Can storage time improve the physical stability of amorphous

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Can storage time improve the physical stability of amorphous pharmaceuticals with tautomerization ability exposed to compression? The case of chloramphenicol drug Justyna Knapik-Kowalczuk, Zaneta Wojnarowska, K. Chmiel, Marzena Rams-Baron, Lidia Tajber, and Marian Paluch Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00099 • Publication Date (Web): 27 Mar 2018 Downloaded from http://pubs.acs.org on March 29, 2018

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Molecular Pharmaceutics

Can storage time improve the physical stability of amorphous pharmaceuticals with tautomerization ability exposed to compression? The case of chloramphenicol drug Justyna Knapik-Kowalczuk1,2*, Zaneta Wojnarowska1,2,3, K. Chmiel1,2, Marzena Rams-Baron1,2, Lidia Tajber3, 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

3

School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, College Green,

Dublin 2, Ireland

*corresponding author: [email protected]

TOC

KEY WORDS amorphous pharmaceuticals, physical stability, improvement stability, compression of amorphous APIs, impact of elevated pressure on physical stability, chemical equilibration, chloramphenicol, molecular dynamics, dielectric spectroscopy, BDS

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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 In this article we thoroughly investigated the physical stability of amorphous form of chloramphenicol drug. The tendency toward re-crystallization of this drug has been examined: (i) at non-isothermal conditions by means of DSC technique; (ii) at isothermal conditions and temperature close to Troom by means of dielectric spectroscopy; (iii) at isothermal conditions and elevated temperatures equal to T = 323 K, and T = 338 K by dielectric spectroscopy; and (iv) at conditions imitating manufacturing procedure (i.e. elevated temperature and compression procedure). Our investigations have shown that amorphous chloramphenicol stored at both standard storage, and elevated temperature conditions, does not reveal tendency toward re-crystallization. However, compression significantly changes this behavior, and destabilizes the examined compound. We found that due to chemical equilibration of the sample, the elongation of the storage time before compression might 34-times improve the physical stability of the examined pharmaceutical exposed to compression.


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INTRODUCTION Amorphous pharmaceuticals are very attractive systems as they may offer higher apparent solubility, faster dissolution rate and better bioavailability than their crystalline counterparts1. Consequently, by using this form of the drugs, it is possible to reduce the dose that is administered to the patient, and thereby minimize the risk of side effects2. Despite the numerous benefits offered by amorphous pharmaceuticals, their use in solid oral dosage forms is limited3. This is because disordered active pharmaceuticals ingredients (APIs) are thermodynamically unstable, and during manufacturing or storage might revert to their initial i.e. crystalline forms4,5,6. Due to the aforementioned recrystallization propensity of amorphous drugs attention must be paid to: (i) determination of their physical stability (shelf life)7,8, (ii) elucidation of the major reasons responsible for the amorphous to crystalline transformation9, as well as (iii) finding efficient methods, which lead to conservation of their amorphous state10,11,12,13. Ongoing studies have shown that crystallization from the amorphous state is a very complex process including nucleation and crystal growth14,15. The interplay between these two stages of crystallization determine the final tendency of amorphous materials toward recrystallization. According to the classical nucleation theory, nucleation and crystal growth exhibit different temperature behavior: lower temperatures favor nucleation, whereas higher temperatures favor crystal growth. The overlapping zone of both these temperature dependences determines the glass forming ability, and indirectly the physical stability of amorphous material16. Although much work has been done to date in relation to studying devitrification of amorphous materials, a complete and satisfactory understanding of all factors governing this process has not yet been achieved. The factors affecting overall crystallization are usually divided into three main categories: thermodynamic, kinetics as well as molecular17,3,18. The best examples of thermodynamic factors are configurational entropy, enthalpy and Gibbs free energy. Molecular mobility belongs to the kinetics factors, while molecular factors may include: hydrogen bonding interactions, steric hindrances, tautomerization ability as well as the possibility of dimers or other oligomers formation19,10,20,21. Furthermore, numerous examples can be found in literature that consider other factors such as the method of amorphisation22,23, moisture content as well as manufacturing conditions (including the thermal history of sample) as those determining the physical stability of disordered APIs24. A large number of factors governing re-crystallization as well as their poor understanding are true reasons why to date there are no strictly defined protocols to estimate 3 ACS Paragon Plus Environment


the physical stability of amorphous APIs. This means that each amorphous pharmaceutical has to be treated individually to found the most effective way of suppression its tendency towards devitrification. The main goal of this paper is to show how unconventional the behavior of amorphous drugs might be in the context of their physical stability. We experimentally proved that some specific materials might undergo a chemical equilibration, which consequently means that over time their physical stability will be improved. Chloramphenicol (CLP) has been studied here as a model API. This pharmaceutical is a naturally occurring antibiotic produced by Strepomyces venezuelae, and has a broad spectrum of antibiotic activity. It is worth to highlight that this drug remains the most commonly prescribed API in Europe for acute infection conjunctivitis. Additionally, due to its good ability to pass the blood brain barrier, CLP is recommended by the WHO (World Health Organization) to treat epidemics of meningococcal meningitis in Africa25. In the literature one can find that bioavailability of amorphous form of CPL is much higher than for its crystalline counterpart26. This, therefore, was the main reason why we decided to thoroughly examine the tendency towards devitrification of amorphous form of this particular pharmaceutical. Due to the fact that molecular dynamics of an amorphous phase is considered as the main factor affecting its physical stability, CLP’s molecular mobility, both above and below its glass transition temperature, has been investigated. For this purpose, broadband dielectric spectroscopy (BDS) has been employed. In order to test the tendency towards devitrification of this antibiotic in detail, short-term physical stability studies have been performed at conditions similar to the standard storage conditions i.e. room temperature as well as ambient pressure. Additionally, since high temperature accelerates devitrification of amorphous APIs, the studies on CLP’s physical stability have been also performed at elevated temperatures. Finally, due to the fact that during the manufacturing process pharmaceuticals are also exposed to elevated pressure, we investigated how compression might change the crystallization behavior of the examined drug.


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MATERIALS Chloramphenicol (CLP) (Mw = 323.13 g/mol) drugs of purity greater than 98% was purchased from Sigma Aldrich (Merck KGaA, Darmstadt, Germany) and used as received. This pharmaceutical

is

described

chemically

as

D-(−)-treo-2,2-dichloro-N-[β-hydroksy-α-

(hydroksymetylo)-β-(4-nitrofenylo)etylo]acetamid. Chemical structure of CLP is presented in the inset of Figure 1. The amorphous form of CHL was prepared by the quench cooling technique (Tm = 424 K). EXPERIMENTAL METHODS Differential Scanning Calorimetry (DSC). Thermal properties of crystalline and amorphous forms of CLP were examined using a Mettler Toledo DSC 1 STARe System. The instrument was equipped with an HSS8 ceramic sensor including 120 thermocouples, and a liquid nitrogen cooling accessory. The measuring device was calibrated for temperature and enthalpy using zinc and indium standards. Melting points were determined as the onset of the peak, while the glass transition temperatures were obtained from the midpoint of the heat capacity increment. The samples were measured in aluminum crucibles with a volume 40 µL. All measurement were carried out in the range from 270 K to 440 K, with a variety heating rates: 30 K/min, 20 K/min, 10 K/min, 5 K/min, 2.5 K/min, and 1 K/min. Each sample subjected to the heating procedure at a rate as specified above, was first quenched to 270 K at a cooling rate of 20 K/min. Broadband Dielectric Spectroscopy (BDS). Molecular dynamics of CLP in both, supercooled liquid and glassy states, was investigated by means of a Novo-Control GMBH Alpha dielectric spectrometer. Dielectric spectra were registered during heating in the broad frequency range from 10-1 Hz to 106 Hz at temperatures from 153 K to 303 K with a step of 5 K, and from 305 K to 355 K with a step of 2 K. During dielectric experiments the temperature was controlled by a Quattro temperature controller with temperature stability better than 0.1 K. The sample was measured in a parallel-plate cell made of stainless steel (diameter of 15 mm, and a 0.1 mm gap with glassy spacers). Dielectric spectroscopy was also utilized to measure the short-term physical stability of CLP. For this purpose time dependent isothermal experiments were performed. To investigate the physical stability of disordered form of the studied antibiotic at standard storage conditions and elevated temperature conditions, three different temperatures were applied: T = 308 K, T = 323 K, as well as T = 338 K. For physical stability measurements which imitate manufacturing process (compression to p = 10 MPa, and quick decompression) we additionally employed a high pressure Unipress U111 setup. Herein, the sample was 5 ACS Paragon Plus Environment


measured in a similar, made of stainless steel, parallel-plate cell (diameter of 15 mm, and a 0.12 mm gap with Teflon spacers). It was sealed and mounted inside a Teflon capsule to separate it from the silicon liquid. Pressure was measured using a Nova Swiss tensometric meter with a resolution of 0.1 MPa, while the temperature was adjusted with a precision of 0.1 K by a Julabo heating circulator.


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Infrared spectroscopy Infrared spectra were recorded on a PerkinElmer Spectrum 1 FT-IR Spectrometer equipped with a universal attenuated total reflectance crystal accessory witted with a ZnSe crystal. Each spectrum was scanned in the range of 650–4000 cm-1 with a resolution of 4 cm-1 and a minimum of 10 scans were collected and averaged. The spectra were then normalized and background corrected.27 Infrared analysis was carried out on crystalline chloramphenicol and a CLP sample, which was first melted at 433K and then annealed for 120 min at 338 K. Computational studies The quantum chemical calculations were performed utilizing DFT with the Gaussian 0328 program. The initial structure (the keto form) for the calculations was taken from the Cambridge Crystallographic Data Centre (a CCDC reference code of CLMPCL02). DFT computational studies were performed in vacuum, using the B3LYP functional and the 631++G(d,p) basis set. No constraints on the geometry of molecules were imposed. A subsequent harmonic frequency calculations were done on optimized structures at the same level of theory. No imaginary frequencies for any of the structures were found.29



RESULTS AND DISCUSSION Evaluation of thermal properties of CLP Thermal properties of both crystalline and amorphous CLP were investigated by DSC. The thermogram obtained during heating (HR = 10 K/min) of the crystalline – as received – drug is presented as a black dashed line in Figure 1. During this measurement, a single sharp peak with an onset at 424 K, and a maximum at 428 K was registered. This endothermic peak corresponds to the melting of CLP, which is in a good agreement with the literature30. Due to the fact that according to the data from reference 25 CLP starts to decompose above 473 K, one can be assured that during the melting procedure this drug will not degrade25. Therefore, the most common method of amorphization i.e. vitrification was employed to prepare the disordered form of the examined antibiotic. As the dark green DSC trace presented in the Figure 1 shows, the glassy CLP heated up at a rate of 30 K/min has a glass transition Tg = 307 K. It is noteworthy that no other thermal effects were observed during this run. This result might suggest that vitrified CLP does not easily revert to its crystalline form. In order to check whether or not the examined antibiotic undergos recrystallization when a slower heating rate is employed, five similar DSC experiments were performed using slower heating rates of 20 K/min, 10 K/min, 5 K/min, 2.5 K/min, and 1 K/min. As the obtained, and presented in Figure 1, DSC traces indicate, the amorphous CLP does not re-crystallize even when applying a 30times slower heating rate than the first scan (30 K/min). Consequently one can conclude that the examined antibiotic indeed does not easily re-crystallizes from its disordered state.

Figure 1. DSC thermograms of: crystalline CLP measured with heating rate equal to 10 K/min – black dashed line; vitrified CLP measured with heating rates equal to: 30, 20, 10, 5, 2.5, 1 K/min – seaweed, moss, pine, green, emerald, tea shades of green, respectively. The inset shows an enlarged temperature region of the glass transitions.


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Molecular dynamics of amorphous CLP above and below the glass transition temperature Since the molecular dynamics of amorphous pharmaceuticals is considered as a key factor affecting their physical stability, in this section we shall concentrate on this aspect. To investigate the molecular mobility of an amorphous form of the examined antibiotic at ambient pressure in both glassy and supercooled liquid states, the BDS technique was employed. The dielectric measurements were performed in a wide temperature (from 153 K to 355 K), and frequency ranges (10-1 Hz to 106 Hz). The representative dielectric loss spectra of glassy CLP are shown in Figure 2. In this experiment the temperature was increased from 153 K to 303 K with a step of 5 K. As it can be seen from the spectra measured below CLP’s Tg, a well-defined secondary, β-relaxation process appears. This mode moves towards higher frequencies with increasing temperature, and at T = 248 K its maximum is no longer visible in the experimental frequency window. It is worth to mention that secondary relaxation processes might reflect two different types of molecular movements. Therefore, they can be classified as either of intra- or intermolecular origin31. The intermolecular secondary relaxations, called also Johari-Goldstein (JG) processes, come from local motions of the entire molecule, while the processes originating from specific motions, which involve only a subset of the entire molecule, are called intramolecular relaxation or non Johari-Goldstein (non-JG) process32. The JG relaxation is regarded as a precursor of the cooperative structural relaxation, and therefore it is more often, than non-JG relaxation, considered to be the reason of amorphous drug’s instability33. The nature of the secondary relaxation of CLP visible in Figure 2 will be discussed in a later part of this section.

Figure 2. Dielectric loss spectra of CLP obtained on heating at T < Tg.



Figure 3a presents dielectric loss spectra of CLP recorded at T > Tg. In this experiment the temperature was increased from 305 K to 355 K with a step of 2 K. In this temperature range the dielectric spectra of CLP exhibit two main features: the dc conductivity associated with translational motions of ions, and the structural (α) relaxation process related to the cooperative rearrangement of the drug molecules. Since, for the measured samples, the dc contribution is significant, the identification of the position of maximum of the α-peak, especially close to Tg, was challenging. To overcome this problem, the low frequency dcconductivity wing was subtracted from each spectrum (see Figure 3b)34. Now, the maximum of the structural relaxation process, which moves towards higher frequency with increasing temperature, is clearly visible.

Figure 3. Dielectric loss spectra of CLP obtained during heating at T > Tg. The panel (a) presents original spectra i.e. without subtraction of the dc-contribution, while panel (b) shows spectra with subtracted dc-contribution.

In order to check if the shape of the CLP’s structural relaxation peak is temperature independent, superposition of a dozen spectra registered at different temperatures was performed. Presented in Figure 4 masterplot indicates that the temperature does not influence the shape of CLP’s structural loss peak. Thus, one can conclude that the time-temperature superposition in case of studied drug is satisfied. To determine the breadth of the structural relaxation peak of the studied antibiotic we fitted the spectrum recorded at 309K by the oneside Fourier transform of the Kohlrausch-Williams-Watts (KWW) function35. Fitted to the CLP’s structural relaxation peak the KWW function with a stretching exponent βKWW equal to 0.8 is shown as a solid red line in Figure 4. It should be mentioned that the value of βKWW 10 ACS Paragon Plus Environment

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might vary within between 0 and 1. If this parameter approaches 0, the shape of the structural relaxation is asymmetric and broad. On the other hand, if the value of βKWW is equal to 1, the structural relaxation peak is narrow and symmetric, and obviously corresponds to the Debye case. According to the recently established by Paluch et al. anticorrelation between the width of the α-loss peak and polarity of the molecule, van der Waals glass formers with a broad αloss peak (i.e. a small value of βKWW) should exhibit a low value of the dielectric strength (∆εα)36. CLP with βKWW = 0.8 and ∆εα = 55, follows this anticorrelation similarly to other antibiotics like azithromycin (βKWW = 0.52, ∆εα = 1.2), clarithromycin (βKWW = 0.62, ∆εα = 2.68), or roxithromycin (βKWW = 0.62, ∆εα = 1.6) (see inset of Figure 4)37.

Figure 4. Masterplot that was constructed by superimposing dielectric spectra at 14 different temperatures above the glass transition temperature of CLP. The red solid line represents the KWW fit. The inset presents a correlation between ∆ε, and βKWW established by Paluch et al., where the large green star represents CLP.

From further analysis of dielectric loss spectra recorded below and above CLP’s Tg, the temperature dependences of α- and β-relaxation times was determined (Figure 5). In order to obtain the values of τα and τβ at various temperature conditions, the asymmetric α-process and the symmetric β-peak were analyzed by the Havrilak-Negami (HN) and Cole-Cole (CC) functions, respectively38. The empirical HN function is given by the formula:

ε * (ω ) = ε ∞ +

∆ε

[1 + (iωτ

a HN ) ]

b

(1)

where: ε∞ is high frequency limit permittivity, ∆ε is dielectric strength, τHN denotes a characteristic (HN) relaxation time, while exponents a and b represent symmetric and asymmetric broadening of the loss peak. When b parameter in above equation is fixed at 1, the HN function becomes the CC function. Consequently, using this modification of eq 1 the



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CLP’s β-relaxation was fitted. The parameters obtained from the fitting procedure were subsequently used to calculate the values of τα and τβ using the following formula (Eq. 2): 

 πa     2 + 2b  

−1 a

τ α / β = τ HN  sin  

  π ab    sin  2 + 2 b     

1a

(2)

Figure 5. Relaxation map of CLP. The temperature dependence of τα (squares) in the supercooled liquid region was described by the VFT equation. The α-relaxation times marked as the open symbols were found by the horizontal shift of the structural relaxation peak from the region above Tg to the region below Tg. The temperature dependence of τβ (open stars) was fitted using the Arrhenius equation.

As Figure 5 presents, in the glassy state of CLP the τβ(T) exhibits a linear dependence and consequently it can be well-described by the Arrhenius equation:

 Ea    RT 

τ β (T ) = τ ∞ exp

(3)

where R is the gas constant, τ∞ is the pre-exponential factor, and Ea is an energy barrier. The resulting fit parameters are: logτ∞ = -14.96 ± 0.09, Ea = 34.5 ± 0.3 kJ/mol. The small value of the energy barrier suggests that the secondary relaxation of CLP originates from specific motions, which involve only a subset of the drug’s molecule. Thus, this secondary relaxation mode should be classified as a non-JG relaxation. Usually, secondary relaxation processes originating from the local motions of the entire molecule (i.e. JG processes) have a significantly greater energy barrier. For example, the Ea of the intermolecular (JG) secondary relaxation of β-adenosine, β-uridine, celecoxib, and telmisartan are equal to 80 kJ/mol, 77 kJ/mol, 80 kJ/mol, and 82 kJ/mol, respectively39.


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In order to parametrize the temperature dependence of the CLP’s structural (α) relaxation time revealing a non-Arrhenius behavior (see squares on Figure 5), we employed the Vogel – Fulcher – Tammann (VFT) equation40,41,42: 

B  T − T0

τ α (T ) = τ ∞ exp 

  

(4)

with corresponding fitting parameters equal to: logτ∞ = -12.27 ± 0.08, B = 1218.7 ± 24.8, and T0 = 264.2 ± 0.6. From the VFT fit the glass transition temperature of CLP, defined as Tg = T(τα =100s), was estimated as Tg = 301 K. It is noteworthy that determined in this manner the value of Tg is in a perfect agreement with the glass transition temperature obtained from calorimetric studies (TgDSC 5 K/min = 301 K; see Figure 1). On the basis of the VFT fit we also calculated CLP’s fragility parameter as 116. This parameter is defined as follows43:

mp =

d log τ cr d (Tg / T )

(5) T =Tg

and is a measure of τα(T) deviation from the Arrhenius behavior. A typical value of mp lies in the range 16 – 200. The higher value of fragility parameter, the more fragile i.e. less strong liquids are. Several authors have argued that the mp parameter is related to the physical stability of amorphous pharmaceuticals. Therefore, recently, numerous studies concentrated on this issue as strong materials should be more stable than the fragile ones43. Taking this into account one might expect that CLP, with a high value of mp (116), should reveal a large tendency towards re-crystallization. Since our finding unambiguously show that the investigated antibiotic does not easily revert to its crystalline form, it can be concluded that CLP does not satisfy the correlation between the physical stability and fragility.

Physical stability studies of chloramphenicol stored at ambient pressure To thoroughly investigate the tendency of disordered CLP toward re-crystallization, time-dependent isothermal dielectric experiments were performed. To recall; by using BDS the progress of devitrification can be monitored measuring both the real (ε′) or imaginary (ε″) parts of the complex dielectric permittivity44. With crystallization, a gradual decrease of the static permittivity (εs) (in this case of ε′) and a systematic drop in the intensity of the αrelaxation peak (in the case of ε″) are observed. This, naturally, is a consequence of the reduction in the total number of actively reorienting dipoles, which contribute to the



relaxation process once the fraction of amorphous phase systematically decrease ( N µ 2 ~ ε s − ε ∞ = ∆ε =

2

∞

38

ε " (ω ) d ln ω ) π∫

.

0

Due to the fact that a vast majority of pharmaceuticals are stored at standard storage conditions, we began the stability tests from a short-term isothermal experiment performed at T = 308 K and p = 0.1 MPa (i.e. temperature close to the room temperature and ambient pressure). The results of this experiment are presented in Figure 6. It can be seen that after 360000 s (i.e. over 4 days) a decrease in the static permittivity was not recorded, indicating that the investigated sample does not reveal any tendency toward re-crystallization when stored at T = 308 K for 360000 s. Instead of the expected drop in the εs, we observed a slight increase in the εs over time. Taking into account that the number of dipoles inside the sample could not increase (the amount of sample inside the capacitor was not changed), but nevertheless the increase in the εs was noticeable, the sample effective dipole moment had to increase during the experiment. There are a few reasons why it might be so. First, the changes in the effective dipole moment of a sample might occur when the compound undergoes tautomerization45. During this reaction the equilibrium between tautomers, i.e. structural isomers which differ from each other by the position of a hydrogen atom or proton, is reached. Because the particular isomers might possess different magnitudes of dipole moment, during this reaction the sample effective dipole moment might be changed. In this context, a number of pharmaceuticals have been reported to exhibit tautomerism46,. Examples of APIs in which the tautomerization reaction was monitored by BDS are bicalutamide, etoricoxib and glibenclamide47,48,49,50. Second, the increase of the sample effective dipole moment can be observed when larger intramolecular structures such as dimers, trimers or even larger oligomers are formed. Examples of pharmaceuticals in which aforementioned oligomerization exists are indomethacin, paracetamol and oxazepam51,. In the third scenario, the change in the value of εs might be linked to some thermally activated conformational changes in the drug molecules. Taking into account that conformational changes usually occur very quickly this scenario is hardly possible. Since: (i) in CLP two different tautomerism types are possible (amide – imidic acid tautomerism as well as keto – enol tautomerism – see structures in Figure 6), (ii) in the literature one can find the evidence for their existence52,53 as well as (iii) estimated values of dipole moments for different tautomeric forms of CLP proves that their magnitude is indeed different, we assumed that the observed increase of εs reflects tautomerization of CLP rather than dimer formation. Calculated by density functional theory (DFT) dipole moments of amide/keto, imidic acid, and enol form of CLP are equal to 7.629 (x 14 ACS Paragon Plus Environment

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= -3.2019, y = 6.9069 and z = -0.4958), 7.964 (x = -6.1688, y = 3.5472 and z = 3.5763) and 8.5555 (x = 5.0540, y = 6.0367 and z = -3.3485), respectively.

Figure 6. The dielectric spectra of the real part of the complex dielectric permittivity of CLP recorded at T = 308 K. The first recorded spectrum is depicted as green line with squares, while the green line with triangles reflects spectrum registered for equilibrated sample (after t = 360000 s). The inset presents an enlarged frequency region of the static permittivity.

As a next step, we performed time-dependent measurements at elevated temperature conditions. The aim of these studies was two-fold: to examine the influence of temperature on the tautomerization kinetics of CLP and, taking into account that elevated temperature should accelerate re-crystallization process, to more precisely investigate the physical stability of the disordered form of the studied antibiotic. The results obtained from these, time dependent isothermal studies performed at T = 323 K and T = 338 K are shown in Figure 7. It can be seen that the disordered form of the examined antibiotic stored at both: 323 K for 209400s and 338 K for 10800s does not revert to its starting i.e. crystalline form – as shown by lack of the drop in ∆ε (see Figure 7). Similarly to the experiment performed at T = 308 K, instead of the expected drop in ∆ε, its increase was seen. It is worth to note that with the increasing experiment temperature, larger differences between the initial and final values of εs (or ∆ε) can be observed. The values of εs ini - εs fin are equal to 1.5, 3, and 4.3 for T = 308 K, T = 323 K, and T = 338 K, respectively. This result suggests that the observed tautomerization 15 ACS Paragon Plus Environment


reaction depends on the temperature. We can assume that the higher the temperature, the greater ratio of the tautomeric conversion.

Figure 7. Comparison of dielectric spectra of the real part of the complex dielectric permittivity of CLP recorded before (black lines) and after (green lines) reaching tautomeric equilibrium at three different temperatures – from right: 338 K, 323 K, 308 K.

Vibrational analysis was done on CLP samples (crystalline and supercooled) comparing calculated and experimental spectra. Figure 8 shows that the bands associated with H-bonds are generally blue-shifted in comparison to the computed bands, due to a persistent intramolecular H-bond with a length of 2.73Å, however a shift towards higher wavenumbers of the bands between 3400 and 3600 cm-1 in the aged, supercooled sample in comparison to crystalline CLP may imply the presence of additional –OH groups from the tautomeric forms. The intensity of the carbonyl stretching vibration (experimental, supercooled CLP) is decreased and becomes skewed towards lower wavenumbers, as the keto/amide form converts probably to the enol form. The tautomeric transition can be viewed as a decrease in intensity of NH and CH bending bands at app. 1550 and 1400 cm-1, respectively.


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Figure 8. Vibrational (infrared) analysis. The top panel presents the calculated infrared spectra of the three tautomeric forms of CLP with bands indicating key differences assigned. The lower panel shows the experimental infrared spectra of crystalline CLP and supercooled CLP (annealed for 7200 s at 338K) with an inset illustrating the persistent intramolecular H-bond (length = 2.73 Å). υ – stretching and δ - bending vibrations.

To establish the rate of the monitored reaction at different temperatures, the time evolution of static permittivity was analyzed. Due to the fact that for each temperature different values of the initial and final εs were observed, we analyzed tautomerization reaction by means of degree of reaction αε which is defined as follow54:

αε =

ε s (0) − ε s (t ) ε s (0) − ε s (∞)

(6).

Herein εs(0) denotes static permittivity at the beginning of the tautomerization process, εs(t) is the value of εs at time t, and εs(∞) is the long-time limiting value. By using dimensionless degree of reaction instead of the original parameter of static permittivity, all kinetic curves recorded at different temperatures are normalized to the same range and vary between 0 (beginning of reaction) and 1 (end of reaction). The comparison of the normalized kinetic curves is presented in Figure 9. The plotted αε(t) dependences have the exponential character, and consequently they might be well described by the first-order kinetic equation: α ε = exp (− kt ) + C

(7),



Page 18 of 29

where: k is value of rate constant, and t is time. From the determined rate constant of tautomerization we can easily calculate the half-life time of tautomerization using the relationship: t1/2 = ln(2)/k. In Table 1 we present a summary of the values: the rate constants and the half-life times of CLP tautomerization reaction performed at different temperatures.

T [K]

k [s-1]

t1/2 [min]

308

2.3 · 10-5

502

323

1.0 · 10-4

116

338

4.8 · 10-4

24

Table 1. Comparison of the values of the rate constant k, and half-life time t1/2 for CLP’s tautomerization reaction.

Figure 9. Comparison of the kinetic curves obtained at T = 308 K, T = 323 K and T = 338 K. To compare the kinetic curves measured at different temperature conditions, the so-called reaction degree (αε) was calculated. The inset presents the temperature dependence of logarithm of the rate constants. Solid line denotes Arrhenius fit.

Finally, the values of the rate constants calculated previously was used to determine the activation energy of the tautomeric conversion of CLP. As presented in the inset of Figure 9, the logarithm of the k value is linearly related to the inverse of temperature. Therefore, the Arrhenius equation defined as follows: ln k = ln A −

Ea RT

(8)

was employed to determine the activation energy barrier of CLP for tautomerization. The lnA in the above formula denotes the pre-exponential factor, R is thegas constant, and T is absolute temperature. The calculated value of Ea is equal to 207 kJ/mol.


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Influence of elevated pressure on the physical stability of amorphous CLP In the previous sections we established that the amorphous form of CLP does not easily re-crystallizes at both, standard storage and elevated temperature conditions. Taking into account that during manufacturing processes, e.g. hot melt extrusion or tableting, the APIs might also be exposed to other unfavorable conditions such as elevated pressure, in this part of the paper we will investigate the influence of compression on the physical stability of disordered CLP. To examine how compression and decompression procedure affects the recrystallization propensity of the investigated antibiotic, high pressure dielectric spectroscopy was employed. As previously CLP did not reveal any tendency towards devitrification at T = 338 K, we decided to compress the sample to 10 MPa and then quickly decompress it at exactly the same temperature conditions. Therefore this experiment consisted of five steps: (i) sample preparation; (ii) temperature stabilization; (iii) 15 min waiting time; (iv) sample compression to 10 MPa and quick decompression; and finally (v) isothermal monitoring of sample reaction (~ 2.5h at 338 K). The results from the last, i.e. the fifth, step are presented in Figure 10a. It can be seen that after compression and decompression, one can observed a drop in the value of εs. Comparing these results to data obtained when the sample was stored continuously at ambient pressure i.e. without compression – see Figure 10a and b – we might conclude that elevated pressure triggers devitrification of disordered CLP. To better visualize these data, we selected one frequency point at which the plateau of εs is well visible (f = 1673 Hz), than normalized it in the accordance with the eq 6 (this time however the degree of reaction αε was named as normalized dielectric constant ε’N), and finally we plotted on one graph: the progress of crystallization recorded after the compression procedure, and the progress of tautomerization from the experiment performed at ambient pressure – not treated by elevated pressure (see Figure 10c). Since in the case of a tautomerization reaction the value of εs does not decrease over time, value of εs(∞) was substituted by ε∞. Now, it is clear to see that the compression and decompression procedure had indeed a huge impact on the physical stability of supercooled CLP. At the same time at which the compressed sample reaches full crystallization, the uncompressed sample remains stable. It is of importance to notice that this is not the first time when compression was found to have a significant influence on the physical stability of amorphous APIs. Recently, a similar behavior was observed in probucol, indomethacin, and celecoxib55,56,57.



Figure 10. (a) Dielectric spectra of the real part of the complex dielectric permittivity of CLP during physical stability time depending isothermal experiment performed after compression and decompression procedure at T = 338 K. (b) Dielectric spectra of the real part of the complex dielectric permittivity of CLP during physical stability time depending isothermal experiment performed without compession at T = 338 K. (c) Normalized dielectric constant ε′N as a function of time from the short-term physical stability tests at 338 K. Green line show the physical stability of CLP stored at ambient pressure after compression and decompression procedure, while black line represents the crystallization tendency of the same pharmaceutical stored at the same conditions, but this experiment has not been proceeded by a compression to p = 10 MPa.

Considering the results obtained, we believe that applying pressure to the sample, initialization of formation of crystallization nuclei occurred. It is well known that once nuclei are formed, and the sample is stored at conditions favorable for crystal growth, the devitrification process will proceed. The lack of crystallization observed during the experiment performed at ambient pressure (without compression) suggests that either these conditions are not favorable for nucleation, or some other factors, which primary inhibit crystallization (e.g. tautomerization) occur. If the latter explanation is truth it would mean that compression triggers CLP’s re-crystallization when only one tautomeric form exists in the sample. It is worth to recall that during the tautomerization reaction a fraction of molecules change their structure to reach the equilibrium between the two isomers. Thus, the formed “composition” of tautomers might behave like a binary amorphous mixture of different drugs. It has frequently been reported that mixtures containing two amorphous APIs might be characterized by a high physical stability even if the neat components have significant tendencies towards re-crystallization. Examples of such a mixtures are: ezetimibe + 20 ACS Paragon Plus Environment

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indapamid,

naproxen

hydrochloride

58,59,60

+

indomethacin,

as

well

as

indomethacin

+

ranitidine

.

To verify if the tautomeric ratio has an influence on the physical stability of amorphous CLP, we performed an additional high pressure dielectric experiment. Herein, a freshly prepared sample was stored for t = 72h (this time is equivalent to the time required for achieving the equilibrium between CLP’s tautomers at this particular T) at T = 308 K, then the sample was heated to T = 338 K and finally compressed to 10 MPa and quickly decompressed. The results obtained from the last step of this experiment are presented in Figure 11b. To better visualize the differences between the physical stability of the sample compressed and decompressed just after preparation, and the sample compressed and decompressed when equilibrium between tautomers was reached (i.e. after waiting 72h at T = 308 K) we plotted their ε’N(t) dependence on one graph (see Figure 11c). It can be seen that CLP exposed to elevated pressure after 72h of waiting begins to re-crystallize after 24360 s (i.e. ~ 7h) from the moment of compression and quick decompression. Interestingly, the second sample (which was compressed just after preparation) was completely crystalline after just 2h from the moment of compression i.e. the equilibrated sample crystallized 34-times slower. Based on the presented comparison, one can conclude that the time of the chemical equilibration influences the physical stability of compressed CLP. It can happen as the tautomeric ratio changes over time. As two different fractions of CLP are formed, the physical stability of the final, equilibrated sample might be improved.



Figure 11. (a) Dielectric spectra of the real part of the complex dielectric permittivity of CLP during physical stability time depending isothermal experiment performed at T = 338 K, after compression and decompression sample just after their preparation. (b) Dielectric spectra of the real part of the complex dielectric permittivity of CLP during physical stability time depending isothermal experiment performed at T = 338 K, after compression and decompression sample which was first stored for 72h at 308K. (c) Normalized dielectric constant ε′N as a function of time from the described above isothermal tests.


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CONCLUSIONS In this article, we have thoroughly investigated the physical stability of amorphous form of chloramphenicol. Non-isothermal calorimetric studies, performed at six different heating rates of 30 K/min, 20 K/min, 10 K/min, 5 K/min, 2.5 K/min, and 1 K/min indicate that amorphous CLP during heating did not reveal any tendency towards re-crystallization. Taking into account that molecular dynamics is considered as the key factor governing the physical stability of amorphous materials, we studied the CLP’s molecular mobility at both supercooled liquid and glassy states. To do that, broadband dielectric spectroscopy was employed. In addition to the structural α – relaxation, CLP exhibited one further, very broad, secondary relaxation process. Since its activation energy has a relatively low value (equal to 34.5 kJ/mol) it can be classify as a non-JG secondary relaxation. Based on dielectric data we determined that the fragility parameter of the investigated antibiotic is 116. Several authors consider this parameter as an indicator of the physical stability of amorphous APIs. In accordance with this assumption fragile materials i.e. those with high values of mp should easily re-crystallize. CLP, with its high value of mp, and quite good physical stability does not meet this assumption. To have a thorough understanding of the physical stability of amorphous CLP towards devitrification, we examined the drug also at isothermal conditions. The time-dependent isothermal experiment were performed by dielectric spectroscopy. As pharmaceuticals, in majority of cases, are stored at standard storage conditions, we began isothermal dielectric studies from a short-term stability experiment performed at T = 308 K (close Troom) and ambient pressure. Results from this investigation indicate that the disordered form of CLP stored at the experimental conditions did not revert to its starting i.e. crystalline form. During the performed experiment, which took over 4 days, no sign of drug devitrification was noted. Taking into account that elevated temperature accelerates devitrification from an amorphous state, in the next part of isothermal time-dependent experiments we held the tested antibiotic at T = 323 K and T = 338 K. During all these tests a decrease in the value of εs was not observed. This indicates that the investigated samples did not even begin to crystallize. Interestingly, instead of the expected decrease in static permittivity, its increase was seen. Such a change in εs (∆ε) indicates that the sample effective dipole moment was changed during the experiment time. The most probable reason for such a change is tautomerization of CLP. The estimated activation energy of this reaction is 206 kJ/mol. As CLP even at elevated temperatures (i.e. conditions that should accelerate re-crystallization of amorphous APIs) does 23 ACS Paragon Plus Environment


not undergoes devitrification, additional stability tests were performed. In this case, the physical stability of the disordered form of CLP was investigated at conditions simulating a manufacturing process. The sample was first compressed to 10 MPa and then quickly decompressed. This experiment showed that after compression the sample immediately recrystallized. To check if the observed process is related to the lack of tautomeric species in the sample, we repeated the above experiment when the chemical equilibrium was reached. This investigation indicates that storage and manufacturing conditions might have an impact on the re-crystallization tendency of CLP. This particular example is extremely interesting from both cognitive as well as application point of view for amorphous APIs. On one hand, it clearly shows that a problem with physical stability of amorphous pharmaceuticals is enormously complex, and still a lot of different scenario might be found in this matter. On the other hand, it demonstrates that even a slight change in the manufacturing protocol might have a profound impact on the physical stability of amorphous APIs.

ACKNOWLEDGEMENT 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). L.T. is funded by the Synthesis and Solid State Pharmaceutical Centre (SSPC), financed by a research grant from Science Foundation Ireland (SFI) and cofunded under the European Regional Development Fund (Grant Number 12/RC/2275) and SFI Career Development Award (Grant Number 15/CDA/3602).


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Can storage time improve the physical stability of amorphous

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