Preparation of pharmaceutical cocrystal formulations via melt mixing technique: A thermodynamic perspective

European Journal of Pharmaceutics and Biopharmaceutics 131 (2018) 130–140

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European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb

Research paper

Preparation of pharmaceutical cocrystal formulations via melt mixing technique: A thermodynamic perspective

T

⁎

P. Barmpalexis , A. Karagianni, I. Nikolakakis, K. Kachrimanis Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece

A R T I C LE I N FO

A B S T R A C T

Keywords: Cocrystals Melt mixing Flory Huggins theory Polymer matrix Thermodynamics

The aim of the present study was to evaluate the thermodynamic properties of in-situ formation of cocrystal formulations by the melt-mixing method. Specifically, the thermodynamic mixing behaviour of carbamazepinenicotinamide and ibuprofen-nicotinamide cocrystals prepared with the aid of Soluplus® (SOL) were evaluated using thermodynamic lattice-based solution theories. Thermodynamic miscibility of both cocrystals with SOL was predicted by calculating Gibb′s free energy based on the Flory-Huggins (FH) interaction parameter (χ), while the activity coefficient of cocrystals estimated with the aid of solid–liquid equilibrium equation and FH lattice theory, showed good thermodynamic miscibility of the components at elevated temperatures used normally during melt-mixing based processes. Complete phase transition diagrams constructed with the aid of DSC measurements and FH solution theory, suggested the existence of two transition zones: (1) a stable cocrystal zone, located at the right-hand-side of the spinodal phase separation curve, where stable cocrystals are prepared and (2) an unstable cocrystal zone, located at the left-hand-side of the spinodal curve up to liquidus, where the matrixforming polymer sets a kinetic barrier to recrystallization and hence, a barrier to the formation of cocrystals. The validity of the suggested thermodynamic phase transition zones was experimentally verified by ATR-FTIR and hot-stage polarized light microscopy.

1. Introduction

sublimation, precipitation, sono-crystallization etc. [1,9–11]. In the case of co-grinding methods, the intermediate phase is formed by neat or wet (liquid assisted) co-grinding of the API with coformer(s) by hand (mortar and pestle) or suitable equipment (e.g. mills) [2]. Generally, although these techniques are capable of producing cocrystals of high purity, scaleup difficulties along with several drawbacks related to the use of large amount of solvents in the case of solvent-based methods, and the risk of inducing amorphization in the case of mechanical energy input methods, possess a major challenge for the large-scale preparation of pharmaceutical cocrystals [1,7]. Recently, significant progress has been made in designing novel, more easily scalable continuous processes such as hot-melt extrusion, for the production of cocrystal formulations [12,13]. In this respect, melt mixing based processes are being tested for the simultaneous preparation of cocrystals and finished dosage forms (i.e. formulations) in a continuous, easily scalable process [4,7]. Melt-mixing based techniques are continuous processes which combine the usage of controlled heat (melt co-mixing) and in some cases shear deformation [1,2]. In these processes, the API along with the coformer and a suitable matrix-forming polymer are fed into a proper melting/mixing device (such as an extruder, or a melt/mixing head etc.) where the simultaneous cocrystallization and dispersion into a polymer

Pharmaceutical cocrystallization is used to modify several properties of active pharmaceutical ingredients (APIs) including stability, dissolution rate, bioavailability, mechanical and physicochemical properties among others, without affecting their pharmacological activity [1–6]. Pharmaceutical cocrystals are defined as solid-crystalline stoichiometric molecular adducts of an API with a coformer(s), bound via non-covalent interactions (such as hydrogen bonds, π-π stacking, and van der Waals) within the crystal lattice [1,2,4]. In contrast to salts, cocrystals do not possess any ionizable centers, as there is no proton transfer between the API and the coformer(s). Cocrystallization process involves the formation of an intermediate phase with increased molecular mobility (i.e. liquid or amorphous state) from which the API and the coformer cocrystallize in order to prepare a physically and molecularly stable solid crystalline form [7,8]. Generally, there are two approaches used for preparing such intermediate phases leading to cocrystals: (1) solution-based and (2) neat cogrinding based methods. In the solution-based methods, the API and coformer(s) are dissolved in a suitable solvent, forming the desired intermediate phase, from which cocrystals can be prepared by several techniques such as slow evaporation, solution crystallization, slurry conversion,

⁎

Corresponding author. E-mail address: [email protected] (P. Barmpalexis).

https://doi.org/10.1016/j.ejpb.2018.08.002 Received 1 April 2018; Received in revised form 12 July 2018; Accepted 2 August 2018 Available online 06 August 2018 0939-6411/ © 2018 Elsevier B.V. All rights reserved.

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the phase diagram can be estimated by fitting FH lattice-based solution theory equation (Eq. (1) to the melting point depression data from DSC measurements.

matrix take place [7,14–16]. Therefore, the selected matrix polymer plays simultaneously the role of the catalytic solvent for cocrystal formation and of the matrix former in the finished dosage form. As the resultant cocrystals and the melted matrix polymer solidify together simultaneously, it is crucial to keep in mind that the physicochemical and mechanical properties of the selected matrix polymer are of equal importance as those of the cocrystal system itself [7]. However, despite the considerable advantages of meltmixing cocrystal formulation approach (i.e. continuous single-step process, solvent-free, high scalability, easy to control via process analytical technology tools), limitations regarding the melt cocrystallization may arise especially when thermolabile compounds are processed [2,7]. In such cases, an in depth understanding of the process thermodynamics is essential in order to fully comprehend and control/predict both underlying phenomena (cocrystallization and matrix formation). The advantages of utilization of thermodynamics, mainly through the application of lattice-based solution models such as Florry-Huggins lattice theory (FH) on melt-mixing based pharmaceutical processes has been recently explored, especially during the preparation of highly energetic state pharmaceutical formulations such as amorphous solid dispersion (ASD) and solid solutions [17–22]. In such systems, construction of phase diagrams by using experimental melt-point depression data from differential scanning calorimetry (DSC) and thermodynamic equations, aid in the evaluation of API′s miscibility within the matrix forming polymer. Thermodynamically miscible blends may lead to single phase amorphous systems which increase the physical stability and reduce the chemical potential of the API by altering the thermodynamic driving force for crystallization [23,24]. In the case of cocrystal melt-mixing formulation processes, these resultant highly miscible API-polymer blends may lead to undesired API amorphization, which, although thermodynamically unstable, may remain amorphous (kinetic stability) for a long but unpredictable period of time. Hence, in order to prepare a stable cocrystal formulation via melt-mixing, the thermodynamic relation of components and the construction of thermodynamic phase diagrams are of crucial importance. To the best of our knowledge, such thermodynamics-based studies on melt-mixing cocrystal formulations have not yet been published. Therefore, in the present study, the thermodynamic mixing properties of cocrystal formulations prepared by melt-mixing were evaluated for the first time. Specifically, component miscibility and binary phase diagrams of carbamazepine - nicotinamide (CBZ-NCT) and ibuprofen - nicotinamide (IBU-NCT) cocrystals with Soluplus® (SOL, polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer) were evaluated with the aid of thermodynamic lattice-based solution theories (under the assumption that the molecular adduct comprising the cocrystal dissolves in the polymer matrix without dissociating to its constituent molecules). The model′s predictions of phase composition vs temperature were experimentally verified by the preparation of CBZ-NCT/SOL and IBU-NCT/SOL cocrystal formulations. This approach is of great significance in pharmaceutical formulation, as it enables the selection of optimal cocrystalpolymer compositions and operating conditions for the simultaneous cocrystallization and dispersion in polymeric matrices via continuous thermal mixing processes, such as hot melt extrusion.

1 1 −R ⎡ 1 ⎛ ⎞ ⎜ ⎟ = − lnΦcocrystal + ⎛1− ⎞ Φpolymer T ( mix ) T ( pure ) ΔH m ⎝ ⎠ m m fus ⎣ ⎠ ⎝ + χ Φ2polymer ⎤ ⎦

(1)

where, Tm(pure) and Tm(mix) are the melting temperatures of the pure cocrystal and of the cocrystal in the presence of SOL, respectively; ΔHfus is the heat of fusion of the pure cocrystal, m is the volume ratio of the polymer to cocrystal (calculated as molar volumes from the true density), R is the gas constant, χ is the FH interaction parameter, and Φcocrystal and Φpolymer are the volume fractions of cocrystals and SOL, respectively. In order to solve the equation, the interaction parameter, χ, has to be determined. Although in reality χ depends on concentration and/or temperature (χ = f(Φ) or χ = f(Φ,T), for simplicity, in many cases it is considered to be either zero (athermal mixing) or constant (χ = α or α ≠ 0) [25,26]. In the present study, the FH interaction parameter was considered to be temperature dependent based on the following equation:

χ=A+

B T

(2)

where, A is the value of the temperature-independent term (entropic contribution), B is the value of the temperature dependent term (enthalpic contribution). For the construction of the spinodal phase separation curve, the second derivative of the following FH free energy equation is set equal to zero:

ΔG = RT ⎡Φcocrystal lnΦcocrystal + ⎛ ⎢ ⎝ ⎣

1−Φcocrystal

⎜

⎞ ln(1−Φcocrystal) ⎠

⎟

m

+ χ Φcocrystal (1−Φcocrystal)⎤ ⎥ ⎦

(3)

Miscibility of the cocrystals in the melt-mixing matrix polymer can be monitored by the changes of the cocrystal′s melting temperature (Tm) and heat of fusion ΔHfus values. A decrease in the Tm and ΔHfus with increasing proportion of polymer indicates miscibility and can be related to the FH interaction parameter χ in Eq. (1) [23]. This parameter accounts for the enthalpy of mixing and is an indication of cosrystal-polymer miscibility [24]. At low polymer weight fractions the interaction parameter, χ, may be assumed as constant (independent of temperature and volume fraction) and hence it can be calculated from the slope of line derived from the graph of Φ2polymer to

(

1 1 − Tm (mix ) Tm (pure )

)(

−ΔHfus R

)−lnΦ

(1− ) Φ

cocrystal −

1 m

polymer ,

where, negative

values of χ indicate miscibility between the cocrystal and the tested polymer. Additionally, the solubility of the cocrystal in the selected matrix polymer (i.e. miscibility profile in terms of varying temperature and concentration) can be calculated based on the activity coefficient of the cocrystal (γcocrystal) with the following equation:

2. Theoretical section

1 ln(γcocsrystal ) x cocrystal = lnΦcocrystal + ⎛1− ⎞ Φpolymer + χ Φ2polymer ⎝ m⎠

In the preparation of in-situ melt-mixing cocrystal-polymer formulations the obtained system can be considered as a two component structure, where the cocrystal and the polymer act as solute and solvent, respectively. In this case, similarly to solid dispersion applications, cocrystal-polymer phase diagrams can be constructed with the aid of FH polymer solution theory. A typical thermodynamic phase diagram consists of a liquid–solid transition curve (known as the liquidus), representing the equilibrium solubility of cocrystals in the polymer matrix at different temperatures, a spinodal curve, representing the area where two separate phases are observed, and a glass transition temperature (Tg) curve [18]. In pharmaceutical applications, where a polymer plays the role of the solvent

(4)

while, the activity coefficient is estimated on the basis of the extended Hansen solubility model [27]:

ln(γcocsrystal ) = ⎧ ⎨ ⎩

Vcocrystal RT

⎫ {(δ cocrystal−δd )2 d ⎬ ⎭

+ 0.25[(δpcocrystal−δp )2 + (δhcocrystal−δh )2]} + ln ⎛ ⎝ Vcocrystal − V

Vcocrystal

⎜

131

⎞+1 ⎠ ⎟

V

(5)

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P. Barmpalexis et al.

temperatures are listed in Table 1 (density values were determined experimentally with a helium pycnometer (Ultrapycnometer 1000, Quantachrome Instruments, USA). By substituting the value of γcocrystal in Eqs. (4) and (5), the temperature T at which the crystalline phase is in equilibrium with the dissolved amorphous phase and the mole fraction of dissolved cocrystal can be estimated according to Flory–Huggins models.

where δ are molar volume weighted solubility parameters and V is the mixture volume derived from the following equations: n

δ =

∑ Φk δk

(6)

k=1

Φk =

xk Vk V

(7)

Vk =

MWk ρk

(8)

3.3. Preparation of cocrystal/SOL thermodynamic phase diagrams The construction of the cocrystal/SOL liquidus in the thermodynamic phase diagrams was made by fitting FH lattice-based solution theory equation (Eq. (1)) to the melting point depression data obtained from DSC measurements. The FH interaction parameter was considered to be temperature dependent based Eq. (2). The construction of the spinodal phase separation curve was made based on Eq. (3).

n

V =

∑ xk Vk

(9)

k=1

where, Φ is the volume fraction, x is the mole fraction, MW the molecular weight, ρ is the density, and the subscript k denotes the different components of the mixture.

3.4. Preparation and characterization of cocrystals and cocrystal formulations

3. Materials and methods 3.1. Materials

3.4.1. Preparation of neat cocrystals: Solvent evaporation method CBZ–NCT and IBU-NCT neat cocrystals to be used as reference samples were prepared using the solvent evaporation method. Equimolar amounts of APIs and coformer (CBZ to NCT in 1.94:1 mass ratio and IBU to NCT in 1.68:1 mass ratio) were dissolved in ethanol under heating and constant stirring until a clear solution was obtained. The resultant solution was cooled and the solvent was allowed to evaporate overnight. The obtained cocrystals were gently ground with mortar and pestle, screened through a 40 mesh sieve and stored airtightly in a desiccator until further analysis.

The drugs CBZ (Ph. Eur. 7.0) and IBU were kindly donated by Galenika AD (Belgrade, Serbia) and Rontis Hellas SA (Athens, Greece) respectively. NCT was purchased from Sigma Aldrich (Sigma Aldrich Co., USA) and together with the drugs was used for the preparation of pharmaceutical cocrystals. SOL (lot no. 84414368E0) kindly donated by BASF (Ludwigshafen, Germany) and used as melt-mixing matrix polymer. All other materials and reagents were of analytical grade and used as received. 3.2. Estimation of thermodynamic miscibility between cocrystals and SOL

3.4.2. Preparation of SOL-cocrystal formulations by melt-mixing SOL-cocrystal formulations were prepared by the melt-mixing technique. Specifically, equimolar amounts of CBZ–NCT and IBU-NCT at various weight ratios to SOL were mixed and heated at 170 °C for CBZ/NCT-SOL (the temperature was selected in order to avoid any thermal decomposition problem as CBZ-NCT cocrystals start to decompose immediately after passing their melting point [28]) and 140 °C for IBU/NCT-SOL (the temperature was selected in order to ensure complete mixing of all compounds), using a mortar and a pestle, until a homogeneous melted mixture was observed. The resultant mixtures were collected after cooling to ambient temperature, gently ground with a mortar and pestle and passed through a 40 mesh sieve before storing air-tightly in a desiccator.

The miscibility of CBZ-NCT or IBU-NCT cocrystals with SOL was estimated based on the following approaches: 3.2.1. Estimation of FH interaction parameter by DSC melting point depression Miscibility of the cocrystal systems with SOL was studied by monitoring the changes of the melting temperature (Tm) in the melt endothermic peak and heat of fusion ΔHfus of the cosrystal based on Eq. (1) and the estimation of the interaction parameter, χ, at low polymer weight fractions from the slope of line derived from the graph of Φ2polymer to

(

1 1 − Tm (mix ) Tm (pure )

)(

−ΔHfus R

)−lnΦ

(1− ) Φ

cocrystal −

1 m

polymer .

3.4.3. Differential scanning calorimetry (DSC) Thermal analysis was carried out on a DSC 204 F1 Phoenix heat-flux differential scanning calorimeter (NETZSCH, Germany). The instrument was calibrated for temperature and energy using indium standards. For melting point depression determination, accurately weighted amounts of samples (3–5 mg) were placed in perforated aluminum pans and

3.2.2. Estimation of temperature at which the crystalline phase is in equilibrium with the dissolved amorphous phase The solubility of the cocrystal in the selected matrix polymer (i.e. miscibility) was calculated based on the activity coefficient of the cocrystal (γcocrystal) using Eqs. (4) to (9). The parameters required for calculation of the miscibility of the cocrystal in the polymer at different Table 1 Data used for the estimation of cocrystal–SOL miscibility using the SLE model. Substance

CBZ IBU NCT SOL CBZ-NCT IBU-NCT

MW (g/mol)

236.26 206.28 122.13 1180000.00 358.39 328.41

Density (g/cm3)

1.34 1.03 1.45 1.20 1.32 1.21

Molecular volume (cm3/mol)

Melting point (K)

*

176.58 200.27 92.90 98333.00 269.48 293.17

467.3 351.0 406.6 – 434.10 368.10

* Melting of CBZ form I

132

Solubility parameters (MPa1/2) δd

δp

δh

23.7 16.44 17.76 17.4 20.52 17.09

8.0 6.39 11.95 0.3 9.78 8.74

10.2 8.89 12.88 8.6 11.46 10.70

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scanned through a temperature range of 20–200 °C at a heating rate of 10 °C/min under a nitrogen purge gas flow of 75 mL/min. 3.4.4. Hot stage optical microscopy A Linkam THMS600 (Linkam Scientific Instruments Ltd, Surrey, UK) heating stage mounted on Olympus BX41 polarized light microscope and controlled through a Linkam TP94 temperature controller, was used for microscopic investigations. CBZ/NCT-SOL and IBU/NCT-SOL physical mixtures were heated from 25 °C to 170 °C, and 25 °C to 140 °C, respectively, at a rate of 10 °C/min. After heating the samples were left to cool at room temperature. When newly formed crystals were observed during cooling, the samples were re-heated again from 25 °C until melting of the formed crystals. Observations were videotaped with a Jenoptik ProgRes C10Plus color video camera (JENOPTIK Optical Systems GmbH, Jena, Germany) directly attached to the microscope. 3.4.5. Attenuated total reflectance FTIR (ATR- FTIR) spectroscopy FTIR spectra in the region of 600–4000 cm−1 were obtained using a Shimadzu IR-Prestige-21 FTIR spectrometer coupled with a horizontal Golden Gate MKII single-reflection ATR system (Specac, Kent, UK) equipped with a ZnSe lense after appropriate background subtraction. Sixty-four (64) scans over the selected wavenumber range at a resolution of 4 cm−1 were averaged for each sample. 4. Results and discussion 4.1. Preparation of CBZ/NCT and IBU/NCT reference cocrystals The formation of the reference CBZ/NCT and IBU/NCT cocrystals, prepared using the solvent evaporation method was verified with the aid of DSC and ATR-FTIR analysis. Specifically, Fig. 1(A) shows the DSC thermograms and the ATR-FTIR spectra of the prepared cocrystals along with the physical mixtures (PM) at 1:1 M ratio and the pure components. Regarding the DSC thermograms of the pure components, IBU and NCT showed a single endothermic peak at 78.0 °C and 133.8 °C, respectively, while CBZ showed a small melting endotherm at 176.8 °C (corresponding to the melting of form III) followed by a second endotherm at 194.2 °C (corresponding to the melting of form I). The DSC thermograms of the physical mixtures showed two melting endotherms at 71.5 °C and 89.8 °C for IBU-NCT physical mixture, corresponding to pure IBU and NCT, respectively, while in the case of CBZ-NCT physical mixture, two endothermic peaks at 127.2 °C and 162.3 °C, corresponding to melting of NCT and the melting of the in-situ formed CBZ/ NCT cocrystal, respectively, were recorded. As expected from previously published data [1,4], DSC thermograms of the prepared reference cocrystals showed a single melting endotherm at 95.1 °C and 161.2 °C for IBU/NCT and CBZ/NCT respectively, indicating that high purity reference cocrystals were prepared with the followed solvent evaporation method. ATR-FTIR spectra in Fig. 1(B) show the characteristic peaks for pure IBU at 3100–2800, 1720 and 1510 cm−1 (corresponding to the -OH of the carboxylic group, the eC]O and the -CH of the aromatic ring stretching, respectively); for pure CBZ at 3465 and 1677 cm−1 (corresponding to the -NH and eC]O stretching, respectively); and for pure NCT at 3364, 1695 and 1680 cm−1 (corresponding to carboxamide -NH and eC]O stretching, respectively). The FTIR spectra of IBU-NCT and CBZ-NCT physical mixtures showed most of the characteristic peaks of pure component, while in the case of cocrystals, FTIR analysis of CBZ/ NCT showed a peak shift corresponding to -NH stretch of CBZ′s amide from 3465 to 3447 cm−1, indicating hydrogen bonding between CBZ and NCT which facilitates the formation of CBZ/NCT cocrystal.

Fig. 1. DSC thermograms (A) and ATR-FTIR spectra (B) of prepare reference CBZ/NCT and IBU/NCT cocrystals along with physical mixtures at 1:1 M ratio (CBZ-NCT PM and IBU-NCT PM) and the pure CBZ, IBU and NCT components.

Additionally, changes compared to the physical mixture were also observed in the -C]O area (1750–1600 cm−1) of CBZ/NCT cocrystals. In the case of IBU/NCT cocrystals, the appearance of two low intensity bands at 1950 and 2500 cm−1 (relative to the heterosynthon bond between ibuprofen and nicotinamide) and the shift of the vibrational peak of eC]O from 1720 cm−1 (IBU) and 1695 cm−1 (NCT) to 1680 cm−1, indicated the formation of pure cocrystals [4,29]. Based on the aforementioned results, it can be concluded that the solvent evaporation method employed in the present study was able to produce high purity reference CBZ/NCT and IBU/NCT cocrystals standards. 4.2. Evaluation of cocrystal-SOL thermodynamic miscibility The DSC thermograms of CBZ/NCT-SOL and IBU/NCT-SOL at various weight fractions of cocrystals to polymer are shown in Fig. 2. From

133

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P. Barmpalexis et al.

Fig. 2. DSC thermograms of CBZ/NCT-SOL (A) and IBU/NCT-SOL (B) mixtures at different weight ratios.

Fig. 2 a reduction in cocrystal melting point is observed (melting point depression) suggesting that an interaction (miscibility) between the two phases (cocrystal and matrix polymer) is taking place.

is not clear whether phase separation or conversion from stable cocrystals to amorphous single-component systems will occur at lower temperatures (storage conditions).

4.2.1. Estimation of miscibility by the FH interaction parameter Fig. 3(A) illustrates plots of Φ2polymer vs. (1/Tm − 1/Tm(pure))*(−ΔH/ R)−ln(Φcocrystal)−(1−1/m)*Φpolymer used to calculate the FH interaction parameter (χ), in a low cocrystal concentration region where χ can be assumed to be constant (independent of T and Φ). The χ values, calculated from the slope of the linear regression fit on the obtained experimental data, were +0.790 (R2 = 0.994) and −0.710 (R2 = 0.928) for the IBU/NCT-SOL and the CBZ/NCT-SOL cocrystal formulations, respectively. In the case of IBU/NCT-SOL, the positive value of χ is indicative of a weak interaction between the cocrystals and the selected matrix polymer, while for CBZ/ NCT-SOL the negative χ value is representative of the formation of a miscible system. Hence, based on the above estimated χ values it can be assumed that the CBZ/NCT cocsrystals possess more favorable mixing properties with SOL compared to the IBU/NCT cocrystals. Based on the calculated χ values the change in Gibb′s free energy for both systems as a function of cocrystal fraction is shown in Fig. 3(B). Results showed that Gibb′s free energy depended upon Φcocrystal and was negative in all tested region, even in the case of IBU/NCT-SOL where a positive χ value was estimated, indicating miscibility for both systems. Based on the above analysis, thermodynamic miscibility between the examined systems in the region close to the melting point of cocrystals is suggested. Consequently, during melt-mixing process, where elevated temperatures are used, it is more likely to produce miscible SOL-cocrystal blends at process temperatures above 100 °C. However, it

4.2.2. Estimation of miscibility via activity coefficient (γcocrystal) calculation In order to evaluate the effect of temperature on cocrystal′s solubility within the selected matrix polymer, miscibility of the components was evaluated on the basis of solubility parameters and activity coefficient. By using the Hansen solubility parameters, activity coefficient, γ, can be calculated as a function of temperature from Eq. (5). In the case of ideal mixing between cocrystals and SOL, γ may be considered equal to 1 (consequently, lnγ = 0), while in the case where γ is lower than 1 (ln γ < 0) a solid solution formation may be feasible [27]. Fig. 4(A) shows the activity coefficient of CBZ/NCT and IBU/NCT vs. temperature plots, for different weight fractions of cocrystals to SOL, along with the ideal mixing line (lnγ = 0). From Fig. 4(A) it is seen that in both cases (CBZ/NCT and IBU/NCT) lnγ curve approaches the ideal mixing line as temperature increases, indicating a strong correlation between miscibility and temperature. In addition, the steepest angle formed by the lnγ curve with temperature axis in the case of CBZ/NCT indicates a stronger dependence on temperature compared to IBU/NCT. Furthermore, a strong correlation between cocrystals′ concentration (expressed % w/w) and activity coefficient is also illustrated in Fig. 4(A). Specifically, decreasing the percentage of cocrystals in the mixture results in decreasing lnγ values, indicating better miscibility between the two components (cocrystals and SOL). In addition, the obtained negative values of lnγ for mixtures containing up to 5.0% w/w in the case of CBZ/NCT and up 20.0% w/w in the case of IBU/NCT, 134

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Fig. 3. FH interaction plot used to determine miscibility of component through the interaction parameter, χ, from the cocrystal melting point depression (A). ΔGmix/ RT vs. cocrystal volume fraction plot based on Eq. (3) (B).

analysis of xcocrystal vs. temperature graphs showed that only a small fraction of cocrystals (up to 5.0% and 20.0% w/w for CBZ/NCT and IBU/NCT, respectively) can be completely dissolved within the polymer matrix (depicted by the xcocrystal lines crossing the ideal mixing line), whereas a certain threshold was reached with increasing cocrystal concentration (above 15% and 20% w/w for CBZ/NCT and IBU/NCT, respectively), showing that the capacity of SOL to solubilize the examined cocrystals is limited.

suggests the possible formation of solid solutions; whereas concentrations above 15% for CBZ/NCT and above 20% for IBU/NCT, show no significant changes in the ln γ values, indicating a possible limit of cocrystal miscibility in the examined SOL matrix. Fig. 4(B) shows the plots of the mole fraction of dissolved cocrystals, xcocrystal, against temperature, based on the FH lattice theory (Eq. (4). Results show a strong temperature and composition dependence for xcocrystal, with mole fraction values increasing as temperature increases and decreasing as the content of cocrystal increases. In addition, 135

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P. Barmpalexis et al.

Fig. 4. Changes in activity coefficient (A) and mole fraction based FH lattice theory (B) on CBZ/NCT-SOL and IBU/NCT-SOL systems as a function of temperature (percentages in the legend correspond to the weight fraction of CBZ/NCT or IBU/NCT in mixtures). Horizontal dashed lines represent the case of ideal mixing (ln γ = 0).

temperatures close to storage conditions, it is important to note that miscibility is also strongly dependent on cocrystal′s concentration. Thus, in order to evaluate the combined effect of temperature and composition in the phase transition profile of both systems, binary phase diagrams (T vs. φ) of CBZ/NCT-SOL and IBU/NCT-SOL were constructed (Fig. 5(B)). Specifically, in order to construct the liquidus and the spinodal phase transition curves, the FH interaction parameter (χ) was replaced in both Eq. (1) and (3) by χ = A + B/T, while the entropic (A) and enthalpic (B) contribution of mixing constants were calculated from DSC melting point depression data as described above. Before continuing with the analysis of the constructed phase diagrams, it is important to clarify the differences between the favorable thermodynamic events of melt-mixing based amorphous solid dispersions (ASD) and cocrystal formulations. In general, temperature-composition phase diagrams have been used for the prediction of drug′s maximum solubility (and amorphous miscibility) in the case of ASD. In these cases (ASD), the liquidus curve (drug solid–liquid phase boundary) shows the fraction of the crystalline API dissolving into the matrix polymer; while the spinodal curve separates two distinct zones [19]: (1) the so-called “unstable” zone on the right-hand-side of spinodal curve, where, from a thermodynamic perspective, phase separation between the API and the polymer is favored (and hence, no stable amorphous drug dispersion/solution is obtained), and (2) the “metastable” zone (left-hand-side of spinodal curve until liquidus) where API′s nucleation and growth mechanism (re-crystallization process) may be prevented by several characteristic properties of the selected matrix polymer which may pose a significant kinetic barrier to

4.3. Construction of cocrystal-SOL phase diagrams Initially, in order to construct the thermodynamic phase diagram, the FH interaction parameter was calculated based on Eq. (2). Specifically, the DSC melting point depression data from Fig. 2 were fitted to Eq. (1), assuming that χ is temperature depended (i.e. χ = A + B/T), and the constants corresponding to the entropic (A) and enthalpic (B) contribution of mixing for both CBZ/NCT-SOL and IBU/NCT-SOL systems were calculated using the full range of cocrystal to SOL fractions during fitting. Constant A was calculated at −22.14 and −53.69, and constant B at 9,883.80 K and 19,979.89 K for CBZ/NCT-SOL and IBU/NCT-SOL, respectively, indicating higher entropic and enthalpic contribution in the mixing process of IBU/ NCT-SOL, compared to CBZ/NCT-SOL. Based on the calculated A and B constants, a diagram depicting the FH interaction parameter vs. temperature is given in Fig. 5(A). Results showed that in the case of IBU/NCT-SOL negative χ values, and hence good miscibility, is achieved at temperatures above 100 °C, while for CBZ/NCT-SOL good miscibility is obtained at higher temperatures (above 160 °C). This suggests that, compared to CBZ/NCTSOL, lower processing temperatures may be used during the melt-mixing of IBU/NCT-SOL formulations in order to obtain good miscibility between API/coformer and SOL. Furthermore, based on the same graph (Fig. 5(A)) the cocrystal-SOL interaction parameter (χ) for both systems was positive at 25 °C, suggesting limited miscibility between the cocrystal and the selected matrix polymer at temperatures close to storage conditions. However, although miscibility dependence on temperature shows good component mixing at high temperatures (close to melt-mixing process temperatures) and low miscibility at 136

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Fig. 5. (A) Plot of FH interaction parameter, χ, vs. temperature (based on Eq. (2). (B) Binary phase diagrams of CBZ/NCT (black - x -) and IBU/NCT (red - Δ -) with SOL: liquidus (solid line), spinodal (dashed line), Tg line (-●-). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

the so called “unstable” zone in the right-hand-side of the spinodal curve, where thermodynamically stable phase separation between the drug and the selected matrix polymer is favored, can be considered as “stable” in cocrystal formulations. Hence, in this case, the selected matrix polymer plays only the role of the matrix former and poses a kinetic barrier to drug recrystallization. Similarly, the “metastable” zone located in the left-hand-side of spinodal curve until liquidus, represents the “unstable” zone in the case of cocrystal formulations, as

recrystallization. In the case of melt-mixing based cocrystal formulations, the liquidus curve represents again the fraction of the crystalline API/coformer system dissolving into the matrix polymer, however, the notion of “unstable” and “metastable” zones distinguished by spinodal curve has to be reconsidered. Contrary to ASD where the goal is to obtain stable amorphous API, in cocrystal formulations, a thermodynamically stable API/coformer crystalline phase formation (cocrystal) is desired. Thus, 137

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NCT-SOL physical mixtures were compared to the spectra of SOL-cocrystal formulations prepared by the melt-mixing approach (Section 3.4.2). Regarding IBU/NCT-SOL, FTIR spectra analysis showed that at high API/coformer concentration (Φcocrystal = 0.5) the melt-mixing process resulted in the formation of pure IBU/NCT cocrystals within the SOL matrix. This was verified by the presence of peaks at 3396, 3178, 1400 and 1315 cm−1 corresponding to the pure IBU/NCT cocrystal (Fig. 6-A). Similarly, in the case of CBZ/NCT-SOL mixtures with high API/coformer concentration, FTIR spectra peaks at 3392, 3209, 1657 and 1583 cm−1 (Fig. 6-B) verified the formation of pure CBZ/NCT cocrystals within SOL matrix after melt-mixing process. In the case of mixtures with low API/coformer concentration (Φcocrystal = 0.02), no changes in the FTIR spectra between the two samples (physical and melt-mixing mixtures) were observed. Specifically, in both cases the obtained spectra were similar to the pure SOL spectra, indicating that the spectroscopic analytical method used was not suitable to detect the presence of APIs, coformer and cocrystals.

amorphous cocrystals (or amorphous separated API and coformer mono-components) may be stabilized kinetically by the selected matrix polymer, leading to ASD rather than the thermodynamically stable cocrystal formulations. On the basis of the above, Fig. 5(A) depicts the temperature-composition phase transition diagram of both cocrystal formulations. The results showed that although the cocrystal solid–liquid phase boundary curve (liquidus) of CBZ/NCT-SOL is located higher compared to IBU/NCT-SOL (due to the higher melting point of CBZ/NCT cocrystals), the “stable” zone at temperatures close to 25 °C (located in the right-hand-side of the spinodal curve) is the same in both systems (Φcocrystal above 0.05). 4.4. Experimental verification of temperature–composition phase diagrams In order to verify the suggested temperature-composition phase transitions zones, the ATR-FTIR spectra (Fig. 6) of the CBZ/NCT-SOL and IBU/

Fig. 6. ATR-FTIR spectra of SOL, IBU/NCT and CBZ/NCT physical mixtures (PM) and cocrystals, and IBU/NCT-SOL and CBZ/NCT-SOL formulations prepared by melt fusion.

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Fig. 7. HSM micrographs obtained under polarized light for the CBZ/NCT-SOL and IBU/NCT-SOL samples during heating and cooling and re-heating.

5. Conclusion

In order to further evaluate the effect of the selected melt-mixing process on the physical state of the APIs, hot-stage polarized light microscopy (HSM) was conducted. Fig. 7 shows the HSM micrographs depicting the changes occurring in the crystal structure of the pure APIs and the in-situ formed cocrystals, during the melting/cooling process. Specifically, heating of the physical mixture (at 140 °C for IBU/NCTSOL and at 170 °C for CBZ/NCT-SOL) resulted in the complete melting of both APIs and coformer within the SOL matrix independently of API/ coformer concentration revealing good mixing of all components during heating. On the other hand, cooling of the melted samples showed the formation of crystals in the case of high API/coformer concentration, while in the case of low concentration both CBZ/NCT and IBU/NCT remained amorphous, indicating that probably the matrix polymer (SOL) is acting as a kinetic barrier to drug recrystallization. This agrees with the presence of the unstable cocrystal zone in the low API/coformer concentration region of the phase diagram. In the case of high API/coformer concentrations, and in order to verify the ATR-FTIR analysis which showed that pure cocrystals are formed after melt-mixing, the obtained crystals after cooling were reheated and the melting temperature of the newly formed crystals was recorded. Based on the results shown in Fig. 7, both IBU/NCT and CBZ/ NCT newly formed crystals melted at nearly the melting temperature of the pure cocrystals (104 °C for IBU/NCT and 169 °C for CBZ/NCT) indicating that the melt-mixing process of the API/coformer – SOL physical mixtures with high API/coformer concentration results in the formation of pure cocrystals within the polymer matrix. Hence, both HSM observation and ATR-FTIR analysis verify the validity of the constructed stable cocrystal forming zone in the high API/coformer concentration region of the phase diagram in Fig. 5(B).

In the present study, the thermodynamic mixing properties of in-situ forming melt-mixing based cocrystal formulations were evaluated for the first time. Thermodynamic miscibility in temperatures used normally during the melt-mixing process was verified with the aid of solid–liquid equilibrium equation and FH lattice theory for both IBU/NCT and CBZ/NCT cocrystals with SOL matrix polymer. The construction of cocrystal-SOL phase transition diagrams suggested the existence of a stable cocrystal formation zone, located at the right-hand-side of the spinodal curve, and an unstable zone, located at the left-hand-side of the spinodal curve up to liquidus. Experiments on in-situ forming meltmixing based cocrystal formulations verified the suggested phase transition zones. ATR-FTIR and HSM results showed that pure cocrystals are being formed within the suggested phase diagram stable zone, while within the unstable zone the matrix forming polymer (SOL) sets a kinetic barrier to drug recrystallization and hence, to the formation of cocrystals. This methodology may be useful for the prediction of miscibility behavior during processes based on melt mixing which are becoming increasingly important in the modern pharmaceutical industry. Acknowledgments This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflicts of interest The authors report no declarations of interest 139

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Appendix A. Supplementary material

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