Crystallization kinetics and molecular mobility of an amorphous active pharmaceutical ingredient: A case study with Biclotymol.

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IJP 14906 1–10 International Journal of Pharmaceutics xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

Crystallization kinetics and molecular mobility of an amorphous active pharmaceutical ingredient: A case study with Biclotymol

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Benjamin Schammé a,b , Nicolas Couvrat a , Pascal Malpeli c, Laurent Delbreilh b, ** , Valérie Dupray a, * , Éric Dargent b , Gérard Coquerel a a

Crystal Genesis Unit, EA 3233 SMS, Normandie Univ. France, Université de Rouen, 76821 Mont-Saint-Aignan Cedex, France AMME-LECAP, EA 4528 International Lab, Av. de l’Universite’, BP12, Normandie Univ. France, Universite’ and INSA Rouen, 76801 Saint-Étienne-du-Rouvray, France c Pharmasynthese (Inabata Group), Saint-Pierre-lès-Elbeuf 76320, France b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 9 April 2015 Received in revised form 11 May 2015 Accepted 12 May 2015 Available online xxx

The present case study focuses on the crystallization kinetics and molecular mobility of an amorphous mouth and throat drug namely Biclotymol, through differential scanning calorimetry (DSC), temperature resolved X-ray powder diffraction (TR-XRPD) and hot stage microscopy (HSM). Kinetics of crystallization above the glass transition through isothermal and non-isothermal cold crystallization were considered. Avrami model was used for isothermal crystallization process. Non-isothermal cold crystallization was investigated through Augis and Bennett model. Differences between crystallization processes have been ascribed to a site-saturated nucleation mechanism of the metastable form, confirmed by optical microscopy images. Regarding molecular mobility, a feature of molecular dynamics in glass-forming liquids as thermodynamic fragility index m was determined through calorimetric measurements. It turned out to be around m = 100, describing Biclotymol as a fragile glass-former for Angell’s classification. Relatively long-term stability of amorphous Biclotymol above Tg was analyzed indirectly by calorimetric monitoring to evaluate thermodynamic parameters and crystallization behavior of glassy Biclotymol. Within eight months of storage above Tg (T = Tg + 2 C), amorphous Biclotymol does not show a strong inclination to crystallize and forms a relatively stable glass. This case study, involving a multidisciplinary approach, points out the importance of continuing looking for stability predictors. ã 2015 Published by Elsevier B.V.

Chemical compounds studied in this article: Biclotymol (PubChem CID: 71878) Keywords: Amorphous Biclotymol Crystallization Molecular mobility Nucleation Stability

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1. Introduction

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In the pharmaceutical industry, crystalline active pharmaceutical ingredients (API hereafter) and/or excipients have been so far preferred for the formulation of drugs because of stability concerns (Singhal and Curatolo, 2004). However, a number of pharmaceutical ingredients are prompt to get amorphized and it has been demonstrated that amorphous API can result in a significant enhancement of dissolution (Gupta et al., 2004) and biodisponibility (Serajuddin, 1999) with reference to the crystallized solid. Thus, development of drugs in the amorphous state offers an interesting route and has motivated a strong interest in the last decades (Bhugra and Pikal, 2008; Hancock and Zografi, 1997). Amorphous APIs can be prepared through various established

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* Corresponding author. Tel.: +33 2 32 39 90 82. ** Corresponding author. Tel.: +33 2 32 95 50 84. E-mail addresses: [email protected] (L. Delbreilh), [email protected] (V. Dupray).

ways: supercooling of the melt (Laitinen et al., 2013; Wojnarowska et al., 2010), high-energy milling (Willart and Descamps, 2008), rapid precipitation from a solution (spray drying) (Tajber et al., 2009), hot melt extrusion (Lakshman et al., 2008) or desolvation (Saleki-Gerhardt et al., 1995). Nevertheless, preparation method as well as thermal and mechanical treatments employed during formulation of the drug have been shown to affect the life expectancy of the amorphous API (Patterson et al., 2005), which is a significant concern from a pharmaceutical perspective. Instability of the amorphous state compared to the crystalline state arises from a higher molecular mobility contributing sometimes to spontaneous recrystallization processes (Bhardwaj et al., 2013; Zhou et al., 2002). Molecular mechanisms governing the kinetic stability of amorphous API remains unclear as a large number of experimental factors may impact the process of crystallization such as temperature, pressure or exposure to humidity (Yu, 2001). These mechanisms need to be clarified in order to design reliable Q4 formulation processes (Morris et al., 2001).

http://dx.doi.org/10.1016/j.ijpharm.2015.05.036 0378-5173/ ã 2015 Published by Elsevier B.V.

Please cite this article in press as: Schammé, B., et al., Crystallization kinetics and molecular mobility of an amorphous active pharmaceutical ingredient: A case study with Biclotymol. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.05.036

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Several researchers have attempted to understand and somehow to predict the life expectancy of organic amorphous compounds by looking for a correlation between crystallization tendency of different glass formers with molecular mobility and thermodynamic properties of the amorphous state. Stability was first correlated with the difference between glass transition and the storage temperature (Hancock and Shamblin, 2001; Zhou et al., 2007). It is recognized that storage well below Tg (usually 50 K) could prevent crystallization and ensure a physically stable drug during its shelf-life (Capen et al., 2012). Storage conditions could also be defined in terms of the Vogel temperature T0 (obtained from the Vogel–Fulcher–Tammann equation) regularly assigned as a hypothetical thermodynamic temperature at which molecular mobility is regarded to be close to zero. Ongoing researches emphasize that molecular mobility could be a factor to account for life expectancy (Andronis and Zografi, 1997; Kothari et al., 2014; Shamblin et al., 1999). However, it appears that molecular mobility is often compound specific and its reduction does not systematically improve the stability (Bhardwaj and Suryanarayanan, 2012; Zhou et al., 2002). Further attempts to determine amorphous stability were made through depth analysis of other parameters such as configurational thermodynamic parameters (entropy, enthalpy). Zhou et al. (2002) suggest that the key parameter should be the configurational entropy while Marsac et al. (2006) established a correlation with configurational enthalpy. Mahlin et al. (2011) for their part, applied statistical metrology (glass transition and molecular weight measurements) in order to predict the stability of various compounds (Mahlin et al., 2011). In parallel to this, several authors have indicated that assessing quantification of crystallization behavior could also be considered through measures of glass-forming ability (Baird et al., 2010; Graeser et al., 2009). Simple parameters have been highlighted such as the reduced glass transition temperature (Trg) (Kauzmann, 1948) and temperature difference (Tcrys,ons Tg), where Tcrys,ons is the onset temperature of crystallization (Lu et al., 2000). Good glass formers, i.e. intrinsically inclined to become amorphous upon solidification by cooling, appears to possess a chemical structure related to a wide molecular weight or/and a poor molecular symmetry as many adjustable torsion angles (Mahlin et al., 2011). Moreover, good glass formers seem also to be inclined to a wide free energy difference between crystalline and amorphous states (Baird et al., 2010). Recently, fragility introduced by Angell (1985, 1991) has been considered as a worthwhile parameter regarding life expectancy of amorphous API systems (Gupta et al., 2004; Grzybowska et al., 2010). Glass formers defined as “fragile” exhibit a rapid molecular mobility variation at the vicinity of Tg unlike “strong” glass formers. It was recently depicted for polymeric systems as “a key parameter for observing modifications of the relaxation environment of macromolecules” (Evans et al., 2013). In this idea, several recent studies have been carried out on the influence of several parameters on fragility index of polymers: microstructure modification (Delpouve et al., 2014), nanostructuration (Arabeche et al., 2014), nanofillers addition (Crétois et al., 2013; Saiter et al., 2013), nanoconfinement (Yin et al., 2012), on a 20-million-year-old amber (Zhao et al., 2013; Zhao and McKenna, 2014), on metallic glasses (Ikeda and Aniya, 2010; Wei et al., 2014), on selfassembled-molecules (Dhotel et al., 2013, 2015; Scott et al., 2008). Similarly, Kunal et al. (2008) highlighted the concept of packing efficiency of glass-forming materials (Kunal et al., 2008). According to this approach, movement limitations of individual repeated units of the material will lead to an inefficient packing ability and in this way to a higher fragility. Recent years have witnessed an increasing exploitation of fragility concept as it allows to classify glass-forming API/excipients based on dynamics

differences (Brás et al., 2014). High fragility index of amorphous systems has been associated with a higher free energy. Thus, a higher physical stability could be expected for strong glass formers compared to fragile glass formers. However, it is worth pointing out that there are exceptions from the above theory and none of them can be considered nowadays as a general rule of thumb. Indeed, some fragile glass-formers do not correlate with crystallization tendencies of pharmaceuticals (Adrjanowicz et al., 2012). It has been highlighted that in the supercooled liquid state, on the basis of a panel of three antibiotics (azithromycin, clarithromycin, and roxithromycin) exhibiting a fragile glass-forming behavior (m 120), only clarithromycin crystallizes below Tg. A recent study conducted on amorphous paroxetine hydrochloride showed that in contrast to a high fragility (m = 107), a stable glass of this drug can be obtained (Pina et al., 2015). Moreover, it has been highlighted that quantification of relaxation time and fragility index can also be subject to a misinterpretation (Johari and Shanker, 2010). A straightforward conclusion could not be drawn since all key factors have to be recognized, analyzed and put in perspective through multivariate analysis. Thus, due to the limited number of active pharmaceutical ingredients analyzed, no interrelationship between complex processes involved in stability has been highlighted. In view to contribute to this challenging inquiry, we characterized the amorphous state of Biclotymol, an active pharmaceutical ingredient which possesses antiseptic properties and is used for the treatment of otolaryngology infections. Biclotymol, 2,20 methylenebis(4-chloro-3-methylisopropylphenol), can be esteemed as a multidisciplinary model compound since it presents a favorable polymorphism as well as a glass transition temperature close to room temperature. Herein, we report our investigation on the kinetics of crystallization and molecular dynamics of this amorphous drug performed through temperature-resolved X-ray powder diffraction (TR-XRPD), differential scanning calorimetry (DSC) and hot stage microscopy (HSM). The relevancy of fragility index, recently considered as an indicator of life expectancy of amorphous APIs, is discussed.

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2. Materials and methods

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2.1. Materials

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Biclotymol crystalline powder (C21H26Cl2O2, Mw = 381.32 g/ mol), was kindly provided by Pharmasynthese (Inabata Group) and was used without further purification. X-ray diffractogram of commercial Biclotymol was recorded and reveals a completely crystalline form in agreement with Rantsordas et al. (1978).

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2.2. Differential scanning calorimetry (DSC)

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DSC experiments were performed using a PerkinElmer 8500 apparatus equipped with a refrigerated cooling system. Small sample masses of 5 0.5 mg were enclosed into sealed standard aluminum pans to improve thermal conductivity and ensure that powder will follow the imposed thermal variations. Baseline was calibrated from 15 C to 160 C with the scanning rate of 5 K/min used in the experiments. Prior to measurement, two standards as benzophenone and indium were used for temperature and enthalpy calibrations. The atmosphere of the analyses was regulated by a nitrogen flux (20 mL/min). The PerkinElmer Pyris Software was used for data processing.

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2.3. Thermogravimetric analysis (TGA)

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TGA analyses were performed using a Netzsch TG 209 apparatus. Baseline has been calibrated from 30 C to 500 C with a

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scanning rate of 10 K/min. A nitrogen flow of 15 mL/min was applied for the measurements.

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2.4. Temperature resolved X-ray powder diffraction (TR-XRPD)

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The temperature resolved X-ray powder diffraction measurements were performed on a Rigaku SmartLab XRD–DSC diffractometer (Rigaku Corporation, Japan). Sample was exposed to Cu Ka radiation (45 kV 200 mA) in the angular range of 5–35 C (2u) with a step size of 0.02 (2u ). Experiments were performed under air from 15 C to 150 C at a heating rate of 2 K/min.

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2.5. Hot-stage microscopy (HSM)

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Thin films samples were prepared by melting a small amount of crystalline powder between one glass slide and one cover glass pre-cleaned with ethanol and placed in a Mettler Toledo FP90 (Thermo System) coupled with a FP82HT hot stage. Optical microscopy observation was performed by means of a polarizing optical microscope Nikon Optiphot-2.

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3. Results and discussion

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3.1. Polymorphism of Biclotymol

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Previous investigations on Biclotymol have led to the identification of two crystalline varieties (one stable and one metastable— i.e., in a monotropic relationship) as well as various solvates (Ceolin et al., 2008; Mahé et al., 2008a,b; Mahé and Nicolaï, 2010). The crystal structure of stable Form I was solved by Rantsordas et al. (1978) and the packing arrangement describes a monoclinic system (P21/c, Z = 4). X-ray diffractogram of commercial Biclotymol was recorded at room temperature and shows that the starting batch is constituted of stable Form I. Metastable crystalline Form II can be obtained by heating the quench-cooled Form I melt until its recrystallization into Form II (Ceolin et al., 2008). Unfortunately, to date, single crystals of this metastable form could not be obtained and the crystalline structure of this form remains unknown. In order to evaluate the thermal stability of Biclotymol, thermogravimetric analyses were performed on the commercial batch which consists of the stable Form I. Results show that the compound

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Fig. 1. DSC curves of crystalline (upper curve) and amorphous (lower curve) Biclotymol at 5 K/min heating rate. (1) Melting of Biclotymol Form I, (2) glass transition region, (3) crystallization of the supercooled melt toward metastable Form II, (4) melting of Biclotymol Form II. The inset shows the glass transition region on an enlarged scale.

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exhibits no degradation up to 180 C (see Fig. A, Supporting information). Differential scanning calorimetry (DSC) was also performed on the commercial batch of Biclotymol. The corresponding thermograms are presented in Fig. 1. Upon heating (5 K/min), a clear endothermic phenomenon at Tm = 127 C (DHm = 94.9 J/g) is observed. It can be ascribed to the melting of monoclinic crystalline Form I (1). Upon quenching from the melt to 15 C at 50 K/min, no sign of crystallization is noticed. On reheating the melt-quenched sample, a well-defined Cp jump is observed which signals the glass transition (2). The amplitude of the Cp jump and the glass transition temperature are respectively DCp = 0.45 J/(g/K) and Tg = 20 C. On further heating, the glass transition is followed by a broad exothermic event and a sharp endothermic contribution. These two events can be ascribed as the recrystallization from the liquid-like state (3) at Trc = 73 C (DHc = 49.4 J/g) and the melting of the monotropic polymorph II (4) at Tm = 101 C (DHm = 54.9 J/g). In order to correlate unambiguously thermal events to structural changes, simultaneous DSC and XRD experiments were carried out using a SmartLab XRD–-DSC from Rigaku Inc. Measurements were performed from room temperature up to above the melting point of stable Form I (Tm = 127 C). Sample was held at 150 C for 10 min to erase possible remnants seeds. After a melt-quenching of 20 K/min to 15 C for 5 min, a heating ramp b (2 K/min) was programed. Dynamic TR-XRPD measurement from 15 C to 150 C are shown in Fig. 2. Results highlight that another polymorphic form crystallizes with diffraction peaks observed from 68 C. It is ascribed to the metastable Form II of Biclotymol. Moreover, crystalline peaks are no more observed above 102.4 C, corresponding to the melting of this metastable crystalline form. It is noteworthy that the crystallization of Form II is happening without remnants traces of Form I seeds. Moreover, apparatus configuration allowed highlighting simultaneous dynamic measurements of XRD and DSC. The DSC curve observed during reheating of amorphous Biclotymol is in complete agreement with Fig. 1 since an exothermic peak and subsequently an endothermic peak were observed at the same characteristic temperatures (see Fig. B, Supporting information). Moreover, regarding the physical stability of the amorphous state, the absence of Bragg peaks and the halo pattern indicate that our compound is X-ray amorphous after a melt-quench and until 68 C. Note that Form II probably appears below 68 C but at a non-detectable level. Detection threshold of XRPD has often been reported to be around 5 wt% Q6 (Coquerel, 2006) and depends among others on the crystal size and

Fig. 2. Experimental XRPD patterns of stable Form I and metastable Form II as a function of temperature. (1) First heating at 5 K/min of the crystalline powder from room temperature to melting. (2) Second heating process at 2 K/min from amorphous Biclotymol to 150 C.


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shape. In particular, we must mention that Form II crystals adopt a needle like shape whose preferential orientation can impact the threshold value (either favorably or detrimentally). It is generally accepted that crystallization could be different depending if the quenched melt has been obtained ex situ (using an external hot plate) or in situ (in a hermetic sealed aluminum DSC pan). Indeed, polymorphic transformations could be favored, depending on the time spent above the melting point without degradation (Mahieu et al., 2013). Thus, it was verified that the time spent in the melt does not affect the recrystallization of the metastable Form II of Biclotymol (data not shown).

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3.2. Kinetics of crystallization from the amorphous state

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It is well established that crystallization results from two independent phenomena, nucleation and crystal growth, each with a different temperature dependency (Descamps and Dudognon, 2014; Sun et al., 2012). Thermodynamic driving force for crystallization from the amorphous state arises from the free energy change between the supercooled liquid and the crystalline state, whatever the temperature. Such changes governing the crystallization process are of utmost importance. As described by Eq. (1), the free energy change is defined as:

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DGa;c ðTÞ ¼ DHa;c ðTÞ ¼ T DSa;c ðTÞ 266 265 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291

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(1)

with DG (T), DH (T), DS (T) the free energy, enthalpy and entropy differences between the amorphous and crystalline states, respectively. The free energy change depends on the heat capacities of the glass and the crystalline phases. Crystallization mechanisms from the amorphous state are widely investigated through non-isothermal and isothermal experimental techniques, by differential scanning calorimetry (DSC) (Kolodziejczyk et al., 2014) and/or by broadband dielectric spectroscopy (BDS) (Kaminski et al., 2011) in order to thoroughly recognize a tendency to crystallization under various conditions. a,c

a,c

a,c

3.2.1. Non-isothermal cold crystallization kinetics study above Tg In this continuous heating method, sample is heated at a fixed heating rate b and the heat flow variation is recorded as function of temperature or time. Through an analysis of the sensitivity of the peak positions in terms of temperature and applied heating rate b, the apparent activation energy Ea can be determined. Several models have already been proposed in order to extract this relevant parameter, each with its advantages and disadvantages (Matusita et al., 1984; Ozawa, 1970). The commonly theoretical model used is the Kissinger analysis (Kissinger, 1957). It should be made clear that Kissinger’s method is based on a first-order reaction which means that the concept of nucleation and growth is not taken into account. Thus, a more accurate method suggested by Augis and Bennett (1978) considers not only the variation of the peak temperature of crystallization Tp but also the onset temperature of crystallization Tonset through the formula: b Ea (2) ¼ F AB ln T p T onset RT p where FAB is a fitting parameter. The apparent activation energy Ea is determined from the slope of the plot ln(b/(Tp Tonset)) versus 1000/Tp. Amorphous Biclotymol was then heated at various heating rates b ranging from 1 to 7 K/min (Fig. 3). Data treatment allowed to collect the onset temperature of crystallization Tonset and the peak temperature of crystallization Tp (Table 1). Augis and Bennett plot based on Eq (2) is reported in Fig. 4. Activation energy from Augis and Bennett equation was found to possess a value of Ea = 46 kJ/mol. One should note that activation

Fig. 3. DSC heating scans of amorphous Biclotymol samples measured at various heating rates from 1 to 7 K/min.

Table 1 Characteristic temperatures of the cold crystallization process from DSC measurements performed at several heating rates. Heating rate b (K/min)

1 3 5 7

Temperature of crystallization ( C) Onset Tonset

Peak Tp

60.1 0.2 71.7 0.2 70.3 0.2 76.1 0.2

65.7 0.2 79.7 0.2 83.2 0.2 89.5 0.2

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energy obtained from Kissinger equation (data not shown) is higher with Ea = 80 kJ/mol. This difference probably lies in the fact that Kissinger model leaves aside the onset temperature of crystallization. In the case of pharmaceutical compounds, this parameter must not be neglected. For Biclotymol, we noted that Tonset is not highly dependent on the heating rate b for b values higher than 3 K/min.

Fig. 4. Augis and Bennett (red squares) plot for cold-crystallization peaks obtained through various heating rates. Red dashed line denote the linear fit to Eq (2). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)


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3.2.2. Isothermal study of amorphous Biclotymol crystallization above Tg Under isothermal conditions, the activation energy of crystallization Ea can be obtained from the evolution of the volume fraction a(t) of the recrystallized material using the Johnson–Mehl–Avrami (JMA) transition equation (Avrami, 1939, 1940, 1941):

aðtÞ ¼ 1 exp½kðTÞðt t0 Þn 316 315 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363

(3)

with t the time of reaction, t0 the induction time, n the Avrami exponent and k(T) the Avrami constant. Amorphous Biclotymol was prepared in-situ by performing a melt-quench from 150 C to 0 C at 50 K/min. Sample was then heated from 0 C to the isothermal crystallization temperatures at 20 K/min. A new amorphous sample was prepared for each experiment which was performed in triplicate for each isothermal temperature. Figures displaying the exothermic peak corresponding to several isothermal temperatures as well as the fraction of the crystallized material a(t) as a function of time are presented in the Supporting information (see Figs. C and D, respectively). Precaution was taken to exclude the extreme experimental values for the fit (due to logarithm divergence). Indeed, Avrami equation is usually not applied to the entire range 0 < a(t) < 1 as the transition mechanism is different at the beginning and at the end of the transition. Nevertheless, from Avrami plots, it appears that accurate values for n and K cannot be obtained at each temperature of isothermal crystallization as evolution of exothermic process as a function of time has shown to be not repeatable (changes were noticed even if each isothermal temperature experiment was performed in triplicate). However, the mean value of Ea for the isothermal crystallization process of Biclotymol was found to be close to 200 kJ/mol and a value for n close to 3. Reasons for differences between non-isothermal and isothermal processes are discussed below. 3.2.3. Comparison of isothermal and non-isothermal crystallization processes Calorimetric experiments have demonstrated that, without seed crystals, there is a significant difference between crystallization processes from isothermal and non-isothermal experiments. If such differences are uncommon for polymers, they have already been observed for organic compounds (Schmitt et al., 1999; Seefeldt et al., 2007). Woldt summarizes isothermal and nonisothermal apparent activation energies through three different nucleation mechanisms: continuous, fixed number of nuclei and site-satured nucleation (Woldt, 1992). Thus, a theoretical separation between activation energies for nucleation and growth could explain in a comprehensive way how excipients in drug formulation affect crystallization processes. From Table 2, apparent activation energies under isothermal and non-isothermal conditions could be different if nucleation appears through a site-saturated nucleation mechanism. In this way, activation energies for nucleation and growth can be separately determined. To thoroughly appreciate if metastable Form II crystallizes through this site-saturated nucleation mechanism, crystallization experiments were monitored by hot-stage microscopy (Brandel et al., 2013). Melt-quenched Biclotymol was heated (5 K/min) to a

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suitable isothermal temperature where it was let to crystallize. Optical microscopy shows the growth of the metastable crystalline Form II, made of very fine birefringent needles (Fig. 5a–c). Micrographs reveals that the metastable crystallization is not homogeneous and appears at different locations through several nucleation sites (left upper corner of Fig. 5b). Upon further heating, no recrystallization into stable Form I or fusion of the stable Form I can be noticed. Only the fusion of these needles at circa 100 C was observed. Isothermal cold-crystallization of amorphous Biclotymol process has shown to possess an isothermal temperature-dependent behavior. It turns out that parameters as dimensionality of the nucleus n and activation energies Ea could not be rigorously determined. Moreover, DSC scans showed that during the reheating part from the isothermal crystallization temperature to 150 C only the melting of the metastable Form II at 100 C was noticed. In a first instance, we should recall that we directed our attention to the crystallization process of a metastable polymorphic form. Moreover, account must be taken that an accurate determination of the induction time could be sometimes complex due to some possible thermal fluctuations at the outset of the integration peak. We must point out that physical meaning of activation energies of crystallization is still matter of debate. It has been reported that even by considering apparently the same glassy system, mechanisms of crystallization are subject to changes due to sample size (Marotta et al., 1980) as well as thermal history. Thus, activation energies of crystallization obtained from different models and plots may sometimes not be in agreement.

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3.3. Molecular mobility of glassy Biclotymol

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Fragility (or steepness index) is a parameter introduced to enable a classification of glass-forming systems established on differences in their molecular dynamics. The concept of fragility has been widely reviewed by Angell several years ago (Angell, 1985, 1991). The fragility index value, m, tends to characterize the dynamic properties of a liquid and changes in the molecular mobility as approaching the glass transition temperature and is expressed as: dðlogt Þ (4) m¼ dðT g =TÞ T¼T f

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According to the above equation, fragility index m is connected to a time constant t related to the structural relaxation time. This structural process is thermally activated and depends on the glass structure. In this way, fragility would refer to the deviation from an Arrhenius temperature dependence of relaxation properties. A classification was introduced by Angell et al. for a variety of glassforming liquids. According to Angell’s classification, glass-forming liquids are called “strong” when their fragility index is low (m 16). They are characterized by an evolution of relaxation time almost Arrhenius like. Glass-forming liquids for which the fragility index is high are called “fragile” (m 200). They exhibits larger structural reorganization with temperature change and relaxation times vary in a non-Arrhenius manner with temperature (Angell, 1995). Alternatively, classification for pharmaceutical glass

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Table 2 Meanings of isothermal and non-isothermal apparent activation energies from (Woldt, 1992). N and G correspond to nucleation and one-dimensional growth, respectively. Nucleation mechanism

Reaction order

Isothermal apparent (Ea)

Non-isothermal apparent (Ea)

Continuous

m+1

G EN a þ mEa =m þ 1

Fixed number of nuclei

m

Site-saturated nucleation

m

EN a EGa EN a

þ

mEGa =m

þ

mEGa =m

þ1

EGa EGa


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Fig. 5. Optical microscopy photographs showing the morphological evolution of amorphous Biclotymol sample during the isothermal crystallization at 60 C at several times. (a) t = 10 min ; (b) t = 20 min; (c) t = 30 min. 417 418 419 420 421 422 423 424 425 426 427

formers has been reviewed with strong glass-formers displaying m values 75 (Yu, 2001). Determination of the relaxation time t can be carried out through the Tool–Narayanaswamy–Moynihan (TNM) equation (Moynihan et al., 1976; Narayanaswamy, 1971; Tool, 1946). In regards to a constant glass structure, the variation of t with the temperature will be related to an apparent activation energy Dh*. This apparent activation energy Dh* can be determined from the variation of the limiting fictive temperature Tf0 with the cooling rate qc (Moynihan et al., 1976):

dlnjqc j Dh ¼ R dð1=T 0f Þ

(5)

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Fictive temperature Tf can be obtained experimentally from calorimetric measurements with Moynihan’s method (Moynihan et al., 1976): Z T>T g Z T>T g ðC p;l C p;g ÞdT ¼ ðC p jC p;g ÞdT (6) Tf 0

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T Tg is confirmed by the recrystallization and melting occurring at higher temperatures but also by the similar values of associated enthalpies (Table 3). It should be noted that there is nearly no variations of enthalpies (crystallization and melting) between the sample analyzed immediately after and the one after eight months of storage. One should note that a small endothermic event appears in addition to the melting of the metastable Form II, after 1 month of storage. It could be ascribed to the size distribution of crystals of Form II. Thus, amorphous Biclotymol appears to remain stable during a relatively long-term storage at T > Tg as DSC measurements showed no tendency toward a full recrystallization within eight months of storage at T = Tg + 2 C. Interestingly, it has also been found that supercooled Biclotymol easily recrystallize to the metastable form upon heating amorphous Biclotymol. Several studies have been recently carried out through storage experiments of amorphous API to provide an accurate prediction of their life expectancy. However, these studies were always conducted by storing the amorphous drug well below Tg while storage of amorphous Biclotymol was carried out at standard conditions i.e., room temperature and ambient pressure, with Tstorage > Tg and a relative humidity of 30% RH. Kolodziejczyk et al. (2013) evidenced physical stability of amorphous sildenafil stored below Tg (T = Tg 30 K). It was shown that X-ray diffraction pattern of this amorphous API exhibits a broad amorphous halo (after six months of long-term storage at room temperature). Likewise, Adrjanowicz et al. (2012) performed long-term stability experiments on amorphous antibiotics. During the 13 months of storage well below Tg (T = Tg 80 C), no signs of crystallizations for these compounds were recorded and confirmed by XRPD. Moreover,

Fig. 9. Evolution of heat flow versus temperature of annealed amorphous Biclotymol at room temperature. DSC thermograms were measured with a heating rate of 5 K/min. Annealing of the amorphous Biclotymol was made in a controlled chamber at 22 C and relative humidity of 30% RH.


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Table 3 Characteristic temperatures and associated enthalpies from DSC measurements performed at several times on glassy Biclotymol. Storage time

Right after 1 Month 2 Months 4 Months 8 Months

547

Temperature of crystallization ( C) Onset (Tonset)

Peak (Tp)

77.1 64.9 64.7 64.5 62.9

82.9 75.5 74.8 75.1 73.4

Crystallization enthalpy DHc (J/g)

49.6 50.9 50.4 51.5 52.1

Temperature of melting ( C) Onset (Tonset)

Peak (Tp)

101.5 100.1 100.1 100.4 100.4

102.7 102.1 102.1 102.5 102.6

Melting enthalpy DHm (J/g)

63.6 64.9 65.7 63.7 60.4

Pointing out factors as apparent activation energy of crystallization Ea, thermodynamic parameters of the amorphous state fragility index and Tg) has given some insights into the molecular mobility of amorphous Biclotymol. However, from a pharmaceutical industrial point of view, future work must concentrate on the separation of such factors in order to determine the most critical. In this way, effects of thermal history and sample handling could be simplified and better understood to develop stable amorphous formulations with a greater physical stability. Even if molecular mobility has been assigned as a relevant parameter to account for determination of life expectancy of amorphous states, this prediction cannot remain mainly in one parameter (Zhou et al., 2008). If introducing an additional kinetic parameter as thermodynamic fragility is of significant concern to identify stability indicators of amorphous compounds, a direct and straightforward relationship between molecular mobility and life expectancy seems difficult with actual database that contains nowadays a restricted number of compounds (Graeser et al., 2009). Thus, a wider panel of pharmaceuticals glass-formers case studies must be considered.

598

568

Grzybowska et al. (2010) highlighted a striking recrystallization process of amorphous celecoxib when stored 33 K below its Tg. Isothermal XRD measurements showed within ten days a complete recrystallization of this amorphous API. Among all these life expectancy studies, thermodynamic fragility index m calculated for each of these amorphous API allowed classifying them as a fragile glass formers. Thus, despite their fragile character, these amorphous compounds does not necessarily show a strong inclination to crystallize. In the case of amorphous Biclotymol, the study of crystallization tendency and molecular mobility indicates that the system does not undergo a recrystallization after eight months under ambient storage conditions above Tg (T = Tg + 2 C), despite its high fragility value. The temperature difference between the glass transition and the onset of crystallization Tcrys,ons Tg) which is for amorphous Biclotymol around circa 53 C, could be a reasonable explanation of the life expectancy of this active pharmaceutical drug at the amorphous state. These experiments therefore confirm that description and prediction of the behavior of amorphous molecular compounds cannot be based on one single parameter but more on a group of several thermodynamic and kinetic parameters.

Author contributions

618

569

4. Conclusion

619

570

In this paper, we investigated the crystallization tendency as well as thermodynamic parameters of the amorphous state of Biclotymol. By using different experimental techniques (XRD, DSC, HSM), we examined the case of this amorphous drug by looking at its crystallization kinetics and molecular mobility. We analyzed isothermal and non-isothermal cold crystallization kinetics of amorphous Biclotymol by means of DSC technique and observed that crystallization mechanisms of the isothermal and nonisothermal cold crystallization appear to be different. Activation energy of non-isothermal process was accurately determined through Augis–Bennett model that takes into account the onset and peak temperature of crystallization. Furthermore, isothermal cold crystallization process was examined from Avrami model. We noted that an accurate fitting could not lead to parameters n and K at each isothermal temperature of crystallization. It was emphasized that we directed our attention to the crystallization of the metastable polymorphic form of Biclotymol and that crystallization occurring under the form of fine birefringent needles could affect the heat flow detection recorded by means of DSC. Depending on the isothermal cold crystallization temperature investigated, nucleation and growth processes seems to be different. Furthermore, we carefully examined the molecular mobility of amorphous Biclotymol. A feature of glass-forming liquids as thermodynamic fragility parameter was found to be around m = 100, describing Biclotymol as a fragile glass-former as Angell’s classification. Life expectancy of glassy Biclotymol was monitored indirectly with DSC measurements. It has not displayed a full recrystallization up to 8 months of storage at T > Tg (Tg + 2 C).

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

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The authors declare no competing financial interest. Acknowledgments The Region Haute Normandie is acknowledged for financial support to B.Schamme via the E.D. No. 351 (SPMII). Thanks are due to Rigaku Corporation for the simultaneous measurement of XRPD and DSC of crystalline and amorphous state of Biclotymol. Rigaku Corporation takes no responsibility on measurement results.

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Appendix A. Supplementary data

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Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. ijpharm.2015.05.036.

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Life cycle analysis within pharmaceutical process optimization and intensification: case study of active pharmaceutical ingredient production.

Classification of the crystallization behavior of amorphous active pharmaceutical ingredients in aqueous environments.

Tregitope peptides: the active pharmaceutical ingredient of IVIG?

Tablet formulation of an active pharmaceutical ingredient with a sticking and filming problem: direct compression and dry granulation evaluations.

Investigation of active pharmaceutical ingredient loss in pharmaceutical compounding of capsules.

Impact of micromeritic properties of an active pharmaceutical ingredient on its compaction behavior.

Validation of an in-line Raman spectroscopic method for continuous active pharmaceutical ingredient quantification during pharmaceutical hot-melt extrusion.

Investigation of solubilising effects of bile salts on an active pharmaceutical ingredient with unusual pH dependent solubility by NMR spectroscopy.

Disintegration rate and properties of active pharmaceutical ingredient particles as determined from the dissolution time profile of a pharmaceutical formulation: an inverse problem.

Evaluation of detection sensitivity in comprehensive two-dimensional liquid chromatography separations of an active pharmaceutical ingredient and its degradants.

Thermal, mechanical and drug release characteristics of an acrylic film using active pharmaceutical ingredient as non-traditional plasticizer.

Quantification of active pharmaceutical ingredient and impurities in sildenafil citrate obtained from the Internet.

Integration of active pharmaceutical ingredient solid form selection and particle engineering into drug product design.

Controlling pharmaceutical crystallization with designed polymeric heteronuclei.

Development of new laboratory tools for assessment of granulation behavior during bulk active pharmaceutical ingredient drying.

Nanometric Cutting of Silicon with an Amorphous-Crystalline Layered Structure: A Molecular Dynamics Study.

Predicting Crystallization of Amorphous Drugs with Terahertz Spectroscopy.

Investigating miscibility and molecular mobility of nifedipine-PVP amorphous solid dispersions using solid-state NMR spectroscopy.

mL) for a clinical trial on the brain tumor metabolism: Pharmaceutical control of active pharmaceutical ingredient and stability study of the finished product].

Evaluation of effects of pharmaceutical processing on structural disorders of active pharmaceutical ingredient crystals using nanoindentation and high-resolution total scattering pair distribution function analysis.

Physical stability of the amorphous anticholesterol agent (ezetimibe): the role of molecular mobility.

Manipulating crystallization with molecular additives.

Assessment of active pharmaceutical ingredient particle size in tablets by Raman chemical imaging validated using polystyrene microsphere size standards.

Polarization of positronium in amorphous polar polymers: a case study.