Investigation of Deteriorated Dissolution of Amorphous Itraconazole

Oct 3, 2017 - Disadvantageous crystallization phenomenon of amorphous itraconazole (ITR) occurring in the course of dissolution process was investigat...
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Investigation of deteriorated dissolution of amorphous itraconazole: description of incompatibility with magnesium stearate and possible solutions B. Demuth, D. L. Galata, E. Szabó, B. Nagy, A. Farkas, A. Balogh, E. Hirsch, H. Pataki, Z. Rapi, L. Bezúr, T. Vigh, G. Verreck, Z. Szalay, Á. Demeter, G. Marosi, and Z. K. Nagy Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.7b00629 • Publication Date (Web): 03 Oct 2017 Downloaded from http://pubs.acs.org on October 5, 2017

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Molecular Pharmaceutics

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Investigation of deteriorated dissolution of amorphous itraconazole: description of

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incompatibility with magnesium stearate and possible solutions

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B. Démuth1, D. L. Galata1, E. Szabó1, B. Nagy1, A. Farkas1, A. Balogh1, E. Hirsch1, H. Pataki1,

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Z. Rapi1, L. Bezúr2, T. Vigh3, G. Verreck3, Z. Szalay4, Á. Demeter4, G. Marosi1, Z. K. Nagy1,*

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1

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Műegyetem rkp. 3., H-1111 Budapest, Hungary

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2

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Szent Gellért tér 4., H-1111, Budapest, Hungary

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3

Drug Product Development, Janssen R&D, Turnhoutseweg 30, B-2340 Beerse, Belgium

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Drug Polymorphism Research, Gedeon Richter Plc., Gyömrői út 30-32., H-1103 Budapest, Hungary

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*Corresponding authors: Zsombor K. Nagy; Phone: +36 1463-1424 Fax: +36 1463-3648; E-mail: zsknagy

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oct.bme.hu

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Abstract

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Disadvantageous crystallization phenomenon of amorphous itraconazole (ITR) occurring in

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course of dissolution process was investigated in this work. Perfectly amorphous form (solid

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dispersion) of the drug was generated by electroblowing method (with vinylpyrrolidone-vinyl

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acetate copolymer) and the obtained fibers were formulated into tablets. Incomplete dissolution

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of tablets was noticed under the circumstances of standard dissolution test, after which a

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precipitated material could be filtered. The filtrate consisted of ITR and stearic acid since no

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magnesium content was detectable in it. In parallel with dissolution, ITR forms an insoluble

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associate, stabilized by hydrogen bonding, with stearic acid deriving from magnesium stearate.

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This is why dissolution curves did not have the plateaus at 100%. Two ways are viable to tackle

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this issue: change the lubricant (with sodium stearyl fumarate >95% dissolution can be

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accomplished) or alter the polymer in the solid dispersion to a type being able to form hydrogen

Department of Organic Chemistry and Technology, Budapest University of Technology and Economics (BME),

Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics (BME),

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bonds with ITR (e.g. hydroxypropyl methylcellulose). This work draws the attention to one of the

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more phenomena that can lead to a deterioration of originally good dissolution of an amorphous

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solid dispersion.

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Abstract graphic

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Keywords: amorphous solid dispersion; crystallization; dissolution; tablet formulation;

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magnesium stearate; oral delivery

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1 Introduction

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The issues related to low solubility and bioavailability of Biopharmaceutical Classification

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System class II and IV type active pharmaceutical ingredients (APIs) are well-known for several

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decades. Formation of amorphous solid dispersions (ASDs) with such compounds has emerged

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almost in parallel as an answer to resolve these issues.1,

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(performing feasibility and screening studies) have become a routine approach in the last 15

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years. In addition, several ASD-containing FDA-approved products have appeared on the

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market.2,

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spinning, freeze drying, ball milling and microprecipitation. The different machine and material

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expenses and different efficacy for amorphization are characteristics for these technologies.

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2

Thorough investigations of ASDs

Most widely applied technologies are melt extrusion, spray-drying, electrostatic

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Dissolution from immediate-release ASDs reaches a higher extent than the crystalline form. A

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supersaturated state of the API is realized under non-sink conditions thus it is prone to

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recrystallize from the solution.3 The recrystallization can occur quickly (‘spring’) and slowly

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(‘spring and parachute’) if a material (practically the polymer in the ASD) acts as a crystallization

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inhibitor in the medium.4 The ‘spring and parachute’ case provides the API enough time for the

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absorption and thus appropriate bioavailability. High bioavailability can also be achieved if those

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ASDs are applied that do not possess the fastest drug release.5, 6 According to a recent study, the

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degree of supersaturation (which is defined as the ratio of dissolved amount of the drug to its

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thermodynamic solubility) is the main driving force for membrane transport during drug

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absorption.7 This renders a trajectory for the development of ASDs and other methods that

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attempt to enhance the bioavailability of poorly water-soluble drugs.

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Amorphous drugs in SDs can have a very fast and complete dissolution. However, they must

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be converted into applicable solid dosage forms, most often tablets. Good dissolution has to be

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maintained in these formulations, too, which can be a challenge. Modifications of dissolution

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properties by downstream processing have not been a major topic about ASDs. In a recent study

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spray-drying and freeze drying were applied to generate ASDs of docetaxel (and paclitaxel) with

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PVP K30.8 In the spray-dried material docetaxel was fully amorphous, but dissolution extent

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from the tablet formulation was not 100% in spite of analyses proving the presence of 95-105%

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API content. Laitinen et al. prepared ASDs of perphenazine with PVP K30 and polyethylene

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glycol 8000 by freeze drying and compressed them into tablets.9 Dissolution was investigated

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only for 4 min, however, tablets containing released significantly less API than pure ASD

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(though the disintegration time was 37 s).

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Wlodarski and co-workers recently published their thorough study of the dissolution of

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tadalafil containing ASDs prepared by spray-drying and ball milling.10 API release was

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investigated in different media and forms (encapsulated and non-encapsulated crystalline, ASDs

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and tablets). At the lowest dose (2.5 mg) dissolution from tablets comprising spray-dried ASD

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reached its maximum after 20 min (~85%, did not change significantly after 1 hour), which was

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lower than from the powder. Agrawal et al. carried out an extensive work about melt extruded

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ASDs of an unknown compound (applied polymers: vinylpyrrolidone-vinyl acetate copolymer

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(PVPVA64), hydroxypropyl methylcellulose acetate succinate (HPMCAS) and Soluplus®).11

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Dissolution was examined in simulated gastric fluid (first stage) and simulated intestinal fluid

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(second stage). Release of the compound from tablets was lower in the case of two polymers,

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PVPVA64 and HPMCAS, than from neat ASD. It was concluded that extragranular excipients

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might modify the dissolution, but making concrete determinations which excipient can lower or

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increase the dissolution of the given ASDs was not included in the objectives of the study. Wu

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and co-workers lately found that poloxamer 188, a commonly used emulsifying and solubilizing

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surfactant, induced crystallization in an ASD.12 It turned into a liquid at 40 °C/75% relative

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humidity and created a supersaturated state from which the API precipitated. In another study,

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not 100% of itraconazole (ITR) dissolved when electrospun ASD, which generally has the

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highest dissolution rate owing to the huge surface area13, was formulated into tablets and exposed

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to in vitro dissolution.14 The tablets contained magnesium stearate (MgSt), which is well-known

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for its hydrophobicity and possible negative effect on dissolution.15, 16 If sodium stearyl fumarate

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(SSF) was applied as lubricant, complete dissolution could be achieved.

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In this study, the amorphous form of ITR was generated by electroblowing since the

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nanofibers prepared by this method have very fast and complete dissolution. The questions why

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and how MgSt deteriorates the dissolution of amorphous ITR from tablet formulation is

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attempted to answer. Extensive dissolution tests were performed to reveal how to enhance

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dissolution of tablets. In order to explain the lower dissolution extent induced by MgSt, a

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separable solid phase of the dissolution medium was characterized by solution NMR, elemental

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analysis, solid state NMR, X-ray powder diffractometry and Raman mapping.

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2 Materials and methods

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2.1 Materials

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ITR was given by Janssen Pharmaceutical N. V. (Beerse, Belgium). MgSt, which is a mixture

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of different hydrate forms, was bestowed by Hungaropharma Ltd (Budapest, Hungary).

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PVPVA64 (Kollidon® VA64) and crospovidone (Kollidon® Cl) were supplied by BASF

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(Ludwigshafen, Germany). Sodium stearyl fumarate (SSF, Pruv®) and microcrystalline cellulose

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(MCC, Vivapur® 200) were provided by JRS Pharma (Rosenberg, Germany). Mannitol

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(Pearlitol® 400DC) was a kind gift from Roquette Pharma (Lestrem, France). Hydroxypropyl-

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methyl-cellulose 2910 5 mPa s (HPMC) was obtained from Aqualon, Hercules (Zwijndrecht, the

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Netherlands). Colloidal silicon dioxide (Aerosil® 200) was purchased from Evonik Industries

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(Hanau-Wolfgang, Germany). Organic solvents and concentrated HCl solution were ordered

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from Merck Ltd. (Budapest, Hungary).

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2.2 Electroblowing

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In this work, electroblowing was applied to generate the amorphous form of ITR.17 Spray air

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pressure was set to 1 bar. Parameters of the solution and electroblowing process are described in

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Table 1. The obtained ASD was not packaged immediately; it was dried on air for 1 day.

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Table 1 Parameters of electroblowing process (contents of the solid materials are

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indicated) API

ITR (40%)

ITR (40%)

Matrix

PVPVA64 (60%)

HPMC (60%)

Solvents

dichloromethane:ethanol 2:1 (3.75 g/10 mL)a

dichloromethane:ethanol 1:1 (1.25 g/10 mL)a

Voltage (kV)

35

35

150

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Feeding rate (mL/h) 110

a

concentrations in the solutions

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2.3 Differential scanning calorimetry (DSC)

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DSC measurement was performed in a Setaram DSC92 type calorimeter (Calure, France).

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Sample with a mass between 10 and 15 mg was heated up to 200 °C from 25 °C (with a 1 min

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isotherm at 25 °C). N2 purge was introduced into the sample airspace with a continuous flow of

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30 mL/min.

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2.4 Tablet formulation

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The obtained electroblown material was pushed through a sieve (hole size is ~0.8 mm) after

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production and drying. Afterward, it was blended with the excipients except for the lubricant in a

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bottle (~2-5 g depending on the amount needed) by manually shaking for 5 min (the lubricant

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was mixed after the first mixing separately during 2 min). The composition of the blend can be

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viewed in Table 2.

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Table 2 Composition of powder with ASD

Percentage ITR

8.3%

PVPVA64/HPMC

12.5%

Fillers

MCC: 33.35-33.6% Mannitol: 33.35-33.6%

Disintegrant

Crospovidone (Kollidon® Cl): 10%

Glidant

Colloidal SiO2 (Aerosil® 200): 1%

Lubricant

MgSt: 1% or SSF: 1.5%

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Powders were compressed into tablets with a compression force of 8 kN on a Dott Bonapace

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CPR-6 eccentric tablet press (Limbiate, Italy) equipped with 14 mm concave punches (Quick

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2000, Tiszavasvári, Hungary).

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Molecular Pharmaceutics

2.5 In vitro dissolution testing

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Dissolution of ITR from tablets was investigated on a Pharmatest PTWS600 dissolution tester

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(Pharma Test Apparatebau AG, Hainburg, Germany) equipped with paddles (United States

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Pharmacopoeia Apparatus II). The rotational speed was set to 100 rpm for dissolution test of

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tablets with disintegrant, while it was 200 rpm for tablets without disintegrant to facilitate the

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disintegration. Dissolution of neat ASD was carried out by a special set up described previously

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by Nagy et al.13 Dissolution tests were carried out in 0.1N HCl at 37±0.5 °C. An on-line coupled

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Agilent 8453 UV-Vis spectrophotometer (Hewlett-Packard, Palo Alto, USA) was applied to

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measure the absorbance of the medium at 254 nm, from which the concentration and the

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percentage of dissolution could be readily calculated. Up to 50 mg of dose, cuvettes of 10 mm

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length were used, while at 100 mg of dose 1 mm cuvettes were assembled with the

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spectrophotometer.

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In order to characterize the non-dissolved material, special tablets were prepared and exposed

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to in vitro dissolution test as described earlier by the authors.14 After the test, the dissolution

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medium was poured through a sieve with a hole size of 300 µm onto a G3 glass filter (pore size

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of 15-40 µm). The material was dried on air for a day (no heating was applied).

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2.6. Fourier-transform infrared (FTIR) spectroscopy

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The FTIR spectra were recorded on a Bruker Tensor 37 type spectrometer (Ettlingen,

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Germany) equipped with DTGS detector. The samples were compressed into pastilles with KBr

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on a Camille OL95 type press (Manfredi, Turin, Italy). The region of 400 to 4000 cm-1 was

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investigated with 4 cm-1 resolution, while 16 scans were accumulated. Afterward, spectra were

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baseline corrected and normalized.

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2.6 Solution nuclear magnetic resonance (NMR) spectroscopy

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1

H NMR spectra were recorded on a Bruker DRX-500 instrument at 500 MHz with

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tetramethylsilane as the internal standard. The pure MgSt could not be dissolved in conventional

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NMR solvents such as CDCl3, CD3OH, D2O or deuterated (CH3)2SO. 10-15 mg of the samples

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(ITR and the filtrate) was dissolved in 0.75-0.80 mL CDCl3 (both could be easily dissolved).

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2.7 Elemental analysis

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Magnesium content determination of the filtrate was performed by two methods. The first is

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the energy dispersive spectroscopy (EDS) carried out on a JEOL6380LVa type scanning electron

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microscope (JEOL, Tokyo, Japan) equipped with EDS unit capable of performing elemental

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analyses. The applied accelerating voltage was set to 15 kV while the scanned energy range was

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0-20 keV. Probe current was 1.00 nA.

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Inductively coupled plasma optical emission spectroscopy (ICP-OES) was also employed for

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elemental analysis in order to corroborate results obtained by EDS. 6 ml 63% HNO3 solution was

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added to 11.4 mg of sample and this mixture was destructed at 200 °C under microwave

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conditions. The element concentrations of the sample were measured by the ICP-OES method in

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simultaneous multielement mode by a 40 channel Labtest Plasmalab ICP-spectrometer

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(Laboratory Testing Inc., Hatfield, PA, USA) using 27 MHz argon plasma.

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2.8 Solid state nuclear magnetic resonance (ssNMR) spectroscopy

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13

C CPMAS NMR spectra were recorded on a Varian NMR System 600 MHz spectrometer

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(14.1 T, 13C 150.8 MHz) equipped with a 3.2 mm HXY probehead. The experiments were carried

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out at 15 kHz spinning rate. Contact time was set to 3 ms while the relaxation delay was 30 s.

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2000 (ITR), 2800 (filtrate) and 8000 (electrospun ASD) scans were accumulated. Adamantane

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was applied as shift reference.

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2.9 X-ray powder diffraction (XRPD)

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X-ray powder diffraction patterns were recorded with a PANalytical X’pert Pro MPD X-ray

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diffractometer (Almelo, The Netherlands) using Cu-Kα radiation (1.542 Å) in transmission mode.

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The applied voltage was 40 kV, while the current was 40 mA. The samples were analyzed

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between 2θ angles of 2° and 40°.

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2.10 Raman mapping

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A Horiba Jobin-Yvon LabRAM system coupled with external 785 nm diode laser source and

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Olympus BX-40 optical microscope was used for collecting Raman mapping spectra. An

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objective of 10× magnification (laser spot size: ~4 µm) was applied in focusing and spectrum

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acquisition. The confocal hole of 500 µm, the half of maximum diameter, was employed in

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confocal system to improve the confocal performance decreasing the analysis volume. Finally,

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950 groove/mm grating monochromator disperses the Raman photons before those reach the

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CCD detector. The spectrograph position was set to provide the spectral range of 460-1680 cm-1

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and 3 cm-1 resolution. The map was collected with 100 µm step size and consisted of 21×21

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points. Every single spectrum was measured with an acquisition time of 60 s and 2 spectra were

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averaged at each measured point.

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The chemometric evaluation was performed by applying classical least square (CLS) method

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in LabSpec 5.41 (Horiba Jobin Yvon, New Jersey, USA). Firstly, spectra of SA, crystalline ITR

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and amorphous ITR were applied as references. However, this evaluation led to significant errors.

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An average spectrum could be calculated from all points of the quite uniform map in the software

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and used as a reference in the second evaluation.

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3 Results and discussion

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3.1 Investigation of precipitation of amorphous ITR

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Conversion of ASDs to final dosage forms while maintaining the good dissolution is of great

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importance nowadays. Therefore, the objective of this study is to understand how dissolution

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extent of an amorphous API, namely ITR, from tablets is reduced by a commonly applied

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lubricant, MgSt.

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Fibrous ASD, containing ITR and PVPVA64 (hereinafter referred to as ASD_PVPVA64), was

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described (e.g. SEM images) in former papers13,

18

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According the DSC examination, the ASD did not contain crystalline ITR (Figure 1).

, and therefore this is not included here.

201 1

Differential

scanning

calorimetry

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Figure

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thermograms of crystalline ITR and untreated

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ASD_PVPVA64 (i.e. after production, before

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grinding).

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Afterward, the obtained ASD_PVPVA64 was passed through a sieve (0.8 mm size) and

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blended with excipients. The prepared blend was compressed into tablets with two different

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weights: 300 mg (25 mg dose) and 600 mg (1 tablet for 50 mg dose, 2 tablets for 100 mg dose). It

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was of interest how many percentages of ITR tablets release at different dose levels during in

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vitro dissolution test (Figure 2) knowing that 100% of the API is dissolved from neat ASD, both

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with 50 and 100 mg dose.

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Figure 2 Dissolution profiles of ITR from pure

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ASD_PVPVA64 and tablets with ASD_PVPVA64

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and MgSt at different doses. Parameters: USP II,

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37±0.5 °C, 100 rpm, 0.1N HCl, 900 mL, n=3.

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A certain fraction of ITR (~15-20%) was not dissolving in course of the dissolution tests from

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(MgSt containing) tablets and only ~75-85% of dissolution extent could be achieved in each case.

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ITR is in supersaturated state, but no ‘spring’ kind of precipitation can be observed. On the other

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hand, MgSt, as a hydrophobic material, may deteriorate the dissolution.

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As it was intended to increase the dissolution extent from tablets, several approaches were

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evaluated (from which only the successful ones are described here). MgSt was changed to a less

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hydrophobic lubricant, sodium stearyl fumarate (SSF) to see whether it affects dissolution or not.

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Tablets with SSF released >95% of ITR even at the higher dose, 100 mg (Figure 3).

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Figure 3 Dissolution profiles of ITR from tablets

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(with SSF lubricant) at different doses. Parameters:

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USP II, 37±0.5 °C, 100 rpm, 0.1N HCl, 900 mL,

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n=3.

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This experiment might suggest the simple explanation that the hydrophobicity of MgSt can be

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the reason for the ~80% dissolution extent. However, if PVPVA64 is replaced with HPMC in the

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ASD and then it is processed into tablets with MgSt lubricant, total dissolution of ITR can be

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achieved (Figure 4).

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Figure 4 Dissolution profiles of ITR from MgSt

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tablets (containing ASDs with different polymers).

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Parameters: USPII, 37±0.5 °C, 100 rpm, 0.1N HCl,

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900 mL, 50 mg dose, n=3.

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Since MgSt containing tablets prepared from HPMC-based ASD released 100% of ITR, it can

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be concluded that not (only) the hydrophobicity of the lubricant causes the decreased dissolution

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extent. PVPVA64 is highly miscible with ITR, but it is not capable of forming hydrogen bonds

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with the API. HPMC can do so and thus increase the stability of ITR.

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Although only a small portion of HPMC hydroxyl groups are able to bond with ITR (due to

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the large number of hydroxyl groups in the HPMC), a slight shift to a lower wavenumber could

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be detected in the FTIR spectrum of the ASD in comparison with the pure HPMC (3479 cm-1 to

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3456 cm-1) (Figure 5). The peak of the C=O bond (~1700 cm-1) and neighboring peaks have

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shifted a bit, and intensities of these peaks have also lowered as it is visible on the spectra, which

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shows the interaction between the polymer and the API.

249 250 251

Figure 5 FTIR spectra of HPMC, ITR, and ASD_HPMC. The b) part shows the region of the C=O bond.

Consequently, the presence of interactions between polymer and drug can also be an important

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factor in this phenomenon.

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3.2 Characterization of the filtrate

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Dissolution of special tablets (Section 2.5) was performed to ‘prepare’ a characterizable

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material. The separable solid phase of the dissolution medium was filtered as described

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previously. The filtered material was exposed to solution NMR spectroscopy, elemental analysis,

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ssNMR, XRPD, and Raman mapping to obtain information about the chemical composition, the

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physical and chemical state and the homogeneity of the filtrate. For comparison purposes, pure

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MgSt was stirred in the acidic medium, filtered and dried (providing the same circumstances as

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with tablets). This process certainly converts MgSt into stearic acid (SA), therefore the obtained

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material is called SA_MgSt hereinafter. Then, Raman spectrum and XRPD diffractogram of this

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material were recorded.

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3.2.1 Solution nuclear magnetic resonance (NMR) spectroscopic examination

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The solution NMR examination was performed to determine what the filtrate comprises. The

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chemical shifts of ITR and the filtrate were recorded (see circumstances in section 2.6). Figure 6

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shows the obvious resemblance between the spectra of ITR and the filtrate. Noticeably, three new

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peaks (marked by A, B, and C) appeared in the filtrate spectrum, which can be assigned to the

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hydrogens in the stearate chain. Peak A (s, chemical shift: 1.26 ppm) belongs to H3C-CH2 and

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CH2-CH2-CH2 hydrogens, peak B (quint, chemical shift: 1.63 ppm) can be associated with CH2-

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CH2-CH2-CO. The new peak at the largest shift (t, chemical shift: 2.33 ppm) can be assigned to

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the hydrogens next to the oxo moiety (CH2-CH2-CO). Integration of the peaks suggests a 1:1

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ratio of the stearate chain and ITR.

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273 274

Figure 6 NMR spectra of the filtrate and ITR (CDCl3,

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500 MHz).

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It is important to note that MgSt could not be dissolved in CDCl3 at all, presumably due to

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its salt-like nature, while it was possible to do so with the filtrate (as a matter of fact, it dissolved

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very easily). This observation points out that MgSt does not exist in its original form in the

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filtrate.

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3.2.2 Elemental analysis

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In order to identify what form the stearate chain was present in (MgSt or SA), measurement of

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magnesium content was performed by EDS. According to this technique, the filtrate did not

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comprise any magnesium. This result was corroborated by an absolute method, AAS, which

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showed negligible, 0.011% magnesium content (this is a significantly lower value than the

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theoretically calculable 1.21% weight fraction for magnesium). This led us to the obvious

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conclusion that the sample from the dissolution medium contained only ITR and SA.

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Consequently, the material obtained after stirring MgSt in acidic medium and filtration is also SA

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(as a matter of fact, complete conversion has occurred) and called SA_MgSt hereinafter.

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3.2.3 Solid state nuclear magnetic resonance (ssNMR) spectroscopic examination

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Solid state NMR experiments were carried out to compare the electroblown ASD and the

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filtrate to the crystalline ITR (Figure 7). Peaks at 170-175 and 15-45 ppm in the spectrum of the

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ASD (denoted by red rectangles) indicate the presence of PVPVA64.19 Peak merges and peak

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broadenings in the whole spectrum confirm the amorphous state of the incorporated drug. This

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technique has a higher sensitivity to detect crystalline phases than DSC (~0.5% versus ~5%).20

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Therefore, it can be stated that ITR was completely amorphous in the PVPVA64 matrix.

296 297

Figure 7 Solid state NMR spectra of crystalline ITR, the electroblown

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ASD_PVPVA64, and the filtered sample.

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At first sight, the spectrum of the filtrate resembles the crystalline ITR spectrum. However,

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there are some peak merges and broadenings, marked by black arrows, which indicates that the

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filtered sample contains a not perfectly crystallized ITR. Peaks in the region of 10-50 ppm (blue

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rectangle) can be assigned to the aliphatic region of the stearate chain, while peak of the carbonyl

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carbon atom appears around 182 ppm.21,

22

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spectrum can imply a forming interaction, hydrogen bond, between ITR and SA.23 ITR has been

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reported interact with different carboxylic acids.23,

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side of ITR by Raman spectrometry in Section 3.2.5.

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3.2.4 X-ray powder diffraction (XRPD) examination

The shift of the latter peak to 175 ppm in this

24

This interaction is corroborated from the

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XRPD analysis was performed to obtain more precise information about the crystallinity of

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the sample. Despite the fact that ssNMR showed an obvious resemblance between crystalline ITR

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and the sample, the characteristic pattern of crystalline ITR was not detected in the diffractogram

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of the filtrate (Figure 8).

312 313

Figure 8 XRPD patterns of crystalline ITR, the filtrate, and

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SA_MgSt.

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Peaks incorporated in the red rectangles can be assigned to SA. However, the largest, sharp

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peak at 17° might correspond to ITR.25 There is long range order in the structure of the filtrate,

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significant peaks appear, but the XRPD diffractogram suggests that perfect crystal lattice of ITR

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could not be formed. The substance shares some peaks with crystalline ITR and SA, but

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significant resemblance cannot be noticed. It seems obvious that this is a new, distinct material

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with semi-crystallinity.

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3.2.5 Raman mapping

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In order to investigate the possible formed interactions between ITR and SA and to study the

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homogeneity of the sample, Raman mapping was carried out. Figure 9 shows the Raman spectra

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of references and two distinct points of the map indicating similarities and slight differences,

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whilst the whole sample was quite uniform. The resemblance between spectra of ITR and the

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filtrate seems quite obvious, but peaks at 1063, 1297 and 1436 cm-1 (marked by black rectangles)

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corroborate the presence of SA.

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Figure 9 Raman spectra of MgSt, crystalline and amorphous ITR, and

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two points of the filtrate from the mapping examination.

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However, there are some bands (two examples are highlighted with red rectangles) that cannot

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be de facto assigned to either component. For instance, peak at 1562 cm-1 appears throughout the

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map, but it hardly visible in the spectrum of ITR, just with a very small intensity. On the other

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hand, the band at 1612 cm-1 in spectra of ITR, which can be assigned to the C=N bonds of the

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triazole group26, appears with smaller intensity in the spectrum of filtrate (C=N bond free of

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hydrogen bond will remain in the molecule). The triazole ring of ITR has been reported to be able

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to form hydrogen bonds with carboxyl groups.24, 27 Shevchenko and co-workers reported similar

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shift of this peak due to hydrogen bond formed between succinic acid and ITR.23 The peak of the

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C=N bond shifts from 1612 cm-1 to 1562 cm-1, probably due to the formation of hydrogen bonds.

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This is a so-called ‘red-shift’, which implies to an increase in wavelength, i.e. a decrease in

341

wavenumber and photon energy. This kind of shift is reflecting on the reduced force constant of

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the oscillational movement and/or the enhanced anharmonicity of the vibration of the given

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bond.28 The discussed section of the spectra is highlighted in Figure 10. The originally

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hydrophobic ITR is coupled with the also hydrophobic SA, which results in a very low solubility

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for this associate.

346 347 348 349

Figure 10 The section of the Raman spectra (amorphous ITR and the filtrate) showing the shift of the peak belonging to C=N bond.

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Chemometry was applied with the Raman map, using CLS multivariate method, based on the

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reference spectra of SA_MgSt, crystalline ITR, and amorphous ITR. As expected, the presence of

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the unknown peaks in the sample spectrum makes the chemometric evaluation more difficult

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since it increases the error. Considering each point, an average spectrum could be calculated (a

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spectrum that can be assigned to the ITR-SA associate) and used as a reference in the CLS

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evaluation (i.e. the reference spectra were the following: amorphous ITR, crystalline ITR,

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SA_MgSt and the average spectrum). The map obtained this way is shown in Figure 11. The

357

whole map was rather uniform, and the error could be decreased. The ITR-SA associate owns

358

large percentages in the map, and its distribution is quite homogeneous. No significant parts of

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the map can be assigned to either crystalline or amorphous ITR. Based on this result, the whole

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sample contains a physically and chemically quite uniform material.

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Figure 11 Distribution of a) ITR-SA associate b) SA in the filtrate based on Raman mappings

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To conclude, ITR and SA forms an insoluble, crystalline material, which is presumably a salt

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or a co-crystal according to the analytical examinations (solution NMR: 1:1 ratio of ITR and SA;

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Raman spectroscopy: hydrogen bonds between ITR and SA). Salts and co-crystals can be

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distinguished by single-crystal X-ray diffraction. However, this does not possess relevance in the

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case of this work. From pharmaceutical point of view, the significance is that a commonly

368

applied excipient can deteriorate the good dissolution of an amorphous API through a previously

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undescribed phenomenon.

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4. Conclusions

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It was found that only incomplete dissolution can be realized with tablets containing perfectly

372

amorphous ITR. Dissolution extent did not decrease to the solubility of the drug and curves

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ended up in plateaus. MgSt, a commonly applied lubricant, dissolves in the acidic medium and

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creates SA shown to form an insoluble associate with the API. Chemical composition and the

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lack of magnesium in the insoluble material were proved by solution NMR spectroscopy and

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elemental analysis, respectively. The NMR spectrum of the filtrate confirmed a 1:1 ratio of SA

377

and ITR in this adduct based on the integral of the peaks. The shift of carboxyl carbon peak (of

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SA) in the ssNMR spectrum and the shift of C=N peak (triazole moiety of ITR) revealed a

379

stabilizing interaction (hydrogen bond) between the two substances of this associate. MgSt was

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reported earlier to gradually decrease the dissolution extent of ITR with its increasing

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concentration: 1%: ~80%; 0.5%: ~85%; 0.25%: ~95%.14 These dissolution extents are slightly

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above the possible lowest values (that can be calculated based on the MgSt contents), which

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suggests that the dissolution and the adduct formation are competitive processes.

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To tackle this issue, two solutions can be developed: one of them is the application of another

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lubricant (SSF); the second one is the changing of the polymer in the initial ASD (HPMC instead

386

of PVPVA64). In the first case, stearyl fumaric acid forming upon protonation of SSF does not

387

interact with ITR, whilst HPMC can stabilize ITR through hydrogen bonds and prevents it from

388

crystallizing with SA. HPMC might also block the surface of the carboxylic acid through

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hydrogen bonds. This MgSt/SA-induced decrease in dissolution extent might be a crucial

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phenomenon to be reckoned with in cases of other amorphous APIs. Nevertheless, MgSt and SA

391

are yet to be evaluated whether they affect dissolution of other amorphous drugs or this

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phenomenon is specific for ITR.

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Acknowledgments

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The authors would like to express their gratitude to Dr. András Simon (Budapest University of

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Technology and Economics) for his help in the NMR measurements. The authors are thankful to

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Richter Gedeon Plc. for the possibility to perform the solid state NMR investigations. This work

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was financially supported by the New Széchenyi Development Plan (TÁMOP-4.2.1/B-

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09/1/KMR-2010-0002, FIEK 16-1-2016-0007), OTKA research fund (grant numbers K112644

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and 124541), the New National Excellence Program (UNKP), and János Bolyai Research

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Scholarship of the Hungarian Academy of Sciences.

401

References

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2. Vo, C. L.-N.; Park, C.; Lee, B.-J. Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs. European Journal of Pharmaceutics and Biopharmaceutics 2013, 85, (3, Part B), 799-813.

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3. Baghel, S.; Cathcart, H.; O'Reilly, N. J. Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs. Journal of Pharmaceutical Sciences 2016, 105, (9), 2527-2544.

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4. Brouwers, J.; Brewster, M. E.; Augustijns, P. Supersaturating drug delivery systems: The answer to solubility-limited oral bioavailability? Journal of Pharmaceutical Sciences 2009, 98, (8), 2549-2572.

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5. Six, K.; Daems, T.; de Hoon, J.; Van Hecken, A.; Depre, M.; Bouche, M.-P.; Prinsen, P.; Verreck, G.; Peeters, J.; Brewster, M. E.; Van den Mooter, G. Clinical study of solid dispersions of itraconazole prepared by hot-stage extrusion. European Journal of Pharmaceutical Sciences 2005, 24, (2–3), 179-186.

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6. Augustijns, P.; Brewster, M. E. Supersaturating drug delivery systems: Fast is not necessarily good enough. Journal of Pharmaceutical Sciences 2012, 101, (1), 7-9.

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7. Borbás, E.; Sinkó, B.; Tsinman, O.; Tsinman, K.; Kiserdei, É.; Démuth, B.; Balogh, A.; Bodák, B.; Domokos, A.; Dargó, G.; Balogh, G. T.; Nagy, Z. K. Investigation and Mathematical Description of the Real Driving Force of Passive Transport of Drug Molecules from Supersaturated Solutions. Molecular Pharmaceutics 2016, 13, (11), 3816-3826.

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9. Laitinen, R.; Suihko, E.; Bjorkqvist, M.; Riikonen, J.; Lehto, V.-P.; Jarvinen, K.; Ketolainen, J. Perphenazine solid dispersions for orally fast-disintegrating tablets: physical stability and formulation. Drug Development and Industrial Pharmacy 2010, 36, (5), 601-613.

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10. Wlodarski, K.; Tajber, L.; Sawicki, W. Physicochemical properties of direct compression tablets with spray dried and ball milled solid dispersions of tadalafil in PVP-VA. European Journal of Pharmaceutics and Biopharmaceutics 2016, 109, 14-23.

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11. Agrawal, A.; Dudhedia, M.; Deng, W.; Shepard, K.; Zhong, L.; Povilaitis, E.; Zimny, E. Development of Tablet Formulation of Amorphous Solid Dispersions Prepared by Hot Melt Extrusion Using Quality by Design Approach. AAPS PharmSciTech 2016, 17, (1), 214-232.

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12. Wu, Q.; Kennedy, M. T.; Nagapudi, K.; Kiang, Y. H. Humidity Induced Phase Transformation of Poloxamer 188 and Its Effect on Physical Stability of Amorphous Solid Dispersion of AMG 579, a PED10A Inhibitor. International Journal of Pharmaceutics 2017, DOI: 10.1016/j.ijpharm.2017.01.059.

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13. Nagy, Z. K.; Balogh, A.; Démuth, B.; Pataki, H.; Vigh, T.; Szabó, B.; Molnár, K.; Schmidt, B. T.; Horak, P.; Marosi, G.; Verreck, G.; Van Assche, I.; Brewster, M. E. High speed electrospinning for scaled-up production of amorphous solid dispersion of itraconazole. International Journal of Pharmaceutics 2015, 480, (1-2), 137-142.

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14. Démuth, B.; Farkas, A.; Balogh, A.; Bartosiewicz, K.; Kállai-Szabó, B.; Bertels, J.; Vigh, T.; Mensch, J.; Verreck, G.; Van Assche, I.; Marosi, G.; Nagy, Z. K. Lubricant-Induced Crystallization of Itraconazole From Tablets Made of Electrospun Amorphous Solid Dispersion. Journal of Pharmaceutical Sciences 2016, 105, (9), 2982-2988.

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15. Hussain, M. S. H.; York, P.; Timmins, P. Effect of commercial and high purity magnesium stearates on in-vitro dissolution of paracetamol DC tablets. International Journal of Pharmaceutics 1992, 78, (1), 203-207.

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16. Levy, G.; Gumtow, R. H. Effect of certain tablet formulation factors on dissolution rate of the active ingredient III. Tablet lubricants. Journal of Pharmaceutical Sciences 1963, 52, (12), 1139-1144.

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17. Sóti, P. L.; Bocz, K.; Pataki, H.; Eke, Z.; Farkas, A.; Verreck, G.; Kiss, É.; Fekete, P.; Vigh, T.; Wagner, I.; Nagy, Z. K.; Marosi, G. Comparison of spray drying, electroblowing and electrospinning for preparation of Eudragit E and itraconazole solid dispersions. International Journal of Pharmaceutics 2015, 494, (1), 23-30.

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18. Démuth, B.; Farkas, A.; Szabó, B.; Balogh, A.; Nagy, B.; Vágó, E.; Vigh, T.; Tinke, A. P.; Kazsu, Z.; Demeter, Á.; Bertels, J.; Mensch, J.; Van Dijck, A.; Verreck, G.; Van Assche, I.; Marosi, G.; Nagy, Z. K. Development and tableting of directly compressible powder from electrospun nanofibrous amorphous solid dispersion. Advanced Powder Technology 2017, DOI: 10.1016/j.apt.2017.03.026.

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19. Song, Y.; Wang, L.; Yang, P.; Wenslow, R. M.; Tan, B.; Zhang, H.; Deng, Z. Physicochemical characterization of felodipine-kollidon VA64 amorphous solid dispersions prepared by hot-melt extrusion. Journal of Pharmaceutical Sciences 2013, 102, (6), 1915-1923.

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20. Shah, B.; Kakumanu, V. K.; Bansal, A. K. Analytical techniques for quantification of amorphous/crystalline phases in pharmaceutical solids. Journal of Pharmaceutical Sciences 2006, 95, (8), 1641-1665.

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21. Delaney, S. P.; Nethercott, M. J.; Mays, C. J.; Winquist, N. T.; Arthur, D.; Calahan, J. L.; Sethi, M.; Pardue, D. S.; Kim, J.; Amidon, G.; Munson, E. J. Characterization of Synthesized and Commercial Forms of Magnesium Stearate Using Differential Scanning Calorimetry, Thermogravimetric Analysis, Powder X-Ray Diffraction, and Solid-State NMR Spectroscopy. Journal of Pharmaceutical Sciences 2017, 106, (1), 338-347.

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22. Tang, X.-P.; Mogilevsky, G.; Kulkarni, H.; Wu, Y. Solid-State NMR Studies of the Formation of Monomers and Dimers in Stearic Acid Confined in Titanate Nanotubes. The Journal of Physical Chemistry C 2007, 111, (50), 18615-18623.

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23. Shevchenko, A.; Miroshnyk, I.; Pietilä, L.-O.; Haarala, J.; Salmia, J.; Sinervo, K.; Mirza, S.; van Veen, B.; Kolehmainen, E.; Nonappa; Yliruusi, J. Diversity in Itraconazole Cocrystals with Aliphatic Dicarboxylic Acids of Varying Chain Length. Crystal Growth & Design 2013, 13, (11), 4877-4884.

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24. Nonappa; Lahtinen, M.; Kolehmainen, E.; Haarala, J.; Shevchenko, A. Evidence of Weak Halogen Bonding: New Insights on Itraconazole and its Succinic Acid Cocrystal. Crystal Growth & Design 2013, 13, (1), 346-351.

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25. Six, K.; Verreck, G.; Peeters, J.; Binnemans, K.; Berghmans, H.; Augustijns, P.; Kinget, R.; Van den Mooter, G. Investigation of thermal properties of glassy itraconazole: identification of a monotropic mesophase. Thermochimica Acta 2001, 376, (2), 175-181.

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26. Maghraby, G.; Alomrani, A. Synergistic Enhancement of Itraconazole Dissolution by Ternary System Formation with Pluronic F68 and Hydroxypropylmethylcellulose. Scientia Pharmaceutica 2009, 77, (2), 401.

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27. Remenar, J. F.; Morissette, S. L.; Peterson, M. L.; Moulton, B.; MacPhee, J. M.; Guzmán, H. R.; Almarsson, Ö. Crystal Engineering of Novel Cocrystals of a Triazole Drug with 1,4-Dicarboxylic Acids. Journal of the American Chemical Society 2003, 125, (28), 8456-8457.

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28. Nibbering, E. T. J.; Dreyer, J.; Kühn, O.; Bredenbeck, J.; Hamm, P.; Elsaesser, T., Vibrational dynamics of hydrogen bonds. In Analysis and Control of Ultrafast Photoinduced Reactions, Kühn, O.; Wöste, L., Eds. Springer Berlin Heidelberg: Berlin, Heidelberg, 2007; pp 619-687.

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Figure 1 Differential scanning calorimetry thermograms of crystalline ITR and untreated ASD_PVPVA64. 238x211mm (300 x 300 DPI)

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Figure 2 Dissolution profiles of ITR from pure ASD_PVPVA64 and tablets with ASD_PVPVA64 and MgSt at different doses. Parameters: USP II, 37±0.5 °C, 100 rpm, 0.1N HCl, 900 mL, n=3. 231x177mm (300 x 300 DPI)

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Figure 3 Dissolution profiles of ITR from tablets (with SSF lubricant) at different doses. Parameters: USP II, 37±0.5 °C, 100 rpm, 0.1N HCl, 900 mL, n=3. 230x174mm (300 x 300 DPI)

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Figure 4 Dissolution profiles of ITR from MgSt tablets (containing ASDs with different polymers). Parameters: USPII, 37±0.5 °C, 100 rpm, 0.1N HCl, 900 mL, 50 mg dose, n=3. 230x175mm (300 x 300 DPI)

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Figure 5 FTIR spectra of HPMC, ITR, and ASD_HPMC. The b) part shows the region of the C=O bond. 501x221mm (300 x 300 DPI)

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Figure 6 NMR spectra of the filtrate and ITR (CDCl3, 500 MHz). 240x211mm (300 x 300 DPI)

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Figure 7 Solid state NMR spectra of crystalline ITR, the electroblown ASD_PVPVA64, and the filtered sample. 234x135mm (300 x 300 DPI)

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Figure 8 XRPD patterns of crystalline ITR, the filtrate, and SA_MgSt. 236x215mm (300 x 300 DPI)

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Figure 9 Raman spectra of MgSt, crystalline and amorphous ITR, and two points of the filtrate from the mapping examination. 295x215mm (300 x 300 DPI)

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Figure 10 The section of the Raman spectra (amorphous ITR and the filtrate) showing the shift of the peak belonging to C=N bond. 220x176mm (300 x 300 DPI)

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Molecular Pharmaceutics

Figure 11 Distribution of a) ITR-SA associate b) SA in the filtrate based on Raman mappings 656x203mm (96 x 96 DPI)

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