Olanzapinium Salts, Isostructural Solvates, and Their Physicochemical

Article pubs.acs.org/crystal

Olanzapinium Salts, Isostructural Solvates, and Their Physicochemical Properties Ranjit Thakuria and Ashwini Nangia* School of Chemistry, University of Hyderabad, Central University PO, Prof. C. R. Rao Road, Gachibowli, Hyderabad 500 046, India S Supporting Information *

ABSTRACT: Solubility and dissolution play a crucial role in the activity and efficacy of an oral drug. Olanzapine is an antipsychotic drug of the Biopharmaceutics Classification System (BCS) class II category. Several solvates, cocrystals, salts, and amorphous forms of olanzapine have been prepared to study materials properties and its X-ray crystal structures were classified. We report herein a few salts, solvates, and solvate polymorphs of olanzapine to improve the physicochemical properties and study novel structural motifs. Olanzapinium dimaleate monofumaric acid is the first case of a ternary cocrystal of an active pharmaceutical ingredients (API) in the CSD database with maleate ion and fumaric acid coformers. The olanzapine disalts, olanzapinium dipicrate, dimaleate, and dimaleate monofumaric acid, contain a novel structural motif, different from the dimer motif characteristic of the four structural categories reported in the literature.

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INTRODUCTION Pharmaceutical salts1 and cocrystals are amenable to the tuning of physicochemical properties of active pharmaceutical ingredients (APIs) using crystal engineering. During the past decade, a large number of pharmaceutical cocrystals were reported with the aim to improve solubility and mechanical properties of crystalline APIs.2 The solubility/dissolution increment in the case of salts is far more dramatic compared with cocrystals (500−1000-fold compared with 4−20-fold) relative to the pure API. Drugs are often formulated as salts, among which HCl and NaOH are the most preferred salt formers for basic and acidic molecules, respectively. However, a limitation with pharmaceutical salts is that the parent API must have ionizable functional groups (COOH, amine, pyridine). Salt formation is guided by the oft-quoted ΔpKa rule.3 Amorphization is an alternative method to improve the solubility of an API, but the main drawback is that the high free energy amorphous phase can transform to the thermodynamic crystalline form.4 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, commonly known as olanzapine (OLN, brand name Zyprexa) is a psychotropic agent that belongs to the thienobenzodiazepine class.5 Zyprexa is among the top 20 prescription drugs based on a recent survey.6 According to the Biopharmaceutics Classification System (BCS),7 olanzapine drug has low solubility and high permeability in the class II category. It is a yellow crystalline solid, practically insoluble in water (43 mg/L), sparingly soluble in acetonitrile and ethyl acetate, and freely soluble in chloroform. The drug is stable at ambient temperature and humidity and its melting point is 190−195 °C. The olanzapine molecule has a central sevenmembered diazepine ring which is fused with benzene, a thiophene, and an N-methyl-piperazine substituent ring. The © XXXX American Chemical Society

boat conformation of the central 1,5-diazepine ring defines the overall butterfly shape of the molecule, but the N-methylpiperazine ring can have conformational variation. Two butterfly-like molecules form centrosymmetric dimers stabilized by C−H···π interactions between their cavities. A total of six polymorphs of the drug were claimed8 and characterized by PXRD (powder X-ray diffraction), but so far only two X-ray crystal structures have been reported for the guest free form (polymorphs II and IV) in the Cambridge Structure Database (CSD).9 In addition to crystalline forms of olanzapine disclosed in patents,10 X-ray crystal structures of five olanzapine salts are reported: two with nicotinic acid (OLN·NIC) and benzoic acid (OLN·BNZ) by Ravikumaret et al.;11a,b one with picric acid (OLN−PIC) by Dayananda et al.;11c and higher solubility and dissolution maleate and dimaleate salts (OLN·MLE) by Thakuria and Nangia.12The free base olanzapine has a tendency to form solvates, hydrates, and cocrystals.13,14 A recent paper by Florence et al.,14e published at the time of writing this manuscript, describes a thorough screening of almost 300 solution crystallizations and PIXEL calculations to determine the energy landscape of olanzapine solid forms. Recently, Zaworotko et al.15 reported a few isostructural quaternary multicomponent crystal forms of olanzapine and classified them into four different packing arrangements (Figure 1). Olanzapine is a dibasic molecule with pKa 7.37 and 4.69 corresponding to the N3 of piperazine and N1 of diazepine ring, respectively. Therefore according to the ΔpKa rule,3 it should form salts with acids of pKa < 5. We prepared salts of olanzapine with malonic acid, maleic acid, fumaric acid, salicylic Received: May 4, 2013 Revised: June 8, 2013

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dx.doi.org/10.1021/cg400692x | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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Figure 1. Four different packing arrangements of olanzapine crystal structures classified by Zaworotko et al.15

Table 1. pKa Values of Olanzapine and Acids Used in This Study

Scheme 1. Molecular Structure of Olanzapine and Carboxylic Acids Used as Coformers

molecule

7.37, 4.69

maleic acid (MLE)

1.92, 6.27

malonic acid (MLO)

2.83, 5.69

fumaric acid (FUM)

3.03, 4.44

p-aminobenzoic acid (PABA) salicylic acid (SAL)

4.65

a

2.97

product complex olanzapine and acid 1:1a olanzapine and acid 1:2a olanzapine and acid 1:1 olanzapine and acid olanzapine and

ΔpKa value

maleic

5.45

maleic

5.45, 2.77

malonic

4.54

fumaric

4.34

PABA

2.72

olanzapine and salicylic acid

4.4

Reference 12.

Olanzapinium Dimaleate Monofumaric Acid (OLN·2MLE·FUM) (1:2:1). Olanzapine (30 mg, 0.096 mmol), maleic acid (5.5 mg, 0.047 mmol), and fumaric acid (11 mg, 0.095 mmol) were dissolved in 10 mL of 1:1 ethyl acetate−nitromethane mixed solvent and heated at 60 °C until the solids disappeared. Yellow blocks of olanzapinium dimaleate monofumaric acid crystallized from solution after 2−3 days at room temperature. Olanzapinium p-Aminobenzoate Hemihydrate (OLN·PABA·0.5H2O) (1:1:0.5). Olanzapine (30 mg, 0.096 mmol) and paminobenzoic acid (10 mg, 0.096 mmol) were dissolved in 10 mL of acetonitrile solvent and heated at 60 °C to get a clear solution. The solution was kept for crystallization at room temperature. Yellow blocks of olanzapinium p-aminobenzoate hemihydrate crystallized from solution after 2−3 days. Olanzapinium Salicylate Benzene (OLN·SAL·1.5BEN) (1:1:1.5). Olanzapine (30 mg, 0.096 mmol) and salicylic acid (13 mg, 0.094 mmol) were dissolved in 10 mL of benzene solvent and heated at 60 °C until the solids disappeared. The clear solution was kept for crystallization at room temperature. Yellow block-shaped crystals of olanzapinium salicylate benzene crystallized after 1−2 days.

acid, and p-aminobenzoic acid, as well as a few isostructural monohydrate solvates of acetone, acetonitrile, nitromethane, and ethanol solvate form II. The salt formers used in this study are shown in the Scheme 1 with their pKa values listed in Table 1.

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pKa value

olanzapine (OLN)

EXPERIMENTAL SECTION

Olanzapinium Hydrogenmalonate (OLN·MLO) (1:1). Olanzapine (30 mg, 0.096 mmol) and malonic acid (10 mg, 0.096 mmol) were dissolved in 10 mL of 1:1 ethyl acetate−acetone mixed solvent and heated at 60 °C until the solids disappeared. The solution was kept for crystallization at room temperature. Yellow blocks of olanzapinium hydrogenmalonate crystallized from solution after 2−3 days. B


a

C

C20H24N4O4S 416.49 triclinic P1̅ 298 9.1759(9) 9.1769(9) 13.6079(14) 92.146(2) 94.031(2) 115.2640(10) 2 1030.81(18) 1.342 0.191 10665 4061 0.0478 0.1211 1.033

C29H32N4O12S 660.65 triclinic P1̅ 298 8.805(6) 9.634(6) 19.461(12) 88.035(11) 83.349(11) 74.023(11) 2 1576.4(18) 1.392 0.172 16185 6164 0.0972 0.1964 1.190

OLN·2MLE·FUM

Crystal structure was redetermined in this study at 298 K.

chemical formula formula wt cryst syst space group T, K a, Å b, Å c, Å α, deg β, deg γ, deg Z V, Å3 Dcalc, g cm−3 μ, mm−1 reflns collected unique reflns R1[I > 2(I)] wR2 (all) GOF

OLN·MLO C24H28N5O2.50S 458.57 monoclinic P21/c 100 12.5118(10) 9.6552(8) 19.3403(16) 90 91.0660(10) 90 4 2336.0(3) 1.304 0.172 23586 4589 0.0480 0.1079 1.098

OLN·PABA·0.5H2O

Table 2. Crystallographic Parameters of Olanzapine Structures C33H35N4O3S 567.71 triclinic P1̅ 100 9.270(4) 10.539(5) 15.713(7) 102.808(7) 104.176(8) 95.930(8) 2 1431.0(11) 1.318 0.155 14968 5664 0.0830 0.1593 1.124

OLN·SAL·1.5BEN C18.50H25N4O1.50S 359.48 monoclinic C2/c 298 24.628(3) 12.5833(15) 15.2002(18) 90 125.803(2) 90 8 3820.5(8) 1.250 0.186 19537 3777 0.0523 0.1472 1.052

OLN·ACE·H2Oa C17H22N4OS 330.45 monoclinic C2/c 298 24.549(2) 12.5131(11) 15.1433(13) 90 125.4670(10) 90 8 3788.6(6) 1.159 0.180 19376 3755 0.0500 0.1412 1.111

OLN·ACN·H2Oa C18H25N4O1.50S 353.48 monoclinic C2/c 298 24.541(7) 12.459(3) 15.178(4) 90 125.485(4) 90 8 3778.8(18) 1.243 0.187 19241 3719 0.0590 0.1537 1.022

OLN·EtOH·H2O form II

C17H22N4OS 330.45 monoclinic C2/c 298 24.850(4) 12.4355(17) 15.128(2) 90 125.521(2) 90 8 3804.9(9) 1.154 0.179 19429 3781 0.0691 0.1697 1.134

OLN·NTM·H2Oa

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polymorphic transformation or dissociation of the salts upon compression by PXRD. The intrinsic attachment was placed in a jar of 900 mL of water at 37 °C and rotated at 50 rpm. Seven milliliter aliquots were collected at specific time intervals, and concentrations of the aliquots were determined with proper dilution from the predetermined calibration curves of the respective salts using their individual molar extinction coefficients measured by UV−vis spectrophotometer.

Apart from benzene, all common laboratory solvents, such as methanol, ethanol, acetone, and ethyl acetate, resulted in pasty material. Olanzapine solvates with acetone, acetonitrile, ethanol, and a nitromethane monohydrate were crystallized by taking 30 mg (0.096 mmol) of olanzapine in the given solvent (10 mL). The above crystalline materials were prepared in bulk quantity and characterized by powder XRD match (see Supporting Information, Figure S1), FT-IR, NIR, Raman spectroscopy (Figures S2−S4, Supporting Information), DSC (Figure S5, Supporting Information), and visual HSM (Figure S6, Supporting Information). Melting points of salts are listed in Table S1, Supporting Information. Single Crystal X-ray Diffraction. X-ray reflections were collected on a Bruker SMART APEX CCD equipped with a graphite monochromator and Mo Kα fine-focus sealed tube (λ = 0.71073 Å). Data integration was done using SAINT.16 Intensities for absorption were corrected using SADABS.17 Structure solution and refinement were carried out using Bruker SHELXTL.18 The hydrogen atoms were refined isotropically, and the heavy atoms were refined anisotropically. N−H and O−H hydrogens were located from difference electron density maps, and C−H hydrogens were fixed using the HFIX command in SHELXTL. Disordered solvent molecules acetonitrile and nitromethane in olanzapine acetonitrile hydrate and olanzapine nitromethane hydrate, respectively, were removed using SQUEEZE in PLATON. The occupancy of water in OLN·PABA hemihydrate was fixed at 0.5 because the isotropic displacement for the water O atom is large (0.1032(13) Å2) compared with the other heavy atom (O2 of 0.0209(4) Å2) and also the R-factor improved when the structure was refined at O3 sof = 0.5. All crystal structures were collected at 298 K except OLN·PABA·0.5H2O and OLN·SAL·1.5BEN (which were collected at 100 K) because these crystals were unstable at room temperature. Crystallographic .cif files are deposited with the CCDC (Nos. 937417−937424) and may be accessed at www.ccdc.cam.ac.uk/ data or as part of the Supporting Information. X-ray data are summarized in Table 2, and hydrogen bond distances and angles are provided in Table S2, Supporting Information. Powder X-ray Diffraction. Powder X-ray diffraction of all samples were recorded on Bruker D8 Advance diffractometer using Cu Kα Xradiation (λ = 1.54056 Å) at 40 kV and 30 mA. Diffraction patterns were collected over a 2θ range of 5−50° at a scan rate of 1° min−1. Powder Cell 2.4 was used for Rietveld refinement.19 Vibrational Spectroscopy. Nicolet 6700 FT-IR spectrometer with an NXR FT-Raman module was used to record IR, NIR, and Raman spectra. IR and NIR spectra were recorded on samples dispersed in KBr pellets. Raman spectra were recorded on solid samples contained in standard NMR diameter tubes or on compressed samples contained in a gold-coated sample holder. Thermal Analysis. DSC was performed on a Mettler Toledo DSC 822e module. Samples were placed in crimped but vented aluminum sample pans. The typical sample size was 3−4 mg, and the temperature range was 30−300 °C at heating rate of 5 °C min−1. Samples were purged by a stream of dry nitrogen flowing at 150 mL min−1. HSM was performed on a Wagner & Munz PolythermA hot stage and Heiztisch microscope. A Moticam 1000 (1.3 MP) camera supported by software Motic Image Plus 2.0 ML was used to record images. Intrinsic Dissolution Rate. Intrinsic dissolution rate (IDR) measurements were carried on a USP-certified Electrolab TDT-08L dissolution tester. Equilibrium solubility was determined in water using the shake flask method. Two hundred milligrams of the powdered materials of the olanzapinium salts and pure base was added to 5 mL of water, and the resulting suspension was stirred at room temperature for 48 h. The suspension was then filtered through 2.5 μm Whatman filter paper. The concentration of the solution thus obtained was determined on a Thermo Scientific Evolution 300 UV−vis spectrometer based on the absorbance maxima with appropriate dilution using a predetermined calibration curve. For IDR experiments, 200 mg of the olanzapinium salt was taken in the intrinsic attachment and compressed to a 0.5 cm2 pellet using a hydraulic press at 2.5 t in.−2 pressure for 5 min. There was no

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RESULTS AND DISCUSSION Structural Analysis. In the crystal structure of olanzapinium hydrogenmalonate salt (P1̅ space group), one proton of

Figure 2. Bifurcated N−H···O−/N+−H···O− hydrogen bond between two olanzapinium and a malonate ion. Two such cyclic synthons are connected in the olanzapine dimer.

Figure 3. Two symmetry-independent maleate ions connected to olanzapinium dication through N+−H···O− hydrogen bond further bonded to two fumaric acid molecules via O−H···O hydrogen bonding (top). A maleate ion is connected to two olanzapinium dications in a bifurcated motif (bottom).

malonic acid is transferred to the N3 of the piperazine ring (N+−H···O−) of olanzapine. The diacid is connected to two olanzapine molecules through bifurcated N−H···O−/N+− H···O− hydrogen bonds to give a cyclic synthon of R24(22) D



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Figure 4. N−H···O−/N+−H···O− and O−H···O− hydrogen bond connecting PABA and water molecule to olanzapinium ion (top). 3D packing of the salt hydrate showing the frequent olanzapine dimer motif (bottom).

Figure 6. Water and acetone solvent associated via hydrogen bond with the olanzapine molecule (top). Two olanzapine dimers stacked orthogonally with the water and acetone molecules occupying the voids space (hydrogen atoms are removed for clarity) (bottom).

and FUM in P1̅ space group contains one olanzapine, two maleic acid, and one fumaric acid (as two half crystallographic molecules), which indicated the success of the planned experiment. In the crystal structure, two protons are transferred from different maleic acid molecules to the imine N1 and piperazine N3 of olanzapine. One of the maleate ions makes bifurcated hydrogen bonds to the imine N1 (N+−H···O−) and N4 (N−H···O−) of olanzapine (Figure 3) in a cyclic R24(14) synthon. The second maleate ion is connected to N3 of piperazine (N+−H···O−) in a discrete hydrogen bond (D motif). The two symmetry independent half fumaric acid molecules act as connectors, which link two olanzapinium maleate motifs through an O−H···O hydrogen bond. In one of the fumaric acid molecules, the carboxylic proton is shared by both fumaric and maleate ion (hydrogen bonded to N3 of piperazine ring), in a case of a partial proton transfer hydrogen bond. Therefore this structure can be considered as a salt cocrystal.23 This is the first case of maleic acid and fumaric acid coformers forming a ternary salt cocrystal because no such structures are reported in the CSD.24 The common olanzapine dimer motif is absent in this crystal structure, similar to the dimaleate salt. This crystal structure is difficult to classify into the four categories of packing motifs for olanzapine. The formation of the OLN·MLE·FUM 1:2:1 salt cocrystal where the 1:0.5:1 stoichiometry was expected may be explained by the pKa differences between the API and the coformers. Because of the larger ΔpKa value for OLN and MLE pair (5.45) compared with that for OLN and FUM (4.34), proton transfer will be facile with maleic acid compared with fumaric acid. Similarly for

Figure 5. Three-dimensional packing of the salt solvate with the olanzapine dimer synthon and two symmetry independent benzene solvent molecules (green and light blue) occupying the void space.

graph set.20 Two such units are connected through olanzapine C−H···π interactions in a dimer motif (Figure 2). The second COOH of malonic acid has an intramolecular hydrogen bond of S(6) geometry. The crystal structure of OLN·MLO shows a packing arrangement of type D in the Zaworotko classification15 (see Figure 1). Starting from the dimaleate of olanzapine reported by us,12 a ternary cocrystal/salt was attempted with maleic and fumaric acid in 1:0.5:1 ratio. The cocrystallization of olanzapine with maleic acid and fumaric acid (a geometrical isomer of maleic acid) was carried out with the objective to study the formation of a ternary salt and a novel packing motif different from the olanzapine dimer. Even as ternary cocrystals/salts are reported,21 ternary salts of an API with two different counterions are rare.22 The crystalline product of OLN, MLE, E



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Figure 7. Three-dimensional packing of (a) olanzapine acetonitrile monohydrate (type C), (b) ethanol monohydrate form II (type C), (c) reported ethanol hydrate form I (type A), and (d) nitromethane monohydrate (type C), all having the olanzapine dimer motif.

the second ionization of olanzapinium ion, the second ΔpKa of OLN and MLE is 2.77 whereas the value with FUM is 1.66 (4.69−3.03). Thus acidity and basicity of the API and coformers drive the transfer of two protons from MLE molecules, while FUM acts as a cocrystal former. OLN·PABA·0.5H2O salt hydrate crystallized in the monoclinic space group P21/c. A proton is transferred from the carboxyl group of PABA to the piperazine N3 of olanzapine. Both the carboxylate and carbonyl O are bifurcated, carboxylate O to N3 of piperazine ring (N+−H···O−) and water (O− H···O−) molecule and the carbonyl O to N4 of the diazepine ring (N−H···O) and amino group (N−H···O) of a second PABA molecule (Figure 4). In this salt hydrate, the common olanzapine dimer synthon is present with type D packing, similar to monosalts. OLN·SAL·1.5BEN solvate contains one olanzapinium, one salicylate ion, and 1.5 benzene molecules in the asymmetric unit. A proton is transferred from salicylic acid to the piperazine N3 (N+−H···O−), and the carbonyl O is hydrogen bonded to N4 of diazepine ring forming a cyclic synthon with graph set notation R44(26). The adjacent cyclic motif is close packed via C−H···π interaction of the olanzapine dimer, which forms a layer with flanking salicylate ions (packing type D). The cavities formed by the olanzapine dimer and the salicylate molecules are occupied by benzene molecules (Figure 5), which form an exact fit of the void size and shape. Other solvents, such as acetone, ethyl acetate, acetonitrile, and nitromethane, which do not fit snugly into this cavity, gave a pasty material. Isostructural Olanzapine Solvates. Crystallization of olanzapine from acetone yielded block-shaped crystals of acetone monohydrate solvate in C2/c space group, OLN·A-

CE·H2O (1:0.5:1). The water molecule is hydrogen bonded to two different olanzapine molecules (N3 and N4) through O− H···N and N−H···O hydrogen bonds. The close packing is driven by the spatial complementarity of the opposite enantiomer olanzapine molecule forming a dimer, which are aligned orthogonally to form a layer parallel to the (100) plane (packing type C). The water and acetone molecules occupy sites between the olanzapine dimers (Figure 6). Olanzapine acetonitrile monohydrate (OLN·ACN·H2O), olanzapine ethanol monohydrate form II (OLN·EtOH·H2O) (1:0.5:1), and olanzapine nitromethane monohydrate (OLN·NTM·H2O) solvates were prepared similarly by crystallizing with acetonitrile, ethanol, and nitromethane, respectively. All the solvate structures crystallize in C2/c space group with similar unit cell parameters and are isostructural to the acetone monohydrate solvate. The molecular packing of these solvates is shown in Figure 7. The olanzapine ethanol monohydrate solvate in this study is different from the crystal structure reported by Koziolet et al.14a of 2:1:2 stoichiometry. As explained by Byrnet et al.,9b this ethanol monohydrate form II (1:0.5:1) solvate is isostructural to the higher hydrate reported. The reported ethanol hydrate form I consists of parallel dimers of olanzapine molecules (packing type A), whereas form II shows orthogonal arrangement of dimers with ethanol and water molecules occupying the cavity (packing type C). Solubility and Dissolution. Improvement in the dissolution rate of weakly acidic or weakly basic drugs that are poorly soluble is a primary motivation for the preparation of pharmaceutical salts. The dissolution profile of olanzapine salts prepared in this study is shown in Figure 8. The amount of drug that dissolved in water as a function of time is shown in F



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Figure 9. PXRD patterns of the samples of OLN and the crystalline salts OLN·MLO, OLN·MLE, OLN·2MLE, OLN·PABA·0.5H2O, OLN·NIC, and OLN·SAL after the dissolution experiment and overlay of the calculated lines from the crystal structure confirm that the salts were stable during the dissolution experiment. The calculated line pattern of salicylate is not overlaid because it is a benzene solvate.

the corresponding salt dissolution is positively correlated; (2) after 12−15 min, the dissolution of dimaleate accelerates because each olanzapine molecule is bonded to two maleate ions, which can hydrate to solvent water molecules through twice as many O acceptors (the N−H···O hydrogen bonding is similar in the two salts, see Figure 2 and Figure S7, Supporting Information). We surmise that it takes about 10−15 min to break the strong ionic hydrogen bonds between OLN and MLE ions prior to hydration. A general trend summarized by Berge et al.1c states that salts of monocarboxylic acids are less soluble in water compared with those of dicarboxylic acids, which have one free carboxylic group. The higher solubility of the dimaleate salt compared with the monomaleate was previously rationalized on structural and hydrogen bonding arguments.12 There are more O atoms available in the disalt structure for hydrogen bonding to solvent water molecules, whereas the O atoms of the monomaleate are flanked by donor groups. Thus the solubility and dissolution trends are explained by crystal structure analysis and hydrogen bonding. The PXRD of olanzapinium salts after the dissolution measurements confirmed that they are stable under the solubility conditions (Figure 9).

Figure 8. (a) Dissolution profiles of crystalline OLN, OLN·MLE, OLN·2MLE, OLN·MLO, OLN·PABA·0.5H2O, OLN·NIC, and OLN·SAL in distilled water. (b) IDR (slope of curve in a) vs time curve of the same salts.

Table 3. Molar Extinction Coefficient and Dissolution Rate of Olanzapine Salts compound

extinction coefficients (mmol−1 cm−1)

dissolution rate (IDR) (mg cm−2 min−1)

λmax (nm)

OLN·MLE OLN·2MLE OLN·MLO OLN·NIC OLN·PABA·0.5H2O OLN·SAL OLN base

24.09 23.07 20.29 22.20 31.56 18.97 18.92

0.91 7.23 3.04 0.59 0.17 0.12 0.09

254 251 254 256 262 250 253

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CONCLUSIONS A few salts and isostructural solvates of the antipsychotic drug olanzapine were prepared, and their crystal structures and dissolution profile were studied. The butterfly-like thienobenzodiazepine ring is conformationally rigid, but the N-methylpiperazine part of the molecule has conformational variation as seen from the overlay (Figure 10) of crystal structures. But this conformational variation hardly affects the crystal packing, because the dimer motif was observed in all monosalts and solvate structures. However, the strong hydrogen bonds in disalt structures can interfere with the normal packing of olanzapine molecules to give unusual motifs for dipicrate, dimaleate, and dimaleate monofumaric acid salts. Crystal structures of more disalts of olanzapine are needed to understand the novel structural motif observed in disalts. Proton transfer in olanzapinium salts is consistent with the ΔpKa rule of 3. The solubility and dissolution studies place

part a, while the change in IDR rate is depicted in part b. The molar extinction coefficient calculated at the λmax for each salt and dissolution rates of olanzapine salts are listed in Table 3. From the dissolution profile, it was observed that olanzapinium dimaleate salt has the highest intrinsic dissolution rate (IDR) followed by malonate salt and then olanzapinium monomaleate and nicotinate (Table 3). The steep increase in the dissolution of the monomalonate salt in the first 15 min while the dimaleate salt is higher after that time is ascribed to two reasons: (1) the solubility of malonic acid (1400 mg/mL) is 1.8 times higher than that of maleic acid (780 mg/mL), and G



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maleate and malonate salts (with diacids) at higher priority for solubility enhancement of this BCS class II drug. The remarkable stability of salts suggests further exploration in drug formulation. To conclude, the inter-relationships between hydrogen bonding, crystal packing, molecular conformation, and dissolution/solubility learned from this study will serve as a starting point for the crystal engineering of improved oral medicines.

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AUTHOR INFORMATION

REFERENCES

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Figure 10. Molecular overlay for the olanzapine conformers in the crystal structures: olanzapine form II (red), olanzapine form IV (blue); OLN·MLO (brown); OLN·2MLE·FUM (dark gray); OLN·PABA·0.5H2O (green); OLN·SAL·1.5BEN (yellow); OLN·ACE·H2O (sky blue); OLN·ACN·H2 O (magenta); OLN·EtOH·H2 O form II (orange); OLN·NTM·H2O (light brown); OLN·MLE (pink), and OLN·2MLE (black). H atoms of the molecule are excluded for clarity.

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Article

S Supporting Information *

Crystallographic information files (.cif format), experimental details of crystallization (LAG), melting points of salts (Table S1), H-bonds distances (Table S2), PXRD patterns (Figure S1), FT-IR, NIR, and Raman spectra (Figures S2, S3, and S4); DSC and hot stage microscopy images (Figure S5 and S6), and hydrogen bonding in OLN·2MLE (Figure S7). This material is available free of charge via the Internet at http://pubs.acs.org. Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS R.T. thanks the UGC for fellowship. We thank the Department of Science and Technology for a J. C. Bose fellowship (SR/S2/ JCB-06/2009), DST-SERB Scheme Novel solid-state forms of API’s (SR/S1/OC-37/2011), and Council of Scientific and Industrial Research for Pharmaceutical Cocrystals (Project 01/ 2410/10/EMR-II). DST (IRPHA) and UGC (PURSE grant) are thanked for instrumentation and infrastructure.

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ABBREVIATIONS API, active pharmaceutical ingredients; BCS, biopharmaceutics classification system; CSD, Cambridge Structure Database; IDR, intrinsic dissolution rate; PXRD, powder X-ray diffraction H



Article

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Olanzapinium Salts, Isostructural Solvates, and Their Physicochemical

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