Isomorphous Salts of Anti-HIV Saquinavir Mesylate: Exploring the

Article pubs.acs.org/crystal

Isomorphous Salts of Anti-HIV Saquinavir Mesylate: Exploring the Effect of Anion-Exchange on Its Solid-State and Dissolution Properties Published as part of the Crystal Growth & Design Margaret C. (Peggy) Etter Memorial virtual special issue Cinira Fandaruff,† Laura Chelazzi,‡ Dario Braga,‡ Silvia Lucia Cuffini,*,§ Marcos Antônio Segatto Silva,† Jackson A. L. C. Resende,∥ Elena Dichiarante,⊥ and Fabrizia Grepioni*,‡ †

Laboratório de Controle de Qualidade, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil Dipartimento di Chimica G. Ciamician, Università degli Studi di Bologna, Via Selmi 2, 40126 Bologna, Italy § Instituto de Ciência e Tecnologia, Universidade Federal de São Paulo, UNIFESP, Rua Talim, 330. Sla 208, Vila Nair, São José dos Campos CEP, 12.231-280, São Paulo, São Paulo, Brazil ∥ Universidade Federal Fluminense, Niteroi, Rio de Janeiro, Brazil ⊥ PolyCrystalLine s.r.l., Via F.S. Fabri, 127/1, 40059 Medicina, Bologna, Italy ‡

S Supporting Information *

ABSTRACT: Saquinavir (SQV) is an important protease inhibitor used for AIDS/HIV antiretroviral therapy. As a free base it is almost insoluble in water, and it is commercialized as its mesylate salt (SQVM), classified as belonging to class IV (low permeability and solubility). Anion exchange has been used in this work to explore the effect of halides replacing the mesylate anion on the solid state and solubility properties of saquinavir at ambient temperature. All solid forms obtained were characterized via X-ray single crystal and powder diffraction, and their thermal behavior was analyzed via differential scanning calorimetry, thermogravimetric analysis, hot-stage microscopy and variable temperature X-ray powder diffraction. Saquinavir chloride (SQVCl), saquinavir bromide (SQVBr), and saquinavir iodide (SQVI) are all hydrates, the difference in the anion size being responsible for the different number of water molecules (3, 2, and 1, respectively). Dissolution properties have also been investigated, and it has been found that the behavior in water of SQVM and SQVCl are very similar, with 43 and 38% dissolved in 90 min, respectively, whereas for SQVBr and SQVI this percentage was 31 and 18%, respectively. Solid SQVCl could therefore be used as a valid alternative to current pharmaceutical formulations.

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INTRODUCTION

molecule and its multidirectional hydrogen bonding capability for linking drug molecules into stable crystal structure.4 A control on the crystal forms resulting from a manufacturing process is also crucial, as final properties of an API may dramatically and unexpectedly change upon solvent loss or addition, or due to appearance of polymorphic modifications.5 Saquinavir (SQV), named (2S)-N-[(2S,3R)-4-[(3S,4aS,8aS)3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-(quinoline-2-carbonylamino) butanediamide, and saquinavir mesylate (SQVM), N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2quinolylcarbonyl)-L-asparaginyl]amino] butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide methanesulfonate (Scheme 1), are anti-HIV drugs, classified by the Biopharmaceutical

Design and synthesis of molecular solid state structures with desired properties is a goal of crystal engineering and a subject of significant interest for pharmaceutical companies, especially when dealing with active pharmaceutical ingredients (APIs) which are characterized by limited bioavailability, therefore with suboptimal efficacy by oral route.1 A thorough understanding of the relevant noncovalent interactions at work between molecules and ions in pure molecular solids, solvates, cocrystals, and ionic co-crystals of APIs allows, at least in principle, modification of the physical and chemical properties of a drug.2 When ionizable groups are present, salt formation is the method most commonly employed to improve the solubility of a poorly soluble API;3 inclusion of solvent, especially water, in the crystalline edifice, often accompanies the salt formation, but the phenomenon is more general and not limited to salts: it is known that approximately one-third of the APIs form crystalline hydrates due to the small size of water © XXXX American Chemical Society

Received: May 20, 2015 Revised: September 23, 2015

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DOI: 10.1021/acs.cgd.5b00696 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

order to compare the solid-state and the solution properties of the new salts, saquinavir mesylate was also characterized at room temperature. All new salts were found to be isomorphous with SQVM.

Scheme 1. Chemical Structures of Saquinavir (SQV) and Saquinavir Mesylate (SQVM)

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EXPERIMENTAL SECTION

́ SQVM was provided by Cristália Produtos Quimicos Farmacêuticos Ltda (São Paulo, Brazil), and it was used without further purification. All other materials and solvents used were analytical grade reagents. Crystallization from Solution. Single crystals of saquinavir chloride trihydrate (SQVCl), saquinavir bromide dihydrate (SQVBr), and saquinavir iodide hydrate (SQVI) were obtained via anion-exchange from SQVM solutions. Stoichiometric amounts of NaCl, NaBr, or KI were added to a solution of 0.047 mmol of SQVM in 4 mL of propylene glycol or methanol; 4 mL of water was then added. The solutions were heated until complete dissolution was achieved. The chloride and bromide containing solutions were kept at room temperature, whereas the solution containing the iodide was allowed to cool very slowly, in order to grow crystals of suitable size for single crystal X-ray diffraction analysis. Colorless single crystals were obtained for each sample. Colorless single crystals of SQVM, to be used for structural solution at room temperature, were obtained via slow evaporation at 4 °C of a methanol solution. The structure of SQVI is heavily affected by positional disorder of the iodide ion. The disorder was modeled with six positions of the anion with a common occupancy factor. In this way we were able to account for most of the electron density, although, as a consequence of the disorder, distances between the anion, the OH group belonging to the cation, and the water molecule are not consistently correct (i.e., they are in many cases either too short or too long). Also the position of the water molecule cannot be sufficiently well described; in this case we choose simply to anisotropically treat the oxygen atom, revealing a strong anisotropy along the direction connecting the NHsaquinavir···water···I− moieties (see Supporting Information). The disorder can be explained with the large volume available to the iodine−water pair, which is more efficiently filled by mesylate, chloride, and three water molecules, or bromide and two water molecules in SQVM, SQVCl, and SQVBr, respectively (see Results and Discussion). X-ray Single Crystal Diffraction. Single crystal X-ray data for SQVM, SQVCl, SQVBr, and SQVI were collected at room temperature on an Oxford X’Calibur S CCD diffractometer equipped

Classification System (BCS) as belonging to class IV,6,7 and their low aqueous solubility is correlated to their extremely low bioavailability ( 2σ(I)] Rint R1 [I > 2σ(I)] wR2 (all data)

SQVM

SQVCl

SQVBr

SQVI

C39H54N6O8S 766.94 monoclinic P21 14.633 (5) 9.370 (5) 15.966 (5) 90.00 114.871 (5) 90.00 1986.1 (1) 2 293 1.283 0.140 15494 7761 4516 0.0553 0.0674 0.0896

C38H51N6O5Cl·3H2O 761.34 monoclinic P21 14.275 (2) 9.6424 (5) 16.008 (2) 90.00 111.617 (12) 90.00 2048.5 (3) 2 293 1.234 0.149 10092 7806 3522 0.0444 0.0965 0.2140

C38H51N6O5Br·2H2O 787.79 monoclinic P21 14.3053 (7) 9.7478 (4) 15.847 (1) 90.00 111.404 (7) 90.00 2057.4 (2) 2 293 1.272 1.051 10264 6901 4168 0.0390 0.0643 0.1214

C38H51N6O5I·H2O 816.76 monoclinic P21 14.3578 (7) 9.4796 (4) 15.982 (1) 90.00 111.131 (7) 90.00 2029.0 (6) 2 293 1.337 0.839 17691 8156 3949 0.0407 0.0840 0.2647

B



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with a graphite monochromator (Mo−Kα radiation, λ = 0.71073 Å). Crystal data and details of measurement are listed in Table 1. All nonhydrogen atoms, except iodine in SQVI, were refined anisotropically; H atoms were added in calculated positions and refined riding on their respective carbon, oxygen, or nitrogen atoms. SHELX9712a was used for structure solution and refinement on F2; PLATON12b was used for packing coefficients and accessible volume calculation; Schakal9912c and Mercury12d were used for molecular graphics. X-ray Powder Diffraction (XRPD). X-ray powder diffractograms in the 2θ range 5−70° (step size 0.011°, time/step 50 s, VXA 40X40) were collected on a PANalytical X’Pert PRO automated diffractometer equipped with an X’celerator detector. The data were collected in Bragg−Brentano geometry, using Cu−Kα radiation without a monochromator. The identity of the bulk material obtained via solution crystallization was verified by comparing the experimental XRPD patterns with those simulated on the basis of single crystal data. Variable Temperature X-ray Powder Diffraction (VTXRPD). X-ray powder diffractograms of SQVCl, SQVBr, and SQVI in the 2θ range 5−50° were collected on a PANalytical X’PertPRO automated diffractometer equipped with an X’Celerator detector and an Anton Paar TTK 450 system for measurements at controlled temperature. The data were collected in open air in Bragg−Brentano geometry using Cu−Kα radiation without a monochromator. Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Calorimetric measurements were performed using a DSC 200 F3Maia differential scanning calorimeter equipped with an intracooler. The samples (2−4 mg) were placed in open aluminum pans, and the heating was carried out at 10 °C min−1 in N2 atmosphere. TGA measurements were performed with a PerkinElmer TGA7 in the temperature range 37−500 °C under an N2 gas flow, at a heating rate of 5 °C min−1. Hot Stage Microscopy (HSM). HSM measurements were carried out using a Linkam TMS94 device connected to a Linkam LTS350 platinum plate. Images were collected with the imaging software Cell, from a Visicam 5.0 stereoscope. All images (100×) were taken with an Olympus optical microscope. Dissolution Properties. The maximum concentration achievable in solution was measured by adding an excess of SQVM, SQVCl, SQVBr, and SQVI in 10 mL of water and kept in a shaker (Kika Werke magnetic stirrer plate) under stirring at 300 rpm for 24, 12, and 3 h at room temperature. Once removed from the plate, the solutions were filtered (0.45 μm), diluted, and analyzed by UV−vis Cary 50 Varian. The program used was “Concentration” (Cary 50 WinUV Software V.3), and the measurements for each sample were recorded at 240 nm. The test was carried out in duplicate, and for each sample five measurements were taken. The calibration curve was constructed by plotting the values of absorbance against those of concentrations for five standard solutions of the sample in a water medium in standard concentrations. The dissolution profile analyses were performed using a dissolution tester. The dissolution profiles were performed on a Hanson’s Vision Classic 6 dissolution tester at 100 rpm stirring, 100 mL of water as dissolution medium at 37 °C in which were added approximately 50 mg of sample. The analyses were carried out in duplicate, and for each sample five measurements were taken. The apparatus 2 (USP) was used, and samples of 2 mL were withdrawn at 5, 10, 15, 20, 30, 45, 60, and 90 min. The samples were filtered and diluted, and the specimens were analyzed by UV−vis as described earlier. The values obtained were converted from Abs/min to concentration/min.

both are the same except for a replacement of one or more atoms in one structure with different types of atoms in the other (isomorphous replacement), such as heavy atoms, or the presence of one or more additional atoms in one of them (isomorphous addition).” Crystalline SQVCl, SQVBr, and SQVI respect this definition, with different amounts of water molecules as components of an isomorphous addition, i.e. three, two, and one water molecules, respectively, are present for every SQV+X− ion pair; the number of water molecules decreases as the size of the anion replacing the mesylate in the new structures increases (see Table 1 and Figure 1).

Figure 1. Images taken at room temperature with an optical microscope (a) and a graphical representation of the asymmetric unit content in crystalline SQVM, SQVCl, SQVBr, and SQVI (b) (H atoms omitted for clarity).

SQVM and its isomorphous halide salts crystallize in the monoclinic P21 space group, with one independent formula unit in the asymmetric unit. In crystalline SQVM the mesylate anions act as bridges between protonated saquinavir units, thus originating hydrogen bonded chains extending parallel to the baxis direction (see Figure 2). These chains are in turn connected via N−H···O hydrogen bonds, thus forming a large ribbon extending parallel to the ac-plane. The packing features of crystalline SQVCl, SQVBr, and SQVI are extremely similar, as they are all isomorphous with SQVM, but the bridging role of the mesylate anion is replaced by a water molecule and the halide anion in SQVCl, SQVBr, and SQVI, with the water molecule directly interacting with the NH group on one saquinavir unit and the anion interacting with the OH group of a second saquinavir along the saquinavir-mesylate chain (see Figure 2). A second (in SQVCl and SQVBr) and a third (in SQVCl) water molecule add to the stability of the crystalline edifice via Owater···Owater and Owater···Cl− interactions and hydrogen bridges between the oxygen and nitrogen atoms

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RESULTS AND DISCUSSION Solid State Characterization. SQVM crystallizes in the monoclinic space group P21 with one protonated saquinavir and one mesylate ion per asymmetric unit (Z′ = 1). Crystalline SQVCl, SQVBr, and SQVI are isomorphous. According to the IUCR definition (http://reference.iucr.org/dictionary/ Isomorphous_crystals) “two crystals are said to be isomorphous if (a) both have the same space group and unit-cell dimensions and (b) the types and the positions of atoms in C



Article

Figure 3. Comparison of experimental XRPD patterns at room temperature for crystalline SQVM, SQVCl, SQVBr, and SQVI.

is observed at different temperatures as an endothermic event (see Figure 5), followed by melting of the anhydrous form at temperatures that, in all cases, are lower than the one observed for SQVM (see Table 2). While the temperature at which water Table 2. Melting Point, Packing Coefficient and Accessible Volume for SQVM, SQVCl, SQVBr, and SQVI as Such and upon Virtual Removal of Anions and Water Molecules

SQVM SQVCl SQVBr SQVI

mp (°C)

p.c. , %

accessible volume (Å3), %

251.79 164.89 187.29 214.95

66.8 64.9 63.7 63.2

25, 1.3 52, 2.5 107, 5.2 102, 5.0

a

a

p.c. , % SQVb SQVc SQVd SQVe

60.6 58.8 58.5 59.1

accessible volume (Å3), % 254, 282, 301, 261,

12.8 13.7 14.7 12.9

a

The packing coefficient is evaluated via the program PLATON12b as the (Molecular volume) × (number of formula units in the cell) × 100/(cell volume). Fifth column: Virtual removal of bmesylate, c chloride and water molecules, dbromide and water molecules, eiodide and water molecule. Figure 2. Ball-and-stick representation of the hydrogen bonding interactions among mesylate, chloride, bromide, and iodide anions, saquinavir cations and water molecules in SQVM (a), SQVCl (b), SQVBr (c), and SQVI (d).

is released from the crystalline edifice increases on passing from the chloride to the bromide salt, thus implying a stronger interaction between the water molecules and between water and the ionic moieties in SQVBr with respect to SQVCl, in SQVI loss of water is observed at lower temperature, with respect to SQVBr. Table 2 lists the accessible volume (calculated with the program PLATON12b) and its percentage on the cell volume, calculated with and without the contribution of the anions and the water molecules. The virtual removal of anions and water molecules results in approximately equal packing efficiencies and accessible volumes for the four compounds (as it should be, given that they are isomorphous); on the contrary, it can be seen that the most efficient real packing occupancy is attained in the case of SQVM (p.c. 66.8%), and the loosest packing is the one observed for SQVI (p.c. 63.2%). The fact that the space occupancy of the iodide−water pair is poor is reflected in the heavy positional disorder of the iodide ion. The loss of one water molecule, though, is a less dramatic event than for SQVCl and SQVBr, which rely on three and two water molecules for

adjacent to the t-butyl group on two different saquinavir cations. Differences in the number of water molecules and in the anion type and size have a moderate effect on the cell axes dimensions (Table 1) and on the position of the diffraction peaks (Figure 3). XRPD patterns measured for the isomorphous crystal forms SQVM, SQVCl, SQVBr, and SQVI are all very similar, especially in the low-theta region. Shifts in the patterns and change in the intensity of specific peaks, with respect to SQVM, can be attributed to the presence and position of different anions, i.e., different scattering elements, and to the different water contents (see Figure 3). Thermal behavior of all forms was investigated via DSC, TGA, and variable temperature XRPD. DSC measurements were conducted in open pan: for all hydrated salts loss of water D



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their stability, and the anhydrous SQVI phase shows the highest melting point of the halide series (see Table 2). Thermogravimetric analysis measurements confirm that SQVCl, SQVBr, and SQVI in their bulk form contain three, two, and one water molecules per formula unit, respectively (see Figure Supporting Information-TGA1). They also show that all salts decompose at a temperature immediately following melting. Hot-stage microscopy was employed to detect possible modifications of crystal habit and texture upon heating and consequent release of water. In all cases a slight darkening of the crystals can be detected under the microscope, accompaniedparticularly in the case of SQVClby the formation of dark lines, indicating stress and partial cracking of the surface, as can be seen in Figure 4. However, in all cases the general shape of the crystal or the crystalline aggregate was maintained upon water removal. Variable temperature XRPD measurements (Figure 6) show that there are no significant modifications on the crystalline structures during both heating and cooling processes. The

Figure 5. DSC traces for (starting from top) SQVM, SQVCl, SQVBr, and SQVI (measurements are in open pan).

Figure 6. Variable temperature X-ray powder diffraction measurements on SQVCl. Analogous behavior has been observed for SQVBr and SQVI. Heating and cooling processes were all conducted at 5 °C min−1.

behavior is identical for the three isomorphous forms; i.e., the crystal edifice is left approximately intact upon water removal. Slight shifts in the peak positions upon heating are due to limited cell parameters modifications and to the change in composition due to water removal. Upon cooling the room temperature XRPD pattern is restored, although some amorphization is now evident. Solubility Studies. In order to determine the solubility of SQVM and its isomorphous forms, the samples were investigated after 12 h in a saturated water solution. The SQVI powder sample obtained by filtration after 12 h had a yellowish color, and for this reason it was analyzed via DSC and XRPD. There was no apparent change between the XRPD patterns measured before and after the solubility test; DSC analysis, on the contrary, showed a decrease of approximately 15 °C in the melting point for the sample that had been used for the solubility test. Standard solutions were then prepared with this sample, and, on the basis of the resulting concentration measurements, it was possible to conclude that a chemical degradation process had occurred. Therefore, the maximum concentration for SQVM, SQVCl, SQVBr, and SQVI in water was determined after 3 h. A maximum concentration value of 174 ± 12 μg/mL was obtained for SQVM, while for SQVI this value was 51.2 ± 0.3 μg/mL. SQVCl and SQVBr presented very similar maximum concentration values, 105 ± 2 μg/mL and 107 ± 10 μg/mL,

Figure 4. Hot-stage microscopy on crystals of SQVCl (a), SQVBr (b), and SQVI (c). E



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When did we make our first “crystal by design”? There was a moment of inspiration during the Italo-Israeli Meeting in 1992.1 Peggy Etter had shown in her talk that benzene could be used to template the hydrogen bonding of six 1,3cyclohexanedione molecules into a hexameric “cyclamer”. When, soon after, Fabrizia Grepioni spoke about the packing analogy between solid benzene and bisbenzene chromium (C6H6)2Cr Peggy suggested the possibility of substituting benzene for bisbenzene chromium in the dione cyclamer. The idea was beautifully simple and we did almost succeed when we finally tried it. However, since shape is not everything in chemistry, the oxidation of (C6H6)2Cr to (C6H6)2Cr+ had led to something similar to, but not quite the same as, Etter’s cyclamer.2b Nonetheless, we had learned that crystal design was indeed possible and, with this, joined the rapidly growing community of crystal makers. The suggestion made by Margaret Etter15 at the meeting was preceded by a short note passed to Fabrizia Grepioni after her talk on organometallic solids. The note survived many changes of location and is shown below in Figure 8.

respectively. The high standard deviation for SQVM is probably due to an agglomeration effect, since raw SQVM is micronized to improve the bioavailability, and this process promotes agglomeration and therefore reduces the surface area in contact with the dissolving medium.13 Also, the size of the SQVBr particles seems to be larger than that observed (via optical microscope) for SQVCl and SQVI, and this might be the origin of the high standard deviation for the sample of SQVBr with respect to the other salts. Powder dissolution profiles for SQVM and its isomorphous halide salts are shown in Figure 7. Statistical analysis was carried

Figure 7. Dissolution Profile of SQVM, SQVCl, SQVBr, and SQVI.

out applying regression analysis: the four samples show different profiles (for confidence interval α = 0.05, p < 0.1). SQVM and SQVCl profiles are the most similar to 43 and 38% dissolved in 90 min, respectively, whereas for SQVBr and SQVI this percentage is 31 and 18%. As shown in Figure 7, SQVI presents a higher standard deviation in comparison with SQVCl and SQVBr, which is likely because this sample showed a tendency to remain on the medium surface.

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Figure 8. Note written by Margaret Etter during the Italo-Israeli Meeting on “The Influence of Steric and Electronic Effects on Molecular and Crystalline Structure”, Tel-Aviv, 1992.

As a consequence of our meeting with Margaret Etter, we brought into the field of crystal engineers our knowledge of and experience with crystalline materials. In our solid-state journey we have passed through vast areas of organometallic, organic and inorganic systems, and helped in “hybridizing” them. We have met and fallen in love with polymorphism, and all this has represented our entry point in the pharmaceutical field. Collaborations with companies have helped in funding our research, and in fair exchange we have founded our own company16 to deal with solid-state problems. Scientists in many disciplines connected to crystal engineering have turned into friends, and annual meetings on Crystal Forms have sprouted since in Bologna. Peggy Etter was passionate about her work which is still a source of inspiration−and in this respect we feel that we certainly are kindred spirits.

CONCLUSIONS

Three isomorphous forms of SQVM, i.e., SQVCl, SQVBr, and SQVI, obtained upon substitution of mesylate with chloride, bromide, or iodide, were prepared and investigated by solid state techniques (SCXRD, XRPD, DSC/TGA, HSM, and VTXRPD). The room temperature form of SQVM was also determined, for the sake of comparison. The dissolution profile was measured for all forms. The dissolution profile in water turned out to be very similar for SQVM and SQVCl, with 43 and 38% dissolved in 90 min, respectively. Hence, SQVCl could represent an excellent alternative to the current pharmaceutical formulation. Work is in progress to further explore crystal forms that can be obtained from SQVM and to investigate salts and co-crystals of saquinavir free base.

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ASSOCIATED CONTENT

S Supporting Information *

DEDICATION TO MARGARET ETTER

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b00696. Crystallographic information files (cif) for all structures described herein have been deposited in the Cambridge Structural Database (CCDC 1401779−1401782).

This paper is dedicated to Margaret Etter, and the reason is the following. In 2003, Dario Braga wrote a focus article for CrystEngComm with the title “Crystal engineering, Where from? Where to?”14a and we copy here below a paragraph taken from the first page (refs 1, 2a, and 2b in the following text are collected together in ref 14 as 14b, 14c, and 14d, respectively):

TGA traces for SQVCl, SQVBr, and SQVI (PDF) Crystallographic information files (CIF) F



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(11) The low-temperature structure of SQVM has recently been reported in Fandaruff, C.; Caon, T.; Rauber, G. S.; Simões, C. M. O.; de Campos, C. E. M.; Bortoluzzi, A. J.; Cuffini, S. L.; Silva, M. A. S. AAPS PharmSciTech, 2015 submitted. (12) (a) Sheldrick, G. M. SHELXL97: Program for Crystal Structure Determination; University of Göttingen: Germany, 1997. (b) Speck, A. L. PLATON; Acta Crystallogr., Sect. A 1990, 46, C34. (c) Keller, E. SCHAKAL99, Graphical Representation of Molecular Models; University of Freiburg: Freiburg, Germany, 1999. (d) Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock, E.; RodriguezMonge, L.; Taylor, R.; van de Streek, J.; Wood, P. A. J. Appl. Crystallogr. 2008, 41, 466−470. (13) Caon, T.; Konig, R. A.; Cardoso, S. G.; Campos, C. E. M.; Cuffini, S. L.; Koester, L. S.; Simões, C. M. O.; de Cruz, A. C. C. Arch. Pharmacal Res. 2013, 36, 1113−1125. (14) (a) Braga, D. Chem. Commun. 2003, 22, 2751−2754. (b) ItaloIsraeli Meeting on The Influence of Steric and Electronic Effects on Molecular and Crystalline Structure, Tel-Aviv, 1992. (c) Etter, M. C.; Urbonczyk-Lipkowska, Z.; Jahn, D. A.; Frye, J. S. J. Am. Chem. Soc., 1986, 108, 5871. Ref 2a in Braga’s papers also reports that Etter’s cyclamer has been chosen as a logo, for CrystEngComm, the RSC journal devoted to crystal engineering (http://www.rsc.org/ CrystEngComm) 10.1021/ja00279a035 (d) Braga, D.; Grepioni, F.; Byrne, J. J.; Wolf, A. J. Chem. Soc., Chem. Commun. 1995, 1023. (15) Margaret Etter and co-workers were pioneers in the study and building of hydrogen bonding patterns, via a careful and selected use and competition of hydrogen bonding donor and acceptor groups, and had largely employed cocrystallization methods to study strength and reproducibility of patterns. See for example: (a) Etter, M. C.; Baures, P. W. J. Am. Chem. Soc. 1988, 110, 639. (b) Etter, M. C.; Frankenbach, G. M. Chem. Mater. 1989, 1, 10. (c) Etter, M. C.; Adsmond, D. A. J. Chem. Soc., Chem. Commun. 1990, 589. (d) Etter, M. C. Acc. Chem. Res. 1990, 23, 120. (e) Etter, M. C.; MacDonald, J. C.; Bernstein, J. Acta Crystallogr., Sect. B: Struct. Sci. 1990, 46, 256. (f) Etter, M. C. J. Phys. Chem. 1991, 95, 4601. (16) PolyCrystalLine (http://www.polycrystalline.it/).

AUTHOR INFORMATION

Corresponding Authors

*(S.L.C.) E-mail: scuffi[email protected]. *(F.G.) E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank Cristalia Laboratory for donating saquinavir mesylate samples, and CNPq, Fundación Sauberan, and CONICET for financial support. CAPES is acknowledged for a one-year Ph.D. student fellowship at the University of Bologna (CF). We thank Dr. Katia Rubini for DSC and TGA measurements.

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REFERENCES

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