and Intramolecular Interactions on the Physical Stability of

Article pubs.acs.org/molecularpharmaceutics

Impact of Inter- and Intramolecular Interactions on the Physical Stability of Indomethacin Dispersed in Acetylated Saccharides E. Kaminska,*,† K. Adrjanowicz,‡ M. Tarnacka,§,¶ K. Kolodziejczyk,§,¶ M. Dulski,§,¶ E. U. Mapesa,∥ D. Zakowiecki,⊥ L. Hawelek,#,§,¶ I. Kaczmarczyk-Sedlak,† and K. Kaminski§,¶ †

School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Pharmacognosy and Phytochemistry, Medical University of Silesia in Katowice, ul. Jagiellonska 4, 41-200 Sosnowiec, Poland ‡ NanoBioMedical Centre, Adam Mickiewicz University, ul. Umultowska 85, 61-614 Poznan, Poland § Institute of Physics, University of Silesia, ul. Uniwersytecka 4, 40-007 Katowice, Poland ¶ Silesian Center of Education and Interdisciplinary Research, University of Silesia, ul. 75 Pulku Piechoty 1A, 41-500 Chorzow, Poland ∥ Insitute for Experimental Physics I, University of Leipzig, Linnestraße 5, 04103 Leipzig, Germany ⊥ Pharmaceutical Works Polpharma SA, ul. Pelplinska 19, 83-200 Starogard Gdanski, Poland # Institute of Non-Ferrous Metals, ul. Sowinskiego 5, 44-100 Gliwice, Poland ABSTRACT: Differential scanning calorimetry (DSC), broadband dielectric (BDS), and Fourier transform infrared (FTIR) spectroscopies as well as theoretical computations were applied to investigate inter- and intramolecular interactions between the active pharmaceutical ingredient (API) indomethacin (IMC) and a series of acetylated saccharides. It was found that solid dispersions formed by modified glucose and IMC are the least physically stable of all studied samples. Dielectric measurements showed that this finding is related to neither the global nor local mobility, as the two were fairly similar. On the other hand, combined studies with the use of density functional theory (DFT) and FTIR methods indicated that, in contrast to acetylated glucose, modified disaccharides (maltose and sucrose) interact strongly with indomethacin. As a result, internal H-bonds between IMC molecules become very weak or are eventually broken. Simultaneously, strong H-bonds between the matrix and API are formed. This observation was used to explain the physical stability of the investigated solid dispersions. Finally, solubility measurements revealed that the solubility of IMC can be enhanced by the use of acetylated carbohydrates, although the observed improvement is marginal due to strong interactions. KEYWORDS: indomethacin, acetylated saccharides, glass transition temperature, theoretical approach, FTIR, molecular interactions, H-bonds

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INTRODUCTION

This is especially important for drugs categorized as Class II according to the Biopharmaceutics Classification System (BCS).7,8 Another very interesting aspect of amorphous pharmaceuticals is that they have a greater ability to form tablets compared to crystalline APIs.9 However, preparation of active substances in this form entails considerable risks. First, the disordered state is thermodynamically less stable than the crystalline one. This may lead to uncontrolled crystallization of the API over time in the course of processing, storage, and use of the product.10−12 Second, as a result of a greater chemical reactivity, amorphous pharmaceuticals are prone to chemical

The majority of solid drugs are utilized in the crystalline state because this form offers greater thermodynamic and chemical stability. Moreover, it is very easy to predict the physicochemical properties and storage conditions of such pharmaceuticals. However, it is well-known that dissolution within the gastrointestinal tract may be the limiting step to absorption for many active pharmaceutical ingredients (APIs) prepared in the crystalline form. The direct consequence of this situation is weak chemical activity and bioavailability of the drug. The alternative to crystalline pharmaceuticals are amorphous APIs.1 From a thermodynamic point of view, a state of higher disorder is always characterized by a higher Gibb’s free energy, enthalpy, and entropy. As a consequence, amorphous APIs usually show higher apparent solubility2 and faster dissolution rates,3,4 which in turn can lead to higher bioavailability5 as well as chemical reactivity.6 © 2014 American Chemical Society

Received: Revised: Accepted: Published: 2935

April 17, 2014 June 15, 2014 July 10, 2014 July 10, 2014 dx.doi.org/10.1021/mp500286b | Mol. Pharmaceutics 2014, 11, 2935−2947

Molecular Pharmaceutics

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degradation as well as isomeric transformations during manufacturing and their shelf lifetime.13 Currently, stabilization of amorphous active substances is of particular interest to the pharmaceutical industry. It is understood that in order to suppress crystallization of labile APIs one should (i) store them at temperatures far below their glass transition temperature (Tg; where the molecular mobility of the sample seems to be completely frozen), (ii) mix them with excipients, typically polymers or saccharides, and (iii) use an appropriate amorphization method so that an improved stability of the amorphous API is achieved.1,4,10,13−15 Preparation of a homogeneous dispersion with high Tg polymeric or saccharide excipients16−19 seems to be the most effective way to improve the stability of amorphous pharmaceuticals. Generally, it is thought that the greater the Tg of the matrix, the higher the level of protection of the disordered formulation, according to the well-known Gordon−Taylor equation.20 Thus, in this way, one can try to delay crystallization of amorphous APIs.21,22 However, it should be noted that an increase in the Tg of the solid dispersion with respect to that of the drug alone cannot be regarded as the main factor responsible for its longterm stability. Recent studies have clearly shown that suppression of crystallization can be achieved even when the Tg is not affected or decreased.23,24 Thus, it seems that specific molecular interactions between APIs and excipients are primarily responsible for the stabilization of active pharmaceuticals.1,16,24−28 Therefore, this issue has been widely discussed in literature. For example, Wegiel et al.29 have shown that specific interactions between resveratrol and different polymers are mainly responsible for the physical stability of its solid dispersions. Similar conclusions were drawn by Tobyn et al. for BMS-48804330 (an investigational drug for the treatment of HIV) and Gupta et al. for celecoxib (CEL),31 both mixed with povidone (PVP). In these cases, the authors confirmed the presence of strong H-bonds between the drugs and PVP, a fact that may account for the better-than-expected physical stability of these systems. It should also be added that recent papers have described the suppression of crystallization of APIs by using low molecular weight compounds. For example, Grzybowska et al. presented a novel way of stabilizing celecoxib against crystallization by preparing amorphous binary mixtures of CEL with acetylated maltose (acMAL). For this purpose, a simple quench cooling technique was applied.32 It is also worth noting that modified carbohydrates can also be used to prevent chemical degradation of cryoground furosemide.33 Finally, we present here a brief discussion concerning indomethacin (IMC), which has become a model drug due to its enhanced crystallization upon storage, even at temperatures much lower than the Tg. Notably, IMC (in the crystalline form) is a nonsteroidal, anti-inflammatory drug commonly used to reduce fever, pain, stiffness, and swelling.34,35 It is practically insoluble in water (its experimental solubility in water is 0.937 mg/L at 298 K34). Most of the recent studies concerning IMC have been focused on explaining the role of various additives (typically, saccharides isomalt,17 cyclodextrins,36 sucrose19 or polymers PVP,16,17 poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1 (Eudragit E PO25)) in the stabilization of its amorphous form. Taylor and Zografi16 suggested a possible link between strong IMC−PVP interactions and the inhibition of crystallization of amorphous API. In fact, detailed IR and FT-Raman investigations confirmed this hypothesis. Furthermore, Zografi, in his later paper,24

proposed the same explanation for IMC mixed with povidone/ vinyl acetate (PVP/VA). Another example has been presented by Liu et al.25 In this case, FTIR analysis provided direct evidence for the intermolecular ionic interactions between Eudragit E PO and IMC leading to the destabilization of IMC dimers. In this article, inter- and intramolecular interactions in solid dispersions formed by series of acetylated saccharides and IMC are investigated. We must note here that the impact of intermolecular interactions between IMC and octaacetylmaltose on the physical stability of resulting binary mixtures has already been thoroughly studied by some of us.37 However, the role of Tg, which was much higher than T = 298 K in the case of each IMC− acMAL solid dispersion, in the stabilization process could not be completely ruled out. Herein, the influence of the chemical structure of the saccharide, the molecular dynamics, the Tg, and the strength of intramolecular interactions on the tendency toward crystallization of solid dispersions are examined in detail. We clearly demonstrate that Tg is not the only criterion for ensuring physical stability of the studied samples; it is found that although some solid dispersions formed by the API and acetylated sucrose or glucose have nearly equal Tg, their crystallization tendencies are completely different. Moreover, DFT calculations show that the chemical structure of the saccharide determines the strength of interactions with IMC. This outcome of theoretical computations was further confirmed by FTIR measurements. All of these findings enable a more complete picture of the role of interactions in controlling the long-term stability of the formed solid dispersions to be drawn.

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EXPERIMENTAL METHODS Materials. Indomethacin (1-(4-chlorobenzoyl)-5-methoxy2-methyl-3-indoleacetic acid, C19H16ClNO4, purity >99%) in the γ-crystalline form and acetylated saccharides (pentaacetylglucose, octaacetylsucrose, and octaacetylmaltose), having purities greater than 98%, were supplied by Sigma-Aldrich and used without further purification. The chemical structures of all compounds are shown in Scheme 1. Methods. Preparation of Amorphous Systems of Indomethacin with Acetylated Saccharides. The amorphous indomethacin (IMC), octaacetylmaltose (acMAL), octaacetylsucrose (acSUC), and pentaacetylglucose (acGLU) and binary systems (IMC−acMAL, IMC−acSUC, and IMC−acGLU, with different weight fractions of acetylated saccharides) were prepared by the Scheme 1. Chemical Structures of Indomethacin (IMC) (a), Octaacetylmaltose (acMAL) (b), Octaacetylsucrose (acSUC) (c), and Pentaacetylglucose (acGLU) (d)

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quench cooling technique in a temperature- and humiditycontrolled glovebox (PLAS Laboratories Inc. 890-THC-DT/ EXP/SP) at the assured relative humidity RH < 10%. In order to obtain the homogeneous IMC−acetylated saccharide solid dispersions, we first thoroughly mixed crystalline powders of both compounds in appropriate proportions in a heat-resistant glass vial (the weight of the powder mixture was about 0.5 g). After that, we put a magnetic stir bar into the vial with the mixture. Next, the crystalline components were melted in the vial on the hot plate magnetic stirrer (CAT M 17.5) at T = 443.15 K. The temperature inside the vial was controlled by using a Pt-100 sensor. After the crystalline mixtures (IMC−acMAL, IMC− acSUC, and IMC−acGLU) were fully melted, they were transferred from the hot plate to a very cold metal plate. Only completely amorphous samples obtained in this way were analyzed immediately after the preparation to protect them from atmospheric moisture. We investigated five mixtures of IMC with acMAL (both components were mixed in the weight ratios 5:1, 3:1, 1:1, 1:3, and 1:5, which correspond, approximately, to 10:1, 6:1, 2:1, 2:3, and 2:5 molar ratios, respectively) and five mixtures of IMC with acSUC or acGLU (IMC−acSUC mixtures: 5:1, 2:1, 1:1, 1:2, and 1:5 weight ratios, which correspond, approximately, to 10:1, 4:1, 2:1, 1:1, and 2:5 molar ratios, and IMC−acGLU mixtures: 5:1, 2:1, 1:1, 1:2, and 1:5 molar ratios). It is worth noting that the same weight ratios in the case of modified mono- and disaccharides do not correspond to the same molar ratios. X-ray Diffraction (XRD). The X-ray diffraction measurements for the amorphous mixtures of IMC with acGLU, acSUC, and acMAL were performed at ambient temperature using a RigakuDenki D/MAX RAPID II-R diffractometer (Rigaku Corporation, Tokyo, Japan) with a rotating anode Ag Kα tube (λ = 0.5608 Å), an incident beam (002) graphite monochromator, and an image plate in the Debye−Scherrer geometry. The pixel size was 100 μm × 100 μm. The samples were placed inside Lindemann glass capillaries (2 mm in diameter). Measurements were run with sample-filled and empty capillaries, and the intensity of the empty capillary was then subtracted. The beam width at the sample was 0.3 mm. The two-dimensional diffraction patterns were converted into the one-dimensional intensity data using the software provided by Rigaku Corporation. All diffraction data are shown in Figure 1. Differential Scanning Calorimetry (DSC). Standard differential scanning calorimetry measurements of amorphous indomethacin, acMAL, acSUC, and acGLU as well as IMCacetylated saccharide mixtures (different weight ratios) were carried out using double-furnace Mettler-Toledo DSC apparatus (Mettler-Toledo International, Inc., Greifensee, Switzerland) equipped with a liquid nitrogen cooling accessory and a HSS8 ceramic sensor (heat flux sensor with 120 thermocouples). Temperature and enthalpy calibrations were performed with indium and zinc standards. Amorphous pure components and their binary mixtures were scanned at a rate of 10 K/min over a temperature range starting from 273 K to well above the respective melting points. Broadband Dielectric Spectroscopy (BDS). Isobaric measurements of the dielectric permittivity ε*(ω) = ε′(ω) − iε″(ω) were carried out using the Novo-Control Alpha dielectric spectrometer (Novocontrol Technologies GmbH & Co. KG, Hundsangen, Germany) over the frequency range from 10−2 to 3 × 106 Hz at ambient pressure. IMC-acetylated saccharide mixtures were placed in a parallel plate cell (diameter, 20 mm; gap, 0.1 mm) immediately after preparation of the amorphous samples. The

Figure 1. Powder X-ray diffraction patterns (XRD) for representative binary mixtures: IMC−acMAL (a), IMC−acSUC (b), and IMC− acGLU (c). In the inset X-ray diffraction pattern of crystalline indomethacin is presented.

temperatures in the range from 133 to 364 K were controlled by a Quatro System using a dry nitrogen gas cryostat with stability better than 0.1 K. Theoretical Calculations. For theoretical calculations, a system consisting of four molecules, i.e., two indomethacin connected via internal H-bonds and two given modified saccharides, was constructed. It should be added that prior to this step the geometries of IMC dimers and modified saccharides were also optimized. Geometries of acMAL, acSUC, acGLU, indomethacin, and binary systems were determined using Becke’s hybrid exchange and correlated three-parameter with the Lee− Yang−Parr correlation functional (B3LYP)38−40 and standard Gaussian basis sets 6-31G(d,p).40 These calculations were carried out in the gas phase using density functional theory (DFT) methods41−43 and the Gaussian09 software package.44 The optimized molecules with the labeling system used for the present computations were visualized using GaussView 5.0.8 software. On the basis of the results obtained, all conformers have positive harmonic vibrations, indicating a true energy minimum.44 Fourier-Transform Infrared Spectroscopy (FTIR). Infrared measurements were performed using an Agilent Cary 660 FTIR spectrometer (Agilent Technologies, CA, USA) equipped with a standard source and a DTGS Peltier-cooled detector. The spectra were collected using a GladiATR diamond accessory (Pike Technologies, Madison, WI, USA) in the 4000−400 cm−1 range. All spectra were measured with a spectral resolution of 4 cm−1 and recorded by accumulating 16 scans. The temperaturedependent infrared measurements were carried out with an accuracy of ±5 K/min. Solubility Studies. Solubility studies were carried out using a traditional shake-flask technique. The samples were pulverized and put into conical flasks containing the suitable solvent and then shaken in a water bath at a temperature of 310 K for 2 h. Solutions thus obtained were filtered through 0.45 μm syringe filters (Pall Poland Ltd., Warsaw, Poland). The determination of the amount of API dissolved proceeded using the GENESYS 10S UV−vis spectrophotometer (Thermo Scientific, Waltham, MA, USA) at a wavelength of 320 nm in a 1 cm path length cell. The solubility was investigated in compendial dissolution solvents prepared in accordance to Ph. Eur. Monograph 2.9.3, 2937



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examined temperature range. There are no additional events that could indicate phase transition, cold crystallization, demixing, or the presence of heterogeneity in the sample. Similar thermograms were obtained for other IMC−acGLU/acSUC systems as well as for IMC−acMAL solid dispersions37 (data not shown). The Tg’s evaluated from the calorimetric data for pure acetylated saccharides and mixtures are listed in Table 1. Because a single

representing the physiological pH range of the human gastrointestinal tract. Solvents such as 0.1 M hydrochloric acid (pH 1.2), phosphate buffer solutions (pH 4.5 and 6.8), and purified water (pH ≈ 6.9−7.0) were used.

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RESULTS AND DISCUSSION After preparation of the solid dispersions consisting of modified saccharides and IMC, long-term structural studies using X-ray powder diffraction (XRD) were carried out to evaluate the stability of the prepared amorphous samples. In Figure 1, representative diffraction patterns of the indicated binary mixtures obtained after half a year of storage at room temperature are shown. It can be seen that in the case of the IMC−acMAL and IMC−acSUC mixtures, there are no Bragg peaks; instead, broad amorphous halo patterns, characteristic of materials having no long-range three-dimensional molecular order, were obtained. Additionally, XRD patterns for IMC−acMAL and IMC−acSUC mixtures were recorded after 1 and 1.5 years of storage at room temperature (data not shown), and no changes that might indicate crystallization were observed. Hence, the applied procedure (quench cooling) was effective at transforming the crystalline substances into amorphous ones. Moreover, these long-term studies demonstrated that IMC is very stable at room temperature and has no propensity to crystallize. On the other hand, a completely different scenario was observed for IMC− acGLU mixtures. In Figure 1c, sharp Bragg peaks are present, indicating advanced crystallization in the investigated sample. By comparing the XRD patterns for pure IMC and acGLU, it was found that both compounds crystallized. However, the fraction of crystalline IMC was very low (data not shown). A similar pattern of behavior was observed for each solid dispersion consisting of acGLU and indomethacin. Having identified that acetylated maltose and sucrose are the best modified carbohydrates with respect to preventing IMC crystallization, detailed investigations were performed to determine the origin of the long-term stability of the API dispersed in these saccharides. First, DSC measurements were carried out on the samples. In Figure 2, representative DSC thermograms recorded on heating (10 K/min) amorphous IMC−acGLU (5:1, 1:1, and 1:5 weight ratios) and IMC−acSUC (5:1 and 1:5 weight ratios) mixtures are presented. In all cases, only one endothermic transition associated with the glass transition (calculated as a midpoint of the glass transition step) can be observed within the whole

Table 1. Glass Transition Temperatures (Tg) for the Studied Systems Obtained from Dielectric (BDS) and DSC Measurementsa material

Tg (K) from DSC measurements

Tg (K)b from dielectric measurements

fragility (m)b

indomethacin (IMC) octaacetylmaltose (acMAL) IMC−acMAL (3:1) IMC−acMAL (1:1) IMC−acMAL (1:3) octaacetylsucrose (acSUC) IMC−acSUC (5:1) IMC−acSUC (2:1) IMC−acSUC (1:1) IMC−acSUC (1:2) IMC−acSUC (1:5) pentaacetyl-α-glucose (acGLU) IMC−acGLU (5:1) IMC−acGLU (2:1) IMC−acGLU (1:1) IMC−acGLU (1:2) IMC−acGLU (1:5)

314.5 326.5 315 316 321 299 312 308 304 299.5 298 288 307 300 293 290 286

315 329 311 311 317 296 309 307 303 300 297 286.5 306 300 296 291.5 289

86 106 77 81 84 92 82 93.5 91 96.5 89.5 90 89 87 92 84 88

a Values of isobaric fragilities (m) determined from BDS curves are also shown. bTg and m were calculated for τα = 100 s.

value of Tg was determined for each mixture, this may be considered a signature of homogeneity of the investigated samples. However, a single T g can also be found for heterogeneous systems. Thus, additional measurements using dielectric spectroscopy were performed to test this notion as well as to characterize the dynamics of solid dispersions. In Figure 3, dielectric loss spectra obtained for the pure components (IMC, acSUC, acMAL, and acGLU) and representative binary mixtures (IMC−acetylated saccharide; 1:1 weight ratio) in a wide temperature range are presented. In each case, one well-separated structural (α) relaxation process, which is related to the dynamic glass transition, can be detected. Upon vitrification, this mode slows down shifting to lower frequencies. Below Tg, it is too slow to be monitored in the accessible frequency window. In the glassy state, the faster secondary (γ) relaxation with smaller amplitude dominates the spectra and provides information on molecular mobility. It is quite interesting to point out that one well-separated γ-process can be observed for each pure component (IMC, acMAL, acSUC, and acGLU) as well as for mixtures of IMC with acetylated carbohydrates. As next step, the obtained data were utilized to verify the homogeneity of the solid dispersions studied herein. Dielectric loss curves of indomethacin and acetylated saccharides measured at the indicated temperatures are compared in Figure 4. It is clear that the positions of the alpha peaks connected to IMC and the acetyl component differ by about 2 (IMC and acMAL), 3 (IMC and acSUC), and 4.5 (IMC and acGLU) decades at the indicated temperatures. Thus, in a (heterogeneous) phase-separating

Figure 2. DSC thermograms obtained for representative IMC−acGLU and IMC−acSUC solid dispersions during heating at 10 K/min. 2938



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Figure 3. Dielectric loss curves for pure IMC, pure acMAL, pure acGLU, and the solid dispersions (1:1 weight ratio) measured at ambient pressure (P = 0.1 MPa) and different temperatures (above and below Tg).

vicinity of Tg were fitted to the one-sided Fourier transform of the Kohlrausch−Williams−Watts (KWW) function46 ⎡ ⎛ ⎞ βKWW ⎤ t ⎥ ΦKWW (t ) = exp⎢ −⎜ ⎟ ⎢⎣ ⎝ τα ⎠ ⎥⎦

(1)

We found that the stretching exponent βKWW = 0.55 (pure acMAL, IMC−acMAL mixtures, pure acSUC, and IMC−acSUC mixtures), βKWW = 0.57 (pure acGLU and IMC−acGLU mixtures), and βKWW = 0.59 (pure IMC). Hence, taking into account the uncertainty of 0.02 in the determination of this parameter, it is certified that the shape of the structural relaxation process remains the same, independent of the sample. Additionally, Power et al.45 showed that heterogeneity (phase separation) can be manifested by significant variations of the shape of the structural relaxation process (i.e., increase of the distribution of τα) upon lowering the temperature. Therefore, temperature evolution of the width of the α-loss peak (βKWW) for each solid dispersion was also studied (see the insets of Figure 5). In order to calculate the Kohlrausch−Williams−Watts exponent, the following formula was used47

Figure 4. Comparison of the dielectric spectra obtained for pure IMC and acetylated saccharides at the indicated temperatures near the Tg.

sample, two structural relaxation processes originating from each component should be observed in dielectric loss spectra. In this context, it is worth mentioning the work of Power et al.,45 who showed that in a microphase-separating system consisting of 5methyl-2-hexanol and isoamyl bromide, two independent αpeaks arising from each component (5 decades apart) are observed. However, as can be seen in Figure 3, only one structural relaxation process is observed in dielectric spectra recorded for each studied solid dispersion. Moreover, the scaled dielectric loss spectra measured at temperatures close to Tg (see Figure 5) reveal that the shapes of the α-relaxation mode of pure acetylated saccharides and their mixtures with IMC are almost the same. To confirm this experimental observation, all α-loss peaks measured in the

αβ = βKWW 1.23

(2)

where α and β are Havriliak−Negami parameters describing the slopes of the high- and low-frequency part of the structural relaxation process. As demonstrated, βKWW changes only slightly with temperature, proving that our binary mixtures were homogeneous in the studied range of temperatures. We now turn our attention to the molecular dynamics of the samples studied. Dielectric loss spectra for both the structural (α) and γ-relaxations obtained for pure IMC, acetylated saccharides, and their mixtures were analyzed using the Havriliak−Negami function.48 2939



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Figure 5. Comparison of representative frequency-dependent dielectric loss spectra measured at temperatures near Tg for pure acMAL, acSUC, acGLU, and IMC as well as their solid dispersions. The spectra obtained for pure IMC and its mixtures with acetylated sugars are shifted horizontally to superimpose with those collected for pure acMAL (a), pure acSUC (b), and pure acGLU (c) at the indicated temperatures. Solid lines represent KWW fits. Insets present temperature dependences of βKWW for representative binary mixtures of indomethacin and acetylated carbohydrates.

Figure 6. Relaxation map for binary mixtures: IMC−aMAL (a), IMC−acSUC (b), and IMC−acGLU (c). log10τ vs 1/T of the α-relaxation (filled symbols) and γ-relaxation (open symbols). τα and τγ for pure components are also included. The solid lines are the best fits to the secondary relaxations using the Arrhenius law (eq 4). The dashed lines represent the VFT behavior (eq 3).

where τ0, D, and T0 are constants, τ0 is the time scale of vibrational motions, D is the strength parameter or fragility, and T0 represents the temperature at which structural times tend to infinity. On the basis of the VFT fits and defining Tg as a temperature at which relaxation time (τα) reaches 100 s, we were able to estimate the Tg’s for IMC, acetylated carbohydrates, and

Temperature dependences of the structural relaxation times were described by a single Vogel−Fulcher−Tammann (VFT) equation (the dashed lines in Figure 6)

⎛ DT0 ⎞ τ = τ0 exp⎜ ⎟ ⎝ T − T0 ⎠

(3) 2940



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Figure 7. Tg’s determined from DSC (red squares) and BDS (black squares) measurements vs weight fraction of indomethacin−XIMC (a, b), acSUC− XacSUC (d, e), and acGLU−XacGLU (g, h). (c, f, i) Dependence of the isobaric fragility estimated from eq 7. The red solid (free fit) and black dashed (k approximated by the Couchman−Karasz approach) lines are the fits to the data using the Gordon−Taylor equation (eq 5).

modified carbohydrates are very close to each other, it was not possible to detect them as separate loss peaks in the glassy state. The other interesting observation is that genuine JG β-relaxation, observed as an excess wing49,50 in the loss spectra of IMC, recorded close to the Tg, was not resolved in solid dispersions. In Figure 7, the Tg’s obtained from dielectric and DSC measurements are plotted versus weight fraction of IMC (panels a and b), acSUC (panels d and e), and acGLU (panels g and h) for the investigated solid dispersions. Experimentally determined dependences (Tg vs XIMC, XacSUC, and XacGLU) were described using the Gordon−Taylor equation20

solid dispersions (IMC−acMAL, IMC−acSUC, and IMC− acGLU). These data are collected in Table 1. It can be seen that the values of Tg obtained from BDS measurements lie within a 1% difference from those obtained by DSC experiments. In the case of the γ-relaxation, the Arrhenius equation was used to fit the temperature dependencies of relaxation times (the solid lines) as well as to evaluate the activation barrier ⎛ E ⎞ τ = τ0 exp⎜ a ⎟ ⎝ kBT ⎠

(4)

It is evident from Figure 6 that relaxation times as well as activation barriers estimated for the γ-relaxation in solid dispersions as well as in pure components are almost the same: Eγ =39−42 kJ/mol, Eγ = 32−35 kJ/mol, and Eγ=33−37 kJ/mol were determined for IMC−acMAL (panel a), IMC−acSUC (panel b), and IMC−acGLU (panel c) solid dispersions, respectively. Thus, in the glassy state of binary mixtures, only one secondary relaxation process is observed. What is more, the dynamics of this process is apparently the same. In this context, we note that in the case of pure IMC Carpentier et al.49 suggested that the rotation of the chlorobenzyl group is responsible for the γ-process. High-pressure measurements carried out by some of us50 confirmed the origin of this secondary mode to be intramolecular indeed. On the other hand, systematic experimental studies and theoretical calculations on the saccharides enabled assignment of the respective γ-process to the motions of the acetyl moieties attached to the sugar rings.32,33,51 Hence, one can state that the secondary relaxation observed in solid dispersions is connected to the intramolecular motions occurring within IMC and the modified carbohydrate. However, due to the fact that relaxation times of both secondary modes in IMC and

Tg(X1) =

X1Tg(1) + k(1 − X1)Tg(2) X1 + k(1 − X1)

(5)

where Tg(1) and Tg(2) are the glass transition temperatures of the components having a lower and a higher Tg, respectively. X1 denotes the weight fraction of the component with lower Tg, and the constant k represents a fitting parameter characterizing the curvature of the evolution of Tg. It is well-observed that in the case of IMC−acSUC and IMC−acGLU mixtures the k values determined from DSC and BDS measurements are very similar, whereas for IMC−acMAL dispersions, the difference is much more significant (k = 0.32 and 0.1, respectively). We must note here that due to different experimental conditions, particularly the cooling rate, employed in dielectric and calorimetric measurements, the Tg’s evaluated from these experimental methods are usually different. Consequently, it is expected that fitting dielectric and calorimetric data presented in Figure 7 may not necessarily provide the same value of k. However, because DSC is well-established and is the most popular experimental 2941



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technique to evaluate Tg, further analysis will be done with respect only to the calorimetric data. Looking at the values of parameters k determined from the fits, one observes that the lowest k value was obtained for the mixture of IMC with MAL, whereas the largest one, for the IMC−acSUC dispersion. It is worth noting that the parameter k in the Gordon−Taylor equation can be approximated by the thermodynamical model proposed by Couchman and Karasz.52 According to this approach, k can be calculated from the following equation k≈

interactions in the investigated samples may vary significantly, further theoretical (DFT) computations and FTIR measurements were carried out to verify this hypothesis. Concerning the theoretical calculations, special effort was made to investigate the influence of the modified carbohydrate on the length of the H-bond in IMC dimers. To better illustrate the calculated binary mixtures, in Figures 8 and 9, systems made up of

Δc pac.saccharide Δc p IMC

(6)

where ΔcIMC and Δcac.saccharide denote the change in heat capacity p p at T g of pure indomethacin and acetylated saccharide, respectively. Taking into account the values of Δcp for all components (ΔcIMC = 0.395, ΔcacMAL = 0.375, ΔcacSUC = 0.28, and ΔcacGLU = p p p p 0.21), one obtains k = 0.95 (IMC−acMAL), k = 0.71 (IMC− acSUC), and k = 0.53 (IMC−acGLU). Notably, the greatest difference between k obtained via the two different approaches (thermodynamical approach, eq 6; fitting procedure, Figure 7) is noted for the mixture of IMC with acetylated maltose (Δk = 0.63), whereas the smallest one is for IMC dispersed in acetylated glucose (Δk = 0.1). The negative deviation of the experimental data (see Figure 7a,d,g) from the ideal behavior predicted by the Couchman−Karasz model (presented in Figure 7 as black dashed lines) is very often considered to be connected to the strength of the intermolecular interactions occurring in binary mixture.53 Hence, on the basis of this, we hypothesize that the interactions between octaacetylmaltose and IMC are the strongest of all the samples studied in this work. This hypothesis will be revisited later in this article. In Figure 7c,f,i, we also plotted the dependences of the isobaric fragility, m (estimated from eq 7), versus the weight fraction of the component with lower Tg. m=

Figure 8. Theoretical prediction of the internal H-bond length in indomethacin dispersed in the modified carbohydrate (black solid line). Blue solid line represents Δd = dO‑...−OH − dOH‑...‑O in the investigated samples.

d log10τα d(Tg /T )

T = Tg

(7)

As is well-known, m is an artificial parameter that was introduced to characterize the whole dynamics of different glass formers. One can add that many authors try to link this parameter to physically grounded quantities.54 Moreover, some new concepts on the relation between fragility and physical stability have been proposed and developed.55 However, this issue does not seem to be completely understood at the moment. By analyzing the data presented in Figure 7 and Table 1, it can be seen that the fragilities of the solid dispersions as well as the ones obtained for the pure components are not very different, within the experimental uncertainty. It is now clear that the molecular dynamics of all investigated mixtures, above and below the Tg, are not very different and hence cannot be used to explain the physical instability of amorphous mixtures consisting of IMC and acGLU. Moreover, we found that Tg’s of some solid dispersions formed between IMC and pentaacetylglucose or octaacetylsucrose were very similar, whereas their crystallization abilities differed. Therefore, we can also exclude the role of the Tg in controlling the physical stability of these solid dispersions. Because analysis of the parameter k in the Gordon−Taylor equation suggested that the strength of

Figure 9. H-bonding interaction energy (EOH‑...‑O = Etot − Eac.saccharide − EIMC) estimated as a difference between the energy of the binary system (Etot), the energy of pure acetylated saccharide (Eac.saccharide), and the energy of pure indomethacin (EIMC) as well as length of H-bond in the IMC−ac.saccharide (1:1 molar ratio) binary system.

one molecule of IMC and acetylated saccharide are presented. One can see that the H-bond length in the IMC dimer is highly affected by the saccharides. It is well-known that in the crystal IMC forms a very strong H-bond between OH-...-O, where the interatomic distance is reported to be close to 1.66 Å.16,50,56,57 Importantly, in the IMC dimer, dOH‑...‑O and dO‑...‑HO are similar to each other (see Figure 8). In the solid dispersions, the situation is completely different due to the interaction between IMC and acetyl carbohydrate. It is worth noting that each modified saccharide destabilizes the dimer structure. Additionally, every individual H-bond in the dimer alters independently of the others (see Figure 8). The data shows that the relatively small acGLU molecule has the least impact on the strength of the H-bond in IMC dimers. Thus, in the solid dispersion composed of modified 2942



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Figure 10. IR spectra of crystal and glassy IMC as well as three representative solid dispersions of IMC−acetylated saccharide in the (a) 800−3800 cm−1 and (b) 1550−1800 cm−1 regions. The infrared spectra were fitted by marking the band associated with the dimer structure (green area). On the basis of the empirical formula given by cd, the content of dimers was calculated for each studied system (c).

distance changes from 1.86 Å (IMC−acGLU) to 1.75 Å (IMC− acMAL) (Figure 9). The data also indicates that the type (furanose or piranose) and number of monosaccharide rings have a strong influence on H-bond formation. Thus, we expect that the most stable binary system should be the one formed by IMC and acMAL. On the other hand, the lowest physical stability is expected for the IMC−acGLU solid dispersion, as revealed by the structural studies. However, one should point out that all calculations were done in the gas phase, where interactions between molecules are pretty weak. Furthermore, DFT computations are performed under artificial conditions that definitely differ from the properties of dense and highly viscous systems, where interactions between molecules become very strong. Thus, to verify the results of the theoretical calculations, further experimental FTIR measurements were carried out. The data obtained for the crystal and glassy IMC as well as for the representative solid dispersions (components mixed in 1:1 weight ratio) are illustrated in Figure 10. According to Strachan et al. and Taylor et al., indomethacin may exist in two polymorphic forms (γ and α), where stable γ-indomethacin can be found in the crystal and the metastable α-form is formed at higher temperatures.16,57 These authors also suggested that the alterations within the dimer structure of indomethacin are the most visible in the 1550−1800 cm−1 region. Therefore, a fitting procedure may be carried out to find the exact location of the bands related to the dimer, benzoyl, and free carboxyl group vibrations. As a result of the fitting, two bands associated with the CO stretching vibration at 1689 cm−1 (benzoyl CO) and

monosaccharide and IMC, the distance between the internal Hbond in IMC increases by only ∼0.012 Å. The influence of acMAL and acSUC on the internal H-bond in dimers is much stronger. In the binary mixture composed of IMC and acMAL, the internal H-bond in API increases by 0.013 and 0.063 Å with respect to the noninteracting dimer. In the case of acSUC, the theoretical data show an increase in one of the H-bonds by 0.037 Å, whereas the length of the second one is reduced by 0.019 Å. The opposing results observed for individual H-bonds in dispersions formed between IMC and acSUC are probably associated with the chemical structure of this carbohydrate, which consists of furanose and pyranose rings. Additionally, Δd, defined as the difference in H-bond distance between dOH‑...‑O and dO‑...‑HO, (see the inset to Figure 8) gives clear evidence of the impact of a given saccharide on the strength of the H-bond in the IMC dimer structure. The relatively small value observed for IMC−acGLU (Δd = 0.014 Å) and the much higher values for IMC−acMAL (Δd = 0.051 Å) and IMC− acSUC (Δd = 0.057 Å) lead to the conclusion that, in contrast to acetylated glucose, modified disaccharides interact very strongly with IMC molecules. As a consequence of that, IMC dimers are significantly destabilized. It is worth emphasizing that each of the studied saccharides also forms H-bonds with API. The theoretical calculations (Figure 9) showed that the strongest H-bonding interactions should be observed in the system consisting of indomethacin and acMAL, whereas the weakest one is in the indomethacin−acGLU dispersion. In this context, one should note that the H-bond 2943



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1714 cm−1 (CO group in OCOH···O chain within dimer) are detected in the crystal spectrum of IMC. The supercooled IMC may be characterized by three bands at 1679 cm−1 (benzoyl CO), 1709 cm−1 (CO group in O = COH···O chain within dimer), and 1735 cm−1 (non-H-bonded CO in monomer), whereas α-indomethacin may be characterized via four bands at 1679 cm−1 (H-bonded CO), 1687 cm−1 (benzoyl CO), 1735 cm−1 (non-H-bonded CO group in NCO···HO), and 1751 cm−1 (non-H-bonded CO in monomer).37,56,57 It is worth noting that in the crystal only dimer structures are observed, whereas the vitrification process as well as addition of the saccharide are responsible for the coexistence of dimers and monomers in the glassy state of API. To gain deeper insight into intermolecular interactions and to make a quantitative discussion, FTIR spectra measured for pure IMC and solid dispersions were renormalized according to the following procedure. Integral intensities of the bands associated with the stretching vibration of the benzene ring were normalized to be the same independent of the sample. This is plausible because the number of benzene rings in API and binary mixtures stays constant upon temperature increase and solid dispersion formation.58 This procedure enabled recalculation of the FTIR spectra and direct comparison of the data. As a result, we found that upon typical vitrification a decrease of up to ∼40% in the dimer population is visible. On the other hand, a more significant reduction of about 80% occurs in the solid dispersions formed by IMC and acetylated saccharides. Interestingly, it was noticed that octaacetylmaltose destroys the dimers of IMC more effectively than does modified monosaccharide (17−22% remaining population of dimers). In this context, one has to take note of the fact that there is a stoichiometric molar ratio in the sample formed by modified monosaccharide and IMC, whereas in the case of solid dispersions composed by disaccharides, the population of IMC molecules is twice as high (1:1 weight ratio corresponds to 2:1 molar ratio). Thus, it is expected that for the stoichiometric molar ratio, interactions between API and acetylated maltose or sucrose should be even more effective. Finally, we also carried out temperature-dependent analysis (Figure 11) of the integral intensity (Ia) of bands at 1679 cm−1 (benzoyl CO), 1709 cm−1 (dimer CO), and 1735 cm−1 (free CO) to monitor the inter- and intramolecular dynamics in pure IMC and representative solid dispersions (1:1 weight ratio). Importantly, from the kink in the temperature-dependent integral intensity of these bands, the Tg for each system can be calculated. We found that Tg is in good agreement (within 1%) with the one evaluated from the calorimetric data. The FTIR spectra for pure IMC and solid dispersions reveal that there is a significant population of non-H-bonded monomers of IMC in the supercooled liquid state (see band at 1735 cm−1 in Figure 11). For pure IMC, the dimer-to-monomer ratio is constant up to the calorimetric Tg (Tg = 316 K; Table 1). The growth of the integral intensities of bands at 1709 and 1679 cm−1 points to reconstruction of the dimer structures up to 328 K, whereas a further rise in temperature leads to breaking of the dimers due to the high thermal energy. Additionally, the α-IMC form appears above 348 K; this is demonstrated by a decrease in the integral intensities of the bands at 1709 and 1679 cm−1 and a simultaneous increase in the absorbance of the other ones (1735 and 1751 cm−1; see Figure 11). The IMC−acGLU solid dispersion is stable up to 318 K, where the growth in the integral intensity of bands at 1709 and 1735 cm−1 and the decrease of the one at 1679 cm−1 are observed. This is due to transformation of amorphous IMC to its α form, similar

Figure 11. Temperature-dependent integral intensity analysis of characteristic bands for pure IMC as well as for IMC−acetylated saccharide (1:1 weight ratio) systems. Two representative infrared spectra in the 1500−1800 cm−1 range correspond to different temperatures marked on the graph. 2944



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Figure 12. Solubility of investigated samples in different media.

to the case of pure IMC. Furthermore, the growth of Ia at 1679 cm−1 above 358 K (see Figure 11) is a clear indication that interaction between the benzoyl group and the saccharide occurs. The IMC−acMAL and IMC−acSUC binary mixtures are stable up to the calorimetric glass transitions. Above the Tg, IMC dimers are reconstructed. It is worth noting that heating the sample further above 368 K does not lead to production of the α form. Additionally, as observed for the IMC−acGLU system, the intermolecular bond between benzoyl and carbonyl groups is formed above 368 K (see the presence of a band at 1679 cm−1 for the IMC−acMAL and IMC−acSUC systems in Figure 11). We suppose that the interaction between disaccharides and indomethacin stabilizes the whole system and protects IMC from chemical degradation even at temperatures 20 K higher than the melting temperature. As a final point, solubility measurements on the obtained solid dispersions were carried out. Indomethacin is a weak organic acid, with pKa equal to 4.5.34 This means that below this value a nonionized form of IMC (which is less water soluble than the ionized one that prevails above its pKa) predominates. Therefore, we observed an increase in solubility with increasing pH of the solution. As can be seen in Figure 12, the amount of dissolved IMC slightly decreases with the increasing content of acetylated saccharides in the lower pH range (below pKa). On the other hand, the reverse situation is observed at higher pH, where solubility of API is continuously enhanced with the increasing amount of modified saccharides. It can also be added that due to strong intermolecular interactions in solid dispersions the solubility of IMC was not as improved as one would expect. Furthermore, it should be stressed that different types of modified carbohydrates do not significantly affect the solubility of API.

studied in detail. We found that neither molecular dynamics nor the Tg can be regarded as key parameters that control the long-term stability of the investigated binary mixtures. The Tg’s of IMC dispersed in acetylated sucrose or glucose, for some concentrations, were very close to each other, whereas the crystallization tendencies of such systems were completely different. FTIR data provided credible proof of the fact that strong interactions between modified disaccharides and IMC ensure the physical stability of the binary mixtures. DFT computations enabled deeper insight into the character of these specific interactions. It was shown that the chemical structure of the acetylated saccharide has strong impact on the geometry, length, and strength of the H-bonds that are formed between API and a given carbohydrate. In the future, one could try to continue this kind of investigation to elucidate the influence of the chemical structure and geometry of the excipient on the interaction strength with API. However, one should also bear in mind that DFT calculations do not completely reproduce experimental conditions, as only few molecules are taken into account. Therefore, the interactions occurring in real, dense systems are not satisfactorily reproduced. The results obtained within the framework of this work will be helpful for resolving some fundamental problems regarding the mechanism of APIs stabilization and elucidating the role of intermolecular interactions in controlling physical stability of amorphous formulations. It is worth noting that this issue should be seriously considered for designing very stable dispersions consisting of amorphous pharmaceuticals.

CONCLUSIONS In this article, the physical stability of the solid dispersions formed between IMC and low molecular weight excipients, octaacetylmaltose, octaacetylsucrose, and pentaacetylglucose, was

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*E-mail: [email protected]. Notes

The authors declare no competing financial interest. 2945



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ACKNOWLEDGMENTS E.K., M.T., and M.D. are thankful for the financial support from the National Center of Science based on decision DEC-2013/09/ D/NZ7/04194. E.U.M. appreciates funding from the German Research Foundation (SPP 1369). K.K is deeply thankful for support through a stipend received within the project “DoktoRIS − the stipend program for the innovative Silesia,” which is cofinanced by the EU European Social Fund. This research was supported in part by PL-Grid Infrastructure. We appreciate Gladys Mumbua for insightful discussions.

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