Molecular salts and co-crystals of mirtazapine with promising physicochemical properties

Journal of Pharmaceutical and Biomedical Analysis 110 (2015) 93–99

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Molecular salts and co-crystals of mirtazapine with promising physicochemical properties Anindita Sarkar, Sohrab Rohani ∗ Department of Chemical and Biochemical Engineering, The University of Western Ontario, London, ON, Canada N6A 5B9

a r t i c l e

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Article history: Received 18 November 2014 Received in revised form 27 February 2015 Accepted 4 March 2015 Available online 12 March 2015 Keywords: Mirtazapine salts Molecular salt Non-sublimating salts Aqueous solubility Single crystal structure

a b s t r a c t Pharmaceutically suitable non-sublimating salts and molecular salts of anti-depressant drug R/Smirtazapine with one of several dicarboxilic acids were studied. The salts/salt molecules were characterized by powder X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis and crystal structure of tartarate and oxalate molecular salt were determined by single crystal X-ray diffraction. The salts/salt molecules of mirtazapine do not show any sublimation at elevated temperature whereas sublimation of mirtazapine has been observed at ambient temperature. The aqueous solubility of the mirtazapine molecular salts was significantly improved with a maximum of citrate salt which was about 180 times more than the solubility of the parent mirtazapine at 35 ◦ C. © 2015 Elsevier B.V. All rights reserved.

1. Introduction Mirtazapine((±)-2-methyl-1,2,3,4,10,14b-hexahydropyrazino [2,1-a]pyrido[2,3-c][2]benzazepine, hereinafter abbreviated as MITZ, shown in Fig. 1 is a noradrenergic and specific serotonergic antidepressant (NaSSA) [1], that is used primarily in the treatment of depression. It is also commonly used as an anxiolytic, hypnotic, antiemetic and appetite stimulant. MITZ has been marketed under several brand names such as Avanza, Axit, Mirtaz, Mirtazon, Remeron, Zispin. In terms of structure, mirtazapine can also be classified as a tetracyclic antidepressant (TeCA) and is the 6-aza analog of mianserin [2]. It is racemic and comes as a combination of both R and S-stereoisomers. It was found that formulations containing MITZ suffer from problems caused by the sublimation of MITZ which is having a half-life of 20–40 h. S- and R-mirtazapine pure bases are slowly sublimating compounds at ambient temperature, but the salts of mirtazapine viz. maleate, fumarate, malonate, adipate, salicylate, sachharinate, hydrobromide reported to be non-sublimating [3–7]. Thus, pharmaceutical composition comprising an enantiomer of MITZ can be improved by selecting a pharmaceutically acceptable non-sublimating salt of an enantiomer of MITZ.

∗ Corresponding author. Tel.: +1 519 661 4116; fax: +1 519 661 3498. E-mail address: [email protected] (S. Rohani). http://dx.doi.org/10.1016/j.jpba.2015.03.003 0731-7085/© 2015 Elsevier B.V. All rights reserved.

There are only two published papers of MITZ salts reported by Bhatt et al. [3] and Sarma et al. [4]. We found contradictory report on solubility of MITZ, as authors of the first paper mentioned MITZ as practically insoluble drug in water (<0.05 mg mL−1 ), while the latter claimed MITZ as highly soluble drug (1 mg mL−1 ). The aim of this study, therefore, was to rationally design and prepare a series of pharmaceutically acceptable MITZ salts, evaluate their sublimation rate and also to make a comparative study of the solubility and dissolution rate of MITZ salts with that of MITZ free base. In recent years, a high-throughput approach has become standard when a salt screening is adopted with due attention to its pKa values. Conventional strategies dictate that in order to form a stable salt, at least a three-unit difference in pKa between the salt and the free base is required. The N-methyl basic site of the piperazine group has a pKa of 7.1. Therefore, according to the pKa rule, it should form salts with acids of pKa < 4. In the previously reported structure [3,4] of mitrazapium salts by Sarma et al. and Bhat et al., the supramolecular interaction was ionic two-point synthon between the carboxylate anion which acts as an acceptor and the protonated N+ H-site and the C H of the asymmetric carbon atom. Our goal was to observe whether the same supramolecular two point synthon formation is universal in all the salt formation of MITZ, even when hydroxyl group is present along with dicarboxilic acid in a molecule. Based on the supramolecular strategy of crystal engineering and the pKa rule, the following MITZ salts were attempted in this study: MITZ-oxalate, MITZ-tartrate and MITZ-citrate. With the aim of formation of salt

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in 10 mL of methanol and heated at 100 ◦ C with constant stirring in a sealed tube for 2 h. The filtered solution was then allowed to evaporate slowly at room temperature. Single crystals of MITZ oxalic molecular salt were obtained after 2 days and were analyzed by single crystal X-ray diffraction. 2.5. Powder X-ray diffraction (PXRD) Fig. 1. Chemical structure of mirtazapine.

of oxalic acid of mirtazapine, molecular salt which is quite unusual was observed in the crystal structure of MITZ with oxalic acid. The chemical structures of successful conformers which formed salts with MITZ are presented in Fig. 2. Solution evaporation techniques were used to prepare the salts. Physical states of MITZ were characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). We also determined the single crystal structure of the tartrate and oxalate molecular salts to understand the salt crystal structures for their enhanced stabilities and also to verify the ionic two point synthon formation. The non-sublimating nature of the MITZ salts was measured and less than 1% of the MITZ salts were found to be sublimating from the sample. 2. Experimental 2.1. Materials Mirtazapine was a gift sample from ApotexPharmaChem Inc. (Canada). Other chemicals were purchased from Sigma Aldrich and were used as received.

The PXRD spectra were collected on a Rigaku-Miniflexbenchtop X-ray powder diffractometer (Carlsbad, CA) using CuK␣ ˚ radiation obtained at 30 kV and 15 mA. The (␭ = 1.54059 A) scans were run from 5.0◦ to 30.0◦ 2, increasing at a step size of 0.05◦ 2 with a counting time of 2 s for each step. The diffractograms were processed using JADE 7.0 software. Calibration was performed using a silicon standard. 2.6. Differential scanning calorimetry (DSC) The melting points were measured with a Mettler Toledo DSC 822e differential scanning calorimeter (Greifensee, Switzerland). Accurately weighed samples (∼3 mg) were prepared in a covered aluminum crucible having pierced lids to allow escape of volatiles. The sensors and samples were under nitrogen purge during the experiments. The temperature calibration was carried out using the melting point of highly pure indium in the medium temperature range. Heating rate of 5 ◦ C/min was selected. 2.7. Thermogravimetric analysis (TGA) TGA was performed on a Mettler-Toledo TGA/SDTA 851e instrument. Approximately 2 mg sample was heated from 25 to 300 ◦ C at 10 ◦ C/min under nitrogen purge.

2.2. Mirtazapine citrate salts (1:1 MITZ/citric acid) 2.8. Single crystal X-ray diffraction This material was prepared by solvent evaporation. Mirtazapine (265 mg, 1 mmol) and citric acid (192 mg, 1 mmol) were dissolved in 10 mL of methanol and heated at 100 ◦ C with constant stirring in a sealed tube for 2 h. The solution was then filtered through 5 ␮m filter paper (VWR brand, 5.5 cm) to remove insolubles. The filtered solution was then allowed to evaporate slowly at room temperature. 2.3. Mirtazapine tartrate salts (1:1 MITZ/tartaric acid) This material was prepared by solvent evaporation. Mirtazapine (265 mg, 1 mmol) and DL-tartaric acid (150 mg, 1 mmol) were dissolved in 10 mL of methanol and heated at 100 ◦ C in a sealed tube with constant stirring for 2 h. The filtered solution was then allowed to evaporate slowly at room temperature. Single crystals suitable for single crystal X-ray diffraction analysis were obtained after 7 days.

Single crystals of MITZ salts were grown from methanol solution at room temperature. The single crystal sample was mounted on a Mitegen polyimide micromount with a small amount of Paratone N oil. X-ray measurements were made on a Bruker Kappa Axis Apex2 diffractometer at a temperature of 110 K. The unit cell dimensions were determined from a symmetry constrained fit of 8574 reflections with 4.9◦ < 2 < 58.56◦ . The frame integration was performed using SAINT [8]. The resulting raw data were scaled and absorption corrected, using a multi-scan averaging of symmetry equivalent data using SADABS [9].

2.4. Mirtazapine oxalic acid salt co-crystal (1:1 MITZ/oxalic acid) This material was prepared by solvent evaporation. Mirtazapine (265 mg, 1 mmol) and oxalic acid (102 mg, 1 mmol) were dissolved

Fig. 2. Dicarboxilic acids that successfully formed salts with mirtazapine.

Fig. 3. PXRD pattern of mirtazapinefree base.

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Fig. 4. PXRD pattern of (a) citric acid, (b) MITZ-citrate, (c) tartaric acid, (d) MITZ-tartrate, (e) oxalic acid, (f) MITZ-oxalte.

The structure was solved by direct methods using the SIR2011 program [10]. Most of the non-hydrogen atoms were obtained from the initial solution. The remaining atomic positions were obtained from a subsequent difference Fourier map. The hydrogen atoms were introduced at idealized positions and were allowed to ride on the parent atom. The structural model was fit to the data using full matrix least-squares based on F2 . The calculated structure factors include corrections for anomalous dispersion from the usual tabulation. The structure was refined using the SHELXL-2013 program from the SHELX suite of crystallographic software [11]. 2.9. Sublimation test Samples of 10 mg were placed in a sealed glass desiccators jars maintaining different relative humidity (RH) conditions. The desiccator was then placed in an oven for 72 h and the temperature was controlled. The degree of sublimation is expressed as the fraction of mass loss (as %) of the initial sample. Appropriate saturated

aqueous salt solutions for different RH values (K2 CO3 for 43%; NaCl for 75%; and K2 SO4 for 98%) were maintained in the desiccators. 2.10. Solubility and dissolution rate The solubility of MITZ and salts/molecular salts of MITZ in water was measured at 35 ◦ C. To measure the saturation concentration of each sample, 20 g of the solvent mixture and an excess amount of solids were added to a vial at a given temperature and mixed using a magnetic stirrer plate (AGE Magnetic Stirrer, Newtec Inc., Hull, IA). These suspensions were then placed on a multi-plate mechanical shaker and were left to equilibrate for 72 h in a temperature controlled water bath. Samples were filtered through 0.45 mm cellulose acetate syringe filters into volumetric flasks. Supernatant were then analyzed by UV spectrophotometric analysis at ␭max 252 nm (Cary 100 Bio UV visible Spectrophotometer, Palo Alto, CA). Subsequently, dissolution experiments were conducted on MITZ and MITZ salts/molecular salts. In order to evaluate the

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Fig. 5. DSC and TGA thermogram of (a) mirtazapine free base, (b) MITZ-citrate, (c) MITZ-tartrate, (d) MITZ-oxalate.

dissolution rate, 100 mg of MITZ and MITZ salts were placed in 200 mL of phosphate buffer saline as dissolution medium at 35 ◦ C for 90 min at 100 rpm in a magnetic stirrer. Aliquots of 5.0 mL were withdrawn every 10 min. The dissolution medium was replaced after every sampling. The concentration of the sample in the solution was measured by UV spectrophotometer Cary 100 Bio (Palo Alto, CA).

3. Results and discussion 3.1. Molecular salts characterization 3.1.1. Powder X-ray diffraction The formation of salts was confirmed by powder X-ray diffraction pattern. The PXRD patterns of MITZ are shown in Fig. 3, those of oxalic acid, MITZ-oxalic acid salt, tartaric acid, MITZ-tartrate, citric acid, MITZ-citrate, in Fig. 4. The PXRD patterns of the salts of MITZ were different from that of MITZ and the corresponding conformer

dicarboxylic acid. The experimental XRPD pattern matched with the calculated lines from the crystal structure in case of mirtazapium tartrate and oxalate salts. 3.1.2. Thermal analysis The melting point of MITZ base as observed in the DSC endotherm was 120 ◦ C which corresponds to the sudden drop in TGA curve at 120 ◦ C. The three salt forms of mirtazapine prepared in our study did not show any evidence of sublimation in TGA. The DSC and TGA thermograms of MITZ salts/molecular salts are depicted in Fig. 5. The DSC thermogram of the salts was distinguishable from MITZ and the corresponding conformer dicarboxilic acids. 3.1.3. Single crystal structure 3.1.3.1. Mirtazapine tartrate. Crystallization of mirtazapine with dl-tartaric acid in methanol gave a hydrated 1:1 salt with two molecules of water and in the salt structure one proton of tartaric acid was transferred to N of the piperazine ring. Interestingly,

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Fig. 6. Tartrate ions are linked together via (a) O H· · ·O hydrogen bonding interactions along c-axis, (b) C H· · ·O hydrogen bonding interactions along a-axis. Moreover, N+ H· · ·O hydrogen bonding between pyridinium N+ H group and C O group of tartrate is shown.

the crystal structure is in chiral non-centrosymmetric space group P21 21 21 for this racemic salt, though a rare phenomenon in salt formation but not unusual as it was found earlier that dl-tartaric acid when used as conformer for the co-crystal formation with caffeine via liquid assisted grinding, a chiral co-crystal was formed [12]. We can assume that mirtazapine is able to differentiate between enantiomeric and racemic forms of a salt/co-crystal former. We are trying to grow single crystals of MITZ with meso-tartaric acid for better understanding the assumption of enantiomeric and racemic conformer selection. The pyridinium N+ H group interacts with the C O group of tartrate to give an N+ H· · ·O hydrogen bond. Tartrate ions are linked together via O H· · ·O and C H· · ·O hydrogen bonding interactions to form zigzag chains along c- and a-axis (Fig. 6), respectively. We could not locate water H atoms in the difference electron density map. The two water molecules act as bridge to connect MITZ+ and tartrate− (Fig. 7). However, the difficulty in locating water H positions makes the structure not as informative for hydrogen bonding analysis.

oxalate salts. Even formation of N+ H· · ·O− which was observed in all the structures of carboxylate salts of MITZ, determined earlier, was not observed in our present cases. Instead a single charged N+ H· · ·O hydrogen bonding motif was observed in both tartrate and oxalate structures. Moreover, in tartrate salt instead of carboxylic group, O H group participated in N+ H· · ·O hydrogen bonding interaction. The crystallographic data are summarized in Table 1. The hydrogen-bonding geometry is listed in Table 2.

3.1.3.2. Mirtazapine oxalic molecular salt. Co-crystallization of mirtazapine with oxalic acid in methanol resulted in mirtazapinium oxalate crystal. The asymmetric unit contains two molecules of MITZ cations, one half oxalate, one half oxalic acid and one oxalate molecule (Fig. 8). The half oxalate ion lies about the inversion center while the half oxalic acid lies about the glide plane. The crystal structure of MITZ with oxalic acid reported here is quite unusual in that both charged and neutral species are present in the same crystal. In true sense, this type of structure should be referred not only as molecular salt, but has been referred to as salt co-crystal [13,14]. Oxalate, hydrogenoxalate and oxalic acid form an infinite zigzag chain via O H· · ·O− and O H· · ·O supramolecular hydrogen bonding interaction and MITZ cations are pendent over the chain (Fig. 9). MITZ cations are connected via oxalate anions through N+ H· · ·O hydrogen bonds. 3.1.3.3. Carboxilic acid-mirtazapium hydrogen bonding motif. Formation of ionic two point synthon is not always necessary for the mirtazapine salt formation as we observed in tartrate and

Fig. 7. A chain of water molecules connecting mirtazapium with tartrate ions.

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Table 1 Crystallographic data of mirtazapine salts. Chemical name

Mirtazapium tartrate dihydrate

Oxalic acid salt co-crystal

Chemical formula Formula weight Crystal size (mm) Crystal system Space group T/K a [Å] b [Å] c [Å] Z V [Å3 ] Dcalcd. [g cm−3 ] [mm−1 ] Reflections collected Unique reflections Reflections I ≥ 2␴I R1 [I > 2(I)] wR2 [all] Goodness-of-fit CCDC no.

C22 H25 N3 O7 443.45 0.33 × 0.09 × 0.05 Orthorhombic P21 21 21 110(2) 7.198(4) 12.006(7) 24.904(14) 4 2152(2) 1.381 0.103 39327 5356 4101 0.0480 0.0732 1.042 1021648

C19 H21 N3 O4 355.39 0.37 × 0.284 × 0.161 Orthorhombic Pbca 110(2) 20.062(6) 16.828(3) 21.164(5) 8 7145(3) 1.321 0.094 27770 7272 5742 0.0553 0.0767 1.029 1021649

Fig. 8. Asymmetric unit with ellipsoidal contribution at room temperature (50% of probability). Molecule of the mirtazapium cation is depicted in blue, the molecule of deprotonated acid is presented in green, the full protonated acid in pink and monoprotonated acid in red.

3.1.4. Sublimation result The sublimation results under several test conditions of MITZ base, MITZ-oxalic acid salt crystal, MITZ-tartrate and MITZ-citrate are listed in Table 3. The results of the sublimation tests indicate that MITZ base showed loss of mass content at all the test conditions, whereas for the MITZ-salts, the loss of mass content was <0.2% at all conditions indicating that the salts were non-subliming. 3.1.5. Solubility and dissolution test Solubility tests performed on mirtazapine free base indicate that the drug is slightly soluble in PBS at 35 ◦ C contrary to Sarma et al. [4] who claimed mirtazapine as highly soluble drug. Solubility of the MITZ salts in PBS at 35 ◦ C was compared with the MITZ free base and the results are summarized in Table 4. MITZ-citrate salt is the most soluble material among all and the thermodynamic solubility values revealed that its solubility is about 180 times more than the solubility of MITZ free base. The trend of solubility of MITZ salts in water is as follows: MITZ-citrate > MITZ-tartrate > MITZoxalic salt crystal. The solubility of the conformers is citric acid

Fig. 9. O H· · ·O− and O H· · ·O supramolecular hydrogen bonding interaction connecting oxalate, hydrogen oxalate and oxalic acid. MITZ cations are connected via oxalate anions through N+ H· · ·O hydrogen bonds.

Table 2 Selected bond lengths and hydrogen-bonding geometry of mirtazapium salts (d in Å and angle in◦ ). D H· · ·A

d(D H)

d(H· · ·A)

d(D· · ·A)

D H· · ·A

Mirtazapium tartratea N1 H12· · ·O4§1 N1 H12· · ·O5§1 O2 H21· · ·O1§2 O1S H1SA· · ·O1 O2S H2SA· · ·O1A O2S H2SB· · ·O1S

0.93 0.93 1.00(10) 0.86(4) 0.86(4) 0.86(4)

2.58 1.89 1.51(10) 1.84(4) 1.97(3) 1.66(4)

3.181(5) 2.773(5) 2.501(5) 2.699(4) 2.823(4) 2.547(4)

151.0 133.7(4) 169(9) 172(5) 174(4) 173(4)

Mirtazapium oxalic acid salt co-crystalb N1A H1A O1C N1A H1A O2C O1E H1E· · ·O1C O1C C1C O3C C1C O2C C2C O4C C2C O1D C1D O2D C1D O1E C1E O2E C1E

0.90(2) 0.90(2) 1.02(3) 1.280(2) 1.223(2) 1.300(2) 1.205(2) 1.277(2) 1.228(2) 1.293(2) 1.209(2)

1.99(2) 2.27(2) 1.48(3)

2.786(2) 2.992(2) 2.4924(18)

146.6(18) 137.0(17) 171.0(3)

a b

Symmetry transformations used to generate equivalent atoms: (§1) −x + 2, y + 1/2, −z + 1/2; (§2) x − 1, y, z; (§3) x − 1, y + 1, z. Symmetry transformations used to generate equivalent atoms:(§1) −x + 3/2, y − 1/2, z; (§2) −x + 3/2, −y + 1, z + 1/2; (§2) x − 1/2, −y + 3/2, −z + 1.

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Table 3 Sublimation test of MITZ and MITZ salts. Material

25 ◦ C

25 ◦ C 43% RH

25 ◦ C 75% RH

40 ◦ C 43% RH

40 ◦ C 75% RH

60 ◦ C 43% RH

60 ◦ C 75% RH

MITZ MITZ-oxalate MITZ-tartrate MITZ-citrate

0.38%

0.42%

0.45%

2.85% 0.10% 0.10% 0.10%

2.88% 0.10% 0.10% 0.10%

4.29% 0.10% 0.10% 0.10%

4.89% 0.20% 0.20% 0.20%

MITZ-citrate (moles/L)

MITZ-tartrate (moles/L)

MITZ-oxalate (moles/L)

0.38 × 10−1

69.98 × 10−1

58.01 × 10−1

52.25 × 10−1

sublimes at ambient temperature. The salts show remarkably higher solubility and faster dissolution compared to parent mirtazapine. Formation of one point single charged hydrogen bonding motif was first observed in mitrazapium salts of tartrate and oxalate. Moreover, unusual molecular salt formation was observed in the crystal structure of mirtazapine with oxalic acid. Taking into account of non-sublimating character and improved physicochemical properties of the mirtazapium salts reported herein, novel formulations of mirtazapine with dicarboxilic acids are possible. Acknowledgement We are thankful to the Natural Sciences and Engineering Council of Canada for its financial support of this project through the Discovery Grant. Appendix A. Supplementary data Fig. 10. Release profile of MITZ salts compared with free base of mirtazapine.

(180 mg/100 mL−1 ) > tartaric acid (133 mg/100 mL−1 ) > oxalic acid (14 mg/100 mL−1 ). The most soluble dicarboxilic acid formed the most soluble salt. From the study, it is evident that the solubility of conformer has strong effect on the solubility of the resulting salt. The dissolution rate has major impact on the bioavailability of pharmaceutical drugs which are poorly soluble in water. The dissolution experiment was conducted on MITZ base and all the three salts in PBS at 35 ◦ C. The highest concentration of MITZ was released approximately after 70 min whereas the peak concentration of MITZ-citrate, MITZ-tartrate and MITZ-oxalic acid salt crystal in the solution appeared approximately 10 min, 30 min and 40 min, respectively (Fig. 10). At the same dissolution time the released amounts of MITZ-salts in the solution were consistently higher than that of MITZ, as for example, at 20 min, the release of MITZcitrate and MITZ were 20.34 and 0.11 mg, respectively. Initially MITZ-citrate salt dissolved rapidly and reached equilibrium after 10 min, but dissolution of MITZ was slow at the beginning and reached the equilibrium point after 50 min. The remaining powder samples, after the dissolution experiment, were examined by PXRD. It was observed that MITZ and the salts remain stable. 4. Conclusions Two pharmaceutically acceptable salts and one molecular salt of mirtazapine with dicarboxilic acids viz., citric acid, tartaric acid and oxalic acid in 1:1 stoichiometric ratio were synthesized and studied. The salts are non-sublimating, whereas mirtazapine

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