Isotope-Edited Infrared Spectroscopy for Efficient Discrimination

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Isotope-edited Infrared Spectroscopy for Efficient Discrimination between Pharmaceutical Salts and Cocrystals Kentaro Iwata, Masatoshi Karashima, and Yukihiro Ikeda Mol. Pharmaceutics, Just Accepted Manuscript • Publication Date (Web): 14 May 2017 Downloaded from http://pubs.acs.org on May 15, 2017

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Molecular Pharmaceutics

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Isotope-edited Infrared Spectroscopy for Efficient Discrimination between Pharmaceutical Salts and Cocrystals Kentaro Iwata*, Masatoshi Karashima and Yukihiro Ikeda Abstract: Isotope-edited infrared spectroscopy using carboxylic acids selectively labeled with C is proposed herein for the efficient discrimination of pharmaceutical salts and cocrystals, whereby proton-transfer probe vibrations are highlighted by isotope shifts. This new technique can accurately discriminate even a confusing salt from a cocrystal for the traditional method, highlighting the diagnostic peaks. In addition, the established technique also provided the OH in-plane bending vibrations corresponding to intermolecular hydrogen bonding at the carbonyl oxygens of the cocrystals. The technique will accelerate the discrimination which is critical process in cocrystal development. 13

*Analytical Development, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited, 2-26-1, Muraoka-Higashi, Fujisawa, Kanagawa, 251-8555, Japan, Tel No. +81-466-32-2855, Fax No. +81-466-29-4432 E-mail address: [email protected]

Keywords: Salt, Cocrystal, Infrared Spectroscopy, Isotope shift and Carboxylic acid

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Isotope-edited Infrared Spectroscopy for Efficient Discrimination between Pharmaceutical Salts and Cocrystals Kentaro Iwata*, Masatoshi Karashima and Yukihiro Ikeda *Analytical Development, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited, 2-26-1, Muraoka-Higashi, Fujisawa, Kanagawa, 251-8555, Japan, Tel No. +81-466-32-2855, Fax No. +81-466-29-4432, E-mail address: [email protected]

Abstract

Isotope-edited infrared spectroscopy using carboxylic acids selectively labeled with 13C is proposed herein for the efficient discrimination of pharmaceutical salts and cocrystals, whereby proton-transfer probe vibrations are highlighted by isotope shifts. This new technique can accurately discriminate even a confusing salt from a cocrystal for the traditional method, highlighting the diagnostic peaks. In addition, the established technique also provided the OH inplane bending vibrations corresponding to intermolecular hydrogen bonding at the carbonyl oxygens of the cocrystals. The technique will accelerate the discrimination which is critical process in cocrystal development.


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Introduction Cocrystal technology has drawn much attention for its application in the development of neutral active pharmaceutical ingredients (APIs) and the improvement of their pharmaceutical profiles1, 2. Pharmaceutical development of cocrystals has recently been highlighted in publications by the U.S. Food and Drug Administration (FDA)3 and the European Medicines Agency (EMA)4. These publications commonly require elucidating whether newly developed API crystals exist as cocrystals, which are homogeneous multicomponent crystals where no proton transfer occurs between the different components, unlike the case of salt crystals. Discrimination of cocrystals and salts is now an essential step to satisfy regulatory requirements, and various techniques have been developed with this aim. While the ∆pKa rule (∆pKa = pKa(base) – pKa(acid)) is commonly used to predict the existence of proton transfer between a given pair of components in a crystal, robust prediction by said rule is limited due to the broad ∆pKa boundaries5, 6 and the experimental difficulties in determining the accurate pKa of poorly soluble APIs. For analytical discrimination, single crystal X-ray and neutron crystal structure analysis are the most definitive and widely applicable techniques7, 8. However, these methodologies are not always suitable due to limitations in the crystal size. Alternatively, infrared (IR) spectroscopy5, 9, solid-state nuclear magnetic resonance (ssNMR)10-13, and X-ray photoelectron spectroscopy (XPS)14, 15 have been investigated as discrimination techniques. Especially, mid-IR spectroscopy is a common analytical method in pharmaceutical development16, and the IR vibrations of various functional groups in coformers and APIs are available for discrimination analysis9, 17-20. Furthermore, IR spectroscopy is an orthogonal method for discrimination compared to ssNMR spectroscopy and XPS, since the spectra from such techniques reflect the electron density of the target atoms, while the IR bands are related to


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the bond strength of the different moieties in the molecules of interest. IR peaks are typically assigned by comparing the spectra of multicomponent crystals to those of single component crystals. However, accurate assignment is difficult because salt and cocrystal formation is often accompanied by frequency shifts and peak overlapping. In this article, we propose isotope-edited IR spectroscopy as a discrimination tool, whereby proton-transfer probe peaks are highlighted using coformers selectively labeled with isotopes in order to discriminate cocrystals and salts more efficiently. The new technique offers significant improvements over the traditional methods: (1) it can be applied to various combinations of APIs and coformers even when their peaks overlap, (2) it is more efficient due to the specific identification of diagnostic peaks for the discrimination, and (3) it is a more reliable assignment approach because only vibrations involving the labeled atoms are highlighted. Carboxylic acids (COOHs) are commonly used in both salt or cocrystal formation21, 22. In this study, the COOH groups in a series of coformers were targeted for isotope substitution, as such interaction sites are easily identified due to their simple structure and the simplicity of their synthesis compared to that of APIs. The element chosen for substitution was carbon, i.e., 12C atoms were substituted by 13

C isotopes, since proton is exchangeable during crystallization and isotopic oxygen is more

expensive with less isotope shift. In general, IR spectra show distinct differences between neutral COOH groups and carboxylate anions (CO2‒)5, 23. COOH groups are characterized by a strong C=O stretching vibration (ν(C=O)) at 1800‒1680 cm‒1 and a symmetric C–O stretching vibration (ν(C–O)) at 1315‒1075 cm‒1. On the other hand, CO2‒ displays a strong symmetric CO2‒ stretching vibration (νsym(CO2‒)) at 1450‒1360 cm‒1 and an asymmetric CO2‒ stretching vibration (νasym(CO2‒)) at 1650‒1540 cm‒1. These vibrations are powerful probes to elucidate the neutral or ionic state of carboxylic moieties.


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The purpose of the present study was to demonstrate the advantages of isotope-edited IR spectroscopy to assign probe peaks for efficient discrimination. In addition, the advantages of IR spectroscopy were also confirmed in comparison with Raman spectroscopy. Benzoic acid (BA) and succinic acid (SA) were used as model systems in eight APIs (Figure 1).

Experimental Section. Materials and Methods. BA and SA selectively substituted with 13C at the carboxylic carbons (1-13C BA and 1,4-13C SA) were purchased from Cambridge Isotope Laboratories. Fluoxetine (FXN) hydrochloride (HCl), Rizatriptan (RTP), and Sumatriptan (STP) were supplied from Sigma-Aldrich, Ark Pharm, and Chem Pacific, respectively. Other APIs, reagents, and solvents were obtained from Wako Pure Chemical Industries. Both non-labeled and labeled crystals were prepared following the same procedure, as described below. Carbamazepine (CBZ)/BA (1/1) cocrystal: CBZ (709 mg, 3 mmol) and BA (370 mg, 3 mmol) were dissolved in 0.6 mL of trifluoroethanol at 75 °C. The cocrystals precipitated during slow cooling to 5 °C and were collected by filtration. Piroxicam (PXM)/1-13C BA cocrystal, form A: PXM (663 mg, 2 mmol) and BA (246 mg, 2 mmol) were dissolved in 2.5 mL of chloroform at 60 °C. The resultant solution was slowly cooled to 5 °C, and the precipitate was collected by filtration. It should be noted that another polymorph of the cocrystal (form B) crystallized when the solution was rapidly cooled24. FXNHCl/BA (1/1) salt–cocrystal (SCC): FXNHCl (347 mg, 1 mmol) and BA (124 mg, 1 mmol) were dissolved in 1.5 mL of acetonitrile at 75 °C. After cooling to ambient temperature,


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the solvent was evaporated until the solution volume was reduced to ca. 0.4 mL. Crystals precipitated during evaporation and were collected by filtration. RTP/BA (1/1) salt: RTP (270 mg, 1 mmol) and BA (124 mg, 1 mmol) were dissolved in 1 mL of methanol at 78 °C and crystallization occurred upon cooling the solution to 5 °C. The precipitated solid was collected by filtration. Sodium benzoate (SBA)/BA (2/1) SCC: BA (370 mg, 3 mmol) was dissolved in 0.6 mL of tetrahydrofuran at 25 °C and spiked with 75 µL of a sodium hydroxide solution (8 M). Crystals precipitated upon stirring and were collected by filtration. ITZ/SA (2/1) cocrystal: ITZ (705 mg, 1 mmol) and SA (60 mg, 0.5 mmol) were dissolved in 10 mL of tetrahydrofuran at 60 °C. The solution was condensed to ca. 1 mL by solvent evaporation, during which cocrystals precipitated and were collected by filtration. FXNHCl/SA (2/1) SCC: FXNHCl (346 mg, 1 mmol) and SA (60 mg, 0.5 mmol) were dissolved in 2 mL of acetonitrile at 78 °C. SCCs precipitated upon cooling to 5 °C and were collected by filtration. Norfloxacin (NFX)/SA (2/1) salt hemihydrate: NFX (319 mg, 1 mmol) and SA (60 mg, 0.5 mmol) were stirred in 5 mL of water at room temperature for 3 d. The remaining solid was collected by filtration and mildly dried at 25 °C in a desiccator with a saturated sodium hydrochloride solution (75% relative humidity)25 to avoid dehydration and subsequent phase transformation. STP/SA (1/1) salt: STP (295 mg, 1 mmol) and SA (120 mg, 1 mmol) were dissolved in 0.5 mL of water and 4.5 mL of 2-propanol was added at 60 °C. The salt crystallized upon cooling to 25 °C and the crystals were collected by filtration.


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Lidocaine (LCN)/SA (1/1) salt: LCN (234 mg, 1 mmol) and SA (120 mg, 1 mmol) were dissolved in 0.5 mL of methanol at ambient temperature. After adding 1.0 mL of tert-butyl methyl ether, the solution was agitated by sonication and a solid precipitated, which was collected by filtration and heated at 90 °C so as to control the crystal formation. All the crystals, except for the NFX/SA (2/1) salt hemihydrate, were dried at 60 °C under reduced pressure. Powder X-ray diffraction (PXRD) was performed to confirm that the crystalline phase was identical in the non-labeled and labeled crystals and in the crystal structures considered (Supporting Information 1 and 2). Same crystal form between the nonlabeled and labeled crystals is essential for the isotope-edited technique because polymorphs generally exhibit different IR and Raman spectra.

Powder X-ray Diffraction (PXRD) PXRD patterns were collected on a Rigaku Ultima IV instrument (Rigaku, Tokyo, Japan) with Cu-Kα radiation (wavelength: 1.5418 Å) generated at 50 mA and 40 kV. The samples were placed on a silicon plate at room temperature. Data were collected from 2° to 35° (2θ) at increments of 0.02° and a scanning speed of 6°/min. Calculated PXRD patterns from crystal structures were generated with Mercury26.

Attenuated Total Reflection (ATR) Fourier Transform Infrared Spectroscopy (FT-IR) ATR FT-IR spectra were acquired on a Shimadzu IR Prestige-21 spectrophotometer (Shimadzu, Kyoto, Japan) equipped with Dura Sample IR II (Smiths Detection, Hertfordshire, UK). The spectra represent 64 co-added scans collected with a spectral resolution of 4 cm‒1. A background spectrum was acquired with a clean diamond crystal. The spectral data set was


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acquired by compressing the samples against the diamond crystal. Differential spectra were obtained by subtracting the normalized spectra of the crystals from those of the 13C-labeled counterparts. The spectrum normalization can reduce baseline noise coming from incomplete reproducibility of peak intensity among the measurements.

Raman Spectroscopy Raman spectra were recorded using a RXN2 1000 system equipped with a light emitting diode laser (1064 nm) as the excitation source and a CCD detector cooled at ‒ 40°C (Kaiser Optical Systems, Inc., Ann Arbor, MI, USA). The laser power at the samples was ~450 mW. A 10-fold objective lens with a probe system was used to collect the spectra. The spectra were acquired from 170 cm‒1 to 3200 cm‒1 with 5 s exposure and two accumulations. Cyclohexane was used to verify accuracy of Raman shift. Differential spectra were also generated by subtracting the normalized spectra of the labeled crystals from those of their non-labeled counterparts.

Isotope Shift Estimation by Mass Effects Assuming that vibrations are undergoing simple harmonic motions without a changing force constant of bonds interested, the frequency upon isotope substitution (ν') can be estimated using the frequency without isotope shift (ν) with the equation27.

= ′

Where µ' and µ are the reduced mass with and without isotope shift, respectively. They are defined using the equation:


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1 1

() = + Here, () = 1 for M1–M2 diatomic vibrations and () = 1 − cos for out-of-phase vibrations in bending M1–M2–M1 systems. Mw1, Mw2 are the atomic weight of M1 and M2, and α is the angle between two M1–M2 bonds in a triatomic system. The ν(C=O) band for COOH and the νasym(CO2‒) band for CO2‒ correspond to the M1–M2 diatomic vibration and out-of-phase vibration of a bending M1–M2–M1 system, respectively.

Result and Discussion. Assignment of COOH Vibrations in the BA Crystal BA (pKa: 4.1921) was chosen as the simplest model for the first study, where only one carbon was substituted by 13C to identify the bands and the corresponding isotope shifts. The IR spectra of BA and its isotopic crystal revealed several peaks at lower frequencies upon 13C substitution (Figure 2). The differential spectrum between the non-labeled and labeled crystals highlights the shifted peaks more clearly than simply comparing the spectra because only shifted peaks remain as up–down spikes nearly cancelling other peaks. Table 1 summarizes the assignments of the COOH vibrations. The substitution-induced peak shift of both the asymmetric ν(C=O) and symmetric ν(C–O) bands and the shifted wavenumber of ν(C=O) are in good agreement with the theoretically estimated shifts (1641 cm‒1) for the labeled crystal. COOH dimers via hydrogen bonding (H-bonding) were identified in the crystal of neutral BA28 (Supporting Information 3) and in-plane bending (δip(O–H)) was also observed at 1420 cm‒1. Since δip(O–H) and ν(C–O) are coupled in COOH29, δip(O–H) also shifted upon substitution, and the isotope shifts of both δip(O–


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H) and ν(C–O) could not be explained only by mass effects. The C–C stretching vibration between COOH and the phenyl ring at 710 cm‒1 also shifted, which is less sensitive to the ionization state of the carboxylic moiety.

Specific Assignment of COOH Peaks in BA Multicomponent Crystals The diagnostic vibrations in the multicomponent crystals were also shifted upon 13C substitution and the isotope shift of the ν(C=O) vibration was almost that theoretically predicted (1648 cm‒1). The CBZ/BA (1/1) cocrystal presented H-bonding between the primary amide of CBZ, a non-ionizable API, and the COOH group of neutral BA30. A pair of C–O distance in crystal structures is used to determine ionic state of COOH5, 31 and neutral BA was supported by asymmetric C–O distance (1.22 Å/1.32 Å) of BA in the crystal structure of the cocrystal30. While the ν(C=O) band of neutral BA at 1686 cm‒1 suggests a cocrystal, this band might be difficult to assign by comparing the IR spectra of the cocrystal to its single components because the amide I band from CBZ is located in close proximity (Supporting Information 4 (a)–(c)). However, the isotope edited technique was able to unambiguously identify the ν(C=O) vibration at 1686 cm‒1 by its peak shift (Figure 3, A). In addition, the ν(C–O) and δip(O–H) bands were also identified by their isotope shift in a region where several other bands are present. PXM (pyridine pKa1: 1.86 and COOH pKa2: 5.4632) form a zwitterion in the PXM/BA (1/1) cocrystal. While its ∆pKa value lay the border between salts and cocrystals, asymmetric C–O distance (1.22 Å/1.33 Å33) of BA in the crystal structure demonstrated its neutral state in the cocrystal. The cocrystal is confused with a salt by 15N ssNMR spectroscopy10 or the XPS15 as the


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pyridinium cation in PXM misleads the analysis by giving the impression that proton transfer is occurring in the cocrystal. While the ν(C=O) band of BA can be assigned by comparing the IR spectra of the cocrystal and PXM (Supporting Information 4 (d) and (e)), the 13C substitution clearly highlights the location of the ν(C=O) and ν(C–O) vibrations, confirming that the crystal contains neutral BA (Figure 3, B). In addition, the technique also suggests that the cocrystal does not exhibit δip(O–H) bending as no isotope shift is observed at ~1400 cm‒1. In the FXNHCl/BA (1/1) SCC34, proton transfer occurs between FXN (pKa: 10.0535) and hydrochloric acid, and BA presents H-bonding with both the secondary amine ion in FXN and the chloride ion (Supporting Information 3 (d)). In fact, neutral BA was supported by asymmetric C–O distance (1.22 Å/1.32 Å or 1.21 Å/1.32 Å) of two asymmetric BAs in the SCC crystal structure34. The peak at 1700 cm‒1 was assigned as the ν(C=O) band of BA in IR spectrum of the SCC, since the peak exhibited a red shift (Figure 3, C). The 13C substitution also highlighted the ν(C-O) band in addition to δip(O–H) and these vibrations demonstrated the neutral state of BA in the crystal. Interestingly, the δip(O–H) band was found to be a good indicator for the detection of Hbonding on the carboxylic oxygens of the cocrystal, and the isotope-edited technique could also be utilized to identify such H-bonds. In fact, the BA crystal, the CBZ/BA (1/1) cocrystal, and the FXNHCl/BA (1/1) SCC commonly exhibited δip(O–H) bands and H-bonding for BA, while the PXM/BA (1/1) cocrystal lacked both δip(O–H) and H-bonding. Such H-bonding information can help locate intermolecular interaction sites in APIs and justify the specific monitoring of nitrogen by 15N ssNMR10, 11 and XPS14, 15 for future discrimination.


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Specific Identification of CO2‒ Peaks in a Salt and in the Presence of COOH Groups The ∆pKa value between RTP (pKa: 15.7036) and BA suggested salt formation5, 6. In fact, BA has almost symmetric C–O distance (1.23 Å /1.25 Å) in the crystal structure of the RTP/BA (1/1) salt37 (Supporting Information 4 (h) and (i)) and the salt did not exhibit vibration bands around 1700 cm‒1. The νasym(CO2‒) band was difficult to assign with precision as three peaks appeared in the ~1600 cm‒1 region. The isotope shift eliminated one of the three peaks and νsym(CO2‒) was finally identified (Figure 4, A). Moreover, the νasym(CO2‒) band was identified at 1586 cm‒1 by analyzing the actual and theoretical isotope shifts. While the isotope shift of νasym(CO2‒) was in good agreement with that obtained theoretically (1542 cm‒1), the other peak, corresponding to the mono-substituted benzene ring vibration, moved from 1607 cm‒1 to 1591 cm‒1 and its isotope shift (16 cm‒1) was much smaller than the theoretical shift of νasym(CO2‒) (~45 cm‒1). Thus, the isotope-edited technique is able to unambiguously identify CO2‒ moieties in a crystal. In the SBA/BA (1/2) SCC (Figure 4, B), the neutral COOH groups of the two BA molecules present H-bonding with the CO2‒ group of BA coordinated to sodium38. Despite the multiple states of BA in the crystal, the ν(C=O) and CO2‒ vibrations were successfully identified using the present technique. The isotope shift of ν(C=O) was smaller than that theoretically expected and its estimated wavenumber was 1516 cm‒1. Most likely, the C–O bonds in CO2‒ are not equivalent as one of the oxygen atoms interacts more strongly with the sodium cation than the other one. In fact, the bond lengths were found to be slightly asymmetric in the crystal structure (1.25 Å and 1.29 Å)38. No δip(O–H) vibration was observed in the spectrum, consistent with the lack of H-


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bonding between the neutral BA molecules. Therefore, the isotope-edited technique is also useful to assign probe peaks even in crystals where both COOH and CO2‒ are present.

Specific Assignment of Crystals Containing SA Dicarboxylic acids have been more frequently used than monocarboxylic acids in both salt21 and cocrystal formation22, and thus, SA (pKa1: 4.21 and pKa2: 5.6421) was selected for further feasibility studies. In the IR spectrum of the SA crystal (Figure 5), both ν(C=O) and ν(C-O) vibrations were highlighted upon isotope substitution and the wavenumber shift of the ν(C=O) band was also consistent with that theoretically predicted (1646 cm‒1). COOH dimers are present in SA crystals39 (Supporting Information 5) and δip(O–H) bending is also present. A band corresponding to the vibrational interaction between the carboxylic acid carbon and the aliphatic carbon in the backbone appeared at ~800 cm‒1, which also exhibited an isotope shift. ITZ (pKa: 3.7040) and SA forms a cocrystal41 and negative ∆pKa between ITZ and SA supported no proton transfer between them5, 6. Therefore, the IR spectrum of the ITZ/SA (2/1) cocrystal should display ν(C=O) bands from SA. However, both SA and ITZ present ν(C=O) bands around 1700 cm‒1, which cannot be unambiguously discriminated when comparing the IR spectra of the cocrystal and its single components (Supporting Information 6 (a)–(c)). Upon isotope substitution, both the ν(C=O) and ν(C–O) bands from SA were identified, supporting the formation of a cocrystal (Figure 6, A). The band shift from 1314 cm‒1 to 1299 cm‒1 is unlikely to correspond to δip(O–H) as the peak is located at a slightly lower wavenumber than the typical δip(O–H) values23. In addition, the cocrystal does not show H-bonding at the carbonyl oxygens of SA41. Even if the peak was that of the δip(O–H) bending, the vibration would arise from Van der


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Waals interactions with neighboring hydrogen atoms rather than from H-bonding, as such a low frequency value suggests a weaker interaction than that in typical H-bonding. The FXNHCl/SA (2/1) SCC34 also displayed proton transfer between the FXN and hydrochloric acid molecules, and both the COOH groups of SA presented H-bonding with the secondary amine ion of FXN and the chloride ion (Supporting Information 5 (c)). While the ∆pKa value between FXN and SA lay in the salt region, neutral state of SA was demonstrated by asymmetric C–O distances (1.22 Å/1.33 Å in both COOH) in the crystal structure34. The FXNHCl spectrum showed no bands at ~1700 cm‒1 and the peak at 1713 cm‒1 in the SCC spectrum was assigned to the ν(C=O) band of SA (Supporting Information 6 (d) and (e)). The isotope shift demonstrated that the peaks were those of ν(C=O) and the highlighted ν(C–O) ((Figure 6, B). The δip(O–H) vibration was also found in the IR spectrum, consistent with its crystal structure where Hbonding exists on the carbonyl oxygen atoms34. NFX (COOH pKa1: 6.2 and piperazine pKa2: 8.742) forms a zwitterion in aqueous solution as both COOHs and piperazine moieties are ionizable. Proton transfer between the piperazine in NFX and SA was estimated by the ∆pKa and both COOH of SA are ionized in the crystal structure because their C-O distance was symmetric (1.26 Å /1.26 Å in both COOH)43. However, the ν(C=O) band for NFX remained unaltered at 1707 cm‒1 after salt formation and the band could be confused with the ν(C=O) vibration of SA (Figure 6, C). The isotope-edited technique revealed that the ν(C=O) band did not correspond to SA and indicated the ionization state of SA by highlighting both the νsym(CO2‒) and νasym(CO2‒) bands. The both bands were clearly highlighted in the differential spectrum while they overlapped with other bands in the IR spectra. Instead of a red shift of the ν(C=O) vibration at ~1700 cm‒1, the isotope substitution shifted the


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strong νsym(CO2‒) band at 1375 cm‒1 and the broad νasym(CO2‒) band at 1516 cm‒1. Therefore, the isotope-edited IR spectroscopy technique is also applicable to dicarboxylic acid systems.

Application to Complex Salts Containing both COOH and CO2‒ The ∆pKa between STP (pKa: 9.6344) and SA suggested proton transfer. The crystal structure of STP/SA salt has an SA molecule where one COOH is neutral (C–O distances:1.30 Å /1.20 Å) and the other one (C–O distances: 1.25 Å /1.25 Å) is ionized (Figure 7, A). While the νasym(CO2‒) band and secondary amine deformation appear at ~1560 cm‒1, the traditional IR approach could mistakenly identify this salt as a cocrystal, since the ν(C=O) vibration of SA remains after salt formation (Supporting Information 6 (h) and (i)). The IR spectrum of the salt after substitution clearly demonstrated that SA was ionized in the crystal, since the νsym(CO2‒) band at 1429 cm‒1 and the νasym(CO2‒) band at 1558 cm‒1 were highlighted upon isotope substitution. In addition, both ν(C=O) and ν(C–O) vibrations were identified and consistent with the actual ionization state of SA in the crystal. LCN (pKa: 7.8645) forms a salt with SA and the salt also contains a monovalent ion of SA (Figure 7, B). Proton transfer was supported by chemical shift perturbation of 15N ssNMR spectra in the salt formation and the monovalent ion was suggested by two chemical shifts of SA carbonyl 13C in ssNMR spectra of the salt46. Compared to the IR spectrum of LCN, the salt spectrum was found to display both a νasym(CO2‒) band from SA and a secondary amine deformation of LCN at ~1560 cm‒1. These vibrations suggest intermolecular proton transfer within the crystal ( Supporting Information 6 (j) and (k)). However, the ν(C=O) vibration from SA also appeared at 1713 cm‒1, hampering the correct discrimination. The isotope shift


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experiments revealed that both COOH and CO2‒ moieties are present in the SA crystal. Both the ν(C=O) band at 1713 cm‒1 and the ν(C–O) band at 1223 cm‒1 suggest a neutral COOH moiety. Moreover, the νsym(CO2‒) vibration at 1406 cm‒1 and the νasym(CO2‒) band at 1564 cm‒1 were also highlighted, indicating the presence of CO2‒ in SA. Therefore, even salts with monovalent dicarboxylic acids are more robustly discriminated using the isotope-edited technique than with the traditional method.

Advantages of IR Spectroscopy over Raman Spectroscopy In principle, the isotope shift method should also be suitable for application in Raman spectroscopy, and as such, isotope-edited Raman spectroscopy was developed to compare the assignment efficiency of both techniques. The isotope-edited Raman spectroscopy also identified the diagnostic vibrations (Table 2). However, several vibrations (in particular, the δip(O–H) bending) were not found due to their low intensity and the interference from residual peaks (Supporting information 7 and 8). Raman spectroscopy detects changes in the molecular electric polarizability, and thus, highly polarized carbonyl groups intrinsically give rise to weak Raman bands47. The low intensity effect in Raman spectroscopy is not limited to COOH moieties, as H-bonding and proton transfer usually occur between polarized functional groups. Therefore, IR spectroscopy is more suitable than Raman spectroscopy due to the strong intensity of its diagnostic peaks.

Conclusion


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In this work, we have demonstrated the advantages of isotope-edited IR spectroscopy for the efficient assignment of diagnostic vibrations to discriminate pharmaceutical salts and cocrystals. The technique is able to efficiently determine the ionization state of COOH groups, highlight the probe peaks with isotope shifts, and accurately discriminate even the confusing salt with a cocrystal for the traditional IR method. The isotope shift also provides δip(O–H) values, indicating intermolecular H-bonding at the carbonyl oxygens of the cocrystals. Such H-bonding information can support the identification of interaction sites in APIs to justify the monitoring of specific nitrogen groups by ssNMR and XPS for further discrimination. This technique is also applicable to Raman spectroscopy; however, IR spectroscopy presents advantages in terms of identification of the diagnostic bands due to the strong intensity of the bands arising from carboxylic moieties. The new technique will accelerate the accurate assignment of probe peaks and salt/cocrystal differentiation, which is a key point in current regulations for cocrystal development.


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Figures

Figure 1. Chemical structures of BA, SA and the model APIs. (A) Benzoic acid (BA), (B) Succinic acid (SA), (C) Carbamazepine (CBZ), (D) Piroxicam (PXM), (E) Fluoxetine hydrochloride (FXNHCl), (F) Rizatriptan (RTP), (G) Itraconazole (ITZ), (H) Norfloxacin (NFX), (I) Sumatriptan (STP) and (J) Lidocaine (LCN). Asterisks shows carbons targeted for the 13C substitution.


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Figure 2. ATR FT-IR (A) and their differential spectra (B) of BA crystals. (a) BA crystal and (b) 1-13C BA crystal.


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Figure 3. H-bonding motifs, ATR FT-IR and differential spectra of CBZ/BA (1/1) cocrystal (A), PXM/BA (1/1) cocrystal (B) and FXNHCl/BA (1/1) SCC (C). (a) H-bonding motifs in the crystal structure. Dash lines indicate H-bonding or ionic bonds. (b) IR spectra of non-labeled (black) and labeled crystals (red). (c) The differential spectra.


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Figure 4. H-bonding motifs, ATR FT-IR and differential spectra of RTP/BA (1/1) salt (A) and SBA/BA (1/2) SCC (B). (a) H-bonding motifs in the crystal structure. Straight dash lines indicate H-bonding or ionic bonds. (b) IR spectra of non-labeled (black) and labeled crystals (red). (c) The differential spectra.


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Figure 5. ATR FT-IR (A) and their differential spectra (B) of SA crystals. (a) SA crystal and (b) 1-13C SA crystal.


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Figure 6. H-bonding motifs, ATR FT-IR and differential spectra of ITZ/SA (2/1) cocrystal (A), FXNHCl/BA(2/1) SCC (B) and NFX/SA(2/1) salt hemihydrate (C). (a) H-bonding motifs in the crystal structure. Straight dash lines indicate H-bonding or ionic bonds. (b) IR spectra of non-labeled (black) and labeled crystals (red). (c) The differential spectra.


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Figure 7. H-bonding motifs, ATR FT-IR and differential spectra of STP/SA salt (A) and LCN/SA salt (B). (a) H-bonding motifs in the crystal structure. Straight dash lines indicate H-bonding or ionic bonds. (b) IR spectra of non-labeled (black) and labeled crystals (red). (c) The differential spectra.


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Tables Table 1. Assignment of the probe IR peaks of BA and SA in various crystals. Wavenumber, cm‒1 Neutral state

Ionized state

ν(C=O)

δip(O–H)

ν(C–O)

νasym(CO2‒)

νsym(CO2‒)

BA

1678 (1639)

1420 (1404)

1288 (1271)

-a

-a

CBZ/BA (1/1) cocrystal

1686 (1655)

1412 (-b,c)

1288 (1275)

-a

-a

PXM/BA (1/1) cocrystal

1711 (1674)

-a

1273 (1251)

-a

-a

FXNHCl/BA (1/1) SCC

1697 (1661)

1389 (1368)

1238c,d(1229)

-a

-a

RTP/BA (1/1) salt

a

a

-

a

-

1586 (1543)

1373 (1346)

-a

1248 (1234)

1560 (1534)

1375 (1348)

SA

1699 (1661) 1678 (1647) 1684 (1643)

1411 (1391)

1198 (1186)

-a

-a

ITZ/SA (2/1) cocrystal

1707 (1668)

-a

1173 (1155)

-a

-a

a

SBA/BA (1/2) SCC

FXNHCl/SA (2/1) SCC NFX/SA (2/1) salt hemihydrate STP/SA (1/1) salt LCN/SA (1/1) salt

1713 (1672)

1395 (1375)

1163 (1152)

-

-a

-a

-a

-a

1516c,d (1474c,d)

1375d (1348d)

1705 (1654)

-a

1206 (1194)

1558 (1532)

1435 (1404)

1713 (1670)

a

1223 (1213)

1564 (1523)

1406 (1379)

-

13

Values in parentheses are obtained from the crystal composed of either 1- C BA or 1,4-13C SA. a: Not observed, b: Not determined, c: Completely overlapped and d: Determined by the differential spectrum.


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Table 2. Assignments of the probe Raman peaks of BA and SA in various crystals. Wavenumber, cm‒1 Neutral state

Ionized state

ν(C=O)

δip(O–H)

ν(C–O)

νasym(CO2‒)

νsym(CO2‒)

BA

1634 (1608c,d)

1443 (1431)

1290 (1274)

-a

-a

CBZ/BA (1/1) cocrystal

1701 (1674)

-b,c (-b,c)

1282 (1272c,d)

-a

-a

PXM/BA (1/1) cocrystal

1711 (1674)

a

-

1273 (1251)

a

-

-a

FXNHCl/BA (1/1) SCC

1700 (1661)

1387 (1363)

1238 (1227)

-a

-a

RTP/BA (1/1) salt

-a

-a

1574 (1557c,d)

1388 (1351c,d)

-a

1253 (1242)

1570 (1541)

1374 (1351)

SA

-a 1700 (1661) 1678 (1647) 1655 (1619)

1448 (1428)

1230 (1213)

a

-

-a

ITZ/SA (2/1) cocrystal

1717 (1678)

-a

1220c,d (1200c,d)

-a

-a

FXNHCl/SA (2/1) SCC NFX/SA (2/1) salt hemihydrate STP/SA (1/1) salt

1724 (1682)

1395 (-b,c)

1166 (-b,c)

-a

-a

-a

-a

-a

-b,c(-b,c)

1413c,d (1386c,d)

1701 (1654)

-a

-b,c(-b,c)

-b,c(-b,c)

1431 (-b,c)

LCN/SA (1/1) salt

1721 (1686)

-a

-b,c(-b,c)

1572 (1558c,d)

1411 (1389c,d)

SBA/BA (1/2) SCC

Values in parentheses are obtained from the crystal composed of either 1-13C BA or 1,4-13C SA. a: Vibration was not observed. b: Not determined c: Completely overlapped and d: Determined by the differential spectrum.


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Corresponding Author. Kentaro Iwata* *Analytical Development, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited, 2-26-1, Muraoka-Higashi, Fujisawa, Kanagawa, 251-8555, Japan, Tel No. +81-466-32-2855, Fax No. +81-466-29-4432 E-mail address: [email protected] Acknowledgement The authors appreciate member of Analytical Development in Takeda Pharmaceutical Company Limited for useful discussions. Supporting Information Available. PXRD patterns of both non-labeled and labeled crystals, pattern matching between the experimental and calculated PXRD patterns of the model crystals, H-bonding pattern in the crystal structures, IR spectra of the model crystals, API and CCF crystals and Raman and its differential spectra are provided in the Supporting Information. These information are available free of charge via the Internet at http://pubs.acs.org/.


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(47) Vankeirsbilck, T.; Vercauteren, A.; Baeyens, W.; Van der Weken, G.; Verpoort, F.; Vergote, G.; Remon, J. P., Applications of Raman spectroscopy in pharmaceutical analysis. TrAC Trends in Analytical Chemistry 2002, 21, (12), 869-877.


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For Table of Contents Use Only. Isotope-edited Infrared Spectroscopy for Efficient Discrimination between Pharmaceutical Salts and Cocrystals Kentaro Iwata, Masatoshi Karashima and Yukihiro Ikeda

Isotope-edited infrared spectroscopy using selectively 13C-labeled carboxylic acids is proposed for efficient salt/cocrystal discrimination, whereby proton-transfer probe vibrations are highlighted. This technique can accurately discriminate even a confusing salt with a cocrystal for the traditional method highlighting the diagnostic peaks. This new technique will accelerate the discrimination which is critical process in cocrystal development.


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Isotope-Edited Infrared Spectroscopy for Efficient Discrimination

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