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Using Terahertz Pulse Spectroscopy to Study the CrystallineStructure of a Drug: A Case Study of the Polymorphs ofRanitidine Hydrochloride P.F. TADAY, I.V. BRADLEY, D.D. ARNONE, M. PEPPER TeraView Limited, 302/304 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK Received 22 July 2002; revised 23 October 2002; accepted 22 November 2002 ABSTRACT: We describe the application of Terahertz pulse spectroscopy to polymorphidentification. The particular compounds investigated were the different crystallineForms 1 and 2 of ranitidine hydrochloride, both in the pure form and also obtained as amarketed pharmaceutical product. Identification was clear. The technique has advant-ages that excitation is not via a powerful laser source, as used in Raman spectroscopy, sophase changes or photochemical reactions in polymorphs do not occur. Terahertz absorp-tion spectral interpretation and instrumentation are similar to basic Fourier transforminfrared (FTIR) spectroscopy and therefore easy to understand. The sample preparationtechniques used are the same as those used in FTIR and Raman spectroscopies. The dataobtained is complementary to Raman Spectroscopy. As the selection rules are differentbetween the two techniques, we are able to obtain new data set directly related tocrystalline structure adding to that obtained by Raman spectroscopy. Terahertz pulsespectroscopy provides information on low-frequency intermolecular vibrational modes;these are difficult to assess in Raman spectroscopy due to the proximity of the laserexciting line. It is concluded that the method has a wide range of applications inpharmaceutical science including formulation, high throughput screening, and inspec-tion in storage. ß 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J PharmSci 92:831–838, 2003Keywords: infrared spectroscopy; analytical chemistry; polymorphism; solid dosage have different rates of dissolution or bioavailabil-ity, and may even effect the stability of the drug.2 It has long been known that many pharmaceu- The formation of different polymorphs can be tical solids can exist in more than one crystalline controlled during crystallization by the solvent form.1 That different forms or polymorphs have used, the rate of cooling, and the degree of super- the same chemical formula but different crystal- saturation of the solution. Once in the desired line structures that can lead to different physical crystalline form the polymorphic state may be and chemical properties of the material. These changed by incorrect storage or even during tablet may also impact on pharmaceutical properties of preparation. At present, there are no quick and the drug, for example, different polymorphs may convenient methods for confirming the poly-morphic state of drugs while in storage or duringmanufacture.
To date, many different physical techniques Correspondence to: Phil F. Taday (Telephone: þ44 (0)1235 have been used to look at characterization of the solid form of pharmaceuticals, including single- crystal X-ray diffraction, optical spectroscopy, Journal of Pharmaceutical Sciences, Vol. 92, 831–838 (2003)ß 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association thermal analysis, and microscopy. Single-crystal JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 4, APRIL 2003 X-ray diffraction is still the benchmark method of include weak blackbody sources and helium cooled determining the existence of a polymorph as it detectors. In other techniques such as FT-Raman gives the crystalline structure directly; however, it spectroscopy, the proximity of the signal wave- does require sufficiently large crystals, and it is length to the laser excitation line gives a require- severely limited when applied to the polycrys- ment for excellent ‘‘notch’’ filters and double or talline or amorphous states. Mid-infrared and even triple grating spectrometers. TPS uses room Raman spectroscopy are based on the intramole- temperature sources and detectors; the former are cular vibrations of molecules; these give rise to 104 times more powerful than conventional inco- different peak positions, or peak intensities, for herent blackbody emitters,4 while the latter have each polymorph the differences in the spectra noise equivalent powers (NEPs) that can ulti- can be small. Because these techniques frequently mately reach the aW (10À18 Watt) level. TPS is probe intramolecular vibrations, they are not a time-gated technique, which minimizes back- direct probes of the intermolecular or collective ground noise and enhances the signal-to-noise modes that characterize the crystal structure.
ratio. This allows a spectrum to be acquired in less Laser Raman spectroscopy can create an extra, than 100 ms, and because it is a transform tech- serious problem in that the laser irradiation can nique there is no requirement for an expensive induce a phase change, or initiate photochemical grating spectrometer. TPS selection rules are the reactions, in samples being interrogated. In near- same dipole selection rules found in infrared infrared (NIR) spectroscopy the situation becomes spectroscopy. The data obtained using this tech- more complex due to the fact that the spectra nique therefore complements the results of Raman obtained will consist of many combination and spectroscopy and allows for the complete descrip- overtone bands of the fundamental vibrations ob- tion of the vibrational structure of a molecule.
served in the mid-infrared, making analysis Moreover, because coherent detection is used in difficult. There have not been many published TPS, one can measure the amplitude and phase of reports of the application of NIR to pharmaceutical the THz pulse, which allows the absorption coef- applications, but a number of spectrometer man- ficient as well as refractive index spectra to be ufactures are developing imaging systems for this determined. The refractive index provides addi- application. Differences in the electronic environ- tional information about the material, but because ment for different crystalline states also allow it is related to absorption (by the Kramers-Kronig the use of solid-state NMR; although the technique dispersion relationship) it only provides confirma- is inherently insensitive,3 it has been applied to finished drug products. Thermal properties are The TPS technique has recently being applied sensitive to differences in the crystal structure to the study of DNA5,6 and low-frequency torsio- and reveal the existence of a phase transition at a nal vibrational modes in long chain carotenoids.7 particular temperature. Optical or electron micro- Because very little experimental work has been scopy can provide secondary or supporting evi- done in this region, there are correspondingly few dence for the existence of a polymorph, but it is theoretical calculations. Hopefully, with recent only spectroscopic techniques (including single- activity in the field theoretical molecular models crystal X-ray diffraction), which can determine will develop and test their models against our the molecular structure. Despite this myriad results. Walther et al.8 have reported the THz- of techniques, no one method has been able to absorption spectra of the isomers of hydroxy- address the issues of high throughput polymorph benzoic-acid (salicylic acid), showing the power of screening or been able to quickly and conveniently the technique to determine different conformers of confirm the polymorphic state of drugs while in a molecule. To our knowledge, TPS has not been used previously for the detection of polymorph- In this article we demonstrate a quick, simple, ism. The sensitivity of THz spectroscopies such and versatile technique for investigating different as TPS to the polymorphic state of the crystal polymorphic forms using the new technique of follows from the fact that vibrations in this region are due either to large-amplitude torsional vibra- There has been very little work reported in the tions (intramolecular) or intermolecular inter- THz-region (0.1 to 3 THz) or far-infrared region actions between nearest neighbour molecules.
of the electromagnetic spectrum due to the con- Provided such vibrations induce a change in the siderable experimental difficulties in far-infrared dipole moment of the crystal, absorption should Fourier Transform spectroscopy. These problems occur. An example of the former would be the vinyl JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 4, APRIL 2003 group torsion in 4-methylstyrene, which has a been reported by Foster et al.20 Taylor and fundamental mode9 at 1.17-THz, while an example Langkilde21 have reported the laser Raman spec- of the latter is the hydrogen-bond translation S- trum of the drug in a tablet formulation. It was band vibration10–12 in water at 6 THz.
noted that the Raman beam was sufficiently in- To test the application of TPS to polymorph tense to induce changes in the spectra of some of detection we investigated ranitidine hydrochlo- their samples. The X-ray diffraction data indi- ride, (N-[2-[({5-(dimethylaminomethyl)]-2-furanyl}- cates that the orientation of the ranitidine molec- methyl)thio} ethyl}-N0-methyl-2-nitro-1,1-ethene- ules in the two forms is different,14,22 and this is diamine Á HCl); the molecular structure is shown thought to be due to a tautomerism in the raniti- in Figure 1. This molecule is used in treatment of duodenal-gastric ulceration and Zollinger-Ellison In this article we report on the technique of syndrome. Crystalline ranitidine is polymorphic obtaining the TPS absorption spectra of the two and exists in two crystalline forms known as Form forms, both as pure samples and in the drug dosage 1 and Form 2, and there are also several pseudo- polymorphic forms.13 The crystalline form de-pends on the solvent used for crystallization; forexample, Form 1 is obtained by crystallizing from an ethanolic solution after the addition of ethylacetate,14 while Form 2 is obtained from a solution Ranitidine-HCl forms 1 and 2 were obtained from of isopropanol-HCl.15 The two form have equal Neuland Laboratories Limited and used without solubilities, and there is no difference in bioavail- any further purification. The following dosage ability.16,17 As far as the pharmaceuticals compa- forms were also purchased; Apo-ranitidine 75-mg nies are concerned, Form 1 is more difficult and (Apotex Inc), Ranitidine 300-mg (Eastern Pharma- expensive to crystallize while Form 2 is cheaper to ceuticals Ltd), Ranitidine 300-mg (Generics UK manufacture, and is used exclusively in GSK Ltd), Zantac (GSK), Ranitidine 300-mg (Noton, products (Zantac). There have been no reports of interconversion between the two forms.18,19 (Tillomed). Table 1 summarizes the percentage of The mid-infrared (500 to 3000 cmÀ1) and Raman the active ingredients in the above formulations.
(1000 to 1400 cmÀ1) spectra of the two forms have All tablets and drugs were lightly crushed and mixed with polyethylene (PE) powder at a percen-tage weight of 25%. In the case of the formulateddrug the percentage weight refers to the percen-tage of tablet, so the amount of ranitidine hydro-chloride may vary between samples. The mixturewas compressed into disc of thickness about 1 mmwith a compression of about 2 tons. PE is trans-parent in the THz region, Thus making it a suit-able material as a matrix for spectroscopy in thisregion. The polyethylene disc mixtures wereprepared at different compressions between 1 to2 tons. The terahertz absorption were recorded foreach compression; there was no observed inter-conversion between the two polymorphic states;this confirms the X-ray diffraction data obtainedby Madan and Kakkar,13 who reported compres-sions between 4 to 6 tons and did not also observeany interconversion between the polymorphs.
The apparatus employed for TPS is shown in Figure 2. The laser used was a Coherent VitesseKerr-lens, mode-locked Ti:Sapphire laser, which (a) Molecular structure of ranitidine hydro- produces near-bandwidth limited pulses of 75-fs chloride (b) indicates a possible tautomeric form ofranitidine hydrochloride that has been suggested to be duration with an average power of 300 mW and a involved in difference between the two polymorphic repetition rate of about 80 MHz. The laser beam is split into two; one beam is attenuated by 25% and JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 4, APRIL 2003 Summary of the Percentage of the Active Ingredients of the Drugs is used to generate the THz radiation. The other of a Wollaston prism, which splits the polarization beam is used as a probe to detect the THz radiation of a beam into its respective components, a pair of using electro-optic sampling (EOS).23 The THz balanced photodiodes can monitor the changes radiation is generated by focusing the laser beam in the probe beam. The signal is then amplified by onto a photoconductive switch,23 which is placed a lock-in amplifier, with a time constant of 100 ms.
on a 500 mm-thick GaAs substrate. The photo- The time delay is either generated in a rapid- conductive emitter consisting of metal strips on a scanning mode by use of a scanning delay line or GaAs substrate, across which a DC bias is applied.
step-scanned by using a motorized translation The mechanism for THz emission is most simply stage. A typical time-gated signal is shown in explained by the device acting as an ultrafast, Figure 3(a). Fast Fourier transforming this time– photoconductive switch. In the presence of a laser domain signal results in the frequency response of pulse, the switch is open and there is a flow of the device as shown in Figure 3(b). The useful electrons across the gap. The acceleration of the bandwidth of detection is from about 100 GHz to electrons results in the emission of terahertzradiation. A more detailed description of themechanism is given by Leitenstorfer et al.24 TheTHz radiation generated by the semiconductor iscollimated by an off-axis parabolic (OAP) mirrorand is focused by another mirror onto sample witha spot size of about 1 mm. The transmitted beamis collected and collimated. Both THz radiationand the probe beam are then focused onto a zinctelluride (ZnTe) crystal. The probe beam pola-rization is modified in the presents of the THzradiation (Pockels effect) in the ZnTe. With the use (a) Representative time–domain interfero- gram obtained from the system used. (b) Frequency– meter. WP is a Wollaston prism. l/4 is a quarter wave- domain spectrum of the time–domain interferogram plate at 800 nm. OAP is an off-axis paraboloic mirror.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 4, APRIL 2003 about 3 THz (6–100 cmÀ1). In a step-scan mode a spectrum can be taken in less than 2 min with a spectral resolution of about 1 cmÀ1. In the rapid- scan mode with slightly less spectral resolution, a few cmÀ1, spectra can be obtained in less than100 ms.
The THz field transmitted through a sample is modified by dispersion and the absorption of the media under examination. The ratio of the electric field strength before Er(o) and after transmission,Es(o), is given by a series of Lorentizian lineshape functions to ob- tain the peak positions; these are given in Table 2.
Temperature-dependent THz absorption spectra where d is the thickness of the sample, o the of the two forms of ranitidine have been obtained.25 frequency of the radiation, c the speed of light in These will aid spectroscopic assignment of the vacuum and T(n(o)) is the reflection loss at the bands. Because the molecular structures of two sample surface. Both the refractive index n(o) and polymorphs are the same, the main changes in the the absorption coefficient a(o) can be determined absorption spectra must be due to the different from the ratios of the measured THz fields.
local crystalline environment induced by nearest Figure 4 shows the THz absorption spectra for neighbour interactions. Form 1 has a series of Form 1 and Form 2 of ranitidine HCl. The insert in vibrations spaced at about 250 GHz stretching Figure 4 highlights the region around 1.10 THz from 0.95 THz to 2.04 THz, which could be a where there are considerable differences in the torsional motion in one of the functional groups in THz spectrum between the two polymorphs; this ranitidine. It is noted that in Form 2, the position can be used in the identification of the two struc- and the intensity of the peaks are different, and in tures. This region selected has been highlighted particular, the almost harmonic character seen in because it shows the most obvious differences Form 1 vanishes. This could be due to the steric between the polymorphs. The data can be fitted to hindrance preventing rotation of the group, which (gray) at 300 K. The insert highlights the region around 1.10 THz where there are considerable changes in the drug formulated Apo-ranitidine (ApoTex) upper graph.
THz-spectrum between the two polymorphs. Terahertz The lower graph shows the change in refractive index.
absorption is defined as log (transmission of reference The arrows indicate the correlation between the refrac- pulse/transmission of sample pulse).
tive index and the absorption coefficient of the material.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 4, APRIL 2003 The terahertz absorption spectrum of drug formulated Zantac (Glaxo) upper graph. The lower graph shows the change in refractive index.
causes the observed bands in the Form 1 spectrum.
the two over the range 300 GHz to 3 THz (Apo- Assignments of these vibrations are difficult due ranitidine is the black curve and Zantac is the gray the lack of theoretical data available and the curve). Figure 8 shows the THz absorption spectra number of ‘‘free-rotators’’ available in the raniti- of other four ranitidine generic formulations out- dine molecule. Understanding of the crystalline lined in Table 1; these all contain Form 1. It is phonon bands could also lead to the assignment of noted that there are considerable differences between the spectra in Figure 8 above 1.5 THz.
These differences could be due to different exci- Figures 5 and 6 shows the absorption spectra and pients used in the preparation of the formulated the change in refractive index of the formulated tablet. We are in the process of studying the version of the drugs, namely, Zantac and Apo- different excipients and their effect on the ter- ranitidine, respectively, in the THz region. By comparing the spectra in Figure 4 with the twoformulations in Figures 5 and 6, it is clear thatZantac is based on form 2 while Apo-ranitidinecontains form 1. Figure 7 shows comparison of drug dosage tablets at room temperature from the following manufactures (a) Eastern Pharmaceuticals shown in Figures 5 and 6. Apo-ranitidine is the black Ltd, (b) Generics UK Ltd, (c) Tillomed, and (d) Norton JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 4, APRIL 2003 album and collagen between 0.1 and 2.0 THz. ChemPhys Lett 320:42–48.
No normal mode calculations have been carried 6. Nagel N, Haring Bolivar P, Brucherseifer M, out for the two forms of ranitidine hydrochloride; Kurz H, Bosserhoff A, Bu¨ttner R. 2002. Integrated thus, assignments of the transitions observed in THz technology for label-free genetic diagnostics.
Appl Phys Lett 80(1):154.
the THz region are currently not possible. But 7. Walther M, Fischer B, Schall M, Helm H, Uhd what the spectra do show is that using TPS it is Jepson P. 2000. Far-infrared vibrational spectrum possible to rapidly (<100 ms) distinguish between of all-trans, 9-cis and 13-cis retinal measured by the two polymorphic forms in drug formulations.
THz time–domain spectroscopy. Chem Phys Lett Because the spectrum in the THz region is very sensitive to intermolecular interactions, we expect 8. Walther M, Plochocka P, Fischer B, Helm H, to resolve the polymorphs of other molecules of modes in biological molecules investigated by We should also point out that because most terahertz time-domain spectroscopy. Biopolymers plastics in which drugs are stored are trans- parent to THz radiation, it is possible to use the 9. Hollas JM, Taday PF, Gordon RD. 1992. Supersonic jet fluorescence spectra of 4-methylstyrene:ground technique to examine substances while in storage.
state vibrtaional wavenumbers and improved tor- The system can also be configured to work in sional potential functions. J Mol Spect 153:587– reflection resulting in an instrument that can monitor a compound while in production, allow- 10. Thrane L, Jacobsen RH, Uhd Jepsen P, Keiding SR.
ing for quality assessment and quality control of 1995. THz reflection spectroscopy of liquid water.
TPS, unlike many other optical techniques, uses 11. Gaiduk VI, Tseitlin BM, Briskina ChM, Crothers radiation of sufficiently long wavelength such that DSF. 2002. Simplified theory of wideband spectra it does not induce any phase changes or photo- of liquid H2O and D2O (from 0 to 1000 cmÀ1) due chemical reactions. In addition, because the tech- to reorienting polar and vibrating H-bond water nique utilizes very low-power densities, in the THz 12. Zelsmann HR. 1995. Temperature dependence of beam is not sufficient to heat the sample. We also note that the potential for using the TPS technique in a rapid-mode scan mode, that is obtaining 13. Madan T, Kakkar AP. 1994. Preparation and spectra in less than 100 ms, makes possible appli- characterisation of ranitidine-HCl crystals. Drug cations in high-throughput environments.
14. Hohnjek M, Kuftinec J, Malnar M, Skreblin M, Kajfez NA, Blazevic N. 1986. Ranitidine: Analyticalprofiles of drug substances, 150. New York: Aca- 15. Crookes DC. 1982. Crystalline ranitidine hydro- 1. Haleblian JK. 1975. Characterization of habits chloride and pharmaceutical composition contain- and crystalline modification of solids and their pharmaceutical applications. J Pharm Sci 64(8): 16. Shen J, Lee D, Mckeag RG. 1995. Bioequialence of two forms of ranitidine. NZ Phamacy 15:24.
2. Byrn S, Pfeiffer R, Ganey M, Hoiberg C, Poochikian 17. Bawazir SA, Gouda MW, El-Sayed YM, Al-Khamis G. 1995. Pharmaceutical solids: A strategic app- KI, Al-Yamani MJ, Niazy EM, Al-Rashood KA.
roach to regulatory considerations. Pharmaceut 1998. Comparative bioavailability of two tablet formulations of ranitidine hydrochloride in healthy 3. Bugay DE. 2001. Characterization of the solid- volunteers. Int J Clin Pharm 36:270–274.
state: Spectroscopic techniques. Adv Drug Del Rev 18. Wu V, Rades T, Saville DJ. 2000. Stability of poly- morphic forms of ranitidine hydrochloride. Phar- 4. Han PY, Tani M, Usami M, Kono S, Kersting R, Zhang X-C. 2001. A direct comparison between 19. Carstensen JT, Franchini MK. 1995. Isoenergetic terahertz time–domain spectroscopy and far-infra- polymorphs. Drug Dev Ind Pharm 21(5):523.
red Fouier transform spectroscopy. J Appl Phys 20. Forster A, Gordon K, Schmierer D, Soper N, Wu V, Rades T. Characterisation of two polymorphic 5. Markelz AG, Roiberg A, Heilweil EJ. 2000. Pulsed forms of Ranitidine-HCl. Int J Vibrat Spectrosc 2.
terahertz spectroscopy of DNA, bovine serum JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 4, APRIL 2003 21. Taylor L, Langkilde FW. 2000. Evalution of solid- 23. Wu Q, Zhang X-C. 1997. Free-space electro-optics state forms present in tablets by Raman spectro- sampling of mid-infrared pulses. Appl Phys Lett scopy. J Pharm Sci 89(10):1342–1353.
22. Kojic-Prodic B, Ruzic-Toros Z. 1982. Structure of 24. Leitenstorfer A, Hunsche S, Shah J, Nuss MC, new H-receptor antagonist, 2-(2{[15-(dimethylam- Knox WH. 2000. Femosecond high-field trans- moniomethyl) -2- furyl ]methylthio} ethylamino)2 - port in compound semiconductors. Phys Rev B 16: (ranitidine hydrogen oxalate). Acta Crystallogr 25. Taday PF, Bradley IV, Arnone DD, Pepper M.


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