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The applications of near-infrared Fourier transform Raman spectroscopy to the analysis of polymorphic forms of cimetidine
0584-8539/91$3.00+0.00 0 1991 Rrgamon Res plc
~p~hi,,,ica Acta, Vol. 47A, No. 9110, pp. 1389-1393, 1991 Printed in Gnat Britain
The applications of near-infrared Fourier transform Raman spectroscopy to the analysis of polymorphic forms of cimetidine A. M. TUDOR, M. C. DAVIES* and C. D. MBLIA Department of Pharmaceutical Sciences, University of Nottingham, Nottingham NG7 2RD, U.K.
D. C. LEE and R. C. MITCHELL SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn AL6 9AR, U.K.
P. J. HENDRA Department of Chemistry, University of Southampton, Southampton SO9 5NH, U.K.
and S.
J. CHURCH
Courtaulds Research, Lockhurst Lane, Coventry CV6 SRS, U.K. (Received 14 March 1991; in revised fom and accepted 12 April 1991) Ahatraet-Fourier transform (lT)-Raman spectroscopy, utilizing a near-infrared (Nd:YAG laser, at 1.064pm) source was used to characterise the three anhydrous polymorphic forms A, B and C of the drug cimetidine (N”-cyano-N-methyl-N’-[2-[(5-methyl-l~-imidaxol-4-yl) methylthio]ethyl]guanidine). The FTRaman spectra were free from fluorescence interference and had good signal-to-noise ratios. Each polymorph has a distinct spectrum, characterised by two regions, 1250-105Ocm-’ and 1500-135Ocm-‘. This work demonstrates that it is possible to use FT-Raman spectroscopy to differentiate between polymorphic forms of the same compound.
INTRODUCTION
crystalline forms of the same compound (polymorphs) may differ markedly both in solubility and rate of dissolution. In the event that a drug shows polymorphism and one polymorph has a poor solubility, the crystal structure can have a crucial influence on the pharmacokinetic levels of drug in the body and hence the therapeutic activity [l]. Minor changes in the physical conditions of the manufacturing process, for example temperature, pressure, concentration or the presence of a foreign compound can alter one polymorphic form of a drug to another and again, may alter the therapeutic efficacy ..of the product. Hence, from a quality control stance, the characterisation of polymorphic forms is critical. Cimetidine,N”-cyano-N-met~yl-N’-[2-[(5-methyl-l~-imidazol-4-yl)methylthio]ethyl]guanidine (Scheme l), is a selective histamine Hz-receptor antagonist and a powerful inhibitor of gastric acid secretion. It has three major anhydrous polymorphic forms, referred to as polymorphs A, B and C [2], and a hydrated form which also exhibits polymorphism [3]. It has been shown that the bioavailabilities and biological activities of the several polymorphic hydrated and salt forms of cimetidine correlate well with the dissolution rates of each different crystal form [4-71. A number of techniques has been employed to characterise polymotphs, including X-ray crystallography [8], differential scanning calorimetry (DSC) [9] and Fourier transform infrared spectroscopy [3]. To date, there are no reports on the application of Fourier transform (PT)-Raman spectroscopy to the study of polymorphism of drugs. The recent combination of 1 Fourier transform format and a near-infrared (NIR) irradiation
DIFFERENT
* Author to whom correspondence should be addressed. Editor’s note: other examples of studies on the FP-Raman spectra of polymorphs will be found in Refs [16-181.
1390
A. M. TUDORet al.
H3C
H--H-H s I
H-C-H I H-C-H I i--H I C=N-CSN I N-H H--C-H I H Scheme 1. Structure of cimetidine.
source has addressed many of the problems previously experienced in Raman spectroscopy. Difficulties, such as laser-induced background fluorescence, long spectral acquisition times and sample photodecomposition and heating from extended exposure have been significantly reduced [lo]. FT-Raman spectroscopy has been applied successfully to the analysis of polymers, paints, catalysts, dyestuffs, explosives and, of particular interest to this paper, biomolecules and drugs [ll-131. In all these applications, the technique is complementary to FTIR. The aim of the work reported here is to extend our previous studies to exploit the recent advent of FT-Raman spectroscopy to an investigation of the polymorphs of cimetidine.
EXPERIMENTAL
Polymorphs A, B and C of cimetidine were kindly supplied by Smith Kline Beecham Pharmaceuticals and were prepared in a similar manner as described previously [2]. For the analysis, the samples were ground to a fine powder using an agate pestle and mortar. The FT-Raman spectrometer used in the analysis was constructed from a Perkin-Elmer 1710 FTIR spectrometer, converted to operate in the (NIR) using a Nd:YAG laser, at 1.064fim. The sample (approximately 0.04 g) was placed in a brass tube (4 mm bore x 3 mm sample depth) solid sample holder. The analysis of the three polymorphs was performed at an instrumental resolution of 6cm-‘, a laser power of 280mW for 100 scans. The full details of the instrumentation are presented elsewhere [14]. The infrared (IR) spectra were recorded on a Bruker IFS 88 FT-IR spectrometer at an instrumental resolution of 4 cm-’ for 50 scans. Briefly, the sample preparation method involved mixing 1 mg of sample with 99 mg of KBr and pressing a disc for analysis.
RESULTS AND DISCUSSION
The FT-Raman spectrum of polymorph A of cimetidine is shown in Fig. 1. Whilst the corresponding FTIR spectrum is included in Fig. 1 for reference purposes, the main discussion will centre on the vibrational assignments in the Raman data. The Raman and IR spectra are complex with a large number of bands in the fingerprint region (1500-500 cm-‘). Such detailed spectra are not unexpected sin& cimetidine contains a 4,Sdisubstituted imidazole ring, and thiaalkane, amine, methyl and nitrile functional groups. The discussion below will attempt to highlight the possible vibrational origins of the more major Raman peaks.
NIR FT-Raman spectroscopy of cimetidine polymorphs
cm-’ Fig. 1. The comparison of the IR spectrum (above) and the FT-Raman spectrum (below) of polymorph A of cimetidine.
The most characteristic bands in the Raman spectra of imidazole and its substituted derivatives originate from ring-stretching vibrations (1600-1350 cm”), in-plane C-H deformations (1300-1250 cm-‘), in-plane ring deformations (930-820 cm-‘) and the out-of-plane ring deformations (690-620 cm-‘) [15]. The ring-stretching region is complicated by the appearance of overtones and by the large frequency shifts which can result from substituent changes. A particularly striking feature in Fig. 1 is the virtual absence of N-H streching bands in the region 3400-2500 cm-’ in the Raman spectrum compared to the IR spectrum. As a result sharp C-H stretching bands are clearly observed in the Raman spectrum whereas they are obscured in the IR spectrum. The thiaalkanes contain a functional group involving sulphur which ‘frequently gives rise to strong Raman scatter. In the Raman spectrum of liquid dimethylsulphide an intense polarised band at 691 cm-’ is assigned to the symmetric C-S-C stretch, and a strong depolarised band at 742 cm-’ to the complementary antisymmetric stretch [15]. Hence the strong band 664 cm-’ in the Raman spectrum of polymorph A can be assigned to the symmetric C-S-C stretching vibration; the band at 741 cm-’ could be due to the antisymmetric C-S-C stretching vibration. As expected these bands are much weaker in the IR spectrum. Corresponding bands occur in the Raman spectra of polymorphs B and C (not shown) at 669 and 743 cm” and 675 and 741 cm-‘, respectively. The frequency range for the nitrile stretching vibration is 2260-2100 cm-’ [15]; hence the solitary, strong band at 2172 cm-’ in Fig. 1 is clearly due to this vibration. The corresponding bands in the Raman spectra of polymorphs B and C (not shown) occur at 2165 and 2156cm-‘, respectively. The nitrile band is observed at 2177, 2174 and 2166 cm-’ in the IR spectra of polymorphs A, B and C, respectively. There are two main areas in the fingerprint region which show clear differences in the Raman spectra of polymorphs A, B and C. A band in the spectrum of one polymorph is seen as possibly two or more in the spectrum of another; this may be due to crystal/ correlation splitting. The first region of interest is 1250-105Ocm-’ (Fig. 2) In the spectrum of polymorph A, two relatively low intensity, well-resolved peaks with a separation of 43 cm-’ are apparent (1200 and 1157 cm-‘). In the spectrum of polymorph B there is a slightly more intense doublet at 1178/1167 cm-‘, whilst the spectrum of polymorph C shows a broad singlet at 1182 cm- ‘. In the IR spectra (not shown) there are similar band-splitting effects. In the region 1220-1130 cm-‘, the spectrum of polymorph M(A)
47:9-R
A. M. TUDOR et al.
1392
PolymcrphA
1250
I I40
1050
cm-’
Fig. 2. The FT-Raman spectra for polymorphs A, B, and C of cimetidine in the region 1250-1050 cm-‘.
A shows two distinct bands (1203 and 1156 cm-‘), the spectrum of polymorph B a broad triplet (1192/1184/l 177 cm-‘) and the spectrum of polymorph C a singlet at 1182 cm-‘. Similarly, in the region 1250-1210 cm-’ of the IR spectra, the spectrum of polymorph A shows two we&resolved peaks (1243 and 1228 cm-‘), the spectrum of polymorph B a doublet (1236 and 1230 cm-‘) and a singlet at 1219 cm-’ (absent in A), and the spectrum of polymorph C, singlets at 1229 and 1271 cm-* (again absent in A). The second region showing differences in the FT.-Raman spectra of the cimetidine polymorphs is 1500-1350cm-’ (Fig. 3). The 1445 cm-’ band in the spectrum of polymorph C (Fig. 3) is very broad and has an intensity similar to the bands at 1441 cm-’ (polymorph A) and 1448 cm-’ (polymorph B). The doublet at 1424/1416cm-’ (polymorph A) appears to be the splitting of the 1421 cm-’ band in the spectrum of polymorph B. The 1397 cm-’ band in the spectrum of polymorph A is absent in the spectra of the other two polymorphs. Conversely, the IR spectra in this region only reveal differences between polymorph A and polymorphs B/C.
J,U8
A7 1500
1350
1440 cm-’
Fig, 3. The FT-Raman spectra for polymorphs A, B and C of cimetidine in the region 1X0-1350 cm-‘.
NIR FT-Raman spectroscopy of cimetidine polymorphs
1393
cO~c~usI0~s
the data presented in this paper, it is evident that it is possible to differentiate between polymorphs A and B, and A and C quite readily, but that the differentiation between B and C is not so clear. In this respect, the FI’-Raman data is comparable to the FTIR data. Currently there is no X-ray crystallography data on the crystal structure of polymorphs B and C; therefore it is impossible to relate any spectral changes with certain structural differences in the crystal lattice of each polymorph. However, the fact that the polymorphs can be characterised without the need for sample preparation, as required in IR analysis, highlights the great potential of FI-Raman spectroscopy in this fied. For
Acknowledgementi-We would like to thank Chutaulds Research and the SERC for funding the CASE studentship for A.M.T. We would also wish to acknowledge the assistance and help provided by Dr P. TURNER at Bruker Instruments, and Perkin-Elmer.
REFERENCES [l] J. T. Carstensen, Solid Pharmaceuticals:Mechanical Propertiesand Rate Phenomena (1st Edn) . Academic Press, New York (1980). [2] British Patent Specification 1 543 238 (1976). [3] B. Hegedus and S. Gorog, J. Pharm. Biomed. Anal. 30,303 (1985). [4] H. Kamiya, K. Morimoto and K. Morisaka, Int. J. Pharm. 26, 197 (1985). [5] M. Shibata, H. Kokobo, K. Morimoto, T. Ishida and K. Morisaka, J. Pharm. Sci. 14,36 (1983). [6] T. Funnaki, S. Furata and N. Kaneniwa, Int. 1. Pharm. 31, 1119 (1986). (71 H. Kokobo, K. Morimoto, T. Ishida, M. Inoue and K. Morisaka, Znt. J. Pharm. 35,181 (1987). [8] E. Hadicke, F. Frickel and A. Franke, Chem. Ber. 111,3222 (1978). [9] J. L. Ford and P. Timmins, Pharmaceutical Thermal Analysis, Chap. 6. Ellis Horwood Series in Pharmaceutical Technology, Chichester (1989). [lo] D. B. Chase, Anafyt. Chem. 59,881A (1987). [ll] M. C. Davies, J. S. Binns, C. D. Melia and D. Bourgeois, Spectrochim. Acta 46A, 277 (1990). [12] G. Ellis, P. J. Hendra, C. M. Hodges, T. Jawhari, C. H. Jones, P. Le Barazer, C. Passingham, I. A. M. Royaud, S. Blazquez and G. M. Wames, Analyst 114,106l (1989). [13] G. A. Neviile, J. Raman Spectrosc. 21, 9-19 (1990). [14] D. J. Cutler, Spectrochitn. Acta 46A, 131 (1990). [15] T. R. Dollish, W. G. Fately and F. F. Bently, CharacteristicRaman Frequencies of Organic Compounds (1st Edn). Wiley, New York (1974). [16] S. 0. Paul, R. Schutte and P. J. Hendra, Spectrochim. Acta 46A, 323 (1990). [17] C. M. Deeley, R. A. Spragg and T. L. Threlfall, Spectrochim. Acta 47, 1217 (1991). [18] M. E. Harju, J. Valkonen and U. A. Jayasooriya, Spectrochim. Acta 47A, 1395 (1991).
~p~hi,,,ica Acta, Vol. 47A, No. 9110, pp. 1389-1393, 1991 Printed in Gnat Britain
The applications of near-infrared Fourier transform Raman spectroscopy to the analysis of polymorphic forms of cimetidine A. M. TUDOR, M. C. DAVIES* and C. D. MBLIA Department of Pharmaceutical Sciences, University of Nottingham, Nottingham NG7 2RD, U.K.
D. C. LEE and R. C. MITCHELL SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn AL6 9AR, U.K.
P. J. HENDRA Department of Chemistry, University of Southampton, Southampton SO9 5NH, U.K.
and S.
J. CHURCH
Courtaulds Research, Lockhurst Lane, Coventry CV6 SRS, U.K. (Received 14 March 1991; in revised fom and accepted 12 April 1991) Ahatraet-Fourier transform (lT)-Raman spectroscopy, utilizing a near-infrared (Nd:YAG laser, at 1.064pm) source was used to characterise the three anhydrous polymorphic forms A, B and C of the drug cimetidine (N”-cyano-N-methyl-N’-[2-[(5-methyl-l~-imidaxol-4-yl) methylthio]ethyl]guanidine). The FTRaman spectra were free from fluorescence interference and had good signal-to-noise ratios. Each polymorph has a distinct spectrum, characterised by two regions, 1250-105Ocm-’ and 1500-135Ocm-‘. This work demonstrates that it is possible to use FT-Raman spectroscopy to differentiate between polymorphic forms of the same compound.
INTRODUCTION
crystalline forms of the same compound (polymorphs) may differ markedly both in solubility and rate of dissolution. In the event that a drug shows polymorphism and one polymorph has a poor solubility, the crystal structure can have a crucial influence on the pharmacokinetic levels of drug in the body and hence the therapeutic activity [l]. Minor changes in the physical conditions of the manufacturing process, for example temperature, pressure, concentration or the presence of a foreign compound can alter one polymorphic form of a drug to another and again, may alter the therapeutic efficacy ..of the product. Hence, from a quality control stance, the characterisation of polymorphic forms is critical. Cimetidine,N”-cyano-N-met~yl-N’-[2-[(5-methyl-l~-imidazol-4-yl)methylthio]ethyl]guanidine (Scheme l), is a selective histamine Hz-receptor antagonist and a powerful inhibitor of gastric acid secretion. It has three major anhydrous polymorphic forms, referred to as polymorphs A, B and C [2], and a hydrated form which also exhibits polymorphism [3]. It has been shown that the bioavailabilities and biological activities of the several polymorphic hydrated and salt forms of cimetidine correlate well with the dissolution rates of each different crystal form [4-71. A number of techniques has been employed to characterise polymotphs, including X-ray crystallography [8], differential scanning calorimetry (DSC) [9] and Fourier transform infrared spectroscopy [3]. To date, there are no reports on the application of Fourier transform (PT)-Raman spectroscopy to the study of polymorphism of drugs. The recent combination of 1 Fourier transform format and a near-infrared (NIR) irradiation
DIFFERENT
* Author to whom correspondence should be addressed. Editor’s note: other examples of studies on the FP-Raman spectra of polymorphs will be found in Refs [16-181.
1390
A. M. TUDORet al.
H3C
H--H-H s I
H-C-H I H-C-H I i--H I C=N-CSN I N-H H--C-H I H Scheme 1. Structure of cimetidine.
source has addressed many of the problems previously experienced in Raman spectroscopy. Difficulties, such as laser-induced background fluorescence, long spectral acquisition times and sample photodecomposition and heating from extended exposure have been significantly reduced [lo]. FT-Raman spectroscopy has been applied successfully to the analysis of polymers, paints, catalysts, dyestuffs, explosives and, of particular interest to this paper, biomolecules and drugs [ll-131. In all these applications, the technique is complementary to FTIR. The aim of the work reported here is to extend our previous studies to exploit the recent advent of FT-Raman spectroscopy to an investigation of the polymorphs of cimetidine.
EXPERIMENTAL
Polymorphs A, B and C of cimetidine were kindly supplied by Smith Kline Beecham Pharmaceuticals and were prepared in a similar manner as described previously [2]. For the analysis, the samples were ground to a fine powder using an agate pestle and mortar. The FT-Raman spectrometer used in the analysis was constructed from a Perkin-Elmer 1710 FTIR spectrometer, converted to operate in the (NIR) using a Nd:YAG laser, at 1.064fim. The sample (approximately 0.04 g) was placed in a brass tube (4 mm bore x 3 mm sample depth) solid sample holder. The analysis of the three polymorphs was performed at an instrumental resolution of 6cm-‘, a laser power of 280mW for 100 scans. The full details of the instrumentation are presented elsewhere [14]. The infrared (IR) spectra were recorded on a Bruker IFS 88 FT-IR spectrometer at an instrumental resolution of 4 cm-’ for 50 scans. Briefly, the sample preparation method involved mixing 1 mg of sample with 99 mg of KBr and pressing a disc for analysis.
RESULTS AND DISCUSSION
The FT-Raman spectrum of polymorph A of cimetidine is shown in Fig. 1. Whilst the corresponding FTIR spectrum is included in Fig. 1 for reference purposes, the main discussion will centre on the vibrational assignments in the Raman data. The Raman and IR spectra are complex with a large number of bands in the fingerprint region (1500-500 cm-‘). Such detailed spectra are not unexpected sin& cimetidine contains a 4,Sdisubstituted imidazole ring, and thiaalkane, amine, methyl and nitrile functional groups. The discussion below will attempt to highlight the possible vibrational origins of the more major Raman peaks.
NIR FT-Raman spectroscopy of cimetidine polymorphs
cm-’ Fig. 1. The comparison of the IR spectrum (above) and the FT-Raman spectrum (below) of polymorph A of cimetidine.
The most characteristic bands in the Raman spectra of imidazole and its substituted derivatives originate from ring-stretching vibrations (1600-1350 cm”), in-plane C-H deformations (1300-1250 cm-‘), in-plane ring deformations (930-820 cm-‘) and the out-of-plane ring deformations (690-620 cm-‘) [15]. The ring-stretching region is complicated by the appearance of overtones and by the large frequency shifts which can result from substituent changes. A particularly striking feature in Fig. 1 is the virtual absence of N-H streching bands in the region 3400-2500 cm-’ in the Raman spectrum compared to the IR spectrum. As a result sharp C-H stretching bands are clearly observed in the Raman spectrum whereas they are obscured in the IR spectrum. The thiaalkanes contain a functional group involving sulphur which ‘frequently gives rise to strong Raman scatter. In the Raman spectrum of liquid dimethylsulphide an intense polarised band at 691 cm-’ is assigned to the symmetric C-S-C stretch, and a strong depolarised band at 742 cm-’ to the complementary antisymmetric stretch [15]. Hence the strong band 664 cm-’ in the Raman spectrum of polymorph A can be assigned to the symmetric C-S-C stretching vibration; the band at 741 cm-’ could be due to the antisymmetric C-S-C stretching vibration. As expected these bands are much weaker in the IR spectrum. Corresponding bands occur in the Raman spectra of polymorphs B and C (not shown) at 669 and 743 cm” and 675 and 741 cm-‘, respectively. The frequency range for the nitrile stretching vibration is 2260-2100 cm-’ [15]; hence the solitary, strong band at 2172 cm-’ in Fig. 1 is clearly due to this vibration. The corresponding bands in the Raman spectra of polymorphs B and C (not shown) occur at 2165 and 2156cm-‘, respectively. The nitrile band is observed at 2177, 2174 and 2166 cm-’ in the IR spectra of polymorphs A, B and C, respectively. There are two main areas in the fingerprint region which show clear differences in the Raman spectra of polymorphs A, B and C. A band in the spectrum of one polymorph is seen as possibly two or more in the spectrum of another; this may be due to crystal/ correlation splitting. The first region of interest is 1250-105Ocm-’ (Fig. 2) In the spectrum of polymorph A, two relatively low intensity, well-resolved peaks with a separation of 43 cm-’ are apparent (1200 and 1157 cm-‘). In the spectrum of polymorph B there is a slightly more intense doublet at 1178/1167 cm-‘, whilst the spectrum of polymorph C shows a broad singlet at 1182 cm- ‘. In the IR spectra (not shown) there are similar band-splitting effects. In the region 1220-1130 cm-‘, the spectrum of polymorph M(A)
47:9-R
A. M. TUDOR et al.
1392
PolymcrphA
1250
I I40
1050
cm-’
Fig. 2. The FT-Raman spectra for polymorphs A, B, and C of cimetidine in the region 1250-1050 cm-‘.
A shows two distinct bands (1203 and 1156 cm-‘), the spectrum of polymorph B a broad triplet (1192/1184/l 177 cm-‘) and the spectrum of polymorph C a singlet at 1182 cm-‘. Similarly, in the region 1250-1210 cm-’ of the IR spectra, the spectrum of polymorph A shows two we&resolved peaks (1243 and 1228 cm-‘), the spectrum of polymorph B a doublet (1236 and 1230 cm-‘) and a singlet at 1219 cm-’ (absent in A), and the spectrum of polymorph C, singlets at 1229 and 1271 cm-* (again absent in A). The second region showing differences in the FT.-Raman spectra of the cimetidine polymorphs is 1500-1350cm-’ (Fig. 3). The 1445 cm-’ band in the spectrum of polymorph C (Fig. 3) is very broad and has an intensity similar to the bands at 1441 cm-’ (polymorph A) and 1448 cm-’ (polymorph B). The doublet at 1424/1416cm-’ (polymorph A) appears to be the splitting of the 1421 cm-’ band in the spectrum of polymorph B. The 1397 cm-’ band in the spectrum of polymorph A is absent in the spectra of the other two polymorphs. Conversely, the IR spectra in this region only reveal differences between polymorph A and polymorphs B/C.
J,U8
A7 1500
1350
1440 cm-’
Fig, 3. The FT-Raman spectra for polymorphs A, B and C of cimetidine in the region 1X0-1350 cm-‘.
NIR FT-Raman spectroscopy of cimetidine polymorphs
1393
cO~c~usI0~s
the data presented in this paper, it is evident that it is possible to differentiate between polymorphs A and B, and A and C quite readily, but that the differentiation between B and C is not so clear. In this respect, the FI’-Raman data is comparable to the FTIR data. Currently there is no X-ray crystallography data on the crystal structure of polymorphs B and C; therefore it is impossible to relate any spectral changes with certain structural differences in the crystal lattice of each polymorph. However, the fact that the polymorphs can be characterised without the need for sample preparation, as required in IR analysis, highlights the great potential of FI-Raman spectroscopy in this fied. For
Acknowledgementi-We would like to thank Chutaulds Research and the SERC for funding the CASE studentship for A.M.T. We would also wish to acknowledge the assistance and help provided by Dr P. TURNER at Bruker Instruments, and Perkin-Elmer.
REFERENCES [l] J. T. Carstensen, Solid Pharmaceuticals:Mechanical Propertiesand Rate Phenomena (1st Edn) . Academic Press, New York (1980). [2] British Patent Specification 1 543 238 (1976). [3] B. Hegedus and S. Gorog, J. Pharm. Biomed. Anal. 30,303 (1985). [4] H. Kamiya, K. Morimoto and K. Morisaka, Int. J. Pharm. 26, 197 (1985). [5] M. Shibata, H. Kokobo, K. Morimoto, T. Ishida and K. Morisaka, J. Pharm. Sci. 14,36 (1983). [6] T. Funnaki, S. Furata and N. Kaneniwa, Int. 1. Pharm. 31, 1119 (1986). (71 H. Kokobo, K. Morimoto, T. Ishida, M. Inoue and K. Morisaka, Znt. J. Pharm. 35,181 (1987). [8] E. Hadicke, F. Frickel and A. Franke, Chem. Ber. 111,3222 (1978). [9] J. L. Ford and P. Timmins, Pharmaceutical Thermal Analysis, Chap. 6. Ellis Horwood Series in Pharmaceutical Technology, Chichester (1989). [lo] D. B. Chase, Anafyt. Chem. 59,881A (1987). [ll] M. C. Davies, J. S. Binns, C. D. Melia and D. Bourgeois, Spectrochim. Acta 46A, 277 (1990). [12] G. Ellis, P. J. Hendra, C. M. Hodges, T. Jawhari, C. H. Jones, P. Le Barazer, C. Passingham, I. A. M. Royaud, S. Blazquez and G. M. Wames, Analyst 114,106l (1989). [13] G. A. Neviile, J. Raman Spectrosc. 21, 9-19 (1990). [14] D. J. Cutler, Spectrochitn. Acta 46A, 131 (1990). [15] T. R. Dollish, W. G. Fately and F. F. Bently, CharacteristicRaman Frequencies of Organic Compounds (1st Edn). Wiley, New York (1974). [16] S. 0. Paul, R. Schutte and P. J. Hendra, Spectrochim. Acta 46A, 323 (1990). [17] C. M. Deeley, R. A. Spragg and T. L. Threlfall, Spectrochim. Acta 47, 1217 (1991). [18] M. E. Harju, J. Valkonen and U. A. Jayasooriya, Spectrochim. Acta 47A, 1395 (1991).