Physical Stabilization of Pharmaceutical Glasses Based on Hydrogen

Article pubs.acs.org/molecularpharmaceutics

Physical Stabilization of Pharmaceutical Glasses Based on Hydrogen Bond Reorganization under Sub‑Tg Temperature Satoshi Tominaka,† Kohsaku Kawakami,*,† Mayuko Fukushima, and Aoi Miyazaki International Center for Materials Nanoarchitectonics, National Institute for Materials Science, 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan ABSTRACT: Amorphous solid dispersions (ASDs) play a key role in the pharmaceutical industry through the use of highenergy amorphous state to improve solubility of pharmaceutical agents. Understanding the physical stability of pharmaceutical glasses is of great importance for their successful development. We focused on the anti-HIV agent, ritonavir (RTV), and investigated the influence of annealing at temperatures below the glass transition temperature (sub-Tg) on physical stability, and found that the sub-Tg annealing effectively stabilized RTV glasses. Through the atomic structure analyses using X-ray pair distribution functions and infrared spectroscopy, we ascertained that this fascinating effect of the sub-Tg annealing originated from strengthened hydrogen bonding between molecules and probably from a better local packing associated with the stronger hydrogen bonds. The sub-Tg annealing is effective as a physical stabilization strategy for some pharmaceutical molecules, which have relatively large energy barrier for nucleation. KEYWORDS: pharmaceutical glass, solid dispersion, crystallization, stability, pair distribution function

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INTRODUCTION Approximately 40% of the marketed drugs are poorly soluble in water,1 and this number increases to 70% for the candidate compounds under development.2 Formulations that increase drug solubility significantly increase the probability of success in drug development. Great attention has thus been paid to amorphous solid dispersions (ASDs),3−7 which show high solubility due to the high energy of amorphous materials relative to their crystalline counterparts. Their high energy also presents a drawback as amorphous solids spontaneously crystallize to form more energetically favored structures. Methods for improving physical stability of amorphous pharmaceuticals are thus in high demand to allow the successful use of oral ASDs, and a better understanding of physical stability of amorphous pharmaceuticals is necessary. Recently, investigations of isothermal crystallization of pharmaceutical glasses revealed a general rule for crystallization of pharmaceuticals: initiation time for the crystallization was dominated solely by the temperature, as expected from thermodynamics. This rule is fascinating because the kinetics of these thermodynamically controlled crystallizations can be expressed as a function of the ratio between the glass transition temperature (Tg) and storage temperature (T), Tg/T.8,9 If this rule was universal, there would be no chance to enhance the physical stability of pharmaceutical glasses, but fortunately, there are exceptions, such as ritonavir (RTV), the anti-HIV drug. Pharmaceutical glasses with low crystallization tendency tend to have molecular features such as high molecular weight, a © XXXX American Chemical Society

high degree of conformational freedom, strong intermolecular interactions, and branched structures,10−12 suggesting that steric hindrance and intra/intermolecular interactions including van der Waals forces and hydrogen bonding13 play key roles in stabilizing pharmaceutical glasses by adding energy barriers for nucleation. From an energy viewpoint, compounds having a large enthalpy of fusion and a high melting temperature are likely to be stable.11 In the field of polymer chemistry, existence of exceptionally stable amorphous phases has been well recognized. Glassy polymers often contain a metastable amorphous phase (so-called “rigid amorphous fraction”), which is not a crystalline phase as it does not have a heat of fusion and does not exhibit Bragg peaks in X-ray diffraction nor a normal amorphous phase as it does not exhibit relaxation behavior.14,15 Though we know the existence of these stable glasses, the origin of their higher physical stabilities is still open to debate, due to a lack of detailed mechanistic understanding. We found a clue to a better understanding of the mechanism of crystallization in RTV studies. Although physical stability of most pharmaceutical glasses was explained as a function of solely Tg/T, quenched RTV glass showed exceptional physical stability to crystallization, most likely because of large energetic barrier for nucleation.9 Structures of glasses are not necessarily the same even for the same molecules and depend on their Received: Revised: Accepted: Published: A

September 25, 2016 November 14, 2016 November 16, 2016 November 16, 2016 DOI: 10.1021/acs.molpharmaceut.6b00866 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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Molecular Pharmaceutics thermal history,16−18 showing the possibility of forming more stable pharmaceutical glasses. This possibility is most promising for molecules with the typical molecular features described above, such as RTV, which can have additional energy/kinetic barriers to rearrangement in their packing. In this scenario, the next question to be answered is “How can we add such barriers?”. Again, the RTV case suggests that amorphous phases can be stabilized by reducing molecular mobility through the formation of different packing and conformations, which accompanies decrease in the free volume. We know that after amorphous solids are formed molecular mobility decreases over time due to structural relaxation to form more energetically favored structures,18 and we expect that these structures have larger barriers to crystallization than their parent structures under assumption of identical activation states for the crystallization. Thus, annealing is a promising strategy to stabilize pharmaceutical glasses, and a temperature just below Tg (subTg) is reasonable choice for effective relaxation without crystallization because only small molecular units such as side chains relax at the sub-Tg region, and the long-range segmental motion necessary for the crystallization is frozen.13,19,20 Herein we report influence of sub-Tg annealing on the physical stabilities and structures of pharmaceutical glasses. First, in order to discuss general trends, we demonstrate the impact of sub-Tg annealing on the stabilities of pharmaceutical agents (acetaminophen, AAP; chlorpropamide, CPA; indomethacin, IDM; tolbutamide, TLB; and ritonavir, RTV), and then analyze details by focusing on RTV, which exhibited a significant stabilization after the annealing. In addition to the detailed calorimetric analysis, we analyze the structures of the RTV glasses using X-ray pair distribution functions (PDFs) as well as infrared spectroscopy (IR) in order to reveal the mechanism from a molecular viewpoint.

samples were evaluated for relaxation and crystallization studies in order to confirm reproducibility. The averaged values are reported. Isothermal Crystallization Experiments. For the isothermal crystallization studies, both as-prepared and annealed glasses (∼3 mg) were treated at a crystallization temperature, Tcry (Tcry > Tg), in the DSC apparatus (AAP, CPA, and TLB) or in temperature-controlled ovens (IDM and RTV). For the latter compounds, the glass samples were transferred from the DSC apparatus to the ovens as quickly as possible. The crystallization conditions were 35 °C for 15 min (TLB), 40 °C for 30 min (CPA), 60 °C for 50 min (AAP), 60 °C for 10 d (IDM), and 60 °C for 6 d (RTV). Regarding RTV, we further investigated influence of the crystallization temperature and time. The crystallinity values, X, for TLB, CPA, and AAP were calculated from the crystallization exotherm observed in the DSC heating curves as follows:9 ΔHan

X=1−

Tas

ΔHas − ∫ ΔCp dT T an

(1)

where ΔH and T are the crystallization enthalpies and crystallization temperature (peak temperature), respectively; the subscripts, “an” and “as” mean annealed and as-prepared samples, respectively; ΔCp is the heat capacity difference of the amorphous and crystalline forms. This equation is applicable only when both as-prepared and annealed glasses crystallize into the same crystal form, which was confirmed for all the model drugs employed.9 X for IDM and RTV were calculated from the melting enthalpy because these samples did not crystallize during the heating process.9

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METHODS Materials. Ritonavir (RTV) (or 1,3-thiazol-5-ylmethyl N[(2S,3S,5S)-3-hydroxy-5-[(2S)-3-methyl-2-{[methyl({[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl})carbamoyl]amino}butanamido]-1,6-diphenylhexan-2-yl]carbamate, C37H48N6O5S2), acetaminophen (AAP) (or 4-acetamidophenol C8H9NO2), and chlorpropamide (CPA) (or 4-chloro-N(propylcarbamoyl)benzenesulfonamide, C 10 H 13 ClN 2 O 3 S) were purchased from LKT Laboratories (St. Paul, USA), MP Biomedicals (Santa Ana, USA), and Sigma-Aldrich (St. Louis, USA), respectively. Indomethacin (IDM) (or 2-{1-[(4chlorophenyl)carbonyl]-5-methoxy-2-methyl-1H-indol-3-yl}acetic acid, C19H16ClNO4) and tolbutamide (TLB) (or N[(butylamino)carbonyl]-4-methylbenzenesulfonamide, C12H18N2O3S) were obtained from Wako Pure Chemicals (Osaka Japan). All compounds were used as supplied. The “as-prepared” amorphous samples (i.e., quenched glass materials) were prepared by heating crystalline samples at 10 °C/min above their melting points using a Q2000 differential scanning calorimetry (DSC) instrument (TA Instruments, New Castle, DE, USA) with nitrogen flow at 50 mL/min, and then quenching the melts at 50 °C/min. These as-prepared amorphous solids were stored at different sub-Tg annealing temperatures in a DSC apparatus or a temperature-controlled oven. Thermal Analysis. Thermal analysis was performed using the DSC instrument with nitrogen flow at 50 mL/min. The samples were loaded on crimped aluminum pans. At least three

X=

Hm,an Hm,cr

(2)

where Hm,an and Hm,cr are the melting enthalpies of the annealed sample and that of the corresponding crystal form, respectively.9 The crystallization behavior was analyzed using the Avrami− Erofeev equation:8,9 X = 1 − exp{−k(t − d)n }

(3)

where k is the crystallization rate constant, d is the induction time, and n is an Avrami exponent, which is a parameter depending on nucleation mechanism and the dimension of the crystal growth. Relaxation Enthalpy Measurements. Relaxation enthalpies were measured for the RTV glasses (∼5 mg) in the modulated DSC mode at 2 °C/min with a 60 s period and 0.5 °C amplitude, using Tzero aluminum pans. Heat capacity was also determined using the modulated DSC according to the protocol reported previously.21 After heating the samples above the melting temperature, they were cooled at 50 °C/min to the annealing temperature, where the annealing was applied for 30, 60, 120, and 180 min. Then, the samples were cooled to 20 °C and the temperaturemodulated measurement was applied. The relaxation behavior was analyzed using the Kohlrausch−Williams−Watts (KWW) equation:18 B

DOI: 10.1021/acs.molpharmaceut.6b00866 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

Article

Molecular Pharmaceutics ⎡ ⎛ t ⎞β⎤ ϕ = exp⎢ −⎜ ⎟ ⎥ ⎣ ⎝τ⎠ ⎦

under the following restraints and constraints: bond length restraints (±0.05 Å to the initial values), bond angle restraints (±5° to the initial values), rigid body constraints (±0.3° of rotation using its centroid as the rotation center, and ±0.2 Å translation along the a, b, and c axes) to the aromatic rings, and symmetry constraints (P212121 space group). The initial structure was formed by optimizing a reported crystal structure in the P212121 space group using a molecular mechanics simulation with the GULP program with the Dreiding force field27 for the crystalline sample, while the refined crystal structure was used for the other samples. The hydrogen atoms were added using the Materials Studio program. Before these iterative runs, the atomic displacement parameters were fitted by the PDF refinement for the data in the interatomic distance within 3 Å. On the basis of the refined structures, Kitaigorodskii packing index was calculated using the Platon program.28 Infrared Spectroscopy. Fourier transform infrared (FTIR) spectra were measured on a Jasco 6200 spectrophotometer (JASCO Corp, Tokyo, Japan) equipped with an ATR stage under dried nitrogen atmosphere. All spectra were recorded in absorption mode at 4 cm−1 intervals.

(4)

where ϕ is the fraction of the remaining excess enthalpy compared to metastable glass, τ is the relaxation time, and β is the fitting parameter (0 < β ≤ 1) reflecting dispersion of the relaxation time.22 Further details on the relaxation analysis can be found elsewhere.18 PDF Measurements. Crystalline RTV powder was introduced into 1 mm ϕ Lindeman glass capillaries (Hilgenberg) using a Hitachi CF16RXII centrifuge at 2000 rpm for 5 min. The amorphous RTV samples were obtained by heating these capillaries at 140 °C for 10 min. The samples were further annealed at 40 °C (i.e., sub-Tg annealing) for 1 h, 4 days, and 27 days in a temperature-controlled oven. The Xray total scattering data were collected on a curved imaging plate with Ag Kα (λ = 0.560883 Å) operated at 50 kV, 40 mA using a Rigaku Rapid-S diffractometer at room temperature (27 °C). Corrections were carried out for background intensity (air and a blank capillary), absorption, fluorescence, X-ray polarization, double scattering, and Compton scattering.23 These corrected intensities were normalized by the Faber−Ziman type scattering form factors calculated using atomic scattering factors24 to obtain structure functions, S(Q).23 The S(Q) in the scattering vector range of Qmax = 20.3 Å−1 was treated with a revised Lorch function (Δ = 1.0).25 The S(Q) was then converted into reduced PDF, G(r), where r is the interatomic distance.

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RESULTS AND DISCUSSION Impact of Sub-Tg Annealing on Physical Stabilities. Figure 1 shows the influence of the sub-Tg annealing on the subsequent isothermal crystallization of pharmaceutical glasses. There was no obvious influence of the annealing on most of the pharmaceutical glasses we investigated (Figure 1a−d); however, crystallization of RTV became slower by the annealing (Figure 1e), that is, RTV was stabilized. Note that the isothermal crystallization behaviors of TLB, CPA, and AAP glasses were dominated by thermodynamics, while IDM and RTV glasses showed better stability when prepared by quenching.9 IDM did not exhibit meaningful stabilization upon annealing though had higher stability than that expected from thermodynamics, while RTV exhibited further stabilization through the sub-T g annealing process. Annealing of pharmaceutical glasses has been suggested as a means for improving physical/chemical stability because it can suppress molecular mobility of the compounds;17 however, no clear physical stabilization has been reported using this annealing strategy. Thus, this is the first example showing a clear physical stabilization by annealing and demonstrates the power of sub-Tg annealing to improve the stability of ASDs. The physical stability of RTV (Tg = ∼47 °C, onset)9 was not increased monotonically (Figure 1e) with annealing temperature from 32 to 43 °C. Since motions of side chains/ substituents can occur even in sub-Tg region, this probably results from relaxation of such side chains. Moreover, as temperature increases, the motion commences from smaller (with lower activation energies) to larger groups (with higher activation energies);13,20 thus, the irregular temperature dependence probably reflects formation of different kinetically trapped structures through such local relaxation. These structures may not be the energetically most favored state, as was observed for small organic molecules, whose relaxation apparently stopped before reaching the energetically expected state.18 Effect of the sub-Tg annealing at 40 °C is modest compared with other temperatures (Figure 1e) but became prominent with increased annealing time (Figure 1f): the crystallinity of as-prepared glass resulted in ca. 56% by isothermal crystallization at 60 °C for 6 days, and this value

G(r ) = 4πρ0 r(g (r ) − 1) =

2 π

∫Q

Q max min

Q (S(Q ) − 1) sin(Qr ) dQ

(5)

where g(r) is the pair distribution function, ρ0 is the number density of atoms in the system, and r is the interatomic distance. In order to run the following reverse Monte Carlo simulation smoothly, termination ripples within r = 0.89 Å were filtered out to form smooth G(r) (below the nearest neighbor distance): the data of the region was assumed to be the sum of a linear function of −4πρ0r and oscillation from the first peak (∼1.4 Å), which had oscillation associated with the nature of the sinc function. We fitted the peak with a combination of a Gaussian function and a sinc function, and then the additional intensities associated with the termination errors were removed from S(Q) through inverse Fourier transform and polynomial fitting of the difference using a python code. This process does not affect the data in the range from the first peak. Analysis of PDFs. The structure of the RTV crystal was analyzed by the PDF refinement using the PDFfit2 program.26 Because the unit cell of form II is composed of a large number of atoms (148 C atoms, 24 N atoms, 18 O atoms, 8 S atoms, and 192 H atoms; Z value is 4), the refinements of the atomic coordinates using the least-squares method of the program could not provide a structurally reasonable bond lengths and angles for the molecule. Thus, the structures of the materials were further analyzed by the reverse Monte Carlo method (or simulated annealing) in order to refine atom coordinates under bond length and angle restraints. We modified the PDFfit2 program26 by adding a code to minimize the weighted Rvalue23 through iterative runs of the PDFfit2 calculation for a configuration where one atom or molecule (as a rigid body) randomly chosen was moved or rotated at a random amount C


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Molecular Pharmaceutics

Figure 2. Kinetics of the isothermal crystallization of RTV glass. (a) Crystallization behaviors of the as-prepared RTV glass (“asp”) and the sample annealed at 40 °C for 12 h (“annealed”). The crystallization was investigated at 60 °C. (b) Crystallization behaviors of the asprepared RTV glass at a different crystallization temperature. The dotted curves show the crystallization behaviors simulated using the Avrami−Erofeev equation. (c) Arrhenius plot based on time to reach 10% crystallinity, t10 (min), which represents kinetics of nucleation. Only the data obtained at Tcry = 45, 50, and 60 °C were used for this plot.

Figure 1. Influence of the sub-Tg annealing on the stability to crystallization in pharmaceutical glasses: the percentage crystallinity after sub-Tg annealing and isothermal crystallization is shown. (a−e) Temperature dependence for (a) tolbutamide, TLB, (b) chlorpropamide, CPA, (c) acetaminophen, AAP, (d) indomethacin, IDM, and (e) ritonavir, RTV. The samples were kept at a sub-Tg temperature for 12 h as noted in each panel (“asp” means as-prepared glass without the sub-Tg annealing) except that RTV was annealed for 1 h because it was sufficient to observe the stabilization effect. (f) Time dependence for RTV. The sample was annealed at 40 °C for indicated periods in the figure. The error bars show standard deviations.

increases further.30,31 For this behavior, several models were proposed and the mechanism is still open to debate; for example, this unique behavior is sometimes accounted for by the change in the crystallization mode near Tg: diffusionless crystallization based on homogeneous nucleation below Tg and normal crystal growth above Tg. However, our findings suggest that the change in crystallization rates could also be accounted for by assuming existence of the temperature region near Tg where the crystallization is suppressed based on the following observation. Calorimetric Analysis on Relaxation of RTV Glass. In order to understand the mechanism of the stabilization by subTg annealing, we carried out calorimetric analysis on the relaxation process of the RTV glasses. The RTV glass relaxed in the sub-Tg temperature range (40 °C) as found from the endothermic recovery behavior in the DSC curves (Figure 3a). The recovery peak just above Tg (i.e., ∼50 °C) grows clearly with the annealing time, meaning that the structures relaxed with annealing time. The relaxation enthalpies were measured for the RTV glasses at a different temperature in 32−43 °C (Figure 3b), showing that the kinetically trapped structure and energy state obtained by the annealing for such a period of time depend on the temperature. Thus, even within a narrow temperature range, different structures can be formed at different annealing temperatures. The relaxation enthalpy reached to ca. 3.9 J/g (2.8 kJ/mol) by annealing at 40 °C for 27 days. The enthalpy data were transformed into the fraction of remaining excess enthalpy ϕ, and the relaxation behaviors

decreased to 32% by 1 h annealing and to 8% by 48 h annealing. Crystallization Behaviors of RTV Glass. The crystallization behaviors are typical as the experimental data follow the simulated behaviors based on the Avrami−Erofeev equation well regardless of whether samples were annealed (Figure 2a) and which crystallization temperature was used (Figure 2b). The activation energy for the nucleation was calculated as 244 kJ/mol from the Arrhenius plot (Figure 2c) using the induction time as the kinetic term, which was defined as the time to reach 10% crystallinity (t10).9 Since t10 is analogous to the induction time, d, in the Avrami−Erofeev equation it can be regarded to represent kinetics of the nucleation process. From these data, we can expect 10% crystallinity is achieved by crystallization at 40 °C for 850 days, but interestingly, crystallization did not commence at all (Figure 2b), indicating the existence of temperature region where crystallization is retarded. Crystallization rates of organic compounds sometimes do not monotonically increase with temperature.29 Moreover, they often peak at a temperature below Tg, show a local minimum around Tg, and then increase monotonically as temperature D


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relatively linear; in fact, the celecoxib glass exhibited a linear behavior in the range of T/Tg = 0.97−1.03.33 Likewise, Aso et al. found relatively linear behaviors of temperature-dependence of molecular mobility of nifedipine and phenobarbital around Tg, which were not explainable by the VTH equation.34 Notably in the case of nifedipine, the linearity appeared to exist in the range of T/Tg = 0.90−1.05. The relaxation and the isothermal crystallization behaviors are investigated in similar temperature regions in our study. The similar activation energy values suggest that the kinetics of the relaxation process (32−43 °C, T/Tg = 0.95−0.99) and the induction period of the crystallization (45−60 °C, T/Tg = 0.99−1.04) might be dominated by the same factors such as molecular mobility, interaction between molecules, and intramolecular motions such as rotation of side chains. Considering the fact that crystallization kinetics of the RTV glass at 40 °C cannot be estimated from the extrapolation of those at slightly higher temperatures of 45−60 °C (Figure 2b), it is reasonable to conclude that there is another kinetic barrier produced during the annealing to prevent RTV glass from crystallizing at 40 °C. Structures of Crystalline RTV and As-Prepared RTV Glass. The atomic structures were analyzed by the X-ray PDF analysis, which is a diffraction method useful for revealing atomic structure in amorphous and/or nanocrystalline materials as well as crystals.23 This technique becomes increasingly attractive in the research of amorphous materials both in fundamental research such as metal−organic frameworks35,36 and more applied research in pharmaceuticals.37−40 X-ray total scattering data were collected, and structure functions, S(Q) (Figure 4a), were obtained through the data corrections described in the experimental section. S(Q) data are similar except for the Bragg peaks observed in the crystalline sample and the slight difference between the as-prepared amorphous sample and the annealed sample. These S(Q) were converted into PDFs as shown in Figure 4b (Qmax = 14.8 Å−1) for investigating long-range orders and Figure 6 (Qmax = 20.3 Å−1) for investigating short- and middle-range structures. In addition to the PDFs, we used infrared (IR) spectroscopy, which is sensitive to hydrogen bonding. RTV has two major crystal forms: (i) a monoclinic structure of “form I” in the P21 space group and (ii) an orthorhombic structure of “form II” in the P212121 space group.41 These two structures are conformational isomers. Thus, the structure of the RTV crystal was analyzed by the PDF refinement (Figure 5),23 and we found that the structure of the crystalline sample was determined to be in the P212121 space group (namely, socalled “form II”).41,42 Since the number of atoms in this structure is huge, we used a RMC analysis (or simulated annealing) to refine the atomic coordinates, and the simulated PDF fits the experimental one remarkably better (Figure 6). The PDF of the as-prepared RTV glass was similar to that of the crystalline RTV (Figures 4b and 6a), but the glass sample does not have the long-range order observed as the broad oscillation extending over 20 Å in the crystalline sample, which corresponds to the crystallite domain size of ca. 15.2 nm. The similarity of the PDFs in the short-range orders observed within 6 Å and the structure refinements (Figure 6a) clarify that the conformation of the RTV molecules in the glass sample is the same as that in crystalline RTV though the rotation of side chains and packing are slightly different (Figure 6b). This lack of long-range orders in the glass sample suggests disorder in the molecular packing. In addition, since the structure of the as-

Figure 3. Calorimetric analyses of the influence of the sub-Tg annealing on RTV glass. (a) DSC curves. The samples were treated at a sub-Tg temperature of 40 °C for 0.5, 1, 2, 3, and 12 h. (b) Relaxation enthalpies during sub-Tg annealing at a different temperature of 32, 35, 37, 40, and 43 °C. (c) Relaxation behaviors analyzed using the KWW equation. The fraction of remaining excess enthalpies, Φ, was transformed from the enthalpy data. (d) Arrhenius plot to obtain the activation energy for the relaxation.

were analyzed using the Kohlrausch−Williams−Watts (KWW) equation as shown in Figure 3c. The relaxation behaviors are qualitatively typical, as both the relaxation time τ and the β parameter in the KWW equation decrease as the temperature approaches Tg (Table 1).16 Table 1. KWW Parameters for the Relaxation of RTV at Different Temperatures temperature (°C) τ (min) β τβ

32

35

37

40

43

957 0.637 79.2

464 0.594 38.4

264 0.515 17.7

105 0.377 5.79

41.5 0.297 3.02

The activation energy for the relaxation time was obtained from the Arrhenius plot (Figure 3d) as 249 kJ/mol. This value agrees excellently with the value for the nucleation in the isothermal crystallization, 244 kJ/mol. Pharmaceutical glasses typically exhibit fragile behavior as generally expressed by the Vogel−Tammann−Fulcher (VTF) equation, and it is also the case for RTV glass.32 This means that activation energy for the physical processes in RTV is temperature dependent, i.e., nonlinear relationship of the Arrhenius plot is expected. Mehta et al. presented such a nonlinear behavior of the Arrhenius plot for celecoxib glass using dielectric measurements.33 However, if we focus on the glass transition region, the Arrhenius plot is E


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Figure 6. Structure analyses of the RTV glasses compared with crystalline RTV. (a) Reduced PDF, G(r) (Qmax = 20.3 Å−1). The samples are as-prepared glass (asp), sub-Tg annealed glasses at 40 °C for a different period, a sub-Tg annealed glass at 40 °C for 27 d followed by annealing at 60 °C for 30 min (>Tg), and the crystalline RTV (cry). The blue dots are the experimental data, the red curves are the simulated ones, and the green curves shown below these PDFs are their difference plotted with shift. The arrow indicates a representative different behavior formed by the annealing. The percentage values (Rw) mean resulting weighted R-value of refinement obtained from the PDFgui program (lower values mean better fit). (b) Structures obtained by the PDF analysis. H atoms of C−H bonds are not shown for clarity. The dotted circles show the functional groups forming hydrogen bonds: carbamate, “c”; hydroxyl, “h”; amide, “a”; and ureido, “u”.

Figure 4. X-ray total scattering data obtained for the crystalline RTV, as-prepared amorphous RTV, and the sub-Tg annealed amorphous RTV (40 °C for 27 d). (a) Structure function, S(Q), with magnified data in the inset. (b) Reduced PDF, G(r) (Qmax = 14.8 Å−1). The inset shows the magnified data in the range of 3−30 Å plotted with shifts for clarity. The black curve shows the data of another sub-Tg annealed amorphous RTV (40 °C for 4 d), and the yellow curve shows the data of a sub-Tg annealed glass kept at 60 °C for 30 min (>Tg).

coherence size, which was smaller than crystal axes (a = 10.01(14), b = 18.75(28), c = 20.62(38) Å), the four RTV molecules in the unit cell are considered to form the similar packing as in the crystalline sample, but as the coherence size suggests, each molecule should be slightly off the crystallographic positions, that is, the intermolecular arrangements (packing) are disordered. Since the form II of RTV crystal has intermolecular hydrogen bonds, we can investigate disordered packing through the analysis of states of hydrogen bonds by IR spectroscopy. In the FT-IR spectrum of the crystalline RTV (Figure 7a), the sharp peak at 3320 cm−1 is attributable to carbamate N−H stretching, which forms the weakest hydrogen bonds with amide CO. Note that typical enthalpy value of weak hydrogen bond (νOH > 3200 cm−1 and O···O distance > 2.7 Å) is 34 kJ/mol.43 The broad peaks in the wavenumbers from 3250 to 3100 cm−1 are attributable to N−H stretching bands of ureido and amide groups, which form weak hydrogen bonds (N−H···O). The peak around 3100 cm−1 is assignable to O−H stretching band of hydroxyl group with intermediate hydrogen bonds. These assignments are supported by the structure obtained from the PDF analysis, where distances between electronegative atoms in N−H(carbamate)···O-

Figure 5. PDF of the crystalline sample analyzed by the PDF refinements using the structure information provided by the CCDC database (form I, no. 710520; form II, no. 710530). The lattice constants and atomic displace parameters (isotropic) were refined, while the atomic coordinates were fixed. The blue curves are the experimental data, the red curves are the simulated ones, and the green curves shown below are their difference plotted with shift. The percentage values (Rw) mean resulting weighted R-value of refinement obtained from the PDFgui program (lower values mean better fit).

prepared glass was obtained by assuming the symmetry of the P212121 space group and with 15.1 Å of the structural F


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acceptors of CO in carbamate groups (1702 cm−1 in Figure 7a, right), ureido groups (1658 cm−1),45,46 and amide groups (1613 cm−1).47,48 In the as-prepared glass sample, the left C O peak shifted to a slightly higher wavenumber of 1712 cm−1 with a tiny shoulder at 1702 cm−1, suggesting most of the C O(carbamate) are free of hydrogen bonds or have weak hydrogen bonding in the glass sample. The right peak and the middle peak approached each other and formed a broad peak at 1630 cm−1, indicating the hydrogen bonding with the C O(amide) became weaker, while that with the CO(ureido) became stronger than in the crystalline one. Structures of the Annealed Samples (Relaxed Glasses). The sub-Tg annealing at 40 °C slightly changed PDFs within 4 days (Figure 4b): for example, the behavior around 6 Å broadened, and the one around 10 Å grew, meaning structure changed slightly. By annealing for 27 days, features associated with the short-range orders (e.g., especially around 5.7 Å) are obviously changed (Figures 4b and 6a). The PDFs reveal the absence of long-range order in the glass samples (Figure 5a) excepting the sample annealed for 27 d, which shows almost the similar PDF to that treated for 4 d though with tiny peaks associated with long-range order different from those of the crystals of form I and form II. RTV glass is known to form liquid crystalline structure before the crystallization (i.e., mesophase) when it is suspended in aqueous media,49 and RTV molecules thereby seem to have ability to form ordered structures without crystallization. In this light, this formation of long-range order might be attributable to such a mesophase. This additional phase, however, disappears when heated at 60 °C for 30 min (Figure 4b), in which crystallization is negligible (Figures 1f and 2a), but the change caused by the sub-Tg annealing for 4 days remained (Figures 4b and 6a). In other words, the structural change occurred at 40 °C was partially erased by the subsequent treatment above Tg; however, it was not sufficient to fully recover the original structure. Such retention of thermal history above Tg was also reported previously; for example, Surana et al. found that annealing of trehalose glass below Tg caused nucleation, which resulted in decrease in the cold crystallization temperature at much higher temperature than Tg by ca. 60 °C.50 This means that nuclei (i.e., some changes in the amorphous structure) formed below Tg were retained above Tg. Thus, the presence of such a long-range order may not be responsible for stabilizing the amorphous domains, but the remaining change in the amorphous domains is considered to be responsible for the prolonged induction time as shown in Figure 2a (or the better stability), though the change might disappear during the further treatment at 60 °C in the crystallization experiments. The difference in enthalpy before and after the sub-Tg annealing at 40 °C for 27 days was ca. 2.8 kJ/mol, suggesting that the structural change during sub-Tg annealing is accompanied by reorganization of weak interactions such as hydrogen bonds (typically, 8−42 kJ/mol) and the weaker van der Waals interactions associated with molecular packing.51,52 This is also supported by the similar heat capacity found in DSC (Figure 3a), which suggests motions of side chains above Tg were not strongly restricted maybe due to flexibility of hydrogen bonding. We summarized the hydrogen bond distances and the packing index, which represents free volume in the structure, in Figure 7b,c The averaged hydrogen bond distances did not change significantly or were slightly increased with the annealing time, while the packing of the atoms decreased. Considering the modest quality of fitting and the

Figure 7. Analysis of hydrogen bonds in the RTV glasses compared with the crystalline RTV. The samples are as-prepared glass (asp), subTg annealed glasses at 40 °C for a different period, a sub-Tg annealed glass at 40 °C for 27d followed by annealing at 60 °C for 30 min (>Tg), and the crystalline RTV (cry). The subscripts: “c”, carbamate; “u”, ureido, “a”, amide; “h”, hydroxyl. (a) FT-IR spectra. The dotted lines show the peak positions of the crystalline sample. The annealed sample (ann) was prepared at 40 °C for 27 days. The annealed sample was further treated at 60 °C for 30 min (ann + 60 °C, bottom curve) in order to investigate the retention of thermal history above the Tg. (b) Trend of N−O or O−O distance and packing index of the structures. These are the averaged values obtained by the PDF fittings. (c) The values (percentages) relative to the data of the as-prepared glass are shown in the panel.

(amide) is far longer (3.416 Å, which is distance between electronegative atoms) than others, i.e., N−H(amide)···O(hydroxyl) 3.238 Å, N−H(ureido)···O(carbamate) 3.152 Å, and O−H(hydroxyl)···O(ureido) 2.721 Å. With these hydrogen bonds, the crystal structure, form II, becomes energetically more favorable than other structures having other hydrogen bonding.41,44 The FT-IR spectrum (Figure 7a) of the as-prepared glass sample has a monomodal broad peak assignable to the N−H stretching around 3200−3450 cm−1, while the O−H stretching appears to be shifted from 3100 to 3080 cm−1, indicating that hydrogen bonding is weaker for N−H and stronger for O−H in glass than in the crystalline sample on average. These are consistent with the distance data obtained by the PDF analysis: far longer N−H(carbamate)···O(amide) 3.605 Å, longer N− H(amide)···O(hydroxyl) 3.269 Å, similar N−H(ureido)··· O(carbamate) 3.120 Å, and the shorter O−H(hydroxyl)··· O(ureido) 2.487 Å. The acceptors of the hydrogen bonds illustrate these changes in hydrogen bonds more clearly: in the crystalline sample, the hydrogen bonds are formed with strong G


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We showed that the relaxation of the ritonavir glass below Tg was not accompanied by drastic change in molecular conformation but by slight rotation and bend of bonds, and the same holds true even during the crystallization. Similar result was reported for an inorganic glass of selenium system, which did not exhibit apparent change in PDFs across Tg.55,56 Thus, these investigations suggest that changes in intermolecular interactions and/or the local free volume, which is accompanied by only slight rotation and bend of bonds, are possibly responsible for the change in macroscopic properties such as viscosity upon glass transition and crystallization. Though further investigation using other compounds is required, some anomalous behaviors upon relaxation and crystallization may be explained by the sub-Tg stabilization effect.

short coherent length in the amorphous samples, these packing values, which are associated with lattice constants, are not definitive but probably suggest that the average free volume between molecules is more-or-less the same or slightly increases with the sub-Tg annealing; thus, this is not the major factor to improve the physical stability of RTV. This averaged structure information obtained by the PDF refinements is not conclusive for ascertaining the origin of the better stability induced by the sub-Tg annealing. The FT-IR spectra were the key to accounting for the mechanism. In the spectrum of the glass sample annealed for 27 days (Figure 7a), the shoulder of the left CO stretching peak at 1702 cm−1 became larger, suggesting that energetically favorable hydrogen bonds were formed with the carbamate CO groups and the ureido N−H groups.44 These additional IR peaks might be attributable to the mesophase having the long-range orders observed in PDF; however, since these IR peaks remained even after the additional heat treatment above Tg (i.e., 60 °C) though the mesophase disappeared, we consider the additional IR peaks are attributable to the change in amorphous structures as PDFs suggested (Figure 4b). The mesophase, which is considered to be little judged from the PDFs, is not observable in IR. In addition, the peak positions different from the crystalline sample confirm the absence of the crystalline phases. Since the main peak remained at the same position, the averaged values associated with hydrogen bonds obtained by the PDF analysis could not reflect these changes. Note that this distance was obtained by using the symmetry constraints where only a single distance was assumed for each bond due to limitation of computational cost, though the IR peaks were bimodal. These results indicate that the reorganization in the hydrogen bonding is the main origin of the higher physical stability to the crystallization of sub-Tg annealed glasses, at least in the case of RTV. Similarly, changes in hydrogen bonding pattern were suggested in other works on pharmaceutical solid dispersions, such as pimozide-poly(vinylpyrrolidone)53 and naproxen-poly(vinylpyrrolidone);54 however, those changes were caused by phase separation, and the hydrogen bonding was formed between different molecular species as well. Therefore, our observation is the first example of showing importance of rearrangements in the hydrogen bonding in a single component glass.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +81-29-8604424. Fax: +81-29-860-4708. ORCID

Kohsaku Kawakami: 0000-0002-3466-9365 Author Contributions †

These authors contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was in part supported by Health Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare of Japan, World Premier International Research Center (WPI) Initiative on Materials Nanoarchitectonics from MEXT, Japan, and by Grant-in-Aid for Scientific Research C (15K04614) from JSPS, Japan.

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REFERENCES

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CONCLUSIONS We investigated the influence of the sub-Tg annealing on the physical stability of pharmaceutical glasses and found that subTg annealing significantly retarded crystallization, especially of molecules whose crystallization was dominated by a large energetic/kinetic barrier for nucleation, as represented by ritonavir. The higher stability can be accounted for by the relaxation of local structures accompanied by formation of stronger hydrogen bonds and a better local packing. We have proved that reorganization of the hydrogen bonding played a key role for the physical stabilization, which may increase the van der Waals interactions by reducing local free volume around the hydrogen bonds. This information is useful for designing organic molecules for creating stable amorphous materials. Finally, we summarize the fundamental importance of our sub-Tg annealing strategy. Such anomalous nature of glasses at/ near Tg has been of great interest in various fields including material physics, physical chemistry, and polymer chemistry. H


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Physical Stabilization of Pharmaceutical Glasses Based on Hydrogen

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