Preferential Orientation Effect of Polymers on Paracetamol

Subscriber access provided by UCL Library Services

Article

The preferential orientation effect of polymers on paracetamol crystallization: experiments and modelling Yang Song, Zhihui Cai, Zhixian Li, Guoqiang Guan, and Yanbin Jiang Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00346 • Publication Date (Web): 13 Jul 2018 Downloaded from http://pubs.acs.org on July 17, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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

Crystal Growth & Design

The preferential orientation effect of polymers on paracetamol crystallization: experiments and modelling Yang Song, Zhihui Cai, Zhixian Li, Guoqiang Guan, Yanbin Jiang*

School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China

* Corresponding author: Yanbin Jiang Tel: +86-20-8711-2051 E-mail address: [email protected] (Y. Jiang)

ACS Paragon Plus Environment

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

Page 2 of 34

ABSTRACT Crystallization is one of the most important unit operations in the quality control of pharmaceutical products. For this study a polymer-induced heteronucleation method was selected to investigate the effect of PA66, PET and PP films on the crystal growth of paracetamol by coupling experiments with modelling. The result of induction time indicated that the order of induced effect was PA66 > PET > PP > no template. XPS results indicated the different functional groups on surface of films. The crystal habits and PXRD results indicated that preferential orientation along certain facets occurred for PA66 and PET, and the results of in-situ Raman microscope verified the different concentration trends near different films, which is consistent with the preferential orientation effect of films. The results of molecular simulation indicated that the difference in van der Waals and electrostatic interaction, as well as H-bond donor/acceptor on the polymer films, is the origin of the preferential orientation effect for paracetamol crystallization. The PP film modified with similar functional groups of PA66 on surfaces caused the same preferential orientation effect as PA66, which verified the functional-induced mechanism of the preferential orientation. This study could

contribute

to

investigation

of

the

mechanism

of

polymer-induced

heteronucleation and screen out the efficient templates.

Keywords: paracetamol, polymer-induced heteronucleation, preferential orientation, in-situ Raman microscope, molecular simulation, surface modification


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


1. INTRODUCTION Pharmaceutical crystallization is one of the most important unit operations for separating and purifying active pharmaceutical ingredients (APIs)1. Over the past several decades, owing to the increasing number of requests for products with specific properties, the development of pharmaceutical crystallization has been accelerated2. Crystal qualities, mainly including the particle size3, polymorphism4 and habit5, could affect dissolution rate, solubility, bioavailability and compressibility of product6 , which are pivotal in the crystal production of APIs. For crystal nucleation and growth, supersaturation and temperature7, solvents8, additives9 and templates10 are the main factors which affect the solid form of products by the induced effect. Recently, polymer-induced heteronucleation (PIHn), an effective template-induced approach, draws attention to drug crystallization control. New

solid

forms

of

paracetamol11,

flufenamic

acid12,

tolfenamic

acid13,

phenobarbital14, and lysozyme15 were successfully obtained using the PIHn method. Pfund and Matzger performed a high-throughput PIHn format containing 288 different polymers to screen new polymorphs16. A method of screening templates for paracetamol has been set up and amino benzene acetic acid, which could induce paracetamol form II, was found17. Sudha et al.18 found that the results of these designed experiments demonstrated the induced effect of several polymers on paracetamol PIHn, and guessed that the mechanism was the induced effect which depended on surface functional groups, also the supersaturation generated in the solution acted as a key factor. Hsu et al.19 conducted PIHn experiments with paracetamol using the chitosan films modified by different acids, and the effect of several functional groups on surfaces was discussed. Lopez-Mejias et al.20 reported the heteronucleation process of paracetamol on PBMA and PMMA films in solution or vapour, the crystal of paracetamol was form I on the surface of a PBMA film in solution, but was form II on the surface of a PMMA film; in vapour deposition, the product was all form I whether on the surface of PBMA or PMMA films, which demonstrated the effect of solvent on PIHn. However, there is a lack of evidence on the functional-induced mechanism, and in-depth research on the PIHn mechanism in molecular level is still a challenge. Preferential orientation, or oriented growth of crystal, affects the morphologies of crystal products. Liang et al.21 found that the oriented attachment of Dirithromycin affected the crystals growing and stacking on the (0 0 1) facet, which significantly ACS Paragon Plus Environment


changed the morphology of Dirithromycin crystals. During the production of APIs, if the crystallization conditions could be controlled to regulate the preferential orientation of crystal growth, then the desired morphology of crystal products would be obtained. And the crystals with preferential orientation might have some different surface properties which are important for drug delivery22. Recently, Wang et al.23 reported that the needle-shaped 10-hydroxycamptothecin nanocrystals, which with longer blood retention time and more effective cellular uptake, made it possible to accumulate drug in tumor tissues and exhibited higher cytotoxicity. To investigate crystallization in molecular level, Raman spectroscopy and molecular simulation are useful tools. Raman spectroscopy with high sensitivity offers a better comprehension of dissolution, crystallization, formation of co-crystals and detection of low-content API24, when using the in-situ Raman microscope, molecular behaviour near the surface of the template could be explored. Molecular simulation is a useful tool to investigate the mechanism of crystallization at molecular scale. Recently, an urea nucleation process from aqueous solution was simulated with a well-tempered dynamic method, the results show that two different polymorphs nucleated competitively, and the urea molecules gathered into a crystal-like cluster of one polymorph, which indicated the mechanism of competitive polymorphs nucleation25. Liu et al.26 simulated the crystallization of explosive crystals, which mainly covered solvent behaviour at the crystal surface and it was found that the interaction energy calculation provided evidence for the differences in crystal face growth rate. Yin et al.27 simulated an α–glycine crystal facet which contacted with supersaturated solution, where the cluster of glycine molecules and H-bond on the crystal surface were found, and the H-bond lifetime distributions varying with glycine concentrations were adopted to explain how supersaturation affected crystallization. Hence, the interaction energy28 and the H-bond29 calculations are important approaches for modelling of crystallization. Nevertheless, for flexible organic molecules, e.g. most APIs, due to the complexity of the structural modelling and parameter determination, the simulation of nucleation and growth is still difficult. In this study, a method coupling experiments with modelling was developed to investigate how the functional polymer films affect the preferential orientation of paracetamol crystal in PIHn, where paracetamol was selected as the model component, and nylon 66 (PA66), polyester (PET) and polypropylene (PP) were model films. Experiments on crystallization kinetics were conducted on different polymer films. ACS Paragon Plus Environment

Page 4 of 34

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


PXRD results confirm the consequences of preferential orientation effect. An in-situ Raman microscope was used to analyze the shift of paracetamol concentration close to the surface during the polymer-induced crystallization process and the possible interactions between paracetamol and polymers. Molecule simulation was employed to analyze the interaction at molecular level and provide insights into the preferential orientation effect. Finally, PP film was modified with the same functional groups as PA66 on surfaces to verify the induced mechanism found.

2. MATERIALS AND METHODS 2.1 Materials Paracetamol was purchased from Shanghai Aladdin Industrial Corporation. PA66, PET and PP film with a thickness of 0.3 mm and a roughness of about 0.2 µm were purchased from Foshan Dafu New Material Co. Ltd. Ammonium persulfate was purchased from Shanghai Aladdin Industrial Corporation, while sulfuric acid, acrylic acid and ethanol were purchased from Tianjing Damao Chemical Reagent Factory. Deionized water was used for aqueous solution preparation. 2.2 Preparation of paracetamol crystals induced by polymer films The paracetamol powder was completely dissolved in deionized water (3 g/100 ml) at 60 oC, then the solution was filtered using a 0.22 µm film filter to remove the insoluble impurity or dust. A piece of polymer film (8 × 5 cm), frizzled as a cylinder, was inserted vertically into a 50 mL beaker, then the beaker was pre-cooled at 10 oC for at least 20 min in a digitally controlled constant temperature bath, while the beaker without polymer film was the reference. 20 mL of overheated paracetamol aqueous solution was pipetted to the pre-cooled beaker, and the system was maintained at 10oC for at least 8 h. The polymer film with deposited crystals was rinsed quickly with deionized water to remove the supersaturated solution, and dried with absorbent paper, then put into the hygrothermostat at 25 oC and a relative humidity of 30% for 1 h. 2.3 Induction time statistics The

paracetamol

aqueous

solution

was

prepared

as

in

Section

2.2.

Micro-crystallizer was assembled using a piece of polymer film (5 × 3 cm) with a steel ring (M10×16×1), while a glass slide with a steel ring was the reference. The micro-crystallizer was set to the hot stage (THMSE 600, Linkam, Britain) and preheated to 60 oC. 40 µL overheated paracetamol aqueous solution was pipetted into the micro-crystallizer and pre-heated for 2 min. The hot stage was cooled to 10 oC ACS Paragon Plus Environment


using liquid nitrogen at a cooling rate of 30 oC/min, and the moment cooling began was taken as time zero. The micro-crystallizer was observed using an optical microscope (BX41, OLYMPUS, Japan) for monitoring the induction time and the habits of the paracetamol crystal, where the induction time was the period from time zero to the first crystal being detected. Each measurement was repeated at least 3 times. 2.4 Powder X-ray diffraction An X-ray diffractometer (D8 ADVANCE, Bruker-AXS, Germany) with Cu-ka radiation generated at 40 mA and 40 kV, was employed to obtain the powder X-ray diffraction (PXRD) patterns of the prepared paracetamol crystals. All samples were scanned between 5o and 50o (2θ) with a scanning step of 0.02 o. 2.5 X-ray photoelectron spectroscopy analysis A Kratos AXIS Ultra Imaging X-ray photoelectron spectrometer was used to collect X-ray photoelectron spectroscopy (XPS) spectra of the polymer films. C 1s spectra were obtained with elemental analysis. Then spectra were fitted using peaks corresponding to different functional groups with XPSPEAK software, which allows the semi-quantification of surface functional groups of different polymer films. 2.6 In-situ Raman microscope analysis The in-situ Raman microscopy (LabRam HR, HORIBA, Japan) was used to monitor the molecular behaviour of paracetamol in solution near the films. A green laser with 532 nm wavelength was employed as an exciting light. The focus point of the Raman is determined using the adjustment of the scale on the microscope. All samples were scanned between 200 cm-1 and 2000 cm-1, where the cumulative number was 2 with an accumulation time of 2 s. The paracetamol aqueous solution was prepared as in Section 2.2. The films and glass slides which were used to obtain the background spectrum, were put on the hot stage at 60 oC. The focal point of the microscope was set to a region 100 µm above the surface. 40 µL overheated paracetamol aqueous solution was pipetted onto the film and pre-heated for 2 min. The hot stage was cooled to 10 oC at the rate of 30 oC/min. Until the hot stage was cooled to 10 oC, Raman spectrum of the solution was obtained every 3 min, while background was subtracted from each spectrum. 2.7 Molecular simulation methods Molecular simulation tools were used to discover the PIHn mechanism and explain the preferential orientation of paracetamol crystal by analyzing the H-bonding, ACS Paragon Plus Environment

Page 6 of 34

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


computing the interaction energy between paracetamol and different films. All simulation work was completed using Materials Studio 2017 (Biovia Software Inc., CA, 2016). The crystal structure and cell parameters of paracetamol Form I were adopted from the Cambridge Structural Database. The optimal force field for the simulation was determined following Cai et al.30, COMPASS and Forcefield assigned were the optimal force field and charge rule respectively. Non-solvated paracetamol-polymer interfaces were established to study nucleation mechanism between paracetamol and PA66, PET or PP. To study the interaction between the paracetamol molecule and film, the structures of PA66, PET and PP originated from the database of Materials Studio, three layers of polymer molecule chain were cleaved through at (1 0 0), (0 1 0) and (0 1 0) facets respectively, and extended to a supercell with dimensions of larger than 30 Å and a vacuum thickness of 50 Å. While all layers were fixed, a paracetamol molecule was added to the middle of the vacuum layer and relaxed, then 100 ps NVT molecular dynamics simulation was performed with the Forcite module (time step = 1 fs, T = 283 K). The interaction energy of paracetamol (Eadsorption) with the film surface was calculated as follows:

Eadsorption = E paracetamol + surface − ( E paracetamol + Esurface )

(1)

where Eparacetamol+surface is the total energy of the interface, Eparacetamol and Esurface is the energy of the paracetamol and the assigned polymer surface, respectively. To study the interaction between paracetamol facets and films, a polymer supercell was established with dimensions of greater than 50 Å and a vacuum thickness of 50 Å, which ensures the side length is greater than the double of cut-off radius of long-range interactions, then fixed. The important crystal facets of paracetamol were cleaved and a molecule cluster was established with 4, 4 and 2 molecules in the X, Y and Z axis, respectively. The cluster was defined as a motion group31, where the relative co-ordinates of each paracetamol molecule were fixed when the cluster could move or rotate in the simulation. The cluster was put over the polymer layer, and it was ensured that the facet was docked to the polymer surface. Quench simulation was performed to optimize the cluster-polymer interface using NVT ensemble at 283 K for 1 ps with a time step of 1 fs. Quench for the interface was performed at every 50 steps of dynamics. The interaction energy of paracetamol crystal facet with the polymer surface can be calculated by Eq. 1. Due to non-solvent, the simulated results can only be used to describe the induction of polymers on the crystallization process of



paracetamol qualitatively. A solvated interface was established to further study the heterogeneous nucleation. A polymer supercell was established with dimensions of larger than 30 Å and a vacuum thickness of 50.00 Å, and fixed except for the top-half layer of polymer chain. An Amorphous Cell module was used to input solvent and paracetamol molecules with the molar ratio of 0.99644 and 0.00356, respectively, which were calculated from the concentration of supersaturated solution (3 g/100 ml) in Section 2.2. The solvated interface was built with a solution layer density of 1.0 g/cm3. 15 paracetamol molecules were added to the middle of the polymer surface. Then Anneal was used to optimize the solvated interface. Considering the magnitude of the time on molecular clustering behavior and computational expense, dynamic simulation was performed for 10 ns, where the first 2 ns was taken as the equilibrium period and the latter 8 ns was used to analyze the interaction between paracetamol molecule and polymer, with a time step of 1 fs and NVT ensemble at 283 K. These simulation parameters above were selected according to the pre-simulation, the experiment details and the computational details of literatures25, 31. 2.8 The modification of PP film The PP film with acylaminos on the surface was modified as follows. The hot solution at 60 oC was prepared with 5 g Ammonium persulfate, 80 ml water, 20 ml ethanol and 2 ml 98% sulfuric acid in a beaker, then 20 ml acrylic acid was added and the PP film was put into the beaker quickly. After 10 minutes, the film was washed and put into a beaker with 200 ml NH3·H2O/NH4Cl buffered solution (0.5 M, pH=10.2) at room temperature. After 8 hours, the PP film was put into a drying oven at 80 oC for 4 hours. The induced crystallization of paracetamol on the modified PP films was conducted to verify the results of experiments and molecular simulation.

3.RESULTS AND DISCUSSION 3.1 Nucleation rate induced by polymer film Nucleation is an energy-activated process which transfers the supersaturated solution into the generation of a new phase, it is a stochastic event. The period of time between the attainment of supersaturation and the generation of the first crystal is known as the induction time, which represents the stochastic nature of crystal nucleation. The induction time is an ideal indicator of the effect of foreign phase on the nucleation of API, as it can be shortened by the induction of the foreign surface, ACS Paragon Plus Environment

Page 8 of 34

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


which can also reduce the kinetic barrier to nucleation. On this basis, the nucleation rates of paracetamol under the induction of PA66, PET or PP films were investigated through the stochastic distribution of induction time. Assuming that there were ξ isolated experiments, and the number of successful crystallization in a given time t was ξ+(t), then the probability P(t) of a successful crystallization in this time is given as follows:

P(t ) =

ξ + (t ) ξ

(2)

based on Poisson distribution, this approach can be applied under the assumption of fast crystal growth and sufficiently high heat transfer32. Figure 1a shows the cumulative probability distribution of the nucleation induction time of paracetamol induced by different films. It suggests that the induction times were all reduced under the induction of PA66, PET and PP with narrower distribution. The probability of no nucleation induced by PA66, PET, PP, or no template after 20 s was 20%, 36%, 55% and 53%, respectively, while 2%, 8%, 12% and 28% after 40 s. Therefore, PA66 was the most effective template among the three polymers to promote the nucleation of paracetamol, while the effect of PP was not significant. The average induction time calculated via probability distribution of crystallization events can be a quantitative indicator for the induction of different films on the heterogeneous nucleation of paracetamol. According to Poisson distribution theory, assuming that the generation of crystal nuclei is an isolated event in constant supersaturation, where the supersaturation ratio of prepared paracetamol aqueous solution was 3.18 at 10 oC, the probability (Pm) that m nuclei are generated in a given time interval is given by: Pm =

Nm exp(− N ) m!

(3)

where N is the average number of generated nuclei in the given time interval. Thus, the probability (P) of no nuclei generated is given by:

t P = exp(− )

(4)

τ

where t is the time and τ is the induction time. Figure 1b shows the linear regression of ln P as a function of induction time according to Eq. 4. The linearly dependent coefficient under the induction of PA66, PET, PP and no template (glass slide) is 0.985, 0.995, 0.980 and 0.996, respectively,



which confirms the effective application of Poisson distribution model in this study. Thus the heterogeneous nucleation of paracetamol induced by PA66, PET, PP or no template is inherently a stochastic event. According to Eq. 4, the average induction time under the induction of PA66, PET, PP or no template is 11.5 s, 15.6 s, 20.2 s and 32.5 s, which indicates that the nucleation rate induced by no template is 35.3% of that induced by PA66, 48.0% by PET and 62.1% by PP, respectively. Therefore, the effect of PA66 on promoting the nucleation of paracetamol is the most significant, while the effect of PP is the weakest. The different effects of polymers may contribute to the differences in surface functional groups. 3.2 Preferential orientation effect In order to analyze the surface chemistry and relative contents of different functional groups, XPS (X-ray photoelectron spectroscopy) was employed to characterize different polymer films. The C1s spectrums of PA66, PET and PP are shown in Figure 2, which suggests that there are C-C, C-N, C-O or C-OH, and CONH groups on PA66 surface with the relative contents of 41.4%, 34.0%, 9.5% and 15.1% respectively, π bond (benzene ring), C-O and COO groups on PET surface with the contents of 59%, 26.8% and 14.2% respectively, C-C on PP surface with few other groups. These results suggest that the CONH and COO group is the main surface functional group of PA66 and PET respectively, which could form H-bonding with paracetamol to induce heterogeneous nucleation. The crystal morphologies and their PXRD data were employed to study the possible preferential orientation of crystal nucleation and growth. Figure 3 shows the habits and PXRD patterns of paracetamol crystals obtained on templates of PA66, PET, PP and glass. As shown in Figure 3a, there was no obvious preferential orientation on the glass surface without the induction of polymers. The peaks of 2θ at 12.1o, 13.9o, 15.4o, 16.7o,18.1o, 23.5o, 24.4o, 26.5o and 28.1o were observed, which indicates that form I crystals were obtained. This PXRD data was indexed to match the peaks with crystal facets. In the photograph of its crystal habits, the block shaped crystals with numbers of facets were obtained under no induction of template, which was consistent with the PXRD results. As shown in Figure 3b, the PXRD pattern of paracetamol crystals nucleated on PA66 film exhibited three predominant reflections at 13.9o (0 0 1), 24.4o (2 2 0) and 28.1o (0 0 2), no new peaks of 2θ indicates no polymorphs. Compared with the PXRD pattern of form I, the reflection at 13.9o was much stronger, which suggests that the


Page 10 of 34

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


preferential orientation along (0 0 1) the facet was significantly strong. Its photograph shows that long stick shaped crystals with limited crystal facets were induced by PA66, which agreed with the PXRD results. As shown in Figure 3c, the PXRD pattern paracetamol crystals induced by PET shows major characteristic peaks at 13.9o (0 0 1), 15.4o (2 0 -1), 18.1o (2 1 0) and 24.4o (2 2 0). Compared with the PXRD pattern of form I, the reflection at 13.9o and 15.4o were both strongest, then at 18.1o, which suggests that PET mainly induced the preferential orientation of paracetamol nucleation along (0 0 1) and (2 0 -1), also no polymorph. However, the preferential orientation induced by PET was less significant than that of PA66. The long stick shaped crystals were induced by PET, but with more crystal facets than that induced by PA66. As shown in Figure 3d, the PXRD pattern of paracetamol crystal nucleated on PP film shows no obvious preferential orientation and polymorphs, which indicates that the induction of PP on crystallization of paracetamol was weak. Its photograph indicates that block shaped paracetamol crystals with a number of crystal faces was obtained under the induction of PP, which was consistent with PXRD results. As shown in Figure 4, the PA66 and PP films have some sharp diffraction peaks in the PXRD patterns, but the PET films have no obvious PXRD diffraction peaks, it indicates that the PA66 and PP films have a high level at crystallinity, but the PET films are amorphous. The crystals nucleated on the PA66 and PET films demonstrate the preferential orientation effect, whereas the PP film not. Hence, the preferential orientation effect is not due to the crystal form of polymers, but would be due to the surface chemical structure. Therefore, the effect of the three polymer films on inducing crystallization of paracetamol was PA66 > PET > PP, and paracetamol crystals nucleate with different preferential orientation, i.e. on PA66 among (0 0 1), on PET among (2 1 0) and (0 0 1) facets, on PP or no template no obvious preferential effect. 3.3 Results of in-situ Raman microscope The concentration trend of paracetamol aqueous solution near the film surface was monitored by in-situ Raman microscope to further investigate the induction effect of polymers on paracetamol crystallization. The Raman spectrum of paracetamol solution at different times near the surface of glass slide, PA66, PET and PP are shown in Figure 5, most characteristic peaks on paracetamol can be found corresponding to functional groups33. For the glass slide in Figure 5a and PP in Figure 5d, the patterns at different times



were not consistent and the characteristic peaks, thus different functional groups were difficult to identify. Only a few peaks corresponded to C-C stretching of the phenyl ring, i.e. 858 cm-1 at 9, 12, 15 and 18 min, 1169 cm-1 at 3, 12, 15 and 18 min near the glass slide, 858 cm-1 at all times, 1324 cm-1 at 0, 6, 12, 15 and 21 min near the PP surface were observed, as well as 1618 cm-1 peaks standing for O-H bending at all times near the PP surface. These indicate that the solution status near the glass-solution and PP-solution interface were both unstable. Due to the complicated optical characteristics of the glass, the Raman peaks of paracetamol exhibited a disordered manner caused by the confused noise signals of the glass. For PA66 in Figure 5b and PET in Figure 5c, the patterns at different times were quite consistent, and characteristic peaks can be well identified, as particularly with the peaks at 858 cm-1, 1169 cm-1, 1278 cm-1 and 1372 cm-1 for C-C stretching of the phenyl ring near both PA66 and PET surface, and 1236 cm-1 for C-O deformation were observed at all times near PA66. These show that the solution status near the PA66-solution and PET-solution interface was stable. The peak near PA66 in Figure 5b at 1633 cm-1 was also observed at all times, it seemed like shift from the one at 1618 cm-1, which stands for O-H bending. It suggests that the O-H group of paracetamols was constrained, which might form strong H-bonding interaction with PA66. The peaks near PET in Figure 5c at 1618 cm-1 for O-H bending are observed at all times too, without apparent Raman shifts. Thus, the O-H group of paracetamol near the PET surface was not constrained, and the interaction of paracetamol with PET is weaker than with PA66. The intensities of Raman characteristic peaks were shown in Figure 6. As shown in Figure 6a, without induction, the peak intensities at 858 cm-1 and 1169 cm-1 do not present a clear trend, which suggests that the concentration of paracetamol near the glass-solution interface varied in fluctuant status, it illustrates that the solute is difficult to gather and heteronucleate. As shown in Figure 6d, under the induction of PP film, the characteristic peak intensities at 858 cm-1, 1324 cm-1 and 1618 cm-1 increase as time increases but also floats a little, suggesting that the solute is difficult to gather and heterogeneously nucleate too. Figure 6c shows the characteristic peak intensity over time under the induction of PET. The intensities of peak at 858 cm-1, 1278 cm-1 and 1618 cm-1 were increased and then decreased with the process of crystallization, but the trend was not drastic. Figure 6c suggests that the paracetamol molecules gathered near the interface induced by PET, and the concentration


Page 12 of 34

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


increased to the maximum, then either decreased or was maintained. Figure 6b shows the characteristic peak intensities at 858 cm-1, 1169 cm-1 1278 cm-1, 1372 cm-1 and 1633 cm-1 under the induction of PA66. The trends of all characteristic peaks are consistent, this indicates that the paracetamol molecules gathered on the interface induced by PA66 too. During crystallization, concentration increased to the maximum, then decreased while the supersaturation was exhausted. Furthermore, the small peaks at 15 min suggest the secondary clustering during crystal growth. Compared with the peaks at the interface of PA66, PET, PP and glass, the order of intensities is PA66 > PET > glass and PP, which demonstrates the same adsorption capacity. The different concentration trend of paracetamol might provide evidence for the different preferential orientation of polymers, but this is not enough. Thus, to further study the mechanism at molecular level, molecular simulations were conducted. 3.4 Results of molecular simulations 3.4.1 Single paracetamol molecule interaction energies When carrying out molecular dynamic simulation, paracetamol molecules were adsorbed stably on the surface of PA66, which formed H-bonds. During the balanced steps, the benzene ring was parallel with the PA66 surface. The interaction energies were calculated using Eq. 1, and are listed in Table 1. The interaction energies between water and PA66 are also listed in Table 1, it can be found that the interaction of paracetamol and PA66 is much stronger than water, thus paracetamol molecules can be adsorbed on the surface of PA66 more easily than water molecules. Due to the hindering of numerous water molecules, it would be more difficult for paracetamol to form an H-bond with PA66 rather than without solvent. As shown in Figure 7a-d, all types of H-bond between paracetamol and PA66 were listed. From Table 1, the stability of different H-bond types can be analyzed, it can be found that the formation of the O—H···O H-bond (Figure 7a) is the easiest, and the N—H···O (Figure 7c) is the most difficult. Paracetamol molecules also can be stably adsorbed on the surface of PET during dynamic simulation, which formed H-bonds. During the balanced steps, the benzene ring was parallel with PET surface too.

The H-bond types of paracetamol adsorbed

on PET are shown in Figure 7e-f. The two main H-bond types between paracetamol and PET are the O—H···O (Figure 7e) and the N—H···O H-bond (Figure 7f), while the former is stronger than the latter, as listed in Table 1. They are weaker than the



H-bonds between paracetamol and PA66, but stronger than water and PET. The conjugate effect of benzene rings might result in the COO groups on PET chains attracting protons more difficult than PA66, also the NH groups on PA66 chains could participate in the formation of H-bonds, thus the inducted effect of PA66 is stronger than PET. Due to the lack of functional groups, there is no formation of H-bonds between paracetamol and PP. In the dynamic steps, paracetamol molecules can be adsorbed or close to the surface of PP, but there is no stable adsorption structure. On the interface, paracetamol molecules showed high mobility and would not stay on a particular surface area for a long time. The interaction energy between paracetamol and PP is -10.6~6.05 kcal·mol-1, which is weaker than that of PA66 and PET. However, the simulation results above still cannot fully explain the specific preferential orientation induced by different polymer films and the solvent effect to the adsorption conformation of paracetamol. Further exploration and mechanism research of the PIHn crystallization needs to be carried out. 3.4.2 Interaction energies of the preferential orientation In order to investigate the effect of PA66, PET and PP on paracetamol crystal facets, and describe the preferential orientation effect of the surface-induced nucleation and growth of paracetamol crystals, a non-solvated interface containing a series of paracetamol crystal facet clusters and different polymers were built. Then Eadsorption of the clusters and polymer was calculated and listed in Table 2, where a larger negative value of Eadsorption means easier absorption. For PA66, the lowest Eadsorption is (0 0 1) facet (-199.7 kcal·mol-1) and the highest is (2 1 0) facet (-76.5 kcal·mol-1). For PET, the lowest Eadsorption is (0 0 1) facet (-143.0 kcal·mol-1), and the highest is (2 1 0) facet (-50.7 kcal·mol-1). Furthermore, because there is no functional group on PP, Eadsorption on PP is much larger on every crystal facet. As a result, its total value sequence is PA66 < PET < PP, which is consistent with the results of induction time and PXRD. The interaction energies were divided into electrostatic and van der Waals components 26. For PA66 and PET, although the van der Waals component had a large proportion, it seems that the electrostatic part is the determinant, because their van der Waals component is quite close. While for PP, the electrostatic component is near to zero, and the van der Waals component contribution is lower than PA66 and PET, thus the total sequence is PA66 < PET < PP. For certain facets on PA66, (2 1 0) fact and (0 2 1) fact is very similar on van der Waals component, but (0 2 1) has more


Page 14 of 34

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


electrostatic component. Thus, the different chemical structures of interfaces result in the different electrostatic and van der Waals interactions, which cause the difference of Eadsorption, finally affecting the crystal growth on different polymers and resulting in the preferential orientation effect. Without considering the influence of solvent, the results above can only qualitatively illustrate the surface-induced effect and the preferential orientation during crystal nucleation and growth. To further investigate the heteronucleation mechanism on the polymer surface, the simulations of solvated interfaces were also performed and discussed as follows. 3.4.3 Interaction on solvated interfaces To simulate the process of paracetamol molecules gathering on the surface of PA66 and PET, as shown in the results of Raman, solvated interfaces were established by adding paracetamol molecules near the surface in a water-polymer two-phase box. Dynamic simulations were carried out to investigate the interactions of paracetamol molecules on solvated interfaces, Figure 8 and Figure 9 show the results for PA66 and PET respectively. All H-bond forms in Figure 7 can be found on interfaces. As the simulation process advances, the gathering of paracetamol molecules on PA66 is more obvious than PET. As shown in Figure 8, for PA66, some short-life clusters of paracetamol molecules are formed, other paracetamol molecules absorb to the interface with the benzene ring parallel. But for PET, Figure 9 indicates that nearly all paracetamol molecules are absorbed with benzene ring parallel. Similar phenomena, i.e. the disordered precursor cluster, was observed by SMRT-TEM technology34. Also, the pre-nucleation clusters were found in surface-induced calcium phosphate crystallization with preferential orientation among the (1 1 0) facet35. Thus, the different absorbed conformations of paracetamol on surface of PA66 or PET may induce the preferential orientation. This ability of clustering on the PA66 surface may be the reason of the second peaks at 15 min in Figure 6b, which affects the morphology of the product obtained. Radial distribution functions (RDFs) are defined as the ratio g(r) of the probability density ρ(r) that a particle distributes around a given particle in a distance and the probability of random distribution ρ:

g (r ) =

ρ (r ) ρ

(5)



thus, RDFs are an indicator which describes the probability that other particles distribute around a given particle. To further analyze the preferential orientation effect, the calculation of RDFs was conducted to characterize the H-bonding between paracetamol and PA66 or PET, Figure 10 shows the results, where the peaks near 2 Å represent H-bond interaction. Figure 10a-d stands for 4 kinds of PA66-paracetamol H-bonds, and Figure 10e-f stands for 2 kinds of PET-paracetamol H-bonds. Obviously, the H-bond interaction on PA66 is much stronger than PET, and there is no H-bond found for PP. For PA66-paracetamol interface, H-bond b, which represent the carbonyl oxygens of paracetamol and the hydrogens on the NH groups in PA66, is the strongest, the H-bond a, which represents the hydrogens on phenolic O-H groups of paracetamol and carbonyl oxygens of PA66, is the second, and H-bond c, which stands for hydrogens on the NH groups of paracetamol and carbonyl oxygens of PA66, is the weakest. Figure 11 shows the structure of (0 0 1) facet (a) and (2 0 -1) facet (b) of paracetamol. As shown in Figure 11a, there are more exposed carbonyl oxygens and phenolic O-H groups on the (0 0 1) facet crystals, and more exposed NH groups on (2 0 -1) facet crystals. The crystals with (0 0 1) facets exposed are more likely to form the stronger H-bond a and b, and the crystals with (2 0 -1) facets exposed are more likely to form the weaker H-bond c, thus the crystals that grew on the surface of PA66 may perform the preferential orientation effect among (0 0 1) facets. For the PET-paracetamol interface, H-bond e, which represents the hydrogens on the NH groups of paracetamol and the carbonyl oxygens of PET, is stronger than H-bond f which represents the hydrogens on phenolic O-H groups of paracetamol and the carbonyl oxygens of PET. As shown in Figure 11b, there are also more exposed carbonyl oxygens and phenolic O-H groups on the (0 0 1) facet crystals while more exposed NH groups on (2 0 -1) facet crystals. The crystals with (2 0 -1) facets exposed are more likely to form the stronger H-bond e, but the crystals with (0 0 1) facet exposed are more likely to form the weaker H-bond f. Thus it is different from PA66, the preferential orientation effect among the (2 0 -1) facets is also strong. Furthermore, during the molecular dynamic simulation, it was found that the H-bonds on PA66 can maintain over 50 ps but the H-bonds on PET cannot maintain over 5 ps at all, thus the H-bonds on PA66 are more stable than H-bonds on PET. This is another reason why the H-bond effect on PA66 is stronger than that on PET. This may explain the results of Raman, i.e. the peaks representing the O-H bending of


Page 16 of 34

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


paracetamol molecules shows a blue shift on PA66, because the phenolic O-H group was constrained, and formed strong H-bonds with PA66. While the H-bonds with PET are too weak to cause the blue shift of O-H bending. Due to the differences in H-bonding orientations caused by respective functional groups on the surface of PA66 and PET, the simulation results above may explain why PA66 caused the preferential orientation along the (0 0 1) facet in the paracetamol nucleation process, while PET along (0 0 1) and (2 0 -1) facet. PP has no orientation induction effect because there were no effective functional groups in preferential orientation growth of paracetamol. In summary, the different functionally-induced effect of polymers results in the different formation of H-bonds, then induces the different crystal facets growth, finally affecting the crystal morphology with preferential orientation. 3.5 Validation by the modified PP films Figure 12a shows the C1s spectrums of surface modified PP, it is different to the XPS results of PP films, which suggests that there are C-C, C-N, C-O or C-OH, and CONH or COO groups on the modified PP surface with a relative content of 40.3%, 17.2%, 12.5% and 30.0% respectively, this result indicates the successful modification of PP, where the part of C-C, C-N, C-O or C-OH groups is similar to PA66 in Figure 2. Figure 12b shows the paracetamol crystal habits and PXRD patterns induced by the modified PP film, interestingly the PXRD pattern exhibits predominant reflections at 13.9o (0 0 1), 15.4o (2 0 -1), 18.1o (2 1 0), 24.4o (2 2 0) and 28.1o (0 0 2). Although there are some facets in the crystals like that induced by PET, i.e. 15.4o (2 0 -1) and 18.1o (2 1 0), the reflection at 13.9o is the strongest, it suggests that the preferential orientation along the (0 0 1) facet happened, which is similar to PA66, because there are similar functional groups on the surface of the film. It verifies the functionally-induced mechanism proposed in Section 3.4.

4. CONCLUSION Paracetamol heteronucleation and growth on PA66, PET and PP films with different functional groups on surfaces was investigated. The average induction time under the induction of PA66, PET, PP or no template is 11.5 s, 15.6 s, 20.2 s and 32.5 s, respectively, i.e. the induced ability was PA66 > PET > PP > no template in the crystallization of paracetamol. PXRD results suggested that the paracetamol crystals



Page 18 of 34

nucleated with a different preferential orientation effect, i.e. for PA66 among (0 0 1), for PET among (2 1 0) and (0 0 1) facets, and for PP or no template there are no obvious preferential effects. The results of in-situ Raman microscope verified the different concentration trends near different films, which is consist with the preferential orientation effect of films. The results of molecular dynamic simulations, i.e. the H-bond energy between paracetamol molecule and films, the adsorption energy between paracetamol cluster and films, and the gathering dynamic of solvated interfaces, agreed with the experiments, which provided a deep insight into preferential orientation differences. It was found that the different functional-induced effects of films resulted in the different formation of H-bonds, then induced the different crystal facets growth with preferential orientation. The PP modified with functional groups similar to PA66 provided a preferential orientation effect similar to PA66, it confirmed the functional-induced mechanism we proposed. The results are useful to deepen understanding of the induced crystallization.

AUTHOR INFORMATION Corresponding Author * Tel.: +86-20-8711-2051. E-mail: [email protected].

Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS Financial support from the National Natural Science Foundation of China (Nos. 21776102,

21676097)

and

Guangdong

Natural

Science

Foundation

(No.

2014A030312007) is greatly appreciated. The authors appreciate Dr. Libo Li for providing thoughtful technology support of molecular simulation.

ABBREVIATIONS API, active pharmaceutical ingredient; MD , molecular dynamic; PA66, nylon 66; PET, polyester; PIHn, polymer-induced heteronucleation; PP, polypropylene; PXRD, powder X-ray diffraction; RDF, Radial distribution function; XPS, X-ray photoelectron spectroscopy.


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


REFERENCES (1) Wu, H.; Dong, Z.; Li, H.; Khan, M., An Integrated Process Analytical Technology (PAT) Approach for Pharmaceutical Crystallization Process Understanding to Ensure Product Quality and Safety: FDA Scientist’s Perspective. Org. Process Res. Dev. 2015, 19, 89-101. (2) Desiraju, G. R., Crystal engineering: from molecule to crystal. J. Am. Chem. Soc. 2013, 135, 9952-9967. (3) Randolph, A. D.; Larson, M. A., Transient and steady state size distributions in continuous mixed suspension crystallizers. Aiche J. 1962, 8, 639-645. (4) Lee, A. Y.; Erdemir, D.; Myerson, A. S., Crystal Polymorphism in Chemical Process Development. Annu. Rev. Chem. Biomol. 2011, 2, 259-280. (5) Mugheirbi, N. A.; Tajber, L., Crystal Habits of Itraconazole Microcrystals: Unusual Isomorphic Intergrowths Induced via Tuning Recrystallization Conditions. Mol. Pharmacol. 2015, 12, 3468-3478. (6) Datta, S.; Grant, D. J., Crystal structures of drugs: advances in determination, prediction and engineering. Nat. Rev. Drug. Discov. 2004, 3, 42-57. (7) Fujiwara, M.; Nagy, Z. K.; Chew, J. W.; Braatz, R. D., First-principles and direct design approaches for the control of pharmaceutical crystallization. J. Process Contr. 2005, 15, 493-504. (8) Nokhodchi, A.; Bolourtchian, N.; Dinarvand, R., Crystal modification of phenytoin using different solvents and crystallization conditions. Int. J. Pharmaceut. 2003, 250, 85-97. (9) Song, R.-Q.; Cölfen, H., Additive controlled crystallization. CrystEngComm 2011, 13, 1249-1276. (10) Meldrum, F. C.; Ludwigs, S., Template‐Directed Control of Crystal Morphologies. Macromol. Biosci. 2007, 7, 152-162. (11) Lang, M.; Grzesiak, A. L.; Matzger, A. J., The use of polymer heteronuclei for crystalline polymorph selection. J. Am. Chem. Soc. 2002, 124, 14834-14835. (12) Lopez-Mejias, V.; Kampf, J. W.; Matzger, A. J., Nonamorphism in flufenamic acid and a new record for a polymorphic compound with solved structures. J. Am. Chem. Soc. 2012, 134, 9872-9875. (13) López-Mejías, V.; Kampf, J. W.; Matzger, A. J., Polymer-induced heteronucleation of tolfenamic acid: Structural investigation of a pentamorph. J. Am. Chem. Soc. 2009, 131, 4554-4555. (14) Roy, S.; Goud, N. R.; Matzger, A. J., Polymorphism in phenobarbital: discovery of a new polymorph and crystal structure of elusive form V. Chem. Commun. 2016, 52, 4389-4392. (15) Grzesiak, A. L.; Matzger, A. J., Selection of protein crystal forms facilitated by polymer-induced heteronucleation. Cryst. Growth Des. 2007, 8, 347-350. (16) Pfund, L. Y.; Matzger, A. J., Towards exhaustive and automated high-throughput screening for crystalline polymorphs. ACS Comb. Sci. 2014, 16, 309-313. (17) Chadwick, K.; Myerson, A.; Trout, B., Polymorphic control by heterogeneous nucleation - A



new method for selecting crystalline substrates. CrystEngComm 2011, 13, 6625-6627. (18) Sudha, C.; Nandhini, R.; Srinivasan, K., Polymer-Induced Selective Nucleation of Mono or Ortho Polymorphs of Paracetamol through Swift Cooling of Boiled Aqueous Solution. Cryst. Growth Des. 2014, 14, 705-715. (19) Hsu, H.; Adigun, O. O.; Taylor, L. S.; Murad, S.; Harris, M. T., Crystallization of acetaminophen on chitosan films blended with different acids. Chem. Eng. Sci. 2015, 126, 1-9. (20) Lopez-Mejias, V.; Knight, J. L.; Brooks, C. L., 3rd; Matzger, A. J., On the mechanism of crystalline polymorph selection by polymer heteronuclei. Langmuir 2011, 27, 7575-7579. (21) Liang, Z.; Wang, Y.; Wang, W.; Han, X.; Chen, J. F.; Xue, C.; Zhao, H., Structural Correspondence of the Oriented Attachment Growth Mechanism of Crystals of the Pharmaceutical Dirithromycin. Langmuir 2015, 31, 13802-13812. (22) Liang, S.; Yu, S.; Zhou, N.; Deng, J.; Gao, C., Controlling the selective and directional migration of hepatocytes by a complementary density gradient of glycosylated hyperbranched polymers and poly(ethylene glycol) molecules. Acta biomater. 2017, 56, 161-170. (23) Wang, H.; Feng, J.; Liu, G.; Chen, B.; Jiang, Y.; Xie, Q., In vitro and in vivo anti-tumor efficacy of 10-hydroxycamptothecin polymorphic nanoparticle dispersions: shape- and polymorph-dependent cytotoxicity and delivery of 10-hydroxycamptothecin to cancer cells. Nanomed. Nanotechnol. 2016, 12, 881-891. (24) Nanubolu, J. B.; Burley, J. C., In situ Raman mapping for identifying transient solid forms. CrystEngComm 2015, 17, 5280-5287. (25) Salvalaglio, M.; Perego, C.; Giberti, F.; Mazzotti, M.; Parrinello, M., Molecular-dynamics simulations of urea nucleation from aqueous solution. P. Natl. Acad. Sci. USA 2015, 112, 6-14. (26) Liu, Y.; Lai, W.; Yu, T.; Ma, Y.; Kang, Y.; Ge, Z., Understanding the growth morphology of explosive crystals in solution: insights from solvent behavior at the crystal surface. RSC Adv. 2017, 7, 1305-1312. (27) Yin, Y.; Chow, P. S.; Tan, R. B. H., Glycine Open Dimers in Solution: New Insights into α-Glycine Nucleation and Growth. Cryst. Growth Des. 2012, 12, 4771-4778. (28) Diao, Y.; Myerson, A. S.; Hatton, T. A.; Trout, B. L., Surface design for controlled crystallization: the role of surface chemistry and nanoscale pores in heterogeneous nucleation. Langmuir 2011, 27, 5324-5334. (29) Poornachary, S. K.; Chow, P. S.; Tan, R. B. H., Effect of solution speciation of impurities on α-glycine crystal habit: A molecular modeling study. J. Cryst. Growth 2008, 310, 3034-3041. (30) Cai, Z.; Liu, Y.; Song, Y.; Guan, G.; Jiang, Y., The effect of tailor-made additives on crystal growth of methyl paraben: Experiments and modelling. J. Cryst. Growth 2017, 461, 1-9. (31) Parambil, J. V.; Poornachary, S. K.; Hinder, S. J.; Tan, R. B. H.; Heng, J. Y. Y., Establishing template-induced polymorphic domains for API crystallisation: the case of carbamazepine. CrystEngComm 2015, 17, 6384-6392. (32) Curcio, E.; Lópezmejías, V.; Profio, G. D.; Fontananova, E.; Drioli, E.; Trout, B. L.; Myerson,


Page 20 of 34

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


A. S., Regulating Nucleation Kinetics through Molecular Interactions at the Polymer–Solute Interface. Cryst. Growth Des. 2015, 14, 678–686. (33) Al-Zoubi, N.; Koundourellis, J.; Malamataris, S., FT-IR and Raman spectroscopic methods for identification and quantitation of orthorhombic and monoclinic paracetamol in powder mixes. J. Pharmaceut. Biomed. 2002, 29, 459-467. (34) Harano, K.; Homma, T.; Niimi, Y.; Koshino, M.; Suenaga, K.; Leibler, L.; Nakamura, E., Heterogeneous nucleation of organic crystals mediated by single-molecule templates. Nat. Mater. 2012, 11, 877-881. (35) Dey, A.; Bomans, P. H.; Muller, F. A.; Will, J.; Frederik, P. M.; de With, G.; Sommerdijk, N. A., The role of prenucleation clusters in surface-induced calcium phosphate crystallization. Nat. Mater. 2010, 9, 1010-1014.



Table and Figure Captions Table 1. Hydrogen bonding parameters of paracetamol and H2O with films Table 2. Interaction energy of different crystal facet clusters with different films including van der Waals and electrostatic components (kcal·mol-1)

Figure 1. Cumulative probability distribution (a) and ln P of induction time (b) for paracetamol nucleation induced by different films

Figure 2. The C1s spectrum of different films from XPS. (a) PA66, (b) PET, (c) PP Figure 3. Paracetamol crystal habits and PXRD patterns induced by different templates. (a) Glass, (b) PA66, (c) PET, (d) PP.

Figure 4. The PXRD patterns of the polymer films. (a) PA66, (b) PET, (c) PP Figure 5. Raman patterns for paracetamol aqueous solution for different templates. (a) Glass, (b) PA66, (c) PET, (d) PP at different times.

Figure 6. The intensities of Raman characteristic peaks for different templates. (a) Glass, (b) PA66, (c) PET, (d) PP at different times.

Figure 7. H-bond types of paracetamol adsorbed on PA66 and PET surface. (Legends: red = O, white = H, gray = C, blue = N, the same below)

Figure 8. Interface between paracetamol aqueous solution and PA66 at different time. Figure 9. Interface between paracetamol aqueous solution and PET at different time. Figure 10. RDF curves of six kinds of H-bond atoms. Figure 11. The structure of (0 0 1) (a) and (2 0 -1) (b) facets for paracetamol crystal. Figure 12. (a) The C1s spectrum of the modified PP films from XPS. (b) Paracetamol crystal habits and PXRD patterns induced by the modified PP films


Page 22 of 34

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


Tables Table 1. Hydrogen bonding parameters of paracetamol and H2O with films Interaction Energy / kcal·mol-1

Hydrogen Bonding Type 1. O—H···O

-28.6~ -25.5

2. O···H—N

-28.6~ -26.8

3. N—H···O

-27.1~ -23.9

4. O···N—H

-26.9~ -26.6

1. O—H···O

-22.0~ -15.7

2. N—H···O

-21.2~ -17.8

/

-10.6~ -6.05

1.O—H···O

-8.42~ -7.59

2.O···H—N

-8.84~ -8.83

PET and H2O

1.O—H···O

-7.11~ -7.10

PP and H2O

/

-1.18~ -0.81

PA66 and paracetamol

PET and paracetamol PP and paracetamol PA66 and H2O

Table 2. Interaction energy of different crystal facet clusters with different films including van der Waals and electrostatic components (kcal·mol-1) PA66

PET

PP

Crystal Facets Van der Electrostatic Waals (1 1 0)

Total

Van der Waals

Electrostatic

Total

Van der Waals

Electrostatic

Total

-71.38

-67.78

-139.16

-72.37

-13.74

-86.11

-15.35

0.21

-15.14

(0 0 1) -119.32

-77.07

-196.39

-94.84

-42.99

-137.83

-81.20

0.57

-80.62

(2 0 -1) -114.90

-49.62

-164.52

-114.47

-17.49

-131.96

-66.38

-0.46

-66.84

(0 1 1)

-59.59

-46.63

-106.22

-45.74

-39.14

-84.88

-34.11

-0.14

-34.25

(2 1 0)

-37.85

-28.47

-66.32

-36.11

-17.96

-54.07

-43.51

0.27

-43.24

(0 2 1)

-99.43

-79.15

-178.59

-86.86

-34.34

-121.20

-74.18

-0.29

-74.47

(2 1 1)

-77.99

-54.38

-132.37

-41.86

-18.85

-60.71

-43.62

-0.19

-43.81



Figures

1.0

Cumulative probability

(a) 0.8

Glass PA66 PET PP

0.6 0.4 0.2

0

20

40

60

80

100

120

140

Induction Time (s) 0.0

(b)

-0.5

Glass PA66 PET PP

-1.0 -1.5

ln P

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

Page 24 of 34

-2.0 -2.5 -3.0 -3.5 -4.0 0

20

40

60

80

100

120

140

Induction Time (s)

Figure 1. Cumulative probability distribution (a) and ln P of induction time (b) for paracetamol nucleation induced by different templates.


Page 25 of 34

30000

(a)

Intensity

25000

C-C

20000 15000 CONH 10000

C-N C-O/C-OH

5000 0

292

290

288 286 284 Binding Energy (eV)

282

280

24000

(b) 20000 π

Intensity

16000 12000 COO- C-O

8000 4000 0

294

50000

292

290

288 286 284 282 Binding Energy (eV)

280

(c)

40000 C-C

Intensity

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


30000 20000 10000 0

290

288

286 284 282 Binding Energy (eV)

280

Figure 2. The C1s spectrum of different films from XPS. (a) PA66, (b) PET, (c) PP.



Figure 3. Paracetamol crystal habits and PXRD patterns induced by different templates. (a) Glass, (b) PA66, (c) PET, (d) PP.


Page 26 of 34

Page 27 of 34

(a)

Relative Intensity

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


(b)

(c)

5

10

15

20

25

30

35

40

45

50

2θ (o)

Figure 4. The PXRD patterns of the polymer films. (a) PA66, (b) PET, (c) PP.



800

(a)

0 min 3 min 6 min 9 min 12 min 15 min 18 min 21 min

counts (a.u.)

600 400 200 0

-200 -400

800

1000

4000

2000

counts (a.u.)

1200 1400 Raman swift (cm-1)

1600

1800


1600

1800


(b) 3000

1000 0 -1000 -2000 800 3000

1000


(c) 800

2500

counts (a.u.)

600

2000

400 200

1500

0

1000

800

900

1000

1100

1200

1300

1400

500 0 800 250

1000


1600

(d)

1800 0 min 3 min 6 min 9 min 12 min 15 min 18 min 21 min

200

counts (a.u.)

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

Page 28 of 34

150 100 50 0 800

1000


1600

1800

Figure 5. Raman patterns for paracetamol aqueous solution for different templates. (a) Glass, (b) PA66, (c) PET, (d) PP at different times.


Page 29 of 34

600

(a)

858 cm-1 1169 cm-1

500

(b)

4000

858 cm-1

1169 cm-1

1278 cm-1

1372 cm-1 1633 cm-1

counts (a.u.)

3000 400

2000

300

1000

200

0

100

-1000 0

3

6

9

12

15

18

21

-2000

0

3

6

time (min)

9

12

15

18

21

time (min) 250

(c)

1600 1400

1000 800

(d)

200

858 cm-1 1169 cm-1 1278 cm-1 1372 cm-1 1618 cm-1

1200

counts (a.u.)

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


858 cm-1 1324 cm-1 1618 cm-1

150 100

600

50

400 200 0

0 0

3

6

9

12

15

18

21

0

3

time (min)

6

9

12

15

18

21

time (min)

Figure 6. The intensities of Raman characteristic peaks for different templates. (a) Glass, (b) PA66, (c) PET, (d) PP at different times.

Figure 7. H-bond types of paracetamol adsorbed on PA66 and PET surface. (Legends: red = O, white = H, gray = C, blue = N, the same below)



Figure 8. Interface between paracetamol aqueous solution and PA66 at different time

Figure 9. Interface between paracetamol aqueous solution and PET at different time.


Page 30 of 34

Page 31 of 34

50 45

Corresponding to Fig. 6a Corresponding to Fig. 6b Corresponding to Fig. 6c Corresponding to Fig. 6d Corresponding to Fig. 6e Corresponding to Fig. 6f

40 35 30

G (r)

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


25 20 15 10 5 0 0

1

2

3

4

5

6

7

8

9

10

R/ang

Figure 10. RDF curves of six kinds of H-bond atoms.

Figure 11. The structure of (0 0 1) (a) and (2 0 -1) (b) facets for paracetamol crystal.



Figure 12. (a) The C1s spectrum of the modified PP films from XPS. (b) Paracetamol crystal habits and PXRD patterns induced by the modified PP films.


Page 32 of 34

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


(For Table of Contents Use Only)

The preferential orientation effect of polymers on paracetamol crystallization: experiments and modelling Yang Song, Zhihui Cai, Zhixian Li, Guoqiang Guan, Yanbin Jiang*

TOC Graphic

Synopsis The preferential orientation effect of polymer films on paracetamol crystal was studied. Concentration trends of paracetamol near films were measured using in-situ Raman microscope. Molecular simulation provided a deep insight into preferential orientation differences. And The mechanism of preferential orientation was validated using modified PP film.



ORCID Yang Song, 0000-0003-3335-3243, Zhihui Cai, 0000-0002-7552-3952, Zhixian Li, 0000-0002-6721-536X, Guoqiang Guan, 0000-0002-4463-2187 Yanbin Jiang, 0000-0001-8984-0302


Page 34 of 34

Preferential Orientation Effect of Polymers on Paracetamol

Recommend Documents