Polymorphism in Paracetamol: Evidence of Additional Forms IV and V

Article pubs.acs.org/JPCA

Polymorphism in Paracetamol: Evidence of Additional Forms IV and V at High Pressure Spencer J. Smith,† Matthew M. Bishop,‡ Jeffrey M. Montgomery,† Tracy P. Hamilton,‡ and Yogesh K. Vohra*,† †

Department of Physics and ‡Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States ABSTRACT: The structural phase stability of N-(4-hydroxyphenyl) acetamide (paracetamol) has been studied at ambient temperature up to 23 GPa using Raman spectroscopy. Spectral changes have provided further evidence for a highly kinetically driven Form I → II transition that occurs as a mixed phase from 4.8 to 6.5 GPa, and might complete as early as 7 GPa. Upon further compression to 8.1 GPa, a drastic shift in spectral signature was observed providing the first evidence for a previously undiscovered Form IV of paracetamol. Additional shifts in mode intensities were observed near 11 GPa indicating a potential restructuring of the hydrogen bonding network and/or structural modification to a potentially new Form V. Phase boundaries at 7 and 8 GPa were confirmed under hydrostatic conditions using Raman spectroscopy. Spectral changes indicate that the transition Form IV → V occurs near 11 GPa. Multiple ab initio harmonic frequency calculations at different levels of theory were performed with a B3LYP/6-31G** being used to provide a more robust mode assignment to our experimentally obtained Raman modes. High pressure X-ray diffraction (XRD) was performed up to 21 GPa, which provided further evidence for a highly kinetically driven Form I → II transition in agreement with our Raman measurements. In addition, the XRD provided further evidence for the existence of Form IV near 8 GPa and Form V near 11 GPa with Form V persisting up to 21 GPa.

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liquids under pressure.26,27 This poses exciting opportunities in the area of high pressure science to discover new polymorphs by accessing higher pressure and temperature regimes that are allowed by modern day diamond-anvil cell (DAC) technology, as well as the ability to detect subtle structural transformations and/or modifications by using second and third generation synchrotron sources. However, the field is still in its infancy compared to other disciplines, and a real understanding of crystallization and/or phase transformation of complex molecular crystals at high pressure is lacking.28 While it is known that three forms of paracetamol exist, there is still debate over the space group assignment for each polymorph. For completeness, we present the crystallographic landscape to date: Form I (monoclinic; P21/n,1−7 P21/a8−12), Form II (orthorhombic; Pcab,13−15 Pbca,7,16,17 P21/c18), and an unstable Form III (orthorhombic; Pca2119). Form I of paracetamol is thermodynamically stable and is used commercially, but it lacks slip planes and therefore is not suitable for direct compression into tablets.29 Form II is characterized by well-developed slip planes in its crystal structure and undergoes plastic deformation making it suitable for tabletting by direct compression.7,29,30 In both forms, the molecules are linked via the −OH···OC− hydrogen bonds, and these chains are additionally connected with each other via

INTRODUCTION Paracetamol (acetaminophen, panadol, o r N-(4hydroxyphenyl)acetamide) is one of the oldest and most commonly used analgesics and antipyretics that are available over the counter in tablet, capsule, and liquid form. Currently three crystal modifications of the same molecule (polymorphs) have been described in the literature.1−19 The ramifications of having multiple polymorphs of an active pharmaceutical ingredient is that they exhibit variations in solubility, stability, optical properties, and melting temperatures that can cause far reaching ramifications on their production and applications.20 It is common to observe solid-state changes due to extreme conditions used in manufacturing operations, such as extensive mechanical and thermal stress and exposure to solvents; as a result, drug product performance may be significantly altered and/or fail to meet the quality specifications.21 In an extreme case, an undesired polymorph can even be toxic.21,22 Intellectual property can also become an issue for the pharmaceutical companies who develop and market new drug products where challenges to patents have been made on the basis of the discovery of a new polymorph.23 It has been suggested that approximately one-third of organic compounds and about 80% of marketed pharmaceuticals exhibit polymorphism under experimentally accessible conditions.24,25 The application of high pressure has been shown to be particularly effective at modifying intermolecular interactions and frequently leads to new polymorphs of simple organic compounds, particularly when crystal growth occurs from © 2014 American Chemical Society

Received: December 2, 2013 Revised: June 27, 2014 Published: July 13, 2014 6068

dx.doi.org/10.1021/jp411810y | J. Phys. Chem. A 2014, 118, 6068−6077

The Journal of Physical Chemistry A

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the −NH···OH− hydrogen bonds, to give layer-pleated in Form I, and flat in Form II; while the OH group acts simultaneously as a proton donor and as a proton acceptor.31 This has direct consequences to the stability of the two forms: while Form I is thermodynamically stable under ambient conditions, Form II is metastable under ambient conditions and has higher density and thus should be more stable at high pressure according to the Le Chatelier principle.32 Previous high pressure studies on paracetamol indicated that no phase transitions could be induced in the single crystals of Form I at pressures at least up to 4 GPa.2,33 In contrast, when a powder sample is pressure cycled slightly beyond 4 GPa, a partial transformation of Form I into Form II was observed, but was cited as being kinetically hindered, irreversible, and poorly reproducible.33 It was later shown to be the thermodynamically preferable phase at high pressure.34 We present further evidence of the Form I → II transition: our in house Raman spectroscopy measurements at high pressure indicate that the I → II transitions begins as early as 4.8 GPa and persist until ∼6.5 GPa and appear to be heavily kinetically driven. We also observed evidence of additional previously undiscovered polymorphs at ∼8 GPa (Form IV) and another near 10−11 GPa (Form V). Our angular dispersive X-ray diffraction (XRD) up to 21 GPa presented additional evidence to our observed transitions with Form V persisting to 21 GPa.

hybrid method36 with the Perdew−Wang generalized gradient approximation functional (B3PW91),40 and Møller−Plesset second-order perturbation (MP2).41 Due to memory constraints, the MP2-level frequency calculation could not be completed. The values of the harmonic vibrational frequencies, determined at different levels of theory, have been uniformly scaled by factors of 0.9024 at HF/6-31G**, 0.9611 at B3LYP/ 6-31G**, and 0.9575 at B3PW91/6-31G**, to correct for systematic error in the calculations.42 The vibrational frequencies at the B3LYP/cc-pVTZ level were scaled by 0.9876 for the low frequencies (below 1000 cm−1) and 0.9691 for the high frequencies (above 1000 cm−1).43 The results were consistent with prior literature results (discussed vide inf ra) with B3LYP/6-31G** matching closest to our experimental values. The B3lYP/6-31G** calculated frequencies and corresponding intensities were used to generate the Raman spectra, and animations of vibrational modes were used to verify normal mode assignments using GaussView03.44

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EXPERIMENTAL METHODS Non-Hydrostatic. The monoclinic Form I of paracetamol (4-acetamidophenol, 98% purity) was purchased from SigmaAldrich. For both Raman and XRD measurements, a polycrystalline sample was loaded into a ∼130 μm hole in a spring steel gasket that was first preindented to ∼80 μm thickness and mounted in a gas-membrane DAC with 600 μm culets. In this study, no pressure medium was employed and structural modifications reported should be considered of the non-hydrostatic case. The high pressure Raman measurements were performed with ruby as a pressure marker, a 300 mW 532 nm laser modulated with a series of neutral density filters with optical-density 1−6, and a liquid nitrogen cooled Princeton Instruments PI ACTION charge-coupled device (CCD) detector. The high pressure XRD measurements were carried out at the beamline 16-ID-B, HPCAT, Advanced Photon Source, Argonne National Laboratory. An angular dispersive technique with a MAR3450 image-plate area detector was employed using a focused monochromatic beam with X-ray wavelength, λ = 0.4246 Å. Experimental geometric constraints and the sample to image plate detector distance were calibrated using a CeO2 diffraction pattern and were held at the standard through the entirety of the experiment.45 An internal copper pressure marker was placed next to the sample and was employed for the calibration of pressure in the XRD experiment.46 Hydrostatic. Raman measurements were performed at the HPCAT online Raman system with ruby pressure marker, argon pressure medium, and a 488 nm laser modulated between 0.1 and 0.3 W. A polycrystalline sample was loaded in a ∼130 μm hole in a spring steel gasket preindented ∼90 μm thickness. Argon was loaded using the COMPRES-GSECARS gas loading system, GSECARS, Advanced Photon Source, Argonne National Laboratory. Resulting analysis of the Raman spectra and XRD patterns was performed by fitting Gaussians using Peakfit Pro in OriginPro (version 9.0.0).

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CALCULATION METHODS At the start of our research, standard ab initio molecular orbital calculations were carried out using the Gaussian 03 suite of programs.35 The geometries of paracetamol (Figure 1) were all

Figure 1. Paracetamol molecule with atom labels: red (oxygen: atoms #1, 2), blue (nitrogen: atom #3), gray (carbon: atoms #4−11), and white (hydrogen: atoms #12−20).

optimized at various independent levels of theory, using the default convergence criteria given by Gaussian 03.35 The most stable geometry at all levels of theory was a Cs molecule with only two H atoms in the methyl group not contained in the σ mirror plane. Harmonic frequency calculations were then performed by using second-order derivatives on the optimized geometries at the specified levels of theory. A split-valence plus d-type and ptype polarization functions (6-31G**)36 basis set was used in most calculations. An additional calculation with Becke’s three parameter hybrid method37 in combination with the Lee, Yang, and Parr correlation functional (B3LYP)38 using a correlation consistent polarized valence triple-ζ (cc-pVTZ)39 basis set was conducted. The wave functions or hybrid density functionals were Hartree−Fock (HF), B3LYP,38 a Becke’s three parameter

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THEORETICAL RESULTS AND DISCUSSION

There have been a number of ab initio calculations done on paracetamol over the years.47−49 Perhaps the earliest was conducted by Binev et al.47 in the late 1990s. Their calculation at the HF/6-31G level provided the first full mode assignment 6069



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for paracetamol. However, our calculations indicate that the HF level does not provide the most accurate results, and indeed, HF was abandoned for a more accurate B3LYP/6-31G* calculation by Burgina et al.48 in 2004. Our results are in good agreement with Burgina et al.,48 but indicate that the use of a split valence plus d-type and p-type polarization functions basis set provides slightly better results in comparison with ambient pressure−temperature Raman measurements. Additional calculations were performed by Danten et al.49 at the B3PW91/(631G*, 6-31+G*, 6-311++G**) levels but provided limited information on the paracetamol monomer vibrational modes. Our calculations also indicate that the B3PW91 frequencies tend to be higher and less in agreement with experimental data than B3LYP calculations. We performed five geometry optimizations and energy minimizations at various levels of theory indicated in Table 1. Table 1. Calculated Energies (Hartrees), Unscaled ZeroPoint Vibrational Energies ZPE (kcal/mol), and Total Dipole Moment for Paracetamol at the Indicated Calculation Level calculation level

energy

ZPE

dipole

HF/6-31G** B3PW91/6-31G** B3LYP/6-31G** B3LYP/cc-pVTZ MP2/6-31G**

−512.395 328 566 −515.304 149 567 −515.499 464 023 −515.679 487 868 −513.976 304 423

107.11 100.41 100.07 99.69

5.07 4.69 4.66 4.69 5.30

Figure 2. Experimental (E) ambient pressure−temperature Raman spectrum of paracetamol (top curve, black). Unscaled theoretical (T) B3LYP/6-31G** gas-phase calculation Raman spectrum of paracetamol (bottom curve, blue).

al.33 indicated that, through pressure cycling slightly beyond 4 GPa, a Form I → II partial transformation was observed, but was highly kinetically hindered and irreversible. The differences in the layer structures between the two polymorphs could explain the sluggish kinetics behind the transition; a drastic rearrangement in the hydrogen bonding network is required to fully transform into Form II. We suspect, then, that the transition will persist over an extended range of pressure due to the large rearrangement in the layering structure, and should have pronounced effects on modes involved in hydrogen bonding, in particular, the CH3 group. With further application of pressure to 5.9 GPa, we observe that two new modes appear at ∼870 and 1190 cm−1, while all other modes uniformly harden. At 6.5 GPa, we observe softening in ν(CO) which can be attributed to a strengthening of hydrogen bonding. As expected, this appears to have drastic effects on the CH3 group, with the ρ(CH3) at ∼1450 cm−1 softening by 6 cm−1, and a slight hardening in the CH3 umbrella mode at ∼1375 cm−1: this could be attributed to (i) the increase in intramolecular hydrogen bonding brought on by the lengthening of the CO bond, (ii) an increase in steric constraints between the CO and CH3 group, or (iii) a combination of both. In addition, the νsym(C7−N3 + N3−C10) at 1241 cm−1 softens by 6 cm−1, which could be the product of a variety of reasons: (i) an increase in intramolecular hydrogen bonding brought on by the CO group, (ii) increase/decrease in protonation of the NH group, (iii) alteration to the angle between the planes of the phenyl ring and the acetamide group, or (iv) a combination of all three effects brought about by a rearrangement of the layering structure. Given that the majority of the phenyl modes soften, we suspect that these observations can best be attributed to a reorganization of the molecular layering, as would be expected in a Form I → II transition. While we observed strong evidence of a molecular layering reorganization, we suspect that the transition is kinetically hindered up to ∼6.5 GPa, and that we are observing a mixture of Forms I and II from 4.8−6.5 GPa. It is important to note that the majority of the spectra remain the same,52 as would be

For all calculations, the geometry was optimized to Cs symmetry and harmonic vibrational frequency calculations were then performed by using analytical second-order derivatives. A comparison of the scaled calculated frequencies was performed with respect to our ambient pressure− temperature collected spectrum of paracetamol, which revealed that the B3LYP/6-31G** agreed best with our experimental data. For a visual comparison, we generated an unscaled theoretical Raman spectrum using GaussView0344 and overlaid the calculated spectrum with our experimentally obtained spectrum (Figure 2). Mode assignments were conducted through viewing the calculated normal mode animations in GaussView0344 and are tabulated for the B3LYP/6-31G** calculation in Table 2.

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EXPERIMENTAL RESULTS AND DISCUSSION Non-Hydrostatic. The ambient temperature Raman spectra are shown, at indicated pressures, in Figure 3. The spectral range was separated into two parts (Figure 3a,b) because of the intense diamond mode at ∼1332 cm−1 brought about by the DAC. With compression of paracetamol to ∼11 GPa, we observed two regions where new modes developed (Figure 4). The change of the molecular orientation (and therefore, interactions between molecules) is likely to be reflected in the spectra, which may manifest in unusual frequency shifts, loss of intensity, or broadening (narrowing) of lines in the spectra.50 The presence of new vibrations and/or discontinuities in dν/dP slopes are strong indicators of a shift in the structural phase composition to a new form of paracetamol.51 With initial compression of Form I to 4.8 GPa, we observe that all modes (Figure 4) uniformly shift to higher frequency (harden) and we observe the presence of a new mode at ∼807 cm −1 which might suggest the onset of a structural modification. Previous high pressure studies by Boldyvera et 6070



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Table 2. Scaled Harmonic Vibrational Frequencies (cm−1) Calculated at the B3LYP/6-31G** Level for Paracetamol scaled freq (cm−1) 33.8 46.8 74.4 151.0 179.2 303.6 312.1 314.5 366.7 405.9 413.2 485.4 501.9 511.2 598.6 605.2 632.9 684.9 770.9 773.2 823.7 835.9 871.3 930.6 944.8 977.2 990.4 1013.5 1093.6 1151.5 1155.1 1198.8 1224.3 1259.0 1291.9 1324.7 1356.9 1410.8 1424.8 1445.4 1494.8 1513.2 1586.8 1615.3 1714.1 2939.1 3015.8 3018.0 3039.1 3055.5 3086.2 3140.1 3496.8 3676.4

exptl freq (cm−1)

174.8 219.3 332.7 340.6 395.2 414.2 468.3 505.9 605.5 628.8 653.1 711.4 798.3 824.8 834.3 858.7 948.7 968.8 1007.0 1017.0 1037.2 1104.4 1123.0 1169.1 1224.1 1236.3 1256.5 1275.9 1323.0 1368.1 1424.8 1442.76 1501.56 1510.56 1556.64 1604.31 1610.67 1642.98 2934.2 3011.62 3055.32 3067.8 3076.96 3106.09 3164.77 3327.51

IR Inten.

Raman act.

sym

mode assignmenta

2.28 2.57 1.47 3.73 0.109 4.62 116.0 3.50 1.13 1.29 7.94 23.4 76.0 0.239 4.49 0.805 2.24 0.189 24.4 1.99 33.0 3.07 0.866 5.64 1.03 19.8 2.47 9.36 12.4 180.0 23.7 26.0 114 63.6 28.9 83.3 26.5 175.1 5.25 12.3 61.1 397.3 44.3 3.0 227.0 10.4 18.2 5.46 21.2 17.1 5.47 5.75 15.9 51.3

0.068 1.55 0.347 0.419 0.167 4.19 3.54 0.643 2.22 0.108 0.637 3.90 2.36 1.13 0.506 3.60 6.18 1.42 4.91 21.1 2.25 24.6 2.51 1.85 1.06 6.60 0.42 0.191 1.50 5.91 20.0 8.10 66.7 21.7 31.0 10.1 36.2 17.8 16.0 12.8 4.12 68.7 15.3 176.8 43.5 188.6 82.6 103.1 60.4 135.4 111.8 46.8 72.3 158.6

A″ A″ A″ A′ A″ A′ A″ A′ A″ A″ A′ A′ A″ A″ A″ A′ A′ A″ A″ A′ A″ A′ A″ A′ A″ A′ A′ A″ A′ A′ A′ A′ A′ A′ A′ A′ A′ A′ A″ A′ A′ A′ A′ A′ A′ A′ A″ A′ A′ A′ A′ A′ A′ A′

τ(CH3) τ(N3−C7) τ(N3−C10) δb(C7−N3−C10) ωsym(C4−O1 + C7−N3) ρsym(C4−O1 + C7−N3) τ(OH) ρas(C10 + CH3) ωas(C4−O1 + C7−N3) δOP‑def(Ph) ρas(C4−O1 + C7−N3) δIP‑def(Ph) ω(NH) ωsym(Ph) (C10) umbrella δIP‑def(Ph) δIP‑def(Ph) (Ph) pucker ωsym(C8−H16 + C9−H17) δIP‑def(Ph) ωsym(C5−H14 + C6−H15) ring breathe ωas(C8−H16 + C9−H17) γ(O2−C10−N3) ωas(C5−H14 + C6−H15) ρ(CH3) δIP(CH) [Ph] ρ(CH3) ρIP(CH) [Ph] ρ(OH) ρIP(CH) [Ph] νsym(C7−N3 + N3−C10) ω(NH + CH) [Ph] ν(C4−O1) ρIP(CH) [Ph] δIP‑def(Ph) CH3 umbrella δIP‑def(Ph) ρ(CH3) γ(CH3) δIP‑def(Ph) δIP‑def(Ph) δIP‑def(Ph) δIP‑def(Ph) ν(CO) νsym(CH3) νas(CH3) νas(C11−H19 + C11−H18) νas(C8−H16 + C9−H17) νsym(C8−H16 + C9−H17) ν(C5−H14) ν(C6−H15) ν(N1−H12) ν(O3−H13)

peak no. in Figure 2

1 2 3 4 5 6

7 8 9 10 11 12 13 14 15 16 17 18 19 20

Abbreviations for assignments: τ = torsion/twisting, δ = deformation (def)/bending (b), ω = wagging, ρ = rocking, γ = scissor, ν = stretching, sym = symmetric, as = asymmetric, IP = in-plane, OP = out-of-plane, Ph = phenyl, [Ph] = mode occurs on phenyl ring.

a

expected in a Form I → II transition, and we believe that we are driving the sample into an orthorhombic Form II due to the presence of new modes. However, the new modes might be a

product of preferred orientation in the DAC giving rise to axial dependent modes. Upon further compression to 7.0 GPa, we observe that nearly all modes remain approximately the same 6071



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Figure 3. Stacks of Raman spectra of paracetamol. Each spectrum is at a different pressure (GPa) indicated on the left side of figure. The spectral range was split into regions from 770 to 1313 cm−1 (a) and 1350−1700 cm−1 (b) with each phase indicated by the following schema: Form I (black), Forms I + II (blue), and Form IV (red).

Figure 4. Pressure dependence of select modes as a function of pressure.

Figure 5. (a) Selected angular dispersive X-ray diffraction patterns taken at the indicated pressure (GPa) on the right side of the figure. Each phase is indicated by the following schema: Form I (black), Forms I + II (blue), Form IV (red), and Form V (purple). (b) d-spacing of select reflections as a function of pressure.

1150−1300 and 1500−1700 cm−1 regions. The changes include dramatic shifts in relative intensities and the presence of new modes at 802, 1381, and 1562 cm−1. In addition, we observe a slight softening in the ν(CO) indicative of further

frequency, which could indicate a complete transition into a Form II polymorph of paracetamol. Increasing pressure to 8.1 GPa, we observe drastically different spectral signatures from Form II: particularly in the 6072



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provides further evidence for a previously undiscovered Form IV polymorph of paracetamol. Form IV appears to persist to 10.5 GPa, where we observe the loss a prominent low angle reflection at 5.9 Å. This might suggest the onset of an additional Form V polymorph of paracetamol. Our Raman data indicated a slight restructuring of the hydrogen bonding network about a pressure region from 9.9 to 11.8 GPa, but was too insensitive to provide solid evidence for the potential existence of Form V. With application of pressure to 11.3 GPa, we observe new reflections at 5.1, 4.8, 4.3, and 3.6 Å that could indicate a transition into Form V of paracetamol. The presence of these new reflections appears to coincide well with observed intensity changes about the same pressure region in our Raman measurements. Upon further compression, we observe our XRD pattern quality drastically diminish and a further increase in preferred orientation, but it appears that Form V has a distinct crystalline phase that persists to our highest investigated pressure of 21.1 GPa (Figure 5a). Structural fits of Form I up to 4.0 GPa using X-ray diffraction analysis54 indicate compressibility consistent with the literature,1,2,33 but with a variability expected from non-hydrostatic conditions (Figure 6). A Birch−Murnaghan equation of state

strengthening of the hydrogen bonding network. However, the CH3 group response is quite different: the ρ(CH3) hardens by 7 cm−1, suggesting a different steric environment between the CH3 and CO groups. We also observe that nearly all modes harden with the exception of two phenyl modes at 1550 and 1600 cm−1. Given the different spectral signature and molecular response, we believe that this is a previously undiscovered (Form IV) polymorph of paracetamol. Increasing pressure to 8.5 GPa, we observe the loss of γ(O2−C10−N3) at ∼975 cm−1 and a uniform hardening in all other modes up to 9.0 GPa. With further application of pressure to 9.9 GPa, we observe softening in ν(CO) at 1647 cm−1 and in phenyl modes at 1585 and 1604 cm−1, while all other modes remain at approximately the same frequency. This might suggest the onset of an additional structural modification, and/or could be slight restructuring in the hydrogen bonding network. With application of pressure to 11.8 GPa, the highest investigated pressure achieved in our Raman measurements, we observe uniform hardening in all modes and an increase in intensity with modes in the 1150−1300 and 1500−1700 cm−1 regions. This might suggest the presence of an additional kinetically driven phase transition to another previously undiscovered (Form V) polymorph of paracetamol, but a more robust probe is required to verify the potential presence. Upon decompression, we observed evidence of the high pressure Form IV, but the spectral quality had drastically diminished, making it difficult to fully resolve. In light of the evidence provided from our high pressure Raman measurements, we performed XRD on a powder crystalline sample of paracetamol up to 21 GPa (Figure 5a). Initial compression to 4.1 GPa revealed a uniform shift in all reflections to lower d-spacing (Figure 5b). At 5.1 GPa, we observed the loss of three reflections at ∼6.7, 5.8, and 3.5 Å. The loss of these reflections coincides with observed changes in our Raman spectra near 5.0 GPa and provides further evidence for a possible onset of a Form I → II transition. With further application of pressure to 6.0 GPa, we observe new reflections at ∼6.2, 5.9, 5.5, 5.3, 4.14, 2.95, 2.8, and 2.7 Å, paired with the loss of reflections at ∼5.4, 4.8, 2.8, 2.7, 2.6, and 2.4 Å. This appears to be the most dynamic pressure region both in Raman and in XRD, suggesting that, at 6.0 GPa, we are observing a greater shift to Form II. These observations also indicate that the restructuring of the hydrogen bonding network, observed in our Raman spectra, has indeed had an effect on the molecular layering of paracetamol: manifested in gain and loss of reflections not previously allowed in the commenced structure. Both techniques appear to confirm a highly kinetically driven phase transition that persists over a larger pressure range. It is important to note that the quality of the XRD patterns continues to diminish with further application of pressure, and the XRD patterns indicate strong preferred orientation within the DAC that makes resolving the structure quite difficult. At this point, we are presenting only the observed changes in the XRD patterns; a more detailed structural analysis of the high pressure phases is ongoing. At 7.0 GPa we observe the presence of a new reflection at 6.8 Å, and the loss of a reflection at 5.9 Å. It appears in both the Raman and XRD that the Form I → II transition might complete as early as 7.0 GPa, but further testing is needed to confirm. With further application of pressure to 8.5 GPa, we observe new reflections at 8.2, 6.6, and 4.5 Å. The presence of these new reflections seems to cooperate with the drastic shift in Raman spectral signature change observed at 8.1 GPa, and

Figure 6. Measured equation of state for paracetamol Form I up 4 GPa. The experimental data points are indicated by symbols, and the fit to the Birch−Murnaghan equation of state is indicated by a solid line. The fit parameters are described in the text.

fit55 yields ambient pressure bulk modulus (B0) of 17.86 GPa with a fixed value of pressure derivative (B0′) of 4.0. An unconstrained fit yields a bulk modulus (B0) of 19.53 GPa with a pressure derivative (B0′) of 2.2 and is shown in Figure 6. The Form II is fitted to an orthorhombic unit cell; however, the quality of the powder diffraction data for the higher pressure phases is insufficient to warrant a full structural refinement. The measured lattice parameters of Form II are a = 12.90 Å, b = 11.18 Å, c = 7.18 Å. Hydrostatic. Upon finding evidence for the existence of previously unexplored high pressure polymorphs, Raman measurements were conducted on a polycrystalline sample loaded with an argon pressure medium at GSECARSCOMPRES, Advanced Photon Source, Argonne National Laboratory. These measurements verify the non-hydrostatic 6073



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Figure 7. Stacks of Raman spectra of paracetamol under hydrostatic pressure conditions. Each spectrum is at a different pressure (GPa). Spectral range is split into regions from 770 to 1313 cm−1 (a) and 1350 to 1700 cm−1 (b) with each phase indicated by the following schema: Form I (black), Forms I + II (blue), Form IV (red), and Form V (purple).

Figure 8. Select hydrostatic Raman modes as a function of pressure.

could be attributed to (i) the increase in intramolecular hydrogen bonding brought on by the lengthening of the CO bond, (ii) an increase in steric constraints between the CO and CH3 group, or (iii) a combination of both. Compression to 7 GPa shows a slight softening of the phenyl modes attributable to a Form I → II transition. Increasing pressure to 8.1 GPa, we observe four new peaks at ∼860, 1250, 1565, and 1614 cm−1, indicating the possible presence of a new Form IV polymorph. Continuing compression up to 10.4 GPa we see uniform hardening in all of these peaks except 1250 cm−1, which seems stationary. We also observe softening of the CH3 umbrella at ∼1395 cm−1 and the ring breathe at ∼850 cm−1, which may correspond to continued strengthening of the hydrogen bonding network. The ρ(CH3) mode hardens, indicating a change in the steric environment between CH3 and CO groups. Raising pressure to 11 GPa we see the appearance of three new modes ∼1185, 1374, and 1486 cm−1 and the loss of mode 830 cm−1, accompanied by softening of all modes. We suspect that this corresponds to the new Form V in mixed phase with Form IV seen also in the XRD data. Further compressing to ∼15.5 GPa we see uniform hardening in all but two modes ∼1620 and 1275 cm−1 which soften. At 14.2 GPa a new mode at ∼1200 cm−1 appears and continues to soften up to 15.5 GPa.

results showing similar spectroscopic behavior at characteristic mode regions. The ambient temperature spectra are shown in Figure 7, separated in two parts (Figure 7a,b) for direct comparison to the non-hydrostatic spectra (Figure 3a,b). With compression up to ∼23 GPa we observed new modes in the characteristic regions. With initial compression of Form I to 4.8 GPa, we observe that modes above 1313 cm−1 (Figure 8 a) uniformly harden and we observe the presence of a new mode at ∼802 cm−1 which softens. This is in agreement with the non-hydrostatic data (Figure 4 a) which shows a new mode ∼807 cm−1. The higher quality data from the HPCAT Raman system indicates that the onset of structural modifications occurs at lower pressure than was indicated by the non-hydrostatic case ∼2.4 GPa. This is further evidenced by softening in ρ(CH3) at ∼1450 cm−1 and ν(CO) at ∼1650 cm−1 starting at ∼2.4 GPa, and it is associated with a change in slope of the hardening modes. This indicates a possible strengthening of the hydrogen bonding network. Upon further compression to 5.8 GPa, we observe a new mode appear ∼804 cm−1, while all other modes uniformly harden (Figure 8 a). Modes below 1300 cm−1 appear to stabilize, showing only slight softening in ρ(CH3) and hardening in all other modes up to 6.7 GPa. As before this 6074



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ACKNOWLEDGMENTS S.J.S. is supported by the Carnegie DOE Alliance Center (CDAC) under Grant No. DE-NA002006. Portions of this work were performed at HPCAT (Sector 16), Advanced Photon Source (APS), Argonne National Laboratory. HPCAT operations are supported by DOE-NNSA under Award No. DE-NA0001974 and DOE-BES under Award No. DEFG0299ER45775, with partial instrumentation funding by NSF. APS is supported by DOE-BES, under Contract No. DE-AC02-06CH11357. Use of the COMPRES-GSECARS gas loading system was supported by COMPRES under NSF Cooperative Agreement EAR 11-5778 and by GSECARS through NSF Grant EAR-1128799 and DOE Grant DE-FG0294ER14466. We thank the Alabama Supercomputer Authority for use of the Dense Memory Cluster.

Seven modes disappear around 14.2 and 15.5 GPa with a sudden softening of all peaks at 15.5 GPa. This may correspond to a completion of the transition from Form IV → V. Hardening of all modes continues up to ∼23 GPa where the quality of the data diminishes rapidly. Differences from the non-hydrostatic case may be due to (i) difference in crystal axis orientation within the cell, (ii) higher quality of data from HPCAT Raman, (iii) absence of shear effects brought on from non-hydrostatic conditions, or (iv) a combination of the three. Overall the structural behavior seems to agree with that of the non-hydrostatic case. This may be due to the high compressibility and large unit cell which may mitigate shear effects.28,33

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CONCLUSION

The study of molecular systems using high pressure remains as an emerging field, and at this state its true potential as a tool for the control of polymorphism and solvate formation has yet be to fully realized.53 Our high pressure studies have shown that, by employing DAC technology, we can mechanically tune the polymorphism in paracetamol. In conducting high pressure Raman measurements, we have shown evidence of a highly kinetically driven Form I → II transformation that appears to persist in a mixed phase from 4.8 to 6.5 GPa and might complete as early as 7 GPa. We have also shown evidence for the additional Form IV and V polymorphs at ∼8 and ∼11 GPa, respectively. In order to corroborate potential structure modifications observed in Raman, we performed angular dispersive XRD. Indeed, these measurements provided further evidence of a highly kinetically driven Form I → II transition about the same pressure regime as observed in Raman. The XRD also elucidated to a potential Form II → IV transition near 8 GPa, which was also seen in the hydrostatic Raman data. Evidence of another kinetically hindered transition near 11 GPa (Form IV → V) with Form V persisting to ∼21 GPa was seen in XRD data. Hydrostatic Raman data show the presence of mixed phase Form IV → V starting at 11 GPa and completing ∼15 GPa. In comparing the non-hydro and (hydro) Raman runs, we observed that a mixed phase of I + II occurs at 4.8 (2.4) GPa, with completion of phase II at 7 (7) GPa. While we cannot currently provide further crystallographic details on the high pressure polymorphs of paracetamol; further investigations would require single crystal data at high pressure. We hope to provide further characterization details in our later work. An exciting part of using DAC to tune polymorphism in molecular crystals is that the pressure-treated metastable forms can be recovered and subsequently used in seeding experiments at ambient pressure.53 This allows for further analytical characterization of the high pressure polymorphs, and offers potential for growth of single crystals for additional structural characterization. It is clear that additional experiments are required, and they are in progress, to further resolve the complex behavior of paracetamol at high pressure.

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*E-mail: [email protected]. Notes

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Polymorphism in Paracetamol: Evidence of Additional Forms IV and V

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