxic. Process engineers devote much of their time to analyzing these steps. The solid-liquid separation step can be by pressure, vacuum or centrifugation as well as ina batch or continuous mode. In this separation step, there is a further choice both of thetype of filter media and the thickness of the cake or the cake depth during which theseparation occurs. Cake washing generally follows and the choices are displacement orreslurry options. Finally, drying may be necessary and there are many possibilities includingvacuum, convection, spray, steam and a combination of techniques. This article discusses the choice of thin-cake (2-25 mm) pressure separation technology forfull containment, no residual heel and their benefits to optimizing the effectiveness of theproduction process. For full containment, the paper then continues with a discussion ofclean-in-place operations to meet current Good Manufacturing Practices (cGMP) guidelinesincluding riboflavin test and validations. ANSI/ISA S88 (and IEC 61512-1 in theinternational arena) batch process control system standards are also examined. Finally,factory and site acceptance testing is described.

JANUARY/FEBRUARY 2016 55TECHNOLOGY

The equation of the trend line for thisspecific chemical product was calculatedby Excel. The exponent of 0.4934 almostexactly corresponds to the root functionand the constant, in this case, equalled4.2534. Accordingly, the filtrate flow rate isat its maximum in the beginning and thendeclines as a result of the constantlyincreasing filtration resistance (as the cakethickens).

The important question that follows iswhat is the optimum filtration time, i.e.when is the most efficient filtrationperformance obtained? The filtrationperformance (P) is calculated using thisformula:P = VF / (A * ttotal), where ttotal = tF + tside

The side time (tside) includes thewashing time, the drying time and thetime for filter opening, cake discharge,closing, cleaning of the filter, if necessary,and other miscellaneous time. Everybatch-operated filter has these side times,which are usually constant from processcycle to process cycle.

When plotting the filtrationperformance (P, in liters/m2/hour), forexample, and including a side time of 15minutes (including washing and dryingtimes), the result is as in Figure 2. Fromthe curve, for this example, the maximumfilter performance is obtained when thefiltration time of 15 minutes equals theside time of 15 minutes. Themathematical formulas follow.

Mathematical Proofs for the FilterPerformance (P)

P = VF / A * ttotal Eqn 1ttotal = tF + tside Eqn 2tF / tF1 = V2 / V12 Eqn 3

By solving Eqn 1 with Eqns 2 and 3, theresult is

P = (V12 tF / tF1)0.5 / A (tF + tside)

From Figure 1, (V12 / tF1)0.5 / A =Constant, and therefore, FilterPerformance (P) is P = Constant * (tF0.5 / (tF + tside))The condition for the maximumfilter performance is based uponthe first derivative (d), where theratio of derivatives of the FilterPerformance (dP) to Filtration Time(dtF) is equal to zero:dP / dtF = 0 Eqn 4

and therefore: (tF0.5 / (tF + tside))’ = 0 (1st der = 0) Eqn 5By solving Eqn 5, the result is as follows: 0.5 tF-0.5 (tF + tside) - tF0.5 / (tF + tside)2 = 0 and therefore, the result is tside = tF.The conclusion is that the side times andthe filtration times must be as short aspossible and as equal as possible whichleads to thin cake filtration. Of course, onehas to ensure that the filter cake can stillbe discharged, as a thin cake.

PARAMETERS THAT INFLUENCEFILTRATION PERFORMANCE

Filtration PressureThe higher the filtration pressure, thehigher the filtration performance for a non-compressible cake. In case of acompressible solid matter, an increase ofpressure will often not result in anincreased performance because the filtercake gets more impermeable due to thecompression. Finally, the filtration pressuremay also impact the cake-forming layer,

which could lead to a turbid filtrate,if there is a “fine particle tail” in theparticle size distribution.

TemperatureThe higher the temperature of theslurry, the lower its viscosity. Thelower the viscosity, the higher thefiltration performance. As a generalrule, therefore, increasing thefiltration temperature will result inan increase in the filtration

performance.

Particle Size / Particle SizeDistribution (PSD)The particle size and particle sizedistribution are important parameters,which can influence the filtrationperformance. As the filter cake begins toform, channels (capillaries) are formedbetween the particles. The smaller thecapillaries, the higher the capillary pressureand thus the resistance of the filter cake.Small particles and a wide particle sizedistribution result in a densely packed filtercake and reduced filtration performance.In cases such as these, a thinner cake willmitigate this impact and allow forsuccessful filtration. Another alternativewould be to use filter aid, either as a

Figure 1 – Example of a typical filtration curve.

Figure 3 – Filter plate.

Figure 4 – Metallic filter plate.

Figure 5 – Filter plate stack.

Figure 6 – Elastomeric spacer forplate-to-plate sealing.

Figure 2 – Filter performance versus filtration time.

precoat or body feed, to increase thefiltration performance.

Particle ShapeThe type and shape of the particles alsoimpact the filtration performance. Hard,spherical particles will form a permeablecake with increased void volume leadingto high rates. Irregularly shaped crystals,platelet-type or flat crystals as well asneedles and amorphous crystals can packtogether and result is a dense and low-permeable cake. In cases such as these,once again, thin-cake filtration, lowfiltration pressures or filteraid mitigate the impacts ofthe particle shape.

Washing of the Filter CakeWhen washing the filtercake, there are twomechanisms that occur:displacement washing anddiffusional washing. Withdisplacement washing, alarge part of the voidvolume – which is still filledor saturated with motherliquor before washing starts –is replaced by the washingliquid. Diffusional washing isthe more importantmechanism to removebound or inner liquid. Theseliquids are removed by thediffusion washing, i.e. the

liquid to be washedout diffuses intothe washing liquid.The driving forceis the concentrationdifference.

Dependingupon the cakeformation, theremay be areas ofthe cake that havelittle or nopermeability.These portions ofthe cake wouldnot be efficientlywashed by eithermechanism. Incases such asthese, there aregenerally twoalternatives.

The first wouldbe a reslurry wash.The cake wouldbe discharged to areslurry vessel orreslurried in situ.The secondalternative, whichwould require lesswash liquid and less handling of solids,would be a thinner cake to minimize theimpermeable areas. This would allow for amore “plug-flow effect” for thedisplacement washing. For the boundliquids, there would be a lower concentrationof bound liquids, which would require lessdiffusional liquids and less contact time.

Finally, in terms of the parameters thatimpact washing, these would generally fallin the same category as the influences onfiltration.

Drying of the Filter CakeWhen dewatering the filter cake, the liquid

remaining in the pores shallbe replaced by gas(mechanical dewatering byblowing) with the objective ofobtaining a residual moisturecontent as low as possible.During blow-out operation,the capillary pressure of thepores must be overcome.The smaller the capillaries,the higher the capillarypressure. As soon as the firstcapillaries are blown through,the gas consumption risesand reduction of the residualmoisture becomes moreineffective. When this pointoccurs on the drying curve,there are two furtherapproaches that areundertaken. First, the cakecan be slowly compressed toallow for reduced gasconsumption during thismechanical dewatering stage.Secondly, vacuum drying canbe employed as well asthermal drying.

During the blowing phase,one of the most importantfactors for a low residual

moisture is a high blow out pressurerather than gas flow. Depending upon theproduct characteristics, time, temperatureand cake thickness will also impact thedrying curve.

THIN-CAKE AUTOPRESS“PRESSURE FILTER” TECHNOLOGY

The AP Pressure Filter technology wasinvestigated by the plant for filtration, cakewashing and drying for full containment ofoperations in an inert environment. TheAP consists of specially designed circularfilter plates with synthetic or sintered metal

6 TECHNOLOGYJANUARY/FEBRUARY 2016

Figure 7 – Plate stack and membrane(shown in red).

Figure 8 – Filter plate housing withmembrane (shown in white).

Figure 9 – AP internals with platestack and housing opened in thedischarge position.

Figure 10 – Elastomeric knivessequentially and automaticallydischarge the circular cakes.

Appendix A – Filtration, washing and drying graphs with scale-up.

77JANUARY/FEBRUARY 2016TECHNOLOGY

filter media. These areshown in Figure 3 andFigure 4.

The filter plates aresealed to each other byspecially designedelastomers to eliminatesolids, gas or liquidbypass. These are shownin Figure 5 and Figure 6.

The filter plates arecontained in a pressurizedfilter housing where agas-inflated membraneseals the annular spacebetween the housingand the filter plates. Alloperations are containedfrom full vacuum to 150psig (10.34 barg). This isshown in Figure 7 and Figure 8.

The entire filter housing is thenenclosed in a pressure-tight outer housingfor complete product containment (Figure 9).

The operation of the AP Filter beginswith slurry filling to form thin filter cakes oftypically 5-25 mm thickness. Pressurefiltration continues operating up to 8 barg.The cake can then be mechanicallycompressed to eliminate cracking toensure maximum washing efficiency in the

forward or reversedirection. Finally, the cakecan be pre-dried or fullydried either by vacuum orblowing gas through thecake in either direction.Final moisture contents ofless than 10% have beenachieved. This gentledrying without agitation ortumbling is important forfragile crystals andthixotropic cakes.Elastomeric knivessequentially andautomatically dischargethe circular cakes afterwhich the filterbegins a newcycle, shown in

Figure 10.

AP FILTER PROCESSOPERATIONS

The AP process operations beginwith filling and filtration. Filling iseither via the bottom of theplates or top and bottom forhigh-settling products. Cakewashing can then be in the

forward or reversedirection. Cakepressing may beused to preventcracks fromdeveloping in thecake. Cake dryingis, as cakewashing, in theforward or reversedirections andwith or withoutcake squeezing.The cake isdischarged andthen dependingupon the productrequirements, aclean-in-place(CIP) operationcan occur or thefilling cycle canbegin again. Thesix processmodules can berun as a manual,semi-automatic orfull automaticsequence. ThePLC provides thechoices to theoperator withfeedback to theplant distributedcontrol system(DCS).

AP FILTER TESTWORK

In this application, an air-sensitive specialtychemical is tested. Appendix A shows thefiltration, washing and drying graphsincluding scale-up. The filter media is asintered-metal screen with a removalrating of rating of 2-5 microns.

The initial testwork is conducted usinga pressurized pocket-leaf filter (PLF) with20 cm2 of filter area. These tests can beconducted in the customer’s lab or in theBHS laboratory and are used to gather thebasic filtration, washing and drying data.The PLF is shown in Figure 11.

Appendix B – PLC control systems with ANSI/ISA S88 batchprocess control system standards.

Appendix C – Riboflavin testing for Clean-In-Place (CIP)testing.

Figure 11 – BHS Pocket Leaf Filter(PLF).

FiltrationThe first optimization concerns the cakedepth versus the filtration rate. Filtration isconducted via pressure. A pre-measuredamount of slurry is added from the topand the unit is pressurized. When thefiltration begins, the amount of filtrateversus time is recorded at constantpressure. Other parameters that are variedsequentially include cake depth, filtrationpressure and filter media. As stated earlier,cake depths can range between 5-25 mm.

Washing Displacement washing tests are alsoperformed in the pocket-leaf filter. Foraccurate testing, it is necessary to smoothout any cracks in the cake. This can bedone in a number of ways either from thetop with a long spatula or by carefullyremoving the bottom part. A measuredabout of methanol wash liquid is added ina pre-determined wash ratio. Once again,pressure and time are measured.

DryingProduct drying in the pocket-leaf filter istested by blowing ambient-temperature or

hot gas through the cake as well as withvacuum. The pressure is kept constant andgas throughput is measured versus time.After a pre-selected drying time, the cakeis removed from the pocket-leaf filter, cakedepth is determined and then it isweighed and analyzed for the moisturecontent. After several iterations, the dryingtimes were optimized along with the gaspressure and flow rate to achieve thebetter than 20% final solvent content inthe cake.

BENEFITS AND CONCLUSION

The Autopress AP Pressure Filtertechnology is able to conduct filtration,cake washing, pressure and vacuum dryingall in a contained environment. Cakedischarge is complete and there is noresidual liquid or solid heel. This is animportant benefit for air-sensitive and toxicproducts.

The materials of construction providedfor all product wetted parts can bepolished stainless steel or alloys withrounded corners to eliminate product

holdup. The filter media can be metallic,synthetic or sintered stainless steel that iswelded to the filter plates. All process andmechanical operations are eitherpneumatic or electric which allowed for aclean installation.

The PLC controls (Appendix B) andincluding the functional specification,Factory Acceptance Test (FAT) and SiteAcceptance Test (SAT) all comply withGood Automated Manufacturing Practices(GAMP) guidelines. Finally, as part of theFAT and SAT, a Riboflavin CIP test,Appendix C, is conducted to demonstratethe ability of the AP Filter to be cleaned forbatch-to-batch integrity or product-to-product campaigns.

In summary, engineers must evaluateall outcomes to make an informed andsuccessful decision. Technical evaluation,laboratory and pilot testing are critical forsuccessful decisions and projects. Thetake-away is that close collaborationbetween the client and the vendorprovides for creative problem-solving andprocess filtration solutions to achieve theproduction objectives.

8 JANUARY/FEBRUARY 2016 TECHNOLOGY