Preparation and Characterization of Aripiprazole Cocrystals with

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Preparation and characterization of aripiprazole co-crystals with coformers of multi-hydroxybenzene compounds Min-Yong Cho, Paul Kim, Ga-Young Kim, Ju-Yeon Lee, Keon-Hyoung Song, Min-Jeong Lee, Woojin Yoon, Hoseop Yun, and Guang J Choi Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01281 • Publication Date (Web): 19 Oct 2017 Downloaded from http://pubs.acs.org on October 19, 2017

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Crystal Growth & Design

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Preparation and characterization of aripiprazole co-crystals with

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coformers of multi-hydroxybenzene compounds

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Min-Yong Cho1, Paul Kim1, Ga-Young Kim2, Ju-Yeon Lee2, Keon-Hyoung Song1,2, Min-Jeong Lee3,

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Woojin Yoon4, Hoseop Yun4, Guang J. Choi1,2*

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1

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2

Department of Pharmaceutical Engineering, Soonchunhyang

University, Asan, Chungnam 31538, South Korea 3

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Department of Medical Science,

Crystallization and Particle Science, Institute of Chemical and Engineering Sciences, A*STAR, Jurong Island, Singapore 627833, Singapore

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Department of Chemistry, Ajou University, Suwon, Gyeonggi 16499, South Korea

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Abstract

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A novel co-crystal of aripiprazole (ARI), the active substance in the atypical antipsychotic Abilify,

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with orcinol (ORC) as a coformer, was prepared, characterized and compared with other ARI co-

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crystals with dihydroxy- and trihydroxy-benzene coformers [catechol (CAT), resorcinol (RES), and

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phloroglucinol (PHL)] reported previously.1 Three preparation methods were used: neat grinding

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(NG), liquid-assisted grinding (LAG), and solvent evaporation (SE). Based on single-crystal X-ray

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diffraction (SC-XRD) measurements, the crystal structure of the ARI-ORC co-crystal was

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determined to be monoclinic. The melting point of ARI-ORC co-crystal was found to be 184–

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185°C, higher than existing ARI co-crystals with multi-hydroxybenzene coformers. Additionally, the

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ARI-ORC co-crystal showed the highest dissolution rate among those in the test group in an

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acetonitrile-water 10/90 cosolvent.

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We investigated how the co-crystallization pathway and the dissolution behavior might correlate

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with the coformer moiety, primarily in terms of its chemical structure and melting point. Co-

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crystallization between ARI and PHL via grinding (NG or LAG) required the highest activation

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energy, mainly due to the coformer’s higher melting point. The dissolution rate of ARI co-crystals

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was not obviously correlated with the coformer’s melting point or its molecular weight. However,

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the high dissolution rate of ARI-ORC co-crystals was possibly associated with the bond angle of

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D-H⋯A for O3-H3O⋯N2 in the co-crystal’s superlattice structure. The stability of ARI co-crystals

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was examined by aging these powders in a controlled oven at 80°C/98% relative humidity for 1

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week. We observed that all of the co-crystal powders, except for the aripiprazole-catechol (ARI-

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CAT) pair, underwent no noticeable degradation or physicochemical change upon treatment. In

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conclusion, we can consider the novel ARI-ORC co-crystal as a potential drug substance with the

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enhanced dissolution behavior in aqueous media and good stability under stressed conditions.

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Key words: aripiprazole, co-crystal, multi-hydroxybenzene, orcinol, dissolution, stability

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* Corresponding author : +82-41-530-4864, [email protected]

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1. Introduction

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Over the last decade, the pharmaceutical co-crystal approach has been investigated as one of the

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potential enabling technologies to significantly moderate critical pharmaceutical properties of

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active pharmaceutical ingredients (APIs), including their dissolution rate and stability. In the 2016

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guidance for industry ‘Regulatory Classification of Pharmaceutical Co-Crystals’,2 the US FDA

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classified co crystals as a special case of solvates and hydrates where the second component, the

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coformer, is nonvolatile, modifying their earlier viewpoint as a drug product intermediate or as an

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in-process material in the 2013 guidance.3 It is described that “Co-crystals can be tailored to

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enhance drug product bioavailability and stability and to enhance the processability of APIs

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during drug product manufacture. Another advantage of co-crystals is that they generate a

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diverse array of solid-state forms for APIs that lack ionizable functional groups, which is a

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prerequisite for salt formation”.2

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There have been many research articles reporting on the discovery and behaviors of

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pharmaceutical co-crystals in terms of their crystal structures and physicochemical properties.

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Recently, several review articles4−6 were published providing an updated overview and

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understanding regarding this subject. Several drugs, such as Entresto, have been launched

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commercially while others, including ertugliflozin, are now in different stages of clinical

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development in pharmaceutical co-crystal forms.6 Various methods and processes have been

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developed to increase the versatility of the co-crystal approach.7 Among them, nano-crystal

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technology has been integrated with co-crystals.8 The problematic stability of nano-sized co-

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crystal particles has steadily improved via a coating with stabilizing polymers.

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Aripiprazole (ARI, Fig. 1) is an atypical antipsychotic medication, used in the treatment of

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schizophrenia. It was approved by the US FDA as Abilify (10-30 mg) to treat acute manic and

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mixed episodes associated with bipolar disorder. This drug appears to mediate its antipsychotic

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effects primarily by partial agonism at the D2 receptor. Up to date, ARI is known to exist in

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unprecedentedly twelve polymorphic anhydrous forms.9-10 Nevertheless, the solubility of the most

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soluble form in water was reported as 0.045 mg/L at 25°C.11 In another database, its solubility is

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listed as even lower, 0.00777 mg/mL.12 Based on its solubility/dissolution performance, ARI was

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reported to have a low solubility13 that necessitates investigations on co-crystals or eutectic

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materials for enhancement.

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Regardless of the potential and possibility of co-crystallization of ARI to enhance dissolution

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and/or permeability, there was no report regarding this subject until information on a group of

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ARI co-crystals with dihydroxy- and trihydroxy-benzene compounds as coformers was published in

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2016.1 This study focused primarily on establishing a correlation between the melting point of ARI



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co-crystals and their supermolecular structures. It was concluded that the melting point was

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significantly associated with how hydrogen bonds were restricted to two-dimensional layers.

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However, key properties such as solubility and dissolution behavior of ARI co-crystals were not

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reported. In addition to the lack of dissolution behavior,1 the preparation method of ARI co-

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crystals was not straightforward or common, but sophisticated and specific to each coformer. A

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simple, reproducible process is needed for the co-crystallization approach to be valuable

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practically.13

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Thus, the main objective of this study was to report the discovery of a novel aripiprazole-orcinol

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(ARI-ORC) co-crystal by simple preparation methods. We compared its characteristics with those

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of existing ARI co-crystals with respect to the physicochemical structures of coformer compounds

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and the co-crystals’ supermolecular structure.

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2. Experimental

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2-1. Materials

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Several multi-hydroxybenzene compounds were examined for pharmaceutical crystallization with

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aripiprazole (ARI) in this study. Their chemical structures are illustrated in Fig. 1. Among those

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coformers, we selected catechol (CAT), resorcinol (RES), phloroglucinol (PHL), and a novel coformer,

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orcinol (ORC), primarily due to their structural similarities as well as differences in chemical

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configuration and properties.

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ARI powder in the form-I was supplied by Daewoong BioPharm (Seoul, Korea) and used without

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further purification. The specific polymorph was confirmed by the highest melting point (~149°C)

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among the API crystal forms reported in literature.9 Key characteristics of the ARI powder, such as

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powder size and distribution, were analyzed in our lab prior to use. Coformer (CAT, RES, PHL, and

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ORC) powders were purchased from Sigma-Aldrich (St. Louis, MO, USA) and used as received.

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Various solvents (chloroform, ethanol, and methanol) were purchased in high-performance liquid

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chromatography (HPLC) grade from Sigma-Aldrich. A water purification system (Human Corp.,

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Seoul, Korea) was used to supply purified water.

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2-2. Preparation of Co-crystal Powders

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Grinding: Neat Grinding and Liquid-assisted Grinding

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Neat grinding (NG) was performed by manually grinding the ARI powder (0.2 mmol) with each

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equimolar coformer powder in a mortar and pestle for 30 min under a dry atmosphere. For


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liquid-assisted grinding (LAG), a few drops of a solvent were added before starting the manual

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grinding. After examining several organic solvents, we decided to use the acetonitrile due to its

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superior performance in terms of the co-crystallization extent.

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After grinding alone, either NG or LAG, did not produce well developed co-crystals. Ground

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mixture powders were treated under various conditions: heating at 80°C, humidifying at 98%

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relative humidity (RH), and humidified heating at 80°C and 98% RH together in a

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temperature/humidity chamber (Model TH-PE-025; Jeio Tech, Seoul, Korea) for designated times.

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In this article, the effect of heat treatments at 80°C was discussed. Prepared and/or treated

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powders were characterized using various analytical instruments.

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Evaporation

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ARI co-crystal powders with the four coformers were also prepared by the evaporation method.

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Equimolar ARI and each coformer powder (1 mmol) were dissolved in the solvent, followed by

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solvent evaporation (SE) at 70°C using a hot plate until each material was dry. After examining

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several common solvents individually and their mixtures, we decided to use the co-solvent of

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chloroform and ethanol at a 4:1 volume ratio. Each solid material after the evaporation went

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through a vacuum drying process for 24 h. The resulting powders were characterized using

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various analytical techniques.

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The co-crystallization of ARI and ORC was performed via a very slow evaporation to obtain co-

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crystal powders of a size sufficiently large for SC-XRD measurements. ARI (0.1 mmol) and

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equimolar ORC powder were dissolved in the 4:1 chloroform/ethanol co-solvent. The solution was

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purified by filtering through a 0.45-µm nylon filter prior to slow evaporation for several weeks.

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The evaporated material went through a vacuum drying process for 24 h.

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2-3. Characterization

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Powder X-ray Diffraction

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Powder X-ray diffraction (PXRD) data were recorded with a powder X-ray diffractometer (model

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MiniFlex 600; Rigaku, Tokyo, Japan) using a Cu-Kα radiation source (λ = 1.5406 Å) at 40 kV and 15

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mA. Diffraction patterns were collected over a 2θ range of 5–30° with a step size of 0.02° and a

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scan rate of 10°/min. Peak position and peak area data were collected and quantified using

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Miniflex guidance software.

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Single-crystal X-ray Diffraction

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The crystal structure of the ARI-ORC co-crystal was determined using a SC-XRD method.

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Preliminary examination and data collection were performed on a Rigaku R-Axis Rapid

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diffractometer equipped with graphite-monochromatized Mo-Kα radiation (λ = 0.71073 Å). The

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unit cell parameters and the orientation matrix for data collection were obtained from a least-

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squares refinement, using the setting angle of 6,679 reflections, in the range of 7.0° < 2θ < 55.0°.

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Further intensity data were collected at 281(1) K with the ω-scan technique. The intensity statistics

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and systematic absences were consistent with the monoclinic space group P21/n. The initial

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positions for all non-hydrogen atoms were obtained using the direct methods of the SHELXS-97

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program. The PART and SAME instructions were applied and a second free variable for the

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occupancy of each component was introduced. The second free variable, the ratio of the two

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components, was refined to be 0.49 and thus the occupancies for both components were fixed at

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0.5.

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The positions of the hydrogen atoms were idealized using the riding model. The structure was

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refined by a full-matrix least-squares technique using the SHELXL-97 program in the WinGX

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program package. Atomic displacement parameters for all non-hydrogen atoms were refined

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anisotropically. The final cycle of refinement performed on F0 = 6679 unique reflections afforded

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residuals wR2 = 0.1260 and the conventional R index, based on the reflections having F02 > 2σ

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(F02 was 0.0404).

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Thermal Analysis

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Differential scanning calorimetry (DSC) was performed using a DSC-60 instrument (Shimadzu,

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Kyoto, Japan). Each sample (1.5 mg) was loaded in an aluminum pan (with a blank pan as a

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reference) and scanned from 30 to 250°C at a heating rate of 10°C/min under a nitrogen

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atmosphere (N2 flow rate: 50 mL/min).

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The weight loss of samples as they were heated to elevated temperature was measured via

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thermogravimetric analysis (TGA; Scinco N-1000, Seoul, Korea). Specifically, each powder sample

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of ~10 mg was placed in an alumina pan and heated over a range of 25–350°C at a heating rate

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of 10°C/min under a nitrogen purge.

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Powder dissolution rate

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The powder dissolution behavior was measured using the shake-flask method, by stirring an


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excess amount (80-100 mg) of each powder (ARI and the four ARI co-crystals) in a designated

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solvent (100 mL) at 37°C for 24 h. All ARI co-crystal powders used for dissolution testing were

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produced by solvent evaporation. Precipitated solids were vacuum dried and ground slightly for

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deagglomeration. In order to minimize the effect of particle size on the dissolution rate, each

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powder was sieved (mesh # 120 and 230) to collect the size range of 63−125 µm. In this study, 10%

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acetonitrile co-solvent was used as a dissolution medium instead of purified water primarily

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because the water solubility of ARI was too low to measure reliably in our lab.

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Samples were withdrawn at designated time intervals and filtered using 0.45-μm nylon filters. The

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concentration of ARI was measured using HPLC (Shimadzu, Kyoto, Japan) with a Shim Pack C18

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column (Shimadzu 4.6×250mm/5μm, Kyoto, Japan). Absorbance was measured at 254 nm to avoid

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interference with other constituents. Calibration plots were constructed through a concentration

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range of 2–50 μg/mL prior to solubility and dissolution experiments. An acceptable calibration line

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(R2 = 0.99, n = 5) was obtained.

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Stability under stress condition at 80°C/98%RH

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Global standard procedures and conditions for stability testing are well documented in ICH

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Q1A(R2) guideline.14 Accelerated testing shall be carried out by storing samples at 40°C(±2°C) and

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75% RH(±5% RH) for six months. In this study, however, much higher temperature and humidity

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than the accelerated test conditions were employed to evaluate and compare the stability of

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various materials in the solid state in a short time.

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Co-crystal powders produced in this study were aged in an atmosphere-controlled oven (Model

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TH-PE-025; Jeio Tech, Seoul, Korea) at 80°C/98% RH for 1 week. The treated powders were cooled

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down before characterization via XRD and DSC to assess any appreciable changes in

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physicochemical or crystalline properties.

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3.

Results and Discussion

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A novel ARI-ORC co-crystal material was synthesized, identified, and characterized in this study.

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We attempted correlations between the resulting characteristics of various ARI co-crystals,

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including the dissolution rate, and the causative parameters, such as the coformer moiety and co-

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crystal structure. Our new coformer, ORC, had the same dihydroxy structure as RES but with one

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methyl group attached additionally, as shown in Fig. 1. Compared with PHL, ORC has a methyl

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group in the position of one hydroxyl functionality. CAT and RES are chemical isomers of

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dihydroxyl benzene.



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XRD patterns and DSC thermograms of ARI and the four coformer compounds are compared in

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Figs. 2(a) and (b). It was observed that the diffraction patterns of the four coformers are clearly

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distinguishable from each other, despite the similarities in chemical structure and molecular

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weight. Based on the intensity of the diffraction peaks, the crystallinity of ARI, which has a higher

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molecular weight, was substantially weaker than the other coformers examined here, especially

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CAT.

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According to DSC measurements, ARI and the four coformer substances showed distinct melting

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behavior, each with a single endothermic peak. The measured melting points are reported in Table

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1, which were close to the values reported in the literature.1 For RES, there was a small peak right

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in front of the main melting peak. A similar DSC thermogram shape was found in an article.15

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Since all coformer powders used in this study were in the high purity (≥99.0%), the small peak for

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RES is not likely to be associated with impurity.

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Figure 3(a) shows the XRD patterns of four ARI combinations after NG for 30 min. For CAT, RES,

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and ORC, the powder mixtures turned to a highly amorphous state after 30 min NG although

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each physical mixture of ARI with the corresponding coformer prior to NG was in a strongly

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crystalline state comprising two XRD patterns. The ARI-PHL pair showed the presence of

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crystalline PHL powder in the XRD pattern to a substantial extent even after 30 min NG.

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DSC thermograms of four ARI combinations after 30 min NG are compared in Fig. 3(b). Each

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profile has a feature in common: that is, one small exothermic peak at the lower temperature for

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co-crystallization and another large endothermic peak at the higher temperature for co-crystal

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melting. Upon heating at 10°C/m during DSC measurements, each amorphous mixture was

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activated to undergo co-crystallization at the lower peak temperature whereas each resulting co-

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crystal was melted at the higher temperature producing a large endothermic peak.

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The co-crystallization peak temperature of the ARI-PHL pair in Fig. 3(b) was substantially higher

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than those of the three other ARI combinations. In contrast, the melting temperature of the ARI-

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CAT co-crystal was substantially lower than the other three co-crystals. The melting point of our

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novel ARI-ORC co-crystal was the highest (~185°C) of the ARI co-crystals with multi-

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hydroxybenzene coformers reported to date. The measured melting points of ARI co-crystals with

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CAT, RES, and PHL are well matched with those reported in the literature.1 These values are

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summarized for comparison in Table 1.

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Figure 4 shows the effect of 1 h of heating at 80°C after the 30 min NG on XRD and DSC results

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for the four ARI combinations. As shown in Fig. 4(a), the ARI-PHL pair did not make much

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progress towards co-crystallization by 1 h heating alone, whereas the other three combinations

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produced co-crystals to a greater extent. Compared with those in the literature,1 the XRD patterns


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of ARI-CAT and ARI-RES co-crystal powders showed good agreement. The XRD pattern of the

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ARI-ORC co-crystal was similar to these two pairs, as we can easily anticipate based on the

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similarity in coformer structure.

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Figure 4(b) compares DSC thermograms of four ARI combinations after the same procedure as in

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Fig. 4(a). For CAT, RES, and ORC, there was no noticeable exothermic co-crystallization peak,

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indicating that co-crystallization was already close to complete by 1 h heating at 80°C. However,

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the ARI-PHL pair still showed a small co-crystallization peak at ~110°C. The detected melting

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points were consistent with those in Fig. 3(b).

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An interesting observation is the substantially higher co-crystallization peak temperature for the

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ARI-PHL pair (~110°C) than the other combinations (73–77°C). As shown in Table 1, the melting

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point of the PHL coformer is 220°C, much higher than those of the three other coformers (105–

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111°C). When grinding was conducted for co-crystal formation, the ARI molecules should be in a

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close contact with coformer molecules to form superlattice structures via hydrogen bonding.

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Accordingly, the mobility of coformer molecules will be the rate-controlling factor toward co-

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crystallization. Therefore, it seems that a heat-treatment at higher temperatures than 80°C shall be

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necessary for the co-crystallization of ARI-PHL materials after 30 min NG.

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According to one study16 on the co-crystal formation with mechanical grinding, especially NG,

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amorphous intermediate phases are produced on the way to co-crystallzation. The final co-

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crystals are created from these intermediate materials slowly or rapidly, depending primarily on

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the energy activation level. For example, if grinding is performed at a temperature lower than the

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glass transition temperature (Tg), vitrification will be favored, facilitating the formation of

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amorphous intermediate phases. In our case, Tg for ARI-PHL was observed ~50°C whereas no

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glass transition region was detectable down to 40°C for other three ARI combinations. The Tg

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estimation was basically based on an article in the literature.17 If NG is conducted at a higher

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temperature, the formation of metal-stable co-crystal polymorphs might have been produced

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over amorphous intermediate materials. Due to the high melting point of PHL, the co-

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crystallization of the ARI-PHL pair did not advance much with 30 min NG at room temperature or

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even with post-NG heating at 80°C for an hour. A longer time at 80°C or a treatment at higher

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temperature would have resulted in a greater extent of co-crystallization for ARI-RES pair.

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Figure 5 illustrates the XRD patterns and DSC thermograms of four ARI combinations after LAG

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for 30 min. As mentioned previously, acetonitrile was added as the solvent. Unlike the

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observations in Fig. 3(a), co-crystallization made progress substantially in all combinations with 30

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min of LAG alone at RT. Regarding the diffraction peak intensity, the ARI-CAT pair was very strong

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while the ARI-PHL couple was the weakest. Essentially the same observation can be made from

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the DSC thermogram comparison in Fig. 5(b). When processed via 30-min LAG, co-crystallization



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was complete for the ARI-CAT pair, whereas small co-crystallization peaks were detected for the

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three other combinations. The intensities of the exothermic peaks, however, were small, indicating

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that the co-crystallization proceeded to a greater extent with 30-min LAG. For the ARI-CAT pair,

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there was no DSC peak for co-crystallization. This means that the co-crystallization was almost

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complete, which could be the reason for the strongest XRD pattern of the ARI-CAT co-crystal (Fig.

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5(a)). Again, the co-crystal melting points showed good agreement with earlier observations.

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It is known that the incorporation of small molecules can facilitate the migration of molecules in a

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multi-compound solid mixture phase. Acetonitrile that was added for the LAG process would have

281

played a plasticizing role. As a consequence, co-crystallization was achieved to a great extent even

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for the ARI-PHL pair. Table 2 summarizes the quantitative analysis of DSC measurements for four

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ARI-coformer combinations by NG and LAG. From NG process data, the enthalpy of co-crystal

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melting seemed to be proportional to that of co-crystallization. Thus, if more energy is released

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for a specific API-coformer pair by co-crystallization, a greater energy will be required to melt the

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co-crystal. Compared with the NG data, the enthalpy of co-crystallization for coformers with a

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relatively low melting point in the LAG process was small, consistent with the interpretation of

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XRD patterns.

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Figure 6 illustrates the XRD patterns and DSC thermograms of four ARI combinations prepared by

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solvent evaporation. The 4:1 chloroform/ethanol mixture was used as co-solvent. Compared to Fig.

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4(a) and 5(a), much stronger diffraction peaks are observed for all ARI combinations in Fig. 6(a).

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Therefore, co-crystallization was almost completed by solvent evaporation alone. The same

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observation can be made from the DSC profiles in Fig. 6(b), because exothermic peaks for co-

294

crystallization were not detectable in any case.

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Figure 7 shows an ORTEP diagram of the ARI-ORC co-crystal structure measured by SC-XRD. The

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anisotropic displacement parameters (ADPs) of the coformer molecule were indicative of

297

positional disorder and the atoms were refined isotropically to find the coordination of both

298

components. A different Fourier synthesis calculated with phases based on the final parameters

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shows no peak heights greater than 0.312e/Å3. No unusual trend was found in the goodness-of-

300

fit as a function of F0, sin θ/λ, or Miller indices. Final values of the atomic positional parameters

301

and equivalent isotropic displacement parameters are given in Supporting Information.

302

Anisotropic displacement parameters (ADPs) and complete tabulations on the X-ray studies can

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be found in CIF format in the Supporting Information. Table 3 summarizes the crystal structure

304

data for a comparison among the ARI co-crystals examined.

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Figure 8 shows the TGA profiles of two ARI-ORC co-crystals in comparison with ARI and ORC

306

powders. The TGA curve for ORC decreased rapidly from ~150°C and reached almost zero at

307

240°C. It is rationalized by its melting at ~110°C followed by thermal decomposition or


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308

evaporation above 160°C. On the other hand, the rapid drop in the TGA profile for ARI took place

309

from ~260°C to ~380°C. This can be explained similarly to ORC. The weight of the co-crystal

310

powder was sustained until the co-crystal melted near 180°C. The TGA profile for the co-crystal

311

was composed of two distinct downhill regions, 180–250°C and 270–350°C.

312

The first region is responsible for a 22% weight reduction whereas the second region takes the

313

rest, 78%. Considering that the mass ratio in the equimolar ARI-ORC co-crystal and molecular

314

weights of ARI and ORC are 448.4 and 124.1, respectively, the 22% weight reduction matches

315

exactly the proportion of ORC. That is, the ARI-ORC co-crystal started melting near 180°C and

316

separated ORC molecules evaporated on further heating. Thus, the formation of a 1:1 equimolar

317

ARI-ORC co-crystal was confirmed by TGA analysis.

318

Figure 9 presents the powder dissolution profiles of four co-crystal materials compared with ARI

319

powder. All data points were averaged arithmetically after triplicate measurements. As mentioned

320

previously, the dissolution test was carried out in acetonitrile-water 10/90 cosolvent, primarily

321

because the water solubility of ARI was too low to measure reliably in our lab. We assumed that

322

the dissolution rate in this cosolvent might be reasonably proportional to that in pure water,

323

especially because the cosolvent contains 90% water and 10% acetonitrile.

324

We can make primarily two observations from Fig. 9: the significant difference in the dissolution

325

rate and the fall in ARI concentration after reaching the maximum for all ARI co-crystals. The

326

dissolution of ARI-ORC and ARI-PHL co-crystals occurred much more quickly than the other three

327

powders. One the other hand, the dissolution rates of ARI-RES and ARI-CAT were similar to or

328

marginally better than that of pure ARI powder. The maximum ARI concentration from the ARI-

329

ORC co-crystal was 6.4 mg/L, which is four times greater than that for the pure ARI powder.

330

All ARI co-crystals showed a rise and fall pattern in Fig. 9, similar to those in the ‘spring and

331

parachute model’.18 This concept interpreted the typical pattern as a rapid dissociation of the co-

332

crystal to result in the peak drug concentration (‘spring’) followed by a transformation to stable

333

crystalline drug forms for several hours (‘parachute’). In the case of ARI-ORC co-crystals, the drug

334

concentration reached the maximum at 15 min of dissolution and fell down gradually to 3.5 mg/L.

335

This phenomenon was not observed in the dissolution of pure ARI powders.

336

We can divide the profiles in Fig. 9 into two groups in terms of the stabilized drug concentration

337

after 6 h. The ARI concentration of ARI-ORC and ARI-PHL co-crystals was sustained higher than

338

the others. It probably indicates that the super-saturated ARI solutions were stabilized to some

339

extent by dissolved coformer molecules. According to a preliminary experiment to determine the

340

solubility of coformer compounds, RES and CAT were much more soluble in acetonitrile-water

341

10/90 cosolvent than ORC and PHL. Consequently, this outcome did not meet the rule-of-thumb



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

342

saying that a co-crystal comprising a coformer compound that has greater solubility makes a co-

343

crystal more soluble in a designated solvent.

344

There was an experimental study to establish how well the melting point and/or the solubility of

345

the co-crystal can be correlated with the coformer.19 Five dicarboxylic acids with differing alkyl

346

lengths were used to produce co-crystals of the anticancer drug, hexamethylene bisacetamide.

347

The melting point of the co-crystal was directly proportional to that of the coformer. As a

348

dicarboxylic acid of a larger alkyl group is less soluble in water, the solubility of the co-crystal was

349

also correlated with that of coformer.

350

The stability of various ARI co-crystals was examined by comparing their XRD patterns and DSC

351

thermograms before and after treating those powders for up to one week at 80°C/98%RH in an

352

atmosphere-controlled oven. As mentioned previously, much more stressed conditions instead of

353

the ICH standard were employed to evaluate the stability of various ARI materials in the solid

354

state in a reduced time. Briefly, all ARI co-crystals, with the exception of the ARI-CAT pair,

355

presented good stability under given conditions. Figure 10 compares the XRD patterns and DSC

356

thermograms of ARI-ORC and ARI-CAT co-crystals before and after the designated treatment.

357

Regarding the XRD patterns (Fig. 10(a)), no appreciable change was observed by treatment at

358

80°C/98% RH for either material.

359

On the other hand, there were some changes in the DSC thermograms for the ARI-CAT co-crystal.

360

The melting peak near 122.5°C was split into two peaks after the treatment. We suggest that

361

there may be some change in the superlattice structure of ARI-CAT co-crystal, which is

362

differentiated by DSC melting characteristics, but not by XRD crystalline structure. A further study

363

including solution NMR measurements might be necessary for a more comprehensive structural

364

interpretation associated with physicochemical degradation in the ARI-CAT co-crystal.

365 366

4. Conclusion

367

We report the preparation and physicochemical properties of a novel ARI-ORC co-crystal, and

368

compared the results with other ARI co-crystals with benzenediol and benzenetriol coformers

369

reported in the literature.1 Three methods were used to prepare ARI co-crystals. The melting point

370

of our new ARI-ORC co-crystal was 184.3–185.0°C, the highest among those of ARI co-crystals

371

known up to now.

372

With a 30-min NG process alone, co-crystallization did not progress well with any ARI

373

combination. When treated at elevated temperature, however, ARI co-crystals were created in all

374

cases. The extent of co-crystallization achieved by the heat treatment at 80°C was heavily


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375

dependent on the melting point of the coformer compound. The addition of few drops of solvent

376

as a plasticizer during grinding facilitated co-crystallization in all ARI combinations. On the other

377

hand, the evaporation method did not require heat treatment for full co-crystallization.

378

The novel co-crystal of ARI-ORC was verified by various characterizations, using SC-XRD, PXRD,

379

DSC, and TGA. Its crystal structure was described as monoclinic, similar to other ARI co-crystals.

380

The dissolution rate of ARI-ORC measured in water/acetonitrile cosolvent was superior to other

381

ARI co-crystal materials and pure ARI. The significant difference in dissolution behavior did not

382

correlate with the solubility of the corresponding coformer compounds. In an analysis of various

383

parameters in each co-crystal structure, a good correlation between the dissolution rate and the

384

D-H⋯A angle was found. A detailed study is necessary for more rational explanations.

385

It was found that the ARI-ORC co-crystal powder did not show any noticeable degradation on

386

treatment at 80°C/98% RH for 1 week, which was anticipated by its rather high melting point. The

387

novel ARI-ORC co-crystal shows great potential as an enhanced pharmaceutical active ingredient

388

for further in vitro and in vivo studies.

389 390 391

Acknowledgement

392

This research was financially supported by the Basic Science Research Program through the

393

National Research Foundation of Korea funded by the Ministry of Education, Science, and

394

Technology (NRF-2014R1A1A2056702). We also acknowledge the support of Soonchunhyang

395

University for this research.

396 397 398

References

399

(1) Nanubolu, J. B.;

400

(2) U.S. FDA. Guidance for Industry: Regulatory Classification of Pharmaceutical Co-crystals. 2016,

Ravikumar K. CrystEngComm. 2016, 18, 1024−1038.

401

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC

402

M516813.pdf (17) Aakeroy, C. B.; Forbes, S.; Desper, J. 2009. J. Am. Chem. Soc. 2009, 131,

403

17048−17049.

404 405

(3) U.S. FDA. Guidance for Industry: Regulatory Classification of Pharmaceutical Co-crystals. 2013, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

406 407 408 409 410

M281764.pdf. (4) Berry, D. J.; Steed, J. W. Adv. Drug Deliv. Rev. 2017. (in press) https://doi.org/10.1016/j.addr.2017.03.003 (5) Healya, A. M.; Workua, Z. A.; Kumara, D.; Madib, A. M. Adv. Drug Deliv. Rev. 2017, (in press) http://dx.doi.org/10.1016/j.addr.2017.03.002

411

(6) Kale, D. P.; Zode, S. S.; Bansal A. K. J. Pharm. Sci. 2017, 106, 457−470.

412

(7) Lee, M-J.; Wang, I-C.; Kim, M-J.; Kim, P.; Song, K-H.; Chun, N-H.; Park, H-G.; Choi, G. J. Kor. J.

413 414 415 416 417 418 419 420 421

Chem. Eng. 2015, 32, 1910−1917. (8) Karashima, M,; Kimono, K.; Yamamoto, K.; Kojima, T.; Ikeda, Y. Euro. J. Pharm. Biopharm. 2016, 107, 142−150. (9) Braun, D. E.; Gelbrich, T.; Kahlenberg, V.; Tessadri, R.; Wieser, J.; Griesser, U. J. J. Pharm. Sci. 2009, 98, 2010−2026. (10) Zeidan, T. A.; Trotta, J. T.; Tilak, P. A.; Oliveira, M. A.; Chiarella, R. A.; Foxman, B. M.; Almarsson, Ö.; Hickey M. B. CrystEngComm. 2016, 18, 1486−1488. (11) U.S. EPA. Estimation Program Interface (EPI) Suite. Ver. 4.11. Available from, as of Feb 17, 2015: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

422

(12) Drugbank, https://www.drugbank.ca/drugs/DB01238. Accessed July 9, 2017.

423

(13) Ardiana, F.; Lestari, M. L.A.D.; Indrayanto, G. Profiles of Drug Substances, Excipients and

424 425

Related Methodology, Chapter 2. Aripiprazole. Vol. 38, Elsevier. 2013. (14) ICH. Stability testing of new drug substances and products; Q1A(R2), 2003,

426

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1A_R2/Step4/Q

427

1A_R2__Guideline.pdf

428

(15) Tata, J.; Scalarone, D.; Lazzari,M.;

Chiantore, O. Euro. Polymer J. 2009, 45, 2520−2528.

429

(16) Friscic, T.; Jones, W. Cryst. Growth Des. 2009, 9, 1621−1637.

430

(17) Jayasankar, A.; Somwangthanaroj, A.; Shao, Z. J.; R.-Hornedo, N. Pharm. Res. 2006, 23, 2381−

431

2392.

432

(18) Babu, N. J.; Nangia, A. Cryst. Growth Des. 2011, 11, 2662−2679.

433

(19) Aakeroy, C. B.; Forbes, S.; Desper, J. J. Am. Chem. Soc. 2009, 131, 17048−17049.

434


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435


[TOC]

436 437

Preparation and characterization of aripiprazole co-crystals with

438

coformers of multi-hydroxybenzene compounds

439 440

Min-Yong Cho1, Paul Kim1, Ga-Young Kim2, Ju-Yeon Lee2, Keon-Hyoung Song1,2, Min-Jeong Lee3,

441

Woojin Yoon4, Hoseop Yun4, Guang J. Choi1,2*

442

443 444 445

A new aripiprazole-orcinol (ARI-ORC) co-crystal was synthesized and characterized together with

446

coformers of multi-hydroxybenzene compounds. A substantial enhancement in dissolution was

447

achieved by AGO-RES co-crystal powders.

448 449



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Page 16 of 35

Table 1. Comparison of the melting and co-crystallization temperatures between coformers and their ARI co-crystals.

Coformer

Coformer Tm(℃)

Co-crystal

DSC data: Neat Grinding (30 min)

Tm(℃)

Co-crystallization

Co-crystal

(reported*)

temperature (℃)

melting pt. (℃)

CAT (catechol)

105.0

121.2

73.5

122.5

RES (resorcinol)

110.0

175.6

76.8

176.8

PHL (phloroglucinol)

220.1

180.0

110.5

181.1

ORC (orcinol)

110.3

NA

75.9

185.4

* reference: (Nanubolu and Ravikumar, 2016)

ARI = aripiprazole


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Table 2. Summarized results of DSC thermograms for four ARI combinations by neat grinding and liquid-assisted grinding. NG (30 min)

LAG (30 min)

coformer

coformer

Co-crystallization

Co-crystal

Co-crystallization

Co-crystal

moiety

Tm(℃)

temperature (℃)

Tm (℃)

temperature (℃)

Tm (℃)

[ΔH(J/g)]

[ΔHm(J/g)]

[ΔH(J/g)]

[ΔHm(J/g)]

73.5

122.5

[-32.3]

[72.4]

76.8

176.8

62.6

176.6

[-59.7]

[123.6]

[-8.5]

[108.0]

110.5

181.1

87.0

181.6

[-43.8]

[67.1]

[-8.7]

[113.4]

75.9

185.4

64.6

185.0

[-63.6]

[141.3]

[-22.0]

[132.3]

CAT (catechol) RES (resorcinol) PHL (phloroglucinol) ORC (orcinol)

105.0 110.0 220.1 110.3

no peak

122.6 [62.8]

DSC: Differential scanning calorimetry; NG: neat grinding; LAG: liquid-assisted grinding.



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Page 18 of 35

Table 3. Crystal data for ARI-ORC co-crystal compared with reported data. Compound

ARI-CAT

ARI-RES

ARI-PHL

ARI-ORC

reference

co-crystal

co-crystal

co-crystal

co-crystal

Chemical

C23H27Cl2N3O2·C6H6O2

formula

·0.293H2O

Formula mass

563.17

558.48

590.48

572.51

Crystal system

Monoclinic

Monoclinic

Monoclinic

Monoclinic

a/Å

14.7513(6)

14.7282(12)

14.8405(6)

14.6340(4)

b/Å

9.9206(11)

9.8820(8)

10.2671(4)

9.8587(3)

c/Å

20.9131(17)

20.8815(14)

20.6587(9)

21.6049(6)

α/°

90

90

90

90

β/°

111.104(6)

111.174(5)

110.2190(10)

110.0530(10)

γ/°

90

90

90

90

2855.2(5)

2834.0(4)

2953.8(2)

2928.0(15)

P21/c

P21/c

P21/c

P21/c

4

4

4

4

26716

28020

27780

28031

0.0286

0.0213

0.0248

0.0317

0.0781

0.0421

0.0824

0.0404

0.1647

0.1075

0.2151

0.1260

1.124

1.026

1.080

1.096

Unit cell volume/Å3 Space group


C23H27Cl2N3O2·C6H6O3 ·H2O


No. of formula units per unit cell, Z No. of reflections measured Rint Final R1 values (all data) Final wR(F2) values (all data) Goodness of fit on F2


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Figure 1. Chemical structures of aripiprazole (ARI) and various coformer compounds.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 2(a). X-ray diffraction (XRD) patterns of ARI and selected coformer compounds.


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Figure 2(b). Differential scanning calorimetry (DSC) thermograms of ARI and selected coformer compounds.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 3(a). XRD patterns of four ARI combinations after neat grinding (NG) for 30 min.


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Figure 3(b). DSC thermograms of four ARI combinations after NG for 30 min.



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Page 24 of 35

Figure 4(a). XRD patterns of four ARI combinations after NG and heat-treatment at 80°C for 1 h.


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Figure 4(b). DSC thermograms of four ARI combinations after NG and heat-treatment at 80°C for 1 h.



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Page 26 of 35

Figure 5(a). XRD patterns of four ARI combinations after liquid-assisted grinding (LAG) for 30 min.


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Figure 5(b). DSC thermograms of four ARI combinations after LAG for 30 min.



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Figure 6(a). XRD patterns of four ARI combinations after the solvent evaporation (SE) process.


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Figure 6(b). DSC thermograms of four ARI combinations after SE.



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Figure 7. ORTEP diagram of ARI-ORC co-crystal in which the thermal ellipsoids are drawn at the 30% probability level.


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Figure 8. Thermogravimetric analysis (TGA) curves of the ARI, ORC, and their combinations.



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Figure 9. Comparison of powder dissolution profiles between ARI and four ARI co-crystals; measured in acetonitrile-water 10/90 cosolvent.


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Figure 10(a). XRD patterns of aripiprazole-catechol (ARI-CAT) and aripiprazole-orcinol (ARIORC) co-crystals before and after the treatment at 80C/98% relative humidity (RH) for 1 week.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 10(b). DSC thermograms of ARI-CAT and ARI-ORC co-crystals before and after the treatment at 80C/98%RH for 1 week.


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[TOC]

Preparation and characterization of aripiprazole co-crystals with coformers of multi-hydroxybenzene compounds

Min-Yong Cho1, Paul Kim1, Ga-Young Kim2, Ju-Yeon Lee2, Keon-Hyoung Song1,2, Min-Jeong Lee3, Woojin Yoon4, Hoseop Yun4, Guang J. Choi1,2*

A new aripiprazole-orcinol (ARI-ORC) co-crystal was synthesized and characterized together with coformers of multi-hydroxybenzene compounds. A substantial enhancement in dissolution was achieved by AGO-RES co-crystal powders.


Preparation and Characterization of Aripiprazole Cocrystals with

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