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.

iii
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

viii
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

ix
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

x
List of Equations

Equation 1 Noyes-Whitney equation ...................................................................................... 1

Equation 2 Mass degree of swelling ..................................................................................... 28

Equation 3 Equilibrium solvent content ............................................................................... 28

xi
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

xii
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]

xiii
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:

dC AD(Cs  C )

dt h (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,

1
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

2
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).

3
 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

4
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

5
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

6
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

7
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
8
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

9
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

10
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.

11
 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
12
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

13
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

14
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).

15
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.

16
Table I Physicochemical properties of the five polymer carriers.

Polymer/ Molecular Tm (oC) Tg (oC) Aqueous reference

properties weight solubility

PVP-K90 1,300,000 / ~174 soluble (1)(67)

Crospovidone >1,000,000 / 190-195 Insoluble, (68, 69)

(XL10) swellable

EC- std 7 6-8 cp* 165-173 129-133 insoluble (70)

HPMCAS-LG 18000 / 115 Soluble in pH ≥ (71)

5.5

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.

17
 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.

18
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

19
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

20
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
21
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
22
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.

23
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.

24
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.

25
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

26
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.

27
 Ws
q
Wd (2)

Equation 2 Mass degree of swelling

Ws  Wd
ESC (%)  100  ( )
Ws (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.

28
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,

29
Delaware, USA). Samples (5-10 mg) were weighed into aluminum pans and hermetically

sealed. Samples were heated to ~200oC at a rate of 10oC/min (first heating run) and quench

cooled to -40oC at a rate of 40oC/min followed by slow heating to 200oC at a rate of 2oC/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.

30
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
31
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.

32
 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.

33
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.

34
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

35
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.

36
 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
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.

38
 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 equilibrium solvent content

(w/w) (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)) ITZ loading level (%(w/w))

In loading solution 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.

39
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.

40
 Figure 10. Solid dispersions of ITZ with various drug loadings in (A) PVP (B)
HPMCAS and (C) HPMCAS-PEO (70%:30%).

41
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.

42
43
 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
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).

45
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%).

46
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 oC, PVP-EC: ~163.44 oC, and HPMCAS: ~115.33 oC) 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 oC), and the transitions become

less pronounced with increasing amount of drug loading (Figure 13 (5)).

47
 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
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.

49
 Figure 14. XRD patterns of (1) PVP (2) crospovidone (3) PVP-EC (70%:30%) (4)
HPMCAS and (5) HPMCAS-PEO (70%:30%).

50
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.

51
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%).

52
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/cm2) 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
53
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.

54
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.

55
 Table IV. Dissolution characteristics of 10% ITZ loaded PVP films at different rotational
speeds.
Speed ω1/2 1/(ω1/2) Plateau Drug flux of the A/ (dm/dt) Drug released at
ω time initial linear portion 45mins (%)
(rpm) (min) (dm/dt)/A (cm2/mg/min)
(mg/min/cm2)
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.
56
 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.

57
 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.
58
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.
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.

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).
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 rpm
with and without SDS.

61
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.

62
 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.

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
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

67
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

68
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.

69
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List of abstracts

Hong L, Lee PI, Solid molecular dispersions of itraconazole for enhanced dissolution
and controlled drug delivery. Presented at Graduate Research In Progress, Faculty of
Pharmacy, University of Toronto.

79