Tuning the solution-mediated concomitant phase transformation

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Tuning the solution-mediated concomitant phase transformation outcome of the Piroxicam monohydrate by two hydroxylcontaining additives: Hydroxypropyl cellulose and H2O Changlin Yao, Yifan Li, Lei Wang, Shuang Song, Yang Liu, and Xutang Tao Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00936 • Publication Date (Web): 06 Dec 2018 Downloaded from http://pubs.acs.org on December 10, 2018

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Crystal Growth & Design

Tuning the solution-mediated concomitant phase transformation outcome of the Piroxicam monohydrate by two hydroxyl-containing additives: Hydroxypropyl cellulose and H2O Changlin Yao,a Yifan Li,b Lei Wang,*a Shuang Song,a Yang Liu,a Xutang Tao* a aState

Key Laboratory of Crystal Materials, Shandong University, Jinan, 250100, China

bKey

Laboratory for Liquid−Solid Structural Evolution and Processing of Materials, Ministry of Education, Shandong University, Jinan, 250100, China ABSTRACT: Solution-mediated concomitant phase transformation (SMCPT) of the Piroxicam (PCM) monohydrate was found. The PCM monohydrate could simultaneously transform to block Form I and needle Form II in acetone at 31 °C. But the Form I and the Form II can be selectively grown in the presence of 0.04 mg/ml HPC and 1 % H2O, respectively. In addition, the morphology of Form I is changed from block to rod-like or even needle with the increase of the concentration of HPC. Based on these phenomena, the role of Hydroxypropyl cellulose (HPC) and H2O in the solution-mediated concomitant phase transformation were studied. The mechanisms of HPC and H2O to affect the process of SMCPT of the PCM monohydrate are different. In the presence of 0.04 mg/ml HPC, the interactions between the HPC molecules and the PCM molecules was the main factor that governed the process of SMCPT of the PCM monohydrate. But in the presence of 1 % H2O, the driving force of SMCPT played the main role. In our work, the outcome of SMCPT could be tuned directly by additives for the first time, which provide a good guide to obtain the pure polymorph in the SMCPT for pharmaceutical industry.

INTRODUCTION Polymorphism has different crystalline forms with the same elemental composition of a given chemical substance, while solvate-polymorphism differs in their elemental composition through the inclusion of one or more molecules of solvent, besides, it has different structure.1 Polymorphism and solvate-polymorphism are common phenomena in the manufacture of pharmaceuticals.2, 3 The crystals of pharmaceutical may form different morphology and polymorphs under different conditions such as the degree of supersaturation, temperature and pressure and so on.4-6 Sometimes, two or more polymorphs would crystallize under essentially conditions simultaneously, which is called concomitant crystallization.7-9 That will affect quality and even safety of a drug product. So the crystallization of pharmaceutical is a requisite step for pharmaceutical industry and it is essential for pharmaceutical industry to control the morphology and obtain the pure polymorph.10-12 During the solution crystallization, the metastable polymorph would initially crystallized from the solution. If the metastable polymorph continues to interact with a bulk solution for a period of time, the metastable polymorph would dissolve and a more stable polymorph would nucle-

ate and grow. That is known as solution-mediated phase transformation (SMPT).13-15 Some studies have found that the different operating parameters such as solvents, temperature, loadings and so on have great influence on the rate of the SMPT.15-17 Especially, some polymer additives including HPC, Hydroxypropyl methylcellulose (HPMC), Ethyl cellulose (EC) could delay the transformation time and even inhibit the process of SMPT.18, 19 The nucleation of the stable polymorph on the metastable polymorph is an important step during the process of SMPT. Therefore, more attentions have been focus on the relationships between the metastable phase and the stable phase to investigate the role of surface of the existing form in solution-mediated phase transformation. The existence of crystallographic and chemical matching (epitaxy) between the surfaces of the metastable polymorph and the stable polymorph has been verified in the literature.20 Recently Croker group reported the FV Sulphathiazole simultaneously transformed into FII and FIV sulphathiazole in ethanol at 10 °C.21 We will term it solution-mediated concomitant phase transformation (SMCPT). However, little has been done to investigate how to tune the outcome of the SMCPT directly by additives. The mechanisms of additives

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Figure 1. The molecular structure of (a) Piroxicam, (b) HPC and (c) BHNH; The photos of (d) Form I, (e) Form II and (f) the PCM monohydrate. The scale bar is 100 μm.

to control the SMCPT is still not understood well. Thus in order to engineer the desirable polymorph in solution, investigating and understanding the possible mechanisms of SMCPT under different conditions are critical. Piroxicam (Figure 1a), a non-steroidal anti-inflammatory drug, is used as the model compound here which was reported to have the monohydrate and four polymorphs.2224 The Form II is the most stable one with respect to others at room temperature. Though Form I is metastable at room temperature, the Form I crystals could also be stable for months in solid. Form I, Form II and the PCM monohydrate (Figure 1 d-f) could be distinguished easily because of the different morphology and colors. Form III and Form IV, which are unstable at room temperature could be produced under extreme conditions will not be discussed here.25,26 In this study, we found that the PCM monohydrate could transform to the Form I and Form II simultaneously in acetone. To avoid the SMCPT, the HPC and H2O containing hydroxyl groups were selected as additives. Here we called H2O as an additive because the amount of it was less than 1% in our study. Interestingly, the outcome of the SMCPT of the PCM monohydrate were totally different in the presence of HPC and H2O. We successfully obtained exclusive Form I and Form II in the presence of 0.04 mg/ml HPC and 1 % H2O, respectively. Besides, in the presence of HPC, the morphology of Form I obtained by SMPT of the PCM monohydrate could be changed from block to rod-like or even needle depended on the concentration of HPC. In order to give a better insight into the mechanisms of the two kinds of hydroxylcontaining additives on the SMCPT of the PCM monohydrate, a detailed analysis of two different aspects including the phase transformation driving force of the PCM monohydrate in acetone and molecular interactions in the absence and presence of additive have been accomplished. Our work enable a better control the crystal morphology and polymorph obtained by the SMPT for pharmaceutical industry.

EXPERIMENTAL SECTION Materials Piroxicam (purity was ≥ 99 % and without further purification, Form I which is verified by PXRD) was purchased from Shanghai Yuanye Bio-Technology Co Ltd. The Form II of PCM was obtained by stirring Form I in acetone for 12 h at room temperature (verified by PXRD). Hydroxypropyl cellulose (HPC, Figure 1b), 2,2Bis(hydroxymethyl)-2,2',2''-nitrilotriethanol (BHNH, Figure 1c), Trimethylolpropane (TMP, Figure S1a), Isonicotinamide (ISO, Figure S1b) and Octacosane (Figure S1c) were purchased from Macklin. Analytical grade acetone and ultrapure water (Milli-Q Gradient A10, Millipore, USA) were used as solvent in our experiments. Analytical Tools of characterization X-ray powder diffraction (XRPD) patterns were obtained on a Bruker D8 Advance with Cu Kα radiation (40 kV, 40 mA). A sample was placed on a silicon plate at room temperature. Data were collected from 10° to 45° (2θ) at a step size of 0.02° and a scanning speed of 6°/min. Polarized optical microscope (Leica DM2700P) equipped with CCD camera and hot stage (Lincoln THMS600, ± 0.1℃) was utilized to monitor the process of SMPT of the PCM monohydrate at constant temperature. The crystallization of the PCM monohydrate 100 mg PCM was dissolved into the 6 ml solvent with 96% acetone and 4% water. The resulting solution was stirred for two hours to make it clear. Then the solution was filtered and evaporated slowly at room temperature. The yellow crystals were obtained after one week and affirmed by PXRD. After that, the PCM monohydrate was stored in a vacuum drying chamber. The “relative stability” of anhydrate and hydrate of PCM was determined by stirring the Form I and Form II powder for a period of time in 96% acetone-4% H2O respectively before the crystallization of the PCM monohydrate. Both the Form I and Form II could transform to the PCM


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monohydrate, indicating the PCM monohydrate is more “stable” in 96% acetone-4% H2O. This is the reason that the 96% acetone-4% H2O was selected as solvent to produce the PCM monohydrate crystals. The anhydrate and hydrate are chemically different, so quotation marks are added in “relative stability” and “stable”. In situ microscopic observation and off-line PXRD experiments of the SMCPT of the PCM monohydrate The pre-saturated solution with respect to Form I (22.5 mg/ml in acetone) was prepared at 31℃. 100 mg PCM was dissolved in 4 ml acetone and held for 30 min at 45℃ to dissolve all the PCM solid. The solution were then held 1 hour at 31 ℃ to make the temperature cool down 31℃ prior to the addition of the PCM monohydrate. A sealable transparent quartz holding cell was home made for observing the process of the SMCPT. The 8 mg PCM monohydrate were added into the cell containing 800 ul pre-saturated solution. The process of SMCPT of the PCM monohydrate was recorded by hot stage polarized optical microscope with the CCD camera (1 picture / 1 second using the automated software). The new formed crystals produced in the process of transformation in the cell were extracted separately by picking up crystals using the microscope and confirmed by PXRD without grind. 20mg PCM monohydrate was added into test tubes with 2 ml pre-saturated solution and kept still at 31 ℃. Samples of crystals formed in individual tubes were immediately filtered after 20, 40, 60, 80, 100 min and dried under vacuum. The polymorphic composition of the dried crystals were confirmed by PXRD.20 The load of the PCM monohydrate in the solution in all experiments is 10 mg/ml. The percentage of the water released by the PCM monohydrate crystals after transformation is 0.52‰ calculated by the equation in Support information. It is the same in all experiments. Besides, the amount of it is so little. As the result, it could be ignored it in our work. The SMPT of the PCM monohydrate with different concentrations of HPC A series of different concentrations of HPC in acetone (0, 0.02 mg/ml, 0.04 mg/ml, 0.2 mg/ml, 2 mg/ml, 4 mg/ml) were prepared. The HPC solution was used as solvent to prepare 22.5 mg/ml PCM solution at 31℃. Later, 20 mg millimeter-sized PCM monohydrate was put into the 2 ml PCM solution (22.5 mg/ml) with the different concentrations of HPC and stayed still at 31℃ for a period of time to observe the SMPT process. After the transformation was completed, the crystals were obtained by filtration and dried under vacuum, then photographed with polarized optical microscope. The polymorph was confirmed by XRPD. The SMPT of the PCM monohydrate with BHNH, TMP, Octacosane and ISO 2 mg/ml BHNH-acetone solution, 15 mg/ml TMP-acetone solution, 0.5 mg/ml Octacosane-acetone solution and 15 mg/ml ISO-acetone solution were prepared and ultrasound for half an hour. The rest of

the operation was the same as above “The SMPT of the PCM monohydrate with different concentrations of HPC”. In situ microscopic observation of the SMPT of the PCM monohydrate with H2O Different volume percentages of H2O (0.25 %, 0.5 %, 0.75 %, 1 % and 1.2 %) acetone solutions were prepared. The water-acetone solutions as solvents to prepare 22.5 mg/ml PCM solutions as the above method. 8 mg PCM monohydrate was added into the cell containing 800 ul PCM solution (22.5 mg/ml ) with different volume percentages of water at 31℃ and the process of SMPT of the PCM monohydrate was observed and recorded by the microscope with the CCD camera ( 1 picture / 5 minutes using the automated software ). Solubility measurements The solubility of Form II in solvents including acetone, (0.25%, 0.5%, 0.75%, 1%) H2Oacetone and 0.04 mg/ml HPC -acetone at 31 ℃ was measured with gravimetric method.16 Excess amounts of the Form II was dissolved in 5 ml solvents to saturate the solution. After stirring Form II in solvents for 3 hours16 at 31℃, a certain amount of suspension was filtered through 0.22 μm filter membrane and dried at room temperature until the solvent was completely evaporated. The solubility was determined from the mass of the remaining crystalline material. Because of the relatively fast transition rate of the Form I and the PCM monohydrate in the same solvents, the above solubility measurements could not be applied well. In order to improve the accuracy of solubility measurements of the Form I and the PCM monohydrate, the saturated solution with respect to Form II was prepared firstly. After that, 3 mg Form I and PCM monohydrate were added into the solution every 10 minutes respectively until the solution could not continue to dissolve,27 the suspension was treated as the above gravimetric method to obtain the solubility of the Form I and the PCM monohydrate.16 To make sure the SMPT did not occur during the solubility measurements, the polymorph of the remaining undissolved crystals was confirmed by XRPD after being filtered and dried. The solubility was obtained by the average of three solubility measurements and the error limits were given in Support information Table S1. Molecular Modeling Density Functional Theory (DFT) Calculations The strength of interaction of PCM-HPC associate ( in order to make the calculation feasible, the degree of polymerization of HPC was set as 3 ) was investigated by DFT calculations using a Gaussian 09 package.28 Meanwhile, (1:1) binding interactions of PCM-PCM dimer of Form I and Form II are also quantified. The geometries of all stationary points were optimized using the B3LYP density functional method with the Gaussian-type 6-31G (d) basis set29 for all the atoms. To consider solvation effects, single-point energy computations using the PCM model with acetone as the solvent were performed based on the optimized gasphase geometries of all species. The single-point energy calculations were carried out using the B3LYP functional in combination with the 6-311++G (d, p) basis set to provide



better energy correction.30 The (1:1) binding energy in a dimer is calculated as follows: ∆𝐸𝑏𝑖𝑛𝑑 = 𝐸𝐴𝐵 ― (𝐸𝐴 + 𝐸𝐵)

(1)

Where EAB is the energy of a dimer AB and EA and EB are energies of the isolated molecules A and B. Recently, this methodology combined experiments has been successfully applied for the nucleation studies of some API molecules including carbamazepine, salicylic acid and parabens.31-33 Molecular Dynamics Simulation Molecular dynamics simulation has been carried out to calculate the interaction energies between HPC and (011), (001) planes of Form I of PCM using the Accelry Materials Studio (Version 6.1). The molecular weight of HPC was set as 10000 g/mol with n = 34. The crystal of Form I was cleaved out to depth of one unit cell and the two surfaces were extended to 8 × 8 and 4 × 12 unit cell respectively to obtain a similar surface area for adsorption, then a 240 Å thick vacuum slab was built above the two crystal faces. The Condensed-phase Optimized Molecular Potentials for Atomistic Simulation Studies (COMPASS) Forcefield34 which has been proven to be successfully applicable for the molecular simulation study of polymer35, 36 and other macromolecules37 was applied to model the atomic interactions in our study. The temperature is chosen at 298 K in the NVT canonical ensemble (number of particles, volume, temperature are

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constant) and the Nose thermostat is used to control the thermodynamic temperature and generate the correct statistical ensemble. The time integration of the Newton’s equation of motion is undertaken using the velocity Verlet algorithm. The simulation time step is 1.0 fs. Each system is simulated for a sufficient time to reach equilibrium. The relaxed, equilibrated and movable additives were placed randomly on the fixed crystal surfaces during the simulation runs. Equilibration was determined by observing the change in the thermodynamic properties as a function of time. The equilibrated structures were then minimized with a geometry optimization procedure and the crystal surfaces-additives interaction energies were obtained using the following equation: 𝐸𝑖𝑛𝑡𝑒𝑟𝑎𝑐𝑡𝑖𝑜𝑛 = 𝐸𝑡𝑜𝑡𝑎𝑙 ― (𝐸𝑠𝑢𝑟𝑓𝑎𝑐𝑒 + 𝐸𝑎𝑑𝑑𝑖𝑡𝑖𝑣𝑒)

(2)

Where Etotal is the total interaction energy of the optimized system (includes all atoms of the first layer of crystal surface and the additive molecule), Esurface and Eadditive are the single-point interaction energies of the atoms on the surface and atoms of the additive molecule, respectively. RESULTS AND DISCUSSION SMCPT of the PCM monohydrate without additives According to the in situ microscopic images in Figure 2 and the PXRD patterns in Figure S2 during the transformation, the detail transformation process are as follow: After putti-

Figure 2. (a)-(f) In situ transformation of the PCM monohydrate in acetone recorded every 20 minute by microscope at 31℃. (g) The PXRD analysis of block shape crystals. (h) The PXRD analysis of needle shape crystals. Scale bar: 200 um.


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Table 1. The solubility of Form I, Form II, the PCM monohydrate, the thermodynamic driving force of SMPT from the PCM monohydrate to Form I and Form II and the outcome of SMPT of the PCM monohydrate in acetone and 0.04 mg/ml HPC -acetone at 31 ℃. Solvents

Additive

Solubility (mg/ml)

∆𝐺𝑀→𝐼𝐼

The Driving Force ―1

Acetone

Form I

Form II

Monohydrate

No additive

23.3

21.5

29.0

0.04 mg/ml HPC

23.3

21.5

29.3

ng the PCM monohydrate crystals (yellow color, are dissolving in Video 1 in Support information) in acetone for 20 min, the PCM monohydrate started to transform to the block crystals (colorless, continue to nucleate and grow in Video 1) and needle crystals simultaneously which are marked by the red circle in Figure 2 (b). At the same time, some characteristic peaks of Form I and Form II were detected in Figure S2 (a), indicating the PCM monohydrate has already begun to transform to the Form I and Form II. The block and colorless crystals and the needle crystals are Form I and Form II respectively, confirmed by PXRD pattern in Figure 2 (g)-(h). With the further transformation of the PCM monohydrate from 20 min to 100 min, the PCM monohydrate continue to dissolve and the Form I and Form II continue to grow shown in Figure 2 (b)-(f). Meanwhile, the characteristic peaks of Form I and Form II developed further, and the peaks of the original PCM monohydrate weakened shown in Figure S2 (b)-(f). At 100 min, the peaks of the original PCM monohydrate disappeared completely and only peaks of Form I and Form II left as shown in Figure S (f), indicating all the PCM monohydrate trans-

576.0

The outcome

∆𝐺𝑀→𝐼

(J ∙ mol ) △GM→I △GM→II 550.1 752.7 778.6

1.37

of SMPT Form I +Form II

1.35

Form I

formed completely into Form I and Form II (The detail transformation process can be seen in Video 1 in Support Information). The thermodynamic driving force (△GM→I

and △GM→II) in acetone could be obtained according to the following equation:14

( ) 𝑓𝑀

∆𝐺𝑀→𝐼 𝑜𝑟 𝐼𝐼 = 𝑅𝑇 𝑙𝑛

𝑓𝐼 𝑜𝑟 𝐼𝐼

( )

≈ 𝑅𝑇 𝑙𝑛

𝑥𝑀

𝑥𝐼 𝑜𝑟 𝐼𝐼

( )

= 𝑅𝑇 𝑙𝑛

𝛼𝑀

𝛼𝐼 𝑜𝑟 𝐼𝐼

(3)

in which f is the fugacity, α is the thermodynamic activity ratio, x is the equilibrium mole fraction, and T is the temperature (K). As shown in Table 1, the similar driving force (△GM→I and △GM→II) in acetone makes the simultaneous appearance of Form I and Form II during the process of SMPT of the PCM monohydrate. The Form II disappeared and the morphology of Form I changed in the presence of HPC As shown in Figure 3 (a), in the absence of HPC, the PCM monohydrate transformed to needle Form II with a few block Form I in acetone at 31 ℃. However, the PCM monohydrate almost

Figure 3. The photos of crystals after the SMPT of the PCM monohydrate in the presence of different concentrations of HPC in



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acetone at 31℃: (a) 0; (b) 0.02 mg/ml; (c) 0.04 mg/ml; (d) 0.2 mg/ml; (e) 2 mg/ml; (f) 4 mg/ml; Scale bar: 1 mm. PCM-H2O in acetone. transformed to block Form I with a few needle Form II in

the presence 0.02 mg/ml HPC, as showed in Figure 3 (b). When the concentration of HPC was increased to 0.04 mg/ml (Figure 3 (c)), all the needle Form II disappeared and only the block Form I left as confirmed by the PXRD pattern (Figure S3). We should notice that the block Form I became longer along a axis (see discussions below) with the further increase of the concentration of HPC. Eventually, the morphology of Form I became needle shape at 4 mg/ml HPC as shown in Figure 3 (c)-(f). In order to clarify the reason for the disappearance of the Form II in the presence of HPC during the process of SMPT of the PCM monohydrate, two aspects including the driving force of SMPT of the PCM monohydrate and molecular interactions were analyzed in the absence and presence of HPC. On the one hand, the effect of 0.04 mg/ml HPC (just could make all the PCM monohydrate transform to Form I) on the driving forces of SMPT of the PCM monohydrate was investigated as shown in Table 1. The results showed that the driving forces of SMPT of the PCM monohydrate in the presence of HPC (0.04 mg/ml) was almost the same as that of the PCM monohydrate in the absence of additives. So the HPC had no influence on the driving forces of SMPT of the PCM monohydrate. On the other hand, we believed hydroxyl groups of the HPC molecules played an important role during the process of SMPT. To test this, the solid additives including BHNH, TMP with many hydroxyl groups and Octacosane, ISO without hydroxyl group were selected. The exclusive Form I could also be selected grown in the presence of BHNH and TMP, while concomitant crystallization of Form I and Form II still happened in the presence of Octacosane and ISO (Figure S4 and Figure S5). So It was confirmed that the -OH groups of HPC molecules made the Form II disappeared during the transformation. Figure S6 (a), (b) showed the main inter-

actions in the crystal structure of Form I and Form II. In Form I, two PCM molecules tend to form a symmetric dimer through S=O…HN H-bonding, which is a building block in Form I. While in Form II, the PCM dimers are formed by S=O…OH H-bonding. After the HPC was added during the PCM monohydrate transformation, the –OH groups of HPC molecules could make the -OH groups of PCM molecules not be identified well by the –SO2– groups of PCM molecules. Our modeling work also was used to explain this. The binding energies in acetone calculated by DFT compare as PCM-HPC (-6.4 kcal/mol) > PCM-PCM of Form I (-0.8 kcal/mol) >PCM-PCM of Form II (-0.3 kcal/mol). The binding interactions of PCM-HPC (∆𝐸𝑏𝑖𝑛𝑑 = ―6.4 𝑘𝑐𝑎𝑙/𝑚𝑜𝑙) was significantly stronger than PCMPCM (∆𝐸𝑏𝑖𝑛𝑑 = ―0.3 𝑘𝑐𝑎𝑙/𝑚𝑜𝑙) of Form II. As a result, in the presence of HPC, the PCM molecules would preferentially bind to HPC molecules by S=O…OH formed between –OH groups of HPC molecules and –SO2– groups of the PCM molecules. The intramolecular connection (S=O…OH) between the PCM molecules of Form II was blocked and Form II disappeared. However, in the presence of HPC with a lot -OH groups, the –NH– groups of PCM molecules could continue to be identified by the – SO2– groups of PCM molecules. The intramolecular connection (S=O … NH) between the PCM molecules of Form I was unaffected and the Form I left.

Figure 4. The binding energies for (1:1) molecular associates of PCM-PCM of Form I, PCM-PCM of Form II, PCM-HPC and

Figure 5. The morphology photos of Form I of PCM without (a) HPC and with (b) 4 mg/ml HPC, single crystal indexing of

The morphology of Form I changed from block to rodlike or even needle with the increase of the concentration of HPC. In the absence of HPC, the block Form I were produced as shown in Figure 5 (a) and (c). As we can see in Figure 6 (a)-(c), the -SO2- groups of the PCM are exposed

on both the (011) plane and the (011) plane of Form I crystals, which would establish strong H-bonding S=O…HN with other PCM molecules. The pyridine groups of the PCM Form I are exposed on the (100) plane, which could attract other PCM molecules by π-π interactions. Thus, the Form I crystal could grow to block shape with similar length in three directions: perpendicular to (100)


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Form I of PCM without (c) and with (d) HPC

Table 2. The interaction energies of HPC molecules with different planes of PCM crystals (Form I) and the time of HPC adsorbed on planes Plane Interaction energies between HPC Absorption time (ps) and plane (kcal/mol)

(011)

-204.6

476

(100)

-114.3

3790 on (100) plane (Video 2 and Video 3 in the Supporting Information). Because of the similar molecular arrangements between (011) and (011) plane of Form I, the HPC molecules would be adsorbed on the (011) plane in a similar way to that adsorbed to the (011) plane. This indicates that the HPC molecules have higher tendency and faster rate to adsorb on (011), (011) planes than on (1 00) plane. Thus, crystal growth should be inhibited along the direction perpendicular to (011) and (011) face, enabling grow along the direction perpendicular to (100) plane (a axis). This resulted in rod-like or even needle Form I and agreed with the experimental results in Figure 5. The Form I of PCM disappeared in the presence of 1 % H2O As shown in Figure 7, in the presence of 1 % H2O, the PCM monohydrate could transform to needle-like Form II exclusively and no Form I was found at 31 ℃. The effect of H2O on the driving force of the SMPT of the PCM monohydrate and molecular interactions were also investigated. On the one hand, as shown in the Table 3, with increase of the percentage of H2O in acetone, the solubility of Form I and Form II remained almost unchanged. However, the solubility of the PCM monohydrate was decreased from 29.0 mg/ml to 24.7 mg/ml. As a result, the driving

Figure 6. The arrangements of the PCM molecules on the (a) (011) plane, (b) (011) plane and (c) (100) plane in Form I.

plane (a axis), (011) plane and (011) plane. However, in the presence of HPC (when its concentration is higher than 0.04 mg/ml), the Form I have been stretched along the a axis and the (011), (011) plane have become the main planes. The (100) plane has become the smallest plane in area as shown in Figure 5 (b) and (d). In order to understand the role of HPC on the morphology change of Form I, the interactions between the HCP molecules and the different planes of Form I were investigated by Molecular Dynamics (MD) model. The interaction energies and the time of HPC adsorbed on different planes were calculated. The results in Table 2 showed that the interactions between the HPC molecules and (011) plane is much stronger than that between the HPC molecules and (100) plane of Form I. In addition, the time that the HPC molecules absorbed on (011) plane is far shorter than the time that the HPC molecules absorbed

Figure 7. (a)-(c) the process of SMPT of the PCM monohydrate under 1 % water –acetone at 31℃; (d) the PXRD



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pattern of polymorph obtained by SMPT under 1 % H2Oacetone at 31℃. Scale bar: 200 um.

Table 3. The solubility of Form I, Form II, the PCM monohydrate, the thermodynamic driving force of SMPT from the PCM monohydrate to Form I and Form II and the outcome of SMPT of the PCM monohydrate in acetone, water (0.25%, 0.5%, 0.75%, 1%, 1.2%) - acetone solutions at 31℃. The Driving Force Solvents

Acetone

Additives

Solubility (mg/ml)

(J ∙ mol ―1)

∆𝐺𝑀→𝐼𝐼

The outcome

∆𝐺𝑀→𝐼

of SMPT

Form I

Form II

Monohydrate

△GM→I

△GM→II

No additive

23.3

21.5

29.0

550.2

752.5

1.37

Form I+ Form II

0.25% H2O

23.3

21.1

29.0

550.2

799.8

1.45

Form I+ Form II

0.5 % H2O

23.5

21.0

28.3

467.3

750.3

1.61

Form I+ Form II

0.75 % H2O

23.5

21.0

27.5

395.2

678.2

1.72

Form I+ Form II

1 % H2O

23.6

20.7

24.7

114.7

446.4

3.89

Form II

1.2 % H2O

_

_

_

_

_

_

No transform

force of the PCM monohydrate to Form I calculated by the equation (3) was decreased dramatically from 550.2 J ∙ mol ―1 to 114.7 J ∙ mol ―1. Besides, the driving force of the PCM monohydrate to Form II far higher than that of the PCM monohydrate to Form I (the ratio between the driving force of the PCM monohydrate to Form II and that of the PCM monohydrate to Form I was increased to 3.89 ) when the percentage of H2O in acetone increased to 1%. On the other hand, though the binding energy of a PCM molecule to H2O (∆𝐸𝑏𝑖𝑛𝑑 = ―2.3 𝑘𝑐𝑎𝑙/𝑚𝑜𝑙) is higher than to another PCM molecule in Form II (∆𝐸𝑏𝑖𝑛𝑑 = ―0.8 𝑘𝑐𝑎𝑙/𝑚𝑜𝑙) (see Figure 4), the amount of H2O is so little that it could not inhibit the PCM molecular connection of Form II and the Form II could also be formed in solution. Continue to increase the amount of H2O in acetone to 1.2 %, the PCM monohydrate would not transform to Form I or Form II and could be stable in acetone. In this case, the change of the driving force of the PCM monohydrate played a more important role than the interactions between the HPC molecular and H2O during the process of the SMPT of the PCM monohydrate. As a result, the Form I disappeared in the presence of 1% H2O during the process of SMPT of the PCM monohydrate, though both H2O and HPC contain hydroxyl groups. CONCLUSIONS The SMCPT of the PCM monohydrate was found and the effects of hydroxyl-containing additives (HPC and H2O) on the SMCPT of the PCM monohydrate were investigated. Though both HPC and H2O contain hydroxyl groups, the Form I and the Form II can be selected grown in the presence of 0.04 mg/ml HPC and 1 % H2O, respectively. The mechanisms behind it are totally different. The HPC had no influence on the driving force of SMPT of the PCM monohydrate. It was the hydroxyl groups of the HPC

molecules that disturbed the recognition of the hydrogen bond connections among the molecules of the Form II, then the Form II disappeared during the process of SMPT of the PCM monohydrate. The conclusion was supported by the same effect of BHNH, TMP with hydroxyl groups on the SMPT of the PCM monohydrate. Furthermore, because of the selective adsorption of the HPC molecules on different planes of Form I, the morphology of Form I was changed from block to rod-like or even needle. In the presence of 1% H2O, the solubility of the Form I and Form II were almost the same, but the PCM monohydrate decreased dramatically, compared to the solubility of Form I, Form II and the PCM monohydrate in the absence of H2O. As a result, the driving force of the PCM monohydrate to Form I was also decreased dramatically from 550.2 J ∙ mol ―1 to 114.7 J ∙ mol ―1and the driving force of the PCM monohydrate to Form II is 3.89 times higher than that of the PCM monohydrate to Form I. In this case, the effect of hydroxyl groups of H2O on the formation of Form II during the SMPT of the PCM monohydrate could be negligible. Eventually, the Form I disappeared during the process of SMPT of the PCM monohydrate in the presence of 1 % H2O. Our research provides a method to control the production of the desired polymorph in the solution and the exclusion of undesired ones, which is important in industrial production. It is also very necessary to explore the mechanism and more methods to control the outcome of the SMPCT in our future work.

ASSOCIATED CONTENT Supporting Information The movie of the SMPCT of the PCM monohydrate in acetone in the absence of additive; The movies of Molecular Dynamics (MD) model with regard to the HPC adsorption on (011) plane and (100) plane; The equation could be used to


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calculate the percentage of the water released by the PCM monohydrate; The molecular structure of Trimethylolpropane, Isonicotinamide and Octacosane; The solubility and error limits of Form I, Form II, the PCM monohydrate in acetone, 0.04 mg/ml HPC -acetone, water (0.25%, 0.5%, 0.75%, 1%, 1.2%) - acetone solutions at 31℃ by three measurements; The PXRD pattern of crystals obtained by the SMPT of the PCM monohydrate in acetone at 0 min, 20 min, 40 min, 60 min, 80 min, 100 min without additives at 31℃ ; The PXRD pattern of the polymorph obtained by SMPT in solution with 0.04 mg/ml HPC at 31 ℃ ; The photos and the XPRD analysis with regard to the SMPT of the PCM monohydrate in the presence of BHNH, TMP, Octacosane and ISO in acetone at 31℃; The different hydrogen bond between molecules of Form I and Form II. The Supporting Information is available free of charge on the ACS Publications website.

AUTHOR INFORMATION

(6) Liu, G.; Liu, J.; Liu, Y.; Tao, X., Oriented Single-Crystal-toSingle-Crystal Phase Transition with Dramatic Changes in the Dimensions of Crystals. J. Am. Chem. Soc. 2014, 136, 590-593. (7) Bernstein, J.; Davey, R. J.; Henck, J. O., Concomitant Polymorphs. Angew. Chem. Int. Ed. 1999, 38, 3440-3461. (8) Yu, L., Nucleation of One Polymorph by Another. J. Am. Chem. Soc. 2003, 125, 6380-6381. (9) Su, Y.; Xu, J.; Shi, Q.; Yu, L.; Cai, T., Polymorphism of griseofulvin: concomitant crystallization from the melt and a single crystal structure of a metastable polymorph with anomalously large thermal expansion. Chem. Commun. 2018, 54, 358-361. (10) Denekamp, C.; Meikler, O.; Zelner, M.; Suwinska, K.; Eichen, Y., Controlling the Crystal Morphology and Polymorphism of 2,4Dinitroanisole. Cryst. Growth Des. 2018, 18, 1350-1357 (11) Pfund, L. Y.; Price, C. P.; Frick, J. J.; Matzger, A. J., Controlling Pharmaceutical Crystallization with Designed Polymeric Heteronuclei. J. Am. Chem. Soc. 2015, 137, 871-875. (12) Yang, H.; Song, C. L.; Lim, Y. X. S.; Chen, W.; Heng, J. Y. Y., Selective crystallisation of carbamazepine polymorphs on surfaces with differing properties. CrystEngComm 2017, 19, 65736578.

Corresponding Author *Email: [email protected]; [email protected] Author Contributions All authors have given approval to the final version of the manuscript.

Funding Sources Notes The authors decalre no competing financial interest.

ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (Grant Nos. 51321091, 51272129, 51227002, 51772170), and the Program of Introducing Talents of Disciplines to Universities in China (111 program no. b06015), the Natural Science Foundation of Shandong Province (ZR2015EM029), the Scientific Research Starting Foundation for Returned Overseas Chinese Scholars, Ministry of Education, China, Science and Technology Development Planning of Shandong Province (2014GSF118057).

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For Table of Contents Use only Tuning the solution-mediated concomitant phase transformation outcome of the Piroxicam monohydrate by two hydroxyl-containing additives: Hydroxypropyl cellulose and H2O Changlin Yao,a Yifan Li,b Lei Wang,*a Shuang Song,a Yang Liu,a Xutang Tao* a aState

Key Laboratory of Crystal Materials, Shandong University, Jinan, 250100, China

bKey

Laboratory for Liquid−Solid Structural Evolution and Processing of Materials, Ministry of Education, Shandong University, Jinan, 250100, China

CORRESPONDING AUTHOR ADDRESS: [email protected]；[email protected]

The graphic shows that the different transformation outcomes of the PCM monohydrate in the absence and presence of additives (HPC, H2O). A detailed analysis including the driving force of SMPT of the PCM monohydrate and molecular interactions reveals the different mechanisms. In the presence of HPC, the interactions between the HPC molecules and the PCM molecules was the main factor that governed the process of SMCPT of the PCM monohydrate. But in the presence of 1 % H2O, the driving force of SMCPT played the main role.


Tuning the solution-mediated concomitant phase transformation

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