Improving compliance and decreasing drug accumulation of

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Improving compliance and decreasing drug accumulation of diethylstilbestrol through cocrystallization Zhen Li, Meiqi Li, Bo Peng, Bingqing Zhu, Jian-rong Wang, and Xuefeng Mei Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b01911 • Publication Date (Web): 23 Jan 2019 Downloaded from http://pubs.acs.org on January 31, 2019

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Crystal Growth & Design

Improving compliance and decreasing drug accumulation of diethylstilbestrol through cocrystallization Zhen Li,†, ‡ Meiqi Li, ‡,§ Bo Peng,‡ Bingqing Zhu, ‡ Jian-rong Wang, ‡ and Xuefeng Mei‡ †

College of Pharmacy, Nanchang University, Nanchang 330006, China

‡

Pharmaceutical Analytical & Solid-State Chemistry Research Center, Shanghai

Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. §

University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049,

China. E-mail: [email protected]; Fax: + 86 21 50800934; Tel: +86 2150800934

Keywords:

dissolution

rate,

diethylstilbestrol,

compliance,

cocrystal,

drug

accumulation ABSTRACT: Diethylstilbestrol (DES), a synthetic non-steroidal estrogen, has been prescribed for advanced breast cancer and prostate cancer. However, its poor compliance, reactive metabolites’ toxicity and hydrophobicity induced drug accumulation limited its applications. In this study, we aimed to modulate its dissolution rate, reduce reactive metabolites and drug accumulation through cocrystallization. Cocrystals of DES with isonicotinamide (INA), picolinamide (PIN), nicotinamide (NIA), urea (UREA), sarcosine (SAR) and flavone (FLA) were obtained. Different crystallization strategies

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Crystal Growth & Design 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

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result in cocrystal polymorphs for DES with INA and FLA. Intrinsic dissolution rate (IDR) characterizations in pH 2.0 buffer solution were conducted. Two assumptions (enhance Cmax or prolong Tmax) with the aim of improving compliance were put forward. On the basis of the IDR results (DES-NIA with 1.5-fold increase in IDR and DES2FLA-B with a 5.5-fold decrease in IDR) and the pharmacological activities of coformers (NIA and FLA with CYPs inhibition and UGTs stimulation effects), the pharmacokinetic behaviors of these two cocrystals were further researched. The 2-fold prolongation of Tmax in the PK profile DES-2FLA-B facilitated the improvement of compliance. In addition, the higher clearance rates as well as the potential to reduce oxidative metabolites in DES-2FLA-B help to decrease the drug accumulation and reduce adverse effects of DES. Introduction Cocrystals are solids composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio.1 Recently, cocrystals have been proven to be an intriguing alternative to manipulate physicochemical properties in the field of optoelectronic communications,2 solid explosives,3,

4

pigments5,

6

as well as

pharmaceuticals7-9 especially for non-ionizable materials. When one of the cocrystal coformers (CCFs) at least is an active pharmaceutical ingredient (API), and the others are pharmaceutically acceptable, it is regarded as a pharmaceutical cocrystal.10 Since the majority of medicines are delivered as solid formulations, the dissolution behaviors of pharmaceutical drug products could have direct impacts on the delivery and absorption performances of the medicines. Cocrystallization for APIs with limited


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dissolution performances could offer the potential of improving dissolution behaviors, thus potentially modulate the bioavailability.11 Besides, cocrystal engineering has been applied on the sustained release of APIs with burst effect as well, which benefits their safety and compliance performances.12 Some CCFs have pharmacological activities and even influence the activities of drug metabolic enzymes such as cytochrome P450 systems

(CYPs)

and

UDP-glucuronosyltransferases

(UGTs).13-15

Thus

the

involvements of these CCFs have the potential to modify the pharmacokinetic profiles, reduce toxicity and even have new indications.10, 16 Diethylstilbestrol (DES), one of the most important synthetic estrogens, is prescribed for advanced breast cancer in postmenopausal women (15 mg/d) and prostate cancer (1~3 mg/d).17-19 Owing to the low dose, it belongs to class I according to the Biopharmaceutics Classification System (BCS) with adequate solubility (12 mg/L) and high permeability (log P = 5.07).20 However, the poor compliance, reactive metabolites’ toxicity and hydrophobic induced drug accumulation limited its applications.21, 22 The oxidative metabolites of DES could covalently bound to DNA and proteins in vivo, which leads to its adverse drug reactions. The hydrophobic character also makes DES easy to accumulate in tissues. In previous studies, eleven solvates of DES were reported.23-25 Herein, we attempt to design cocrystals of DES to prolong the duration above its effective concentration in plasma, which may be favorable for overcoming its poor compliance by controlling its dissolution rate. On the basis of the DES chemical structure and the single crystal data in CSD database, the phenolic hydrogen group could form supramolecular synthons with pyridinic-nitrogens



(O-H···Narom, 40.6%) and carbonyl oxygen (O-H···O=C, 46.9%) via intermolecular hydrogen bonds in the crystal structures (Table 1). Due to the two phenolic hydroxyl groups, we suggested that CCFs containing pyridinic nitrogen, carboxylic acid or amide group have the potential to form hydrogen bonds with DES molecules. Therefore, a series of CCFs with pyridinic nitrogens, carboxylic acid or amide moiety were selected (Scheme S1). Nine cocrystals of DES with isonicotinamide (INA), picolinamide (PIN), nicotinamide (NIA), urea (UREA), sarcosine (SAR) and flavone (FLA) were successfully synthesized (Scheme 1). Among them, polymorphs existed in DES-2INA (form A and B) and DES-2FLA (form A and B) cocrystals. Others only lead to physical mixtures of individual components in line with X-ray powder diffraction (XRPD) characterizations. The crystal structures of these DES cocrystals were determined by single-crystal X-ray diffraction (SCXRD). The intrinsic dissolution rates (IDR) of DES as well as its cocrystals were measured in pH 2.0 buffer solution. The dissolution behavior could mainly affect the absorption phase of APIs. Besides, NIA and FLA have been reported to inhibit the activities of CYPs and stimulate the activities of UGTs in previous studies.26-29 Thus, PK experiments were performed on DES cocrystals and pure DES to confirm our conjectures. Scheme 1 Molecular structures of components used for cocrystal synthesis, diethylstilbestrol (DES), isonicotinamide (INA), picolinamide (PIN), nicotinamide (NIA), urea (UREA), sarcosine (SAR) and flavone (FLA).


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Table 1. CSD statistics of possible suparmolecular synthons in DES with phenolic hydroxyl functionalities No.

Synthon

Percentage

I

40.6%

Survey Constrains Intermolecular shorter than sum of VdW radii + 0.0; Rfactor ≤ 0.05

II

46.9% No disordered, errors and ions.

EXPERIMENTAL SECTION Materials. Diethylstilbestrol (purity >98%) was purchased from Beijing InnoChem Science&Technology Co.Ltd. Isonicotinamide (INA) and sarcosine (SAR) were purchased from Aladdin Chemistry Company Limited (purity >98%). Pyridine-2carboxamide (PIN) was purchased from Bide Pharmatech Ltd (purity >97%). Nicotinamide (NIA) and flavone (FLA) were purchased from J&K Chemicals (purity >99%). Glibenclamide (internal standard, 97%) was purchased from Shanghai Macklin Biochemical Co., Ltd. Urea and all analytical grade solvents were purchased from the Sinopharm Chemical Reagent Company and were used without further purification.



Preparation of DES-2INA-A. DES and INA in a 1:2 stoichiometric ratio were ground without solvent dropping for a few minutes at room temperature. The solid phase was verified by means of XRPD. The DES-2INA-A single crystals with good quality for structure determination could be obtained occasionally after slow evaporating DES2INA in methanol after 72 h (yield 83.97%). Anal. Calcd for C30H32N4O4: C, 70.29; H, 6.29; N, 10.93%. Found: C, 70.41; H, 6.21; N, 11.01%. Preparation of DES-2INA-B. DES and INA in a 1:2 molar ratio were dissolved in tetrahydrofuran and evaporated slowly at ambient condition. Colorless block like crystals were obtained (yield 98.57%) for structure determination and other characterizations. Anal. Calcd for C30H32N4O4: C, 70.29; H, 6.29; N, 10.93%. Found: C, 70.35; H, 6.24; N, 11.07%. Preparation of DES-PIN. Equal molar amounts of DES and PIN were dissolved in methanol and evaporated slowly at room temperature. The single crystals suitable for structure determination were obtained (yield 97.91%) and cocrystal formation was verified by means of XRPD and SCXRD. Anal. Calcd for C24H26N2O3: C, 73.82; H, 6.71; N, 7.17%. Found: C, 73.90; H, 6.62; N, 7.23%. Preparation of DES-NIA. The equal molar ratio of DES and NIA were dissolved in methanol at 50 °C and evaporated slowly at that temperature. The colorless prism like DES-NIA single crystals with good quality for structure determination could be obtained (yield 98.62%) after slow evaporating DES-NIA in methanol after 72 h. Anal. Calcd for C24H26N2O3: C, 73.82; H, 6.71; N, 7.17%. Found: C, 73.93; H, 6.60; N, 7.25%. Preparation of DES-2NIA-MH. A 1:2 stoichiometric ratio of DES and NIA was


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dissolved in ethyl acetate and evaporated slowly a room temperature. Colorless prism like crystals were obtained (yield 97.99%) for structure determination and other characterizations. Anal. Calcd for C30H34N4O5: C, 67.91; H, 6.46; N, 10.56%. Found: C, 68.01; H, 6.40; N, 10.62%. Preparation of DES-UREA. The equal molar ratio of DES and UREA were dissolved in ethanol and evaporated slowly at ambient condition. Colorless plate like crystals were obtained (yield 98.43%) for structure determination and other characterizations. Anal. Calcd for C19H24N2O3: C, 69.49; H, 7.37; N, 8.53%. Found: C, 69.53; H, 7.30; N, 8.59%. Preparation of DES-SAR-MH. Equal molar amounts of DES and SAR were dissolved in methanol and evaporated slowly at room temperature. Colorless block like crystals were obtained (yield 99.01%) for structure determination and other characterizations. Anal. Calcd for C21H29NO5: C, 67.18; H, 7.79; N, 3.73%. Found: C, 67.23; H, 7.72; N, 3.78%. Preparation of DES-2FLA-A. A 1:2 molar ratio of DES and FLA was dissolved in methanol and evaporated slowly at room temperature. Colorless block like crystals were obtained occasionally (yield 98.72%). Anal. Calcd for C48H40O6: C, 80.88; H, 5.66%. Found: C, 80.91; H, 5.60%. Preparation of DES-2FLA-B. A 1:2 molar ratio of DES and FLA was dissolved in tetrahydrofuran and evaporated slowly at room temperature. Colorless block like crystals were obtained (yield 98.69%) for structure determination and other characterizations. Anal. Calcd for C48H40O6: C, 80.88; H, 5.66%. Found: C, 80.93; H,



5.57%. Single Crystal X-ray Diffraction (SCXRD). X-ray diffraction data for various cocrystals in the present study was collected on a Bruker Smart Apex II CCD diffractometer, using Mo−Kα radiation (λ = 0.71073 Å) with a graphite monochromator. Data collection for all single crystals were done at 205 (2) K except that the measurement for DES-NIA was conducted at 173(2) K. Data integration and scaling was completed by using the SAINT software. Besides, the SADABS program was used for multi-scan absorption corrections. The structures were solved by direct methods using SHELXTL, and refined with a full-matrix least-squares technique using SHELXL-2014 program package. All non-hydrogen atoms were refined with anisotropic displacement parameters, and hydrogen atoms were placed in calculated positions and refined with a riding model. X-ray Powder Diffraction (XRPD). XRPD patterns were obtained using a Bruker D8 Advance X-ray diffractometer with a Cu-Kα radiation. The tube voltage and current of the generator were set to 40 kV and 40 mA, respectively. Data over the range 3 – 40 ° in 2θ were collected with a continuous scan rate of 0.1 s/step at ambient temperature. Data were imaged and integrated with RINT Rapid and peak-analyzed with Jade 6.0 software. Thermogravimetric Analysis (TGA). Thermogravimetric analysis was conducted on Netzsch TG 209F3 equipment, using nitrogen as the purge gas with a flow of 20 mL min−1. Samples were placed in open aluminum oxide pans and heated at 10 °C min−1 to 400 °C.


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Differential Scanning Calorimetry (DSC). The DSC experiments were performed on a DSC TA Q2000 instrument under nitrogen gas flow of 50 mL min−1 purge. The instrument was calibrated the temperature axis and heat flow via indium and tin. Samples weighing 2 − 4 mg were heated in sealed nonhermetic aluminum pans from 20 to 300 °C with a heating rate of 10 °C min−1. Polarizing microscopy (PM). All polarizing photos were taken on a XPV-400E polarizing microscope. Crystals of DES cocrystals were filmed by using microscope (5×10). Intrinsic dissolution rate (IDR). IDR experiments were performed via a Mini-Bath dissolution apparatus equipped with a Julabo ED-5 heater/circulator. In each experiment, approximately 20 mg of samples (DES and its cocrystals, n= 3) were compressed into a 0.07 cm2 disk in a rotating disk intrinsic dissolution die using a MiniIDR press at a pressure of 35 bar for one minute. Only one side of the disk was exposed to the dissolution medium. The intrinsic attachment was placed in a jar of 15 mL of pH 2.0 buffer containing 0.5% Tween 80 preheated at 37 °C and stirred at 100 rpm. At time intervals (5, 10, 15, 20, 30, 40, 60, 90, 120, 180 min), 100 μL of the sample was withdrawn manually. The collected samples were diluted with equal amount of buffer and assayed for DES concentration using HPLC. An Agilent 1260 series Infinite HPLC instrument was equipped with a ZORBAX ECLIPSE-C18 column (4.6 × 150 mm, 5 μm). An injection volume of 10 μL was used with 1 mL/min flow rate. The detection UV-vis wavelength was set at 254 nm. The sample were gradient eluted with a mobile phase containing a mixture of methanol and water. The gradient started at 30%



methanol and 70% water. After 2 minutes, it was changed to 80% methanol and 20% water in the following 8 minutes, which was maintained for 2 minutes. After each gradient analysis, the column was equilibrated with the started mobile phase (30% methanol). The observed retention time points for DES is 11.6 minutes. No overlap between peaks for DES or any CCFs was observed. In Vivo Pharmacokinetic (PK) experiment. DES, DES-NIA and DES-2FLA-B were employed in rats PK study. The PK experimental protocol was approved by the Institutional Animal Care and Use Committee of Shanghai Institute of Mateia Medica and conformed to the Guide for Care and Use of Laboratory Animals. Eighteen male Sprague-Dawley rats (200-230 g) were randomly divided into three groups. And the suspension formulation (0.5% CMC-Na aqueous solution) was delivered as oral administration at a dose of 5 mg/kg DES (expressed as DES equivalents). The rats were allowed to have free access to water and fasted overnight before drug administration. Freshly prepared suspension formulation was immediately delivered orally to rats. Then 200 μL blood sample were obtained from orbital sinus and placed into heparinized tubes at 0.5, 0.75, 1, 2, 4, 6, 8, 12 and 24 h after dosing. Plasma was immediately separated by centrifugation (4 °C, 5000rpm, 5 min) and kept frozen at -80 °C until analysis. 500 μL ethyl acetate containing 200 ng/mL glibenclamide as internal standard was added in the plasma sample (100 μL), and the samples were placed in vortex mixer for 5 min and centrifuged for 10 min (14000 rpm). The 450 μL supernatant was dried with dry instrument, re-dissolved in 100 μL methanol, vertex-mixed for 3 min and centrifuged for 20 min (14000 rpm). 90 μL supernatant was transferred for analysis.


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The ThermoFisher TSQ QUANTIVA/DIONEX UltiMate 3000 LC-MS/MS was utilized for the separation and determination of DES in plasma. The separation was operated on a Waters SunfireTM C18 column (2.1 × 100 mm, 3.5 μm) with a gradient (acetonitrile / 5 mM ammonium acetate in water) from 40:60 to 95:5 in a 6.5 min run at a flow rate of 0.25 mL/min. The injection volume was 10 μL. Mass spectrometer was operated in the negative ion detection. The heat block temperature was maintained at 400 °C. Nitrogen was used as the nebulizing gas and drying gas. Detection and quantification were employed in the multiple reactions monitoring mode (MRM), with m/z 267.2 → 237.0 for DES, and m/z 492.2 → 170.1 for IS. PK parameters were obtained based on a model-independent method using a DAS 2.1.1 program. RESULTS AND DISCUSSION X-ray Powder Diffraction (XRPD) and Single Crystal Structure analysis. On the basis of crystal engineering principle, the phenolic hydroxyl groups tend to assemble supramolecular synthons with CCFs containing pyridine, or carbonyl group. Twenty-one CCFs were employed and resulted in nine successful examples. The formation of cocrystal could be verified by XRPD. In figure 1, each XRPD pattern of DES cocrystals is different from either that of DES or the corresponding CCFs (Figure S1). All of the peaks displayed in the measured XRPD patterns of the DES cocrystals’ bulk powder are closely in accordance with those in the simulated patterns acquired from single crystal diffraction data, which confirm the formation of high pure phases.



Figure 1. XRPD patterns of DES cocrystals. DES cocrystals were obtained by means of solution evaporation approach and all of them were conducted for single crystal analysis. The morphology are mostly prism or block-like structures (Figure 2). Crystallographic data and H-bond parameters were summarized in table S1 and table S2, respectively. As shown in single crystal structures, polymorphs presented in both DES-2INA and DES-2FLA cocrystals.

Figure 2. Polarizing microscopy images of DES cocrystals, (a) DES-2INA-A, (b) DES-2INA-B, (c) DES-PIN, (d) DES-NIA, (e) DES-2NIA-MH, (f) DES-UREA, (g)


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DES-SAR-MH, (h) DES-2FLA-A, (i) DES-2FLA-B. DES has two hydroxyl substitutes on the benzene ring, which can act as both Hbond donors and acceptors with CCFs. On the basis of the single crystal structures, two dominating modes of synthon exist in DES cocrystals. Thus, we divided these DES cocrystals into two groups (Group A and B). Group A (Synthon I: O-H…Narom) consist of DES-2INA (form A and B), DES-PIN, DES-NIA and DES-2NIA-MH, and group B (Synthon II: O-H…Ocarbonyl) consist of DES-UREA, DES-SAR-MH and DES2FLA (form A and B). During the cultivation of single crystals, two polymorphs (DES-2INA-A and DES2INA-B) of DES-2INA were discovered. We found that DES-2INA-B could be harvested in most cases, while DES-2INA-A was only once obtained via slow evaporation from methanol solvent. Colorless prism-like DES-2INA-A crystals crystallized in triclinic P -1 space group. The asymmetric unit of DES-2INA-A contained one molecule of DES and two molecules of INA. In figure 3a, two INA molecules first form typical amide dimers through 𝑅22 (8) supramolecular synthon (N2H2B …O4). INA dimers link with DES molecules (O2-H2 … N1) to form infinite onedimensional (1D) linear structure. Two-dimensional (2D) planar structures as are built by N-H…O interactions among these 1D lines. Then π-π interactions as well as C-H···π (3.036 Å) interactions between the aromatic hydrogen atoms and the benzene rings of DES help to form its three-dimensional (3D) architecture (Figure 3b).



(a)

(b) Figure 3. (a) 2D planar structure of DES-2INA-A; (b) Packing pattern of DES2INA-A. As for DES-2INA-B, it crystallized in monoclinic C 2/c space group and its asymmetric unit consisted of half of the DES molecule and one INA molecules. Even though INA dimers exist, the fold linear structures emerge (Figure 4a). This difference is due to the different twist angles of DES molecules in these two polymorphs (61.46º for DES-2INA-A, 80.42ºfor DES-2INA-B, Figure S2). N2-H2B…O1 and C10-H10…O2 help to form crossed 3D packing pattern (Figure 4b, 4c).


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(a)

(b)



(c) Figure 4. (a) Fold linear structures in DES-2INA-B; (b) Linkages among linear structures in DES-2INA-B; (c) Packing pattern of DES-2INA-B. Different from DES-2INA (form A and B), no dimer structures exist in DES-PIN. Instead, strong O2-H2 … N1 and O3-H1 … O1 interactions between DES and orthosubstitute PIN result in the formation of 1D linear structure (Figure 5a). These lines connect to each other via N2-H2B…O2 H-bond interactions to form 2D planar structures. Planes stacking along b-axis help the formation of its 3D architecture (Figure 5b).


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(a)

(b) Figure 5. (a) H-bond pattern of DES-PIN; (b) Packing pattern of DES-PIN. DES and NIA could generate cocrystals with two different stoichiometric: DESNIA (1:1) and DES-2NIA-MH (1:2:1). These two cocrystals present obviously different crystal arrangements relative to their basic building blocks. With 1:1 stoichiometry, the asymmetric unit of DES-NIA contains one molecule of DES and one molecule of NIA.

In figure 6a, meta-substitute NIA molecules link with DES

molecules via N2-H2B…O2 and N2-H2C…O1 interactions to form infinite wavy lines.



Robust O1-H1…N1 as well as O2-H2…O3 interactions among these lines contribute to the formation of 3D wavy architecture (Figure 6a and 6b). While in DES-2NIA-MH, the asymmetric unit consists of one DES molecule, two NIA molecules and one water molecule. 1D NIA lines are formed via N-H … O interactions among staggered molecules. Then NIA lines link with water and DES molecules through H-bond interactions (N2-H2A… O2, O2-H2C …O1, O1-H1 …N3, N4-H4A… O3 and O3-H3 …N1) to form a sheet motif (Figure 7a). Such sheets are further extended into 3D layer structures via O2-H2D…O5 interaction and π-π stacking (Figure 7b).

(a)


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(b) Figure 6. (a) H-bond pattern of DES-NIA; (b) Packing pattern of DES-NIA.

(a)

(b) Figure 7. (a) H-bond pattern of DES-2NIA-MH; (b) Packing pattern of DES-2NIAMH. For cocrystals in group B, phenolic hydroxyl groups have strong H-bond interaction with carboxyl oxygen. In DES-UREA, the hydroxyl groups of DES link with the carboxyl groups of urea (O-H…O) to form 1D lines (Figure 8a). The N-H…O



interactions among these lines facilitate the formation of crossed 3D architecture (Figure 8b).

(a)

(b) Figure 8. (a) H-bond pattern of DES-UREA; (b) Packing pattern of DES-UREA. SAR presents as zwitterions indicated by the comparable C-O bond lengths of the carboxylate in the DES-SAR-MH cocrystal structure. Unlike the DES-UREA discussed above, the DES and SAR molecules do not interact with each other directly and no 1D lines exist. Instead, DES, ionic SAR and water molecules link in turn (O2H2 … O5, O3-H3B … O2 and O3-H3A … O4) to form cyclic structures (Figure 9a). The remaining potential acceptor sites on water molecules and the donor sites of amino ions on SAR help these cyclic units further interweave into 3D fabrication by means of N1H1B…O3 and O1-H1…O4 H-bond interactions (Figure 9b).


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(a)

(b) Figure 9. (a) H-bond pattern of DES-SAR-MH; (b) Packing pattern of DES-SARMH along b-axis. DES and FLA cocrystallized in two polymorphs, namely, DES-2FLA-A and DES2FLA-B. Similar to the single crystal cultivation process of DES-2NIA, DES-2FLAA single crystals were also once obtained via slow evaporation from methanol solvent. Two available hydroxyl substitutes on the benzene ring of DES acting as H-bond donors connect with the carbonyl groups on the benzopyran ring of FLA through O-H…Ocarbonyl interactions to form trimers in these two cocrystals. However, these two polymorphs



exhibit different types of linkage among trimers. In DES-2FLA-A, adjacent trimers are further interconnected through non-classical C2-H2 … O2 H-bond interaction. As for DES-2FLA-B, C-H···π (2.907 Å) interaction acts as the main driving force for the 3D networks. Different connection types accounts for the packing polymorphism in DES2FLA cocrystals.

(a)

(b)

(c) Figure 10. (a) The trimer structure in DES-2FLA cocrystals; (b) The linkage of trimers


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in DES-2FLA-A; (c) The linkage of trimers in DES-2FLA-B. Thermal properties. To evaluate the physicochemical stability, thermal analysis of these nine DES cocrystals were conducted by TGA, DSC and VT-XRPD. The DSC patterns of DES starting material (determined according to XRPD data and compared with literature30, figure S3), CCFs and cocrystals presented in figure S4 revealed the different thermal properties of various DES solid forms. The melting point (Tonset, in table S3) of five DES cocrystals are found to lie in between the melting point values of individual components, in accordance with most cocrystal cases.31 While the melting points of DES-2INA-A, DES-2INA-B, DES-UREA and DES-SAR-MH are higher than both starting materials. As shown in figure S5, the TGA plots of DES-2INA-A, DES-2INA-B, DES-PIN, DES-NIA, DES-UREA, DES-2FLA-A and DES-2FLA-B reveal no significant weight loss before melting point, confirming their unsolvated characteristics. In the case of the DSC pattern of DES-2INA-A, an additional endothermic peak with the Tonset at 133.5 ºC appeared (ΔH = 19.98 J/g). Since no solvate included, this endothermic peak can be ascribed to a phase transformation. This assumption was further confirmed by VT-XRPD (Figure S6). DES-2INA-A powder sample was held for 10 min at 160 ºC and then conducted for XRPD analysis. After this heating process, additional peaks at 2θ = 4.6 and 16.7ºappeared. These new peaks are identified as the characteristic peaks of DES-2INA-B. As for DES-2FLA-A, an additional shoulder peak could be observed, indicating an uncompleted phase transition during the melting process. To verify this



conjecture, DES-2FLA-A powder samples was heated for 20 min at 120 ºC, and then submitted for XRPD analysis. The emergence of characteristic peaks at 2θ = 6.2, 12.2, 12.5 and 13.5ºindicated the solid-state transition from DES-2FLA-A to DES-2FLAB (Figure S7). For DES-2NIA-MH and DES-SAR-MH, weight loss could be observed before their melting points. The thermal behaviors of DES-2NIA-MH and DES-SAR-MH are quite similar. In the case of DES-2NIA-MH, a gradual mass loss of 3.32% was observed, corresponding to the loss of 1 equiv of water molecule (calculated 3.39%). While for DES-SAR-MH, a weight loss of 4.82% corresponding to 1 equiv of water (calculated 4.79%) was presented. Accordingly, endothermic peaks before the melting point of DES-2NIA-MH and DES-SAR-MH in the DSC diagram were exhibited (Tonset at 99.53 ºC for DES-2NIA-MH, 145.04 ºC for DES-SAR-MH). To analyze their phase transition processes, both DES-2NIA-MH and DES-SAR-MH powder were heated at 150 ºC for 30 min, and then further characterized by XRPD. For DES-2NIA-MH, new characteristic peaks at 2θ = 5.21, 10.06, 10.50, 13.57 and 14.49ºare different with both DES-NIA and individual components, which indicates the formation of a new desolvated cocrystal of DES and NIA (Figure S8). The desolvation process of DESSAR-MH also results in a new desolvated cocrystal of DES and SAR with new characteristic peaks at 2θ = 7.15, 12.55 and 13.75º(Figure S9). Solid-state transformations and controlled crystallizations. To verify the relative thermodynamic stabilities at room temperature, interconversion slurry experiments were conducted. For DES-2INA cocrystals,


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approximately equal amounts of form A and form B were slurried together in a methanol solution at ambient condition for 24 h. This suspension was centrifuged and submitted for XRPD analysis. The residual solids were found to convert to DES-2NIAB (Figure S10). The relative stability between DES-2FLA polymorphs was also investigated. A similar slurry experiment was conducted and the remaining solids were found to transform to DES-2FLA-B (Figure S11). As a significant part in the pharmaceutical industry, polymorph control has attracted a lot of attention. In recent decades, strategies such as crystallization from organogel and grinding (neat or liquid assisted) have been put forward to control crystallization outcomes of cocrystals.32-35 In this study, we used these abovementioned strategies in order to obtain the meta-stable DES-2INA-A and DES-2FLAA. DES and CCFs (INA or FLA) with 1:2 stoichiometry (0.05 mmol: 0.1 mmol) were added together. Mechanochemical cocrystallization was first applied. When neat grinding was conducted, meta-stable DES-2INA-A was obtained successfully. However, when solvents (MeOH or THF) were assisted during grinding, only thermodynamic stable DES-2INA-B was obtained. As for DES-2FLA cocrystals, only stable DES-2FLA-B was obtained whether neat or liquid assisted grinding was applied. Under this circumstance, the pH-switchable vitamin B9 gel was used as cocrystallization media.33 VB9 in DMSO/nitromethane (2:8) solvent condition resulted in the formation of a faint yellow gel. After adding Et3N onto the gel surface, a rapid gel-to-solution phase transition was observed. White powders were obtained by filtration and these powders were characterized by XRPD. As shown in table 2, meta-



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stable DES-2FLA-A was obtained successfully in VB9 gels, while physical mixtures were harvested in the cultivation of DES-2INA-A cocrystal. Table 2. Crystallization experiments in the cultivation of meta-stable DES-2INA-A and DES-2FLA-Aa Methods

a

Results DES and 2INA

DES and 2FLA

VB9 gels

DMSO/Nitromethane (2:8)

Physical mixtures

DES-2FLA-A

Grinding

Neat

DES-2INA-A

Physical mixtures

Methanol

DES-2INA-B

DES-2FLA-B

Tetrahydrofuran

DES-2INA-B

DES-2FLA-B

The relative XRPD characterization in each cocrystallization experiment was

presented in figure S12. In vitro Intrinsic Dissolution Rate (IDR). After delivery, drugs in oral preparations first dissolve in gastric and intestinal fluid to be absorbed in systemic circulation. Due to the involvement of CCFs in pharmaceutical cocrystals, changes in the dissolution behavior will manipulate the amount of API available for absorption and then modify the pharmacokinetic profiles. Therefore, in this study, the IDRs of pure DES and its cocrystals were determined in pH 2.0 buffer solution (to simulate gastric fluids) with the presence of 0.5% Tween 80 (Figure 11 and table 3). DES-2FLA-A is excluded from IDR test for its difficulty in magnification. Compared with DES, DES-NIA presented the improvement on IDR by approximately 1.5-fold in pH 2.0 buffer solution. While DES-SAR-MH and DES-


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2FLA-B exhibited the decrease on IDR for about 2-fold and 5.5-fold in pH 2.0 buffer solution.

Figure 11. The IDRs of DES and its cocrystals in pH 2.0 buffer solution with the presence of 0.5% Tween 80. Table 3. Summary of IDRs of DES and its cocrystals. IDR (µg·cm-2·h-1) material

pH 2.0

DES

1.85

DES-2INA-A

1.79

DES-2INA-B

1.80

DES-PIN

1.71

DES-NIA

2.73



Page 28 of 38

DES-2NIA-MH

1.41

DES-UREA

1.91

DES-SAR-MH

1.00

DES-2FLA-B

0.33

In vivo bioavailability. Since dissolution behaviors can strongly affect the absorption phase of APIs, we hypothesized that the strategy of enhancing Cmax (improvement in dissolution rate) or prolonging Tmax (decrease in dissolution rate) has a strong potential for improving drug compliance. According to IDR results, DES-NIA with enhanced IDR, as well as DESSAR-MH and DES-2FLA-B with reduced IDR can be candidates. Besides, NIA and FLA could inhibit CYPs and activate UGTs, modulate the formation of metabolites, and consequently decrease the toxicity and accumulation of DES.27, 36 Therefore, in vivo pharmacokinetic experiments were conducted on DES-NIA and DES-2FLA-B to confirm our previous conjectures. Pure DES was also tested for comparison. After a single oral dose of the suspensions of DES, DES-NIA and DES-2FLA-B (equivalent to 5 mg/kg pure DES, containing 0.5% CMCNa), the pharmacokinetic parameters of DES were provided for statistical comparison and bioavailability calculation. The mean plasma concentrations of DES versus time diagrams for pure DES, DES-NIA and DES2FLA-B cocrystals were shown in figure 12. The pharmacokinetic parameters in table 3 were calculated from the concentration of DES. In the absorption phase, an increase of Cmax was presented in the PK profile of DES-NIA. This phenomenon verified that higher IDR of DES-NIA could lead to a modest increase in Cmax. However, DES-NIA


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and pure DES present the same parameters on Tmax, similar elimination behavior within 2 hours, which is unfavorable for the improvement of compliance. As for DES-2FLAB, its Tmax was 2 times longer than that of pure DES. This prolongation is correlated with its reduced IDR profile. The sustained released DES-2FLA-B is helpful to maintain longer time above minimum effective concentration (MEC), which makes it has a strong potential to improve compliance. Not only the absorption phase (by altering dissolution rate), the involvements of CCFs also have great possibilities to modulate the elimination processes of APIs. In this study, the relative bioavailability (AUC0-24h) of DES-NIA and DES-2FLA-B are about 1.2 and 2 times lower than pure DES. This phenomenon was attributed to the higher clearance in their PK profiles. In figure 12, no DES could be detected 12 hours after oral administration of these two cocrystals. Considering the pharmacological activities, we supposed that FLA may increase the phase II metabolites and thus decrease the accumulation of estrogens. In addition, less toxic phase I metabolites owing to the inhibitory effects of FLA on CYPs could also help to reduce the adverse effects of DES.



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Figure 12. Plasma DES concentration-time curves of the pure DES, DES-NIA and DES-2FLA-B cocrystals (data are expressed as means ±SD, n = 6). Table 3. Pharmacokinetic parameters from the plasma concentration of pure DES, DES-NIA and DES-2FLA-B cocrystal. DES material

Tmax (h)

Cmax (μg/mL)

CL/F (mL/h/kg)

AUC0-24h (h·ng/mL)

DES

0.8

42.0

26195.5

145.5

DES-NIA

0.8

51.7

33485.4

118.4

DES-2FLA-B

1.6

24.9

50788.7

77.3

Conclusions. With the aim of improving compliance and reducing drug accumulation of DES, a synthetic estrogen, cocrystals with isonicotinamide (INA), picolinamide (PIN), nicotinamide (NIA), urea (UREA), sarcosine (SAR) and flavone (FLA) were


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successfully prepared. Polymorphs were obtained for DES-2INA and DES-2FLA cocrystals by means of different cocrystallization methods. Single crystal structures of all the DES cocrystals were determined by SCXRD. On the basis of their basic supramolecular motifs, we can divide these nine cocrystals into two groups (A: O-H… Narom; B: O-H…Ocarbonyl). Furthermore, IDRs were conducted for eight DES coccrystals and pure DES for comparison. DES-NIA shows about 1.5-fold enhancement while DES-SAR-MH and DES-2FLA-B exhibit 2-fold and 5.5-fold decrease in pH 2.0 buffer solution, respectively. In order to investigate the influences of IDR and pharmacological activities of CCFs on PK performances, experiments were subjected on DES-NIA and DES-2FLA-B. According to PK profiles, the Tmax of DES-2FLA-B presents 2-fold enhancement than pure DES, which facilitated the improvement of compliance. The higher clearance rates in DES cocrystals conduce to the decrease on drug accumulation of estrogens. Furthermore, less toxic phase I metabolites owing to the inhibitory effects of FLA on CYPs could also help to reduce adverse effects of DES. Acknowledgements This research work was financially supported by Shanghai Natural Science Foundation (Grant No. 18ZR1447900), Youth Innovation Promotion Association CAS (Grant No. 2016257), CAS Key Technology Talent Program, and SANOFI-SIBS Scholarship.

ASSOCIATED CONTENT Supporting Information.



Page 32 of 38

The Supporting Information is available free of charge on the ACS Publications website at DOI: . Schemes of library of coformers; XRPD patterns; crystallographic data for DES cocrystals; tables of H-bond lengths and angles; H-bond and packing patterns; figures of TGA diagrams, DSC diagrams; XRPD patterns and polarizing microscopy photos for DES cocrystals.

Accession codes CCDC 1840236-1840242 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, or by emailing [email protected], or by containing The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]; fax: +86 21 50807088; tel: +86 21 50800934.

Notes The authors declare no competing financial interest. References (1) Aitipamula, S.; Banerjee, R.; Bansal, A. K.; Biradha, K.; Cheney, M. L.; Choudhury, A. R.; Desiraju, G. R.; Dikundwar, A. G.; Dubey, R.; Duggirala, N.; Ghogale, P. P.; Ghosh, S.; Goswami, P. K.; Goud, N. R.; Jetti, R. R. K. R.; Karpinski,


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TOC

SYNOPSIS Cocrystallization strategy was applied to improve compliance and reduce drug accumulation of diethylstilbestrol.


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Improving compliance and decreasing drug accumulation of

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