Improving mechanical properties of desloratadine via ...

European Journal of Pharmaceutical Sciences 111 (2018) 65–72

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European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps

Improving mechanical properties of desloratadine via multicomponent crystal formation

MARK

Ahmad Ainurofiqa,b,⁎, Rachmat Mauludina, Diky Mudhakira, Daiki Umedac, Sundani Nurono Soewandhia, Okky Dwichandra Putrac,⁎⁎, Etsuo Yonemochic,⁎⁎ a b c

School of Pharmacy, Institut Teknologi Bandung, Jalan Ganesha No. 10, Bandung 40132, Indonesia Department of Pharmacy, Sebelas Maret University, Jalan Ir. Sutami No. 36A, Surakarta 57126, Indonesia School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan

A R T I C L E I N F O

A B S T R A C T

Keywords: Desloratadine Multicomponent crystal Salt Tabletability Plasticity Solubility

We report the first multicomponent crystal of desloratadine, an important anti-histamine drug, with a pharmaceutically acceptable coformer of benzoic acid. The single crystal structure analysis revealed that this novel multicomponent crystal is categorized as salt due to the proton transfer from benzoic acid to the desloratadine molecule. By forming the salt multicomponent crystal, we demonstrated that the tabletability and plasticity of the multicomponent crystal was improved from the parent drug. In addition, neither capping nor lamination tendency was observed in the desloratadine-benzoic acid multicomponent crystal. The existence of a layered structure and slip planes are proposed to be associated with this improvement. The desloratadine-benzoate in this case shows an improved solubility in water and HCl 0.1N media and a better dissolution profile in water. However, the dissolution rate in HCl 0.1N media was found to be essentially indifference.

1. Introduction Successful commercialization and development of active pharmaceutical ingredients (APIs) require good characteristics in manufacturability, stability, and bioavailability (Blessy et al., 2014; Gutmann et al., 2015; Kawakami, 2012). However, several drugs that have a good pharmacological efficacy face some challenges in commercialization and development due to their unfavorable physicochemical properties—that is, low solubility (Elder et al., 2013; Putra et al., 2017), slow dissolution rate (Blagden et al., 2007; Putra et al., 2016a), high hygroscopicity (Newman et al., 2008; Putra et al., 2016b), poor tabletability (Shi and Sun, 2011), instability (Arora et al., 2013; Tao et al., 2012), etc. Preparation of multicomponent crystals which includes cocrystallization and salt formation is well known in solid-state chemistry to remedy the deficiencies in those unfavorable physicochemical properties. By intentionally modifying the crystal structure of APIs, the modulation of physicochemical properties is expected to occur, and its rationalization can be proposed by comparing the structural differences between the original and novel structures (Aakeröy et al., 2009; Desiraju, 2013; Putra et al., 2016c). Therefore, exploring new crystal

forms of APIs such as cocrystals and salts is important for both fundamental and applied sciences. One of the important physicochemical properties of APIs is their mechanical properties. Mechanical properties such as plasticity and elasticity have been related to the tableting performances of bulk APIs powders, which can be analyzed systematically by using tabletability, compressibility, and compactability (Chang and Sun, 2017; Joiris et al., 1998; Patel et al., 2006; Tye et al., 2005). The mechanical properties are interesting because they are strictly related to the molecular arrangement in the crystal lattice (Bag et al., 2012). One of the typical examples is well represented by polymorphic forms of acetaminophen, in which the existence of parallel packing of flat hydrogen-bonded layers in form 2 (metastable form) results in better mechanical properties than corrugated hydrogen-bonded layers in form 1 (the most stable form) (Karki et al., 2009). This was later adapted by solid state scientists to build a layered, thermodynamically stable paracetamol form by making multicomponent crystals, such as cocrystals and salts (Karki et al., 2009; Perumalla et al., 2012). In this paper, we explore desloratadine (DES), a derivative of loratadine that is used to treat rhinitis allergy, urticaria (Aberer, 2009;

Abbreviations: APIs, active pharmaceutical ingredients; DES, desloratadine; BA, benzoic acid; HCl, hydrochloric acid; PXRD, powder X-ray diffraction; DSC, different scanning calorimetry; TG, thermal gravimetry; TD, tapped density; BD, bulk density; GRAS, generally recognized as safe ⁎ Corresponding author at: School of Pharmacy, Bandung Institute of Technology, Jalan Ganesha No. 10, Bandung 40132, Indonesia. ⁎⁎ Corresponding authors at: School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41, Ebara, Shinagawa, Tokyo 142-8501, Japan. E-mail addresses: rofi[email protected] (A. Ainurofiq), [email protected], [email protected] (O.D. Putra), [email protected] (E. Yonemochi). http://dx.doi.org/10.1016/j.ejps.2017.09.035 Received 15 August 2017; Received in revised form 19 September 2017; Accepted 24 September 2017 Available online 27 September 2017 0928-0987/ © 2017 Elsevier B.V. All rights reserved.


A. Ainurofiq et al.

H N

ray diffractometer (Japan). The powder pattern was collected from 2θ = 5° to 40° in a reflection mode at 25 °C with a step and scan speed of 0.01° and 20° min− 1, respectively (Cu Kα source, 45 kV, 200 mA). 2.2.3. Single crystal X-ray diffraction and refinements The single crystal X-ray diffraction data was collected at 93(2) K. The measurement was carried out in n ω-scan mode with an R-AXIS RAPID II Rigaku (Japan) using the Cu Kα X-ray obtained from a rotating anode source with a graphite monochromator (50 mA, 200 kV). The integrated and scaled data were empirically corrected using ABSCOR (Rigaku, 1994). The initial structure was solved using a direct method with SIR 2014 and refined on Fo2 with SHELXL 2014 (Burla et al., 2005; Sheldrick, 2008). All non‑hydrogen atoms were refined anisotropically. All of the hydrogen atom positions were calculated geometrically and included in the calculation using the riding model atom. All of the hydrogen atoms attached to the nitrogen atom were located using a differential Fourier map. All hydrogen atoms were refined isotropically. The molecular graphics were produced using Mercury 3.7 software (Macrae et al., 2008). CCDC 1567185 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by e-mailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336,033.

N Cl Scheme 1. The chemical structure of desloratadine (DES).

DuBuske, 2005), and inflammation (Bryce et al., 2003; DuBuske, 2005; Gelfand, 2002). DES pharmacologically works by selectively blocking the H1 histamine receptor; therefore, DES is categorized as an inverse agonist (Canonica and Blaiss, 2011). DES also exhibits only peripheral activity since it does not readily cross the blood-brain barrier; hence, it does not cause drowsiness because it does not enter the central nervous system (Mann et al., 2000). DES is commercially available as its base form and some salts are reported in patent literature (Fischer et al., 2002). Yet, DES exhibits poor mechanical behaviors and low solubility. Notably, the poor mechanical behaviors of DES are manifested by capping, which occurs during tabletation and results in difficulty during drug processing (Kumar et al., 2006). In addition, poor solubility becomes the rate limiting step for its bioavailability in DES (Kolašinac et al., 2012, 2013) (Scheme 1). To the present date, either cocrystal or salt structure has been reported to tackle the unfavorable issues associated with DES. Herein, we attempted to address the solid-state deficiencies in DES by preparing multicomponent crystals. DES offers a good opportunity for multicomponent crystal formation since it contains pyridine and piperidine rings. Therefore, the derivatives of both aliphatic and cyclic carboxylic acid were both used as a coformers for multicomponent crystal formation.

2.2.4. Different scanning calorimetry (DSC) and thermal gravimetry (TG) DSC and TG measurements were performed using LINSEIS PT-1600 simultaneous thermal analysis (US). The temperature and enthalpic scale were calibrated using fusion temperature and fusion enthalpy of indium. Approximately 2–5 mg of sample was accurately weighted into an aluminum pan, and the sample pan was heated at a temperature rate of rate 10 °C min− 1 from 25 to 300 °C under a nitrogen purge 100 mL min− 1; an empty aluminum pan was used as a reference. 2.2.5. Tabletability and flowability properties The DES and DES-BA powders were milled using Retsch MM400 mixer mill (Germany) at a frequency of 25 Hz for 1 h to minimize possible effects of particle size and shape. The powder was subsequently sieved and only powder with particle size between 100 and 150 μm was used for physicochemical properties evaluations. Tabletability was performed by accurately weighing 500 ± 2 mg samples. The samples were subsequently placed into die with a diameter of 13 mm. Samples were compressed under different pressures between 25 and 350 MPa using a hydraulic pressure Perkin Elmer (US). In addition, the punch and die were lubricated using magnesium stearate before a compaction process. The diameter (d) and height (h) were measured using a Mitutoyo caliper (Japan) after 24 h, and a crushing strength (F) was measured using a PharmaTest PTB 111 hardness tester (Germany). Tensile strength (σ) was calculated using the following equation (Fell and Newton, 1970; Patel et al., 2008):

2. Materials and methods 2.1. Materials DES and benzoic acid (BA) were purchased from Xi'An Wango Biopharm Co., Ltd., (China) and Sigma Aldrich (US), respectively. Other chemicals were analytical grade and used without any further purification.

Tensile strength =

2.2. Methods

2F πdt

(1)

The elastic recovery is correlated with the amount of retained energy during the compression process and released after compression process. The elastic recovery could be calculated using the diameter before (Hc) and after (He) being stored for 24 h using the following equation (Sun and Grant, 2001):

2.2.1. Multicomponent crystal preparation An equimolar mixture of DES and BA was dissolved in methanol at 35 °C until a clear solution was obtained. The resulting solution was then evaporated using Buchi Rotavapor (Switzerland) (50 °C, 20.8 kPa). The obtained solid of the multicomponent crystal DES-BA was collected and stored at ambient temperature for further analysis. The obtained solid was examined under a polarized microscope, and a single largeblock crystal (0.200 × 0.250 × 0.200 mm3) suitable for single crystal X-ray diffraction was obtained.

%Elastic recovery =

He − Hc × 100 Hc

(2)

The compressibility and flowability was determined by measuring the bulk density (BD) and the tapped density (TD). 10-g samples were weighed and placed into a Copley Scientific tapper (UK). The volume before and after tapping were used to determine BD and TD, respectively. The Carr index and the Hausner ratio were calculated using the

2.2.2. Powder X-ray diffraction (PXRD) PXRD measurements were performed using a SMART-LAB Rigaku X66



following equations:

Carr index =

TD − BD × 100% TD

Hausner ratio =

BD TD

(3) (4)

2.2.6. Solubility test Solubility tests were performed under different aqueous media, i.e., water and 0.1N HCl. An exceed amounts of samples was added into the test tube containing 10 mL aqueous media. The test tube was shaken in an orbital shaker (120 Hz, 37 ± 0.5 °C) for 48 h until the equilibrium condition was achieved. The solution was filtered using a 0.22-μm nylon filter, and the solution was later analyzed using a Beckman Coulter DU720 spectrophotometer (US) at a wavelength of 290 nm using a validated analytical method. Fig. 1. The PXRD patterns of (a) DES, (b) BA, and DES-BA from (c) experimental and (d) simulation data from a single crystal.

2.2.7. In-vitro dissolution test Dissolution experiments for DES and DES-BA were carried out using 900 mL water and 0.1N HCl as a dissolution medium. A USP apparatus II using the Hanson SR8Plus (US) dissolution tester was used at a temperature of 37 ± 0.5 °C, and the solution was stirred at a rate of 50 rpm. A sample equivalent to 25-mg DES was added, and a 5-mL aliquot was withdrawn at different intervals (i.e., 5, 10, 15, 20, 30, 45, and 60 min) and filtered using a 0.45-μm membrane filter. A fresh medium, which was pre-warmed at 37 °C, was added to maintain a constant volume. Each experiment was carried out three times, and the results from the three experiments were averaged. The drug content was analyzed using a Beckman Coulter DU720 spectrophotometer (US) at a wavelength of 290 nm.

Table 1 Crystallographic details of DES-BA multicomponent crystal.

3. Results and discussions In order to remedy the deficiencies in the physicochemical properties of DES, we attempted to prepare a multicomponent crystal of this drug. It is somehow surprising that a search of the Cambridge Structural Database (Groom et al., 2016) (version 5.38, update July 2017) revealed that no multicomponent crystal has been reported since the crystal structure of DES was reported by a group of researchers led by Desiraju. The attempts to prepare a multicomponent crystal of DES used highly efficient cocrystal screening methods, such as liquid-assisted grinding, slurry, dry milling, and solvent evaporation techniques. DES has pyridine and piperidine rings that potentially form any intermolecular interactions with mildly acidic carboxylic acids. Therefore, we created coformer lists consisting of GRAS-listed substances (see supplementary materials for a list of coformers used in this study). Interestingly, only BA shows a change in the PXRD patterns, which indicates that a new phase could be obtained. The new single pure phase of the multicomponent crystal between DES and BA was prepared using a solvent evaporation method aided by a rotary evaporator; conversely, liquid-assisted grinding, slurry, and dry milling were not successful. Notably, the utilization of a rotary evaporator was found to be important, because without it, a mixture between solid and oilyliquid is always obtained. As illustrated in Fig. 1, no trace of impurity from DES and BA is observable. Also, the experimental and calculated PXRD patterns are similar, indicating the absence of significant amounts of impurities. It should be noted here that the differences between experimental and simulated powder patterns in this case may be caused by experimental factors, i.e., different temperature and preferred orientation. During preparation of the DES-BA multicomponent crystal, a single large-block crystal suitable for single crystal X-ray diffraction was obtained. The single crystal X-ray diffraction shows that DES-BA is crystallized in the triclinic crystal system and the P-1 space group. The crystallographic data are summarized in Table 1. The thermal ellipsoid

Moeity formula

C19H20ClN2 ∙ C7H5O2

Formula weight Crystal system Space group a (Å) b (Å) c (Å) α(°) β(°) γ (°) V (Å3) Z,Z′ T (K) Measured ref. Independent ref. Refined parameters Goodness-of-fit on F2 Final R indices [I > 2σ(I)]

432.93 Triclinic P-1 5.4091 (2) 13.2642 (4) 16.2445 (5) 104.495 (7) 98.108 (7) 101.044 (7) 1085.38 (8) 2,1 93(2) 3873 3569 (Rint = 0.104) 288 1.04 R1 = 0.041

Fig. 2. The molecular structure of DES-BA with atom labelling and displacement ellipsoids drawn at the 50% probability level.

drawing for DES-BA is presented in Fig. 2. An asymmetric unit contains one cationic DES molecule and one anionic BA molecule. As DES-BA appears as a multicomponent crystal, it is very important to note whether the multicomponent molecular crystal specifically exists in the ionic salt or neutral cocrystal. During the crystal structure 67



Table 2 Details of the hydrogen bonds in the DES-BA crystal. DeH…A

DeH

H…A

D…A

DeH…A

N2eH…O21 N2eH…O12 C18eH…O23 C17eH…N13 C13eH…O14

0.93 (2) 0.95 (2) 0.99 0.99 0.95

1.84 (2) 1.72 (2) 2.38 2.60 2.37

2.7586 (19) 2.6484 (18) 3.3064 (18) 3.508 (2) 3.2315 (19)

169.7 (18) 163.1 (18) 155 152 150

Symmetry codes: 1 −x + 1, −y + 1, − z; 2 − x, − y + 1, − z; 3x − 1, y, z; 4x + 1, y + 1, z.

refinement, two significant residual density peaks were observed in the difference Fourier map at a position suitable for the N-H distance in N2 of the DES molecule. One of these hydrogen atoms acts as protonated hydrogen atom in this case. In addition, there is no residual density peak around O1 and O2, indicating BA exists in anionic form. Therefore, the proton has been transferred to N atom of piperidine. The anionic form occurrence of BA was also confirmed geometrically by two C-O distances in BA molecules. The C-O distances of C20-O1 and C20O2 are 1.2618 (18) and 1.2622 (19) Å, respectively. As the difference between the C-O distances is < 0.07 Å, the BA molecule exists in an anionic form because of the manifestation of a carboxylate moiety (Putra et al., 2016d). The occurrence of the salt instead of the cocrystal itself is not unexpected since the ΔpKa is large enough at 4.45 (Chou and Huang, 1999; ter Laak et al., 1994). The crystal structure of DES-BA is constructed both by conventional NeH…O and unconventional CeH…O hydrogen bonds. The numerical details of the hydrogen bonds in DES-BA are listed in Table 2. The charge-assisted hydrogen bonds of N2eH…O1 and N2eH…O2 are observed to connect DES and BA along the c axis. Thus, each DES molecule is hydrogen-bonded to two neighboring BA molecules, and conversely, each BA molecule is hydrogen-bonded to two DES molecules. The outcome of these interactions is a layered structure formed by a one-dimensional chain structure. A weak hydrogen bond of C17eH…N1 is also involved to stabilize this layered structure by connecting DES molecules within the chain (Fig. 3a). The layered structure is connected to two other layered structures through weak hydrogen bonds. As illustrated in Fig. 3b, C13eH…O1 and C18eH…O2 connect one layer to other two adjacent layers. These weak hydrogen bonds form slip planes parallel to (001) and are considerably important for the

Fig. 4. The DSC and TG scans of DES (red), BA (green), and DES-BA (blue). Solid and dashed lines represent DSC and TG scans, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

tabletability behavior of the DES-BA salt multicomponent crystal (Fig. 3c). The thermal profiles of the materials investigated here are presented in Fig. 4. The thermal profiles of DSC and TG were investigated to understand their thermal behavior during heating. Moreover, careful attention must be given to the pharmaceutical process to avoid undesired solid-state phase changes during heating when this crystal form in this study is used for real application. Notwithstanding the fact that there are some differences among the baseline in each of DSC scans, a sharp endothermic peak was observed in DSC scans of DES, BA, and DES-BA at 157.0 °C, 120.8 °C, and 175.6 °C, respectively. We attribute these peaks to the melting points. It should be noted here that the second endothermic peak in BA represents evaporation. Remarkably, the melting point of DES-BA is arguably higher than DES. We predict that the abundant hydrogen bonds, which consist of not only OeH…O but also CeH…O hydrogen bonds in DES-BA, contribute to the higher melting point compared to DES. Notably, the DES parent drug has only one CeH…O hydrogen bond (Bhatt and Desiraju, 2006). Similar results have been reported in the Fig. 3. Molecular packing motifs in the crystal showing (a) a layered structure formed by a one-dimensional chain hydrogen bond between DES-BA along the c axis, and (b) the interaction among layered structures. (c) The packing view along the c axis shows the existence of slip planes parallel to (001). DES and BA are drawn in capped stick and spacefill settings in (c), respectively. The conventional NeH…O and unconventional CeH…O hydrogen bonds are drawn as blue and orange dashed lines, respectively. Hydrogen atoms are omitted for clarity. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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salt of sulfamethizole with oxalic acid (Suresh et al., 2015), flurbiprofen with 2-amino-2-methylpropan-1-ol (Supuk et al., 2013), and flurbiprofen with tris(hydroxymethyl) aminomethane (Supuk et al., 2013), in which a higher melting point was obtained from salt multicomponent crystals. Since no thermal moment could be observed prior to the melting point of DES-BA, no polymorphism could not be obtained from the currently reported multicomponent crystal. Interestingly, all solids investigated in this study have a tendency to decompose after melting, as confirmed by TG measurements. To demonstrate that preparation of multicomponent crystal can alter the physicochemical properties of DES, the tabletability and solubility of DES-BA was evaluated and compared with its parent drug. Prior studies have demonstrated that preparation of multicomponent crystals could alter tabletability and solubility, especially where slip planes and a layered structure exist in the crystal structure. Tabletability here was measured by comparing the ability of the powder to be transformed into a tablet with specific tensile strength under certain amount of compaction pressure (Chang and Sun, 2017; Di Martino et al., 2007). Herein, both DES and DES-BA powders formed a tablet without requiring the use of any excipients. The tabletability profiles of DES and DES-BA as a function of compaction pressure between 25 and 350 MPa are shown in Fig. 5. The tensile strength of the DES tablet is lower than DES-BA, i.e., it starts at ~ 0.9 MPa at 25 MPa compaction pressure, continuously reaches ~ 1.6 MPa at 250 MPa compaction pressure, and decreases at compaction pressures higher than 250 MPa. The tablet tensile strength of DES is poor (< 1 MPa) at compaction pressures < 150 MPa. However, DES can form a relatively good tablet between compaction pressure 150–250 MPa. A tendency of capping is observed in the DES tablet if the compaction pressure is increased higher than 250 MPa (Fig. 6a). Such profiles are called ‘over-compaction’ profiles due to the elastic deformation of DES (Garekani et al., 2001; Sun and Hou, 2008). Interestingly, DES-BA shows better tabletability profiles compared with DES. DES-BA could be made into a good tablet up to 350 MPa, which is the highest compaction pressure employed in this study. Furthermore, a tensile strength > 2 MPa could be attained at compaction pressures > 200 MPa. It should be noted here that a minimum tensile strength of 2 MPa has been proposed for ensuring integrity of a pharmaceutical tablet (Perumalla et al., 2012; Perumalla and Sun, 2014). Therefore, a formulation containing DES-BA will not have any substantial problems with tabletability – even at a high compaction pressure. Neither capping nor lamination tendency was observed in the DES-BA multicomponent crystal, as illustrated in Fig. 6b. Next, we investigated the elasticity-plasticity of DES and DES-BA. Plasticity and elasticity is described by elastic recovery in this case. The profiles of elastic recovery under different compression pressures are presented in Fig. 7. The elastic recovery of DES gradually increases up

to a compaction pressure of 150 MPa and decreases for higher compaction pressures. Therefore, a tendency of depletion in elastic recovery is observed with increasing compaction pressure in DES. We predict that corrugated or interlocked hydrogen-bonded structure in DES parent drug is responsible for depletion in elastic recovery with increasing compaction pressure. Similar result was reported in piroxicamsaccharin cocrystal case (Chattoraj et al., 2014). By comparing the elastic recovery of DES and DES-BA, it is clear that a novel multicomponent crystal reported in this study is more plastic than the parent drug; this may imply that DES-BA has a lower porosity and is a stronger tablet at the same compaction pressure compared to DES. In the solid dosage form, the compressibility and flowability are two other important aspects that ensure the quality of the final product. The compressibility and flowability of DES and DES-BA in this study were calculated by measuring the Carr index and the Hausner ratio, respectively. The details of the Carr index and the Hausner ratio are listed in Table 3. The multicomponent crystal of DES-BA has better compressibility and flowability characteristics than DES. Notably, good flowability of the multicomponent crystal DES-BA is expected to provide a constant filling of the powder into the die. The fact that DES-BA has better tabletability profiles than DES can be understood from a structural point of view. Therefore, it is very useful to compare the crystal structure of DES and DES-BA. As illustrated in Fig. 8, the crystal structure of DES shows a corrugated hydrogen-bonded chain structure composed by only one weak CeH…N hydrogen bond. This corrugated hydrogen-bonded chain structure will respond hardly to the stress through plastic deformation due to its rigidity. In contrast with DES, the existence of the layered structure and a slip plane parallel to (001) provides the enhanced ability to form a tablet. It has been previously demonstrated that layered structures show significant tabletability improvement in many pharmaceutical multicomponent crystals (Chattoraj et al., 2010; Supuk et al., 2013). In addition, the existence of the slip plane, which is only composed of weak CeH…O hydrogen bonds, will also facilitate shearing and will allow the layered structure to easily slide. These features eventually will lead to the improvement of plastic deformation during compaction. A similar case was proposed and reported in a theophylline pseudopolymorphic crystals system (Chang and Sun, 2017). Not only tabletability but also the solubility and dissolution rate are fundamental to formulate a solid oral dosage form. Solubility and dissolution rates are important characteristics that are related to bioavailability. Previously, several studies have reported solubility and dissolution rate improvements of DES via preparation of cyclodextrin complex and solid dispersion (Ali et al., 2007; Kolašinac et al., 2013, 2012). However, these systems have some disadvantages i.e., they lack stability during storage and have the tendency to transform into the crystalline state. Therefore, development of new stable crystalline phase is necessary. As shown in Table 4, the DES-BA multicomponent crystal shows improvement of solubility in water and 0.1N HCl by around 51 and 3 folds, respectively. DES is a practically insoluble in water, and the salt formation results in an improvement of solubility in this case. We predict that the cationic and anionic forms of the molecule have better affinity to water compared to the parent drugs. In this study, the solubility results were accompanied by its kinetic aspect represented by the dissolution rate. The dissolution profile of DES and DES-BA is presented in Fig. 9. Based on the dissolution profile, the percent of dissolution is used to compare the amount of drug released in water and the 0.1N HCl media. DES and DES-BA have a final drug release (after 60 min) of 2.5 ± 0.6% and 25.9 ± 0.8%, respectively, in water, and therefore, salt formation increases the drug release rate by around 10 folds. However, there is no significant difference of drug release in 0.1N HCl. We predict that a simple case of ionic equilibrium of DES base at low pH media cause the dissolution rate improvement to become statistically insignificant in this case. A close examination of the remaining powder after solubility and dissolution experiments showed that DES-BA remains stable at the end of the

Fig. 5. Tabletability profiles of DES (red) and DES-BA (blue). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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Fig. 6. Tablet overview of (a) DES and (b) DES-BA at a compaction pressure of 350 MPa.

Table 4 Solubility data of DES and DES-BA in water and 0.1N HCl. Compound

DES DES-BA

Solubility (mg/mL) in Water

HCl 0.1N

0.32 ± 0.01 16.43 ± 0.04

36.19 ± 0.07 96.85 ± 0.01

4. Conclusions Here, we reported the formation of the first multicomponent crystal of desloratadine, an anti-histamine drug. A pharmaceutically acceptable coformer of benzoic acid was used in this case. In this study, the multicomponent crystal was prepared using a solvent evaporation technique. Single-crystal structure analysis was performed to elucidate the structure of this multicomponent crystal, and it was found that proton transfer occurred from benzoic acid to desloratadine molecule. Therefore, this multicomponent crystal was considered to be a salt crystal. This novel salt multicomponent crystal had better tabletability and plasticity profiles than the parent drug. The good plasticity and tabletability was validated using a selection criterion based on the crystal structure, i.e., the presence of a layered structure and a slip plane. The desloratadine-benzoate exhibited an improved solubility in water and 0.1N HCl media as well as a better dissolution profile in water.

Fig. 7. Elastic recovery of DES (red) and DES-BA (blue) tablets as a function of compaction pressure. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Table 3 Flowability characteristics for DES and the multicomponent crystal DES-BA. Flow properties

DES

DES-BA

Carr index (%) Hausner ratio Flow character

42.73 1.75 very poor

20.82 1.26 fair

dissolution experiments. The improvement of solubility and dissolution rate in water are proposed based on crystal structure in this study. As previously mentioned, a layered structure is formed by alternate arrangements of DES and BA molecules. This configuration, instead of an extended layered structure only composed by DES molecules in parent drug, predictably facilitates the improvement of solubility and dissolution rate by facilitating contact with the solvent. When the coformer, which is more soluble, is in contact with the solvent, it dissolves and the remaining part of layered structure which consists of DES molecule will also dissolve and eventually result in an improvement of solubility.

Acknowledgements This research was supported financially by Ministry of Research, Technology and Higher Education, Republic of Indonesia with a Grant for Dissertation Research (No. 098/SP2H/LT/DRPM/IV/2017).

Notes The authors declare no competing financial interest. Author contribution All authors have approved the final version of the manuscript. Fig. 8. Corrugated hydrogen-bonded chain structure in DES parent drugs (Bhatt and Desiraju, 2006). The hydrogen atoms are omitted for clarity. The crystal structure was obtained from Cambridge Structural Database (REFCODE: GEHXEX).

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Fig. 9. Dissolution profiles of DES (red) and DES-BA (blue) in water (solid lines) and 0.1N HCl (dashed lines) dissolution media. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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