- Email: [email protected]
Investigation of itraconazole ternary amorphous solid dispersions based on povidone and Carbopol
Accepted Manuscript Investigation of itraconazole ternary amorphous solid dispersions based on povidone and Carbopol
Fan Meng, Jordan Meckel, Feng Zhang PII: DOI: Reference:
S0928-0987(17)30353-6 doi: 10.1016/j.ejps.2017.06.019 PHASCI 4104
To appear in:
European Journal of Pharmaceutical Sciences
Received date: Revised date: Accepted date:
5 February 2017 15 May 2017 12 June 2017
Please cite this article as: Fan Meng, Jordan Meckel, Feng Zhang , Investigation of itraconazole ternary amorphous solid dispersions based on povidone and Carbopol, European Journal of Pharmaceutical Sciences (2017), doi: 10.1016/j.ejps.2017.06.019
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Investigation of Itraconazole Ternary Amorphous Solid Dispersions Based on
CR
IP
Fan Meng, Jordan Meckel, Feng Zhang
T
Povidone and Carbopol
US
College of Pharmacy, the University of Texas at Austin, 2409 University Avenue, A1920,
ED
M
AN
Austin, TX 78712, USA
College of Pharmacy
PT
Corresponding Author: Feng Zhang
The University of Texas at Austin
Austin, TX 78712
CE
2409 University Avenue, A1920
AC
Phone: (512) 471-0942 Fax: (512) 471-7474
Email: [email protected]
1
ACCEPTED MANUSCRIPT ABSTRACT We investigate a ternary system that consists of itraconazole (ITZ) and two polymers: povidone K12 and Carbopol 907. The interactions between these two polymers and their effects on the properties of ternary ITZ amorphous solid dispersions (ASDs) are studied. These two
IP
T
polymers can form a water-insoluble complex in acidic aqueous media. The critical pH is
CR
determined to be 4.17. The weight percentage of Carbopol 907 in the interpolymer complex range from 59 to 70%, depending on the initial ratios between these two polymers in the starting
US
solutions. This complexation is driven by a negative enthalpy change from the H-bonding between the two polymers and a positive entropy change from the freed water molecules. Due to
AN
the slow precipitation of the interpolymer complex in aqueous media, the attempt to prepare
M
ternary ASD using solvent-controlled coprecipitation is not successful. Melt extrusion is identified to be the only viable method to prepare this ternary ASD. We find that interpolymer
ED
complex–based ASDs are physically less stable and demonstrate the poorest drug-release
PT
properties when compared to individual polymer-based binary ASDs. This study illustrates that
CE
the too strong interaction between polymers in ternary ASDs is detrimental to their performance. KEYWORDS: itraconazole, ternary amorphous solid dispersion, interpolymer complex,
AC
solvent-controlled coprecipitation, melt extrusion, poly(acrylic acid), povidone
Page 2 of 39
ACCEPTED MANUSCRIPT 1. Introduction Over the last three decades, amorphous solid dispersions (ASDs) have received extensive attention as an approach to improve the dissolution rate of BCS Class II and Class IV drugs.1-3 Approximately 15 commercial products (e.g., Noxafil®, Kaletra®, Harvoni®, and Belsomar®) that
T
use the ASD technique have been marketed.4,5 Conventionally, an ASD has been regarded as a
IP
simple two-component system in which the drug and the polymer act as solute and solvent,
CR
respectively. In an ASD, a polymer (usually a hydrophilic polymer) is used to inhibit drug precipitation and crystallization, and thus maintain a high supersaturation level in gastrointestinal
US
tract. Recently, however, the use of ternary ASDs, which contain a mixture of two polymer, has
AN
attracted a lot of interest.6-8
M
Multiple polymers may be present in ASDs for a variety of reasons. For example, (a) a hydrophilic polymer may be blended with a hydrophobic polymer to improve dissolution
ED
properties, (b) a hydrophobic polymer may be added to a hydrophilic polymer to introduce
PT
hydrophobic interactions with a poorly soluble drug, or (c) a combination of both strategies may be used.9 Prasad et al. found that indomethacin was miscible with Eudragit® E 100 and
CE
povidone K90, and it maintained specific interactions with each polymer.10 In a stability study, a
AC
synergistic effect was observed in the ternary ASD. The ternary ASDs remained amorphous following 180 days stored at 40 °C and 33% RH, while the binary dispersions exhibited partial crystallinity at 90 days and complete crystallinity at 180 days. A similar synergistic effect has been observed in dissolution studies in which the ternary systems inhibited crystallization to a greater extent compared to dissolution of the binary dispersions.10 In this study, we investigate a ternary itraconazole (ITZ) ASD based on a combination of povidone and poly(acrylic acid). Both povidone and poly(acrylic acid) have been used Page 3 of 39
ACCEPTED MANUSCRIPT individually as polymeric carriers for ASDs.11 However, the use of a combination of both povidone and poly(acrylic acid) in ASDs has not been reported. Miller et al. investigated the use of poly(acrylic acid) to improve the dissolution and oral absorption of ITZ.12 They achieved a prolonged supersaturated level of ITZ in vitro and a five-fold improvement in oral absorption. In
IP
T
addition, Engers et al. reported the use of povidone as a crystallization inhibitor in ITZ ASDs.13
CR
Previous work has reported on the interpolymer complexation between povidone and poly(acrylic acid) and the unique properties of the interpolymer complex, such as increased
US
viscosity or gel formation in aqueous media.14-16 Chun et al. utilized an interpolymer complex of povidone and poly(acrylic acid) as a novel mucoadhesive drug carrier.17 The complexation
AN
between povidone and poly(acrylic acid) is stabilized by H-bonding. The formation of hydrogen
M
bonds generates negative enthalpy changes, which is thermodynamically favorable effect. In the meantime, the overall positive entropy changes that result from the freed water molecules also
ED
plays a crucial role in hydrogen bond–based complexation. The interpolymer complexation and
PT
the precipitation of the complex frees water molecules that were previously tightly bound to individual polymers.18 Additionally, hydrophobic interaction as well as overall changes in
CE
polymer chain configuration may also induce complexation between povidone and poly(acrylic
AC
acid), which results in a positive enthalpy change in most cases.19 The first objective of our study is to characterize the interactions between povidone and poly(acrylic acid) and the physicochemical properties of the complex they form. Poly(acrylic acid) is available either as linear chain or cross-linked polymers under the trade name Carbopol®. For this study, we selected Carbopol 907, a linear-grade poly(acrylic acid). Povidone K12 was selected as the povidone used for this study, and an acidic aqueous medium was chose
Page 4 of 39
ACCEPTED MANUSCRIPT as the antisolvent. The critical pH, the composition of the complex, and the glass transition temperature of the complex will be determined. Our second objective is to study the effect of interpolymer interaction on the physical stability of ITZ ASDs. In the solid state, these two polymers interact via hydrogen bonding (H-
IP
T
bonding), with povidone as the H-bond acceptor and poly(acrylic acid) as the H-bond donor. Hbond interaction between these two polymers can result in an increase in the glass transition
CR
temperature of the polymer matrix.20 Since the physical stability of ASDs in the solid state is
US
enhanced by the high glass transition temperature of the polymeric carrier, we anticipate that the interpolymer complexation between povidone and Carbopol will improve the physical stabilities
AN
of ITZ ASD.
M
We also study an antisolvent coprecipitation method for the preparation of ITZ ternary ASDs
ED
as well as the enteric drug release properties of ternary ITZ ASDs. Antisolvent coprecipitation is a well-established manufacturing technology for drug substance crystallization.21-23 However, its
PT
application to the preparation of ASDs was not investigated until Shah and coworkers at
CE
Hoffmann-La Roche applied the technology to prepare an ASD to improve the bioavailability of BCS Class II and Class IV drugs.24 Shah et al. developed the process to address the needs of
AC
poorly water-soluble compounds that have a solubility in volatile organic solvents that is too low to be suitable for spray drying and also have a melting point that is too high for melt extrusion. In the coprecipitation process, the drug and polymer are dissolved in a high–boiling point solvent such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), or dimethylacetamide (DMA). The formation of the ASD results from the coprecipitation of the drug and polymer when the drug–polymer solution is introduced into an antisolvent. Acidic media are commonly used as antisolvents to trigger the precipitation of poorly water-soluble drug and an enteric polymer. In Page 5 of 39
ACCEPTED MANUSCRIPT this study, we explore a water-insoluble povidone–Carbopol complex formed in situ. As individual polymers, povidone K12 and Carbopol 907 are not suitable for the solvent-controlled coprecipitation process. However, a mixture of povidone K12 and Carbopol 907 is suitable due
AC
CE
PT
ED
M
AN
US
CR
IP
T
to the in situ complexation and precipitation in acidic aqueous media.
Page 6 of 39
ACCEPTED MANUSCRIPT 2. Materials Povidone N.F. (K12 grade) was supplied by BASF Chemical Company (Ludwigshafen, Germany). Carbopol® 907 was supplied by Lubrizol Advanced Materials (Louisville, Kentucky). Itraconazole, USP, was purchased from Spectrum Chemical (New Brunswick, NJ).
T
All other materials used in this study are reagent grade.
Turbidity Method to Evaluate the Effect of pH on the Interpolymer Complexation
CR
3.1.
IP
3. Methods
In this study, we used the transmitted light turbidity method, described in JIS (Japanese
US
Industry Standard Committee) K0101. Since the solubility of the interpolymer complex was pH-
AN
dependent, the effect of pH on the interpolymer complexation was determined by measuring the turbidity of aqueous solutions containing both polymers as a function of pH. A UV-visible
M
spectroscopy system (Model 8453, Agilent, Santa Clara, CA) was used to determine the intensity
ED
of the light absorption. A 0.25% (w/w) polymer solution was tested at a wavelength of 660 nm
solution for pH titration.
Differential Scanning Calorimetry (DSC)
CE
3.2.
PT
over a pH range of 2.0–8.0, using a 0.1 N hydrochloride acid and a 1 N sodium hydroxide
AC
Differential scanning calorimetry (Model DSC Q20, TA Instruments, New Castle, DE) was used to measure the thermal events of materials under constant heating and cooling. The instrument was calibrated with an indium standard. The sample size was accurately weighed and recorded at around 5 mg. Experiment was conducted at temperature ramp of 10 °C/min from 25– 200 °C. Universal Analysis 2000 software was used for data analysis. 3.3.
Solid-State Hygroscopicity of the Complex
Page 7 of 39
ACCEPTED MANUSCRIPT The hygroscopicity of the polymers and the interpolymer complex was determined using dynamic vapor sorption (Model DVS Advantage, Surface Measurement Systems Ltd., London, UK). Each sample (sample size at around 10 mg) was tested for a full sorption/desorption cycle from 10–90% RH, then back to 10% RH in steps of 10% at 25 °C. The instrument was run in
T
step dm/dt mode. The equilibrium point was defined as a dm/dt less than 0.005%, with a
Attenuated Total Reflectance–Fourier Transform Infrared Spectroscopy (ATR– FTIR)
US
3.4.
CR
analyzed using DVSWinTM software (version 3.01).
IP
minimum stage time of 30 min and a maximum stage time of 360 min. Data was processed and
AN
The molecular interaction between povidone and Carbopol 907 was determined using ATR–FTIR. Spectra were collected using a NicoletTMiSTM spectrometer (Thermo Scientific,
M
USA, Waltham, Massachusetts). Samples sufficient to cover the crystal area were placed on the
ED
germanium crystal, and constant torque was applied with the built-in pressure tower to achieve uniform contact between the solid and the crystal. The samples were tested using a total of 32
PT
scans with 4 cm−1 resolution from 600 cm−1 to 3,000 cm−1 at room temperature. OMNICTM
Quantitative 13C Solution-State NMR to Measure the Weight Ratio between Povidone and Carbopol 907 in the Interpolymer Complex
AC
3.5.
CE
software was used to analyze the normalized spectra.
The weight ratio between povidone and Carbopol 907 in the interpolymer complex was quantitated using
13
C NMR (Varian® NMR 600 MHz Spectrometer, Palo Alto, CA). The
interpolymer complex of povidone and Carbopol 907 (obtained from the precipitation method) was dissolved in dimethyl sulfoxide-d6 at a concentration of 50 mg/mL. For quantitation, we used signals that correspond to the carbonyl carbon of the acrylic acid repeat units in Carbopol 907 and the pyrrolidone repeat units in povidone. We conducted 5,000 scans at 25 °C with a Page 8 of 39
ACCEPTED MANUSCRIPT recycle delay of 10 s. MestReNovaTM software was used to process and analyze the data, and the polynomial fit method was used for baseline correction and signal integration. 3.6.
Preparation of the ITZ Ternary Amorphous Solid Dispersions Using SolventControlled Precipitation Method
T
ITZ, povidone K12, and Carbopol 907 were dissolved in dimethyl sulfoxide (DMSO) or
IP
dimethylformamide (DMF). The total solid content of the solution was 4%, and the weight ratio
CR
between ITZ, povidone K12, and Carbopol 907 was 1:1:2. Under constant mixing, the solution containing the drug and polymers was slowly added to an antisolvent (e.g., water, 0.1N HCl,
US
ethanol). The precipitate was collected using a vacuum filtration device. The filtrate was rinsed
AN
with purified water and then dried using a vacuum oven at 50 °C for 6 hours. The dried material was then pulverized to particles finer than 420 µm (40 mesh) using a mortar and pestle. Preparation of ITZ–Carbopol 907 Amorphous Solid Dispersions Using Spray Drying
M
3.7.
ED
ASDs of ITZ in Carbopol 907 at 25% (w/w) drug loading was prepared by spray drying
PT
4% (w/v) solutions of the drug and polymer in a cosolvent that contained 60% ethanol and 40% DCM. The solutions were spray-dried using a Buchi mini B290 spray dryer (Buchi, Flawil,
CE
Switzerland) with an inlet temperature of approximately 100 °C to maintain a 60 °C outlet
AC
temperature, 100% aspiration (475 L/h) heated nitrogen gas, 5 mL/min feed rate, and −5 °C condenser temperature. Immediately following spray drying, the ASDs underwent secondary drying in a vacuum oven at 40 C for overnight to remove residual solvent. 3.8.
Preparation of Ternary ITZ Amorphous Solid Dispersions Using Hot Melt Extrusion
ITZ–povidone and ITZ–povidone–Carbopol 907 physical blends at 25% (w/w) drug loadings were prepared using geometric dilution. The final blends were passed through a 40-mesh sieve to
Page 9 of 39
ACCEPTED MANUSCRIPT further improve homogeneity. The blends were subsequently extruded on a Leistritz Nano-16 corotating twin screw extruder (American Leistritz Extruder Corp., Somerville, New Jersey). The volumetric bottom feeder was set to 4 cm3/min. Screw speed was maintained at 150 rpm, and the material was extruded though a 3-millimeter round die. Conveying, kneading, and mixing
T
elements were used in the screw design as shown in Figure 1. The barrel configuration consisted
IP
of a feed zone, a closed barrel, a venting zone, and a closed zone before the die. The feeding
CR
zone was maintained at room temperature conditions with water circulation. The other barrel temperatures were 165 °C (Zone 1), 175 °C (Zone 2), 175 °C (Zone 3), and 175 °C (at the die).
US
We milled the rods of extrudate using a coffee grinder, and large granules were separated with a
In Vitro Drug-Release Testing
M
3.9.
AN
40-mesh sieve.
We conducted the in vitro release of ITZ from the ASDs by the paddle method, using a
ED
USP apparatus II (Vankel dissolution apparatus, Model 7000). The paddle speed was set at 50
PT
rpm. We used a dissolution bath containing 900 mL of dissolution medium at 37 °C for the dissolution testing. A 0.1 N hydrochloric acid solution at pH 1.2 was used as the dissolution
CE
media to simulate the gastric environment. A sample of 500 mg extruded ASD, containing
AC
100 mg ITZ, was introduced into each vessel. 1-milliliter samples were collected at intervals of 5, 15, 30, 45, 60, 90, and 120 min, and we filtered these samples through a 0.45-micrometer membrane. All dissolution testing was performed in triplicate. The concentration of ITZ was determined by the reversed-phase HPLC method. We used Hypersil® Gold C18, 5 mm x 30 mm, 3 μm (Thermo Scientific, Waltham, MA) as the HPLC column. A mixture of water and an acetonitrile mixture (3:2 volume ratio) containing 0.05% trifluoroacetic acid was used as the mobile phase. The flow rate was set at 1.0 mL/min, and the injection volume was 10 μL. A UV
Page 10 of 39
ACCEPTED MANUSCRIPT detector (Waters® 2998 PD detector, Milford, MA) was used to quantitate at 485 nm. The
AC
CE
PT
ED
M
AN
US
CR
IP
T
retention time of ITZ was 4 min.
Page 11 of 39
ACCEPTED MANUSCRIPT 4. RESULTS AND DISCUSSION This section is divided into three parts. First, we discuss the mechanisms of complexation and the physicochemical properties of the complex. Next, we discuss the preparation of ITZ ternary ASDs. Last, we discuss the physical properties of ITZ ASDs, including both physical
IP
Interpolymer Complexation between Povidone K12 and Carbopol 907 in Aqueous Media
CR
4.1.
T
stabilities and dissolution behaviors.
4.1.1. Complexation of povidone K12 and Carbopol 907 as a function of pH
US
Figure 2 shows the chemical structures of povidone, Carbopol 907, and ITZ; while Table 1 shows their critical physical properties. We anticipated hydrogen bonding interaction
AN
between the carboxyl groups of Carbopol 907 (H-bond donor) and the carbonyl groups of
M
povidone (H-bond acceptor) (Figure 3a). We also anticipated that the complexation between
ED
povidone K12 and Carbopol 907 would be a function of the pH of the medium, since the carboxyl group’s ionization is pH-dependent and it can only function as an H-bond donor in its
PT
unionized state.
CE
The transmitted-light turbidity method is used to evaluate the effect of pH on the interpolymer complexation between povidone and Carbopol 907 over a physiological pH range.
AC
We prepared a 50 mM phosphate buffer solution at pH 8.0 containing both polymers at 0.25% (w/w). We then titrated the solution with a 0.1 N HCl solution to reduce the pH to 2.0. The turbidity as a function of pH is plotted in Figure 4. Individual polymer solutions were used as the controls in this study. As shown in Figure 4, a povidone K12 solution (0.25%) remained clear throughout the entire pH range. The Carbopol 907 solution (0.25%), however, became slightly cloudier when the pH of the solution dropped below 4.0. The pKa of Carbopol 907 was reported as 6.0. Carbopol 907 became mostly unionized below pH 4.0, effectively reducing its solubility Page 12 of 39
ACCEPTED MANUSCRIPT in the aqueous medium. In contrast, a solution containing both polymers at equal concentrations showed drastic changes in turbidity as pH was lowered. At pH 4.17, a sudden increase in turbidity was accompanied by the precipitation of the interpolymer complex from the solution. This critical pH is dependent on the molecular weight of the polymer. Generally, the higher the
IP
T
molecular weight, the higher the critical pH.25
We used solution-state
13
CR
4.1.2. Composition of the interpolymer complexes formed in acidic media C NMR to quantitate the molar ratio between povidone and Carbopol
US
907 in the interpolymer complex. NMR has been widely used to elucidate chemical structure because it can quantitate the molar ratios of protons in different functional groups.26 Similarly,
AN
the composition of a given mixture can be quantitated using the area ratio of chemical shift
M
signals of functional groups from individual components of the mixture.27 In NMR, all nuclei have an identical extinction coefficient for any given NMR spectrum. Therefore, the integrated
ED
intensity of signals for a given NMR spectrum is proportional to the number of nuclei, and this 13
C NMR
PT
can be used for quantitation. Compared to solution-state 1H NMR, solution state
CE
spectra cover a much wider range, making it easier to identify and count individual nuclei28.
AC
In this study, we characterized the complexes using solution-state 13C NMR. Deuterated DMSO was used as the solvent for NMR analysis. We prepared interpolymer complexes of povidone K12 and Carbopol 907 by precipitating a DMSO solution containing these two polymers at various ratios in a 0.1 N HCl solution. Figure 5 presents the NMR spectra for the interpolymer complexes prepared using DMSO solutions that contained povidone K12 and Carbopol 907 at different weight ratios. We attribute the carbon signals at 176 ppm and 174 ppm to the carbonyl C in Carbopol 907 and povidone K12, respectively. Table 2 illustrates the detailed calculation for determining the weight ratios between povidone K12 and Carbopol 907. The weight percentage of Carbopol 907 in the interpolymer complexes remains in a narrow range of 60–70%, despite the wide weight percentage range of Carbopol 907 (20–80%) as the percentage of total polymer content in the DMSO solutions. Page 13 of 39
ACCEPTED MANUSCRIPT Polymer composition in the DMSO solution (66.6%) and the interpolymer complex (68.3%) was essentially identical when Carbopol 907 was at 66.6% of the total polymer in DMSO solution. Therefore, we selected this composition for the preparation of the ITZ ASD using solventcontrolled coprecipitation.
IP
T
4.1.3. Characterization of interpolymer complex using DSC and FTIR techniques
CR
We characterized the interpolymer complex of povidone and Carbopol 907 using differential scanning calorimetry (DSC) for thermal properties and Fourier transform infrared
US
spectroscopy (FTIR) to understand the molecular-level interactions between these two polymers. As summarized in Table 1, both povidone and Carbopol 907 were amorphous, with a glass
AN
transition temperature (Tg) of 101 ºC and 131 ºC, respectively. The interpolymer complex is a
M
single-phase amorphous material with Tg of 172 ºC. Due to the strong interaction between povidone and Carbopol 907, the Tg of the complex was significantly higher than that of the
ED
individual polymers.
PT
Figure 6 shows the FTIR spectra of povidone K12, Carbopol 907, and their complex. We
CE
observed the band for the C=O stretch of carboxyl in Carbopol 907 and the amide group in povidone K12 at 1,702 cm−1 and 1,671 cm−1, respectively. These characteristic C=O stretch
AC
peaks shifted significantly in the interpolymer complex. The C=O stretch for Carbopol 907 was shifted to 1,721 cm−1, while the C=O stretch for povidone K12 was shifted to 1,631 cm−1. This significant peak shift indicates the strong interaction between the two polymers, and the different directions (i.e., bathochromic versus hypsochromic) in peak shift was indicative of the different roles of the functional groups involved in the interaction (i.e., H-bond donor versus H-bond acceptor).
Page 14 of 39
ACCEPTED MANUSCRIPT 4.2.
Preparation of Ternary Amorphous Solid Dispersion
4.2.1. Solvent-controlled coprecipitation Our detailed procedures for preparing solutions containing both drug and polymers and for preparing coprecipitate are disclosed in the method section. We evaluated both DMSO and
T
DMF as solvents, and we evaluated water, a 0.1 N hydrochloric acid solution, and ethanol as
IP
anti-solvents. Precipitation was conducted at ambient temperature and at −5 C. We observed
CR
that gel-like clusters were formed during coprecipitation instead of cotton-like precipitates. All
US
solvent-controlled coprecipitation runs are summarized in Table 3.
We were surprised to observe that ITZ, a drug with low crystallization tendency, was not
AN
completely amorphous across all coprecipitates.29 As presented in Table 3, crystalline ITZ was detected in all samples. During the coprecipitation process, the precipitation rate has a significant
M
influence on the properties of the coprecipitates.30 Both the drug and the polymer must
ED
precipitate simultaneously in order to inhibit phase separation and inhibit drug crystallization of
PT
the coprecipitates. We hypothesized that the interpolymer complex of povidone K12 and Carbopol 907 precipitated too slowly, even though it is not soluble in acidic aqueous media. A
CE
DVS study was conducted to compare the hygroscopicity of the complex and the individual
AC
polymers at 25 ºC.
As shown in Figure 7, the water absorption profiles of the individual polymers and the interpolymer complex all followed Type III isotherms of the BDDT classification. Water absorption occurred via a cluster mechanism.31 Both povidone K12 and Carbopol 907 were found to be hygroscopic, absorbing 73% and 47% of the water at 90% RH and 25 C. The interpolymer complex of these two polymers was less hygroscopic than the individual components. The lower hygroscopicity of the interpolymer complexes could be explained by HPage 15 of 39
ACCEPTED MANUSCRIPT bonding between the carboxylic groups of Carbopol 907 and the carbonyl groups of povidone, which block these functional groups’ interaction with water.32 It should be noted that the equilibrium water content of the interpolymer complex was high (21.46% at 90% RH), although it was lower than povidone and Carbopol 907 alone. As a comparison, hypromellose acetate
T
succinate, the polymer present in the vemurafenib ASD prepared using solvent-controlled
IP
coprecipitation absorbed 11.2% at 25 C/90% RH (Figure 7D). The DVS data demonstrate that,
CR
even though the interpolymer complex was not soluble in water or the acidic medium, it was still
US
quite hydroscopic. The hygroscopicity of the complex was also later demonstrated in the swelling study of melt-extruded ternary ITZ ASDs in 0.1 N hydrochloric acid dissolution
AN
medium (section 4.3.2).
M
The high hydrophilicity of the interpolymer complex may also lead to high water content in the coprecipitate, which increases the hydrophilicity of the microenvironment in the
ED
coprecipitate, thus favoring ITZ crystallization. In addition, both the polymer and the drug must
PT
precipitate at similar rates in order to inhibit phase separation and to prepare a homogenous ASD using the solvent-controlled coprecipitation process. Since the complex is hygroscopic, we
CE
hypothesized that ITZ would precipitate more quickly than the interpolymer complex, resulting
AC
in phase separation and crystallization of ITZ. 4.2.2. Preparation of ternary amorphous solid dispersion using spray drying The spray drying process was not applicable for preparing ternary ITZ ASDs, because we could not prepare solutions of ITZ, povidone K12, and Carbopol 907 in volatile organic solvents or solvent mixtures. The solubility properties of ITZ and the polymers in volatile organic solvents are summarized in Table 1. Even though an individual polymer is soluble in polar volatile solvents (e.g., ethanol, isopropyl alcohol) or solvent mixtures, povidone K12 and Page 16 of 39
ACCEPTED MANUSCRIPT Carbopol® 907 complexed and precipitated out of the solution when solutions of individual polymers were combined. We found that the interpolymer complexes of povidone K12 and Carbopol 907 are soluble only in nonvolatile organic solvents (e.g. DMSO, DMF). 4.2.3. Preparation of ternary amorphous solid dispersion using melt extrusion
IP
T
Figure 1 presents the screw design and processing parameters for extruding a ternary
CR
ASD consisting of ITZ, povidone K12, and Carbopol 907. When Carbopol 907 was used as the only polymeric carrier in ITZ ASDs, the formulations could not be processed due to degradation
US
of Carbopol 907. Even with the presence of triethyl citrate as a plasticizer at 10 %, Carbopol 907
AN
degraded and could not be converted into a polymer melt.
ITZ was at 20% of the formulation, while the weight ratio of povidone K12 and Carbopol
M
907 was maintained at 1:2. Triethyl citrate was present in the formulation as a plasticizer at 10%
ED
to further lower the processing temperature in order to minimize the degradation of Carbopol 907. The miscibility of Carbopol 907 and povidone K12 at the elevated temperature enabled us
PT
to process the formulation at a relatively low temperature. The same processing condition was
CE
also used to prepare an ITZ ASD based on povidone K12. We prepared binary ASDs, consisting of ITZ and an individual polymer, as the control
AC
samples for this study. Povidone K12 is thermoplastic, and an ITZ ASD based on povidone K12 was successfully prepared using melt extrusion. The processing conditions for an ITZ–povidone K12 ASD are the same as the conditions for the ternary ASD. Because of the thermal instability of Carbopol 907 when used as the only polymeric carrier during melt extrusion, an ITZ ASD based on Carbopol 907 was prepared using spray drying. 4.3.
Physical Properties of ITZ Amorphous Solid Dispersions Page 17 of 39
ACCEPTED MANUSCRIPT 4.3.1. Effect of interpolymer interaction on the physical stability of ternary ITZ amorphous solid dispersion Figure 8 presents DSC thermograms of crystalline ITZ and its ASDs. Pure ITZ shows an endothermic melting peak at 166.8 ºC. All ASDs show a single glass transition event that
T
indicates the formation of a single-phase amorphous material. Among all the ASDs, the ternary
IP
amorphous solid dispersion showed the highest Tg at 160ºC. This high Tg results from the
CR
interpolymer complexation between povidone K12 and Carbopol 907. A similar phenomenon has been reported for interpolymer complex systems that consist of polyethylene oxide and
US
Carbopol or consist of copovidone and Carbopol.33 Systems with high glass transition
AN
temperatures tend to possess higher miscibility as well as greater physical stability.34
M
The Carbopol 907–based binary ASD was observed to be more stable than the povidone K12–based ASD. The Carbopol 907–based ASD remained a single-phase amorphous
ED
material following two weeks of storage at 40 C at ambient RH (Figure 8-b). Even though it is
PT
amorphous, we observed the povidone-based ASD undergo amorphous–amorphous phase separation and two glass transition temperatures that represent a drug-rich (Tg of 49.89 C) and a
CE
polymer-rich (Tg of 132.78 C) phase (Figure 8-c). The difference in physical stability between
AC
the Carbopol 907-based and povidone K12-based solid dispersions could be explained by the molecular-level interactions between ITZ and the polymer.35 ITZ is a weak base drug with a pKa of 3.7, and it can function as a hydrogen bond acceptor. Carbopol 907 is an acidic polymer with a pKa of 5.0–6.0, and it can function as hydrogen bond donor. Carbopol 907 can form hydrogen bonds with ITZ via acid–base interaction. Povidone, however, can only function as a hydrogen bond acceptor, and it cannot strongly interact with ITZ. As a result, we observed poor physical stability in the povidone K12–based ITZ ASD. Page 18 of 39
ACCEPTED MANUSCRIPT Despite its high Tg, the ternary ITZ ASD demonstrated the poorest physical stability. As shown in Figure 9, ITZ recrystallized from the ternary ASD following two weeks of storage at 40 C/ambient RH, and it melted at 151 ºC. The depression of ITZ melting was due to the defect of the ITZ crystalline lattice.36 We attribute the poor physical stability of the ternary ASD to the
T
weakened drug–polymer interaction as the result of strong polymer–polymer interaction. The
IP
intermolecular interactions between Carbopol 907 and povidone K12 are so strong that their
CR
interactions with ITZ are weakened.
US
4.3.2. The effect of interpolymer complexation on the drug release of ITZ amorphous solid dispersions
AN
We conducted non-sink dissolution testing to evaluate the effect of interpolymer
M
complexation on the release of ITZ. The testing was performed using a 0.1 N hydrochloric acid solution at pH 1.2 and a 50 mM phosphate buffer solution at pH 6.8. The intrinsic solubility of
ED
crystalline ITZ at pH 1.2 was 1.2 µg/mL, and the solubility at pH 6.8 was below the quantitation
PT
limit of the HPLC method (0.1 µg/mL). We did not observe transient solubility enhancement in the pH 6.8 buffer, and the concentration of ITZ was below the quantitation limit for the ASD
CE
samples. Figure 10 presents the dissolution profiles of ITZ ASDs in 0.1 N hydrochloric acid.
AC
Dissolution profiles of ITZ-polymer physical mixtures were not shown in this figure, because the concentrations of ITZ in the first 30 mins were below the quantitation limit of the HPLC method. We observed solubility enhancement in both binary ASDs. After two hours, the ITZ concentration reached a plateau of 14 µg/mL in the povidone-based ASD and 120 µg/mL in the Carbopol 907–based ASDs. We anticipated that the Carbopol 907–based ASD would have the highest supersaturation level because of its strong intermolecular interaction with ITZ, and this
Page 19 of 39
ACCEPTED MANUSCRIPT intermolecular interaction between the drug and the polymer has been reported as an important factor in controlling drug release.37 The
interpolymer
complex–based
ASD
demonstrated
the
lowest
degree
of
supersaturation, with a final concentration of 7 μg/mL after two hours. We attribute the lower
IP
T
supersaturation level to the interaction between Carbopol 907 and povidone, which (a) interferes
CR
with H-bonding between Carbopol 907 and ITZ and (b) imparts enteric properties on the formulation. As shown in Figure 11, the interpolymer complex–based ITZ ASD gelled (Figure
US
11-a) and crystallized (Figure 11-b) during dissolution. As discussed in the previous section, the interpolymer complex was hygroscopic and could absorb a significant amount of moisture even
AN
though it was not water-soluble. The presence of water induced the crystallization of ITZ. This
M
study illustrates that excessive interpolymer interaction is detrimental to the dissolution behavior of ASDs. Additionally, povidone-based solid dispersions reached supersaturation within 60 min,
ED
while both the Carbopol 907–based ASD and the interpolymer complex–based ASD did not
PT
reach supersaturation until after two hours. We expected this result based on the turbidity study, in which Carbopol 907 gelled and the interpolymer complex was insoluble at pH 1.2. This
AC
CE
creates a gel layer and an insoluble matrix that surrounds the ITZ.
Page 20 of 39
ACCEPTED MANUSCRIPT 5. Conclusion We investigated the interaction between povidone K12 and Carbopol 907 and their effects on the properties of ternary ITZ ASDs. An insoluble interpolymer complex was formed in aqueous media below a critical pH of 4.17. Depending on the initial ratio between these two polymers in
IP
T
the starting solutions, the weight percentage of Carbopol 907 in the interpolymer complex ranged from 59–70%. Although it is insoluble in acidic aqueous media, the complex was hydroscopic
CR
and absorbed about 22% moisture at 25 C and 90% RH. Because of its hydrophilicity, the
US
interpolymer complex precipitated too slowly to allow for the preparation of an ITZ ternary ASD using the solvent-controlled coprecipitation process. The ternary ASD also could not be prepared
AN
using a spray drying process, since there is no common volatile organic solvent into which both
M
polymers can dissolve without forming an insoluble complex. The ternary ASD was successfully
ED
prepared using melt extrusion.
The molecular interaction between povidone and Carbopol exerts a negative effect on the
PT
physical stabilities of the ASD in the solid state. Ternary ASD was less physically stable in the
CE
solid state than binary ASDs. Recrystallization of ITZ was observed with ternary ASD following two weeks storage at 40 C/ambient RH. Carbopol-based ASD was most stable because of the
AC
acid-base interaction between Carbopol and ITZ. The molecular interaction between povidone and Carbopol also has a negative effect on the dissolution behavior of the ASD in a 0.1 N HCl solution. Since povidone and Carbopol form an insoluble complex in situ, the ternary ASD does not dissolve during the dissolution testing. However, the absorption of water due to the high hydrophilicity of the interpolymer complex results in the crystallization of ITZ. The ternary ASD demonstrated the lowest degree of
Page 21 of 39
ACCEPTED MANUSCRIPT supersaturation (i.e., six times the crystalline ITZ solubility) in 0.1 N HCl, compared to 12-fold supersaturation for the binary povidone-based ASD and 100-fold supersaturation for the binary Carbopol-based ASD. This study illustrates that too strong interpolymer interaction in ternary ASDs is detrimental to their performance.
IP
T
6. Acknowledgement
CR
We gratefully acknowledge the University of Texas at Austin for funding and the use of
7. Conflict of Interest
AC
CE
PT
ED
M
AN
The authors report no conflicts of interest.
US
instruments in completing this project.
Page 22 of 39
ACCEPTED MANUSCRIPT 8. Reference
AC
CE
PT
ED
M
AN
US
CR
IP
T
1. Yu L 2001. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Deliv Rev 48(1):27-42. 2. Bhardwaj SP, Arora KK, Kwong E, Templeton A, Clas SD, Suryanarayanan R 2014. Mechanism of amorphous itraconazole stabilization in polymer solid dispersions: role of molecular mobility. Mol Pharm 11(11):4228-4237. 3. Huang Y, Dai WG 2014. Fundamental aspects of solid dispersion technology for poorly soluble drugs. Acta Pharm Sin B 4(1):18-25. 4. Vo CL, Park C, Lee BJ 2013. Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs. Eur J Pharm Biopharm 85(3 Pt B):799-813. 5. Meng F, Gala U, Chauhan H 2015. Classification of solid dispersions: correlation to (i) stability and solubility (ii) preparation and characterization techniques. Drug Dev Ind Pharm 41(9):1401-1415. 6. Al-Obaidi H, Buckton G 2009. Evaluation of griseofulvin binary and ternary solid dispersions with HPMCAS. AAPS PharmSciTech 10(4):1172-1177. 7. Yoo Su, Krill SL, Wang Z, Telang C 2009. Miscibility/stability considerations in binary solid dispersion systems composed of functional excipients towards the design of multi‐component amorphous systems. Journal of pharmaceutical sciences 98(12):4711-4723. 8. Wang X, Michoel A, Van den Mooter G 2005. Solid state characteristics of ternary solid dispersions composed of PVP VA64, Myrj 52 and itraconazole. International journal of pharmaceutics 303(1):54-61. 9. Marks JA, Wegiel LA, Taylor LS, Edgar KJ 2014. Pairwise polymer blends for oral drug delivery. J Pharm Sci 103(9):2871-2883. 10. Prasad D, Chauhan H, Atef E 2014. Amorphous stabilization and dissolution enhancement of amorphous ternary solid dispersions: combination of polymers showing drug–polymer interaction for synergistic effects. Journal of pharmaceutical sciences 103(11):3511-3523. 11. Bhardwaj SP, Arora KK, Kwong E, Templeton A, Clas S-D, Suryanarayanan R 2014. Mechanism of amorphous itraconazole stabilization in polymer solid dispersions: Role of molecular mobility. Molecular pharmaceutics 11(11):4228-4237. 12. Miller DA, DiNunzio JC, Yang W, McGinity JW, Williams III RO 2008. Enhanced in vivo absorption of itraconazole via stabilization of supersaturation following acidic-to-neutral pH transition. Drug development and industrial pharmacy 34(8):890-902. 13. Engers D, Teng J, Jimenez‐Novoa J, Gent P, Hossack S, Campbell C, Thomson J, Ivanisevic I, Templeton A, Byrn S 2010. A solid‐state approach to enable early development compounds: Selection and animal bioavailability studies of an itraconazole amorphous solid dispersion. Journal of pharmaceutical sciences 99(9):3901-3922. 14. Bimendina L, Bekturov E, Roganov V 1976. Poly (acrylic acid)-poly (vinyl pyrrolidone) complexes in solutions. Chemical Papers 30(3):301-305. 15. Biswas A, Willet J, Gordon SH, Finkenstadt V, Cheng H 2006. Complexation and blending of starch, poly (acrylic acid), and poly (N-vinyl pyrrolidone). Carbohydrate polymers 65(4):397-403. 16. Lau C, Mi Y 2002. A study of blending and complexation of poly (acrylic acid)/poly (vinyl pyrrolidone). Polymer 43(3):823-829. 17. Chun M-K, Cho C-S, Choi H-K 2002. Mucoadhesive drug carrier based on interpolymer complex of poly (vinyl pyrrolidone) and poly (acrylic acid) prepared by template polymerization. Journal of controlled release 81(3):327-334. 18. Perez-Gramatges A, Argüelles-Monal W, Peniche-Covas C 1996. Thermodynamics of complex formation of polyacrylic acid with poly (N-vinyl-2-pyrrolidone) and chitosan. Polymer Bulletin 37(1):127134.
Page 23 of 39
ACCEPTED MANUSCRIPT
AC
CE
PT
ED
M
AN
US
CR
IP
T
19. Bizley SC, Williams AC, Khutoryanskiy VV 2014. Thermodynamic and kinetic properties of interpolymer complexes assessed by isothermal titration calorimetry and surface plasmon resonance. Soft matter 10(41):8254-8260. 20. Kuo S-W, Kao H-C, Chang F-C 2003. Thermal behavior and specific interaction in high glass transition temperature PMMA copolymer. Polymer 44(22):6873-6882. 21. Reverchon E 1999. Supercritical antisolvent precipitation of micro-and nano-particles. The journal of supercritical fluids 15(1):1-21. 22. Matteucci ME, Hotze MA, Johnston KP, Williams RO 2006. Drug nanoparticles by antisolvent precipitation: mixing energy versus surfactant stabilization. Langmuir 22(21):8951-8959. 23. Kalogiannis CG, Pavlidou E, Panayiotou CG 2005. Production of amoxicillin microparticles by supercritical antisolvent precipitation. Industrial & engineering chemistry research 44(24):9339-9346. 24. Shah N, Iyer RM, Mair HJ, Choi DS, Tian H, Diodone R, Fähnrich K, Pabst‐Ravot A, Tang K, Scheubel E 2013. Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer‐stabilized solid dispersion prepared by a solvent‐controlled coprecipitation process. Journal of pharmaceutical sciences 102(3):967-981. 25. Nurkeeva Z, Mun G, Khutoryanskiy V, Bitekenova A, Dubolazov A, Esirkegenova SZ 2003. pH effects in the formation of interpolymer complexes between poly (N-vinylpyrrolidone) and poly (acrylic acid) in aqueous solutions. The European Physical Journal E 10(1):65-68. 26. Pretsch E, Bühlmann P, Affolter C, Pretsch E, Bhuhlmann P, Affolter C. 2009. Structure determination of organic compounds. ed.: Springer. 27. Simmler C, Napolitano JG, McAlpine JB, Chen S-N, Pauli GF 2014. Universal quantitative NMR analysis of complex natural samples. Current opinion in biotechnology 25:51-59. 28. Ando I, Webb GA 1983. Theory of NMR parameters. 29. Baird JA, Van Eerdenbrugh B, Taylor LS 2010. A classification system to assess the crystallization tendency of organic molecules from undercooled melts. Journal of pharmaceutical sciences 99(9):37873806. 30. Shah N, Sandhu H, Phuapradit W, Pinal R, Iyer R, Albano A, Chatterji A, Anand S, Choi DS, Tang K 2012. Development of novel microprecipitated bulk powder (MBP) technology for manufacturing stable amorphous formulations of poorly soluble drugs. International journal of pharmaceutics 438(1):53-60. 31. Adolphs J, Setzer MJ 1996. Energetic classification of adsorption isotherms. Journal of colloid and interface science 184(2):443-448. 32. Cao Y, Chen Y, Wang X, Mu T 2014. Predicting the hygroscopicity of imidazolium-based ILs varying in anion by hydrogen-bonding basicity and acidity. RSC Advances 4(10):5169-5176. 33. Zhang F, Meng F, Wang ZY, NA W 2016. Interpolymer complexation between copovidone and carbopol and its effect on drug release from matrix tablets. Drug Development and Industrial Pharmacy:1-14. 34. Meng F, Dave V, Chauhan H 2015. Qualitative and quantitative methods to determine miscibility in amorphous drug–polymer systems. European Journal of Pharmaceutical Sciences 77:106-111. 35. Meng F, Trivino A, Prasad D, Chauhan H 2015. Investigation and correlation of drug polymer miscibility and molecular interactions by various approaches for the preparation of amorphous solid dispersions. European Journal of Pharmaceutical Sciences 71:12-24. 36. Marsac PJ, Shamblin SL, Taylor LS 2006. Theoretical and practical approaches for prediction of drug–polymer miscibility and solubility. Pharmaceutical research 23(10):2417-2426. 37. Chauhan H, Kuldipkumar A, Barder T, Medek A, Gu C-H, Atef E 2014. Correlation of inhibitory effects of polymers on indomethacin precipitation in solution and amorphous solid crystallization based on molecular interaction. Pharmaceutical research 31(2):500-515.
Page 24 of 39
ACCEPTED MANUSCRIPT Table 1. Critical physical attributes of ITZ, povidone K12, and Carbopol 907. Tm (ºC)
Tg (ºC)
pKa
ITZ
706
166.8
52c
3.7
Povidone K12
111a
-
101c
-
Carbopol 907
72a
-
131c
6.0
Interpolymer complexb
-
-
172c
-
Solubility Soluble in dichloromethane, not soluble in water and most of other volatile solvents. Freely soluble in water and polar organic solvents including ethanol, isopropyl alcohol, DMF and DMSO. Swellable in water; soluble in alkaline aqueous media; soluble in polar solvents including ethanol, DMF, and DMSO.
US
CR
IP
T
Mw (g/mol)
Not soluble in volatile solvents; soluble in DMF and DMSO.
AC
CE
PT
ED
M
AN
a. molecular weight of repeating units b. the weight percentage of Carbopol 907 in the interpolymer complex is 68.3%. c. the Tg values of ITZ and polymer were measured using DSC in our lab.
Page 25 of 39
ACCEPTED MANUSCRIPT
Table 2. Weight percentage of Carbopol 907 in the interpolymer complexes as a function of its weight percentage in the initial stock solutions. Ratio between integrated area under signals (R)a 2.23
Complex #2
33.3
2.57
Complex #3
50.0
2.91
Complex #4
66.6
3.32
Complex #5
80.0
3.61
59.1
T
20.0
CR
Complex #1
Wt% of Carbopol 907 in complexesb
IP
Wt% of Carbopol 907 in total polymer in DMF solution
62.5 65.4 68.3 70.1
13
AC
CE
PT
ED
M
AN
US
a. Ratio of integrated area of signal 1 over integrated area under signal 2 from C solution-state NMR analyses. Please refer to Figure 5 for the detailed information of each signal. b. Carbopol 907 weight percentage of the interpolymer complex = . Molar mass of acrylic acid and N-vinylpyrrolidone is 72 and 111, respectively.
Page 26 of 39
ACCEPTED MANUSCRIPT
Table 3. Physical statea (crystalline or amorphous) of interpolymer-based ITZ solid dispersions prepared using solvent-controlled coprecipitation. Solvent Antisolvent DMF
Ethanol–water (1:1)
Crystalline
Crystalline
Water
Crystalline
0.1 HCL
Crystalline
Ethanol–water (1:1)b
Crystalline
CR
IP
T
DMSO
Crystalline Crystalline Crystalline
AC
CE
PT
ED
M
AN
US
a. The physical state of interpolymer complex was determined using DSC, endothermic peak at ITZ melting point indicates the presence of crystalline ITZ. b. Ethanol–water mixture was cooled with acetone/dry ice cooling bath.
Page 27 of 39
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
PT
ED
M
AN
Figure 1. Screw configuration and barrel setup of Leistritz Nano 16 mm extruder.
Page 28 of 39
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
PT
Figure 2. Chemical structures of itraconazole, povidone K12, and Carbopol 907.
Page 29 of 39
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
PT
Figure 3. Illustration of hydrogen bonding: (a) ITZ and Carbopol 907 and (b) povidone K12 and Carbopol 907.
Page 30 of 39
PT
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
Figure 4. Turbidity (light absorption at 660 nm) of polymer solutions as a function of pH.
Page 31 of 39
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
PT
Figure 5. Solution-state 13C NMR spectra for the interpolymer complexes prepared using DMSO solution containing povidone K12 and Carbopol 907 at various weight ratios (a) 4:1, (b) 2:1, (c) 1:1, (d) 2:1, (e) 4:1. Chemical shifts at 176 and 174 ppm represent C from carbonyl groups in Carbopol 907 and povidone K12, respectively.
Page 32 of 39
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
PT
Figure 6. FTIR spectra of povidone, Carbopol 907, and their interpolymer complex.
Page 33 of 39
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
PT
Figure 7. Dynamic vapor absorption profiles of povidone, Carbopol 907, and their interpolymer complex.
Page 34 of 39
CE
PT
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
Figure 8. DSC thermograms (a) ITZ, (b) melt-extruded ITZ-Povidone-Carbopol ASD, (c) melt-extruded ITZ-Povidone ASD, and (d) spray-dried ITZ-Carbopol ASD.
Page 35 of 39
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
PT
ED
Figure 9. DSC thermograms (a) ITZ, (b) melt-extruded ITZ-Povidone-Carbopol ASD, (c) melt-extruded ITZ-Povidone ASD, and (d) spray-dried ITZ-Carbopol ASD following two weeks storage at 40 C and ambient RH.
Page 36 of 39
PT
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
Figure 10. In vitro dissolution profiles of ITZ ASD containing Carbopol 907, povidone, and interpolymer complex; 900 mL 0.01 N HCl solution pH 1.2 at 37 C as the dissolution medium, USP paddle method at 50 rpm (n = 3).
Page 37 of 39
PT
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
Figure 11. Morphology of interpolymer complex based ITZ ASD before (left) and after (right) dissolution (0.1 N HCl solution, pH 1.2) using (a) digital camera with no magnification and (b) polarized microscopy with 500x magnification.
Page 38 of 39
ACCEPTED MANUSCRIPT
AC
CE
PT
ED
M
AN
US
CR
IP
T
Graphical abstract
Page 39 of 39
Fan Meng, Jordan Meckel, Feng Zhang PII: DOI: Reference:
S0928-0987(17)30353-6 doi: 10.1016/j.ejps.2017.06.019 PHASCI 4104
To appear in:
European Journal of Pharmaceutical Sciences
Received date: Revised date: Accepted date:
5 February 2017 15 May 2017 12 June 2017
Please cite this article as: Fan Meng, Jordan Meckel, Feng Zhang , Investigation of itraconazole ternary amorphous solid dispersions based on povidone and Carbopol, European Journal of Pharmaceutical Sciences (2017), doi: 10.1016/j.ejps.2017.06.019
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Investigation of Itraconazole Ternary Amorphous Solid Dispersions Based on
CR
IP
Fan Meng, Jordan Meckel, Feng Zhang
T
Povidone and Carbopol
US
College of Pharmacy, the University of Texas at Austin, 2409 University Avenue, A1920,
ED
M
AN
Austin, TX 78712, USA
College of Pharmacy
PT
Corresponding Author: Feng Zhang
The University of Texas at Austin
Austin, TX 78712
CE
2409 University Avenue, A1920
AC
Phone: (512) 471-0942 Fax: (512) 471-7474
Email: [email protected]
1
ACCEPTED MANUSCRIPT ABSTRACT We investigate a ternary system that consists of itraconazole (ITZ) and two polymers: povidone K12 and Carbopol 907. The interactions between these two polymers and their effects on the properties of ternary ITZ amorphous solid dispersions (ASDs) are studied. These two
IP
T
polymers can form a water-insoluble complex in acidic aqueous media. The critical pH is
CR
determined to be 4.17. The weight percentage of Carbopol 907 in the interpolymer complex range from 59 to 70%, depending on the initial ratios between these two polymers in the starting
US
solutions. This complexation is driven by a negative enthalpy change from the H-bonding between the two polymers and a positive entropy change from the freed water molecules. Due to
AN
the slow precipitation of the interpolymer complex in aqueous media, the attempt to prepare
M
ternary ASD using solvent-controlled coprecipitation is not successful. Melt extrusion is identified to be the only viable method to prepare this ternary ASD. We find that interpolymer
ED
complex–based ASDs are physically less stable and demonstrate the poorest drug-release
PT
properties when compared to individual polymer-based binary ASDs. This study illustrates that
CE
the too strong interaction between polymers in ternary ASDs is detrimental to their performance. KEYWORDS: itraconazole, ternary amorphous solid dispersion, interpolymer complex,
AC
solvent-controlled coprecipitation, melt extrusion, poly(acrylic acid), povidone
Page 2 of 39
ACCEPTED MANUSCRIPT 1. Introduction Over the last three decades, amorphous solid dispersions (ASDs) have received extensive attention as an approach to improve the dissolution rate of BCS Class II and Class IV drugs.1-3 Approximately 15 commercial products (e.g., Noxafil®, Kaletra®, Harvoni®, and Belsomar®) that
T
use the ASD technique have been marketed.4,5 Conventionally, an ASD has been regarded as a
IP
simple two-component system in which the drug and the polymer act as solute and solvent,
CR
respectively. In an ASD, a polymer (usually a hydrophilic polymer) is used to inhibit drug precipitation and crystallization, and thus maintain a high supersaturation level in gastrointestinal
US
tract. Recently, however, the use of ternary ASDs, which contain a mixture of two polymer, has
AN
attracted a lot of interest.6-8
M
Multiple polymers may be present in ASDs for a variety of reasons. For example, (a) a hydrophilic polymer may be blended with a hydrophobic polymer to improve dissolution
ED
properties, (b) a hydrophobic polymer may be added to a hydrophilic polymer to introduce
PT
hydrophobic interactions with a poorly soluble drug, or (c) a combination of both strategies may be used.9 Prasad et al. found that indomethacin was miscible with Eudragit® E 100 and
CE
povidone K90, and it maintained specific interactions with each polymer.10 In a stability study, a
AC
synergistic effect was observed in the ternary ASD. The ternary ASDs remained amorphous following 180 days stored at 40 °C and 33% RH, while the binary dispersions exhibited partial crystallinity at 90 days and complete crystallinity at 180 days. A similar synergistic effect has been observed in dissolution studies in which the ternary systems inhibited crystallization to a greater extent compared to dissolution of the binary dispersions.10 In this study, we investigate a ternary itraconazole (ITZ) ASD based on a combination of povidone and poly(acrylic acid). Both povidone and poly(acrylic acid) have been used Page 3 of 39
ACCEPTED MANUSCRIPT individually as polymeric carriers for ASDs.11 However, the use of a combination of both povidone and poly(acrylic acid) in ASDs has not been reported. Miller et al. investigated the use of poly(acrylic acid) to improve the dissolution and oral absorption of ITZ.12 They achieved a prolonged supersaturated level of ITZ in vitro and a five-fold improvement in oral absorption. In
IP
T
addition, Engers et al. reported the use of povidone as a crystallization inhibitor in ITZ ASDs.13
CR
Previous work has reported on the interpolymer complexation between povidone and poly(acrylic acid) and the unique properties of the interpolymer complex, such as increased
US
viscosity or gel formation in aqueous media.14-16 Chun et al. utilized an interpolymer complex of povidone and poly(acrylic acid) as a novel mucoadhesive drug carrier.17 The complexation
AN
between povidone and poly(acrylic acid) is stabilized by H-bonding. The formation of hydrogen
M
bonds generates negative enthalpy changes, which is thermodynamically favorable effect. In the meantime, the overall positive entropy changes that result from the freed water molecules also
ED
plays a crucial role in hydrogen bond–based complexation. The interpolymer complexation and
PT
the precipitation of the complex frees water molecules that were previously tightly bound to individual polymers.18 Additionally, hydrophobic interaction as well as overall changes in
CE
polymer chain configuration may also induce complexation between povidone and poly(acrylic
AC
acid), which results in a positive enthalpy change in most cases.19 The first objective of our study is to characterize the interactions between povidone and poly(acrylic acid) and the physicochemical properties of the complex they form. Poly(acrylic acid) is available either as linear chain or cross-linked polymers under the trade name Carbopol®. For this study, we selected Carbopol 907, a linear-grade poly(acrylic acid). Povidone K12 was selected as the povidone used for this study, and an acidic aqueous medium was chose
Page 4 of 39
ACCEPTED MANUSCRIPT as the antisolvent. The critical pH, the composition of the complex, and the glass transition temperature of the complex will be determined. Our second objective is to study the effect of interpolymer interaction on the physical stability of ITZ ASDs. In the solid state, these two polymers interact via hydrogen bonding (H-
IP
T
bonding), with povidone as the H-bond acceptor and poly(acrylic acid) as the H-bond donor. Hbond interaction between these two polymers can result in an increase in the glass transition
CR
temperature of the polymer matrix.20 Since the physical stability of ASDs in the solid state is
US
enhanced by the high glass transition temperature of the polymeric carrier, we anticipate that the interpolymer complexation between povidone and Carbopol will improve the physical stabilities
AN
of ITZ ASD.
M
We also study an antisolvent coprecipitation method for the preparation of ITZ ternary ASDs
ED
as well as the enteric drug release properties of ternary ITZ ASDs. Antisolvent coprecipitation is a well-established manufacturing technology for drug substance crystallization.21-23 However, its
PT
application to the preparation of ASDs was not investigated until Shah and coworkers at
CE
Hoffmann-La Roche applied the technology to prepare an ASD to improve the bioavailability of BCS Class II and Class IV drugs.24 Shah et al. developed the process to address the needs of
AC
poorly water-soluble compounds that have a solubility in volatile organic solvents that is too low to be suitable for spray drying and also have a melting point that is too high for melt extrusion. In the coprecipitation process, the drug and polymer are dissolved in a high–boiling point solvent such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), or dimethylacetamide (DMA). The formation of the ASD results from the coprecipitation of the drug and polymer when the drug–polymer solution is introduced into an antisolvent. Acidic media are commonly used as antisolvents to trigger the precipitation of poorly water-soluble drug and an enteric polymer. In Page 5 of 39
ACCEPTED MANUSCRIPT this study, we explore a water-insoluble povidone–Carbopol complex formed in situ. As individual polymers, povidone K12 and Carbopol 907 are not suitable for the solvent-controlled coprecipitation process. However, a mixture of povidone K12 and Carbopol 907 is suitable due
AC
CE
PT
ED
M
AN
US
CR
IP
T
to the in situ complexation and precipitation in acidic aqueous media.
Page 6 of 39
ACCEPTED MANUSCRIPT 2. Materials Povidone N.F. (K12 grade) was supplied by BASF Chemical Company (Ludwigshafen, Germany). Carbopol® 907 was supplied by Lubrizol Advanced Materials (Louisville, Kentucky). Itraconazole, USP, was purchased from Spectrum Chemical (New Brunswick, NJ).
T
All other materials used in this study are reagent grade.
Turbidity Method to Evaluate the Effect of pH on the Interpolymer Complexation
CR
3.1.
IP
3. Methods
In this study, we used the transmitted light turbidity method, described in JIS (Japanese
US
Industry Standard Committee) K0101. Since the solubility of the interpolymer complex was pH-
AN
dependent, the effect of pH on the interpolymer complexation was determined by measuring the turbidity of aqueous solutions containing both polymers as a function of pH. A UV-visible
M
spectroscopy system (Model 8453, Agilent, Santa Clara, CA) was used to determine the intensity
ED
of the light absorption. A 0.25% (w/w) polymer solution was tested at a wavelength of 660 nm
solution for pH titration.
Differential Scanning Calorimetry (DSC)
CE
3.2.
PT
over a pH range of 2.0–8.0, using a 0.1 N hydrochloride acid and a 1 N sodium hydroxide
AC
Differential scanning calorimetry (Model DSC Q20, TA Instruments, New Castle, DE) was used to measure the thermal events of materials under constant heating and cooling. The instrument was calibrated with an indium standard. The sample size was accurately weighed and recorded at around 5 mg. Experiment was conducted at temperature ramp of 10 °C/min from 25– 200 °C. Universal Analysis 2000 software was used for data analysis. 3.3.
Solid-State Hygroscopicity of the Complex
Page 7 of 39
ACCEPTED MANUSCRIPT The hygroscopicity of the polymers and the interpolymer complex was determined using dynamic vapor sorption (Model DVS Advantage, Surface Measurement Systems Ltd., London, UK). Each sample (sample size at around 10 mg) was tested for a full sorption/desorption cycle from 10–90% RH, then back to 10% RH in steps of 10% at 25 °C. The instrument was run in
T
step dm/dt mode. The equilibrium point was defined as a dm/dt less than 0.005%, with a
Attenuated Total Reflectance–Fourier Transform Infrared Spectroscopy (ATR– FTIR)
US
3.4.
CR
analyzed using DVSWinTM software (version 3.01).
IP
minimum stage time of 30 min and a maximum stage time of 360 min. Data was processed and
AN
The molecular interaction between povidone and Carbopol 907 was determined using ATR–FTIR. Spectra were collected using a NicoletTMiSTM spectrometer (Thermo Scientific,
M
USA, Waltham, Massachusetts). Samples sufficient to cover the crystal area were placed on the
ED
germanium crystal, and constant torque was applied with the built-in pressure tower to achieve uniform contact between the solid and the crystal. The samples were tested using a total of 32
PT
scans with 4 cm−1 resolution from 600 cm−1 to 3,000 cm−1 at room temperature. OMNICTM
Quantitative 13C Solution-State NMR to Measure the Weight Ratio between Povidone and Carbopol 907 in the Interpolymer Complex
AC
3.5.
CE
software was used to analyze the normalized spectra.
The weight ratio between povidone and Carbopol 907 in the interpolymer complex was quantitated using
13
C NMR (Varian® NMR 600 MHz Spectrometer, Palo Alto, CA). The
interpolymer complex of povidone and Carbopol 907 (obtained from the precipitation method) was dissolved in dimethyl sulfoxide-d6 at a concentration of 50 mg/mL. For quantitation, we used signals that correspond to the carbonyl carbon of the acrylic acid repeat units in Carbopol 907 and the pyrrolidone repeat units in povidone. We conducted 5,000 scans at 25 °C with a Page 8 of 39
ACCEPTED MANUSCRIPT recycle delay of 10 s. MestReNovaTM software was used to process and analyze the data, and the polynomial fit method was used for baseline correction and signal integration. 3.6.
Preparation of the ITZ Ternary Amorphous Solid Dispersions Using SolventControlled Precipitation Method
T
ITZ, povidone K12, and Carbopol 907 were dissolved in dimethyl sulfoxide (DMSO) or
IP
dimethylformamide (DMF). The total solid content of the solution was 4%, and the weight ratio
CR
between ITZ, povidone K12, and Carbopol 907 was 1:1:2. Under constant mixing, the solution containing the drug and polymers was slowly added to an antisolvent (e.g., water, 0.1N HCl,
US
ethanol). The precipitate was collected using a vacuum filtration device. The filtrate was rinsed
AN
with purified water and then dried using a vacuum oven at 50 °C for 6 hours. The dried material was then pulverized to particles finer than 420 µm (40 mesh) using a mortar and pestle. Preparation of ITZ–Carbopol 907 Amorphous Solid Dispersions Using Spray Drying
M
3.7.
ED
ASDs of ITZ in Carbopol 907 at 25% (w/w) drug loading was prepared by spray drying
PT
4% (w/v) solutions of the drug and polymer in a cosolvent that contained 60% ethanol and 40% DCM. The solutions were spray-dried using a Buchi mini B290 spray dryer (Buchi, Flawil,
CE
Switzerland) with an inlet temperature of approximately 100 °C to maintain a 60 °C outlet
AC
temperature, 100% aspiration (475 L/h) heated nitrogen gas, 5 mL/min feed rate, and −5 °C condenser temperature. Immediately following spray drying, the ASDs underwent secondary drying in a vacuum oven at 40 C for overnight to remove residual solvent. 3.8.
Preparation of Ternary ITZ Amorphous Solid Dispersions Using Hot Melt Extrusion
ITZ–povidone and ITZ–povidone–Carbopol 907 physical blends at 25% (w/w) drug loadings were prepared using geometric dilution. The final blends were passed through a 40-mesh sieve to
Page 9 of 39
ACCEPTED MANUSCRIPT further improve homogeneity. The blends were subsequently extruded on a Leistritz Nano-16 corotating twin screw extruder (American Leistritz Extruder Corp., Somerville, New Jersey). The volumetric bottom feeder was set to 4 cm3/min. Screw speed was maintained at 150 rpm, and the material was extruded though a 3-millimeter round die. Conveying, kneading, and mixing
T
elements were used in the screw design as shown in Figure 1. The barrel configuration consisted
IP
of a feed zone, a closed barrel, a venting zone, and a closed zone before the die. The feeding
CR
zone was maintained at room temperature conditions with water circulation. The other barrel temperatures were 165 °C (Zone 1), 175 °C (Zone 2), 175 °C (Zone 3), and 175 °C (at the die).
US
We milled the rods of extrudate using a coffee grinder, and large granules were separated with a
In Vitro Drug-Release Testing
M
3.9.
AN
40-mesh sieve.
We conducted the in vitro release of ITZ from the ASDs by the paddle method, using a
ED
USP apparatus II (Vankel dissolution apparatus, Model 7000). The paddle speed was set at 50
PT
rpm. We used a dissolution bath containing 900 mL of dissolution medium at 37 °C for the dissolution testing. A 0.1 N hydrochloric acid solution at pH 1.2 was used as the dissolution
CE
media to simulate the gastric environment. A sample of 500 mg extruded ASD, containing
AC
100 mg ITZ, was introduced into each vessel. 1-milliliter samples were collected at intervals of 5, 15, 30, 45, 60, 90, and 120 min, and we filtered these samples through a 0.45-micrometer membrane. All dissolution testing was performed in triplicate. The concentration of ITZ was determined by the reversed-phase HPLC method. We used Hypersil® Gold C18, 5 mm x 30 mm, 3 μm (Thermo Scientific, Waltham, MA) as the HPLC column. A mixture of water and an acetonitrile mixture (3:2 volume ratio) containing 0.05% trifluoroacetic acid was used as the mobile phase. The flow rate was set at 1.0 mL/min, and the injection volume was 10 μL. A UV
Page 10 of 39
ACCEPTED MANUSCRIPT detector (Waters® 2998 PD detector, Milford, MA) was used to quantitate at 485 nm. The
AC
CE
PT
ED
M
AN
US
CR
IP
T
retention time of ITZ was 4 min.
Page 11 of 39
ACCEPTED MANUSCRIPT 4. RESULTS AND DISCUSSION This section is divided into three parts. First, we discuss the mechanisms of complexation and the physicochemical properties of the complex. Next, we discuss the preparation of ITZ ternary ASDs. Last, we discuss the physical properties of ITZ ASDs, including both physical
IP
Interpolymer Complexation between Povidone K12 and Carbopol 907 in Aqueous Media
CR
4.1.
T
stabilities and dissolution behaviors.
4.1.1. Complexation of povidone K12 and Carbopol 907 as a function of pH
US
Figure 2 shows the chemical structures of povidone, Carbopol 907, and ITZ; while Table 1 shows their critical physical properties. We anticipated hydrogen bonding interaction
AN
between the carboxyl groups of Carbopol 907 (H-bond donor) and the carbonyl groups of
M
povidone (H-bond acceptor) (Figure 3a). We also anticipated that the complexation between
ED
povidone K12 and Carbopol 907 would be a function of the pH of the medium, since the carboxyl group’s ionization is pH-dependent and it can only function as an H-bond donor in its
PT
unionized state.
CE
The transmitted-light turbidity method is used to evaluate the effect of pH on the interpolymer complexation between povidone and Carbopol 907 over a physiological pH range.
AC
We prepared a 50 mM phosphate buffer solution at pH 8.0 containing both polymers at 0.25% (w/w). We then titrated the solution with a 0.1 N HCl solution to reduce the pH to 2.0. The turbidity as a function of pH is plotted in Figure 4. Individual polymer solutions were used as the controls in this study. As shown in Figure 4, a povidone K12 solution (0.25%) remained clear throughout the entire pH range. The Carbopol 907 solution (0.25%), however, became slightly cloudier when the pH of the solution dropped below 4.0. The pKa of Carbopol 907 was reported as 6.0. Carbopol 907 became mostly unionized below pH 4.0, effectively reducing its solubility Page 12 of 39
ACCEPTED MANUSCRIPT in the aqueous medium. In contrast, a solution containing both polymers at equal concentrations showed drastic changes in turbidity as pH was lowered. At pH 4.17, a sudden increase in turbidity was accompanied by the precipitation of the interpolymer complex from the solution. This critical pH is dependent on the molecular weight of the polymer. Generally, the higher the
IP
T
molecular weight, the higher the critical pH.25
We used solution-state
13
CR
4.1.2. Composition of the interpolymer complexes formed in acidic media C NMR to quantitate the molar ratio between povidone and Carbopol
US
907 in the interpolymer complex. NMR has been widely used to elucidate chemical structure because it can quantitate the molar ratios of protons in different functional groups.26 Similarly,
AN
the composition of a given mixture can be quantitated using the area ratio of chemical shift
M
signals of functional groups from individual components of the mixture.27 In NMR, all nuclei have an identical extinction coefficient for any given NMR spectrum. Therefore, the integrated
ED
intensity of signals for a given NMR spectrum is proportional to the number of nuclei, and this 13
C NMR
PT
can be used for quantitation. Compared to solution-state 1H NMR, solution state
CE
spectra cover a much wider range, making it easier to identify and count individual nuclei28.
AC
In this study, we characterized the complexes using solution-state 13C NMR. Deuterated DMSO was used as the solvent for NMR analysis. We prepared interpolymer complexes of povidone K12 and Carbopol 907 by precipitating a DMSO solution containing these two polymers at various ratios in a 0.1 N HCl solution. Figure 5 presents the NMR spectra for the interpolymer complexes prepared using DMSO solutions that contained povidone K12 and Carbopol 907 at different weight ratios. We attribute the carbon signals at 176 ppm and 174 ppm to the carbonyl C in Carbopol 907 and povidone K12, respectively. Table 2 illustrates the detailed calculation for determining the weight ratios between povidone K12 and Carbopol 907. The weight percentage of Carbopol 907 in the interpolymer complexes remains in a narrow range of 60–70%, despite the wide weight percentage range of Carbopol 907 (20–80%) as the percentage of total polymer content in the DMSO solutions. Page 13 of 39
ACCEPTED MANUSCRIPT Polymer composition in the DMSO solution (66.6%) and the interpolymer complex (68.3%) was essentially identical when Carbopol 907 was at 66.6% of the total polymer in DMSO solution. Therefore, we selected this composition for the preparation of the ITZ ASD using solventcontrolled coprecipitation.
IP
T
4.1.3. Characterization of interpolymer complex using DSC and FTIR techniques
CR
We characterized the interpolymer complex of povidone and Carbopol 907 using differential scanning calorimetry (DSC) for thermal properties and Fourier transform infrared
US
spectroscopy (FTIR) to understand the molecular-level interactions between these two polymers. As summarized in Table 1, both povidone and Carbopol 907 were amorphous, with a glass
AN
transition temperature (Tg) of 101 ºC and 131 ºC, respectively. The interpolymer complex is a
M
single-phase amorphous material with Tg of 172 ºC. Due to the strong interaction between povidone and Carbopol 907, the Tg of the complex was significantly higher than that of the
ED
individual polymers.
PT
Figure 6 shows the FTIR spectra of povidone K12, Carbopol 907, and their complex. We
CE
observed the band for the C=O stretch of carboxyl in Carbopol 907 and the amide group in povidone K12 at 1,702 cm−1 and 1,671 cm−1, respectively. These characteristic C=O stretch
AC
peaks shifted significantly in the interpolymer complex. The C=O stretch for Carbopol 907 was shifted to 1,721 cm−1, while the C=O stretch for povidone K12 was shifted to 1,631 cm−1. This significant peak shift indicates the strong interaction between the two polymers, and the different directions (i.e., bathochromic versus hypsochromic) in peak shift was indicative of the different roles of the functional groups involved in the interaction (i.e., H-bond donor versus H-bond acceptor).
Page 14 of 39
ACCEPTED MANUSCRIPT 4.2.
Preparation of Ternary Amorphous Solid Dispersion
4.2.1. Solvent-controlled coprecipitation Our detailed procedures for preparing solutions containing both drug and polymers and for preparing coprecipitate are disclosed in the method section. We evaluated both DMSO and
T
DMF as solvents, and we evaluated water, a 0.1 N hydrochloric acid solution, and ethanol as
IP
anti-solvents. Precipitation was conducted at ambient temperature and at −5 C. We observed
CR
that gel-like clusters were formed during coprecipitation instead of cotton-like precipitates. All
US
solvent-controlled coprecipitation runs are summarized in Table 3.
We were surprised to observe that ITZ, a drug with low crystallization tendency, was not
AN
completely amorphous across all coprecipitates.29 As presented in Table 3, crystalline ITZ was detected in all samples. During the coprecipitation process, the precipitation rate has a significant
M
influence on the properties of the coprecipitates.30 Both the drug and the polymer must
ED
precipitate simultaneously in order to inhibit phase separation and inhibit drug crystallization of
PT
the coprecipitates. We hypothesized that the interpolymer complex of povidone K12 and Carbopol 907 precipitated too slowly, even though it is not soluble in acidic aqueous media. A
CE
DVS study was conducted to compare the hygroscopicity of the complex and the individual
AC
polymers at 25 ºC.
As shown in Figure 7, the water absorption profiles of the individual polymers and the interpolymer complex all followed Type III isotherms of the BDDT classification. Water absorption occurred via a cluster mechanism.31 Both povidone K12 and Carbopol 907 were found to be hygroscopic, absorbing 73% and 47% of the water at 90% RH and 25 C. The interpolymer complex of these two polymers was less hygroscopic than the individual components. The lower hygroscopicity of the interpolymer complexes could be explained by HPage 15 of 39
ACCEPTED MANUSCRIPT bonding between the carboxylic groups of Carbopol 907 and the carbonyl groups of povidone, which block these functional groups’ interaction with water.32 It should be noted that the equilibrium water content of the interpolymer complex was high (21.46% at 90% RH), although it was lower than povidone and Carbopol 907 alone. As a comparison, hypromellose acetate
T
succinate, the polymer present in the vemurafenib ASD prepared using solvent-controlled
IP
coprecipitation absorbed 11.2% at 25 C/90% RH (Figure 7D). The DVS data demonstrate that,
CR
even though the interpolymer complex was not soluble in water or the acidic medium, it was still
US
quite hydroscopic. The hygroscopicity of the complex was also later demonstrated in the swelling study of melt-extruded ternary ITZ ASDs in 0.1 N hydrochloric acid dissolution
AN
medium (section 4.3.2).
M
The high hydrophilicity of the interpolymer complex may also lead to high water content in the coprecipitate, which increases the hydrophilicity of the microenvironment in the
ED
coprecipitate, thus favoring ITZ crystallization. In addition, both the polymer and the drug must
PT
precipitate at similar rates in order to inhibit phase separation and to prepare a homogenous ASD using the solvent-controlled coprecipitation process. Since the complex is hygroscopic, we
CE
hypothesized that ITZ would precipitate more quickly than the interpolymer complex, resulting
AC
in phase separation and crystallization of ITZ. 4.2.2. Preparation of ternary amorphous solid dispersion using spray drying The spray drying process was not applicable for preparing ternary ITZ ASDs, because we could not prepare solutions of ITZ, povidone K12, and Carbopol 907 in volatile organic solvents or solvent mixtures. The solubility properties of ITZ and the polymers in volatile organic solvents are summarized in Table 1. Even though an individual polymer is soluble in polar volatile solvents (e.g., ethanol, isopropyl alcohol) or solvent mixtures, povidone K12 and Page 16 of 39
ACCEPTED MANUSCRIPT Carbopol® 907 complexed and precipitated out of the solution when solutions of individual polymers were combined. We found that the interpolymer complexes of povidone K12 and Carbopol 907 are soluble only in nonvolatile organic solvents (e.g. DMSO, DMF). 4.2.3. Preparation of ternary amorphous solid dispersion using melt extrusion
IP
T
Figure 1 presents the screw design and processing parameters for extruding a ternary
CR
ASD consisting of ITZ, povidone K12, and Carbopol 907. When Carbopol 907 was used as the only polymeric carrier in ITZ ASDs, the formulations could not be processed due to degradation
US
of Carbopol 907. Even with the presence of triethyl citrate as a plasticizer at 10 %, Carbopol 907
AN
degraded and could not be converted into a polymer melt.
ITZ was at 20% of the formulation, while the weight ratio of povidone K12 and Carbopol
M
907 was maintained at 1:2. Triethyl citrate was present in the formulation as a plasticizer at 10%
ED
to further lower the processing temperature in order to minimize the degradation of Carbopol 907. The miscibility of Carbopol 907 and povidone K12 at the elevated temperature enabled us
PT
to process the formulation at a relatively low temperature. The same processing condition was
CE
also used to prepare an ITZ ASD based on povidone K12. We prepared binary ASDs, consisting of ITZ and an individual polymer, as the control
AC
samples for this study. Povidone K12 is thermoplastic, and an ITZ ASD based on povidone K12 was successfully prepared using melt extrusion. The processing conditions for an ITZ–povidone K12 ASD are the same as the conditions for the ternary ASD. Because of the thermal instability of Carbopol 907 when used as the only polymeric carrier during melt extrusion, an ITZ ASD based on Carbopol 907 was prepared using spray drying. 4.3.
Physical Properties of ITZ Amorphous Solid Dispersions Page 17 of 39
ACCEPTED MANUSCRIPT 4.3.1. Effect of interpolymer interaction on the physical stability of ternary ITZ amorphous solid dispersion Figure 8 presents DSC thermograms of crystalline ITZ and its ASDs. Pure ITZ shows an endothermic melting peak at 166.8 ºC. All ASDs show a single glass transition event that
T
indicates the formation of a single-phase amorphous material. Among all the ASDs, the ternary
IP
amorphous solid dispersion showed the highest Tg at 160ºC. This high Tg results from the
CR
interpolymer complexation between povidone K12 and Carbopol 907. A similar phenomenon has been reported for interpolymer complex systems that consist of polyethylene oxide and
US
Carbopol or consist of copovidone and Carbopol.33 Systems with high glass transition
AN
temperatures tend to possess higher miscibility as well as greater physical stability.34
M
The Carbopol 907–based binary ASD was observed to be more stable than the povidone K12–based ASD. The Carbopol 907–based ASD remained a single-phase amorphous
ED
material following two weeks of storage at 40 C at ambient RH (Figure 8-b). Even though it is
PT
amorphous, we observed the povidone-based ASD undergo amorphous–amorphous phase separation and two glass transition temperatures that represent a drug-rich (Tg of 49.89 C) and a
CE
polymer-rich (Tg of 132.78 C) phase (Figure 8-c). The difference in physical stability between
AC
the Carbopol 907-based and povidone K12-based solid dispersions could be explained by the molecular-level interactions between ITZ and the polymer.35 ITZ is a weak base drug with a pKa of 3.7, and it can function as a hydrogen bond acceptor. Carbopol 907 is an acidic polymer with a pKa of 5.0–6.0, and it can function as hydrogen bond donor. Carbopol 907 can form hydrogen bonds with ITZ via acid–base interaction. Povidone, however, can only function as a hydrogen bond acceptor, and it cannot strongly interact with ITZ. As a result, we observed poor physical stability in the povidone K12–based ITZ ASD. Page 18 of 39
ACCEPTED MANUSCRIPT Despite its high Tg, the ternary ITZ ASD demonstrated the poorest physical stability. As shown in Figure 9, ITZ recrystallized from the ternary ASD following two weeks of storage at 40 C/ambient RH, and it melted at 151 ºC. The depression of ITZ melting was due to the defect of the ITZ crystalline lattice.36 We attribute the poor physical stability of the ternary ASD to the
T
weakened drug–polymer interaction as the result of strong polymer–polymer interaction. The
IP
intermolecular interactions between Carbopol 907 and povidone K12 are so strong that their
CR
interactions with ITZ are weakened.
US
4.3.2. The effect of interpolymer complexation on the drug release of ITZ amorphous solid dispersions
AN
We conducted non-sink dissolution testing to evaluate the effect of interpolymer
M
complexation on the release of ITZ. The testing was performed using a 0.1 N hydrochloric acid solution at pH 1.2 and a 50 mM phosphate buffer solution at pH 6.8. The intrinsic solubility of
ED
crystalline ITZ at pH 1.2 was 1.2 µg/mL, and the solubility at pH 6.8 was below the quantitation
PT
limit of the HPLC method (0.1 µg/mL). We did not observe transient solubility enhancement in the pH 6.8 buffer, and the concentration of ITZ was below the quantitation limit for the ASD
CE
samples. Figure 10 presents the dissolution profiles of ITZ ASDs in 0.1 N hydrochloric acid.
AC
Dissolution profiles of ITZ-polymer physical mixtures were not shown in this figure, because the concentrations of ITZ in the first 30 mins were below the quantitation limit of the HPLC method. We observed solubility enhancement in both binary ASDs. After two hours, the ITZ concentration reached a plateau of 14 µg/mL in the povidone-based ASD and 120 µg/mL in the Carbopol 907–based ASDs. We anticipated that the Carbopol 907–based ASD would have the highest supersaturation level because of its strong intermolecular interaction with ITZ, and this
Page 19 of 39
ACCEPTED MANUSCRIPT intermolecular interaction between the drug and the polymer has been reported as an important factor in controlling drug release.37 The
interpolymer
complex–based
ASD
demonstrated
the
lowest
degree
of
supersaturation, with a final concentration of 7 μg/mL after two hours. We attribute the lower
IP
T
supersaturation level to the interaction between Carbopol 907 and povidone, which (a) interferes
CR
with H-bonding between Carbopol 907 and ITZ and (b) imparts enteric properties on the formulation. As shown in Figure 11, the interpolymer complex–based ITZ ASD gelled (Figure
US
11-a) and crystallized (Figure 11-b) during dissolution. As discussed in the previous section, the interpolymer complex was hygroscopic and could absorb a significant amount of moisture even
AN
though it was not water-soluble. The presence of water induced the crystallization of ITZ. This
M
study illustrates that excessive interpolymer interaction is detrimental to the dissolution behavior of ASDs. Additionally, povidone-based solid dispersions reached supersaturation within 60 min,
ED
while both the Carbopol 907–based ASD and the interpolymer complex–based ASD did not
PT
reach supersaturation until after two hours. We expected this result based on the turbidity study, in which Carbopol 907 gelled and the interpolymer complex was insoluble at pH 1.2. This
AC
CE
creates a gel layer and an insoluble matrix that surrounds the ITZ.
Page 20 of 39
ACCEPTED MANUSCRIPT 5. Conclusion We investigated the interaction between povidone K12 and Carbopol 907 and their effects on the properties of ternary ITZ ASDs. An insoluble interpolymer complex was formed in aqueous media below a critical pH of 4.17. Depending on the initial ratio between these two polymers in
IP
T
the starting solutions, the weight percentage of Carbopol 907 in the interpolymer complex ranged from 59–70%. Although it is insoluble in acidic aqueous media, the complex was hydroscopic
CR
and absorbed about 22% moisture at 25 C and 90% RH. Because of its hydrophilicity, the
US
interpolymer complex precipitated too slowly to allow for the preparation of an ITZ ternary ASD using the solvent-controlled coprecipitation process. The ternary ASD also could not be prepared
AN
using a spray drying process, since there is no common volatile organic solvent into which both
M
polymers can dissolve without forming an insoluble complex. The ternary ASD was successfully
ED
prepared using melt extrusion.
The molecular interaction between povidone and Carbopol exerts a negative effect on the
PT
physical stabilities of the ASD in the solid state. Ternary ASD was less physically stable in the
CE
solid state than binary ASDs. Recrystallization of ITZ was observed with ternary ASD following two weeks storage at 40 C/ambient RH. Carbopol-based ASD was most stable because of the
AC
acid-base interaction between Carbopol and ITZ. The molecular interaction between povidone and Carbopol also has a negative effect on the dissolution behavior of the ASD in a 0.1 N HCl solution. Since povidone and Carbopol form an insoluble complex in situ, the ternary ASD does not dissolve during the dissolution testing. However, the absorption of water due to the high hydrophilicity of the interpolymer complex results in the crystallization of ITZ. The ternary ASD demonstrated the lowest degree of
Page 21 of 39
ACCEPTED MANUSCRIPT supersaturation (i.e., six times the crystalline ITZ solubility) in 0.1 N HCl, compared to 12-fold supersaturation for the binary povidone-based ASD and 100-fold supersaturation for the binary Carbopol-based ASD. This study illustrates that too strong interpolymer interaction in ternary ASDs is detrimental to their performance.
IP
T
6. Acknowledgement
CR
We gratefully acknowledge the University of Texas at Austin for funding and the use of
7. Conflict of Interest
AC
CE
PT
ED
M
AN
The authors report no conflicts of interest.
US
instruments in completing this project.
Page 22 of 39
ACCEPTED MANUSCRIPT 8. Reference
AC
CE
PT
ED
M
AN
US
CR
IP
T
1. Yu L 2001. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Deliv Rev 48(1):27-42. 2. Bhardwaj SP, Arora KK, Kwong E, Templeton A, Clas SD, Suryanarayanan R 2014. Mechanism of amorphous itraconazole stabilization in polymer solid dispersions: role of molecular mobility. Mol Pharm 11(11):4228-4237. 3. Huang Y, Dai WG 2014. Fundamental aspects of solid dispersion technology for poorly soluble drugs. Acta Pharm Sin B 4(1):18-25. 4. Vo CL, Park C, Lee BJ 2013. Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs. Eur J Pharm Biopharm 85(3 Pt B):799-813. 5. Meng F, Gala U, Chauhan H 2015. Classification of solid dispersions: correlation to (i) stability and solubility (ii) preparation and characterization techniques. Drug Dev Ind Pharm 41(9):1401-1415. 6. Al-Obaidi H, Buckton G 2009. Evaluation of griseofulvin binary and ternary solid dispersions with HPMCAS. AAPS PharmSciTech 10(4):1172-1177. 7. Yoo Su, Krill SL, Wang Z, Telang C 2009. Miscibility/stability considerations in binary solid dispersion systems composed of functional excipients towards the design of multi‐component amorphous systems. Journal of pharmaceutical sciences 98(12):4711-4723. 8. Wang X, Michoel A, Van den Mooter G 2005. Solid state characteristics of ternary solid dispersions composed of PVP VA64, Myrj 52 and itraconazole. International journal of pharmaceutics 303(1):54-61. 9. Marks JA, Wegiel LA, Taylor LS, Edgar KJ 2014. Pairwise polymer blends for oral drug delivery. J Pharm Sci 103(9):2871-2883. 10. Prasad D, Chauhan H, Atef E 2014. Amorphous stabilization and dissolution enhancement of amorphous ternary solid dispersions: combination of polymers showing drug–polymer interaction for synergistic effects. Journal of pharmaceutical sciences 103(11):3511-3523. 11. Bhardwaj SP, Arora KK, Kwong E, Templeton A, Clas S-D, Suryanarayanan R 2014. Mechanism of amorphous itraconazole stabilization in polymer solid dispersions: Role of molecular mobility. Molecular pharmaceutics 11(11):4228-4237. 12. Miller DA, DiNunzio JC, Yang W, McGinity JW, Williams III RO 2008. Enhanced in vivo absorption of itraconazole via stabilization of supersaturation following acidic-to-neutral pH transition. Drug development and industrial pharmacy 34(8):890-902. 13. Engers D, Teng J, Jimenez‐Novoa J, Gent P, Hossack S, Campbell C, Thomson J, Ivanisevic I, Templeton A, Byrn S 2010. A solid‐state approach to enable early development compounds: Selection and animal bioavailability studies of an itraconazole amorphous solid dispersion. Journal of pharmaceutical sciences 99(9):3901-3922. 14. Bimendina L, Bekturov E, Roganov V 1976. Poly (acrylic acid)-poly (vinyl pyrrolidone) complexes in solutions. Chemical Papers 30(3):301-305. 15. Biswas A, Willet J, Gordon SH, Finkenstadt V, Cheng H 2006. Complexation and blending of starch, poly (acrylic acid), and poly (N-vinyl pyrrolidone). Carbohydrate polymers 65(4):397-403. 16. Lau C, Mi Y 2002. A study of blending and complexation of poly (acrylic acid)/poly (vinyl pyrrolidone). Polymer 43(3):823-829. 17. Chun M-K, Cho C-S, Choi H-K 2002. Mucoadhesive drug carrier based on interpolymer complex of poly (vinyl pyrrolidone) and poly (acrylic acid) prepared by template polymerization. Journal of controlled release 81(3):327-334. 18. Perez-Gramatges A, Argüelles-Monal W, Peniche-Covas C 1996. Thermodynamics of complex formation of polyacrylic acid with poly (N-vinyl-2-pyrrolidone) and chitosan. Polymer Bulletin 37(1):127134.
Page 23 of 39
ACCEPTED MANUSCRIPT
AC
CE
PT
ED
M
AN
US
CR
IP
T
19. Bizley SC, Williams AC, Khutoryanskiy VV 2014. Thermodynamic and kinetic properties of interpolymer complexes assessed by isothermal titration calorimetry and surface plasmon resonance. Soft matter 10(41):8254-8260. 20. Kuo S-W, Kao H-C, Chang F-C 2003. Thermal behavior and specific interaction in high glass transition temperature PMMA copolymer. Polymer 44(22):6873-6882. 21. Reverchon E 1999. Supercritical antisolvent precipitation of micro-and nano-particles. The journal of supercritical fluids 15(1):1-21. 22. Matteucci ME, Hotze MA, Johnston KP, Williams RO 2006. Drug nanoparticles by antisolvent precipitation: mixing energy versus surfactant stabilization. Langmuir 22(21):8951-8959. 23. Kalogiannis CG, Pavlidou E, Panayiotou CG 2005. Production of amoxicillin microparticles by supercritical antisolvent precipitation. Industrial & engineering chemistry research 44(24):9339-9346. 24. Shah N, Iyer RM, Mair HJ, Choi DS, Tian H, Diodone R, Fähnrich K, Pabst‐Ravot A, Tang K, Scheubel E 2013. Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer‐stabilized solid dispersion prepared by a solvent‐controlled coprecipitation process. Journal of pharmaceutical sciences 102(3):967-981. 25. Nurkeeva Z, Mun G, Khutoryanskiy V, Bitekenova A, Dubolazov A, Esirkegenova SZ 2003. pH effects in the formation of interpolymer complexes between poly (N-vinylpyrrolidone) and poly (acrylic acid) in aqueous solutions. The European Physical Journal E 10(1):65-68. 26. Pretsch E, Bühlmann P, Affolter C, Pretsch E, Bhuhlmann P, Affolter C. 2009. Structure determination of organic compounds. ed.: Springer. 27. Simmler C, Napolitano JG, McAlpine JB, Chen S-N, Pauli GF 2014. Universal quantitative NMR analysis of complex natural samples. Current opinion in biotechnology 25:51-59. 28. Ando I, Webb GA 1983. Theory of NMR parameters. 29. Baird JA, Van Eerdenbrugh B, Taylor LS 2010. A classification system to assess the crystallization tendency of organic molecules from undercooled melts. Journal of pharmaceutical sciences 99(9):37873806. 30. Shah N, Sandhu H, Phuapradit W, Pinal R, Iyer R, Albano A, Chatterji A, Anand S, Choi DS, Tang K 2012. Development of novel microprecipitated bulk powder (MBP) technology for manufacturing stable amorphous formulations of poorly soluble drugs. International journal of pharmaceutics 438(1):53-60. 31. Adolphs J, Setzer MJ 1996. Energetic classification of adsorption isotherms. Journal of colloid and interface science 184(2):443-448. 32. Cao Y, Chen Y, Wang X, Mu T 2014. Predicting the hygroscopicity of imidazolium-based ILs varying in anion by hydrogen-bonding basicity and acidity. RSC Advances 4(10):5169-5176. 33. Zhang F, Meng F, Wang ZY, NA W 2016. Interpolymer complexation between copovidone and carbopol and its effect on drug release from matrix tablets. Drug Development and Industrial Pharmacy:1-14. 34. Meng F, Dave V, Chauhan H 2015. Qualitative and quantitative methods to determine miscibility in amorphous drug–polymer systems. European Journal of Pharmaceutical Sciences 77:106-111. 35. Meng F, Trivino A, Prasad D, Chauhan H 2015. Investigation and correlation of drug polymer miscibility and molecular interactions by various approaches for the preparation of amorphous solid dispersions. European Journal of Pharmaceutical Sciences 71:12-24. 36. Marsac PJ, Shamblin SL, Taylor LS 2006. Theoretical and practical approaches for prediction of drug–polymer miscibility and solubility. Pharmaceutical research 23(10):2417-2426. 37. Chauhan H, Kuldipkumar A, Barder T, Medek A, Gu C-H, Atef E 2014. Correlation of inhibitory effects of polymers on indomethacin precipitation in solution and amorphous solid crystallization based on molecular interaction. Pharmaceutical research 31(2):500-515.
Page 24 of 39
ACCEPTED MANUSCRIPT Table 1. Critical physical attributes of ITZ, povidone K12, and Carbopol 907. Tm (ºC)
Tg (ºC)
pKa
ITZ
706
166.8
52c
3.7
Povidone K12
111a
-
101c
-
Carbopol 907
72a
-
131c
6.0
Interpolymer complexb
-
-
172c
-
Solubility Soluble in dichloromethane, not soluble in water and most of other volatile solvents. Freely soluble in water and polar organic solvents including ethanol, isopropyl alcohol, DMF and DMSO. Swellable in water; soluble in alkaline aqueous media; soluble in polar solvents including ethanol, DMF, and DMSO.
US
CR
IP
T
Mw (g/mol)
Not soluble in volatile solvents; soluble in DMF and DMSO.
AC
CE
PT
ED
M
AN
a. molecular weight of repeating units b. the weight percentage of Carbopol 907 in the interpolymer complex is 68.3%. c. the Tg values of ITZ and polymer were measured using DSC in our lab.
Page 25 of 39
ACCEPTED MANUSCRIPT
Table 2. Weight percentage of Carbopol 907 in the interpolymer complexes as a function of its weight percentage in the initial stock solutions. Ratio between integrated area under signals (R)a 2.23
Complex #2
33.3
2.57
Complex #3
50.0
2.91
Complex #4
66.6
3.32
Complex #5
80.0
3.61
59.1
T
20.0
CR
Complex #1
Wt% of Carbopol 907 in complexesb
IP
Wt% of Carbopol 907 in total polymer in DMF solution
62.5 65.4 68.3 70.1
13
AC
CE
PT
ED
M
AN
US
a. Ratio of integrated area of signal 1 over integrated area under signal 2 from C solution-state NMR analyses. Please refer to Figure 5 for the detailed information of each signal. b. Carbopol 907 weight percentage of the interpolymer complex = . Molar mass of acrylic acid and N-vinylpyrrolidone is 72 and 111, respectively.
Page 26 of 39
ACCEPTED MANUSCRIPT
Table 3. Physical statea (crystalline or amorphous) of interpolymer-based ITZ solid dispersions prepared using solvent-controlled coprecipitation. Solvent Antisolvent DMF
Ethanol–water (1:1)
Crystalline
Crystalline
Water
Crystalline
0.1 HCL
Crystalline
Ethanol–water (1:1)b
Crystalline
CR
IP
T
DMSO
Crystalline Crystalline Crystalline
AC
CE
PT
ED
M
AN
US
a. The physical state of interpolymer complex was determined using DSC, endothermic peak at ITZ melting point indicates the presence of crystalline ITZ. b. Ethanol–water mixture was cooled with acetone/dry ice cooling bath.
Page 27 of 39
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
PT
ED
M
AN
Figure 1. Screw configuration and barrel setup of Leistritz Nano 16 mm extruder.
Page 28 of 39
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
PT
Figure 2. Chemical structures of itraconazole, povidone K12, and Carbopol 907.
Page 29 of 39
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
PT
Figure 3. Illustration of hydrogen bonding: (a) ITZ and Carbopol 907 and (b) povidone K12 and Carbopol 907.
Page 30 of 39
PT
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
Figure 4. Turbidity (light absorption at 660 nm) of polymer solutions as a function of pH.
Page 31 of 39
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
PT
Figure 5. Solution-state 13C NMR spectra for the interpolymer complexes prepared using DMSO solution containing povidone K12 and Carbopol 907 at various weight ratios (a) 4:1, (b) 2:1, (c) 1:1, (d) 2:1, (e) 4:1. Chemical shifts at 176 and 174 ppm represent C from carbonyl groups in Carbopol 907 and povidone K12, respectively.
Page 32 of 39
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
PT
Figure 6. FTIR spectra of povidone, Carbopol 907, and their interpolymer complex.
Page 33 of 39
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
PT
Figure 7. Dynamic vapor absorption profiles of povidone, Carbopol 907, and their interpolymer complex.
Page 34 of 39
CE
PT
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
Figure 8. DSC thermograms (a) ITZ, (b) melt-extruded ITZ-Povidone-Carbopol ASD, (c) melt-extruded ITZ-Povidone ASD, and (d) spray-dried ITZ-Carbopol ASD.
Page 35 of 39
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
PT
ED
Figure 9. DSC thermograms (a) ITZ, (b) melt-extruded ITZ-Povidone-Carbopol ASD, (c) melt-extruded ITZ-Povidone ASD, and (d) spray-dried ITZ-Carbopol ASD following two weeks storage at 40 C and ambient RH.
Page 36 of 39
PT
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
Figure 10. In vitro dissolution profiles of ITZ ASD containing Carbopol 907, povidone, and interpolymer complex; 900 mL 0.01 N HCl solution pH 1.2 at 37 C as the dissolution medium, USP paddle method at 50 rpm (n = 3).
Page 37 of 39
PT
ED
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
AC
CE
Figure 11. Morphology of interpolymer complex based ITZ ASD before (left) and after (right) dissolution (0.1 N HCl solution, pH 1.2) using (a) digital camera with no magnification and (b) polarized microscopy with 500x magnification.
Page 38 of 39
ACCEPTED MANUSCRIPT
AC
CE
PT
ED
M
AN
US
CR
IP
T
Graphical abstract
Page 39 of 39