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Ab initio structure determination of anhydrous sodium alendronate from laboratory powder X-ray diffraction data
PHARMACEUTICAL TECHNOLOGY Ab Initio Structure Determination of Anhydrous Sodium Alendronate from Laboratory Powder X-Ray Diffraction Data MINAKSHI ASNANI,1 K. VYAS,2 APURBA BHATTACHARYA,3 SURYA DEVARAKONDA,1 SANTU CHAKRABORTY,4 ALOK KUMAR MUKHERJEE4 1 Center for Excellence in Polymorphism and Particle Engineering, Integrated Product Development, Dr. Reddy’s Laboratories Limited, Hyderabad, India 2
Department of Analytical Research, Integrated Product Development, Dr. Reddy’s Laboratories Limited, Hyderabad, India
3
Department of Research & Development, Integrated Product Development, Dr. Reddy’s Laboratories Limited, Hyderabad, India 4
Department of Physics, Jadavpur University, Kolkata, India
Received 5 May 2008; revised 22 July 2008; accepted 2 August 2008 Published online 9 September 2008 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21561
ABSTRACT: Sodium alendronate, a member of bisphosphonate class of compounds commonly used for treatment of generalized bone disorders, exists in various hydrated forms. Dehydration of sodium alendronate trihydrate has been studied using variable temperature X-ray powder diffraction technique. The crystal structure of anhydrous sodium alendronate, prepared by heating the trihydrate sodium alendronate at 1508C, has been determined from X-ray powder data using direct space global optimization technique for structure solution, followed by the Rietveld refinement. The structure of the anhydrous form of sodium alendronate is compared with that of the trihydrate form, which was determined previously from single crystal X-ray diffraction data. Both anhydrous and trihydrate sodium alendronate crystallize in monoclinic system with space group P21/n. The crystal structure of the anhydrous sodium alendronate is built by edge-sharing of NaO6 octahedra into a two-dimensional molecular sheet in the (011) plane, whereas in the trihydrate compound, one-dimensional chain along the (010) direction is generated by corner sharing of NaO6 octahedra. ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2113–2121, 2009
Keywords: X-ray powder diffractometry; crystal structure; crystallography; hydrates/solvates; polymorphism; ab initio calculations
DRL internal communication number: IPDO-IPM00047. Minakshi Asnani’s present address is Analytical Research, Ranbaxy Labs Ltd., Gurgaon 122015, India. Apurba Bhattacharya’s present address is Department of Chemistry, Texas A&M University, Kingsville, TX 78363. Correspondence to: Surya Devarakonda (Telephone: 91-404434-6111; Fax: 91-40-4434-6164; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 98, 2113–2121 (2009) ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association
INTRODUCTION Bisphosphonates form a class of compounds that can act as selective inhibitors of osteoclastic bone resorption, and are commonly used in the treatment of a variety of generalized bone disorders, for example, osteoporosis, Paget’s disease.1 Crystal
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structures of many bisphosphonates have been extensively studied over the last few years due to their diverse therapeutic activity.2–6 Sodium alendronate (I), a member of bisphosphonate class of compounds, is chemically described as 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt. Several hydrated forms of sodium alendronate have been reported.7–9 While the preparations of sodium alendronate trihydrate and other variable hydrates (1/4, 1/3, 1/2, 3/4, 1, 5/4, 4/3, 3/2, 5/3, 7/4, 2) have been described in the US patent 4,922,007 and US patent application 6,696,601B2, respectively, crystal structure of only the trihydrate form is available in the literature.10 In addition to these hydrated forms, anhydrous sodium alendronate has also been patented.11 A detailed study of structural features of these compounds is an important step towards understanding their interaction mechanism in biological systems and provides useful information for designing suitable pharmaceutical product. In fact, once the crystal structure has been established, morphology modification can readily be made by analysis of forces that cause directional growth and through the addition of ‘‘tailor made’’ inhibitors that disrupt growth and alter crystal morphology in a predictable way. From a pharmaceutical standpoint, the reactivities and stabilities of different hydrated and anhydrous crystal forms of a pharmaceutical substance can have a severe impact on the feasibilities of prospective formulations. Although single crystal X-ray diffraction is undoubtedly the most widely used technique for elucidating the structure of organic and pharmaceutical compounds, an intrinsic limitation of this technique is the requirement to prepare single crystals of appropriate size and quality, which is not always met for all compounds of interest. In such circumstances, X-ray powder diffraction can be used as an alternative route for structural analysis. Recent developments in the direct space methodologies as implemented in FOX,12 DASH,13 EAGER14 have shown that crystal structures of several molecular compounds and pharmaceuticals materials can be determined from X-ray powder diffraction data.15,16 The aim of the present work was to study the dehydration of sodium alendronate trihydrate and compare crystal structures of the anhydrous and the trihydrate forms, recognizing that knowledge of crystal structures of two forms provides an opportunity for exploring the relationship JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009
between structure and property. Such relationships are useful to design materials with targeted properties.
MATERIALS AND METHODS Synthesis Sodium alendronate trihydrate was synthesized following the procedure described previously (US patent 4,922,007). During the synthesis, aminobutyric acid (20 g, 0.19 mol), methanesulphuric acid (80 mL) and phosphorous acid (24 g, 0.29 mol) were charged in a flask fitted with a reflux condenser and aged for 15 min at 70–758C. The solution was cooled to 358C and phosphorous trichloride (40 mL, 0.46 mol) was added cautiously. The reaction mixture was then heated to 658C and aged at that temperature for 20 h. Further, the contents were cooled to 258C and added to deionized water (200 mL). The solution was then aged at 95–1008C for 5 h. The reaction was cooled to 208C while pH was adjusted to 4.3 with NaOH (50%, 80 mL). The resulting white suspension was then cooled to 0–58C and aged for 1 h. The product was collected by filtration, then washed with cold water and 95% EtOH. The yield after air drying was 53.26 g (85%). FTIR, DSC and TGA analysis confirmed the formation of sodium alendronate trihydrate. The sodium alendronate trihydrate was slowly heated to 1508C and kept at elevated temperature for 1 h. The sample was cooled to room temperature to obtain the anhydrous sodium alendronate.
Characterization Methods X-Ray Powder Diffraction X-ray powder diffraction data were collected on a PANalytical X’pert Pro powder diffractometer ˚ ) radiation. The diffraction using Cu Ka (1.5418 A pattern was recorded at room temperature (228C) with step size of 0.0088 (2u) and counting time 50 s/ step over angular range 3–1008 (2u) using the Bragg-Brentano geometry and a rotating flatplate sample holder. The zero point error estimated was lower than 0.028 (2u). Variable temperature XRD patterns of sodium alendronate trihydrate were recorded at 18C interval (measurement accuracy 0.18C) with a heating rate of 18C/min in the temperature range 30–3008C. DOI 10.1002/jps
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Thermal Analysis and Optical Microscopy Thermogravimetric and differential scanning calorimetric analyses (TG-DSC) were carried out with a Mettler Toledo DSC PT15 instrument under a flow of nitrogen (30 mL/min) from 30 to 3008C at 108C/min. Optical microscopy was performed using a polarizing microscope equipped with a Mettler Toledo FPGO hot stage and 35-nm Colorview Camera (Soft Imaging, Munster, Germany). The sample was placed on a glass slide, covered with a covered slip and heated in the temperature range 25–1358C at a rate of 28C/min.
Structure Determination from X-Ray Powder Diffraction Data The first 20 peaks of the powder pattern were fitted using the program TOPAS,17 and the refined 2u positions were used for indexing with program TREOR9018 of CRYSFIRE package. The solution with highest figure of merit [M(20) ¼ 40, F(20) ¼ 81 (0.0062, 40)]19,20 indexed all peaks in the monoclinic system with cell parameters ˚, b¼ a ¼ 7.631(3), b ¼ 9.144(2), c ¼ 14.456(1) A 3 ˚ 112.61(2)8 and V ¼ 930.97(4) A . The results of indexing with DICVOL21 also indicated the same solution. The full pattern decomposition was performed with TOPAS following Le Bail algorithm22 using a split-type pseudo-Voigt peak profile function23 and the Laue-symmetry (2/m) for the monoclinic system. Analysis of the powder pattern indicated P21/n as the probable space group, which was subsequently confirmed by successful structure solution and refinement. The structure was solved by global optimization of a structural model in direct space using the program FOX. The initial configuration was obtained from the molecular modeling program CS Chem3D, where energy of the alendronate moiety was minimized using the semi-empirical quantum mechanical methods MOPAC.24 The starting configuration for global optimization was obtained by randomly placing one Na atom and one alendronate moiety with geometry as calculated from an earlier MOPAC run using the AM1 Hamiltonian.25 During structure solution, bond lengths and bond angles were ˚ and 1.158, respectively, constrained with 0.02 A but the torsion angles were allowed to change. The parallel tempering algorithm of program FOX was used for the data range 3–458(2u). After 4 108 trials, requiring almost 20 h of computer time on a Pentium IV (512 MB RAM) PC, a DOI 10.1002/jps
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solution with Rwp ¼ 0.124 and GOF ¼ 3.1 was obtained. Atomic coordinates derived from parallel tempering procedure of FOX were taken as the starting model for Rietveld refinement with the program GSAS.26 The 2u range used in Rietveld refinement was from 38 to 1008. The atomic coordinates of 15 nonhydrogen atoms were refined with restraints on bond lengths and bond angles. The mean-square deviations of assigned values for ˚ and 18, bond lengths and bond angles were 0.01 A respectively. The background was described by Shifted Chebyshev function with 36 regularly distributed points over the entire 2u range and a linear interpolation was made between two successive points. The peak profiles were fitted with pseudo-Voigt functions using the ThompsonCox-Hastings formalism, which could take into account experimental resolution and broadening due to size and strain effects.27 H-atoms were introduced in GSAS at their expected positions with N–H, O–H, and C–H distances restrained. ˚ 2 for P, Three isotropic thermal parameters, 0.02 A 2 2 ˚ ˚ 0.04 A for Na and 0.05 A for N, C and O atoms, were refined. In the final stage of refinement, preferred orientation correction was applied using the generalized spherical harmonics (order 20) model. Final Rietveld refinement of 220 parameters (45 coordinates, 4 lattice parameters, 36 background, 11 profile parameters, 3 isotropic thermal parameters, 120 orientation distribution function coefficients, and 1 scale factor) resulted in Rp ¼ 0.0479 and Rwp ¼ 0.0639 with excellent agreement between the observed and calculated patterns (Fig. 1). Crystallographic data, profile and structural parameters are listed in Table 1. The atomic coordinates, selected bond distances and bond angles are given in Tables 2 and 3, respectively.
RESULTS AND DISCUSSIONS Dehydration of Sodium Alendronate Trihydrate X-ray powder diffraction patterns of sodium alendronate trihydrate at different temperatures are shown in Figure 2. From 30 to 1148C, no significant change in the powder diffraction patterns was observed. However, peaks corresponding to a new crystalline phase (anhydrous sodium alendronate) were visible at 1158C (the measurement accuracy or the temperature uncertainty of the instrument is 0.18C). On further heating, the intensity of JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009
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Table 2. Atomic Coordinates and Isotropic ˚ 2) Obtained from Displacement Parameters (A Rietveld Refinement
Figure 1. Final Rietveld refinement plot for anhydrous sodium alendronate. Orange crosses: observed pattern, green curve: calculated pattern, brown curve: difference curve.
peaks corresponding to the dehydrated phase gradually increased and that due to the trihydrate phase decreased. Finally, at 1308C the peaks corresponding to the trihydrate phase disappeared and pure anhydrous sodium alendronate was obtained. It is to be noted that on slow heating, sodium alendronate trihydrate transformed into single-phase anhydrous form and no intermediate hydrated species were observed. Table 1. Crystal Data and Refinement Parameters for Anhydrous Sodium Alendronate Empirical formula Formula weight Data collection temperature Crystal system Space group Unit cell dimensions
Volume Z Density (calculated) Data collection range Step size Wavelength No. of data points No. of contributing reflections No. of refined parameters Rp Rwp R2F x2
NaC4H12NO7P2 271.08 293 K Monoclinic P21/n (no. 14) ˚ a ¼ 7.6298(6) A ˚ b ¼ 9.1458(7) A ˚ c ¼ 14.4573(11) A b ¼ 112.6(1)8 ˚3 931.4(2) A 4 1.933 gm/cm3 3–1008 (2u) 0.0088 (2u) ˚ 1.5418 A 12160 1937 220 0.0479 0.0639 0.0910 5.692
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Atom
x
y
z
Uiso
P1 P2 NA1 O1 O2 O3 O4 O5 O6 O7 N1 C1 C2 C3 C4
0.2241(5) 0.5371(6) 0.0381(8) 0.5381(13) 0.1713(11) 0.0997(13) 0.1811(7) 0.7524(8) 0.4816(13) 0.4112(10) 0.6297(6) 0.6794(8) 0.5330(7) 0.6030(7) 0.4861(7)
0.7697(5) 0.9157(5) 1.0536(6) 0.6382(6) 0.8948(9) 0.7938(7) 0.6212(7) 0.9514(9) 0.8404(9) 1.0442(7) 0.6239(6) 0.7444(6) 0.7424(5) 0.7991(5) 0.7749(6)
0.6009(3) 0.7790(3) 0.6249(3) 0.7270(6) 0.5274(6) 0.6595(7) 0.5443(5) 0.8125(4) 0.8574(6) 0.7326(7) 0.3805(4) 0.4550(4) 0.5050(6) 0.6139(5) 0.6785(5)
0.007(1) 0.007(1) 0.039(3) 0.011(1) 0.011(1) 0.011(1) 0.011(1) 0.011(1) 0.011(1) 0.011(1) 0.011(1) 0.011(1) 0.011(1) 0.011(1) 0.011(1)
The DSC curve for sodium alendronate trihydrate (Fig. 3a) revealed a sharp endotherm at 1268C. The TG analysis of the trihydrate sample (Fig. 3b) showed a weight loss of 16.6% due to liberation of three water molecules (theoretical weight loss 17.2%) in the temperature range 120–1708C. The thermal events beyond 2208C can be attributed to decomposition of the molecule. ˚ ) and Bond Angles Table 3. Selected Bond Lengths (A (8) for Anhydrous Sodium Alendronate
Atoms P(1)–O(2) P(1)–O(3) P(1)–O(4) P(1)–C(4) P(2)–O(5) P(2)–O(6) P(2)–O(7) P(2)–C(4) Na(1)–O(1ii) Na(1)–O(2) Na(1)–O(2i) Na(1)–O(3) Na(1)–O(6ii) Na(1)–O(7) O(1)–C(4) N(1)–C(1) C(2)–C(1) C(2)–C(3) C(3)–C(4)
Bond ˚) Distance (A 1.508(5) 1.511(5) 1.555(5) 1.879(4) 1.559(5) 1.515(5) 1.504(5) 1.871(5) 2.545(5) 2.496(10) 2.218(9) 2.436(5) 2.646(10) 2.670(10) 1.413(5) 1.484(5) 1.546(5) 1.544(5) 1.536(5)
Atoms
Bond Angle (8)
O(2)–P(1)–O(4) O(4)–P(1)–C(4) C(4)–P(1)–O(3) O(3)–P(1)–O(4) O(2)–P(1)–C(4) O(2)–P(1)–O(3) O(7)–P(2)–C(4) C(4)–P(2)–O(5) O(5)–P(2)–O(6) O(6)–P(2)–O(7) O(7)–P(2)–O(5) O(6)–P(2)–C(4) C(4)–C(3)–C(2) C(3)–C(2)–C(1) C(2)–C(1)–N(1)
110.2(5) 107.2(3) 114.5(5) 111.8(4) 109.7(4) 103.3(4) 106.4(5) 105.3(4) 115.4(5) 112.1(5) 113.0(5) 103.5(4) 121.1(4) 116.3(4) 107.5(5)
Symmetry codes: (i) x, 2y, 1z; (ii) 1/2x, 1/2 þ y, 3/2z. DOI 10.1002/jps
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Figure 2. Variable temperature PXRD patterns of sodium alendronate trihydrate.
The morphological changes during dehydration as monitored by hot-stage microscopy indicated that the crystals of sodium alendronate trihydrate were transparent (Fig. 4a) at room temperature (228C). At 1208C, the edges of the crystals started darkening indicating commencement of dehydration (Fig. 4b). On further heating, darkening propagated towards center of the crystals denoting the progress of dehydration (Fig. 4c and d). Finally at 1288C, entire surface of the crystals turned dark suggesting that the dehydration process was complete.
Structural Description of Anhydrous Sodium Alendronate The asymmetric unit of anhydrous sodium alendronate consists of one alendronic anion and one
sodium cation (Fig. 5). Similar to previously reported free acid (4-ammonium-1-hydroxybutylidene-1,1-bisphosphonic acid), and 1:1 or 2:1 alendronate salts with Naþ or Ca2þ ions,10,28 the title complex has zwitterionic character with the protonated amine group bearing the positive charge. The geometry around the P atoms is tetrahedral (Tab. 3), and the P–O bond lengths are ˚ for the P–O (unprotoclose to 1.51 and 1.56 A nated) and P–O (protonated) distances, respectively. The P–C bond distances 1.879(4), 1.871(5) ˚ ] and P–C–P bond angle [109.7(4)8] are in good A agreement with the corresponding values found in analogous structures.10,28 The coordination environment around Naþ ion can be best described as distorted octahedral and consists of one bidentate and four monodentate PO3 chelators. The equatorial plane is defined by atoms O2, O3, O1ii (½x, ½ þ y, 3/2z) and O6ii (½x, ½ þ y, 3/2z) with the metal center ˚ from the least-squares displaced by 0.238(2) A plane through the equatorial atoms. Apical atoms O7 and O2 (x, 2y, 1z) lie above 2.389(5) ˚ below this plane, respectively, and 2.037(5) A forming an O7 Na O2i (x, 2y, 1z) angle of 141.8(3)8. The Na O contact distances range ˚ (Tab. 3). from 2.218(9) to 2.670(10) A
Comparison of Anhydrous and Trihydrate Sodium Alendronate Structures
Figure 3. (a) DSC and (b) TGA curves of sodium alendronate trihydrate. DOI 10.1002/jps
Both the trihydrate and anhydrous compounds crystallize in monoclinic system with space group P21/n. The lattice parameter c of anhydrous ˚ ] compared compound is shortened [14.4573(11) A JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009
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Figure 4. Hot-stage microscope images of sodium alendronate trihydrate at (a) 30, (b) 120, (c) 124, (d) 126, and (e) 1288C.
˚ ], while to that in the trihydrate one [19.503(4) A the a and b dimensions did not show marked difference (Tab. 4). The molecular conformation in both compounds as established from various torsion angles is essentially similar. The torsion angles in the anhydrous structure [C2–C3–C4–P2 154.7(4)8, C2–C3–C4–P1 30.8(6)8, N1–C1–C2–C3 150.9(4)8, C1–C2–C3–C4 167.8(5)8] show that the C2 atom is trans with respect to the P2 atom, and C–C–C–C–N backbone is in all-trans
conformation with the chain length stretched close to its maximum possible value. Similar alltrans conformation of the C–C–C–C–N chain has been reported for the trihydrate structure and alendronic acid.29 As indicated by the nonbonding torsion angles about P P direction [O6–P2–P1– O3 40.1(2)8, O7–P2–P1–O2 31.1(3)8, O5–P2–P1– O4 57.7(4)8, O7–P2–P1–O3 71.6(3)8, O6–P2–P1– O4 78.6(3)8, O5–P2–P1–O2 80.9(4)8], the two phosphonate groups in the anhydrous compound are partially staggered with respect to each other. The corresponding values of torsion angles in the parent trihydrate structure are 39.4(4)8, 28(5)8, 72.5(5)8, 76.1(3)8, 67.6(5)8 and 76.2(5)8, respectively. The natural orientation of two PO3 groups can also be described by the relationship between the P1–C4–P2 (w) angle and certain staggering angle among the PO3 groups when viewed along the P P direction (r). In the anhydrous sodium alendronate the observed w/r value, 109.7(4)/43.0(3)8, is similar to that reported for sodium alendronate trihydrate [110.0(3)/ 34(2)8].
Table 4. Comparison of Unit Cell Parameters of Trihydrate and Anhydrous Forms of Sodium Alendronate Crystal System
Figure 5. Asymmetric unit of anhydrous sodium alendronate. Symmetry codes: (i) x, 2y, 1z; (ii) 1/ 2x, 1/2 þ y, 3/2z. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009
Space group ˚) a (A ˚ b (A) ˚) c (A b (8)
Trihydrate Monoclinic
Anhydrous Monoclinic
P21/n 7.275(1) 9.002(2) 19.503(4) 100.61(1)
P21/n 7.6298(6) 9.1458(7) 14.4573(11) 112.6(1) DOI 10.1002/jps
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Figure 6. Edge sharing of NaO6 units in anhydrous sodium alendronate. Symmetry code: (i) x, 2y, 1z; (ii) 1x, 1y, 2z; (iii) 1/2 þ x, 3/2y, 1/2 þ z.
The octahedral coordination around the Na atom in the anhydrous compound is established by one hydroxyl and five phosphonyl O atoms, whereas in the trihydrate compound the coordination sphere is completed by one hydroxyl O, four phosphonyl O atoms, and one water molecule. The deviation of the metal center from the equatorial plane is also much less in the trihydrate structure ˚ ] compared to that in the anhydrous [0.051(1) A ˚ ]. form [0.238(2) A
The packing arrangements of molecules in the anhydrous and trihydrate sodium alendronate are markedly different. The phosphonyl atoms O2 and O2i (x, y þ 2, z þ 1) in the anhydrous compound bridge adjacent NaO6 octahedra forming centrosymmetric dimers (Fig. 6). The dimers are connected through the phosphonyl P and hydroxyl C atoms, so generating a two-dimensional molecular sheet of 20-membered Na6P4O10 rings ˚ ) in the (011) plane (approximate diameter 10 A
Figure 7. A part of molecular packing viewed along bc-plane (a) anhydrous form and (b) trihydrate form of sodium alendronate. Organic chain of alendronate has been omitted for clarity. DOI 10.1002/jps
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(Fig. 7a). Similar edge sharing NaO6 octahedra has been reported for disodium pamidronate pentahydrate,30 where the two-dimensional structure is built up of 8-membered Na2P2O4 rings and 12-membered Na4P2O6 rings in the (110) plane. In the trihydrate sodium alendronate, corner sharing of phosphonyl and hydroxyl tetrahedral links the NaO6 octahedra to form one-dimensional chain along the (010) direction (Fig. 7b). As expected, density of the trihydrate compound (1.72 g/cm3) is less than the dehydrated one (1.93 g/cm3).
CONCLUSIONS The synthesis, thermal analysis and variable temperature X-ray powder diffraction study of sodium alendronate trihydrate have been described. The crystal structure of anhydrous sodium alendronate has been established from powder X-ray diffraction data using Monte–Carlo simulated annealing method. Although the accuracy of structural information that can be obtained in structure determination from powder diffraction data is, in general, not as high as that could be obtained from single crystal X-ray studies, powder X-ray diffraction methodology is sufficient for understanding the structural features, specially, the packing arrangements of molecular materials. The versatility of X-ray powder diffraction method is particularly suited for the pharmaceutical industry, since many compounds of interest are not always available as single crystals, and X-ray powder diffraction data are intrinsically representative of the bulk phase under investigation.
ACKNOWLEDGMENTS MA, KV, AB and SD thank Dr. Reddy’s management for their support and encouragement.
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3. Van Brussel EM, Gossman WL, Wilson SR, Oldfield E. 2003. Hydronium (cycloheptylammonio)methylene-1,1-bisphosphonate (hydronium incadronate). Acta Cryst C59:o93–o94. 4. Vega D, Baggio R, Piro O. 1998. Monosodium 3(dimethylammonio)-1-hydroxy-1,1-propanediyldiphosphonate monohydrate (monosodium olpadronate monohydrate). Acta Cryst C54:324–327. 5. Gossman WL, Wilson SR, Oldfield E. 2002. Monosodium [1-hydroxy-2-(1H-imidazol-3-ium-4-yl)ethane1,1-diyl]bis(phosphonate) tetrahydrate (monosodium isozoledronate). Acta Cryst C58:m599–m600. 6. Fernandez D, Polla G, Vega D, Ellena JA. 2004. The Zn2þ salt of pamidronate: A role for water in the metal-cation binding properties of bisphosphonates. Acta Cryst C60:m73–m75. 7. Merck & Co., Inc. Process for preparing 4-amino-1hydroxybutylidene-1,1-bisphosphonic acid or salts thereof. US patent 4,922,007. 8. Pliva Research & Development Ltd. Solid-State form of Alendronate sodium and preparation thereof. US 2005/0113343 A1. 9. Teva Pharmaceutical Industries Ltd. Hydrate forms of Alendronate sodium, processes for manufacture thereof, and pharmaceutical compositions thereof. US 6,696,601 B2. 10. Vega D, Baggio R, Garland MT. 1996. Monosodium 4-amino-1-hydroxy-1,1-butanediyldiphosphonate trihydrate (alendronate). Acta Cryst C52:2198– 2201. 11. Merck & Co., Inc. Anhydrous Alendronate monosodium salt formulations. US patent 5,849,726. 12. Favre-Nicolin V, Cern RJ. 2002. FOX, ‘free objects for crystallography’: A modular approach to ab initio structure determination from powder diffraction. J Appl Cryst 35:734–743. 13. David WIF, Shankland K, Cole J, Maginn S, Motherwell WDH, Taylor R. 2001. DASH User Manual. Cambridge, UK: Cambridge Crystallographic Data Center. 14. Harris KDM, Johnston RL, Albesa Jove D, Chao MH, Cheung EY, Habershon S, Kariuki BM, Lanning OJ, Tedesco E, Turner GW. 2001. EAGER, University of Birmingham. 15. Harris KDM, Tremayne M, Lightfoot P, Bruce PG. 1994. Crystal structure determination from powder diffraction data by Monte Carlo methods. J Am Chem Soc 116:3543–3547. 16. Stephenson GA, Liang C. 2006. Structural determination of the stable and meta-stable forms of atomoxetine HCl using single crystal and powder X-ray diffraction methods. J Pharm Sci 95:1677– 1683. 17. Coelho AA. 2003. Indexing of powder diffraction patterns by iterative use of singular value decomposition. J Appl Crystallogr 36:86–95. 18. Werner P-E, Eriksson L, Westdahl M. 1985. TREOR, a semi-exhaustive trial-and-error powder
DOI 10.1002/jps
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indexing program for all symmetries. J Appl Crystallogr 18:367–370. De Wolff PM. 1968. A simplified criterion for the reliability of a powder pattern indexing. J Appl Crystallogr 1:108–113. Smith GS, Snyder RL. 1979. FN: A criterion for rating powder diffraction patterns and evaluating the reliability of powder-pattern indexing. J Appl Crystallogr 12:60–65. Boultif A, Louer D. 1991. Indexing of powder diffraction patterns for low-symmetry lattices by the successive dichotomy method. J Appl Crystallogr 24:987–993. Le Bail A, Duroy H, Fourquet JL. 1988. Ab-initio structure determination of LiSbWO6 by X-ray powder diffraction. Mater. Res. Bull 23:447–452. Toroya H. 1986. Whole-powder-pattern fitting without reference to a structural model: Application to X-ray powder diffraction data. J Appl Cryst 19:440– 447. Stewart JJP. 1988. MOPAC, Version 5.0, Quantum Chemistry program exchange 581; Indiana University.
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25. Dewar MJS, Zoebisch EG, Healy EF, Stewart JJP. 1985. Development and use of quantum mechanical molecular models. 76. AM1: A new general purpose quantum mechanical molecular model. J Am Chem Soc 107:3902–3909. 26. Larson AC, von Dreele RB. 1994. General Structure Analysis System (GSAS). Los Alamos National Laboratory, NM: Los Alamos National Laboratory, LAUR 86-748. 27. Thompson P, Cox DE, Hastings JB. 1987. Rietveld refinement of Debye-Scherrer synchrotron X-ray data from Al2O3. J Appl Crystallogr 20:79–83. 28. Ferna´ndez D, Polla G, Vega D, Ellena JA. 2004. The Zn2þ salt of pamidronate: A role for water in the metal-cation binding properties of bisphosphonates. Acta Cryst C60:m73–m75. 29. Leroux Y, El Manouni D, Safsaf A, Neuman A, Giller H. 1991. Etude Structurale De L’acide Butane Hydroxy-1 Amino-4 Diphosphonique-1,10 . Phosphorous Sulfur Silicon Relat Elem 63:181–191. 30. Vega D, Fernandez D, Ellena JA. 2002. Disodium pamidronate. Acta Cryst C58:m77–m80.
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Department of Analytical Research, Integrated Product Development, Dr. Reddy’s Laboratories Limited, Hyderabad, India
3
Department of Research & Development, Integrated Product Development, Dr. Reddy’s Laboratories Limited, Hyderabad, India 4
Department of Physics, Jadavpur University, Kolkata, India
Received 5 May 2008; revised 22 July 2008; accepted 2 August 2008 Published online 9 September 2008 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21561
ABSTRACT: Sodium alendronate, a member of bisphosphonate class of compounds commonly used for treatment of generalized bone disorders, exists in various hydrated forms. Dehydration of sodium alendronate trihydrate has been studied using variable temperature X-ray powder diffraction technique. The crystal structure of anhydrous sodium alendronate, prepared by heating the trihydrate sodium alendronate at 1508C, has been determined from X-ray powder data using direct space global optimization technique for structure solution, followed by the Rietveld refinement. The structure of the anhydrous form of sodium alendronate is compared with that of the trihydrate form, which was determined previously from single crystal X-ray diffraction data. Both anhydrous and trihydrate sodium alendronate crystallize in monoclinic system with space group P21/n. The crystal structure of the anhydrous sodium alendronate is built by edge-sharing of NaO6 octahedra into a two-dimensional molecular sheet in the (011) plane, whereas in the trihydrate compound, one-dimensional chain along the (010) direction is generated by corner sharing of NaO6 octahedra. ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2113–2121, 2009
Keywords: X-ray powder diffractometry; crystal structure; crystallography; hydrates/solvates; polymorphism; ab initio calculations
DRL internal communication number: IPDO-IPM00047. Minakshi Asnani’s present address is Analytical Research, Ranbaxy Labs Ltd., Gurgaon 122015, India. Apurba Bhattacharya’s present address is Department of Chemistry, Texas A&M University, Kingsville, TX 78363. Correspondence to: Surya Devarakonda (Telephone: 91-404434-6111; Fax: 91-40-4434-6164; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 98, 2113–2121 (2009) ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association
INTRODUCTION Bisphosphonates form a class of compounds that can act as selective inhibitors of osteoclastic bone resorption, and are commonly used in the treatment of a variety of generalized bone disorders, for example, osteoporosis, Paget’s disease.1 Crystal
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structures of many bisphosphonates have been extensively studied over the last few years due to their diverse therapeutic activity.2–6 Sodium alendronate (I), a member of bisphosphonate class of compounds, is chemically described as 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt. Several hydrated forms of sodium alendronate have been reported.7–9 While the preparations of sodium alendronate trihydrate and other variable hydrates (1/4, 1/3, 1/2, 3/4, 1, 5/4, 4/3, 3/2, 5/3, 7/4, 2) have been described in the US patent 4,922,007 and US patent application 6,696,601B2, respectively, crystal structure of only the trihydrate form is available in the literature.10 In addition to these hydrated forms, anhydrous sodium alendronate has also been patented.11 A detailed study of structural features of these compounds is an important step towards understanding their interaction mechanism in biological systems and provides useful information for designing suitable pharmaceutical product. In fact, once the crystal structure has been established, morphology modification can readily be made by analysis of forces that cause directional growth and through the addition of ‘‘tailor made’’ inhibitors that disrupt growth and alter crystal morphology in a predictable way. From a pharmaceutical standpoint, the reactivities and stabilities of different hydrated and anhydrous crystal forms of a pharmaceutical substance can have a severe impact on the feasibilities of prospective formulations. Although single crystal X-ray diffraction is undoubtedly the most widely used technique for elucidating the structure of organic and pharmaceutical compounds, an intrinsic limitation of this technique is the requirement to prepare single crystals of appropriate size and quality, which is not always met for all compounds of interest. In such circumstances, X-ray powder diffraction can be used as an alternative route for structural analysis. Recent developments in the direct space methodologies as implemented in FOX,12 DASH,13 EAGER14 have shown that crystal structures of several molecular compounds and pharmaceuticals materials can be determined from X-ray powder diffraction data.15,16 The aim of the present work was to study the dehydration of sodium alendronate trihydrate and compare crystal structures of the anhydrous and the trihydrate forms, recognizing that knowledge of crystal structures of two forms provides an opportunity for exploring the relationship JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009
between structure and property. Such relationships are useful to design materials with targeted properties.
MATERIALS AND METHODS Synthesis Sodium alendronate trihydrate was synthesized following the procedure described previously (US patent 4,922,007). During the synthesis, aminobutyric acid (20 g, 0.19 mol), methanesulphuric acid (80 mL) and phosphorous acid (24 g, 0.29 mol) were charged in a flask fitted with a reflux condenser and aged for 15 min at 70–758C. The solution was cooled to 358C and phosphorous trichloride (40 mL, 0.46 mol) was added cautiously. The reaction mixture was then heated to 658C and aged at that temperature for 20 h. Further, the contents were cooled to 258C and added to deionized water (200 mL). The solution was then aged at 95–1008C for 5 h. The reaction was cooled to 208C while pH was adjusted to 4.3 with NaOH (50%, 80 mL). The resulting white suspension was then cooled to 0–58C and aged for 1 h. The product was collected by filtration, then washed with cold water and 95% EtOH. The yield after air drying was 53.26 g (85%). FTIR, DSC and TGA analysis confirmed the formation of sodium alendronate trihydrate. The sodium alendronate trihydrate was slowly heated to 1508C and kept at elevated temperature for 1 h. The sample was cooled to room temperature to obtain the anhydrous sodium alendronate.
Characterization Methods X-Ray Powder Diffraction X-ray powder diffraction data were collected on a PANalytical X’pert Pro powder diffractometer ˚ ) radiation. The diffraction using Cu Ka (1.5418 A pattern was recorded at room temperature (228C) with step size of 0.0088 (2u) and counting time 50 s/ step over angular range 3–1008 (2u) using the Bragg-Brentano geometry and a rotating flatplate sample holder. The zero point error estimated was lower than 0.028 (2u). Variable temperature XRD patterns of sodium alendronate trihydrate were recorded at 18C interval (measurement accuracy 0.18C) with a heating rate of 18C/min in the temperature range 30–3008C. DOI 10.1002/jps
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Thermal Analysis and Optical Microscopy Thermogravimetric and differential scanning calorimetric analyses (TG-DSC) were carried out with a Mettler Toledo DSC PT15 instrument under a flow of nitrogen (30 mL/min) from 30 to 3008C at 108C/min. Optical microscopy was performed using a polarizing microscope equipped with a Mettler Toledo FPGO hot stage and 35-nm Colorview Camera (Soft Imaging, Munster, Germany). The sample was placed on a glass slide, covered with a covered slip and heated in the temperature range 25–1358C at a rate of 28C/min.
Structure Determination from X-Ray Powder Diffraction Data The first 20 peaks of the powder pattern were fitted using the program TOPAS,17 and the refined 2u positions were used for indexing with program TREOR9018 of CRYSFIRE package. The solution with highest figure of merit [M(20) ¼ 40, F(20) ¼ 81 (0.0062, 40)]19,20 indexed all peaks in the monoclinic system with cell parameters ˚, b¼ a ¼ 7.631(3), b ¼ 9.144(2), c ¼ 14.456(1) A 3 ˚ 112.61(2)8 and V ¼ 930.97(4) A . The results of indexing with DICVOL21 also indicated the same solution. The full pattern decomposition was performed with TOPAS following Le Bail algorithm22 using a split-type pseudo-Voigt peak profile function23 and the Laue-symmetry (2/m) for the monoclinic system. Analysis of the powder pattern indicated P21/n as the probable space group, which was subsequently confirmed by successful structure solution and refinement. The structure was solved by global optimization of a structural model in direct space using the program FOX. The initial configuration was obtained from the molecular modeling program CS Chem3D, where energy of the alendronate moiety was minimized using the semi-empirical quantum mechanical methods MOPAC.24 The starting configuration for global optimization was obtained by randomly placing one Na atom and one alendronate moiety with geometry as calculated from an earlier MOPAC run using the AM1 Hamiltonian.25 During structure solution, bond lengths and bond angles were ˚ and 1.158, respectively, constrained with 0.02 A but the torsion angles were allowed to change. The parallel tempering algorithm of program FOX was used for the data range 3–458(2u). After 4 108 trials, requiring almost 20 h of computer time on a Pentium IV (512 MB RAM) PC, a DOI 10.1002/jps
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solution with Rwp ¼ 0.124 and GOF ¼ 3.1 was obtained. Atomic coordinates derived from parallel tempering procedure of FOX were taken as the starting model for Rietveld refinement with the program GSAS.26 The 2u range used in Rietveld refinement was from 38 to 1008. The atomic coordinates of 15 nonhydrogen atoms were refined with restraints on bond lengths and bond angles. The mean-square deviations of assigned values for ˚ and 18, bond lengths and bond angles were 0.01 A respectively. The background was described by Shifted Chebyshev function with 36 regularly distributed points over the entire 2u range and a linear interpolation was made between two successive points. The peak profiles were fitted with pseudo-Voigt functions using the ThompsonCox-Hastings formalism, which could take into account experimental resolution and broadening due to size and strain effects.27 H-atoms were introduced in GSAS at their expected positions with N–H, O–H, and C–H distances restrained. ˚ 2 for P, Three isotropic thermal parameters, 0.02 A 2 2 ˚ ˚ 0.04 A for Na and 0.05 A for N, C and O atoms, were refined. In the final stage of refinement, preferred orientation correction was applied using the generalized spherical harmonics (order 20) model. Final Rietveld refinement of 220 parameters (45 coordinates, 4 lattice parameters, 36 background, 11 profile parameters, 3 isotropic thermal parameters, 120 orientation distribution function coefficients, and 1 scale factor) resulted in Rp ¼ 0.0479 and Rwp ¼ 0.0639 with excellent agreement between the observed and calculated patterns (Fig. 1). Crystallographic data, profile and structural parameters are listed in Table 1. The atomic coordinates, selected bond distances and bond angles are given in Tables 2 and 3, respectively.
RESULTS AND DISCUSSIONS Dehydration of Sodium Alendronate Trihydrate X-ray powder diffraction patterns of sodium alendronate trihydrate at different temperatures are shown in Figure 2. From 30 to 1148C, no significant change in the powder diffraction patterns was observed. However, peaks corresponding to a new crystalline phase (anhydrous sodium alendronate) were visible at 1158C (the measurement accuracy or the temperature uncertainty of the instrument is 0.18C). On further heating, the intensity of JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009
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Table 2. Atomic Coordinates and Isotropic ˚ 2) Obtained from Displacement Parameters (A Rietveld Refinement
Figure 1. Final Rietveld refinement plot for anhydrous sodium alendronate. Orange crosses: observed pattern, green curve: calculated pattern, brown curve: difference curve.
peaks corresponding to the dehydrated phase gradually increased and that due to the trihydrate phase decreased. Finally, at 1308C the peaks corresponding to the trihydrate phase disappeared and pure anhydrous sodium alendronate was obtained. It is to be noted that on slow heating, sodium alendronate trihydrate transformed into single-phase anhydrous form and no intermediate hydrated species were observed. Table 1. Crystal Data and Refinement Parameters for Anhydrous Sodium Alendronate Empirical formula Formula weight Data collection temperature Crystal system Space group Unit cell dimensions
Volume Z Density (calculated) Data collection range Step size Wavelength No. of data points No. of contributing reflections No. of refined parameters Rp Rwp R2F x2
NaC4H12NO7P2 271.08 293 K Monoclinic P21/n (no. 14) ˚ a ¼ 7.6298(6) A ˚ b ¼ 9.1458(7) A ˚ c ¼ 14.4573(11) A b ¼ 112.6(1)8 ˚3 931.4(2) A 4 1.933 gm/cm3 3–1008 (2u) 0.0088 (2u) ˚ 1.5418 A 12160 1937 220 0.0479 0.0639 0.0910 5.692
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Atom
x
y
z
Uiso
P1 P2 NA1 O1 O2 O3 O4 O5 O6 O7 N1 C1 C2 C3 C4
0.2241(5) 0.5371(6) 0.0381(8) 0.5381(13) 0.1713(11) 0.0997(13) 0.1811(7) 0.7524(8) 0.4816(13) 0.4112(10) 0.6297(6) 0.6794(8) 0.5330(7) 0.6030(7) 0.4861(7)
0.7697(5) 0.9157(5) 1.0536(6) 0.6382(6) 0.8948(9) 0.7938(7) 0.6212(7) 0.9514(9) 0.8404(9) 1.0442(7) 0.6239(6) 0.7444(6) 0.7424(5) 0.7991(5) 0.7749(6)
0.6009(3) 0.7790(3) 0.6249(3) 0.7270(6) 0.5274(6) 0.6595(7) 0.5443(5) 0.8125(4) 0.8574(6) 0.7326(7) 0.3805(4) 0.4550(4) 0.5050(6) 0.6139(5) 0.6785(5)
0.007(1) 0.007(1) 0.039(3) 0.011(1) 0.011(1) 0.011(1) 0.011(1) 0.011(1) 0.011(1) 0.011(1) 0.011(1) 0.011(1) 0.011(1) 0.011(1) 0.011(1)
The DSC curve for sodium alendronate trihydrate (Fig. 3a) revealed a sharp endotherm at 1268C. The TG analysis of the trihydrate sample (Fig. 3b) showed a weight loss of 16.6% due to liberation of three water molecules (theoretical weight loss 17.2%) in the temperature range 120–1708C. The thermal events beyond 2208C can be attributed to decomposition of the molecule. ˚ ) and Bond Angles Table 3. Selected Bond Lengths (A (8) for Anhydrous Sodium Alendronate
Atoms P(1)–O(2) P(1)–O(3) P(1)–O(4) P(1)–C(4) P(2)–O(5) P(2)–O(6) P(2)–O(7) P(2)–C(4) Na(1)–O(1ii) Na(1)–O(2) Na(1)–O(2i) Na(1)–O(3) Na(1)–O(6ii) Na(1)–O(7) O(1)–C(4) N(1)–C(1) C(2)–C(1) C(2)–C(3) C(3)–C(4)
Bond ˚) Distance (A 1.508(5) 1.511(5) 1.555(5) 1.879(4) 1.559(5) 1.515(5) 1.504(5) 1.871(5) 2.545(5) 2.496(10) 2.218(9) 2.436(5) 2.646(10) 2.670(10) 1.413(5) 1.484(5) 1.546(5) 1.544(5) 1.536(5)
Atoms
Bond Angle (8)
O(2)–P(1)–O(4) O(4)–P(1)–C(4) C(4)–P(1)–O(3) O(3)–P(1)–O(4) O(2)–P(1)–C(4) O(2)–P(1)–O(3) O(7)–P(2)–C(4) C(4)–P(2)–O(5) O(5)–P(2)–O(6) O(6)–P(2)–O(7) O(7)–P(2)–O(5) O(6)–P(2)–C(4) C(4)–C(3)–C(2) C(3)–C(2)–C(1) C(2)–C(1)–N(1)
110.2(5) 107.2(3) 114.5(5) 111.8(4) 109.7(4) 103.3(4) 106.4(5) 105.3(4) 115.4(5) 112.1(5) 113.0(5) 103.5(4) 121.1(4) 116.3(4) 107.5(5)
Symmetry codes: (i) x, 2y, 1z; (ii) 1/2x, 1/2 þ y, 3/2z. DOI 10.1002/jps
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Figure 2. Variable temperature PXRD patterns of sodium alendronate trihydrate.
The morphological changes during dehydration as monitored by hot-stage microscopy indicated that the crystals of sodium alendronate trihydrate were transparent (Fig. 4a) at room temperature (228C). At 1208C, the edges of the crystals started darkening indicating commencement of dehydration (Fig. 4b). On further heating, darkening propagated towards center of the crystals denoting the progress of dehydration (Fig. 4c and d). Finally at 1288C, entire surface of the crystals turned dark suggesting that the dehydration process was complete.
Structural Description of Anhydrous Sodium Alendronate The asymmetric unit of anhydrous sodium alendronate consists of one alendronic anion and one
sodium cation (Fig. 5). Similar to previously reported free acid (4-ammonium-1-hydroxybutylidene-1,1-bisphosphonic acid), and 1:1 or 2:1 alendronate salts with Naþ or Ca2þ ions,10,28 the title complex has zwitterionic character with the protonated amine group bearing the positive charge. The geometry around the P atoms is tetrahedral (Tab. 3), and the P–O bond lengths are ˚ for the P–O (unprotoclose to 1.51 and 1.56 A nated) and P–O (protonated) distances, respectively. The P–C bond distances 1.879(4), 1.871(5) ˚ ] and P–C–P bond angle [109.7(4)8] are in good A agreement with the corresponding values found in analogous structures.10,28 The coordination environment around Naþ ion can be best described as distorted octahedral and consists of one bidentate and four monodentate PO3 chelators. The equatorial plane is defined by atoms O2, O3, O1ii (½x, ½ þ y, 3/2z) and O6ii (½x, ½ þ y, 3/2z) with the metal center ˚ from the least-squares displaced by 0.238(2) A plane through the equatorial atoms. Apical atoms O7 and O2 (x, 2y, 1z) lie above 2.389(5) ˚ below this plane, respectively, and 2.037(5) A forming an O7 Na O2i (x, 2y, 1z) angle of 141.8(3)8. The Na O contact distances range ˚ (Tab. 3). from 2.218(9) to 2.670(10) A
Comparison of Anhydrous and Trihydrate Sodium Alendronate Structures
Figure 3. (a) DSC and (b) TGA curves of sodium alendronate trihydrate. DOI 10.1002/jps
Both the trihydrate and anhydrous compounds crystallize in monoclinic system with space group P21/n. The lattice parameter c of anhydrous ˚ ] compared compound is shortened [14.4573(11) A JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009
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Figure 4. Hot-stage microscope images of sodium alendronate trihydrate at (a) 30, (b) 120, (c) 124, (d) 126, and (e) 1288C.
˚ ], while to that in the trihydrate one [19.503(4) A the a and b dimensions did not show marked difference (Tab. 4). The molecular conformation in both compounds as established from various torsion angles is essentially similar. The torsion angles in the anhydrous structure [C2–C3–C4–P2 154.7(4)8, C2–C3–C4–P1 30.8(6)8, N1–C1–C2–C3 150.9(4)8, C1–C2–C3–C4 167.8(5)8] show that the C2 atom is trans with respect to the P2 atom, and C–C–C–C–N backbone is in all-trans
conformation with the chain length stretched close to its maximum possible value. Similar alltrans conformation of the C–C–C–C–N chain has been reported for the trihydrate structure and alendronic acid.29 As indicated by the nonbonding torsion angles about P P direction [O6–P2–P1– O3 40.1(2)8, O7–P2–P1–O2 31.1(3)8, O5–P2–P1– O4 57.7(4)8, O7–P2–P1–O3 71.6(3)8, O6–P2–P1– O4 78.6(3)8, O5–P2–P1–O2 80.9(4)8], the two phosphonate groups in the anhydrous compound are partially staggered with respect to each other. The corresponding values of torsion angles in the parent trihydrate structure are 39.4(4)8, 28(5)8, 72.5(5)8, 76.1(3)8, 67.6(5)8 and 76.2(5)8, respectively. The natural orientation of two PO3 groups can also be described by the relationship between the P1–C4–P2 (w) angle and certain staggering angle among the PO3 groups when viewed along the P P direction (r). In the anhydrous sodium alendronate the observed w/r value, 109.7(4)/43.0(3)8, is similar to that reported for sodium alendronate trihydrate [110.0(3)/ 34(2)8].
Table 4. Comparison of Unit Cell Parameters of Trihydrate and Anhydrous Forms of Sodium Alendronate Crystal System
Figure 5. Asymmetric unit of anhydrous sodium alendronate. Symmetry codes: (i) x, 2y, 1z; (ii) 1/ 2x, 1/2 þ y, 3/2z. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009
Space group ˚) a (A ˚ b (A) ˚) c (A b (8)
Trihydrate Monoclinic
Anhydrous Monoclinic
P21/n 7.275(1) 9.002(2) 19.503(4) 100.61(1)
P21/n 7.6298(6) 9.1458(7) 14.4573(11) 112.6(1) DOI 10.1002/jps
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Figure 6. Edge sharing of NaO6 units in anhydrous sodium alendronate. Symmetry code: (i) x, 2y, 1z; (ii) 1x, 1y, 2z; (iii) 1/2 þ x, 3/2y, 1/2 þ z.
The octahedral coordination around the Na atom in the anhydrous compound is established by one hydroxyl and five phosphonyl O atoms, whereas in the trihydrate compound the coordination sphere is completed by one hydroxyl O, four phosphonyl O atoms, and one water molecule. The deviation of the metal center from the equatorial plane is also much less in the trihydrate structure ˚ ] compared to that in the anhydrous [0.051(1) A ˚ ]. form [0.238(2) A
The packing arrangements of molecules in the anhydrous and trihydrate sodium alendronate are markedly different. The phosphonyl atoms O2 and O2i (x, y þ 2, z þ 1) in the anhydrous compound bridge adjacent NaO6 octahedra forming centrosymmetric dimers (Fig. 6). The dimers are connected through the phosphonyl P and hydroxyl C atoms, so generating a two-dimensional molecular sheet of 20-membered Na6P4O10 rings ˚ ) in the (011) plane (approximate diameter 10 A
Figure 7. A part of molecular packing viewed along bc-plane (a) anhydrous form and (b) trihydrate form of sodium alendronate. Organic chain of alendronate has been omitted for clarity. DOI 10.1002/jps
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(Fig. 7a). Similar edge sharing NaO6 octahedra has been reported for disodium pamidronate pentahydrate,30 where the two-dimensional structure is built up of 8-membered Na2P2O4 rings and 12-membered Na4P2O6 rings in the (110) plane. In the trihydrate sodium alendronate, corner sharing of phosphonyl and hydroxyl tetrahedral links the NaO6 octahedra to form one-dimensional chain along the (010) direction (Fig. 7b). As expected, density of the trihydrate compound (1.72 g/cm3) is less than the dehydrated one (1.93 g/cm3).
CONCLUSIONS The synthesis, thermal analysis and variable temperature X-ray powder diffraction study of sodium alendronate trihydrate have been described. The crystal structure of anhydrous sodium alendronate has been established from powder X-ray diffraction data using Monte–Carlo simulated annealing method. Although the accuracy of structural information that can be obtained in structure determination from powder diffraction data is, in general, not as high as that could be obtained from single crystal X-ray studies, powder X-ray diffraction methodology is sufficient for understanding the structural features, specially, the packing arrangements of molecular materials. The versatility of X-ray powder diffraction method is particularly suited for the pharmaceutical industry, since many compounds of interest are not always available as single crystals, and X-ray powder diffraction data are intrinsically representative of the bulk phase under investigation.
ACKNOWLEDGMENTS MA, KV, AB and SD thank Dr. Reddy’s management for their support and encouragement.
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