Co-stabilization of amorphous pharmaceuticals - the case of nifedipine

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Co-stabilization of amorphous pharmaceuticals - the case of nifedipine and nimodipine Justyna Knapik-Kowalczuk, Wenkang Tu, Krzysztof Chmiel, Marzena Rams-Baron, and Marian Paluch Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00308 • Publication Date (Web): 08 May 2018 Downloaded from http://pubs.acs.org on May 9, 2018

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Molecular Pharmaceutics

Co-stabilization of amorphous pharmaceuticals - the case of nifedipine and nimodipine

Justyna Knapik-Kowalczuk1,2*, Wenkang Tu1,2, Krzysztof Chmiel1,2, Marzena Rams-Baron1,2 and Marian Paluch1,2 1

Institute of Physics, University of Silesia, ul. Pułku Piechoty 1a, 41-500 Chorzów, Poland

2

SMCEBI, ul. 75 Pułku Piechoty 1a, 41-500 Chorzów, Poland

*corresponding author: [email protected]

TOC:

KEY WORDS: amorphous

pharmaceuticals,

physical

stability,

molecular

dynamics,

nifedipine,

nimodipine, crystallization kinetics, dielectric spectroscopy, impact of elevated pressure on physical stability, compression of amorphous APIs, co-amorphous system

ACS Paragon Plus Environment

Molecular Pharmaceutics 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

ABSTRACT: Currently, a research hotspot in amorphous active pharmaceutical ingredients (APIs) is to understand the key factors that dominate the recrystallization and to develop effective methods for stabilizing the amorphous forms. Consequently, we investigated the influence of the global molecular mobility and structural properties on the crystallization tendency of three 1, 4-dihydropyridine derivatives (nifedipine, nisoldipine and nimodipine) in their supercooled states using differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS) techniques. The BDS is also employed to monitor the isothermal crystallization kinetics of supercooled nifedipine and nimodipine at T= 333 K under ambient pressure. As a result, we found that nimodipine exhibits much slower crystallization in comparison to nifedipine. However, nimodipine crystallizes much faster when little pressure of 10 MPa is exerted on sample. Such compression-induced crystallization of nimodipine as well as the inherent instability of nifedipine can be solved effectively by preparing co-amorphous nifedipine/nimodipine combinations. Interestingly, the high physical stability of nifedipine/nimodipine mixtures is achieved despite that the nimodipine acts as a plasticizer.


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INTRODUCTION: Amorphization of poorly water-soluble pharmaceuticals has become an exciting method to enhance the solubility-limited oral bioavailability since several decades. Nevertheless, the number of currently marketed amorphous drug products is still substantially less than expected due to their inherent physical instability together with unpredictable potential to crystallize during manufacture or storage.1 It is known that amorphous indomethacin and griseofulvin stored at temperatures far below Tg can even not avoid crystallization.2,3 Therefore, the understanding of key factors governing the stabilization of amorphous drugs against crystallization is crucial for pharmaceutical industry, and has fascinated numerous investigations on molecular mechanism of the transformation from either the supercooled liquid or glassy state into the crystalline state.4,5,6 It is worth noting that molecular mobility is one relevant factor among many that can determine the tendency of amorphous materials to crystallize.1, 7 , 8 For instance, the global mobility reflected in structural relaxation (α -relaxation) above Tg is believed to closely associate with the crystallization processes of amorphous states. Bhugra et al. 9 found a strong coupling between the structural relaxation time τα and crystallization onset time τ0 above Tg for indomethacin, which enabled the prediction of τ0 values for temperatures below Tg as well. The predicted data matched well with the experimental results. It indicates that the global mobility can play a role in the devitrification of amorphous indomethacin. Analogous linear correlations between τα and τ0 above Tg have been also reported for several pharmaceuticals, such as felodipine,9 flopropione,9 itraconazole,10 trehalose,11 and sildenafil.12 Nevertheless, some other factors correlated to diverse pharmaceutical structures, i.e., specific interactions (e.g., hydrogen bonding or ionic interactions), flexibility and conformational changes of molecules, can affect the physical stability as well.1,13 Good examples are for etoricoxib and celecoxib. These two drugs have comparable molecular dynamics (approximate temperature dependences of τα and same Tg values of 330 K) while distinct crystallization behaviors in amorphous states (etoricoxib is resistant against crystallization but celecoxib crystallizes very easily) are simultaneously observed. However, etoricoxib was found to exist as a dynamic mixture of two different tautomers, which prevents the crystallization, while celecoxib molecules form homodimers by hydrogen bonding that can facilitate the formation of crystal nuclei.13 As mentioned above, it is crucial to understand how molecular mobility and structure-related properties of pharmaceuticals will influence the physical stability. Thus,



we selected a model drug nifedipine (NIF) and its two structural analogues, nisoldipine (NIS) and nimodipine (NIM) for studying here. These drugs are three frequently used calcium antagonists for treating angina pectoris and hypertension, and all belong to the class of so-called 1, 4-dihydropyridine derivatives of similar structures.14 As shown in Figure 1, NIF is of the simplest structure, compared to which minor modifications are made for two other chemicals by introducing the functional groups such as methyl, isopropyl, and methoxymethyl and changing the position of nitryl group in the benzene ring. The broadband dielectric spectroscopy (BDS) is a powerful technique capable of detecting various global and local molecular motions featured by wide timescale differences at different temperatures. And more notably, studies at elevated pressures are also available by means of BDS. As we know, it has been experimentally proved that compression strongly affects the physical stability of disordered materials. It can both suppress and promote crystallization tendencies as reported in a number of papers.15,16,17 For example, our previous study on crystallization kinetics of supercooled ibuprofen at ambient and elevated pressures by BDS showed that both the induction time τ0 and overall crystallization time τcr values were significantly elongated for compressed samples.18 In contrary, our latest study revealed that even a small compression (10 MPa) to the supercooled probucol induced a crystallization process – quickly completed in 66 min. On the other hand, the same samples at ambient pressure did not show any crystallization tendency even after 2880 min.19 In fact, in the past years a tremendous amount of papers studying the supercooled and glassy states of numerous chemicals at various combinations of temperature and pressure by BDS have been published.20,21,22 Our group recently pioneered the use of BDS as a tool to monitor online the tendency toward recrystallization of amorphous probucol at conditions mimicking the process of manufacturation.19 In the present work, we focus on the molecular dynamics and thermodynamic behaviors of NIF, NIS and NIM in the supercooled liquids to identify their stability differences against crystallization, and perform the analyses from perspectives of molecular mobility and structure-related properties. The ambient-pressure isothermal crystallization behaviors monitored by BDS for the supercooled NIF and NIM at a same temperature of 333 K are compared. Additionally, the impact of compression on the crystallization tendency of supercooled NIM at 333 K is also studied under a condition mimicking the manufacturing process. Ultimately, co-amorphous NIF/NIM mixtures are prepared with the aim of


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enhancing the physical stability of NIF by using NIM as a crystallization inhibitor.



EXPERIMENTAL METHODS: Materials Nifedipine (NIF, Mw = 346.3 g/mol), nisoldipine (NIS, Mw = 388.4 g/mol) and nimodipine (NIM, Mw = 418.4 g/mol) drugs of purity greater than 98% were purchased from Sigma-Aldrich and used as received. The relevant molecular structures are presented in Fig. 1. The amorphous form of all these systems has been obtained by rapid quenching process. Differential Scanning Calorimetry (DSC) Thermodynamic properties of neat NIF, NIS, and NIM as well as binary blends of NIF 10:1 NIM, NIF 5:1 NIM and NIF 2:1 NIM were studied using a Mettler-Toledo DSC 1STARe System. The instrument was equipped with a HSS8 ceramic sensor having 120 thermocouples and a liquid nitrogen cooling station. Zinc and Indium standards were used to calibrate the devices prior to the measurements. Samples sealed in aluminum crucible (40 µL) were measured at a fixed heating rate of 10 K/min. Broadband Dielectric Spectroscopy (BDS) Broadband Dielectric Spectroscopy (BDS) is a powerful experimental technique to investigate the molecular dynamics of an amorphous APIs. This method enables measurements of relaxation processes over a broad range of temperature, frequencies and even pressures. Consequently, it is possible to observe relaxation processes occurring both below and above the drug’s glass transition temperature. In the supercooled liquid region i.e. above Tg, the structural (α) relaxation process is dominant on the dielectric spectrum. This process originates from the cooperative motion of many molecules. In the glassy state i.e. below Tg, where the structural relaxation becomes too slow to be monitored in the experimental window, the secondary relaxations processes, reflecting fast local motions with an inter- or intramolecular origin, can be detected. Dielectric measurements of neat NIF, NIS, NIM and NIF/NIM mixtures were carried out using a Novo-Control GMBH Alpha dielectric spectrometer equipped with a Quattro temperature controller, which ensures the temperature stability to be within 0.1 K. The measurement frequency ranges from 10-1 Hz to 106 Hz. The samples were examined in a parallel-plate cell (stainless steel, diameter 15 mm) with a gap of 0.1 mm formed by glassy spacers. For the dielectric measurements which mimicked the manufacturing process, we used a capacitor (diameter 15 mm, 0.1 gap formed by Teflon spacers) filled with neat NIM or


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NIF/NIM mixture. The samples were only in contact with the stainless steel and Teflon, and were compressed by silicone fluid via a piston in contact with a hydraulic press, during which a Nova Swiss tensometric pressure meter with a resolution of 0.1 MPa was applied to monitor the pressure. The temperature was controlled within 0.1 K by means of liquid flow in a thermostatic bath. All time dependent experiments have been repeated twice in order to check the reproducibility of the data.



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THERMODYNAMICS AND RELAXATION KINETICS OF NEAT DRUGS AT TEMPERATURES ABOVE THE GLASS TRANSITION:

Figure 1. DSC heating curves for tested compounds in the (a) crystalline and (b) amorphous states with fixed heating rates of 10 K/min. In panel (a), the molecular structures of the compounds are shown. The inset of panel (b) shows an enlarged temperature for the glass transition. Tm [K] samples

Tg [K] fragility param m

βKWW

∆ε

315

84

0.73

22

307

305

86

0.73

14

289

285

81

0.73

19.3

DSC

DSC

BDS

10 K/min

10 K/min

τa= 100 s

Nifedipine

444

317

Nisoldipine

420

Nimodipine

390

Table I. Values of the melting temperatures (from DSC technique), glass transition temperatures (from DSC and BDS techniques), fragilities (mp), βKWW parameters and dielectric strength at Tg (∆ε) of nifedipine, nisoldipine and nimodipine.


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As shown in Figure 1a, the melting behaviors of crystalline NIF, NIS and NIM samples were detected by means of DSC with the characteristic melting points Tm (onset temperature) determined. A rapid quenching process was followed to vitrify each sample. And then, the glassy samples were reheated to ascertain their respective glass transition temperatures, Tg (midpoint temperature) as shown in Figure 1b. Moreover, different reheating phenomena were clearly observed within supercooled liquid regions, i.e., NIF crystallized while NIS and NIM did not. The heating and cooling rates in the aforementioned processes are fixed to be 10 K/min. Table I collects all the Tm and Tg values determined from calorimetric data, and these values agree well with those reported in Ref [14].

Figure 2. Dielectric loss spectra of (a) nifedipine, (b) nisoldipine and (c) nimodipine collected above their respective Tgs upon heating in steps of 2 K. The black vertical dashed lines in panels (a) - (c) mark the frequency position of 103 Hz. In panel (d), activation plots are constructed for the tested compounds with olive stars, royal squares and red up-triangles referring to temperature dependences of α-relaxation times for nifedipine, nisoldipine and nimodipine, respectively. The solid lines are the fitting results by VFT equation.

The dielectric measurements were performed by means of BDS to characterize the molecular mobility of NIF, NIS and NIM. All these compound were examined in a same



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frequency range (from 10-1 to 106 Hz) but different temperature ranges above their own Tgs (defined as temperatures at which τα reaches 100 s) in steps of 2 K as depicted in panels (from a to c) of Figure 2. Prior to the measurements, amorphous NIF, NIS and NIM were prepared by firstly melting crystalline samples (~5 K above their respective Tms) in the parallel-plate cell and subsequently being quenched on copper blocks which are precooled to 262 K. As can be seen in Figure 2 a –c, in the supercooled liquid region, the dielectric loss spectra of investigated pharmaceuticals reveal a pronounced α-relaxation, which shifts toward higher frequencies as temperatures increased, indicating the enhanced global mobility. The τα value at each temperature can be determined from the fitting to given spectrum an empirical Havrilak – Negami (HN) function, which is expressed by the formula23,24: * ε HN (ω ) = ε ' (ω ) − iε '' (ω ) = ε ∞ +

∆ε [1 + (iωτ HN ) a ]b

(1)

where ε ' (ω ) and ε '' (ω ) are real and imaginary parts of complex permittivity; ε ∞ , ∆ε and τ HN are high frequency dielectric constant, dielectric strength and relaxation time of a relaxation peak; ω equals 2πf ; a and b are profile shape factors of the relaxation dispersion. The fitting results for the samples at 333 K are presented in Figure 3 (see the inset) as examples. Based on the fitting parameters, the τ α values were calculated in terms of the followed expression25:

πa   τ α = τ HN sin( ) 2 + 2b  

−1 / a

πab   * sin( ) 2 + 2b  

1/ a

(2)

Figure 2d depicts the reciprocal temperature dependences of τ α for NIF, NIS and NIM, which can be well described by means of the Vogel – Fulcher – Tamman (VFT) equation26,27:

τ α = τ ∞ exp(

B ) T − T0

(3)

where τ ∞ , B and T0 are fitting parameters. It is clearly visible in Table I that the kinetic Tg values identified as the temperature at which τ α reaches 100 s are comparable with the thermodynamic ones. Based on the plots shown in Figure 2d, we can calculate not only the values of Tg, but also another significant parameter, namely the fragility parameter m (also called steepness index). The m value can be defined as the extent to which τ α - T relation deviates from


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the Arrhenius case ( T0 = 0 ) at Tg,28

m=

d log10 τ α d (Tg T )

= T =Tg

B * Tg (Tg − T0 ) 2

(4)

Based on the value of fragility parameter the glass forming liquids can be usually classified into three categories: strong ( m ≤ 30 ), intermediate ( 30 < m < 100 ), and fragile ( m ≥ 100 ), respectively.1 As depicted in Table I, the m values for NIF, NIS and NIM are determined to be 84, 86 and 81, indicating that they are typical intermediate glass formers. In the inset of Figure 3, we construct the so-called masterplots by horizontal shifting of the dielectric spectra from different temperatures near the glass transition, i.e., 323 K for NIF (olive solid hexagon), 313 K for NIS (royal solid diamond) and 295 K for NIM (red solid circle), to superimpose on the reference spectra at 333 K (empty symbols). As can be noted the shapes of structural relaxations of examined APIs remain invariant to the temperature changes. The spectra at 333 K were fitted by means of the HN (see dashed lines in the inset of Figure 3) and another empirical function, namely the one-side Fourier transform of the Kohlrausch-Williams-Watts (KWW) function29:



t

)β φ (t ) = exp− ( τ KWW 

KWW

  

(5)

where τ KWW is the characteristic KWW relaxation time and the stretching parameter 0 < β KWW ≤ 1 quantifies the degree of departure of φ (t ) from the Debye exponential decay (for which β KWW = 1 ). The wine solid lines presented in the inset of Figure 3 are KWW fits to the α- peaks. The β KWW values of all three compounds has been determined to be equal to 0.73.



Figure 3. Dielectric strength ∆ε (Tg) as a function of the stretching parameter βKWW. All black empty stars are data collected in Ref. [30]. The data for nifedipine (olive star), nisoldipine (royal suqare) and nimodipine (red up-triangle) in this work are added herein for comparison. In the inset, the masterplots for each compound are constructed by horizontal shifting of spectra to superimpose on those at 333 K. The wine solid lines are the KWW fits to the α-peaks at 333 K with the same βKWW= 0.73 ascertained for each compound. The black dashed lines represent the HN fits to the α-peaks.

In Figure 3, we review a remarkable correlation of β KWW with dielectric strength at Tg, ∆ε (Tg ) for 88 glass formers as established in our previous work.30 The origin of the

correlation can be rationalized theoretically from the dipole-dipole interaction potential Vdd (r ) , which contributes to the overall attractive part of the intermolecular potential determining the α-relaxation dynamics and β KWW as well.31 It appears obviously that larger ∆ε (Tg ) corresponds to higher β KWW , namely narrower α-loss peak. The data of ∆ε (Tg ) and β KWW ascertained for NIF, NIS and NIM (see Table I) have been also added

to Figure 3, and show great accordance with other glass formers, what further strengthen the established correlation. Many attempts have been made to correlate the fragility m with the physical stability of amorphous materials,1 including pharmaceuticals.12,32,33,34 It is argued that the fragility parameter reflects the sensitivity of molecular dynamics to temperature change, and the molecular mobility of fragile liquids should vary more rapidly than that of strong liquids upon approaching the glass transition. In fact, experimentally, extensive studies have associated the strong liquids with higher physical stability.12,32,33 Besides, theoretically, the two-order-parameter (TOP) model proposed by Tanaka also emphasizes that the frustrations of fragile glass formers against crystallization are weaker than those of stronger ones.35 Likewise, the stretching parameter β KWW has been proposed to act as an alternative measure of the physical stability. Shamblin et al.36 suggested that the ‘shelf life’ of a pharmaceutical should be correlated to the β KWW parameter. In addition, they reported that when β KWW parameter decreases (i.e., when the distribution of structural relaxation times broadens), the physical stability should decrease. Unfortunately, though the herein studied drugs have comparable m values together with same β KWW values, they show different crystallization tendencies in the supercooled liquid regions. As revealed in Figures 1 and 2, NIF crystallizes during the DSC and BDS measurements while NIM does not show any crystallization tendency under the same


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heating conditions. In fact, such phenomena are not unique when the examples for celecoxib (m= 97, β KWW = 0.67) and etoricoxib (m=98, β KWW =0.64), which show diverse crystallization tendencies (see the Introduction part), are recalled here.13 Considering that molecular mobility is commonly acknowledged to associate with the physical stability of amorphous materials,37 we attempt to examine how the three compounds will behave when they show the same global mobility. That is, the dielectric spectra with their structural relaxation peaks located at the same frequency (such as 103 Hz in Figures 2 (a) – (c)) are focused. And apparently, the three drugs are at distinctly different temperatures. This temperature for NIF is extremely close to its crystallization onset temperature, Tx, while that for NIS is ~20 K lower than its own Tx. In view of the fact that NIM does not show crystallization tendency, we can infer that NIF will crystallize rapidly while considerably increased time is required for NIS and NIM to crystallize. More importantly, it seems that certain factors should play a more significant role than global mobility in affecting the crystallization tendencies of these pharmaceuticals. Herein, the structure-related properties, such as hydrogen bonding, are taken into consideration. Tang et al. 38 studied the hydrogen bond patterns in crystalline and amorphous phases in a group of dihydropyridine calcium channel blockers by means of both FT-Raman and FT-IR spectroscopy, and they found that NIF, NIS and NIM formed hydrogen bonds between the only one hydrogen donor, the dihydropyridine NH group, and proton acceptors including carbonyl and ether groups. Additionally, they investigated the hydrogen bonding strengths, which are assumed to be reflected by the NH peak positions, for these compounds in both crystalline and amorphous states, and found the NH peak wave-numbers to follow a order of NIM< NIS < NIF, indicating the strongest, intermediate and weakest hydrogen bonding for NIM, NIS and NIF. Besides, they proposed that hydrogen bonds in amorphous NIM had to experience the disruption and reformation with another acceptor group prior to crystallization while only little rearrangement of hydrogen bonding is required for NIF and NIS to achieve crystallization. Therefore, it can be speculated that the stronger hydrogen bonding in NIM should impact on its more stable physical stability when compared to NIS and NIF. Meanwhile, the most symmetric structure of NIF may also contribute to its weakest stability.

PHYSICAL STABILITY STUDIES OF NEAT NIFEDIPINE AND NIMODIPINE: AMBIENT VS. ELEVATED PRESSURES



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As shown in the inset of Figure 3, the molecular mobility of supercooled NIF, NIS and NIM samples are visually compared by their respective dielectric loss spectra at a fixed temperature, T= 333 K, showing that the α -relaxation peaks locate at disparate frequencies, namely fNIM is 2 orders of magnitude higher than fNIS and ~4 orders of magnitude higher than fNIF. Similarly, the results of τα(NIF) > τα(NIS) > τα(NIM) (see Figure 2d) are also observed at certain fixed temperatures where all the compounds are in the supercooled states, representing that NIM always shows the molecular mobility which is several orders of magnitude faster than NIF at such temperatures. Despite this, to in-depth explore the physical stability of supercooled NIF and NIM, the additional studies of their isothermal crystallization kinetics at T= 333 K and p= 0.1 MPa has been performed by means of BDS. The crystallization processes can be usually identified from the changes in real ( ε ' ) and imaginary ( ε ' ' ) parts of the complex dielectric permittivity since the static permittivity ε s as well as the intensity of a structural relaxation peak will decrease gradually.13

Figure 4. Panel (a) shows the real ( ε ' ) part of nimodipine dielectric spectra recorded during an isothermal crystallization at T= 333 K under p= 0.1 MPa. The red up-triangles and circles represent the spectra depicting the initial and final stages of crystallization process, respectively. Panel (b) presents the time evolution of normalized real permittivity ε N' (red cross) and its first derivative dε N' d ln t (red solid circles) against the natural logarithm of the time. The corresponding olive symbols represent the ε N' and its first derivative data for nifedipine recorded at the same conditions from Ref. [39].

Figure 4a shows the real ( ε ' ) part of NIM dielectric spectra recorded during its real-time crystallization at T= 333 K and p= 0.1 MPa. For analyzing the crystallization process, a normalized parameter, ε N' , is introduced on the basis of the following equation:

ε N' (t ) =

ε ' ( 0 ) − ε ' (t ) ε ' ( 0) − ε ' ( ∞ )


(6)

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where ε ' (0) and ε ' (∞) are the values of static dielectric permittivity at the initial and ultimate stage of crystallization, and ε ' (t ) is the value at time. In the following process,

ε N' and its first derivative against natural logarithm of time ( dε N' d ln t ) for NIM are presented in Figure 4b in terms of the so-called Avramov approach,40 from which a critical parameter, τcr, which denotes the characteristic time for the isothermal overall crystallization time, can be determined.12 Furthermore, the related NIF data taken from our lately published work were also added in Figure 4b.39 As can be seen an enormous differences in τcr values, namely 463 min for NIF while 2267 min for NIM, can be observed. This reinforces the fact that supercooled NIM simultaneously possesses faster molecular mobility and better stability against recrystallization than NIF at the same temperature.

Figure 5 Panel (a) shows the real-time isothermal crystallization of nimodipine recorded at T= 333 K but in a condition mimicking the manufacturing process, i.e., compressed to 10 MPa and quickly decompressed. The wine up-triangles and circles represent the dielectric ε ' spectra depicting the initial and final stages of crystallization process. Panel (b) compares the differences in the relations of ε N' – ln t (cross) as well as dε N' d ln t - ln t (solid circles) ascertained for nimodpine held at ambient pressure (red symbols) and nimodipine experienced compression and decompression (wine symbols).

Generally, elevated pressure can significantly affect the crystallization tendency of a compound, and compression is an essential process for the pharmaceutical manufacturing. In order to check how the supercooled NIM behaves at elevated pressure, we performed high pressure dielectric spectroscopy measurements. This experiment allow us to mimic manufacturing condition (e.g. pressurization of the molten sample through the extruder



die). The glassy NIM has been placed inside the high pressure chamber, next the sample was heated up to T = 333K. After 30 min from temperature stabilization sample has been compressed to 10 MPa and then quickly decompressed, and from that moment the real-time dielectric ε ' spectra for NIM sample at 333 K were recorded as shown in Figure 5a. For further analysis, the time dependences of ε N' and its first derivative for the compressed and quickly decompressed NIM are subsequently illustrated in Figure 5b using the aforementioned Avramov method with a τcr value of 894 min identified, which is dramatically shortened when compared to the case of NIM held at ambient pressure. As mentioned above, NIM is capable of forming intermolecular hydrogen bonding formed between the -NH group and the ether or carbonyl group.41 It is noted that such faster compression-induced crystallization has also been reported in several pharmaceuticals, such as probucol,19 ezetimibe,42 celecoxib,13 indomethacin,1 which are characterized by hydrogen bonds. Unfortunately, there still lacks of a unified explanation on such phenomena. In terms of the diverse pharmaceutical structures, celecoxib and indomethacin molecules can form homodimers by hydrogen bonding,13,43 which may facilitate the crystallization especially when the hydrogen bonding effect is strengthened during compression. Nevertheless, molecules of probucol, ezetimibe as well as the nimodipine studied here have been rarely reported to be capable of forming dimers. Based on the classical crystallization theory, the overall crystallization consists of nucleation and crystal growth, which involve both thermodynamic and kinetic contributions that vary with changing thermodynamic conditions (T and p).1 To answer the question why nimodipine and other hydrogen-bonding pharmaceutical molecules show faster compression-induced crystallization, further studies are required from the thermodynamic and kinetic perspectives.

NIMODIPINE USED AS AN INHIBITOR EFFECTIVELY STABILIZING NIFEDIPINE AGAINST CRYSTALLIZATION Preparation of binary co-amorphous mixtures of APIs with appropriate excipients (polymers, acetylated carbohydrates and another API) is currently a simple and feasible


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method to suppress the crystallization of the objective drug. Usually, the principal consideration for finding suitable excipients is the antiplasticization effect of the additives on APIs, i.e., a decrease in the global mobility associated with an increase in Tg for the prepared mixtures when compared to that of the pure API.1 Therefore, polymers of high Tg are always superior candidates used as excipients in mixtures, for instance, the prominent improvement of drug physical stability of flutamide (Tg= 274 K) by a copolymer Kollidon VA64 (PVP/VA, Tg= 376 K).44 However, it is worth noting that the API dispersions with polymers usually involve simultaneously specific interactions, such as hydrogen bonding and ionic interactions between molecules of drug and excipients, which contribute to enhancing the physical stability as well. Mistry et al

45

studied the crystallization

inhibition in amorphous solid dispersions of ketoconazole (KTZ) with three polymers, poly(acrylic

acid)

(PAA),

poly(2-hydroxyethyl

methacrylate)

(PHEMA)

and

polyvinylpyrrolidone (PVP), and found the interaction strengths between drug and polymers, which can be ranked as PAA (ionic interactions and hydrogen bonding) > PHEMA (hydrogen bonding) > PVP (dipole and dipole interactions), drastically affect the crystallization behaviors that most effective, less effective and negligible crystallization inhibitions were observed in mixtures of KTZ with PAA, PHEMA and PVP, respectively. Nevertheless, co-amorphous binary combinations of two different APIs have proven to be interesting alternatives of drug-polymer combinations since tangible benefits, including improved dissolution rates and higher physical stability, could be achieved for either one or two components.46 A plenty of successful cases have been reported for co-amphorous drug mixtures, such as cimetidine – naproxen, 47 naproxen – indoemthacin, 48 probucol – atorvastatin,19 and etc..49 Besides, numerous studies also discovered that combined therapy of two drugs gives better results than monotherapy.50,51



Figure 6. DSC heating curves for amorphous nifedipine, nimodipine as well as binary NIF/NIM mixtures with weight ratios of 10 : 1, 5 : 1 and 2: 1. The inset shows the concentration dependence of the ascertained Tg values for the tested samples. Symbols of red up-triangle, purple right-triangle, dark cyan left-triangle, orange down-triangle and olive star represent the Tg data for pure NIM, NIM 1:2 NIF, NIM 1:5 NIF, NIM 1:10 NIF and pure NIF, respectively. The prediction from Gordon – Taylor equation for the binary system over the whole concentration range is shown as the dashed line.

For the model drug NIF, many attempts were made to successfully inhibit its amorphous state against crystallization by using different additives, including polymers (such as PVP52 and poly(vinyl acetate) (PVAC)53), acetylated carbohydrates (such as acetylated maltose (acMAL) and acetylated sucrose (acSUC)) 54 and another API (such as cimetidine)55 . However, in the present work, we managed to stabilize NIF using its dihydropyridine analogues, NIM. Three co-amorphous mixtures containing various weight ratios of NIM and NIF (NIF – NIM: 10:1, 5:1, and 2:1) were prepared and detected using both DSC and BDS techniques. Figure 6 depicts the reheating behaviors for three NIF/NIM mixtures and two neat samples within temperature ranges covering both the glass transition and melting processes. It is clearly seen that the binary mixtures show a prominent Tg, representing the complete miscibility of two components. Moreover, the Tg values depress with the increasing addition of NIM when compared to Tg of neat NIF, which easily reminds us of the


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plasticization effect rather than the antiplasticization one. Here, another known plasticizer, water (Tg= 135 K), has to be mentioned due to its powerful capabilities of reducing Tg while increasing molecular mobility in objective amorphous drugs, which usually facilitates the crystallization tendency.56 However, it seems peculiar for the case of NIF – NIM since the decreased Tg values are simultaneously accompanied by the increased crystallization onset temperatures, Tx that extended supercooled liquid regions ( ∆Tx = Tx − Tg ) are observed for mixtures of NIF 10:1 NIM and NIF 5:1 NIM, which represents enhanced stabilities of the supercooled liquid states. Furthermore, we can infer even higher stability of supercooled NIF 2:1 NIM mixture since no crystallization is recognizable during the reheating process. And obviously, these results validate the effectiveness of NIM in stabilizing NIF. We presents the composition dependence of Tg for such binary system of NIF – NIM in the inset of Figure 6, and conducted further analysis via an empirical Gordon – Taylor equation, which can be expressed as follows57: Tg =

w1Tg1 + w2Tg 2

(7)

w1 + Kw2

where Tg and Tgi are glass transition temperatures for binary mixture and pure components (i= 1, 2); w1 and w2 are weight fraction of pure components. K is a coefficient that can be calculated from the formula: K = ∆C p 2 ∆C p1 , where ∆Cp1 and ∆Cp2 denote the heat capacity increments at glass transition for pure components. The dashed line (see the inset of Figure 6) represents the calculated Tg results by GT equation over the whole composition range with a distinct negative deviation from the experimental values to predicted ones being noticed. The DSC-determined Tgs, ∆Cp and theoretically calculated Tg values for pure NIF, NIM as well as their binary mixtures are all collected in Table II.

Tg [K] NIM-NIF

Molar fraction

Tg [K]

DSC

BDS

∆Cp

τa= 100 s

[J/g-K]

[weight

Of NIM

10

ratio]

[%]

K/min

Predicted

0:1

0

319

315

0.38

319

1:10

7.64

315

312

0.39

316

1:5

14.20

312

308

0.40

313

-GT



Page 20 of 31

1:2

29.27

305

304

0.43

308

1:0

100

287

285

0.42

287

Table 2 Comparison of the Tg and ∆Cp Values of Pure NIM and NIF Drugs and Their Binary Amorphous Mixtures at Weight Ratios of 1:10, 1:5, 1:2.

Figure 7. Dielectric loss spectra of binary mixtures of (a) NIM 1:10 NIF, (b) NIM 1:5 NIF and (c) NIM 1:2 NIF collected above their respective Tgs upon heating in steps of 2 K.


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Figure 8. Activation plots of both pure samples of NIF and NIM as well as binary NIF – NIM mixtures with different weight ratios of 10:1, 5:1 and 2:1.

The dielectric measurements were also performed for NIF/NIM mixtures with weight ratios of 10:1, 5:1 and 2:1, for which dielectric loss spectra in the supercooled states are presented in Figure 7 (see each panel). Comparisons of the crystallization tendencies are made for such three mixtures, and the highest stability of supercooled NIF 2:1 NIM sample is reconfirmed due to its apparent inability to recrystallize. The aforementioned Equations 1 and 2 have been applied to analyze the structural relaxations as illustrated in each panel, and the determined τα values are plotted as functions of their corresponding reciprocal temperatures, for which the fittings are performed using the Equation 3 with respective Tgs determined for three binary mixtures (see Figure 8). The Tg values determined based on both calorimetric and dielectric data, which have been presented in Figures 6 and 7, respectively, show comparable consistency (see Table II).



Figure 9. Panel (a) shows the real-time isothermal crystallization of binary sample of NIM 1:2 NIF recorded at T= 333 K and in the condition mimicking the manufacturing process, i.e., compressed to 10 MPa and quickly decompressed. The purple open-squares and solid right-triangles represent the dielectric

ε ' spectra depicting the initial and final stages of crystallization process. Panel (b) compares

the differences in the relations of ε N' – ln t ascertained for various samples, namely neat NIF (olive cross) and neat NIM (red cross) samples held at ambient pressure, pure NIM (wine cross) and binary NIM 1:2 NIF sample (purple cross) experienced compression and decompression.

Now that NIM proves to be a promising crystallization inhibitor of NIF at ambient pressure, the same method mimicking the manufacturation condition as mentioned in Figure 5 is employed to examine the stability of NIF 2:1 NIM sample by BDS at elevated pressures. Figure 9a exhibits the real-time ε ' measurement results at T= 333 K for the sample which experienced the processes of compression by a pressure of 10 MPa and immediate decompression. It is striking that no sign of crystallization is observed even after ~100 h. For a more intuitive indication of the superior stability in NIF 2:1 NIM, to which comparisons are made using the results of neat NIF and neat NIM at p= 0.1 MPa (from Figure 4) and of neat NIM at mimicked manufacturing condition (from Figure 5), and all the time dependences of ε N' results are illustrated in Figure 9b. It is readily seen that both NIF and NIM are stabilized against crystallization in the binary mixture. Naturally, a question arises on how NIF and NIM can stabilize each other. It seems that hydrogen bonds, which are prone to form in both compounds, should play a role especially when considering the fact that experimental Tgs deviate negatively from the corresponding theoretical values by GT equation in binary mixtures as verified in Figure 6. Generally, it is


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argued that such negative deviations are indicative of an overall loss in the number and strength of hydrogen bonding upon mixing. 58 However, the amount and strength of hydrogen bonds in NIF 2:1 NIM mixture might still exceed those of neat NIF and neat NIM, and consequently affect the stability of the binary mixture. In addition, it is possible that NIF and NIM molecularly act as steric hindrance for each other in the mixture, which limits the ordering of molecular arrangement required for crystallization. Our further study from these points in the NIF/NIM system is in progress.



CONCLUSIONS This paper has carried out studies on a group of structural analogues, viz., NIF, NIS and NIM, of which the thermodynamic behaviors and relaxation kinetics in the supercooled liquid states are firstly detected by means of the DSC and BDS techniques at ambient pressure. Strikingly, when global mobility in the three compounds are comparable, represented by the same structural relaxation peak positions, NIF shows high crystallization tendency while it is difficult for NIM to crystallize. It can be speculated that the diverse hydrogen bonding strengths in these compounds should play a more crucial role than the global mobility in affecting the crystallization. Subsequently, the BDS is employed to monitor the real-time crystallization kinetics of amorphous NIF and NIM held at a constant temperature (T= 333 K) exceeding their respective Tgs though NIM has molecular mobility that is several orders faster than NIF. The more sluggish crystallization of NIM than that of NIF is observed once again. Considering that pressure can also greatly affect the molecular dynamics in the relaxation as well as crystallization processes, we studied the behaviors of NIM at a condition mimicking the manufacturing process wherein supercooled NIM at T= 333 K experienced a compression by 10 MPa and immediate decompression. An accelerated crystallization of NIM in this process is observed, indicating the sensitivity of supercooled NIM to compression, which brings about concerns that crystallization will occur during the tableting process. Nevertheless, the coamorphous drug-drug system of NIF – NIM can successfully solve the problem about the weak stability of amorphous NIF at ambient pressure and that of amorphous NIM at elevated pressure since the supercooled NIF - NIM binary mixture with a weight ratio of 2:1 does not show any crystallization even after ~ 100 h at the same mimicked manufacturing condition. It is worth noting that the NIM/NIM mixture shows prominently reduced Tg than neat NIF, namely the plasticization effect for NIF, and such effect usually leads to promoted crystallization tendency of the objective chemicals in other coamorphous binary systems. The attempt to use NIM as an effective crystallization inhibitor for NIF is of significance since it encourages preparing stable binary co-amorphous mixtures of certain APIs and


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appropriate additives despite of the plasticization effect.

ACKNOWLEDGMENTS The authors, K.C., M.R.-B., and M.P., are grateful for the financial support received within the Project No. 2015/16/W/NZ7/00404 (SYMFONIA 3) from the National Science Centre, Poland. Moreover, J.K-K. thank FNP for awarding grants within the framework of the START Programme (2017).



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Co-stabilization of amorphous pharmaceuticals - the case of nifedipine

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