The role of alkyl chain length in the melt and solution crystallization of paliperidone aliphatic prodrugs

Chen, A.; Cai, P.; Peng, Y.; Guo, M.; Su, Y.; Cai, T.

doi:10.1107/S2052252523009582

research papers

IUCrJ

Volume 11| Part 1| January 2024| Pages 23-33

ISSN: 2052-2525

https://doi.org/10.1107/S2052252523009582

CHEMISTRY | CRYSTENG

Open

access

The role of alkyl chain length in the melt and solution crystallization of paliperidone aliphatic prodrugs

An Chen,^a Peishan Cai,^a Yayun Peng,^a Minshan Guo,^a Yuan Su ^b ^* and Ting Cai ^a,^b ^*

^aDepartment of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China, and ^bDepartment of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 211198, People's Republic of China
^*Correspondence e-mail: suyuan@cpu.edu.cn, tcai@cpu.edu.cn

Edited by L. R. MacGillivray, University of Iowa, USA (Received 26 June 2023; accepted 2 November 2023)

Fatty acid-derivative prodrugs have been utilized extensively to improve the physicochemical, biopharmaceutical and pharmacokinetic properties of active pharmaceutical ingredients. However, to our knowledge, the crystallization behavior of prodrugs modified with different fatty acids has not been explored. In the present work, a series of paliperidone aliphatic prodrugs with alkyl chain lengths ranging from C4 to C16 was investigated with respect to crystal structure, crystal morphology and crystallization kinetics. The paliperidone derivatives exhibited isostructural crystal packing, despite the different alkyl chain lengths, and crystallized with the dominant (100) face in both melt and solution. The rate of crystallization for paliperidone derivatives in the melt increases with alkyl chain length owing to greater molecular mobility. In contrast, the longer chains prolong the nucleation induction time and reduce the crystal growth kinetics in solution. The results show a correlation between difficulty of nucleation in solution and the interfacial energy. This work provides insight into the crystallization behavior of paliperidone aliphatic prodrugs and reveals that the role of alkyl chain length in the crystallization behavior has a strong dependence on the crystallization method.

Keywords: paliperidone; prodrugs; alkyl chain lengths; crystallization kinetics; crystal engineering; crystal morphology; intermolecular interactions; pharmaceutical solids.

CCDC references: 2271248; 2271249; 2271250; 2271251

1. Introduction

A prodrug is a molecule with little or no pharmacological activity on its own but can be converted to an active substance through a chemical or enzymatic process or a combination of the two in the body (Rautio et al., 2018 ; Fattahi et al., 2020 ; Huttunen et al., 2011 ). Prodrugs have been widely utilized in drug delivery to improve the physicochemical, biopharmaceutical and/or pharmacokinetic properties of the parent drug (Fattahi et al., 2020; Markovic et al., 2019 ). Several long-acting injectable formulations based on the prodrug strategy have been approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia, including fluphenazine enanthate, fluphenazine decanoate, haloperidol decanoate, paliperidone palmitate and aripiprazole lauroxil, whereby prodrugs were applied to reduce solubility and slow dissolution to achieve extended drug release (Remenar, 2014 ; Shi, Lu et al., 2021 ).

Fatty acids, a class of essential compounds for the maintenance of health and normal physiological development, have received much attention in prodrug synthesis owing to their excellent biocompatibility (Fattahi et al., 2020; Sun et al., 2017 ; Sprecher, 1981 ; Dijkstra, 2008 ). The commonly used strategy is to conjugate the carboxyl end of the lipid with a hydroxyl group of the drug to form a stable ester linkage. It has been reported that physicochemical properties, such as melting point, solubility, dissolution, permeability, metabolic stability and self-assembly behavior, and biological activities including cell cytotoxicity, side effects and pharmacokinetic characteristics of prodrugs can be affected by the chain length and degree of substitution of fatty acids covalently linked to the parent drug (Zhang et al., 2016 ; Zhong et al., 2018 ; Thanki et al., 2019 ; Singh et al., 2021 ; Im et al., 2011 ).

Crystallization is an essential process in the purification and production of substances in the pharmaceutical, agrochemical and fine chemical industries. The crystallization process comprises two stages: nucleation and crystal growth, both of which have a decisive influence on the properties of the crystalline product, such as crystalline form, purity, crystal habit, particle size distribution. In-depth understanding of the mechanism facilitates the design of the crystallization of crystalline products with desired properties. One option is to investigate the relationship between the molecular structure and crystallization behavior in a series of model analogs systematically (Cruz-Cabeza et al., 2017 ; Tang et al., 2021 ; Shi, Xu et al., 2021 ; Powell et al., 2014 ; Yang et al., 2014 ; Kakkar et al., 2020 ; Huang et al., 2018 ). It has been reported in glycine homopeptides that longer chains prolonged the induction time (Guo et al., 2023 ). Several alkyl-derivative compounds with shorter alkyl chain lengths present a reduced crystallization tendency (Honda et al., 2021 ; Ishikawa et al., 2022 ; Zheng et al., 2017 ). Intuitively, a more flexible compound is more difficult to crystallize. Khan & Sundararajan (2011 , 2013 ) reported that the spherulite size and growth rate of biscarmates varied with the alkyl side chain length; however, the growth kinetics increase first and then decrease significantly with increasing chain length. To our knowledge, the impact of alkyl chain length on crystallization behavior of fatty acid-derivative prodrugs has not been explored, despite their extensive utilization in physicochemical, biopharmaceutical and pharmacokinetics.

In the present study, a series of derivatives of the antipsychotic drug paliperidone has been selected for the model compounds (Fig. 1). The fatty acids covalently linked with paliperidone only vary in alkyl chain length, ranging from C4 to C16, hence we can explore the link between alkyl chain length and crystallization behavior. For the first time, we solved the crystal structures of the paliperidone aliphatic derivatives, including paliperidone palmitate, the active pharmaceutical ingredient of INVEGA HAFYERA, by single-crystal X-ray diffraction (SCXRD). Moreover, the crystal morphology, nucleation and crystal growth kinetics of the paliperidone derivatives were investigated in both melt and solution environments.

Figure 1
Chemical structure of paliperidone derivatives.

2. Experimental

2.1. Materials

Paliperidone butyrate (PC4), paliperidone caprylate (PC8), paliperidone laurate (PC12) and paliperidone palmitate (PC16) were purchased from Zhuzhou Focus Pharmaceutical Technology Co. Ltd, China (purity >99%). All solvents were obtained from Nanjing Chemical Reagent Co. Ltd, China (purity >95%). All materials were used without further purification.

2.2. Solid-state characterization

Differential scanning calorimetry (DSC) was performed using Q2000 instruments (TA, USA). Samples (3–5 mg) were enclosed in sealed aluminium pans and heated to a specified temperature under a nitrogen atmosphere (with a fixed flow rate of 50 ml min⁻¹). The instrument was calibrated with indium. To determine the glass transition temperature (T_g), all paliperidone derivatives were heated to 130°C for 3 min, equilibrated to −60°C, and then reheated to the melting point of the derivatives (Fig. S1 of the supporting information).

Thermogravimetric analysis (TGA) was carried out with a TA Q500 instrument (TA, USA) to determine the thermal stability of the sample. In brief, samples (5–15 mg) were added to a platinum plate and heated to 500°C at a rate of 20°C min⁻¹ under a 60 ml min⁻¹ nitrogen purge. The thermal data were analyzed using the TA Universal Analysis software.

Powder X-ray diffraction (PXRD) was carried out on a SmartLab XE diffractometer (Rigaku, Japan) with Cu Kα radiation. Approximately 30 mg samples were placed on glass supports and exposed to radiation (3 ≤ 2θ ≤ 40°) at a scan rate of 10° min⁻¹.

SCXRD was carried out on a Bruker D8 venture diffractometer (Bruker, USA) using Mo Kα radiation. Unit-cell determination, diffraction data collection, integration and refinement were achieved using the program SAINT. SHELX2014/7 (Sheldrick, 2015 ) was used to solve and refine the structure by direct methods and full-matrix least-squares on the F² procedure. The data were corrected for the effects of absorption by a multiscan method using SADABS. Non-hydrogen atoms were refined anisotropically, and hydrogen atoms were located in geometrically calculated positions with the riding model.

2.3. Melt crystallization of paliperidone derivatives

2.3.1. Single-crystal growth of paliperidone derivatives

The experimental details are similar to the procedures reported in the literature (Ou et al., 2020 ; Su et al., 2018 ; Chen et al., 2023 ). In brief, a small quantity of the sample was melted on a round coverslip at a specified temperature until a small single crystal remained. This seed was allowed to grow to a specified size at a temperature near the T_m (0.97–0.98 T_m) and was then submitted for SCXRD analysis.

2.3.2. Growth kinetic measurement

The crystal growth rate of paliperidone derivatives in the melt was measured using a polarized light microscope (Olympus BX53) equipped with a THMS 600 hot stage (Linkam, UK). The sample (3–5 mg) was melted between two clean coverslips until no crystals remained. The resulting sandwiched sample was quenched at room temperature on an aluminium block to obtain a clear amorphous film. The seeds were placed in contact with the amorphous film to initiate crystal growth. The growth rate was measured by tracking the advance of the crystal front over time. The reported growth rate was obtained from at least three measurements for three independent samples.

2.3.3. Viscosity measurement

The viscosities of amorphous paliperidone derivatives were measured at various temperatures using a HAAKE MARS 60 rheometer (Thermo Fisher Scientific, USA). Viscosity measurements were performed between two parallel plates 20 mm in diameter with a gap size of 0.3 mm. The crystalline powder of paliperidone derivatives was added and melted at 5°C above the T_m of the corresponding derivatives for 1 min to ensure no crystals remained. The system was then cooled to the desired temperature and isothermed for 2 min. Shear deformation was implemented at a rate of 1 s⁻¹ with the temperature held constant, and the shear viscosity was recorded when the measurement reached a steady state.

2.4. Solution crystallization of paliperidone derivatives

2.4.1. Induction time measurement

The solubility of paliperidone derivatives in isopropanol at 20°C was determined by the gravimetric method prior to induction time measurement (experimental details and results are given in the supporting information). According to the solubility data, a saturated solution of paliperidone derivatives was prepared by heating the desired amount of solid phase and solvent. The supersaturation was calculated as a mole fraction ratio (S = x/x₁). The experimental method for induction time measurement follows the work of Jiang & Horst (2011 ). The saturated solution of paliperidone derivatives was filtered through a 0.22 µm nylon membrane, aliquoted into 15 preheated 10 ml glass vials and sealed immediately with poly(tetrafluoroethylene) (PTFE)-coated caps to minimize evaporation. The glass vial was reheated and stirred again at 50°C to dissolve the solid that crystallized from the process of filtration and dispensing. Then, the saturated solution was held at the nucleation temperature (20°C) for induction time measurement with a stirring speed at 400 rpm. The experimental temperature was controlled by a thermostatic water bath with an accuracy of ±0.01°C. Nucleation was observed by visual methods, and the time required for the solution to change from clear to cloudy was recorded as the induction time t. After nucleation, the vials were removed and reheated at 50°C to dissolve the crystals before the next nucleation experiment. The number of parallels in each set of experiments was 80–100. No solid phase transformation occurred during the nucleation study, which was confirmed by PXRD analysis (Fig. S2).

2.4.2. Crystal growth rate measurement

Single crystals of paliperidone derivatives were obtained in isopropanol (IPA) by slow solvent evaporation. Single crystals with a well developed facet were selected for crystal growth experiments. The crystal growth rate measurements were carried out in IPA at 20°C (S = 3). The saturated solution was prepared and filtered following the procedures used in the nucleation induction time measurements. Then, the filtrate was transferred to a growth tank for 15 min at 20°C to generate supersaturation. A single crystal of a paliperidone derivative was placed in the growth tank for the growth rate measurements. The crystal growth rates of paliperidone derivatives were measured using an inverted fluorescence microscope (ECLIPSE Ts2R, Nikon, Japan) at regular time intervals. The reported growth rate was obtained from six parallel sets of experiments.

3. Results and discussion

3.1. Solid-state characterization

The thermal properties of paliperidone derivatives were analyzed by DSC and TGA. A single distinct sharp endothermic peak appeared in the DSC trace of each paliperidone derivative [Fig. 2(a)], indicating high phase purity for all model compounds. The glass transition temperatures of the paliperidone derivatives are provided in Fig. S1. The melting point (T_m) and glass transition temperature (T_g) of paliperidone derivatives were plotted against the number of carbon atoms in their respective fatty acid fractions [Fig. 2(d)]. A paliperidone derivative with a longer alkyl chain length has a higher T_m and a lower T_g. The TGA showed that all paliperidone derivatives have good thermal stability and that degradation occurs far above their T_m values [Fig. 2(b)]. The X-ray diffraction patterns of the paliperidone derivatives are similar [Fig. 2(c)] but there are distinct differences in the diffraction peaks present at low diffraction angles (<10°).

Figure 2
(a) DSC thermograms. (b) TGA thermograms. (c) PXRD diffraction patterns. (d) T_m and T_g of paliperidone derivatives.

3.2. Crystal structure analysis

Thin plate-like single crystals of paliperidone derivatives (Fig. 5) were successfully obtained by the melt droplets method and studied by SCXRD. The crystallographic parameters of the paliperidone derivatives are shown in Table 1. The paliperidone derivatives crystallized isostructurally in the monoclinic system with the P2₁/c space group regardless of the length of the alkyl chain, and each contains four molecules in the corresponding unit cell. With increasing length of alkyl chain, the unit-cell parameters a and c increase, whereas the b axis decreases.

Table 1
Crystallographic parameters of paliperidone derivatives

	PC4	PC8	PC12	PC16
Empirical formula	C₂₇H₃₃FN₄O₄	C₃₁H₄₁FN₄O₄	C₃₅H₄₉FN₄O₄	C₃₉H₅₇FN₄O₄
Formula weight	496.57	552.68	608.78	664.88
Crystal system	Monoclinic	Monoclinic	Monoclinic	Monoclinic
Space group	P2₁/c	P2₁/c	P2₁/c	P2₁/c
Temperature (K)	170	170	170	100
a (Å)	23.295 (4)	26.953 (11)	31.029 (3)	34.188 (3)
b (Å)	10.179 (2)	10.080 (4)	9.9381 (10)	9.8280 (9)
c (Å)	10.6479 (19)	10.753 (4)	10.8384 (11)	10.8068 (9)
α (°)	90	90	90	90
β (°)	97.284 (6)	92.658 (12)	99.374 (3)	92.992 (3)
γ (°)	90	90	90	90
V (Å³)	2504.4 (8)	2918 (2)	3297.6 (6)	3626.1 (5)
Z	4	4	4	4
ρ_calc (g cm⁻³)	1.317	1.258	1.228	1.218
R₁, wR₂ [I > 2σ(I)]	0.0974, 0.2334	0.0827, 0.1807	0.059, 0.1112	0.0556, 0.1165
R₁, wR₂ (all data)	0.1746, 0.2707	0.1921, 0.2323	0.1392, 0.1483	0.1155, 0.1462
CCDC No.	2271248	2271249	2271250	2271251

Despite varied alkyl chain lengths, the paliperidone derivatives exhibit isostructural crystal packing, sharing the same conjugated backbones and crystal-packing motifs. The paliperidone derivative molecule consists of a paliperidone head and a fatty acid tail. In the case of PC16, as a representative example of the paliperidone derivatives, multiple PC16 molecules connect with each other by the hydrogen on the phenyl ring and the oxygen on isoxazole (C7—H7⋯O1: 2.42 Å) stacking along the c axis, forming a 1D chain [Fig. 3(a)]. These 1D chains are stacked along the b axis by C—H⋯O hydrogen bonding interactions (C9—H9⋯O2: 2.47 Å, C13—H13A⋯O2: 2.57 Å, C23—H23⋯O1: 2.46 Å), leaving the paliperidone heads aligned and the fatty acid tails opposite and parallel, forming the 2D layer of PC16 [Fig. 3(b)]. This 2D layer is further extended by C—H⋯F interactions (C39—H39A⋯F1: 2.51 Å) which consequently form a lamellar structure of two segregated layers: an alkyl layer and a paliperidone layer [Fig. 3(c)].

Figure 3
(a) 1D chain consisting of multiple PC16 molecules. (b) 2D packing of PC16. (c) Projection of the crystal structure of PC16.

The thickness of the alkyl layer (represented by A in Fig. 4) significantly increases with increasing number of carbon atoms in the paliperidone derivatives, whereas the thickness of the paliperidone layer (represented by P in Fig. 4) remains constant [Fig. 4(a)]. The elongated straight alkyl chains of the molecules are almost parallel and tilted from the bc plane. The tilt angle decreases with increasing alkyl chain length in the derivatives, with the ranking θ_PC4(62.52°) > θ_PC8(49.39°) > θ_PC12(47.68°) > θ_PC16(47.37°).

Figure 4
(a) Molecular packing structures of paliperidone derivatives. (b) Alkyl layer and paliperidone layer thicknesses of the paliperidone derivatives. (c) Summary of the various contact contributions in the paliperidone derivatives.

Hirshfeld surfaces analysis, an effective tool to investigate and visualize the intermolecular interactions in the crystal, was performed on the paliperidone derivative crystals (Spackman & McKinnon, 2002 ; Spackman & Jayatilaka, 2009 ; He et al., 2015 ). 2D fingerprint plots are provided in Fig. S3. A detailed analysis of the relative contributions of the intermolecular contacts is shown in Fig. 4(c). The H⋯H interaction made the largest contribution, suggesting that van der Waals interactions are the dominant interactions in paliperidone derivative crystals, and the relative contribution increases with increasing alkyl chain length due to the longer alkyl chains providing a higher proportion of hydrogen atoms in the structure (Martin et al., 2015 ). In addition, the paliperidone derivatives also connect with each other by weak hydrogen bonds (Table S2). In contrast to van der Waals interactions, the relative contribution of hydrogen-bonding interactions decreases with increasing alkyl chain length.

3.3. Crystal morphology in melt and solution

The Bravais–Friedel–Donnay–Harker (BFDH) model was applied for the crystal morphology prediction of the paliperidone derivatives. It revealed that the predicted crystal habits of the paliperidone derivatives are quite similar and the (100) faces are predominant in the crystals regardless of the length of the alkyl chain [Fig. 5(a)]. Figs. 5(b) and 5(c) show the crystals of paliperidone derivatives obtained from the melt and solution crystallization, respectively. The morphologies of crystal growth of paliperidone derivatives over time are provided in Fig. S4. It can be seen that the experimental morphology does not fit well with the predicted morphology. The difference can be rationalized because the BFDH model is mainly based on lattice parameters and symmetry; in fact, crystal morphology is controlled by both internal structure and crystallization conditions. In general, the crystals grown from the melts were very thin and plate-like with predominant (100) faces, and the morphology is almost the same independent of alkyl chain length. Conversely, the crystal morphology of paliperidone derivatives crystallized in IPA is quite different with respect to alkyl chain length. PC4 and PC8, the derivatives with shorter alkyl chains, appeared to grow as plate-shaped crystals with smaller aspect ratios. PC12 and PC16, derivatives with longer alkyl chains, tended to grow as rod-like crystals with larger aspect ratios. The distinct difference in crystal morphology of the paliperidone derivatives from solution crystallization may be caused by the solvent–solute interactions between the solvent and the crystal facets, which are absent in the melt (Ji et al., 2022 ).

Figure 5
(a) Predicted crystal morphologies of paliperidone derivatives and the experimental morphologies grown from (b) the melt and (c) solution.

3.4. Crystallization kinetics of paliperidone derivatives in the melt

The paliperidone derivatives show distinctive crystallization behavior in the melt. The crystallization tendency increases with alkyl chain length. At room temperature, PC16 crystallized within one day, PC12 and PC8 crystallized after three days, and the crystallization was much more difficult for PC4 (Fig. S5). The crystal growth kinetics of paliperidone derivatives in the melt were determined by seeding crystallization (for details, see Methods) through tracking the advance of the crystal front between two coverslips at set time intervals. Fig. 6(a) shows the morphologies of PC16 crystals grown over a wide range of temperatures from 30 to 105°C. At the temperature approaching the melting point of PC16 crystals (e.g. 105°C), the crystals grew as single crystals. When the liquid was cooled to 60°C, the product was a fine-grained polycrystalline material. Compact spherulites were observed when grown at relatively low temperatures (e.g. 30°C).

Figure 6
(a) Crystal growth morphologies of PC16 crystals in the melt at different temperatures. (b) Melt crystallization kinetics of paliperidone derivatives. (c) Crystal growth rates of paliperidone derivatives in the melt as a function of T/T_g. (d) Viscosity of paliperidone derivatives (solid line represents VFT equation-fitting curves). (e) Crystal growth rate plotted against viscosity for paliperidone derivatives.

The crystal growth rates of paliperidone derivatives as a function of temperature (from 30 to 105°C) are overlaid in Fig. 6(b). The growth kinetics of the paliperidone derivatives between 30 and 105°C exhibit characteristic bell-shaped curves, as a result of the competition between molecular mobility and the thermodynamic driving force for the crystallization (Zhang et al., 2021 ; Shi & Cai, 2016 ). The order of growth rate of paliperidone derivatives is PC16 ≃ PC12 > PC8 ≫ PC4. However, the four paliperidone derivatives have similar crystal growth rates within an order of magnitude when compared at the same temperature relative to T_g [Fig. 6(c)]. Additionally, the viscosity of the supercooled liquid of paliperidone derivatives [Fig. 6(d)] decreases with increasing alkyl chain length at the same temperature. This order was consistent with the order of paliperidone derivative crystal growth rates. Fig. 6(e) shows the growth rates of paliperidone derivatives as a function of liquid viscosity in the form of a log–log format, where a linear correlation was present, suggesting liquid viscosity contributes to the differences in growth rates of the four paliperidone derivatives. The slight deviation at temperatures close to T_m can be attributed to the fact that crystal growth is mainly limited by the thermodynamic driving force in that temperature region. Generally, the kinetic contributions of crystal growth depend on the molecular diffusion. According to the Stokes–Einstein equation, the diffusion coefficient is inversely related to the viscosity η for weakly supercooled liquids, whereas decoupling of diffusion and viscosity occurs at temperatures close to T_g (at T < 1.3 T_g) (Grzybowska et al., 2016 ). Thus, the growth rate depends on the viscosity of the supercooled liquid at a temperature far above T_g, wherein molecules diffuse faster with lower liquid viscosities, and thus kinetically favor crystal growth. It is reasonable that PC4, which has the shortest chain length, grows the slowest at the same temperature due to its higher viscosity. As the chain length increases, the viscosity of the paliperidone derivative liquid decreases, leading to increased molecular mobility, and thus the growth rate increases. This trend is evident from C4 to C8. However, the viscosity or mobility is less affected as the chain length increases further, and the difference in growth rate between PC12 and PC16 is relatively small.

3.5. Crystallization kinetics of paliperidone derivatives in solution

Solution crystallization is widely used for separation and purification of pharmaceutical compounds. It is of interest to investigate the effect of alkyl chain length on the crystallization behavior of paliperidone derivatives in solution. The study of nucleation induction times was conducted as a function of supersaturation at 20°C in IPA, a commonly used solvent for the synthesis of paliperidone derivatives. Due to the stochastic nature of nucleation, over 1200 isolated experiments were carried out for all paliperidone derivatives, the measured induction times can be approximated to a cumulative probability distribution P(t):

$[P(t) = {{N(t)} \over {N}}, \eqno (1)]$

where N is the number of isolated experiments and N(t) is the number of experiments in which crystals are detected at time t. According to the Poisson distribution, the nucleation rate (J) is given by

$[P(t) = 1 - \exp\left[- JV(t - t_{\rm g}) \right], \eqno (2)]$

where V is the solution volume and t_g is the detection time delayed by crystal growth, which can be approximated as the minimum induction time observed under each supersaturation. Fitting equation (2) to the experimental probability distribution P(t) can lead to a value for the nucleation rate (J) and the growth time (t_g) at a given supersaturation. The probability distributions P(t) of induction time of the paliperidone derivatives in IPA at different supersaturations are shown in Figs. 7(a)–7(d). As expected, the induction time t decreases with increasing degree of supersaturation S. To evaluate the difficulty of nucleation among the paliperidone derivatives, the median induction times (t₅₀) were extracted from the experimental induction time distribution (McTague & Rasmuson, 2023 ). Fig. 7(e) illustrates the correlations of the median nucleation time of the paliperidone derivatives against the required driving force. The results show that the nucleation of PC16 is the most difficult in IPA, followed by PC12, PC8 and PC4. That is, the paliperidone derivatives nucleate with more difficultly with a longer chain length.

Figure 7
Induction time distributions of (a) PC4, (b) PC8, (c) PC12 and (d) PC16 at different supersaturations in IPA at 20°C. (e) Nucleation times versus the thermodynamic driving force in IPA at 20°C. (f) ln(J/S) versus 1/ln²S for the induction time measurements enables the determination of the nucleation parameters A and B from equation (3

According to classical nucleation theory, the nucleation rate J can be described as

$[J = AS \exp \left(-{{B} \over {\ln^{2}S}}\right), \eqno (3)]$

where A and B represent nucleation kinetic and thermodynamic parameters, respectively, and S is the supersaturation. The kinetic parameter A reflects the attachment rate of solute molecules to the nuclei. The thermodynamic parameter B is related to the energy barrier that needs to be overcome to form nuclei from solution. The thermodynamic parameter B can be defined as

$[B = {{16\pi\gamma^{3}V^{2}} \over {3(kT)^{3}}}, \eqno (4)]$

where γ is the solid–liquid interfacial energy per unit area, V is the molecular volume, T is the nucleation temperature and k is the Boltzmann constant. The parameters A and B could be determined using a plot of ln(J/S) against ln⁻²S [Fig. 7(f)], and from the latter, the interfacial energy γ is determined. The A and γ parameters determined for the paliperidone derivatives in IPA are listed in Table 2. The value of the nucleation kinetic parameter A increases with increasing the alkyl chain length of paliperidone derivatives in IPA, and the value of the nucleation kinetic parameter A of PC16 is several orders of magnitude larger than that of PC4 in the same solution. Conversely, the solid–liquid interfacial energy γ of the paliperidone derivative crystals in IPA decreases with increasing alkyl chain length in the order PC16 > PC12 > PC8 > PC4. The solute–solvent interaction energy is reported to be proportional to γ, and stronger interactions enable higher energy barriers for nuclei formation from solution (Chai et al., 2019 ). The overall solute–solvent interaction energies were calculated from molecular dynamics simulations, showing the following order (see Table 3 and the supporting information for details): PC4 < PC8 < PC12 < PC16, which is consistent with the order of magnitude of the solid–liquid interfacial energy γ derived from classical nucleation theory as expected. Given the relation between the induction time and alkyl chain length determined above, the nucleation behavior of paliperidone derivatives is dominated by thermodynamics within the supersaturation range investigated rather than kinetics, suggesting that overcoming the interfacial energy barrier is the rate-limiting process for nucleation of the paliperidone derivatives.

Table 2
Nucleation parameters derived from classical nucleation theory

	PC4	PC8	PC12	PC16
A (m⁻³ s⁻¹)	2.8 × 10³	5.1 × 10³	7.6 × 10³	8.3 × 10⁷
γ (mJ m⁻²)	1.67	2.02	3.64	5.40

Table 3
Solvent–solute interaction energies calculated from molecular dynamics simulations at 20°C

Data are presented as means ± the standard deviation (n = 10).

Solute + solvent	PC4 + IPA	PC8 + IPA	PC12 + IPA	PC16 + IPA
ΔE_int (kJ mol⁻¹)	−267.96 ± 13.71	−295.89 ± 5.86	−439.54 ± 6.78	−486.73 ± 5.92

Crystal growth experiments of the paliperidone derivatives in solution were conducted at high supersaturation (S = 3) because PC16 grew too slowly in IPA at low supersaturation. We determined the growth rate of the axial [represented by A in Fig. 8(a)] and radial [represented by R in Fig. 8(b)] directions of the crystals. The morphologies and growth rates are summarized in Figs. 8(a) and 8(b). The results reveal that all paliperidone derivatives crystals grow faster in the axial direction than in the radial direction and the order of the growth rate of paliperidone derivatives in IPA is PC4 > PC8 ≫ PC12 ≃ PC16 in both the axial and the radial directions. The order of growth rates of paliperidone derivatives in IPA is consistent with the order of the nucleation rates. According to classical nucleation theory, the clusters are assumed to have a similar structure and morphology to the mature crystal. The cluster growth rate will be consistent with or proportional to the crystal growth rate (Kashchiev, 2000 ). Thus, it can be rationalized that the fastest growth rate of the PC4 molecules contributes to the fastest nucleation rate among paliperidone derivatives (Cruz-Cabeza et al., 2017; Liu et al., 2019 ).

Figure 8
(a) Crystal growth morphology of paliperidone derivatives in IPA. (b) Growth rates of paliperidone derivatives in IPA at 20°C (histograms: growth rate in axial direction, striped histograms: growth rate in the radial direction).

4. Conclusions

In summary, the role of alkyl chain length for a series of fatty acid-derivative paliperidone prodrugs in the crystallization behavior in both melt and solution was investigated. The paliperidone aliphatic derivatives showed isostructural crystal packing, a characteristic lamellar structure, and the crystals exhibited the dominant (100) face in both melt and solution crystallization, which are independent of the alkyl chain length. It revealed that paliperidone derivatives are more difficult to crystallize with a shorter chain length in the melt, but the trend in solution is the opposite. The relation between the alkyl chain length and the crystallization tendency of the paliperidone derivatives in melts is mainly associated with molecular mobility. In contrast, the interfacial energy dominates the crystallization of paliperidone derivatives in solution. This work provides insights into the relation between alkyl chain length in fatty acid-based prodrugs and crystallization behavior, deepening our understanding of the correlation between molecular structure and crystallization. It is also relevant to predict the crystallization behavior of derivatives with varied alkyl chain lengths, which in turn guides the prodrug design and the development of prodrug-based extended-release formulations.

Supporting information

CCDC references: 2271248; 2271249; 2271250; 2271251

Crystal structure: contains datablocks PC4, PC8, PC12, PC16. DOI: https://doi.org/10.1107/S2052252523009582/lq5053sup1.cif

Structure factors: contains datablock PC4. DOI: https://doi.org/10.1107/S2052252523009582/lq5053PC4sup2.hkl

Structure factors: contains datablock PC8. DOI: https://doi.org/10.1107/S2052252523009582/lq5053PC8sup3.hkl

Structure factors: contains datablock PC12. DOI: https://doi.org/10.1107/S2052252523009582/lq5053PC12sup4.hkl

Structure factors: contains datablock PC16. DOI: https://doi.org/10.1107/S2052252523009582/lq5053PC16sup5.hkl

Supporting information, tables and figures. DOI: https://doi.org/10.1107/S2052252523009582/lq5053sup6.pdf

Computing details top

(PC4) top

Crystal data top

C₂₇H₃₃FN₄O₄	F(000) = 1056
M_r = 496.57	D_x = 1.317 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 23.295 (4) Å	Cell parameters from 1901 reflections
b = 10.179 (2) Å	θ = 2.2–22.6°
c = 10.6479 (19) Å	µ = 0.09 mm⁻¹
β = 97.284 (6)°	T = 170 K
V = 2504.4 (8) Å³	Plate, colourless
Z = 4	0.08 × 0.05 × 0.01 mm

Data collection top

Bruker D8 VENTURE diffractometer	2389 reflections with I > 2σ(I)
φ and ω scans	R_int = 0.107
Absorption correction: multi-scan SADABS-2016/2 (Bruker,2016/2) was used for absorption correction. wR2(int) was 0.0934 before and 0.0596 after correction. The Ratio of minimum to maximum transmission is 0.8484. The λ/2 correction factor is Not present.	θ_max = 25.1°, θ_min = 2.2°
T_min = 0.632, T_max = 0.745	h = −27→27
16080 measured reflections	k = −10→12
4356 independent reflections	l = −12→12

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.097	H-atom parameters constrained
wR(F²) = 0.271	w = 1/[σ²(F_o²) + (0.0644P)² + 11.5309P] where P = (F_o² + 2F_c²)/3
S = 1.11	(Δ/σ)_max < 0.001
4356 reflections	Δρ_max = 0.39 e Å⁻³
327 parameters	Δρ_min = −0.41 e Å⁻³
0 restraints

Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O2	0.3536 (2)	0.5565 (4)	0.7972 (4)	0.0369 (11)
O3	0.15633 (18)	0.3698 (4)	0.5335 (4)	0.0349 (11)
F1	0.91856 (17)	0.2338 (4)	1.0494 (4)	0.0608 (13)
O1	0.7919 (2)	0.4916 (4)	0.7616 (4)	0.0412 (12)
O4	0.0912 (2)	0.2057 (5)	0.5146 (5)	0.0516 (14)
N3	0.2751 (2)	0.4355 (5)	0.7128 (4)	0.0278 (12)
N2	0.5258 (2)	0.4280 (5)	0.7407 (5)	0.0325 (13)
N4	0.2809 (2)	0.2923 (5)	0.5419 (5)	0.0343 (13)
N1	0.7299 (2)	0.4858 (5)	0.7293 (5)	0.0392 (14)
C22	0.7577 (3)	0.3293 (6)	0.8740 (6)	0.0297 (14)
C9	0.2526 (3)	0.3430 (6)	0.6288 (6)	0.0304 (15)
C11	0.3647 (3)	0.4201 (6)	0.6203 (5)	0.0272 (14)
C18	0.6480 (3)	0.3604 (6)	0.7903 (6)	0.0309 (15)
H18	0.644506	0.269490	0.824223	0.037*
C20	0.5520 (3)	0.3344 (6)	0.6607 (6)	0.0323 (15)
H20A	0.531218	0.338223	0.573685	0.039*
H20B	0.547757	0.244404	0.693514	0.039*
C5	0.1920 (3)	0.2956 (7)	0.6321 (6)	0.0364 (16)
H5	0.189639	0.199783	0.611293	0.044*
C21	0.7113 (3)	0.3907 (6)	0.7958 (6)	0.0324 (15)
C27	0.8065 (3)	0.3968 (6)	0.8482 (6)	0.0363 (16)
C4	0.1053 (3)	0.3139 (7)	0.4849 (7)	0.0369 (16)
C14	0.4269 (3)	0.4608 (6)	0.6275 (6)	0.0295 (14)
H14A	0.429506	0.557647	0.634524	0.035*
H14B	0.442118	0.434449	0.548618	0.035*
C10	0.3329 (3)	0.4771 (6)	0.7154 (6)	0.0299 (14)
C8	0.2449 (3)	0.4902 (7)	0.8143 (6)	0.0373 (16)
H8A	0.250925	0.586440	0.818155	0.045*
H8B	0.262020	0.452707	0.896397	0.045*
C19	0.6155 (3)	0.3632 (6)	0.6568 (6)	0.0336 (15)
H19A	0.619823	0.450688	0.618508	0.040*
H19B	0.632036	0.296782	0.603706	0.040*
C12	0.3372 (3)	0.3322 (6)	0.5371 (6)	0.0329 (15)
C15	0.4636 (3)	0.3991 (7)	0.7399 (6)	0.0347 (16)
H15A	0.450806	0.432485	0.819083	0.042*
H15B	0.457819	0.302721	0.737492	0.042*
C23	0.7637 (3)	0.2243 (6)	0.9614 (6)	0.0358 (16)
H23	0.730798	0.176408	0.980279	0.043*
C16	0.5552 (3)	0.4230 (8)	0.8689 (6)	0.0417 (17)
H16A	0.550494	0.334175	0.904171	0.050*
H16B	0.536980	0.486762	0.921819	0.050*
C7	0.1811 (3)	0.4623 (7)	0.7956 (7)	0.0436 (18)
H7A	0.161732	0.520383	0.728692	0.052*
H7B	0.164624	0.480369	0.875029	0.052*
C13	0.3643 (3)	0.2667 (7)	0.4331 (6)	0.0412 (18)
H13A	0.361336	0.171118	0.441378	0.062*
H13B	0.405194	0.291849	0.439035	0.062*
H13C	0.344220	0.294259	0.350884	0.062*
C25	0.8654 (3)	0.2660 (7)	0.9895 (7)	0.0404 (17)
C6	0.1705 (3)	0.3188 (7)	0.7576 (6)	0.0408 (17)
H6A	0.191218	0.260425	0.822627	0.049*
H6B	0.128665	0.298792	0.750996	0.049*
C24	0.8182 (3)	0.1932 (7)	1.0182 (6)	0.0438 (18)
H24	0.823643	0.122450	1.076736	0.053*
C17	0.6191 (3)	0.4539 (7)	0.8753 (6)	0.0394 (17)
H17A	0.637769	0.445268	0.963710	0.047*
H17B	0.624116	0.545592	0.847723	0.047*
C26	0.8627 (3)	0.3693 (7)	0.9060 (7)	0.0421 (17)
H26	0.895710	0.417536	0.888900	0.050*
C3	0.0721 (3)	0.4062 (7)	0.3947 (7)	0.0459 (18)
H3A	0.096606	0.430949	0.329048	0.055*
H3B	0.064177	0.487110	0.441139	0.055*
C2	0.0152 (3)	0.3529 (8)	0.3298 (8)	0.057 (2)
H2A	0.022874	0.279005	0.273785	0.069*
H2B	−0.008084	0.318971	0.394298	0.069*
C1	−0.0184 (4)	0.4580 (10)	0.2527 (11)	0.091 (3)
H1A	0.004370	0.490702	0.188047	0.136*
H1B	−0.026632	0.530462	0.308358	0.136*
H1C	−0.054927	0.421120	0.211666	0.136*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O2	0.049 (3)	0.030 (2)	0.030 (2)	−0.003 (2)	0.003 (2)	−0.011 (2)
O3	0.034 (3)	0.034 (3)	0.036 (3)	−0.001 (2)	0.002 (2)	0.005 (2)
F1	0.040 (2)	0.065 (3)	0.074 (3)	0.011 (2)	−0.009 (2)	0.008 (3)
O1	0.044 (3)	0.034 (3)	0.046 (3)	−0.005 (2)	0.006 (2)	0.007 (2)
O4	0.047 (3)	0.043 (3)	0.064 (3)	−0.012 (2)	0.006 (3)	0.004 (3)
N3	0.034 (3)	0.028 (3)	0.023 (3)	0.001 (2)	0.005 (2)	−0.002 (2)
N2	0.033 (3)	0.038 (3)	0.027 (3)	0.001 (2)	0.006 (2)	−0.002 (2)
N4	0.041 (3)	0.032 (3)	0.031 (3)	−0.002 (3)	0.009 (3)	−0.009 (2)
N1	0.038 (3)	0.035 (3)	0.043 (3)	−0.001 (3)	0.002 (3)	0.009 (3)
C22	0.033 (4)	0.028 (3)	0.029 (3)	−0.003 (3)	0.006 (3)	−0.006 (3)
C9	0.036 (4)	0.027 (3)	0.029 (3)	−0.001 (3)	0.006 (3)	−0.001 (3)
C11	0.038 (4)	0.023 (3)	0.021 (3)	−0.003 (3)	0.003 (3)	0.004 (3)
C18	0.037 (4)	0.026 (3)	0.029 (3)	−0.001 (3)	0.003 (3)	0.007 (3)
C20	0.035 (4)	0.034 (4)	0.028 (3)	−0.002 (3)	0.005 (3)	−0.004 (3)
C5	0.040 (4)	0.033 (4)	0.037 (4)	0.004 (3)	0.010 (3)	0.006 (3)
C21	0.041 (4)	0.029 (3)	0.028 (3)	−0.001 (3)	0.010 (3)	−0.003 (3)
C27	0.053 (4)	0.028 (3)	0.030 (4)	0.006 (3)	0.011 (3)	−0.002 (3)
C4	0.033 (4)	0.034 (4)	0.045 (4)	0.000 (3)	0.009 (3)	−0.008 (3)
C14	0.036 (4)	0.029 (3)	0.023 (3)	−0.002 (3)	0.000 (3)	0.004 (3)
C10	0.034 (4)	0.023 (3)	0.033 (4)	0.003 (3)	0.003 (3)	0.000 (3)
C8	0.053 (4)	0.036 (4)	0.026 (3)	0.009 (3)	0.017 (3)	−0.002 (3)
C19	0.043 (4)	0.033 (4)	0.025 (3)	0.002 (3)	0.008 (3)	−0.001 (3)
C12	0.043 (4)	0.021 (3)	0.036 (4)	−0.004 (3)	0.012 (3)	−0.007 (3)
C15	0.029 (4)	0.046 (4)	0.029 (3)	−0.002 (3)	0.000 (3)	0.007 (3)
C23	0.035 (4)	0.034 (4)	0.039 (4)	0.004 (3)	0.009 (3)	0.004 (3)
C16	0.041 (4)	0.059 (5)	0.024 (3)	0.002 (4)	0.000 (3)	−0.003 (3)
C7	0.041 (4)	0.054 (5)	0.038 (4)	0.011 (3)	0.013 (3)	0.003 (3)
C13	0.049 (4)	0.036 (4)	0.043 (4)	−0.006 (3)	0.022 (4)	−0.016 (3)
C25	0.034 (4)	0.036 (4)	0.051 (4)	0.003 (3)	0.000 (3)	−0.007 (3)
C6	0.036 (4)	0.048 (4)	0.040 (4)	0.000 (3)	0.011 (3)	0.007 (3)
C24	0.058 (5)	0.040 (4)	0.036 (4)	0.003 (4)	0.014 (4)	0.006 (3)
C17	0.044 (4)	0.044 (4)	0.031 (4)	−0.002 (3)	0.010 (3)	−0.006 (3)
C26	0.032 (4)	0.042 (4)	0.051 (4)	0.004 (3)	0.004 (3)	0.000 (4)
C3	0.042 (4)	0.043 (4)	0.050 (4)	−0.001 (3)	−0.006 (4)	−0.006 (4)
C2	0.039 (4)	0.065 (5)	0.066 (5)	0.001 (4)	−0.003 (4)	−0.004 (5)
C1	0.055 (6)	0.085 (7)	0.119 (9)	0.026 (5)	−0.037 (6)	−0.007 (7)

Geometric parameters (Å, º) top

O2—C10	1.240 (7)	C11—C14	1.498 (8)
O3—C5	1.463 (8)	C11—C10	1.450 (8)
O3—C4	1.360 (8)	C11—C12	1.361 (8)
F1—C25	1.359 (8)	C18—C21	1.501 (9)
O1—N1	1.444 (7)	C18—C19	1.524 (8)
O1—C27	1.349 (8)	C18—C17	1.527 (8)
O4—C4	1.203 (8)	C20—C19	1.514 (8)
N3—C9	1.357 (8)	C5—C6	1.504 (9)
N3—C10	1.407 (8)	C27—C26	1.401 (9)
N3—C8	1.472 (7)	C4—C3	1.487 (10)
N2—C20	1.461 (7)	C14—C15	1.516 (8)
N2—C15	1.477 (7)	C8—C7	1.500 (9)
N2—C16	1.448 (8)	C12—C13	1.500 (8)
N4—C9	1.309 (7)	C23—C24	1.373 (9)
N4—C12	1.379 (8)	C16—C17	1.515 (9)
N1—C21	1.305 (8)	C7—C6	1.527 (10)
C22—C21	1.423 (9)	C25—C24	1.392 (9)
C22—C27	1.385 (9)	C25—C26	1.374 (10)
C22—C23	1.412 (9)	C3—C2	1.515 (10)
C9—C5	1.497 (9)	C2—C1	1.506 (11)

C4—O3—C5	116.5 (5)	O1—C27—C22	110.4 (6)
C27—O1—N1	106.9 (5)	O1—C27—C26	125.7 (6)
C9—N3—C10	120.7 (5)	C22—C27—C26	123.9 (6)
C9—N3—C8	124.4 (5)	O3—C4—C3	109.8 (6)
C10—N3—C8	114.7 (5)	O4—C4—O3	122.5 (6)
C20—N2—C15	110.4 (5)	O4—C4—C3	127.7 (7)
C16—N2—C20	110.1 (5)	C11—C14—C15	111.8 (5)
C16—N2—C15	110.2 (5)	O2—C10—N3	119.7 (5)
C9—N4—C12	118.4 (5)	O2—C10—C11	124.3 (6)
C21—N1—O1	107.0 (5)	N3—C10—C11	116.0 (5)
C27—C22—C21	104.3 (5)	N3—C8—C7	112.9 (5)
C27—C22—C23	119.5 (6)	C20—C19—C18	110.0 (5)
C23—C22—C21	136.2 (6)	N4—C12—C13	112.9 (5)
N3—C9—C5	119.7 (5)	C11—C12—N4	122.8 (5)
N4—C9—N3	123.5 (6)	C11—C12—C13	124.4 (6)
N4—C9—C5	116.8 (6)	N2—C15—C14	112.2 (5)
C10—C11—C14	115.5 (5)	C24—C23—C22	118.2 (6)
C12—C11—C14	126.0 (5)	N2—C16—C17	112.3 (5)
C12—C11—C10	118.4 (6)	C8—C7—C6	109.9 (5)
C21—C18—C19	113.7 (5)	F1—C25—C24	117.9 (6)
C21—C18—C17	110.7 (5)	F1—C25—C26	116.9 (6)
C19—C18—C17	109.7 (5)	C26—C25—C24	125.2 (7)
N2—C20—C19	111.8 (5)	C5—C6—C7	108.9 (6)
O3—C5—C9	105.6 (5)	C23—C24—C25	119.5 (6)
O3—C5—C6	109.5 (5)	C16—C17—C18	110.4 (6)
C9—C5—C6	113.0 (6)	C25—C26—C27	113.6 (6)
N1—C21—C22	111.4 (6)	C4—C3—C2	114.9 (6)
N1—C21—C18	121.6 (6)	C1—C2—C3	111.0 (7)
C22—C21—C18	127.0 (5)

(PC8) top

Crystal data top

C₃₁H₄₁FN₄O₄	F(000) = 1184
M_r = 552.68	D_x = 1.258 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 26.953 (11) Å	Cell parameters from 1672 reflections
b = 10.080 (4) Å	θ = 2.3–24.0°
c = 10.753 (4) Å	µ = 0.09 mm⁻¹
β = 92.658 (12)°	T = 170 K
V = 2918 (2) Å³	Plate, colourless
Z = 4	0.08 × 0.05 × 0.03 mm

Data collection top

D8 VENTURE diffractometer	2336 reflections with I > 2σ(I)
φ and ω scans	R_int = 0.126
Absorption correction: multi-scan SADABS-2016/2 (Bruker,2016/2) was used for absorption correction. wR2(int) was 0.1208 before and 0.0718 after correction. The Ratio of minimum to maximum transmission is 0.7034. The λ/2 correction factor is Not present.	θ_max = 25.1°, θ_min = 2.2°
T_min = 0.524, T_max = 0.745	h = −32→32
14664 measured reflections	k = −11→11
5113 independent reflections	l = −11→12

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.083	H-atom parameters constrained
wR(F²) = 0.232	w = 1/[σ²(F_o²) + (0.1P)²] where P = (F_o² + 2F_c²)/3
S = 1.01	(Δ/σ)_max < 0.001
5113 reflections	Δρ_max = 0.28 e Å⁻³
363 parameters	Δρ_min = −0.29 e Å⁻³
0 restraints

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O3	0.20218 (11)	0.3695 (3)	0.3361 (3)	0.0421 (9)
O2	0.37225 (11)	0.5559 (3)	0.1468 (3)	0.0417 (9)
F1	0.85536 (11)	0.2285 (4)	0.1042 (3)	0.0709 (10)
O1	0.74808 (11)	0.4898 (4)	0.3437 (3)	0.0477 (10)
O4	0.14756 (13)	0.2013 (4)	0.3289 (3)	0.0567 (11)
N3	0.30498 (13)	0.4371 (4)	0.2026 (3)	0.0342 (10)
N4	0.30907 (14)	0.2933 (4)	0.3744 (3)	0.0371 (10)
N2	0.51960 (13)	0.4280 (4)	0.2669 (3)	0.0384 (11)
N1	0.69505 (14)	0.4849 (5)	0.3542 (4)	0.0487 (12)
C15	0.38172 (16)	0.4202 (5)	0.3268 (4)	0.0342 (12)
C18	0.35450 (17)	0.4767 (5)	0.2201 (4)	0.0345 (12)
C7	0.67865 (17)	0.3898 (5)	0.2810 (4)	0.0385 (12)
C16	0.35752 (17)	0.3316 (5)	0.3992 (4)	0.0359 (12)
C19	0.28506 (16)	0.3455 (5)	0.2796 (4)	0.0365 (12)
C8	0.62465 (15)	0.3602 (5)	0.2636 (4)	0.0370 (13)
H8	0.621401	0.268380	0.229018	0.044*
C4	0.71863 (16)	0.3266 (5)	0.2190 (4)	0.0363 (12)
C10	0.54238 (16)	0.3346 (5)	0.3568 (4)	0.0387 (13)
H10A	0.538883	0.243393	0.323395	0.046*
H10B	0.524534	0.338897	0.435085	0.046*
C14	0.43488 (15)	0.4597 (5)	0.3443 (4)	0.0371 (12)
H14A	0.447655	0.431059	0.427879	0.045*
H14B	0.437434	0.557534	0.340361	0.045*
C13	0.46690 (16)	0.3986 (5)	0.2457 (4)	0.0407 (13)
H13A	0.462189	0.301198	0.245300	0.049*
H13B	0.455627	0.432644	0.162777	0.049*
C11	0.54510 (16)	0.4215 (6)	0.1502 (4)	0.0453 (14)
H11A	0.529451	0.484767	0.089842	0.054*
H11B	0.541469	0.331184	0.114679	0.054*
C20	0.23309 (16)	0.2965 (5)	0.2524 (4)	0.0391 (13)
H20	0.231301	0.199512	0.271114	0.047*
C9	0.59680 (16)	0.3639 (5)	0.3846 (4)	0.0390 (13)
H9A	0.611035	0.297176	0.443673	0.047*
H9B	0.600513	0.452518	0.423626	0.047*
C3	0.76046 (18)	0.3949 (5)	0.2623 (4)	0.0392 (13)
C5	0.72317 (18)	0.2225 (5)	0.1347 (4)	0.0426 (13)
H5	0.694728	0.175521	0.103192	0.051*
C24	0.15949 (18)	0.3090 (6)	0.3658 (4)	0.0437 (14)
C17	0.38085 (17)	0.2656 (5)	0.5135 (4)	0.0427 (13)
H17A	0.363134	0.292719	0.586917	0.064*
H17B	0.415764	0.292320	0.523869	0.064*
H17C	0.378808	0.169080	0.504023	0.064*
C12	0.59981 (15)	0.4542 (5)	0.1693 (4)	0.0423 (14)
H12A	0.603621	0.546749	0.199126	0.051*
H12B	0.616154	0.446796	0.088977	0.051*
C26	0.08652 (17)	0.3265 (6)	0.5043 (4)	0.0477 (14)
H26A	0.098324	0.244662	0.547130	0.057*
H26B	0.062680	0.300151	0.435983	0.057*
C25	0.13022 (17)	0.3953 (6)	0.4495 (5)	0.0515 (15)
H25A	0.117951	0.473471	0.401545	0.062*
H25B	0.152655	0.427955	0.518344	0.062*
C22	0.22406 (17)	0.4661 (6)	0.0870 (4)	0.0493 (15)
H22A	0.209398	0.485344	0.002852	0.059*
H22B	0.207836	0.524277	0.147186	0.059*
C1	0.80991 (19)	0.2628 (6)	0.1441 (5)	0.0495 (15)
C21	0.21487 (18)	0.3212 (6)	0.1196 (4)	0.0478 (15)
H21A	0.178943	0.301125	0.109930	0.057*
H21B	0.232710	0.262670	0.062785	0.057*
C6	0.76968 (19)	0.1898 (6)	0.0985 (4)	0.0469 (14)
H6	0.774203	0.118011	0.042916	0.056*
C23	0.27883 (17)	0.4941 (6)	0.0905 (4)	0.0468 (14)
H23A	0.293176	0.456424	0.015074	0.056*
H23B	0.284156	0.591236	0.089393	0.056*
C2	0.80803 (18)	0.3651 (6)	0.2266 (5)	0.0485 (14)
H2	0.836712	0.411795	0.257021	0.058*
C28	0.01920 (17)	0.3393 (6)	0.6606 (4)	0.0540 (16)
H28A	0.034124	0.262674	0.706109	0.065*
H28B	−0.004863	0.304079	0.596466	0.065*
C27	0.05977 (18)	0.4125 (6)	0.5963 (5)	0.0525 (15)
H27A	0.084278	0.446228	0.659991	0.063*
H27B	0.045049	0.489871	0.551514	0.063*
C29	−0.00855 (19)	0.4233 (6)	0.7509 (5)	0.0593 (16)
H29A	0.015646	0.462245	0.812704	0.071*
H29B	−0.025004	0.497379	0.704726	0.071*
C30	−0.0471 (2)	0.3476 (7)	0.8189 (5)	0.0698 (19)
H30A	−0.030375	0.277937	0.870445	0.084*
H30B	−0.069880	0.303130	0.757291	0.084*
C31	−0.0775 (2)	0.4360 (8)	0.9028 (6)	0.097 (3)
H31A	−0.095681	0.502121	0.851754	0.145*
H31B	−0.055138	0.481184	0.963511	0.145*
H31C	−0.101106	0.381276	0.946688	0.145*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O3	0.040 (2)	0.050 (2)	0.0365 (18)	−0.0003 (17)	0.0040 (15)	−0.0024 (17)
O2	0.054 (2)	0.042 (2)	0.0298 (17)	−0.0045 (17)	0.0072 (15)	0.0059 (17)
F1	0.0516 (19)	0.084 (3)	0.079 (2)	0.0131 (18)	0.0185 (17)	−0.001 (2)
O1	0.045 (2)	0.053 (3)	0.046 (2)	−0.0016 (18)	0.0005 (16)	−0.0082 (19)
O4	0.053 (2)	0.064 (3)	0.053 (2)	−0.017 (2)	0.0058 (18)	−0.008 (2)
N3	0.041 (2)	0.040 (3)	0.0226 (19)	0.002 (2)	0.0025 (16)	0.0032 (19)
N4	0.043 (3)	0.042 (3)	0.027 (2)	−0.005 (2)	0.0024 (18)	0.0013 (19)
N2	0.039 (2)	0.054 (3)	0.0228 (19)	0.002 (2)	0.0018 (16)	−0.001 (2)
N1	0.047 (3)	0.055 (3)	0.044 (3)	0.000 (2)	0.005 (2)	−0.008 (2)
C15	0.041 (3)	0.038 (3)	0.023 (2)	0.003 (2)	0.002 (2)	−0.002 (2)
C18	0.044 (3)	0.033 (3)	0.027 (2)	−0.002 (2)	0.007 (2)	−0.001 (2)
C7	0.045 (3)	0.039 (3)	0.032 (3)	0.004 (3)	0.005 (2)	0.002 (2)
C16	0.040 (3)	0.043 (3)	0.025 (2)	−0.002 (2)	0.004 (2)	0.001 (2)
C19	0.041 (3)	0.043 (3)	0.026 (2)	−0.002 (2)	0.001 (2)	0.000 (2)
C8	0.036 (3)	0.047 (4)	0.028 (2)	−0.001 (2)	0.004 (2)	−0.004 (2)
C4	0.035 (3)	0.043 (3)	0.031 (2)	−0.002 (2)	0.001 (2)	0.000 (2)
C10	0.046 (3)	0.045 (4)	0.025 (2)	−0.002 (3)	0.008 (2)	0.000 (2)
C14	0.044 (3)	0.041 (3)	0.026 (2)	−0.006 (2)	0.001 (2)	0.000 (2)
C13	0.040 (3)	0.055 (4)	0.027 (2)	−0.005 (3)	0.004 (2)	−0.006 (2)
C11	0.048 (3)	0.066 (4)	0.022 (2)	0.002 (3)	0.005 (2)	0.002 (3)
C20	0.040 (3)	0.042 (4)	0.035 (3)	0.000 (2)	0.007 (2)	−0.006 (2)
C9	0.042 (3)	0.050 (4)	0.025 (2)	0.000 (2)	0.003 (2)	−0.002 (2)
C3	0.046 (3)	0.041 (4)	0.031 (3)	0.007 (3)	0.003 (2)	0.005 (2)
C5	0.047 (3)	0.048 (4)	0.033 (3)	−0.001 (3)	0.002 (2)	0.005 (3)
C24	0.038 (3)	0.056 (4)	0.037 (3)	−0.006 (3)	−0.001 (2)	0.004 (3)
C17	0.053 (3)	0.043 (4)	0.032 (3)	−0.004 (3)	−0.001 (2)	0.007 (2)
C12	0.041 (3)	0.060 (4)	0.027 (2)	0.004 (3)	0.006 (2)	0.003 (2)
C26	0.040 (3)	0.061 (4)	0.042 (3)	0.000 (3)	0.001 (2)	0.005 (3)
C25	0.044 (3)	0.068 (4)	0.043 (3)	0.005 (3)	0.007 (2)	0.001 (3)
C22	0.047 (3)	0.070 (5)	0.030 (3)	0.008 (3)	−0.003 (2)	−0.001 (3)
C1	0.041 (3)	0.061 (4)	0.047 (3)	0.010 (3)	0.016 (3)	0.006 (3)
C21	0.044 (3)	0.067 (4)	0.032 (3)	−0.007 (3)	−0.005 (2)	−0.007 (3)
C6	0.051 (3)	0.054 (4)	0.036 (3)	0.005 (3)	0.010 (2)	0.001 (3)
C23	0.053 (3)	0.058 (4)	0.028 (3)	0.006 (3)	−0.004 (2)	0.004 (3)
C2	0.041 (3)	0.055 (4)	0.049 (3)	−0.001 (3)	0.001 (2)	0.009 (3)
C28	0.040 (3)	0.082 (5)	0.040 (3)	0.003 (3)	0.006 (2)	0.005 (3)
C27	0.047 (3)	0.065 (4)	0.046 (3)	0.005 (3)	0.009 (2)	0.005 (3)
C29	0.057 (3)	0.074 (5)	0.048 (3)	−0.002 (3)	0.015 (3)	0.008 (3)
C30	0.060 (4)	0.098 (6)	0.053 (3)	0.008 (4)	0.016 (3)	0.013 (4)
C31	0.083 (5)	0.127 (7)	0.084 (5)	0.007 (5)	0.041 (4)	0.005 (5)

Geometric parameters (Å, º) top

O3—C20	1.454 (5)	C3—C2	1.388 (6)
O3—C24	1.354 (6)	C5—H5	0.9500
O2—C18	1.234 (5)	C5—C6	1.370 (6)
F1—C1	1.361 (5)	C24—C25	1.502 (7)
O1—N1	1.440 (5)	C17—H17A	0.9800
O1—C3	1.349 (6)	C17—H17B	0.9800
O4—C24	1.195 (6)	C17—H17C	0.9800
N3—C18	1.397 (6)	C12—H12A	0.9900
N3—C19	1.366 (6)	C12—H12B	0.9900
N3—C23	1.484 (6)	C26—H26A	0.9900
N4—C16	1.376 (6)	C26—H26B	0.9900
N4—C19	1.294 (5)	C26—C25	1.510 (7)
N2—C10	1.464 (6)	C26—C27	1.521 (7)
N2—C13	1.458 (6)	C25—H25A	0.9900
N2—C11	1.460 (5)	C25—H25B	0.9900
N1—C7	1.304 (6)	C22—H22A	0.9900
C15—C18	1.449 (6)	C22—H22B	0.9900
C15—C16	1.369 (6)	C22—C21	1.525 (7)
C15—C14	1.491 (6)	C22—C23	1.502 (6)
C7—C8	1.489 (6)	C1—C6	1.381 (7)
C7—C4	1.442 (6)	C1—C2	1.363 (7)
C16—C17	1.509 (6)	C21—H21A	0.9900
C19—C20	1.501 (6)	C21—H21B	0.9900
C8—H8	1.0000	C6—H6	0.9500
C8—C9	1.532 (6)	C23—H23A	0.9900
C8—C12	1.521 (6)	C23—H23B	0.9900
C4—C3	1.383 (6)	C2—H2	0.9500
C4—C5	1.396 (7)	C28—H28A	0.9900
C10—H10A	0.9900	C28—H28B	0.9900
C10—H10B	0.9900	C28—C27	1.513 (7)
C10—C9	1.512 (6)	C28—C29	1.513 (7)
C14—H14A	0.9900	C27—H27A	0.9900
C14—H14B	0.9900	C27—H27B	0.9900
C14—C13	1.527 (6)	C29—H29A	0.9900
C13—H13A	0.9900	C29—H29B	0.9900
C13—H13B	0.9900	C29—C30	1.505 (7)
C11—H11A	0.9900	C30—H30A	0.9900
C11—H11B	0.9900	C30—H30B	0.9900
C11—C12	1.516 (6)	C30—C31	1.532 (8)
C20—H20	1.0000	C31—H31A	0.9800
C20—C21	1.508 (6)	C31—H31B	0.9800
C9—H9A	0.9900	C31—H31C	0.9800
C9—H9B	0.9900

C24—O3—C20	115.8 (4)	C16—C17—H17B	109.5
C3—O1—N1	107.6 (3)	C16—C17—H17C	109.5
C18—N3—C23	114.5 (4)	H17A—C17—H17B	109.5
C19—N3—C18	120.7 (4)	H17A—C17—H17C	109.5
C19—N3—C23	124.6 (4)	H17B—C17—H17C	109.5
C19—N4—C16	118.3 (4)	C8—C12—H12A	109.6
C13—N2—C10	110.4 (4)	C8—C12—H12B	109.6
C13—N2—C11	110.5 (3)	C11—C12—C8	110.5 (4)
C11—N2—C10	109.8 (4)	C11—C12—H12A	109.6
C7—N1—O1	106.8 (4)	C11—C12—H12B	109.6
C18—C15—C14	116.3 (4)	H12A—C12—H12B	108.1
C16—C15—C18	118.0 (4)	H26A—C26—H26B	107.7
C16—C15—C14	125.6 (4)	C25—C26—H26A	108.9
O2—C18—N3	119.6 (4)	C25—C26—H26B	108.9
O2—C18—C15	124.3 (4)	C25—C26—C27	113.2 (5)
N3—C18—C15	116.1 (4)	C27—C26—H26A	108.9
N1—C7—C8	121.7 (4)	C27—C26—H26B	108.9
N1—C7—C4	111.3 (4)	C24—C25—C26	114.1 (5)
C4—C7—C8	126.9 (5)	C24—C25—H25A	108.7
N4—C16—C17	112.9 (4)	C24—C25—H25B	108.7
C15—C16—N4	123.1 (4)	C26—C25—H25A	108.7
C15—C16—C17	124.0 (4)	C26—C25—H25B	108.7
N3—C19—C20	119.6 (4)	H25A—C25—H25B	107.6
N4—C19—N3	123.8 (4)	H22A—C22—H22B	108.1
N4—C19—C20	116.6 (4)	C21—C22—H22A	109.6
C7—C8—H8	107.5	C21—C22—H22B	109.6
C7—C8—C9	113.8 (4)	C23—C22—H22A	109.6
C7—C8—C12	110.9 (4)	C23—C22—H22B	109.6
C9—C8—H8	107.5	C23—C22—C21	110.1 (4)
C12—C8—H8	107.5	F1—C1—C6	117.1 (5)
C12—C8—C9	109.5 (4)	F1—C1—C2	117.3 (5)
C3—C4—C7	103.8 (4)	C2—C1—C6	125.6 (5)
C3—C4—C5	119.9 (4)	C20—C21—C22	109.0 (4)
C5—C4—C7	136.3 (5)	C20—C21—H21A	109.9
N2—C10—H10A	109.2	C20—C21—H21B	109.9
N2—C10—H10B	109.2	C22—C21—H21A	109.9
N2—C10—C9	112.2 (4)	C22—C21—H21B	109.9
H10A—C10—H10B	107.9	H21A—C21—H21B	108.3
C9—C10—H10A	109.2	C5—C6—C1	119.0 (5)
C9—C10—H10B	109.2	C5—C6—H6	120.5
C15—C14—H14A	109.2	C1—C6—H6	120.5
C15—C14—H14B	109.2	N3—C23—C22	112.1 (4)
C15—C14—C13	112.0 (4)	N3—C23—H23A	109.2
H14A—C14—H14B	107.9	N3—C23—H23B	109.2
C13—C14—H14A	109.2	C22—C23—H23A	109.2
C13—C14—H14B	109.2	C22—C23—H23B	109.2
N2—C13—C14	112.8 (4)	H23A—C23—H23B	107.9
N2—C13—H13A	109.0	C3—C2—H2	123.0
N2—C13—H13B	109.0	C1—C2—C3	114.0 (5)
C14—C13—H13A	109.0	C1—C2—H2	123.0
C14—C13—H13B	109.0	H28A—C28—H28B	107.6
H13A—C13—H13B	107.8	C27—C28—H28A	108.7
N2—C11—H11A	109.3	C27—C28—H28B	108.7
N2—C11—H11B	109.3	C27—C28—C29	114.2 (5)
N2—C11—C12	111.6 (4)	C29—C28—H28A	108.7
H11A—C11—H11B	108.0	C29—C28—H28B	108.7
C12—C11—H11A	109.3	C26—C27—H27A	108.9
C12—C11—H11B	109.3	C26—C27—H27B	108.9
O3—C20—C19	105.6 (4)	C28—C27—C26	113.2 (5)
O3—C20—H20	109.6	C28—C27—H27A	108.9
O3—C20—C21	109.4 (4)	C28—C27—H27B	108.9
C19—C20—H20	109.6	H27A—C27—H27B	107.7
C19—C20—C21	113.0 (4)	C28—C29—H29A	108.8
C21—C20—H20	109.6	C28—C29—H29B	108.8
C8—C9—H9A	109.7	H29A—C29—H29B	107.7
C8—C9—H9B	109.7	C30—C29—C28	113.6 (5)
C10—C9—C8	109.6 (4)	C30—C29—H29A	108.8
C10—C9—H9A	109.7	C30—C29—H29B	108.8
C10—C9—H9B	109.7	C29—C30—H30A	109.0
H9A—C9—H9B	108.2	C29—C30—H30B	109.0
O1—C3—C4	110.4 (4)	C29—C30—C31	113.0 (6)
O1—C3—C2	126.3 (5)	H30A—C30—H30B	107.8
C4—C3—C2	123.2 (5)	C31—C30—H30A	109.0
C4—C5—H5	120.8	C31—C30—H30B	109.0
C6—C5—C4	118.3 (5)	C30—C31—H31A	109.5
C6—C5—H5	120.8	C30—C31—H31B	109.5
O3—C24—C25	110.9 (5)	C30—C31—H31C	109.5
O4—C24—O3	123.3 (5)	H31A—C31—H31B	109.5
O4—C24—C25	125.8 (5)	H31A—C31—H31C	109.5
C16—C17—H17A	109.5	H31B—C31—H31C	109.5

(PC12) top

Crystal data top

C₃₅H₄₉FN₄O₄	F(000) = 1312
M_r = 608.78	D_x = 1.226 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 31.029 (3) Å	Cell parameters from 3105 reflections
b = 9.9381 (10) Å	θ = 2.4–23.9°
c = 10.8384 (11) Å	µ = 0.08 mm⁻¹
β = 99.374 (3)°	T = 170 K
V = 3297.6 (6) Å³	Plate, colourless
Z = 4	0.15 × 0.08 × 0.03 mm

Data collection top

Bruker APEX-II CCD diffractometer	3505 reflections with I > 2σ(I)
φ and ω scans	R_int = 0.093
Absorption correction: multi-scan SADABS-2016/2 (Bruker,2016/2) was used for absorption correction. wR2(int) was 0.1229 before and 0.0630 after correction. The Ratio of minimum to maximum transmission is 0.8944. The λ/2 correction factor is Not present.	θ_max = 26.4°, θ_min = 2.0°
T_min = 0.667, T_max = 0.745	h = −38→38
24015 measured reflections	k = −12→11
6579 independent reflections	l = −13→13

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.059	H-atom parameters constrained
wR(F²) = 0.148	w = 1/[σ²(F_o²) + (0.0493P)² + 0.8196P] where P = (F_o² + 2F_c²)/3
S = 1.05	(Δ/σ)_max = 0.001
6579 reflections	Δρ_max = 0.25 e Å⁻³
399 parameters	Δρ_min = −0.28 e Å⁻³
0 restraints

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O3	0.23640 (6)	0.62974 (18)	0.24745 (16)	0.0325 (5)
O2	0.38649 (6)	0.44427 (18)	0.10713 (17)	0.0349 (5)
O1	0.71757 (6)	0.50851 (19)	0.41873 (18)	0.0393 (5)
F1	0.81205 (5)	0.76964 (19)	0.20827 (18)	0.0603 (5)
O4	0.18864 (6)	0.8020 (2)	0.22467 (19)	0.0460 (6)
N3	0.32698 (7)	0.5633 (2)	0.14367 (19)	0.0270 (5)
N2	0.51639 (7)	0.5718 (2)	0.27161 (19)	0.0295 (5)
N4	0.33060 (7)	0.7076 (2)	0.3170 (2)	0.0294 (5)
N1	0.67094 (7)	0.5152 (2)	0.4140 (2)	0.0382 (6)
C18	0.37097 (8)	0.5241 (3)	0.1757 (2)	0.0275 (6)
C16	0.37348 (8)	0.6690 (3)	0.3557 (2)	0.0274 (6)
C6	0.69174 (8)	0.6726 (3)	0.2839 (2)	0.0282 (6)
C7	0.65659 (9)	0.6110 (3)	0.3340 (2)	0.0293 (6)
C15	0.39450 (8)	0.5807 (3)	0.2900 (2)	0.0266 (6)
C19	0.30949 (8)	0.6551 (3)	0.2146 (2)	0.0276 (6)
C1	0.72857 (9)	0.6046 (3)	0.3399 (2)	0.0320 (7)
C8	0.60890 (8)	0.6406 (3)	0.3009 (2)	0.0291 (6)
H8	0.605959	0.734230	0.266770	0.035*
C5	0.69571 (9)	0.7769 (3)	0.2005 (3)	0.0344 (7)
H5	0.670700	0.824393	0.160648	0.041*
C24	0.19887 (9)	0.6908 (3)	0.2646 (3)	0.0351 (7)
C14	0.44173 (8)	0.5400 (3)	0.3223 (2)	0.0303 (6)
H14A	0.443884	0.440726	0.317994	0.036*
H14B	0.453068	0.567784	0.409203	0.036*
C9	0.58452 (8)	0.6350 (3)	0.4115 (2)	0.0327 (7)
H9A	0.587890	0.544497	0.450050	0.039*
H9B	0.597105	0.701636	0.475157	0.039*
C10	0.53639 (8)	0.6648 (3)	0.3697 (2)	0.0311 (6)
H10A	0.520924	0.657719	0.442449	0.037*
H10B	0.533037	0.758204	0.337818	0.037*
C12	0.58690 (8)	0.5460 (3)	0.1982 (2)	0.0345 (7)
H12A	0.601277	0.554608	0.123471	0.041*
H12B	0.590174	0.451764	0.227835	0.041*
C20	0.26335 (8)	0.7037 (3)	0.1727 (2)	0.0304 (6)
H20	0.261611	0.802157	0.190352	0.036*
C23	0.30402 (9)	0.5060 (3)	0.0249 (2)	0.0369 (7)
H23A	0.309117	0.407624	0.024659	0.044*
H23B	0.316364	0.545343	−0.045693	0.044*
C2	0.77041 (9)	0.6328 (3)	0.3184 (3)	0.0387 (7)
H2	0.795528	0.585001	0.357066	0.046*
C17	0.39397 (9)	0.7348 (3)	0.4753 (2)	0.0368 (7)
H17A	0.390123	0.832483	0.467924	0.055*
H17B	0.425206	0.713405	0.492024	0.055*
H17C	0.379972	0.701481	0.544126	0.055*
C26	0.13481 (9)	0.6752 (3)	0.3800 (3)	0.0384 (7)
H26A	0.113305	0.697431	0.304899	0.046*
H26B	0.144897	0.760833	0.421738	0.046*
C22	0.25543 (9)	0.5324 (3)	0.0056 (3)	0.0408 (8)
H22A	0.241427	0.472848	0.060704	0.049*
H22B	0.242464	0.512828	−0.082198	0.049*
C13	0.46994 (8)	0.6026 (3)	0.2346 (2)	0.0331 (7)
H13A	0.460063	0.569024	0.148671	0.040*
H13B	0.465917	0.701475	0.233711	0.040*
C11	0.53879 (8)	0.5799 (3)	0.1636 (2)	0.0372 (7)
H11A	0.535685	0.671938	0.128417	0.045*
H11B	0.524962	0.516604	0.098374	0.045*
C4	0.73661 (9)	0.8091 (3)	0.1775 (3)	0.0393 (7)
H4	0.740553	0.880520	0.122158	0.047*
C21	0.24740 (9)	0.6783 (3)	0.0356 (3)	0.0400 (7)
H21A	0.263063	0.737756	−0.015515	0.048*
H21B	0.215800	0.698541	0.015307	0.048*
C25	0.17344 (9)	0.6047 (3)	0.3395 (3)	0.0391 (7)
H25A	0.193185	0.572780	0.414896	0.047*
H25B	0.162760	0.524619	0.289301	0.047*
C27	0.11234 (9)	0.5918 (3)	0.4686 (3)	0.0411 (7)
H27A	0.099873	0.509990	0.424294	0.049*
H27B	0.134381	0.562604	0.540128	0.049*
C28	0.07640 (9)	0.6671 (3)	0.5176 (3)	0.0437 (8)
H28A	0.054196	0.694436	0.445798	0.052*
H28B	0.088881	0.750152	0.559495	0.052*
C3	0.77208 (9)	0.7360 (3)	0.2362 (3)	0.0415 (8)
C30	0.01881 (9)	0.6664 (3)	0.6596 (3)	0.0437 (8)
H30A	0.032191	0.747344	0.703314	0.052*
H30B	−0.003114	0.697353	0.588511	0.052*
C29	0.05399 (9)	0.5887 (3)	0.6084 (3)	0.0452 (8)
H29A	0.076265	0.559329	0.679270	0.054*
H29B	0.040768	0.506922	0.565911	0.054*
C31	−0.00444 (10)	0.5882 (3)	0.7488 (3)	0.0485 (8)
H31A	−0.018033	0.507578	0.704913	0.058*
H31B	0.017481	0.556698	0.819627	0.058*
C32	−0.03923 (9)	0.6663 (3)	0.8001 (3)	0.0460 (8)
H32A	−0.060555	0.700557	0.729105	0.055*
H32B	−0.025422	0.745154	0.846471	0.055*
C33	−0.06374 (10)	0.5868 (3)	0.8862 (3)	0.0505 (8)
H33A	−0.078069	0.509001	0.839343	0.061*
H33B	−0.042358	0.550955	0.956328	0.061*
C34	−0.09781 (11)	0.6657 (4)	0.9394 (3)	0.0609 (10)
H34A	−0.117962	0.707149	0.869438	0.073*
H34B	−0.083186	0.739590	0.991451	0.073*
C35	−0.12440 (12)	0.5838 (5)	1.0178 (4)	0.0824 (13)
H35A	−0.139051	0.510152	0.967317	0.124*
H35B	−0.146325	0.641631	1.046663	0.124*
H35C	−0.105028	0.546523	1.090204	0.124*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O3	0.0290 (10)	0.0363 (11)	0.0338 (11)	0.0021 (9)	0.0094 (9)	0.0045 (9)
O2	0.0444 (11)	0.0288 (11)	0.0320 (11)	0.0025 (9)	0.0079 (9)	−0.0044 (9)
O1	0.0362 (11)	0.0387 (12)	0.0423 (12)	0.0036 (9)	0.0045 (9)	0.0072 (10)
F1	0.0382 (10)	0.0704 (13)	0.0772 (13)	−0.0099 (9)	0.0238 (10)	0.0012 (11)
O4	0.0431 (12)	0.0437 (13)	0.0526 (13)	0.0107 (10)	0.0113 (10)	0.0099 (11)
N3	0.0327 (12)	0.0256 (12)	0.0225 (11)	−0.0022 (10)	0.0041 (10)	−0.0004 (10)
N2	0.0296 (12)	0.0335 (13)	0.0253 (12)	−0.0011 (10)	0.0044 (10)	−0.0004 (10)
N4	0.0327 (13)	0.0312 (13)	0.0247 (12)	0.0023 (10)	0.0063 (10)	0.0003 (10)
N1	0.0324 (13)	0.0407 (15)	0.0422 (15)	−0.0005 (11)	0.0082 (11)	0.0046 (12)
C18	0.0358 (15)	0.0220 (14)	0.0260 (15)	−0.0004 (12)	0.0093 (12)	0.0033 (12)
C16	0.0322 (15)	0.0238 (14)	0.0269 (15)	0.0003 (12)	0.0071 (12)	0.0012 (12)
C6	0.0329 (15)	0.0265 (14)	0.0266 (15)	−0.0021 (12)	0.0091 (12)	−0.0036 (12)
C7	0.0351 (15)	0.0263 (15)	0.0268 (15)	−0.0002 (12)	0.0060 (12)	−0.0012 (12)
C15	0.0308 (14)	0.0249 (14)	0.0252 (14)	−0.0023 (12)	0.0076 (12)	0.0017 (12)
C19	0.0311 (14)	0.0271 (14)	0.0257 (15)	0.0006 (12)	0.0085 (12)	0.0010 (13)
C1	0.0384 (16)	0.0299 (15)	0.0281 (15)	0.0005 (13)	0.0067 (13)	−0.0002 (13)
C8	0.0308 (14)	0.0296 (15)	0.0269 (15)	−0.0004 (12)	0.0050 (12)	0.0016 (12)
C5	0.0369 (16)	0.0328 (16)	0.0334 (16)	−0.0002 (13)	0.0048 (13)	−0.0022 (13)
C24	0.0302 (15)	0.0397 (18)	0.0351 (17)	0.0011 (14)	0.0041 (13)	−0.0032 (14)
C14	0.0348 (15)	0.0312 (15)	0.0254 (15)	0.0007 (12)	0.0068 (12)	−0.0002 (12)
C9	0.0353 (15)	0.0350 (16)	0.0282 (15)	0.0008 (13)	0.0064 (13)	0.0004 (13)
C10	0.0367 (15)	0.0299 (15)	0.0283 (15)	0.0019 (13)	0.0104 (13)	−0.0010 (13)
C12	0.0356 (16)	0.0429 (17)	0.0262 (15)	−0.0018 (14)	0.0085 (13)	−0.0045 (13)
C20	0.0310 (15)	0.0323 (16)	0.0284 (15)	0.0003 (12)	0.0060 (12)	0.0058 (13)
C23	0.0442 (17)	0.0383 (17)	0.0267 (15)	−0.0036 (14)	0.0018 (13)	−0.0054 (13)
C2	0.0298 (15)	0.0440 (18)	0.0427 (18)	0.0037 (14)	0.0070 (14)	−0.0039 (15)
C17	0.0421 (17)	0.0345 (16)	0.0324 (16)	−0.0005 (14)	0.0015 (13)	−0.0090 (14)
C26	0.0312 (15)	0.0459 (18)	0.0393 (17)	0.0014 (14)	0.0093 (14)	−0.0032 (15)
C22	0.0395 (17)	0.052 (2)	0.0283 (16)	−0.0060 (15)	−0.0013 (13)	−0.0040 (15)
C13	0.0310 (15)	0.0414 (17)	0.0270 (15)	0.0008 (13)	0.0055 (12)	0.0052 (13)
C11	0.0362 (16)	0.055 (2)	0.0217 (15)	−0.0044 (15)	0.0083 (13)	−0.0036 (14)
C4	0.0426 (17)	0.0394 (17)	0.0378 (17)	−0.0059 (15)	0.0121 (14)	−0.0013 (14)
C21	0.0374 (16)	0.053 (2)	0.0292 (16)	0.0020 (15)	0.0036 (13)	0.0066 (15)
C25	0.0358 (16)	0.0422 (18)	0.0404 (17)	−0.0025 (14)	0.0100 (14)	−0.0008 (15)
C27	0.0341 (16)	0.0502 (19)	0.0398 (17)	−0.0008 (15)	0.0085 (14)	−0.0026 (16)
C28	0.0348 (16)	0.056 (2)	0.0422 (18)	−0.0005 (15)	0.0122 (14)	−0.0024 (16)
C3	0.0338 (17)	0.0472 (19)	0.0459 (19)	−0.0085 (15)	0.0139 (15)	−0.0083 (16)
C30	0.0348 (16)	0.056 (2)	0.0430 (18)	−0.0002 (15)	0.0138 (14)	−0.0024 (16)
C29	0.0410 (17)	0.051 (2)	0.0448 (19)	−0.0027 (15)	0.0115 (15)	−0.0028 (16)
C31	0.0433 (18)	0.060 (2)	0.0450 (18)	−0.0019 (16)	0.0170 (15)	−0.0016 (17)
C32	0.0392 (17)	0.058 (2)	0.0420 (18)	−0.0043 (16)	0.0113 (15)	−0.0063 (17)
C33	0.0437 (18)	0.062 (2)	0.050 (2)	−0.0011 (17)	0.0200 (16)	−0.0034 (18)
C34	0.0458 (19)	0.085 (3)	0.055 (2)	−0.006 (2)	0.0177 (17)	−0.007 (2)
C35	0.064 (2)	0.114 (4)	0.079 (3)	−0.009 (2)	0.042 (2)	−0.002 (3)

Geometric parameters (Å, º) top

O3—C24	1.353 (3)	C2—C3	1.365 (4)
O3—C20	1.455 (3)	C17—H17A	0.9800
O2—C18	1.237 (3)	C17—H17B	0.9800
O1—N1	1.441 (3)	C17—H17C	0.9800
O1—C1	1.361 (3)	C26—H26A	0.9900
F1—C3	1.366 (3)	C26—H26B	0.9900
O4—C24	1.210 (3)	C26—C25	1.514 (4)
N3—C18	1.408 (3)	C26—C27	1.521 (4)
N3—C19	1.361 (3)	C22—H22A	0.9900
N3—C23	1.481 (3)	C22—H22B	0.9900
N2—C10	1.468 (3)	C22—C21	1.515 (4)
N2—C13	1.464 (3)	C13—H13A	0.9900
N2—C11	1.458 (3)	C13—H13B	0.9900
N4—C16	1.382 (3)	C11—H11A	0.9900
N4—C19	1.302 (3)	C11—H11B	0.9900
N1—C7	1.315 (3)	C4—H4	0.9500
C18—C15	1.446 (3)	C4—C3	1.384 (4)
C16—C15	1.362 (4)	C21—H21A	0.9900
C16—C17	1.498 (3)	C21—H21B	0.9900
C6—C7	1.433 (4)	C25—H25A	0.9900
C6—C1	1.380 (4)	C25—H25B	0.9900
C6—C5	1.393 (4)	C27—H27A	0.9900
C7—C8	1.494 (4)	C27—H27B	0.9900
C15—C14	1.505 (3)	C27—C28	1.510 (4)
C19—C20	1.509 (4)	C28—H28A	0.9900
C1—C2	1.385 (4)	C28—H28B	0.9900
C8—H8	1.0000	C28—C29	1.510 (4)
C8—C9	1.519 (4)	C30—H30A	0.9900
C8—C12	1.530 (3)	C30—H30B	0.9900
C5—H5	0.9500	C30—C29	1.514 (4)
C5—C4	1.371 (4)	C30—C31	1.512 (4)
C24—C25	1.491 (4)	C29—H29A	0.9900
C14—H14A	0.9900	C29—H29B	0.9900
C14—H14B	0.9900	C31—H31A	0.9900
C14—C13	1.526 (4)	C31—H31B	0.9900
C9—H9A	0.9900	C31—C32	1.508 (4)
C9—H9B	0.9900	C32—H32A	0.9900
C9—C10	1.517 (3)	C32—H32B	0.9900
C10—H10A	0.9900	C32—C33	1.518 (4)
C10—H10B	0.9900	C33—H33A	0.9900
C12—H12A	0.9900	C33—H33B	0.9900
C12—H12B	0.9900	C33—C34	1.504 (4)
C12—C11	1.516 (4)	C34—H34A	0.9900
C20—H20	1.0000	C34—H34B	0.9900
C20—C21	1.509 (4)	C34—C35	1.515 (5)
C23—H23A	0.9900	C35—H35A	0.9800
C23—H23B	0.9900	C35—H35B	0.9800
C23—C22	1.511 (4)	C35—H35C	0.9800
C2—H2	0.9500

C24—O3—C20	115.8 (2)	C27—C26—H26A	108.9
C1—O1—N1	107.33 (19)	C27—C26—H26B	108.9
C18—N3—C23	114.7 (2)	C23—C22—H22A	109.8
C19—N3—C18	120.4 (2)	C23—C22—H22B	109.8
C19—N3—C23	124.7 (2)	C23—C22—C21	109.4 (2)
C13—N2—C10	110.4 (2)	H22A—C22—H22B	108.2
C11—N2—C10	110.3 (2)	C21—C22—H22A	109.8
C11—N2—C13	110.2 (2)	C21—C22—H22B	109.8
C19—N4—C16	118.3 (2)	N2—C13—C14	112.5 (2)
C7—N1—O1	106.7 (2)	N2—C13—H13A	109.1
O2—C18—N3	119.1 (2)	N2—C13—H13B	109.1
O2—C18—C15	125.0 (2)	C14—C13—H13A	109.1
N3—C18—C15	115.9 (2)	C14—C13—H13B	109.1
N4—C16—C17	113.2 (2)	H13A—C13—H13B	107.8
C15—C16—N4	122.6 (2)	N2—C11—C12	111.6 (2)
C15—C16—C17	124.2 (2)	N2—C11—H11A	109.3
C1—C6—C7	104.5 (2)	N2—C11—H11B	109.3
C1—C6—C5	119.7 (2)	C12—C11—H11A	109.3
C5—C6—C7	135.8 (2)	C12—C11—H11B	109.3
N1—C7—C6	111.2 (2)	H11A—C11—H11B	108.0
N1—C7—C8	121.1 (2)	C5—C4—H4	120.5
C6—C7—C8	127.6 (2)	C5—C4—C3	119.0 (3)
C18—C15—C14	115.5 (2)	C3—C4—H4	120.5
C16—C15—C18	118.7 (2)	C20—C21—C22	109.4 (2)
C16—C15—C14	125.7 (2)	C20—C21—H21A	109.8
N3—C19—C20	119.4 (2)	C20—C21—H21B	109.8
N4—C19—N3	123.9 (2)	C22—C21—H21A	109.8
N4—C19—C20	116.7 (2)	C22—C21—H21B	109.8
O1—C1—C6	110.2 (2)	H21A—C21—H21B	108.2
O1—C1—C2	125.8 (2)	C24—C25—C26	114.0 (2)
C6—C1—C2	123.9 (3)	C24—C25—H25A	108.8
C7—C8—H8	107.4	C24—C25—H25B	108.8
C7—C8—C9	113.9 (2)	C26—C25—H25A	108.8
C7—C8—C12	111.1 (2)	C26—C25—H25B	108.8
C9—C8—H8	107.4	H25A—C25—H25B	107.7
C9—C8—C12	109.3 (2)	C26—C27—H27A	109.0
C12—C8—H8	107.4	C26—C27—H27B	109.0
C6—C5—H5	120.9	H27A—C27—H27B	107.8
C4—C5—C6	118.3 (3)	C28—C27—C26	113.1 (3)
C4—C5—H5	120.9	C28—C27—H27A	109.0
O3—C24—C25	111.2 (2)	C28—C27—H27B	109.0
O4—C24—O3	122.8 (3)	C27—C28—H28A	108.6
O4—C24—C25	126.0 (3)	C27—C28—H28B	108.6
C15—C14—H14A	109.1	C27—C28—C29	114.8 (3)
C15—C14—H14B	109.1	H28A—C28—H28B	107.6
C15—C14—C13	112.4 (2)	C29—C28—H28A	108.6
H14A—C14—H14B	107.9	C29—C28—H28B	108.6
C13—C14—H14A	109.1	F1—C3—C4	116.9 (3)
C13—C14—H14B	109.1	C2—C3—F1	117.5 (3)
C8—C9—H9A	109.6	C2—C3—C4	125.6 (3)
C8—C9—H9B	109.6	H30A—C30—H30B	107.5
H9A—C9—H9B	108.1	C29—C30—H30A	108.6
C10—C9—C8	110.5 (2)	C29—C30—H30B	108.6
C10—C9—H9A	109.6	C31—C30—H30A	108.6
C10—C9—H9B	109.6	C31—C30—H30B	108.6
N2—C10—C9	111.9 (2)	C31—C30—C29	114.8 (3)
N2—C10—H10A	109.2	C28—C29—C30	114.3 (3)
N2—C10—H10B	109.2	C28—C29—H29A	108.7
C9—C10—H10A	109.2	C28—C29—H29B	108.7
C9—C10—H10B	109.2	C30—C29—H29A	108.7
H10A—C10—H10B	107.9	C30—C29—H29B	108.7
C8—C12—H12A	109.6	H29A—C29—H29B	107.6
C8—C12—H12B	109.6	C30—C31—H31A	108.6
H12A—C12—H12B	108.1	C30—C31—H31B	108.6
C11—C12—C8	110.4 (2)	H31A—C31—H31B	107.6
C11—C12—H12A	109.6	C32—C31—C30	114.6 (3)
C11—C12—H12B	109.6	C32—C31—H31A	108.6
O3—C20—C19	105.9 (2)	C32—C31—H31B	108.6
O3—C20—H20	109.5	C31—C32—H32A	108.6
O3—C20—C21	109.7 (2)	C31—C32—H32B	108.6
C19—C20—H20	109.5	C31—C32—C33	114.8 (3)
C21—C20—C19	112.7 (2)	H32A—C32—H32B	107.5
C21—C20—H20	109.5	C33—C32—H32A	108.6
N3—C23—H23A	109.1	C33—C32—H32B	108.6
N3—C23—H23B	109.1	C32—C33—H33A	108.6
N3—C23—C22	112.4 (2)	C32—C33—H33B	108.6
H23A—C23—H23B	107.9	H33A—C33—H33B	107.6
C22—C23—H23A	109.1	C34—C33—C32	114.7 (3)
C22—C23—H23B	109.1	C34—C33—H33A	108.6
C1—C2—H2	123.3	C34—C33—H33B	108.6
C3—C2—C1	113.5 (3)	C33—C34—H34A	108.6
C3—C2—H2	123.3	C33—C34—H34B	108.6
C16—C17—H17A	109.5	C33—C34—C35	114.5 (3)
C16—C17—H17B	109.5	H34A—C34—H34B	107.6
C16—C17—H17C	109.5	C35—C34—H34A	108.6
H17A—C17—H17B	109.5	C35—C34—H34B	108.6
H17A—C17—H17C	109.5	C34—C35—H35A	109.5
H17B—C17—H17C	109.5	C34—C35—H35B	109.5
H26A—C26—H26B	107.7	C34—C35—H35C	109.5
C25—C26—H26A	108.9	H35A—C35—H35B	109.5
C25—C26—H26B	108.9	H35A—C35—H35C	109.5
C25—C26—C27	113.3 (2)	H35B—C35—H35C	109.5

(PC16) top

Crystal data top

C₃₉H₅₇FN₄O₄	F(000) = 1440
M_r = 664.88	D_x = 1.218 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 34.188 (3) Å	Cell parameters from 4887 reflections
b = 9.8280 (9) Å	θ = 2.2–25.7°
c = 10.8068 (9) Å	µ = 0.08 mm⁻¹
β = 92.992 (3)°	T = 100 K
V = 3626.1 (5) Å³	Plate, colourless
Z = 4	0.14 × 0.06 × 0.03 mm

Data collection top

Bruker D8 VENTURE diffractometer	4434 reflections with I > 2σ(I)
φ and ω scans	R_int = 0.071
Absorption correction: multi-scan SADABS-2016/2 (Bruker,2016/2) was used for absorption correction. wR2(int) was 0.1514 before and 0.0838 after correction. The Ratio of minimum to maximum transmission is 0.7678. The λ/2 correction factor is Not present.	θ_max = 26.4°, θ_min = 2.2°
T_min = 0.572, T_max = 0.745	h = −42→42
25113 measured reflections	k = −11→12
7346 independent reflections	l = −12→13

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.056	H-atom parameters constrained
wR(F²) = 0.146	w = 1/[σ²(F_o²) + (0.0631P)² + 0.7558P] where P = (F_o² + 2F_c²)/3
S = 1.02	(Δ/σ)_max = 0.001
7346 reflections	Δρ_max = 0.23 e Å⁻³
435 parameters	Δρ_min = −0.25 e Å⁻³
0 restraints

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
F1	0.22118 (4)	0.22916 (16)	−0.49279 (13)	0.0393 (4)
O2	0.60261 (4)	0.55596 (16)	−0.32215 (14)	0.0249 (4)
O3	0.73717 (4)	0.36979 (16)	−0.08570 (14)	0.0243 (4)
O1	0.30521 (4)	0.49246 (17)	−0.21963 (14)	0.0271 (4)
O4	0.77988 (4)	0.19510 (18)	−0.08016 (15)	0.0319 (4)
N3	0.65572 (5)	0.43689 (19)	−0.24739 (16)	0.0204 (4)
N007	0.65233 (5)	0.2923 (2)	−0.07490 (17)	0.0233 (5)
N2	0.48587 (5)	0.4299 (2)	−0.23786 (16)	0.0235 (5)
N1	0.34701 (5)	0.4859 (2)	−0.19484 (17)	0.0274 (5)
C19	0.61639 (6)	0.4764 (2)	−0.24249 (19)	0.0211 (5)
C16	0.59518 (6)	0.4198 (2)	−0.14332 (19)	0.0216 (5)
C17	0.61387 (6)	0.3315 (2)	−0.0632 (2)	0.0219 (5)
C8	0.36006 (6)	0.3899 (2)	−0.2648 (2)	0.0232 (5)
C6	0.32561 (6)	0.2205 (2)	−0.4241 (2)	0.0246 (5)
H6	0.348102	0.172055	−0.447534	0.030*
C9	0.40289 (6)	0.3594 (2)	−0.26832 (19)	0.0212 (5)
H9	0.405582	0.264789	−0.300907	0.025*
C24	0.67141 (6)	0.3443 (2)	−0.1642 (2)	0.0217 (5)
C11	0.46789 (6)	0.3353 (2)	−0.1527 (2)	0.0242 (5)
H11A	0.481630	0.342015	−0.070037	0.029*
H11B	0.470963	0.241126	−0.183148	0.029*
C5	0.32879 (6)	0.3259 (2)	−0.3381 (2)	0.0225 (5)
C4	0.29553 (7)	0.3951 (2)	−0.3054 (2)	0.0244 (5)
C14	0.55275 (6)	0.4613 (3)	−0.1402 (2)	0.0229 (5)
H14A	0.550856	0.561690	−0.145101	0.028*
H14B	0.542428	0.432401	−0.060439	0.028*
C10	0.42456 (6)	0.3654 (3)	−0.1410 (2)	0.0231 (5)
H10A	0.421425	0.456944	−0.104570	0.028*
H10B	0.413191	0.297980	−0.085106	0.028*
C25	0.77084 (6)	0.3069 (3)	−0.0459 (2)	0.0255 (6)
C7	0.28877 (7)	0.1884 (3)	−0.4742 (2)	0.0270 (6)
H7	0.285384	0.116713	−0.532746	0.032*
C23	0.71279 (6)	0.2950 (3)	−0.17731 (19)	0.0231 (5)
H23	0.714258	0.195472	−0.158213	0.028*
C20	0.67661 (6)	0.4938 (3)	−0.3521 (2)	0.0266 (6)
H20A	0.672044	0.593217	−0.356199	0.032*
H20B	0.665692	0.453387	−0.430368	0.032*
C3	0.25808 (7)	0.3668 (3)	−0.3545 (2)	0.0280 (6)
H3	0.235520	0.415532	−0.332089	0.034*
C21	0.72022 (6)	0.4672 (3)	−0.3406 (2)	0.0288 (6)
H21A	0.732656	0.527936	−0.276936	0.035*
H21B	0.731957	0.486531	−0.420624	0.035*
C13	0.42256 (6)	0.4556 (3)	−0.3569 (2)	0.0265 (6)
H13A	0.409884	0.446852	−0.440947	0.032*
H13B	0.419357	0.550745	−0.329007	0.032*
C26	0.79402 (6)	0.3940 (3)	0.0446 (2)	0.0265 (6)
H26A	0.776492	0.427040	0.108194	0.032*
H26B	0.803770	0.474469	0.000462	0.032*
C15	0.52767 (6)	0.3988 (3)	−0.2466 (2)	0.0251 (5)
H15A	0.536598	0.433738	−0.326257	0.030*
H15B	0.531297	0.298812	−0.245884	0.030*
C27	0.82868 (6)	0.3210 (3)	0.1088 (2)	0.0279 (6)
H27A	0.819470	0.234547	0.144297	0.034*
H27B	0.847921	0.298300	0.046669	0.034*
C22	0.72749 (7)	0.3200 (3)	−0.3047 (2)	0.0293 (6)
H22A	0.713700	0.259293	−0.365656	0.035*
H22B	0.755867	0.299874	−0.304550	0.035*
C18	0.59554 (6)	0.2657 (3)	0.0448 (2)	0.0272 (6)
H18A	0.598166	0.166655	0.038807	0.041*
H18B	0.567729	0.289974	0.044064	0.041*
H18C	0.608756	0.297478	0.122136	0.041*
C28	0.84880 (6)	0.4049 (3)	0.2113 (2)	0.0271 (6)
H28A	0.829074	0.434531	0.269497	0.033*
H28B	0.860088	0.487493	0.174656	0.033*
C29	0.88114 (6)	0.3274 (3)	0.2828 (2)	0.0280 (6)
H29A	0.901370	0.301393	0.224909	0.034*
H29B	0.870020	0.242584	0.315673	0.034*
C2	0.25671 (6)	0.2627 (3)	−0.4378 (2)	0.0285 (6)
C33	0.98417 (6)	0.3264 (3)	0.6404 (2)	0.0281 (6)
H33A	1.004423	0.300800	0.582444	0.034*
H33B	0.972822	0.241288	0.672015	0.034*
C12	0.46592 (6)	0.4224 (3)	−0.3610 (2)	0.0262 (6)
H12A	0.468961	0.329622	−0.394859	0.031*
H12B	0.478343	0.487087	−0.417127	0.031*
C37	1.08789 (7)	0.3259 (3)	0.9980 (2)	0.0287 (6)
H37A	1.076591	0.242201	1.032542	0.034*
H37B	1.107718	0.297908	0.939480	0.034*
C34	1.00364 (6)	0.4042 (3)	0.7488 (2)	0.0281 (6)
H34A	1.014884	0.489463	0.717173	0.034*
H34B	0.983371	0.429599	0.806814	0.034*
C36	1.05548 (7)	0.4042 (3)	0.9269 (2)	0.0282 (6)
H36A	1.035355	0.430238	0.985108	0.034*
H36B	1.066665	0.489068	0.894251	0.034*
C32	0.95208 (6)	0.4059 (3)	0.5697 (2)	0.0286 (6)
H32A	0.963437	0.490837	0.537718	0.034*
H32B	0.931858	0.431751	0.627618	0.034*
C31	0.93258 (6)	0.3273 (3)	0.4614 (2)	0.0282 (6)
H31A	0.952842	0.300996	0.403783	0.034*
H31B	0.921086	0.242732	0.493473	0.034*
C30	0.90061 (6)	0.4072 (3)	0.3899 (2)	0.0284 (6)
H30A	0.880399	0.434149	0.447576	0.034*
H30B	0.912108	0.491458	0.357154	0.034*
C35	1.03578 (6)	0.3255 (3)	0.8196 (2)	0.0283 (6)
H35A	1.055896	0.299214	0.761488	0.034*
H35B	1.024469	0.240878	0.852237	0.034*
C38	1.10810 (7)	0.4066 (3)	1.1031 (2)	0.0302 (6)
H38A	1.119885	0.489307	1.068416	0.036*
H38B	1.088202	0.436167	1.160808	0.036*
C39	1.13986 (7)	0.3272 (3)	1.1755 (2)	0.0343 (6)
H39A	1.158675	0.291538	1.116964	0.041*
H39B	1.127732	0.248380	1.215745	0.041*
C40	1.16213 (8)	0.4116 (3)	1.2744 (3)	0.0486 (8)
H40A	1.175492	0.487012	1.234916	0.073*
H40B	1.181502	0.354092	1.319315	0.073*
H40C	1.143699	0.447964	1.332525	0.073*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
F1	0.0251 (7)	0.0487 (10)	0.0429 (9)	−0.0062 (7)	−0.0091 (6)	−0.0020 (8)
O2	0.0289 (8)	0.0254 (10)	0.0200 (8)	0.0027 (8)	−0.0027 (7)	0.0026 (7)
O3	0.0218 (8)	0.0284 (10)	0.0223 (8)	0.0016 (8)	−0.0042 (7)	−0.0016 (7)
O1	0.0239 (8)	0.0286 (10)	0.0285 (9)	0.0014 (8)	−0.0006 (7)	−0.0039 (8)
O4	0.0288 (9)	0.0345 (11)	0.0317 (9)	0.0045 (8)	−0.0056 (7)	−0.0044 (8)
N3	0.0226 (9)	0.0215 (11)	0.0169 (9)	−0.0006 (9)	−0.0002 (8)	0.0007 (8)
N007	0.0242 (10)	0.0250 (12)	0.0205 (10)	0.0004 (9)	−0.0014 (8)	−0.0004 (9)
N2	0.0206 (9)	0.0317 (12)	0.0181 (9)	−0.0005 (9)	−0.0015 (8)	0.0013 (9)
N1	0.0212 (10)	0.0325 (13)	0.0280 (11)	0.0013 (9)	−0.0017 (8)	−0.0034 (10)
C19	0.0235 (11)	0.0214 (13)	0.0179 (11)	0.0004 (11)	−0.0034 (9)	−0.0039 (10)
C16	0.0220 (11)	0.0250 (14)	0.0177 (11)	−0.0005 (11)	−0.0012 (9)	−0.0046 (10)
C17	0.0211 (11)	0.0237 (14)	0.0207 (11)	−0.0018 (11)	−0.0004 (9)	−0.0022 (10)
C8	0.0256 (12)	0.0248 (14)	0.0191 (11)	0.0005 (11)	−0.0008 (10)	0.0042 (10)
C6	0.0261 (12)	0.0255 (14)	0.0219 (12)	0.0012 (11)	−0.0014 (10)	0.0014 (10)
C9	0.0229 (11)	0.0211 (14)	0.0195 (11)	−0.0008 (10)	−0.0009 (9)	−0.0008 (10)
C24	0.0239 (11)	0.0219 (14)	0.0188 (11)	−0.0005 (11)	−0.0037 (9)	−0.0018 (10)
C11	0.0256 (12)	0.0266 (14)	0.0199 (11)	−0.0003 (11)	−0.0024 (10)	0.0008 (10)
C5	0.0222 (11)	0.0256 (14)	0.0195 (11)	−0.0004 (11)	−0.0004 (9)	0.0018 (10)
C4	0.0284 (12)	0.0231 (14)	0.0215 (11)	0.0007 (11)	−0.0007 (10)	0.0021 (10)
C14	0.0228 (11)	0.0254 (14)	0.0204 (11)	−0.0005 (11)	−0.0009 (9)	−0.0009 (10)
C10	0.0244 (11)	0.0249 (14)	0.0198 (11)	0.0002 (11)	0.0001 (9)	0.0006 (10)
C25	0.0224 (12)	0.0321 (16)	0.0220 (12)	−0.0012 (12)	0.0001 (10)	0.0038 (11)
C7	0.0312 (13)	0.0264 (15)	0.0232 (12)	−0.0019 (12)	−0.0016 (10)	0.0013 (11)
C23	0.0202 (11)	0.0289 (15)	0.0198 (11)	−0.0015 (11)	−0.0018 (9)	−0.0051 (10)
C20	0.0287 (12)	0.0314 (15)	0.0198 (11)	−0.0056 (11)	0.0036 (10)	0.0027 (11)
C3	0.0234 (12)	0.0318 (15)	0.0287 (13)	0.0018 (11)	0.0008 (10)	0.0060 (12)
C21	0.0265 (12)	0.0352 (16)	0.0248 (12)	−0.0041 (12)	0.0025 (10)	0.0019 (11)
C13	0.0272 (12)	0.0316 (15)	0.0203 (12)	0.0001 (12)	−0.0029 (10)	0.0028 (11)
C26	0.0223 (12)	0.0307 (15)	0.0258 (12)	−0.0011 (11)	−0.0034 (10)	0.0025 (11)
C15	0.0234 (11)	0.0295 (15)	0.0222 (12)	0.0007 (11)	−0.0001 (10)	−0.0031 (11)
C27	0.0213 (11)	0.0372 (16)	0.0248 (12)	0.0020 (11)	−0.0030 (10)	0.0022 (11)
C22	0.0246 (12)	0.0385 (17)	0.0249 (12)	0.0013 (12)	0.0013 (10)	−0.0045 (12)
C18	0.0285 (12)	0.0285 (15)	0.0244 (12)	0.0004 (11)	0.0017 (10)	0.0038 (11)
C28	0.0234 (12)	0.0339 (15)	0.0236 (12)	−0.0018 (12)	−0.0022 (10)	0.0023 (11)
C29	0.0240 (12)	0.0365 (16)	0.0230 (12)	0.0006 (12)	−0.0046 (10)	0.0002 (11)
C2	0.0220 (12)	0.0350 (16)	0.0277 (13)	−0.0055 (12)	−0.0062 (10)	0.0055 (12)
C33	0.0238 (12)	0.0352 (16)	0.0251 (12)	−0.0007 (12)	−0.0018 (10)	−0.0015 (11)
C12	0.0247 (12)	0.0358 (16)	0.0179 (11)	−0.0013 (12)	−0.0017 (9)	0.0025 (11)
C37	0.0268 (12)	0.0354 (16)	0.0237 (12)	−0.0011 (12)	−0.0026 (10)	−0.0010 (11)
C34	0.0243 (12)	0.0335 (16)	0.0262 (12)	−0.0005 (11)	−0.0026 (10)	−0.0007 (11)
C36	0.0253 (12)	0.0335 (16)	0.0254 (12)	0.0012 (12)	−0.0028 (10)	0.0023 (11)
C32	0.0259 (12)	0.0363 (16)	0.0231 (12)	0.0014 (12)	−0.0033 (10)	0.0005 (11)
C31	0.0223 (11)	0.0387 (16)	0.0232 (12)	0.0005 (12)	−0.0036 (10)	0.0004 (11)
C30	0.0246 (12)	0.0357 (16)	0.0243 (12)	0.0001 (12)	−0.0030 (10)	0.0002 (11)
C35	0.0252 (12)	0.0348 (16)	0.0244 (12)	−0.0017 (12)	−0.0031 (10)	−0.0007 (11)
C38	0.0272 (12)	0.0376 (16)	0.0256 (12)	−0.0008 (12)	−0.0011 (10)	0.0027 (12)
C39	0.0279 (13)	0.0464 (18)	0.0282 (13)	0.0009 (13)	−0.0043 (11)	0.0008 (12)
C40	0.0409 (16)	0.064 (2)	0.0393 (16)	−0.0030 (16)	−0.0151 (13)	0.0013 (15)

Geometric parameters (Å, º) top

F1—C2	1.364 (2)	C26—H26A	0.9900
O2—C19	1.238 (3)	C26—H26B	0.9900
O3—C25	1.356 (3)	C26—C27	1.522 (3)
O3—C23	1.459 (3)	C15—H15A	0.9900
O1—N1	1.441 (2)	C15—H15B	0.9900
O1—C4	1.361 (3)	C27—H27A	0.9900
O4—C25	1.205 (3)	C27—H27B	0.9900
N3—C19	1.403 (3)	C27—C28	1.516 (3)
N3—C24	1.369 (3)	C22—H22A	0.9900
N3—C20	1.479 (3)	C22—H22B	0.9900
N007—C17	1.382 (3)	C18—H18A	0.9800
N007—C24	1.298 (3)	C18—H18B	0.9800
N2—C11	1.465 (3)	C18—H18C	0.9800
N2—C15	1.469 (3)	C28—H28A	0.9900
N2—C12	1.465 (3)	C28—H28B	0.9900
N1—C8	1.303 (3)	C28—C29	1.520 (3)
C19—C16	1.437 (3)	C29—H29A	0.9900
C16—C17	1.362 (3)	C29—H29B	0.9900
C16—C14	1.509 (3)	C29—C30	1.523 (3)
C17—C18	1.500 (3)	C33—H33A	0.9900
C8—C9	1.497 (3)	C33—H33B	0.9900
C8—C5	1.442 (3)	C33—C34	1.523 (3)
C6—H6	0.9500	C33—C32	1.521 (3)
C6—C5	1.392 (3)	C12—H12A	0.9900
C6—C7	1.381 (3)	C12—H12B	0.9900
C9—H9	1.0000	C37—H37A	0.9900
C9—C10	1.529 (3)	C37—H37B	0.9900
C9—C13	1.526 (3)	C37—C36	1.524 (3)
C24—C23	1.509 (3)	C37—C38	1.522 (3)
C11—H11A	0.9900	C34—H34A	0.9900
C11—H11B	0.9900	C34—H34B	0.9900
C11—C10	1.522 (3)	C34—C35	1.518 (3)
C5—C4	1.387 (3)	C36—H36A	0.9900
C4—C3	1.388 (3)	C36—H36B	0.9900
C14—H14A	0.9900	C36—C35	1.521 (3)
C14—H14B	0.9900	C32—H32A	0.9900
C14—C15	1.527 (3)	C32—H32B	0.9900
C10—H10A	0.9900	C32—C31	1.526 (3)
C10—H10B	0.9900	C31—H31A	0.9900
C25—C26	1.496 (3)	C31—H31B	0.9900
C7—H7	0.9500	C31—C30	1.523 (3)
C7—C2	1.391 (3)	C30—H30A	0.9900
C23—H23	1.0000	C30—H30B	0.9900
C23—C22	1.510 (3)	C35—H35A	0.9900
C20—H20A	0.9900	C35—H35B	0.9900
C20—H20B	0.9900	C38—H38A	0.9900
C20—C21	1.513 (3)	C38—H38B	0.9900
C3—H3	0.9500	C38—C39	1.520 (3)
C3—C2	1.362 (3)	C39—H39A	0.9900
C21—H21A	0.9900	C39—H39B	0.9900
C21—H21B	0.9900	C39—C40	1.524 (4)
C21—C22	1.515 (4)	C40—H40A	0.9800
C13—H13A	0.9900	C40—H40B	0.9800
C13—H13B	0.9900	C40—H40C	0.9800
C13—C12	1.521 (3)

C25—O3—C23	115.48 (18)	C26—C27—H27B	109.0
C4—O1—N1	107.40 (16)	H27A—C27—H27B	107.8
C19—N3—C20	115.22 (18)	C28—C27—C26	112.9 (2)
C24—N3—C19	120.17 (18)	C28—C27—H27A	109.0
C24—N3—C20	124.45 (18)	C28—C27—H27B	109.0
C24—N007—C17	118.40 (19)	C23—C22—C21	109.4 (2)
C11—N2—C15	110.44 (18)	C23—C22—H22A	109.8
C12—N2—C11	110.31 (17)	C23—C22—H22B	109.8
C12—N2—C15	109.84 (17)	C21—C22—H22A	109.8
C8—N1—O1	106.89 (17)	C21—C22—H22B	109.8
O2—C19—N3	118.63 (19)	H22A—C22—H22B	108.2
O2—C19—C16	125.1 (2)	C17—C18—H18A	109.5
N3—C19—C16	116.28 (19)	C17—C18—H18B	109.5
C19—C16—C14	115.78 (19)	C17—C18—H18C	109.5
C17—C16—C19	118.88 (19)	H18A—C18—H18B	109.5
C17—C16—C14	125.3 (2)	H18A—C18—H18C	109.5
N007—C17—C18	112.91 (19)	H18B—C18—H18C	109.5
C16—C17—N007	122.4 (2)	C27—C28—H28A	109.0
C16—C17—C18	124.6 (2)	C27—C28—H28B	109.0
N1—C8—C9	121.7 (2)	C27—C28—C29	112.9 (2)
N1—C8—C5	111.6 (2)	H28A—C28—H28B	107.8
C5—C8—C9	126.6 (2)	C29—C28—H28A	109.0
C5—C6—H6	121.0	C29—C28—H28B	109.0
C7—C6—H6	121.0	C28—C29—H29A	108.8
C7—C6—C5	118.0 (2)	C28—C29—H29B	108.8
C8—C9—H9	107.7	C28—C29—C30	114.0 (2)
C8—C9—C10	113.47 (18)	H29A—C29—H29B	107.7
C8—C9—C13	110.80 (18)	C30—C29—H29A	108.8
C10—C9—H9	107.7	C30—C29—H29B	108.8
C13—C9—H9	107.7	F1—C2—C7	116.5 (2)
C13—C9—C10	109.33 (18)	C3—C2—F1	117.9 (2)
N3—C24—C23	119.28 (19)	C3—C2—C7	125.5 (2)
N007—C24—N3	123.76 (19)	H33A—C33—H33B	107.7
N007—C24—C23	116.9 (2)	C34—C33—H33A	108.8
N2—C11—H11A	109.3	C34—C33—H33B	108.8
N2—C11—H11B	109.3	C32—C33—H33A	108.8
N2—C11—C10	111.78 (18)	C32—C33—H33B	108.8
H11A—C11—H11B	107.9	C32—C33—C34	113.8 (2)
C10—C11—H11A	109.3	N2—C12—C13	111.77 (18)
C10—C11—H11B	109.3	N2—C12—H12A	109.3
C6—C5—C8	136.2 (2)	N2—C12—H12B	109.3
C4—C5—C8	103.9 (2)	C13—C12—H12A	109.3
C4—C5—C6	119.9 (2)	C13—C12—H12B	109.3
O1—C4—C5	110.18 (19)	H12A—C12—H12B	107.9
O1—C4—C3	126.0 (2)	H37A—C37—H37B	107.7
C5—C4—C3	123.8 (2)	C36—C37—H37A	108.8
C16—C14—H14A	109.2	C36—C37—H37B	108.8
C16—C14—H14B	109.2	C38—C37—H37A	108.8
C16—C14—C15	112.15 (19)	C38—C37—H37B	108.8
H14A—C14—H14B	107.9	C38—C37—C36	113.8 (2)
C15—C14—H14A	109.2	C33—C34—H34A	108.7
C15—C14—H14B	109.2	C33—C34—H34B	108.7
C9—C10—H10A	109.6	H34A—C34—H34B	107.6
C9—C10—H10B	109.6	C35—C34—C33	114.0 (2)
C11—C10—C9	110.21 (18)	C35—C34—H34A	108.7
C11—C10—H10A	109.6	C35—C34—H34B	108.7
C11—C10—H10B	109.6	C37—C36—H36A	108.7
H10A—C10—H10B	108.1	C37—C36—H36B	108.7
O3—C25—C26	111.0 (2)	H36A—C36—H36B	107.6
O4—C25—O3	123.1 (2)	C35—C36—C37	114.1 (2)
O4—C25—C26	126.0 (2)	C35—C36—H36A	108.7
C6—C7—H7	120.5	C35—C36—H36B	108.7
C6—C7—C2	119.0 (2)	C33—C32—H32A	108.8
C2—C7—H7	120.5	C33—C32—H32B	108.8
O3—C23—C24	106.22 (17)	C33—C32—C31	113.6 (2)
O3—C23—H23	109.4	H32A—C32—H32B	107.7
O3—C23—C22	109.31 (18)	C31—C32—H32A	108.8
C24—C23—H23	109.4	C31—C32—H32B	108.8
C24—C23—C22	113.04 (19)	C32—C31—H31A	108.8
C22—C23—H23	109.4	C32—C31—H31B	108.8
N3—C20—H20A	109.1	H31A—C31—H31B	107.7
N3—C20—H20B	109.1	C30—C31—C32	113.7 (2)
N3—C20—C21	112.68 (19)	C30—C31—H31A	108.8
H20A—C20—H20B	107.8	C30—C31—H31B	108.8
C21—C20—H20A	109.1	C29—C30—C31	113.2 (2)
C21—C20—H20B	109.1	C29—C30—H30A	108.9
C4—C3—H3	123.1	C29—C30—H30B	108.9
C2—C3—C4	113.7 (2)	C31—C30—H30A	108.9
C2—C3—H3	123.1	C31—C30—H30B	108.9
C20—C21—H21A	109.8	H30A—C30—H30B	107.8
C20—C21—H21B	109.8	C34—C35—C36	113.9 (2)
C20—C21—C22	109.5 (2)	C34—C35—H35A	108.8
H21A—C21—H21B	108.2	C34—C35—H35B	108.8
C22—C21—H21A	109.8	C36—C35—H35A	108.8
C22—C21—H21B	109.8	C36—C35—H35B	108.8
C9—C13—H13A	109.6	H35A—C35—H35B	107.7
C9—C13—H13B	109.6	C37—C38—H38A	108.8
H13A—C13—H13B	108.1	C37—C38—H38B	108.8
C12—C13—C9	110.33 (19)	H38A—C38—H38B	107.7
C12—C13—H13A	109.6	C39—C38—C37	113.7 (2)
C12—C13—H13B	109.6	C39—C38—H38A	108.8
C25—C26—H26A	108.8	C39—C38—H38B	108.8
C25—C26—H26B	108.8	C38—C39—H39A	108.9
C25—C26—C27	113.7 (2)	C38—C39—H39B	108.9
H26A—C26—H26B	107.7	C38—C39—C40	113.5 (2)
C27—C26—H26A	108.8	H39A—C39—H39B	107.7
C27—C26—H26B	108.8	C40—C39—H39A	108.9
N2—C15—C14	112.17 (18)	C40—C39—H39B	108.9
N2—C15—H15A	109.2	C39—C40—H40A	109.5
N2—C15—H15B	109.2	C39—C40—H40B	109.5
C14—C15—H15A	109.2	C39—C40—H40C	109.5
C14—C15—H15B	109.2	H40A—C40—H40B	109.5
H15A—C15—H15B	107.9	H40A—C40—H40C	109.5
C26—C27—H27A	109.0	H40B—C40—H40C	109.5

Funding information

The authors are grateful for the financial support from the National Natural Science Foundation of China (grant Nos. 22108313; 82204291; 82273880), the Natural Science Foundation of Jiangsu Province (grant No. BK 20200576), Fundamental Research Funds for the Central Universities (grant No. 2632022ZD16) and the China Postdoctoral Science Foundation (grant No. 2021M703597).

References

Chai, Y., Wang, L., Bao, Y., Teng, R., Liu, Y. & Xie, C. (2019). Cryst. Growth Des. 19, 1660–1667. Web of Science CrossRef CAS Google Scholar
Chen, A., Cai, P., Luo, M., Guo, M. & Cai, T. (2023). Pharm. Res. 40, 567–577. Web of Science CrossRef CAS PubMed Google Scholar
Cruz-Cabeza, A. J., Davey, R. J., Sachithananthan, S. S., Smith, R., Tang, S. K., Vetter, T. & Xiao, Y. (2017). Chem. Commun. 53, 7905–7908. CAS Google Scholar
Dijkstra, A. J., Hamilton, R. J. & Hamm, W. (2008). Trans Fatty Acids. Oxford: Blackwell Publishing Ltd. Google Scholar
Fattahi, N., Shahbazi, M.-A., Maleki, A., Hamidi, M., Ramazani, A. & Santos, H. A. (2020). J. Control. Release, 326, 556–598. Web of Science CrossRef CAS PubMed Google Scholar
Grzybowska, K., Capaccioli, S. & Paluch, M. (2016). Adv. Drug Deliv. Rev. 100, 158–182. Web of Science CrossRef CAS PubMed Google Scholar
Guo, M., Jones, M. J., Goh, R., Verma, V., Guinn, E. & Heng, J. Y. Y. (2023). Cryst. Growth Des. 23, 1668–1675. Web of Science CrossRef CAS PubMed Google Scholar
He, H., Jiang, L., Zhang, Q., Huang, Y., Wang, J.-R. & Mei, X. (2015). CrystEngComm, 17, 6566–6574. Web of Science CSD CrossRef CAS Google Scholar
Honda, A., Kakihara, S., Kawai, M., Takahashi, T. & Miyamura, K. (2021). Cryst. Growth Des. 21, 6223–6229. Web of Science CSD CrossRef CAS Google Scholar
Huang, C., Chen, Z., Gui, Y., Shi, C., Zhang, G. G. Z. & Yu, L. (2018). J. Chem. Phys. 149, 054503. Web of Science CrossRef PubMed Google Scholar
Huttunen, K. M., Raunio, H. & Rautio, J. (2011). Pharmacol. Rev. 63, 750–771. Web of Science CrossRef CAS PubMed Google Scholar
Im, J. S., Balakrishnan, P., Oh, D. H., Kim, J. S., Jeon, E.-M., Kim, D.-D., Yong, C. S. & Choi, H.-G. (2011). Drug Dev. Ind. Pharm. 37, 841–848. Web of Science CrossRef CAS PubMed Google Scholar
Ishikawa, T., Honda, A. & Miyamura, K. (2022). CrystEngComm, 24, 5900–5906. Web of Science CrossRef CAS Google Scholar
Ji, X., Wang, J., Wang, T., Huang, X., Li, X., Wang, N., Huang, Y., Li, R., Zhao, B., Zhang, T. & Hao, H. (2022). CrystEngComm, 24, 2226–2240. Web of Science CSD CrossRef CAS Google Scholar
Jiang, S. & ter Horst, J. H. (2011). Cryst. Growth Des. 11, 256–261. Web of Science CrossRef Google Scholar
Kakkar, S., Devi, K. R., Svärd, M. & Rasmuson, Å. (2020). CrystEngComm, 22, 3329–3339. Web of Science CrossRef CAS Google Scholar
Kashchiev, D. (2000). Nucleation: basic theory with applications. Oxford: Butterworth Heinemann Publishing Ltd. Google Scholar
Khan, M. K. & Sundararajan, P. R. (2011). J. Phys. Chem. B, 115, 8696–8706. Web of Science CrossRef CAS PubMed Google Scholar
Khan, M. K. & Sundararajan, P. R. (2013). J. Phys. Chem. B, 117, 5705–5717. Web of Science CrossRef CAS PubMed Google Scholar
Liu, Y., Xu, S., Zhang, X., Tang, W. & Gong, J. (2019). Cryst. Growth Des. 19, 7175–7184. Web of Science CrossRef CAS Google Scholar
Markovic, M., Ben–Shabat, S., Keinan, S., Aponick, A., Zimmermann, E. M. & Dahan, A. (2019). Med. Res. Rev. 39, 579–607. Web of Science CrossRef PubMed Google Scholar
Martin, A. D., Britton, J., Easun, T. L., Blake, A. J., Lewis, W. & Schröder, M. (2015). Cryst. Growth Des. 15, 1697–1706. Web of Science CSD CrossRef CAS PubMed Google Scholar
McTague, H. & Rasmuson, Å. C. (2021). Cryst. Growth Des. 21, 2711–2719. Web of Science CrossRef CAS PubMed Google Scholar
Ou, X., Li, X., Rong, H., Yu, L. & Lu, M. (2020). Chem. Commun. 56, 9950–9953. Web of Science CSD CrossRef CAS Google Scholar
Powell, C. T., Paeng, K., Chen, Z., Richert, R., Yu, L. & Ediger, M. D. (2014). J. Phys. Chem. B, 118, 8203–8209. Web of Science CrossRef CAS PubMed Google Scholar
Rautio, J., Meanwell, N. A., Di, L. & Hageman, M. J. (2018). Nat. Rev. Drug Discov. 17, 559–587. Web of Science CrossRef CAS PubMed Google Scholar
Remenar, J. F. (2014). Mol. Pharm. 11, 1739–1749. Web of Science CrossRef CAS PubMed Google Scholar
Sheldrick, G. M. (2015). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Shi, P., Xu, S., Yang, H., Wu, S., Tang, W., Wang, J. & Gong, J. (2021). IUCrJ, 8, 161–167. Web of Science CrossRef CAS PubMed IUCr Journals Google Scholar
Shi, Q. & Cai, T. (2016). Cryst. Growth Des. 16, 3279–3286. Web of Science CrossRef CAS Google Scholar
Shi, Y., Lu, A., Wang, X., Belhadj, Z., Wang, J. & Zhang, Q. (2021). Acta Pharm. Sin. B, 11, 2396–2415. Web of Science CrossRef CAS PubMed Google Scholar
Singh, A. K., Italiya, K. S., Narisepalli, S., Chitkara, D. & Mittal, A. (2021). J. Med. Chem. 64, 14217–14229. Web of Science CrossRef CAS PubMed Google Scholar
Spackman, M. A. & Jayatilaka, D. (2009). CrystEngComm, 11, 19–32. Web of Science CrossRef CAS Google Scholar
Spackman, M. A. & McKinnon, J. J. (2002). CrystEngComm, 4, 378–392. Web of Science CrossRef CAS Google Scholar
Sprecher, H. (1981). Prog. Lipid Res. 20, 13–22. CrossRef CAS PubMed Google Scholar
Su, Y., Xu, J., Shi, Q., Yu, L. & Cai, T. (2018). Chem. Commun. 54, 358–361. Web of Science CSD CrossRef CAS Google Scholar
Sun, B., Luo, C., Cui, W., Sun, J. & He, Z. (2017). J. Controlled Release, 264, 145–159. Web of Science CrossRef CAS Google Scholar
Tang, S. K., Davey, R. J., Sacchi, P. & Cruz-Cabeza, A. J. (2021). Chem. Sci. 12, 993–1000. Web of Science CrossRef CAS Google Scholar
Thanki, K., Date, T. & Jain, S. (2019). Mol. Pharm. 16, 4519–4529. Web of Science CrossRef CAS PubMed Google Scholar
Yang, H., Svärd, M., Zeglinski, J. & Rasmuson, C. (2014). Cryst. Growth Des. 14, 3890–3902. Web of Science CrossRef CAS Google Scholar
Zhang, C., Jin, S., Xue, X., Zhang, T., Jiang, Y., Wang, P. C. & Liang, X.-J. (2016). J. Mater. Chem. B. 4, 3286–3291. Web of Science CrossRef CAS PubMed Google Scholar
Zhang, J., Liu, Z., Wu, H. & Cai, T. (2021). Biomater. Sci. 9, 4308–4316. Web of Science CrossRef CAS PubMed Google Scholar
Zheng, C., Jalan, I., Cost, P., Oliver, K., Gupta, A., Misture, S., Cody, J. A. & Collison, C. J. (2017). J. Phys. Chem. C, 121, 7750–7760. Web of Science CrossRef CAS Google Scholar
Zhong, T., Hao, Y.-L., Yao, X., Zhang, S., Duan, X.-C., Yin, Y.-F., Xu, M.-Q., Guo, Y., Li, Z.-T., Zheng, X.-C., Li, H. & Zhang, X. (2018). Bioconjug. Chem. 29, 437–444. Web of Science CrossRef CAS PubMed Google Scholar

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.

IUCrJ

Volume 11| Part 1| January 2024| Pages 23-33

ISSN: 2052-2525

https://doi.org/10.1107/S2052252523009582

CHEMISTRY | CRYSTENG

Open

access

Format		BIBTeX
		EndNote
		RefMan
		Refer
		Medline
		CIF
		SGML
		Plain Text
		Text

Format		BIBTeX
		EndNote
		RefMan
		Refer
		Medline
		CIF
		SGML
		Plain Text
		Text

Search IUCr Journals		doi		Advanced search
Author		volume	page

research papers\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

The role of alkyl chain length in the melt and solution crystallization of paliperidone aliphatic prodrugs

1. Introduction

2. Experimental

2.1. Materials

2.2. Solid-state characterization

2.3. Melt crystallization of paliperidone derivatives

2.3.1. Single-crystal growth of paliperidone derivatives

2.3.2. Growth kinetic measurement

2.3.3. Viscosity measurement

2.4. Solution crystallization of paliperidone derivatives

2.4.1. Induction time measurement

2.4.2. Crystal growth rate measurement

3. Results and discussion

3.1. Solid-state characterization

3.2. Crystal structure analysis

3.3. Crystal morphology in melt and solution

3.4. Crystallization kinetics of paliperidone derivatives in the melt

3.5. Crystallization kinetics of paliperidone derivatives in solution

4. Conclusions

Supporting information

Funding information

References

research papers