10 1021@acs Molpharmaceut 9b00227

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Article
Molecular Basis of Water Sorption Behavior
of Rivaroxaban-Malonic Acid Cocrystal
Dnyaneshwar P. Kale, Bharat Ugale, C. M. Nagaraja,
GURUDUTT DUBEY, Prasad V. Bharatam, and Arvind K Bansal
Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/
acs.molpharmaceut.9b00227 • Publication Date (Web): 03 Jun 2019
Downloaded from http://pubs.acs.org on June 5, 2019
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Page 1 of 33 Molecular Pharmaceutics
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Molecular Basis of Water Sorption Behavior of Rivaroxaban-Malonic Acid
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Cocrystal
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8 Dnyaneshwar P. Kale,1 Bharat Ugale,2 C. M. Nagaraja,2 Gurudutt Dubey,3 Prasad V.
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10 Bharatam,3 Arvind K. Bansal1 *
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13 1Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research
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15 (NIPER), S.A.S. Nagar - 160 062, Punjab, India
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18 2Department of Chemistry, Indian Institute of Technology (IIT) Ropar, Rupnagar - 140 001, Punjab,
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3Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research
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23 (NIPER), S.A.S. Nagar - 160 062, Punjab, India
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30 *Corresponding author:
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32 Arvind K. Bansal
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34 Professor and Head, Department of Pharmaceutics
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36 National Institute of Pharmaceutical Education and Research (NIPER),
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38 S.A.S. Nagar, Mohali, Punjab- 160 062, India
39 Tel.: +91-172-2214682-2126; Fax: +91-172-2214692
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41 Email address: akbansal@niper.ac.in
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Molecular Pharmaceutics Page 2 of 33
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3 ABSTRACT
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The present study aims to investigate the molecular basis of water sorption behavior of
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8 rivaroxaban-malonic acid cocrystal (RIV-MAL). It was hypothesized that the amount of
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10 water sorbed by a crystalline solid is governed by surface molecular environment of different
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crystal facets, and their relative abundance to crystal surface. Water sorption behavior was
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15 measured using dynamic vapor sorption analyzer. Surface molecular environment of different
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17 crystal facets and their relative contribution were determined using single crystal structure
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19 evaluation and face indexation analysis, respectively. The surface area normalized water
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22 sorption for rivaroxaban (RIV), malonic acid (MAL) and RIV-MAL at 90% RH/25 °C was
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24 0.28%, 92.6% and 11.1% w/w, respectively. The crystal surface of MAL had larger
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26 contribution (58.7%) of hydrophilic (Hphi) functional groups, showed the ‘highest’ water
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sorption (92.6% w/w). On the contrary, RIV had larger surface contribution (65.2%) of
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31 hydrophobic (Hpho) functional groups and the smaller contribution (34.8%) of ‘Hphi+Hpho’
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33 groups, exhibited the ‘lowest’ water sorption (0.28% w/w). The ‘intermediate’ water sorption
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(11.1% w/w) by RIV-MAL as compared to RIV, was ascribed to the increased surface
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38 contribution of ‘Hphi+Hpho’ groups (from 34.8% to 42.1%) and reduced hydrophobic
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40 surface contribution (from 65.2% to 57.9%). However, the significantly higher water gained
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42 (~39 fold) by the cocrystal as compared to RIV, despite the nominal change in the surface
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45 contributions, was further attributed to the relatively stronger hydrogen bonding interactions
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47 between the surface exposed carboxyl groups and water molecules. The study highlights that
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49 the amount of water sorbed by the cocrystal is governed by the surface molecular
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environment, and additionally by the strength of hydrogen bonding. This understanding has
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54 implications on designing materials with desired moisture-sorption property.
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57 Keywords: Hygroscopicity, Cocrystal, Face Indexing, Surface chemistry, Strength of
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59 interactions
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3 Table of Contents/ Abstract Graphic
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INTRODUCTION
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6 The term ‘hygroscopicity’ can be described as the amount of water vapor sorbed by a sample
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8 when exposed to a known relative humidity (RH) at constant temperature.1, 2 Hygroscopicity
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10 of materials is of paramount importance in pharmaceutical, fine chemical and food industries.
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13 In pharmaceutical industry, it is well accepted that water content associated with drugs or
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15 excipients in the solid state can have profound impact on variety of physicochemical
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17 properties, such as physical and chemical stability3-5, dissolution6, flow properties and
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compaction properties.7 Therefore, assessment of equilibrium water content of drug substance
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22 and excipients has become integral part of preformulation activities, and is a parameter that
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24 should be monitored during entire journey from discovery to drug product development.1, 2, 8,
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26 9 Water sorption data is used as a guide in selecting a solid form of drug substance with better
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29 RH stability and processability.1, 10
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32 Modes of water sorption by solids are broadly divided into three categories: (1) adsorption, a
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34 surface phenomenon involving the interaction between water molecules and surface of solid
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without penetration into bulk phase, (2) absorption, which involves penetration of water
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39 molecules into the bulk phase of solid, (3) liquefaction of water on surface of solid below
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41 100% RH, which is caused due to either deliquescence or capillary condensation.11
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43 Hygroscopicity of crystalline solids (crystalline salts, cocrystals, crystalline free
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46 base/polymorphs) is mainly governed by adsorption while that of amorphous materials
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48 (amorphous drug, co-amorphous systems, amorphous salts) by absorption process. However,
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50 additionally, in crystalline solids, penetration of water into crystal lattice may lead to the
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formation of stoichiometric or non-stoichiometric crystal hydrate, driven by solution-
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55 mediated crystallization process.9
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58 At a molecular level, the amount of water gained by a crystalline solid is mainly governed by
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60 hydrogen bonding interactions between water molecules and functional groups that are
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3 exposed on the crystal surface.2, 12Surface chemistry can vary significantly from facet to
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6 facet, a phenomenon known as ‘surface anisotropy’.13-16 Surface anisotropy can be
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8 understood by recognizing the 3D structure of molecules in a crystal, wherein the various
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10 crystallographic planes corresponding to each crystal facet dissects (cut-up) the unit cell at
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different planer orientations and angles. This exposes different chemical groups with varying
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15 surface densities of those groups, resulting into varied surface chemical environments.13, 15 It
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17 has been anticipated that the amount of water gained by a particular facet of crystal surface is
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likely higher if hydrophilic functional groups are present, while the lesser amount of water
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22 sorption is expected if hydrophobic (nonpolar or lipophilic) groups are exposed. This is
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24 because, hydrophilic functional groups such as carboxyl (‒COOH), amino (‒NH2) or (‒OH)
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26 favor hydrogen bonding interactions with water molecules (H‒O‒H). Accordingly, a total
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29 amount of water sorbed by a crystal can be ascribed to the sum of hydrophilic contributions
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31 from all crystal facets. Thus, it becomes important to find out the relative contribution
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33 (relative abundance) of each facet and their affinity towards water molecules (hydrophilic or
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36 hydrophobic). This approach of understanding the molecular mechanism of water sorption by
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38 crystalline solids has not been experimentally validated for organic compounds.
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41 Cocrystals are being increasingly utilized for modulating numerous physicochemical
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properties including hygroscopicity. A number of studies have demonstrated the role of
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46 cocrystals in alteration of hygroscopicity (moisture stability) of active pharmaceutical
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48 ingredients (APIs) and excipients.17-25 Co-crystallization leads to a significant change in the
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50 surface chemistry (surface molecular environment) of resultant crystalline solid because of
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53 incorporation of two or more different compounds in the same crystal lattice and the altered
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55 molecular arrangements. Understanding the relationship between hygroscopicity behavior of
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57 cocrystals and their surface chemistry is a vital step in designing materials with desired water
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sorption tendency. Therefore, the present study aims to understand the molecular basis of
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3 water-sorption behavior of cocrystal using rivaroxaban: malonic acid cocrystal (RIV-MAL)
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6 as a model system. Molecular basis of water sorption behavior was comprehended by
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8 correlating the amount of water sorbed per unit surface area with the surface molecular
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10 environment of rivaroxaban (RIV), malonic acid (MAL) and their cocrystal, RIV-MAL. It
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was hypothesized that water-sorption behavior is governed by‒ (i) nature of crystal facets
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15 (hydrophilic or hydrophobic or mixed) (ii) relative abundance (%contribution) of crystal
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17 facets to total crystal surface and (iii) strength of interactions between exposed functional
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groups and water molecules.
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23 Dynamic vapor sorption (DVS) analysis was carried out to determine sorption-desorption
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25 profile. Single crystal XRD was utilized to identify the exposed chemical groups on different
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27 facets of a crystal, and face indexation analysis was used to measure % relative contributions
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(relative abundance) of different facets onto crystal surface. Molecular lipophilic potential
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32 (MLP) calculations of RIV and MAL were utilized to identify hydrophilic or hydrophobic
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34 nature of functional groups. Strength of hydrogen bonding interactions was estimated using
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36 Density Functional Theory (DFT) calculations. The surface molecular environment, in terms
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39 of hydrophilic or hydrophobic nature of chemical groups and strength of hydrogen bond
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41 formations, was correlated to the percentage of water sorption per unit surface area.
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44 EXPERIMENTAL SECTION
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Materials
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49 RIV was received as a gift sample from Lupin Pharmaceuticals Ltd., India (Purity >99.5%).
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MAL (Sigma-Aldrich, USA) and 2,2,2-trifluoroethanol (Spectrochem Pvt. Ltd, India) were
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54 of analytical grade and used as received.
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3 Crystallization Experiments
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6 Crystallization experiments were performed to obtain good quality crystals for crystal
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structure solution and face indexation studies. These crystalline samples were also employed
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11 in DVS experiments so as to achieve minimal differences in their surface and morphological
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13 characteristics.
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16 RIV Crystals: RIV (25 mg) was dissolved in acetonitrile (10 mL) by heating in a water bath
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at 60 °C for 5 min and cooled at room temperature (RT). The resultant solution was filtered
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21 through a 0.2 µm pore size nylon membrane filter and kept in a 15 ml screw cap vial, which
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23 was loosely capped to allow the slow solvent evaporation at RT. Columnar shaped crystals
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were generated within a week.
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29 MAL Crystals: MAL powder was dissolved in acetone at RT with continuous stirring till the
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31 point of saturation. Single crystals were obtained after 5 to 7 days by slow evaporation of the
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33 obtained solution.
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36 RIV-MAL Crystals: RIV (87 mg) and MAL (60 mg) were dissolved in 2,2,2-trifluoroethanol
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39 (1 mL) by heating in water bath at 75 to 80 °C to form a clear solution, and allowed to cool
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41 first at 50 °C for 30 min and subsequently at RT. The resultant solution was kept in a 5 ml
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43 loosely capped vial to allow slow evaporation of the solvent at RT. Single crystals appeared
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46 within 1-2 weeks. The crystals were stored in the mother liquor to retain their morphological
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48 and surface properties.
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51 Differential Scanning Calorimetry (DSC)
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54 Thermal analysis of the samples was performed using a Differential Scanning Calorimeter,
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56 (model Q2000, TA Instruments, Delaware, USA) operating with TA Universal Analysis®
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software, version 4.5A. About 2−4 mg of sample was weighed in Tzero aluminium pan,
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3 crimped and subjected to thermal scanning at a heating rate of 10.0 °C/min. A dry nitrogen
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6 purge was maintained at 50 mL/min. The instrument was calibrated for temperature and heat
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8 flow using high purity standard indium prior to analysis.
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11 Hot Stage Microscopy (HSM)
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14 Thermally-induced physical changes in the crystal sample were observed under Leica DMLP
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16 polarized microscope (Leica Microsystems Wetzlar GmbH, Wetzlar, Germany) equipped
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19 with Linkam LTS 350 hot stage. The sample was mounted on a glass slide and subjected to
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21 temperature from 30° to 240 °C at a heating rate of 10 °C/min. Photomicrographs were
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23 acquired using JVS color video camera and analyzed using Linksys32 software.
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26 X-ray Powder Diffractometry (XRPD)
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29 XRPD patterns of the samples were recorded at room temperature using a parallel beam
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geometry X-ray diffractometer (Rigaku Ultima IV diffractometer, Tokyo, Japan) equipped
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34 with a Cu Kα source (1.54 Å), 2.5° primary and secondary solar slits, 0.5° divergence slit
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36 with 10 mm height limit slit, sample rotation stage attachment and DTex Ulta detector. The
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X-ray generator was operated at 40 kV and 40 mA power settings. Samples were mounted on
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41 a poly(methyl methacrylate) (PMMA) sample holder and subjected to a continuous scan over
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43 5−40° 2θ at a step size of 0.01° and a dwell time of 1 sec per step. The data were analyzed
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with OriginPro software.
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Attenuated Total Reflectance−Fourier Transform Infrared Spectroscopy (ATR-FTIR)
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51 The IR spectra of cocrystal, RIV and MAL were recorded from scanning range of 4000 cm-1
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54 to 650 cm-1 on an FTIR Spectrometer (Perkin Elmer Inc, Waltham, USA) equipped with
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56 diamond/zinc selenide crystal attenuated total reflectance accessory. The data were analyzed
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58 using Spectrum® software (Version 3.02.01).
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3 Single-Crystal X-Ray Diffraction (SC-XRD) and Face indexing
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6 Single crystal structure data of RIV and RIV-MAL were collected on a Bruker based D8
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Venture diffractometer equipped with INCOATEC micro-focus source with graphite
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11 monochromated Mo Kα radiation (λ = 0.71073 Å). A single crystal was selected and
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13 mounted with paratone oil on a glass fiber of 0.2 mm diameter using gum, on the
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15 diffractometer operating at 50 kV and 30 mA, which used a CMOS-PHOTON area detector
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18 for determining unit cell parameters and orientation matrices at 295 K. Cell constants were
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20 determined from reflections harvested from two sets of 12 frames. These initial sets of frames
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22 were oriented such that orthogonal wedges of reciprocal space were surveyed. SAINT26
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program was applied for data integration and SADABS27 program was used for absorption
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27 correction. The structures were initially solved by SIR 9228 and refined using SHELXL-
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29 201429 and WinGX system30, Ver 2013.3. All the non-hydrogen atoms were located from the
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difference Fourier map and refined anisotropically and all the hydrogen atoms were fixed by
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34 HFIX and included in the refinement process with isotropic thermal parameters and in few
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36 cases with no constraints wherever required. Crystal information files (CIF) are deposited to
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38 Cambridge Crystallographic Data Centre (CCDC), Cambridge, UK with the CCDC numbers
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41 1854617 and 1854618 for RIV and RIV-MAL, respectively.
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43 Face indexing was carried out to determine Miller indices of the different facets of a crystal.
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45 Importantly, face indexation data help in determining the relative abundance (%
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contributions) of each facet of a crystal surface. A series of photographs were taken with a
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50 video microscope as the crystal is rotated through 360° about the ψ axis. Miller indices of
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52 various facets of the crystal were identified using, the face indexing plug-in of APEX 2, also
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known as T-tool.
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3 Dynamic Vapor Sorption (DVS)
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6 Hygroscopicity behavior (sorption-desorption profiles) of the samples were studied at 25 ±
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0.1 °C using a DVS instrument (Q5000SA, TA Instruments, New Castle, Delaware, USA).
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11 The crystals of RIV, MAL and RIV-MAL were used as samples for the present study. The
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13 instrument was calibrated for humidity by taking the deliquescence point of sodium bromide
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15 at 25 ± 0.1 °C to be 57.6 ± 1% RH as recommended by the manufacturer. Samples (15 ± 5
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18 mg) were loaded onto a tared metal-coated quartz sample pan and an empty pan was used as
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20 the reference. The sample was pre-dried at 25 °C/0% RH for 60 min and the instrument was
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22 programmed for moisture sorption-desorption mode from 0 → 90 → 0% RH in 10% RH/step
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and 5% RH/step from 90 → 95 → 90% RH. The equilibrium condition was set to <0.002%
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27 of total mass change over 5 min or maximum dwell time of 2-4 h if the weight change criteria
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29 could not meet. Each experiment was carried out in triplicate.
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32 Molecular Dynamics Simulation Study
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35 The purpose of molecular dynamics study was to identify hydrogen binding sites available in
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37 the crystal structure of RIV, MAL, and RIV-MAL. This knowledge helps in determining the
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40 accessible hydrogen bonding sites present on the different surfaces of the crystal. The
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42 structure of RIV dimer, MAL dimer, and RIV-MAL (2:1) cocrystal from single crystal
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44 solution were taken as a model for these studies. The molecular dynamics simulation was
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47 performed using Desmond v3.2 program31 of Schrodinger software package using OPLS3
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49 force field.32, 33 The solvent system was built for the simulation using a predefined water
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51 model (TIP3P). The cubic shape box with dimensions 10Å × 10Å × 10Å was selected and
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calculation methods were set to buffer. The simulation restraining of non solvent atoms was
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56 performed by implementing Nose-Hoover chain thermostat method to maintain a constant
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58 temperature of 298K and Martyna-Tobias-Klein barostat method to maintain a constant
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3 pressure of 1.01325 bar under NPT ensemble. The relaxed system was simulated for 20ns
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6 with the time step of 2fs and record interval of 1.2ps.
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9 Determination of Molecular Lipophilic Potential (MLP)
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12 Molecular lipophilic potential (MLP) analysis of RIV and MAL was carried out by selecting
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14 the global range type using MOLCAD program available in SYBYL 7.1 molecular modeling
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16 package. It provides lipophilic potential surrounding each atom or group of atoms. The nature
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of functional groups (hydrophilic or hydrophobic) present in RIV and MAL was identified by
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21 measuring MLP. Lower the value of lipophilic potential (represented as LP value) indicates
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23 hydrophilic/polar groups, while the higher value of lipophilic potential indicates
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25 hydrophobic/nonpolar groups.
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Identifications of Surface Molecular Environment
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31 The molecular packing corresponding to different crystallographic planes (Miller indices) for
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34 RIV, MAL, and RIV-MAL was visualized using the respective CIF files in Mercury software
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36 V3.7 (CCDC, UK). The visualization of molecular packing across different crystallographic
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38 planes helped to precisely identify the chemical groups exposed onto a particular facet of the
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crystal.
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44 Density Functional Theory Calculation
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The hydrogen bonding strength can be measured as a function of interaction energy. It can be
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49 calculated by subtracting the total energy of the H-bond donor and acceptor from the energy
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51 of H-bond donor-acceptor complex.34 Density Functional Theory (DFT) based quantum
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53 chemical studies were performed to evaluate the strength of intermolecular hydrogen bonding
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56 of RIV and MAL with water molecule(s). The geometry optimization was performed on
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58 Gaussian09 suite software35 using B3LYP/6-31+G(d,p) level of theory.36 The absolute
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60 energies of the geometries were taken into consideration for further calculation.
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3 RESULTS AND DISCUSSION
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Generation and Solid-State Characterization of RIV and RIV-MAL
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8 Overlay of DSC heating curves and XRPD patterns of RIV, MAL and RIV-MAL are
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11 presented in Figure 1. Columnar shaped RIV crystals were generated from acetonitrile by
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13 slow solvent evaporation. DSC analysis of RIV showed a melting onset at 230.24 °C with a
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15 heat of fusion (∆Hf) of 110.3 J/g, which corresponds to the melting temperature of
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rivaroxaban form I (Figure 1a). XRPD pattern of RIV sample exhibited diffraction peaks at
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20 2Ɵ values of 9.1°, 12.2°, 14.4°, 16.6°, 17.6°, 18.2°, 19.6°, 20.0°, 21.8°, 22.6°, 23.5°, 24.1°,
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22 24.8°, 25.8°, 26.8°, 29.6°, 30.3°, 31.9° ± 0.2° (Figure 1b). The most intense diffraction peak
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was observed at 2Ɵ value of 22.6° ± 0.2°. The diffraction peaks of the sample also
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27 correspond to form I of RIV.37 Thick plate-shaped crystals of MAL were generated by slow
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29 solvent evaporation of a saturated solution of MAL in acetone. The observed melting
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31 temperature for MAL crystals was 134.6 °C (∆Hf ≈ 235 J/g), which relates to β form of
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34 malonic acid.
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37 Rectangular-shaped crystals of RIV-MAL were generated by slow solvent evaporation of
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39 RIV and MAL solution, which was previously cooled in a step-wise manner. The step-wise
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41 cooling of the hot solution, as described in the method section, was critical for the successful
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44 generation of crystals suitable for single-crystal XRD analysis. DSC analysis of RIV-MAL
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46 sample displayed a transition point at between 113-120 °C followed by endothermic peak
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48 pertaining to cocrystal melting at ~169 °C (ΔHf is 38.8 J/g) (Figure 1a and Figure S1).
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Subsequent to the cocrystal melting, an exothermic event for recrystallization of RIV and its
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53 melting endothermic event at ~232 °C were observed.
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20 Figure 1. Overlay of DSC (a) and XRPD scans (b) of RIV, MAL, and RIV-MAL
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23 The thermal events in the DSC scan were further verified by HSM analysis of the cocrystal
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25 and shown as Figure S1. In HSM analysis, phase transition was observed as a change in
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27 particle boundaries and slight movement of the particles at a temperature between 113-120
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30 °C. The thermal event at ~169 °C was assigned as melting point of the cocrystal because a
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32 phase conversion from solid-to-liquid state (an indicator of melting process for a material)
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34 was clearly observed at this point (Figure S1). Thus, the melting point of the cocrystal (i.e.
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169 °C) was between the melting points of the pure starting materials indicating the
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39 formation of cocrystal phase. The characteristic peaks of RIV-MAL observed at 2Ɵ values of
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41 11.9°, 13.6°, 15.8°, 18.8°, 19.4°, 24.0°, 27.5°, and 28.7° ± 0.2° correspond to the reported
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values, confirming the successful generation of cocrystal (Figure 1b). IR frequencies of RIV,
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46 MAL, and RIV-MAL are provided in Supporting Information.
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49 Single Crystal Structure Analysis
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52 RIV, which is 5-chloro-N-[[2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-1,3-oxazolidin-5
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54 yl]methyl]thiophene-2-carboxamide), was crystallized in the triclinic crystal system with the
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56 non-centrosymmetric, P1 space group. Crystal data and structure refinement parameters for
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59 RIV and RIV-MAL are presented in Table S1. X-ray structure determination revealed the
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3 molecular structure of RIV with a hydrogen-bonded network (Figure 2). The crystal structure
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6 parameters are in a good agreement with the recently published crystal structure of RIV by
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8 Shen and coworkers.38 Further discussion on crystallographic features of RIV can be found in
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10 Supporting Information.
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RIV-MAL also crystallized in the triclinic crystal system with the non-centrosymmetric, P1
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15 space group and the structure consists of four molecules of RIV along with two molecules of
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17 MAL (2:1 stoichiometry) (Figure 3). The antiparallel arrangement of RIV molecules as found
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in the crystal structure of RIV remained intact, i.e. RIV molecules interacted with each other
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22 via the similar N–H···O hydrogen bonding (N3–H3···O18, N12–H12···O3, N9–H9N···O7
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24 and N6–H6N···O13 as shown in Table S3) as observed in the crystal structure of RIV. Thus,
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26 the original dimeric arrangement of RIV molecules as observed in the RIV crystal structure
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29 did not change upon cocrystallization with MAL. Further, the dimeric units of RIV are
30
31 engaged in O-H···O (O28–H28···O7, O25–H25A···O17, O24–H24···O12 and O22–
32
33 H22B···O2) H-bonding interactions with the MAL molecules resulting in a 2D
34
35
36
supramolecular network arrangement as shown in Figure 3. Additionally, the comparable
37
38 strength of interaction between two RIV molecules in cocrystal structure vis-à-vis RIV
39
40 structure was confirmed based on the observed similar bond length and bond angles
41
42
(directionality). However, many C–H···O type weaker intermolecular interactions were also
43
44
45 observed in the cocrystal structure (Table S4, Supporting Information). The hydrogen bond
46
47 details for RIV and RIV-MAL are provided in Tables S2 and S3, respectively. Selected bond
48
49
50
lengths and angles are given in Table S4-S5 (Supporting Information).
51
52
53
54
55
56
57
58
59
60
14
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24 Figure 2. RIV crystal structure showing the antiparallel arrangement of two RIV molecules,
25
26 interacting through a bilateral N–H···O hydrogen bonding to form a dimer in AB-AB fashion.
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
Figure 3. RIV-MAL crystal structure showing the presence of N–H···O H-bonding between RIV
53
54 molecules and O-H···O H-bonding interactions between RIV and MAL molecules.
55
56
57
58
59
60
15
1
2
3 Water Sorption Behavior (Hygroscopicity Studies)
4
5
6 The sorption-desorption profiles of RIV, MAL and RIV-MAL are shown in Figure 4. No
7
8
significant weight gain was observed in all three samples until 60% RH (<0.1% w/w).
9
10
11 However, all samples gained a significant amount of water when exposed at RH >70%. The
12
13 amount of water sorbed at 90% RH was the highest in MAL (64.8% w/w) while it was the
14
15 lowest in RIV (0.13% w/w). Hygroscopicity of RIV-MAL was observed to be intermediate
16
17
18 between RIV and MAL (6.0% w/w). A similar trend of hygroscopicity was observed when
19
20 percentage of water gained was normalized by the surface area of the respective sample
21
22 (Figure 4b). The surface area values of crystal samples measured using a Nitrogen BET
23
24
25
method (Supporting Information, Table S6). The rank order of surface area normalized
26
27 hygroscopicity of crystal samples was given to all three samples, i.e. RIV < RIV-MAL <
28
29 MAL. The overlapping of sorption and desorption profiles for RIV and RIV-MAL ruled out
30
31
the possibility of polymorphic/solid form changes during hygroscopicity studies and also
32
33
34 verified the nonexistence of crystal defects in the samples. This was further confirmed by
35
36 DSC analysis of the samples collected after DVS experiment (Supporting Information, Figure
37
38 S2-S4). Conversely, the sorption-desorption curve of MAL showed hysteresis, and 11.4%
39
40
41 water retained at the end of desorption cycle. This behavior was attributed to the deliquescent
42
43 nature of MAL.39 It is noteworthy that, the morphologies of crystals used in DVS
44
45 experiments were kept similar to that of those used in SC-XRD and face indexing
46
47
48
experiments.
49
50
51
52
53
54
55
56
57
58
59
60
16
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19 Figure 4. DVS analysis of RIV, MAL, and RIV-MAL samples (a) adsorption-desorption isotherm;
20
(b) % water gain at 90% RH/25°C (Values on bar graph show ‘Mean’ and error bar represents SD,
21
22 n=3).
23
24
25 Hydrogen Bonding Sites Available for Interaction with Water Molecules
26
27
To understand the role of surface-water interaction, it is important to identify the available
28
29
30 hydrogen bonding sites in a given crystal structure. Hydrogen bond donor/acceptor groups in
31
32 a given structure can be potential sites for hydrogen bonding with water molecules.
33
34 Nevertheless, the configuration of molecules in crystal structure affects the orientation and
35
36
37 accessibility (geometry, bond length, steric factors) of a particular H-bond donor/acceptor
38
39 and in turn the hydrogen bond formation tendency.40 Hydrogen bond is directional viz. the
40
41 bond angle, (∠X-H…Y) should be linear or near to linear (120°‒180°), therefore the H-bond
42
43
44
formation tendency of compound depends on the atomic arrangements in the crystal
45
46 structure.41 Therefore, molecular dynamics simulations were performed to better understand
47
48 the contribution of each functional group in the hydrogen bonding using the crystal structure
49
50
of RIV, MAL, and RIV-MAL. The hydrogen bonding sites available for interaction with
51
52
53 water molecules were identified in the simulations studies and are presented in Table 1. The
54
55 results show that the available hydrogen bonding sites in the cocrystal structure were equals
56
57 to sum of H-bonding sites in the individual structure of RIV and MAL.
58
59
60
17
1
2
3 Table 1. Hydrogen bonding sites available for interaction with water molecules
4
5
6 RIV MAL RIV-MAL
7 Carboxamide Carboxylic Carboxamide
8 C=O O-H (Acidic) C=O
9
C=O (Acidic)
10
11 Morpholine Morpholine
12 C=O C=O
13 Ring O Ring O
14 Oxazolidinone Oxazolidinone
15
Centre C=O Centre C=O
16
17 Central ring ‘O’ was Central ring ‘O’ was not
18 not involved. involved.
19 Carboxylic in Malonic acid
20 O-H (Acidic)
21
22
C=O (Acidic)
23 Correlating Surface Molecular Environment and Water Sorption Tendency
24
25
26 SC-XRD and face indexing are powerful techniques to understand the interactions of water
27
28
with the surface of organic solid because of two reasons: 1) Using a basic structure of the
29
30
31 solid surface one can better comprehend the properties of water as adsorbate and its
32
33 interactions with the surface, (2) powder samples are not perfect crystals and may possess
34
35 crystal defects and impurities. The water adsorption in powder samples will be influenced by
36
37
38 defects, impurities and the polycrystalline nature of the sample.12, 42 Therefore, instead of
39
40 using powdered samples, the recrystallized samples in the form of small crystals were used
41
42 for investigating molecular basis of water-sorption behavior. Face indexing and SC-XRD
43
44
45
together provided surface molecular environment (surface chemistry) of crystal samples of
46
47 RIV, MAL, and the cocrystal. Figure 5 shows photomicrographs of crystal samples of RIV,
48
49 MAL and RIV-MAL captured from face indexation analysis.
50
51
52
53
54
55
56
57
58
59
60
18
1
2
3
4
5
6
7
8
9
10
11
12
13
14 Figure 5. Images of crystal samples captured during face indexation analysis of RIV (a), MAL (b),
15 RIV-MAL (c).
16
17
18 Face indexing of RIV revealed predominant facets with their relative contributions as
19
20 follows: (011), (0-1-1), 34.8%; (010), (0-10), 28.4%; (001), (00-1), 24.7; and (01-1), (0-11),
21
22 12.1%. Visualization of RIV structure along the identified crystallographic planes helped to
23
24
25 determine exposed chemical groups onto surface of the crystal facets. Table 2 compiles the
26
27 exposed chemical groups on the crystal facets for RIV, MAL, and RIV-MAL. As shown in
28
29 Table 2, the predominant facets expose 5-chlorothiophene and a part of the aminomorpholine
30
31
ring and carbonyl (C=O) group from carboxamide. The nature of these functional groups,
32
33
34 whether hydrophilic or hydrophobic, was identified based on LP values, determined by MLP
35
36 calculations (Figure 6). The relatively higher LP value around 5-chlorothiophene
37
38 demonstrates its hydrophobic nature, while the lower LP value of the carbonyl group
39
40
41 indicates its hydrophilic nature. The carbonyl functionality in 4-aminomorpholine-3-one is
42
43 hydrophilic, whereas the rest part of the ring is hydrophobic, indicated by the higher LP
44
45 value.
46
47
48
In RIV crystal, facets namely (010), (001) and (01-1), which majorly contribute to the crystal
49
50
51 surface, exposed hydrophobic chemical groups (5-chlorothiophene and hydrophobic part of
52
53 4-aminomorpholine-3-one) (Figure 7). On the other hand, (011) facets exhibited both
54
55 hydrophilic (C=O) and hydrophobic groups (5-chlorothiophene). Summation of the
56
57
58 hydrophilic contributions (Hphi), hydrophobic contributions (Hpho), and hydrophilic plus
59
60 hydrophobic contributions (Hphi+Hpho) from all facets indicated that the RIV crystal surface
19
1
2
3 covers 65.2% hydrophobic feature, 0.0% hydrophilic feature, 34.8% both hydrophobic and
4
5
6 hydrophilic features. Thus, the lower water sorption tendency of RIV was attributed to the
7
8 presence of predominantly hydrophobic groups on the surface of crystal.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26 Figure 6. Surface representation of MLP for RIV (Lower LP sites are shaded as blue, while higher LP
27
sites are shaded as brown).
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44 Figure 7. Molecular packing diagrams illustrating surface chemistry of different facets of RIV. The
45
46 surface chemistry of (011) and its opposing (0-1-1) facets (a), and that of (010) and its opposing (0-
47
10) facets (b).
48
49
50 Unit cell parameters of MAL were in agreement with reported parameters for MAL (CSD
51
52 Reference code MALNAC02, deposition number 1209218).43 The crystal system was
53
54
55
triclinic with space group Pī (2), and cell parameters were a=5.152(1)Å, b=5.347(1)Å,
56
57 c=8.407(1)Å, α =71.42(2)°, β=76.09(2)°, γ= 85.07(2)°. MAL is a dicarboxylic acid in which
58
59 two carboxyl groups linked by a methylene-bridge. Two strong hydrogen bond acceptors
60
20
1
2
3 (C=O, carbonyl groups) and two hydrogen bond donors (‒OH, hydroxy groups) from these
4
5
6 two carboxylic functions can impart substantial hydrophilicity to MAL if they will expose
7
8 onto the crystal surface. The lower LP value around two carboxylic (‒COOH) groups of
9
10 malonic acid (blue shade) assures the hydrophilic nature (Figure 8). A small light brown
11
12
13 portion in Figure 8 represents a weak hydrophobic nature of methylene group (-CH2-) in
14
15 MAL.
16
17
18 Face indexation and crystal structure visualization using Mercury software revealed that
19
20
carbonyl and hydroxyl groups (from carboxyl group), hydrophilic groups, were
21
22
23 predominantly exposed onto (-111) and (001) facets of MAL crystal contributing ~ 57.9% of
24
25 total crystal surface area (Figure 9 and Table 2). The weakly hydrophobic methylene (‒CH)
26
27
28
group and hydrophilic carboxyl group (‒COOH) offered a mixed domain (Hphi+Hpho
29
30 contributions) onto (101) and (10-1) facets with relative abundance of ~42.1% (Figure 9 and
31
32 Table 2). In summary, the higher contribution of hydrophilic functional groups with a strong
33
34
35
intermolecular H-bond formation tendency with water molecules made MAL crystal surface
36
37 more hygroscopic. The higher strength of hydrogen bonding interaction between surface
38
39 functional groups in MAL and water molecules could be responsible for its deliquescence
40
41
nature when exposed at higher humidity. The deliquescence relative humidity of MAL at 298
42
43
44 K was reported to be 71%.39
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
21
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 Figure 8. Surface representation of MLP for MAL (Lower LP site are shaded as blue, while higher
16 LP sites are shaded as brown).
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41 Figure 9. Molecular packing diagrams illustrating surface chemistry of different facets of MAL. The
42
surface chemistry of (001) and its opposing (00-1) facet (a), and that of (101) and its opposing (-10-1)
43
44 facets (b).
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
22
1
2
3 Table 2. Compilation of relative contribution of crystal facets, exposed functional groups on the
4
5 surface of each facet, and their nature
6
7 Facets Relative Exposed groups Nature of exposed
8
contribution of functional group
9
facet (%)
10
11 RIV
12 (011), (0-1-1) 34.8 5 -Chlorothiophene, Hydrophobic (Hpho),
13 (-C=O), Hydrophilic (Hphi),
14 Hydrophobic part of 4-Aminomorpholine-3-one Hydrophobic (Hpho)
15 (i.e. except ether oxygen and free carbonyl)
16
(010), (0-10) 28.4 5 –Chlorothiophene Hydrophobic (Hpho)
17
18 (001), (00-1) 24.7 Hydrophobic part of 4-Aminomorpholine-3-one Hydrophobic (Hpho)
19 (01-1), (0-11) 12.1 5 –Chlorothiophene Hydrophobic (Hpho)
20 MAL
21
(001), (00-1) 52.3 (-COOH) Hydrophilic (Hphi)
22
23 (101), (-10-1) 28.8 (-COOH), Hydrophilic (Hphi),
24 (-CH2) Hydrophobic (Hpho)
25 (1 0-1), (-101) 12.5 (-COOH), Hydrophilic (Hphi),
26 (-CH2) Hydrophobic (Hpho)
27 (-111), (1-1-1) 6.4 (-COOH) Hydrophilic (Hphi)
28
29 RIV-MAL
30 (001), (00-1) 57.9 5 –Chlorothiophene Hydrophobic (Hpho)
31 (101), (-10-1) 21.1 (- COOH), Hydrophobic (Hpho),
32 5 –Chlorothiophene Hydrophilic (Hphi)
33
(11-1), (-1-11) 10.9 Hydrophobic part of 4-Aminomorpholine-3-one, Hydrophobic (Hpho),
34
(- COOH) Hydrophilic (Hphi)
35
36 (111), (-1-1-1) 10.2 5 -Chlorothiophene, Hydrophobic (Hpho),
37 (- COOH), Hydrophilic (Hphi),
38 -CONH- (carboxamide) Hydrophilic (Hphi)
39
40
41
42
43 Molecular Basis of Water Sorption Behavior of the Cocrystal
44
45
Role of Relative % Contribution of Crystal Facets
46
47
48 In the crystal structure of RIV-MAL, MAL molecules were embedded in between RIV
49
50
51
molecules (Figure 10a). Visualization of different facets corresponding to Miller indices
52
53 unveiled that hydrophobic group, 5-chlorothiophene was exposed onto major (001) facet of
54
55 the cocrystal contributing 57.9% of the total surface area. Interestingly, a strongly hydrophilic
56
57
(carboxyl from MAL) as well as hydrophobic (5-chlorothiophene) groups were exposed onto
58
59
60
23
1
2
3 (101) and (111) facets accounting 42.1% relative contributions to entire crystal surface
4
5
6 (Figure 10b, Table 2).
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26 Figure 10. Molecular packing diagrams illustrating surface chemistry of different facets of RIV-
27
28 MAL. The surface chemistry of (001) and its opposing (00-1) facet (a), and that of (101) and its
29
opposing (-10-1) facets (b). Insert and arrows indicate the position of MAL molecules.
30
31
32 As represented in Figure 11 pie-diagram, cocrystallization of RIV with MAL imparted
33
34 hydrophilic groups onto its crystal surface as the ‘Hphi+Hpho’ character was found to have
35
36
37
increased from 34.8% in RIV to 42.1% in RIV-MAL. At the same time, the hydrophobic
38
39 contributions decreased from 65.2% in RIV to 57.9% in RIV-MAL. The increased
40
41 (Hphi+Hpho) character and the decreased hydrophobicity could be responsible for the higher
42
43
amount of water sorption by the cocrystal in comparison with RIV. However, the amount of
44
45
46 water gained per unit surface area by RIV-MAL cocrystal was around 39 times higher as
47
48 compared to RIV. The reason for the significant change in sorption tendency of RIV-MAL,
49
50 despite only small changes in contributions of ‘Hphi+Hpho’ (from 34.8% in RIV to 42.1% in
51
52
53 RIV-MAL), was further examined. The further investigation was carried out by comparing
54
55 the exposed hydrophilic groups in RIV-MAL and RIV for the strength of hydrogen bonding
56
57 interaction between the surface-exposed hydrophilic groups and the water molecule.
58
59
60
24
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27 Figure 11. Pie diagram showing hydrophilic (Hphi), hydrophobic (Hpho) and hydrophilic plus
28
29 hydrophilic (Hphi+Hpho) contributions onto the crystal surface of MAL, RIV, and RIV-MAL.
30 Cocrystallization of RIV with MAL led to an increase in ‘Hphi+Hpho’ surface contribution from 34.8
31
32 to 42.1% while a decrease in Hpho surface contribution from 65.2 to 57.9%.
33
34 Impact of Strength of Hydrogen Bonding Interactions
35
36
37 At molecular level, adsorption process involves formation of a surface monolayer of water
38
39 molecules. At given temperature and RH, equilibrium exists between adsorbed and desorbed
40
41
42 molecules on a crystal surface. Adsorption process becomes favorable when water molecules
43
44 form a relatively strong hydrogen bonding interactions with exposed chemical groups on
45
46 crystal surface.12, 42 The stabilization of monolayer of water molecules on crystal surface
47
48
49 triggers multilayer (up to three layers) formation, and subsequently higher amount of water
50
51 sorption can be seen. Thus, the presence of surface chemical groups that have strong
52
53 hydrogen bonding interaction with water molecules, may favor the water sorption tendency
54
55
of crystalline solid as compared to those with weak hydrogen bonding interactions. Thus, the
56
57
58 strength of hydrogen bonding interaction between exposed chemical groups on crystal
59
60 surface and water molecules would be more important in the cases where different amounts
25
1
2
3 of water sections has been observed in two crystal systems, despite having similar
4
5
6 ‘Hphi+Hpho’ contributions on their crystal surfaces.
7
8
9 ‘Hphi+Hpho’ nature imparted to RIV was due to 5-chlorothiophene and carbonyl (C=O)
10
11 groups. Similarly, ‘Hphi+Hpho’ in RIV-MAL was due to the presence of 5-chlorothiophene
12
13
and carboxyl (‒COOH) groups. In both cases, 5-chlorothiophene is common and hence they
14
15
16 had similar interactions with water molecules. A carboxyl group (‒COOH) from MAL in
17
18 RIV-MAL consists of both H-bond donor (hydroxyl, ‒OH group) and H-bond acceptor
19
20
21 (carbonyl, C=O group). In contrast, only a hydrogen bond acceptor (C=O) was exposed in the
22
23 case of RIV. DFT calculations were performed to quantify the strength of hydrogen bonding
24
25 between exposed functional groups on the crystal surface and water molecule. The
26
27
comparative analysis of the strength of hydrogen bonding interaction for C=O in RIV vis-à-
28
29
30 vis C=O and –OH (from MAL) in RIV-MAL was carried out. The hydrogen bonding
31
32 interaction energies (∆E) for RIV-H2O and MAL-H2O complexes (dual-bonded) were found
33
34 to be -5.1 and -10.2 kcal/mol, respectively. In RIV-MAL, the interaction energy for MAL-
35
36
37 H2O complex (dual-bonded) was found to have 5.1 kcal/mol lower than the interaction
38
39 energy of RIV-H2O, depicting the stronger H-bonding in the cocrystal (Figure 12). The
40
41 crystal surface of RIV-MAL contains both carbonyl and hydroxy groups of MAL, which
42
43
44 form bilateral H-bonds (dual H-bond) with a water molecule and yields the more stable
45
46 complex as compared to carbonyl groups of RIV (Figure 12a and b). Moreover, even the
47
48 carbonyl group in MAL forms relatively stronger hydrogen bond (∆E= -6.1 kcal/mol) in
49
50
comparison with the exposed carbonyl groups in RIV (∆E= -5.1 kcal/mol) (Figure 12c). The
51
52
53 formation of a strong H-bond between the carboxyl group (from acid) and another hydroxy
54
55 group (from water) has been well reported in the literature,41, 44 which further supports the
56
57 findings of DFT studies. Collectively, the relative % contributions of ‘Hphi+Hpho’ domain
58
59
60
26
1
2
3 and the strength of hydrogen bonding interaction explained the reason for the relatively
4
5
6 greater amount of water gained by RIV-MAL as compared to RIV.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28 Figure 12. The hydrogen bonding interaction energy for interaction of water with (a) carbonyl of
29
30 RIV, (b) carbonyl and hydroxy group of MAL and (c) only carbonyl of MAL.
31
32 The crystal packing density can be another important factor in the cases where hydrate
33
34
formation is evident during sorption-desorption studies. The crystal packing densities were
35
36
37 1.554, 1.621 and 1.548 g/cm2 for RIV, MAL, and RIV-MAL, respectively. The crystal
38
39 structure with inefficient packing and large void allows easy penetration of water molecules
40
41 inside crystal lattice to form crystal hydrate.1, 45, 46 The absence of hydrate formation in RIV-
42
43
44 MAL indicated no role of crystal packing density.
45
46
47 Summary of the approach adopted for investigating the molecular basis of water sorption
48
49 behavior of the cocrystal is presented in Scheme 1. This scheme also captures a
50
51 comprehensive summary of this work. We believe that this systematic approach shall be
52
53
54 utilized to comprehensively understand the mechanistic basis of water-sorption behavior
55
56 using a large set of single and multi-components crystalline organic solids.
57
58
59
60
27
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28 Scheme 1. Approach adopted to understand the molecular basis of water sorption behavior of the
29
30 cocrystal
31
32
33
CONCLUSIONS
34
35 The present study revealed that the extent of water sorption by RIV-MAL is governed by the
36
37 nature of the surface chemical groups exposed, their relative contributions onto the crystal
38
39 surface, and the strength of hydrogen bonding between the exposed chemical groups and
40
41
42 water molecules. Remarkably, the strength of hydrogen bonding has a profound impact on
43
44 the hygroscopicity of the cocrystal as the significantly higher water sorption (~39 times) was
45
46 observed in the cocrystal than RIV, despite only small changes in the surface contribution of
47
48
‘Hphi+Hpho’ domain. In a broad sense, the study highlighted that the moisture sorption
49
50
51 property of single-component (RIV and MAL) and multi-component (RIV-MAL) systems
52
53 depends on the surface chemical environment of a crystal and not the entire crystal structure,
54
55 provided there is no hydrate formation. In the framework of crystal engineering and structure-
56
57
58 property correlations, the present understandings have implications on designing materials
59
60 with desired moisture-sorption property.
28
1
2
3 SUPPORTING INFORMATION
4
5
6
Supporting information provided include: HSM analysis of RIV-MAL, IR frequencies of
7
8 RIV, MAL and the cocrystal, Crystal structure description of RIV, Specific surface area of
9
10 crystal samples, DSC heating curves of all three samples collected after DVS experiments,
11
12
Original (black and white) crystal image of RIV-MAL, Crystal size of samples used for face
13
14
15 indexing, List of coordinates and the absolute energies of the optimized geometry in DFT
16
17 calculations, Selected bond length and bond angle, and Details of hydrogen bond geometry
18
19 for RIV and RIV-MAL.
20
21
22
23 ACCESSION CODES
24
25 CCDC 1854617-1854618 contain the supplementary crystallographic data for this paper.
26
27 These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
28
29 emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic
30
31
32 Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
33
34
35 ACKNOWLEDGMENTS
36
37 We are grateful to Ikjot Sodhi for her help in MLP calculations, and Sneha Sheokand for her
38
39
valuable suggestions in DVS study. Authors also would like to thank Gunjan Kohli, Jyoti
40
41
42 Garg, Samarth D. Thakore and Sandeep S. Zode for insightful discussions (all from NIPER,
43
44 SAS Nagar). Dnyaneshwar acknowledges Department of Pharmaceuticals, Ministry of
45
46 Chemicals and Fertilizers, Government of India for the financial support.
47
48
49
50 REFERENCES
51
52 1. Reutzel-Edens, S. M.; Newman, A. W., The physical characterization of hygroscopicity in
53 pharmaceutical solids. In Polymorphism in the Pharmaceutical Industry, Wiley-VCH, Weinheim:
54 2006; pp 235-258.
55 2. Newman, A. W.; Reutzel-Edens, S. M.; Zografi, G. Characterization of the “hygroscopic”
56 properties of active pharmaceutical ingredients. Journal of Pharmaceutical Sciences, 2008, 97,
57 (3), 1047-1059.
58 3. Callahan, J.; Cleary, G.; Elefant, M., et al. Equilibrium moisture content of pharmaceutical
59
excipients. Drug Development and Industrial Pharmacy, 1982, 8, (3), 355-369.
60
29
1
2
3 4. Ahlneck, C.; Zografi, G. The molecular basis of moisture effects on the physical and chemical
4 stability of drugs in the solid state. International Journal of Pharmaceutics, 1990, 62, (2-3), 87-
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