Impact of polymeric excipient on cocrystal formation via hot-melt extrusion and subsequent downstream processing

International Journal of Pharmaceutics 566 (2019) 745–755

Contents lists available at ScienceDirect

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

Impact of polymeric excipient on cocrystal formation via hot-melt extrusion and subsequent downstream processing

T

⁎

Maryam Karimi-Jafari , Ahmad Ziaee, Javed Iqbal, Emmet O'Reilly, Denise Croker, Gavin Walker Synthesis & Solid State Pharmaceutical Centre (SSPC), Department of Chemical Sciences, Bernal Institute, University of Limerick, Limerick, Ireland

A R T I C LE I N FO

A B S T R A C T

Keywords: Cocrystal Hot-melt extrusion Downstream processing Compaction triangle Compactibility Tabletability Compressibility

Pharmaceutical cocrystals have gained increasing interest due to their potential to modify the physicochemical properties of drugs. Herein, a 1:1 cocrystal of ibuprofen (IBU) as a BCS class II active pharmaceutical ingredient (API) and nicotinamide as coformer was produced using a hot-melt extrusion (HME) process. The effect of process parameters such as barrel temperature and screw speed were studied. It was shown that the addition of polymeric excipient such as soluplus (Sol) decreases the cocrystallization temperature by enhancing the interaction between API and coformer. In order to study the effect of cocrystallization on the tableting properties of IBU-NIC cocrystal, 5 different formulations of pure IBU, IBU-NIC cocrystal, IBU-NIC physical mixture, IBU-NICSol physical mixture and IBU-NIC-Sol cocrystal were tableted by a compaction simulator. Tabletability, compactibility and compressibility were investigated. The sample with IBU-NIC-Sol cocrystal formulation outperformed all the other formulations in terms of tabletability, compactibility and compressibility. Interestingly, this sample was even superior to the IBU-NIC cocrystal sample which verified the advantageous effect of the presence of an excipient. Moreover, dissolution test confirmed a noticeable increase in the dissolution of not only the cocrystal samples but even the physical mixtures of IBU and NIC compared with pure IBU.

1. Introduction Cocrystallization is an emerging technique for manipulating a wide range of physical properties of active pharmaceutical ingredients (APIs) such as solubility (Luo et al., 2018), physical stability (Trask et al., 2006), mechanical strength (Chow et al., 2012; Karki et al., 2009), bioavailability (Serrano et al., 2018), taste masking (Maeno et al., 2014) and extension of intellectual property (Douroumis et al., 2017; Karimi-Jafari et al., 2018). Cocrystals are “solids that are crystalline single-phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio.” (Aitipamula et al., 2012). A pharmaceutical cocrystal is a cocrystal that in which at least one of the cocrystal formers is an API (Weyna et al., 2009). Cocrystals have been synthesized through two main processes of solid-state or solution-based techniques. Solid state techniques use very little or no solvents during the production process, while solution-based techniques involve a large amount of excess solvent with subsequent isolation steps. Solvent evaporation is the traditional technique for screening cocrystals. Solid-state techniques are advantageous compared with solution-based techniques in terms of their scalability and low environmental impacts (Dhumal et al., 2010). Methods such as solid ⁎

state grinding (Trask and Jones, 2005; Zhang et al., 2012), liquid assisted grinding (Shan et al., 2002), ball-milling (Friscic et al., 2013) and hot-melt extrusion (HME) (Rodrigues et al., 2018) have been employed for production of cocrystals. HME is a versatile one-step process which involves mechanical force and thermal energy to provide the required activation energy for reactions (Lang et al., 2014). Moreover, HME is a continuous process and an attractive candidate for producing and formulating cocrystal APIs (Maniruzzaman and Nokhodchi, 2017; Treffer et al., 2013). HME involves applied shear via screws which can be controlled using the rotation speed of the screws (Patil et al., 2016). The available screw configurations are co-rotating or counter-rotating. Screws can have different configurations including conveying and kneading elements (Thiry et al., 2015). Heating is another critical factor during HME process. The temperature is controllable in the current setup of HMEs at different lengths of screws which is highly advantageous in terms of optimizing the process based on formulation parameters. Thus, due to this complexity, optimization of the process is recommended based on the formulation and process parameters. Ibuprofen (IBU) is a BCS class II API with low solubility (Yazdanian et al., 2004). In addition to its low solubility it is poorly flowable and compactable powder which makes it a challenging API for being formulated in common oral solid dosage forms (Nokhodchi et al., 2015).

Corresponding author at: AD1-009-Analog Devices Building, University of Limerick, Limerick, Ireland. E-mail address: [email protected] (M. Karimi-Jafari).

https://doi.org/10.1016/j.ijpharm.2019.06.031 Received 29 January 2019; Received in revised form 12 June 2019; Accepted 14 June 2019 Available online 15 June 2019 0378-5173/ © 2019 Elsevier B.V. All rights reserved.

International Journal of Pharmaceutics 566 (2019) 745–755

M. Karimi-Jafari, et al.

Table 1 Formulation and process parameters used for hot melt extrusion of IBU-NIC cocrystal. Soluplus (wt%)

Screw Speed (rpm)

Temperature (°C)

0 0 0 0 0 10 20 30

40 60 80 100 120 40 40 40

70 70 70 70 70 70 70 70

± ± ± ± ± ± ± ±

1, 1, 1, 1, 1, 1, 1, 1,

75 75 75 75 75 80 80 80

± ± ± ± ± ± ± ±

1, 1, 1, 1, 1, 1, 1, 1,

Feeding rate (g/h) 80 80 80 80 80 90 90 90

± ± ± ± ± ± ± ±

1, 1, 1, 1, 1, 1 1 1

85 85 85 85 85

± ± ± ± ±

1, 1, 1, 1, 1,

90 90 90 90 90

± ± ± ± ±

1 1 1 1 1

25 25 25 25 25 25 25 25

they reveal the potential of cocrystallization in improving physicochemical properties of challenging APIs. To the best of our knowledge, these aspects of IBU-NIC cocrystals produced via HME have not been studied in the literature so far.

Paradkar et al. produced cocrystals of IBU and nicotinamide (NIC) with higher solubilities compared with pure IBU via HME for the first time (Dhumal et al., 2010). However, the drawback of this process was incomplete transformation of IBU to IBU-NIC cocrystal. Andrews et al. tried to improve the efficiency of cocrystallization of ibuprofen by introducing an inert excipient with low melting point temperature (Li et al., 2016). Healy et al. compared the inclusion of excipients during cocrystallization between spray drying and HME. The feasibility of production of cocrystal via either of the techniques was confirmed (Walsh et al., 2018). However, the effect of inclusion of inert excipient in cocrystallization process via HME on mechanical properties of IBU has not been investigated yet. Tablets account for more than 80% of all dosage forms due to their ease of manufacture and administration. Given the fewer processing steps, direct compression (DC) is the method of choice during API formulation development (Grymonpré et al., 2018). Direct compression refers to tableting powders without any pregranulation steps. For this purpose, powders should possess suitable physical characteristics which enable them to be directly compressed. Direct compressibility of powder is dependent on its intrinsic properties such as flowability, compressibility and compactibility (Patel et al., 2006). Owing to ibuprofen’s high sticking tendency which is attributed to its low melting point (Saniocki et al., 2013) and poor flowability and compressibility (Rasenack and Müller, 2002), producing tablets via direct compression is highly challenging. Moreover, the need for inclusion of high dosage of ibuprofen in each tablet makes the process more complicated (AlKarawi et al., 2018). Many approaches such as dry or wet granulation, addition of various excipients such as magnesium stearate (Qu et al., 2015) or fumed silica (Zhou et al., 2013) and crystal engineering i.e. modification of its crystal habit (Seton et al., 2010) have been employed to improve its properties. As a result, optimizing the powder properties and simultaneous cocrystallization via HME can be highly beneficial. In this research, the production of cocrystal via hot-melt extruding IBU and NIC in 1:1 M ratio was investigated. Two critical factors of screw speed and temperature were optimized for cocrystal formation. The addition of a soluplus as a melting matrix for enhancing the cocrystallization was investigated. In the second stage, the downstream processing i.e. tableting and the effect of cocrystallization on tabletability, compressibility, compactibility, friability, dissolution rate and disintegration were investigated in order to evaluate the effect of presence of excipient on direct compression of IBU-NIC cocrystal tablets. Studying these aspects are highly relevant to the pharmaceutical industry since

2. Materials and methods 2.1. Materials A racemic mixture (RS)-ibuprofen (IBU) (CAS no.: 15687-27-1) was purchased from Phion chemicals Ltd. (Poole, UK). Nicotinamide was purchased from Sigma Aldrich Limited Ireland (Co. Wicklow, Ireland). Soluplus was purchased from BASF (Ludwigshafen, Germany). 2.2. Materials selection rationale Ibuprofen is a BCS class II API with low aqueous solubility, particularly in acidic environment. The presence of carboxylic acid group makes it a proper hydrogen bond donor which facilitates its intermolecular interaction with coformer. Nicotinamide was selected as conformer which has been reportedly used in combination with IBU as a hydrogen bond acceptor. Soluplus is a thermoplastic polymeric excipient with relatively low glass transition temperature (70 °C) which alleviates the concerns about thermal stability of IBU and NIC due to the need for high temperature extruding. Li et al. have shown the feasibility of use of soluplus as a polymeric matrix for cocrystallization purposes (Li et al., 2016). Moreover, use of soluplus offers the ease of post extruding tableting which is of huge interest for direct compaction applications. 2.3. Methods 2.3.1. Hot-melt extrusion (HME) The formulations were prepared with IBU-NIC with 1:1 M ratio (Dhumal et al., 2010; Kelly et al., 2012). Formulations with 0 to 30 wt% soluplus were also prepared with 1:1 M ratio of IBU-NIC. All different process and formulation parameters can be seen in Table 1. Cocrystallization of ibuprofen and nicotinamide in 1:1 M ratio was carried out in a co-rotating twin screw extruder (Hybrid extruder ZE 5/ 12, Three-Tec GmbH, Switzerland) with screw diameter 5 mm and length-to-diameter ratio 32:1 (Fig. 1). The screws were configured only with conveying elements. A 3-zoned barrel with three heating elements

Fig. 1. (a) 3-zoned barrel used for HME process, (b) 16 cm corotating screws with conveying elements used for HME process. 746

International Journal of Pharmaceutics 566 (2019) 745–755

M. Karimi-Jafari, et al.

ibuprofen was added to each dissolution media. The paddles were then immediately rotated at 50 rpm. Samples of 5 mL were collected from the media and filtered by using Nylon 0.45 μm filters at specified intervals of 5, 10, 15, 20, 30, 45 and 60 min. The samples were then analysed using a high-performance liquid chromatography UV setup (HPLC-UV).

was used for heating (for each experiment all the zones were kept at the same temperature). IBU and NIC were mixed (in 0.05 kg batches) in a turbular mixer for 10 min before feeding at a rate of 0.025 kg/h through a gravimetric double screw feeder (ZD 5 FB-C-1M-50 i6000, Three-Tec GmbH, Switzerland) to the extruder. The extruder was operated with a die with the diameter of 1.75 mm and its torque was monitored continuously during extrusion. Die was used to prepare samples with a consistent rod shape in case it is possible. Moreover, presence of die enhances the collection of the powder post extrusion. The physical form of the final extrudate can have significant effects on selecting the next processing steps (see Figs. S1 and S2).

2.3.7. High performance liquid chromatography UV (HPLC-UV) The concentration of ibuprofen (IBU) was determined using HPLCUV as described below. 2.3.7.1. Preparation of standards and calibration curve. Stock solution of ibuprofen (1 mg/mL) was prepared in 1:1 (v/v) acetonitrile:0.1% (v/v) orthophosphoric acid. Calibration curves (0.122 µg/mL–250 µg/mL) were freshly prepared by subsequent dilution in the mobile phase (See Fig. S3).

2.3.2. Powder X-ray diffraction (PXRD) The powders were analysed by PXRD to define their crystallinity and using a PANalytical X’Pert PRO MRD (PANalytical, Almelo, the Netherlands) with monochromatized Cu Kα radiation (λ = 0.15405 nm). The High Score Plus software was used for running the instrument. The X-ray generator settings were set at 40 kV and 40 mA. The scans were performed over 2θ range of 5–50°, with step size of 0.02°/step and step time of 40 s/step.

2.3.7.2. Sample preparation. An aliquot of 500 μL of mobile phase was added to the same volume of each collected dissolution sample. Diluted samples were then vortexed, filtered through 0.25 µm syringe filters and transferred to glass vials for the analysis by HPLC-UV.

2.3.3. Differential scanning calorimetry (DSC) The formation of cocrystal or eutectic compound after HME process was tested via using a 214 Polyma DSC (NETZSCH Group). A 30 mL/ min flow of nitrogen was used as purge gas. Samples of approximately 5.0 mg were weighted into aluminium pans and crimped. Heating rate of 20°/min was used to ramp up the temperature in the range of 20–180 °C.

2.3.7.3. HPLC–UV analysis and quantification. HPLC was performed with an Agilent 1260 Infinity Series system (Agilent Technologies, Waldbronn, Germany) equipped with a G1311B 1260 quaternary pump, G1329B 1260 autosampler, vacuum degasser, G1316A 1260 temperature-controlled column compartment and G1315D 1260 DAD VL detector. The mobile phase consisted of 1:1 (v/v) acetonitrile and 0.1% (v/v) orthophosphoric acid. A Kromasil C18 5 μm, 4.6 d 250 mm column (MZ-Analysentechnik GmbH, Mainz-Germany) was used at a flow rate of 1.0 mL/min. An isocratic (total run time 15 min) was used for the separation of ibuprofen. Typical injection volume was 10 μL. Ibuprofen was detected at a retention time equivalent to 7.805 min at a wavelength of 195 nm. The lower limit of quantification was established as 0.122 µg/mL for ibuprofen. HPLC data was collected and analysed by Agilent OpenLAB 2.2 chromatography data systems (CDS) software.

2.3.4. Raman spectroscopy Raman spectroscopy was carried out using a LabRAM HR Evolu-tion (HORIBA UK Ltd., Stanmore, UK) in a backscatter configuration with 532 nm excitation, laser power 150 mW and exposure time of 5 s for 2 accumulations. Spectra were collected using a ×50 objective at a 4 cm−1 resolution from 200 to 1800 cm−1 using a grating of 600 g/mm. 2.3.5. True density True density of samples was measured at ambient temperature using the Accupyc II gas displacement pycnometry system (Micromeritics®, Nocross, GA, USA) based on USP 699 standard procedure. Helium was purged into the sample chamber to determine its volume. True density is the mass of a substance divided by its volume, excluding open and closed (or blind) pores.

2.3.8. Tableting A Gamlen R-series compaction simulator (Gamlen tableting limited, UK) was used to compact the extrudates and physical mixtures into tablets. Samples of ∼100 mg were tableted using flat-face cylindrical 6 mm punch and die with 30 mm/s punch speed. In order to understand the behaviour of the powders under different compaction pressures, powders were compacted under a wide range of compaction pressures (34–173 MPa). Powders mechanical properties were assessed by determining their tabletability, compactibility and compressibility (Table 2).

2.3.6. Dissolution The dissolution studies were performed following USP29 procedure for ibuprofen solubility studies. USP II apparatus was employed with paddle rotation speed at 50 rpm for 60 min. The dissolution flasks were filled with 900 mL of prepared 0.1 M phosphate buffer with pH 7.2. They were immersed in a water bath to provide fixed and approved temperature at 37 ± 0.5 °C before starting the experiment. The paddles were then assembled and rotated with 50 rpm for 15 min to equilibrate the dissolution media. After the equilibration is achieved, the paddles were stopped and a fixed amount of each formulation containing 50 mg equivalent of

2.3.8.1. Tensile strength. Tensile strength of tablets was calculated based on well-known Fell-Newton equation:

σ=

2F πDt

(1)

where, σ is the tensile strength of the tablets (MPa), F is tablet diametral breaking force (N), D is the diameter and t is the thickness (m) of the

Table 2 Prepared formulations and their acronyms for assessing cocrystal mechanical properties. Formulation

Acronyms

Pure ibuprofen Physical mixture of ibuprofen and nicotinamide 1:1 M ratio Cocrystal prepared via HME of ibuprofen and nicotinamide 1:1 M ratio Physical mixture of ibuprofen, nicotinamide 1:1 M ratio and soluplus (10 wt%) Cocrystal prepared via HME of ibuprofen, nicotinamide 1:1 M ratio and soluplus (10 wt%)

IBU IBU-NIC-phys IBU-NIC-Cocryst IBU-NIC-Sol-Phys IBU-NIC-Sol-Cocryst

747

International Journal of Pharmaceutics 566 (2019) 745–755

M. Karimi-Jafari, et al.

2.3.8.6. Friability. Friability of tablets compressed at compression pressure of 173 MPa were tested using a Pharma Test, Germany friability test apparatus. An equivalent of 650 mg of carefully dedusted tablets were weighted precisely and placed in the drum. After the drum was rotated for 100 times, all the loose dust was removed completely from the tablets before weighing. The weight loss of each formulation was reported at the end.

tablet which were all measured at once using a PharmaTest hardness tester. The diametral breaking force was measured using a PharmaTest hardness tester (Pharma Test Apparatebau AG, Germany) immediately after tableting. 2.3.8.2. Porosity. Solid fraction and porosity of tablet were calculated based on Eqs. (2) and (3):

Solid fraction =

ρapp ρtrue

3. Results and discussions

(2)

Tablet porosity = 1 − − Solid fraction

3.1. Hot-Melt extrusion (HME)

(3)

where, ρapp is apparent density and ρtrue is the true density (g/cm3). Apparent density was calculated by dividing the weight of each tablet by its volume which was calculated by measuring the dimensions of each tablet manually.

3.1.1. IBU-NIC cocrystallization 3.1.1.1. The effect of temperature. The product collected from HME process was analysed with PXRD, DSC, and Raman to assess the impact of process parameters on the extent of cocrystal formation. Initially, samples were extruded at constant screw speed (40 rpm) and different temperatures (70, 75, 80, 85, 90 °C) to investigate the effect of temperature on cocrystallization. PXRD spectra of extruded samples showed the partial formation of cocrystal at temperatures below 90 °C. The prominent characteristic peak of ibuprofen (Soares and Carneiro, 2013) at 2θ = 6.10° was still visible in all samples that were extruded below 90 °C indicating the presence of residual ibuprofen content. However, the intensity of this peak was gradually decreased at higher temperatures until it was no longer detected at 90 °C. Thus, PXRD data shows the full transformation of initial materials to cocrystal at 90 °C. DSC thermograms showed the presence of an endothermic peak at 74 °C with onset of ∼65 °C in samples extruded below 90 °C. This peak at this temperature has already been identified as eutectic peak of IBU and NIC physical mixture in the literature (Dhumal et al., 2010; Lu et al., 2008). The DSC results for samples extruded below 90 °C confirm the presence of excess ibuprofen and nicotinamide in the final product due the partial formation of cocrystal which agrees well with PXRD spectra. Therefore, 90 °C was selected as the optimal temperature for cocrystallization of IBU-NIC (1:1) mixture. Raman spectra of all samples extruded at various temperatures is shown in Fig. 2. The most prominent peak in NIC spectra is the peak at 1041 cm−1, relating to the CeNeH stretch (Socrates, 2004). This peak is shifted to 1032 cm−1 in the cocrystal which is related to the homosynthon interaction between two NIC molecules in the cocrystal structure. The other two peaks that differentiate IBU from cocrystal are the 746 cm−1 of C]O stretch and between 820 and 850 cm−1 of aromatic stretch (Socrates, 2004). These peaks are not present in the cocrystal spectra of all samples except the sample prepared at 70 °C showing the presence of residual amounts of IBU in the final product after extrusion. On the other side, the sample extruded at 90 °C showed the lowest similarity to IBU and NIC Raman spectra indicating the maximal transformation of initial materials to cocrystal.

2.3.8.3. Tabletability. Tabletability is one of the main characteristics of powders when it comes to studying their compaction properties. The ability of a material to form compacts with a certain tensile strength under exerted compaction pressure is called tabletability. It is usually represented by a graph of tensile strength as a function of compaction pressure. Newton et al. proposed the linear correlation between tensile strength and compaction pressure of the tablets as follows (Newton et al., 1971):

σt = Cp P + b

(4)

where, Cp is the tabletability parameter, P is the compaction pressure and b is a constant. 2.3.8.4. Compactibility. The compactibility of a powder is evaluated by plotting tablets tensile strength as a function of tablets porosity. This relationship is usually described mathematically using RyshkewitchDuckworth equation (Ryshkewitch, 1953):

σt = σt 0 e−bP

(5)

where, σt and σt0 are tablets tensile strength (MPa) and tablets tensile strengths at zero porosity (MPa), respectively. P denotes the tablet porosity and b is an empirical constant representing bonding capacity. A higher b value corresponds to stronger bonding of primary particles (Steendam and Lerk, 1998). It has been proved that the variations of tensile strength with porosity is well represented by RyshkewitchDuckworth equation. 2.3.8.5. Compressibility. Heckel, modified Walker was used to investigate the compressibility of the formulations. Out of die method was used to distinguish between elastic and plastic deformations. The heckle model which explores the porosity reduction upon applied compression pressure is as shown in Eq. (5):

1 ⎞ = k. P + A − lnε = ln ⎛ ⎝1 − D ⎠

3.1.1.2. The effect of screw speed. Fig. 3 shows the DSC thermograms, PXRD and Raman spectra of the samples extruded at 90 °C and various screw speeds. In order to define the effect of screw speed on the cocrystallization process, the temperature was kept constant at optimal value i.e. 90 °C, while the screw speed was varied between 40 and 120 rpm with 20 rpm steps. No eutectic peak was detected in DSC thermograms at any of the screw speeds which confirmed the full transformation of initial components to the final IBU-NIC cocrystal regardless of the screw speed. This is most likely due to the fast formation of the cocrystal even at high screw speeds and low residence times which leaves no eutectic mixture within the system. However, PXRD results revealed that the intensity of the characteristic peak of IBU-NIC cocrystal was increased at lower screw speeds, the highest intensity being at 40 rpm. This has been reported by Dhumal et al. as well that the lower screw speeds results in longer residence times, therefore higher conversion of IBU and NIC to cocrystal (Dhumal et al., 2010). Hence, 40 rpm and 90 °C were identified as optimal conditions

(6)

where, ε is tablet density, D shows the relative density of the tablets, k is the Heckel coefficient which is the slope of the linear part of the curve), P is the applied compression pressure and A is the y-intercept. Py is yield pressure which is the reciprocal value of the Heckel coefficient. Both k and Py are the measures of the powder’s compressibility. High k and low Py values are indications of a more compressible powder. The modified Walker model was used as another means of analysis which considers the change in the specific volume of a tablet under compression pressure (Sonnergaard, 2006; Walker, 1923) as follows: ' V ' = w '. logP + V sp '

(7) '

where, V is the specific volume of a tablet, w is the Walker coefficient ' (linear part of the graph), P is the applied compression pressure and V sp is the specific volume of a tablet at zero logP or 1 MPa pressure. 748

International Journal of Pharmaceutics 566 (2019) 745–755

M. Karimi-Jafari, et al.

Fig. 2. (a) DSC thermograms of molar mixture of IBU-NIC extruded at various temperatures, (b) PXRD spectra of molar mixture of IBU-NIC extruded at various temperatures, (c) Raman spectra of molar ratio mixture of IBU-NIC extruded at various temperatures, characteristic peaks of cocrystal are highlighted by blue box. * Shows the characteristic peak of cocrystal. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

3.1.2. IBU-NIC-soluplus cocrystallization The addition of soluplus as a polymeric matrix to the IBU:NIC optimized formulation was performed to investigate the effect of molten polymeric bed on the formation of cocrystal. Soluplus was added to the IBU-NIC 1:1 M ratio mixture in 10, 20 and 30 w% ratio. The formation of cocrystal was verified at all ratios of soluplus via DSC, PXRD and Raman analysis. The melting peak of cocrystal was present for all

for cocrystallization of IBU-NIC (1:1). Raman spectra of the samples showed the presence of the two characteristic peaks of cocrystal at all screw speeds. This is due to the presence of enough thermal energy and molecular motion which promotes the cocrystal formation at all screw speeds. However, based on the PXRD results 40 rpm was selected as the optimal screw speed for cocrystal formation.

Fig. 3. (a) DSC thermograms of molar mixture of IBU-NIC extruded at various screw speeds, (b) PXRD spectra of molar mixture of IBU-NIC extruded at various screw speeds, (c) Raman spectra of molar ratio mixture of IBU-NIC extruded at various screw speeds, characteristic peaks of cocrystal are highlighted by blue box. * Shows the characteristic peak of cocrystal. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) 749

International Journal of Pharmaceutics 566 (2019) 745–755

M. Karimi-Jafari, et al.

Fig. 4. (a) DSC thermograms of molar mixture of IBU-NIC with 10, 20 and 30 wt% soluplus, (b) PXRD spectra of molar mixture of IBU-NIC with 10, 20 and 30 wt% soluplus, (c) Raman spectra of molar ratio mixture of IBU-NIC with 10, 20 and 30 wt% soluplus, characteristic peaks of cocrystal are highlighted by blue box. * Shows the characteristic peak of cocrystal. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

noticeably faster and higher. It has been shown that the presence of NIC with higher dissolution rate compared with IBU leads to its faster dissolution into the dissolution medium. Wei et al. proposed that NIC is the first component escaping from IBU-NIC cocrystal to the dissolution medium. It is speculated that the IBU dissolves into the medium due to the formation of complex with dissolved NIC. The calculated hydrogen bond energies of IBU-NIC cocrystal system showed that water first disrupts the hydrogen bond between two NIC molecules in cocrystal system since they are the weakest hydrogen bonds. Following the dissolution of NIC, complexation of IBU with dissolved NIC in solution is speculated as the main mechanism of IBU dissolution. However, the synchronized release of IBU and NIC as a complex is not completely disregarded. Interestingly, the dissolution profile of physical mixture of IBU and NIC is closely following that of IBU-NIC cocrystal. Wei et al. attributed this to the significant increase in pH of physical mixture solution compared to that of IBU because of the presence of NIC (4.91 vs. 4.28). Additionally, Yuliandra et al. suggested that the inclusion of nicotinamide as a coformer led to increased analgesic activity compared with intact ibuprofen and physical mixture (Yuliandra et al., 2018).

samples with different values of soluplus (Fig. 4). Moreover, the PXRD and Raman analysis confirmed the formation of cocrystal at all of the soluplus ratios. The sample with 10% soluplus content had the closest melting point to the pure cocrystal. The formation of cocrystal was also confirmed in the formulation with 20 and 30 wt% of soluplus. However, the melting point depression observed in samples with > 10 wt% soluplus signifies the presence of a portion of amorphous material which is not desirable. Also, the higher area under the melting peak of cocrystal in presence of 10% soluplus proves the formation of higher cocrystal content. Thus, 10 wt% soluplus was selected as the optimal amount of excipient in the formulation. The presence of soluplus as a polymeric excipient in the formulation could help to decrease the cocrystallization temperature as well. This was studied by extruding samples at 90, 80 and 70 °C. The PXRD, DSC and Raman spectra of these samples can be seen in Fig. 5. The presence of eutectic point is detected in DSC thermogram of sample extruded at 70 °C which relates to the presence of eutectic mixture of IBU and NIC and partial conversion of them to cocrystal. However, no eutectic point was observed in sample extruded at 80 °C which verifies the complete transformation of IBU and NIC to cocrystal. The lowest yield of the process was approximately 60% which was in case of extruding a sample at 120 rpm screw speed and 90 °C without addition of soluplus due to the stickiness of the extrudate. Alternatively, highest yield of more than 80% was achieved for samples with 10 wt% soluplus extruded at 40 rpm and 80 °C.

3.3. Downstream processing Tablets were produced using Gamlen compaction simulator. Five different formulations were selected in order to reveal the effect of cocrystallization via HME on the mechanical properties of IBU. 3.3.1. Microstructure of tablets SEM images of the surface of all the tableted samples at the maximum compaction pressure used in this study i.e. 173 MPa are shown in Fig. 6. IBU sample was revealed to be the most porous sample among all the formulations. The crystals of IBU have retained their original shape even under the highest compression pressure. Moreover, no visible interparticle bindings could be detected. This is most likely the reason behind the low tensile strength and brittle behaviour of these tablets.

3.2. Dissolution Dissolution profiles are shown in Fig. 12. All powders were sieved with 100 µm sieve to make sure that particle size has no effect on the dissolution results. Crystalline IBU showed a very slow and low dissolution in phosphate buffer, while dissolution of IBU-NIC-Phys, IBUNIC-Cocryst, IBU-NIC-Sol-Phys and IBU-NIC-Sol-Cocryst samples was 750

International Journal of Pharmaceutics 566 (2019) 745–755

M. Karimi-Jafari, et al.

Fig. 5. (a) DSC thermograms of molar mixture of IBU-NIC with 10 wt% soluplus extruded at different temperatures, (b) PXRD spectra of molar mixture of IBU-NIC with 10 wt% soluplus extruded at different temperatures, (c) Raman spectra of molar ratio mixture of IBU-NIC with 10 wt% soluplus extruded at different temperatures. characteristic peaks of cocrystal are highlighted by blue box. * Shows the characteristic peak of cocrystal. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

soluplus was revealed. The presence of a more plastically deformed phase (soluplus) has led to the formation of a continuously interconnected matrix which has embedded the IBU and NIC crystals. Unlike the other samples, surface of the IBU-NIC-Sol-Cocryst tablets were smooth with no major faults or porosities. This can be an indication of a change in mechanical properties of the cocrystal after addition of polymer from elastic to plastic behaviour.

This is mostly due to the low plasticity of IBU crystals. The IBU-NICPhys sample is almost in the same condition. However, the presence of the second phase such as NIC has changed the appearance of the surface. An interconnected matrix with less surface porosity is formed around IBU crystals. The surface appearance of the IBU-NIC-Cocryst sample is similar to the IBU-NIC-Phys sample. No major difference could be detected between the two samples. However, a significant change in the surface appearance in samples with addition of 10 wt%

Fig. 6. SEM images of the outer surface of the tablets produced by tableting pristine IBU, IBU-NIC-Phys, IBU-NIC-Cocryst, IBU-NIC-Sol-Phys and IBU-NIC-Sol-Cocryst. 751

International Journal of Pharmaceutics 566 (2019) 745–755

M. Karimi-Jafari, et al.

Fig. 7. Tabletability profile of the tablets produced by tableting pristine IBU, IBU-NIC-Phys, IBU-NIC-Cocryst, IBU-NIC-Sol-Phys, IBU-NIC-Sol-Cocryst. Each point is representative of three measurements.

Fig. 8. Compactibility profile of the tablets produced by tableting pristine IBU, IBU-NIC-Phys, IBU-NIC-Cocryst, IBU-NIC-Sol-Phys and IBU-NIC-Sol-Cocryst. Each point is representative of three measurements.

3.3.2. Mechanical properties 3.3.2.1. Tabletability. The mechanical properties of the powder samples were assessed via comparing their tabletability, compressibility and compactibility profiles. Tabletability is regarded as the ability of the powder to be pressed into tablets with specific tensile strength (Fig. 7). It is usually illustrated as a graph of tensile strength versus compaction pressure. Tablets tensile strengths was monotonically increased by increasing compaction pressure in all samples. Sample of IBU-NIC-Sol-Cocryst showed the highest increase in tensile strength of 3.5 MPa up to compaction pressure of 170 MPa. However, the highest achieved tensile strength of IBU sample was 1.2 MPa. Tabletability parameter of all formulations was derived using linear regression. The slope of each line is an indicative parameter of the tabletability of each formulation (Table 3). The highest tabletability parameter was observed in IBU-NICSol-Cocryst sample which suggests the feasibility of compressing tablets with higher tensile strength at a specific compaction force with this sample compared with other formulations. On the other hand, pure IBU sample has the lowest tabletability parameter which shows its poor tabletability properties.

Table 4 Fitted values derived from Ryskewitch-Duckworth equation of tensile strength at zero density (σt0) and bonding capacity (b) of the tablets produced by tableting pristine IBU, IBU-NIC-Phys, IBU-NIC-Cocryst, IBU-NIC-Sol-Phys and IBU-NIC-Sol-Cocryst.

R2

IBU IBU-NIC-Phys IBU-NIC-Cocryst IBU-NIC-Sol-Phys IBU-NIC-Sol-Cocryst

0.0057 0.0085 0.0085 0.0079 0.0156

0.8574 0.9284 0.9062 0.9281 0.8945

−b

R2

IBU IBU-NIC-Phys IBU-NIC-Cocryst IBU-NIC-Sol-Phys IBU-NIC-Sol-Cocryst

1.8786 2.0685 2.2256 2.2042 3.4038

18.57 8.03 13.72 10.29 7.25

0.93 0.86 0.85 0.73 0.78

3.3.2.3. Compressibility. Fig. 9 shows the graph of −ln(Porosity) as a function of compaction pressure. The compressibility of all formulations was analysed using Heckel and modified Walker equations. The Heckel and Walker coefficients are listed in Table 5. K represents the Heckel coefficient (slope of the Heckel plot) and Py represents yield pressure as its inverse value. IBU shows very poor plasticity and low compressibility properties based on its low Heckel coefficient and high yield pressure. On the other hand, even physical mixing of IBU and NIC improved its compressibility properties by improving the plasticity of the powder mixture. Interestingly, the IBU-NIC-Cocryst sample is less plastic than the physical mixture of IBU and NIC. This means that the cocrystallization by itself has been less effective in terms of increasing compressibility of IBU. However, inclusion of 10 wt% of a polymeric excipient such as

Table 3 Tabletability parameters derived through the linear regression of the tensile strength versus compaction pressure the tablets produced by tableting pristine IBU, IBU-NIC-Phys, IBU-NIC-Cocryst, IBU-NIC-Sol-Phys and IBU-NIC-SolCocryst. Cp

σt0

strength with porosity for a wide range of materials (Barralet et al., 2002; Gbureck et al., 2003; Steendam and Lerk, 1998; Wu et al., 2005). The fitted parameters are shown in Table 4. IBU-NIC-Sol-Cocryst sample showed notably higher σt0 value among all other samples showing that these tablets will reach to higher tensile strength at zero porosity compared with other formulations. Moreover, higher b value i.e. bonding capacity, represents a stronger bonding between primary particles. The lowest b value of IBU showed the low tendency of bonding between primary particles of this formulation. Interestingly, even the physical addition of nicotinamide helps to increase the bonding capacity of IBU. However, the highest value of b was detected in IBU-NIC-Sol-Cocryst sample showing that the mechanical properties of IBU can be improved by cocrystallization via HME while soluplus is present as one of the initial components since the start of the process.

3.3.2.2. Compactibility. The graph of tensile strength as a function of porosity is used to show the compactibility of powders (Fig. 8). Compatibility relates the powder plastic deformation and its ability to reduce volume under applied pressure. Ryshkewitch-Duckworth equation was used to analyse the compactibility of all samples. Ryshkewitch-Duckworth showed that the tensile strength of porous sintered alumina and zirconia is related to their porosity. Since then it has been approved that it can well represent the variation of tensile

Formulation

Formulation

752

International Journal of Pharmaceutics 566 (2019) 745–755

M. Karimi-Jafari, et al.

Fig. 10. Modified Walker profile of the tablets produced by tableting pristine IBU, IBU-NIC-Phys, IBU-NIC-Cocryst, IBU-NIC-Sol-Phys and IBU-NIC-SolCocryst. Each point is representative of three measurements.

Fig. 9. Heckel profile of the tablets produced by tableting pristine IBU, IBUNIC-Phys, IBU-NIC-Cocryst, IBU-NIC-Sol-Phys, IBU-NIC-Sol-Cocryst. Each point is representative of three measurements.

Table 5 Heckel and modified walker coefficient derived from linear regression Heckel and modififed Walker equations for the tablets produced by tableting pristine IBU, IBU-NIC-Phys, IBU-NIC-Cocryst, IBU-NIC-Sol-Phys and IBU-NIC-SolCocryst. Formulation

k

Py (Mpa)

R2

− w' × 100 (%)

R2

IBU IBU-NIC-Phys IBU-NIC-Cocryst IBU-NIC-Sol-Phys IBU-NIC-Sol-Cocryst

0.00914 0.01156 0.00936 0.00749 0.01413

109.41 86.50 106.84 133.51 70.77

0.85 0.72 0.67 0.70 0.87

6.12 15.24 10.25 13.76 21.57

0.92 0.82 0.88 0.85 0.89

soluplus during the cocrystallization process via HME, has significantly enhanced the plasticity of the IBU-NIC cocrystals. This confirms that the addition of a polymeric excipient can not only enhance cocrystallization at lower temperature but also improve the mechanical properties of cocrystal. The graph of specific volume as a function of logarithmic compaction pressure for all formulations can be seen in Fig. 10. The slope of the linear lines fitted to the data points is called modified Walker coefficient (w ' ) which was derived from linear regression of Walker equation to the compression data point. Walker coefficient shows the volume reduction of powder corresponding to one-decade increase of applied compression pressure. The higher w ' correlates to the more readily volume reduction of powders under compression pressures. Thus, powders with higher Walker coefficient are more compressible with higher plasticity. The data shows a threefold increase in plasticity of IBU by cocrystallization of IBU-NIC in presence of soluplus via HME. The IBU-NIC-Sol-Cocryst formulation had the highest Walker coefficient confirming the Heckel analysis showing higher plasticity of this formulation compared with IBU.

Fig. 11. Percentage of the weight loss after friability test for tablets produced by tableting pristine IBU, IBU-NIC-Phys, IBU-NIC-Cocryst, IBU-NIC-Sol-Phys and IBU-NIC-Sol-Cocryst.

4. Conclusions A comprehensive study on the manufacturing of a model cocrystal system was performed. The process parameters such as temperature and screw speed were optimized for complete conversion of initial materials to cocrystal. Moreover, it was shown that the presence of a low-melting point polymeric excipient not only decreases the cocrystallization temperature but also enhanced the mechanical properties of the cocrystal tablets. This was confirmed through studying the three components of compaction simulator i.e. tabletability, compactibility and compressibility. It was shown that the presence of NIC improves the dissolution properties of IBU as a BCS class II API by at least 3-fold in all samples. Cocrystallization of APIs with low aqueous solubility, poor flowability and weak tabletability properties is a promising strategy for simultaneous improvement of their dissolution and mechanical properties.

3.3.2.4. Friability. A friability test was run on samples produced for different formulations at 173 MPa. Fig. 11 shows the friability of all the formulations. The weight loss due to the breakage and wear of the tablets with the walls of the drum are less than 2 wt% in all samples. However, among all samples, IBU-NIC-Sol-Cocryst had the lowest friability weight loss. This indicates the mechanical strength of the cocrystal prepared with soluplus.

753

International Journal of Pharmaceutics 566 (2019) 745–755

M. Karimi-Jafari, et al.

Karki, S., Friščić, T., Fabian, L., Laity, P.R., Day, G.M., Jones, W., 2009. Improving mechanical properties of crystalline solids by cocrystal formation: new compressible forms of paracetamol. Adv. Mater. 21, 3905–3909. Kelly, A.L., Gough, T., Dhumal, R.S., Halsey, S.A., Paradkar, A., 2012. Monitoring ibuprofen-nicotinamide cocrystal formation during solvent free continuous cocrystallization (SFCC) using near infrared spectroscopy as a PAT tool. Int. J. Pharm. 426, 15–20. Lang, B., McGinity, J.W., Williams, R.O., 2014. Hot-melt extrusion – basic principles and pharmaceutical applications. Drug Dev. Ind. Pharm. 40, 1133–1155. Li, S., Yu, T., Tian, Y.W., McCoy, C.P., Jones, D.S., Andrews, G.P., 2016. Mechanochemical synthesis of pharmaceutical cocrystal suspensions via hot melt extrusion: feasibility studies and physicochemical characterization. Mol. Pharm. 13, 3054–3068. Lu, E., Rodríguez-Hornedo, N., Suryanarayanan, R., 2008. A rapid thermal method for cocrystal screening. CrystEngComm 10, 665–668. Luo, C., Liang, W.D., Chen, X., Wang, J.M., Deng, Z.W., Zhang, H.L., 2018. Pharmaceutical cocrystals of naringenin with improved dissolution performance. CrystEngComm 20, 3025–3033. Maeno, Y., Fukami, T., Kawahata, M., Yamaguchi, K., Tagami, T., Ozeki, T., Suzuki, T., Tomono, K., 2014. Novel pharmaceutical cocrystal consisting of paracetamol and trimethylglycine, a new promising cocrystal former. Int. J. Pharm. 473, 179–186. Maniruzzaman, M., Nokhodchi, A., 2017. Continuous manufacturing via hot-melt extrusion and scale up: regulatory matters. Drug Discovery Today 22, 340–351. Newton, J.M., Rowley, G., Fell, J.T., Peacock, D.G., Ridgway, K., 1971. Computer analysis of the relation between tablet strength and compaction pressure. J. Pharm. Pharmacol. 23, 195S–201S. Nokhodchi, A., Homayouni, A., Araya, R., Kaialy, W., Obeidat, W., Asare-Addo, K., 2015. Crystal engineering of ibuprofen using starch derivatives in crystallization medium to produce promising ibuprofen with improved pharmaceutical performance. RSC Adv. 5, 46119–46131. Patel, S., Kaushal, A.M., Bansal, A.K., 2006. Compression physics in the formulation development of tablets. Crit. Rev. Ther. Drug Carrier Syst. 23, 1–65. Patil, H., Tiwari, R.V., Repka, M.A., 2016. Hot-melt extrusion: from theory to application in pharmaceutical formulation. AAPS PharmSciTech 17, 20–42. Qu, L., Zhou, Q., Gengenbach, T., Denman, J.A., Stewart, P.J., Hapgood, K.P., Gamlen, M., Morton, D.A.V., 2015. Investigation of the potential for direct compaction of a fine ibuprofen powder dry-coated with magnesium stearate. Drug Dev. Ind. Pharm. 41, 825–837. Rasenack, N., Müller, B.W., 2002. Ibuprofen crystals with optimized properties. Int. J. Pharm. 245, 9–24. Rodrigues, M., Baptista, B., Lopes, J.A., Sarraguca, M.C., 2018. Pharmaceutical cocrystallization techniques. Advances and challenges. Int. J. Pharm. 547, 404–420. Ryshkewitch, E., 1953. Compression strength of porous sintered alumina and zirconia. J. Am. Ceram. Soc. 36, 65–68. Saniocki, I., Sakmann, A., Leopold, C.S., 2013. How suitable is the measurement of takeoff forces for detection of sticking during direct compression of various ibuprofen tablet formulations? Pharm. Dev. Technol. 18, 257–265. Serrano, D.R., Walsh, D., O'Connell, P., Mugheirbi, N.A., Worku, Z.A., Bolas-Fernandez, F., Galiana, C., Dea-Ayuela, M.A., Healy, A.M., 2018. Optimising the in vitro and in vivo performance of oral cocrystal formulations via spray coating. Eur. J. Pharm. Biopharm. 124, 13–27. Seton, L., Roberts, M., Ur-Rehman, F., 2010. Compaction of recrystallised ibuprofen. Chem. Eng. J. 164, 449–452. Shan, N., Toda, F., Jones, W., 2002. Mechanochemistry and co-crystal formation: effect of solvent on reaction kinetics. Chem. Commun. 2372–2373. Soares, F.L.F., Carneiro, R.L., 2013. Green synthesis of ibuprofen-nicotinamide cocrystals and in-line evaluation by raman spectroscopy. Cryst. Growth Des. 13, 1510–1517. Socrates, G., 2004. Infrared and Raman Characteristic Group Frequencies: Tables and Charts. John Wiley & Sons. Sonnergaard, J.M., 2006. Quantification of the compactibility of pharmaceutical powders. Eur. J. Pharm. Biopharm. 63, 270–277. Steendam, R., Lerk, C.F., 1998. Poly(DL-lactic acid) as a direct compression excipient in controlled release tablets – Part I. Compaction behaviour and release characteristics of poly(DL-lactic acid) matrix tablets. Thiry, J., Krier, F., Evrard, B., 2015. A review of pharmaceutical extrusion: critical process parameters and scaling-up. Int. J. Pharm. 479, 227–240. Trask, A.V., Jones, W., 2005. Crystal engineering of organic cocrystals by the solid-state grinding approach. In: Toda, F. (Ed.), Organic Solid State Reactions. Springer Berlin Heidelberg, Berlin, Heidelberg, pp. 41–70. Trask, A.V., Motherwell, W.D.S., Jones, W., 2006. Physical stability enhancement of theophylline via cocrystallization. Int. J. Pharm. 320, 114–123. Treffer, D., Wahl, P., Markl, D., Koscher, G., Roblegg, E., Khinast, J.G., 2013. Hot melt extrusion as a continuous pharmaceutical manufacturing process. In: Repka, M.A., Langley, N., DiNunzio, J. (Eds.), Melt Extrusion: Materials, Technology and Drug Product Design. Springer, New York, New York, NY, pp. 363–396. Walker, E.E., 1923. The properties of powders. Part VI. The compressibility of powders. Trans. Faraday Soc. 19, 73–82. Walsh, D., Serrano, D.R., Worku, Z.A., Madi, A.M., O'Connell, P., Twamley, B., Healy, A.M., 2018. Engineering of pharmaceutical cocrystals in an excipient matrix: spray drying versus hot melt extrusion. Int. J. Pharm. 551, 241–256. Weyna, D.R., Shattock, T., Vishweshwar, P., Zaworotko, M.J., 2009. Synthesis and structural characterization of cocrystals and pharmaceutical cocrystals: mechanochemistry vs slow evaporation from solution. Cryst. Growth Des. 9, 1106–1123. Wu, C.-Y., Best, S.M., Bentham, A.C., Hancock, B.C., Bonfield, W., 2005. A simple predictive model for the tensile strength of binary tablets. Eur. J. Pharm. Sci. 25, 331–336.

Fig. 12. Dissolution profile of the tablets produced with pristine IBU, IBU-NICPhys, IBU-NIC-Cocryst, IBU-NIC-Sol-Phys and IBU-NIC-Sol-Cocryst.

Declaration of Competing Interest None. Acknowledgment The authors acknowledge Science Foundation Ireland for supporting the work undertaken at the Synthesis and Solid State Pharmaceutical Centre (Grants SFI SSPC2 12/RC/2275 and 15/US-C2C/I3133). Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.ijpharm.2019.06.031. References Aitipamula, S., Banerjee, R., Bansal, A.K., Biradha, K., Cheney, M.L., Choudhury, A.R., Desiraju, G.R., Dikundwar, A.G., Dubey, R., Duggirala, N., Ghogale, P.P., Ghosh, S., Goswami, P.K., Goud, N.R., Jetti, R.R.K.R., Karpinski, P., Kaushik, P., Kumar, D., Kumar, V., Moulton, B., Mukherjee, A., Mukherjee, G., Myerson, A.S., Puri, V., Ramanan, A., Rajamannar, T., Reddy, C.M., Rodriguez-Hornedo, N., Rogers, R.D., Row, T.N.G., Sanphui, P., Shan, N., Shete, G., Singh, A., Sun, C.C., Swift, J.A., Thaimattam, R., Thakur, T.S., Kumar Thaper, R., Thomas, S.P., Tothadi, S., Vangala, V.R., Variankaval, N., Vishweshwar, P., Weyna, D.R., Zaworotko, M.J., 2012. Polymorphs, salts, and cocrystals: what’s in a name? Cryst. Growth Des. 12, 2147–2152. Al-Karawi, C., Cech, T., Bang, F., Leopold, C.S., 2018. Investigation of the tableting behavior of Ibuprofen DC 85 W. Drug Dev. Ind. Pharm. 44, 1262–1272. Barralet, J.E., Gaunt, T., Wright, A.J., Gibson, I.R., Knowles, J.C., 2002. Effect of porosity reduction by compaction on compressive strength and microstructure of calcium phosphate cement. J. Biomed. Mater. Res. 63, 1–9. Chow, S.F., Chen, M., Shi, L.M., Chow, A.H.L., Sun, C.C., 2012. Simultaneously improving the mechanical properties, dissolution performance, and hygroscopicity of ibuprofen and flurbiprofen by cocrystallization with nicotinamide. Pharm. Res. 29, 1854–1865. Dhumal, R.S., Kelly, A.L., York, P., Coates, P.D., Paradkar, A., 2010. Cocrystalization and simultaneous agglomeration using hot melt extrusion. Pharm. Res. 27, 2725–2733. Douroumis, D., Ross, S.A., Nokhodchi, A., 2017. Advanced methodologies for cocrystal synthesis. Adv. Drug Deliv. Rev. 117, 178–195. Friscic, T., Halasz, I., Beldon, P.J., Belenguer, A.M., Adams, F., Kimber, S.A.J., Honkimaki, V., Dinnebier, R.E., 2013. Real-time and in situ monitoring of mechanochemical milling reactions. Nat. Chem. 5, 66–73. Gbureck, U., Grolms, O., Barralet, J.E., Grover, L.M., Thull, R., 2003. Mechanical activation and cement formation of β-tricalcium phosphate. Biomaterials 24, 4123–4131. Grymonpré, W., Verstraete, G., Vanhoorne, V., Remon, J.P., De Beer, T., Vervaet, C., 2018. Downstream processing from melt granulation towards tablets: In-depth analysis of a continuous twin-screw melt granulation process using polymeric binders. Eur. J. Pharm. Biopharm. 124, 43–54. Karimi-Jafari, M., Padrela, L., Walker, G.M., Croker, D.M., 2018. Creating cocrystals: a review of pharmaceutical cocrystal preparation routes and applications. Crystal Growth Des.

754

International Journal of Pharmaceutics 566 (2019) 745–755

M. Karimi-Jafari, et al. Yazdanian, M., Briggs, K., Jankovsky, C., Hawi, A., 2004. The “high solubility” definition of the current FDA guidance on biopharmaceutical classification system may be too strict for acidic drugs. Pharm. Res. 21, 293–299. Yuliandra, Y., Zaini, E., Syofyan, S., Pratiwi, W., Putri, L., Pratiwi, Y., Arifin, H., 2018. Cocrystal of ibuprofen–nicotinamide: solid-state characterization and in vivo analgesic activity evaluation. Sci. Pharm. 86, 23.

Zhang, G.C., Lin, H.L., Lin, S.Y., 2012. Thermal analysis and FTIR spectral curve-fitting investigation of formation mechanism and stability of indomethacin-saccharin cocrystals via solid-state grinding process. J. Pharm. Biomed. Anal. 66, 162–169. Zhou, Q., Shi, L., Marinaro, W., Lu, Q., Sun, C.C., 2013. Improving manufacturability of an ibuprofen powder blend by surface coating with silica nanoparticles. Powder Technol. 249, 290–296.

755