new compound (KP23SS) and its epimer (KP23RS) wascarried out using classical and synchrotron radiation powder diËraction . Enantiopurity of the.
V ol . 1 0 1 ( 2002)
A CT A P HY SIC A P O LO N IC A A
No . 5
P r oceedi ng s o f t h e Sy m p o siu m o n Syn chr otr on Cr y st all ogr ap hy, Kr y n ica, Po l an d 200 1
St r u ctu r al C h arac t er izati on of C aran e De ri v ative Ste re oi som ers | P ote nt L o cal An esth etic s J. G r oc ho w sk i a , P. Ser d a a , M. Pasen k iew ic z- Gie r ul a b , R . Cz a rne ck i c , T. Li brow sk i c , S. Lo ch y ¥ ski d and B. Fr ¨ c kow ia k d a
Regi on al La b ora to ry, Jagi ell oni an Uni ver sity Ing ar dena 3, 30-060 Kra k§w, Po l and
b
Insti t ute of Mo l ecular Bi ol ogy, Jag iel lo ni an Uni versi ty , Kra k§w, Po l and c d
Depart m ent of P ha rm acodyna m ics, CM JU, Kra k§ w, Po l and
Insti tute of Org ani c Chem i stry , Bi ochem i stry and Bi otechno l ogy W ro c¤aw Uni versi ty of Technol ogy, W ro c¤aw, Po l and
T h e pap er rep or t s on str u ctura l investi gation and phase anal ysis of a new ly synthesi zed p otent lo cal anesthetic with chiral molecula r structure . A bsolute structure and absolute conÙguration on four chiral centres w as determined using micro crystal li ne single -cry stal di ˜racti on w ith anomalous scattering of X -ray radiation azimuthal scan techni que. Phase analysis for new comp ound ( K P23SS) and its epimer (K P23 RS) w as carried out using classical and synchrotron radiation powder di˜raction . Enantiopurity of the bul k material w as veriÙed for both isomers by comparison of exp erimental and simulated high- resol utio n p owder di˜raction diagrams. T he presence of tw o new p olymorphi c phases of K P23RS w as documented. C omparative conf ormational analysi s w as carried out using di˜erential F ourier synthesis and least- squares molecule overlap technique. A mo del of epimeric disorder w as discussed for the homo chiral phase.
PACS numb ers: 82. 30.Qt , 61.10. {i
(6 65)
666
J . G r ochowski et al . 1. I n t r o d u ct io n
Chi ra l pha rm aceuti cal s are bui l t o f m ol ecules p ossessing one or more chira l centres. Si nce 1956, when Pf ei˜er do cum ented hi s thesi s: \ l ower e£ ci ent do se of drug i mpl ies l arg er stereospeci Ùc di ˜erence i n i ts enanti om er acti on" [1], chira l m ol ecules ha ve b een i n focus o f pha rm acol ogists [2], pha rm aceuti cal and chem i cal i ndustry [3], and l egi slati ve agencies worki ng on sta nda rdi zati on of medi cal pro ducts [4{ 6]. Pro ducti on gro wth ra te of chi ra l pha rm aceuti cals rea ches no w m ore tha n 10% p er year, especial l y wi th empl oym ent of asymm etri c cata l ysi s [7] and, recentl y, geneti c engi neeri ng [8]. Duri ng the la st decade, the develo pment of chira l drug s i s the resul t of e˜o rt of multi disci pl i nary team s [9]. R esearch area covers physi ol ogical acti vi ty of i somers, thei r i ntera cti on and i n Ûuence of chira l i t y on adm i ni stra ti on of tra nsderm al drug s (see for exa mpl e [10{ 12]). Interna ti onal rul es [4{ 6] requi re sophi sti cated pro cedures for pro vi ng sta bi l i ty and puri ty of stereoi som ers i n vit ro and i n vivo. Mul ti -di recti onal i nterest i n chi ra l drug s results i n i ncompa ti bl e no menclature. Theref ore som e deÙniti ons are i ncl uded i n the pap er. A chira l centre i s created by an ato m wi th substi tuents or l i gands no t superi m p osabl e on i ts m i rro r i m age, i t ha s no sym metry op erati ons of the second ki nd, i .e., m i rro r pl ane, centre of inv ersion, ro to -i nv ersion axi s. ¯
¯
¯
¯
¯
¯
Abso l ute conÙgura ti on | the spati al arra ngement of the ato ms of a physi call y i denti Ùed chi ra l m ol ecular enti ty (o r gro up) and i ts stereo chem i cal descri pti on | chira l i t y sense. The chi ra li t y sense denoted R(ectus) or S(i ni ster) deÙnes the absol ute conÙgura ti on of stereoi som er. Absol ute conÙgura ti on i s assigned by X- ray anom al ous scatteri ng or circul ar di chro i sm (CD ) experi m ent. Co nform ati on | spati al arra ng ement (shap e) of a mol ecule of gi ven conÙgura ti on deÙned by the set of i ts to rsi onal ang l es. Stereoi som ers wi th i nv erted al l chira l centres are cal l ed enanti omers. Inversion of one of mul tipl e chi ra l centres gi ves epi m ers. Epi m ers form a subset of di astereoi som ers. D i astereom ers are i som ers wi th multi pl e chi ra l centres tha t di ˜er i n conÙgura ti on at one or some, but not al l, chi ra l centres. R acemate i s a 1:1 mi xture of two enanti o mers.
At present, ab out 70% of lo cal anestheti cs are chira l . Chi ra l resol uti on, i .e., separa ti on of enanti omeri cal ly pure form s, of several ra cemi c anestheti cs resul ted i n l ower to xi city o f the enanti opure form [13]. The i nvesti gated com p ound, expressing stro ng l o cal anestheti c acti vi ty (- )- 3-[2-hydroxy- 3 -( N - isopro pyl ami no )- pro p oxyi mi no ]- ci s -cara ne hydro chl ori de (C 1 6 H 3 0 N 2 O 2 Â HCl ), acronym KP2 3 [14{ 17], i s synthesi zed partl y fro m com p onents of Pi nus syl vestri s turp enti ne [18]. Bo th parts of the mol ecule: cara ne head
Str uct ural Charact er i zat i on
669
. ..
T ABLE U nit cell parameters for K P23RS, its p olymorph a
[¡A ]
b
[ ¡A ]
c
[ ¡A ]
˜
£
[ ]
and epimer. £
Ù [ ]
£
Û [ ]
V
[ ¡A 3 ]
K P23RS, unit cell parameters measured for various single crystal samples 7.3504
7.5304
17. 4922
82. 66
83. 82
84. 39
951. 20
7.3600 7.3637
7.5320
17. 5090
82. 62
83. 85
84. 48
953. 68
7.5405
-17. 4865
82. 76
83. 91
84. 52
954. 44
7.3680
7.5490
17. 4760
82. 76
84. 12
84. 64
956. 00
7.3647
7.5431
17. 5020
82. 74
83. 88
84. 53
955. 70
7.3600
7.5392
17. 4967
82. 69
83. 85
84. 42
954. 00
Superstructural 7.352(1)
polymorphi c form ( a
37. 65(1)
34. 94(2)
0
a; b
b; c
c)
82. 70(3)
83. 98(2)
84. 42(1)
9508(5)
83. 26(5)
85. 56(5)
85. 66(5)
954. 0
K P23SS unit cell parameters 7.4024(5)
7. 5552(5)
17.2493(8)
(single crystal)
of cara ne heads wa s i denti cal for bo th m ol ecules and the sam e as i n KP2 3RS. The absol ute conÙgura ti on on chi ra l centres i n the side chai n i s S for b oth centres C6 and C6A, as expected by synthesi s. Si nce a stereospeciÙc reacti on ra rel y resul ts in enanti om eri c excess abo ve 9 5%, careful ana l ysi s of electro n density i n the vi ci ni ty of C6 and C6 A ato ms was carri ed out using di ˜erence Fouri er synthesi s. No residua l density abo ve 0.28 e/ ¡A was observed on the di ˜erence Fouri er m ap, whi ch conÙrm s the ho m ochira l it y of the di m er. T o com pare the conf orm ati ons of two mol ecules form i ng the di mer, ro ot- m ean- square (R MS) di spla cement for two l east- squares (LS Q) superi mp osed mol ecules was cal cul ated, gi vi ng the val ue 0.71. Thi s val ue seems ra ther hi gh, because ana log ous pa ra meter cal cul ated for epi meri c m ol ecules (wi th opp osite absol ute conÙgura ti ons on C6) fro m the crysta l structure of KP2 3R S i s 0.77. Thi s l eads to a conclusio n tha t there are tw o signi Ùcantl y di fferent conf orm ati ons i n the uni t cell. Fi gure 3 shows superi m p osed cara ne m oi eti es of the m olecul es and di verg i ng side chains due to di ˜erent to rsiona l angl es aro und b ond C8{ O9 | 83.4 and 72.0 degrees, respecti vel y.
Fig. 3.
Molecules of homo chiral K P23SS isomer w ith sup erimp osed carane moieties.
670
J . Gro chowski et al .
It was observed tha t i n one m ol ecule, the val ence ang les a round the chira l centre C6A ha ve val ues very clo se to tho se corresp ondi ng to tetra hedra l ( sp 3 ) hybri di zati on, as expected , whereas ato ms C5, O7 , C8 to gether wi th C6 chira l centre ha ve nearl y Ûat conÙgura ti on | the sum of the three corresp ondi ng val ence b onds equal s 3 5 9 : 7 . It i s no ti ceabl e tha t C8 and O9 ato ms ha ve el ongated therm al ell i psoi ds. Deta il ed ana l ysi s i ncludi ng the reÙnement of pa rti al occupa ncy facto rs wa s carri ed out for ato ms wi th l arg e ani sotro py of therm al vi bra ti ons: C8, O9 . For the C8 ato m b onded to C6 and O9 , a di sorder m odel was reÙned resul ti ng i n two al terna ti ve p ositi o ns of thi s atom wi th nearl y equal o ccupanci es. The Ûat conÙgura ti on aro und C6 suggests the o ccurrence of epi m eri c di sorder. La rg e therm al vi bra ti ons observed for term i na l m ethyl gro ups of cara ne, C17, C19, C20, coul d b e attri buted to thei r m obi li t y. D isorder of the side chai n i s tra nsm i tted to the cara ne head. Stati sti cal character of therm al di spl acements for al l cara ne ato ms i s conÙrm ed by the fact tha t R MS di splacem ent for two LSQ superi mp osed cara ne m oi eti es of the di m er has a l ow val ue of 0.09. £
3 . Co m p ar i so n o f KP 23 R S an d KP 2 3S S m o l ecu l ar st r u ct u res Bo th comp ounds preserve a simi la r vol ume (pa cki ng density), i n spi te of sli ght vari abi li t y of l atti ce consta nts. T abl e compa res uni t- cell para m eters for b oth comp ounds and i l l ustra tes the vari abil it y of the uni t- cell pa ra meters of the epi meri c form . The crysta l and m olecul ar structure s o f b oth com pounds (KP2 3RS and KP2 3SS) reveal a signi Ùcant sim i lari t y. The existence of pol ym orphi c form and structura l simi la ri ty of both comp ounds, as well as app eara nce of KP2 3RS f orm duri ng recrysta l l i zati on of enanti om eri cal l y pure KP2 3SS, ra i ses three questi ons: ¯
¯
¯
whether a substi tuti on of epi meri c mo lecules i s p ossibl e duri ng the nucl eati o n sta ge of crysta l l i zati on ; whether a cong l omera te crysta l l i zati on coul d occur; ho w representa ti ve the inv esti gated sing l e crysta l sam pl e i s for the bul k m ateri al .
T o answer these questi ons pha se anal ysi s was carri ed out. 4 . P o wd er d i ˜ r act i o n exp er i m ents La rger qua nti ti es of KP2 3RS, KP2 3SS and KP2 3RR bul k ma teri al s were obta i ned by crysta l l i zati on of the rea cti on pro duct in the mi xture of anhydro us hexane and aceto ne. Fi gure 4a i l l ustra tes envi ro nm enta l scanni ng electro n mi cro scope pi cture of a typi cal crysta l l i te of KP2 3R S bul k m ateri al , wi th fai rl y wel l develop ed gra i ns i n the shap e of pa ra ll el epip eds; Fi g. 4b presents a spherol yti c congl om erate, chara cteri sti c o f KP2 3SS l am ella e. The m orpho logy of KP2 3RR is no t uni form : m i crocrysta l l i ne spherol ites and recta ng ul ar form s are vi sibl e (Fi g. 4c), suggesti ng the presence of two di ˜erent pha ses.
Str uct ural Charact er i zat i on
Fig. 4.
671
. ..
SEM pictures of (a) typical crystalli te of K P23RS bulk material, (b) spherolyti c
conglomerate, rectangular
characteristic
of K P23SS lamellae, (c) micro crystall i ne spheroli tes and
forms of two di˜erent
phases of K P23RR.
D i ˜ra cti on pa ttern recorded wi th a l ab ora to ry X- ra y source (Phi l i ps X 'Pert, Cu K ˜ ra di ati on, Bra gg{ Brenta no geom etry) for KP2 3RS (Fi g. 5a) wa s successful l y i ndexed using TR EOR pro gra m yi el di ng cell pa ra m eters (a = 7 : 3 7 1 ; b = 7 :5 6 0 ; c = 1 7 : 5 2 9 ¡A ; ˜ = 82: 63; Ù = 83: 85; Û = 84: 34 ) wi th Ùgure of meri t M2 0 equa l to 40 and F2 0 equal to 86. However, the numb er of resol ved di ˜ra cti on i ntensi ty pro Ùles wi thi n the sampl e di ˜ra cti on li m i t ra ng e was to o smal l ta ki ng i nto considera ti on the numb er of structura l para m eters of the simpl est structura l m odel (1 68). A di ˜ra cti on experi m ent for KP2 3R S carri ed out at ESR F G reno bl e (BM- 16 b eam l i ne, wa velength 0.803107(1 ) ¡A, capi l l ary 0.8 mm ) resulted i n a well -resol ved p owder pa ttern (Fi g. 5b). The pa ttern was i ndexed using the pro gra m TMO g ivi ng the l atti ce pa ra meters a = 7 : 3 6 1 ; b = 7 :5 3 5 ; c = 1 7 : 5 1 4 ¡A ; ˜ = 82: 68; Ù = 83 :86; Û = 84: 34 ; V = 954: 35 ¡A 3 , wi th Ùgure of meri t M2 0 equal to 84.5. The pattern was consistent wi th tha t cal culated fro m sing l e-crysta l structure. T aki ng i nto considera ti on the spread of l atti ce consta nts determ i ned for di ˜erent singl e-crysta l gra i ns (T abl e), the sim ula ted pa ttern wa s cal cul ated assuming the correctne ss of l atti ce para m eters fro m p owder pa ttern i ndexi ng . D ue to hi gh resol uti o n of the SR pa ttern, i t was p ossibl e to i denti fy 11 p eaks not b elong ing to the predo m i na nt structure of KP2 3R S; they were indexed separa tel y gi vi ng ortho rho m bic pa ra m eters ( a = 1 1 : 0 3 5 ; b = 1 2 : 1 0 8 ; c = 1 4 : 2 6 8 ¡A ; ˜ = 90: 0; £
£
672
J . Gro chowski et al .
9 0:0; Û = 90: 00 ; V = 1 9 0 6 : 5 ¡A 3 ). The uni t cell vo l ume of thi s adm i xture i s al m ost exactl y twi ce tha t of R S pha se, whi ch suggests the presence of yet ano ther p ol ym orph i n the bul k m ateri al . £
Ù =
Fig. 5.
Pow der di˜raction
X ' Pert, C u
patterns
of K P23 stereoisomers: (a) K P23RS |
Philip s
geometry , (b) K P23RS | synchrotron radiatio n, ESRF ¡ , (c) K P23SS | synchrotron radiaGrenoble, BM- 16 beamline, w avelength 0.803107 A tion, DES Y - HA SY LA B, B2 beamline, w avelength 1.3572 ¡A , (d) K P23RR phase mixture |
K
˜
synchrotron
, Bragg{Brentano
radiation , DESY -H A SY LA B, B2 beamline, wavelength 1.3572 ¡A .
The m easurem ents for KP2 3SS were p erform ed at the b eam l i ne B2 at the Ha mburg er Synchro tro n Stra hl ung slab or (HAS YLAB), G ermany [21 ]. A di vergence reduci ng, cyl i ndri cal , Pt- coated m irro r and a G e(111) do ubl e crysta l mono chro m ato r were used for b eam condi ti oni ng. The selected wa velength was 1.3572(1 ) ¡A. The sam pl e was Ùll ed i n a capi l l ary wi th 0.9 mm di ameter. Intensi ty da ta were detected wi th a NaI scinti l l atio n counter wi th a G e(111) channel cut ana l ysi ng crysta l m oun ted at the detecto r arm to reduce backg ro und and i ncrease resol uti o n. The di ˜ra cti on pattern of the KP2 3SS form (Fi g. 5c) was successful l y i ndexed usi ng TR EOR pro gra m yi eldi ng cell pa ra meters ( a = 7 : 4 0 9 ; b = 7 : 3 9 6 ; c = 1 7 : 7 4 5 ¡A, ˜ = 8 1 : 7 6 ; Ù = 8 5 : 1 7 ; Û = 8 7 : 1 0 ) wi th Ùgure of m eri t M2 0 equal to 79 £
Str uct ural Charact er i zat i on
. ..
673
and F2 0 equal to 241. The cal cul ated pattern based on sing l e-crysta l di ˜ra cti on of a m i crocrysta l l i ne grai n matched fai rl y wel l wi th the exp eri menta l one, pro vi ng pha se ho mogeneit y of the species. Two di ˜ra cti on pa tterns of the KP2 3RR m ateri al (two ba tches synthesi zed by di ˜erent m etho ds) recorded under the same condi ti ons reveal ed a more com pl ex spectrum . At low Bra gg ang l es, the p eaks were appa rentl y spli t (Fi g. 5d), and the i ntensi ty ra ti o i n each pa i r wa s reversed i n the other ba tch. Thi s i ndi cated tha t each sam pl e consists of two pha ses. Bo th pha ses were successful l y i ndexed wi th TR EOR yi el di ng cell pa ra meters: pha se 1: a = 5 :3 7 0 ; b = 1 0 : 3 6 0 ; c = 1 7 : 1 3 2 ¡A ; ˜ = 90: 0; Ù = 90: 0, 3 Û = 9 0 : 0 0 ; V = 9 5 3 : 0 6 ¡A ; pha se 2: a = 1 9 :1 9 0 ; b = 8 : 6 3 5 ; c = 8 : 7 1 6 ¡A ; ˜ = 90: 0; Ù = 94: 66, Û = 9 0 : 0 0 ; V = 1 4 3 9 : 4 9 ¡A 3 : Af ter the recrysta l l i zati on pro cess, selected gra i ns of a size suita bl e for singl e-crysta l di ˜ra cti on turned out to b e the KP2 3RS vari ety . Addi ti ona l l y, sing le crysta l s of KP2 3R R synthesi zed wi tho ut hydro chloride, C 1 6 H 3 0 N 2 O2 , were al so exam ined on a Ka ppa CCD (No ni us) di ˜ra cto m eter i ndi cati ng turb ostati c structure. 5 . Co n cl u si o n s The epim eri c fo rm of the i nvesti gated (- )- 3 -[2-hydroxy- 3-( N - isopro pyla mi no )- pro p oxyi m ino ]-cis - cara ne hydro chl ori de (C 1 6 H 3 0 N 2 O 2 Â HCl ), KP2 3RS, turned out to b e the easiest to crysta l l i ze. Apa rt fro m the predo m i nan t tri cli ni c pha se, two p ol ym orphi c form s were detected. The observed spread of uni t cell para m eters i s pro ba bl y ori gina ti ng fro m the natura l substra te (cara ne). A structura l sim i l ari ty of form s KP2 3R S and KP2 3SS facil i ta tes the congl om erate crysta l l i zati on. Co nform ati o nal ana l ysi s of KP2 3SS structure reveal ed epim eri c di sorder aro und the C6 ato m. For l ow- symmetry , no n- perf ect org ani c crysta l s, mi cro crysta l l ine and hi gh- resol uti on p owder di ˜ra cti on techni ques wi th synchro tro n ra di a ti on app eared to be suita bl e to ol s f or structure determ i nati on and pha se characteri zati on. £
£
Ac kn owl ed gm en t s The work wa s supported by the State Com mittee for Scienti Ùc R esearch, gra nt No. 4PO5 F01916 , a nd D ESY- HASYLAB, category I experi m ent I-0 0-024 and by IHP | contra ct HPR I- CT- 19 99-00040 of the Euro p ean Com mi ssion. The autho rs wi sh to tha nk Dr. A. Fi tch of ESR F for test HR PD m easurem ents and D r. Ma rek Faryna of the R egi ona l La bora to ry , Ja giel l oni an Uni versi ty , for conducti ng exp eri ments i n Envi ro nm ental Scanni ng El ectro n Mi croscop e. R ef er en ces [1] C.C . Pf ei˜er, Sci ence 124 , 29 (1956). [2 ] B. T esta, M. Reist, P.A . C arrupt, A nn . P har m. Fr. 58, 239 (2000). [3 ] S.C . Stinson, Chem. En g. N ews
79 (2001).
[4] T est Pro cedures and A cceptance Criteria for N ew Drug Substances and N ew Drug Pro ducts, Food and Drug A dministratio n: DA , , V ol. 62, N o. 227 (1997).
674
J . Gro chowski et al .
[5] T est Pro cedures and A cceptance Criteria for N ew Drug Substances and N ew Drug Pro ducts: C hemical Substances. T he Europ ean Agency for the Ev aluation of Medicina l Pro ducts, MEA /C PMP/ IC H /367/96 corr. , 1999. [6 ] Investigations
of C hiral A ctive Substances, EMEA /C V MP/128/95.
FI N A L, 1998.
[7] P. De K oning, Chem. En g. N ews 79, 251 (2001). [8] T .K . N evanen, L. Soederhol m, K . K ukkonen, T . Suortti, T . T eerinen, M. Linder, H . Soederlund, T .T. T eeri, J. Chroma togr. A 925, 89 (2001). [9] R. C . Willi ams, C .M. Riley , K .W. Sigvardson, J . Fortunak, P. Ma, E.C . N icolas, S.E. U nger, D. F. K rahn, S.L. Brenner, J. Ph arm. Bi omed. A nal. 17, 917 (1988). [ 10] E. Recansk a, F. Gregan, Ph arma zi e 54, 68 (1999). [11] T . Eriksson, S. Bio erkman, P. H oeglund, Eur. J. Cli n . Ph arma col. 57, 365 (2001). [12] I.K . Reddy , T .R. K ommuru, A .A . Zaghloul , M. A . K han, Cri t. R ev. Th er. Dru g Carri er Sy st. 17, 285 (2000). [ 13] G.A . McLeo d, D. Burke, A n aesthesia [14] R. Czarnecki, P. Serda,
331 (2001).
K . C zerw insk a, K . Gro chow ska, J . Gro chow ski, T . Librow ski, 1279 (1992).
[15] T . Librow ski, R. C zarnecki, M. Pasenkiew icz- Gieru la, J . Gro chow ski, P. Serda, S. Lo chy ¥ski, B. Fr ¨ck ow iak, Suppl. , 113 (2000). [16] J. Gro chow ski, P. Serda, M. Pasenkiew icz-Gierul a, P. T alik, R. C zarnecki, T . Librow ski, S. Lo chy¥ski, in: , A bstracts, p. 345. [17] T . Librow ski, R. C zarnecki, S. Lo chy¥ski, kiew icz-Gi erul a, J. Gro chow ski, P. Serda, 535 (2001). [ 18] S. Lo chy¥ski, B. Fr¨ck ow iak, M. Pasenkiew icz-Gieru la, in:
T . Librow ski,
[19] B. F r¨ck owiak, S. Lo chy¥ski, M. Pasenkiew icz- Gieru la , in: p. P- 64.
T . Librow ski,
B.
R.
F r¨ck owiak,
Czarnecki,
M.
Pasen-
J . Gro chow ski,
, Abstr. , p. PSA -04. R.
Czarnecki,
J . Gro chow ski, ,
[20] T he follow ing computer programs were used for calculati ons and Ùgures: WinGX { A Window s Program for C rystal Structure A nalysis { L. J . F arrugia (1998), U niversity of Glasgow , Scotland ; SH ELX L97 { Program for C rystal Structure ReÙnement, G. M. Sheldrick (1997), U niversity of Go ettingen, Germany; SH ELX S97 { Program for Crystal Structure Soluti on, G. M. Sheldrick (1997), U niversity of Go ettingen, Germany; ORT EP- 3 for Window s, L. J. Farrugia (1997), 565 (1997); WinPLO T R { A Graphic T ool for Pow der Di˜raction, T . Roisnel, J . Ro driguez- Carv aj al (2001), Lab oratoire L Ç eon Brillou in , Saclay , France; T REO R90 { Program for Pow der Pattern Indexing, P.-E. W erner; T MO { Program for Pow der Pattern Indexing, F. K ohlb eck, T echnical U niversity , V ienna. [21] J. Gro chow ski, P. Serda, M. Pasenkiew icz-Gieru la, R. C zarnecki, T . Librow ski, S. Lo chy¥ski, B. F r¨ck ow iak, C . Baehtz, M. K napp, , 2001.
