Elucidating the Structure of Ranitidine Hydrochloride Form II: Insights

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Elucidating the Structure of Ranitidine Hydrochloride Form II: Insights from Solid-State Spectroscopy and ab initio Simulations Kacper Dru#bicki, Aleksandra Pajzderska, Dorota Chudoba, Jacek Jenczyk, Marcin Jarek, Jadwiga Mielcarek, and Jan Wasicki Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00639 • Publication Date (Web): 03 Jul 2018 Downloaded from http://pubs.acs.org on July 4, 2018

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Crystal Growth & Design

Elucidating the Structure of Ranitidine Hydrochloride Form II: Insights from Solid-State Spectroscopy and ab initio Simulations Kacper Drużbicki,∗,†,‡ Aleksandra Pajzderska,† Dorota Chudoba,†,‡ Jacek Jenczyk,¶ Marcin Jarek,¶ Jadwiga Mielcarek,§ and Jan Wąsicki†,¶ †Department of Radiospectroscopy, Faculty of Physics, Adam Mickiewicz University, Umultowska 85, 61-614, Poznan, Poland ‡Frank Laboratory of Neutron Physics, Joint Institute for Nuclear Research, 141980, Dubna, Russian Federation ¶NanoBioMedical Centre, Adam Mickiewicz University, Umultowska 85, 61-614, Poznan, Poland §Department of Inorganics and Analytical Chemistry, Poznan Univeristy of Medical Sciences, Grunwaldzka 6, 60-780 Poznan, Poland E-mail: [email protected] Phone: +48 618 295 205

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Abstract We present a complex, computationally-supported solid-state spectroscopy study, elucidating the local order in a blockbuster anti-ulcer drug, ranitidine hydrochloride form II. To this end, dispersion-corrected periodic density functional theory calculations were combined with powder X-Ray diffraction, solid-state nuclear magnetic resonance and low-frequency vibrational spectroscopy, delivering a refined structural model. We found that a competition of nearly iso-energetic sub-structures, formed by enamine type species, give rise to formation of several potential polymorphs. The considered models were critically examined both in terms of the stabilization energy and the spectral response. While previous studies left the crystal structure considered as a conformationally disordered at a molecular level, we found that the disorder is realized far beyond the local molecular arrangement, elucidating formation of infinite nets of hydrogen-bonded chains, linking both Z and E enamine fragments. On the contrary to the previously proposed model, such an arrangement is found to be highly energy favorable, disclosing the source of a high-stability of the form II. An improved atomistic model has been proposed, successfully accounting for all available spectroscopic data. Particularly, we examine the presented structural arrangement to perfectly describe both optical and neutron terahertz fingerprints, representing string and robust assessment of the validity of the crystal structure with its sensitivity to the crystal packing and the intermolecular forces present therein.

Introduction Polymorphism, that is the ability of a molecule to exist in different crystal structures, has gained a lot of importance in the pharmaceutical industry, owing to striking differences in the physico-chemical properties exhibited by different crystal forms of active pharmaceutical ingredients (APIs). Properties varying between polymorphs may include different stability, bulk and tap density, crystal shape, compressibility as well as the dissolution rate. Polymorphism is not only of pharmacological significance, with a great deal of influence on a drug’s 2

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bioavailability, but it has also relevant economic implications, being an object of development of different strategies of patenting in the pharmaceutical industry. Ranitidine is probably the best-known case of a polymorph patent controversy, which has given rise to several long court battles. It is a high potency H2 receptor antagonist, being used in the treatment of stomach ulcers and related gastrointestinal disorders. 1 It is commonly delivered in the form of a hydrochloride, hereafter Ran·HCl. Two polymorphic forms of Ran·HCl are now available in the market, namely, form I and form II. Although they were found to be bioequivalent in the clinical setting, a great interest has been given to both forms due to patenting issues. 2 In the first few years of its development, Ran·HCl was produced only as the form I, for which a US patent was issued in 1978. 3 Soon after patenting, a new polymorph was found, the form II. It had a considerably improved filtering and drying characteristics, which formed the basis for a patent application, granted in 1985. 3 The form II was also thought to be more stable and easier to manufacture R than the form I, and it eventually became the active ingredient of Zantac (Glaxo), becoming

the world’s biggest-selling prescription drug by 1992. 3,4 The form II also tends to exist as a contamination of an earlier-discovered polymorph I. When the patent for the first form expired in 1997, it opened the market to generic manufacturers. However, the existence of the patent-protected second polymorph made it hard for competitors to make the product free of the contamination. This allowed the producer to delay the appearance of generic versions of the drug on the market. A great interest in Ran·HCl made the drug one of the most archetypal examples of polymorphism in the pharmaceutical science, serving as a test bed for a number of analytical techniques used for polymorph identification and characterization. 5–11 While most of the spectroscopy research focus on the quantification of the polymorphism, the nature of the spectral response in Ran·HCl remained uncovered to a great extent. This particularly stems from a lack of a structural model of the short-range ordering, which would facilitate the use of a theoretical modeling. In this work, we intend to fill the gap by elucidating the structural

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properties of Ran·HCl form II.

Figure 1: a.) Chemical structure of ranitidine hydrochloride along with the atom numbering adopted for non-hydrogen atoms. The nitroethenediamine moiety (NED) is highlighted in a bracket. Two possible enamine conformers (Z /E ) within the NED moiety (b.) are given for comparison, along with selected tautomers of the nitronic acid (c.) and the imine form (d.). The polymorphism in Ran·HCl is determined to a great extent by the presence of a nitroethenediamine moiety, hereafter NED (see the fragment given in a bracket in Fig. 1 a.). This may give rise to an occurrence of three tautomeric species, namely the enamine tautomer (Fig. 1 b.); the nitronic acid (Fig. 1 c.) and the imine form (Fig. 1 d.). Probably the most exhaustive exploration of the conformational properties of NED in vacuo and in solvent conditions was presented by Dhaked et al., 12 employing non-local density functional theory (DFT); Møller-Plesset perturbation theory (MP2); and the coupled-cluster approach (CCSD). These calculations indicate that the enamine form is the most preferred tautomeric state, characterized by a dynamic equilibrium for the two related isomers, due to considerably low barriers for rotation across the C=C double bond (ca. 14 kcal/mol in solution). 4

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The enamine tautomers (Fig. 1 b.) were indeed found in both crystal forms of Ran·HCl, belonging to the same monoclinic crystal class, with P 21 /n symmetry and with four formula units per unit cell, but differing in the crystal packing (see Fig. 2). As confirmed with powder X-Ray diffraction (PXRD), 13 the originally unnamed polymorph structure, determined by Hempel et al. 14 corresponds to the form I. In the form I, the molecules exclusively adopt the Z conformation. The structure of the form II was first determined by Ishida, 15 and then was subsequently studied by the other authors, by means of PXRD, 16 and single-crystal X-Ray, 17 respectively. The form II was thought to be a mixture of both Z and E enamine conformers. 15,16 Mirmehrabi et al. have further suggested that the form II is a 1:1 mixture of the nitronic acid (E ) and the enamine (Z ) form. 17 The quoted papers, however, do not address the question on the local ordering in Ran·HCl form II, considering the structure as a globally-disordered mixture of the aforementioned configurations. This motivates us to perform a complementary solid-state spectroscopy study, supporting the search of possible molecular arrangement in the polymorph of question. To this end, we combine extensive dispersion-corrected density functional theory calculations (DFT-D) with a validating experimental protocol, which employs PXRD, solid-state nuclear magnetic resonance (SS-NMR), along with optical and neutron vibrational spectroscopy. In such a way we discern between possible molecular arrangements and protonation states, trying to further elucidate the structure of this important drug. Such strategy provides an improved atomistic model of Ran·HCl, which is able to successfully account for all the spectroscopic data.

Experimental Section Sample A polycrystalline sample of Ran·HCl form II was used as purchased from Alpha Aesar (99 % purity). 5

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Figure 2: Crystallographic structure of ranitidine hydrochloride form I (solved at 100 K; left panel) 14 and form II (solved at 298 K; right panel), 17 along with the corresponding asymmetric units. The thermal ellipsoids were drawn with 50 % (100 K data) and 20 % (298 K data) probabilities, respectively. Please note that according to Mirmehrabi et al., 17 the E conformer in the polymorph II corresponds to the nitronic acid rather than the enamine form.

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Thermal Analysis Differential scanning calorimetry (DSC) measurements were performed with a TA-Q2000 calorimeter. The DSC runs were recorded upon heating and cooling, with a scan speed of 10 K/min. Pure indium was used for calibration. The melting temperature was found at 140 o

C, in line with the literature findings for the form II. 18

Solid-state Nuclear Magnetic Resonance High-resolution solid-state

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C NMR spectrum was acquired at ambient conditions, at a

magnetic field of 9.4 T, using an Agilent spectrometer operating at a Larmor frequency of 400 MHz for protons. The sample was placed within a 4 mm diameter zirconia rotor and spun at a frequency of 8 kHz, using ramped 1 H-13 C cross-polarization (CP) contact time of 1300 ms. Two-pulse phase-modulated decoupling was utilized during the acquisition period. 4096 transients were accumulated to achieve a satisfactory signal-to-noise (S/N) ratio, with a total suppression of spinning sidebands (TOSS) used to detect solely isotropic signals. The

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C

chemical shifts were referenced to the 38.3 ppm signal of adamantane, with tetramethylsilane (TMS) used as the primary reference.

Far-infrared Spectroscopy Fourier-transform infrared spectroscopy (FT-IR) measurements were performed at room temperature, using a dry-air purged Thermo Scientific Nicolet iS50 spectrometer, equipped with a DLaTGS detector and a Globar IR-source. The measurements were performed both in transmission (using a high-density polyethylene, HDPE, pellet) and attenuated total reflection (ATR; using a monolitic diamond crystal) modes. The spectra were recorded with a resolution of 4 cm-1 , by accumulating 32 scans in both cases.

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Inelastic Neutron Scattering Inelastic neutron scattering (INS) measurements were performed with an indirect-geometry spectrometer NERA, set at the high flux pulsed nuclear reactor IBR-2 at the Joint Institute for Nuclear Research, Dubna, Russia. The incident neutron energies were determined by measuring the neutron time-of-flight (TOF) across the flight path of ca. 110 m. The neutrons were thermalized with a mesitylene/p-xylene moderator. The INS spectra were recorded at the final energy of the scattered neutrons of Ef = 4.65 meV, fixed by the crystal analyzers and the beryllium filters. The ca. 5 g sample was placed in a flat aluminum container and measured across the temperature range of 40 - 300 K, using of a closed-cycle helium refrigerator. The spectra were recorded for ten hours at 40, 120 and 298 K, respectively. The neutron powder patterns (NPD) were recorded simultaneously, confirming the phase stability upon cooling.

Powder X-ray Diffraction The room-temperature PXRD measurements were performed on a PANalytical Empyrean powder diffractometer, equipped with a PIXcel3D detector and working in the Bragg-Brentano geometry. The diffractometer operated at 45 kV and 40 kA using CuKα radiation (λ = 1.5418 Å). The patterns were collected in the 2θ range of 5 to 70o , the step size was 0.006 o . The powder-profile processing and Rietveld refinement of the crystal structures derived from ab initio calculations was made with Reflex program. 19 Non-linear least-square fitting was performed using a rigid body scheme, i.e. by varying the cell parameters and motion groups but fixing the bonds and valence angles according to periodic DFT optimization described below.

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Theoretical Calculations All theoretical calculations were performed in periodic boundary conditions (PBC), starting from the crystal structures reported in the literature. We based on the structure of the form II reported by Mirmehrabi et al. (CSD ref code: TADZAZ03). 17 Additional calculations for the form I were based on the structure presented by Hempel et al. 14 (CSD ref code: TADZAZ01). The plane-wave/pseudopotential formulation of density functional theory (PW-DFT) was employed as implemented in CASTEP code (version 16.1). 20,21 Exchange and correlation were approximated with a generalized-gradient-approximation-type (GGA) functional from Perdew-Burke-Ernzerhoff (PBE), 22 combined with the semi-empirical dispersion corrections (DFT-D). 23 In all the calculations the pairwise dispersion-corrections from Tkatchenko and Scheffler were employed, 24 as we have earlier proven the approach to be extremely successful in description of the structural and dynamic properties of a large-class of materials. 25–30 The core electrons were described by the set of hard, norm-conserving pseudopotentials, while the electronic wave functions were defined using a PW basis set, with a kinetic energy cutoff of 950 eV. The Monkhorst-Pack grid was maintaining the constant k -spacing of 0.05 Å-1 . The convergence criteria in variation of the total energy, maximum force, external stress, maximum displacement, and the self-consistent field (SCF) were defined as 1 × 10-10 eV/atom, 1 × 10-5 eV/Å, 0.0001 GPa, 1 × 10-6 Å, and 1 × 10-12 eV/atom, respectively. Prior to vibrational analysis, the crystal structures were fully relaxed under the atmospheric pressure conditions. The harmonic lattice dynamics (HLD) calculations were then performed, by diagonalization of the dynamical matrices, computed with density functional perturbation theory (DFPT). 31–33 The provided phonon frequencies and eigenvectors served as an input for the INS spectra calculations, performed with the help of the AbINS program. 34 The IR/Terahertz activities were modeled from DFPT, using provided dielectric permittivity and Born charge tensors. 9

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In addition, for the finally selected models, the classically-thermostatted (NVT; NoséHoover), time-evolved simulations were conducted at selected temperatures in order to account for anharmonicity and finite-temperature effects. The simulations were performed in the framework of the Born-Oppenheimer Molecular Dynamics (BOMD). The SCF convergence accuracy was reduced down to 1×10-7 eV/atom, keeping the remaining convergence criteria at the same level of accuracy. After successful equilibration, the production runs of ca. 8 ps were collected at each temperature. Using 360 processors at the PL highperformance computing facility PROMETHEUS, 35 these calculations took about 7 days per ps. The collected trajectories served as an input for modeling of anharmonic, hydrogenprojected vibrational densities of states (VDOS) through the calculations of the velocity autocorrelation function (VACF), allowing for a direct comparison with the INS experiment. The processing of the production runs was made with the help of the MDANSE code. 36 The calculations of the

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C NMR shielding tensors were performed with the gauge-

including projector-augmented wave (GIPAW) method. 37 The all-electron information was reconstructed by employing scalar relativistic ultrasoft pseudopotentials (USPP) generated on-the-fly. 38

Results and discussion Tautomeric Preferences Although the form II of Ran·HCl had been patent-protected for two decades, the commonly accepted description of the structure should be taken with a pinch of a salt, since it is not even clear if it solely consists of the enamine isomers or includes the nitronic form, as later stated by Mirmehrabi et al. (see Fig. 2). 17 To address this question, we first examine the relative stability of each hypothetical form of ranitidine within the P 21 /n arrangement, 17 by employing the ab initio structure 10

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refinement using CASTEP. To this end, a number of possible tautomers, defined by a different arrangement of the hydrogen atoms in the NED moiety, was considered according to Fig. 3. Each crystal model was built solely by a given tautomer considered.

Figure 3: Hypothetic tautomers defining the nitroethenediamine (NED) fragment of Ran·HCl form II (0. - 12.). Please note that each nitronic acid tautomer (1. - 8.) can exists with an alternative orientation of the hydroxyl (OH) group, denoted with an apostrophe (’). The results of the first-principles calculations for all the hypothetic tautomeric states of ranitidine are presented in Table 1, taking the energy of the form I as the reference. Following the methodology presented by Rivera et al., 39 the enthalpy difference of two crystal forms can be defined as the lattice energy difference, ∆ESCF , plus the difference in the vibrational contributions to the enthalpy. The vibrational difference contribution is further defined as 11

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the sum of the vibrational zero-point energy difference, ∆EZPE , and the thermal energy term, ∆EVib , which is due to excitation of the molecular and lattice vibrations at a given temperature. 39 Table 1: Analysis of relative stability (DFT/PBE-TS) of different tautomeric forms in the Ran·HCl form II (see Fig. 3), packed into the P21 /n arrangement, 17 as referred to the form I. The lattice energy differences, ∆ESCF , are presented along with the zero-point energy, ∆EZPE , the thermal vibrational energy differP ences, ∆EVib (at 298.15 K), and their total sum, ∆E (298.15 K). All values are given in kJ/mol per molecule. The results are derived from the fully optimized geometries. Note the transformation of unstable tautomers into the stable forms (→). Model

∆ESCF ∆EZPE ∆EVib

0. (Z ) 1. (E-E ) 1’. (E-E ) → 2. (E-Z ) 2’. (E-Z ) 5. (Z-E ) → 5’. (Z-E ) 6. (Z-Z ) 6’. (Z-Z ) → 9. (Z ) 10. (E ) Form I (Z ) =

7.48 130.25 0. (Z ) 141.49 153.85 0. (Z ) 142.76 174.40 0. (Z ) 88.96 92.93 0.00

P

-1.67 -8.23

0.62 1.71

∆E (298.15 K) 6.43 123.74

-7.13 -7.91

1.42 1.19

135.78 147.13

-9.43 -10.24

1.11 2.81

134.44 166.97

-4.25 -6.39

1.34 2.44

86.04 88.97

Model

∆ESCF ∆EZPE ∆EVib

0. (E ) 3. (E-E ) 3’. (E-E ) 4. (E-Z ) 4’. (E-Z ) → 7. (Z-Z ) → 7’. (Z-Z ) 8. (Z-E ) 8’. (Z-E ) → 11. (Z ) 12. (E )

7.75 139.08 158.11 133.34 0. (E ) 0. (E ) 160.30 159.06 0. (E ) 91.26 85.92

P

-2.05 -6.65 -10.08 -6.93

1.21 1.15 2.36 1.66

∆E (298.15 K) 6.91 133.58 150.39 128.07

-9.18 -8.41

2.55 2.02

153.66 152.66

-6.05 -5.21

2.02 1.36

87.23 82.07

The inspection of Table 1 clearly shows that, in terms of the stabilizing energy, all the possible configurations of the polymorph II packed in the P 21 /n arrangement, lay considerably above the energy of polymorph I. Such a conclusion deny the common assumption on a greater stability of form II, deduced from its higher melting point w.r.t. form I. 2 It means that, either, the formation of form II is a kinetically promoted process and, hence, the form II should be considered as a metastable one, or, possibly, there is some alternative, energy-preferable molecular arrangement. The former aspect has never been been confirmed experimentally, with no evidence of possible transformation of the form II into the polymorph I, 2,18 while the latter possibility will be examined further on. Among all the considered tautomers, only the enamine isomers lay in the reliable energy window, i.e. with an energy difference w.r.t. the form I smaller than 10 kJ/mol. The isomer 12

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Z was found to be lower in energy by ca. 0.5 kJ/mol w.r.t. the isomer E, highly promoting co-existence of both configurations. The remaining tautomers are either characterized by strikingly higher energy or naturally relax to the enamine forms upon structural optimization (→ Z / E ). The formation of the nitronic moiety postulated by Mirmehrabi et al. 17 becomes, hence, highly improbable and will not be considered here anymore. In line with the experimental findings, the presented analysis favors the co-existence of both Z and E isomers, but do not resolve the problem of the molecular arrangement in the form II of Ran·HCl. To address this question we refer to the extended configuration space of the polymorph under interest.

In Search of the Refined Model In order to further explore a possible molecular arrangement in the form II of Ran·HCl we refer to a supercell with eight formula units per cell (Z=8), which was built by doubling the conventional unit cell, allowing to account for different hydrogen bond configurations (see the left panel in Fig. 4). By convention, we label the eight molecules as AA’-BB’-CC’-DD’. In the conventional unit cell with four formula units (Z=4), each molecule can form the hydrogen-bond with its periodic replica of either [Z-Z ] or [E-E ] type (see the right panel in Fig. 4). Expanding the conventional cell toward the hydrogen-bonding direction allows one to extend the configuration space toward the mixed configurations, [Z-E ]. The number of considered, hypothetical structures is collected in Table 2, reduced by a number of confirmed iso-energeric combinations (e.g. Z E ’-Z E ’-Z E ’-Z E ’ versus E Z ’-E Z ’E Z ’-E Z ’). The structures forming the homo-isomeric hydrogen-bonded patterns, i.e. [Z-Z ] or [E-E ], can be further reduced by symmetry to a smaller unit cell with Z = 4, and with two molecules in the asymmetric part. The three remaining models, forming the homo-isomeric hydrogen-bonded patterns adopt the P-1 symmetry, with four molecules in the asymmetric unit. Please note that, while comparing the energetics of each model under consideration, a special attention was given to avoid possible differences due to a k -point sampling following 13

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Figure 4: The periodic box with eight formula units per cell (Z=8), used for the structural search in Ran·HCl form II (left panel), presented along with possible hydrogen-bonded chains configurations, formed by the Z and E enamine isomers (right panel). The forward and backward hydrogen-bonded molecules are denoted as X and X’, respectively. The supercell was built by doubling the cell reported by Mirmehrabi et al. 17 toward the a-direction.

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the changes in the size of the reciprocal space. An inspection of Table 2 leads to a very important conclusion on the stability of both known forms of Ran·HCl. While the lattice energies of the homo-isomeric species are very close to the parent models (pure E and Z forms in the P 21 /n symmetry), being less stable than the form I by ca. 7 kJ/mol, the formation of the mixed, hetero-isomeric hydrogen-bond patterns, [Z-E ], solve the thirty-years-old puzzle on the stability of polymorph II. Formation of the hetero-isomeric hydrogen patterns leads to a dramatic gain in the stabilization energy, putting the formation enthalpy very close to the form I. Considering the zero-temperature contributions, the formation of the [Z-E ] hydrogen-bond patterns leads to an emergence of polymorphs even lower in energy than the form I. Hence, it potentially discerns the source of the court defeats with the generic manufacturers, who could not preserve emergence of trails of the form II in their products. Table 2: Analysis of relative stability (DFT/PBE-TS) of different models of the Ran·HCl form II as referred to the form I. Different configurations are defined in convention of AA’-BB’-C C ’-DD’ (see Fig. 4). The P lattice energy differences, ∆ESCF , the zero-point energy, ∆EZPE , and their sum, ∆E (0 K), are given to present the relative polymorph stability at 0 K. The polymorph stability at room P temperature, ∆E (298.15 K), is analyzed by accounting for the thermal vibrational energy differences, ∆EVib . All values are given per molecule in kJ/mol. The results are derived from the fully optimized geometries. AA0 -BB 0 -CC 0 -DD0 Z Z ’-E E ’-Z Z ’-E E ’ Z Z ’-Z Z ’-E E ’-E E ’ Z Z ’-E E ’-E E ’-Z Z ’ Z E ’-Z E ’-Z E ’-Z E ’ Z E ’-E Z ’-Z E ’-E Z ’ Z E ’-E Z ’-E Z ’-Z E ’ Form I (Z ) = 0.00

∆ESCF 8.79 7.78 7.33 0.30 0.33 0.33

∆EZPE -2.47 -2.06 -1.85 -0.48 -0.66 -0.66

P

∆E (0 K) 6.32 5.72 5.48 -0.18 -0.33 -0.33

∆EVib 1.18 1.02 0.86 0.94 0.95 0.95

P

∆E (298.15 K) 7.51 6.74 6.35 0.76 0.62 0.62

Symmetrized Pc ; Z = 4 P 21 ; Z = 4 P-1 ; Z = 4 P-1 ; Z = 8 P-1 ; Z = 8 P-1 ; Z = 8

By analyzing the vibrational contributions, one may note that the stabilization of the form II comes from the softer phonons and so from a lower zero-point energy contributions, ∆EZPE . On the contrary, the red-shifted phonon frequencies result in a greater thermal vibrational energy contributions, ∆EVib , being more easily populated with the temperature. While destabilizing the structure, the thermal vibrational energy makes the polymorph slightly less 15

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stable than the form I (by ca. 0.5 kJ/mol) at room-temperature. However, due to a limited accuracy of the adopted computational methodology (pairwise-dispersion-corrected GGA), one should avoid drawing far-reaching conclusion on the relative stabilities of the crystal structures, differing in energy by such a small amount. Hence, this work leaves the problem of relative stability of the polymorphs under question, with a hope to be revisited in the future by means of more sophisticated approaches. This include the methods reaching the chemical accuracy, with Quantum Monte-Carlo (QMC) and modern many body dispersioncorrected DFT, given as the prime examples.

Figure 5: a.) A perspective view of the Z E ’-Z E ’-Z E ’-Z Z ’ model, projected in the direction of the [Z-E ] H-bonded chains. b.) Superposition of nearly iso-energetic structures Z E ’-Z E ’Z E ’-Z E ’ (blue) and Z E ’-E Z ’-E Z ’-Z E ’ (red), illustrating a lack of considerable structural differences. No doubt, the presented analysis clearly indicates that formation of the hetero-isomeric structures, [Z-E ], is far more preferable than the homo-isomeric enamine configurations of either [Z-Z ] or [E-E ] type. That has been further supported by analyzing the reproduction of the cell-parameters by the PBE-TS calculations (see the Section 1 of the Supplementary Information), 17 where it was, surprisingly, found that the deviations from the experimental values are reduced according to the lattice-energy trend presented. The analyzed models with P-1 symmetry and Z = 8, were, however, found to be nearly 16

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iso-energetic, which indicates that the infinite nets of the [Z-E ] hydrogen-bonding patterns can be mutually oriented in any way (see Fig. 5), without any considerably change in the enthalpy values (see Table 2). The energy differences at the order of 0.1 kJ/mol are certainly beyond the accuracy of the adopted methodology. To give some rough estimate of a deficiency of the pairwise-dispersion corrections, we have performed additional calculations with the full-geometry optimization using the PBE augmented with many-body dispersion (MBD) corrections added on top of the self-consistent-screening (SCS), hereafter PBE-SCSMBD. 40,41 In such an approach, the MBD term is computed using the coupled Quantum Harmonic Oscillator (QHO) model hamiltonian, with the short-ranged screened polarizabilities used as the input in the MBD energy expression. Such an approach accounts for two important contributions that are missing in the PBE-TS approach, namely, the manybody energy and the long-range Coulomb response (screening) that effectively modifies the polarizabilities of the interacting species and prevent to overestimate of the dispersion contributions. Due to the cost and the limitations of the present implementation, we have limited our analysis to the lattice energy contributions, ∆ESCF . According to the PBESCS-MBD calculations, the Z E ’-Z E ’-Z E ’-Z E ’ model becomes less stable than the form I by 1.98 kJ/mol, however, more stable than the Z E ’-E Z ’-E Z ’-Z E ’ model, by 0.5 kJ/mol. We further note that, while dealing with organic salt and the semi-local approximation of the exchange-correlation functional (GGA), some errors due to poor treatment of the Pauli exchange-repulsion and the self-interaction error, might also be of importance, calling for the use of a hybrid functional. 42–44 Nevertheless, a kind of insensitivity of the crystal energy on the hydrogen-chains orientation stems from the lack of specific forces, which would considerably affect the hydrogenbonded chains in the cell. An inspection of the Hirshfeld surface analysis (see the Section 1 of the SI), 45,46 indicates that [Z-E ] the hydrogen-bonded chains are only subjected to a minor influence of adjacent methyl and methylene groups. The revealed differences of contributions of various intermolecular contacts to the Hirshfeld surface for both low-energy structures are

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below 1 %, confirming a high similarity of the structures under interest. We believe that such an orientation freedom stays at the source of the global disorder in Ran·HCl form II, which might be in fact considered as a mixture of the low-energy configurations. Such an assumption would clarify, why to date, the structure could not be resolved with standard single-crystal X-Ray diffraction, probing the global order in the sample. While introducing a number of potential structures, which are favorable in terms of the lattice energy, the final conclusions were derived from the analysis of experimental diffraction and spectroscopic results.

Validation of the Structural Model Powder X-Ray Diffraction The experimental diffraction patterns undoubtedly confirm that the studied sample corresponds to the form II. These results are presented in the Supplementary Information (see the Section 1 therein). The Rietfeld refinement of the P 21 /n structure reported by Mirmehrabi et al., 17 along with the fully DFT-D relaxed alternative P-1 symmetry models, leads to a virtually the same solution. The PXRD analysis, cannot, hence, discern between the earlier proposed and the improved models, however, it unambiguously confirms that the theoretically predicted structures are acceptable for further consideration.

13

C CP/MAS NMR

The room-temperature

13

C CP/MAS NMR spectrum is displayed in Fig. 6, along with the

results of the GIPAW predictions, performed for the set of the trial models. The presented spectrum is consistent with the one originally presented by Mirmehrabi et al., 17 being, however, much better resolved. The theoretical calculations provide a reasonable reproduction of most of the chemical

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Figure 6: Comparison between the experimental 13 C CP/MAS NMR spectrum of Ran·HCl form II (top panel) and the results of GIPAW calculations for different representative models under consideration (see Tables 1 and 2 and the text for more details). Please note that different colors and heights of bars in the GIPAW spectra serve as guide for eye only.

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shifts, allowing for a trustful spectral assignment, which is, however, considerably different from the one provided by Mirmehrabi et al. 17 The upper part of the spectrum can be unambiguously assigned to the furanyl ring (i.e. C(5) = 159.4 ppm; C(2) = 144.1 ppm; C(3) = 114.4 ppm and C(4) = 109.5 ppm) along with the enamine framework of both isomers (i.e. C(15) = 153.1; C(18) = 100.5 and 98.6 ppm). The -C(6)H2 - fragment at the dimethylamine part gives a well-defined feature, split at 50.5 and 49.9 ppm. The upper part of the spectrum is barely sensitive to a selection of the model as it refers to the rigid and well-ordered part of the structure. Owing to a good resolution of the recorded spectrum, a number of features appears within the range of 45 - 20 ppm, which assignment is, however, somehow challenging, due to a limited accuracy of employed computations, 47 as well as due to an influence of finite-temperature/molecular dynamics. 48,49 The low spectral range discloses three structured features, centered at around 40, 30 and 25 ppm. On the contrary to the assignment presented by Mirmehrabi et al., 17 two highest components of the 40 ppm feature can be assigned to the methyl groups in the dimethylamine part (C(9) = 42.1 ppm and C(8) = 40.2 ppm), while the remaining ones at 38.4 and 36.9 ppm are due to the C(13)H2 - fragment. The presence of two triplet features, centered at 30.8 and 24.7 ppm, respectively, is conclusive as it directly supports our findings on the preferable hydrogen-bond configuration. The dominating, center components have been assigned to the methyl groups within the enamine moieties, i.e. C(17). The satellite components, found at 31.9 / 29.4 ppm and 25.9 / 23.7 ppm are due to sulfur-linked methylene groups (i.e. C(10) and C(12)). These signals are allowed to be widely spread by computations, being poorly tracked by static GIPAW methodology, due to an aforementioned finite-temperature influence. An inspection of performance of the computational models, clearly shows that formation of homo-isomeric, i.e. [Z -Z ] / [E -E ] hydrogen-bonded chains would result in the presence of only one methyl band. Formation of the hetero-isomeric hydrogen-bonded chains makes the C(17)H3 groups no more equivalent.

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Vibrational Spectroscopy The optical terahertz spectroscopy probes a change in the dipole moment (polarization) of the crystal, and hence, follows the slow and large-amplitude nuclear dynamics of rather heavier and charged structural fragments. The sensitivity of terahertz spectroscopies to the crystal structure stems from the fact that vibrations in this region are of external type, due to either molecular translations or large-amplitude libration modes, being greatly affected by intermolecular interactions between the nearest neighbor molecules. In the case of such a large and flexible molecular unit as Ran·HCl, the intramolecular modes, such as torsion and deformation vibrations, are further widely spread across the low-wavenumber range, mixing with the external modes and resulting in an extremely complex nature of the vibrational features observed. The optical THz-TDS spectra of both forms of Ran·HCl were extensively studied by Taday et al., 50,51 however, they were left uninterpreted due to a lack of the phonon calculations. The THz-TDS spectrum of the form II was found to hardly depend on the temperature. We extend these experimental data toward higher-wavenumber range by using the FT-FIR spectroscopy. In Fig. 7, the room-temperature THz data were confronted with the results of the first-principles harmonic lattice dynamics (HLD) calculations, performed in the framework of the perturbation theory and following and earlier optimized computational procedure for THz spectroscopy presented elsewhere. 26,27 A throughout analysis of the calculated phonon frequencies reveals an excellent overall match to the experimental data all across the range below 1000 cm-1 (see the Section 2 of the SI). In line with our findings, the models based on the homo-isomeric hydrogen-bonded patterns, [Z -Z ] / [E -E ], are clearly unable to reproduce the absorption features found experimentally (see an example in the bottom panel of Fig. 7). On the contrary, employing the proposed, refined models with four molecules in the asymmetric part, allows one to reproduce the fingerprint spectrum of the form II, with an excellent reproduction of the spectral intensity relations. An obvious, systematic frequency shift toward higher wavenumbers can 21

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Figure 7: Comparison between the experimental optical terahertz spectrum of Ran·HCl form II (top panel) and the results of the harmonic lattice dynamics (HLD) calculations for different representative models under consideration (see the text for more details). The computed THz activities were broadened with Lorentzian functions using a half-width of 10 cm-1 . The far-infrared spectrum recorded in a transmission mode has been extended beyond the low-wavenumber threshold with the THz-TDS data reported by Taday et al. 50 The THz-TDS spectrum reprinted with permission from Elsevier.

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be clearly attributed to a deficiency of both the PBE-TS approach 26 and the harmonic approximation employed (see the Section 2 of the SI). Considering the lowest-energy models, the Z E ’-Z E ’-Z E ’-Z E ’ one tends to describe the spectrum more accurately. This particularly refers to the lower-spectral range, which is less susceptible to an influence of specific spectral effects. This include the Davydov splitting, affecting the low-wavenumber phonon frequencies to a considerable extent and resulting in the loss of the frequency degeneracy, as well as the LO-TO splitting. The latter is related to the long-range dipole coupling, arising from the symmetry-breaking by the THz-active modes. The LO-TO splitting is expected to affect both the frequencies and the intensities, and it is particularly expected to influence the characteristic and the most intense part of the spectrum, centered at around 100 cm-1 , which is due to the hydrogen-bonding related vibrations. The fact that one cannot unequivocally select the superior P-1 model confirms their extreme similarity, both in terms of the crystal packing and the intermolecular forces present. Despite of nearly one hundred fifty transitions spread over the terahertz range, with the half allowed by symmetry to be THz-active, the calculations still allows one to provide a reliable overall assignment of the main absorption features, owing to dominant absorption activities of the phonons under interest and their consistency in terms of both accepted models. A tentative assignment of the vibrational features observed experimentally is presented in the Supplementary Information (see the Section 3 therein). By analyzing the phonon eigenvectors one may note that a heavy sulfur atom, with the C-S bonds as long as 1.8 Å, divides the molecule into the two, loosely coupled fragments. This reflects in a considerably different nature of the vibrations from each molecular part, contributing simultaneously to a given phonon mode. Indeed, this is confirmed by the X-Ray crystallography, where the alkyl-furan-methylamine part (hereafter A-F-M+ ), hydrogen-bound to the chlorine atom, is ordered, while the disorder is realized at the alkyl-nitroethenediamine part (hereafter ANED). 17

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Further analysis of the THz spectrum reveals that the weak features spread below 90 cm-1 are associated with the modes due to translational/librational motions, while the intense, overlapped features at around 100 cm-1 and above are clearly involving the hydrogen-bridge stretchings, ν[N...O]. An extension of the infrared response toward the higher-wavenumber regime is given in Fig. 8, with an intense band observed at around 190 cm-1 . The Z E ’-Z E ’-Z E ’-Z E ’ model was found to be superior in description of this particular range, with the characteristic feature assigned to the ν[NH+ ...Cl- ] stretching of the ionic pair, which give rise to a considerable IRactivity. A number of complex, internal deformation modes contribute with a low intensity to the far-IR spectrum, up to ca. 600 cm-1 (see the Section 3 of the SI). While the distribution of the predicted intensities stay in favor of the Z E ’-Z E ’-Z E ’-Z E ’ model, the evidence of the dominating presence of the quoted model is found at around 700 - 750 cm-1 . This range reflects the out-of-plane deformations of the hydrogen-bonded chains, γ[Z -E ], which are sensitive to the local environment. By inspection of the theoretical spectra, one may note that the representative, Z E ’-E Z ’-E Z ’-Z E ’, model fails in description of the relative modes. While the FT-IR experiment does not support the presence of both configurations, it cannot be unambigously ruled out that the Z E ’-E Z ’-E Z ’-Z E ’ model contributes with much lower intensity. Since the Hirshfeld surface analysis indicates that most of the close-contacts are of the H...H type (see the Section 3 of the SI), we shed light on the vibrational dynamics in the hydrogen atom projection, by referring to the inelastic neutron scattering spectroscopy. Recently, we have proven the low-wavenumber INS spectroscopy to be very effective in disclosing the structural peculiarities, which are hardly accessible to standard X-Ray crystallography experiments. 30,52 The data recorded in the time-of-flight experiment were converted into the form of the scattering function, S(Q, ω), which contains the dynamic information of the system. For a powdered sample, the scattering function can be defined according to a simplified relation-

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Figure 8: Comparison between the experimental far-infrared spectrum of Ran·HCl form II (top panel) and the results of DFPT calculations for different representative models under consideration (see Tables 1 and 2 and the text for more details). The recorded spectrum has been extended beyond the low-wavenumber threshold with the THz-TDS data reported by Taday et al. 50

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ship: S(Q, ω) ∝ (QUω )2 exp[−(QUT ot )2 ]σ,

(1)

where σ (barn) is the neutron-scattering cross section, being the isotope-related property, which is independent of its chemical environment. The scattering cross section of hydrogen (80 barns) far exceeds that of all other elements (typically ca. 5 barns). 53 Therefore, the modes of significant hydrogen displacement (U ω ) dominate the INS spectra. Q(-1 ) is the momentum transferred from the neutron to the sample, and UT ot is related to the mean-square atomic displacement (MSD). The scattering is fully kinematic, ie. there is no interaction of a neutron with an electron. The observed intensity is, hence, directly proportional to the amplitude of atomic displacement and the scattering cross-section. For each vibrational transition with the eigenfrequency, ω, the atomic displacements defined by the phonon eigenvector, U ω , are, hence, available directly from an experimental observation. 53 This significantly enhances the information obtainable from the vibrational spectrum and makes the computational predictions even more straightforward and robust. The experimental INS spectrum of Ran·HCl form II is presented in Fig. 9, as compared to the results of the HLD predictions involving the representative models. The kinematic nature of the INS response results in the absence of selection rules, enabling the detection of some low frequency modes unavailable to other optical techniques, e.g. methyl groups librations. Since the spectral intensities can be quantitatively compared with those calculated by the theoretical methods, it is hence possible to provide a final appraisal of the models under interest. Due to an absence of optical selection rules, there is nearly four hundred fifty transitions predicted throughout the 0 - 800 cm-1 range covered with the INS experiment. The most-intense bands observed experimentally directly reflect the large-amplitude motions of the hydrogen atoms, which are highly-localized in terms of the internal coordinates of the ranitidine molecule. An inspection of both FT-IR (Fig. 8) and INS (Fig. 9) spectra clearly uncovers the complementarity of both techniques. While the FT-IR spectrum can be roughly 26

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Figure 9: Comparison between the experimental inelastic neutron scattering spectrum of Ran·HCl form II at 40 K (top panel) and the results of harmonic-lattice dynamics (HLD) calculations (DFPT at 0 K) for different representative models under consideration. The theoretical spectra were simulated with the help of the AbINS code. 34

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described as dominated by the nuclear dynamics of the N, Cl and O atoms, which affect the charge distributions to the greatest extent, the INS spectrum is dominated by the dynamics of non-polar molecular fragments, ie. the alkyl fragments and the methylene groups. The INS spectrum can be roughly divided into several characteristic regimes, namely, the latticevibrations (external) range of approximately 0 - 150 cm-1 ; the range due to methyl groups librations, τ [CH3 ], i.e. 150 - 325 cm-1 ; the skeletal-deformation range of roughly 325 - 600 cm-1 ; and the spectral regime due to the out-of-plane deformations of the hydrogen-bonds, ie. 600 - 800 cm-1 (see the Section 3 of the SI for the band assignment). The comparison of the theoretical spectra with the experimental one, directly confirms inability of the homo-izomeric model to reproduce the experimental spectrum all throughout the analyzed range. Particularly, a reasonable reproduction of the most intense features over the 150 - 325 cm-1 range requires the presence of more than two inequivalent formula in the asymmetric unit. Both the Z E ’-Z E ’-Z E ’-Z E ’ and Z E ’-E Z ’-E Z ’-Z E ’ models give a similar description of the INS spectrum at the range above 450 cm-1 , while differing considerably in the lower range of frequencies. We may hence, use the dynamics of methyl and methylene groups as a judging probe of the local environment. The analysis of the 150 - 325 cm-1 range due to methyl groups librations, τ [CH3 ], favors the Z E ’-Z E ’-Z E ’-Z E ’ model, what is further corroborated by excellent reproduction of the intensities relations in the range of the latticevibrations, 0 - 150 cm-1 . An inspection of the hydrogen dynamics can be further extended beyond the limit of the low-temperature, as emphasizing the anharmonic effects. In order to compare the experimental, variable-temperature spectra with the ones derived from the ab initio MD simulations, the scattering function was converted to the form of the generalised phonon density of states (G(ω); GDOS), according to the formula:

G(ω) =

S(Q, ω)ω , + 1]

Q2 [B(ω, T ) 28

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(2)

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where, B(ω, T ) is the Bose factor. GDOS accounts for the temperature dependence of the S(Q, ω), related to the thermal population of excitations. Any temperature dependence of the GDOS would be, hence, an indication of deviation from harmonic motion of the molecular dynamics of the system. 54 The GDOS is then calculated by Fourier-transform of the velocity autocorrelation function (VACF) provided by the AIMD simulations:

G(ω) =

N Z X i

0



< ν(t)i ν(0)i > exp (−iωt) dt, < ν(0)2i >

(3)

where ν(t)i is the velocity of the species i at time t. This calculated GDOS is then weighted by the incoherent neutron scattering cross section of each species, for a direct comparison with the INS data. The experimental and theoretical, temperature-dependent INS spectra of Ran·HCl form II are displayed in Fig. 10. A simultaneous sample screening with a lowresolution neutron powder diffraction (NPD) did not reveal any trails of potential phase transitions. The comparison between both models analyzed here is conclusive, as it puts, without any doubt, the Z E ’-Z E ’-Z E ’-Z E ’ structure as the most probable one. On the contrary, the Z E ’-E Z ’-E Z ’-Z E ’ model fails to reproduce the temperature-evolution of the INS spectrum. The finally selected model of Ran·HCl form II gives a correct reproduction of the most characteristic spectral features up to the room-temperature limit. The molecular dynamics simulations reveals the alkyl and methyl modes to be highly anharmonic, being considerably affected by the temperature (see the range 150 - 375 cm-1 ). The analysis of the hydrogen evolution within the N...O and N...Cl bridges, did not reveal any proton-transfer events, hence, further denying formation of the nitronic acid form, suggested by Mirmehrabi et al. 17

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Figure 10: Comparison between the variable-temperature INS spectra of Ran·HCl form II (middle panel) and the results of the anharmonic, finite-temperature ab initio MD simulations (AIMD; bottom and top panels). The theoretical results are presented for two lowest-energy models under consideration (see the text for more details), as derived from the NVT production runs at given temperatures. The teoretical spectra were modeled with the help of the MDANSE code. 36

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Conclusion Previous literature reports have proven the crystallographic structure of Ran·HCl form II elusive, with an average structure being defined as disordered between two possible conformational states. We present here an extensive, computationally-supported spectroscopic study, successfully disclosing the local ordering in this important pharmaceutical solid. Based on the first-principles calculations formulated for the solid-state, we confirm the form II to be built solely by the enamine Z and E isomers. We examine a manifold of possible structural configurations to address the question on the preferable local ordering in the system of interest. We found that formation of hetero-isomeric, infinite hydrogen-bonded chains, linking the nitroethenediamine moieties is the most characteristic feature of the form II. While this feature had never been recognized before, it is proven to be highly-preferable in terms of the stabilization energy and clearly evidenced from solid-state spectroscopy. Such a characteristic hydrogen-bonding pattern is believed to disclose the long-history debate on the source of stability of the form II, being highly competitive to formation of the form I. Based on the theoretical considerations, we propose the most probable structural model of the form II. Several, nearly iso-energetic structures were further exposed, which occurrence potentially stays at the source of an earlier disclosed disorder in the polymorph of interest. This has been further studied in terms of the intermolecular interactions present therein. The most probable model of the crystal structure has been critically validated in light of the X-Ray diffraction along with NMR and vibrational spectroscopies and confronted with the state-of-the-art computational modeling in both static as well as in the time and temperature evolved manners. While successfully elucidating the molecular arrangement in Ran·HCl form II, this work gives an appraisal of the use of modern dispersion-corrected DFT, calling for a further revaluation of the system beyond the pairwise-dispersion scheme and semi-local approximations to the exchange-correlation functional. While the potential source of the structural disorder has been initially uncovered, this 31

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work stimulates further experimental and theoretical interest beyond the standard Bragg diffraction, with the total and thermal diffuse scattering experiments given as the prime direction.

Acknowledgement The work has been partially financed by the National Science Centre of Poland, Grant No. 2015/17/B/ST5/00104 and supported by PL-Grid Infrastructure and PROMETHEUS facility (Grant IDs: latticedynamics03-07; aimd). K.D. acknowledges the Plenipotentiary of Poland to JINR, Dubna for the financial support. K. D. also gratefully thanks the PL-GRID Helpdesk Team for a continuous technical assistance at the PROMETHEUS facility. Dr Anthony Reilly (Dublin City University) is acknowledged for his valuable comments on the many-body dispersion corrections.

Supporting Information Available The analysis of the refined structural models and the intermolecular interactions present therein, correlation between the calculated and experimental phonon frequencies, tentative assignment of the phonon modes, crystal coordinates for selected theoretical models used in this study. This material is available free of charge via the Internet at http://pubs.acs.org/.

References (1) Grant, M. S.; Langtry, D. H.; Brogden, N. R. Ranitidine: An Updated Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Use in Peptic Ulcer Disease and Other Allied Diseases. Drugs 1989, 37, 801–70.

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(2) Chieng, N. Formation and Physical Stability of the Amorphous Phase of Ranitidine Hydrochloride Polymorphs Prepared by Cryo-milling. Eur. J. Pharm. Biopharm. 2008, 68, 771–780. (3) Bučar, D. K.; Lancaster, R. W.; Bernstein, J. Disappearing Polymorphs Revisited. Angew. Chem., Int. Ed. 2015, 54, 6972–6993. (4) Ganellin, C. R. Development of Anti-Ulcer H2-Receptor Histamine Antagonists; WileyVCH Verlag GmbH & Co. KGaA, 2006; pp 69–80. (5) Newman, A. Specialized Solid Form Screening Techniques. Org. Process Res. Dev. 2012, 17, 457–471. (6) McGoverin, C. M.; Ho, L. C.; Zeitler, J. A.; Strachan, C. J.; Gordon, K. C.; Rades, T. Quantification of Binary Polymorphic Mixtures of Ranitidine Hydrochloride Using NIR Spectroscopy. Vib. Spectrosc. 2006, 41, 225–231. (7) Agatonovic-Kustrin, S.; Tucker, I. G.; Schmierer, D. Solid State Assay of Ranitidine HCl as a Bulk Drug and as Active Ingredient in Tablets Using DRIFT Spectroscopy with Artificial Neural Networks. Pharm. Res. 1999, 16, 1477–1482. (8) Agatonovic-Kustrin, S.; Rades, T.; Wu, V.; Saville, D.; Tucker, I. Determination of Polymorphic Forms of Ranitidine-HCl by DRIFTS and XRPD. J. Pharm. Biomed. Anal. 2001, 25, 741–750. (9) Mirmehrabi, M.; Rohani, S. An Approach to Solvent Screening for Crystallization of Polymorphic Pharmaceuticals and Fine Chemicals. J. Pharm. Sci. 2005, 94, 1560–1576. (10) Chieng, N.; Zujovic, Z.; Bowmaker, G.; Rades, T.; Saville, D. Effect of Milling Conditions on the Solid-state Conversion of Ranitidine Hydrochloride Form 1. Int. J. Pharm. 2006, 327, 36–44.

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For Table of Contents Use Only Elucidating the Structure of Ranitidine Hydrochloride Form II: Insights from Solid-State Spectroscopy and ab initio Simulations Kacper Drużbicki, Aleksandra Pajzderska, Dorota Chudoba, Jacek Jenczyk, Marcin Jarek, Jadwiga Mielcarek, Jan Wąsicki

Synopsis: Solid-state spectroscopy combined with periodic DFT computations bring new insight into understanding of the local ordering in an archetypal pharmaceutical solid, ranitidine hydrochloride form II.

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