Effect of Compression on the Molecular Arrangement of Itraconazole

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Effect of compression on the molecular arrangement of Itraconazole-Soluplus solid dispersions: induction of liquid crystals or exacerbation of phase separation? Abhishek Singh, Avanish Bharati, Pauline Frederiks, Olivier Verkinderen, Bart Goderis, Ruth Cardinaels, Paula Moldenaers, Jan Van Humbeeck, and Guy Van den Mooter Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.6b00046 • Publication Date (Web): 19 Apr 2016 Downloaded from http://pubs.acs.org on April 23, 2016

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Molecular Pharmaceutics

Effect of compression on the molecular arrangement of Itraconazole-Soluplus solid dispersions: induction of liquid crystals or exacerbation of phase separation? Abhishek Singh1, Avanish Bharati2, Pauline Frederiks1, Olivier Verkinderen3, Bart Goderis3, Ruth Cardinaels2,4, Paula Moldenaers2, Jan Van Humbeeck5 and Guy Van den Mooter1* 1

2

Drug Delivery and Disposition, KU Leuven, Leuven, Belgium

Soft Matter, Rheology and Technology, Department of Chemical Engineering, KU Leuven, Leuven, Belgium 3

4

Polymer Chemistry and Materials, Department of Chemistry, KU Leuven, Leuven

Polymer Technology, Department of Mechanical Engineering, TU Eindhoven, The Netherlands 5

Department of Metallurgy and Materials Engineering, KU Leuven, Belgium

*Corresponding author: Address- Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven; Campus Gasthuisberg O+N2; Herestraat 49 b921, 3000 Leuven; BELGIUM Tel.: +32 16 330 304

fax: +32 16 330 305

Mobile: +32 473 356 132

e-mail: [email protected]

1 ACS Paragon Plus Environment


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Graphical abstract


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Abstract Pre-densification and compression are unit operations imperative to the manufacture of tablets and capsules. Such stress-inducing steps can cause destabilization of solid dispersions which can alter their molecular arrangement and ultimately affect dissolution rate and bioavailability. In this study, itraconazole-soluplus solid dispersions with 50% (w/w) drug loading prepared by hotmelt extrusion (HME) were investigated. Compression was performed at both pharmaceutically relevant and extreme compression pressures and dwell times. The amorphous starting materials, powder and compressed solid dispersions were analysed using modulated differential scanning calorimetry (MDSC), X-ray diffraction (XRD), small and wide angle X-ray scattering (SWAXS), Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and broadband dielectric spectroscopy (BDS). MDSC analysis revealed that compression promotes phase separation of solid dispersions as indicated by an increase in glass transition width, occurrence of a peak in the non-reversing heat flow signal and an increase in the net heat of fusion indicating crystallinity in the systems. SWAXS analysis ruled out the presence of mesophases. BDS measurements elucidated an increase in the soluplus rich regions of the solid dispersion upon compression. FTIR indicated changes in the spatio-temporal architecture of the solid dispersions mediated via disruption in hydrogen bonding and ultimately altered dynamics. These changes can have significant consequences on the final stability and performance of the solid dispersions.

Key words



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Solid dispersions, tablets, compression, small-angle X-ray scattering, broadband dielectric spectroscopy, FTIR, molecular mobility, itraconazole, soluplus, liquid crystals Abbreviations API

Active pharmaceutical ingredient

ASD

Amorphous solid dispersions

ATR-FTIR

Attenuated total reflectance Fourier transform infrared

AUC

Area under curve

BDS

Broadband Dielectric Spectroscopy

CRR

Cooperatively rearranging regions

D

Strength parameter

Ev

Vogel activation energy

fmax

Frequency at which the dielectric loss is maximal

∆Hf

Heat of fusion

HME

Hot-melt extrusion

HPMCAS

Hydroxypropylmethylcellulose acetate succinate

kB

Boltzmann constant

m

Fragility

MDSC

Modulated Differential Scanning Calorimetry

rc

Size of the CRR


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R

Universal gas constant

RCS90

Refrigerated cooling system

sc

Configurational entropy of a subsystem

Sc

Configurational entropy

Tg

Glass transition temperature

Tg width

Width of the glass transition region

Tv

Vogel scaling temperature

TGA

Thermogravimetric analysis

PVP

Polyvinylpyrrolidone

PVP K25

Polyvinylpyrrolidone K25

PVPVA64

Poly (1-vinylpyrrolidone-co-vinyl acetate)

SWAXS

Small and wide angle X-ray scattering

Tm

Melting point

VFT

Vogel-Fulcher-Tamman

XRD

X-ray diffraction

εs

Dielectric constant at limiting low frequency

ε∞

Dielectric constant at limiting high frequency

∆ε

Dielectric strength

ω

Angular frequency

τ

Relaxation time

τo

Pre-exponential factor



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1. Introduction Poorly water soluble drugs (BCS class 2) can be delivered as solid dispersions to enhance solubility and bioavailability.1 Despite decades of research only a few solid dispersions formulations have entered the market mainly due to stability issues.2 The amorphous form is inherently thermodynamically unstable owing to higher values for the thermodynamic descriptors of the state of these systems. It is known that amorphous solid dispersion (ASD) formulations are highly sensitive to high temperature and moisture.3 Increasingly growing attention is also being given to the phase behavior altering effects of unit operations involved in the down-stream processing of ASD.4-8 One of such unit operations which is widely used in the manufacture of ASD tablets is compression. The determining factors of the final result of compression as far as stability of ASD is concerned can be an interplay of the absence/presence of the specific interactions between the drug and the carrier, drug loading, compression pressure, dwell time, free volume and polymer deformation characteristics. Since tablets are the preferred and popular dosage form it is relevant to study the influence of aforementioned factors on ASD stability thereby paving the way for more marketed products and avoiding product failure. The amorphous active pharmaceutical ingredient (API) is stabilized in the carrier matrix by virtue of either an antiplasticization effect or specific API-carrier interactions or both.9 If compression alters any of these mechanisms, solid dispersion stability might be influenced with implications for its in-vitro and in-vivo performance. Compression of binary ASD can result in various outcomes as shown in figure 1. A well-mixed ASD (as indicated by a single glass 6 ACS Paragon Plus Environment

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transition temperature (Tg)) can undergo either amorphous-amorphous phase separation or directly result in amorphous-crystalline/ amorphous-amorphous-crystalline phase separation. Naproxen- Polyvinylpyrrolidone K25 (PVP K25) ASD is an example of a system, which undergoes amorphous-amorphous phase separation. Ayenew et al. showed that compression of 30 and 40% compositions at 565 MPa during 60 seconds results in demixing of the initial single phase Naproxen-PVP K25 solid dispersions as shown by two Tg’s and an altered IR spectral profile.7 Demixing was attributed to the change in strength/disruption of the hydrogen bonding between the amide carbonyl of PVP and the hydroxyl of the carboxylic moiety of naproxen in the solid dispersion. Remarkably compression does not always lead to ASD destabilization. Naproxen- Poly (1-vinylpyrrolidone-co-vinyl acetate) (PVP VA64) ASD with 30-50% drug loading was stabilized upon compression at 1130, 753, and 188 MPa for 10 seconds dwell time.8 The stabilization was attributed to enhanced weak drug−polymer interaction. In a different scenario whereby there was no H-bonding, Miconazole-PVP VA64 ASD also underwent mixing albeit due to enhanced miscibility owing to increased molecular mobility as a result of plastic deformation.4 In all the systems mentioned above there was stability alteration involving commonly encountered solid states, i.e., crystalline and amorphous. Another possibility in addition to the scenarios portrayed in figure 1 is the involvement of an API capable of forming a mesophase. Itraconazole is a typical example of an API known to form mesophases,10 whose presence was detected even in small layers using Broadband Dielectric Spectroscopy (BDS).10,

11

These

mesophases can be manifested in the ASD formulation containing polymers as well.12 The mesophase was detectable in itraconazole-Eudragit E100 solid dispersions at 20% drug loading. The role of global structural relaxation (α-relaxation) in determining the physical stabilization of



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API’s in solid dispersions has formed the basis of several recent studies. Bhardwaj et al. showed a strong correlation between the α-relaxation and stability of itraconazole in polymer dispersions of itraconazole with polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose acetate succinate (HPMCAS).13 Moreover, a slower molecular mobility (related to the α-relaxation) of the API ezetimibe in a soluplus matrix (20% w/w) than pure ezetemibe resulted in improved physical stability of the API.14 BDS at high pressures has indicated a very high sensitivity of the structural dynamics of pure itraconazole to compression.15 However, there are no reports of the effect of compressive stress on binary itraconazole solid dispersions. In this study we investigate the effect of compression on itraconazole-soluplus solid dispersions. We investigated in detail the changes occurring in the modulated differential scanning calorimetry (MDSC) thermograms and X-ray diffraction (XRD) patterns. Furthermore, specific observations were further investigated in depth using small and wide angle X-ray scattering (SWAXS), Fourier transform infrared spectroscopy (FTIR) and BDS. The ultimate goal of this work was to identify compression induced molecular level changes which can be induced by compressive stress and to elucidate the mechanisms responsible for it.


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Figure 1: Possible scenarios of phase-behavior alteration due to compression. Amorphousamorphous phase separation promotes crystallization (+) whereas mixing can delay (-) it.



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2.

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Materials and methods

2.1. Materials Itraconazole was a gift sample from Janssen Pharmaceutica (Beerse, Belgium). Soluplus (Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer) was generously provided by BASF (Ludwifshafen, Germany). Solvents and chemicals (analytical or HPLC grade) were used as received. 2.2. Methods 2.2.1. Preparation of itraconazole-soluplus solid dispersions by hot-melt extrusion (HME) The itraconazole-soluplus solid dispersion was prepared using the Xplore DSM (Geleen, The Netherlands) twin-screw hot-melt extruder. 5 grams of a 50:50 (w/w; drug:polymer) physical mixture was injected using a piston feeding mechanism into the mixing compartment of the extruder. The equipment core consisted of two separable metal halves consisting of three controlled heating zones enveloping the double, conical screws. The temperature of the metal halves was kept constant at 165°C and a screw speed of 100 rpm was used. The internal circulation time was fixed at 5 minutes to ensure complete mixing. The extrudates were collected without any cooling accessory and subsequently milled using a cutter mill (Janke and Kunkel GmbH and Company, Baden-Wuttemberg, Germany). Approximately 10 g of extrudate was milled for 1 minute, sieved (

Effect of Compression on the Molecular Arrangement of Itraconazole

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