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Investigation of polymer-surfactant interactions and their impact on Itraconazole solubility and precipitation kinetics for developing spray dried amorphous solid dispersions Tanvi Mahesh Deshpande, Helen Shi, John Pietryka, Stephen W. Hoag, and Ales Medek Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.7b00902 • Publication Date (Web): 18 Jan 2018 Downloaded from http://pubs.acs.org on January 19, 2018

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Molecular Pharmaceutics

1

Investigation of polymer-surfactant interactions and

2

their impact on Itraconazole solubility and

3

precipitation kinetics for developing spray dried

4

amorphous solid dispersions

5

Tanvi M. Deshpande,ǂ Helen Shi,§ John Pietryka, § Stephen W. Hoag, ǂ Ales Medek§*

6

ǂ

7

Baltimore, MD 21201.

8

§

Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland,

Vertex Pharmaceutical Incorporated, Boston, MA 02210.

9 10 11 12 13

*

11 Fan Pier Boulevard, Boston, MA 02210; Phone: (617) 341 6399; E-mail: [email protected] 1 ACS Paragon Plus Environment

Molecular Pharmaceutics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Abstract Methods were developed to systematically screen different polymer-surfactant combinations for

16

the purpose of enhancing amorphous active pharmaceutical ingredient (API) solubility while

17

maintaining its physical stability. Itraconazole (ITZ) was chosen as the model API mostly due to

18

its low aqueous solubility. Special attention was paid to determine the effect of a reduction in the

19

critical micelle concentration (CMC) by specific polymer/surfactant combinations on the ITZ

20

solubility and physical stability. However, only a slight correlation was actually found. Only the

21

polymer/surfactant combinations with the smallest effect on CMC improved solubility and

22

stability of ITZ in simulated intestinal fluids (SIF). Surfactants were found to negate the

23

stabilizing effects of polymers. ITZ crystallization tendency generally depended on the degree of

24

supersaturation and the type of polymer/surfactant combinations used. In general, we found that

25

instead of focusing solely on reducing the CMC, a systematic screening of systems that maintain

26

high ITZ supersaturation proved to be a successful approach.

27 28

Keywords Itraconazole,

29

crystallization, sodium lauryl sulfate, TPGS, PVP-VA, Soluplus®, HPMCAS-HF, Eudragit®

30

L100-55, NMR, fluorescence spectroscopy, critical micelle concentration, critical aggregation

31

concentration, binding affinity, spray dried dispersions.

32 33

Abbreviations ITZ, Itraconazole; BCS, Biopharmaceutical classification system; SLS, Sodium lauryl sulfate;

34

TPGS,

35

concentration; CAC, Critical aggregation concentration; NMR, Nuclear magnetic resonance;

solubility

D-α-Tocopheryl

enhancement,

kinetic

supersaturation,

supersaturation

ratio,

polyethylene glycol 1000 succinate; CMC, Critical micelle

2 ACS Paragon Plus Environment

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PVP-VA, Polyvinylpyrrolidone vinyl acetate; HPMCAS, Hydroxypropyl methylcellulose acetate

37

succinate; ASD, Amorphous solid dispersions; SDD, Spray dried dispersions.

38 39

Introduction About 75% of new chemical entities fall under BCS Class II (low solubility, high permeability)

40

and Class IV (low solubility, low permeability) categories. Amongst the 75%, more than half fall

41

under BCS Class II and most of these compounds are crystalline in nature.1-4 Itraconazole (ITZ,

42

Figure 1), a broad spectrum antifungal agent, was chosen as a model compound because it is a

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BCS Class II compound with very poor water solubility (1 – 5 ng/mL) in its crystalline form.5 It

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is a highly hydrophobic weak base with a logP of 5.66 and pKa of 3.70.6, 7 ITZ’s low aqueous

45

solubility leads to its limited bioavailability.8

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Rendering an API amorphous to produce a solid form with higher free energy has generally

47

shown higher solubility and bioavailability.3, 9-16 Even though neat amorphous forms generally

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display higher solubility, they are often physically unstable. The amorphous form may convert to

49

the thermodynamically favored crystalline form, and precipitation will ultimately occur from a

50

solution that is supersaturated with respect to the crystalline form. These undesirable outcomes

51

can be mitigated by the inclusion of additional components such as amorphous drug carriers. The

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efficacy of drug carrier(s) in this regard is assessed by measuring the thermodynamic solubility

53

and kinetic supersaturation stability of the amorphous form of the drug in the presence of

54

different drug carrier excipients.17

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Polymers are often used as drug carriers since they can form molecular mixtures with poorly

56

water-soluble drugs to enhance the thermodynamic and kinetic solubility of the drug.11 In

57

addition to polymers, other solubility enhancing excipients like surfactants can be used. The



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incorporation of surfactants with polymers is expected to enhance the wettability of hydrophobic

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drugs and their solubility by the way of micellar solubilization.18,

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concentration above the critical micelle concentration (CMC), aggregate and form micelles in

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solution, which have the ability to encapsulate poorly water soluble drugs.20 When polymers are

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used in combination with surfactants, a change in the CMC of the system may be observed. The

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concentration at which the surfactant molecules start to interact with or adsorb to certain regions

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of the polymer is referred to as the critical aggregation concentration (CAC).21,22 We

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hypothesized that if specific polymer/surfactant combinations decrease the CMC of the system,

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then a reduced amount of excipients (polymer and surfactants) could be used to improve the

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dispersion solubility and stability in GI fluids. Different screening methodologies have been

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employed in literature to select drug carriers (mostly polymers): determining the miscibility of

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drug and excipients by thermal methods and comparing their solubility parameter values;23 in

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silico miscibility prediction;24 atomic force microscopy-based miscibility screening;25 and

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solvent casting method;26,

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have been studied as drug carriers for formulating SDDs.21, 28

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The systematic screening methodology employed here using ITZ consists of the following steps:

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(1) Screening polymer/surfactant systems by determining the CAC of surfactants in the presence

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of polymers. (2) Determining the thermodynamic solubility, supersaturation ratios, and

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nucleation induction time of ITZ in aqueous solutions. (3) Preparing ITZ SDDs using the

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polymer/surfactant systems that displayed increased solubility and prolonged induction time. (4)

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Characterizing ITZ SDDs to detect the presence of ITZ crystallinity, testing SDD drug release,

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and performing solid state stability studies under stressed conditions. In addition, ITZ-polymer-

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surfactant binding studies were performed to explain some of the thermodynamic observations.

27

19

Surfactants present at a

amongst others. More recently, polymer/surfactant combinations


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The following polymers were selected for the screening study based on the literature reports of

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their use in the application of amorphous solid dispersions: Polyvinylpyrrolidone (PVP),28-31

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Kollidon® VA64 (PVP-VA),28, 30 hydroxypropyl methylcellulose E 50 LV (HPMC E 50 LV),31,

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32

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acetate succinate HF grade (HPMCAS-HF),31, 32, 39 and Eudragit® L100-55.40, 41 Two surfactants,

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sodium lauryl sulfate (SLS) and

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were chosen for the study.6 SLS, an anionic surfactant with CMC of 8 mM, is a commonly used

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surfactant for wetting and drug solubilization.42 Unlike SLS, TPGS is a non-ionic surfactant with

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a lower CMC of 0.13 mM that makes it a useful candidate for drug solubilization.43 This low

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CMC may allow TPGS to be used at lower concentrations for micellar solubilization.

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Experimental Section

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Materials All products were used as received. Itraconazole (Lot# YQ3010) and HPMC E50 LV (Lot#

94

2EF0240) were obtained from Spectrum Chemicals (New Brunswick, NJ). PVP K30

95

(Polyvinylpyrrolidone) (Lot# QR10278) was obtained from MP Biomedicals LLC (Solon, OH).

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PVP-VA (Kollidon VA 64) (Lot# 39936956P0) and Soluplus (Lot# 84414368) were obtained

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from BASF Chemical Company Ltd. (Ludwigshafen, Germany). SLS (Lot# 136823) was

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obtained from Fisher Chemical (Pittsburgh, PA) and TPGS from Antares Health Products, Inc

99

(Jonesborough, TN). HPMCAS-HF (Lot # 3073182) and Eudragit® L100-55 (Lot#

100

B130404014) were obtained from Shin-Etsu (Japan) and Evonik Industries (Germany),

101

respectively. Pyrene (Lot# JYC8C-IF) was obtained from Tokyo Chemical Industry Co. Ltd.

102

(Cambridge, MA). PEG 4000 (Lot# 81242), D2O (99.9 atom %D) (Lot# MKBR4176V) and

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DMSO (Lot# BCBN3355V) were obtained from Sigma-Aldrich (St. Louis, MO).

polyethylene glycol 4000 (PEG 4000),33,

34

Soluplus,35-38 hydroxypropyl methyl cellulose

D-α-Tocopheryl

polyethylene glycol 1000 succinate (TPGS)



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Fasted simulated intestinal media (FaSSIF, pH 6.5) was prepared according to the procedure

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developed by Galia et al,44 and contained sodium hydroxide (Lot# MKBV3988V) obtained from

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Sigma-Aldrich (St. Louis, MO), sodium chloride (Lot# 155950) and monobasic sodium

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phosphate monohydrate (Lot# 158542) obtained from Fisher Chemical (Pittsburgh, PA), and SIF

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powder (Lot# 01-1609-02NP (02)) obtained from Phares AG (Basel, Switzerland).

109 110

1

111

were recorded at a temperature of 300 K (27 °C) in standard 5 mm NMR tubes. Each sample

112

spectrum was collected over 16 scans. Proton resonances were referenced against

113

tetramethylsilane (TMS) at 0 ppm. 1H NMR was used for the determination of CMC/CAC,

114

binding stoichiometry, and binding affinity.

115 116

Determination of CMC/CAC The molecular interactions, correlating to CMC/CAC changes, between SLS and polymers in the

117

aqueous environment were characterized by 1H NMR. The CMC/CAC measurements of SLS

118

solutions (in deionized water with 10% D2O) were determined at 3 mg/mL polymer

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concentration. Chemical shifts of SLS protons (H1 or H12, Figure 2) were plotted against the

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inverse SLS concentration. The surfactant concentration at which a break in the curve was

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obtained on the graph was noted as the CMC of SLS or CAC of the SLS – polymer complex.45

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Each CMC/CAC measurement was conducted in duplicates. In addition to the CAC

123

determination at a fixed polymer concentration, concentration dependent CAC determination

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was performed for the SLS/PVP-VA system, to serve as a reference for further binding studies.

125 126

Fluorescence Spectroscopy Fluorescence spectroscopy was used for determining CMC of TPGS and CAC of TPGS in

127

combination with other polymers. Fluorescence measurements conducted using the hydrophobic

NMR Measurements H NMR spectra were measured using a Bruker Avance-III (400 MHz) instrument. All spectra


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fluorescent probe, pyrene, were found to be more sensitive than NMR spectroscopy.

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Fluorescence spectra were obtained using the Fluorolog®-3 (Horiba Instruments Inc, Edison, NJ)

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spectrometer. Pyrene exhibits different fluorescent behavior in micellar and nonmicellar

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solutions.46 TPGS/polymer solutions (10 mL) were prepared containing different concentrations

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of TPGS, 3 mg/mL of polymer and 0.25x10-6 M of pyrene. The solutions were filtered through a

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0.45 µm syringe filter and then characterized by fluorescence spectroscopy. All samples were

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analyzed at 27°C. The emission spectra of pyrene in the solutions were obtained by applying an

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excitation light of 330 nm. The CMC/CAC of the mixtures were determined by plotting the ratio

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of the intensities of the two emission peaks at 374 nm (I1) and 385 nm (I3), I1/I3 vs surfactant

137

concentration.47, 48

138 139

Thermodynamic Solubility Measurement of Crystalline Itraconazole Due to its weakly basic nature, ITZ shows pH-dependent solubility. It dissolves well in acidic

140

stomach pH, but it is poorly soluble in the more neutral small intestinal pH. ITZ could thus

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partially precipitate in the small intestine, which can negatively impact its bioavailability.

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Therefore, crystalline ITZ solubility was determined in FaSSIF (pH 6.5), a media with a lower

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solubilization capacity for weak bases.28, 44, 49, 50 Furthermore, the apparent solubility of ITZ was

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determined either in the presence of pre-dissolved polymer or surfactant (SLS/TPGS), or in a

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polymer/surfactant combination using a randomized 32 full factorial model design of

146

experiments (DOE) strategy. The factors and levels for the DOE are given in Table 1. An excess

147

amount of crystalline ITZ (20 mg) was suspended in a vial containing FaSSIF solution (3 mL)

148

with pre-dissolved polymers and surfactants (SLS or TPGS). This was followed by vortexing for

149

1 min, sonication (Branson B3510R - DHT, Danbury, CT) for 30 min, and then mixing using a

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temperature controlled mechanical stirrer for 72 hours at 37°C. The suspensions were

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subsequently centrifuged at 10,000 rpm for 5 min (EppendorfTM 5418 Microcentrifuge). The 7 ACS Paragon Plus Environment


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residues were collected for XRPD analysis while the ITZ solubility was analyzed using Agilent

153

1200 series HPLC/UV-Vis (Agilent Technology, Palo Alto, CA).

154 155 156

Itraconazole Supersaturation Kinetics and SDD Dissolution Rate Determination using the Micro-dissolution System Supersaturation kinetics of ITZ in different polymer/surfactant systems were studied using an in

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situ fiber optic UV monitoring system, Pion µDISS ProfilerTM (Billerica, MA), by real time

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dissolution monitoring under non-sink conditions. To minimally impact the total weight of the

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tablet, a maximum of 300 mg of excipient was selected. Considering about 900 mL of GI

160

volume, the maximum polymer and surfactant concentration was limited to 0.3 mg/mL. A 32

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factorial design was implemented using three concentrations for the polymer and surfactants: 0

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mg/mL, 0.15 mg/mL, and 0.3 mg/mL. For all nine surfactant/polymer combinations, six

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surfactant:polymer ratios (mg/mL) were chosen: 0:0, 0.3:0, 0:0.3, 0.15:0.3, 0.15:0.15, 0.3:0.3.

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Solutions (20 mL) were prepared by pre-dissolving polymer, surfactant, or surfactant/polymer

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combination in FaSSIF and allowed to equilibrate at 37ºC with a stirring speed of 250 rpm. Then

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200 µL of DMSO supersaturated stock solution of ITZ (4 mg/mL) was added into the pre-

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equilibrated 20 mL media to achieve a target supersaturation of 40 µg/mL and the kinetic

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solubility tests were performed for 24 h or until precipitation was complete. A limited dissolution

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volume (20 mL) used instead of the standard 900 mL dissolution vessels, which enabled the use

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of smaller amount of compound to form a supersaturated solution and may more closely

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resemble the environment in the GI tract.3, 51

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Supersaturation ratios were calculated from the thermodynamic solubility for the desired

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polymer-surfactant concentrations, using Equation 1. The dissolved/ supersaturated ITZ

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concentration was detected in situ with integrated fiber optic UV dip probes, which were inserted

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into the vessels. 8 ACS Paragon Plus Environment

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(1)

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For SDD dissolution rate studies using the µDISS system, SDD corresponding to 6 mg ITZ was

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added to the FaSSIF media. The dissolution rates were measured in 20 mL media at 37°C with a

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cross stirrer speed of 315 rpm (to facilitate mixing of the SDD powder in the media). The

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dissolution rates for the SDDs were compared to that of crystalline ITZ. Due to their poor

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wettability, all powder samples (crystalline ITZ and SDD) were pre-wet for less than a minute in

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FaSSIF before adding to the dissolution media. The dissolved ITZ concentration was detected in

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situ with an integrated fiber optic UV dip probe and validated using HPLC. Each data point

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represents was obtained with two replicates (n=2) and presented as mean ± SD.

185 186

Powder X-ray Diffraction (XRPD) Analysis X-ray diffraction was used to investigate the crystallinity of ITZ in the residues obtained from

187

the thermodynamic solubility studies. XRPD patterns were collected on the Bruker D8 Advance

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Powder X-ray Diffractometer (copper X-ray tube, 40 kV, 40 mA, Madison, WI, USA). The

189

diffractometer was calibrated every day using corundum (NIST 1976 standard reference

190

material) with respect to line position and intensity as a function of 2Θ angle. Thermodynamic

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solubility residues or SDD samples were placed on the standard zero background reflection

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mode holders. The XRPD samples were collected in the angular range of 3 – 40º 2Θ in a step

193

scan mode and analyzed by EVA V4 software (Bruker, Madison, WI).

194 195

Determination of Binding Stoichiometry Job’s plot also known as the method of continuous variation was used to determine the

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stoichiometry of binding between ITZ and PVP-VA.52 In this method, the combined

197

concentration of the drug and polymer is kept constant, but the relative mole fraction of each is

198

varied in a compensatory manner to maintain the total molarity of the solution constant.50, 53 A



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series of samples containing ITZ and PVP-VA (monomer MW = 197 g/mol) were prepared by

200

mixing the two DMSO stock solutions (5.67 mM) at varying proportions and qs to a constant

201

volume so that a complete range of mole fraction (χ) from 0 – 1 is obtained. 1H NMR spectra

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were collected and the chemical shifts of ITZ proton labeled H3 (Figure 1) were noted. The

203

differences in the chemical shifts (χ * ∆H3) were plotted against ITZ mole fraction (χ).

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Depending on the stoichiometry, a symmetric (1:1 binding) or asymmetric (not 1:1 binding) bell

205

shaped curve is obtained. Tangents to the Job’s plot are drawn and the mole fraction at which the

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two tangents intersect is considered as the stoichiometry of binding.50

207 208

Determination of Binding affinity The binding affinities were analyzed according to the method of Ramstad et al.54 Scheme 1

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shows the drug-polymer association equilibrium where [D] is the concentration of the free drug

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[ITZ], [P] is the concentration of the free polymer [PVP-VA], [D – P] is the concentration of the

211

drug-polymer complex, and KD-P is the binding or equilibrium constant of drug and polymer.

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Scheme 1. Interaction and association constant between drug (D) and polymer (P).

213 =

[ − ] [][ ]

214 215

Changes in the chemical shift of the ITZ triazole proton at position 3 (H3, Figure 1) were

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measured as a function of the fraction ITZ bound. A difference in chemical shifts (∆) between

217

free (δD) and bound ITZ (δ) results from the changes in the environment surrounding the protons

218

when bound to the polymer (PVP-VA). When all of the ITZ is bound to the polymer, there is no

219

further change in the chemical shift (∆max) of ITZ (δDP) even after a further increase in the


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220

polymer concentration. Due to the limited solubility of ITZ in water, the samples of ITZ and

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ITZ/PVP-VA complex were prepared in DMSO. ITZ concentration was fixed at 3 mg/mL and

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the total PVP-VA concentration (PVP-VAt) was varied from 0 – 10 mg/mL.

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The binding isotherm was obtained by plotting the measured change in chemical shift of the ITZ

224

H3 proton (∆ = δ - δD) against the free PVP-VA ([PVP-VA]). The [PVP-VA] was in turn

225

calculated from PVP-VAt (concentration of the total polymer) using Equation 2:

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[PVP-VA] = PVP-VAt − ITZt

227

where ∆max (∆max = δDP - δD) is the maximum chemical shift obtained on complete binding.

228

This binding isotherm was fit and analyzed according to Equation 3 using non-linear regression

229

analysis from which both ∆max and KD-P were obtained.

230

∆ =

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The above binding isotherm was derived for a 1:1 stoichiometry of binding.55

232

To establish the effect of SLS on ITZ-polymer binding, 2 mg/mL SLS was added to the same

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NMR tubes, sonicated until SLS was completely dissolved and then equilibrated for an hour at

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room temperature. NMR spectra were collected on these ternary solutions to obtain a binding

235

isotherm and to determine the KD-P-S (binding constant between the drug, polymer, and

236

surfactant.

237 238

Preparation of Amorphous Solid Dispersions Amorphous solid dispersions were prepared by the spray drying technique. Binary and ternary

239

solid dispersions were prepared in the presence of polymer or surfactant/polymer systems,

240

respectively. SDDs were prepared using the Buchi mini spray dryer B290 (Buchi, DE). Spray

∆ [] []

∆

∆

∆ =

∆ [] []

(2)

(3)



Page 12 of 46

241

drying was performed from a solution of 10% solids dissolved in methylene chloride/methanol

242

(2:1 v/v) mixture. A drug loading of 50% w/w was maintained throughout the binary and ternary

243

mixtures. The inlet temperature was set at 80°C and the outlet temperature was maintained

244

between 45°C and 50°C. The aspirator was set at 100%, the feed rate was maintained at 12

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mL/min, and spray flow rate was set at 40 mm (rotameter setting) which corresponded to 667

246

liter/h. All samples were dried for 24 h in a vacuum oven at 40°C and stored in a desiccator over

247

silica gel at 25°C until further analysis.

248 249

Particle Size of Spray Dried Dispersions The particle size distribution of the spray dried dispersions were characterized by laser

250

diffraction method using Malvern® Mastersizer 2000 particle size analyzer (Malvern Inc.,

251

Worcestershire, UK). Average particle size and span index (polydispersity) was determined for

252

the SDDs. The Fraunhofer model in the Malvern software was used. The dry powder feeder was

253

operated at 1.5 bar at a constant feed rate of 75%.

254 255

Differential Scanning Calorimetry (DSC) Analysis of the crystalline ITZ and SDD samples was performed using a DSC 2500 (TA

256

Instruments; New Castle, DE, USA) equipped with a refrigerated cooling system and analyzed

257

using Trios 4.0 Software to determine the glass transition temperature (Tg). The instrument was

258

calibrated using indium for the temperature and cell constant. About 6 – 10 mg of the crystalline

259

ITZ and SDD samples were sealed in Tzero aluminum pans and subjected to heat-cool-heat

260

cycle. The experiments were conducted with heating/cooling rate of 10°C/min, from -20°C to

261

200°C. All experiments were performed in duplicate. The Tg reported in this study was derived

262

from the inflection point obtained from the first heating cycle.


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263 264

Scanning Electron Microscopy (SEM) The SDD samples were mounted onto SEM specimen holders with conductive carbon adhesive

265

tabs (Ted Pella, Inc, Redding, CA) and sputter coated with 10 to 20 nm of platinum/palladium in

266

a sputter coater EMS 150T ES (Electron Microscopy Sciences, Hatfield, PA). SEM images were

267

taken using a Quanta 200 SEM (FEI. Co. Hillsboro, OR) with a horizontal field width (HFW) of

268

59.7 µm, spot of 3.0, secondary electron (SE) mode, working distance (WD) of 5.3 mm using a

269

large field detector (LFD) in the low vacuum mode.

270 271

Accelerated Stability Studies The accelerated stability studies were performed using conditions per ICH guidelines. The SDDs

272

were stored in parafilm-sealed scintillation vials at 40ºC/ 75% RH in a stability chamber. They

273

were sampled and tested for crystallinity using XRPD and DSC at 0 day, 15 day, 1 month, and 3

274

month time points.56, 57

275

Results

276 277

CMC/CAC Determination of Surfactants and Polymer/Surfactant Combinations SLS and TPGS CMC (in the absence of polymer) and CAC (in the presence of polymers) are

278

shown in Figure 3A and Figure 3B, respectively. The CMC of SLS in aqueous media was found

279

to be approximately 6.8 mM as determined by NMR. The SLS/PVP-VA combination exhibited a

280

maximum decrease in the CMC, whereas SLS/Soluplus showed the smallest decrease (Figure

281

3A). These results suggested a strong interaction/ synergistic effect between PVP-VA and SLS,

282

which could be attributed to PVP-VA possessing functional groups that interact strongly with

283

SLS. Soluplus, on the other hand, presented a weaker interaction with SLS.

284

The CMC of TPGS was found to be 0.11 mM as determined by fluorescence spectroscopy. In the

285

presence of Eudragit, a synergistic effect was observed with a maximum decrease in CMC. On



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the other hand, an increase in the CMC was observed in the presence of HPMCAS-HF,

287

indicating an antagonistic effect between TPGS and HPMCAS-HF for micelle formation.

288

Four polymer/surfactant combinations were selected for further thermodynamic and kinetic

289

solubility studies: Two combinations showing a significant decrease in the CMC (SLS/PVP-VA

290

and TPGS/Eudragit), one system showing a weaker synergistic effect (SLS/Soluplus), and one

291

showing antagonistic effect (TPGS/HPMCAS-HF).

292 293 294 295

Thermodynamic Solubility of Crystalline Polymer/Surfactant Combinations

296

SLS/PVP-VA and SLS/Soluplus

297

The thermodynamic solubility of crystalline ITZ in FaSSIF containing SLS/PVP-VA and

298

SLS/Soluplus is shown in Figure 4A and Figure 4B, respectively. Without a surfactant or

299

polymer, the ITZ solubility was low (about 50 ng/mL). No change was observed on increasing

300

the PVP-VA concentration alone but a significant increase was observed (from 50 ng/mL to

301

about 880 ng/mL) when SLS was present at 2 mg/mL without any polymer. When both the

302

surfactant and polymer were combined, the apparent ITZ solubility was slightly lower than that

303

in the presence of SLS only. This observation indicates that the interactions between SLS and

304

PVP-VA have a negative impact on the solubility of crystalline ITZ.

305

SLS/Soluplus interactions displayed a stronger antagonistic effect on the ITZ solubility as seen

306

in Figure 4B. A significant increase in the solubility to ~ 10 µg/mL was observed in the presence

307

of 2 mg/mL Soluplus. At the same concentration of 2 mg/mL Soluplus, a sharp decrease in the

ITZ

in

the

Presence

of

Selected


Page 15 of 46 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


308

apparent ITZ solubility from 10 µg/mL to approximately 1.5 µg/mL was observed with

309

increasing SLS concentrations.

310 311

TPGS/Eudragit® L100-55 and TPGS/HPMCAS-HF For the TPGS/Eudragit combination, an increase in the polymer concentration alone increased

312

the ITZ solubility up to 4 µg/mL, whereas a negligible increase was observed for TPGS. In the

313

presence of both TPGS and Eudragit, a decrease in ITZ solubility to 2.5 µg/mL was observed

314

(Figure 5A).

315

For the TPGS/HPMCAS system, an increase in the polymer concentration alone produced an

316

increase in ITZ solubility to approximately 7 µg/mL. Unlike other systems, TPGS/HPMCAS-HF

317

combination showed a synergistic ITZ solubility increase (up to ~11 µg/mL; Figure 5B).

318

The results obtained from the thermodynamic solubility studies were contrary to our working

319

hypothesis. All the surfactant/polymer combinations with a lower CMC yielded decreased ITZ

320

solubility and some combinations (TPGS/HPMCAS-HF) with an increased CMC displayed

321

increased ITZ solubility. Amphiphilic substances such as phospholipids and bile salts used as

322

part of the SIF recipe could interfere with the polymer-surfactant interaction. The resulting

323

system in SIF could be far more complex than the simpler polymer induced surfactant

324

aggregation model. Therefore, the hypothesis based on CMC reduction in water may not be

325

translatable to the solubility determination in simulated fluids (FaSSIF).

326 327 328

X-ray Powder Diffraction to Determine Change in ITZ Solid Form The XRPD data indicated no change in the ITZ solid form for any of the thermodynamic

329

solubility study residues. All diffractograms showed sharp diffraction peaks similar to the

330

crystalline ITZ. 15 ACS Paragon Plus Environment


Page 16 of 46

331 332

Crystallization Induction Time The goal of the supersaturation kinetic studies was to evaluate the impact of polymers,

333

surfactants, and their combinations on the nucleation and crystal growth tendency of ITZ.

334

Systems that yielded a prolonged supersaturation of ITZ for at least three hours would be

335

considered successful.

336

For all four polymer/surfactant systems, ITZ precipitated sooner from the media containing pre-

337

dissolved surfactants as compared to media with no excipients (Figure 6A, 6B, 7A and 7B). For

338

the SLS/PVP-VA combination, media containing the polymer alone maintained ITZ in its

339

supersaturated metastable state for about 2.5 h. Addition of SLS decreased the nucleation time.

340

The rank order for the precipitation induction time for the SLS:PVP-VA ratios was found to be

341

0:0.3 > 0.15:0.3 ≥ 0.15:0.15 > 0.3:0.3 > 0:0 > 0.3:0. These results suggested that SLS competes

342

with ITZ for binding to PVP-VA and hence reduces the PVP-VA activity to maintain ITZ in the

343

supersaturated state. This outcome is consistent with the findings of Liu et al.28 Binding affinity

344

studies between ITZ/PVP-VA in the absence and in the presence of SLS were subsequently

345

conducted to obtain a better understanding of the mechanism by which SLS promotes the ITZ

346

precipitation.

347

For the SLS/Soluplus system, pre-dissolved Soluplus (Figure 6B) by itself maintained ITZ in its

348

supersaturated state without precipitation for 24 h. SLS concentration dependent reduction of

349

ITZ nucleation time was observed (down to 10 h). The rank order for the SLS:Soluplus induction

350

time was found to be 0:0.3 > 0.15:0.15 > 0.15:0.3 > 0.3:0.3 > 0:0 > 0.3:0. These results could be

351

rationalized by SLS promoting the precipitation of ITZ, in this case by competing for Soluplus.


Page 17 of 46 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


352

Similar to the SLS/polymer systems, TPGS/Eudragit (Figure 7A) also displayed surfactant

353

dependent precipitation, once again pointing to the competitive effect between surfactant and

354

ITZ.

355

An interesting observation for TPGS/HPMCAS-HF combination was no ITZ precipitation for up

356

to 24 h in spite of the presence of pre-dissolved TPGS. Hence the presence of TPGS did not

357

affect the HPMCAS-stabilized supersaturated state of ITZ. The antagonistic CMC effect between

358

TPGS and HPMCAS-HF perhaps prevents TPGS from competing with ITZ for binding with

359

HPMCAS-HF. Therefore, HPMCAS-HF activity to stabilize ITZ from precipitating is not

360

affected.

361

The nucleation induction differences between the four systems can be linked to the degree of

362

supersaturation. A higher degree of supersaturation increases the probability of nucleation and

363

crystal growth. The fact that SLS/Soluplus and TPGS/HPMCAS-HF system maintains ITZ in its

364

supersaturated state for beyond 10 h can be attributed, at least in part, to their lower

365

supersaturation ratio. As compared to PVP-VA and Eudragit, Soluplus and HPMCAS-HF were

366

found to be the more suitable to be used in combination with SLS and TPGS, respectively.

367

From inspecting the induction time as a function of supersaturation (Figure 8), we could predict

368

which supersaturation ratio leads to the failure point (i.e. precipitation).

369 370

Stoichiometry and Binding affinity using NMR Spectroscopy In order to rationalize the rapid nucleation of ITZ in the presence of SLS and the competitive

371

effect between SLS and ITZ, the binding affinities of ITZ/PVP-VA alone and in the presence of

372

SLS were determined. Based on the kinetic supersaturation study, it was expected that the

373

binding affinity between ITZ and PVP-VA would decrease in the presence of SLS.



Page 18 of 46

374

From the Job’s plot symmetric shape with a maximum at 0.5, the binding stoichiometry was

375

determined to be 1:1. As the PVP-VAt concentration increased, the H3 proton resonance shifted

376

downfield (to higher ppm). This shift was proportional to the ITZ-PVP-VA complex

377

concentration and can be attributed to the de-shielding of the proton. The binding curve in Figure

378

9 was fitted using Equation 3 yielding KD-P = 137.5 ± 6.7 mol-1. Similarly, the binding affinity of

379

ITZ/PVP-VA/SLS was determined (Figure 9). SLS at 2 mg/mL was added to the same NMR

380

samples containing ITZ/PVP-VA. This SLS concentration was selected to maintain all the

381

samples above their CAC. A significant decrease in the binding affinity from KD-P = 137.5 ± 6.7

382

mol-1 to KD-P-S = 47.6 ± 20.5 mol-1 was seen in the presence of SLS. These results are in

383

agreement with the kinetic data and the competitive effect between SLS and ITZ.

384 385

Amorphous Solid Dispersions of Binary and Ternary Systems The polymer/surfactant combinations that maintained supersaturated ITZ for the longest period

386

of time were selected to prepare SDDs. Constant API loading of 50% w/w was chosen. The

387

following SDDs were prepared: 1) ITZ:PVP-VA (50:50), 2) ITZ:Soluplus (50:50), 3)

388

ITZ:SLS:Soluplus (50:25:25), 4) ITZ:Eudragit® L100-55 (50:50), 5) ITZ:TPGS:Eudragit®

389

L100-55 (50:25:25), 6) ITZ:HPMCAS-HF (50:50), and 7) ITZ:TPGS:HPMCAS-HF (50:25:25).

390

The ITZ SDDs with PVP-VA, Soluplus, SLS/Soluplus, and HPMCAS-HF (Figure 10B, Figure

391

10C, Figure 10D, Figure 10F, respectively) formed spherical microparticles (D0.5 < 10µm with a

392

narrow particle size distribution). They exhibited the SDD characteristic irregular dimpled

393

surfaces or pores (Table 4). However, ITZ/Eudragit SDD displayed a different morphology with

394

a mixture of spheres and fibers (Figure 10G), with larger particle size and broader distribution

395

(Table 4).


Page 19 of 46 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


396

All SDDs were characterized by DSC and XRPD, and compared to pure crystalline ITZ.

397

Crystalline ITZ shows a single narrow melting endotherm at 168°C (∆H of 88 J/g) (Figure 11)

398

and sharp diffraction peaks (Figure 12). Upon cooling from above the ITZ melting temperature,

399

the DSC shows no evidence of recrystallization exotherm. The lack of ITZ recrystallization is

400

confirmed upon second heating cycle (data not shown), whereby only a glass transition at 60.2 ±

401

0.2°C is observed (Table 4).

402

For all the freshly prepared SDDs except those with TPGS, no ITZ crystallinity was observed by

403

DSC (Figure 11) and XRPD (Figure 12), confirming the amorphous nature of these materials.

404

The two SDDs containing TPGS did not process well and resulted in larger agglomerated

405

particles. An endothermic ITZ melting peak was observed, indicating a degree of ITZ

406

crystallinity. SEM images (Figure 10E) showed an aggregated fused mass of solid, probably due

407

to the presence of waxy TPGS. Both TPGS containing SDDs were therefore excluded from

408

further studies.

409

On the other hand, the SLS containing SDD (ITZ/SLS/Soluplus) showed DSC with crystalline

410

endotherms (Figure 11) and XRPD with sharp diffraction peaks (Figure 12). These features

411

clearly demonstrated the presence of crystalline SLS and implicated SLS phase separation and

412

crystallization during spray-drying process.

413 414

SDD Dissolution Rate SDD dissolution studies (Figure 13) were performed to determine the maximum ITZ

415

concentration and to assess ITZ precipitation potential during intestinal transit. As shown in

416

Figure 13, all SDDs displayed a rapid ITZ release with a substantial concentration boost as

417

compared to the crystalline drug. All SDDs showed a similar ITZ concentration of about 4

418

µg/mL up to 60 min. ITZ released from ITZ/PVP-VA SDD and ITZ/Eudragit SDD started to 19 ACS Paragon Plus Environment


Page 20 of 46

419

precipitate after 60 min and 160 min, respectively. All other SDDs maintained solubilized ITZ

420

without precipitation for at least 180 min. After 24 h, precipitation from all but ITZ/HPMCAS

421

SDD was seen. This SDD showed only a marginal ITZ concentration decrease (from 4 µg/mL to

422

3 µg/mL).

423 424

Accelerated Stability Studies of Spray-dried Dispersions Due to the propensity of amorphous materials to crystallize, it is important to assess the

425

possibility of conversion of the amorphous drug into its poorly soluble crystalline counterpart

426

upon storage. Temperature and humidity play an important role on the stability of formulated

427

amorphous products. Hence accelerated stability studies were performed at elevated temperature

428

and humidity conditions to determine ITZ crystallization kinetics.

429

By XRPD, all the SDDs were found to be physically stable with no traces of crystallinity for at

430

least 3 months at 40°C /75% RH. By DSC, all SDDs except for ITZ/Soluplus displayed a single

431

Tg and no crystalline ITZ melting endotherm. The DSC scan of ITZ/Soluplus SDD (Figure 14A)

432

at the 15 and 30 day time points showed a Tg at 42°C and an endothermic peak at 155°C. This

433

peak is close to that reported for ITZ Form II with a melting point of 156°C.58, 59 However, this

434

sample was fully amorphous by XRPD (Figure 14B). The presence of the melting endotherm in

435

the stressed ITZ/Soluplus SDD could be an evidence of structural changes in this material (such

436

as a phase separation) leading to heat-induced drug crystallization during the DSC scan.60

437

Discussion

438 439 440

Thermodyamic Solubility of Crystalline ITZ in the Presence of Different Polymer/Surfactant Systems DOE type of thermodynamic ITZ solubility study was designed to assess the excipients main and

441

interaction effects. As compared to the other polymers, the nonionic PVP-VA had minimal effect

442

on ITZ solubility. On the other hand, Soluplus, HPMCAS-HF and Eudragit, which fall under the 20 ACS Paragon Plus Environment

Page 21 of 46 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


443

amphiphilic category, induced a significant increase in the ITZ thermodynamic solubility in

444

addition to displaying good ITZ stabilizing property. Even though the excipients individually

445

enhanced ITZ solubility, their combination did not always follow the same trend. The interaction

446

effect on ITZ solubility was either a synergistic (TPGS/HPMCAS-HF) or antagonistic

447

(SLS/Soluplus).

448

Ternary systems with a CMC reduction decreased rather than increased ITZ solubility. We can

449

conclude that the interaction between the two solubility enhancing components reduces the

450

activity of either to enhance the solubility of ITZ. On the other hand, the system showing an

451

increase in CMC displayed a synergistic solubility increase. This may be due to the availability

452

of both the excipients to interact with and enhance ITZ solubility. It should be noted that

453

solubilization follows a complex mechanism and our original hypothesis of lower CMC giving

454

higher apparent solubility clearly does not always hold, especially considering other interactions

455

in complex SIFs.61

456 457

Polymer/Surfactant combination Effects on Nucleation and Crystal Growth of Itraconazole The nucleation rate (Rn) and the crystal growth rate (Rg) are both dependent on the

458

supersaturation ratio (S) of the drug in the GI fluids.62-65 Clearly, the higher the supersaturation

459

ratio, the faster the onset of nucleation induction and the crystal growth rate.65 "#

*

& (()+

$

4

460

= exp !−

461

where A is pre-exponential factor, σ is interfacial tension between the nucleus and the

462

supersaturated solution, ν is molecular volume, k is Boltzmann constant and T is absolute

463

temperature.

$

%

,-

. /01 23 5

(4)



Page 22 of 46

464

Rg = kgSg

465

where kg is growth rate constant, and g is overall order. Therefore, at higher supersaturation

466

(SLS/PVP-VA), crystalline ITZ was found to precipitate faster as compared to the other systems.

467

Stabilizing polymers may inhibit crystal growth by adsorbing onto or interacting with the

468

growing crystal surface. They may also provide a mechanical barrier by preventing drug

469

molecules from occupying the growth site of the crystal.66-69 Polymers with higher molecular

470

weight may increase the viscosity of the solution and slow the diffusion of the drug molecules,

471

hence slowing nucleation and crystal growth.66-69

472

For all the systems tested, ITZ from pre-dissolved surfactant only media exhibited the shortest

473

nucleation times. This phenomenon can be explained by the rapid ITZ supersaturation in the

474

presence of surfactants and the absence of polymer stabilization. Surfactants clearly have the

475

ability to enhance nucleation and crystal growth and accelerate solution mediated polymorph-

476

transformations.42, 70-72

477

We observed that the stronger the interaction between surfactant and polymer, the shorter the

478

induction time of crystallization. This decreased stability of ITZ supersaturated aqueous solution

479

is likely due to the lower polymer activity to stabilize ITZ.

480 481

NMR Spectroscopy to Determine Binding Stoichiometry and Binding Affinity Interactions between drug and polymer molecules involve several weak bonds such as

482

electrostatic interactions including hydrogen bonding, electrostatic, ionic interactions, van der

483

Waals forces, and/ or hydrophobic bonds.73 Relatively weak ITZ-PVP-VA binding was observed

484

as indicated by the small ∆H3 shifts in the range of 0 – 1 x 10-4 ppm. Note that although the

485

kinetic supersaturation studies and CMC/CAC measurements were conducted in aqueous media,

(5)


Page 23 of 46 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


486

the binding studies were performed in DMSO to mitigate the limited ITZ water solubility.

487

DMSO was chosen to maintain the polarity of the sample environment for the NMR studies.

488 489

Spray Dried Dispersions of ITZ in Binary or Ternary Systems The 25% SLS and TPGS level used in our SDDs would typically be considered above the

490

realistic surfactant concentration and was chosen just to test our hypothesis. The agglomerated

491

and fused particles of TPGS containing SDDs may be attributed to the waxy, sticky nature and

492

low melting point of TPGS (37°C).74 Therefore, TPGS containing SDDs were not characterized

493

further. The formation of fibers instead of spherical particles for Eudragit containing SDDs

494

(without TPGS) was probably due to insufficient energy present to break up the liquid into

495

droplets during the spray-drying, which was previously reported by Mu et al.75 A decrease in the

496

solid content during spray drying could probably prevent fiber formation.

497 498

In vitro Drug Dissolution and Release The faster ITZ precipitation from PVP-VA and Eudragit only SDDs can be explained by their

499

higher supersaturation ratio as compared to the other SDDs. Maintaining the API in its

500

amorphous state without precipitation during the intestinal transit time (> 180 min) would often

501

be sufficient for achieving the necessary bioavailability.62 It was interesting to observe that after

502

24 h almost complete ITZ precipitation was observed for all SDDs except for ITZ/HPMCAS-HF

503

one which showed only a slight ITZ concentration decrease. HPMCAS-HF was found to be the

504

most efficient polymeric carrier for ITZ by not only increasing its thermodynamic solubility, but

505

also by stabilizing the supersaturated aqueous ITZ state released from the SDD.

506 507

Accelerated Stability Study and ITZ Polymorphic Forms Accelerated stability studies were performed to determine the ITZ solid state stability on storage.

508

Strong ITZ-polymer interactions can enhance the SDD physical stability by decreasing its

509

molecular mobility.76, 77 Water absorption by hydrophilic polymers could lead to the disruption 23 ACS Paragon Plus Environment


Page 24 of 46

510

of the ITZ-polymer interactions and cause ITZ to crystallize. Since hydrophobic polymers like

511

HPMCAS-HF and Eudragit absorb less moisture, they may provide comparably better solid state

512

stability.78

513

Comparing the results obtained from the thermodynamic and kinetic solubility, drug release, and

514

stability studies, ITZ/Soluplus, ITZ/SLS/Soluplus, and ITZ/HPMCAS SDDs were found to be

515

the most efficient in increasing the ITZ thermodynamic solubility. The also provided rapid drug

516

release in simulated fluids without ITZ precipitation and maintained the solid state stability

517

under accelerated stability conditions. SLS/Soluplus was the only surfactant/polymer system that

518

not only displayed a reduction in the CMC but also improved ITZ solubility as well as SDD

519

aqueous and solid state stability. Although our hypothesis (of decrease in CMC equals enhanced

520

solubility) did not hold for most of the polymer/surfactant combinations, we could explain how

521

the interactions between the two components affected the amorphous ITZ solubility and stability

522

in aqueous media. Summarized in the flowchart in Figure 15, these interaction studies provided

523

insight into screening excipients for ITZ SDD development. The most efficient systems were

524

those that maintained high supersaturation of ITZ irrespective of the presence or absence of

525

surfactants. It should be noted that this methodology was developed for ITZ and therefore may

526

not be applicable to all compounds. The solubility and stability responses are highly drug

527

specific and the excipients used here for ITZ may not show the same behavior for other

528

compounds, as also seen by Liu et al.28

529 530

Conclusion The combination of multiple tools (NMR, fluorescence spectrometry, and thermodynamic and

531

kinetic solubility) was found useful to study polymer/surfactant interactions. These tools were

532

beneficial in assessing polymer/surfactant compatibility to enhance ITZ solubility and to inhibit 24 ACS Paragon Plus Environment

Page 25 of 46 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


533

its solution crystallization. Combining DOE type solubility measurements with kinetic

534

supersaturation studies provided a better insight on polymer/surfactant selection for SDD

535

development. The positive surfactant/polymer interaction observed by CMC/CAC determination

536

in water did not necessarily translate to enhancing ITZ thermodynamic and kinetic solubility in

537

SIF. We believe the competitive effect between surfactant and ITZ for polymer binding led to the

538

decreased ITZ stability in the aqueous media. This effect was confirmed by studying the binding

539

affinities of ITZ and polymer in the presence and absence of SLS. In addition to exhibiting good

540

solid state stability, ITZ/HPMCAS-HF SDD was found to be most efficient in maintaining ITZ

541

supersaturation in SIF. In general, we found that maintaining high ITZ supersaturation was the

542

key factor to target by the systematic screening.

543 544

Acknowledgement Authors would like to thank Mark Strohmeier, Arun Mohanty, Kwame Nti-Addae, Rupa Sawant,

545

Carl Zwicker, Mettachit Navamal, and Harsh Shah for their advice and technical assistance. We

546

would also like to thank Peter Y. Zavalij at University of Maryland College Park for the XRPD

547

analysis of the SDD samples and Ru-ching Hsia at the Core imaging facility at University of

548

Maryland, Baltimore for the SEM analysis of the SDD samples. This research was supported in

549

part by FDA grant 1U01FD005946.

550

This work was completed in partial fulfilment of the dissertation to be submitted by Tanvi M.

551

Deshpande to the Graduate School of the University of Maryland, Baltimore for the Doctor of

552

Philosophy 2017.

553 554 555

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26. Barillaro, V.; Pescarmona, P. P.; Van Speybroeck, M.; Thi, T. D.; Van Humbeeck, J.; Vermant, J.; Augustijns, P.; Martens, J. A.; Van Den Mooter, G., High-Throughput Study of Phenytoin Solid Dispersions: Formulation Using an Automated Solvent Casting Method, Dissolution Testing, and Scaling-Up. J. Comb. Chem. 2008, 10 (5), 637-643.

625 626 627

27. Gumaste, S. G.; Gupta, S. S.; Serajuddin, A. T. M., Investigation of Polymer-Surfactant and Polymer-Drug-Surfactant Miscibility for Solid Dispersion. The AAPS Journal 2016, 18 (5), 1131-1143.



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631 632 633

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634 635 636 637

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35. Singh, A.; Bharati, A.; Frederiks, P.; Verkinderen, O.; Goderis, B.; Cardinaels, R.; Moldenaers, P.; Van Humbeeck, J.; Van den Mooter, G., Effect of Compression on the Molecular Arrangement of Itraconazole–Soluplus Solid Dispersions: Induction of Liquid Crystals or Exacerbation of Phase Separation? Mol. Pharmaceutics 2016, 13 (6), 1879-1893.

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36. Lu, J.; Cuellar, K.; Hammer, N. I.; Jo, S.; Gryczke, A.; Kolter, K.; Langley, N.; Repka, M. A., Solid-state characterization of Felodipine–Soluplus amorphous solid dispersions. Drug Dev. Ind. Pharm. 2016, 42 (3), 485-496.

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739 740 741

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72. Garti, N.; Zour, H., The effect of surfactants on the crystallization and polymorphic transformation of glutamic acid. J. Cryst. Growth 1997, 172 (3), 486-498.

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756 757 758

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762 763 764

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774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792

TABLES

793

Table 1. Factors and levels for thermodynamic solubility determination. Factors\ Levels Surfactant Polymer

mg/mL 0 0

0 mg/mL 1 1

+ mg/mL 2 2

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799 800 801 802 803 804 805 806 807 808 809 810 811 812 813

Table 2. Supersaturation ratio range of ITZ in different surfactant/polymer systems (at

814

concentrations (mg/mL) studied for the kinetic supersaturation study). Surfactant:Polymer System (mg/mL) SLS/PVP-VA SLS/Soluplus TPGS/Eudragit® L100-55 TPGS/HPMCAS-HF

0:0 772 772 772 772

Approximate supersaturation ratio 0.3:0 0:0.3 0.15:0.3 0.15:0.15 504 772 597 593 772 25 23 20 772 108 127 153 772 33 45 68

0.3:0.3 438 19 127 45

815 816 817 818 819 820



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821 822 823 824 825 826 827 828 829 830 831 832 833 834

Table 3. PVP-VA concentration dependent change in CMC/CAC of SLS/PVP-VA system.

PVP-VA concentration (mg/mL) 0 0.3 1.5 3 10

CMC/CAC of SLS (mM) 6.8 7.7 0.9 1.1 1.3

CMC/CAC of SLS (mg/mL) 1.9 2.2 0.3 0.3 0.4

835 836 837 838 839 840 841 842


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843 844 845 846 847 848 849 850 851 852 853

Table 4. Particle size, span and Tg of crystalline ITZ, polymers, and SDDs (The particle size

854

and span of the polymers alone was not determined). Binary/Ternary System Raw ITZ PVP-VA ITZ/PVP-VA SDD Soluplus ITZ/Soluplus SDD ITZ/SLS/Soluplus SDD Eudragit® L100-55 ITZ/Eudragit® L100-55 SDD HPMCAS-HF ITZ/HPMCAS-HF SDD

% w/w 100 100 50:50 100 50:50 50:25:25 100 50:50 100 50:50

D0.5 (μm) 6

Span 2

5

2

5 5

3 3

24

11

8

1

Tg (°C) 60.2 111 86.1 78.6 62.7 57.0 81.6 80.3 122.0 78.9

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863 864 865 866 867 868 869 870 871 872 873

FIGURE LEGENDS

874

Figure 1. Chemical structure of Itraconazole (ITZ).

875 876

Figure 2. Chemical structure of sodium lauryl sulfate (SLS).

877 878 879

Figure 3. CMC/CAC of (A) SLS and SLS/Polymer systems, (B) TPGS and TPGS/Polymer systems determined at 27 °C.

880 881 882

Figure 4. Thermodynamic solubility of crystalline ITZ in the presence of (A) SLS/PVP-VA system and (B) SLS/Soluplus system.

883 884 885

Figure 5. Thermodynamic solubility of crystalline ITZ in the presence of (A) TPGS/Eudragit® L100-55 and (B) TPGS/HPMCAS-HF.

886 887 888

Figure 6. Supersaturation kinetics of ITZ in (A) SLS/PVP-VA system (B) SLS/Soluplus system; where the surfactant:polymer ratio is in mg/mL.

889 890 891

Figure 7. Supersaturation kinetics of ITZ in (A) TPGS/Eudragit® L100-55 system (B) TPGS/HPMCAS system; where the surfactant:polymer ratio is in mg/mL. 36 ACS Paragon Plus Environment

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892 893 894

Figure 8. ITZ induction time (hours) as a function of supersaturation ratio for different polymer/surfactant systems.

895 896 897

Figure 9. Binding curve between ITZ-PVP-VA in the absence (open boxes) and presence of SLS (filled boxes).

898 899 900 901

Figure 10. SEM images of (A) Crystalline ITZ, (B) ITZ/PVP-VA SDD, (C) ITZ/Soluplus SDD, (D) ITZ/SLS/Soluplus SDD, (E) ITZ/TPGS/HPMCAS-HF SDD, and (F) ITZ/HPMCAS-HF SDD at 5000-fold magnification, (G) ITZ/Eudragit® L100-55 SDD at 1000-fold magnification.

902 903 904 905

Figure 11. DSC thermograms of SDDs displaying amorphous SDDs with a single Tg and no ITZ crystalline peak for PVP-VA, Soluplus, SLS/Soluplus, HPMCAS-HF, and Eudragit® L100-55 containing SDDs.

906 907 908

Figure 12. XRPD patterns of SDDs compared to crystalline ITZ, showing the absence of ITZ crystallinity.

909 910

Figure 13. Drug release from SDDs in simulated intestinal media (FaSSIF, pH 6.5) at 37 °C.

911 912 913 914

Figure 14. (A) DSC thermogram showing a Tg and melting endotherm, (B) XRPD diffraction pattern showing amorphous content with absence of ITZ crystallinity for ITZ/Soluplus SDD 3 month stability samples (40 °C/ 75% RH).

915 916 917 918 919

Figure 15. Methodology for screening polymer/surfactant systems for SDD development with Itraconazole. N designates the initial number of polymer/ surfactant systems screened. N-a is the reduced number of systems after CMC/ CAC screen. N-a-b is the further reduced number of systems after additional thermodynamic and kinetic solubility screen.

920 921 922 923



Page 38 of 46

924 925 926 927 928 929 930 931 932 933 934

Figure 1.

935 936 937 938 939

Figure 2.

940 941 942 943 944

Figure 3.


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945 946 947 948 949 950

Figure 4.

951 952 953 954

Figure 5.



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955 956 957 958 959 960 961 962 963 964

Figure 6.

965 966 967 968

Figure 7.


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969 970 971 972 973

Figure 8.

974 975

Figure 9.

976 977 978 979



980

Page 42 of 46

Figure 10.

981 982 983

Figure 11.

984 985 42 ACS Paragon Plus Environment

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986 987 988

Figure 12.

989 990 991 992 993 994 995 996 997 998

Figure 13.

999 1000 1001 43 ACS Paragon Plus Environment


1002

Page 44 of 46

Figure 14.

1003 1004 1005 1006 1007 1008 1009 1010 1011

Figure 15.


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1012 1013 1014

Table of Contents/Abstract Graphic

1015 1016 1017 1018



249x170mm (150 x 150 DPI)

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Investigation of polymer-surfactant interactions and their impact on

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