Technical Article

Single Pot Processing

Microw wave D Drying

Microwave d drying is an a accepted dryi method fo pharmaceutical formula ing or ations, which is nonethele still relatively h ess unknown to some. This p paper attemp to give an overview of the most imp pts portant aspec of microw cts waves and the eir o tical processing. relevance to pharmaceut First a brief h history of the u of microwa use aves in the ph harmaceutical industry is giv ven. Some the eoretical backg ground on microwave properties is dis scussed to pro ovide a better insight into th reasons for the use of miicrowaves and for the existe r he r d ence of y Also the design of the curren available single pot proc n ntly s cessors equip pped with micr rowave drying is certain safety measures. A briefly discus ssed. Finally some consider rations related to the proces itself, such as parameter design, stability and regula d ss a atory concerns, are addressed. e

History
The first appl lications of microwave ener for heating and drying da back to the nineteen-thiirties (1). The development of the rgy g ate e magnetron during the Seco World Wa presented a challenge to the engineering and scientiific world to de ond ar evelop industr rial for ology. During the decades th followed major developm t hat m ments in the d design of magn netrons and applications f this techno extensive inv vestigation of m material prope erties have led to the adoption of microwa application in several industry sectors, d ave ns such as the f food, rubber, c ceramics, paper and other in ndustries (2). Also medical applications fo microwaves were develo or s oped as early as the n nineteen-fifties (3) (4). s Compared to other industr sectors, the pharmaceutic industry ha been a late adopter of miicrowave tech o ry cal as hnology. Only in 1979 the initial con ncept of combining microwa and vacuu was propos by ICI, and the first stattic-bowl microw ave um sed wave-dryer prototypes w were developed in collaborat d tion with T.K.F Fielder. In the same year, Dr. Schwabe an IMI develop a microwa nd ped ave vacuum belt dryer for dryin plant extrac (5). ng cts Although the static microw wave dryer prov the poten ved ntial qualities of microwave drying for the p o d pharmaceutical industry, pr roblems such as cakin and local o ng overheating led to the develo d opment of agitated microwa dryers in t mid-eightie and the firs ave the es st combined hig gh-shear granulator-microw wave dryer (Sp pectrum) was introduced by T.K.Fielder in 1987 (5) (6), followed by C n Collette N.V. in 1989 with the Vactr ron. The interest i microwave technology wa very high, a demonstrated by the fact that as early as 1989, an FDA workshop was in as as y F p held on which 4 major Ame h erican pharma aceutical comp panies presen nted their expe eriences with tthe technology to more than 100 y n FDA staff, an AAPS dedic nd cated a sympo osium to this n new technolog at their Ann gy nual Meeting (7 During the next decade, 7). e , microwave drying has gain a strong fo ned oothold in pha armaceutical production al p lthough the ad doption of the technology ha as more slowly the first anticipated and cu en urrently more then 100 micro owave dryers are in use at pharmaceutica p al proceeded m companies w worldwide to m manufacture a variety of drug of which many are appro gs, m oved by the F DA (5).

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Theory o Microw of wave Drying

Microwaves a a form of e are electromagnet energy with frequencies tic h between 300 MHz and 300 GHz, genera 0 0 ated by magne etrons under the t combined for of an elect and a mag rce tric gnetic field per rpendicular to each other (f figure 1). In the electro omagnetic spe ectrum they fal between rad waves and ll dio optical waves For domestic, scientific, medical and in s. m ndustrial purposes two frequencies are allocated that do not int o terfere with communicatio frequencies: 915 MHz and 2450 MHz ons a z.
Figure 1: an electromagn e netic wave in free sp pace

aceutical indu In the pharma ustry the most common freq uency used is s 2450 MHz, because of the advantages this frequency offers in conjunction with vacuum (8). e t y v Microwave fie elds are reflec cted off metals which they d not heat. For this reason metals are us as condui for the s, do sed its microwaves, or wave-guide and as wa for a micro es, alls owave oven. As pharmaceut A tical equipmen is manufact nt tured from sta ainless cuum chambe acts as conf er finement for th microwaves by reflecting them back intto the chambe he s er. steel, the vac Many materia are transpa als arent to micro owaves and do not heat eith Examples of such mater o her. rials are quart glass and P tz PTFE, which can be used as micr e rowave window ws. The most imp portant proper of microwa fields howe rty ave ever is absorp ption of microw waves by the m materials, as materials that absorb m microwaves a heated (9) are ). Microwave he eating is a dire method of heating. In th rapidly ect f he alternating el lectric field generated by microwaves, po lar materials orient o themselves ac ccording to the direction of t field. The rapid e the and reorient t changes in th field at 24 MHz, the orientation of the field chan he 450 nges 2450 million t times per seco cause rapid reorienta ond r ation of the molecules, re esulting in frict tion and heat creation (figur 2). re This type of h heating is insta antaneous, un niform and pen netrating throughout th material, which is a great advantage fo the process he t or sing of pharmaceu utical compou unds (9).
Figure 2: Di-pole rotattion in a microwave field e

As already m mentioned above, different materials have different m e properties wh exposed t microwaves related to th extent of ab hen to s, he bsorption of the microwaves s. The amount o microwave energy absor of rbed is expres sed by the following equatio (10): on P = 2 f v E0 Er tan Where P = th power dens of the material = energy absorbed (W he sity y W/m) f=f frequency (Hz z) v = electric field (V V/m) rmissivity of fr space (8.8 x 10 ree 85 E0 = dielectric per Er = dielectric con nstant of the material m tan = loss tangent
-12

F/m) )

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For a given m material and a given electric field, 2 f v E0 is constant, and the abs c sorbed microw wave energy is proportional t the s to term Er tan, called the los factor. Mate ss erials with a hiigh loss factor will readily ab r bsorb microwa energy, while materials with a ave w low loss facto are either re or eflecting or tra ansparant for m microwave energy. Given the cha aracteristics o the materials commonly u of s used in pharmaceutical prod duction (table I), microwave energy is very well suited for dry ying of pharma aceutical formulations. The liquids most fr requently used for wet gran d nulation (water alcohol, ) have r, much higher loss factors th the other standard ingre han edients for a wet granulation (lactose, cor starch, ), leading to hig w n rn gher absorption of microwave e f energy and thu preferential heating of the liquids. us e For many ma aterials these properties hav been invest ve tigated and ar published in tables and m re n monographs (1 11). Table I: Loss factors of c s commonly us ingredien for pharma sed nts aceutical form mulations
Commonly used excipients Ma aize starch Avicel Ca arbonate Manitol Calcium Phosphate Calciu Carbonate um L Lactose (Polypropylene (Teflon 0.41 0.15 0.08 0.06 0.06 0.03 0.048 0.0027) 0.0003) Metha anol Wat ter Etha anol Isoprop panol Aceto one (Ice Commonly used solvents y 13.6 12.0 8.6 2.9 1.25 0.003)

t e s t This phenomen is related to the non An important fact about the loss factor is that it chang es with the temperature of the product. T relaxation fre equency of ma aterials. The re elaxation frequ uency is the time required fo build-up and decay of the order induce by or d e ed an electric fie This frequency increase with the tem eld. es mperature of th material. As the efficienc or the amo he A cy, ount of energy converted int heat by eac cycle of dipole rotation, is optimum whe the microw to ch s en wave frequency coincides with the relaxation cy frequency, th amount of m he microwaves ab bsorbed by a m material and thus the loss factor will d d s differ with the temperature o the of material. In fi igure 3, the ch hange in loss factor with the temperature of some food products is ill ustrated. f e As can be se in figure 3 the loss fact of water een 3, tor decreases with increasing temperature. The reason f this w g for is that at roo temperatur the relaxation frequency of the om re, y small water molecules is a already larger then the micr rowave frequency, and with increa a asing tempera ature it moves further from the mic crowave freque ency, resulting in a lower g absorption of microwave e o energy. ever, the relax For larger molecules howe m xation frequen at ncy room temperature is often lower then th microwave n he a asing tempera ature it moves closer frequency, and with increa
Figure 3: Loss factor vs. Temperatur re

to the microw wave frequenc resulting in more energy cy, n y

conversion. T This increased absorption of microwave e d o energy will res in an incre sult eased tempera ature, which in its turn will again n lead to increa ased absorptio This pheno on. omenon is callled thermal ru un-away, and is illustrated in figure 4. As most pharmac n ceutical processes ar executed at a temperatur lower then t critical tem re t re the mperature of th most comm pharmace he mon eutical ingredie ents and the mode microwave dryers are executed with a ern e e accurate prod duct temperatu control, the risk of encou ure e untering therm runmal away in a pha armaceutical process is min nimal (2) (9).

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ortant characte eristic of micro owaves, espec cially related to the combina t ation Another impo with vacuum drying is the b breakdown ele ectric field of g gases. This ch haracteristic is the s at place. At atmo ospheric press sures, electric field a which a discharge of the gas will take p the risk of a b breakdown is low, because the high frequ uency breakdo own electric fie is eld high. When the pressure is reduced, the breakdown e s e electric field is significantly reby increasing the risk for a breakdown. lowered, ther A discharge o the gas can be observed as a glow or arc, and is dis of n sadvantageous because of p possible damage to the prod duct or the equ uipment and because it b represents lo of power (2 In modern microwave dr oss 2). ryers, many pr recautions hav ve been taken to avoid such d o discharges (se next paragr ee raph).
Fig gure 4: Thermal run n-away phe enomenon

Microwa Drying System ave g ms

Although mic crowaves are u used in differe types of eq ent quipment for example microwave vacuu belt dryers (5) this pap will r um per only discuss the so-called Single-Pot systems, or high shear granulator-dryers, equipped with microwave dr h e rying capacity. . Magne etrons are the source of mic crowave energ and have either a fixed o gy output or a va ariable output. . Fixed o output magne etrons regulate the forwarde power to the processing v e ed e vessel by cyc cling on and of Usually they have a low p ff. y power and sev veral magnetro ons are mo ounted on the lid of the bow to allow step wl p-wise control of the microw wave input in the produc nto ct. Variab output mag ble gnetrons contr power direc by adjustin wattage an rol ctly ng nd usually have a highe output level They are loc y er l. cated in a separate area and the d microw waves are guid to the processing vesse by wave-guides. This setup ded el allows easier access for servicing but requires proper tuning of the wave-g s g, g guides f to avoiid reflection of microwaves to the magnettron. As ma agnetrons gene erate heat, the have to be cooled using either air of w ey water. The la atter is the mos efficient way of cooling m st y magnetrons giv the greate heat ven er
Figure 5: Top drive Single Pot Proces e ssor: UltimaPro 600 ( (GEA Pharma Syste nv) ems

capaciity (8).

owave dryers are equipped with several f features to ensure safe ope eration of the s system for the operator, the Modern micro product and t equipment. the e All microwave equipment h to comply with the guide has elines for micr rowave leakag specified by the Center for Devices an ge y f nd Radiological Health within the FDA and by the Americ National Standards Institute (12) (13) which is 5-m can S ), mW/cm maxim mum y c T exposure at a distance of 5 cm from any surface of th e microwave cavity and at a frequency off 2450 MHz. The equipment manufacturer include safe features su as microw rs ety uch wave chokes and conductive seals into th design of microwave proc a e he m cessors to avoid any microwave lea akage from the vessel. In addition to these feature to avoid lea o es akage, the ava ailable microwave systems are designed w safety interlocks to avo a with oid accidental ex xposure. For e example, micro owaves can o nly be activate when the process vesse is operating under vacuum and ed p el m all bowl open nings are seale off. ed

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nts rototypes of m microwave drye often reported problems with tempera ers s ature control of the Early reports on experimen with the pr ng, heating and ev burning of the product. These problems were main related to design issues or lack ven f nly d product, arcin local overh of experience with microwa drying. e ave All modern m microwave drye have an optimized desig for microwa drying fo example, sh ers gn ave or harp edges an loose conta nd acts between met parts are av tal voided, becau discharges could occur there. Also the control syste use s ems have bee optimized to en o include differ rent process controls, such as temperatur control, mic re crowave reflec ction control an arc detectio Important nd on. parameters s such as forwar rded power, re eflected powe r, product tem mperature, ene ergy added, ettc. can be mon nitored in real-time and maximum limits can be set to contro the process . m e ol Finally, to avo local overh oid heating of the product the p possibility to mix at low spee or to use a swinging bow to move the m ed, wl e product is off fered.

Process Conside erations

Directly conn nected to the e early observations mentione in the previous paragraph came also th concerns about a possib ed h he a ble influence of m microwave dry ying on the gra anule characte eristics and stability of the product. p Many studies have been p s published in the mean time s showing no dif fference in either stability or physicochem r mical propertie of es granules drie with microw ed wave-vacuum processing, co ompared to ot ther drying me ethods such as tray drying or fluid bed dry s o ying. As microwav are nonion ves nizing and do not posses the necessary amount of ener required fo the formatio of free radic n e a rgy or on cals or n ter, n g d ster product instability (8) (14) (15) the liberation of bound wat there are no conditions created during microwave drying that fos (16) (17). The fact that many drugs, manufactured with microwa d ave-vacuum processing, hav been appro ve oved by the FDA and other odies world-wide without req quiring additio nal stability or analytical tes r sting apart from that normally required for other m r regulatory bo manufacturin methods co ng orroborates the safety of usiing microwave for drying pharmaceutica formulations (8). e es al s It also refutes the fear of m s many companies that in case of a change of the manufa e acturing proce to microwa drying the ess ave e regulatory bo odies would re equire extensiv validation, s ve stability and analytical data. A conversion from an approved manufa a n acturing process to a microwave dr rying process for an immediiate release so oral dosag form in the US is governed by the FDA f olid ge As SUPAC IR G Guidance docu ument (18), jus like any othe change in such a manufa st er s acturing proce ess. In 1992, a survey was d done by Robin and co olleagues of 8 European reg gulatory bodie to determine the implications of conver es e rting an approv fluid bed d ved drying process to a microwave dr rying process. None of the a agencies required more data than could b expected fo similar types of a be or ng hange in process or equipm ment). Most of the agencies required only process validation data, an 3 nd manufacturin changes (ch suggested lim mited stability data (up to 6 months of acc celerated data (19). a) The design o a microwave drying proce however st requires the careful cons of e ess till sideration of th different pa he arameters invo olved and their inte eraction to arrive at an optim result. mal One of the m most important interactions th need to be taken into ac hat e ccount is the interaction bettween the pres ssure in the bo owl and the micro owave level. A explained above, the risk of electric breakdown incre As a k eases when th pressure in the bowl he n decreases. H However, when a higher pre n essure is used for the proces the evapor ss, ration tempera ature of the gr ranulation liquid is also higher, leading to the fact that in the initial phase of the drying process, the microwave en e m nergy will most likely be used to t d product instead of for evapo d oration. Depen nding on the te emperature se ensitivity of the product, an optimal balanc e o ce heat up the p between pres ssure and mic crowave level needs to be d determined. To avoid any ad o dverse effects of the use of microwaves o outside the practical range of press sures, most manufacturers of microwave single pot pro m e ocessors have restricted the pressure ran in e e nge waves can be activated to 30 100 mbara a. which microw

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ower levels ar also importa in relation to the porosity of the granu re ant y ules. As microw waves are instant Vacuum and microwave po on e orate immediately after the m microwaves are switched on If the n. and penetrating, granulatio liquid inside of the granu les can evapo rate exceeds t migration rate of the vap towards th granule sur the por he rface, a pressu build-up in ure nside of the gr ranule evaporation r can occur, po ossibly leading to explosion of the granule and creatio of fines. Low g es on wering the mic crowave powe level or incr er reasing the working p pressure may eliminate this effect. eters to consid are the me Other parame der ethod and freq quency of agit tation of the pr roduct. Agitatiing the produc is necessary to ct y ensure an ev power dist ven tribution throughout the prod duct bed. Too much agitatio can howeve lead to attri o on er ition of the gra anules and creation of fines. For this reason, ve low mixer s ery speeds and th possibility fo intermittentt mixing are av he or vailable for all single ors. ng t he winging bowl is offered by GEA s pot processo As an alternative to usin the mixer a rm to agitate the product, th use of a sw Pharma Syst tems nv in the UltimaPro range. eir Finally, the co ontrol of the ja acket tempera ature during m microwave drying can have an important im a mpact on the yield of the pro y ocess. As the microw waves supply most of the energy needed for drying, the heated jacket of the bowl does not nee to act as an d ed n energy sourc Therefore, its temperature can be con ce. ntrolled to a tem mperature slig ghtly above or below the pro r oduct tempera ature to avoid caking of the produc ct. Endpoint con ntrol of the dry ying process is another impo s ortant aspect of the microwa drying pro o ave ocess. All micr rowave dryers offer s the possibility to use produ temperatur as endpoint for microwav drying. Prod y uct re t ve duct temperatu is a good indicator for th end ture he of the drying process if the formulation contains ingred e c dients with a relatively high loss factor su as cornsta r uch arch. However if the r, formulation c contains only ingredients wit a low loss fa th actor (for exam mple lactose), product temp perature will rise very slowly and y, over-drying c could occur if t endpoint of drying is onlly based on pr the o roduct temper rature. In those cases, the amount of refle e a ected power gives a good additio onal indication for the endpo n oint, as reflect power will increase towa ted ards the end of the process, o because less microwave e s energy is abso orbed into the p product. Addit tionally, the UltimaPro of GEA Pharma Systems nv is s equipped with a calibrated power measu urement (forwa arded and reflected) allowin the calculattion of the exa amount of energy ng act nergy added ca then be us as a valida sed ated endpoint for drying if a known amoun of nt added to the product. This amount of en an d. liquid has to be evaporated

Conclusions
Although mic crowave techn nology has bee around sinc the Second World War, its application in the pharma en ce d i aceutical industry is relatively rece Single Po Processors equipped with microwave drying were on introduced 15 years ago. The properties of ent. ot h d nly microwaves m make them ho owever very well suited to d ry pharmaceu w utical formulations in a fast a elegant way. The mode and w ern microwave drying systems are all equipp with the n s ped necessary safe measures to ensure com ety mpletely safe processing for both p r reful design of the process parameters is necessary to obtain optima results from the f p al operator and product. Nevertheless, car echnology in p pharmaceutica production. al microwave te For more det tailed and exte ensive background about th theory of microwaves and its industrial applications, I refer to the b he d book Industrial Mi icrowave Heat ting by A.C. Metaxas and R Meredith (2). M R.J.

n by Griet Van Vaerenbergh Product Manager Single P Processing Pot g GEA Pharma Systems nv a v Keerbaan 70 0 B-2160 Wom mmelgem, Belg gium Tel. +32 3 35 1211 50 Fax +32 3 35 2055 53 griet.vanvaer renbergh@gea agroup.com GE Pharma Sy EA ystems

Referenc ces
1. 2. Pus schner H. Wr rme durch Mik krowellen. Phil ips Tech Bibl., Eindhoven, 1964. Met taxas, A.C.; Meredith R.J. In ndustrial Micro owave Heating Power Engineering Serie 4; Peter Per g, es regrinus Ltd.: London, 1983 3. 4. Rob berts, J.E.; Cook, H.F. Micro owaves in Med dical and Biolo ogical Researc Brit. Journ Of Appli. Ph ch. n. hys. 1952, 3, 3 33. B.W Clark. Micro W. owave Diather rmy in Ophtalm mology Clinical Evaluation Trans. Of th Americ. Aca Of Ophth. 1952, n. he ad. 56, 600. 5. 6. hl, Pot or rmaceutical Granules. Phar Techn. Eu G rm. urope 2000, 12 (5), 23. 2 Stah H. Single P Systems fo Drying Phar Wal ldron, M.S. A History of Microwave Drying Proceeding of the 2nd Single Pot Pro g. gs S ocessing Work kshop, Collette e, Wom mmelgem, Be elgium, Feb 25 5-26, 2002. 7. 8. Lucisano, L.J.; Po oska, R.P. Mic crowave Tech nology Fad or the Future? Pharm. Tec Int. 1990, 14, 38. ?. ch. 1 Gar rcia, T.P.; Luci isano, J.L. Sin ngle-Pot Proce essing. Handb book of Pharm maceutical Gra anulation Tech hnology, Parikh h, D.M Ed.; Drugs and the Pharm M., maceutical Sc ciences; Marce Dekker: New York, 1997; Vol. 81, 303-331. el w 9. Krie eger, B.; Allen, R.D. Industrial Microwave Technology, joint paper pre , j esented at the Annual Meet e ting of the Rub bber Division of the Am merican Chem mical Society. 10. Wal ldron, M.S. Microwave Vacu uum Drying of Pharmaceuticals: the deve f elopment of a p process. Phar Eng. 1988 8, 9. rm. 8, 11. Wad A. Handbo of Pharma de, ook aceutical Excip pients, The Ph harmaceutical Press, Washiington, 1994. 12. Perf formance stan ndards for mic crowave and ra adiofrequency emitting prod y ducts, 21 CFR Part 1030, Washington, DC R W C: Gen neral Services Administratio 1 April 198 461-464. s on, 88, 13. Elec ctromagnetic f fields, safety le evels with resp spect to human exposure to radiofrequenc ANSI C.95 n cy, 5.1-1982; Ame erican Nati ional Standard Institute, New York, 1982 9-10. ds 2, 14. Man ndal, T.K. Eva aluation of microwave drying for pharmace g eutical granula ations. Drug D Dev. Ind. Pharm. 1995, 21, 1 1683. 15. Mos R.A. Demo ss, onstration microwave/vacu uum drying of pharmaceutic cals. AAPS An nnual Meeting, Washington, DC, , Nov 17, 1991. v. 16. Pos ska, R. Integra ated mixing gra anulating and microwave dr rying: a develo opment experiience. Pharm. Eng. 1991, 11, 9. . 17. Van Scoik, K. Mic n crowave vacuu processing in the Vactro 300. AAPS Annual Meetiing, Washingt um g on ton, DC, Nov. 1991. 18. Imm mediate releas solid oral do se osage forms: s scale-up and postapproval changes: chem p c mistry, manufa facturing, and controls; in vitro d dissolution tes sting; in vivo biioequivalence documentatio guidance. Fed. Reg 60:6 e on; 61638-61643; FDA, ; Was shington, DC, 1995 19. Rob P.; Lucisano, J.L.; Pearl bin, lswig, D.M. Ra ationale for the selection of a single pot m e manufacturing process using g micr rowave/vacuu drying. Pha um arm. Technol. 1994, 18, 28

version of this paper was originally pub s o blished in the Autumn 200 issue of Ph e 03 al harmaceutica Visions A reduced v GE Pharma Sy EA ystems