Mechanochemical Synthesis of Olanzapine Salts and Their Hydration

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Mechanochemical Synthesis of Olanzapine Salts and Their Hydration Stability Study Using Powder X-Ray Diffraction Kashyap Kumar Sarmah, Pranamika Sarma, Dharmaraj R Rao, Poonam Gupta, Naba K. Nath, Mihails Arhangelskis, and Ranjit Thakuria Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01593 • Publication Date (Web): 01 Mar 2018 Downloaded from http://pubs.acs.org on March 3, 2018

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Crystal Growth & Design

Mechanochemical Synthesis of Olanzapine Salts and Their Hydration Stability Study Using Powder X-Ray Diffraction Kashyap Kumar Sarmah,a Pranamika Sarma,a Dharmaraj R. Rao,b Poonam Gupta,c Naba K. Nath,c Mihails Arhangelskisd,* and Ranjit Thakuriaa,* a

Department of Chemistry, Gauhati University, Guwahati 781014, Assam, India

b c

Cipla Ltd., Research & Development Centre, L B S Marg, Vikhroli, Mumbai 400083, India

Department of Chemistry, NIT Meghalaya, Bijni Complex, Laitumkhrah, Shillong 793003, Meghalaya,

India d

Department of Chemistry, McGill University, 801 Sherbrooke Sreet. West, Montréal, Canada

Abstract A series of olanzapine (OLN) dicarboxylic acid salts including earlier reports on olanzapinium malonate (1:1) and maleate (1:1 and 1:2) were prepared mechanochemically using liquid assisted grinding (LAG) in order to study their hydration stability. Powder X-ray diffraction (PXRD) was used as a characterization tool during the investigation. Based on the single crystal structures of respective OLN salts a negative correlation between the dicarboxylic acid chain length and the hydration stability of the corresponding OLN salt was found. Our observations suggested, that the overall crystal packing, beyond the stronger hydrogen bond synthon (N+–H···O– in OLN salts compared to O–H···N in OLN hydrates) play an important role in designing OLN salts with better hydration stability. In addition, melting point analysis showed that OLN dicarboxylic acid salts follow melting point alteration behavior similar to the pure diacids. Introduction Mechanochemistry is a well-established technique used for solid-state supramolecular and covalent chemical synthesis induced by the input of mechanical energy.1-3 The minimal amount of solvent used in mechanochemical experiments has made mechanochemistry a widely explored greener alternative to the solution mediated chemical synthesis. The method has been used to synthesize materials such as cocrystals,4,5 salts,6,7 pharmaceutical solids,8 discrete metal complexes,9 metal organic frameworks,10,11 zeolitic imidazolate frameworks.12 Mechanochemistry has been also applied to organic synthesis including C–C, C–O, C–N bond formation reactions,13 synthesis of heterogeneous catalysts,14 and porous organic polymers,15-18 etc which have been well explored in the literature.19,20 Grinding is one of the ways to carry out mechanochemical synthesis. Grinding can be carry out in absence or in presence of a small

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(catalytic) amount of liquid. Former process is termed as neat (dry) grinding whereas the latter is known as liquid assisted grinding (or kneading). Friščić et. al. popularized the term “liquid assisted grinding”4,20,21 whereas Braga et. al. choose the term “kneading”5,22-24 to describe the same process. Hydration instability is a major threat in pharmaceutical industry from the prospect of drug formulation, processing and storage.25,26 As relative humidity (RH) varies across the globe depending on climatic condition and geographical location, the possibility of hydrate formation cannot be ignored in case of drug substances.27 Among the drug compounds which undergo hydrate formation at high humidity is olanzapine (OLN),28-30 an antipsychotic drug used for the treatment of schizophrenia and bipolar disorder.31 Molecular structure of OLN contains a seven membered diazepine ring fused with benzene, thiophene and a 4-methylpiperazine resulting a butterfly shaped conformation.32 Olanzapine is a dibasic molecule with pKa 7.37 and 4.69 for piperazine and diazapine nitrogens, respectively. Along with polymorphic guest-free forms,33-35 a large number of OLN solvates,36,37 salts38,39 and cocrystals40,41 were reported in the literature including a recent report from our group.42 In their recent work Florence and coworkers investigated the hydrate formation of OLN with the aid on atomic force microscopic (AFM) analysis.43,44 Analysis of available crystal structures revealed that all the hydrated forms (hemi, mono and dihydrate) contain O–H···N hydrogen bond between water and piperazine nitrogen of OLN. Consequently, one way to suppress hydrate formation, is to synthesize OLN salts where the O–H···N hydrogen bond is replaced with a much stronger ionic N+–H···O– bond based on ∆pKa rule45,46 (Figure 1).

N

+

H O

N H

O

-

O

H N

N

N

N N H

(a)

S

N H

S

(b)

Figure 1. (a) Olanzapine hydrate resulted due to formation of N···H–O hydrogen bond between OLN and water molecule. (b) Stronger ionic N+–H···O– hydrogen bond formation on grinding with acid coformer resulting olanzapinium salts. Herein, mechanochemical synthesis, more specifically liquid assisted grinding (LAG) is used to synthesize several molecular salts of OLN with HOOC(CH2)nCOOH (n = 0, 1, 2*, 3 and 4). Molecular structures of OLN base and the aliphatic dicarboxylic acids used in our study are shown in scheme 1. The hydration stability is evaluated under controlled humidity conditions using powder X-ray diffraction


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(PXRD) as a characterization tool. We then correlate the relative hydration stability of OLN salts with their corresponding crystal structures. Jones group carried out a systematic study on hydration stability of dicarboxylic acid cocrystals of caffeine47 and theophylline48 under controlled humidity. A few other reports on hydration stability of cocrystals/salts were reported in literature.49-53 HO N

O

N

O OH

Oxalic acid (OA)

N

O HO

N H

S

Olanzapine (OLN)

HO

O OH HO

O Succinic acid (SA)

OH

Malonic acid (MOA)

O

O

O

O HO

OH

Maleic acid (MA) O

O OH

Glutaric acid (GA)

OH

HO O Adipic acid (AA)

Scheme 1. Molecular structure of olanzapine (OLN) and dicarboxylic acid molecules considered for this study (2* = maleic and succinic acid) Experimental Section Materials used: All the dicarboxylic acids were purchased from TCI, India and were used as received. Bulk materials for controlled humidity studies were prepared by manually grinding stoichiometric amounts of OLN (30-40 mg) and respective dicarboxylic acids with mortar pestle under LAG conditions. Liquid assisted grinding was performed by adding 2-3 drops of acetonitrile and grinding the material for about 45 minutes. The materials were subsequently placed in an oven and heated at 80 °C for about 15-20 minutes to exclude the possibility of forming solvated salts. The OLN salts with SA, GA and AA showed strong hygroscopic properties, rapidly absorbing moisture in ambient conditions, resulting in a sticky material. Solution crystallization: Solution crystallization for OLN-OA and OLN-SA salts was unsuccessful, and form polycrystalline precipitate. The crystal structure of OLN-OA salt was determined from PXRD data, while the quality of the powder data for OLN-SA salt did not permit structure determination. PXRD structure solution using data from instruments with reflection geometry is well established in literature.54-59 Single crystal of OLN-MOA, OLN-MA and OLN-diMA salts were prepared according to the reported procedures.38,39 Olanzapinium glutarate acetonitrile (1:1:1 Olanzapine/Glutaric acid/Acetonitrile). OLN (30 mg, 0.096 mmol) and GA (12.6 mg, 0.096 mmol) were dissolved in 10 mL of acetonitrile and heated at 80 °C until complete dissolution. The solution was then stored at room temperature for slow crystallization.



Yellow block shaped single crystal of OLN-GA acetonitrile solvate crystallized from the solution after 23 days. Olanzapinium hemiadipate hemiadipic acid acetonitrile hydrate (1:1:1:1 Olanzapine/Adipic acid/Acetonitrile/Water). OLN (30 mg, 0.096 mmol) and AA (14 mg, 0.096 mmol) were dissolved in a 1:1 mixture of acetonitrile and nitromethane and heated at 80 °C for complete dissolution of starting materials. The resulting solution was filtered and kept at room temperature for crystallization. Yellow colored block shaped single crystals of olanzapinium hemiadipate hemiadipic acid acetonitrile hydrate were obtained after 2-3 days. General methods. The various humidity environments were generated at ambient temperature (~28 °C) within sealed glass desiccator jars containing P2O5 for 0%, saturated K2CO3 for 43% and K2SO4 for 98% RH.60 A humidity level inside the bell jars was confirmed using humidity indicator cards (Sigma-Aldrich Company). To compare the stability of OLN base and respective dicarboxylate salts, powder materials prepared by manual grinding were stored inside the different humidity jars (0, 43 and 98% RH) and analyzed by PXRD at regular time intervals i.e. 1 day, 2 days, 3 days, 4 days, 5 days, 2 weeks, 4 weeks, 6 weeks and 8 weeks. PXRD measurements were performed on a Rigaku Ultima IV X-ray powder diffractometer operating a CuKα X-ray source, equipped with a Ni filter to suppress Kβ emission and a D/teX Ultra high-speed position sensitive detector, and measurements were performed at room temperature, with a scan range 2θ = 5-50 º, step size of 0.02º and scan rate of 2º min–1. Crystal structure of OLN-OA salt was determined from X-ray powder data. The powder pattern was indexed with DICVOL 06 software,61 while simulated annealing structure solution was performed using EXPO2014.62 Rietveld refinement63 was performed with TOPAS-Academic version 6.64 During the refinement diffraction peak shapes were modelled by pseudo-Voigt function, background was described by a Chebyshev polynomial function. Geometries of OLN and OA moieties were defined using rigid bodies. Positions and orientations of both rigid bodies were refined independently. In addition, two flexible degrees of freedom were introduced, one allowing rotation of the piperazine ring of OLN, the other for describing rotation around C–C bond of OA. The composition of materials stored in the humidity jars was analysed by comparing experimental PXRD patterns with the calculated patterns of the corresponding crystal. FT-IR spectra were collected on an Agilent Cary 630 spectrometer equipped with a ZnSe beamsplitter and a ZnSe ATR accessory, spectral resolution was set to 2 cm-1. TGA measurements were performed on a Mettler Toledo instrument with a temperature range 30–700 °C and a heating rate of 10 °C min–1. Samples were placed in silica crucibles and purged by a stream of nitrogen flowing at 80 mL min–1. DSC measurements were performed on a


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Perkin Elmer DSC 8000 with a temperature range 30–300 °C and heating rate of 10 °C min–1. Thermal microscopy images were recorded on a Linkam hot stage mounted on a LEICA 2700 P microscope attached with LEICA MC170HD camera. Single crystal X-ray diffraction data were collected on a Bruker SMART APEX II CCD diffractometer equipped with a graphite monochromator and a Mo Kα fine-focus sealed tube (λ = 0.71073 Å). Data integration was done using SAINT. Intensities for absorption were corrected using SADABS.65 Structure solution and refinement were carried out using Bruker SHELXTL.66,67 The hydrogen atoms were refined isotropically, and all the other 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. Molecular graphics were prepared using X-SEED68 and Mercury licensed version 3.9.69 Database search Cambridge Structural Database (CSD v 5.38)70 was used to survey the conformational preferences of oxalate anion in solid state. The search for oxalate dianion was limited to organic structures with 3D coordinates, containing no disorder and no errors. Polymeric structures were also excluded. The O–C–C– O torsion angle describing the mutual orientation of two carboxylate groups was recorded for each structure, and a histogram plot was generated. DFT calculations Density functional theory (DFT) energy scan was used to characterize the conformational landscape of the oxalate anion. The calculation was performed with Gaussian 16 program,71 using the B3LYP72 functional and 6311G(d,p) basis set. The conformational energy scan involved varying the O–C–C–O torsion angle of the oxalate anion from -90° to 90° in 10° steps. Results and discussion Crystal structure analysis Crystallographic parameters and hydrogen bond parameters of selected OLN salts are summarized in table 1 and table 2 respectively. Table 1. Crystallographic parameters of OLN salts Olanzapinium oxalate (1:1)

Olanzapinium 38

malonate (1:1)

a

Olanzapinium 3

monomaleate 9

(1:1)

Olanzapinium dimaleate39 (1 : 2)a

a


Olanzapinium

Olanzapinium

glutarate

hemiadipate

acetonitrile

hemiadipic acid


Page 6 of 25

(1:1:1)

acetonitrile hydrate (1:1:1:1)

Chemical

C17H22N4S·C2

C17H21N4S·C3

C17H21N4S·C4

C17H22N4S·2(

C17H21N4S·C5

C17H21N4S·C6H

formula

O4

H 3O 4

H 3O 4

C4H3O4)

H 6O 4

8O4·C2H3N·O

Formula wt

402.47

416.49

428.50

544.57

443.53

514.61

Cryst syst

Monolinic

Triclinic

Monoclinic

Triclinic

Triclinic

Triclinic

Space

P21

P1

P21/n

P1

P1

P1

T, K

298

298

298

298

298

298

a, Å

10.3247(10)

9.1759(9)

10.852(5)

8.518(3)

9.6963(8)

9.8975(8)

b, Å

8.2245(5)

9.1769(9)

13.748(7)

9.804(4)

10.4293(8)

10.5769(8)

c, Å

10.8567(7)

13.6079(14)

13.879(7)

16.210(6)

13.4787(10)

14.1578(11)

α, deg

90

92.146(2)

90

95.956(7)

109.081(3)

76.636(3)

β, deg

92.685(6)

94.031(2)

97.856(8)

97.945(7)

93.710(3)

89.719(4)

γ, deg

90

115.2640(10)

90

107.789(7)

101.038(4)

73.739(4)

Z

2

2

4

2

2

2

920.88(12)

1030.81(18)

2051.3(17)

1261.2(8)

1252.36(17)

1381.45(19)

1.452

1.342

1.387

1.434

1.176

1.237

µ, mm−1

-

0.19

0.19

0.19

0.16

0.16

reflns

-

10665

20986

13184

15938

22226

-

4061

3375

3737

4270

4945

R1[I > 2(I)]

-

0.048

0.042

0.086

0.071

0.056

wR2 (all)

-

0.1211

0.119

0.199

0.228

0.194

Rwp

0.056

-

-

-

-

-

GOF

8.546

1.033

1.07

1.24

1.08

1.08

Data

Rigaku

Reported

Reported

Reported

Bruker APEX

Bruker APEX II

collection

Ultima IV

CCDC no.

1585240

group

3

V, Å

Dcalc,

g

−3

cm

collected unique reflns

(powder data)

a

II HIRYUE

AMIYUR

AMIZAY

1585242

reported crystal data

Table 2. Hydrogen bonds in the crystal structures of olanzapinium salts


1585241

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Compound

Interaction

Donor···Acceptor

H···Acceptor

Donor–

(Å)

(Å)

H···Acceptor

Symmetry code

(°) Olanzapinium

N3+–H3···O1–

2.637

1.61

172.4

x–1, +y, +z+1

glutarate

N3+–H3···O2

3.225

2.55

122.6

x–1, +y, +z+1

acetonitrile

N4–H4···O2

2.948

1.99

153.8

–x+1, –y+1, –z

Olanzapinium

N4–H4···O3

2.914

1.89

174.4

x, y, z

hemiadipate

N3+–H3···O4–

2.598

1.57

172.8

–x+1, –y+1, –z+1

hemiadipic

N3+–H3···O3

3.566

2.78

133.4

–x+1, –y+1, –z+1

acid acetonitrile hydrate

1. Olanzapinium oxalate Powder structure solution reveals that OLN forms a salt with two proton transfer from two carboxylic acid group of OA to the two basic nitrogens of OLN. The crystal structure was solved in monoclinic P21 space group containing one ion pair of OLNH22+ and OA2– in the asymmetric unit. Rietveld refinement of experimental powder pattern of OLN-OA is shown in supporting information figure S1. Due to double protonation of OLN, the commonly occurring OLN dimer motif is not observed in this crystal structure. Instead the oxalate anion acts as a bridge connecting three OLN cations from two adjacent layers forming a hydrogen bonded helical chain along the 21 screw axis (Figure 2). The van der Waals forces are responsible for holding the helical chains stacked together, defining the overall long range 3D crystal packing. The OLN-OA salt structure is inherently close packed; leaving no voids that could be used for incorporating solvent molecules, resulting in a stable guest-free salt structure. In order to maximize the hydrogen-bonding interactions with neighboring OLNH22+ cations, OA2– adopts a non-planar conformation with a 50.5° dihedral angle between carboxylate planes. The lack of inversion symmetry in the non-planar OA2– is the reason why the material adopts a chiral space group P21 despite all the other herein reported salts crystallizing in centrosymmetric space groups.



(a)

Page 8 of 25

(b)

Figure 2. (a) OLN connecting oxalic acid using N+–H···O–/ N–H···O hydrogen bond. (b) 3D crystal packing showing layers of helical chains stacked together using van der Waals interaction. CSD survey of organic structures containing OA2– anion revealed strong preference for planar geometry (Figure S2). Nonetheless structures with oxalates distorted all the way to staggered perpendicular conformation were also observed. In order to better understand the conformational profile of OA2– we have performed a DFT energy scan for the rotation along the C–C bond. The calculation revealed that the staggered conformation of oxalate anion is, in fact an energy minimum. The planar conformation corresponds to a maximum on the energy surface, 20 kJ mol-1 above the staggered conformation (Figure S3). The likely reason for the prevalence of high energy planar conformation in crystal structures is lower molecular volume which facilitates more efficient crystal packing. Nonetheless, given the possibility of forming strong intermolecular interactions, such as hydrogen bonds, oxalate can easily distort from planarity. The OLN-OA salt structure is an example of such behavior. 2. Olanzapinium glutarate acetonitrile The 1:1 mixture of OLN and GA was dissolved in acetonitrile and crystallized by slow evaporation to yield single crystals of olanzapinium glutarate acetonitrile solvate. Crystal structure was solved in triclinic space group containing olanzapinium ion, glutarate anion and disordered acetonitrile solvent in the P1 asymmetric unit. Solvent disorder could not be modeled and hence removed using SQUEEZE command. The pKa difference between OLN base (7.37) and GA (4.31) (∆pKa = 3.06) indicates a possibility of proton transfer from one carboxylic acid group of GA to the piperazine N3 of OLN base (N3+–H3···O1–). Carbonyl oxygen of the carboxylate group interacts with a second OLN cation forming N4–H4···O2 hydrogen bond with the diazepam ring. The other carboxylic acid group of GA (proton could not be located in a difference map) forms O4–H···O1– hydrogen bond with the carboxylate oxygen of adjacent acid molecule producing a dimer motif (Figure 3a). GA dimer further interacts with OLN cations on both


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sides, forming an extended hydrogen-bonded chain parallel to (01-1) plane as shown in figure 4. Parallel chains of olanzapinium-glutarate stack together resulting 3D crystal packing. OLN dimer is observed between adjacent olanzapinium-glutarate extended chains (See SI figure S4). The 3D arrangement of OLN-GA chains produced packs of void space occupied by disordered acetonitrile solvent forming a host-guest complex as shown in figure 3b.

(a)

(b)

Figure 3. (a) Hydrogen bonded GA dimer connecting OLN molecule. One proton from GA molecule is transferred to the piperazine N of OLN results a salt structure. (b) 3D packing of OLN-GA salt solvate showing solvent accessible voids that results a host-guest complex.

Figure 4. Extended chains of OLN-GA parallel to (01-1) connecting via N+–H···O– hydrogen bond. 2. Olanzapinium hemiadipate hemiadipic acid acetonitrile hydrate



Page 10 of 25

Crystallization of a 1:1 mixture of OLN and AA from acetonitrile solvent produced a solvate of an ionic cocrystal. The asymmetric unit contains one OLN cation, half adipate anion, half molecule of adipic acid, one molecule of acetonitrile and one molecule of water. The ionic cocrystal solvate crystallizes in the space group. Acidic proton of one centrosymmetric AA was transferred to piperazine N3 of triclinic P1 OLN forming an ionic N3+–H3···O4– hydrogen bond (∆pKa value for the pair is 2.94). In contrast to all 1:1 OLN salts, here the dianion is bonded to two cationic olanzapinium cations (Figure 5a). A similar hemiadipate salt of mirtazapine has been reported earlier by Nangia and coworkers.73 The carbonyl oxygen of the dianion is forming an N4–H4···O3 hydrogen bond with diazepam ring of adjacent OLN, producing a ring motif74,75 (26) as shown in figure 5b.

(a)

(b)

Figure 5. (a) One adipate anion interacts with two olanzapinium cations via N3+–H3···O4– hydrogen bond. (b) Carbonyl oxygen of adipate anion interacts with two olanzapinium cations through piperazine and diazepine nitrogens via N3+–H3···O4–/ N4–H4···O3 hydrogen bonds forming a (26) ring motif. The second symmetry independent adipic acid molecule forms O–H···O hydrogen bonds with water (the proton could not be located in the Fourier difference map) on both sides resulting in an extended hydrogen bonded chain. Possibility of proton transfer is omitted due to formation of centrosymmetric tetramer synthon between adipic acid and water molecule (see SI figure S5). Surprisingly this symmetry independent AA does not form any hydrogen bonds with olanzapinium cation. Due to poor quality single crystal, proton of the carboxylic acid of AA as well as water molecule could not be located from the Fourier map. The bifurcated water molecule interacts with the adipate anion producing a 3D close packed structure. In this the OLN dimer and adipic acid/adipate layers are well separated (Figure 6a, SI figure S6). The channel void space created by OLN dimer layers is occupied by acetonitrile solvent molecules as shown in figure 6b. The structure is therefore an example of inclusion compound.


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(a)

(b)

Figure 6. (a) Three dimensional crystal packing of olanzapinium hemiadipate hemiadipic acid acetonitrile hydrate. (b) Solvent accessible voids are forming a channel structure occupied by acetonitrile molecule results an inclusion complex. Comparison of all the structures reported herein reveals that, with the exception of olanzapinium oxalate and maleate 1:1 salts, all other OLN salts have hydrogen bonded supramolecular ring motif. Carboxylate group of acid coformer interacts with two OLN molecules through piperazine and diazepam nitrogens as shown in figure 7. Reaction of OLN with oxalic (1:1), malonic (1:1) and maleic acids (1:1 and 1:2 salt) results guest-free structures, whereas glutaric and adipic acid yields salt/ ionic cocrystal solvates. Hygroscopic nature of OLN-SA powder prepared by LAG confirms the formation of salt solvate further verified using thermogravimetric analysis (TGA) and FT-IR spectroscopy. OLN dimer motif is present in all 1:1 salt structures (except OLN-OA); therefore solvent inclusion in salt structure depends primarily on the chain length of the dicarboxylic acid salt former. Increase in chain length of dicarboxylic acid (n > 2) introduces conformationally flexible hydrophobic –CH2– group causing poor crystal packing, results salt structure with solvent accessible voids.



Page 12 of 25

(a)

(b)

(c)

(d)

(e)

(f)

Figure 7. OLN dicarboxylic acid ring motif present in salt structures (except a and c) considered for our study: (a) OLN-OA, (b) OLN-MOA, (c) OLN-MA, (d) OLN-diMA, (e) OLN-GA and (f) OLN-AA. Spectroscopic and PXRD analysis Bulk purity of the OLN-dicarboxylic acid salts is confirmed using PXRD. The PXRD patterns measured for samples of OLN salts involving short-chain dicarboxylic acids (OA, MOA and MA) match well to those simulated for the corresponding single crystal structures. The PXRD patterns for OLN salts of GA and AA, however, do not. This may be attributed to the formation of salt hydrate of different stoichiometry compared to single crystal structure, as suggested by TGA measurements (see figure 17). PXRD of all the LAG samples along with their respective calculated powder patterns are shown in figure 8. Salt formation of OLN base with dicarboxylic acids is further confirmed using FT-IR spectroscopy. Vibrational frequencies observed within the range 1516-1541 cm-1 correspond to C–O stretching of carboxylate (COO–) groups present in all OLN-dicarboxylic acid LAG materials. Stretching frequencies within the range 1744-1638 cm-1 represent C=O stretching vibrations of carbonyl group of neutral COOH which suggests only one proton is transferred from the dicarboxylic acid molecules to OLN base, which is consistent with single crystal data (see figure S7).


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Figure 8. PXRD patterns of OLN, OLN-OA, OLN-MOA, OLN-MA, OLN-diMA, OLN-SA, OLN-GA and OLN-AA (bottom to top) salts prepared by LAG. Analysis of hydration stability All the prepared LAG samples of OLN-dicarboxylic acid salts were stored under controlled humidity. The summary of the PXRD data under various controlled humidity are listed in table 3. Table 3. Hydration stability of pure OLN base and olanzapinium dicarboxylic acids salts in different humidity environments. Olanzapine

Conditions

salts

(% RH)

0

1

2

3

4

5

2

4

6

8

day

day

day

day

day

day

week

week

week

week

Olanzapine

0

√

√

√

√

√

√

√

√

√

√

base (OLN)

43

√

√

√

√

√

√

√

√

√

√

98

√

√

√

√

√

√

Olanzapinium

0

√

√

√

√

√

√

√

√

√

√

oxalate

43

√

√

√

√

√

√

√

√

√

√

(OLN-OA)

98

√

√

√

√

√

√

√

√

√

√

Olanzapinium

0

√

√

√

√

√

√

√

√

√

√

malonate

43

√

√

√

√

√

√

√

√

√

√

(OLN-MOA)

98

√

√

√

√

√

√

√

√

√

√

Olanzapinium

0

√

√

√

√

√

√

√

√

√

√



Page 14 of 25

maleate (1:1)

43

√

√

√

√

√

√

√

√

√

√

(OLN-MA)

98

√

√

√

√

√

√

√

√

√

√

Olanzapinium

0

√

√

√

√

√

√

√

√

√

√

dimaleate

43

√

√

√

√

√

√

√

√

√

√

(1:2)

(OLN-

98

√

√

√

√

√

√

√

√

√

√

Olanzapinium

0

succinate

43

(OLN-SA)

98

Olanzapinium

0

glutarate

43

(OLN-GA)

98

Olanzapinium

0

adipate

43

(OLN-AA)

98

diMA)

Note: The symbol √ indicates the powder material was stable and matches with its guest-free crystal structure. The symbol indicates the powder material exhibited physical instability (hygroscopic in nature) and results hydrated salt structure. From the relative humidity data it was observed that upon storage at 98% RH for two weeks, OLN base (form II) began to convert to its monohydrate and dihydrate polymorphs (see figure 9 and figure S8). At the same time, olanzapinium oxalate, malonate and maleate (1:1 and 1:2) salts showed complete stability without any phase change even after eight weeks under 98% RH (see figure 10-13). The olanzapinium succinate, glutarate and adipate salts, on the other hand, were found to absorb moisture and form solvated salts (see figure 14-16) immediately after grinding, which was further confirmed by TGA (see figure 17). PXRD of OLN base and salts under 0% and 43% RH are given in the SI (see figure S9-22).


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Figure 9. PXRD pattern of OLN base (form II) stored under 0, 43 and 98% RH over a period of 8 weeks. Under 98% RH, after 2nd week form II partially converts to OLN monohydrate and dihydrate polymorphs. Peaks corresponds to monohydrate and dihydrate polymorphs are shown with * and † respectively.

Figure 10. PXRD pattern of OLN-OA LAG kept under 98% RH over a period of 8 weeks. LAG material matches well with the calculated pattern of guest-free OLN-OA confirming stability of the powder over the period of investigation.



Figure 11. PXRD pattern of OLN-MOA LAG kept under 98% RH over a period of 8 weeks. LAG material matches well with the calculated pattern of guest-free OLN-MOA confirming stability of the powder over the period of investigation.

Figure 12. PXRD pattern of OLN-MA LAG kept under 98% RH over a period of 8 weeks. LAG material matches well with the calculated pattern of guest-free OLN-MA confirming stability of the powder over the period of investigation.


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Figure 13. PXRD pattern of OLN-diMA LAG kept under 98% RH over a period of 8 weeks. LAG material matches well with the calculated pattern of guest-free OLN-diMA confirming stability of the powder over the period of investigation.

Figure 14. PXRD pattern of OLN-SA LAG kept under 98% RH over a period of 8 weeks. From TGA analysis it was confirmed that OLN-SA salt is a sesquihydrate.



Figure 15. PXRD pattern of OLN-GA LAG kept under 98% RH over a period of 8 weeks. Hydrated structure does not match with calculated pattern of OLN-GA salt solvate which may be due to different stoichiometric salt hydrate (monohydrate).

Figure 16. PXRD pattern of OLN-AA LAG kept under 98% RH over a period of 8 weeks. Hydrated structure does not match with calculated pattern of OLN-AA salt solvate which may be due to different stoichiometric salt hydrate (hemihydrate). The overall hydration stability of all OLN dicarboxylic acid salts can be summarized as OLN-oxalate OLN-malonate OLN-maleate OLN-succinate OLN-glutarate OLN-adipate. Thermal analysis


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According to European pharmacopeia a mass change of 2-15% at 25 °C and 80% RH is considered to be hygroscopic material.51,52,76 TGA of OLN salts (Figure 17) kept under 98% RH for a period of 8 weeks nicely supports our humidity analysis. OLN-OA salt is non-hygroscopic and does not show any weight loss below 200 °C. Two stages of weight loss observed during decomposition of OLN-OA salt above 200 °C correspond to dissociation of oxalic acid (experimental weight loss 21.1%) followed by olanzapine (experimental weight loss 75.4%) in good agreement with theoretical weight loss of 22.4% and 77.6% respectively. OLN-SA powder showed a weight loss of ~ 6% starting at ~100 °C which is equivalent to 1.5 mole of water i.e. OLN-SA salt may be a sesquihydrate; whereas 4.3% and 2.1% weight loss starting at ~100 °C for OLN-GA and OLN-AA powder materials confirm their hygroscopic nature. Percentage weight loss of OLN-GA and OLN-AA confirms monohydrate and hemihydrate nature of the respective OLN salt structures. This may be the reason for non-matching PXRDs of the corresponding powder materials with their calculated powder patterns.

OLN-OA LAG

OLN-SA LAG

OLN-GA LAG

OLN-AA LAG

Figure 17. Thermogravimetric analysis of OLN dicarboxylic acid powder namely OLN-OA, OLN-SA, OLN-GA and OLN-AA kept under 98% RH for a period of 8 weeks in order to check possible water absorption during storage. Melting point analysis using hot stage microscopy and differential scanning calorimetry (DSC) revealed (see SI figure S23 and S24) melting point alteration behavior for odd and even dicarboxylic acid salts of OLN similar to that of pure diacids (Figure 18). Melting point alteration behavior for single component and cocrystal systems containing odd and even diacids is reported in literature;77-80 however there is no report on melting point alteration behavior for salt systems.



Figure 18. Melting point alteration behavior of 1:1 OLN salts (OLN-OA, OLN-MOA, OLN-SA, OLNGA and OLN-AA) compared with pure diacids (OA, MOA, SA, GA and AA). Conclusion A series of olanzapinium salts with dicarboxylic acid were prepared mechanochemically using LAG. OLN-oxalate salt structure was determined using X-ray powder diffraction structure solution and was found to be guest-free in nature. The RH stability analysis using high-throughput PXRD showed that increase in chain length of dicarboxylic acid coincides with a decrease in hydration stability of the respective OLN salts. Crystal structure and TGA analysis also supported this observation. DSC analysis showed melting point alteration behavior for odd and even OLN dicarboxylic acid salts similar to pure diacids. A possible explanation for the observed trend in hydration stability may be the inefficient crystal packing induced by flexible, hydrophobic –CH2– groups of higher members of dicarboxylic acid family, namely OLN-SA, OLN-GA and OLN-AA resulting in the formation of solvent accessible voids.21 Multiple batches prepared by solution crystallization as well as mechanical grinding produced guest-free salts with OA, MOA and MA. For the first time, increase in chain length of dicarboxylic acid in a series of pharmaceutical salts was correlated with hydration stability. As the majority of the available drugs are market as salts,81 their stability under high humidity is of prime concern to pharmaceutical industry. We believe that our detailed analysis will improve our understanding of structural effects controlling hydration stability of pharmaceutical salts and help designing materials with better characteristics. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected], [email protected]


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Notes The authors declare no competing financial interest. Acknowledgement Author dedicates this work to his mentor Prof. William Jones on his retirement from Department of Chemistry, University of Cambridge. Olanzapine was a gift from Cipla, India. Dr. Yusuf K. Hamied, chairman of Cipla Pharmaceutics Ltd., is thanked for scientific discussion. K.K.S. thanks the Science and Engineering Research Board (SERB), Young Scientists Scheme for a fellowship (PhD student). P.S. (master’s student) thank the Department of Chemistry, Gauhati University (GU); R.T. thanks the Department of Science and Technology (DST) for a SERB Young Scientists project (Project No. SB/FT/CS-101/2013); Department of Chemistry, B. Borooah College for the FT-IR spectrometer; Prof. P. J. Das for providing laboratory space; Dr. S. Karmakar for collecting single crystal X-ray data; the Sophisticated Analytical Instrumentation Facility (SAIF), GU for use of the single crystal X-ray diffractometer; Department of Chemistry, GU for the powder X-ray diffractometer, TGA, basic instrumentation facility and infrastructure; Department of Chemistry, NIT Meghalaya for the DSC and thermal microscopy instruments; Department of Chemistry, McGill University for providing the Gaussian 16 site license. References: (1) James, S. L.; Adams, C. J.; Bolm, C.; Braga, D.; Collier, P.; Friscic, T.; Grepioni, F.; Harris, K. D. M.; Hyett, G.; Jones, W.; Krebs, A.; Mack, J.; Maini, L.; Orpen, A. G.; Parkin, I. P.; Shearouse, W. C.; Steed, J. W.; Waddell, D. C. Chemical Society Reviews 2012, 41, 413-447. (2) James, S. L.; Friscic, T. Chemical Society Reviews 2013, 42, 7494-7496. (3) Boldyreva, E. Chemical Society Reviews 2013, 42, 7719-7738. (4) Friščić, T.; Jones, W. Crystal Growth & Design 2009, 9, 1621-1637. (5) Braga, D.; Maini, L.; Grepioni, F. Chemical Society Reviews 2013, 42, 7638-7648. (6) Trask, A. V.; Haynes, D. A.; Motherwell, W. D. S.; Jones, W. Chemical Communications 2006, 51-53. (7) Tan, D.; Loots, L.; Friscic, T. Chemical Communications 2016, 52, 7760-7781. (8) Delori, A.; Friscic, T.; Jones, W. CrystEngComm 2012, 14, 2350-2362. (9) Garay, A. L.; Pichon, A.; James, S. L. Chemical Society Reviews 2007, 36, 846-855. (10) Friščić, T.; Reid, D. G.; Halasz, I.; Stein, R. S.; Dinnebier, R. E.; Duer, M. J. Angewandte Chemie 2010, 122, 724-727. (11) Crawford, D.; Casaban, J.; Haydon, R.; Giri, N.; McNally, T.; James, S. L. Chemical Science 2015, 6, 1645-1649. (12) Beldon, P. J.; Fábián, L.; Stein, R. S.; Thirumurugan, A.; Cheetham, A. K.; Friščić, T. Angewandte Chemie International Edition 2010, 49, 9640-9643. (13) Wang, G.-W. Chemical Society Reviews 2013, 42, 7668-7700. (14) Ralphs, K.; Hardacre, C.; James, S. L. Chemical Society Reviews 2013, 42, 7701-7718. (15) Rajput, L.; Banerjee, R. Crystal Growth & Design 2014, 14, 2729-2732.



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Graphical Abstract

TOC text A series of olanzapine (OLN) dicarboxylic acid salts were prepared mechanochemically in order to study their hydration stability. Powder X-ray diffraction (PXRD) was used as a characterization tool during the investigation. Based on the single crystal structures of respective OLN salts a negative correlation between the dicarboxylic acid chain length and the hydration stability of the corresponding OLN salt was found. Our observations suggested, that the overall crystal packing, beyond the stronger hydrogen bond synthon play an important role in designing OLN salts with better hydration stability.


Mechanochemical Synthesis of Olanzapine Salts and Their Hydration

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