364 Lactose, Monohydrate 16. Young PM eta Characterisation af x surfer modifi dy powder inhalation carve peared by ‘parsile snooty) Pharm Pbarmocol aang, $4 1359-1348, 17 babe D era. Novel tmperatre controlled curice desolation of ‘excipient paces for caret based dy powder tales formulation, ‘Drug Dev ind Phar 2006, 32: 243-25h, 18 Kaman Me wl Appheation and rachanism of inhaacon_ pote improvement of DPLoemelscons by mechavofosion with mes stcurate, Chet Phar Bal (Tokyo) 20085 86 17-528, 19 Gichaed Be al nlaence of fn lactose and magnesim stearate on low dose dry powder inal formlatons. be) Phorm 2008; 348: 10 i 20 General References ‘CDE. Guidance fr industey Metered dose nhaler (MD) and Uy powder inhaler (DP) drag. peoduets (deaf. Kock, MD. United. States Depstiment of Health and Human Secvices, Food and Deig Adin testo, Caner Drag Evaaton and Reseach 1998, DMV.Fenterea Exeipients Tecbsieal Merature: Rerpitse, 2008, bp ‘woizdi-foncereaexcpints.com (accessed 27 Februsy 2009), Dyno. Technical erature: Laeroble, 2008, hpyhwedeme. phar Taesesed 37 Flay 2008), Lactose, Monohydrate 1 Nonproprictary Nemes BP: Lactase Phe: Lactose Monohydrace Pe Lactose Hydeate USP-NE: Lactose Monohydrate 2 Synonyms Capsul.acy Granulac Lactochem; lactoswm monohydicum; Monohydrate; Pharmatose, PrismaLae; SacheLac SorboLac, Spherol.acy SuperTah 30GR; Tabletiose For grades, ee Tables land Ii 3 Chemical Name and CAS Registry Number (©-P-v-Galactopyranosyl-{1—r4)-s-D-glucopyranose drate (5989-81-1], [10039.26-6]; [64044515] ‘CAS Registy numbers for lactose monohydrate are [5989-81 1} (lactose monohydrate}, [10039-26-6} (lactose monohydrate, cyclic) ar [64044-51-3] (lactose monohydrate, open form) monohy- 4 Empirical Formula and Molecular Weight CyHaaOy HO 360.31 EMEA. Commie tor Medial Peoductsfor Human Use, Godaner on the Dhasratcutal quai of talason and meal products EMEAICHTMY QwePs4931 512008 Core Landon 12 fe 2006, Fesland Foods Dou hupdiwreloctecom! assessed 27 Felnuary 300%) Kacruee [5 e al Casio or DDI: formulation and ceglarory challenges. Phar Toh Bar 2006, 18(103 25-30, Kassendrager K eal. A new DSC metho for the deetion of very low “amorphous contents in leton cares for dry powder tales, Fre APS “Annnsl Moet, 2005. hapslaew-asporglabsctd ‘AML 200578,52008 0017p (ceed 27 Febnonry 2009}, Merule GmbH. Technical erates Inulae, 2008. npirwnegae- plier de (accessed 27 Ferasry 2009) Sell Darna Ingreane.Techotcalineaeure ubaltion actos, 2008 Ihupsfowe shethel-producucoms (ace 27 Febery 2009), 21 Authors 5 Edge, JS Kacrger,} Shur 22 Date of Revision 27 February 2009, 5 Structural Formula HoH 0 HoH oOo. on 0, rt “Ho on ‘sLactose monchyerate The USP32-NF27 describes lactose monohydrate as a natural disaccharide, obtained fran milk, which consists of ane galactose fund one glicose moiety. The PhEur 6.5 and JP XV describe lactose ‘monohydrate as. the monohydrate of O-f-o-galactopyranosyl- (Inod)aeb-glucopyranose, It ie stated in the USPS2-NF27 that lactose monohydrate may be modified as to its physical charactor istics, and may contain varying proportions of amorphous lactoxe 6 Functional Category Dry powder inhaler carrer lyophilization aid eabler binder; table, nl capsule dens; cable and capsule file 7 Applications in Pharmaceutical Formulation or [Lactose is widely used a8 afiller and diluent in eablets and capsules, and co 4. more linitad extent in lyophilized products, and infant Formalas."""" Lactose is also used as a diluent in dry-powder inhalations seeLactose, Inhalation. Various lactose grades are mercially available that bave dtferent physical” progertos such a6 particle size distribution and flow characteristics, This permits the selection of the most suitable material for a particular application; for example, the particle size range selected for capsules Js often dependent on the type of encapsulating machine: wed.lactose, Monohydrate 368 Umally, fine grades oflactore ate used inthe preparation oftablem SR 2; Excipen SuperTab OG; monuacrer: OMWowero bythe wecaranulationmethod or when sling dering proccsing eben ced ou, since che ne ae allows, beter mong wih ther Crm edd she nd ae ey Other applications of lator inctate use fyi prodacs, where atone faded to free ried solutions to Frese pl sot Sand aid cohesion, Lactore is also wd n combination with sucrose [approximately 1:3) to prepare sugar-coating solutions. It may also be used in intravenous etons. Uetose also cd io the manuficwre. of dry_ powder Jormilations for use se agucous film-costing solitons or Suet Dine sompret grads of ate monohydrate ar vaiable 4s granuistedigglomvrated velactene monohydrate, containing farous of anhydrous actors Divecrcomprestion grades ate ofien used, to carry lower nitetcomprsson grades are ogy Oo ea we 2H 3: Expl lagechon Copa: morlccma: Fedand Foods granites of drop and this permis ables to be made without 5 ee Reat a 360s vchig’ TOW Other del compressible latoses ae spray-dried lactose a ankydrous locos se Lactose, Spray-Diied and Tey Nays drow. 8 Deseription In the solid state, lstose appears a6 various isomeric forms, ependmg on the enstalization and dying, conditions, ke 3. Inctose monohydrate, lactose anhydrous, and clacose hy~ deous, The sable crystalline forms of terose ate olatone ‘monchydrae,lactos: anhydrous, and sable lactose aliydrous Tactose otcurs as white to olf white erysalline parler or powder Lactose odorless and Slightly sweetttings lta Approximately 20% asset a9 s¥cose, while Pactose 0% 48 9 Pharmacopeiel Specifications See Table I. See alo Seton 18. 10. Typical Properties {304 Expo tadochom Crystals, morloewer: Freon Foods Dono mogaeaten 700%" Brite ear tudor magncaon. 700 wahage: TOW (0.0749 (at compeesion pressure 189.5 MPa) 8.0883 (at compresion pressure 191.0 MP) soning macs 0.0081 {ot compreson pressure 189.5 MPa 0.0052 (at compresion pressure 191.0 Mf). Density fue) 1345 fam (lactose nonhydrate} Density (bull) see ible I ti 1+ Excipion: Phometose 125M monufgcuer: DMV-ontara Exeipients magrifcarion: 100%; voogo: 1-5 KV. Deetsity (tapped) see Table T. Loss om drying Typically 0.3% for Monobydrate 80M, Mono- Dyerate lmpalpable, and 010.2% for Mepale products, Melfing point 201-202°C. (for dehydrated a-itetose monohy- rate} Moisture content Lactose monohydrate contains approximately 5% whw water of erystllization and nosinally bas a range of 4.5-5.5% wh water conten, See Table I [NI spectra see Figure 1366 Lactose, Monohydrote Tole: Phormacopeiel specications fr lactose, mondhydote. Tet px Pheu 65 UsPan.nra7 Weieston + ' horace : ; L Papers st ? + cider olay + 7 + Speke opel on 154A Io SAA‘ 154A Na se ssa s5e Pron ond ight 4 - . ‘baoring iepetiee abeotoanee. 1210-2200 — <025 0.25 0.25, S276-000m Soar = 200? Sar 000m Zoo, = E004 20.04 Hoy met SSppm, Ssrpn 514 ‘wero Eke BER EI Subood oo = sume Residveonignion GOK, 201%, toes on ding cose SOR" ‘ers hint “Kerbie boaaio <100ev/y 10%elv/g— 100c/g Fangiond yea =50eh/9 =s0d/9 Abeer ‘ > ' “chovchia cob Abeonce ah ' - = Pee eet te) Moated marcha frm, not mate ho 1%, Particle size distribution see Table 1. Permanent deformation pressure 370.0 MPs (a compression pressure 189.5 MPa}; 485.0 MPa (a compression presure 191,0 MPa)" Reduced modulus of elasticity 1472 fat compression presure 189.5 MPa}; 5155 (at compression pressure 191.0 MPa)" Soluble Tae. Shecifie rotation [xi = 54.4" t0-+55.9° asa 10% st solaion Tacse exhib mutaroration, anda equirium mixture conmaining 62% JMacese and 38% lactose is abeained ‘astanly on the addition of a tace of ammonia, ‘Temil strong 2.987 Ma (at compression pressure 189.5 MPa) 2.517 Ma (at compression presute 191.0 MPa)" Water content sce Table Methods for charactercing the mechanical properties of ‘compacts of pharmaceutialingredicns are specified in the Hama book of Pharmacentical Excipionts, bl edn!" Table IV: Soli oflodore. Solvent Sobbilty of 20°C unless stherwice stated CChorlorm Pracicly insoluble onal Procol insoluble Eher Prociealyinsolble Water Ving2d 1n3'05 ot 40-c 1n2.30 01 50°C Vin 71 ot 60 1in0'96 61 80°C 11 Stability and Storage Conditions: Mold growth may occur under hurnid condicions (80% relative humidity and above) Lactose may develop a brown coloration on. Tablet ical proper of selected commercially owe Icom ney M Sopp /rade ensty Deny Water teak” Roped can teven’) fem DMV-FontorraExcpionts Phomere Sone 70 og = Promote cone Sm 998 = Promotes 744 ar get Promoter 60! 8% om = Promenee 90te of 990 = Pomorie 100M 87 Smet homers 1084 ee Plomote 12594 03 as = Promote 13084 283 O98 = Pheotss 130¥e 982 G90 = Phomaois 200% 037 Og = Pramas 33046 pe Plomance 460 oe om = To 3008 933048 = Frledond Foods Domo Insechon Cause Cys «O75, 8B ittchon Cyucs S76 {tcechon Fine Cae er {tovchon uroRlecatok 0788 = inckchan CoonePowder” = O71 G98 = lacechon frond = O32 O98 tach Powder O84 089 {ecocha Fie Powder ost See S {Sckcham Butane owder O45. O74 = taoccham Sipsrfne Power O47 «O74 = tego Om Copan 60 059 070 52 Sihrtac 28 87 9% 33 Srontac 140 858 fg 32 Seatac 200 851 08 52 Sronetac 280 8a 8% 3 fratae 40 a 43833 Sorfelac 66 880 G71 33 Sees 400 83 (O7e 33 Sphrtac 100 O39 08a 8 those 70 os 08233 Icloose 60, an ‘eden 100 So 0433 Sheffield Phorma Ingredients Maahycram B01 0s og © 40-52 Merle npopebe 83) bar 4533 storage, the eaetion being accelerated by warm, damp conditions, see Section 12. The purities of differen lacroses can vary and color evaluation may be important, particularly if white tablets are being formulated. The color stabilities of varions lactones also dfer ‘Solutions show murarotation; se Section 10. TEactose should be stored i a well-closed! container place 12. Incompetibilities A Maillad-type condensation reaction is likely to acour between lnetose and compounds witha primary amine group to form brown, or yllow-brown-colored products." The Maillacd interaction has also been shown to occur between lactose and secondary amine. However, the reaction sequence stops with the formation of the {ine, and go yellow-brown coloration develops: Lactose s algo incompatible with aruino zcids, amfeeamuines," and lisinopril!" cool, dry 13 Mothod of Manufacture Lactore is a nacural disaccharide consisting of galactose and flucose, and i presencia the milk of most manatoals, Commercially, Inetose is produced fom the wey of cows" milks whey being the367 Lactose, Monohydrate - - - - = 9662 = bees = ot 86 = “ = o wz = wo & = = wes = 7 = poor “a = - 96 s = - ~ ~ = ses 8 Be = = = oot = o = = 5 Cr ~ - 7 ° = = ~ ~ - = - 2 = 568 = - = = = = = 58 - = = = = = oot 08 = gots = = = ~ oe = qoot 6 - o 7 st $ = = = = = 9s = = = a > use = = = = = we = = = = = = ase = = = - = = = = = = = : = BE = sess 7 - — pss - RE = eve - = HPL = nose = = cor - = 7 = = = = fete = = ~ - = oo = = we = = = = ase = we ase - - = oot ~ = Se one = = = = Zee = = = = = = = = we ase = = = oot = = osse omve = = = — 662 = Foe = = = = oo - = ess ors = = =e eae = = oes = ws = = 08-08 = sre - = Be = = so = oro = = = ove — = oe ~ = ee a HUB rion ' f oc : = - = w= age = = = oe = = = sees = = = Ose = os = = = = oor ore = = Se 2 = = 8 = = =e = = cs = = = se = = = (od wourgun ons epuid oth, p08 " “2iaifouou “aso5e aqaIENS KypseKkua> persaex > UONTAURP Bem ePwN AN FOL368 Loctose, Monohydrate ie fi 1000 x [2nd deriv. logl 1/2] -12 *00 13001500 1760 T960 760 7200 7500 Woavelength/am Figura 1: Nears spectum of acoso morohycae eased by reflectance. residual liquid of the mil following cheese and casein production, Cows’ mille contains 44=5.2% lactose; lactose constiauzes 38% of| the total solid content of milk, ‘eLaciose monohydrate i prepseed by crystallisation from supersarueated solutions balow 93.5°C. Various crystalline shapes 41€ prism, pyramidal, and tomahawk; these ace dependent on the method of precipication and erysalliztion. Direct compression trades of cclactowe monohydate are prepared by granulation! Agglomeration and spray-drying 14 Safety Lactose is widely used in pharmaceutical formulations asa ile and fillee-bindce in oral eapsle sd tablet forenslations. tay also be used in intravenous injections. Adverse reactions co lactose are largely attributed to lactose intolerance, which ovets i individuals With a deficiency ofthe intestinal enayine lactase!" Ths esuls fin laccose being. undigested and may lead ta cramps, diarrhea, Ustnsion, and flatulence. In lactosetolerant individuals, netase bhydrolyzes lactose in the smal intestine ro gliacose and galactose, which are then absorbed, Lactse levels are normally high at bith, and levels decline rapidly in early childhood. Malabsorption of ctase thypolactasia) may occur a¢ an carly age (4-8 years) and aries among diferent ethnic groups, Lactose is excreted unchanged ‘when adausisteredinctavenouly. “Tse symptoms of lactose intolerance are caused by the osmotic effect ofthe unabsorbed lactose, which increases water and sodium levels in the lomen. Unabsorhed lactose, upon reaching the colon, ‘can be fermented by colonic Mora, which produces gas, causing Abdominal distension and discomfort lactose tolerance test has teen developed hased on the measirement of blood glucose level and the hydrogen level in the breath, However, ie usefulness has been questioned asthe tes is based on 2 50g dose of lactose. ‘Approximately 10-20% of actore-ntolerant individuals io two, seucies, showed clinical symptoms of intolerance after ingestion of 3-54, of lactose" Tn one ofthe stacies,"*" 75% ofthe subjects had Symptoms with 12 g of lactose (equivalent 10 250 mo rll In another" eight que of 13 individdals developed diarrhea atte, the administration of 20 of laccose, and nine out of 18 afer the administration of 25, Lower doses of lactose produce fewer adverse effets, and lactose is boner colerated if caken with other foods, Asa result, there i a significant population with lactose malabsorption who are sil able to ingest normal amounts of eto, wach that in ly, wont the development of adverse side effects!” Mose adults consume abut 25 4 of lactose per day (S00mL of cnilk) without sympioms."®""" When symptoms appear they are usually mild) and dose-related. ‘The dose af lactose’ inmost pharmaceuticals seldom exeveds 2 per day. It is unlikely that Severe gastrointestinal symptoms can be attributed tothe lactose in ‘conventional oral sold-dosage form, especially in adults wha have not previously been diagnosed as severely. lactosesintolerant However, anecdotal reports of drug-induced diaerhea de to lactose Inplerance have been made following administration of pharma ‘ceutical preparations centaining lactose has also becn suggested that lactose intolerance may have a role in, itrtable bowel syndrome, ue this role is currenly tance?” In the past, there have been concems over the transmissible spongiform creephalopathies (TSE) contamination of animal: derived products. However, in the light of current scientific knowiedge, and ierespective of geographical oxigi, mail and milk derivatives ate reporced 48 unhkely to present any risk of TS ‘contamination; TSE tsk is negligible ithe calf rennet i prod in accordance with regslacions. LD5p (sat, IP: >10 gig Ds (ea, oral) > 10 gk [Dg (eat, SC: >5 wk 15 Handling Precautions Observe normal precautions appropriate to the cicumstances and uantiry of material handled. Excessive generation of dusty or halation of dust, should be avoided, 16 Regulatory Status GRAS listed, Included in the FDA Inactive Ingredients Database (IM, TV, and SC: powder for injections; oral capsules and tablets, halation preparations; vaginal preparations). Incladed in son prenceral and parenteral medicines licensed in che UK. Included in fhe Canadian List of Acceptable Non-medicinal Ingredients. 17° Related Substances hydrous; lactose inhalation; lactose, monohydrate and. ‘com starch lactose, mouohydace and mieroctystaline celluloses Inctose, monohydrate and povidone; lactose, monohydrate and powdered cellulose; lactose, spray-dried. 18 Comments Lactose monohydrace is one of the miterials chat have been selected for harmonization by the Pharmnacopeial Diseussion Group. For further information see the General Information Chapter 1196 in the USP52-NF27, the General Chapter 5.8 in PhEu 60, along sith the "State of Work’ document on the PhEwr EDQM websie, and also the Genera Information Chapter 8 inthe JP XV. ‘A. number of diferent grades of lactose are. commercially auailable chat vary in their physical properties, and many studies have been reported in he literature comparing the behavior of these vacious materials in differnt formulations." A number of co- processed excipients which contain lactase are available for direct Compression applications: co-processed lactose and starch (Strloc, MogglefR oquste Freres)" lactose and rnirocrystaline cllaose (Microcelac, Megaleh lactase and cellulose powder (Cellactose, Meggleh*59 Iactose, povidone, and erospovidone (Ludipress Ludipress LOB, BASE). Lactose. may exhibit complex. therinoanalytical_ transitions because ofits several crystalline, as well as amorphows, foc Differenal scanning calorimetry, (DSC) can be used effectively 0 characceize dhe composition ©” For example, olastore becomes anhydrous at approximately 120°C. a-Lactoxe monohydrate may also contain a sal quantity of de Poem. ‘A specification for lactose i incladed in the Food Chemicals Gaex (FCC).“The EINECS mumber for lactose is 200-589-2. The PubChem ‘Compound ID”‘CID} for lactose monohydrate includes 62223 and 104938, 19° Specific References 1 Alpsr O tal. The compression properties of lctose. J Pharm Pharmacol 15703 DesSuppl: 15-78 2 Maman eo Sudies om he abletin properties of actus: he let cf Tital parce usc on. binding feoperues and. dehydration charset of toe ooghydete Rebiostin ME el Pann. ‘eteal Tecmo Tableang Technology, we Chichester Eis Horwood, 19; Si 3. Thwates PW ea. An investigation of dhe elf of high pes ming gat the mecsaiesh ad phys! proper of dre mpression incoe Dr tnd Pharm 1991417 905-317 4 Rlepma KA af The fcr of moire sor the aes ad intral soe are of arose tablets it) Poarm 1992; 87 149-159, 5 Gale My, Okargen EA feasible sady for the development of > Drospetive compaction Gonctonay text ar the cxalment of & Sompacton dia bank: Deg De Ind Phan (993,19 230502335 6 Len CR Genslideion and compaction of Ice, Drag Dew Ind Par 1993 19. 259°0398 7 Crabs M4 a Elen of humidcy on soldateinmeruton of varios kind of factone ding rindi. } Pharm Pharmacol 1993; 48 os 1 Paronen. ear of sme dies counesson advan daring the tah proces STP Pham 1985; 3: Ghia, 9 Zaveman" eo The tlatonship. bce bulk density and rmpacbity of incre eamlasons nt) Phar (994, 102 1-3. 10. Kibbe ATs Hanbook of Pharmactcal Fait, ed edn london and Washington, DC: Phacmaccucl Pest aod’ American Ucetal Asoston, 2000 GtTcet 11 Castello A, Mateoeks AM Diicoloation of ales containing ines fod aoe Par Se 1962, 5 08 12 Wie DD et al Mailed. reaction of Iacose and. fuostine Ipdebli Secondary aun. J Phe Se 1988; 87-31-38 13 Bh 3, Heng neracion of dssosrphesamie ulate wih sprapdeed lrse ) Pharm Set 19725 61 1770-1778 14. Hyjolson Rsnop-tcton incmpaiiy. Drug Dev fd Pharm 1954, 34 797-79% 15 Hedi MS, Boyles TM, Intolerance of sal anne of lactose by Inde wih ow lean eel Cartrntrlogy 1973, 63.738 16. Gudimand Hoyer, Sinony K.Indvideal sensivey 0 lstose in {econ malshorpten: An] Dig Dis 1999, 23008 1728 17 tomer MC aa Reviw ail fcr noerane ntl pace = inv an elie, Ament Pharmacol Ther 2008, 272 94-103 18 Suna F, Sivatano Dennis A. Die, geneoes, and lactose ntlerace ood Techn 199%; SIG} 7476 19) Sines FU eval comparison of symptoms ar the consunpion of rior lncosedydelyad mle by people with seepored lactone insane. NPrgl) Mad 1998 3301-4 20. Spasier JA, A sytem cevew of akerotive therapies in he iitale ime! some Ach tno Med 2003, 16303). Ause274 21. The Baropean Agency forthe Evalvaon of Medica, Prodr. estan ef Made for Human Ue Pond, 9 Dae 002; EMEAT ini Rea 22 THnchld Ky Pihertreyer KM. Evaluation of & new coproses Sampo hae ae and mai starch tr eb oats ‘ASE Phan Se Te 2008 gre 369 25, Mishoc! A eal Compacative evaluation of coprosened lactose and rmirocrysalneclllse with thee physeal natures te fon Mion of foc aid ales Pharm Dev Tel 2002; 1): 79-87 24 Caaldercy Mf al A compasaon of drug losing expaciy of cllcrne with neo ad he prnceseed acter dest compe Son cxcipients, Chem Phar Il (Tokyo) 2004, 52/4 398-401, 25 Arde Aly ALTabaldha MM, Cellactse 4 coprocesd excpiene ‘oumpaison stad, Phar» Dev Technol 2008 5: 165-175. 26 Heinr R otal Footing and development of tables hosed on LLidipess id acaleup from laboratory to prodkstio sale, Drag Dev Ind Phar 200 2613-824 2 Chidevarni OC et a, The we of dermal tdhiques to ses the imypace of ed concern cm the_xmarphons.content and polrmorphic forms present i spray deed Inte ne) Pharm 19973, {soars 25 ‘Hil VI eta, Charatessaion of sprayed lcose wing modulated dill scasing elorimenry. Int J Pharm 129%, 161: 98-107. 29 Kerk CF eal Alterations of lactose during diferent scanning alone} orm Ss 1984, 73 BSE-8S7, 30 Food ‘Chomicals Codex, 6th ed. Bethsds, MD: United States Phaematopess, 20082 522 Lactose, Monchydrate 20 General References BASE Technical hsratre: Lanpress, Lasipress LOB, 2008, biel ‘rer phareo-slions bat com acces 10 Murch 2009), Botha GK, Chowhan 27. Marcle for divest vomaetion. Alder Gy, ‘Nystoon Gy eds, Pharmaceutical Poroder Compaction Technolog, New Yorke Mascel Deke, 1995; 455-469. Bothus GK; Armstrong NA, Txcipient for diet campaction: an upd Pharm Dev Technol 2008; 1s 111-124 DMVéFonerea Excrens Technical iterate: Pharmatose, SuperTak 30GR, 2008. hrpuwowvednw-fonterwenspiet com tascesed 1 March 2009), Buropean Directorate for the Quality of Maines and Healteare EDOM Baropean Pburmacopoea ~ State OF Wek Of Intcoational Harmonisirion” Pharmearopa’ 20095 21(1)- 142-143:wwwedqniew! Sie nl (acesed 10 Mavch 2009 Frisland Food Dom, Technial Uteatae: Lactochem, 2008, hep ‘wore domualpharma secessed 10 March 2003), Kine JH eral Lactose a dette guide tw polynweps dterminicion. Ia | Phar 2007; 334 105-107. MepgleGiblt. Technical lteratre: Lactose excipient, 200%. spit ‘Worw meggle pharma de (acened 10 Mach 2009 Rejak KK, Bletord DE, els. Dhe ALM Guide fo Lactose Properties and ‘er. The Hague: Aviation of Lactose Maniacs, 1998 oguette Frew. TechnealIeeratue: Starla, 2008, hugelwnrwsegute aeima.cm (accessed 10 March 2009). Shelld Pharma Tngrediens. Techies! Mert: Freon, 2008, bp "wwtahefeld-prodacscom (acesed 10 Maceh 2009) 21 Authors ‘Badge, AH Kilbbe, J Shur 22 Date of Revision 10 Mach 2008.