Impact of Polymers on the Melt Crystal Growth Rate of Indomethacin

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Impact of Polymers on the Melt Crystal Growth Rate of Indomethacin Polymorphs Bin Tian, Wei Gao, Xiaoguang Tao, Xing Tang, and Lynne S. Taylor Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01145 • Publication Date (Web): 13 Nov 2017 Downloaded from http://pubs.acs.org on November 14, 2017

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Crystal Growth & Design

Impact of Polymers on the Melt Crystal Growth Rate of Indomethacin Polymorphs Bin Tiana,b, Wei Gaob, Xiaoguang Taoa, Xing Tanga,*, Lynne S. Taylorb,* *

: Corresponding author

a

: Department of Pharmaceutics, Shenyang Pharmaceutical University, Wenhua Road 103,

Shenyang 110016, People's Republic of China b

: Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University,

West Lafayette, Indiana 47907, United States E-mail: Bin Tian: [email protected] Wei Gao: [email protected] Xiaoguang Tao: [email protected] Xing Tang: [email protected] Lynne S. Taylor: [email protected]

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Abstract: Crystal growth from amorphous drugs is of interest in the context of solubility enhancing formulations. Herein, the impact of polymers on the crystal growth of different polymorphs from the undercooled liquid was investigated using indomethacin (IDM) as a model compound and hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS) and polyvinylpyrrolidone (PVP) as polymeric inhibitors. Samples sandwiched between two coverslips were prepared by melt quenching and polymorphs were identified using Raman spectroscopy, hot stage microscopy and X-ray diffraction. Crystal growth rates of δ, α and γ polymorphs were measured in the absence and presence of polymers. Polymorphs grown from pure IDM melt showed different crystal growth rates at a given temperature, that persisted when differences in the extent of undercooling were accounted for. The crystal growth rates of IDM crystals were reduced by the three polymers. At lower temperatures, the effectiveness of the polymers in inhibiting crystal growth decreased in the order of PVP > HPMC > HPMCAS. Interestingly, it was found that the same polymer had different inhibitory effects on the crystal growth of different polymorphs, with polymers being least effective in inhibiting the growth of the γ polymorph. Clearly the impact of polymers on crystal growth from undercooled melts is highly complex, depending not only on the properties of the liquid phase, but also on the growing crystal polymorph.

Keywords: crystal growth, polymer, inhibitory effect, polymorph, interface free energy


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Introduction Poor solubility is a significant challenge for oral drug delivery, and can result in insufficient and variable bioavailability.1 It has been reported that approximately 40% of marketed drugs and 75% of new candidates in drug development pipelines are poorly watersoluble.2 Several solid state modification strategies have been proposed to address this challenge, including particle size reduction, salt or cocrystal formation, and generation of metastable polymorphs.3-6 Preparation of amorphous materials is one of the more promising ways to enhance the solubility, dissolution and bioavailability of poorly water-soluble drugs.7 The amorphous form of a drug lacks long-range order, and is characterized by excess thermodynamic properties. The solubility advantage provided by the amorphous drug can be attributed to the higher free energy relative to its crystalline forms.8 However, due to the higher free energy, amorphous drugs tend to convert to the more stable crystalline counterpart, thus negating the solubility advantage of amorphous form.9 Physical

instability,

i.e.

crystallization,

is

one

hindrance

to

the

extensive

commercialization of amorphous products.10 The most common approach used to inhibit the crystallization of an amorphous drug is molecular level dispersion of the drug in a polymeric matrix, generating a system referred to as an amorphous solid dispersion (ASD).11 Crystallization from amorphous systems involves nucleation and subsequent crystal growth. Polymers impact both processes. It has been reported that polymers can either increase or decrease the rate of nucleation or crystal growth.12,

13

It is worth noting that there is no correlation between the

inhibitory effect of polymers on nucleation and on crystal growth.12 If a polymer is a good crystal growth inhibitor, that does not mean it is also a good nucleation inhibitor. Crystallization can occur both at the surface of the amorphous material as well as in the bulk. It has been shown that crystal growth at the surface of an amorphous glass is much faster than growth in the bulk.14 This enhanced surface crystallization may arise from high surface mobility and can be inhibited by nanocoating.15, 16 Previous work demonstrated effective polymeric inhibition of crystallization from undercooled liquids, whereby various factors have been suggested to be important for the inhibitory effect, including the crystallization tendency and mobility of the drug,17-20 the concentration, molecular weight and glass transition temperature of the polymer,21, 22 and the 3 ACS Paragon Plus Environment


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strength of drug-polymer interactions.23-25 However, the mechanism(s) by which polymers inhibit crystallization is still not well understood. For example, it was shown that PVP had a similar inhibitory effect on the crystal growth of felodipine polymorphs,26 while in another study, PVPVA64 and HPMCAS showed different crystal growth inhibition effects for itraconazole polymorphs.27 Polymer selection is crucial to ASD formulation development, and can determine the physical stability of the final product, however, polymer selection for ASD formulation development is still empirical. Therefore, additional studies on the crystallization behavior of amorphous drugs in the absence and presence of polymers are required. In this work, indomethacin (IDM) was selected as the model compound due to its tendency to form different polymorphs. Seven polymorphs of IDM have been reported,28 and the crystal structures of the γ and α polymorphs are known.29-32 The crystal structure of γ IDM was determined by Kistenmacher et al.29 The γ form which crystallizes in the P1 space group (triclinic) with Z = 2, contains mutually hydrogen-bonded carboxylic acid dimers in the asymmetric unit. The indole and phenyl rings are prevalent on the peripheral faces of γ IDM. Thus, the dimers are caged inside a hydrophobic shield.30 The crystal structure of α IDM was analyzed by Chen et al.30 The α IDM form crystallized in the P21 space group (monoclinic) with Z = 6, and contains three molecules in the asymmetric unit. The three molecules form a trimer, in which two of the molecules form a carboxylic acid dimer and the third molecule forms a hydrogen bond between its carboxylic acid and the amide carbonyl in the dimer. Compared with γ polymorph, both hydrophobic phenyl and indole rings and polar carboxylic acid groups are exposed on the peripheral faces. The polymeric inhibitors investigated were hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS) and polyvinylpyrrolidone (PVP). Amorphous IDM was prepared between two coverslips in the absence and presence of various polymers, and the bulk crystal growth rate was determined using an optical microscope coupled with a hot stage. The growth rate difference between various polymorphs crystallizing from the supercooled IDM melt was studied. The effect of various polymers on the crystal growth of IDM polymorphs was then evaluated to provide insight into potential mechanisms of polymeric growth inhibition. Somewhat unexpectedly, a given polymer showed a variable inhibitory effect on the growth rate of different polymorphs.

Materials and Methods 4 ACS Paragon Plus Environment

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Materials. IDM (γ polymorph) was purchased from Letco Medical, INC. (Decatur, AL, U.S.A.) and used as received. HPMC (Methocel E5) was obtained from The Dow Chemical Company (Midland, MI, U.S.A). HPMCAS (MF grade) was obtained from Shin-Etsu Chemical Co. Ltd. (Tokyo, Japan). PVP (K30) was obtained from the BASF Corporation (Ludwigshafen, Germany). Polymers were dried in a vacuum oven for 24 h before use. Chemical structures of IDM and polymers are shown in Figure 1. Methanol and dichloromethane were purchased from Fisher Scientific International, Inc. (Geel, Belgium) and Avantor Performance Materials (Phillipsburg, NJ, U.S.A.) respectively.

Figure 1. Chemical structures of IDM, HPMC, HPMCAS and PVP. Preparation of Amorphous IDM. Samples of amorphous IDM in the absence and presence of polymers were prepared by the melt quenching method and used to study the bulk crystal growth. Pure amorphous IDM was prepared by melting 3-5 mg of γ IDM at 170 °C for 1 min between two 18×18 mm2 coverslips, and then cooling the liquid to room temperature on an aluminum block. Amorphous IDM in the presence of 10% w/w polymer was prepared using the same procedure as described above but replacing the γ IDM with an IDM ASD, prepared by rotary evaporation. The preparation process has been described in detail elsewhere.33 Crystal growth rate measurement. The obtained samples, sandwiched between two coverslips, were confirmed to be amorphous using a polarized light microscope (Nikon Eclipse E600 POL microscope, Nikon Corp, Tokyo, Japan). Samples were then stored in a desiccator 5 ACS Paragon Plus Environment


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over desiccant at 60 or 80 °C to induce nucleation and growth, generating the δ and α polymorphs respectively. To study the crystal growth of the γ polymorph, samples were seeded with γ crystals placed in contact with the edge of the IDM glass, and then stored at 80 °C to obtain sufficient crystal growth into the bulk. Isothermal crystal growth rates from these samples were determined by hot stage microscopy over a temperature range from 80 °C to close to the melting point of corresponding polymorph. A hot stage (Linkam THMS 600, Surrey, U.K.) was used to control the temperature. Samples were examined and images were captured at predetermined intervals with time-lapse mode using a polarized light microscope equipped with a digital camera (Nikon DS-Fi1, Nikon Corp, Tokyo, Japan). The increase in growth front was measured using the NIS-Elements software and plotted against time. The slope was taken as the growth rate. For each temperature, the growth rate of at least three independently prepared samples was determined and the mean was reported. Determination of melting point using hot stage microscopy. Melting points of crystals presenting different morphologies were determined using hot stage microscopy to identify the polymorphs. Samples were placed on the hot stage and heated starting from 80 °C at a heating rate of 5 °C /min. Pictures were taken at predetermined intervals with time lapse photography using the polarized light microscope and the temperature range corresponding to the melting process was recorded. Raman microscopy. Polymorphs of IDM crystals was identified using a DXR Confocal Raman Microscope (Thermo Scientiﬁc, Madison, WI, USA). A 10X objective was used and samples were irradiated with a 532 nm laser. The laser power used was 8.0 mW. Raman spectra were obtained over a wavenumber range of 2000-200 cm-1. For each spectrum, 10 scans were collected and averaged. The spectrometer was calibrated using polystyrene. X-ray Diffraction (XRD). XRD was used to identify the polymorphs of IDM crystals observed in the growth rate measurements. For pure IDM, the δ polymorph was obtained by nucleation at 60 °C followed by growth at 40 °C. The α polymorph was obtained by nucleation at 80 °C, elimination of the δ polymorph by heating to a temperature above its melting temperature and growth at the temperature of maximum crystal growth rate (Tmax). The γ polymorph was obtained by crystal growth from a sample seeded with γ crystals at Tmax. For drug-polymer samples, the δ polymorph was obtained by nucleation and growth at 60 °C. The α and γ 6 ACS Paragon Plus Environment

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polymorphs were obtained using the same method as for pure drug. After obtaining completely crystallized samples, top coverslips were removed and XRD patterns were recorded using a SmartLab X-ray diffractometer (Rigaku Corporation, Tokyo, Japan) over a 2θ range of 5-40°. Measurements were performed using CuKα radiation at 40 kV and 44 mA with a scan rate of 4°/min and a step size of 0.02°. Viscosity Measurement. The steady shear viscosities of amorphous IDM in the presence of 10% w/w polymer were determined over the temperature range of 80-130 °C using a AR2000ex rheometer (TA Instrument, DE, USA). Indomethacin ASDs (130 mg) were placed onto the lower plate, heated to 175 °C and held at this temperature for 3 min. Measurements were performed using a 20 mm diameter parallel plate geometry with a gap size of 0.34 mm between the two plates. Temperature was controlled by Peltier plates inside a heating hood. Before measurements, the sample was equilibrated at the test temperature for 10 min. A shear deformation was applied at a rate of 1 s-1 at a constant temperature. The steady-state reading was reported as the shear viscosity. All the measurements were performed in duplicate. The viscosity of pure IDM could not be determined due to crystallization during the measurement.

Results Identification of IDM Polymorphs. Seven polymorphs of IDM have been reported28 and the crystal growth of the δ, α, and γ polymorphs was studied in this work. The melting points of δ, α, and γ polymorphs, reported as the onsets, are 127, 152 and 160 °C, and the enthalpies of fusion are 24.4, 32.5 and 39.5 kJ/mol respectively. The data for α and γ polymorphs were determined in this study using DSC, and the data for the δ polymorph was taken from the literature.34,

35

Crystallization was induced in amorphous IDM by storage at elevated

temperatures. The δ polymorph had the fastest nucleation rate and accounted for most of the crystals formed from the melt following storage at 60 °C. The crystallization of the α polymorph was favored by storage at a higher temperature, therefore a temperature of 80 °C was used to generate α crystals. The γ polymorph did not nucleate readily and hence seeded samples were used in this study. Figures 2A-C show the morphologies of IDM polymorphs crystallized from spontaneously nucleated or seeded pure IDM melt. The δ and α polymorphs grew as spherulites



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with clear boundaries with the amorphous phase, and can be readily differentiated by appearance using a polarized light microscope. The γ polymorph was a polycrystalline cluster that grew from added seeds. Raman spectra of three polymorphs crystallized from the melt are shown in Figure 3, and are in good agreement with spectra reported in the literature.34 In addition, the Raman spectra of α IDM prepared by recrystallization from ethanolic solution,36 γ IDM as received, and amorphous IDM prepared by melt quenching are also shown for reference. It was found that α and γ polymorphs showed consistent morphologies over the entire temperature range used in this study, while the morphology of δ polymorph changed with temperature. Figures 2G, A and H show the morphologies of δ polymorph crystallized at 40, 60 and 80 °C respectively. At 40 °C, the crystal had a spherulitic shape with a smooth solid-liquid interface. As temperature increased, the interface became rougher, and at 80 °C, the spherulite showed needle-like protrusions at the solid-liquid interface and a fine-grained texture. Due to different melting points of the δ, α and γ polymorphs, the various forms with diverse morphologies could be also identified using hot stage microscopy (Figure 4), confirming results obtained from Raman microscopy.


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Figure 2. Morphologies of δ, α and γ crystals crystallized from IDM melt under different conditions. (A-C) from left to right, δ, α and γ crystals grown from pure IDM melt at 60 ℃ (δ crystal) or 80 °C (α and γ crystals); (D-F) from left to right, δ, α and γ crystals grown from IDM melt at 80 °C in the presence of HPMCAS; (G, H) δ crystals grown from pure IDM melt at 40 and 80 °C; (I) α and δ crystals grown from IDM melt at 105 °C in the presence of HPMCAS.



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Figure 3. Normalized Raman spectra of (a-c) δ, α and γ IDM polymorphs grown from melt; (d) α IDM polymorph recrystallized from ethanol; (e) γ IDM polymorph as received; (f) amorphous IDM prepared by melt quenching.

Figure 4. Hot stage microscopic images of IDM polymorphs grown from pure IDM melt at different temperatures during heating.

Impact of Polymers on the Crystal Morphology. The addition of polymers retarded nucleation and crystal growth from the IDM melt, therefore a higher temperature was used to induce crystallization in the presence of polymers. Figures 2D-F show the morphologies of different polymorphs crystallized from the IDM undercooled melt in the presence of HPMCAS at 80 °C. The γ polymorph showed the same morphology as the corresponding crystals grown from pure IDM, and the morphology did not change with temperature. The δ polymorph obtained in the presence of HPMCAS had similar morphology to crystals formed from pure IDM crystallized at lower temperature (40 °C, Figure 2G), and showed similar trends in terms of the 10 ACS Paragon Plus Environment

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morphology changing with temperature. As shown in Figure 2D and I, a rougher needle-like solid-liquid interface was observed for the δ polymorph as the temperature increased (115 °C). The α polymorph obtained in the presence of HPMCAS showed a different texture and optical properties compared with those obtained from pure IDM (Figure 2B), although all crystals were spherulites with a smooth solid-liquid interface. In addition, the morphology of the α polymorph from the IDM-HPMCAS system was found to be temperature dependent. As can be seen from Figure 2E and I, the α polymorph became a densely branched spherulite with a rough fiber-like interface as the temperature increased. XRD, confocal Raman and hot stage microscopies were performed to identify the polymorphs grown in the presence of polymers. Figure 5 shows the microscopic images and corresponding XRD patterns of polymorphs grown from IDMHPMCAS system, whereby the XRPD patterns show good agreement with those reported in the literature.36 Crystals formed in the presence of HPMC or PVP showed similar morphologies to those observed from the IDM-HPMCAS system.

Figure 5. Microscopic images of (A-C) δ, α and γ IDM polymorphs grown from the IDM melt at the Tmax of each polymorph in the presence of HPMCAS and (D) corresponding XRD patterns of (a-c) δ, α and γ polymorphs grown from melt; (d) α polymorph recrystallized from ethanol; (e) γ polymorph as received.



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Figure 6. Crystal growth rates (A) and crystal growth rates normalized for thermodynamic driving force (B) of δ, α and γ IDM polymorphs in the absence of polymers as a function of temperature. The normalization of crystal growth rates of IDM polymorphs to account for differences in thermodynamic driving force was performed as described previously.34 Effect of Polymers on Crystal Growth Rate. The crystal growth rates of three polymorphs of IDM were determined by tracking the increase in growth front in an orthogonal direction in the absence and presence of different polymers. Figure 6A shows the crystal growth rates of the three polymorphs from pure IDM undercooled melts as a function of temperature, while Figure 6B shows the same data after normalization to account for differences in the thermodynamic driving force for each system. Each polymorph shows a bell-shaped curve with a maximum crystal velocity (MCV, taken as the peak value of the curve) observed at a different temperature. It can be seen that the γ polymorph has a slower growth rate than the α polymorph whereby the MCV is about an order of magnitude lower (4.0710-7 vs. 4.3410-6 m/s). The growth rate of the δ polymorph is slightly higher than that of the α polymorph at lower temperatures (80-90 °C), but reaches its MCV at a much lower temperature than the other polymorphs, and at higher temperatures, the growth rate is slower than for the other polymorphs. The temperature at which the MCV occurs is approximately 0.95 of the melting temperature for all of the polymorphs, in agreement with previous observations.37


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Figure 7. Crystal growth rates of (A-C) δ, α and γ IDM polymorphs as a function of temperature in the absence and presence of polymers, and the ratios of crystal growth rates in the absence of polymers to those in the presence of (D-F) HPMC, HPMCAS and PVP respectively at different temperatures. The dash line indicates a ratio of 1.

Figures 7A-C show the crystal growth rates of different polymorphs in the absence and presence of polymers at different temperatures. It can be seen that the growth rates were reduced 13 ACS Paragon Plus Environment


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when the polymers were present. For the δ polymorph (Figure 7A), PVP showed the best inhibitory effect on crystal growth at lower temperatures (80-105 °C), while HPMC was the best inhibitor at higher temperatures (115-120 °C), and HPMCAS was the least effective inhibitor for all temperatures studied. For the α polymorph (Figure 7B), the polymers had a similar influence on crystal growth. PVP and HPMC were the most effective inhibitors at lower (80-100 °C) and higher temperatures (105-120 °C) respectively, while HPMCAS was least effective. For the γ polymorph (Figure 7C), HPMCAS was again the least effective inhibitor. PVP showed better inhibitory effect over a lower temperature range (80-115 °C) and comparable effectiveness at higher temperatures (120-150 °C) as compared to HPMC. Thus, in general, PVP was more effective at lower temperatures, HPMC was more effective at higher temperatures, and HPMCAS was least effective in inhibiting the growth of δ, α and γ IDM polymorphs. It is also of interest to compare the effect of a specific polymer on the crystal growth of different polymorphs. Figures 7D-F show the ratios of crystal growth rates of IDM polymorphs in the absence of any polymer to those in the presence of each polymer as a function of temperature. It can be seen that HPMC (Figure 7D) was less effective at inhibiting the growth of the γ polymorph relative to its effect on the other polymorphs. At lower temperatures (80-90 °C), HPMC was a better growth inhibitor for the δ polymorph than for α polymorph (7.5 times vs. 5 times reduction in growth rates) while at higher temperatures (> 95 °C), HPMC was a better growth inhibitor for the α polymorph. HPMCAS was also a better inhibitor for the δ polymorph at lower temperatures (80-90 °C), for the α polymorph at higher temperatures (> 100 °C), and had the least on γ polymorph growth. As seen from Figure 7F, a similar scenario was observed for PVP. In summary, all three polymers were more effective in inhibiting the growth of the δ polymorph at lower temperatures and the α polymorphs at higher temperatures, and showed the least inhibitory effect on the γ polymorph. Further, all polymers were generally relatively more effective at higher temperatures, in particular for the α and γ polymorphs. Viscosity of IDM in the Presence of Polymers. The viscosity of IDM melt containing polymers was determined over the temperature range of 80-130 °C and results are shown in Figure 8. It can be seen that IDM-HPMC and IDM-HPMCAS systems had similar viscosities for the temperature range studied. The IDM-PVP system showed higher viscosities at lower temperatures (80-105 °C), and comparable viscosities at higher temperatures. The viscosities of


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IDM-polymer systems decreased with increasing temperature as expected. The temperature dependence of viscosity may follow an Arrhenius-type relationship,38 in particular over small temperature ranges: log log / 2.303) 1) where is the viscosity, is a constant, is the activation energy for viscous flow, is the gas constant and is absolute temperature. If a linear relationship is observed, the viscous flow

activation energy can be calculated from the slope of the log viscosity versus 1/T plot (Figure 8). The regression equations of the fitted data and estimated activation energies for viscous flow for the various IDM-polymer systems are listed in Table 1, where R is the correlation coefficient of the regression line. Activation energies for viscous flow increase in the order of IDM-HPMCAS < IDM-HPMC < IDM-PVP.

Figure 8. Viscosities of IDM melt in the presence of polymers as a function of temperature. The straight lines were obtained by linear regression of log η vs. 103/T.

Table 1. The regression equations and activation energies for viscous flow obtained from the viscosity data of IDM-polymer IDM-Polymer

Regression equations

Activation energies (kJ/mol)

IDM-HPMC

log η = 8340.7 / T – 19.4 (R2 = 0.9970)

159.7

IDM-HPMCAS

log η = 7494.5 / T – 17.1 (R2 = 0.9998)

143.5 15

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IDM-PVP

log η = 9950.2 / T – 23.4 (R2 = 0.9934)

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190.5

Discussion Crystal Growth of Polymorphs from Pure IDM. In this study, crystal growth rates of δ, α and γ polymorphs from pure IDM melts were determined. Several theories have been proposed to describe the growth of crystals from melt.17, 39 To add a new crystal monolayer, molecules need to diffuse across the solid-liquid interface and attach to the growth sites, integrating into the crystal lattice. Both kinetic and thermodynamic factors play important roles and the temperature dependence of these factors needs to be taken into consideration. The kinetic factor involved is molecular mobility, which is commonly described by the viscosity or the self-diffusion coefficient.34, 40 The thermodynamic driving force for crystal growth is the free energy difference, ΔG, between the melt and crystalline phase, and it is proportional to the degree of undercooling ΔT (ΔT − , is the melting point and is the temperature) for a specific polymorph.

The free energy difference is zero at the melting temperature and increases with the degree of undercooling. Hence, at temperatures just below the melting point, there is little thermodynamic driving force and the crystal growth is slow. In contrast, the molecular mobility is high due to the lower viscosity. As the temperature decreases, ΔG increases, but the molecular mobility decreases, resulting in a reduction in growth rate and leading to the bell shaped curves seen in Fig 6A; at temperatures higher than the maximum rate, growth is under thermodynamic control, while at temperatures lower than the maximum, growth is under kinetic control. Thus, as a result of their different melting characteristics, the δ polymorph exhibits a MCV at a lower temperature than the other polymorphs, as summarized in Table 2. The growth rates are also different for each polymorph, even after normalization for the different thermodynamic driving forces (Figure 6B), whereby the α polymorph has the highest MCV (Table 2). It has been suggested that the most dense polymorph will grow faster when considering crystals growing in glasses,41 and it has been noted that the denser polymorph of felodipine grew faster from the glass.26 However, this rule is unlikely to be applicable to crystals growing from liquids; it was found that the lower density polymorph of itraconazole grew faster than the more dense form at temperatures above Tg.27 Although, it was observed that the denser α polymorph of IDM grew faster than the γ polymorph (1.427 vs. 1.377 g/cm3)32 at temperatures above Tg, the growth rate differences


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between the polymorphs observed herein may arise from the kinetics of integration at the crystalliquid interface, which will depend on the structure of the interface. Crystal Growth Inhibition by Polymers. Several studies have discussed the inhibitory effect of polymer on the crystal growth and parameters reported to have an influence include molecular weight, glass transition temperature and concentration of the polymer, and drugpolymer interactions.21-25 However, the mechanism by which polymers inhibit melt crystallization is still not well understood, although this is a topic of increasing interest, in particular as melt extrusion gains momentum as a processing technique for amorphous solid dispersions. The polymer can affect the crystal growth by impacting both kinetic and thermodynamic factors. The IDM-PVP system has the highest viscosity (Figure 8) which correlates with the generally more pronounced impact of this polymer on crystal growth in the mobility controlled growth region. At temperatures below the temperature of maximum growth rate (80-100 °C), PVP reduced the growth rates by a factor of 5-25, while the corresponding reductions over the same temperature range were 2-12 for HPMC and 2-3 for HPMCAS. Clearly the viscosity differences between HPMC and HPMCAS systems cannot explain why the former polymer is a more effective inhibitor. The addition of polymer is also expected to alter the thermodynamic driving force for crystal growth based on the magnitude of the free energy of mixing Δ , which for a binary system is given by42: Δ !"

1− #

ln 1 − ) % 1 − )& 2)

Where is the gas constant, is the absolute temperature,

is the volume fraction of the drug,

m is the number of lattice sites occupied by a polymer chain and χ is the drug-polymer interaction parameter. Systems with stronger drug-polymer interactions would have lower free energy, and hence a reduced driving force for crystal growth. It has been reported that the drugpolymer interactions decreased in the order of IDM-PVP > IDM-HPMC > IDM-HPMCAS.33 Thus the improved inhibitory effect of PVP at low temperature is most likely accounted for based on both the reduced molecular mobility and a decreased thermodynamic driving force. The lower effectiveness of HPMCAS relative to HPMC over the same temperature range can perhaps be attributed to the reduced extent of drug-polymer interactions. 17 ACS Paragon Plus Environment


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Table 2. Maximum crystal velocity (MCV) and MCV temperature (Tmax) for IDM polymorphs in the absence and presence of polymers. System

MCV (108 m/s)

Tmax (°C)

δ

α

γ

δ

α

γ

IDM

40.72

434.29

14.95

110

135

135

IDM-HPMC

1.34

1.55

9.25

105

100

125

IDM-HPMCAS

7.36

14.95

24.01

110

110

130

IDM-PVP

1.23

6.16

8.99

115

125

130

The impact of the polymers on the thermodynamically controlled region of crystal growth, i.e. for temperatures above the maximum growth rate, is particularly intriguing. Few, if any studies have evaluated the impact of polymers in this growth regime, although it is likely of great importance in the context of hot melt extrusion, where drug-polymer blends are processed at temperatures close to the drug melting point where residual crystals can potentially grow, depending on the temperature regimen used for processing. We note that HPMC, in particular, reduces the temperature where the maximum crystal velocity is seen, relative to the corresponding polymer-free system. This reduction in the temperature of the MCV is particularly striking for the α polymorph with HPMC (Table 2). The effectiveness of the polymers at inhibiting crystallization at temperatures above the MCV temperature can be seen from Figures 7D-F which show that there is a sharp increase in the ratio of the growth rates in the absence and presence of polymers in this temperature region. The melting point depression of IDM crystals and the decrease in thermodynamic driving force for crystal growth in the presence of polymers may be possible reasons for the observed effectiveness in this temperature regimen. For the same temperature regimen, Figures 7D-F also show that a given polymer has varying inhibitory effects on the crystal growth of different polymorphs of IDM. The three polymers showed the least effectively inhibitory effect on the crystal growth of the stable γ polymorph while they were most effective for the faster growing α polymorph. This can also be seen from the impact of the polymers on the MCV values of the different polymorphs in the presence and absence of the polymers (Table 2). The impact of polymers on the crystal growth of different polymorphs has not been studied extensively. Kestur et al. reported that PVP showed a similar inhibitory effect on the crystal growth of felodipine polymorphs and they suggested that the inhibitory effect of the 18 ACS Paragon Plus Environment

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polymer on crystal growth arose from its impact on the liquid phase.26 In another study by Shuai et al., polymers showed different extents of crystal growth inhibition for itraconazole polymorphs and the authors attributed this to different crystal-melt interfacial free energy changes caused by the polymers.27 In the current study, the three polymers evaluated exhibited different inhibitory effects on the crystal growth of IDM polymorphs growing from the same liquid. These observations cannot be rationalized by considering the impact of the polymer on the liquid phase per se, for example in terms of impact on mobility. Rather, it appears that the polymers impact the crystal-melt interface of the various polymorphs differently.

Conclusion In this work, crystal growth rates of δ, α and γ polymorphs of IDM were determined in the absence and presence of polymers. The growth rates of three polymorphs from the pure IDM supercooled melt varied suggesting differences in the crystal-melt interface between the polymorphs. The crystal growth was significantly inhibited by polymeric additives whereby the various polymers showed different inhibitory effects on the crystal growth of the same polymorph. Further, the same polymer had different inhibitory effects on the crystal growth of different polymorphs. These observations are of importance in terms of understanding the crystallization behavior of amorphous formulations, in particular at higher temperatures, such as those that might be encountered during processing.

Acknowledgements This work was partially funded by the China Scholarship Council (File No. 20148210116) and National Natural Science Foundation of China (Grant No. 81673378). The authors also acknowledge the U.S. Food and Drug Administration for financial support under grant award 1U01FD005259-01.

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For Table of Contents Use Only Impact of Polymers on the Melt Crystal Growth Rate of Indomethacin Polymorphs Bin Tian, Wei Gao, Xiaoguang Tao, Xing Tang, Lynne S. Taylor

The crystal growth rates of indomethacin polymorphs in the absence and presence of polymers were studied as a function of temperature. Polymers had different impacts on the growth rate of each polymorph.


Impact of Polymers on the Melt Crystal Growth Rate of Indomethacin

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