Studying the Crystallization of Various Polymorphic Forms of

Subscriber access provided by CORNELL UNIVERSITY LIBRARY

Article

Studying the crystallization of various polymorphic forms of nifedipine from binary mixtures with the use of different experimental techniques O. Madejczyk, E. Kaminska, M. Tarnacka, M. Dulski, K. Jurkiewicz, K. Kaminski, and M. Paluch Mol. Pharmaceutics, Just Accepted Manuscript • Publication Date (Web): 10 May 2017 Downloaded from http://pubs.acs.org on May 15, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Molecular Pharmaceutics is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Molecular Pharmaceutics

Studying the crystallization of various polymorphic forms of nifedipine from binary mixtures with the use of different experimental techniques

O. Madejczyk1,2*, E. Kaminska3*, M. Tarnacka1,2, M. Dulski2,4, K. Jurkiewicz,1,2 K. Kaminski1,2, M. Paluch1,2 1

Institute of Physics, University of Silesia, Uniwersytecka 4, 40-007 Katowice, Poland Silesian Center for Education and Interdisciplinary Research, University of Silesia, 75 Pulku Piechoty 1A, 41-500 Chorzow, Poland 3 Department of Pharmacognosy and Phytochemistry, Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Jagiellonska 4, 41-200 Sosnowiec, Poland 4 Institute of Material Science, University of Silesia, 75 Pulku Piechoty 1a, 41-500 Chorzow, Poland 2

ABSTRACT In this paper the crystal growth of nifedipine from pure system and from binary mixtures composed of active substance (API) and two acetylated disaccharides: maltose and sucrose (NIF-acMAL, NIF-acSUC, 5:1 weight ratio) was investigated. Optical snapshots supported by X-Ray diffraction (XRD) and Fourier Transform Infrared Spectroscopy (FTIR) measurements showed that mainly β and α forms of nifedipine grow up in all investigated samples. They also revealed that the morphology of growing crystals strongly depends on the presence of modified carbohydrates and temperature conditions. Interestingly, it was found that the activation barrier for the crystal growth of β polymorph is not affected by acetylated saccharides while the one estimated for α form changes significantly from 48.5 kJ/mol (pure API) up to 122 kJ/mol (NIF-acMAL system). Moreover, the relationship between the crystal growth rate and structural relaxation times for pure NIF and solid dispersions were analyzed. It turned out that there is a clear decoupling between the crystal growth rate and structural dynamics in both NIF-acMAL and NIF-acSUC binary mixtures. This is in line with recent

1 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 28

reports indicating decoupling phenomenon to be an universal feature of the soft matter in the close vicinity of the glass transition temperature. KEY WORDS: nifedipine, acetylated disaccharides, crystal growth, molecular dynamics, viscosity INTRODUCTION When a liquid is cooled from high temperatures, two different scenarios are possible. It is generally considered that if the slow cooling rate is applied crystallization takes place. On the other hand, by cooling a liquid with sufficiently high cooling rate a glassy state can be reached. Crystallization and glass transition are two competitive phenomena. There are numerous studies devoted to these processes [1,2,3]. Their goal is to answer the question, why some liquids exhibit greater glass-formation abilities, while others crystallize very quickly and cannot be supercooled below Tg. It is commonly believed that understanding the factors responsible for the crystallization will allow for deeper insight into the glass transition and vice versa. Interestingly, the crystallization is a very important process not only from the scientific, but also from the technological point of view. Knowing its nature enables engineers to produce materials with strictly defined geometry and properties (i.e. thermal conductivity, resistivity, polarizability, etc.). Crystallization consists of two steps: nucleation and crystal growth, both having their own specific characteristics [4]. First of them starts with the formation of a crystalline aggregate of molecules through structural fluctuation of the liquid, while the second one proceeds when each molecule on the surface of the crystal front changes its orientation to fit to the molecular arrangement of the crystal. An essential physics of both stages of crystallization can be understood in the framework of Classical Nucleation Theory (CNT) [5,6,7]. According to CNT, nucleation is favored at lower temperatures, while the crystal


Page 3 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


growth at higher T. That is why the temperature window, where the crystallization is observed, is very narrow. It is worth mentioning that crystallization is especially important phenomenon in case of amorphous active pharmaceutical ingredients (APIs). This is related to the fact that many of them reveal strong tendency to revert to more stable crystalline state. Classical examples of such compounds are nifedipine (a poorly water soluble calcium channel blocker, widely used to treat hypertension and ischemic heart disease caused by contraction of blood vessels [8]) and indomethacin (very popular, nonsteroidal anti-inflammatory drug, commonly used to reduce fever, pain, stiffness, and swelling [9]). It should be noted that there are many papers devoted to studies of crystallization in various pharmaceuticals as well as in binary systems composed

of

API

and

polymeric

or

saccharide

excipients

[10,11,12,13,14,15].

Macromolecules (especially polymers) as well as low molecular compounds (acetylated carbohydrates) are regarded as very effective inhibitors of crystallization. These compounds can i) slow down molecular dynamics in the supercooled liquid and glassy states of APIs, ii) interact with pharmaceuticals, iii) raise the activation energy of API crystallization, iv) affect the activation barrier for crystal growth, etc. Furthermore, as shown in paper by Toxvaerd et al. [16] the greater physical stability of binary mixture may be associated with the difference between melting temperature (Tm) of pure compound and Tm of the same substance in binary mixture. The higher it is, the more negative mixing Gibbs free energy and greater protection against crystallization is achieved. Nifedipine (NIF) is a model API to study crystallization process. It is worth adding that it forms three various polymorphic forms (α, β, γ) [17]. As shown in recent papers, different additives (mainly polymers or modified saccharides) can successfully stabilize amorphous nifedipine against crystallization [10,11,12,18,19,20,21]. For example, Kothari et al. [18] have investigated solid dispersions composed of API and three different



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 28

macromolecules. They noticed that enhanced physical stability in case of NIFpolyvinylpyrrolidone (PVP) and NIF-hydroxypropylmethyl cellulose acetate succinate (HMPCAS) solid dispersions (10% w/w polymer) is caused by the greater extent of drugpolymer interactions, leading to the observed reduction in mobility. Interestingly, Powell et al. [19] have shown that even small amounts of polymer excipient (1% w/w) can inhibit the crystal growth of NIF in binary systems with PVP, HPMCAS, as well as poly(vinylacetate) (PVAc), polyvinylpyrrolidone/vinyl acetate (PVP/VC), polystyrene (PS) and poly(ethylene oxide) (PEO). They suggested that the observed behavior is related to the polymer segmental mobility, not to the strength of intermolecular interactions (H-bonds). In turn Cai et. al. [20] have noticed that PVP (various grades) influences bulk and surface crystal growth differently. For every weight percent of polymer added, surface crystal growth slows by two times at 12 K below the Tg, whereas bulk crystal growth slows by ten times. It was also found that PVP’s ability to inhibit crystal growth greatly diminishes upon lowering its molecular weight to that of a dimer, indicating that the effectiveness of crystal growth inhibitors depends on their molecular sizes. Very interesting results were also presented in paper by Caron et al. [21]. Authors suggested that the crucial effect of PVP in delaying crystallization is associated to the surface interactions between polymer and drug nuclei and/or small crystal such that nucleation and crystal growth are impeded. Finally, it is worth mentioning our recent paper [14] where molecular dynamics of pure nifedipine and its solid dispersions with low molecular excipients (modified carbohydrates) as well as crystallization kinetics of API were studied in detail. We have shown that acetylated saccharides (acGLU, acGAL, acMAL and acSUC), just like polymers affect crystallization of NIF in a significant way both above and below the glass transition temperature. Herein, we present the results of optical measurements showing the impact of acetylated maltose and acetylated sucrose on the rate and activation barrier for crystal growth


Page 5 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


of various polymorphic forms of nifedipine from binary mixtures. It is worth adding that we tested the relationship between structural relaxation times, which in the first approximation provide information about temperature dependence of viscosity, and the crystal growth rate. This is quite important point since in literature crystallization process is mainly investigated as a function of temperature. Finally, the strong decoupling between growth rate and structural relaxation times was found, which is in line with recent reports showing decoupling to be universal feature of supercooled systems [22,23,24].

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) and octaacetylsucrose (acSUC, C28H38O19, Mw=678.6 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 Scheme 1. Methods 1. Preparation of amorphous systems of nifedipine with acetylated disaccharides The amorphous solid dispersions (NIF−acMAL and NIF−acSUC, 5:1 weight ratio), 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 the homogeneous NIF−acetylated disaccharide solid dispersions, we first thoroughly mixed crystalline powders of both compounds in appropriate proportions in a heat-resistant glass vial. The weight of powder mixtures was about 0.5 g. Afterwards, we put a magnetic stir bar into the vial with the mixture. In the next step, the crystalline components were melted in the vial on the hot plate magnetic stirrer (CAT M 17.5) at T = 443.15 K. The 5 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 28

temperature inside the vial was controlled by using a Pt-100 sensor. After the crystalline mixtures (NIF−acMAL, NIF−acSUC) 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. 2. Differential Scanning Calorimetry (DSC) Calorimetric measurements of binary mixtures of nifedipine with acetylated disaccharides were carried out by a Mettler-Toledo DSC apparatus equipped with a liquid nitrogen cooling accessory and an HSS8 ceramic sensor (heat flux sensor with 120 thermocouples). Temperature and enthalpy calibrations were performed by using indium and zinc standards. Crucibles with prepared samples were sealed and scanned at a heating rate of 10 K/min over a temperature range from 200 K to well above the respective melting points (up to 440 K). Each measurement at the given heating rate was repeated three times. 3. Broadband Dielectric Spectroscopy (BDS) Isobaric measurements of the complex dielectric permittivity ε*(ω) = ε′(ω) − iε″(ω) were carried out using the Novocontrol Alpha dielectric spectrometer (Novocontrol Technologies GmbH & Co. KG, Hundsangen, Germany) over the frequency range from 10−2 to 106 Hz at ambient pressure. The temperature stability controlled by a Quatro Cryosystem using a nitrogen gas cryostat was better than 0.1 K. Dielectric measurements of NIP-acetylated disaccharide mixtures were performed in a parallel-plate cell (diameter 20 mm, gap 0.1 mm) immediately after preparation of the amorphous samples. 4. X-ray diffraction X-ray diffraction measurements of time-dependent crystallization of pure NIF as well as mixtures of NIF with acSUC and acMAL (5:1 weight ratio) were performed at 353 K and 393 K using a Rigaku Denki 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 6 ACS Paragon Plus Environment

Page 7 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


monochromator, and an image plate in the Debye−Scherrer geometry. During monitoring of the crystallization process the temperature was controlled using an Oxford Cryostream Plus and Compact Cooler with a resolution of 0.1 K. The samples were measured in glass capillaries (1.5 mm in diameter). Measurements were run with sample-filled and empty capillaries, and the intensity of the empty capillary was then subtracted. The collimated X-ray beam width at the sample was 0.3 mm. Obtained two-dimensional diffraction patterns were converted into the one-dimensional intensity data versus the scattering angle 2Thetausing the software provided by Rigaku Corporation. 5. Optical microscopy Optical images on the crystal growth were carried out using Olympus BX51 polarized microscope, equipped with an Olympus SC30 camera and a halogen source light. The measurement’s procedure was applied as for dielectric measurements. Optical figures were collected using Olympus Soft Imaging Solutions GmbH 5.1 (analysis getIT software) at UMPlanFI 10x objective and at 0.3 NA. The quality of collected figures were corrected using Adobe Photoshop 12 software. 6. Infrared spectroscopy Infrared measurements were performed using an Agilent Cary 640 FTIR spectrometer (Agilent Technologies, CA, USA) equipped with a standard source and a DTGS Peltiercooled detector. The spectra of pure amorphous NIF as well as NIF-acSUC and NIF-acMAL binary mixtures after their crystallization at 353 K and 393 K have been collected using GladiATR diamond accessory (Pike Technologies, Madison, WI, USA) in the 4000 - 400 cm1

range. All spectra were accumulated with a spectral resolution of 4 cm-1 and recorded by

accumulating of 16 scans. The water vapor and carbon dioxide as well as baseline correction were subtracted from each spectrum and peak fitting was done using GRAMS Software package. 7 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 28

RESULTS AND DISCUSSION In our recent paper [14], the kinetics of crystallization of nifedipine from solid dispersions formed with acetylated mono- and disaccharides has been investigated with the use of Broadband Dielectric Spectroscopy (BDS) above and below the glass transition temperature. We found that there is quite significant difference in activation energies for crystallization of active substance from binary mixtures composed of nifedipine and acetylated maltose (acMAL) and sucrose (acSUC) with respect to the ones composed of API and modified: glucose (acGLU) and galactose (acGAL). As shown, it is due to i) different diffusion of NIF in the saccharide matrices as well as ii) strength and character of intermolecular interactions between API and modified carbohydrates, which vary dependently on the excipient. Herein, it should be stressed that broadband dielectric spectroscopy is very useful to monitor the overall kinetics of various chemical and physical processes occurring in highly viscous system, However, it is not sufficient to study crystallization process in certain compounds (e. g. Roy, nifedipine), which form different polymorphic forms. In these cases, BDS (or DSC) investigations must be supported by other techniques, such as diffraction or optical (microscopic) ones. In fact, the combination of results coming from the optical as well as molecular dynamics studies seems to be the most valuable. It is due to close relationship between the crystal growth rate and kinetic factor that can be approximated by the reorientational dynamics. Herein, we start our investigation from molecular dynamics studies. In Fig. 1 (panels (a), (b) and (c)) representative loss spectra measured above the glass transition temperature for pure nifedipine and solid dispersions with acetylated disaccharides (NIF-acSUC and NIF-


Page 9 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


acMAL, 5:1 weight ratio) are presented. In each case, a single dominant structural relaxation process moving towards lower frequencies with lowering temperature is observed. This shift is directly related to the increasing viscosity upon approaching the glass transition temperature (Tg). It is worth adding that the presence of a single α-relaxation peak in dielectric spectra is an important hint indicating the homogeneity of measured samples (solid dispersions). This crucial point has been discussed and addressed in detail in our previous paper [14]. Having loss spectra measured in wide range of temperatures above the Tg, we analyzed them with the use of Havriliak Negami function [25] to get insight into temperature evolution of the structural relaxation times:

ε (ω )" =

2  ∆ε i σ dc + Im ∑  ε ∞ + ε 0ω [1 + (iωτ HNi )α ]β i =1  HNi

HNi

 , 

(1)

where ε∞ is the high-frequency limit permittivity, ∆ε is the relaxation strength, τHN is the HN relaxation time, αHN and βHN are shape parameters characterizing the breadth and asymmetry of relaxation peaks and ω is an angular frequency (ω =2πf). Next, obtained α-relaxation times were plotted versus inverse temperature in panel (d) of Fig. 1. Then, they were fitted to commonly used Vogel-Fulcher-Tammann (VFT) equation (red solid lines):  D T0   ,  T − T0 

τ = τ 0 exp

(2)

where D, T0 and τ0 are constants (D is the strength parameter, T0 represents the temperature at which the structural relaxation times tend to infinity and τ0 is the time scale of vibrational motions). In addition, the glass transition temperature for each sample was determined using arbitrary definition of Tg as the temperature at which τα = 100 s. We obtained Tg = 314.5 K (pure NIF), 316.5 K (NIF-acMAL, 5:1 w/w) and 310.5 K (NIF-acSUC, 5:1 w/w).



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 28

The main aim of determination of temperature dependence of structural relaxation times was to approximate the temperature evolution of viscosity in the investigated systems. This is quite important aspect since in the basic equations of the Classical Nucleation Theory (CNT) [5,6,7] describing the nucleation as well as crystal growth rate, the viscosity is explicitly mentioned. On the other hand, using Maxwell approach the viscosity, η, can be calculated from the following equation :

τ α = Cη / G ,

(3)

where G - the high frequency shear modulus is generally equal to 2 GPa for organic liquids [22]. It is worth stressing that equation 3 predicts linear dependence of η (τα), while recent studies demonstrate decoupling between both quantities in the supercooled region [22,23,24]. Herein, we assumed the coupling between both quantities. In the next step, we carried out thorough measurements with the use of optical microscope on the crystal growth of active substance from pure amorphous system (NIF) as well as solid dispersions (NIF-acMAL and NIF-acSUC, 5:1 weight ratio) in the temperature range from 343 K to 393 K. Representative snapshots were presented in Fig. 2. It should be mentioned that the crystal growth as well as morphology of the growing crystals closely depend on temperature and the type of saccharide excipient. In general, there are two stages of crystallization separated in time, where various forms of NIF crystals grow from pure API and from solid dispersions (Fig. 2). One can add that the morphology of the growing crystals in the first stage changes as temperature increases above T = 373 K. Just to mention that at lower temperatures (< 373 K), the growth of needle-like crystals in so-called acicular habit is favored, while at higher temperatures (> 373 K) crystallization of spherical, radial aggregates radiating from a "star" like point in so-called stellate habit is promoted. The snapshot images collected for the second stage of crystallization illustrate the growth of tabular-like crystals of the same habits. Interestingly, in pure supercooled API system and NIF-acSUC solid 10 ACS Paragon Plus Environment

Page 11 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


dispersion, crystals of similar morphology are observed, while in NIF-acMAL binary mixture thin lath-like crystals with one blade are growing (see Fig. 2). One can add that recently similar change in morphology of the growing crystals due to presence of acetylated saccharides has been reported for naproxen [26]. The variety of morphology of crystals growing from pure API system and solid dispersion makes it difficult to assign them properly to given polymorphic form basing on the optical microscope data. Therefore, a detailed studies with the use of X ray diffraction as well as FTIR spectroscopy were carried out. The diffraction patterns obtained during the time-dependent crystallization of pure NIF, as well as NIF-acMAL and NIF-acSUC binary mixtures at 353 K are presented in Fig. 3. The shapes and positions of the diffraction peaks at the early and late stages of crystallization suggest the occurrence of more than one component in all studied systems. Thus, in order to verify the possible polymorphism of API in the samples the diffraction patterns of the α and β polymorphic forms of NIF taken from literature [27,28] were included in Fig. 3 (red and blue lines). The comparison of the experimental diffraction data of pure NIF with the theoretical diffractograms suggests crystallization of α and β forms of API from the pure supercooled nifedipine. What is more, one can estimate the ratio of both polymorphs depending on the crystallization stage. In the initial one, the β form is predominant and as the process is progressing the β polymorph is transformed into the α one. Similar observations were reported through crystallization of API from NIF-acMAL and NIF-acSUC binary mixtures. However in contrast to pure nifedipine system, the presence of diffraction peaks coming from β form of NIF can be discerned only at very early stage of the process. The presence of α polymorph is overwhelming at all steps of crystallization in both investigated solid dispersions. One can also add that we carried out structural studies at higher temperature (T = 393 K)- data not shown. It was found that there is only a residue of β form at very early stage



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 28

of recrystallization. The higher crystal growth rate at 393 K compared to 353 K and the presence of saccharides affecting the number of nuclei of β form are responsible for such situation. Complementary results were also derived from infrared data. As suggested in literature, the full width, half maximum (FWHM) and relative intensities of characteristic bands can be an indicator of various forms of nifedipine (infrared spectra obtained at 353 Kleft panel of Fig. 4). The presence of polymorphic forms (α, β or γ) of API can be confirmed by the analysis of the 3650 - 2850 cm-1 (1) and 1710 – 1650 cm-1 (2) ranges that are linked to the amine ν(NH) and H-bond as well as ester ν(C=O) stretching vibration, respectively. It is worth adding that the position of amine band observed in the region (1) is determined by intermolecular hydrogen bonding interactions between ester carbonyl and the NH group of the adjacent nifedipine molecule [29]. Infrared spectra of pure NIF as well as NIF-acSUC binary mixture collected upon crystallization at T=353 K show only slight modification of the intensity of amine band at about 3329 cm-1. On the other hand, in NIF-acMAL solid dispersion the amine band is split into two visible maxima at 3357 and 3318 cm-1 indicating that there are two distinct arrangements of nifedipine molecules [30]. At the same time in both binary mixtures one can observe additional bands (green lines) related to the formation of Hbonds between acetylated saccharide and API molecule. Interestingly, the position of these bands in case of NIF-acSUC mixture is slightly (~10 cm-1) shifted towards lower wavenumbers relative to NIF-acMAL system. This indicates the greater probability of the formation of stronger H-bonds in the mixture with modified sucrose. In this place, it should be mentioned that intermolecular H-bonding scheme observed in solid dispersions is reflected by i) the red shift of amine band as well as ii) the interactions between amine group and carbonyl moieties (see Fig. 4). For pure nifedipine, the range (2) is affected by the vibrations of carbonyl groups, which due to resonance effects with the C=C bonds of the dihydropyridine


Page 13 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ring are arranged nearly coplanar and shifted towards lower wavenumbers [30]. Basing on the analysis of C=O ester band intensities, one can suppose that pure NIF has a tendency to crystallize into a combination of β (band at 1688 cm-1) and α (band at 1678 cm-1) forms with dominant contribution of more thermodynamically stable α polymorph. In binary systems, crystallization leads to the formation of both α form as well as other less energetically stable β or possibly γ polymorphs. In NIF-acSUC solid dispersion, characteristic band of α polymorph (1678 cm-1) is observed. Interestingly, the broadening of carbonyl vibration and increase in the intensity of band at 1688 cm-1 indicate probable appearance of γ-NIF form. Although, it is worth adding that this effect can be due to some conformation of non-crystallized API that reminds arrangements of molecules in γ-form. This explanation becomes more reliable when we take into account that this polymorphic form of API was not observed neither in X-ray diffraction measurements nor in calorimetric ones (data not shown). On the other hand, in NIF-acMAL solid dispersion the intensity, position and FWHM of carbonyl band suggest the presence of β and α polymorphs of NIF (Fig. 4). The interesting situation was found during crystallization observed at higher temperature (T = 393 K) - see right panel of Fig. 4. Here, due to great similarity of infrared spectra (nearly identical band positions, FWHM and intensities) of pure NIF as well as binary mixtures one can state that the formation of the dominant α form of API is preferred. Other polymorphs are in minority and might be hidden in the background. Therefore, X-ray diffraction measurements supported by the infrared data [30,31,32] allowed to conclude that there are two polymorphic forms of API, which crystallize from amorphous binary mixtures. Moreover, according to previously reported data, we could assign various crystals observed under microscope to different polymorphs of nifedipine. As a result, the growth of β form of NIF might be assigned to the acicular or stellate crystal in habit while the growth of α polymorph to the tabular one.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 28

Taking advantage of the data measured under microscope, we were also able to show how the number of nuclei of given polymorphic form changes with temperature for all investigated herein samples. As shown in Fig. 5, in each case the number of nuclei drops as temperature increases. It is in line with the theory saying that nucleation process is much more favored at low temperatures due to higher thermodynamic driving force for nucleation. Although, one has to note that the presence of acetylated saccharides decreases the number of nuclei of β form in rather significant way with respect to the α one. We think that interactions between API and excipients contribute to this effect. Interestingly, such observation stays in agreement with the X-ray diffraction results discussed above. To determine the rates of crystal growth (µr) of nifedipine from binary mixtures recorded snapshots were analyzed with respect to the length of growing crystals of both polymorphic forms of API. Furthermore, in Fig. 6 the lengths of crystal forms, L, were plotted as a function of time. It should be added that optical measurements for pure API, NIF-acMAL and NIF-acSUC solid dispersions were performed in the temperature range from 343 K to 393 K and they were repeated three times. Fig. 6 presents only representative kinetic curves obtained at several indicated temperatures. Interestingly, in each case the dependence L(t) could be described using linear function with the slope identified as µr [33]. The determined values of log10µr are presented versus inverse temperature in panels (a) and (b) of Fig. 7. As can be seen, there is quite a significant difference in crystal growth rate of α and β form of NIF from pure API system and from NIF-acMAL solid dispersion. It appears that at given temperature acetylated maltose slows down the crystal growth of both polymorphic forms in the most significant way. Subsequently, Arrhenius equation was used to determine the activation barrier for crystal growth of both polymorphic forms of API from each investigated sample:  Ecg  .  k BT 

µ r = µ 0 exp

(4) 14 ACS Paragon Plus Environment

Page 15 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


where µ0 is the pre-exponential factor and Ecg is an activation energy. As expected, we found that Ecg(β) for the growth of β-form of nifedipine is similar for all studied systems (111-126.5 kJ/mol). On the other hand, Ecg(α) for the growth of α-NIF polymorph is the highest in binary mixtures with modified maltose (122 kJ/mol). Although, it should be added that estimated activation barriers can be slightly biased since the Arrhenius model fitting makes a fundamental assumption that the crystal growth is isotropic. For non-isotropic morphologies of the growing crystals (present case) Arrhenius equation may yield underestimated barrier for the crystal growth. As a final point of our investigations, we decided to plot the crystal growth rates of both forms of nifedipine versus structural relaxation times (see panels (c) and (d) of Fig. 7). Such representation of the data enabled us to elucidate the relationship between the kinetic factor responsible for crystallization, related to the reorientational dynamics (τα) and the crystal growth rate of specific polymorphs of API. As shown, for given structural relaxation time the pace of crystal growth of α and β forms of API is the slowest in binary mixtures with acetylated maltose. Interestingly, nearly the same behavior as presented in all panels of Fig. 7 took place in case of solid dispersion composed of this carbohydrate (acMAL) and naproxen [26]. This is quite interesting observation taking into account the chemical structures of excipients which are almost the same. Moreover, one can suppose that modified maltose and sucrose are characterized by the same kind, pretty weak van der Waals interactions. However, recently [26] we have estimated dipole moments (µ) of both acetylated saccharides using Avogadro software, which is an advanced molecule editor and visualizer designed for crossplatform use in i.e. computational chemistry, molecular modeling, bioinformatics and materials science [34] licensed under the GNU GPLv2: GNU General Public License v2.0 2012 [35]) (calculations were performed in a gas phase for single molecules). It turned out that the value of µ of the former carbohydrate is higher (µ=5.60 D) with respect to the latter



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 28

one (µ=4.17 D). Hence, one can expect stronger dipole-dipole interactions between modified maltose and nifedipine (µ=2.4 D). We think that this hint can be used to explain increasing rate of crystal growth of both polymorphic forms of API. This scenario seems to be even more reliable when we take into account recent paper by Koperwas et al. [36] where it was presented that enhanced dipole–dipole interactions warrant better stability of the supercooled liquid. In this context, it is also worth to mention the paper by Mehta et al. [37] who studied the crystallization of nifedipine dispersed in various polymers. They also found that strong drug-polymer intermolecular interactions reduce the mobility and enhance physical stability of solid dispersions. In addition, log10µr versus log10τα dependences were fitted to the linear function to check whether there is some correlation between both variables. We found a significant decoupling (s oscillating around 0.60) for the growth of β-form of API. Interestingly, the degree of decoupling between crystal growth rates and structural relaxation times is almost the same and seems not to be affected by the presence of acetylated saccharide. Completely different situation is observed when we analyze log10µr vs log10τα dependence for the growth of α-polymorph of nifedipine. In this case, the decoupling parameter varies significantly from 0.68 to 0.22 dependently on the sample. This experimental finding can be explained taking into account that α-form grows on the surface of β-polymorph. In such conditions, the viscosity of the system does not correspond to the initial one. Moreover, investigated system becomes more heterogeneous since some fraction of nifedipine molecules have already crystallized. Therefore, the relationship between the rate of crystal growth and structural relaxation times must be significantly affected. Based on above, one can recall recent studies by some of us [26] as well as Ediger et al. [22] or Mehta et al. [38] who have shown that there is a clear decoupling between the crystal growth rate and structural relaxation times. Although, one can note that Mehta et al. studied


Page 17 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the relationship between the time of overall crystallization and characteristic structural and secondary relaxation times. Interestingly, they found decupling (s=0.8) in the supercooled state. That means that although there is a link between molecular mobility and crystal growth there are also other factors, such as thermodynamic driving force for the crystal growth, heterogeneous nature of the liquids around the glass transition temperature, interactions between sample and interface that affect crystallization process. In this context, one can mention that in the supercooled state generally the decoupling between various physical quantities i.e. structural relaxation times, viscosity, dc conductivity, diffusion, rates of chemical reaction, crystal growth is rather an universal feature [39].

CONCLUSIONS In this paper, the crystal growth of NIF from pure system and from solid dispersions with acetylated maltose and acetylated sucrose have been investigated. It was found that irrespective on the composition of the system two polymorphic forms of API, namely α and β, grow up. Although, the morphology of the growing crystals seems to be significantly modified by the presence of acetylated carbohydrates. Interestingly, the morphology of growing crystals also depends on the crystallization temperature. Additionally, the relationship between the rate of crystal growth and structural relaxation times was tested for all samples. It was shown that for given τα the growth of crystals is the fastest in pure API. On the other hand, the most significant slowing down of this process for both polymorphs of nifedipine is noted for binary mixtures composed of API and modified maltose. Most likely it is due to stronger dipole-dipole interactions in the system. Moreover, we demonstrated that there is a strong decoupling between the rate of crystal growth and structural relaxation times irrespective of the sample. Interestingly, it is another finding showing that decoupling



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 28

between various physical quantities seems to be quite universal feature of the glass formers around the glass transition temperature. Corresponding Authors: *(OM) [email protected] * (EK) [email protected] ACKNOWLEDGEMENT E.K. acknowledges support from Polish National Science Centre (decision no DEC2016/22/E/NZ7/00266). K.K and O.M are thankful for a financial assistance from Polish National

Science

Centre

within

OPUS

9

project

based

on

decision

DEC-

2015/17/B/ST3/01195. We are also want to thankful D. Przybylak for a great help through making the optical measurements.

FIGURES

(a)

(b)

(c)

Scheme 1. Chemical structures of nifedipine (a), acetylated maltose (acMAL) (b) and acetylated sucrose (acSUC) (c).


Page 19 of 28

a)

pure NIF

100

α-process 10

T=347 K T=319 K ∆T=4 K

c)

NIF-acMAL 5:1

100

T=343 K T=319 K ∆T=4K

α-process

ε"

ε"

10

1

1

0.1 0.1 0.01

10-1

100

101

102

103

104

105

106

10

-1

10

0

10

b)

NIF-acSUC 5:1 100

T=351 K T=311 K ∆T=4 K

α-process

10

2

10

3

10

d)

1

4

10

5

10

6

Relaxation map

0

Tg=314,5K

-1

log10τmax[s]

10

1

Frequency [Hz]

Frequency [Hz]

ε"

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


-2

1

Tg=310,5K

-3 -4

0.1

T>Tg 100

101

pure NIF NIF-acMAL 5:1 NIF-acSUC 5:1 VFT fit

-5

0.01

10-1

Tg=316,5K

102

103

Frequency [Hz]

104

105

106

-6

0.0027

0.0028

0.0029

0.0030

0.0031

0.0032

1/T [1/K]

Fig. 1. Dielectric loss spectra measured for pure NIF (panel (a)), NIF-acSUC (panel (b)) and NIF-acMAL (panel (c)) solid dispersions (5:1 weight ratio) above the glass transition temperature. Panel (d) presents structural relaxation times plotted versus inverse temperature for pure nifedipine and both studied binary systems. Solid lines are fits to α-relaxation using the VFT equation (Eq. 2).



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 28

Fig. 2. Time-dependent optical images of crystallization of nifedipine from pure API system (panels (a) and (d)) and binary mixture of API with acetylated disaccharides: acSUC (panels (b) and (e)) and acMAL (panels (c) and (f)) at 353 K and 393 K, respectively. The images were collected at 5x magnification.


Page 21 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Fig. 3. X-ray diffraction patterns showing thermal evolution of pure nifedipine glass (panel (a)) as well as amorphous binary systems of nifedipine with acetylated maltose (panel (b)) and acetylated sucrose (panel (c)) at 353 K.



number of nucleus / 1000µm

2

Fig. 4. Infrared spectra in the 3800 – 2700 cm-1 and 1850 – 1550 cm-1 ranges obtained after crystallization of nifedipine from pure API system and from solid dispersions at T= 353 K and T=393 K. The bands of H-bond pattern (green), ν(NH) (dark blue) and ν(C=O) (orange) stretching vibrations within the NIF molecule as well as ν(C=O) stretching modes (violet) originate from acetylated saccharides (light blue) were illustrated.

NIF NIF-acMAL 5:1 NIF-acSUC 5:1

20 15

β form

10 5 0 340

350

360

370

380

390

400

2

T [K] number of nucleus /1000µm

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 28

NIF NIF-acMAL 5:1 NIF-acSUC 5:1

25 20 15 10 5

α form

0 340

350

360

370

380

390

400

T [K]

Fig. 5. Number of β and α nucleus of nifedipine observed during crystallization from pure API system and from binary mixtures at indicated temperatures.


Length, L [µm]

1200 1000

T = 343 K T = 353 K T = 363 K T = 373 K T = 383 K T = 393 K linear fit

β form

800 600 400 200 0

1400 1200 1000 800 600 400 200 0

2000 4000 Time [s]

β form

0

3000

6000

9000

Time [s] 1400 1200

pure NIF 350 300 250 200 150 100 50 0

α form

0

6000

NIF - acSUC 400 α 350 300 250 200 150 100 50 0 0 12000

2000

4000 Time [s]

6000

8000

form

Length, L [µm]

Length, L [µm]

0

Length, L [µm]

20000

β form

500

40000

60000

Time [s]

NIF - acMAL

α form

400

1000 Length, L[µm]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Length, L [µm]

Page 23 of 28

800 600 400 200

300 200 100 0

0 0

7000

14000

21000

28000

0

40000 80000 120000 160000

Time [s]

Time [s]

Fig. 6. The kinetics of crystal growth of β and α forms of nifedipine from pure API system and binary mixtures with acetylated saccharides at selected temperatures from 343 K to 393 K.



β form NIF NIF-acSUC 5:1 NIF-acMAL 5:1 Arrhenius fit

0.0 -0.5 -1.0 -1.5

Ecg,β = (120.0 ± 5.1) kJ/mol

-2.0

E cg,β = (111.0 ± 2.2) kJ/mol Ecg,β = (126.5 ± 5.0) kJ/mol

-2.5 0.0025

1.5

NIF NIF-acSUC 5:1 NIF-acMAL 5:1 Arrhenius fit

(b) -0.5

-1

0.5

α form

0.0

0.0026

0.0027

0.0028

-1.0 -1.5 -2.0 -2.5 E = (48.5 ± 2.4) kJ/mol cg.β -3.0 E cg,β = (62.5 ± 2.3) kJ/mol Ecg,β = (122.0 ± 3.2) kJ/mol -3.5 0.0025 0.0026 0.0027

0.0029

1/T [1/K]

β form

NIF NIF-acSUC 5:1 NIF-acMAL 5:1 linear fit

(c) 1.0 -1

0.5 0.0 -0.5 -1.0

s=0.56

0.5

α form

0.0029


(d) -0.5 -1.0 -1.5

s=0.22

-2.0

-1.5

s=0.54

-2.5

-2.0

s=0.62

-3.0

-2.5

0.0028

1/T [1/K]

0.0 -1

-1

log10(µr [m/s ])

1.0

0.5

log10(µr[m/s ])

(a)

log10(µr[m/s ])

1.5

log10(µr [m/s ])

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 28

s=0.32

s=0.68

-3.5 -8

-7

-6

-5

-4

-3

-8

-7

-6

-5

-4

-3

log10(τα[s])

log10(τα[s])

Fig. 7. Activation energy plots for crystallization of nifedipine from pure amorphous system (NIF) and binary mixtures composed of API and acetylated disaccharides (panels (a) and (b)) The correlation between optical data (log10(µr)) and structural relaxation times (log10(τα)). (panels (c) and (d)).


Page 25 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


REFERENCES (1) Hancock, B. C.; Zografi, G. Characteristics and significance of the amorphous state in pharmaceutical systems. J. Pharm. Sci. 1997, 86, 1–12. (2) Kaminski, K.; Adrjanowicz, K.; Wojnarowska, Z.; Dulski, M.; Wrzalik, R.; Paluch, M.; Kaminska, E.; Kasprzycka, A. Do Intermolecular Interactions Control Crystallization Abilities of Glass-Forming Liquids? Phys. Chem. B. 2011, 115, 11537-11547. (3) Gutzow, I.; Schmelzer, J. W. P.; Petroff, B. The phenomenology of metastable liquids and the glass transition. J. Eng. Thermophys. 2007, 16, 205-223. (4) Uhlmann, D. R. in Materials Science Research Plenum, New York, 1969, vol. 4, p. 172, (5) Debenedetti, P. G. Metastable Liquids Concepts and Principles. Princeton Univ Press. 1996, p. 146–199. (6) Onuki, A. Cambridge Univ Press, Phase Transition Dynamics. 2002, p. 488–551. (7) Turnbull, D. Under what conditions can a glass be formed? Contemp. Phys. 1969, 10, 73– 488. (8) www.drugs.com (9) Sweetman, S. C. Martindale: The Complete Drug Reference. Pharmaceutical Press, London. 2005. P. 47. (10) Ueda, K.; Higashi, K.; Yamamoto, K.; Moribe, K. The effect of HPMCAS functional groups on drug crystallization from the supersaturated state and dissolution improvement. Int. J. Pharm. 2014, 464, 205-213. (11) Sun, Y.; Zhu, L.; Wu, T.; Cai, T.; Gunn, E. M.; Yu, L. Stability of Amorphous Pharmaceutical Solids. Crystal Growth Mechanisms and Effect of Polymer Additives. The AAPS J. 2012, 14, 380-388. (12) Marsac, P. J.; Konno, H.; Taylor, L. S. A Comparison of the Physical Stability of Amorphous Felodipine and Nifedipine Systems. Pharm. Res. 2006, 23, 2306-2316. (13) Kaminska, E.; Adrjanowicz, K.; Tarnacka, M.; Kolodziejczyk, K.; Dulski, M.; Mapesa, E.U.; Zakowiecki, D.; Hawelek, L.; Kaczmarczyk-Sedlak, I.; Kaminski, K. The impact of inter and intramolecular interactions on physicalstability of Indomethacin dispersed in acetylated saccharides. Mol. Pharm. 2014, 11, 2935-2947. (14) Kaminska, E.; Tarnacka, M.; Wlodarczyk, P.; Jurkiewicz, K.; Kolodziejczyk, K.; Dulski, M.; Haznar-Garbacz, D.; Hawelek, L.; Kaminski, K.; Wlodarczyk, A.; Paluch, M. Studying the impact of modified saccharides on the molecular dynamics and crystallization tendencies of model API nifedipine. Mol. Pharm. 2015, 12, 3007-3019. (15) Zhu, S.J.; Toth, S.J.; Simpson, G.J.; Hsu, H-Y.; Taylor, L.S.; Harris, M.T. Crystallization and Dissolution Behavior of Naproxen/Polyethylene Glycol Solid Dispersions. J. Phys. Chem. B. 2013, 117, 1494−1500. (16) Toxvaerd, S.; Pedersen, U. R.; Schrøder, T. B.; Dyre, J. C. Stability of supercooled binary liquid mixtures. J. Chem. Phys. 2009, 130, 224501. (17) Eckert, T.; Muller, J. Überpolymorphe Modifikationen des Nifedipine aus unter kühlten Schmelzen. Arch. Pharm. 1977, 310, 116− 118.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 28

(18) Kothari, K.; Ragoonanan, V.; Suryanarayanan, R. The Role of Drug−Polymer Hydrogen Bonding Interactions on the Molecular Mobility and Physical Stability of Nifedipine Solid Dispersions. Mol. Pharm. 2015, 12, 162−70. (19) Powell, C. T.; Cai, T.; Hasebe, M.; Gunn, E. M.; Gao, P.; Zhang, G.; Gong, Y.; Yu, L. Low-Concentration Polymers Inhibit and Accelerate Crystal Growth in Organic Glasses in Correlation with Segmental Mobility. J. Phys. Chem. B. 2013, 117, 10334-10341. (20) Cai, T.; Zhu, L.; Yu, L. Crystallization of Organic Glasses: Effects of Polymer Additives on Bulk and Surface Crystal Growth in Amorphous Nifedipine. Pharm. Res. 2011, 28, 24582466. (21) Caron, V.; Bhugra, C.; Pikal, M. J. Prediction of Onset of Crystallization in Amorphous Pharmaceutical Systems: Phenobarbital, Nifedipine/PVP, and Phenobarbital/PVP. J. Pharm. Sci. 2010, 99, 3887−3900. (22) Ediger, M. D.; Harrowell, P.; Yu, L. Crystal growth kinetics exhibit a fragility-dependent decoupling from viscosity. J. Chem. Phys. 2008, 128, 034709. (23) Masuhr, A.; Waniuk, T. A.; Busch, R.; Johnson, W. L. Time Scales for Viscous Flow, Atomic Transport and Crystallization in the Liquid and Supercooled Liquid States of Zr41.2 Ti13.8 Cu12.5 Ni10.0 Be22.5. Phys. Rev. Lett. 1999, 82, 2290. (24) Swallen, S.F.; Bonvallet, P. A.; McMahon, R. J.; Ediger, M. D. Self-Diffusion of trisNaphthylbenzene near the Glass Transition Temperature. Phys. Rev. Lett. 2003, 90, 015901. (25) Havriliak, S.; Negami, S. A complex plane analysis of α-dispersions in some polymer systems. J. Polym. Sci. C. 1966, 14, 99−117. (26) Kaminska, E.; Madejczyk, O.; Tarnacka, M.; Jurkiewicz, K.; Kaminski, K.; Paluch, M. Studying of crystal growth and overall crystallization of naproxen from binary mixtures. Eur. J. Pharm. Biopharm. 2017, 113, 75-87. (27) Triggle, A. M.; Shefter, E.; Triggle, D. J. Crystal structures of calcium channel antagonists: 2, 6-dimethyl-3, 5-dicarbomethoxy-4-[2-nitro-, 3-cyano-, 4-(dimethylamino)-, and 2, 3, 4, 5, 6-pentafluorophenyl]-1, 4-dihydropyridine. J. Med. Chem. 1980, 23, 14421445. (28) Gunn, E.; Guzei, I. A.; Cai, T.; Yu, L. Polymorphism of nifedipine: crystal structure and reversible transition of the metastable β polymorph. Cryst. Growth Des. 2012, 12, 2037-2043. (29) Fossheim, R.; Svarteng, K.; Mostad, A.; Rømming, C.; Shefter, E.; Triggle, D. J. Crystal structures and pharmacological activity of calcium channel antagonists: 2,6-dimethyl-3,5dicarbomethoxy-4-(unsubstituted, 3-methyl-, 4-methyl-, 3-nitro-, 4-nitro-, and 2,4dinitrophenyl)-1,4-dihydropyridine. J. Med. Chem. 1982, 25, 126-131. (30) Chan, K. L. A.; Fleming, O. S.; Kazarian, S. G.; Vassou, D.; Chryssikos, G. D.; Gionis, V. Polymorphism and devitriﬁcation of nifedipine under controlled humidity: a combined FTRaman, IR and Raman microscopic investigation. J. Raman Spectrosc. 2004, 35, 353–359 (31) Burger, A.; Koller, K. T. Polymorphism and pseudopolymorphism on nifedipine. Sci. Pharm. 1996, 64, 293-301.


Page 27 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(32) Forster, A.; Hempenstall, J.; Rades, T. Investigation of drug/polymer interaction in glass solutions prepared by melt extrusion, Internet Journal of Vibrational Spectroscopy. www.ijvs.com. 2001, 5, 6. (33) Kaminski, K.; Adrjanowicz, K.; Wojnarowska, Z.; Dulski, M.; Wrzalik, R.; Paluch, M.; Kaminska, E.; Kasprzycka, A. Do Intermolecular Interactions Control Crystallization Abilities of Glass Forming Liquids. J. Phys. Chem. B. 2011, 115, 11537-11547. (34) Hanwell, M. D.; Curtis, D. E.; Lonie, D. C.; Vandermeersch, T.; Zurek, E.; Hutichison, G. R. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform, J. Cheminf. 2012, 4, 17. (35) http://www.gnu.org/licenses/gpl-2.0.html. (36) Koperwas, K.; Adrjanowicz, K.; Wojnarowska, Z.; Jedrzejowska, A.; Knapik, J.; Paluch, M. Sci. Rep. 2016; 6, 36934. (37) Mehta, M.; McKenna, G. B.; Suryanarayanan, R. Molecular Mobility in Glassy Dispersions J. Chem. Phys. 2016, 144, 204506. (38) Mehta, M.; Ragoonanan, V.; McKenna, G. B.; Suryanarayanan, R. Correlation between Molecular Mobility and Physical Stability in Pharmaceutical Glasses. Mol. Pharm. 2016, 13, 1267−1277. (39) Ngai, K. Relaxation and Diffusion in Complex Systems, New York, 2011.



Guidelines for Table of Contents/Abstract Graphics

Studying the crystallization of various polymorphic forms of nifedipine from binary mixtures with the use of different experimental techniques

O. Madejczyk, E. Kaminska, M. Tarnacka, M. Dulski, K. Jurkiewicz, K. Kaminski, M. Paluch 1.5


1.0

log10(r[m/s-1])

0.5 0.0

s=0.56

-0.5 -1.0

s=0.54 s=0.62

-1.5 -2.0

 form

-2.5 -8

-7

-6

-5

-4

-3

log10([s]) 0.5


0.0

log10(r[m/s-1])

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

-0.5 -1.0 -1.5

s=0.22

-2.0

s=0.32

-2.5 -3.0

 form

s=0.68

-3.5 -8

-7

-6

-5

-4

-3

log10([s])

ACS Paragon Plus Environment

Page 28 of 28

Studying the Crystallization of Various Polymorphic Forms of

Recommend Documents