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Studying the Impact of Modified Saccharides on the Molecular Dynamics and Crystallization Tendencies of Model API Nifedipine E. Kaminska,*,† M. Tarnacka,‡,§ P. Wlodarczyk,∥ K. Jurkiewicz,‡,§ K. Kolodziejczyk,‡,§ M. Dulski,⊥ D. Haznar-Garbacz,# L. Hawelek,∥ K. Kaminski,‡,§ A. Wlodarczyk,∇ and M. Paluch‡,§ †

Department of Pharmacognosy and Phytochemistry, Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, ul. Jagiellonska 4, 41-200 Sosnowiec, 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 ∥ Institute of Non-Ferrous Metals, ul. Sowinskiego 5, 44-100 Gliwice, Poland ⊥ Institute of Material Science, University of Silesia, 75 Pulku Piechoty 1a, 41-500 Chorzow, Poland # Institute of Pharmacy, Center of Drug Absorption and Targeting, Felix-Hausdorff-Strasse 3a, 17489 Greifswald, Germany ∇ Department of Animal Histology and Embryology, University of Silesia, ul. Bankowa 9, 40-007 Katowice, Poland ABSTRACT: Molecular dynamics of pure nifedipine and its solid dispersions with modified carbohydrates as well as the crystallization kinetics of active pharmaceutical ingredient (API) above and below the glass transition temperature were studied in detail by means of broadband dielectric spectroscopy (BDS), differential scanning calorimetry (DSC), and Xray diffraction method. It was found that the activation barrier of crystallization increases in molecular dispersions composed of acetylated disaccharides, whereas it slightly decreases in those consisting of modified monocarbohydrates for the experiments carried out above the glass transition temperature. As shown by molecular dynamics simulations it can be related to the strength, character, and structure of intermolecular interactions between API and saccharides, which vary dependently on the excipient. Long-term physical stability studies showed that, in solid dispersions consisting of acetylated maltose and acetylated sucrose, the crystallization of nifedipine is dramatically slowed down, although it is still observable for a low concentration of excipients. With increasing content of modified carbohydrates, the crystallization of API becomes completely suppressed. This is most likely due to additional barriers relating to the intermolecular interactions and diffusion of nifedipine that must be overcome to trigger the crystallization process.

KEYWORDS: nifedipine, glassy state, crystallization, stabilization, acetylated saccharides

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INTRODUCTION

benefits, amorphous pharmaceuticals are thermodynamically unstable and tend to revert to a more stable crystalline state,

Amorphization of poorly soluble active pharmaceutical ingredients (APIs) is one promising method for improving their dissolution rate, solubility, and consequently the overall bioavailability. There are a lot of advantages offered by amorphous systems as a result of their physical properties (higher enthalpy, entropy, and specific volume in comparison to the crystalline states).1−4 However, in spite of so many © XXXX American Chemical Society

losing their key properties.5,6 Received: April 7, 2015 Revised: May 27, 2015 Accepted: June 23, 2015

A

DOI: 10.1021/acs.molpharmaceut.5b00271 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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Molecular Pharmaceutics

Figure 1. Chemical structure of nifedipine (a), octaacetylmaltose (b), octaacetylsucrose (c), pentaacetylglucose (d), and pentaacetylgalactose (e).

better protection against crystallization (API-SOP, 20% w/w, stable for more than 4 years at room temperature). Moreover, a significant role of global mobility in controlling the crystallization ability has been shown by Bhardway et al. for an amorphous system formed between itraconazole (ITZ) and two polymers: polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose acetate succinate (HPMCAS);41 Aso et al. for nifedipine (NIF)-PVP solid dispersions42 and by us for ITZ−acMAL molecular dispersion.33 Numerous studies have also discussed the potential role of specific interactions (e.g., hydrogen bonding, dipole−dipole, ion−dipole, and electrostatic forces) in improving the stability of amorphous APIs.1,8,23,24,27−32,40,43−48 For example, Matsumoto et al. have studied amorphous solid dispersions formed between indomethacin (IMC) and various molecular weight grades of PVP and poly(vinylpyrrolidone-co-vinylacetate), PVP/VA.40 Authors found that inhibition of crystallization is controlled by H-bonds between polymers and API. Amorphous IMC turned out to be stable over a 20 week period (at 303 K), when different molecular weight PVP was used at a 5% w/w level. Similar conclusions about the impact of H-bonds have also been shown by Wegiel et al. for binary systems of resveratrol and several polymers24 and Gupta et al. for celecoxib (CEL)−PVP solid dispersion.45 Moreover, in our recent works we have suggested that such specific bonds are formed between IMC and low molecular excipients, acetylated saccharides, and that they are likely to determine the long-term stability of amorphous API in binary systems.31,32 Regarding nifedipine, the role of specific interactions has been investigated by Kothari et al. for solid dispersions of this API with three polymers: PVP, HPMCAS, and PAA (10% w/w polymer).46 Authors showed that the most pronounced drug crystallization inhibition is observed with PVP (20% w/w polymer, ∼65-fold increase), which is associated with the higher strength and consequently greater extent of drug polymer interactions. In turn, Powell et al. studied the stabilization of amorphous nifedipine using six polymer additives, but with a much lower content of excipient (1% w/w).49 They noticed that the ability to inhibit crystal growth is not well ordered by the strength of host−polymer hydrogen bonds, but correlates remarkably well with the neat

Within the past few years significant progress has been made in exploring the knowledge of the physical stability of amorphous materials. However, there is still much to do since the entire recrystallization phenomenon cannot be simply explained. Ongoing studies have shown that various factors affect physical stability of amorphous APIs including kinetic (molecular mobility)7−12 and thermodynamic factors (e.g., heat of fusion, heat capacity, configurational entropy),7−9,11,12 amount of water,13−15 existence of isomers,16,17 the specific surface area/mobility,18−21 and method of preparation.1,7,15,22 Moreover, an increasing number of investigators have discussed the role of some chemical species (additives) in suppressing the crystallization from the amorphous state.8,23−35 It is believed that their application can lead to improved stability of many physically as well as chemically unstable APIs. The most common groups of excipients are polymers or saccharides.8,23−33 In general, various mechanisms for the stabilization of amorphous solids in the presence of additives have been debated in the literature. One involves increasing the glass transition temperature of the dispersion by adding a high Tg excipient,23,27,36,37 which in turn results in a greater level of protection of the glassy formulation, according to the wellknown Gordon Taylor equation.38 However, in some cases high Tg of a matrix does not guarantee the greater stability of a pharmaceutical binary system.36,39,40 Another mechanism concerns the role of molecular mobility (both global, associated with α-relaxation, and local, linked to secondary processes) in inhibiting the crystallization.25,26,30,33,41,42 Very recently Grzybowska et al. have shown that the molecular mobility (reflected in the β- and γ-relaxations) of the solid dispersion formed by celecoxib (CEL) and acetylated maltose, acMAL (10% w/w), in the glassy state is much more limited than that in the case of pure CEL, which correlates with the better physical stability of the amorphous binary system.30 In turn, Knapik et al. investigated physicochemical properties of anticholesterol agent, ezetimibe (EZB), in a Soluplus (SOP) matrix.25 Authors also noticed that the molecular mobility (related to the structural relaxation) of the EZB-SOP (20% w/w) solid dispersion is slower than that of pure EZB, which results in B


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Molecular Pharmaceutics polymer’s Tg, suggesting that polymer segmental mobility is an important factor in suppressing crystal growth in organic glasses. Very interesting results have also been obtained by Caron et al. for nifedipine and phenobarbital (PHE) both mixed with PVP (5% w/w polymer).19 They found that the dramatic effect of PVP in retarding crystallization is related to the surface interactions between polymer and drug nuclei. In this article, we focus our attention on the role of small molecular compounds, acetylated saccharides, in controlling crystallization of amorphous nifedipine. Both molecular dynamics simulations as well as FTIR measurements have shown that modified disaccharides interact more strongly with nifedipine with respect to the monosaccharides. As a consequence the activation barrier for the crystallization of API increases significantly. Furthermore, it has been found that upon storage below Tg the crystallization of API can be slowed down only by the use of modified disaccharides for solid dispersions of high concentration of nifedipine. However, with increasing content of acetylated carbohydrates the crystallization of API is completely suppressed in all binary systems. It is obvious that the interactions between excipient and nifedipine as well as diffusion of API seem to be very important in discussing the crystallization ability of this drug.

Table 1. Values of the Glass Transition Temperatures (from DSC and BDS Techniques) and Isobaric Fragilities (m) Determined from eq 2 for Nifedipine, Acetylated Saccharides, and Investigated Solid Dispersions of API with Excipients samples pure NIF NIF + acMAL pure acMAL NIF + acSUC pure acSUC NIF + acGLU pure acGLU NIF + acGAL

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pure acGAL

MATERIALS AND METHODS Materials. Nifedipine (NIF, IUPAC name: 3,5-dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, C17H18N2O6, Mw = 346.34 g/mol), octaacetylmaltose (acMAL, C28H38O19, Mw = 678.6 g/mol), octaacetylsucrose (acSUC, C28H38O19, Mw = 678.6 g/mol), pentaacetylglucose (acGLU, C16H22O11, 390.34 g/mol), and pentaacetylgalactose (acGAL, C16H22O11, 390.34 g/mol), having purities greater than 98%, were obtained from Sigma-Aldrich and used as received. The chemical structures of all compounds are shown in Figure 1. Methods. Preparation of Amorphous Systems of Nifedipine with Acetylated Saccharides. The amorphous: nifedipine (NIF), octaacetylmaltose (acMAL), octaacetylsucrose (acSUC), pentaacetylglucose (acGLU), pentaacetylgalactose (acGAL), and binary systems: NIF-acMAL, NIF-acSUC, NIF-acGLU, and NIF-acGAL, with different amounts of acetylated compounds were prepared by the quench cooling technique in a temperature and humidity controlled glovebox (PLAS LABORATORIES Inc. 890-THC-DT/EXP/SP) at the assured relative humidity RH < 10%. In order to obtain homogeneous NIF-acetylated saccharide (acSACCH) molecular dispersions, first we thoroughly mixed crystalline powders of both compounds in appropriate proportions in a heatresistant glass vial (weight of powder mixture was about 0.5 g). After that, we put a magnetic stir bar into the vial with binary system. Next, the crystalline mixture sample was melted in the vial on the hot plate magnetic stirrer (CAT M 17.5) at T = 443 K. The temperature inside the vial was controlled using a Pt100 sensor. After the crystalline solid dispersions (NIF-acMAL, NIF-acSUC, NIF-acGLU, and NIF-acGAL) were fully melted they were transferred from the hot to a very cold metal plate. The amorphous samples obtained in this way were analyzed immediately after preparation to protect them from atmospheric moisture. We investigated three molecular dispersions of NIF with acMAL, acSUC, acGLU, and acGAL, with different weight ratios of acetylated carbohydrates; see Table 1. It should also be added that additional HPLC measurements were carried

weight ratio 5:1 1:1 1:5 5:1 1:1 1:5 5:1 1:1 1:5 5:1 1:1 1:5

Tg [K] (DSC)

Tg [K] (BDS) τα = 100 s

m

317 312 315 322 332 311 303 300 298.5 308 298 288 288 309 300 297 300

314.5 ± 2 316.5 ± 2 318.5 ± 2 323.5 ± 2 329 ± 2 310.5 ± 2 305 ± 1 299.5 ± 1 296 ± 1 310 ± 2 299 ± 1 292 ± 1 286.5 ± 1 309 ± 2 300 ± 1 297 ± 1 295.5 ± 1

87 ± 2 94 ± 2 97 ± 2 95 ± 2 106 ± 3 86 ± 2 91 ± 2 92 ± 2 93 ± 2 92 ± 2 87 ± 2 93 ± 2 90 ± 2 79 ± 2 83 ± 2 76 ± 2 90 ± 2

out to test the purity of API. We found that degradation of NIF was well below 0.5% in all solid dispersions. Differential Scanning Calorimetry (DSC). Thermodynamic properties of pure NIF, acMAL, acSUC, acGLU, acGAL, and NIF-acetylated saccharide solid dispersions (different weight ratios) were examined using a Mettler−Toledo DSC 1 STAR System (Mettler−Toledo International, Inc., Greifensee, Switzerland). The measuring device was equipped with liquid nitrogen cooling and a HSS8 ceramic sensor having 120 thermocouples. The instrument was calibrated for temperature and enthalpy using indium and zinc standards. Crystallization and melting points were determined at the onset of the peak, whereas the glass transition temperature was at the midpoint of the heat capacity increment. Amorphous samples and their solid dispersions were scanned at a rate of 10 K/min over a temperature range of 273 K to well above the respective melting points. The samples were measured in an aluminum crucible (40 μL). X-ray Diffraction (XRD). The X-ray diffraction measurements for the amorphous molecular dispersions of NIF with acMAL, acSUC, acGLU, and acGAL were performed at ambient temperature using a Rigaku MiniFlex 600 diffractometer (Rigaku Corporation, Tokyo, Japan) with Cu Kα radiation (λ = 1.5406 Å), a tube voltage of 40 kV, and a current of 15 mA using a D/teX Ultra silicon strip detector. Moreover we also used Rigaku-Denki D/MAX RAPID II-R diffractometer equipped with Ag rotating anode (λKα = 0.5608 Å), an incident beam (002) graphite monochromator, and an image plate in the Debye−Scherrer geometry as a detector. The X-ray beam width at the sample was 0.3 mm. Powder samples were placed inside glass capillaries with a diameter of 1.5 mm and wall thickness of 0.01 mm. The measurements were performed for the sample-filled and empty capillaries. The intensity of background measured for the empty capillary was then subtracted. The obtained two-dimensional diffraction patterns were converted into one-dimensional functions of intensity C


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approach a small perturbation force is adopted to initiate acceleration of the system. Viscosity is then calculated from the velocity profile for different acceleration factors (k). Finally, in order to get shear viscosity for the equilibrated system the following procedure was applied. Shear viscosity values obtained for different k were fitted by linear function, and following this, the data was extrapolated to k = 0, which corresponds to the shear viscosity of the equilibrated system. The details of this method can be found in ref 66.

versus the scattering angle. All diffraction patterns are shown in Figures 7 and 9. 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 a frequency range from 1 × 10−2 to 3 × 106 Hz at ambient pressure. NIF-acSACCH solid dispersions were placed in a parallel plate cell (diameter, 20 mm; gap, 0.1 mm) immediately after preparation of the amorphous samples. The temperature ranging from 173 up to 363 K was controlled by a Quatro System using a dry nitrogen gas cryostat with an accuracy of ±0.1 K. For more details on research equipment, see seminal work by Kremer et al.50 Infrared Measurements. Infrared measurements for the amorphous NIF as well as for the molecular dispersions of NIF with acSUC, acMAL, acGAL, and acGLU were carried out 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 GladiATR diamond accessory (Pike Technologies) in the 4000−400 cm−1 range. All spectra were accumulated with a spectral resolution of 4 cm−1 and recorded by accumulating 16 single scans. Theoretical Calculations. All calculations were done with the use of GROMACS 5.0.4 package51−57 and GROMOS 54A7 force field,58 which is widely used for biomolecules and pharmaceuticals. Initial configurations were calculated by packmol software,59,60 while topologies for molecules were obtained using the automated topology builder.61−63 Molecular dynamics is a method based on classical equations of motion, which is used to simulate the behavior of thousands of atoms in time up to 1 μs. From the saved trajectory of atoms (containing information about energy, atom positions, and velocity) many thermodynamic quantities may be obtained. In our simulation, cubic simulation boxes filled with 500 molecules (approximately 20000 atoms) with periodic boundary conditions were built. The use of periodic boundary conditions allows us to approximate the behavior of macroscale systems by application of only a small simulation box (in our case the system composed of 500 molecules was sufficient). Time step used in simulations was equal to 0.5 fs allowing bonds to relax, while simulation time varied for different temperatures, i.e., from 2 ns at 500 K to 10 ns at 460 K (minimal time required to determine hydrogen bond lifetimes, i.e., time of decay of autocorrelation function to the values close to 0). In all calculations, isothermal−isobaric, i.e., NPT (constant number of particles, pressure, and temperature) ensemble was used with thermostat based on velocity rescaling with stochastic term and Berendsen pressure coupling. Such ensemble corresponds most closely to laboratory conditions. As a result of the molecular dynamics study we get a trajectory of all atoms obtained during the simulation. By analyzing trajectories we are able to estimate physical properties of interest. Hydrogen bond lifetimes were calculated from the autocorrelation function (obtained from trajectory) and with the use of the kinetic model of hydrogen bonds. The details of this method are given in ref 64. Diffusion constants were derived from the Green−Kubo formula by integrating the velocity autocorrelation function.65 Shear viscosity was obtained by performing nonequilibrium molecular dynamics. This quantity can be calculated from the equilibrium molecular dynamics by means of Einstein’s relation; however, the nonequilibrium method gives more accurate results. In this

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RESULTS AND DISCUSSION It is known that nifedipine is prone to crystallization above and below the glass transition temperature. This is due to surface enhanced crystallization.21 We decided to check the impact of low molecular weight excipients on the enhanced crystallization of NIF above and below the glass transition temperature. For this purpose solid dispersions of varying concentration of nifedipine and four acetylated saccharides, i.e., octaacetylmaltose, octaacetylsucrose, pentaacetylglucose, and pentaacetylgalactose, were prepared, and their basic physical properties were determined. In Figure 2 representative thermograms obtained upon heating runs of the glassy nifedipine, octaacetylmaltose, and

Figure 2. Thermograms measured for pure NIF (a) and pure acMAL (e) and molecular dispersions of NIF and acMAL with weight ratios of 5:1 (b), 1:1 (c), and 1:5 (d).

their solid dispersions are presented. In each case, a visible heat capacity jump at lower temperatures assigned to the glass transition phenomenon can be detected. However, in pure API (panel a) and the one binary system (NIF-acMAL 5:1 weight ratio, panel b), additional exothermal and endothermal processes relating to the crystallization and melting of nifedipine, respectively, are observed. Interestingly, we found that the melting temperature of the investigated pharmaceutical is strongly shifted to lower temperatures in solid dispersion suggesting interactions between NIF and matrix or appearance of the additional polymorphic form of API. It is worth noting at this point that Tm = 445−445.5 K, Tm = 435−437 K, and Tm = 407−410 K, for α, β, and γ polymorphic forms of nifedipine, respectively.67 One can also mention that a strong depression D


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Figure 3. Dielectric loss spectra measured at atmospheric pressure, above and below the glass transition temperature, Tg, for pure nifedipine (a) and three representative solid dispersions: (b) NIF-acMAL (1:1 weight ratio), (c) NIF-acSUC (5:1 weight ratio), and (d) NIF-acGAL (5:1 weight ratio).

above T = 353 K, similarly as recorded by DSC measurements (see Figure 3c,d). Although, it should be stated that with increasing content of excipient (modified disaccharides) crystallization of nifedipine was completely suppressed and no longer observed above Tg. In addition, deep below the glass transition temperature one clearly visible secondary relaxation process of very weak amplitude was seen in each binary system. However, this issue is out of scope for this article. Analysis of the dielectric data with the use of the Havriliak− Negami function69 enabled us to fully characterize the dynamics of the investigated solid dispersions above the glass transition temperature. Obtained structural relaxation times are plotted in Figure 4. Temperature dependences of α-relaxation times were described by a single Vogel−Fulcher−Tammann (VFT) equation (the solid lines in Figure 4):

of the melting temperature may be due to the inclusion of some additive impurities in the crystalline lattice of nifedipine. With increasing content of modified maltose, crystallization of API was completely suppressed. A similar scenario was seen in the case of NIF-acSUC solid dispersion. For two other molecular dispersions, (NIF-acGLU and NIF-acGAL, data not shown) crystallization was still observed, even for high concentrations of acetylated monosaccharides. It should be pointed out that a single glass transition and lack of any additional thermal events in the studied samples strongly indicate their homogeneity. In order to confirm this theory and probe the molecular dynamics of binary systems, dielectric measurements were performed for a wide range of frequencies and temperatures. In Figure 3 the loss spectra measured for pure nifedipine and three representative solid dispersions are shown. In each case only one dominant relaxation, called the structural process, responsible for the liquid−glass transition, is well detected above Tg. In this context it is worth remembering that for the microphase separating samples, additional relaxation processes coming from the single components can be observed.68 Hence, this is further evidence that our solid dispersions were homogeneous in the range of temperatures studied. Interestingly, our dielectric data also showed that in some binary systems, where the amount of nifedipine was the greatest (NIFacSACCH, 5:1 weight ratios), API recrystallized very easily

⎛ DT0 ⎞ τ = τ0 exp⎜ ⎟ ⎝ T − T0 ⎠

(1)

where τ0, D, and T0 are constants (τ0 is the time scale of vibrational motions, D is the strength parameter or alternative measure of fragility, and T0 represents the temperature at which the structural times tend to infinity). We found that the glass transition temperatures, defined herein as the temperatures at which τα = 100 s, are very close (within few K) to the ones E


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Figure 4. Relaxation maps for molecular dispersions of nifedipine with acetylated saccharides (maltose (a), sucrose (b), glucose (c), and galactose (d)). The relaxation times obtained for pure components are also included. The red solid lines are fits to α-relaxation using the VFT eq 1.

amplitude of the structural relaxation process and static permittivity decrease due to the freezing out of molecular mobility. In order to analyze the progress of crystallization, the static permittivity ε′n was renormalized using the following formula:

determined from calorimetry for each solid dispersion (see Table 1). In addition, the fragility was estimated from the equation70 m=

d log10τα d(Tg /T )

T = Tg

ε′n (t ) =

(2)

It should be stressed that fragility (m) is a single parameter that is very often used to describe the whole dynamics of glass forming systems.3,25,29−33 It can be seen that m of NIF is the lowest, while it tends to increase with addition of acetylated saccharides in solid dispersions. All determined parameters (Tgs and fragilities) are depicted in Table 1. One can mention herein that there are theoretical and experimental studies that try to link fragility and the physical stability of glass forming liquids.71,72 However, in our case we did not find any clear relationship between fragility and physical stability. What is more, fragility does not change enough to make any credible discussion about the role of this parameter in controlling and delaying the crystallization process. Crystallization above Tg. Since calorimetry and dielectric measurements showed that crystallization of nifedipine can be observed in the solid dispersions of higher content of API we decided to check the impact of acetylated saccharides on the speed of crystallization, as well as its activation barrier in these binary systems. For this purpose isothermal dielectric measurements were carried out at different temperatures. Representative dielectric loss and dispersion spectra recorded upon isothermal crystallization of pure NIF and some representative solid dispersions are shown in Figure 5. It can be noted the

ε′(0) − ε′(t ) ε′(0) − ε′(∞)

(3)

where ε′(0) is the static dielectric permittivity at the beginning of the crystallization, ε′(∞) is the long-time limiting value, and ε′(t) is the value at a given time of crystallization, t. In Figure 6, a plot of ε′n as a function of time for pure NIF (panel a) and NIF-acMAL solid dispersion (5:1 weight ratio, panel b) is presented. At first glance, it is clearly seen that crystallization slows down with lowering temperature. However, to quantify these observations and evaluate the rate of crystallization the Avrami model73 was used to describe kinetic curves, presented in Figure 6 (panels a and b): ε′n (t ) = 1 − exp( −kt n)

(4)

where k is a crystallization rate constant, which depends on the crystallization temperature and geometry of the sample, n is the Avrami exponent that is related to the time dependence of the nucleation rate and to the dimensionality of the crystallization. As can be seen in Figure 6, Avrami fits describe the experimental data in a satisfactory way. All parameters characterizing the crystallization process are collected in Table 2. One can see that parameter n varies between 4.1 and 2.7 for pure nifedipine and solid dispersions, which suggests a change in the mechanism of crystallization in binary F


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Figure 5. Time evolution of the imaginary (a−c) and real (d−f) parts of complex dielectric permittivity plotted versus frequency during crystallization of pure nifedipine, NIF-acMAL, and NIF-acGLU (5:1 weight ratio) binary systems at T = 298 K.

Figure 6. Time dependence of normalized real permittivity ε′n for pure NIF (a) and NIF-acMAL solid dispersion, 5:1 weight ratio (b). Solid lines represent Avrami fits in terms of eq 4. (c) Temperature dependence of the logarithm of the crystallization constant rate k. The solid lines denote the linear fits to eq 5.

systems or variation in morphology or concentration of the formed crystals. To confirm this, further X-ray diffraction studies on the sample crystallized above the glass transition temperature were carried out. The collected X-ray diffraction patterns obtained using Ag Kα radiation for crystalline nifedipine, acetylated saccharides (octaacetylmaltose, octaacetylsucrose, pentaacetylglucose, and

pentaacetylgalactose), and recrystallized solid dispersions (NIFacSACCH, 5:1 weight ratio) at T = 353 K are presented in Figure 7. Based on the obtained results, one can precisely identify the structure of nifedipine used for the preparation of the investigated molecular dispersions as the thermodynamically stable α polymorph, as reported in the literature.74 The diffraction patterns of recrystallized solid dispersions of G


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Molecular Pharmaceutics Table 2. Values of Parameter n, Calculated from the Avrami eq 4 samples

of pentaacetylglucose and pentaacetylgalactose recrystallized in binary systems. The peaks at about 3.5 degrees for acetylated glucose and at about 8.1 degrees for acetylated galactose bring a noticeable increase in diffraction intensity for the studied dispersions. Finally, it was also observed that modified disaccharides do not recrystallize from the investigated solid dispersions. To calculate the activation barrier for the crystallization of pure nifedipine and solid dispersions the determined constant rates were plotted vs reciprocal temperature and fitted to the well-known Arrhenius equation:

Avrami parameter (n)

NIF NIF-acMAL (5:1 weight ratio) NIF-acSUC (5:1 weight ratio) NIF-acGLU (5:1 weight ratio) NIF-acGAL (5:1 weight ratio)

4.1 2.7 2.9 2.7 3.2

± ± ± ± ±

0.1 0.1 0.1 0.1 0.1

⎛ ΔE ⎞ k = k 0 exp⎜ ⎟ ⎝ kBT ⎠

(5)

We found that the activation barrier for this process in pure nifedipine is equal to 145 kJ/mol, which is very close to 149 kJ/ mol, as evaluated from complementary DSC isothermal crystallization studies (see Figure 6c). What is more, it turned out that Ea for the crystallization of NIF increases significantly in the solid dispersions with modified disaccharides (206−230 kJ/mol), whereas it gets lower for the binary systems consisting of acetylated monocarbohydrates (110−137 kJ/mol). This can be related to the fact that acetylated glucose and acetylated galactose recrystallize from solid dispersions, while modified disaccharides do not. However, there might be another explanation of this finding originating from the strength of interactions between API and excipients. To fully understand this experimental observation, detailed molecular dynamics (MD) simulations were performed to get a deeper insight into interactions between molecules in the investigated binary systems. All the simulations were carried out at thermodynamic conditions characteristic of a low viscous liquid in order to ensure a reasonable simulation time. Differences in hydrogen bond patterns between solid dispersions in a low viscous liquid should also be the same as for the supercooled liquid state. Parameters such as density, shear viscosity, diffusion constant, and hydrogen bond free enthalpy were obtained for temperature equal to 500 K and 1 bar pressure. All these physical parameters for the investigated systems were gathered in Table 3. As one can see, addition of large acetylated disaccharide molecules increases viscosity. Such an increase also affects the diffusion coefficient of nifedipine, which becomes significantly lower. Hence one can expect that this factor is an important parameter that enhances the physical stability of amorphous API. The other interesting results obtained from MD simulations are hydrogen bond lifetimes and free enthalpies. Our data revealed that addition of modified

Figure 7. X-ray diffraction patterns obtained for pure nifedipine, acetylated saccharides (glucose, galactose, maltose, and sucrose), and solid dispersions (NIF-acSACCH, 5:1 weight ratio) recrystallized at T = 353 K.

nifedipine and acetylated saccharides show sharp Bragg peaks that are characteristic of crystalline materials. However, it is evident that the reflections come from several phases of these complex systems. In each system, a contribution from the α polymorph of nifedipine can be observed. Moreover, further detailed analysis revealed that there are reflections (at about 2.7, 3.9, and 8.8 degrees) that come from another structural type of nifedipine-β polymorph. In this context it is worth mentioning the paper by Gunn et al., who reported that β nifedipine is favored during crystallization from the supercooled and glassy state.75 In addition, we also found that some extent

Table 3. Data from Molecular Dynamics Simulations for T = 500 K and p = 1 bara data at T = 500 K, p = 1 bar NIF NIF-GLU (NIF) NIF-GLU (acGLU) NIF-acGAL (NIF) NIF-acGAL (acGAL) NIF-acMAL (NIF) NIF-acMAL(acMAL) NIF-acSUC (NIF) NIF-acSUC (acSUC) a

diffusion constant (m2/s) 1.5 1.8 1.7 2.6 1.3 3.3 3.0 3.3 1.3

× × × × × × × × ×

10−10 10−10 10−10 10−10 10−10 10−11 10−11 10−11 10−11

viscosity (cP)

HB lifetime (ps)

HB free enthalpy (kJ/mol)

density (g/cm3)

7.4 7.1

5.6 8.1 13.9 6.5 11.4 173.4 49.5 159.3 62.1

16.9 18.4 20.7 17.5 19.9 31.2 26.0 30.8 26.9

1.138 1.142

8.5 32.7 39.9

1.143 1.181 1.178

All simulations were conducted for NIF-acSACCH solid dispersions (5:1 weight ratio). H


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the temperature range from 460 to 520 K. As one can see, quite significant differences in hydrogen bond lifetimes for nifedipine-acetylated disaccharides and nifedipine-acetylated monosaccharides binary systems become even more evident as the temperature drops. The average value of donor−acceptor distance between NIF molecules is equal to 0.28 nm in the case of NIF-acMAL solid dispersion and 0.30 nm in pure NIF and NIF-acGLU dispersion at T = 500 K; thus, the difference seems to be significant. Summarizing this part, one can state that H-bond interactions between nifedipine and acetylated disaccharides are rather strong, while in the case of modified monosaccharides they are pretty weak (see Table 3). Hence one can assume that there is some relationship between the strength of intermolecular interactions in the investigated systems and activation barrier for the crystallization of API. However, it must be pointed out that crystallization is quite a complex process and other factors such as configurational entropy, diffusion coefficient, and surface tension can affect the activation barrier for the crystallization as well. Crystallization below Tg. In addition, we have also studied the crystallization of nifedipine and solid dispersions stored below the glass transition temperature at T = 293 K with the use of X-ray technique (Cu Kα radiation). It was found that nifedipine recrystallizes within 2 weeks from each dispersion where the amount of API was the greatest (see Figure 9a). Although, it should be noted that the progress of crystallization was significantly slower in the case of binary systems formed by modified disaccharides. This finding can be explained by taking into account the results of molecular dynamics simulations, which showed that both acetylated sucrose and acetylated maltose interact much more strongly with nifedipine with respect to the modified monosaccharides. However, since extrapolation of the results of molecular dynamics simulation to the glassy state can be quite controversial, further experimental FTIR investigations on the studied samples were carried out. The infrared spectra of glassy nifedipine and its solid dispersions with acetylated saccharides (5:1 weight ratio) were illustrated in Figure 10a. The fitting procedure in the hydroxyl stretching region (2500−3800 cm−1) allowed us to find a lowintensity band close to 3500 cm−1, characteristic of the H-bond (see Figure 10b), which is most likely related to the intramolecular interactions between the carbonyl (CO) group from one NIF molecule and (NH) group from another one. In the case of all solid dispersions a small intensity band close to 3500 cm−1 was also found. This band indicates the presence of intramolecular or intermolecular H-bonds. Hence, to analyze the impact of modified saccharides on the H-bond strength in the glassy nifedipine we performed integrated analysis of the band at 3500 cm1. Using the simple formula

disaccharides causes an enormous strengthening of NIF−NIF interactions. The hydrogen bonds between nifedipine molecules become much stronger than mixed interactions between nifedipine and acetylated disaccharides. The opposite situation is observed for nifedipine and modified monosaccharide systems, i.e., nifedipine−nifedipine interactions are much weaker than nifedipine-acetylated carbohydrates. According to this picture one could expect phase separation and enhanced nifedipine crystallization from the solid dispersions consisting of modified disaccharides, which is in contrast to the experimental data. However, it is most likely that the acetylated disaccharides introduce chemical pressure into the NIF system, enforcing a new molecular order and space arrangement of nifedipine clusters. As a consequence, the geometry of NIF clusters does not fit to the order characteristic of the crystal lattice, which in turn prevents the effective crystallization of API. It should also be stressed that the difference in HB free enthalpy of NIF and the NIF-modified carbohydrate system is not so significant to lead to phase separation between API and matrix. In this context one can recall dielectric data, which showed that investigated molecular dispersions were homogeneous in the studied range of temperatures. A more detailed description of hydrogen bonds has been presented in Figure 8. Hydrogen bond lifetimes were plotted in

cd[%] = Figure 8. On the upper panel, hydrogen bond lifetimes calculated for different temperatures have been presented. The left side of the bottom panel shows visualization of a mixture composed of 500 molecules (black, nifedipine atoms; red, octaacetylmaltose atoms), while the right side presents donor−acceptor (D−A) distance distribution of hydrogen bonds (D-HA). In the description the first part of the label is related to the type of interaction while in the bracket the type of mixture has been shown. For example, NIF−NIF (NIF-acMAL) abbreviation means that the interactions of nifedipine molecules in the NIF-acMAL molecular dispersion are described.

I3500ac × 100 I3500p

(6)

(where I3500p and I3500ac are integral band intensities for pure glassy NIF and NIF-acSACCH binary systems, respectively) the change in populations of these specific interactions for investigated solid dispersions can be calculated. Our data showed that monosaccharides (acGLU and acGAL) do not significantly affect the interactions between NIF molecules as well as populations of internal H-bonds between them (Figure 10c). A similar effect was seen on the band position associated with the stretching vibration of amine (νNH), where only a I


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However, FTIR data showed that in the latter dispersion intermolecular interactions are the strongest (see Figure 10c). Hence, it seems that both experimental findings are in clear conflict. However, it should be added that crystallization is a very complex process, so beside intermolecular interactions there are many factors that may affect the activation barrier. What is more, Ea determined in the supercooled phase can be quite different in the glassy state. In addition, we performed long-term studies on physical stability of nifedipine in solid dispersions having a greater content of excipient (NIF-acSACCH, 1:5 weight ratio) (Figure 9b). It was found that with addition of modified carbohydrate crystallization of API becomes completely suppressed, despite the fact that in the majority of cases the glass transition temperature of binary systems gets lower (this means that the kinetic factor related to the global mobility in the investigated systems should be significantly enhanced leading to API crystallization) (see Table 1). Moreover, taking into account that local mobility, measured by dielectric spectroscopy (data not shown), shows very little difference in various samples, one can state that in fact the kinetic factor associated with molecular mobility cannot be responsible for the observed experimental finding. We think that the long-term stability of API in these solid dispersions is connected to the better spatial separation of nifedipine molecules. One can expect that for a higher content of acetylated carbohydrates an additional barrier connected to the NIF diffusion as well as intermolecular interactions between API and excipients needs to be overcome for the formation of clusters of appropriate geometry and dimension to trigger a crystallization process possible. This issue seems to be quite an important factor, especially in systems where intermolecular interactions are rather strong (as in the case of acetylated disaccharides). Interestingly, data presented in the lower panel of Figure 9b also indicates that, for the highest concentration of modified saccharides, two of them, i.e., acetylated glucose and acetylated galactose, start to recrystallize. However, there is no trace of crystallization of nifedipine in the X-ray diffraction patterns registered even after six months (data not shown). This observation supports our theory that better stability of nifedipine might be related to the API diffusion that is significantly suppressed due to intermolecular interactions in the solid dispersions of higher content of the excipient.

Figure 9. X-ray diffraction patterns (Cu Kα radiation) for NIFacSACCH solid dispersions (5:1 and 1:5 weight ratios), measured after 14 (a) and 50 (b) days of storage at 293 K.

small blue shift was observed. The influence of disaccharides (acMAL and acSUC) was much more visible. In this case the decrease of weak H-bond population in comparison to the pure sample was observed (see Figure 10c). Thus, we conclude that the impact of modified disaccharides is significant, implying stronger interactions between API and excipients. Interestingly, the clearly visible shift of the (NH) band toward a higher wavenumber is further evidence supporting the above conclusions. Based on the above it can be stated that in fact intermolecular interactions are one of the most important factors responsible for delaying crystallization. However, in the case of solid dispersions consisting of acetylated maltose, kinetic factors relating to the global mobility may play some role since the Tg of this molecular dispersion is the highest. On the other hand, one can note that glass transition temperatures of the other molecular dispersions formed by modified sucrose, glucose, and galactose (5:1, w/w) are almost the same (within 2 K), while the pace of API crystallization is quite different. Thus, the kinetic factor is definitely important, but it seems that intermolecular interactions control physical stability of the studied samples. Herein one more issue needs to be explained. It was demonstrated that the activation barrier for the crystallization of nifedipine is slightly higher in the solid dispersion consisting of modified sucrose with respect to NIF-acMAL binary system.

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CONCLUSIONS In this article molecular dynamics as well as crystallization of pure nifedipine and its solid dispersions with acetylated carbohydrates were investigated on an experimental and theoretical level. It was found that in contrast to acetylated monosaccharides, modified disaccharides affect crystallization of API both above and below the glass transition temperature in a significant way. It was shown that the activation barrier for the crystallization of NIF increases significantly in binary systems consisting of acetylated disaccharides, for the experiments carried out above Tg. Molecular dynamics simulations indicated that it can be related to the character, strength, and overall Hbond pattern in the studied solid dispersions, which change dependently on the excipient. Interestingly the same conclusions were derived from FTIR measurements performed at room temperature. Furthermore, long-term studies on the physical stability of the investigated binary systems stored close and below the Tg showed that for the higher amount of API, nifedipine tends to recrystallize from each solid dispersion, J


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Figure 10. IR spectra of glassy NIF as well as four solid dispersions of NIF with acetylated saccharides (5:1 weight ratio) measured in the (a) 400− 4000 cm−1 and (b) 2500−3800 cm−1 regions. The infrared spectra in the hydroxyl stretching region was fitted by marking the band associated with H-bond (blue area). Based on the empirical formula given by cd eq 6, (c) the content of H-bond was calculated for each studied system. (2) Yamamoto, K.; Nakano, M.; Arita, T.; Takayama, Y.; Nakai, Y. Dissolution behavior of phenytoin from a ground mixture with microcrystalline cellulose. J. Pharm. Sci. 1976, 65, 1484−1488. (3) Adrjanowicz, K.; Kaminski, K.; Paluch, M.; Wlodarczyk, P.; Grzybowska, K.; Wojnarowska, Z.; Hawelek, L.; Sawicki, W.; Lepek, P.; Lunio, R. Dielectric relaxation studies and dissolution behavior of amorphous verapamil hydrochloride. J. Pharm. Sci. 2010, 99, 828−839. (4) Pikal, M. J.; Lukes, A. L.; Lang, J. E.; Gaines, K. Quantitative crystallinity determinations for beta-lactam antibiotics by solution calorimetry: correlations with stability. J. Pharm. Sci. 1978, 67, 767−73. (5) Fukuoka, E.; Makita, M.; Yamamura, S. Some physicochemical properties of glassy indomethacin. Chem. Pharm. Bull. 1986, 34, 4314− 21. (6) Yoshioka, M.; Hancock, B. C.; Zografi, G. Crystallization of indomethacin from the amorphous state below and above its glass transition temperature. J. Pharm. Sci. 1994, 83, 1700−5. (7) Bhugra, C.; Pikal, M. J. Role of thermodynamic, molecular, and kinetic factor in crystallization from amorphous state. J. Pharm. Sci. 2008, 97, 1329−1349. (8) Marsac, P. J.; Konno, H.; Taylor, L. S. A Comparison of the Physical Stability of Amorphous Felodipine and Nifedipine Systems. Pharm. Res. 2006, 23, 2306−16. (9) Adrjanowicz, K.; Zakowiecki, D.; Kaminski, K.; Hawelek, L.; Grzybowska, K.; Tarnacka, M.; Paluch, M.; Cal, K. Molecular dynamics in supercooled liquid and glassy states of antibiotics: azithromycin, clarithromycin and roxithromycin studied by dielectric spectroscopy. Advantages given by the amorphous state. Mol. Pharmaceutics 2012, 9, 1748−63. (10) Bhardwaj, S. P.; Suryanarayanan, R. Molecular mobility as an effective predictor of the physical stability of amorphous trehalose. Mol. Pharmaceutics 2012, 9, 3209−17.

while for the higher content of excipient this process seems to be completely suppressed (despite the fact that in the majority of cases the glass transition temperature of solid dispersions decreases). We think that in such situations additional barriers related to the (i) diffusion of API and (ii) intermolecular interactions between API and excipient must be overcome. Consequently, formation of clusters of the size and geometry satisfying the criteria for the formation of nuclei to trigger the crystallization process is hardly possible.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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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. D.H.-G. would like to thank the German Federal Ministry of Education and Research for the financial support (BMBF FKZ 03IPT612C). P.W. and L.H. are thankful for the financial support from the National Center of Science, grant no. UMO-2013/09/D/ST3/03758. M.D. would also like to acknowledge the support of the National Center of Science, based on decision DEC-2012/07/N/ST5/02221.

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