Characterization of Bisphosphonate Hydrate Crystals by Phosphorus K-Edge X-Ray Absorption Near-Edge Structure Spectroscopy

Abstract

X-ray absorption near-edge structure (XANES) spectroscopy is a new method for the characterization of active pharmaceutical ingredients. XANES spectra show unique features depending on the electronic states of the X-ray absorbing elements and provide information about the chemical environment that affects the electronic states. In this study, six bisphosphonate hydrate crystals were used to investigate, for the first time, how the phosphorus K-edge XANES spectra are affected by the interatomic interactions and charged states of phosphonate moieties. Phosphorus K-edge XANES spectra showed several differences among the bisphosphonates. In particular, the chlorine atoms covalently bonded near the phosphonate and the number of electric charges of the phosphonate moieties seemed to have large effects on peak shape in XANES spectra. Unique shapes of the XANES spectra demonstrated that differences in interactions at the oxygen atoms of the phosphonate moieties could change the shapes of the XANES spectrum peaks to the extent that each material was distinguished based on the spectra. Since slight differences in interatomic interactions and charged states lead to variations in the spectra, XANES spectroscopy could be widely applied as the fingerprint method to evaluate active pharmaceutical ingredients.

Introduction

Characterization of the physical properties of the active pharmaceutical ingredient (API) is essential for the manufacture of solid dosage forms, as these physical properties can affect the manufacturability, stability, and efficacy of the solid dosage form. The physical properties of APIs have been evaluated by many methods,^1–8) such as X-ray powder diffraction (XRPD), thermal analysis, dynamic vapor sorption, Fourier transform IR spectroscopy, Raman spectroscopy, and solid-state NMR. We have reported on a new method for API, X-ray absorption near-edge structure (XANES) spectroscopy.⁹⁾ Although XANES spectroscopy has been used in material sciences, it is a new technique in the pharmaceutical sector. The X-ray absorption spectrum has an edge where the absorption increases sharply at the energy of the electron orbitals such as the K shell, and the energy range from this edge to about +50 eV is called the XANES region. XANES spectra show unique features depending on the electronic states of the X-ray absorbing elements and provide information about the chemical environments that affect electronic states. One advantage of XANES spectroscopy is its high element specificity. When an element is included only in the drug molecule, the XANES spectrum of the element provides information about the interactions formed at the drug molecules in the samples. The high element specificity of XANES spectroscopy allows its application even in the presence of large amounts of excipients.^10,11) Another advantageous characteristic of XANES spectroscopy is that it can be used to analyze not only solid state materials including crystals and amorphous structures,^3,10) but also liquids and even gases. Our previous study applied XANES spectroscopy to discriminate the crystal polymorphs and amorphous forms of various APIs containing phosphorus,^3,4) chlorine,^10,12,13) bromine^11,14,15) and sulfur.^16,17) In addition, the study about the phosphorus K-edge XANES spectra of organophosphorus compounds in aqueous solution has been reported.¹⁸⁾

Bisphosphonates inhibit osteoclast-mediated bone resorption and are widely used to treat bone diseases such as osteoporosis and Paget’s disease.¹⁹⁾ Bisphosphonates have two phosphonate moieties bound to the same carbon atoms and the phosphorus atoms are available for phosphorus K-edge XANES spectroscopy. Although the phosphorus atoms in the phosphonate moieties cannot interact directly with the atoms of the neighboring molecules or ions in the crystals, the oxygen atoms of the phosphonate moieties can form various bonds, including hydrogen bonds and coordination bonds. These interactions might affect the electronic states of the phosphorus atoms, resulting in the shape change of the phosphorus K-edge XANES spectra. However, the relationship between the interactions of the X-ray absorbing atoms of the APIs and the shapes of the XANES spectra remains unclear. In this study, six bisphosphonate hydrate crystals (Fig. 1) were used to investigate, for the first time, how the phosphorus K-edge XANES spectra are affected by the interatomic interactions and charged states of phosphonate moieties in the crystals.

Fig. 1. Chemical Structure of Bisphosphonates

(a) Alendronate, (b) clodronate, (c) etidronate, (d) ibandronate, (e) pamidronate, and (f) risedronate.

Experimental

Materials

Disodium etidronate anhydrate reagent was supplied by Sumitomo Pharma Co., Ltd. Sodium alendronate trihydrate, disodium clodronate tetrahydrate, sodium ibandronate anhydrate, disodium pamidronate pentahydrate, and sodium risedronate hemipentahydrate were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan).

Preparation of Hydrated Crystalline Powders

Anhydrous disodium etidronate is known to be hydrated at high relative humidity (RH), such as 60–80%.³⁾ Crystals of disodium etidronate tetrahydrate were prepared by storing the supplied disodium etidronate anhydrate crystals in a constant temperature and humidity device LH33-12M (Nagano Science Co., Ltd., Osaka, Japan) at 40 °C and 90% RH over 7 d.

Crystals of sodium ibandronate monohydrate were prepared by the anti-solvent method. Approximately 100 mg of the sodium ibandronate anhydrate was completely dissolved in 2 mL of water at room temperature. The solution was mixed with 8 mL of ethanol as anti-solvent, sealed, and left overnight at room temperature. The precipitated monohydrate crystals of sodium ibandronate were collected by filtration and dried overnight under vacuum at room temperature.

Other bisphosphonate crystals were used as supplied.

XRPD Analysis

XRPD patterns were measured by an Empyrean diffraction system (PANalytical, Almelo, Netherlands). CuKα radiation was generated at 45 kV and 40 mA. The samples were placed on silicone plates and XRPD patterns were obtained from 4 to 40° (2θ) at room temperature. The step size was 0.017° and the scan speed was 0.033° per sec.

Single-Crystal X-Ray Structure Analysis

Single crystals suitable for structure analyses of sodium alendronate trihydrate, disodium clodronate tetrahydrate, and disodium pamidronate pentahydrate were prepared by the recrystallization method.

Approximately 20 mg of the sodium alendronate trihydrate was dissolved in 1 mL of water /methanol (3/1) at 80 °C. The solution was sealed and allowed to stand at room temperature. The cube-shaped single crystals appeared in the solution within two days.

Approximately 20 mg of disodium clodronate tetrahydrate was dissolved in 1 mL of water/methanol (1/1) at 80 °C. The solution was sealed and allowed to stand at room temperature. The rod-shaped single crystals appeared in the solution within two days.

Approximately 20 mg of disodium pamidronate pentahydrate was dissolved in 0.3 mL of water at 80 °C and then mixed with 0.3 mL of water/methanol (1/1). The solution was sealed and allowed to stand at room temperature. The rod-shaped single crystals appeared in the solution within two days.

Although these bisphosphonate crystal structures were reported,^20–22) their crystal structures were refined using the high-resolution X-ray diffraction data collected for these crystals to improve coordinate accuracies. Single-crystal X-ray diffraction data were collected at 93 K using a Rigaku XtaLAB P200 diffraction system (Rigaku Co., Ltd., Tokyo, Japan) and Mo Kα X-rays. The structure was determined using SHELXT software.²³⁾ Crystallographic refinement was performed using SHELXL²⁴⁾ with the shelXle graphical interface.²⁵⁾ Hydrogen atoms were located using a difference Fourier map and were constrained to ride on their parent atoms. The refined crystal structures and their diffraction data had been deposited in the Cambridge Structural Database. Their crystallographic data together with the deposition numbers are summarized in Table 1. These crystal structures and those of disodium etidronate tetrahydrate (CCDC deposition number 2097632),³⁾ sodium ibandronate monohydrate (729728)⁵⁾ and sodium risedronate hemipentahydrate (205288)²⁶⁾ were used for investigating the relationship between XANES spectra and the interactions at various electronic states of the phosphonate groups.

Table 1. Crystallographic Data of Each Single Crystal for Bisphosphonate Hydrates

Sample	Alendronate	Clodronate	Etidronate	Ibandronate	Pamidronate	Risedronate
CCDC ID	2314300	2314301	2097632	792728	2314302	205288
Reference	This study	This study	3	5	This study	26
Chemical formula	C4H12NO7P2・Na・3(H2O)	CH2Cl2O6P2・Na2・4(H2O)	C2H6O7P2・Na2・4(H2O)	C9H22NO7P2・Na・H2O	C3H9NO7P2・Na2・5(H2O)	C7H10NO7P2・Na・2.5(H2O)
Space group	P21/n	P1	P21/c	P1	P1	C2/c
Cell parameters (Å, °)
a	7.26445(9)	5.88392(15)	10.5176(2)	5.9730(10)	5.93440(10)	21.664(7)
b	8.95664(11)	9.1425(3)	5.97018(13)	9.1930(10)	10.8658(4)	8.930(3)
c	19.4137(2)	11.2028(3)	18.1576(4)	14.830(2)	11.2371(4)	15.123(5)
α	90	89.347(2)	90	98.221(2)	113.845(4)	90
β	100.3271(12)	87.389(2)	92.086(2)	98.974(2)	93.032(2)	114.692(5)
γ	90	88.567(2)	90	93.743(2)	92.129(2)	15.123(5)
Cell volume (Å3)	1242.69	601.795	1139.4	792.877	660.453	2658.18
Temperature (K)	93	93	93	93	93	93
Diffraction data
Wavelength	Mo Kα	Mo Kα			Mo Kα
No. of reflections
Measured	41251	51273			76132
Unique	4039	4389			4667
(sinθ/λ)max	0.742	0.769			0.759
Rint	0.0188	0.0832			0.0222
Refinement
R [F2 > 4σ(F2)]	0.0217	0.0333			0.0194
wR(F2)	0.1178	0.1069			0.1052
Goodness-of-fit	1.130	0.812			1.0091
Δρmax, Δρmin (e/Å3)	0.50, −0.48	0.88, −0.59			0.52, −0.40

XANES Spectroscopy

XANES spectra were obtained at the BL6N1 beamline of the Aichi Synchrotron Radiation Center (Aichi, Japan). To obtain good quality data, the synchrotron radiation is typically used for the XANES measurements. Powdered crystals of bisphosphonates were placed on electrically conductive double-sided adhesive carbon tapes and set in the chamber for XANES measurements. The XANES measurements were performed in a helium gas atmosphere at 25 °C. X-ray energy was calibrated with reference to the sulfur K-edge spectrum of dipotassium sulfate crystalline powder, which is often used for the energy calibration of this beamline. The XANES spectra were obtained in the total-electron-yield mode. The spectra were normalized so that the absorption edge jumps were 1. The spectrum data were processed using ATHENA software.²⁷⁾

Accession Codes

CCDC 2314300–2314302 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [e-mail], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone].

Results and Discussion

XRPD Analysis

For bisphosphonate crystalline powders, all experimental XRPD profiles of XANES measurements were consistent with those calculated from the single-crystal structures (Fig. 2). These confirmed that each bisphosphonate crystal was prepared.

Fig. 2. XRPD Patterns of Bisphosphonates

Exp. represents experimental data. Calc. represents calculated patterns generated from the crystal structures.

Single-Crystal X-Ray Structure Analysis

The interactions related to the phosphate moieties are summarized in Supplementary Table S1. Bisphosphonates had various interactions such as coordination bonding between sodium ions and phosphonate moieties, hydrogen bonding between water and phosphonate moieties, and hydrogen bonding between the nitrogen atom of basic moieties and the phosphonate moieties.

The protonation states of the phosphonate groups revealed by the crystal structure analyses confirmed that alendronate, clodronate, etidronate, ibandronate, and risedronate had two mono-anionic phosphonate moieties and that pamidronate had one mono-anionic and one di-anionic phosphonate moiety (Table 2). Further investigations of the P–O bond distances in the phosphonate moieties revealed that the localization of the negative charges differed among these bisphosphonates (Fig. 3). For alendronate, clodronate, etidronate, and risedronate, the P–O distances of the two unprotonated oxygen atoms in both mono-anionic phosphonate moieties were comparable (i.e., in the range of 1.489–1.517 Å) and the differences between the two P–O distances in the same phosphonate moieties were 0.000–0.013 Å. These results indicate that the negative charges at each phosphonate moiety were delocalized over the two oxygen atoms.

Table 2. Electric Charges and Distances for Phosphate Moieties

Distancea) (Å)		Alendronate	Clodronate	Etidronate	Ibandronate	Pamidronate	Risedronate
P(1) phosphate moiety	Electric charges	−1	−1	−1	−1	−2	−1
	P(1)-O(1)Hb)	1.583(1)	1.584(1)	1.588(1)	1.566(4)	1.527(1)	1.566(1)
	P(1)-O(2)	1.517(1)	1.499(1)	1.513(1)	1.487(3)	1.521(1)	1.510(1)
	P(1)-O(3)	1.513(1)	1.504(1)	1.505(1)	1.517(3)	1.542(1)	1.510(1)
P(2) phosphate moiety	Electric charges	−1	−1	−1	−1	−1	−1
	P(2)-O(4)H	1.578(1)	1.579(1)	1.580(1)	1.584(3)	1.612(1)	1.581(1)
	P(2)-O(5)	1.511(1)	1.489(1)	1.507(1)	1.494(3)	1.495(1)	1.509(1)
	P(2)-O(6)	1.504(1)	1.502(1)	1.510(1)	1.497(3)	1.515(1)	1.498(1)
The difference between P(1)-O(2) and P(1)-O(3)		0.004	0.005	0.008	0.030	0.021	0.000
The difference between P(2)-O(5) and P(2)-O(6)		0.007	0.013	0.003	0.003	0.020	0.011
The maximum difference between P(1)-O(1)H and; P(1)-O(2) or P(1)-O(3)		0.069	0.085	0.083	0.079	0.016	0.056
The maximum difference between P(2)-O(4)H and; P(2)-O(5) or P(2)-O(6)		0.075	0.090	0.073	0.090	0.117	0.083

a) Distances between P and O atoms of phosphate moieties with their standard errors of the last digits in parentheses. b) The pamidronate is P(1)-O(1). The numbering of oxygen atoms was adjusted to that of etidronate.

Fig. 3. Coordination Bonds and Hydrogen Bonds Formed at the Phosphonate Moieties of Bisphosphonates

(a) Alendronate, (b) clodronate, (c) etidronate, (d) ibandronate, (e) pamidronate, and (f) risedronate. H, C, N, O, P, and Cl atoms are shown in white, gray, dull blue, red, orange, and light green, respectively. Na ions are shown as purple spheres. Hydrogen bonds between O atoms are indicated by blue dashed lines and those between O and N atoms are indicated by sky blue dashed lines. Coordination bonds are indicated by purple dashed lines. The numbering of oxygen atoms was adjusted to that of etidronate.

Regarding ibandronate, the P–O distances of the two unprotonated oxygen atoms in the P(2) phosphonate moiety were comparable to those of alendronate and others, indicating that the negative charge of the P(2) phosphonate moiety was delocalized over the two oxygens. On the other hand, the P–O bonds of the two unprotonated oxygen atoms in the P(1) phosphonate moiety showed different bond distances: the P(1)–O(2) distance was shorter by 0.030 Å than the P(1)–O(3) distance. The shorter and longer P–O bonds suggested that they were double and single bonds, respectively, and that the negative charge were localized to O(3). Thus, the O(2) atom with the sp² hybrid orbital in the P(1)–O(2) bond might be stabilized by the two coordination bonds with sodium ions in a planar triangular geometry (Fig. 3d).

In the case of pamidronate, the mono-anionic P(2) phosphonate moiety showed different P–O distances (Table 2). The distance of P(2)–O(5), 1.495 Å, was shorter than that of P(2)–O(6), 1.515 Å, and the O(5) atom formed two coordination bonds with sodium ions in a planar triangular geometry (Fig. 3e). This suggested that the P(2)–O(5) bond retained its double bond nature and the negative charge was localized in O(6), as in the ibandronate P(1) phosphonate moiety. The other di-anionic phosphonate moiety of pamidronate showed three P–O bonds with comparable distances, 1.521–1.542 Å (Table 2). Each oxygen atom of the P(1) phosphonate moiety formed a total of three hydrogen bonds or coordination bonds with tetrahedral geometries (Fig. 3e). These data suggested that the two negative charges at the P(1) phosphonate group are delocalized over three oxygen atoms.

XANES Spectroscopy

The phosphorus K-edge XANES spectra of bisphosphonates showed highest peaks, which is known as the white line, around 2150–2152 eV and a number of small peaks in the XANES region of 2153–2185 eV (Fig. 4a). The shapes of the spectra were unique to each bisphosphonate, considering the high reproducibility of XANES measurements.³⁾ These demonstrated that these crystals were identified based on the XANES spectra.

Fig. 4. Phosphorus K-Edge XANES Spectra of Bisphosphonates

(a) Overall view. (b) Enlarged view around highest peak. (c) Enlarged view around small peaks.

The spectrum of clodronate was significantly different from the others. The absorbance and the energy of the peak tops of the highest peak at 2152 eV and a peak at 2169 eV of clodronate were highest among the bisphosphonates, and the absorbance of a peak at 2155 eV of clodronate was highest (Figs. 4b, c). Only clodronate showed small peaks at 2158 and 2162 eV. The prominent differences of clodronate may be attributable to its unique chemical structure. Only clodronate has two chlorine atoms that are highly electronegative and exhibit a high electron-withdrawing ability. Although the chlorine atoms are not bonded to the phosphorus atoms directly, the electron-withdrawing effect might reduce the electron density of the phosphorus atoms and therefore affect the electronic states of the phosphorus atoms, resulting in the unique spectrum shape of clodronate compared to those of other bisphosphonates without chlorine atoms. When the electron density of the phosphorus atoms decreases, the influence of the atomic nucleus of phosphorus atoms becomes stronger, and the electrons are more tightly bound to the nucleus. As a result, the energy for the excitation of the electron, which is absorbed X-ray energy, becomes larger, and the energy of the peak top might shift to the higher energy side. This would explain the high energy of the peak top of clodronate.

Bisphosphonates other than clodronate have differences in chemical structures away from the phosphonate moieties. Therefore, the differences in their XANES spectra can be attributed to the differences in the interatomic interactions and charged states of phosphonate moieties. Since bisphosphonates other than clodronate had various interactions as shown in Supplementary Table S1, there seems to be some difference in electron density among the bisphosphonates. However, the energy shift of the peak top was not noticeable in the spectra, suggesting that the effect to the energy of XANES spectra might have been small.

The highest peak tops of the bisphosphonates spectra were broader and flattened (Fig. 4b). Especially, the peak top shapes of alendronate, etidronate, and risedronate were clearly bimodal. These bisphosphonates contain two phosphonate moieties forming different interactions in the crystals, and the observed spectra of each bisphosphonate were the average of the spectra of two phosphonate moieties. This might account for the bimodal nature of the highest peaks. On the other hand, the XANES spectrum of clodronate was almost monomodal. Although the interactions of two phosphate moieties were different, the difference of the absorbance and/or the energy between two phosphate moieties might not be very pronounced in the case of clodronate which had highly electronegative chloride atoms, and then the peak may have been observed as monomodal.

The absorbance of the X-rays depends on the probability of the electron excitation by X-rays and transition, and the probability depends on the shapes of the orbitals. Since bisphosphonates had various interactions as shown in Supplementary Table S1, the shapes of the electron orbitals of phosphorus atoms were changed by these interactions and then the absorbances were also changed.

The highest peak of pamidronate was the lowest and most flattened among the bisphosphonates (Fig. 4b). Pamidronate had phosphonate moieties of different electrical charge, −2 and −1, respectively, whereas the rest of the bisphosphonates had only phosphonate moieties of −1 as mentioned in “Single-Crystal X-Ray Structure Analysis” (Table 2). It is known that the electric states of sample can be evaluated based on the XANES spectra.²⁸⁾ The difference of the electric states between the two phosphorus atoms in pamidronate was much larger than those in other bisphosphonates and, therefore, the spectral difference of the two phosphorus atoms would be expected to be larger and the overlap of the spectra of two phosphonate moieties would be reduced. This might lead to the reduced height and flattened shape of the highest peak of pamidronate.

Regarding the bimodal peak shapes of the bisphosphonates other than pamidronate and clodronate, the absorbance of the lower-energy peaks (around 2151.0 eV) was higher than the shoulder peaks around 2151.5 eV. These characteristics were also confirmed from the plot of absorption ratio at 2151.0/2151.5 eV against the energy of the peak maximum intensities (Fig. 5). In the plot, bisphosphonates with two mono-anionic phosphonate moieties were clustered in a different region than pamidronate that possessed one di-anionic and one mono-anionic phosphonate moiety and chlodronate with two chloride atoms which are highly electronegative and exhibit a high electron-withdrawing ability. Possibly, the charge states of bisphosphonates might be estimated from the simple plot. Among the bisphosphonates with two mono-anionic phosphonate moieties, ibandronate showed the least prominent shoulder peak in the spectrum and the highest absorption ratio in the plot. Ibandronate had a characteristic negative charge on one of the phosphonate ions at one oxygen atom as mentioned in “Single-Crystal X-Ray Structure Analysis,” and this might explain the characteristics of ibandronate in the spectrum and also in the plot.

Fig. 5. Plot of Absorption Ratio at 2151.0/2151.5 eV against the Energy of the Peak Maximum Intensity

The above phosphorus K-edge XANES spectra showed several differences among the bisphosphonates. In particular, the bonding to the chlorine atom and the number of electric charges of the phosphonate moieties seemed to have largest effects on peak shape in the XANES spectra. Phosphorus K-edge XANES spectroscopy may be particularly useful for analyzing the number of electric charges on phosphonate moieties. In addition, unique XANES spectra shapes may also be due to a number of factors including the localization of the negative charge in phosphonate moieties, hydrogen bonding between the nitrogen atom of basic moieties and the phosphonate moieties, coordination bonding between sodium ions and phosphonate moieties, and hydrogen bonding between water and phosphonate moieties. These data demonstrated that differences in interactions at the oxygen atoms of the phosphonate moieties could change peak shapes in the XANES spectrum to the extent that each material was distinguished by its spectrum. This demonstrates that the phosphorus K-edge XANES spectroscopy were useful for the evaluation of pharmaceutics containing phosphonate moieties. This also suggests that sulfur K-edge XANES spectroscopy might be also useful in pharmaceutical research because there are many APIs containing sulfonate moieties that share similar chemical properties and structures with phosphonate moieties.

Conclusion

Six bisphosphonate hydrate crystals were used to investigate, for the first time, how phosphorus K-edge XANES spectra are affected by the interatomic interactions and charged states of phosphonate moieties in the crystals. The results demonstrated that bonding to the chlorine atom, the number of electric charges of phosphonate moieties, and the difference in interactions at the oxygen atoms of the phosphate moieties seemed to affect peak shapes in the XANES spectra. Since slight differences of interatomic interactions and charged states led to various differences in the spectra, XANES spectroscopy could be widely applied as a fingerprint method to evaluate APIs.

Acknowledgments

The synchrotron radiation experiments were performed at the BL6N1 beam line of the Aichi Synchrotron Radiation Center, Aichi Science & Technology Foundation, Seto, Aichi, Japan (Approval Number: 2021L3001).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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