The Polymorphic Phase Transformations in the Chlorpropamide under Pressure

RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

The Polymorphic Phase Transformations in the Chlorpropamide under Pressure 2 SERGEY E. KICHANOV,1 DENIS P. KOZLENKO,1 JAN WASICKI, WOJCIECH NAWROCIK,2 LEONID S. DUBROVINSKY,3 ˛ HANNS-PETER LIERMANN,4 WOLFGANG MORGENROTH,5 BORIS N. SAVENKO1 1

Frank Laboratory of Neutron Physics, JINR, Dubna 141980, Moscow Region, Russia Faculty of Physics, A.Mickiewicz University, Poznan´ 61-614, Poland 3 Bayerisches Geoinstitute, University Bayreuth, Bayreuth D-95440, Germany 4 Photon Science, Deutsches Elektronen Synchrotron, Hamburg D-22607, Germany 5 Institute of Geosciences, University of Frankfurt, Frankfurt D-60438, Germany 2

Received 30 June 2014; revised 26 September 2014; accepted 13 October 2014 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24241 ABSTRACT: The crystal structure and vibrational spectra of the chlorpropamide have been studied by means of the X-ray diffraction and Raman spectroscopy at pressures up to 24.6 and 4.4 GPa, respectively. Two polymorphic phase transitions, between initial orthorhombic form-A and a monoclinic form-AI at P ∼ 1.2 GPa and, in additional, to another monoclinic form-AII at P ∼ 3.0 GPa, were observed. At pressures above 9.6 GPa, a transformation to the amorphous phase of chlorpropamide was revealed. The lattice parameters, unit cell C volumes, and vibration modes as functions of pressure were obtained for the different polymorphic modifications of chlorpropamide.  2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci Keywords: crystal structure; polymorphism; Raman spectroscopy; X-ray powder diffractometry; amorphous

INTRODUCTION One of the model compound to study pressure-induced polymorphic transformations in drugs is a chlorpropamide C10 H13 ClN2 O3 S.1–3 It belongs to a group of sulfonylurea compounds and is used as antidiabetic drug.4 Several polymorphs of chlorpropamide are known.5–7 The commercially manufactured form-A with the orthorhombic crystal structure P21 21 21 8 is stable at ambient conditions. It is known that after heating of chlorpropamide up to 393 K and keeping it at this temperature for 4 h the polymorphic form-C appears.9 Recently, the partial transformation from initial form-A to form-C in chlorpropamide has been found under compression to 196 MPa at room temperature.10 The stability of form-A under compression has been studied extensively3,11–14 because of the potential for uncontrolled changes into drugs during pharmaceutical manufacturers. In particular, during tablet formation some pressures is required and one could cause irreversible changes to the initial crystal structure by rearranging molecules or disordering of the structure.15,16 New polymorphic phases of pharmaceutical compounds, which appears during tableting or grinding processes, can differ in physical properties, stability on storage, or bioactivity in comparison with their initial form.15–17 However, the information about pressure-induced polymorphic transformation in chlorpropamide is contradictory and it is considerable discrepancies between the previously reported data. Previously, two polymorphic transformations in chlorpropamide at pressures 0.9 and 2.0 GPa into unknown phases have been observed by means of Raman spectroscopy experiments.18 In additional, the X-ray Correspondence to: Sergey E. Kichanov (Telephone: +7-49621-62047; Fax: +749621-65882; E-mail: [email protected]) Journal of Pharmaceutical Sciences

 C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association

diffraction experimental results indicated polymorphic phase transition into a monoclinic phase with space group P21 at high pressures above 1.2 GPa.13 On the other hand, no polymorphic transformations have been observed in dry samples of chlorpropamide by a X-ray powder diffraction at pressures up to 5.5 GPa3 or by a NMR measurements at pressure up to 0.8 GPa.11 In same time, the polymorphic phase transition from initial form-A to new high pressure form-A of chlorpropamide have been found at P ∼ 2.8 GPa under hydrostatic compression.12 Since form-C of chlorpropamide can be prepared from most other chlorpropamide forms, with exception of initial form-A, the observed discrepancy in experimental results have been explained by effects from additional factors like as local heating, partial melting or recrystallization processes. It has been suggested that one of a factors can be the hydrostatic conditions of high-pressure experiments. Further analysis of various applied stress states demonstrates that shear stresses have the key role in mechanism of the pressure-induced transformation in chlorpropamide.19 In particular, experiments using ethanol solution as pressure transmission medium12 in comparison with another ones, there compression of chlorpropamide in quasihydrostatic conditions have been studied.3,13,14 Nonetheless, the above-mentioned experimental results clearly demonstrate that the pressure-induced polymorphic phase transitions in chlorpropamide are quite complex and require further elucidation. It is very important to study the pressure-induced polymorphic transformations to understand and take advantage of the mechanisms effects on polymorphic phase transition in chlorpropamide. In order to study in detail the high-pressure effects on the crystal structure and vibrational properties of chlorpropamide, we have performed X-ray diffraction and Raman spectroscopy experiments at pressures up to 24.6 and 4.4 GPa, respectively. In an attempt to account for inner stresses effects,12,19 we used Kichanov et al., JOURNAL OF PHARMACEUTICAL SCIENCES

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RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Figure 1. (a) X-ray diffraction patterns of chlorpropamide measured at selected pressures and room temperature, and refined by the profile matching method using FullProf. Experimental points and calculated profiles are shown. The ticks at the bottom and top indicates the calculated positions of a diffraction peaks for the orthorhombic form-A of chlorpropamide at ambient pressure and for the monoclinic form-AI (at P = 1.4 GPa), respectively. (b) The enlarged parts of X-ray diffraction patterns of chlorpropamide for low-angles region.

Figure 2. (a) Lattice parameters as a functions of pressure for the AI and AII forms of chlorpropamide. The solid lines represent the linear fit of the experimental data. (b) Baric dependences of unit cell volume and monoclinic angle $ (inset) for the AI and AII forms of chlorpropamide. Solid lines represents fit based on the Birch–Murnaghan equation of state [25].

The angle-dispersive X-ray powder diffraction patterns at high pressures up to 24.6 GPa and at room temperature were obtained at the Extreme Conditions Beamline22 (ECB) P02.2 at the third-generation synchrotron radiation source PETRAIII located at the Deutsches Elektronen Synchrotron (DESY), Hamburg, Germany. The diffraction images were collected with ˚ on the amorphous silicon a wavelength of 8 = 0.29118 A flat panel detector bonded to a ScI scintillator (XRD 1621) from PerkinElmer and located at a distance of 402.33 mm from the sample. The two-dimensional XRD images were converted to one-dimensional diffraction patterns using the FIT2D program.23 Powder diffraction patterns were refined in the Fullprof24 program. Raman spectra at ambient temperature and pressures up to 4.4 GPa were collected using a LabRam spectrometer (NeHe excitation laser) with a wavelength of 632.8 nm, 1800 grating, confocal hole of 1100 :m, and a 50× objective. The pressurisation rate in both of a Raman spectroscopy and an X-ray diffraction experiments was 10–20 MPa min−1 .

RESULTS AND DISCUSSION powder sample of chlorpropamide and performed high-pressure experiments without any pressure-transmitting medium.

EXPERIMENTAL Dry powder sample of chlorpropamide form-A was obtained from Sigma Chemical Company (St. Louis, Missouri) and used as received. The BX90 type diamond anvil cell20 was used for the X-ray diffraction and Raman experiments. The sample was loaded into the hole of the 120 :m diameter made in the Re gasket intended to about 30 :m thickness. The diamonds with culets of 250 :m were used. The pressure was determined by the ruby fluorescence technique.21 Kichanov et al., JOURNAL OF PHARMACEUTICAL SCIENCES

X-Ray Diffraction The X-ray diffraction patterns of chlorpropamide at selected pressures and room temperature are shown in Figure 1. At ambient conditions, the orthorhombic form-A with the space group P21 21 21 8,13 was identified. The obtained values of lattice parameters at ambient conditions for the form-A were a = ˚ b = 9.052(3) A, ˚ c = 26.478(8) A, ˚ and are consistent 5.255(3) A, with previous studies.12,13 At low pressures P ∼ 1.2 GPa, some changes in the X-ray diffraction patterns were observed as illustrated in Figure 1. The diffraction peaks indexed as (102) and (112) at 22 ∼ 3.4◦ and 3.9◦ , correspondingly, was disappeared and new peak at 22 = 2.9◦ developed. In additional, a drastic change in relative intensity of the diffraction peaks located at 22 = 2.2◦ and 2.5◦ DOI 10.1002/jps.24241

RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

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Figure 3. (a) The part of Raman spectra of chlorpropamide at selected pressures. The strong Raman line from diamond anvils is marked as “D”. (b) The enlarged parts for 2800–3200 cm−1 , (c) 740–800 cm−1 , (d) 1060–1220 cm−1 , and (e) 1550–1750 cm−1 regions. The tentative assignment of some Raman peaks are marked.

was detected (Fig. 1). The above changes in diffraction pattern are evidence for a structural phase transformation. The structural models for expected form-C of chlorpropamide10,13 and the high-pressure orthorhombic form with space group P21 1112 were tested during diffraction data refinement. In additional, we check two form-A and form-C coexistence model.19 However, no acceptable fitting quality have been achieved with these models. Powder diffraction patterns indexing preparing and testing with other structural models resulted in successful indexing of diffraction patterns with a monoclinic unit cell P21 symmetry and it was finally chosen for the consideration. We DOI 10.1002/jps.24241

introduce the notation “form-AI” for this monoclinic phase of chlorpropamide. Using the above model, we refined unit cell parameters of chlorpropamide at P = 1.5 GPa resulting in a = ˚ b = 14.580(4) A, ˚ c = 9.961(5) A, ˚ and $ = 91.2◦ . 8.951(3) A, After subsequent compression up to P = 3.6 GPa, the structure peak at 22 ∼ 3.0◦ disappeared and redistribution in relative intensity of the diffraction peaks located at 22 ∼ 2.4◦ and 2.5◦ was observed (Fig. 1). These observations are evidence for another structural phase transition in chlorpropamide. We labeled the new pressure-induced phase of chlorpropamide as “form-AII”. From the diffraction patterns analyses, it was Kichanov et al., JOURNAL OF PHARMACEUTICAL SCIENCES

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RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

found that the structure of the high-pressure form-AII of chlorpropamide could also be described as monoclinic one with P21 symmetry, but with some differences in lattice parameters with respect to low-pressure form-AI. So, the corresponding weighted R-factor24 (for diffraction data at P= 3.6 GPa) is Rwp = 5.9% for the our proposed monoclinic model and 9.9% for the orthorhombic model with space group P21 11, which obtained in,12 and it is indicating a better fit to the monoclinic structure model. The pressure dependencies of lattice parameters and unit cell volume of the observed pressure-induced forms AI and AII of chlorpropamide are shown in Figures 2a and 2b. The lattice compression is anisotropic with the most compressible b-axis in the monoclinic form-AI, but after second polymorphic transformation at P = 3.6 GPa the lattice parameters compressibility becomes more isotropic (Fig. 2a). In both monoclinic forms, the monoclinic angle increases slightly upon compression and it exhibits a distinguishable break at the transition pressure P = 3.6 GPa (insert of Fig. 2b). The volume compressibility data (Fig. 2b) were fitted with the third-order Birch–Murnaghan equation of state25 :   3 3 P = B0 (x−7/3 − x−5/3 ) 1 + (B − 4)(x−2/3 − 1) , 2 4 where x = V/V0 is the relative volume change, V0 is the unit cell volume at P = 0, and B0 , B are the bulk modulus (B0 = −V(dP/dV)T ) and its pressure derivative (B = (dB0 /dP)T ). The fitted values are B0 = 20(3) GPa and B = 4.0(5) for phase AI of chlorpropamide and B0 = 27(1) GPa and B = 4(0) for phase AII. The bulk module values of the pressure-induced phases of chlorpropamide are slightly larger in comparison with the once obtained previously for form-A (B0 ∼ 15 GPa),13 for formC (B0 ∼ 8 GPa)14 or for resorcinol crystal (B0 ∼ 11 GPa).26 This fact can be explained by significant effect from inner stresses and strains due quasihydrostatic conditions in high-pressure experiments. At P > 9.6 GPa, a gradual broadening of diffraction peaks is followed by their disappearance up on further compression (Figs. 1a and 1b). Such a behavior corresponds to a gradual phase transition to the amorphous phase of the chlorpropamide. During subsequent compression most of diffraction peaks disappear altogether until at P = 24.6 GPa only one weak reflection on 22 ∼ 3.7◦ is present. Although in the previous study, the amorphous phase of chlorpropamide was found to appear at P ∼ 3 GPa14 only after additional recrystallization, in initial dry chlorpropamide it was observed at significantly higher pressures. Raman Spectroscopy The Raman spectra of the chlorpropamide measured at selected pressures and room temperature are shown in Figures 3a–3d. The tentative assignment of band frequencies based on a previous Raman spectroscopy data and theoretical calculation27 are listed in Table 1. Here, we used notations from Ref. 27. At P > 1.4 GPa, a significant changes in Raman spectra were observed, indicating a pressure-induced phase transformation into monoclinic form-AI in accordance to our X-ray diffraction measurements. The comparison of our data with previous27 ones shown that presented Raman spectroscopy data Kichanov et al., JOURNAL OF PHARMACEUTICAL SCIENCES

Table 1. The Wavenumbers (cm−1 ) and Tentative Assignment of the Experimental Observed Raman Bands of Different Forms of Chlorpropamide P = 0 GPa Form-A

3075.8 3067.9

2980.4 2961.4 2935.1 2923.6 2871 1668.2 1590.8 1578.8 1538.2 1239.4 1172.2 1163 1112.7 1089

1038.5 997.52 915.55 885.89 757.99 635.13 627.64 582.96

P = 1.9 GPa Form-AI

3097.5 3085.9 3077.9 3011.0 2985.6 2958.4 2934.4 2906.8 2870.2 1669.1 1602.1 1586.9 1538.3 1272 1244.6 1184.3 1175.2 1168.2 1123.2 1100.1 1055 1042.2 1024.6 1010.7 931.5 899.6 766.7 760.7 639.3 630.6 585.9

475.36

478.8 374.6

263.9

296.4 274.2

P = 4.4 GPa Form-AII 3124.1 3113.1 3099.2

Tentative Assignment <(CH) ring
2977.9 2960.7 2939.5 2899.3


1665.2

<(CC) ring

1598.3 1542.2 1278.3 1245.7 1189.4 1178.5 1169.5 1139.5 1125.3 1111.7 1065.0 1019.6 943.8

<(CC) ring <(CN) amid II J(CH2 ), *s (CH3 ) *(HCC) ring J(CH2 ), *(HNC) <(CC), <(CH) <(CS), <(CN)
912.4 768.8

<(C–C) J(CH2 ), J(CH3 )

646.2 640.6 632.9 589.2 484.5 453.6 385.1 311.5 280.9

*(CCC) ring

*(OSO), *(CCC)
Abbreviations: <, stretching; *, bending; J, torsion; subscript “as” and “s”, asymmetry and symmetry, correspondingly.

does not corresponded with any known polymorphic forms of chlorpropamide.27 In the region of the polymorphic transition, appearances of the new Raman lines (Figs. 3a–3e) were observed. In particular, the appearance of a Raman peak shoulder at around 3080 cm−1 (Fig. 3b), corresponding to СH2 vibration modes have been observed. In additional, the occurrence of peak shoulder at 1180 cm−1 (Fig. 3d) as well as the well resolved splitting of Raman peak at 760 cm−1 (Fig. 3c) cab be attributed to the torsion vibration modes J(CH2 ). The drastic changes in vibration modes assigned to the stretching vibrations <(CC) around ∼1600 cm−1 have also been detected (Fig. 3e). Moreover, an appearance of other new Raman lines was observed that, however, could not be attributed to certain vibrational modes (Table 1). DOI 10.1002/jps.24241

RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

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Figure 4. (a) Pressure dependence of symmetric stretching modes of methylene group of chlorpropamide. (b) The baric dependences of several torsion vibration modes of methylene group J(CH2 ), methyl group J(CH3 ), and bending ring vibration *(HNC) of chlorpropamide. (c) Pressure dependence of bending ring vibration *(CCC) of chlorpropamide. (d) Pressure dependence of stretching vibration <(CC) and <(CN) modes. The estimated error bars are within symbol sizes. The solid lines are linear interpolations of the experimental data.

At further pressure increasing up to 3 GPa, the more changes in the Raman spectra reflects new phase transformation into monoclinic form-AII (Figs. 3a–3e). These changes manifest them self in drastic changes in Raman spectra regions 2800–3100 cm−1 (Fig. 3b) and 1500–1700 cm−1 (Fig. 3e) corresponding to characteristic regions of stretching vibration of C–H and C–C. There are also significant modifications in Raman spectra related with symmetry stretching vibration
DOI 10.1002/jps.24241

the phase transition have been detected. It should be note that anomalies in baric dependences of frequencies of the most vibration modes is less pronounced for phase transformation between monoclinic forms AI and AII in comparison with the ones near the form-A–AI transformation (Fig. 4). As conclusion remarks, we wants to note that presented result concerning pressure-induced polymorphic transformations in the chlorpropamide is much different to thus reported previously.3,12 This difference can be explained by effect from inner stresses and strains due to quasihydrostatic conditions during the experiments in comparison with previous ones. However, the presented result clearly indicates that the stability of the initial form-A of chlorpropamide may be compromised during tableting or grinding processes.

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RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

CONCLUSIONS In the present work high pressure effect on the crystal structure and vibrational spectra of a chlorpropamide have been studied. Our results clear demonstrate that the application of high pressure leads to successive polymorphic phase transformation in chlorpropamide. The X-ray diffraction and Raman spectra exhibits subtle changes at the form-A–AI phase transformation at P ∼ 1.2 GPa and more significant modifications at the AI–AII polymorphic transition at P ∼ 3 GPa in chlorpropamide. The observed result concerning pressure-induced polymorphic transformations in the chlorpropamide is much different to thus reported previously due inner stresses and strains existing coursing of quasihydrostatic conditions of pressure experiments. However, the obtained results clearly indicates the possible way of stability breaking of the initial form-A of chlorpropamide during tableting or grinding processes. In additional, the pressure-induced amorphization of chlorpropamide have been found.

ACKNOWLEDGMENTS The work has been supported by the RFBR grant 14–02–00353a. The authors acknowledge A. Medek and B.C. Hancock for providing a sample material for the studies. Parts of this research were carried out at the light source PETRA III at DESY, a member of the Helmholtz Association (HGF).

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DOI 10.1002/jps.24241