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    2 views297 pages

    Byrn

    Uploaded by

    rafael_nicolay9196

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PDF or read online from Scribd
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    of 297
    Solid-State Chemistry of Drugs SECOND EDITION Stephen R. Byrn Ralph R. Pfeiffer Joseph G. Stowell Sct. tne. 3068 Kent Avene, West Lafayet Indiana 47906-1076 cond Fton © 1999 SSCI Is, Pas 1999, AI Righis Reseed ied in he Uns Stes of Area fining ino 3 02 01a) 99 343.20 citer tka yp iy opie oan yf yy eae Ste enna “inary of Congress Cataloging -Pabieton Data yim Stephen R Sot Sate Chemis of Drugs Stephen R By, Ralph Reif, ough sStowell2ndet ‘i STG. ils 2 em neler ibopapclefeences an ine, ISan oser007103 ISBN 0967-67111 (aperbck tude edton ony) 1 Pharacttcal Chemis. 2 Sold se chem. 3, Chemisty. Pharma cual 1 Tile QVTABIBSS 1999 ‘The publisher oes a ico papeack sition of this ook registered stents ‘Say Quay dst on the haedoer eatin aa valle Prin en aides pe Cover itusrton: The reste aceflingrepesettons of pedisloe 21 feresaylectt ya cing agra. On th op is Fem 1 lusting he ‘lel pacted cis face, On the botom ss Farm V showing the oxygen ‘Sees tnt rodced by desolation. In memory of Peggy Etter PREFACE easing apparent at once a dis dacovered,cafceing te sli ‘dig development. We nite he reader to conier the ceidence oe creasing importa he ld wi sae heey. Pharmaceutical companies are crea groups sty devoted 0 the study of solu pharmaceutical There are sigan and caging advances italy ‘meoogs X-Ray Aifacton has bosome widely aed and eal o many Worker inte fell” Soliate NM sso neal ted, Innovative ane Intring etnies ranstorming dg dive. wt tet ofl forms have tecome vides by bth enor and generic ug companies, "The amber of people involved in academic india solié-staecheisry is growing fe As pharceateal chem, we ow cote song cur colleges people with many stfeing dines a sil chemi engineers, mae a ter iis anders aed i ena delay ‘oda study ae apearig. an. nt suis pulcaons in te eld have Erown sii Any ise ofthe Jounal of Pharmaceutee!Seecesonas ‘Sve person the sol-tate chemo ge, ts, inling te fare ome deve poses in he socalled eter dug scandal Several dg price ad omelton ve heen ald bec the crystal ‘hon ofthe producto amore sabe form. In every ways efor ths new eon of Sai Site Chemstryof Drage. ‘This sosnd edits ewe, eos and prey expand. Al Figures have been era nd supmeted fr const he eGR ed he figures eer tote source ofthe otal gras of the source ofthe dat wed > ‘Ste the igute preset in his Dok. The sn of the boo io give te vener SSienco-bated understanding ofthe slit proper of poarmacecly acve ‘impound and 10 make the reader aware of calls suc, a pals that an tee dang development ad manufacturing of dap sabetance or des prot Many examples ar oclude. Although the book may aot adress every Specie bln. wil prove te ackroa taprsch a roblm an pit he readin pen mee odes with we gf sil om einer 10 Fat chaeers ose sei pis The book covers all npc of Slate tis seutce oh properties, nang aaj chemisy of so ‘Meglury owes id speci upc The bok contin a compeeens index Snel allo the sy Yea on topes realy al glossary that define all teva er The rs gal acknowledge bell emmets nd sgeeson fm Dr. ny Phen Clske nd Be. Wiliam Cleson on ea ersten of is mane ‘pan Dr Ulsch Gn, Dr Rotana Shia an Ann Meee onthe final A Weal tank Pamels Grene Stith ar cpy eto. Dr. Sepen Byrn ‘koes hs new cvuutors, wo have ontabuted rea} 1che expanded se ‘Sh atonof Soll Sae Conti of rage. We hope that ur bok wl tule Tees anes, od fre serch in support an exci ik Seon Ryn igh Pier Joseph 6. Sowell ‘et Lafont, Idina PREFACE TO THE First EDITION ‘Son of dug can be unr interns ofthe molecular sacar fhe Sold andthe chesty othe reac portant sloely we jes tne iso provide enmugh information and eneurageen fo enable he reader owe the underundng ofsol-sat easton a dovelp sale, fle: ‘ive sold du prot. Ine ccomplsh eu tystvs his monograph is aranged scoring to the ype of ean and ie scoring id sx parts The it pat iodces The Helo sold ae chem aed its he ede of aay edo ay ‘hide ection andthe hints of tlt rections Te sco pst fuss pia ansfermatins,tladng polymorphic nsrmains an Serle tne hid pt dncser wld reaction, alain sos outa tnd ation of eats to sl. The out and ih pars ei said te photo ‘hema ar ema reatns spectively. Tesh pr uses miscellaneous Tepe inl the portant developing el of sold tae mler magi eso rane spetostoy “The soll sae ection inal sx pars re eat in ts of a ote hypo shail eaton sequence that at fist inooced hy Paul and Carta in 1973, These four spe acu forthe nfloene of bth ey ssa andthe chemical Fenton a th sole process. The is tp lear cesig_ Tah sep. the mel gsm noweh oecla oom to eat Sola-zas reactions. hs Idecolr boening sep aa votes ison of th io he eacton se The {Satad se the molecular change te. The mele change at ccc oh Step is silat hat which oan the vending soluion recon. night Jn th step can be une by tying the coesponing recto a soliton The thd and fourth stp of ssl reaction ae slid olution Formation of the Dre nthe eat rsa nd separation of he produc ins own eye pase “Te etn of solitons in rms toe for steps ined a taihng he molecu ass for endantaning the slit chemist of dap. fim hoe tha ureter nthe eld fst chemsry of des wl Se the molar enetanding Seveoped i this Monograph bah asa defor ‘nung experiments an av ts forint ofthe rea. etre ates at T: bijective ofthis monograph is to cane he ede tht soit wt roving ity an fey fad uss fo be eon te lee Tea Mig ats senechomiy deepens mnng Cfo achouledge ihe sssane ofa those who enabled he ran ie marci However: paar ani owed to Camila Cox ‘Patan Ta iso gulf the copra hols prt the {Ray Phureacouiclasscaon a te mencan Chenizl Soe Fe ‘Sono rye ges fom te Kec potest Sephen By so ant, inde inne CONTENTS art 1 Introduction tthe Solid-State Chemisty of Drugs : Chapter | Drugeas Molec Sli nnn 3 1.1 RoleoSl ae Technology in th Pharmac Instry -— 3 12 TheCrline Sete Be Concepts 5 A Packngand Syme 5 Fee Responuble fr Cryst Packing : C. Hydrogen Bonding ‘ 13 AGienSitwancecan Csi Dil Wap, 2 Ke Proper at let Parmaceticl Belair 4 Sohbay 3 1 Neston % Tensions Been Gt Forms 7 D, OtherSpontanews Changer in the Sod tae a 1.6 Properies of Amorphous sbi = 7 Mostar UptkebySalds : 3 18 Lyophiied Powders = = 19 Bxetson Varios Crt Forme 3 Ho Sal State Resctons of Droge » LOL Sb Tsing ” 2. Sammy ° Reem = o Part2. Methods of ANAS one —— (Chapter? X-Ray Cestalography, ner AP 2 Inodcton e 22 Cope : ° ik 7 stripe en Cy ce “ eel ns ofa 1 eaten i Se eon imma Hi ta. Goatlne Daeg 3 jog) oe ne Pwd Din Mado 5 21 mens ree ion ene ° 2 apa Pwo $ 3S SEE loca km a — —- Be enemy tony 5 2 cer 3 S Sere — 46 Scanning eto Mires. eli Microscopy an Namie Force Microsopy Retrenes Chapter Thermal Method of Anas 5.1 ‘Thermogrvimei Anahas (IGA) nm 52 Diller Sexi Calories (DSC) a 53. Microcar = etree » Chapter Slain and isolton Testing mm —s 61 Teng 62 Meshansn : 2 63 Dilton Apart : o £4 Inns Dolton Tein. : 2 (65) Acura and Inerreaion ~ 5 (6 Cancsons : oe Reterenes — 160 Chapter? Partie Sze Analysis mom - 7 Methods for Parca Anahss 73 Analysis Particles in Metered Dose alr 74 Parle Sie Reon Referens (Chater Inne Speeoscopy of Slk — S81 Inaed Spectra of ajmorphs 82° Infard Spec oSlater 83. Anal of Matresby Infor pectoxopy elects Chapter Solid-State NMR Spectroscopy mmm 81 AnOveriw of Soli tte "CCPIMAS NMR Spestoopy 92 Sol Sate NMR Sie of Pharmaceuticals 53° Pha Menton in Dose Forms 3a Onspeed Suet rine meta aie 1 Inerupted Decoupling for Protons Carbons B. Blch-Decy Experiments er Scening Sueno chy 95. Summary Retest Part 3 Polymorphs Solvats, and Amorphous ors mn-annn {Chapter 10 Polymorph one-one — 10.1 Cas Eampes of eyo his, : ‘A ¥Chlorophena 3, Dibes{ahlantraene € peng = 102 Conformational nd Conigational Palmar = “iva Naphiyfboronamine By [phenlnetyhamio)?-butenate ‘(N-Chloobenidene)-+chlromine 30x01 bem -ehersbenzte ‘Tauomeraxtonal Polymorphism " Palyhomisn =~ 103. Saifonamie ‘Sula ~ 1 Salle - Soest ©, Samet ~ Other Sonam ne a6 6 adi Cmte F. Condision 3 Prelone € Siontactone D. Metpednssone , Hyocortuone 2 Bice F Conchson ‘A Arobsta| Phen 107 Orker Drage rome Aol lapel Male eter nd Metolpramie Manoldrochorise rremide Lsiyrommorphinene Color Dimorpism ‘Maelansis Ses Kunr- Srantiter and Co-workers (GRAS) Hor 2 metipi ichroman 4 sideline Soe japan 1 Tannen Cae 1 Anicer get FR18S3 108 Carat 109. Palmonphso Anti 18 Conformation! morphism of Spierne 5. Supine 1010 Pebymasphiss and Chem Sabi 10.1 Polmarism and Bioraiiy 10.12 Romer and ts Phamacesia Aplicton eens CChpaer 1 Hydestsand Sates meme TA Hyde 112. Canons Under which Hyetes may Form = 113. Formation of tyres SERN ie eae mies 114 Deiquocene an orc, 115 Potas Goering the Format Sater in ie Soe Tig. Saliy ef orn Sarr 13. Sommay - Reece (Chapter 12 Amero Sim 121 Properties of Amorphous Fons 1» Glas anton Tempentre 1 yalintion ca Part. Physical Teansformations of Crystalline Si Chater. Polymorphic Interconvesions 11 nerconsersin of Poms inthe Sal Snte Ae Dehorobenaene Satyr this Sarycootne oxide Pestle 132. Thelndacton of Pe Tansormations by Ses 13) Polymorphic Transformation of aac ‘A Phemtazoe Sucinbultaele ©, tcf Seal Cine on Tasormatons of Chomp Pate 369 fn Polmorphic Transormations fCorpropamibe Tales a 1s sii tinting ne CChaper 14 Low of Solvent of Cetlliation nnn 1 Review of Detohaton Rect nm Carne Hyde ‘Thymine Hydateand Cyne Hydate Theopilice pdr Date A pate {Merepropurne Hptate oo xtosrine Fyne Deiyrophenilanine Hyde - Fenoroen Si yt Manginovs Formate Diya Indapetsone 20-4 Butea ‘Nipherideone Actonte 1, Bisaeldetpaejehyenedmine Cobalt Chorformate 1. Coplloghen and Copan “ = a GER SSESEESER ee atv caine M. tydocorne Buca hale 20 N. Pawns yeohloride oo 5, Phcnylsnaeoopmetiane Erte = 42. The Mchana of Dane Reactions = 1 nln of Atmosphere es 1b Coaeapic Properties of Nate oer Desolation 3 € Thetauenceof Cys Packing 3 Dvn of sl eet (Naleon Stes) 2 faplanaon ofthe Thess Teper of isobation [eset Cys ackngand iron Bonding 295 , Memuremen afte feof Sl Sate Debut Reacts = 397 143 Desahatd Slates a a Sonos al PartS. Chemical Transformations in the Solid Sate. Chapter 15. Theos Ansys of Sli State Chem Hentons som 307 154 Caleta foe Solid-State Recon 152. Sain So Ste Reaction we 153. Mole Mobily 3 134 ‘The Topodhenal Foust = een = : m Chapter 16. Oxiaton Reston ener 38 161 Onidton of Linear Poaenes — : as 162. Onno often : ae 163. Rex of Pee Rada wih Ong = {6 Oxidation of Vitamin & a 163. Onion of Vania C (Asari Acid) Tables ma 16 Onion of Wtain Dyn bs {67 Onin of MetinineinPepties and Proteins i {68 Photosiaton of Dyer usd Cetin Tale om 7 169 Ondtion of Plene Anita — = 1610 Onto of Reserpine bo {ett Onion Recon Preceded by Los Sent oo 1 Digdrophertlnine : 4 Porgy Model = : a Phot ie = = 3s , Ost of Stas — 38 te. Orda of Dini Acid Monae —— on Tet Staiy ofa Sa Suite Oxidation sing Microalorimeey -— M4 e612 Sammy ~ a6 Refrences —— _ aI Chapter 17 Addions of Gate: Sot State Hydra nnn Reatins of Crs wth noni Rates eatin of Crstaline aby As wth Ammonia 73. Rewtonsot Solr wih ore 4 Sobd-St Hyayes, Napa ©. Melon 12-benoctn ane DB. 2 Met 1 tbencoain-one Reference (Chapter 8. Gas Producing Decomposition Reactions - ‘Soli Sate Dehn of Hon Compounds Hyeoartarinehanas 1-Day: -ydonbenzl ane tnd 3-(Bbenzo phenydranindae one thChrophen pase Ais Solid Sine Decoration Kesctons 1 MechaniatSades of Soktion Decbonion Reactions Malo ci and Dera Trcladng alc and Cabeciin (Catenin, Palin an Malcarn "GA tude of Pheyinalonc Aid Mod Compounds Satie Ai ws The Photrhenical Derbneation of Diberayipoxde PhorhsisotAcsybenorperoie Davimporton of Explosives 28 Desomposions hat Prada Nitrogen Gas Stary Retrence ~ Chapter 19 Photochem Reactions nnn ‘Gianamic Ait Syytiogbene, and Denes Seefepaha Boe ‘thane, Pons and Oxrinones: ‘Topher! Powe seeps . tivones - Indigo the Roe of Molecular Conformation Patera: " Dimerization Fyrene: ~ Nuke All mn Photochemistry and Mobily in Amorphous Sls fet of long Radeon on ‘Cyst le Important Compounds cy so 364 7 0 mt come 1 Irion of Cyst Amin Ais 5: tmaiaon of Chine Chose Crt aati of Hist Acid D: Hiei pina on Cryst of Nac Aas 19.10 Drags And Natal Prods Serle, 8 Phorele © Reepne , Famagiin Githerlie FPyrones Himes Shaper 20 Thermal Rectan omen 2011 Soi State Rearangemen Reactions A Teepe se Bde Tangent Ber (Amtznbemylmetanes Dledstenoy Pros E, 2 emathonp hen 2ydaheatiene14-dine 202 Thermal Reto. Cylon Reacos 1k Trigdo[¢ 200° ocans BS Gjanantacene ise CC. Betancbanracene 212 Diugand eter Compounds of Bik Iert 1 Rpts Andee B. Tetametyghine tt Ese Matin + (Dinethmio}serencllonte D, ACEInhibion 1 enone 24 Stuiesssing lornery 205 Summary References - Chapter 21- Reaction Kiss nn nnn 21a for Kinetic Anis of Solid-State Rentons [Retin avin ueton exons Gotti by Pas Bounds. Dison. Cantal acons the Equations = Retin nveling Patil Liguiton "Computer Program fr Anan Sl Sate Kinetic Dat 242 name ofS Sate inte Stas = 1 Pha Trndormaions es © Thekincse Danone dened Sa & Thebes Me sa o 1 Keath Ph Dep of coe & 1 Sond Sl io Recon ° feteemee » pte? lanes Tap nnn “ 1 Conennon (age of apaatran) je © Sedan ston te 5 newness Pr © Conponton hn pH ‘ee 23, Nol ys o BBA Matty det of Sods pis BS Reet betcrn sald Se Ros s 2 Slits of Pata rr 227. Panke Dean ihe Phys Taer Compa ws 25 raison Cl Sard Pn re 23. ‘somi Fore Maroy (AO = = 22.10 Replay Apc eS Set Chay ef ras » ‘Pm — oe Somer ids) o € Donte es DB. AnophosFome is 2211 Conca faa feleenas = ty a +05 Subj Ie nen Part 1 INTRODUCTION TO THE SOLID-STATE CHEMISTRY OF DrucGs 1 Drugs as Molecular Solids Specify eats the suet on paces of atte ches: ‘teerptaline se, amorous molt pe, tents, yi vel a chemical sfrmatons In ses. 2 subject ocd in hit hap and assed depth che, boped ht he eae wl gn an Syren of wha! is cgi encompares yrenng tschaer, T: per provides a general overview of sake cheminy of ds, 1_ ROLE OF SOLID-STATE TECHNOLOGY INTHE PHARMACEUTICAL INDUSERY Figur 1.1 dept cera le a slate reach plays he pharmaco indy. Rett onthe par of anyone even ight with etry will. fi many of the coer shown in Figur Ib sme speci tamper will Furte poi chow unpranieseconoctensca ein given cases. Sold parmsceicl exis s polymorphs, solvates, ori amorphous ferns collectively described as solld forms. Fgue 1? sbows the sob bear of wo oly eth inex clara he obi of et ofthe sok orm ‘Sang Doce ofthe eyelet of «mere sublet form (Cues a. 16H) Thu hee nates the es of pyar change om sepension sai, “Obvicely these anges tet on he sy ofthe psc tel Figwe A dagnot te les toc ea te amas indy, 3 4 Chanter Drage Maar Sa - i ian | _——— aMymeaersce J eguntory sss unlty cont formalation and rg caval. Figure 1.3 ‘Este fest of panel sz on the dslulon rate of pense and thus te ole of wl-sate inlay nh formation ad drug delivery. ity ono a eulry aes ‘Stole of icosne ert uyseate nd pedicle ela (By rly 198, Line, 1982) anyone (Reser, 1972) sow tht it icc fos ofthese subanss have diferent cena acy. For ex pie te benagonal cal for of ot drcurtsene terface and pedis- [one reece oth wd tae whereas th i stl for Of se ‘wo poamacetas ae comical stable "Te shape an patie ie oh sd vg subeance can ase an iponan t on he omabiity syringeablity, lerabilty, tableing behavior, and tule {density ofthe drip. Forex suspension of phe-sapa eras may be ine 12 econ Sate Became 5 Simi thai evi le shaped ys nul er fr thao oe Sleshuped esa. Furenor te shape onsite pails pel eed tothe er esl sce ote sl. Tho h neal sre ofthe sod Iota ean dasa nen he apps thd Thse pope in tn easton, nacre. guy conrad yor ‘Sy chr seas net oie 1.2 THE CRYSTALLINE SravE asic Concarns ‘An understanding of he sola chemise of drugs begins wih a semen of Sev rl general pms: + os dus are se in arya orm + Ctl ed opty molar ese ‘ tearangemet of molecu na ryt detent physical ropes ‘te pyscal proper oa rca aft formance Ween thn prose lam bows undensanding ofthe costliest eds un Sestandnga up popes. (A weamen of toca cr amorous slide ‘Salven in Chapter 12) "To ammo he geval eae in folowing his dsceson ofthe ening stat, bt dts f some tom ae itt In ghey at he ond ofthe book. Mary ofthe ems ay rque fuer exits Which bl be pen hen pgm wie, crane AND Semen (One defitn f ct i tof ain ich he campos lsu a ‘ange ce packed” In ight need fio, When the pci ol or fined by te unl cell, gos preserved wihow imeruptin trogtoa he boundries ofa gen fare tarp Is cle sgl ert. Tis ode pking Was state wi vey ile vod space which exass why mest b> ances ae more dense hi sl sth tad By wy ota thon, Figure shows a prcion of at eal nds shows bow Sly he mol ‘ules packed ina yp erste susan such a he ‘Looking ths ramps snd comenpiing te enorme namber of rystalloe compound known © modem secs, tt meen those to be dicavered.& be ee a J Fe een hes ara oes ie yg et comet hem te naa ay of ste dn eat {iterate dene hcl se fen compun? ‘We he uso sow many ton wy ean isha elec scars pu onset ast a sc Show a ota symmetry > ‘Bens Cr metry operations) ved an tat al posible sombaiesof theca Sard rca 230 ay, cl pace group. The syne) ‘perma tel Tle (Fa eens of ei achenconpsal sven esta tems al posle ombinatns of Syme Topsuion ond ine hsretra! Tae for Celogaphy (8. "miweiser ee ney gern te sce po tay bel eae flowing vane ot ‘Bowe 13) Tipe 13 shows «dapam oe sey men pee own Fran Th Pinca thee ro pve ae thn bod centered facccentered The mn eas th cl srs miro plane tw Ps Tole Le Smmary Bae of yl ai! terre! 5 eet tt sry ves ns Seen eat ne sae ee ‘re a is conn pine mn ene ‘echorecrsierte grape mrt setae 1a TheCoalie te Compe 7 Lp ica ttt an axes and two-fold rotation along the ais “ebing block | ays 2) and eligi aos he imo th ite te aanis a, Dock 2s ota, Refosing Neck ? arose miter Secs the bai at peers eck 3 and Hck 4 es frm lock 3 ben fe ected cos the mor ate. (nctual cass, o coun hee Wocks seme bathe operation te sme snd this the, cds ech tr in me ale Ia rast 1 he erespodig (I) nth gp, (Ion ‘he eat sep and (s.-y.) the la sep) Noe th hs Conbtion of ae planes ness eres the Wold tan ses prt he cal Th sep Ian ore, ar conned ino teeing units, Int eens we wens ese mniching seta ryt goth Fonces Reston tom Carers Packtne 1 his oi ii appropriate wo consi he forces responsible for badges ‘oguter Tone erst ae hl tse by lonte bonds wis ongente crystals Ind ogee age by now-ovalentUneraction, Tie noo cet terns {2 ater hyden-bonding or non-covalent attractive frees, Bush hyoge tring wd oncovle active terns rest ine eto ropa a. rangement of mazes nthe cyst Non-cvalet attractive interactions; wich tn teins called now bonded Interaction, dopnd onthe dple mae: po lazy, andlacwo baton of he malo, Hyaogen boing, of couse, retires door and acepoc fuse group Aner porn factor i the sym ‘ety ofthe molecules, Kisgooishi (1961) proved reve ofthe free haldng ‘Sys oper nhs else Beak Organic Cems Cylography. The woe 5 chapter Drags arent rohan Snrre Carlin (Bir and unt, 1984) dssibes in ail he ese Jew ofl poking “I mee fr ick of symtoms detemies how itis kd in cena, some cats eres he oe syne of te costa. Male wean semen at low te yo ogee 2 cose packed ranges [mol om beer cyto cya ures han meglio. TS frist aways det om molecu ode ‘Several tocchers have desorbed ral packing forces in specie clases of scans "Renal an ie (92) cae the cern doen Sending and eystal-ocking forces of ape ies Crs gacking foes pln gmena wate eval by Brock and Minn 1980, Gaveznt and De Sis (988) have aad pckng eos and packing pares for Fosse ‘romatchysocaton. ‘Kisigresu 961) has assed the elose-packing theory © exon Be feces ingests oster, He eget tha he hase air tht fet fee yt te pking dey wtih fe Af ety The denser or more closely ELSE Spt ante sao fee enn. Ths ean Da he Bea of suimsion Tea ft poutine po eases she pking deny increas seit in snes of pulymarphs te dese poles he mos stable. Ths {teil bs of te demu re which es fone mdieian of mo- acyl rower deity anh ray Be assumed es able Ios Yo (Burger and Ramp, 19795)” Howes is ingot 1 nt ha Thou ccoptee tis le Some exepon rota ane eee tong 1) trogen tas a ep es dese pking (et. cee csi he ss. dense {ulymorh be mere thnnednamial) moe sable (unger and Render {91808 Brook rel (191) sued he vat of Wallac’ ale whch sis a Theracemic estas pif amomer are denser a thas mat ale Ba >= labo the ind enuomer an showed tha forthe 65 chiral pai ‘esd he cei ea only “1 mae dense tan te comeing cial ‘ls ether res dese lo many inal psi. ‘Kiaigreshi (161 alo od ote inprance of symmetry which lets as.crpy. The fcr of wept dae teases a the mane fe ‘algranclly Independent molecule she cyl ieee Thus high yee {mich ede umber inspec acevo nes he fe ‘hcny tne ey and oft th th recon ne ery ged fo close shin. The mega of fee opposing eects vase fom reo rt Hronocen Hox ‘Of he various forces dnt old organic wells in the sli, hydrogen Doing is Fert the mos nat, Ber (1990) has eviews he et an pes of ho- Ec bnding tnt cr ext nse a pol eu at polar eguie mls 0- ‘total foam hydrogen Sond ggg. These sggeles w pecans theerysls whch fa whe th sleion superauated. Ths const Help 0 e% Pinte ny ifr hySroee-bontig see in iret sls, ‘Sever leat per of etx sis have een ted, For example in e- atkonyenaie ct he resco ners o th oman of anole iyo- ‘Boon depen th sac hese In oss, diners ar bse in ee ee | the slid ste wile namo hydopen boas we observe ie sation However m othoxybnai ack ony iannisua hope bos ceed intows th sod sate mn sla te 100) er ok ch ot -mhngana myn er a (198) also ta the bysrogen boning insane divans tn pointed cu hartge of hse boning pets ee plein se a funds. One pte involves an nolan —-N—H-OH— hyo nd ard th emoleuie -O-H--O=€ hycgen bed while th ter pte ines intemlealr —N-H-OH-Aydopen ond and an tae 0-0 or of A So ¢ ot ean co-workers (198 dite system which we ap ta lay nd sal epee he ern per of tyne nd ember. ‘shone ofthe ga set shown in igus 1. A pat tent rsh teers Dordt ote fines and rinse yen tnd) ied ty doing hes spe o te Noga Ce me of {sesh aber of ssn al none of tos ninth te Tas ‘Seaton ks eve ‘er (19906) ab dvd ks grein hygen boning in lid ope ormpouns Hyrogerbend denser a sce sie ec te Seren doe ups a Tae 2. sg ee 1. Al elable prot dire and aceon ae wed in hydrogen 2, Siemembered sing nko bonds form in pee ect ermoeclr hydrogen bod OLR > t ‘uber fhe td soc ial me ftom he 3, The bent pun donors a acer emg afer namo [eigen bond font wl form interme hy oseh om These les apy ite wel to dog nig of mal leas Howere ia Soe layer cos og cynic by he grey of trl wl ge mer of Sos sss pose tay ae ie bloat al ees fas zn donated a te ya ty of epee stl wich conan need srnget of to owt sal mesic at ent men ‘Ses cn edo igh merge tr ntencingHaopen tod ys Beran awe, fe Era Po tea Aso (80 et of hes wo Kn of faces would te alee. we tow contr dona yal of ete componnd, the anette rca “arty mos he eared anew occ polymer and she “Aout aw vou ha oa of Ctl fran i of ext im poranee hs contol sot alvayseasy onli. What geval ips ite the How cavstais Fon Tn this secon we dics how eater and the fos a aflame cyl thn Tale 1 Its he common enslizon metas enplyed fo parmacit {als Mot oe methods cover in Table 5 depend on reducing he oly of "he compound ty one ease anther. Is tle necessary to cull defie he Solita terns ha wil be se repeal he dscusions hat fo. A So “Theol of asl suhane ee conenaton wich the scion phase in nil with gto sold pasate sted peat and presen hse Sens th sos ner solving nor conaing To enstalae Note hat he {rien imps th resense of psi oi phase. Once deri de He 16 Charrette sted conn, however, we can ak abot he slit of agen pase 2 “peste palymoh or peudopalyinagh) st & gan, even in he abence a at ‘3h pase Use ofthe em “ei in ccmscon with rystliing ystems requires larication. Whe aban exis in ore tan ne crystal fo th is when ‘ie poymorbare pose, onl th a ale of tse agen emperate nsec het psa sible form attempt, ll ers ae considered {ibe metastable forms, Inve ss. satan of subtance may bein ape ‘Siam wit oe of tee metastable pes fra log ine, in whe ese the ‘Shem nin mata qua ands exgesing te termi soa Of tha ti fom Ts ingot o sess te deems een polymorphs and slates (pear plymarg) th ons Ka paeupolymoh ext, lays (wi Te excep on) he noe tbe fare oven hat races he pscadpolmoh ‘Underntration pans to soon lower concen han te sation als Ce itd les). Ctl wl dazole in wndertatrated solo. ‘Sateraton ste st efapte eh ld rou wih he soe ions tet won, esl wil ether dove crys Nor hem gro (ict the concen oth slain eset the slit ae fr trestle pias. "‘Superstration sins to soins th, for ne ress o ante apd contng of strated slaion without Toe ess) a a higher eoeearaion| than he statin vale. Seperation raged for rl rv: Seperated wow can sometimes remain tha conto or og pros wit ‘at fooing cae, For example. he rede may have he of stow cooing er ‘ean nro il dow ering pi of 0°C wit he fran of ees tang lice The rt step informing sls oma superstrated soon res the asembly lsc uri of edetel mess (ant eal) io le nue "Thi oes i toned primary mcletion.Assenbls telow te cial mer {end dave whe hee shoe the il nomber pe and 20 Ho ogni ‘he cysts Thisbtavors bandon he single fat athe sti ves a spher ‘abou ices withthe gure of sade hat he volume creas wih he ee er Li Fee ns 0) hor eine lel ofthe eas. tn oer won, aan asembly becomes lager, the neal bonis Nong i tgeter Bose clay moe spin than he saris Free olen Solute actions) tng wo pl pile pa A mae formal explanation fs ‘honarenn igen in pore 10 ‘Despevaous hy heel sles fouls fomation ha have Ben sve neato ne aor ends stig eas very died ena inperhgethe maj fees, de 1 the mary dure aco tha we See tect aces Tale 1.6). In dice opm nolo, fc sa phenorenon now ae secondary mleation wich vats frar cyst ale ‘Syl ate fee ete om eter sed oe priarymcleton) Among the Taos which fet soondarynleaion ae aston cating he ds sd pe ‘of elation veel and aga, snp anf ence ras Tae (teat) cyst Frm o nit an cst regs ease hy pies, Sa ‘nd cin somes has unstable cnseqenes sine tes ode ‘excessive numbers of very smal acs. Futhermore, come ciation begins, fastor ike conenation, supesauaion sd many Oe prante io Te 1.6 may change, podicing» dytumicenioren th males cosines onal oF Se Proves exergy dict "The mow imgrant lesson nhs ics ith mabe of ale ond the cl form rein from a crtlizaton procedure ae dace by muon ‘grr sole a tng ih ded pe {ed ypeantn ye eae ‘Sunol rae nig emg tpn again ee) [alc sns¢ce ys eognsn rpe 18 Cheer Drepse alec Sode ‘vet Ths: “soe news, one lage esa ion mil bilo in ets Inolyonhic stems ml fee strates ca en ad eit in @ en ‘tyne, nck ease iu fel farms maybe ean the Sal rod ‘Sle inte ctor: event achcvement of ellen “Cone tests shown Fg Inthe tp (80 pels, a cyst. son prover, wing appre these rool Me ise palmar on Sept cans (eles and ple) athe Do pnd th "sae proce” filma mitre ofthe plymomhsIn thee eases, ck eo fhe meeaion Process ns lak of cont of ke poymos fesent_ Iris ttre common Fracceto old ack ofthe dsied pe dere tah agyopisge Sharleen Tis proces sealed seeding nd one of ty estes ‘Sedto coal he cone of sla When diferent stl forms ae pose for a abstnce cack for has oy ‘ale uber a Ree of conns sole compete: teers ad esse Even if els of to fos hve Bon proces, however the yer wil ays Aumaact am ansFom ces ge ll Uncle ian asymm sem song te ioe pobmene ‘lee me noon ohsom oa 1S Howcomletam 19 tendo rode nl he ess sole of to oms evenly ee Figue 1.1). To be Se, tne kes wo expres ts tenny Spends os Mew factors aye {pe aie; Putin any ever aes sll form never caves ote ves {fem ene goons deed cnn ’Afew seats ofthe disoluion beavo of some pymexpic drugs ay telp ree hese elansps a they apy to slstons cos trate Figure 11D shower conenton ves ime plas or fee and Figure 113 ‘hows the concern erin lt fr tepey ine. In Figure 2 hi 90 aversion othe mor sabe cyl frm during expen. Incora, in Figure [ie less sabe aires converts tthe Ryne dans he eperine” poidng neqivrl poh he yaa sere sable (es sll han he nate Ue thee exams bviour ich fm of eptliei b les slble Under § & corentation mnt 3 ewe 112 iscin so ei yl ns facc als ‘ee era SC eso, Is metas i i as ge 15 Conan ers ce ens Ml em nh einer (Shen ae) these conto this fom wil eer conver he hr, i an tee alo be ‘ert waste throecoamicly more table form, ven erm nace veal, weve, fer dictions con eminently sre ors nes be made The erwalsramic Sti Cosy sere a soli) each om ay change ite ley a3 fencon of tnprtre. Mmetrope stems we dfn sytem whee siege fom savays moveable ogues ofthe mpetre, Bnanltrope sts ie ‘hte a stems where he ela salty of the two foes inven a some as sh empertre ‘These rlatostge ein pape om ee Bague 11) nl pate. estat) wo pot og sly verse iT fr eh id phase ens 0a v' Tse ps ive. ost cases he daa Iai fon at ede etapa, sot raion psc Be te Io even when comple daa fora pen sal pase ae ule oe uaa Figure 115 shows avant Hoff po soit ser 1/7 In ths ease here 2 tent oi wher the ines cs ne elie ties of he wo os ae he ‘Sine (80°70), Esaptaton fi 10K eyond the experimental mage roe reduce age ees and inet ibe “anton fone sd pe oa an oor inthe absence of sven The mecbanans ad kes fsck slate tans ean be very plex ad {evades a Chaps, 13 a 20 For evap, Kiros ra (1968) $Nowed thr a pi-pek can nite soldsate tarforaton of erp-chlercben tencto Bpclosbecene with singe ctl The tanto of 1 Bi

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