Correlation between Molecular Mobility and Physical Stability of

Article pubs.acs.org/molecularpharmaceutics

Correlation between Molecular Mobility and Physical Stability of Amorphous Itraconazole Sunny P. Bhardwaj,†,‡ Kapildev K. Arora,†,⊥ Elizabeth Kwong,§,∥ Allen Templeton,§ Sophie-Dorothee Clas,§ and Raj Suryanarayanan*,† †

Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, United States Basic Pharmaceutical Sciences, Merck & Co, West Point, Pennsylvania 19486, United States

§

S Supporting Information *

ABSTRACT: The goal was to investigate the correlation between molecular mobility and physical stability in amorphous itraconazole and identify the specific mobility mode responsible for its instability. The molecular mobility of amorphous itraconazole, in the glassy as well as the supercooled liquid state, was comprehensively characterized using dynamic dielectric spectroscopy. Isothermal frequency sweeps in the 5−40 °C temperature range revealed a βrelaxation which exhibited Arrhenius temperature dependence. As the temperature approached Tg, β-relaxation became progressively less resolved due to interference from the high frequency tail of the α-relaxation and then transformed into an excess wing. Above Tg, nonlinear temperature dependence of the αrelaxation was described by the Vogel−Tammann−Fulcher (VTF) model. Itraconazole was found to be a fragile glass former with a VTF strength parameter of ∼4. Isothermal crystallization kinetics, at several temperatures over the range of 75 to 95 °C, was best described by the 3-dimensional nucleation and growth model. Primary relaxation appeared to be the mobility responsible for the observed physical instability at temperatures above Tg as indicated by the linear correlation of α-relaxation with both crystallization onset and kinetics (represented by the inverse of the crystallization rate constant). A strong coupling between global mobility and crystallization onset was evident. However, for growth kinetics, the coupling was less pronounced, indicating the involvement of factors other than global mobility. KEYWORDS: itraconazole, amorphous, dielectric spectroscopy, molecular mobility, crystallization kinetics, crystallization onset

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INTRODUCTION Itraconazole (ITZ) is an antifungal agent which has a poor aqueous solubility at room temperature (∼1 ng/mL at pH 7.4 and ∼4 μg/mL at pH 1).1 It possesses good permeability as indicated by a high octanol−water partition coefficient (log P ∼ 6.2), and belongs to class II of the Biopharmaceutics Classification System.1,2 Since the oral bioavailability of ITZ is dissolution rate limited, approaches to improve its solubility and dissolution rate have been explored.3−8 Its use in the amorphous state (mostly in solid dispersions) has been suggested as a possible strategy to enhance oral bioavailability.3−5,9 However, the use of an amorphous active pharmaceutical ingredient is fraught with risk due to its inherent physical instability and the potential for crystallization, either during manufacture or product storage. In many amorphous compounds, a correlation has been reported between molecular mobility and stability.10−16 Therefore, a reduction in molecular mobility is often associated with improved physical stability. Molecular mobility comprises both global and local motions. Global mobility (or α-relaxation) refers to molecular motion which becomes progressively cooperative in nature as the temperature is decreased toward the glass transition temperature (Tg). Local motions (β© 2012 American Chemical Society

relaxation or secondary relaxation) include noncooperative modes involving either a part or a complete molecule.17−19 In numerous compounds, global mobility has been linked to physical instability while there are only few examples where local motions have been implicated.13,20,21 In other words, the type of mobility modulating the physical instability appears to be compound specific. It is therefore necessary to study the different molecular motions in order to identify the specific mobility responsible for instability in an amorphous material. Dynamic dielectric spectroscopy is a technique which is amenable to studying different modes of mobility in amorphous materials.22 It not only enables the characterization of global mobility but is also sensitive to several local motions. It is therefore an excellent tool for characterizing mobility in amorphous materials, as was demonstrated in the case of amorphous trehalose.17,18,22−27 This not only enabled us to demonstrate the link between global molecular mobility and physical stability but also led to the development of a model for Received: Revised: Accepted: Published: 694

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predicting crystallization onset at temperatures around and below Tg.28 In the current study, our goal was to apply the same approach in an amorphous drug with poor solubility. We used dielectric spectroscopy to characterize different relaxations in amorphous ITZ in order to identify the specific mobility linked to instability. This would enable the development of stabilization approaches which would be aimed at modulating the specific mobility responsible for physical instability.

ε*(ω) = ε∞ +

Δε (1 + (iωτ )βHN )γHN

ε*(ω) = ε′(ω) − iε″(ω)

(1) (2)

In eqs 1 and 2, ω is the angular frequency, which is equal to 2πf with f being the frequency in Hz, ε*(ω) is the complex dielectric permittivity (eq 2) consisting of real (ε′) and imaginary (ε″) components, and dielectric strength is given by Δε = εs − ε∞, where εs gives the low frequency limit (ω → 0) of ε′(ω) and ε∞ is the high frequency limit (ω → ∞) of ε′(ω). The shape parameters, βHN and γHN, account for the symmetric and asymmetric peak broadening respectively with 0 < β (or γ) < 1. The data analyses were done using WinFit and Matlab software. A representative dielectric spectrum of itraconazole and the original data with fitted profile as well as estimates with confidence intervals for the different fitted Havriliak−Negami parameters and their correlation matrix are presented in the Supporting Information. For the temperature sweep experiments, measurements were made in increments of 5 °C, over the range of −100 to 110 °C at a fixed frequency of 1 kHz.

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EXPERIMENTAL SECTION Preparation of Spray-Dried ITZ. Crystalline ITZ (Bepharm Limited, Shanghai, China; purity ∼98%) was used as received. ITZ dissolved in tetrahydrofuran (1% w/v) was introduced at a feed rate of 5 mL/min (Micro-Spray Co-flow spray-dryer/chiller, ProCepT, Zelzate, Belgium). The inlet temperature was maintained at 105 °C, and the resulting outlet temperature was 60 °C. The flow rate of drying gas was 0.35 m3/min, while cooling air and side air flow rate was set at 0.15 m3/min. Atomization air flow was maintained at ∼0.005 m3/ min. The spray-dried samples were stored in capped glass containers which were in turn placed in a larger capped glass jar containing anhydrous calcium sulfate and stored at −20 °C. Further handling, including sample preparation for thermal, Xray, and dielectric analyses, was done in a glovebox maintained at RH < 5% (RT). Powder X-ray Diffractometry (XRD). A powder X-ray diffractometer (D8 ADVANCE; Bruker AXS, Madison, WI) equipped with a variable temperature stage (TTK 450; Anton Paar, Graz-Straßgang, Austria) and Si strip one-dimensional detector (LynxEye; Bruker AXS) was used. Samples were exposed to Cu Kα radiation (40 kV × 40 mA), in the angular range of 5−35° 2θ, with a step size of 0.05° 2θ and a dwell time of 1 s. Nitrogen was continuously purged in the sample headspace to minimize water uptake from the environment. For the isothermal crystallization studies at temperatures above Tg, the holder containing the powder sample was transferred to the sample stage maintained at the desired experimental temperature. Samples were periodically subjected to XRD while maintained at the desired temperature. Dielectric Spectroscopy. Using a broadband dielectric spectrometer (Novocontrol Alpha-A high performance frequency analyzer, Novocontrol Technologies, Germany), isothermal dielectric measurements were conducted usually over the frequency range of 10−1 to 106 Hz at several temperatures from 0 to 105 °C. About 100 mg of sample was placed between two round copper electrodes (20 mm diameter) and a PTFE spacer. The PTFE spacer (thickness, 1 mm; area, 59.69 mm2; capacity, 1.036 pF) was used to keep the sample confined between electrodes at high temperatures and also to minimize errors due to stray capacitance or edge effects. Excess sample was compressed between the electrodes to ensure uniform sample contact with the electrode surface. Replicate measurements (n ≥ 3) were carried out to check data reproducibility. The sample temperature was maintained with a Novocool Cryosystem temperature controller. Samples of different thicknesses were analyzed to ensure that, in the frequency region of interest, there was no interference from interfacial polarization. The sources of error in the dielectric analysis of powder samples as well as the steps that can be taken to identify and minimize these errors were discussed earlier.26 The Havriliak−Negami function (eq 1) was used to fit the dielectric data so as to obtain the average relaxation time (τ) and shape parameters (βHN and γHN).

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RESULTS AND DISCUSSION Baseline Characterization. Spray-dried ITZ was found to be X-ray amorphous with a calorimetric Tg onset (determined at a 10 °C/min heating rate) of 50.6 °C. Based on the thermogravimetric analysis, the volatile solvent content was 45 °C that this secondary relaxation transformed into an excess wing. This is a characteristic of α-relaxation which commonly exhibits stronger temperature dependence than the secondary relaxation. Moreover, this shows that the excess wing is the high frequency segment of an unresolved β-relaxation. As the temperature was increased above Tg, the α-relaxation peak could be observed in the frequency range of the instrument. The increase in the frequency of the structural relaxation with a rise in temperature is apparent in Figure 3. There was a decrease in the dielectric strength at 95 °C due to crystallization. The crystallization was complete before the next measurement at 100 °C, indicated by the absence of any loss peak (data not shown). Temperature Dependence of Different Relaxations. To obtain the average relaxation times as well as the other parameters, the relaxation peaks were fitted using the Havriliak−Negami equation (eq 1). Figure 4 shows the

Figure 4. Temperature dependence of α- and β-relaxation times. The dotted and the dashed lines indicate Arrhenius and VTF behavior respectively. Mean ± SD; n = 3.

temperature dependence of average relaxation times for the two mobility modes in amorphous ITZ. For the β-relaxation, irrespective of the temperature, the best fit was obtained with βHN and γHN values of 0.47 and 0.49 respectively. As expected, the secondary relaxation exhibited Arrhenius behavior (eq 3) over the entire experimental temperature range in which it was observed: ⎛E ⎞ τ(T ) = τ0 exp⎜ a ⎟ ⎝ RT ⎠

(3)

In this expression, τ is the average relaxation time and T is the temperature, τ0 is the relaxation time of the unrestricted material, R is the gas constant, and Ea is the activation energy. The activation energy for the β-relaxation was calculated to be ∼42.9 kJ/mol. As already mentioned, the β-relaxation transformed into an excess wing as the temperature was increased closer to Tg. Therefore, the average relaxation time for this mobility mode was determined only up to 35 °C. Above this temperature, the contribution of α-relaxation high temperature tail to the β-relaxation was significant. The average α-relaxation times were determined at several temperatures above Tg. The temperature dependence of α696

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complete (Figure 6b). For quantification purposes, we integrated the intensities of the peaks at 17.1°, 17.7°, and 20.2° 2θ. The corresponding value of the completely crystallized sample was used to calculate the fraction crystallized at different time points. Figure 7 shows the fraction crystallized as a function of time at different temperatures. The crystallization rate constant, k, and crystallization onset time, t0, were obtained by fitting the Johnson−Mehl−Avrami (JMA) model (eq 6) to the isothermal crystallization data.35−37

relaxation time was not linear (Figure 4) and was described by the Vogel−Tammann−Fulcher (VTF) model (eq 4):29 ⎛ DT0 ⎞ τ(T ) = τ0 exp⎜ ⎟ ⎝ T − T0 ⎠

(4)

In eq 4, D is the strength parameter, which is an indicator of kinetic fragility of the material, and T0 represents the zero mobility temperature (theoretical Kauzmann temperature). The other symbols were explained earlier. The values of τ0 and T0 obtained from the VTF fit were 7.4 × 10−12 s and 285 K respectively. The strength parameter or the D value was ∼3.9, indicative of a very fragile glass former. The calculated value of dielectric Tg using the VTF fit, assuming a relaxation time of 100 s, was ∼48.5 °C (indicated by an arrow in Figure 4).29−31 This is in excellent agreement with the calorimetric Tg onset temperature of 50.6 °C, validating the VTF fit. The loss peak for α-relaxation was considerably asymmetric as indicated by the low value of asymmetric shape parameter (γHN < 0.5 at all the temperatures, Figure 3). This indicates that ITZ has a wide distribution of relaxation times. To get a more quantitative estimate, the relaxation time distribution parameter from the Kohlrausch−Williams−Watts equation (βKWW) was calculated from the Havriliak−Negami peak width parameters βHN and γHN using the empirical equation (eq 5):32 1.23 βKWW = βHNγHN

α(t ) = 1 − exp[−(k(t − t0))n ]

(6)

In eq 6, α represents the fraction crystallized at time t, and n is the reaction order, which is determined by the nucleation mechanism and the growth dimensions. Crystallization, at all temperatures, was best described by the JMA nucleation and growth model with n = 3. This allowed us to obtain both k and t0 as a function of crystallization temperature. Since k is a measure of the growth kinetics and t0 is expected to be influenced by nucleation, these parameters were considered the two markers of the physical stability of ITZ. Correlation between Molecular Mobility and Stability above Tg. In order to link the observed instability to a specific mobility, we investigated the correlation between the physical stability of amorphous ITZ and its two relaxations. The objective was to identify the specific mobility mode responsible for instability. The first step was to determine the relationship between crystal growth kinetics and molecular mobility. For this purpose, the inverse of k, referred to as “crystallization time” or “τcryst”, was calculated at different temperatures. The temperature dependence of both the relaxations as well as the crystallization kinetics (τcryst) was plotted in the same graph, which enabled a visual comparison (Figure 8). A parallel relationship was observed between τcryst and average αrelaxation time in spray-dried ITZ, indicating that these two processes are affected by the temperature in a similar manner. On the other hand, the temperature dependence of τcryst was markedly different from the linear behavior exhibited by the secondary relaxation. It is instructive to note that the temperature dependence of β-relaxation was studied at sub-Tg temperatures whereas the crystallization studies were carried out at temperatures above Tg. We have implicitly assumed that β-relaxation exhibits the same temperature dependence above and below Tg. However, there are reports in the literature that suggest a change in the temperature dependence of β-relaxation at temperatures above Tg.38,39 However, as is clear from Figures 2 and 3, it is not possible to study the temperature dependence of β-relaxation around Tg and at higher temperatures (T > Tg) since the α-relaxation starts to interfere with β-relaxation. As a result, unambiguous determination of β-relaxation time is not possible. It will be interesting and relevant to study crystallization in the sub-Tg range and compare its temperature dependence with that of the secondary relaxation. These sub-Tg crystallization experiments are ongoing and will be the subject of a future manuscript. We further investigated the relationship between τcryst and average α-relaxation time (τα). To determine the extent of coupling between these two quantities, a coupling coefficient M was included according to eqs 7 and 8.

(5)

This parameter was then plotted as a function of measurement temperature (Figure 5). At temperatures close to Tg, a

Figure 5. Plot of βKWW as a function of temperature for α-relaxation. Mean ± SD; n = 3.

value of ∼0.36 indicated a pronounced heterogeneity in the distribution of relaxation times. With an increase in temperature, the βKWW value initially increased, indicating a decrease in the heterogeneity, after which it reached a plateau. Such a decrease in the heterogeneity of amorphous state dynamics with temperature has also been observed for other materials.33,34 Isothermal Crystallization Kinetics by XRD. Crystallization of ITZ was studied isothermally, at several temperatures in the range of 75−95 °C, and was considered a measure of its physical instability. As a representative example, the results obtained at 85 °C are presented in Figure 6. The characteristic peaks of crystalline ITZ appeared after 65 min (Figure 6a), and their intensities progressively increased until crystallization was 697

τcryst = Aτα M

(7)

ln(τcryst) = M ln τα + ln A

(8)

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Figure 6. XRD patterns of amorphous ITZ at 85 °C from (a) 0 to 90 min and (b) 100 to 500 min.

Figure 7. Fraction of ITZ crystallized as a function of time at different temperatures. Figure 9. Plot of natural log of crystallization time versus natural log of average α-relaxation time. Regression equation is given in the graph. Each data point in the figure represents a unique temperature. Mean ± SD; n = 3.

The second goal was to identify the mobility mode playing a dominant role in the nucleation propensity, represented by onset of crystallization. It is however recognized that significant growth has already taken place before the crystallization onset is observed by XRD. Similar to τcryst (Figure 8), t0 as well as αand β-relaxation times were plotted as a function of temperature (Figure 10). The temperature dependence of t0 and α-relaxation time were parallel, indicating that the same molecular motion is involved in these two processes. The temperature dependence of β-relaxation time was considerably different from that of t0. To investigate the extent of coupling between t0 and αrelaxation time, a model similar to that described by eq 8 was used with the substitution of t0 for τcryst. Figure 11 shows such a plot where the value of M was determined to be 0.94, indicating a strong coupling between these two processes. This shows that the global mobility is the primary determinant of crystallization onset and the other factors are likely to be much less significant. A similar observation was made in the case of amorphous trehalose where a strong coupling was observed between structural relaxation time and crystallization onset time.28 The utility of this approach is that these correlation models can potentially be used in predicting the physical stability at other temperatures of interest. However, stability prediction at

Figure 8. Temperature dependence of crystallization time (plotted on the right y-axis) and average relaxation times (plotted on the left yaxis) for different mobility modes. Mean ± SD; n = 3.

In eqs 7 and 8, A is a constant. The crystallization time versus structural relaxation time plot was linear (Figure 9), and the M value was determined to be 0.68. This suggests a significant coupling between these two processes. In other words, global mobility is involved in the growth kinetics of the supercooled melt of ITZ. However, a coupling coefficient of less than unity also indicates that factors other than the global molecular mobility are likely playing a role in growth kinetics. 698

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ASSOCIATED CONTENT

S Supporting Information *

This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, United States. Phone: 612624-9626. Fax: 612-626-2125. E-mail: [email protected]. Present Addresses ⊥

Pfizer Global Research & Development, Groton, Connecticut 06340, United States. ‡ Basic Pharmaceutical Sciences, Merck & Co, Rahway, New Jersey 07605, United States. ∥ Kwong Eureka Solutions, Kirkland, QC H9J 4C9, Canada.

Figure 10. Temperature dependence of crystallization onset time (plotted on the right y-axis) and average relaxation times (plotted on the left y-axis) for different mobility modes. Mean ± SD; n = 3.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS James Ormes and Jiang Chang (Basic Pharmaceutical Sciences, Merck & Co, Rahway, NJ) are thanked for their help in preparing spray-dried itraconazole. Discussions with Patrick Marsac (Molecular and Materials Characterization, Merck & Co, West Point, PA) and Ronald Siegel (University of Minnesota) were very helpful. Powder XRD work was carried out at the Characterization Facility, University of Minnesota, which receives partial support from NSF through the Materials Research Science and Engineering Centers (MRSEC) program.

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Figure 11. Plot of natural log of onset time versus natural log of average α-relaxation time. Regression equation is given in the graph. Each data point in the figure represents a unique temperature. Mean ± SD; n = 3.

relevant storage temperatures may require measurement of αrelaxation times at temperatures substantially below the Tg of the material of interest. Since the structural relaxation at such temperatures can be very long, the frequency domain methods are usually not practical and time domain techniques, though less accurate, may have to be used.

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CONCLUSIONS Itraconazole (ITZ), a very fragile glass former, exhibited two relaxation processes. Primary relaxation, observed only in the supercooled liquid region, exhibited VTF temperature dependence. The secondary relaxation followed Arrhenius temperature dependence in the sub-Tg range. The α-relaxation time correlated to both crystallization onset and kinetics, indicating the role of this mobility mode in physical instability of the supercooled ITZ. The extent of coupling with global mobility was much greater for the crystallization onset than for the growth kinetics, indicating that mobility alone did not govern the latter. 699

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