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Impact of Crystal Structure and Polymer Excipients on the Melt Crystallization Kinetics of Itraconazole Polymorphs Shuai Zhang,† James F. Britten,‡ Albert H. L. Chow,*,† and Thomas W. Y. Lee*,† †

School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong, China Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada

‡

S Supporting Information *

ABSTRACT: The crystal structure of itraconazole (ITZ) Form II has been determined by single-crystal X-ray diffraction, and the effects of crystal structure and two polymer excipients, Kollidone VA64 (PVPVA64) and hydroxypropylmethyl cellulose acetate succinate (HPMCAS), on the melt crystallization kinetics of ITZ Forms I and II have been investigated. Form II structure is characterized by a unit cell similar to that of Form I, but with a different orientation of the dichlorophenyl groups. Form II displays a considerably higher crystal growth rate than Form I, which cannot be explicated by their difference in crystal density alone. Both polymers at 20% (w/w) significantly retard the crystallization of Forms I and II without altering the crystal structure of either polymorph. Crystallization kinetic analysis by the two-dimensional surface nucleation model suggests that the polymers inhibit the crystallization of ITZ from amorphous dispersions by reducing the molecular mobility in the molten state as well as augmenting the crystal−melt interfacial free energy. Form II is more sensitive than Form I to the growth inhibition by either polymer, which can be attributed to a much larger increase in the crystal−melt interfacial free energy brought about by much stronger polymer adsorption on the crystal surface of Form II.

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INTRODUCTION Amorphous drugs are normally stabilized by molecular dispersion in inert polymers having a relatively high glass transition temperature or low molecular mobility.1−3 It has been well documented that such polymers can serve as stabilizers or crystallization inhibitors to significantly reduce the crystal growth rates of amorphous drugs.4−7 Despite the numerous research efforts being devoted to the identification of effective polymers for inhibiting the recrystallization of amorphous drugs, the underlying inhibition mechanisms remain obscure, particularly when the crystallization process involves the formation of more than one crystal form or polymorph. It can be envisaged that each of such polymorphs will behave differently during growth toward the crystallization inhibitors. Consequently, a good understanding of the inhibitory impact of these polymers on the nucleation and crystal growth of drug polymorphs is paramount to the design and formulation of kinetically stable amorphous solid dispersion (ASD) systems as well as the control of crystal polymorphism in pharmaceutical manufacturing. In this regard, polymers capable of inhibiting the crystallization of the most readily formed polymorph are expected to offer the most effective stabilization for the amorphous drug of interest. As demonstrated in our previous study,8 ITZ could be crystallized from melt into three different polymorphsForms I, II, and III, each with distinctly different crystallization © XXXX American Chemical Society

behavior and physical stability. Form I, the commercially available form, is most stable among the three known polymorphs, while Form II is a metastable polymorph which was first documented in U.S. Patent Application Publication No. 2003/0100568.9 Form III is another metastable polymorph newly discovered by our group, and all the related data and discussion presented in our previous study will provide the groundwork for further development of this novel form into a drug product. Thus far, the reported structural data on ITZ polymorphs obtained by single-crystal X-ray diffraction (SCXRD) have been limited to Form I.10 Similar structural characterization on the other two known polymorphs would be necessary in order to probe further into the phase transformation of the various ITZ polymorphs and their crystallization from the amorphous form. In this study, we have elucidated the crystal structure of ITZ Form II for the first time using SCXRD and highlighted its major differences from the well-characterized Form I structure. Additionally, we have investigated the impact of two widely used polymer excipients in amorphous drug formulation studies, namely, Kollidone VA64 (PVPVA64) and hydroxypropylmethyl cellulose acetate succinate (HPMCAS), on the Received: March 15, 2017 Revised: April 12, 2017 Published: April 26, 2017 A

DOI: 10.1021/acs.cgd.7b00375 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Figure 1. Chemical structures of itraconazole, PVPVA64, and HPMCAS.

crystallization of ITZ Form I and Form II from melt, and in particular, the kinetic and thermodynamic factors involved in the associated crystallization processes with these polymers based on the two-dimensional surface nucleation model. These two polymers were selected from five of the polymers we tested in preliminary screening studies. All of these five polymers, viz. hydroxypropyl cellulose (HPC-SSL), hydroxypropyl methylcellulose (HPMC-E5), polyvinlypyrrolidone (PVP-K30), PVPVA64, and HPMCAS, have relatively high glass transition points (>100 °C) except HPC-SSL which has a Tg below 0 °C. The first three polymers were excluded from further consideration for specific reasons. The major issue with HPC-SSL is its relatively weak inhibition on the ITZ crystallization compared with the other four polymers, while HPMC-E5 shows poor flowability in the molten state, which renders it extremely difficult to be processed into a homogeneous blend with ITZ. On the other hand, while PVP-K30 does not share the same problems as HPC-SSL and HPMC-E5, it is largely comparable to PVPVA64 in its inhibition against the ITZ crystallization, and thus offers no special advantage over the latter for stabilizing the amorphous drug. Therefore, we finally selected PVPVA64 and HPMCAS for further evaluation. Our selection also took into account the difference in hydrophilicity between these two polymers; PVPVA64 is more hydrophilic than HPMCAS, and comparative studies between them would serve to highlight the impact of environmental moisture level or relative humidity on the physical stability of ASDs prepared with these polymers. For the subsequent crystal growth studies, we chose a polymer concentration of 20% (w/w), primarily because the polymer at this concentration could afford a more-than-double inhibition of the ITZ crystallization, enabling more reliable quantitative differentiation of the abilities of these two polymers to retard crystal growth. We hypothesize that the polymers exert selective inhibition on the crystallization of particular ITZ polymorph, thereby controlling the physical stability of the ITZ amorphous solid dispersion.

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MATERIALS AND METHODS

Chemicals and Reagents. Itraconazole ((2R,4S)-rel-1-(butan-2yl)-4-{4-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1ylmethyl)-1,3-dioxolan-4-yl]methoxy phenyl)piperazin-1yl] phenyl}4,5-dihydro-1H-1,2,4-triazol-5-one; ITZ; Form I) with purity over 99% was purchased from YICK-VIC (Hong Kong). Kollidone VA64 (PVPVA64; MW = 45000−70000; 5% w/w moisture) was obtained from BASF (Guangzhou, China). Hydroxypropyl methylcellulose acetate succinate (HPMCAS-HF; MW = 18 000; 2% (w/w) moisture) was supplied by Shin-Etsu (Dalian, China). All other chemicals used were of analytical grade and had a purity >99.0%. Figure 1 shows the chemical structures of ITZ and the two polymers. Preparation of Amorphous Samples. About 10 mg of pure ITZ or a physical mixture of ITZ and polymer (ITZ/polymer = 4:1 w/w) was melted at 175 °C between two cover glasses for 5 min to ensure complete melting, followed by rapid melt quenching to room temperature in an aluminum block to form an amorphous solid. The samples were confirmed to be crystal-free under a polarized light microscope (Axioplan 2 imaging and Axiophot 2 microscope, Carl Zeiss Corp, Germany). Single-Crystal X-ray Diffraction (SCXRD). A single ITZ crystal (Form I or Form II) of appropriate size and quality obtained from melt was mounted on a MiTeGen loop with n-paratone oil on a Rigaku RU200/Bruker D8/Bruker Smart 6000 diffractometer with standard Bruker Apex2 v2014.11-0 data collection software. The crystals were kept at 173.15 K during data collection. Employing the Olex2 software,11 the crystal structure of each sample was solved with the aid of ShelXT structure solution program using Direct Methods and refined with the XL refinement package by Least Squares minimization.12,13 Measurement of Crystal Growth Rates of ITZ Polymorphs in the Presence of Polymers. All crystal growth rate measurements were conducted at elevated temperatures (i.e., 80−120 °C) owing to the relatively high Tg and slow crystallization of ITZ from melt at lower temperatures. To measure the crystal growth rate at 80−100 °C, samples were seeded with either ITZ Form I or II, and stored over P2O5 (0% RH) at a constant temperature inside a forced air oven. Samples were removed from the oven at predetermined time points for measurement of the increase in distance of the advancing growth front of the crystal under a polarized light microscope. Each reported growth rate was the average value from three separate melt samples. To measure the crystal growth rate at temperatures above 110 °C, melt samples were seeded and heated on a hot stage (Linkam THMS B



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600, Linkam Scientific Instruments, UK), and real-time measurements were taken under a polarized light microscope. Powder X-ray Diffraction (PXRD). Powder X-ray diffraction (PXRD) data were collected using a Panalytical X-ray diffractometer (Philips X’pert PRO, The Netherlands) equipped with a Cu radiation source operating at 40 kV and 40 mV. Sample was uniformly packed into an aluminum holder with a 2 mmm depth and scanned from 2θ of 3° to 40° at a rate of 4°/min with a step size of 0.017°. Viscosity Measurement. The steady shear viscosities of pure amorphous ITZ, ITZ with HPMCAS, and ITZ with PVPVA were measured at different temperatures using an ARES rheometer (TA Instruments, USA). The method was essentially the same as that reported previously.8,14 Briefly, ITZ or its physical mixture with the polymer was melted between two parallel 25 mm-diameter plates with a 0.8 mm gap size between them. The sample was held isothermally at a temperature 5 °C higher than the melting point of ITZ (∼165 °C) for a few minutes to ensure complete melting. Afterward, the temperature was lowered to a predefined temperature, and the sample was equilibrated for 10 min. A shear deformation was then applied at a rate of 0.01 s−1 to 1 s−1, and the shear viscosity value was recorded when the shear rate reading became steady.

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RESULTS Crystal Structures of ITZ Form I and Form II. The crystallographic data of both Forms I and II are summarized in Table 1. Both polymorphs crystallize in the triclinic system. Table 1. Crystallographic Data of ITZ Form I and Form II empirical formula formula weight diffraction data collection temperature (K) crystal system space group a/Å b/Å c/Å α/° β/° γ/° volume/Å3 Z ρcalc g/cm3 μ/mm−1 F(000)

Form I

Form IIa

C35H38Cl2N8O4 705.63 173.15

C35H38Cl2N8O4 705.63 173.15

triclinic P1̅ 8.5870(14) 20.099(3) 20.899(3) 73.501(3) 88.936(4) 79.299(3) 3396.1(9) 4 1.380 2.150 1480.0

triclinic P1̅ 11.1092(11) 12.4063(12) 25.687(2) 76.410(2) 89.261(2) 86.455(2) 3434.6(6) 4 1.365 2.126 1480.0

Figure 2. Crystal structures of ITZ Form I (a) and Form II (b) in a unit cell. Ellipsoids are drawn at 50% probability; hydrogen atoms and minor disorder components are not shown.

not to significantly alter the rate of crystal growth of individual polymorph, as confirmed by statistically nonsignificant differences in crystal growth rate between seeded and unseeded samples (n = 4). Figure 3 shows the morphologies of Form I and Form II crystals grown at 100 °C in the presence and absence of 20% (w/w) PVPVA or HPMCAS. To investigate the impact of polymers on the crystal lattice structure of ITZ, ITZ samples recrystallized with PVPVA or HPMCAS were analyzed by PXRD. ITZ recrystallized with 20% (w/w) of either polymer from melt was found to exhibit no discernible changes in the diffraction pattern (Figure 4) or lattice spacing (d-values; data not shown) compared with the corresponding pure ITZ materials or physical mixtures of ITZ and polymer, indicating that neither polymer was incorporated into the crystal lattice of ITZ during crystallization. Impact of Polymers on the Crystal Growth Rates of ITZ Polymorphs. At temperatures below 70 °C, the crystal growth rates of both polymorphs were too slow to be measured within a reasonable time frame. Thus, measurements were performed at higher temperatures (82 °C, 90 °C, 100 °C, 110 °C, and 120 °C). Figure 5 shows a typical plot of the distance of crystal growth as a function of time. In general, linear relationships between growth distance and time were observed for both Forms I and II with or without polymers, indicating that the crystal growth rates, as determined by the slopes of the linear plots, are independent of time.

a

CCDC 1537721 contains the supplementary crystallographic data on itraconazole Form II for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www. ccdc.cam.ac.uk/structures.

The stacking of the molecules of two polymorphs in the unit cell is similar, but the orientation of the dichlorophenyl groups of ITZ is different. The angle of the molecular axis to the mean crystallographic plane containing the chlorine atoms is also different for the two structures. Similar to the ITZ Form I,10 Form II also crystallizes with a disorder of the two conformationally distinct molecular enantiomers. Depicted in Figure 2 are the unit cells of the crystal structures of these two polymorphs. Crystallization of ITZ Polymorphs in the Presence of Polymers. In the present study, seeding was employed to initiate or induce the crystallization of a particular polymorph for the growth kinetic measurements. This treatment was found C



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Figure 3. Growth of ITZ Form I and Form II crystals from melt between two microscope cover glasses at 100 °C in the presence and absence of polymer after seeding on the outer edge of the melt: (A) 0% (w/w) polymer; (B) 20% (w/w) PVPVA64; (C) 20% (w/w) HPMCAS. Scale bar equals 1000 μm.

Figure 4. PXRD patterns of Form I, Form II, PVPVA64, HPMCAS, Form I recrystallized with 20% (w/w) PVPVA64 or HPMCAS, and Form II recrystallized with 20% (w/w) PVPVA64 or HPMCAS.

Figures 6 and 7 show the crystal growth rates of ITZ polymorphs in the presence and absence of PVPVA and HPMCAS, respectively, as a function of temperature. Both polymers at 20% (w/w) attenuated the crystal growth rates of Form I and Form II by several fold at different temperatures. Figure 8 shows the growth rate ratios of ITZ crystals without and with 20% (w/w) polymer at different temperatures, and the same data are also provided as Supporting Information in table format (S1). Here we can clearly discern the relative ITZ growth inhibition by the two polymers for the two polymorphs. First, HPMCAS exerted a stronger inhibition than did PVPVA on the crystallization of Form I or Form II though the difference in crystallization-inhibitory strength between the two polymers appeared moderate (i.e., less than 2-fold in most cases). Second, Form II was apparently more sensitive to the growth inhibition by the two polymers than Form I at all temperatures studied. The crystal growth rate of Form II was

about 3−4 fold higher than that of Form I for phase pure ITZ within the temperature range studied, but this difference in growth rate was narrowed to less than 2 fold after the addition of 20% (w/w) polymer. Impact of Polymers on the Dynamic Properties of Amorphous ITZ. To evaluate the influence of polymers on the dynamic properties of amorphous ITZ, the zero-shear viscosities of 20% (w/w) PVPVA and 20% (w/w) HPMCAS dispersions in supercooled liquid form were measured as a function of temperature (80−120 °C). The shear viscosities of all the prepared supercooled liquids were independent of the shear rate in the range of 0.01−1 s−1, reflecting Newtonian behavior within this shear rate range. The extrapolated zeroshear viscosity data are presented in Figure 9. As expected, the presence of polymers significantly increased the viscosity of the systems relative to pure ITZ. PVPVA and HPMCAS at 20% (w/w) increased the viscosity of ITZ ASDs by a factor of 50− D



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Figure 5. Plot of growth distance of ITZ Form I or Form II crystals grown at 100 °C in the presence and absence of 20% (w/w) polymers as a function of time. The data were treated by simple linear regression, and the slope of the regression line was taken as the rate of crystal growth.

Figure 6. Crystal growth kinetics of ITZ Form I and Form II in the presence and absence of 20% (w/w) PVPVA64 at different temperatures.

Figure 7. Crystal growth kinetics of ITZ Form I and Form II in the presence and absence of 20% (w/w) HPMCAS at different temperatures.

90 and 200−300 respectively at different temperatures; however, the crystal growth rate of ITZ was not reduced to

the same extent. As discussed earlier, the crystal growth rate of ITZ in the presence of polymers was retarded by ∼5−10 fold E



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Figure 8. Plot of ratio of crystal growth rate of ITZ without polymer to that with 20% (w/w) PVPVA64 or HPMCAS as a function of temperature.

glasses.15−17 Konishi and Tanaka found that the denser and more stable salol Form I polymorph (∼1.1% denser) grew approximately 10-fold faster than its metastable counterpart, which they attributed to crystal−liquid volume contraction.15 In contrast, our studies with ITZ revealed the opposite effects; i.e., ITZ Form II with a lower density (1.2% less dense) grew faster than Form I at all temperatures studied. Sun and co-workers found that for the polymorphs of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (named ROY for its red, orange, and yellow polymorphs); those that differ in density by as much as 2.5% could still exhibit similar crystal growth rates.17 Thus, it would appear that the observed difference in crystallization rate between the two ITZ polymorphs in our case cannot simply be explicated by their difference in crystal density alone and possibly also involves other contributing factors, such as crystal packing and crystal anisotropy. Effect of Polymer Excipients on the Crystallization Kinetics of ITZ Polymorphs Based on Two Dimensional Surface Nucleation Model. To assess the effect of polymers on the kinetics and thermodynamics of crystal growth of ITZ Form I and Form II, the growth rate and viscosity data were analyzed using the same two-dimensional nucleation model equation as previously applied to individual phase-pure polymorphs.8 Theoretical background for the applied model equation has been documented elsewhere and will not be elaborated here.18,19 Briefly, the crystal growth rate, v, can be expressed by

Figure 9. Zero-shear viscosities of pure ITZ, ITZ with 20% (w/w) PVPVA64, and ITZ with 20% (w/w) HPMCAS in supercooled liquid state at various temperatures.

(Figure 8; Table S1) within the same temperature range, and the crystal growth rate of ITZ was reduced more with PVPVA than with HPMCAS despite the considerably higher viscosity observed with HPMCAS. This suggests that viscosity may not be a good predictor of molecular mobility, a major contributing kinetic factor to crystal growth.

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DISCUSSION Effect of Crystal Structure on the Crystallization Kinetics of ITZ Polymorphs. We have demonstrated in previous studies that ITZ Forms I and II are monotropically related with Form I being the thermodynamically stable form, as based on thermal analysis and solubility measurements.8 Upon heating, the metastable Form II melts at 157 °C without any solid−solid transition to the stable Form I. In the present study, we also showed that Form II crystal possesses a unit-cell structure similar to that of Form I, but with different orientation of the dichlorophenyl groups. Crystal densities calculated from crystallographic data in Table 1 indicated that Form II has a lower density than Form I, consistent with its less closely packed molecular arrangement and less stable structure. Kinetically, Form II grows faster than Form I from melt by about 3−4 fold. The tension-induced-interfacial-mobility model predicts that growth of denser polymorphs is favored in

v=

⎛ ΔG* ⎞ k exp⎜ − ⎟ η ⎝ kBT ⎠

(1)

where k is a constant; η is the viscosity of the supercooled liquid; ΔG* is the energy barrier to the nucleation of a new crystal monolayer; kB is the Boltzmann constant, and T is the absolute temperature in Kelvin. The free energy of activation, ΔG*, can be estimated from ΔG* = −

πbγ 2 ΔGv

(2)

where b is the height of the two-dimensional nuclei; γ is the crystal-melt interfacial free energy; and ΔGv is the free energy change per unit volume from the amorphous phase to the F



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Figure 10. Plot of ln(vη) versus 1/TΔT for ITZ Form I and Form II with and without 20% (w/w) polymers. The straight lines were obtained by linear regression of the data.

which comprises both a positive γ term and a negative ΔGv term, as defined by eq 2. From Figure 10 and Table 2, it can be seen that the presence of polymers renders the intercepts (ln k) of the lines larger, and slopes of the lines more negative (or larger in absolute value) for both Forms I and II. The larger ln k (or k) values are apparently linked to the disproportionate decrease in crystal growth rate with increasing viscosity. At present, it is still unclear how such an apparent increase in k in the presence of polymer should be interpreted, since k depends, among other factors, on the growth mechanism (which is assumed to be purely two-dimensional surface nucleation here), the size of building unit (or the height of the two-dimensional nuclei for the surface nucleation model), and temperature (which is assumed to have weak contribution). However, it is interesting to note that the ln k values are statistically comparable (within the standard errors of parameter estimates) for the two polymorphs, be they recrystallized from melt with or without the polymers (Table 2). This observation may be explained by the fact that k is jointly linked with the viscosity term (η) to the kinetic energy barrier, which is mainly a function of the molecular properties of the system in the molten state, and as such, the k values should be essentially identical for the two polymorphs (see also subsequent discussion on the effect of viscosity on molecular mobility). On the other hand, the observed increase in slope value may reflect an increase in crystal−melt interfacial free energy, γ, and/or a decrease in the free energy of crystallization, since the presence of miscible additive can decrease the chemical potential of the drug in the liquid phase.20,21 The latter is normally revealed by a depression in the melting point and a decrease in the enthalpy of fusion, ΔHf. However, since we did not observe any significant changes in Tm, ΔHf (data not shown) and the PXRD pattern of the recrystallized ITZ with the polymer (Figure 4), it is unlikely that there would be any incorporation of the polymer into the crystal lattice of ITZ during crystallization. Thus, the thermodynamic driving force for crystallization, ΔGv, can be assumed to be constant, and hence the observed increase in slope value can be ascribed to an increase in γ, which gives rise to a larger ΔG*, as shown in Figure 11. The data in Table 2 show that the extent of interfacial free energy increases is both polymer- and polymorph-dependent; PVPVA affords a larger percentage increase in γ than does HPMCAS for Forms I and II

crystalline phase, which can be related to the enthalpy of fusion, ΔHf, and melting point, Tm, of the crystal form as follows: ΔGv =

−ΔH f ΔT Tm

(3)

where ΔT = Tm − T. Thus, eq 1 can also be expressed by the following linear form: ln(vη) = ln k −

πbγ 2Tm kBT ΔH f ΔT

(4)

2

Good linearity with r values ranging from 0.833 to 0.949 (n = 5) was observed for all the plots of ln(vη) versus 1/TΔT (Figure 10). The parameter estimates and related statistics from the regression analysis are summarized in Table 2. Additionally, Table 2. Parameter Estimates and Related Statistics from Linear Regression Analysis Based on Equation 4 ln k

πbγ2Tm/kBΔHf

r2

HPMCAS in

−9.73 ± 0.24 −9.34 ± 0.16 −4.50 ± 0.40

−35357 ± 5636 −12534 ± 3238 −47953 ± 9331

0.90 0.78 0.86

HPMCAS in

−4.81 ± 0.25

−29510 ± 5039

0.89

PVPVA64 in

−5.46 ± 0.32

−56729 ± 7581

0.93

PVPVA64 in

−4.96 ± 0.43

−51914 ± 8514

0.90

sample Form I Form II 20% (w/w) Form I 20% (w/w) Form II 20% (w/w) Form I 20% (w/w) Form II

the free energies of activation of crystal growth, ΔG*, at various temperatures were computed from the slopes of the lines, and the results are presented in Figure 11. The results suggest that the crystal growth rates of Forms I and II in the presence and absence of polymers are influenced by both kinetic and thermodynamic factors. The kinetic factor refers to the free energy barrier resulting from the movement and rearrangement of molecular mass in space to allow the growth of an ordered crystalline phase from a disordered liquid, which can be expressed by the η term in eq 1. The thermodynamic factor is defined by the free energy barrier, ΔG*, associated with the formation of a new crystal monolayer, G



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Figure 11. Temperature dependency of the free energy of activation, ΔG*, of crystal growth of ITZ polymorphs in the presence and absence of polymers.

Figure 12. Possible locations of the polymer in amorphous solid dispersions during crystallization.

(60% and 314% versus 35% and 135%, respectively), and the percentage increase in γ is much higher for Form II. Employing a similar approach, Kestur et al. studied the inhibitory effect of PVPs of different molecular weights on the crystal growth of felodipine, and similarly concluded that the additives did not significantly affect the thermodynamic driving force for crystallization, ΔGv.14 These authors also remarked that the observed crystal growth inhibition by polymer additives is purely kinetic in nature. However, if this is indeed the case, the growth-inhibitory effects of PVPVA or HPMCAS on the two different ITZ polymorphs in the present study should be comparable, since the molecular mobility of ITZ in the disordered molten state, as reflected by the viscosity term η in eq 1, should be the same for both polymorphs prior to crystallization. However, our data showed that both PVPVA and HPMCAS exerted a much stronger growth inhibition on Form II than on Form I, suggesting that the surface free energy of recrystallized material rather than the molecular diffusivity in the molten state plays a major role in mediating the growth inhibition. In other words, different polymorphs may exhibit different thermodynamic free energy barriers to crystallization

in the presence and absence of the same polymer or growth inhibitor [eq 1].22 It is important to note that for the two-dimensional surface nucleation model, the crystal surface is assumed to be atomically smooth and free from defects, and thus adsorption of any foreign substance (e.g., polymer) on the surface is expected to decrease rather than increase the interfacial free energy. However, as demonstrated for other systems, surfaceadsorbed polymer can raise the interfacial free energy, depending on the strength of adsorption.23−26 Hall and Lips suggested that crystallization additives might be so strongly adsorbed to the surface of a growing crystal that the crystal might be forced to grow around the adsorbed additive. As a result, the curvature of the crystal or step gives rise to a larger surface area, thereby augmenting the specific edge energy and interfacial tension as well as elevating the two-dimensional surface nucleation barrier.22,24 As the concentration of additive is raised to a level where the distance between adsorbed molecules becomes less than twice the critical two-dimensional radius r*, the step on the crystal surface will be forced to assume a radius below r* and hence growth propagation will be halted.22 H



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particular polymorph and the physical stability of amorphous solid dispersions.

While the mechanisms of ITZ crystal growth inhibition by the polymers remain to be elucidated, three possible ways exist by which the polymers interact with the drug during crystallization, as illustrated in Figure 12. First, the polymer may be continuously expelled from the crystal lattice during crystallization, leading to a decrease of polymer concentration in the crystal with time. If this is indeed the case, the polymer will gradually accumulate on the crystal surface, resulting in a reduction in crystal growth rate with time. However, in our case, a linear (i.e., time-independent) growth rate was still observed for ITZ in the presence 20% (w/w) polymer. A plausible explanation for this observation is that the polymer diffuses to the outer surface of the growing crystal much faster than the rate of crystal growth so that the latter is not being affected. However, Kestur and co-workers investigated the steady-state diffusion of PVP in PVP-felodipine dispersion based on the mass transfer model and demonstrated that even if only a very small percentage of polymer was being expulsed out from the drug crystal, there would still be significant retardation of crystal growth due to the gradual accumulation of expelled polymer at the crystal−melt interface, and hence the crystal growth rate would still be strongly time-dependent.14 In addition, owing to the extremely slow diffusion rate of the polymer, there would not be any significant migration of the polymer from the crystal−melt interface to the outer amorphous melt zone, nor would there be any possible diffusion of the polymer from the outer disordered amorphous zone into the inner ordered crystalline zone.24 Consequently, during crystallization, the polymer might appear relatively immobile with all its chains being incorporated into the crystalline domain as either a substitutional or an interstitial solid solution, as depicted in Figure 12. Wegner et al. demonstrated that polymers could be encaged in the lattice structure of an inorganic crystal and concluded that the polymers may be adsorbed onto the steps of the growth spirals and thus retard crystal growth and give rise to large crystal defects.27 However, our PXRD data showed that the polymers being tested did not alter the unit-cell structure of the recrystallized drug. Thus, it would appear that the polymer might only adsorb tenaciously onto the crystal surface, and the crystal was being forced to grow around the adsorbed polymer, leading to an apparent increase in the crystal−melt interfacial free energy and hence a higher free energy barrier to crystallization.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.7b00375. Ratios of crystal growth rates of ITZ without polymer to those with 20% (w/w) polymer at different temperatures (PDF) Accession Codes

CCDC 1537721 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*(A.H.L.C.) Address: School of Pharmacy, The Chinese University of Hong Kong, Rm 801E, Lo Kwee-Seong Integrated Biomedical Sciences Building, Area 39, Shatin, N.T. Hong Kong. E-mail: [email protected]. Tel: 852 39436829. Fax: 852 26035295. *(T.W.Y.L.) School of Pharmacy, The Chinese University of Hong Kong, Rm 801H, Lo Kwee-Seong Integrated Biomedical Sciences Building, Area 39, Shatin, N.T. Hong Kong. E-mail: [email protected]. Tel: 852 39439795. Fax: 852 26035295. ORCID

Albert H. L. Chow: 0000-0001-6858-3554 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the Chinese University of Hong Kong (Research Seed Grant Ref. No. 4930033 for T.W.Y.L. and postgraduate studentship for S.Z.. We also thank Prof. Y. Zheng, Institute of Chinese Medical Sciences, University of Macau, for assistance with the hot-stage microscopic studies.

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CONCLUSIONS As with ITZ Form I, Form II crystallizes in the triclinic system and with a disorder of the two conformationally distinct molecular enantiomers. Form II exhibits a much higher crystallization rate than Form I, which cannot be explained by their difference in crystal density alone. Both PVPVA and HPMCAS at 20% (w/w) significantly retard the crystal growth rates of ITZ Forms I and II in the temperature range of 80−120 °C without altering the crystal structure of either polymorph. Analysis of the ITZ crystal growth kinetics by the two-dimensional surface nucleation model suggests that the polymers inhibit the crystallization of ITZ from amorphous dispersions by reducing the molecular mobility in the supercooled liquid as well as elevating the crystal−melt interfacial free energy. In addition, the extent of interfacial free energy augmentation is both polymer- and polymorph-dependent. The present findings may have important implications for regulating both the formation of

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