Subscriber access provided by READING UNIV
Article
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
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Molecular Pharmaceutics is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 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
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
Page 2 of 46
14 15
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
Page 3 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
Molecular Pharmaceutics
36
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
43
BCS Class II compound with very poor water solubility (1 – 5 ng/mL) in its crystalline form.5 It
44
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
46
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
48
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
52
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
55
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
3 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
Page 4 of 46
58
incorporation of surfactants with polymers is expected to enhance the wettability of hydrophobic
59
drugs and their solubility by the way of micellar solubilization.18,
60
concentration above the critical micelle concentration (CMC), aggregate and form micelles in
61
solution, which have the ability to encapsulate poorly water soluble drugs.20 When polymers are
62
used in combination with surfactants, a change in the CMC of the system may be observed. The
63
concentration at which the surfactant molecules start to interact with or adsorb to certain regions
64
of the polymer is referred to as the critical aggregation concentration (CAC).21,22 We
65
hypothesized that if specific polymer/surfactant combinations decrease the CMC of the system,
66
then a reduced amount of excipients (polymer and surfactants) could be used to improve the
67
dispersion solubility and stability in GI fluids. Different screening methodologies have been
68
employed in literature to select drug carriers (mostly polymers): determining the miscibility of
69
drug and excipients by thermal methods and comparing their solubility parameter values;23 in
70
silico miscibility prediction;24 atomic force microscopy-based miscibility screening;25 and
71
solvent casting method;26,
72
have been studied as drug carriers for formulating SDDs.21, 28
73
The systematic screening methodology employed here using ITZ consists of the following steps:
74
(1) Screening polymer/surfactant systems by determining the CAC of surfactants in the presence
75
of polymers. (2) Determining the thermodynamic solubility, supersaturation ratios, and
76
nucleation induction time of ITZ in aqueous solutions. (3) Preparing ITZ SDDs using the
77
polymer/surfactant systems that displayed increased solubility and prolonged induction time. (4)
78
Characterizing ITZ SDDs to detect the presence of ITZ crystallinity, testing SDD drug release,
79
and performing solid state stability studies under stressed conditions. In addition, ITZ-polymer-
80
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
4 ACS Paragon Plus Environment
Page 5 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
Molecular Pharmaceutics
81
The following polymers were selected for the screening study based on the literature reports of
82
their use in the application of amorphous solid dispersions: Polyvinylpyrrolidone (PVP),28-31
83
Kollidon® VA64 (PVP-VA),28, 30 hydroxypropyl methylcellulose E 50 LV (HPMC E 50 LV),31,
84
32
85
acetate succinate HF grade (HPMCAS-HF),31, 32, 39 and Eudragit® L100-55.40, 41 Two surfactants,
86
sodium lauryl sulfate (SLS) and
87
were chosen for the study.6 SLS, an anionic surfactant with CMC of 8 mM, is a commonly used
88
surfactant for wetting and drug solubilization.42 Unlike SLS, TPGS is a non-ionic surfactant with
89
a lower CMC of 0.13 mM that makes it a useful candidate for drug solubilization.43 This low
90
CMC may allow TPGS to be used at lower concentrations for micellar solubilization.
91
Experimental Section
92 93
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).
96
PVP-VA (Kollidon VA 64) (Lot# 39936956P0) and Soluplus (Lot# 84414368) were obtained
97
from BASF Chemical Company Ltd. (Ludwigshafen, Germany). SLS (Lot# 136823) was
98
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
103
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)
5 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
Page 6 of 46
104
Fasted simulated intestinal media (FaSSIF, pH 6.5) was prepared according to the procedure
105
developed by Galia et al,44 and contained sodium hydroxide (Lot# MKBV3988V) obtained from
106
Sigma-Aldrich (St. Louis, MO), sodium chloride (Lot# 155950) and monobasic sodium
107
phosphate monohydrate (Lot# 158542) obtained from Fisher Chemical (Pittsburgh, PA), and SIF
108
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
119
concentration. Chemical shifts of SLS protons (H1 or H12, Figure 2) were plotted against the
120
inverse SLS concentration. The surfactant concentration at which a break in the curve was
121
obtained on the graph was noted as the CMC of SLS or CAC of the SLS – polymer complex.45
122
Each CMC/CAC measurement was conducted in duplicates. In addition to the CAC
123
determination at a fixed polymer concentration, concentration dependent CAC determination
124
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
6 ACS Paragon Plus Environment
Page 7 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
Molecular Pharmaceutics
128
fluorescent probe, pyrene, were found to be more sensitive than NMR spectroscopy.
129
Fluorescence spectra were obtained using the Fluorolog®-3 (Horiba Instruments Inc, Edison, NJ)
130
spectrometer. Pyrene exhibits different fluorescent behavior in micellar and nonmicellar
131
solutions.46 TPGS/polymer solutions (10 mL) were prepared containing different concentrations
132
of TPGS, 3 mg/mL of polymer and 0.25x10-6 M of pyrene. The solutions were filtered through a
133
0.45 µm syringe filter and then characterized by fluorescence spectroscopy. All samples were
134
analyzed at 27°C. The emission spectra of pyrene in the solutions were obtained by applying an
135
excitation light of 330 nm. The CMC/CAC of the mixtures were determined by plotting the ratio
136
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
141
partially precipitate in the small intestine, which can negatively impact its bioavailability.
142
Therefore, crystalline ITZ solubility was determined in FaSSIF (pH 6.5), a media with a lower
143
solubilization capacity for weak bases.28, 44, 49, 50 Furthermore, the apparent solubility of ITZ was
144
determined either in the presence of pre-dissolved polymer or surfactant (SLS/TPGS), or in a
145
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
150
temperature controlled mechanical stirrer for 72 hours at 37°C. The suspensions were
151
subsequently centrifuged at 10,000 rpm for 5 min (EppendorfTM 5418 Microcentrifuge). The 7 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
Page 8 of 46
152
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
157
situ fiber optic UV monitoring system, Pion µDISS ProfilerTM (Billerica, MA), by real time
158
dissolution monitoring under non-sink conditions. To minimally impact the total weight of the
159
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
161
factorial design was implemented using three concentrations for the polymer and surfactants: 0
162
mg/mL, 0.15 mg/mL, and 0.3 mg/mL. For all nine surfactant/polymer combinations, six
163
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.
164
Solutions (20 mL) were prepared by pre-dissolving polymer, surfactant, or surfactant/polymer
165
combination in FaSSIF and allowed to equilibrate at 37ºC with a stirring speed of 250 rpm. Then
166
200 µL of DMSO supersaturated stock solution of ITZ (4 mg/mL) was added into the pre-
167
equilibrated 20 mL media to achieve a target supersaturation of 40 µg/mL and the kinetic
168
solubility tests were performed for 24 h or until precipitation was complete. A limited dissolution
169
volume (20 mL) used instead of the standard 900 mL dissolution vessels, which enabled the use
170
of smaller amount of compound to form a supersaturated solution and may more closely
171
resemble the environment in the GI tract.3, 51
172
Supersaturation ratios were calculated from the thermodynamic solubility for the desired
173
polymer-surfactant concentrations, using Equation 1. The dissolved/ supersaturated ITZ
174
concentration was detected in situ with integrated fiber optic UV dip probes, which were inserted
175
into the vessels. 8 ACS Paragon Plus Environment
Page 9 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
Molecular Pharmaceutics
176
(1)
177
For SDD dissolution rate studies using the µDISS system, SDD corresponding to 6 mg ITZ was
178
added to the FaSSIF media. The dissolution rates were measured in 20 mL media at 37°C with a
179
cross stirrer speed of 315 rpm (to facilitate mixing of the SDD powder in the media). The
180
dissolution rates for the SDDs were compared to that of crystalline ITZ. Due to their poor
181
wettability, all powder samples (crystalline ITZ and SDD) were pre-wet for less than a minute in
182
FaSSIF before adding to the dissolution media. The dissolved ITZ concentration was detected in
183
situ with an integrated fiber optic UV dip probe and validated using HPLC. Each data point
184
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
188
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
191
solubility residues or SDD samples were placed on the standard zero background reflection
192
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
196
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
9 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
Page 10 of 46
199
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
202
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).
204
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
206
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
209
shows the drug-polymer association equilibrium where [D] is the concentration of the free drug
210
[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.
212
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
216
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
10 ACS Paragon Plus Environment
Page 11 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
Molecular Pharmaceutics
220
polymer concentration. Due to the limited solubility of ITZ in water, the samples of ITZ and
221
ITZ/PVP-VA complex were prepared in DMSO. ITZ concentration was fixed at 3 mg/mL and
222
the total PVP-VA concentration (PVP-VAt) was varied from 0 – 10 mg/mL.
223
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:
226
[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
∆ =
231
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
233
NMR tubes, sonicated until SLS was completely dissolved and then equilibrated for an hour at
234
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)
11 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
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
245
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.
12 ACS Paragon Plus Environment
Page 13 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
Molecular Pharmaceutics
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
13 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
Page 14 of 46
286
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
14 ACS Paragon Plus Environment
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
Molecular Pharmaceutics
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
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
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.
16 ACS Paragon Plus Environment
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
Molecular Pharmaceutics
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.
17 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
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).
18 ACS Paragon Plus Environment
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
Molecular Pharmaceutics
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
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
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
Molecular Pharmaceutics
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)
21 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
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)
22 ACS Paragon Plus Environment
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
Molecular Pharmaceutics
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
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
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
Molecular Pharmaceutics
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
References 1. Di, L.; Fish, P. V.; Mano, T., Bridging solubility between drug discovery and development. Drug Discovery Today 2012, 17 (9), 486-495. 25 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
Page 26 of 46
556 557
2. Di, L.; Kerns, E. H.; Carter, G. T., Drug-like property concepts in pharmaceutical design. Curr. Pharm. Des. 2009, 15 (19), 2184-2194.
558 559 560
3. Lu, Z.; Yang, Y.; Covington, R.-A.; Bi, Y. V.; Dürig, T.; Ilies, M. A.; Fassihi, R., Supersaturated controlled release matrix using amorphous dispersions of glipizide. Int. J. Pharm. 2016, 511 (2), 957-968.
561 562 563
4. Williams, H. D.; Trevaskis, N. L.; Charman, S. A.; Shanker, R. M.; Charman, W. N.; Pouton, C. W.; Porter, C. J., Strategies to address low drug solubility in discovery and development. Pharmacol. Rev. 2013, 65 (1), 315-499.
564 565 566
5. Grant, S. M.; Clissold, S. P., Itraconazole. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses. Drugs 1989, 37 (3), 310-344.
567 568
6. Williams, R. O.; Watts, A. B.; Miller, D. A., Formulating Poorly Water Soluble Drugs. Springer International Publishing: 2016.
569 570 571
7. Obara, S.; Kokubo, H., Application of HPMC and HPMCAS to Aqueous Film Coating of Pharmaceutical Dosage Forms. In Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, 2008; pp 279-322.
572 573 574
8. Thakkar, H. P.; Khunt, A.; Dhande, R. D.; Patel, A. A., Formulation and evaluation of Itraconazole nanoemulsion for enhanced oral bioavailability. J. Microencapsulation 2015, 32 (6), 559-569.
575 576
9. Serajuddin, A., Solid dispersion of poorly water‐soluble drugs: Early promises, subsequent problems, and recent breakthroughs. J. Pharm. Sci 1999, 88 (10), 1058-1066.
577 578
10. Leuner, C.; Dressman, J., Improving drug solubility for oral delivery using solid dispersions. Eur. J. Pharm. Biopharm. 2000, 50 (1), 47-60.
579 580 581
11. Xie, T.; Taylor, L. S., Dissolution performance of high drug loading celecoxib amorphous solid dispersions formulated with polymer combinations. Pharm. Res. 2016, 33 (3), 739-750.
582 583 584
12. Van den Mooter, G., The use of amorphous solid dispersions: A formulation strategy to overcome poor solubility and dissolution rate. Drug Discovery Today: Technol. 2012, 9 (2), e79e85.
585 586
13. Sriamornsak, P.; Burapapadh, K., Characterization of recrystallized itraconazole prepared by cooling and anti-solvent crystallization. Asian J. Pharm. Sci. 2015, 10 (3), 230-238.
587 588 589
14. Murdande, S. B.; Pikal, M. J.; Shanker, R. M.; Bogner, R. H., Solubility advantage of amorphous pharmaceuticals: I. A thermodynamic analysis. J. Pharm. Sci. 2010, 99 (3), 12541264.
590 591
15. Murdande, S. B.; Pikal, M. J.; Shanker, R. M.; Bogner, R. H., Solubility advantage of amorphous pharmaceuticals: II. Application of quantitative thermodynamic relationships for
26 ACS Paragon Plus Environment
Page 27 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
Molecular Pharmaceutics
592 593
prediction of solubility enhancement in structurally diverse insoluble pharmaceuticals. Pharm. Res. 2010, 27 (12), 2704-2714.
594 595 596
16. Dave, V. S.; Hepburn, S.; Hoag, S. W., Physical States and Thermodynamic Principles in Pharmaceutics. In Pharmaceutics: Basic Principles and Application to Pharmacy Practice, Academic Press: 2013; pp 17-50.
597 598 599
17. Van Duong, T.; Van den Mooter, G., The role of the carrier in the formulation of pharmaceutical solid dispersions. Part II: amorphous carriers. Expert Opin. Drug Delivery 2016, 13 (12), 1681-1694.
600 601
18. Rangel-Yagui, C. O.; Pessoa, A., Jr.; Tavares, L. C., Micellar solubilization of drugs. J. Pharm. Sci. 2005, 8 (2), 147-165.
602 603
19. Seedher, N.; Kanojia, M., Micellar solubilization of some poorly soluble antidiabetic drugs: a technical note. AAPS PharmSciTech 2008, 9 (2), 431-436.
604 605
20. Mall, S.; Buckton, G.; Rawlins, D. A., Dissolution behaviour of sulphonamides into sodium dodecyl sulfate micelles: a thermodynamic approach. J. Pharm. Sci. 1996, 85 (1), 75-78.
606 607 608 609
21. Qi, S.; Roser, S.; Edler, K. J.; Pigliacelli, C.; Rogerson, M.; Weuts, I.; Van Dycke, F.; Stokbroekx, S., Insights into the Role of Polymer-Surfactant Complexes in Drug Solubilisation/Stabilisation During Drug Release from Solid Dispersions. Pharm. Res. 2013, 30 (1), 290-302.
610 611
22. Abuin, E. B.; Scaiano, J., Exploratory study of the effect of polyelectrolyte surfactant aggregates on photochemical behavior. J. Am. Chem. Soc. 1984, 106 (21), 6274-6283.
612 613 614 615
23. Piccinni, P.; Tian, Y.; McNaughton, A.; Fraser, J.; Brown, S.; Jones, D. S.; Li, S.; Andrews, G. P., Solubility parameter‐based screening methods for early‐stage formulation development of itraconazole amorphous solid dispersions. J. Pharm. Pharmacol. 2016, 68 (5), 705-720.
616 617
24. He, Y.; Ho, C., Amorphous Solid Dispersions: Utilization and Challenges in Drug Discovery and Development. J. Pharm. Sci. 2015, 104 (10), 3237-3258.
618 619 620
25. Lauer, M. E.; Grassmann, O.; Siam, M.; Tardio, J.; Jacob, L.; Page, S.; Kindt, J. H.; Engel, A.; Alsenz, J., Atomic force microscopy-based screening of drug-excipient miscibility and stability of solid dispersions. Pharm. Res. 2011, 28 (3), 572-584.
621 622 623 624
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.
27 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
Page 28 of 46
628 629 630
28. Liu, C.; Chen, Z.; Chen, Y.; Lu, J.; Li, Y.; Wang, S.; Wu, G.; Qian, F., Improving oral bioavailability of sorafenib by optimizing the “Spring” and “Parachute” based on molecular interaction mechanisms. Mol. Pharmaceutics 2016, 13 (2), 599-608.
631 632 633
29. Marsac, P. J.; Rumondor, A. C.; Nivens, D. E.; Kestur, U. S.; Stanciu, L.; Taylor, L. S., Effect of temperature and moisture on the miscibility of amorphous dispersions of felodipine and poly (vinyl pyrrolidone). J. Pharm. Sci. 2010, 99 (1), 169-185.
634 635 636 637
30. Yuan, X.; Xiang, T.-X.; Anderson, B. D.; Munson, E. J., Hydrogen bonding interactions in amorphous indomethacin and its amorphous solid dispersions with poly (vinylpyrrolidone) and poly (vinylpyrrolidone-co-vinyl acetate) studied using 13C solid-state NMR. Mol. Pharmaceutics 2015, 12 (12), 4518-4528.
638 639 640
31. Jackson, M. J.; Kestur, U. S.; Hussain, M. A.; Taylor, L. S., Dissolution of danazol amorphous solid dispersions: supersaturation and phase behavior as a function of drug loading and polymer type. Mol. Pharmaceutics 2015, 13 (1), 223-231.
641 642 643
32. Konno, H.; Handa, T.; Alonzo, D. E.; Taylor, L. S., Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine. Eur. J. Pharm. Biopharm. 2008, 70 (2), 493-499.
644 645
33. Liu, C.; Desai, K. G., Characteristics of rofecoxib-polyethylene glycol 4000 solid dispersions and tablets based on solid dispersions. Pharm Dev. Technol. 2005, 10 (4), 467-477.
646 647 648
34. El-Badry, M.; Fetih, G.; Fathy, M., Improvement of solubility and dissolution rate of indomethacin by solid dispersions in Gelucire 50/13 and PEG4000. Saudi Pharm. J. 2009, 17 (3), 217-225.
649 650 651 652
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.
653 654 655
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.
656 657 658
37. Shamma, R. N.; Basha, M., Soluplus®: A novel polymeric solubilizer for optimization of Carvedilol solid dispersions: Formulation design and effect of method of preparation. Powder Technol. 2013, 237, 406-414.
659 660
38. Lim, H.; Hoag, S. W., Plasticizer Effects on Physical–Mechanical Properties of Solvent Cast Soluplus® Films. AAPS PharmSciTech 2013, 14 (3), 903-910.
661 662
39. Tanno, F.; Nishiyama, Y.; Kokubo, H.; Obara, S., Evaluation of hypromellose acetate succinate (HPMCAS) as a carrier in solid dispersions. Drug Dev. Ind. Pharm. 2004, 30 (1), 9-17.
663 664 665
40. Sarode, A. L.; Sandhu, H.; Shah, N.; Malick, W.; Zia, H., Hot melt extrusion (HME) for amorphous solid dispersions: Predictive tools for processing and impact of drug–polymer interactions on supersaturation. Eur. J. Pharm. Sci. 2013, 48 (3), 371-384. 28 ACS Paragon Plus Environment
Page 29 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
Molecular Pharmaceutics
666 667 668 669
41. Song, Y.; Zemlyanov, D.; Chen, X.; Su, Z.; Nie, H.; Lubach, J. W.; Smith, D.; Byrn, S.; Pinal, R., Acid-base interactions in amorphous solid dispersions of lumefantrine prepared by spray-drying and hot-melt extrusion using X-ray photoelectron spectroscopy. Int. J. Pharm. 2016, 514 (2), 456-464.
670 671 672 673
42. Chen, Y.; Wang, S.; Wang, S.; Liu, C.; Su, C.; Hageman, M.; Hussain, M.; Haskell, R.; Stefanski, K.; Qian, F., Sodium lauryl sulfate competitively interacts with HPMC-AS and consequently reduces oral bioavailability of posaconazole/HPMC-AS amorphous solid dispersion. Mol. Pharmaceutics 2016, 13 (8), 2787-2795.
674 675
43. Guo, H. X.; Heinämäki, J.; Yliruusi, J., Stable aqueous film coating dispersion of zein. J. Colloid Interface Sci. 2008, 322 (2), 478-484.
676 677 678
44. Galia, E.; Nicolaides, E.; Hörter, D.; Löbenberg, R.; Reppas, C.; Dressman, J. B., Evaluation of Various Dissolution Media for Predicting In Vivo Performance of Class I and II Drugs. Pharm. Res. 1998, 15 (5), 698-705.
679 680
45. Zhao, J.; Fung, B. M., NMR study of the transformation of sodium dodecyl sulfate micelles. Langmuir 1993, 9 (5), 1228-1231.
681 682
46. Goddard, E.; Turro, N.; Kuo, P.; Ananthapadmanabhan, K., Fluorescence probes for critical micelle concentration determination. Langmuir 1985, 1 (3), 352-355.
683 684 685
47. Sawant, R. R.; Sawant, R. M.; Torchilin, V. P., Mixed PEG–PE/vitamin E tumor-targeted immunomicelles as carriers for poorly soluble anti-cancer drugs: improved drug solubilization and enhanced in vitro cytotoxicity. Eur. J. Pharm. Biopharm. 2008, 70 (1), 51-57.
686 687 688
48. La, S. B.; Okano, T.; Kataoka, K., Preparation and characterization of the micelle‐ forming polymeric drug indomethacin‐incorporated poly (ethylene oxide)–poly (β‐benzyl L‐ aspartate) block copolymer micelles. J. Pharm. Sci. 1996, 85 (1), 85-90.
689 690 691
49. Fagerberg, J. H.; Tsinman, O.; Sun, N.; Tsinman, K.; Avdeef, A.; Bergström, C. A. S., Dissolution Rate and Apparent Solubility of Poorly Soluble Drugs in Biorelevant Dissolution Media. Mol. Pharmaceutics 2010, 7 (5), 1419-1430.
692 693
50. Huang, C. Y., Determination of binding stoichiometry by the continuous variation method: The job plot. Methods Enzymol. 1982, 87, 509-525.
694 695
51. Avdeef, A., Absorption and drug development: solubility, permeability, and charge state. John Wiley & Sons: 2012.
696 697
52. Job, P., Formation and stability of inorganic complexes in solution. Ann. Chim. Appl. 1928, 9, 113 - 203.
698 699 700
53. Renny, J. S.; Tomasevich, L. L.; Tallmadge, E. H.; Collum, D. B., Method of continuous variations: applications of job plots to the study of molecular associations in organometallic chemistry. Angew Chem. Int. Ed. Engl. 2013, 52 (46), 11998-12013.
701 702
54. Ramstad, T.; Hadden, C. E.; Martin, G. E.; Speaker, S. M.; Teagarden, D. L.; Thamann, T. J., Determination by NMR of the binding constant for the molecular complex between 29 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
Page 30 of 46
703 704
alprostadil and α-cyclodextrin: Implications for a freeze-dried formulation. Int. J. Pharm. 2005, 296 (1), 55-63.
705 706
55. Connors, K. A., Binding constants: the measurement of molecular complex stability. Wiley-Interscience: 1987.
707 708 709
56. . ICH Guidelines, Stability testing of new drug substances and products, Q1A(R2) Current Step 4 version, dated 6 February 2003. http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html.
710 711 712
57. Ambike, A. A.; Mahadik, K. R.; Paradkar, A., Spray-dried amorphous solid dispersions of simvastatin, a low tg drug: in vitro and in vivo evaluations. Pharm. Res. 2005, 22 (6), 990998.
713 714
58. Zhang, S.; Lee, T. W. Y.; Chow, A. H. L., Crystallization of Itraconazole Polymorphs from Melt. Cryst. Growth Des. 2016, 16 (7), 3791-3801.
715 716
59. Werling, J.; Doty, M.; Rebbeck, C.; Wong, J.; Kipp, J., Polymorphic form of itraconazole. Google Patents: 2003.
717 718
60. Molaire, M. F., Heat-induced formation of co-crystalline composition containing titanyl phthalocyanine and titanyl fluorophthalocyanine. Google Patents: 2006.
719 720 721
61. Ainousah, B. E.; Perrier, J.; Dunn, C.; Khadra, I.; Wilson, C. G.; Halbert, G., Dual Level Statistical Investigation of Equilibrium Solubility in Simulated Fasted and Fed Intestinal Fluid. Mol. Pharmaceutics 2017, 14 (12), 4170-4180.
722 723 724
62. Matsui, K.; Tsume, Y.; Amidon, G. E.; Amidon, G. L., The Evaluation of In Vitro Drug Dissolution of Commercially Available Oral Dosage Forms for Itraconazole in Gastrointestinal Simulator With Biorelevant Media. J. Pharm. Sci. 2016, 105 (9), 2804-2814.
725 726
63. Hendriksen, B. A.; Grant, D. J., The effect of structurally related substances on the nucleation kinetics of paracetamol (acetaminophen). J. Cryst. Growth 1995, 156 (3), 252-260.
727 728 729
64. Alonzo, D. E.; Raina, S.; Zhou, D.; Gao, Y.; Zhang, G. G.; Taylor, L. S., Characterizing the impact of hydroxypropylmethyl cellulose on the growth and nucleation kinetics of felodipine from supersaturated solutions. Cryst. Growth Des. 2012, 12 (3), 1538-1547.
730 731
65. Debenedetti, P. G., Metastable Liquids: Concepts and Principles. Princeton University Press: 1996.
732 733 734
66. Ilevbare, G. A.; Liu, H.; Edgar, K. J.; Taylor, L. S., Understanding Polymer Properties Important for Crystal Growth Inhibition- Impact of Chemically Diverse Polymers on Solution Crystal Growth of Ritonavir. Cryst. Growth Des. 2012, 12 (6), 3133-3143.
735
67.
736 737 738
68. Patel, D. D.; Anderson, B. D., Effect of precipitation inhibitors on indomethacin supersaturation maintenance: mechanisms and modeling. Mol. Pharmaceutics 2014, 11 (5), 1489-1499.
Mullin, J. W., Crystallization. Butterworth-Heinemann: 2001.
30 ACS Paragon Plus Environment
Page 31 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
Molecular Pharmaceutics
739 740 741
69. Trasi, N. S.; Oucherif, K. A.; Litster, J. D.; Taylor, L. S., Evaluating the influence of polymers on nucleation and growth in supersaturated solutions of acetaminophen. CrystEngComm 2015, 17 (6), 1242-1248.
742 743 744
70. Chen, J.; Ormes, J. D.; Higgins, J. D.; Taylor, L. S., Impact of surfactants on the crystallization of aqueous suspensions of celecoxib amorphous solid dispersion spray dried particles. Mol. Pharmaceutics 2015, 12 (2), 533-541.
745 746 747
71. Rodríguez‐Hornedo, N.; Murphy, D., Surfactant‐facilitated crystallization of dihydrate carbamazepine during dissolution of anhydrous polymorph. J. Pharm. Sci. 2004, 93 (2), 449460.
748 749
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.
750 751 752 753
73. 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. J. Pharm. Sci. 2016, 105 (9), 2527-2544.
754 755
74. Jin, F.; Tatavarti, A., Tabletability assessment of conventional formulations containing Vitamin E tocopheryl polyethylene glycol succinate. Int. J. Pharm. 2010, 389 (1-2), 58-65.
756 757 758
75. Mu, L.; Teo, M.-M.; Ning, H.-Z.; Tan, C.-S.; Feng, S.-S., Novel powder formulations for controlled delivery of poorly soluble anticancer drug: Application and investigation of TPGS and PEG in spray-dried particulate system. J. Controlled Release 2005, 103 (3), 565-575.
759 760 761
76. Xie, T.; Taylor, L. S., Effect of Temperature and Moisture on the Physical Stability of Binary and Ternary Amorphous Solid Dispersions of Celecoxib. J. Pharm. Sci. 2017, 106 (1), 100-110.
762 763 764
77. Mistry, P.; Mohapatra, S.; Gopinath, T.; Vogt, F. G.; Suryanarayanan, R., Role of the Strength of Drug–Polymer Interactions on the Molecular Mobility and Crystallization Inhibition in Ketoconazole Solid Dispersions. Mol. Pharmaceutics 2015, 12 (9), 3339-3350.
765 766 767
78. Friesen, D. T.; Shanker, R.; Crew, M.; Smithey, D. T.; Curatolo, W.; Nightingale, J., Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol. Pharmaceutics 2008, 5 (6), 1003-1019.
768 769 770 771 772 773 31 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
Page 32 of 46
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
794 795 796 797 798 32 ACS Paragon Plus Environment
Page 33 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
Molecular Pharmaceutics
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
33 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
Page 34 of 46
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
34 ACS Paragon Plus Environment
Page 35 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
Molecular Pharmaceutics
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
855 856 857 858 859 860 861 862 35 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
Page 36 of 46
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
Page 37 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
Molecular Pharmaceutics
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
37 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
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.
38 ACS Paragon Plus Environment
Page 39 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
Molecular Pharmaceutics
945 946 947 948 949 950
Figure 4.
951 952 953 954
Figure 5.
39 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
Page 40 of 46
955 956 957 958 959 960 961 962 963 964
Figure 6.
965 966 967 968
Figure 7.
40 ACS Paragon Plus Environment
Page 41 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
Molecular Pharmaceutics
969 970 971 972 973
Figure 8.
974 975
Figure 9.
976 977 978 979
41 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
980
Page 42 of 46
Figure 10.
981 982 983
Figure 11.
984 985 42 ACS Paragon Plus Environment
Page 43 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
Molecular Pharmaceutics
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
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
1002
Page 44 of 46
Figure 14.
1003 1004 1005 1006 1007 1008 1009 1010 1011
Figure 15.
44 ACS Paragon Plus Environment
Page 45 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
Molecular Pharmaceutics
1012 1013 1014
Table of Contents/Abstract Graphic
1015 1016 1017 1018
45 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
249x170mm (150 x 150 DPI)
ACS Paragon Plus Environment
Page 46 of 46