用于药物开发的晶体多晶型的拉曼光谱分析

拉曼光谱在制药工业中的应用  •杂质分析（微量杂质的识别-尺寸小于1µm）  •合成化合物的评估（结合IR的结构分析）  •绘图（DDS研究用片剂的评估）  •PAT（制药生产过程中的实时控制）晶体多晶型的评估（评估方法而不是XRD和DSC）Three analytical techniques are used in the evaluation of crystal polymorphism‍Raman Spectroscopy Analysis of Crystalline Polymorphsfor Pharmaceutical Development2/12Application Note Raman Spectroscopy Analysis of Crystalline Polymorphs for Pharmaceutical Development Ram a n Ap p l i cations in the Pha r maceu t ical Industrv · Impurity Analys i s (Identification of micro i mpurities - sizes less than 1 um) ·Evaluation of Syntheti z ed Compounds (Struct u ral analysis i n combinat i on wi t h IR) ·Mapping (Evaluation of tablets for DDS research ) Jasco NRS Series Raman Micro-spectrometers ·PAT (Real-time control in pharma production process) Evaluation of Crysta l Polymorphs (Evaluation method instead of XRD and DSC) Keywords： N RS-5000 ， N RS-7000， d i s p e r s iv e R a m a n ，Ra m a n s p e c t r osc o p y ， R a m a n i m a g i n g， t h e rm a l m e l t i n g，DS C， X R D ， ph a rm ac e u t i c a l a nal ys i s ， Ace t y ls a l i cyl i c ac i d ，aspi r i n， cr y s t a l po l y m o r p h is m ， c r ys t a l s t r u c t ur e ， tr e ha l os e ，a m p i ci li n ， b e t a l a c t a m ， T i O 2， Tit a ni um d i ox i de ， I ndo m e t h ac in Wha t is a C rysta l Po l ymorph ....? Crys t al polymo r phis m i s a pheno m eno n whe r e com p o u n ds wi t h th e same chem i cal f or m u l a can be crystal l ized i nto d i f f erent crystal li n e str u ctures. The crysta l st r ucture depends on t he condi ti ons (such as t emperature and p ressure) used in the crysta l format i on process. T h e r esult i ng crystal s t ruct u res are conven i ent l y cl assif i ed as Form l， l l， I ll o r T a n d T I n m ed i cine， t h e so l ubili t y， stabili t y a n d b i o-ava i l a b i li t y will d ep en d on t he crys t al p oly m orp h i sm ； compo u nds wi t h d i f f e rent crysta l st r uctu r es may even be r e cognized as d if fere n t compound s . T he r e f ore， research into crys t al poly m orph i sm is wid e ly u sed i n a r eas s u ch as basic stud i es，s t ruc t ure/funct i on co r re l at i on o f co m pound s and ind u str i al applica t io n s suc h as paten t appl i cat i ons . In t h e ph a rma c e u t i c a l in dust r y ， t h e s t u dy o f c r y s t a l fo r m a t i o n t e chniques i s ve r y im port a nt fo r th e c o n tr o l o f c r y s t a l st r u c ture a n d t h e manu f a c t u re of hi g h qual i t y me d i ci n e s . Methods for Evaluation of Crystal Polymorphism T hree analytica l tec h niques a r e used i n t he eva l uat i on of crysta l polymo r phism Instrument Principle Advantage Disadvantage XRD Evaluation of crystal structureby X-ray diffraction. Accurate distance betweenatoms in crystals. XRD is widely used for crystal structure analysis. Amorphous structurecannot be evaluated bvXRD. DSC Stability and melting point of crystals are evaluated byendothermic/exothermic reaction of the crystal whenheating/cooling the sample Properties of the crystal canbe observed. Crystal structure cannotbe determined by DSC. Chemical structure is evaluatedby detecting scattering light atlow wavenumbers derived fromlattice vibration， by laser irradiation of the sample. Both crystal and amorphous structures can be evaluated.Vibrational information of molecules can also be obtained from high wavenumber spectra. High spatial resolution and micromeasurement can be done. Sample preparation is not required. It is difficult for Raman toevaluate the absolute configuration of a crystal. Raman Spec tr oscopy is o n e of the h ot ana l yt i ca l t ec h n iques f or t he stud y of crys t a l polymo r phism! Features of Raman Spectroscopy for Evaluating Crystal Polymorphism 「vs. XRD1 (reference citation) T he above spect r a s h ow r esults f or bot h c r ysta l line and amo r phous st r uctu r es of I ndometaci n u si n g XRD and Ram a n spec tro sco py. Gene r a l ly i t i s dif f ic ult to m e asure samples wi t h l ess reflection (less d i f f ract i on spot) s uc h as amorphous and/o r mi n ut e c rys t a l s using X-ray crysta l a n a lysi s . Si n ce th e a c t u al medi c i n e fo r mlati o n s i ncl u d e a mo r pho u s a n d m i n ut e c r ys t als in a m ix t u r e ， R am a n sp e ct r osco py i s m o r e e ff ec t i ve as shown in the ri ght f igur e . P r es e n t ly X-Ray crysta l a n alysis i s used for t h e b asic study o f crysta l st r uctur e f or patent r eg i s t r atio n ， howeve r due t o th e above reasons， Raman is expec t ed to beco m e a m ore w i d e ly u sed techn i que i n th e pha r maceutica l i nd u st r i es f or patent r egist r ation. Features of Raman Spectroscopy in Crystal Polymorph Eval u ation [vs. DSC] It i s k n own t h a t Ace t ylsal i cyl i c acid ca n ex i sts in c r ys t alline Forms l a n d l I . XRD can b e used f or c r ys t al struc t u re a n alys i s ， bu t t he r ma l stabi lity cann o t be eva l u ated a n d u s e f u l spec tr a ca n not b e obta i ned for amorpho u s st r uctures at t emperatures h i g h e r than t h e melt i ng p oint. Conve r sely， DSC ca n be used to eva l uate t he t he r mal sta b i li ty of a crys t al， bu t structural i n f or m a t i on ca n not be obtained. Raman spectra of Acetylsalicylic acid of different particle size Raman Shift [cm'] Co m merc i al Ace t ylsalicyl i c ac i d wi t h several d i ffe r ent partic l e sizes were selec t ed and meas u red u sing Raman. T he r esul t s s h ow a cha n ge i n peak ra t io obse r ved i n t he higher wavenumber region， t h i s i s due to the di f fere n c es i n t h e crys t al ax i s. I n add i tion ， di f fere n ces i n t he Rama n spectra were obse r ved i n the r egio n b elow 200 cm-1 due to di f ferences i n p artic l e size and measured positi o n. These r esul t s ind i cates t h a t t he comm er cia l m ed ici n e is in a m ixed crysta l s t a t e and it is t h erefore di f ficul t t o a n alyze using DSC d u e t o t h e d i ffe r ent m e l tin g p oint s of t h e c rys t al fo rms . NRS-5000 system with heating stage Temperature controlled cell NRS-5100 (with temperature controlled cell ) Temperature controller B y mount ing t e m p erat ur e co n tr ol sy s t em on N R S-5000 s er i e s， i t i s po ss i bl e to mo n i t or i n-si t u t he stru c t ural cha n ges in sa m p l es. J ASCO INC. Lsc o Tel ： (800) 333-5272，F a x ：(410) 822-7526 Appl i cat i on L i brary ：ht t p：//w ww.j ascoinc .com/ap p lications Raman spectra of Acetylsalicylic acid of different particle size Raman Shift [cm'] Co m merc i al Ace t ylsalicyl i c ac i d wi t h several d i ffe r ent partic l e sizes were selec t ed and meas u red u sing Raman. T he r esul t s s h ow a cha n ge i n peak ra t io obse r ved i n t he higher wavenumber region， t h i s i s due to the di f fere n c es i n t h e crys t al ax i s. I n add i tion ， di f fere n ces i n t he Rama n spectra were obse r ved i n the r egio n b elow 200 cm-1 due to di f ferences i n p artic l e size and measured positi o n. These r esul t s ind i cates t h a t t he comm er cia l m ed ici n e is in a m ixed crysta l s t a t e and it is t h erefore di f ficul t t o a n alyze using DSC d u e t o t h e d i ffe r ent m e l tin g p oint s of t h e c rys t al fo rms . NRS-5000 system with heating stage Temperature controlled cell NRS-5100 (with temperature controlled cell ) Temperature controller B y mount ing t e m p erat ur e co n tr ol sy s t em on N R S-5000 s er i e s， i t i s po ss i bl e to mo n i t or i n-si t u t he stru c t ural cha n ges in sa m p l es. J ASCO INC. Lsc o Tel ： (800) 333-5272，F a x ：(410) 822-7526 Appl i cat i on L i brary ：ht t p：//w ww.j ascoinc .com/ap p lications Real -time Monitoring of Trehalose using a Heating Stage [1] I n -situ mo n i t oring of T r eha l ose 2H20 (whic h has h i g h wate r r ete n t io n and is used fo r foods and medicines)at 80 deg. C -spectra meas u red at one mi n ute i nterva l s. T he resu l t s shows t im e-dependent changes i r the spec t r a . Real -time Monitoring of Trehalose using a Heating Stage [2] Ra m an Shif t [c m -1】 T he h al f ba n dwidt h a n d th e p ea k s h i ft of two p ea k s whic h d em o ns t r a t e t he hydrat i on f eature i n t h e p r e vi o u s page we r e ana l yz e d. The r es u l t s i ndicate tha t th e c h a n g i n g pr oc e s s of th e p e a k s h i ft and half bandwidt h was observed i n three steps and by anal yz in g p e aks i n t h e r e gio n 1000-700 c m -1. It was confirmed t h at the c r ystal structure o f T r ehalose c h anges f rom a p r e-s t able s t r ucture (cr ystal or A m o r phous) t o a stable s tr uctu r e. The combinat i on of Raman f i t t ed w i th a t empe r ature co nt r ol sy st em ena b les the a n alysis o f k inetic structural changes with sample meltin g . Features of the NRS-5200 i n the evaluation of crystal polymorphism -High spatial resolution IR and Raman spectra (L-cystine[-SCH，CH(NH，)CO，H]) T he above figu r e s h ows IR a n d R aman spectra of L -cystine. R a m an spectroscopy enables measuremen t in the l ow wavenumber region be l ow 400 cm-1； i n addi t i on， the N RS-5200 can prov i de i n f orma t io n fo r t h e crysta l la t t ice v ib ra t io n s i n t h e very l ow wavenumber region down to 10 cm1. Since R ama n scatter i n g from aqueous so l u t i ons or glass is wea k ， sa m p l e p r etreatment i s not necessary and samples in g l ass or a q u e o us samples ca n be m eas u red ea s i l y a n d n o n-d es t r uctively. O n e of the fea tu r es of the NRS-5000i s t h a t crysta l po l ym orp hism can b e eva l ua t ed qua nti ta t ively a n d qua l i tatively at a high s p a tial r e so lu ti on d o wn to ~1 pm. Low Wavenumber Measurements using a Notch Filter N RS-5000 ser i es a l l ows not only mea s uremen t o f t h e us u a l i no r ga n i c and o r ga ni c sa m p l es， b ut also measureme n t in th e low wave n u mbe r r an g e u si n g t h e most s u i t a b l e optica l a r ra ng e m ent . I t is possible f or t h e u ser t o ea s i l y a d j ust t h e op ti m a l ang l e of t he notch f i lte r fo r l ow wavenu m b er m e as u r e m ent as req u ired for eac h sa mp l e. I n ad d i t i o n the NRS-7200 a l l ows ver y low wave n umbe r m e as ur e me nt d ow n t o 5 c m-1u s i ng the l ow wavenumber m e as u r em ent u ni t . N R S-5100/7100 ： d own to 50 c m -1 N R S-5200 with l ow w a ve n um b e r me asu r e ment u n it ： d o wn t o 10 cm -1 N R S -7200 w i th lo w w av e n um b e r me a s u r e m e nt un it ： do wn t o 5 cm-1 J ASCO INC. Jsc o Tel ： (800) 333-5272，F a x ：(410) 822-7526 Low Wavenumber Measurement of Bismuth Oxide by Adjusting the Notch Filter Angle Difference in low wavenumberregion depending on Notch filter angle (Bismuth oxide) S in ce peaks o f mi n erals o r l a t tice vibrat i on der i ved f rom crystals are detec t ed i n t h e l ow wavenumber r egio n ， Ra m an measuremen t in the low wave n umbe r r eg i on i s very i mporta n t . Rejectio n of Rayleigh sca t tering is t he k ey p oint to detect peaks i n t h e l ow wavenum b er r egio n ， so ca r e f ul opt i m i z a ti on i s n ec essa r y t o adjust the angl e of t h e not c h fil t er de p end in g on t h e sam pl e req ui rements. Low Wavenumber Measurement using a Notch Filter： Titanium Oxide with Crystal Polymorphs 100 Raman Shift [cm-11 N RS-5000 se r i es a l l ows not only mea s urem en t of t he usual i no r ga n i c and o r ga n i c sa m p l es， but also measurement i n t he low waven u mbe r r a ng e usin g t he most s u i t ab l e o pt ica l a r ra n g e m ent . It is pos sible f or th e user t o eas ily ad j ust t h e op ti mal a ngl e of the notch f ilte r fo r l ow wavenumber measu r e m ent as req ui red fo r eac h sa mp l e. I n add i tio n the NRS-7200 a l l ows ve r y l ow wa v e n umbe r measureme nt down to 5 cm u s i n g the l ow wavenumber measu r e m ent u nit. Measurement of Trehalose using the Low Wavenumber Measurement option on the NRS-7200 30 Raman Shif t [cm ] Sometimes i mporta n t peaks are obscured by t he notch f il ter when u sed with a si n g l e monochromato r ， h o wever， t h e l ow wavenumber measureme n t un i t f i tted t o t h e N RS-7200 ena b l es c l ear meas u rements in t h e l ow wavenumber regi o n. NRS-7200 w it h low waven u mber m e a surem e nt u n it Measurement of Acetylsalicylic acid using the NRS-7200 Low Wavenumber Measurement Unit Ace t ylsalicylic ac i d was m easured wi t h t h e N RS-7200. The up pe r s p ectr u m was ob t ained u s i n g the N RS-7200 f i t t ed wit h a l ow wavenumber meas u rement u nit， the low e r spect r um， wi t ho ut using t he optio n .Using t he l ow wavenumber measurement unit， peaks f or t he lat t i ce v i br a t io n s i n th e a n a l ges i c co m pouno can be c l ear l y observed and i mportan t i nfo r matio n fo r c r ystal polymo r ph i denti f i catio n can be obta i ned Measurement of Carbamazepine Polymorphs using the NRS-7200 Low Wavenumber Measurement Unit 35cm-1 10 Pat r i c k A . A nqu e ti l et al ， J. P harm . S ci ，92，149-160(2003).A .L . G r z es ia k ， M. L a ng， K K im，A.J. Ma t z g er ， J. Ph a r m. Sc i .，92，2260-2271(2004). Spectra of carbamazepine (Form II I ) measured by NRS-7200 C.J . S tr a c h e n ， S.L . Ho w e l l ， T . R ad es ，K .C. Go r d o n，J. Raman S p e ctros c .，35，401-408(2004). S i n ce Ra m an s p ec t roscopy can e asily d et ect p ea k s i n t he wavenumber reg i on b e l ow 100 cm -1， i t is possible t o i d e nti f y t h e d i ff ere n ces be tween Forms l a n d Il of ca rb amaze pi n e whose crysta l s t r uct ur e s are qu i te simi l ar. Howeve r ， the low wavenumber m e asu r em e n t u n i t is r equ ir ed t o charac t erize t h e Fo r m ⅢI I polymorph . Measurement of Acetaminophen [Paracetamol] using the NRS-7200 Low Wavenumber Measurement Unit Co m mercial l y ava i lab l e A cetaminophe n was measured us i ng t h e N RS -7200. I t is k nown that t h e r e are three c r ys t al p ol ymor p hs of P ara c etamol - F o r ml ， ll an d Il. T h e above spectra s h ows th e Fo r ml p olymorph . Measurement Indomethacin Polymorphs using the NRS-7200Low Wavenumber Measurement Unit： Patent of Crystal Polymorphs an ethical drug. T he a b ove spec tr a were o b t aine d by m easuri n g c om me r cia l l y available I nd o m et ha ci n usi n g t h e N RS-7200wi t h and wit h out t h e l ow wavenumb e r meas u r e ment u nit . It is k nown that I n do m e t h ac i n e xis t s as thr ee d i f f e rent crystal po l ymo r phs： a l p ha (acic u l ar c r ystal)， b eta and gamma (plate c r ystal). Ga m ma i s t h e m o s t s t able st r uctu r e f ollowed by the a l pha structure. Recently， a l pha has been se l ectively manu f actured (and patented ) to be used f or exte r na l med i ci n e f or enha n ced sk in abso r pt i on and stabili t y. T he m et h od f or effective ma n ufacturing of a speci f i ed crysta l polymo r ph is extremely i mpo r t ant. Research papers including low wavenumber measurement- Ampicillin which has several polymorphs- Ampici l lin 1A beta-lactam antibiotic Measurement Indomethacin Polymorphs using the NRS-7200 Low Wavenumber Measurement Unit： Patent of Crystal Polymorphs Comparing with XRD and DSC Raman enables ... > Measurement of amorphous structures >Measurement of micro samples > Provides information regarding crystal and molecular structure Raman can be used to directly measure commercially available medicine， suggesting use for the evaluation of final products Low wavenumber measurement is essential for evaluation of crystal polymorphs ! In comparison with other Raman instruments，the NRS-7200 allows ... >Measurement in low wavenumber range by angle adjustable notch f ilter >N Measurement in very low wavenumber range using the low wavenumber measurement unit