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SOLID MOLECULAR DISPERSIONS OF ITRACONAZOLE FOR ENHANCED
DISSOLUTION AND CONTROLLED DRUG DELIVERY
by
Liu Hong
A thesis submitted in conformity with the requirements
for the degree of Master of Science
Graduate Department of Pharmaceutical Sciences
University of Toronto
© Copyright by Liu Hong (2009)
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Abstract
Solid Molecular Dispersions of Itraconazole for Enhanced Dissolution and Controlled
Drug Delivery
Liu Hong, Master of Science 2009
Graduate Department of Pharmaceutical Sciences, University of Toronto
The purpose of this study was to investigate the formation of solid molecular dispersions
of Itraconazole (ITZ) in a number of glassy polymers including PVP, crospovidone, PVP-EC,
HPMCAS and HPMCAS-PEO to enhance its dissolution and achieve release control.
Polarizing light microscopy was found to be more sensitive than DSC and XRD for
detecting crystallinity. PVP, PVP-EC & crospovidone generated loading levels of ~20%,
substantially greater than that of HPMCAS and HPMCAS-PEO (5%). The loaded ITZ was
stabilized though molecular interactions with the polymer and reduced molecular mobility in
a glassy polymer matrix. Overall, immediate release was achieve d using PVP and
crospovidone, enteric delivery provided by HPMCAS, and controlled release generated with
EC and PEO. Among all polymers studied, only ITZ in PVP failed to generate sufficient
stability in the presence of moisture. In general, solid molecular dispersion is a useful
approach to improve the poor solubility and bioavailability of Itraconazole.
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Acknowledgement
I would like to convey my sincere gratitude to my supervisor Dr. Ping I. Lee for his
supervision, encouragement, advice and enormous support throughout my research. His level
of professionalism and attitude for science exceptionally inspired and enriched my growth as
a scientific researcher.
I gratefully acknowledge Dr. Tigran Chalikian and Dr. Robert Macgregor for taking
the time to be my advisory committee members and offering insightful guidance and
suggestions during my committee meetings. I would also like to record my gratitude to Dr.
Edgar Acosta for being an external committee member for my thesis defense. Many thanks
go in particular to Dr. Christine Allen for kindly allowing access to her various laboratory
equipments and special thanks are due to PhD candidate Payam Zahedi for his valuable DSC
and FTIR training.
I would like to thank Dr. Srebri Petrov for the XRD service.
I gratefully thank my fellow lab members Beibei Qu, Yan Li, and Yanhong Luo for
considering me as an important member of our big family and their continuous availability
and support when I needed help.
Lastly, I would like to thank my parents for having faith in me and giving me
encouragement and financial support in the past two years. I could not have completed my
master’s project without their love and persistent confidence in me.
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Table of Contents
ABSTRACT ............................................................................................................................ II
ACKNOWLEDGEMENTS .................................................................................................... I
TABLE OF CONTENTS ....................................................................................................... IV
LIST OF TABLES ............................................................................................................... VII
LIST OF FIGURES ........................................................................................................... VIII
LIST OF EQUATIONS ......................................................................................................... XI
ABBREVIATIONS .............................................................................................................. XII
NOTATIONS ...................................................................................................................... XIII
1. INTRODUCTION ............................................................................................................... 1
1.1 AMORPHOUS VS. CRYSTALLINE ................................................................................................................. 4
1.2 IMPROVED LOCAL SOLUBILITY AND WETTABILITY OF POORLY SOLUBLE DRUG .......................................... 5
1.3 CARRIERS ................................................................................................................................................. 6
1.4 SOLID DISPERSIONS PREPARATION METHOD .............................................................................................. 8
1.5 ITRACONAZOLE ....................................................................................................................................... 11
1.6 ITRACONAZOLE SOLID DISPERSION ......................................................................................................... 12
1.7 POLYMERIC CARRIERS FOR THE PRESENT STUDY .................................................................................... 16
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1.7.1 PVP 17
1.7.2 Crospovidone (crosslinked PVP) 19
1.7.3 Ethyl cellulose (EC) 19
1.7.4 Hydroxypropyl methyl cellulose acetate succinate (HPMCAS) 21
1.7.5 Poly ethylene oxide (PEO) 22
1.8 UNEXPLORED AREAS .............................................................................................................................. 24
2. HYPOTHESIS AND RESEARCH OBJECTIVES ........................................................ 25
3.EXPERIMENTAL DESIGN AND METHODOLOGY .................................................. 26
3.1 MATERIALS ............................................................................................................................................. 26
3.2 PREPARATION OF SOLID DISPERSION IN FILMS ......................................................................................... 27
3.3 PREPARATION OF SOLID DISPERSION WITH CROSPOVIDONE ..................................................................... 27
3.4 CHARACTERIZATION OF SOLID DISPERSION SAMPLES .............................................................................. 29
3.4.1 Polarizing microscope 29
3.4.2 Stereomicroscope 29
3.4.3 Thermal analysis (Differential scanning calorimetry) 29
3.4.4 X-Ray Diffractometry (XRD) 30
3.4.5 Polymer drug interaction in film 31
3.5 DISSOLUTION TESTING ............................................................................................................................ 31
3.6 STABILITY ............................................................................................................................................... 33
4.RESULTS AND DISCUSSION .......................................................................................... 34
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4.1 POLYMER COMPATIBILITY ....................................................................................................................... 34
4.1.1 Compatibility of PVP-EC blends 34
4.1.2 Compatibility of HPMCAS-PEO blends 35
4.2 CROSPOVIDONE LOADING LEVEL DETERMINATION ................................................................................. 38
4.2.1 Equilibrium swelling duration and ITZ loading concentration 38
4.3 CHARACTERISTICS OF ITZ SOLID DISPERSIONS IN POLYMERIC CARRIERS ................................................ 40
4.3.1 Physical observation 40
4.3.2 Polarizing Microscopy 42
4.3.3 DSC results 45
4.3.4 X-ray results in detection of crystalline ITZ peaks 49
4.4 POLYMER-DRUG INTERACTION ............................................................................................................... 51
4.5 DISSOLUTION .......................................................................................................................................... 53
4.5.1 Intrinsic dissolution rate of ITZ from PVP film 53
4.5.2 Dissolution of ITZ from PVP-EC (70%:30%) blend 58
4.5.3 Dissolution of ITZ from crospovidone powders 59
4.5.4 Dissolution of ITZ from HPMCAS and HPMCAS-PEO (70%:30%) blend 60
4.6 STABILITY ............................................................................................................................................... 62
5.CONCLUSIONS AND RECOMMENDATIONS ............................................................ 67
REFERENCES ...................................................................................................................... 70
LIST OF ABSTRACTS ......................................................................................................... 79
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List of Tables
Table I Physicochemical properties of the five polymer carriers. ........................................ 17
Table II Swelling ratios (w/w) and equilibrium solvent contents (%) of crospovidone
powders in dichloromethane at day 3, day 5 and day 9. ...................................................... 39
Table III ITZ concentrations in loading solution and resulting ITZ loading levels in
crospovidone powders. ........................................................................................................ 39
Table IV. Dissolution characteristics of 10% ITZ loaded PVP films at different rotational
speeds. .................................................................................................................................. 56
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List of Figures
Figure 1. Chemical structure of Itraconazole. ...................................................................... 12
Figure 2. Chemical structure of PVP. ................................................................................... 18
Figure 3. Chemical structure of EC. ..................................................................................... 20
Figure 4. Chemical structure of HPMCAS. .......................................................................... 21
Figure 5. Chemical structure of PEO. ................................................................................... 22
Figure 6. (A) Disk intrinsic dissolution rate testing setup (B) film holder. .......................... 33
Figure 7.Polarizing microscopic pictures of PVP with various amounts of EC. .................. 35
Figure 8. (A) Polarizing microscopic images of HPMCAS-PEO polymer blend with
various PEO concentrations (B) Polarizing microscopic images of HPMCAS-PEO
(80%:20%) blend and (C) XRD patterns of HPMCAS-PEO polymer blend with various
PEO concentrations. ............................................................................................................ 37
Figure 9. The partition coefficient of ITZ from loading solution into crospovidone
powders. ............................................................................................................................... 39
Figure 10. Solid dispersions of ITZ with various drug loadings in (A) PVP (B)
HPMCAS and (C) HPMCAS-PEO (70%:30%). ................................................................. 41
Figure 11. Polarized images of films with various ITZ loadings in (A) PVP (B) PVP-EC
(70%:30%) (C) HPMCAS and (D) HPMCAS-PEO (70%:30%). ....................................... 44
Figure 12. DSC analysis in detection of melting peaks in films with different ITZ
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loading levels in (1) PVP (2) crospovidone (3) PVP-EC (70%:30%) (4) HPMCAS and
(5) HPMCAS-PEO (70%:30%). .......................................................................................... 46
Figure 13. Tg patterns of ITZ solid dispersions in (1) PVP (2) crospovidone (3) PVP-EC
(70%:30%) (4) HPMCAS and (5) HPMCAS-PEO (70%:30%).......................................... 48
Figure 14. XRD patterns of (1) PVP (2) crospovidone (3) PVP-EC (70%:30%) (4)
HPMCAS and (5) HPMCAS-PEO (70%:30%). .................................................................. 50
Figure 15. FTIR spectra of ITZ solid dispersions in (1) PVP (2) crospovidone (3) PVP-
EC (70%:30%) (4) HPMCAS and (5) HPMCAS-PEO (70%:30%). .................................. 52
Figure 16. Dissolution profile of 10% ITZ-loaded PVP films at 37°C in 1L 0.1N HCL
(pH 1.2) at 50 rpm, 100 rpm, 150 rpm, and 200 rpm without SDS. .................................... 55
Figure 17. Drug flux of 10% ITZ loaded PVP films vs. square root of rotation speed. ....... 56
Figure 18. Area/dissolution rate (cm2/mg/min) of 10% ITZ loaded PVP films vs.
reciprocal of square root of rotation speed. ......................................................................... 56
Figure 19. Dissolution of 10% and 20% ITZ loaded PVP films at 37oC in 1L 0.1 N HCl
(pH 1.2) at 100rpm with and without SDS. ......................................................................... 58
Figure 20. Dissolution of 20% ITZ-loaded PVP-EC (70%:30%) films at 37°C in 1L 0.1
N HCl (pH 1.2) at 100 rpm with and without 0.3% SDS. ................................................... 59
Figure 21. Dissolution of 16% ITZ-loaded crospovidone powders at 37°C in 500 ml
0.1N HCl (pH 1.2) at 100 rpm with and without SDS. ....................................................... 60
Figure 22. Dissolution of 5% ITZ-loaded HPMCAS and HPMCAS-PEO (70%:30%)
blend in an acidic (pH 1.2, first 1.5 hours)-to-neutral (pH 6.8) medium at 37°C at 100
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rpm with and without SDS. ................................................................................................. 61
Figure 23. Physical stability of 20% ITZ-loaded PVP film. ................................................. 63
Figure 24. Physical stability of 16% ITZ-loaded crospovidone powders (a) DSC (b) X-
ray. ....................................................................................................................................... 63
Figure 25. Physical stability of 20% ITZ-loaded EC-PVP film (a) DSC (b) X-ray and (c)
polarizing microscope. ......................................................................................................... 64
Figure 26. Physical stability of 5% ITZ-loaded HPMCAS film (a) DSC (b) X-ray and (c)
polarizing microscope. ......................................................................................................... 65
Figure 27. Physical stability of 5% ITZ-loaded HPMCAS-PEO film (a) DSC (b) X-ray
and (c) polarizing microscope. ............................................................................................ 66
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List of Equations
Equation 1 Noyes-Whitney equation ...................................................................................... 1
Equation 2 Mass degree of swelling ..................................................................................... 28
Equation 3 Equilibrium solvent content ............................................................................... 28
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Abbreviations
PEG Polyethylene glycol
PVP Polyvinylpyrrolidone
HPMC Hydroxypropyl methylcellulose
HPMCAS Hydroxypropyl methylcellulose acetate succinate
FTIR Fourier transform infrared
HPC Hydroxypropyl cellulose
SCF Supercritical fluid
ITZ Itraconazole
HP-β-CD Hydroxypropyl beta cyclodextrin
PVPVA Polyvinylpyrrolidone vinyl acetate
EC Ethyl cellulose
SPU Segmented polyurethane
PEO Polyethylene oxide
DSC Differential scanning calorimetry
XRD X-ray diffractometry
SLS Sodium lauryl sulfate
SDS Sodium dodecyl sulfate
ESC Equilibrium solvent content
RH Relative humidity
RDIDR Rotating disk intrinsic dissolution rate
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Notations
dC/dt Rate of dissolution [M/s]
A Surface area of the drug exposed to the dissolution medium [m2]
D Drug diffusion coefficient in solution [m2/s]
Cs Solubility of the drug [M]
C Concentration of drug in the bulk dissolution medium at time t [M]
t Time [s]
h Diffusion layer thickness [m]
Tm Melting temperature [ºC]
Tg Glass transition temperature [ºC]
q Swelling ratio
Ws Swollen powder weight [g]
Wd Dry powder weight [g]
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1. Introduction
It is generally recognized that poor solubility is one of the most frequently encountered
difficulties in the field of pharmaceutics. Low solubility and subsequent unsatisfactory
dissolution rate often compromise oral bioavailability. The wide implementation of high
throughput screening for potential therapeutic entities by the pharmaceutical industry had
dramatically raised the number of poorly soluble drug candidates. As a result, the
improvement of solubility and dissolution rate of poorly soluble compounds is of great
importance.
The Noyes-Whitney equation [Eq.1] provides clear indication of parameters that can be
modified in order to enhance the dissolution rate of poorly soluble drugs:
h
CCsAD
dt
dC )(
(1)
Equation 1 Noyes-Whitney equation
Where dC/dt is the dissolution rate, A is the surface area exposed to dissolution medium, D
is the diffusion coefficient of the drug in solution, Cs is the solubility of the drug, C is the
concentration of drug in the bulk dissolution medium at time t, and h is the thickness of
diffusion boundary layer. Several parameters in this equation can be adjusted to achieve
enhanced dissolution rate. For example, an increase in either the surface area or diffusion
coefficient can lead to a higher dissolution rate. Similarly, enhanced drug solubility can
generate the same effect. Furthermore, a decrease in diffusion boundary layer thickness can
result in a faster dissolution rate. It has been suggested that among all potential approaches,
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increasing drug solubility and/or available surface area through formulation is most likely to
be achieved both in vitro and in vivo (1). Accordingly, many approaches have been
developed in an attempt to overcome the problem of poor solubility. These include particle
size reduction (2), formation of salts, polymorphs and pseudopolymorphs (3),
complexation/solubilization using hydrotropes and surfactants (4), and formation of soluble
prodrugs (5). Unfortunately, these approaches are not entirely satisfactory due to various
practical limitations. For example, it is not feasible to obtain salt formation for neutral
compounds and practical difficulties exist for salt formation of weekly acidic or weekly
basic substance. Even if salt formation is feasible, the conversion of such salt back to its
original acid or base can occur leading to slower dissolution rate in the gastrointestinal
environment (6). The application of surfactant and complexing agent to enhance the
solubility and dissolution rate is frequently limited by potential safety concerns with the
large quantities of surfactant or complexing agent that may be required. Particle size
reduction via micronization or nanosizing does not always work due to potential particle
aggregation problem with fine powders which can affect product manufacturing and stability
(7). Producing more soluble polymorphs and pseudopolymorphs may risk potential failure in
stability due to their conversion to more stable but less soluble polymorph (7).
Solid dispersions and solid solutions have shown promising results in enhancing the
solubility and dissolution rate of poorly soluble drugs. They refer to the dispersion of drug
substance in a pharmaceutically acceptable polymeric carrier matrix (8). It is worthwhile to
clarity that the terms ―solid dispersion‖ and ―solid solution‖ have been used interchangeably
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in the pharmaceutical literature, often incorrectly. In fact, ―solid solution‖ only refers to drug
molecules dissolved or molecularly dispersed throughout the carrier polymer matrix (no
precipitation/crystallization), whereas ―solid dispersion‖ describes systems containing
dispersed particles which can be amorphous or crystalline.
Applications of solid dispersions and solid solutions have been actively investigated for
over four decades. Back in 1961, formulation of eutectic mixture of sulphathiazole and urea
was first published (9). This formulation, which was later termed solid dispersion,
incorporated poorly soluble drug in highly water soluble matrix by melting their physical
mixtures and resulted in enhancements in drug solubility and bioavailability. Later in 1963
and 1964, Levy and Kanig reported the use of solid dispersion with the dispersed component
molecularly dissolved in the matrix (10, 11). Ever since then, due to its great promise in
solubility and dissolution rate enhancement for poorly soluble drugs, solid dispersion has
been studied and used extensively for this purpose. For example, Solid dispersions of
Piroxicam in polyvinylpyrrolidone K-30 at 1:4 ratio generated amorphous state of the drug.
An approximately 38-fold increase in dissolution rate compared with that of the pure drug
was also observed (12). Moreover, ibuprofen solid dispersion in polymers such as Kollicoat
IR has demonstrated faster dissolution rate than the drug alone (13). Solid dispersion method
is employed in some of the marked products including Griseofulvin in polyethylene glycol
(PEG) (Gris-PEG® from Novartis), Nabilone in polyvinylpyrrolidone (PVP) (Cesamet®
from Lilly), and Itraconazole in hydroxypropyl methylcellulose (HPMC) (Sporanox® from
Janssen) (14).
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The promising results of solid dispersion in solubility and dissolution rate enhancement
of poorly soluble drugs can be attributed to various aspects: from amorphous structure
replacing crystalline structure (1, 15, 16) to improved local solubility and wettability of the
poorly soluble drug in the solid dispersion matrix (17, 18), from the ability of carrier
functional groups to form interactions with the drug (19, 20) to the increase in glass
transition temperature (Tg) (21, 22) of the solid dispersion mixture, and from inhibited drug
precipitation from supersaturated solution (23, 24) to resulting metastable drug
polymorphous with higher solubility and dissolution rate in the presence of the carrier (25).
1.1 Amorphous vs. crystalline
Amorphous solids have useful properties and frequent occurrence in the field of
pharmaceutical formulations. Similar to crystalline solids, amorphous solids may exhibit
short-range order. However, the long-range translational-orientation symmetry, a distinctive
characteristic of crystalline solids, is absent in amorphous solids (15). From a
thermodynamic point of view, amorphous solids, compared with corresponding crystalline
solids, demonstrate excess in properties meaning they have higher free energy, entropy and
specific volume (15, 16). As a result of the enhanced thermodynamic properties, amorphous
solids exhibit higher transient solubility, dissolution rate, vapor pressure and molecular
mobility. Normally, in order to dissolve a crystalline drug, energy is required to break up the
crystalline lattice. This required energy is often considered as a barrier for the drug
dissolution (1). In solid molecular dispersions, long-range crystalline structure is absent and
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the drug is dissolved or molecularly dispersed in a polymeric carrier. Here, the drug exists in
an amorphous state which exhibits a higher kinetic solubility (up to a few orders of
magnitude) and dissolution rate than that of the crystalline drug (1, 15, 16). The metastable
nature of amorphous solids leads to instability as reflected by precipitation and/or
crystallization. As a result, the level of heat and humidity of storage condition is critical in
preventing the undesirable amorphous-to-crystalline transition. Elevated temperature and
higher moisture level give rise to higher molecular mobility in amorphous solids leading to
the formation of corresponding crystals which are thermodynamically more stable (15, 16).
1.2 Improved local solubility and wettability of poorly soluble drug
The enhancement in solubility and dissolution rate of poorly soluble drugs is also related
to the ability of matrix carrier to improve the local solubility (1, 17, 18) and wettability of
the drug (1, 8, 18). Goldberg et al. (17) reported the effect of hydrophilic carrier urea on the
solubility of chloramphenicol in his experiments where the physical mixture of
chloramphenicol and urea was melted, well mixed and solidified for subsequent solubility
and dissolution rate studies. It was observed that as the urea concentration increased from
0% (w/v) to slightly above 60% (w/v), the solubility of chloramphenicol in the presence of
urea increased by greater than sevenfold. In addition, Verheyen et al. (18) reported the
observed solvent effect of PEG 6000 on the solubility of diazepam and temazepam as they
showed 3.5 fold and 2.5 fold increases in solubility, respectively, in the presence of 15%
(w/w) PEG 6000 at 30°C. Moreover, Verheyen et al. suggested that the mechanism of
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improved solubility and dissolution rate of diazepam and temazepam in PEG 6000 matrix
also involves enhanced wettability of the drug in a polymer-rich microenvironment as the
polymer dissolves.
1.3 Carriers
In addition to the ability of carrier matrix to improve the local solubility and wettability
of the drug, they also contribute to the stabilization of amorphous state of the drug through
specific interactions with the drug (19, 20) and elevating the Tg of the solid dispersion
mixtures (21, 22). Based on FTIR results, Konno and Taylor (19) reported that hydrogen
bonding interactions existed in felodipine solid dispersions with polyvinylpyrrolidone (PVP),
hydroxypropyl methylcellulose acetate succinate (HPMCAS), and hydroxypropyl
methylcellulose (HPMC) where all polymers were able to maintain the amorphous state of
the drug even at low excipient concentrations. Similarly, in Tantishaiyakul et al.’s studies
(20), the intermolecular hydrogen bonding between piroxicam and PVP in their solid
dispersions was also confirmed by FTIR. In addition to forming molecular interactions with
the drug molecule, polymeric carriers have been shown to retard amorphous drug
crystallization by increasing the viscosity and glass transition temperatures (Tg) of the
polymer-drug mixtures. Glass transition temperature is the temperature below which the
amorphous mixture exists in a glassy state where coordinated molecular motion becomes
very slow and restricted (26). It is desirable to elevate the Tg of the solid dispersion mixture
in order to restrict the mobility of drug molecules in the carrier matrix and to prevent
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subsequent recrystallization. In principle, such stability can be maintained by storage at a
temperature well below Tg. The stabilizing effect of polymeric carriers in solid dispersions
has been discussed by Van den Mooter et al. (21) and Yoshioka et al. (22) in their studies
where increasing the content of PVP was shown to increase the Tgs of the solid dispersions
of ketoconazole and indomethacin, respectively.
Owing to the enhanced kinetic solubility of the amorphous form of the drug, it is
possible to generate a supersaturated solution with the drug concentration well above the
solubility of the crystalline drug. Over time, the drug tends to precipitate out to reach much
lower equilibrium solubility. The presence of dissolved carrier may also inhibit the
precipitation of the drug from the supersaturated solution (23, 24). Simonelli et al. (23)
reported the application of dissolved PVP to maintain the supersaturated sulfathiazole
solution. Similarly, Usui et al. (24) demonstrated the inhibitory effect of hydrophilic
polymers such as HPMC, hydroxypropylcellulose (HPC) and PVP on the precipitation of RS
8359 from its supersaturated solutions.
In cases where polymeric carriers fail to generate complete amorphous state of the drug,
they may still be able to improve the solubility and dissolution rate of the drug by forming
metastable crystalline polymorphs of the drug substance which exhibits higher solubility
than that of the crystalline drug alone. For example, Mart´ınez-Oha rriz et al. (25) has
reported that the resulting crystalline polymorphic form of Diflunisal in its solid dispersions
with PEG 4000 is determined by the preparation method, drug loading level and the type of
solvent used. Specifically, the presence of polymorphs 1, 3, and 4 were observed in the solid
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dispersion products.
1.4 Solid dispersions preparation method
Melting method and solvent evaporation method are two most widely used approaches in
preparing solid dispersions and solid solutions. Back in 1961, the melting method was first
employed by Sekiguchi and Obi (9) for the eutectic mixture of sulphathiazole and urea. The
temperature was elevated to above the eutectic temperature and their molten mixture was
solidified in the ice bath followed by the milling process. Later, Chious and Riegelman (8)
modified the cooling process by rapid cooling of molten mixtures on stainless steels.
Another type of modification involving using a spray drier and spraying molten mixtures
onto cold metal surface was invented by Kanig (11). This method was considered
advantageous because the finished products were in the form of pellets and no grinding
process was involved and thus the grinding induced crystallization was avoided. Examples
of other modifications to the melting method include injection molding by Wacker et al. (27)
and liquid melt filled capsules by Walker et al. (28). The method of hot melt extrusion has
been frequently used for solid dispersion preparation in recent years. Being a common
plastics manufacturing method, it was first introduced to pharmaceutical applications by
Speiser (29), El-Egakey et al. (30), and Huttenrach (31). In hot melt extrusion, drug and
carrier polymers are heated to their molten states, mixed and extruded. This preparation
method is advantageous from practical application, cost and the environmental
considerations due to the absence of organic solvents (1). Nevertheless, several drawbacks
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associated with this method can be identified. Firstly, the method requires the miscibility of
drug and polymer in the molten state (32). Immiscibility of drug and polymer could result in
irregular crystallization which leads to only moderate increase in solubility and dissolution
of poorly soluble drugs (32). Secondly, highly elevated temperature is usually necessary to
create the molten state of some common pharmaceutically acceptable carriers (i.e. PVP) and
as a result, the drug substance has to be thermally stable to tolerate high temperature and
avoid degradation (1, 17).
The alternative technology to melting method in preparation of solid dispersion is via the
solvent evaporation method. In this method, solid dispersions are prepared by first dissolving
the drug and carrier polymers in a common solvent followed by fast removal of the solvent
which favors the formation and stabilization of amorphous state of the drug (1). It is an
effective alternative for processing thermally unstable drugs. Moreover, polymers with high
melting points, which would have to be excluded from the hot melt method, can now be
incorporated into the formulation as carriers (1, 32).
Alternative approaches (33) in the manufacture of solid dispersions have been applied
and reported as well and they include: spray coating on sugar beads with a fluidized bed
coating system, electrospinning, and supercritical fluid technology. The technology of spray
coating on sugar beads involves fluidized bed coating system in which drug and carrier, upon
dissolving in a common solvent, are sprayed onto the granular surface of excipients or sugar
spheres. The former results in granules for tableting and the latter produces pellets for
encapsulation with drug dissolved in the coating layer (33). Beten et al. (34) reported the
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application of the fluidized-bed coating method to spray an organic solvent based mixture
containing dipyridamole and enteric polymers Eudragit L 100-55, L, and S onto pellets
consisting of sugar and starch for controlled drug release.
Electrospinning method is a technology that combines solid dispersion with
nanotechnology. The drug-carrier solution is subjected to a sufficiently high voltage. The
liquid droplet becomes charged, and when electrical forces overcome the surface tension of
the liquid at the air interface, the droplet is stretched and fibers with nanometer-scale
diameters are formed. Due to the extremely small fiber diameter, the surface area of the
fibers is maximized for dissolution and absorption. In addition, the resulting fibers exhibit
great flexibility in mechanical strength (33). In the study of Yu et al. (35), electrospinning
was used to form nanosolid dispersions of ibuprofen with PVP K30 to achieve fast-
dissolving drug delivery.
Supercritical fluid (SCF) technology was first introduced to pharmaceutical development
in early 1980. The properties of SCF are intermediate between those of pure liquid and gas.
Carbon dioxide is one of the most frequently used SCF because its low critical temperature
and pressure can be very advantageous to thermally unstable substances. Lee et al. (36)
reported the application of supercritical fluid in aerosol solvent extraction to form
amorphous Itraconazole in its solid dispersion in HPMC 2910 where a 610-fold increase in
kinetic solubility was observed.
Despite the fact that technologies involving a drug-carrier polymer solution such as
solvent evaporation spray coating, electrospinning and supercritical fluid technology have
11
been successfully employed to form solid dispersions, several general limitations have been
identified. For example, the contradictory nature of a hydrophobic poorly soluble drug and a
hydrophilic polymeric carrier can create difficulties in solvent selection thus limiting the
application of the solvent evaporation method due to the lack of a common solvent (32).
Moreover, large volume of organic solvent is usually needed in industrial applications and
the added costs on solvent removal and disposal in addition to special requirements relating
to the environmental and toxicity issues arising from the use of organic solvent.
1.5 Itraconazole
Itraconazole (ITZ) is one of the triazole antifungal drugs (37). Its formula is
C35H38CL2N8O4, with a molecular weight of 705.64 g/mol. It is a cytochrome P450 3A4
isoenzyme inhibitor and works against histoplasmosis, blastomycosis, and onychomycosis
by inhibiting the synthesis of fungal cell membranes. A dose of 100-400 mg/day is usually
administered to patients. Under fed condition, an administration of a single 100-mg dose of
itraconazole demonstrates Cmax, Tmax, AUCinfinition, and t1/2 of 110 ng/ml, 2.8 hours, 1320
ng•h/ml and 15 hours, respectively (38). Itraconazole oral bioavailbility is compromised due
to its extremely low aqueous solubility and poor dissolution rate. Its aqueous solubility is
approximately 1 ng/ml at neutral pH and 4 µg/ml at pH 1. It has a pKa of 3.7 and a log P of
5.66 (39, 40, 41). Itraconazole has a melting endotherm at 167ºC. It also has a low glass
transition temperature of 59ºC (42). Figure 1 shows the chemical structure of itraconazole.
12
Figure 1. Chemical structure of Itraconazole.
Three types of commercial brand ITZ products are available. They include oral Sporanox®
capsules filled with sugar beads coated with HPMC solid dispersion of ITZ which are
protected by a layer of PEG (43), and Sporanox® intravenous injections and oral solutions
containing a solubilizing agent hydroxypropyl beta cyclodextrin (HP-β-CD) (44). It was
found that in oral capsules, both amorphous and crystalline ITZ exist in the HPMC film coat
(43). In other words, it is not present as a pure ITZ-containing solid solution. Instead, finely
divided ITZ particles are also dispersed in the polymer film. Moreover, HP-β-CD, the
solubilizer, may give rise to toxicity issues when the amount of intake exceeds a certain
threshold level.
1.6 Itraconazole solid dispersion
Other than the above mentioned commercial product Sporanox capsules, hot melt
extrusion has been tried in ITZ solid dispersion to stabilize the amorphous ITZ and to
facilitate the dissolution process (45, 46). Alternatively, dissolving ITZ and polymers
together in a suitable solvent followed by rotovapor drying (47), spray drying (48, 49) or
ultra rapid freezing (50) with minimized evaporation time led to the formation of films or
micron sized fine powders. Other reported approaches for preparing ITZ solid dispersions
13
include aerosol solvent extraction using supercritical fluid (36), electrospinning of
nanofibers (51, 52), controlled precipitation (53), and evaporative precipitation (54).
Various types of polymers have been incorporated into ITZ solid dispersions to achieve
different drug release profiles. Examples of hydrophilic polymers employed include
hydroxypropyl methylcellulose (HPMC), aminoalkyl methacrylate copolymer (Eudragit
E100), polyvinylpyrrolidone vinyl acetate (PVPVA), polyvinylpyrrolidone (PVP),
polyethylene glycol (PEG), polyoxyethylene–polyoxypropylene copolymers (Poloxamer),
crosslinked polyacrylic acid (Carbopol), polyvinyl alcohol–polyethylene glycol graft
copolymer (Kollicoat IR),polyvinylacetal diethylaminoacetate (AEA) and sometimes their
mixtures (45, 48, 52, 55, 56, 57 ). Hydrophobic polymers such as ethylcellulose (EC) and
segmented polyurethane (SPU) have also been used as solid dispersion carriers as well. For
example, ITZ solid dispersion in EC (58, 59) using the hot melt extrusion method resulted in
an enhanced surface area when CO2 was used as a plastisizer and foaming agent. Segmental
polyurethane (52), a water insoluble material, was used in ITZ solid dispersion for topical
formulation.
In addition to a large variety of polymers incorporated in ITZ solid dispersions,
solubilizers and various pharmaceutical excipients have also been employed either alone or
in solid dispersion to further enhance the drug solubility. These include the use of solubilizer
HP-ß-CD in the formation of extrudates (60) and glassy thermoplastic system (61),
superdisintegrant such as Primogel, Kollidon CL, and Ac-Di-Sol in forming solid
dispersions for tableting (62), surfactants such as polysorbate 80, Transcutol, Pluronic, and
14
tocopherol acetate and acids including citric acid and oleic acid in forming self-emulsifying
systems (63, 64), and CO2 as a temporary plastisizer and foaming agent in hot melt
extrusion (58, 59).
The solid dispersion approach can improve the solubility and dissolution rate of ITZ.
Intuitively, one may assume this formulation method is for immediate release only as the
majority of the ITZ solid dispersion studies focused on the applications of hydrophilic
polymeric carriers (i.e. HPMC (52), PVP (56), PVPVA (55)) for immediate release of the
drug. However, controlled release drug delivery such as sustained release and pH-dependent
release of ITZ are of great importance as well.
Sustained drug release has its unique benefits because it reduces the frequency of drug
administration thereby allowing for better patient compliance (65). For therapeutic agents
with short half-lives, sustained drug release is desirable because after the administration of
an immediate release dosage form, the blood concentration peaks rapidly potentially causing
side effects. In addition, immediate drug release leads to inadequate time course of drug
concentration within the therapeutic window (66). Moreover, it has been shown that a
sustained drug delivery can prolong the duration of supersaturation of the drug which leads
to an enhancement in drug absorption (57). Miller et al. (57) reported the incorporation of
Carbopol in ITZ solid dispersion with Eudragit L100-55 to prolong the supersaturation
duration of ITZ and to provide targeted intestinal delivery. It was found that in neutral
medium, supersaturation of ITZ with sole Eudragit L100-55 carrier was transient. The rapid
elimination of drug led to a dramatic drop in drug concentration to an unquantifiable level
15
within one hour. However, the addition of 20% Carbopol extended the duration of ITZ
release and supersaturation to two hours, with 8000 and 1600 fold of ITZ supersaturation
detected at one and two hours, respectively.
Enteric coating materials such as hydroxypropylmethyl cellulose phthalate (HP-55) and
Eudragit L100 (50) were used in ITZ release systems to target drug delivery and absorption
within a specific region of the GI tract. Miller et al. (57) confirmed the hypothesis that only
small intestine targeted delivery of supersaturated ITZ can generate adequate drug
absorption. It is believed that only minimal absorption is attained when ITZ dissolution
primarily occurs in gastric environment. Owing to lower solubility of ITZ at the neutral pH,
as dissolved ITZ particles travel through the GI tract and reach small intestine, the elevated
pH could potentially trigger precipitation of ITZ thus reducing the ITZ absorption and
bioavailibility. In addition, due to the lack of thermodynamic stability, supersaturation of
ITZ is a transient process, as dissolved ITZ gradually precipitates out until the low
equilibrium solubility is again reached. As a result, it is important to enhance the ITZ
dissolution in small intestine to prevent undesirable premature amorphous-to-crystalline
transition and generate enhanced kinetic solubility to boost the driving force for absorption
such that the time course of exposure of dissolved ITZ to the large area of intestinal surface
can be maximized (50, 57).
16
1.7 Polymeric Carriers for the present study
Five polymeric materials are investigated as carriers in the current project of ITZ solid
dispersion to study the properties of solid dispersion and subsequent dissolution behaviors.
Polyvinylpyrrolidone (PVP; trade name: Plasdone K90) and crospovidone (trade name:
Polyplasdone XL-10), a cross-linked PVP, are employed to deliver the immediate release of
ITZ. A water insoluble material ethylcellulose (EC; trade name: Ethocel-std 7) is
incorporated into the ITZ-PVP solid dispersion to impart a sustaining effect on the drug
release. Moreover, an enteric coating material hydroxypropyl methylcellulose acetate
succinate (HPCMAS; trade name: Shin-Etsu Aqoat AS-LG) is also studied to provide
targeted intestinal release of ITZ from the solid dispersion, and high molecular weight
polyethylene oxide (PEO: trade name: Polyox WSR coagulant) is incorporated into the ITZ-
HPMCAS solid dispersion to extend the drug release duration of ITZ from HPMCAS.
Crospovidone and HPMCAS have not been studied as solid dispersion carriers for ITZ, and
studies on PVP, EC and PEO by the polymer blend approach as solid dispersion carriers for
ITZ are clearly lacking as well.
Physicochemical properties including molecular weight, melting temperature (Tm), glass
transition temperature (Tg) and aqueous solubility of the five polymer carriers used in the
current project are listed in Table Ι.
17
Table I Physicochemical properties of the five polymer carriers.
Polymer/
properties
Molecular
weight
Tm (oC) Tg (
oC) Aqueous
solubility
reference
PVP-K90 1,300,000 / ~174 soluble (1)(67)
Crospovidone
(XL10)
>1,000,000 / 190-195 Insoluble,
swellable
(68, 69)
EC- std 7 6-8 cp* 165-173 129-133 insoluble (70)
HPMCAS-LG 18000 / 115 Soluble in pH ≥
5.5
(71)
PEO coagulant 5,000,000 68 -52 soluble (72, 73)
* Solution viscosity (cP) of 5% EC solution at 25oC
1.7.1 PVP
PVP is a water-soluble pharmaceutically acceptable polymer. Due to its ability to
improve solubility and wettability of poorly soluble drugs, it is frequently used in solid
dispersions to enhance solubility and dissolution rate (1, 67). Due to its hydrophilicity and
rapid dissolution in an aqueous medium, PVP is very frequently applied as a carrier in
immediate release dosage forms (1). In addition to its applicability in delivering immediate
release of drug from solid dispersion of poorly soluble drugs in the pharmaceutical industry,
PVP is also employed widely as wet granulation binder, solubility and bioavailability
enhancement agent, viscosity modifier, crystal inhibitor, stabilizer and film former (67).
Figure 2 shows the chemical structure of PVP.
18
Figure 2. Chemical structure of PVP.
High molecular weight grade PVP K90 dissolves in a large variety of organic solvents. A
highly elevated temperature is needed to create its molten state which makes it unsuitable for
hot melt extrusion and limits its utility to primarily the solvent evaporation method. PVP has
a high Tg of ~174 oC making it particularly suitable for the stabilization of amorphous drug
in solid dispersions as the Tg of the drug-carrier mixtures will be increased with increasing
amounts of PVP. PVP has a long history of use in human drug products and high molecular
weight PVPs generally do not get absorbed in the GI tract. In general, low molecular weight
PVPs have been extensively studied as carriers in solid dispersions and this is attributed to
their higher aqueous solubility, lower viscosity in the diffusion boundary layer, and faster
dissolution rate (67). For example, solid dispersions of indomethacin from co-precipitation
and spray drying processes showed faster release from PVP with low molecular weight (PVP
K17) than those with high molecular weight (PVP K90) (74). However, due to its
hydrophilicity, its moisture uptake level is high (67) which may result in difficulties in its
physical stability leading to drug crystallization in the carrier polymer caused by the
plastisizing effect of absorbed water.
19
1.7.2 Crospovidone
Crospovidone is crosslinked PVP and therefore is insoluble in water and all other
solvents. It is commonly used as a superdisintegrant in granulations and direct compression.
It imparts good compressibility and disintegration to tablet formation. The general chemical
structure of crospovidone is the same as Figure 2.
As a superdisintegrant, upon hydration, it undergoes fast swelling and wicking which are
its primary mechanisms of action (68). It can also be used as a drug carrier to deliver
hydrophobic drugs. For example, Shin et al. (75) performed dissolution studies of
Furosemide in crospovidone through cogrinding and coprecipitation. Amorphous
Furosemide was detected in both ground mixture and coprecipitate which led to a
corresponding dissolution rate appreciably higher than that of the drug alone. However,
whether the amorphous Furosemide really is entrapped in the crospovidone network or
simply resides on the crospovidone particle surface as a result of the cogrinding process
remains unclear. As a result, further applications of crospovidone in such cogrinding and
coprecipitation process to enhance solubility and dissolution rate would be very limited.
1.7.3 Ethyl cellulose (EC)
Cellulose derivatives are safe naturally occurring polysaccharides consisting of long
chain polymers of β-anhydroglucose units. Ethyl cellulose is one of the pharmaceutically
acceptable water-insoluble cellulose derivatives. Ethyl cellulose has long been employed in
20
controlled release delivery systems in film formation and bead coating. Figure 3
demonstrates the chemical structure of EC.
Figure 3. Chemical structure of EC.
Due to its hydrophilicity, EC, when combined with water-soluble polymers (i.e. methyl
cellulose) in a blend, can effectively regulate the rate of drug diffusion through the film
coating (70). Dissolution behavior of the drug can be modified by varying the weight portion
of EC as increasing its concentration in the film coat can be rate-limiting. An increase in EC
concentration results in subsequent decrease in dissolution rate. EC has also been
incorporated in formulations as granulation binder and film-former to improve appearance,
strength, integrity, and good dissolution property of tablets (70). In addition, it has been
applied to taste masking of active pharmaceutical ingredients. EC is soluble in many organic
solvents and it has excellent thermal plasticity. EC has been incorporated in solid dispersions
(76, 77) and in controlled release forms. Its common methods of preparation include the
solvent method, hot melt extrusion, and spray-drying (70). For example, Huang et al. (76)
reported the application of hydrophobic EC and hydrophilic Eudragit RL 100 in solid
molecular dispersion of Nifedipine by the co-precipitation method to achieve sustained drug
21
delivery. As expected, it was found that an increasing amount of EC in the binary
composition led to a decrease in drug release rate.
1.7.4 Hydroxypropyl methyl cellulose acetate succinate (HPMCAS)
Granular HPMCAS-LG consists of 8% acetyl group and 15% succinoyl group. Figure 4
demonstrates the chemical structure of HPMCAS.
Figure 4. Chemical structure of HPMCAS.
HPMCAS is soluble in various organic solvents including acetone and methanol. It is
soluble in aqueous media when pH exceeds 5.5 (71). Advantages of HPMCAS solid
dispersions are several fold: it becomes soluble in pH ≥ 5.5 initiating the metastable
supersaturation of drug upon reaching GI absorptive region; it has a relatively low moisture
uptake level compared to water-soluble polymers making it an excellent carrier for physical
stability; when charged, the ionized portion prevents large polymer aggregation; lastly, the
hydrophobic methoxy substituents allow for specific interactions with insoluble drug
22
substances while the hydrophilic succinate group stabilizes the insoluble drug in solution (71,
78). Examples of application of HPMCAS in enhancing the solubility of poorly soluble
drugs include amorphous solid dispersions of a VR1 Antagonist and Piroxicam (79, 80).
1.7.5 Poly ethylene oxide (PEO)
PEO is a free-flowing water soluble polymer of ethylene oxide which is widely used as
excipients in human drug products. It has been successfully employed as matrix tablets in
controlled release solid dosage forms. Figure 5 shows the chemical structure of PEO.
Figure 5. Chemical structure of PEO.
PEO with molecular weights of greater than 4,000,000 exhibits strong mucoadhesive
properties, along with its hydrophilicity, hydrogen bonding functionality, and
biocompatibility (72). As the process of hydration of the dry PEO proceeds, an increase in
the mobility of the polymer chains occurs resulting in a greater hydrodynamic volume which
leads to the swelling of the polymer. As swelling progresses, PEO starts to disentangle as
more aqueous solution is imbibed in the swelling process and gel becomes more diluted. The
disentanglement of the polymer results in the dissolution and erosion of PEO (81). When
hydrated, PEO tablet undergoes a swelling process followed by the formation of a gel layer
at the surface. In general, a greater swelling capacity is associated with PEO with higher
23
molecular weight whose corresponding gel strength is enhanced resulting in a decrease in
drug diffusion. The drug release mechanism from PEO is known to be diffusion-erosion
controlled (72). A reduction in drug release rate can be achieved by increasing the amount
of PEO or replacing the current grade with one of a higher molecular weight. For example, a
shift from 10% Polyox WSR 303 to 20% Polyox WSR 303 (72) showed a decrease in
release rate of caffeine with an extended duration prior to reaching the same level of drug
eluted. Another study of caffeine release by Cruz et al. (82) also demonstrated the sustaining
effect of PEO in drug delivery.
24
1.8 Unexplored areas
To date, Itraconazole solid solution prepared by the solvent evaporation method has
not been well characterized. In particular, only limited information exists for determining the
threshold drug loading level above which crystallization occurs in the solid solution. This is
due in part to the fact that the methods typically employed for such determination (e.g. DSC
or XRD) have limited sensitivity of detection for the crystalline content. Also, only limited
stability studies of finished products have been reported. Moreover, the applicability of
commercially available crosslinked polymers to form solid solutions of itraconazole has not
been explored. In addition, the polymer blend approach has not been explored for
itraconazole to provide drug release profiles not achievable by a single polymer carrier.
Ordinarily, the solid dispersion approach is employed to achieve drug delivery in an
immediate-release fashion. However, poorly soluble drugs with short half lives also require
release-rate modulation to enhance release duration and minimize side effects. Available
studies relating to the aspect of controlled release from solid dispersions have been very
limited. The importance of using enteric polymers to target intestinal absorption of
itraconazole and for incorporating rate-controlling agents to prolong the supersaturation for
better bioavailability has been suggested (57). However, this aspect has not been sufficiently
pursued.
25
2. Hypothesis and research objectives
The loading capacity and stabilization of the amorphous Itraconazole in solid solutions
are influenced by parameters including drug to polymer ratio, glass transition temperature of
polymer, and interactions between the polymer and the drug. Immediate release of
Itraconazole can be delivered from solid solutions with water soluble carriers and cross-
linked hydrophilic polymers. Whereas controlled release Itraconazole formulation can be
achieved from solid solutions based on the polymer blend approach using water insoluble
carrier and enteric coating material.
The objectives of this project are:
(1) To evaluate selected polymeric carriers not previously studied for their suitability to form
solid solutions with ITZ and to examine the applicability of a commercially available
cross-linked hydrophilic polymer crospovidone, in preparing solid solution by the
equilibrium solvent loading method for immediate release applications.
(2) To identify polymeric carriers that can be used to generate sustained release using a
polymer blend approach to control the drug release as well as to target the release under
intestinal pH conditions.
(3) To determine the threshold drug loading level above which the crystallization of
amorphous Itraconazole occurs in the solid solution.
(4) To investigate the effect of polymer carriers on the retardation of drug crystallization.
(5) To better understand the mechanism of drug release from solid dispersions.
26
3. Experimental design and methodology
As mentioned earlier, hydrophilic polymers PVP, crospovidone and PEO, hydrophobic
polymer EC and enteric polymer HPMCAS are employed as carrier materials for ITZ solid
dispersion in the current project. In order to determine the threshold ITZ loading level in the
carriers, visualization, polarizing microscopy, differential scanning calorimetry (DSC), and
X-ray diffractometry (XRD) are used to detect the presence of crystalline ITZ. Polymer-drug
interactions are studied using Fourier transform infrared (FTIR) and the ability of polymer to
increase the Tgs of the ITZ solid dispersion mixtures is identified by DSC. ITZ is loaded into
crosslinked crospovidone by the equilibrium solvent loading method and the properties of
ITZ-crospovidone solid dispersion are investigated. Lastly, dissolution studies are conducted
for PVP, crospovidone, HPMCAS and polymer mixtures of PVP-EC and HPMCAS-PEO to
deliver sustained release of ITZ using the polymer blend approach.
3.1 Materials
Itraconazole was kindly provided by Neuland Laboratories (Hyderabad, India) and
Albemarle Corporation (South Haven, USA). The solvents dichoromethane (≧99.9%,
HPLC grade) and Methanol (≧99.8%, A.C.S. reagent) were purchased from Sigma-Aldrich.
Plasdone K-90 (Povidone USP K90) and Polyplasdone (crospovidone XL 10) were donated
by ISP Technologies. Ethocel (standard 7 ethylcellulose NF premium) and Sentry Polyox
(poly (ethylene oxide), WSR Coagulant) were donated by the Dow Chemical Company.
Hypromellose Acetate Succinate-LG granules were kindly provided by Shin-Etsu. Sodium
27
Lauryl sulfate (SLS) / sodium dodecyl sulfate (SDS) NF/FCC was purchased from Fisher
Scientific. All solids were dried prior to use.
3.2 Preparation of solid dispersion in films
Drug loaded films of various weight percentages were prepared using the solvent
evaporation method. PVP and PVP blends with EC were co-dissolved with ITZ in
dichloromethane, and HPMCAS and its blends with PEO were co-dissolved with ITZ in a
mixture of methanol and dichloromethane (1:1). Films of thickness between 0.7 to 0.9 mm
were prepared in Teflon dishes and air-dried for 3 days followed by drying under the vacuum
for 24 hours. Thinner films of 0.05 mm and 0.062 mm were prepared for the PVP-EC and
HPMCAS-PEO blends to examine the polymer compatibility. Films containing an
equivalence of approximately 1.5-8.5 mg of ITZ were made for dissolution studies.
3.3 Preparation of solid dispersion with crospovidone
(a) Equilibrium solvent swelling:
Crospovidone powders (10% w/v) were continuously mixed in the swelling medium of
dichloromethane in capped vials on a laboratory rotor for 9 days. Portions of the swollen
powders were collected, filtered, weighed and dried on a daily basis. The wet and dry
weights of the powder were recorded and swelling ratio (q) and equilibrium solvent content
(ESC) values were calculated by the following equations.
28
Wsq
Wd
(2)
Equation 2 Mass degree of swelling
(%) 100 ( )Ws Wd
ESCWs
(3)
Equation 3 Equilibrium solvent content
Where Ws is the swollen powder weight and Wd is the dry powder weight.
(b) Equilibrium drug loading method
Crospovidone powders (10% w/v) were continuously mixed in capped vials with ITZ
solutions in dichloromethane for 5 days at six different ITZ concentrations: 2%, 4%, 6%, 8%,
10% and 12% (w/w). Dichloromethane is also a swelling solvent for crospovidone.
Afterwards, the powders were filtered, dried, and milled in dry ice with a pestle and mortar.
The fine powders were dried at 50oC for another 24 hours until constant weights were
achieved. Fine powders which passed through a 60-mesh sieve (< 250µm) were then
collected for subsequent tests.
(c) Loading level determination
The drug loading capacity was determined by the total ITZ release from a known amount
of ITZ-loaded crospovidone powders. The ITZ concentration was then measured by Cary 50
UV-VIS spectrophotometer (Varian, Ontario, Canada) at 260nm wavelength.
29
3.4 Characterization of solid dispersion samples
3.4.1 Polarized light microscope
Polarized light microscope has been used to examine the nucleation and crystal
growth kinetics (19). However, it has not previously been employed in determining the
threshold drug loading level in a solid solution above which crystallization occurs. In this
study, we show that polarized light microscope is more sensitive than DSC or XRD in
detecting the onset of conversion from the amorphous to crystalline drug in solid solutions.
Typically, samples were examined under the polarized light microscope (Motic BA 400,
Opti-tech Scientific, objective lenses: 4Χ/0.10, 20Χ/0.40, and 40Χ/0.65, eyepiece: 10Χ/22)
and images were taken using Moticam 2000 digital camera and analyzed by the Motic
Images Plus 2.0 software.
3.4.2 Stereomicroscope
Films were examined under a stereomicroscope (Motic, Opti-tech Scientific, objective
lenses: 3X, eyepiece: 10X) and pictures were obtained using Moticam 2000 digital camera
and analyzed by the Motic Images Plus 2.0 software.
3.4.3Thermal analysis (Differential scanning calorimetry)
DSC is a frequently used thermoanalytical technique that generates data on melting
endotherms and glass transitions (45, 46, 47, 48). Thermal analysis of samples was carried
out on a TA instrument Q100 differential scanning calorimetry (DSC) (TA Instruments,
30
Delaware, USA). Samples (5-10 mg) were weighed into aluminum pans and hermetically
sealed. Samples were heated to ~200oC at a rate of 10
oC/min (first heating run) and quench
cooled to -40oC at a rate of 40
oC/min followed by slow heating to 200
oC at a rate of 2
oC/min
(second heating run). The first heating run was carried out to detect any presence of melting
endotherm of ITZ while the second heating run was performed to locate the Tg of the ITZ
solid dispersion. Tg values were determined by calculating the temperature of the half step
height at the transition point during the second heating.
3.4.4 X-Ray Diffractometry (XRD) (services provided by the Chemistry Department on a fee
per service basis)
(a) D8 diffractometer (microdiffraction system)
X-Ray diffractometry is a powerful tool in detecting crystallinity (45, 48, 49). The
samples were run on Bruker AXS D8 Discovery Microdiffraction system with Cu k point-
focus x-ray source operating at 40 kV/40 mA. Data were collected in the reflection mode
with the beam spot (0.3 mm) focused on the selected spots on the polymer films. The 2-theta
range was covered.
(b) D5000 diffractometer
Film samples were placed onto a low background Silicon sample holder and run on an
automated Siemens/Brukker AXS D5000 diffractomter. The diffraction patterns were
collected on a theta/2-theta Bragg-Brentano reflection geometry. Data acquisition with step
size of 0.02o 2-theta and single counting time of 2.5 s was obtained. A Bruker AXS data
processing software Eva v.8.0 was used to analyze data.
31
3.4.5 Polymer drug interaction in film
FTIR spectra can be used to detect polymer-drug interactions by following the shift in
vibrational or stretching bands of key functional groups. This method has been employed to
identify polymer-drug interactions in solid molecular dispersions (19, 20). Polymer drug
interactions in films were detected from the FTIR spectra obtained on a universal Attenuated
Total Reflectance Spectrum-one Perkin-Elmer spectrophotometer (Perkin-Elmer,
Connecticut, USA). For powder samples, Perkin-Elmer Spectrum BX was used with a KBr
disk method. The spectra were recorded from 4000 to 650 cm-1
. All spectra were collected as
an average of 16 scans at a resolution of 2 cm-1
.
3.5 Dissolution testing
The rotating-disk apparatus consists of a USP dissolution vessel maintained at constant
temperature, a rotating shaft mounted with a small paddle to generate sufficient mixing, and
a removable sample holder. Small circular (1.9cm in diameter) ITZ-loaded polymer films
were placed in the sample holder designed with beveled edges to prevent the stagnant zone
between the holder and the sample surface during rotation. A thin plastic spacer was placed
in between the film and the surface of the stirring shaft to prevent sample sticking and drug
leakage. Dissolution testing of ITZ solid dispersions in PVP and PVP-EC blend was
performed on an ERWEKA DT600 dissolution apparatus (ERWEKA, Ontario, Canada)
using 1000ml of 0.1N HCL (pH1.2) at various rotating speeds. Dissolution studies of enteric
polymer HPMCAS and its blend with PEO employed an acidic-to-neutral method. Drug
32
loaded polymer films were exposed to 900ml of 0.1N HCL (pH 1.2), and after 1.5h, 85ml of
0.4M tribasic sodium phosphate (Na3PO4) was added to the dissolution medium to elevate
the pH to 6.8. Dissolution performance of ITZ-loaded crospovidone powders was conducted
in a vessel with 500 ml of 0.1N HCL with the paddle speed of 100 rpm. Dissolution medium
was maintained at 37±0.5oC in all cases. Data were collected in studies in the absence and
presence of 0.3% sodium lauryl sulfate (a.k.a. sodium dodecyl sulfate) (SLS/SDS). SDS is
an amphiphilic surface active agent used to improve aqueous solubility and wettability of
insoluble drug substances to ensure achievement of sink condition in the dissolution
experiment. Upon incorporation of SDS in the dissolution medium, both the amount of drug
release and dissolution rate can be further improved compared to that with formulations of
polymer carriers alone because the enhanced drug solubility generates greater driving force
for drug release while maintaining a near sink condition in the dissolution medium (1). 5ml
aliquots were removed at predetermined time intervals and filtered (0.2µm) before tested on
a Cary 50 UV-VIS spectrophotometer (Varian, Ontario, Canada) for UV absorbance. 5 ml of
fresh dissolution medium was added to the vessel to replace the sample aliquot and to
maintain a constant volume of dissolution medium. Triplicate runs were carried out and the
results were averaged. Figure 6 shows the dissolution rate testing setup and the dimension of
the rotating disk.
33
Figure 6. (A) Disk intrinsic dissolution rate testing setup (B) film holder.
3.6 Stability
A constant relative humidity (RH) level of 64% was generated from a saturated sodium
nitrite solution placed in a sealed desiccator. The equilibrium RH level of 64% was
confirmed by a VWR traceable radio-signal remote hydrometer (VWR International, Ontario,
Canada). This relative humidity was used for stability testing at a constant temperature of 22
ºC for a maximum period of 6 months. Changes in the physical state of these samples were
monitored at predetermined time intervals using physical observation, polarizing microscope,
DSC and X-ray diffractometer.
34
4.Results an discussion
4.1 Polymer compatibility
Polymer compatibility of EC-PVP blends and HPMCAS-PEO blends were examined
using polarizing microscope, stereomicroscope and X-ray diffractometer.
4.1.1 Compatibility of PVP-EC blends
Polarizing microscopic images are used to examine the compatibility of EC with PVP in
EC-PVP blends. Polymer compatibility generates a single homogenous miscible phase
whereas incompatibility leads to a separation into two immiscible phases. As shown in
Figure 7, for film samples of 0.05 mm thickness, EC-PVP incompatibility starts to occur at
very low EC level of 10% (w/w). Orange peel-like separation of EC domain from that of
PVP becomes more obvious as the amount of EC increases. In order to ensure sufficient
sustaining effect in the controlled release of ITZ, an EC level higher than 10% would be
appropriate. Since, on average, 30% (w/w) EC is used in industrial polymer matrix and
coating systems (70), a 30% EC: 70% PVP ratio was used in all subsequent experiments.
35
Figure 7.Polarizing microscopic pictures of PVP with various amounts of EC.
4.1.2 Compatibility of HPMCAS-PEO blends
HPMCAS and PEO polymer compatibility is determined using both polarizing
microscope and X-ray diffractometer. Polarizing microscopic images (Figure 8A) indicate
that rod shaped crystals exist in the HPMCAS film while spherulites exist in the PEO film. It
is observed that PEO starts to separate from the HPMCAS polymer base and exhibits
36
spherulite morphology once the PEO concentration exceeds 15%-20% (w/w). Separations of
PEO from HPMCAS become more pronounced as the PEO concentration increases. Figure
8B shows the polarized image of a HPMCAS-PEO (80%:20%) blend where both rod shaped
crystals from HPMCAS and spherulites from PEO are present indicating the polymer
incompatibility. X-ray diffractometer results fail to detect any immiscibility between the
polymers with PEO concentration of up to 30% (w/w) (Figure 8C). As a result, the method
of polarizing microscopy was considered more sensitive for polymer immiscibility detection.
Again, in order to better evaluate the sustaining effect of PEO in the controlled release of
ITZ from HPMCAS, a 70%HPMCAS: 30%PEO ratio of HPMCAS-PEO blend was used in
all subsequent experiments.
37
Figure 8. (A) Polarizing microscopic images of HPMCAS-PEO polymer blend with
various PEO concentrations (B) Polarizing microscopic images of HPMCAS-PEO
(80%:20%) blend and (C) XRD patterns of HPMCAS-PEO polymer blend with various PEO
concentrations.
38
4.2 Crospovidone loading level determination
4.2.1 Equilibrium swelling duration and ITZ loading concentration
The time for crospovidone to reach equilibrium swelling in dichloromethane is
determined to be around five days with the maximum swelling ratio of 3.86 and the
corresponding equilibrium solvent content value of 74.08% (Table II). Six ITZ loading
solution concentrations (% (w/w)) in dichloromethane of 2%, 4%, 6%, 8%, 10%, and 12%
result in corresponding ITZ loading levels of 5%, 10%, 16%, 19%, 23%, and 26%,
respectively in crospovidone powders (Table III). Plotting the resulting ITZ loading levels
versus the loading solution concentrations permits the evaluation of the partition coefficient
from the slope of the linear plot (Figure 9). The resulting partition coefficient of 2.17 reflects
the greater tendency of ITZ to partition from the solvent dichloromethane into the
crospovidone networks. The swelling of the crospovidone powders in ITZ-containing
solvent suggests the entrapping of the ITZ in the crospovidone network rather than simply
residing on the crospovidone particle surface.
39
Table IV Swelling ratios (w/w) and equilibrium solvent contents (%) of crospovidone
powders in dichloromethane at day 3, day 5 and day 9.
swelling ratio
(w/w)
equilibrium solvent content
(ESC) (%)
day 3 3.78 73.56
day 5 3.86 74.08
day 9 3.82 73.77
Table V ITZ concentrations in loading solutions and resulting ITZ loading levels in
crospovidone powders.
ITZ concentration (%(w/w))
In loading solution
ITZ loading level (%(w/w))
in crospovidone powders
1 2 5
2 4 10
3 6 16
4 8 19
5 10 23
6 12 26
Figure 9. The partition coefficient of ITZ from loading solution into crospovidone
powders.
40
4.3 Characteristics of ITZ solid dispersions in polymeric carriers
4.3.1 Physical observation
As shown in Figure 10A, film samples of ITZ solid dispersions in PVP at 0%, 10% and
20% drug loading appear to be transparent, whereas films with ITZ loading above 30%
appear translucent or opaque indicating the presence of precipitated Itraconazole. The area
containing precipitated ITZ expands as the drug loading increases. On the other hand, in ITZ
solid dispersions prepared in HPMCAS (Figure 10B) and HPMCAS-PEO blends (Figure
10C), precipitations of ITZ are observed in samples with drug loading of ≥10%. These
precipitated regions are later confirmed to be crystalline by the method of polarizing
microscopy (Figure 11) and X-ray Diffractometry (Figure 14). Physical observation is not
feasible for crystallized ITZ detection in ITZ solid dispersions in PVP-EC blends and
crospovidone powders because PVP-EC polymer blends and crospovidone powders are
opaque and white themselves, respectively, and any additional opacity/precipitation from
crystallized drug is difficult to be detected.
41
Figure 10. Solid dispersions of ITZ with various drug loadings in (A) PVP (B)
HPMCAS and (C) HPMCAS-PEO (70%:30%).
42
4.3.2 Polarizing Microscopy
The presence of crystallized ITZ in solid dispersions of PVP, PVP-EC blends, HPMCAS
and HPMCAS-PEO blends has been confirmed using the polarizing microscope. As shown
in Figure 11, aggregates of crystalline drug (bright halo or dots under polarized light) appear
in films of above 20% drug loadings in both PVP (Figure 11A) and PVP-EC samples (Figure
11B) where more aggregates are present in films with higher drug loadings. As a result, the
threshold drug loading levels of ITZ solid dispersions in PVP and PVP-EC blends above
which crystallization may occur can be determined to be around 20% (w/w). Similarly,
crystalline drugs are observed in films of above 5% drug loading in both HPMCAS (Figure
11C) and HPMCAS-PEO samples (Figure 11D) and therefore, the threshold drug loading
levels of ITZ solid dispersions in both HPMCAS and HPMCAS-PEO blends above which
crystallization may occur can be determined to be around 5% (w/w). Lastly, the method of
polarizing microscopy is not feasible for crospovidone powders due to the lack of
transparency of the powders.
44
Figure 11. Polarized images of films with various ITZ loadings in (A) PVP (B) PVP-EC
(70%:30%) (C) HPMCAS and (D) HPMCAS-PEO (70%:30%).
45
4.3.3 DSC results
4.3.3.1 Detection of melting endotherms in ITZ solid dispersions
Results from DSC analysis of ITZ solid dispersions with all polymer carriers are shown
in Figure 12, where pure ITZ exhibits a melting endotherm at ~171.21oC. Observation of
melting endotherm is associated with the occurrence of crystalline ITZ while the absence of
melting peak is due to the presence of pure amorphous drug. The lowest ITZ loading levels
where melting peaks are detected by DSC are 50% in PVP, 23% in crospovidone and 25% in
HPMCAS. However, locations of the observed melting peaks are found to be slightly lower
than 171.21 oC. This may be attributed to the formation of an Itraconazole polymorph (83).
DSC fails to detect any crystallinity in ITZ solid dispersions in PVP-EC and HPMCAS-PEO
blends probably due to its relatively lower sensitivity (1) than the polarizing microscope. The
melting peaks around 59.73 oC associated with the melting temperature of crystalline PEO in
HPMCAS-PEO blends indicates only partial compatibility of PEO in HPMCAS at a weight
ratio of 30%:70% (Figure 12 (5)) which is consistent with results reported in Section 4.1.2
(Figure 8A).
46
Figure 12. DSC analysis in detection of melting peaks in films with different ITZ loading
levels in (1) PVP (2) crospovidone (3) PVP-EC (70%:30%) (4) HPMCAS and (5)
HPMCAS-PEO (70%:30%).
47
4.3.3.2 Stabilizing effect of polymers on amorphous ITZ
It takes two heating runs to generate DSC data on the glass transition temperatures of
ITZ solid dispersions. The first heating run with a relatively faster heating rate of 10 oC /min
to above the melting temperature (~171.21oC ) of ITZ is conducted to create the molten state
of the drug. This is followed by quench cooling the sample at a rate of 40 oC /min to -40
oC
to generate the amorphous state of ITZ. The second heating run has a relatively slower
heating rate of 2 oC /min to above the Tg of the polymers (PVP: ~172.01
oC, crospovidone:
~178.68 o
C, PVP-EC: ~163.44 o
C, and HPMCAS: ~115.33 o
C) to capture the Tg(s) of the
ITZ solid dispersions. As shown in Figure 13, in the second heat run, no drug was
crystallized out due to the absence of melting endotherm. In all cases, the incorporated
polymers have successfully increased the Tg(s) of ITZ solid dispersions from that of the pure
drug (~56.01 oC) resulting in more restricted molecular mobility of ITZ which contributes to
its physical stability (1). However, in ITZ solid dispersions with HPMCAS-PEO blends, the
locations of Tg(s) become difficult to identify most likely due to the interference from the
extremely low glass transition temperature of PEO (~ -52 o
C), and the transitions become
less pronounced with increasing amount of drug loading (Figure 13 (5)).
48
Figure 13. Tg patterns of ITZ solid dispersions in (1) PVP (2) crospovidone (3) PVP-EC
(70%:30%) (4) HPMCAS and (5) HPMCAS-PEO (70%:30%).
49
4.3.4 X-ray results in detection of crystalline ITZ peaks
X-ray diffractometry provides useful information about the physical state of ITZ in its
solid dispersions in polymer carriers. As shown in Figure 14, the sharp peaks observed in the
XRD pattern of the pure ITZ are characteristics of its crystalline form. On the other hand,
pure carrier polymers exhibit characteristic broad amorphous halos. Similar amorphous halos
are seen in all carriers at low ITZ loading concentrations. As the amount of ITZ increases
and exceeds a threshold level, crystalline peaks start to appear indicating the occurrence of
an amorphous-to-crystalline transition. Detectable ITZ crystallinity appears at 30%, 19%,
10% and 15% for PVP, crospovidone, HPMCAS and HPMCAS-PEO blends, respectively.
However, ITZ loadings of up to 50% in PVP-EC are found to be amorphous by XRD results
alone.
Upon examining the effectiveness of various techniques in detecting ITZ crystallinity in
its solid dispersions, it is believed that microscopy has a higher sensitivity than XRD which
is followed by DSC. For each polymer type, the lowest drug concentration with detectable
crystallinity by the best detection method is identified to be the ITZ threshold drug loading
level above which crystallization will occur. As a result, the ITZ threshold drug loading
levels of PVP, crospovidone, PVP-EC, HPMCAS and HPMCAS-PEO are determined to be
20%, 16%, 20%, 5% and 5%, respectively.
50
Figure 14. XRD patterns of (1) PVP (2) crospovidone (3) PVP-EC (70%:30%) (4)
HPMCAS and (5) HPMCAS-PEO (70%:30%).
51
4.4 Polymer-drug interaction
FTIR spectroscopy has been frequently used to detect the effect of hydrogen bonding
and other intermolecular interactions in solid dispersions. The IR stretching patterns of free
or hydrogen-bonded functional groups can be easily distinguished and used to identify the
existence of such interactions. For example, the IR spectrum of PVP displays a distinctive
band at 1651 cm-1
which can be attributed to the vibration of amide peak from a
combination of two functional groups of C=O (1750-1700 cm-1
) and C-N (84). As shown in
Figure 15, an upward shift in the amide band from 1651 cm-1
occurs with increasing
concentration of ITZ in the PVP solid dispersion, and it is shifted to 1668cm-1
at 40% ITZ.
Also, an upward shift of the C-H stretching band (75) from 2919 cm-1
is seen with increasing
concentration of ITZ solid dispersion in crospovidone, reaching 2961 cm-1
at 23% ITZ
loading. On the other hand, in ITZ solid dispersions in PVP-EC blend, 50% incorporated
ITZ content failed to generate band shift in any functional group of either PVP or EC
indicating the absence of potential drug-polymer interactions. Despite the observed
interaction between ITZ and PVP, polymer-drug interaction is absent in the PVP-EC blend.
The exact mechanism is unclear. However, it is possible that this could be due to the fact that
polymer incompatibility occurs in PVP-EC (70%:30%) blend forming EC aggregates. The
hydrophobic nature of ITZ leads to most of its distribution in the hydrophobic EC phase
therefore minimizing its interaction with PVP. In this case, no apparent interaction exists
between ITZ and EC. In ITZ solid dispersions in both HPMCAS and HPMCAS-PEO
(70%:30%), a peak around 3349 cm-1
becomes more distinctive with increasing ITZ loading.
52
The peak can be attributed to the ITZ’s triazole group originally located at 3381 cm-1
(85)
whose band position is shifted to 3349cm-1
when incorporated into these polymers. All of the
abovementioned shifts are indications of potential drug-polymer interactions which are
known to be important to the stability of the amorphous solid dispersions.
Figure 15. FTIR spectra of ITZ solid dispersions in (1) PVP (2) crospovidone (3) PVP-
EC (70%:30%) (4) HPMCAS and (5) HPMCAS-PEO (70%:30%).
53
4.5 Dissolution
4.5.1 Intrinsic dissolution rate of ITZ from PVP film
A rotating disk intrinsic dissolution rate (RDIDR) method as described in Section 3.5
was used to generate the drug dissolution data from a given film sample of the solid
dispersion being studied, where the total exposed surface area, temperature, agitation-stirring
speed, pH, and ionic strength of the dissolution medium are kept constant. The levich’s
rotating disk method was used because it offers unique advantages. First, the levich’s
rotating disk system has a very well defined hydrodynamic condition which offers constant
surface flux from the disc surface (86). Second, in a rotating disk model, the surface area
exposed to the dissolution medium is kept constant thereby minimizing the interference of
varying surface area in drug dissolution (86). In addition, RDIDR is measuring a rate
phenomenon instead of an equilibrium phenomenon and thus, it is expected to have a better
correlation with in vivo drug dissolution kinetics (87). Lastly, RDIDR model enables the
calculations of drug diffusion coefficient in the dissolution medium as well as its intrinsic
dissolution rate (88, 89). In a well defined and established RDIDR model, a linear
relationship between the drug flux, J, ((dm/dt)/A, mg/min/cm
2) and the square root of
rotation speed (ω1/2
) can be established. Accordingly, a plot of the ratio of available surface
area (cm2) to dissolution rate (dm/dt, mg/min) versus reciprocal of square root of rotation
speed (1/ ω1/2
) allows the calculation of the intrinsic dissolution rate (mg/min) from the
product of area and reciprocal of the positive y-intercept of the plot (88, 89). The
experimental setup of rotating disk intrinsic dissolution in this study was similar to the one
54
employed in a previous study of drug release from erodible polymer systems by Xu and Lee
(90) with some slight adjustment in the distances of the drug disk from the walls and the
bottom of the dissolution vessel. The adherence of Xu and Lee’s setup to the Levich model
was ensured by calibrating a series of benzoic acid followed by obtaining an intrinsic
dissolution rate of benzoic acid in good agreement with the literature value. Moreover, it was
reported recently that the dissolution volume and position of the rotating drug disk in the
vessel had no apparent influence on the dissolution rate (87). Thus, Levich’s theory can be
well applied in the current study. Initial dissolution data of 10% ITZ loaded PVP films reveal
that the dissolution profile consists of a rapid release of drug (45 minutes, ≈40.0% drug
release) followed by a much slower release portion (22hours, ≈62.0% drug release). This is
most likely due to fact that all the PVP film dissolves during this initial period of time and
the supersaturated drug then converts to crystalline drug therefore slowing down the further
dissolution. The concentration of ITZ was controlled to be below the saturation limit by
employing a near sink condition in 1000 ml of 0.1N HCl. Thus, subsequent studies focused
only on the first 45 minutes of ITZ dissolution to generate initial dissolution rates for
comparison.
55
Figure 16. Dissolution profile of 10% ITZ-loaded PVP films at 37°C in 1L 0.1N HCL (pH
1.2) at 50 rpm, 100 rpm, 150 rpm, and 200 rpm without SDS.
Figure 16 shows that as the speed is accelerated from 50rpm to 200rpm, the time took to
reach a concentration plateau dropped from 30 mins to 21 mins. The initial drug flux
((dm/dt)/A, mg/min/cm2) are calculated from the approximately linear portion of the initial
dissolution curve (in the first 20 mins) and are calculated to be 0.023, 0.033, 0.043, 0.048 at
50 rpm, 100 rpm, 150 rpm and 200 rpm, respectively (Table IV). As shown in Figure 17 and
18, linear relationships between the drug flux and square root of rotation speed, and between
the area/ dissolution rate and reciprocal of square root of rotation speed are obtained with
good linearity (R2= 0.994 and 0.99, respectively). The positive y-intercept (0.391) is used to
calculate the intrinsic dissolution rate, being (1/y-intercept)×A = 2.560×1.693=4.334 mg/min
corresponding to the dissolution rate at infinite rotation speed. Two linear relationships and a
positive y-intercept are successfully constructed and dissolution results obtained is consistent
with the rotating disk dissolution theory.
56
Table IV. Dissolution characteristics of 10% ITZ loaded PVP films at different rotational
speeds. Speed
ω
(rpm)
ω1/2
1/(ω1/2
) Plateau
time
(min)
Drug flux of the
initial linear portion
(dm/dt)/A
(mg/min/cm2)
A/ (dm/dt)
(cm2/mg/min)
Drug released at
45mins (%)
50 7.07 0.14 30 0.023 42.9 36.3
100 10.00 0.10 24 0.033 30.9 35.8
150 12.24 0.08 21 0.043 23.6 37.9
200 14.14 0.07 21 0.048 22.5 41.2
Figure 17. Drug flux of 10% ITZ loaded PVP films vs. square root of rotation speed.
Figure 18. Area/dissolution rate (cm2/mg/min) of 10% ITZ loaded PVP films vs.
reciprocal of square root of rotation speed.
57
Figure 19 demonstrates that both dissolution profiles of 10 % and 20% ITZ loaded solid
dispersions in PVP films (100 rpm, no SDS) show a fast drug release up to 21-24 minutes
followed by a slower drug release with low maximum percentage release. The low
percentage release can be attributed to the poor aqueous solubility of ITZ and possible fast
onset of amorphous-to-crystalline transition upon exposure of the film to the dissolution
medium. A total drug release of 58.5% is observed in 20% blends compared to a much lower
total release of 35.8% in 10% blends. This could be attributed to the fact that a higher drug
loading level is associated with a higher degree of free volume in the polymer, and porosity
is increased as the dissolved drug molecules diffuse into the medium resulting in a faster
dissolution rate.
The limitation of low total percentage release is overcome by incorporating 0.3% SDS in
the dissolution medium to further enhance the solubility of ITZ thereby generating a better
sink condition for the dissolution of ITZ to reach completion. The addition of 0.3% SDS in
dissolution medium of PVP films with 10% loading shortens the plateau time from 24 min to
14 min and enhances the amount of release from 35.8% to ~100.0%. Since PVP is highly
water soluble, upon contact with dissolution medium, it quickly dissolves completely
forming ITZ crystalline suspensions in the medium, which then dissolves slowly. As a result,
the rate limiting step is ITZ solubility.
58
Figure 19. Dissolution of 10% and 20% ITZ loaded PVP films at 37oC in 1L 0.1 N HCl
(pH 1.2) at 100rpm with and without SDS.
4.5.2 Dissolution of ITZ from PVP-EC (70%:30%) blend
The use of hydrophobic EC is well recognized in industrial film and coating processes.
As the PVP-EC film enters the stomach and GI tract, the water soluble polymer dissolves
resulting in a film with disrupted integrity. A higher concentration of EC is expected to
generate a much lower drug diffusion rate (70). Figure 20 shows the dissolution behavior of
20% ITZ-loaded PVP-EC (70%:30%) film in 1 L of pH 1.2 medium at 37oC at 100 rpm.
Comparing Figure 19 and Figure 20, the sustaining effect of EC in the dissolution of ITZ
solid dispersions can be seen and the presence of 0.3% SDS in the dissolution medium has
dramatically enhanced the solubility of ITZ therefore facilitating the full release of the drug.
Initially, films slowly erode, and at around 2 hours, they disintegrate generating a sudden
increase in the film surface area exposed to the dissolution medium which results in an
increase in dissolution rate. Primary dissolution mechanism is swelling and erosion of PVP.
59
However, due to the presence of hydrophobic EC, slow diffusion in the initial stage also
plays an important role in the current dissolution profile.
Figure 20. Dissolution of 20% ITZ-loaded PVP-EC (70%:30%) films at 37°C in 1L 0.1
N HCl (pH 1.2) at 100 rpm with and without 0.3% SDS.
4.5.3 Dissolution of ITZ from crospovidone powders
In this case, ITZ is entrapped in the insoluble but swellable crospovidone network during
the equilibrium loading process. Upon hydration, crospovidone powders undergo rapid
swelling after which ITZ is released. Thus, the primary releasing mechanism is polymer
swelling followed by drug diffusion. As shown in Figure 21, in the absence of SDS in the
dissolution medium, rapid delivery of ITZ is achieved with its low average percentage
release of 40.0% reached within the first 4 mins. However, the addition of 0.3% SDS in the
dissolution medium has facilitated the complete release of ITZ with a much faster
dissolution rate.
60
Figure 21. Dissolution of 16% ITZ-loaded crospovidone powders at 37°C in 500 ml
0.1N HCl (pH 1.2) at 100 rpm with and without SDS.
4.5.4 Dissolution of ITZ from HPMCAS and HPMCAS-PEO (70%:30%) blend
The carrier polymer HPMCAS is an enteric polymer which dissolves in water at
pH≧5.5. As shown in Figure 22, in the first 1.5 hours, when pH 1.2 is maintained, both
HPMCAS and HPMCAS-PEO films exhibit only 5.0% of drug release in the absence of
SDS which is only slightly activated upon switching the dissolution medium pH to 6.8. In an
acidic environment, the drug release is limited to the ITZ on or near the surface of the film
sample. Upon changing the pH to 6.8, the enteric polymer and its blend with PEO start to
erode leading to an increased amount of drug release, however, owing to its poor solubility,
the majority (90.0%) of the ITZ remains undissolved. In the presence of SDS in the
dissolution medium, complete release of ITZ is achieved. Moreover, the PEO component
imparts a sustaining effect in the HPMCAS-PEO blend regardless the presence of surfactant
due to its high molecular weight and gel-forming property (72, 82).
61
Figure 22. Dissolution of 5% ITZ-loaded HPMCAS and HPMCAS-PEO (70%:30%)
blend in an acidic (pH 1.2, first 1.5 hours)-to-neutral (pH 6.8) medium at 37°C at 100 rpm
with and without SDS.
62
4.6 Stability
Figures 23, 24, 25, 26, and 27 demonstrate the physical stability of, respectively, 20%
ITZ-loaded PVP film, 16% ITZ-loaded crospovidone powders, 20% ITZ-loaded EC-PVP
film, 5% ITZ-loaded HPMCAS film, and 5% ITZ-loaded HPMCAS-PEO film under 64%
RH at 22 ºC. Upon moisture exposure in the current accelerated condition, the plastisizing
effect of water leads to a reduction in Tg and greater molecular mobility of the amorphous
drug. This triggers the onset of phase separation and amorphous-to-crystalline transition of
ITZ which could reduce its solubility and bioavailability. The initial physical state of ITZ in
all five carriers was determined to be amorphous. The appearance of the PVP film changed
from clear to opaque in one month indicating the presence of crystalline drug. Solid
dispersions of ITZ in crospovidone powders and PVP-EC blends remain amorphous (no halo
under polarized light, no trace of melting endotherm or XRD crystalline peaks) for 6 months,
and solid dispersions of ITZ in HPMCAS film and HPMCAS-PEO blends remain
amorphous (no halo under polarized light, no trace of melting endotherm or XRD crystalline
peaks) for 3 months suggesting their better physical stability. However, the presence of
crystalline PEO is observed in the sample exposed to the stability condition therefore
suggesting the great crystallization tendency of PEO. The fast onset of opacity in PVP film
can be attributed to the hydrophilicity of the polymer and corresponding higher moisture
uptake, while the crosslinked structure of crospovidone, hydrophobicity of EC, and low
moisture uptake level of HPMCAS stabilized the amorphous state of ITZ.
63
Figure 23. Physical stability of 20% ITZ-loaded PVP film.
Figure 24. Physical stability of 16% ITZ-loaded crospovidone powders (a) DSC (b) X-ray.
64
Figure 25. Physical stability of 20% ITZ-loaded EC-PVP film (a) DSC (b) X-ray and (c)
polarizing microscope.
65
Figure 26. Physical stability of 5% ITZ-loaded HPMCAS film (a) DSC (b) X-ray and (c)
polarizing microscope.
66
Figure 27. Physical stability of 5% ITZ-loaded HPMCAS-PEO film (a) DSC (b) X-ray
and (c) polarizing microscope.
67
5.Conclusions and Recommendations
The results of the current study suggest that solid molecular dispersions of Itraconazole
prepared by the solvent evaporation method with various polymers can be used to enhance
the apparent solubility and subsequent dissolution rate of this poorly soluble drug. Polymeric
carriers play an important role in stabilizing the amorphous form of the drug through
molecular interactions with ITZ and by increasing the glass transition temperatures of the
resulting mixtures. In addition, they regulate the associated drug release properties. It has
been shown that the drug loading level, polymer type and storage condition can effectively
influence the physical state of ITZ. An increase in dissolution rate is observed in ITZ solid
dispersions compared to that of the crystalline ITZ alone. Dissolution properties of the solid
dispersions can also be altered by incorporating either a hydrophobic or hydrophilic polymer
to retard the drug release or an enteric polymeric material to target intestinal release. Thus,
solid molecular dispersion should be a useful approach to improve the poor solubility and
bioavailability of Itraconazole. Among all polymers studied, PVP, crospovidone and PVP-
EC generated loading levels of around 20% which were substantially higher than those
obtained by HPMCAS or its blend with PEO (5%). This could be due to the fact that
HPMCAS and PEO have relatively weak polymer-drug interactions with the ITZ. Despite
the higher drug loading capacity, PVP based solid molecular dispersion appears to be less
stable when exposed to moisture. The greater tendency of ITZ crystallization in PVP can be
attributed to the higher moisture absorption of ~20% (at 64% RH, room temperature) than
that of HPMCAS (<5%, at 64% RH, room temperature) (78). On the other hand, the
68
hydrophobic nature of EC enabled itself to function as a moisture barrier thereby
contributing to its better moisture stability. The commercially available crosslinked polymer
crospovidone is considered a suitable carrier for ITZ due to its high loading level, polymer-
drug interaction, and high Tg. In addition, its three dimensional polymeric crosslink network
may have further contributed to its stability. Overall, PVP and crospovidone were able to
deliver immediate release of ITZ from a solid molecular dispersion, whereas HPMCAS
offered greater enteric protection. The sustaining effect of EC and PEO made it possible to
generate controlled release of ITZ. However, PVP alone may not be a proper carrier for ITZ
due to its instability in the presence of moisture and HPMCAS is considered a less desirable
choice due to its low drug loading capacity.
Based on results obtained in this Master’s project, it would be interesting to address the
following areas in future studies:
A well controlled drying process and technique for polymer film samples should be
explored. The temperature and rate of air flow are the two variables that can alter the drying
rate and drying degree which can affect the physical properties of the solid dispersions (i.e.
in terms of amorphous or crystalline state).
A more precise relationship between the amount of EC in the PVP-EC blend and its
sustaining effect should be established. In the current study, only a single composition of
70%:30% PVP-EC has been investigated. The degree of controlled drug release can be
directly related to the amount of EC incorporated in the blend. The extent to which the drug
release is delayed at various EC concentrations should be studied to generate a more
69
complete picture.
It would be interesting to examine the sustaining effect of PEO of different molecular
weights. In the current study, PEO Polyox WSR Coagulant (MW: 5,000,000) has been
shown to provide sustaining effect in dissolution. However, other grades of Polyox such as
WSR N-10, 1105 and 303 have been studied in controlled release achieving various degrees
of delayed drug release. In addition, the degree to which the drug release can be sustained
should be investigated with various PEO concentrations.
Further studies on stability testing should be conducted. Moisture content and
temperature of the storage condition can affect the onset of amorphous-to-crystalline
transition which can result in a much lower solubility and bioavailability. The correlation
between storage condition and the duration of physical stability of solid molecular
dispersions investigated in this study should be completed for future references.
Lastly, an in vitro in vivo correlation of ITZ solid molecular dispersions should be
investigated in animal models. The values of pharmacokinetic parameters (i.e. AUC infinity,
Cmax, Tmax and t1/2) should be obtained to demonstrate the improvement of blood
concentration profile and bioavailability with these stabilized amorphous ITZ systems.
70
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