药物中晶型检测方案(激光拉曼光谱)

Polymorphy in Pharmaceuticals During the last 5-10 years， the molecular solidstate has gained recognition bytthepharmaceutical industry for its role in drugmanufacturing， stability，and activity.. Inaddition， definition of the crystalline phase hasbecome as important as molecular compositionin patent protection. The importance of this entire field has lead tocomplete texts such as Solid-State Chemistryof Drugs’(Byrn， Pfeiffer and Stowell， 1999)being devoted to this subject. Since thephysical state can effect the pharmaceuticalbehaviour of drug substances， it is important toknow what controls crystallisation， solid statereactions， phase stability， and solubility. Thereare numerous methods that have been used tomeasurethe solid state composition ofpharmaceuticals； these include x-ray diffraction，optical rmicroscopy， thermal analysis，dissolution testing， particle size analysis， NMR，andinfrared(IR))sspectroscopy.. CuriouslyRaman spectroscopy does not appear on thislist as yet， because it has not seen suchwidespread use as an analytical tool in thisclosely regulated industry. Raman spectroscopy can thowever， providequalitative and quantitativeinformation1 onpolymorphy， with 1pm spatial resolution whennecessary. The new generation in Ramantechnology， provides many advantages overthe other techniques. Nonn contact.t，non-destructivee analysis.Samplescanevenbe examined intransparent glass or plastic containers. Microscopic samples as small as 1um canbe easily characterised with the Ramanmicroprobe. Polymorphiccand pseudo-polymorphicphases in microscopic samples can bemapped. Little or no sample preparation is required. The lack of necessary sample preparation， andthe ability to examine samples in-situ and inmany types of transparent vial is an importantadvantage of Raman as a new characterisationtool. If we considerinfrared (IR) spectroscopy， which is the other widely used】vibrationalspectroscopy， we see that many containermaterials have limited transmission to the IRlight. Furthermore， IR examination， oftenrequires samples to be mixed with salts ornujol oils aandpresseddintopellets； forxamination. Theseprocedures are time-consuming， and introduce additional chemicaland physicalvariables：；： for iinstance， thepelletizing can create pressure-inducedpolymorphic transformation. The sensitivity of the information provided bydrug analysiswithinthepharmaceuticalindustry， means that little Raman data hasbeen openly published. We present in thisapplication note， spectra of organic crystalswhich may be used as non-commerciallysensitive models to illustrate the potential ofRaman spectroscopy in providing the usefulcharacterisation of pharmaceuticalformulations. 1. Fructose，，aanhydrous dextrose， andhydrated dextrose These three compounds are obviously notactive drugs， but they do bear a close similarityto many pharmaceutical compounds.s.Theinspectra illustrate several points Fructose and anhydrous dextrose share thesame chemical formula， butare differentchemicalisomers. Anhydrous and hhydrousdextrose differ in the water of hydration in thecrystal of ：thehydrousfform- in thepharmaceutical nomenclature， it is a pseudo-polymorph. For clarity the spectra have beensplit into the fingerprint regions (100-1750cm-)andCH/OH regions(2500-3700cm-1 ).Inspectionof the spectra shows clear differences between these species that wouldenakle rapid identification of them. Suchspectroscopic differences could easily be usedto establish presence and indeed distribution ofthe different compounds. 2. Stearic acid The spectra shown in the following figure weregeneratedfrommaterialtlthaatt hadbeendissolved in hexane， and then precipitatedduring evaporation. Twophases Wereobserved with optical microscopy- a grey，fairly planar material， and a white： 'fluffier’material of very fine crystals. Although the spectra in the accompanyingfigure lookfairly similar there are someobservable differences. The bottom spectrum，recorded from the white phase， shows a well-definedfeatureatabout165cm-1，anddifferences in relative intensities in the 1400-1500cm- region when compared to the secondform. An explanation of the origin of thesedifferences is that the grey material representsa lesscrystallineandmore amorphousmaterial than the bottom spectrum of the whitefine crystals. Evidence for this is shown by thepresence of the well-defined band at about 165cm-i which is consistent with a lattice vibration(only present in a crystalline phase)， and alsoin the behaviour of the bands in the region ofthe CHz bending motion (1400-1500cm-). Thespectral differences in this region have astrong precedent in the comparison with the behaviour of polyethylene where， crystallinityalso effects the spectral features in this region.Systematic studies of polyethylene， which canhave different states of crystallinity， indicatethat when crystalline there is a fairly strongband at about 1420 cm-which is absent in theamorphous phase1，2. 3.Summary Simple Raman measurements of even 'off-the-shelf organic materials； illustrate that itispossible to differentiate between materials thatdiffer by ： stereo isomer. polymorphy， pseudo polymorphy(duee tto0 Vwater(ofhydration). The potential of analytical Ramaninstrumentation in qualifying pharmaceuticalproducts in this area is only now beginning tobe exploited. 1- G.R. Strobl and W. Hagedorn， RamanSpectroscopic Method for Determining theCrystallinity of Polyethylene， J. Polymer Sci.：Polymer Phys. Ed. 16， 1181-1193 (1978)2- M. Glotin and L. Mandelkern， A RamanSpectroscopic Study of the MorphologicalStructure of the Polyethylenes， Colloid&Polymer Sci. 260，182-192(1982) ( Fax： +33 (0)3 20 59 18 08. Email ： raman@jobinyvon.fr www.jobinyvon.fr ) ( USA： HORIBA Jobin Yvon Inc.， 3880 Park Avenue， Edison， N J 08820-3012. Te l ：+1-732-494-8660，Fax： +1-732-549-2571. Email ： raman@jobinyvon.com w ww.jobinyvon.com Japan ： HORIBA Ltd.， JY Optical Sales Dept.， 1 - 7-8 Higashi-kanda， Ch i yoda-ku， Tok y o 101-0031. T el： +81 (0)3 3861 8231， Fax：+81 (0) 3 38618259.E m ail： raman@horiba.com ) Germany： +49(0) 6251 8475-0 Italy： +39 0257603050 UK： +44 (0)20 8204 8142 China： +86 (0) 10 6849 2216 ORIBAExplore the future France： HORIBA Jobin Yvon S.A.S.， rue de Lille， Villeneuve d'Ascq. Tel：+() All HORIBA Jobin Yvon companies were formerly known as Jobin Yvon)HORIBAExplore the future Simple Raman measurements of even ’off-theshelf’ organic materials illustrate that it is possible to differentiate between materials that differ by: • stereo isomer,• polymorphy, • pseudo polymorphy (due to water of hydration).