Research Article Hot Melt Extruded Amorphous Solid...

Research ArticleHot Melt Extruded Amorphous SolidDispersion of Posaconazole with Improved BioavailabilityInvestigating Drug-Polymer Miscibility withAdvanced Characterisation

Ritesh Fule and Purnima Amin

Department of Pharmaceutical Sciences and Technology Institute of Chemical Technology Nathalal Parekh MargMatunga Mumbai Maharashtra 400019 India

Correspondence should be addressed to Ritesh Fule riteshphdictgmailcom

Received 13 February 2014 Revised 31 March 2014 Accepted 2 April 2014 Published 21 July 2014

Academic Editor Frederic Lagarce

Copyright copy 2014 R Fule and P AminThis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Invasive antifungal infections are reasons for morbidity and mortality in immunogenic patients worldwide Posaconazole is a mostpromising antifungal agent against all types of invasive infectionswith highof cure rateThemarketed suspension formulation haslow bioavailability and is needed to be taken with food In this paper PCZ hot melt extruded amorphous solid dispersion (SD) withimmediate release and improved bioavailability was prepared using Soluplus (Sol) as primary carrier for solubilization Surfactantssuch as PEG 400 Lutrol F27 Lutrol F68 and TPGS are also used in combination with Soluplus to improve the physicochemicalperformance of the formulation when it comes in contact with GI (gastrointestinal) fluid Drug-polymer miscibility of SD wasinvestigated using advanced techniques In the in vivo study the AUC(0ndash72) and Cmax of PCZSoluplus were 115 and 1174 time higherthan those of pure PCZ The formulation of the extrudate SD had an AUC(0ndash72) and Cmax higher than those with the commercialcapsule (Noxafil) Molecular dynamic (MD) simulation studies were carried out using in silicomolecular modelling to understandthe drug-polymer intermolecular behaviourThe results of this research ensure enhanced dissolution and bioavailability of the soliddispersion of PCZ prepared by HME compared with the PCZ suspension

1 Introduction

The solubility and dissolution rate of drugs relics one ofthe most challenging traits in formulation developmentHot melt extrusion (HME) has been established as novelstrategy to produce delivery system with enhanced bioavail-ability as well as solubility of dissolution rate limited APIsin pharmaceutical drug development research [1ndash3] Thistechnology employs the combination of optimized parameterand temperature to formulate drug-polymer molecularlydispersed systems which can be termed as solid dispersion(SD) or solid solution [4 5] The singularity and workabilityof the procedural features allow the development of severaldrug delivery systems Also various marketed formulationsare available prepared via HME [6] The formation of meltextrusion involves the exchange of heat energy during HMEprocess and followed by instant cooling of the melt which

affects thermodynamic and kinetic properties of forming SDapparently [7 8] Use of highly water soluble carrier in SDalways increases the chances of crystallization due to swellingbehavior when it comes in contact with the aqueous GIfluid [9] Therefore surface active agents or surfactants areused as inhibitors for recrystallization HME has the uniqueproperty to maintain the amorphous state of the drug afterthe formation of SD and improves the solubility of the drugSolubility of the drug substance has a significant impact onits bioavailability performance The literature cited variousmethods for preparing amorphous SD such as melt methodsolvent evaporation cyclodextrin inclusion complex andcryomilling which explained the importance of SD type offormulation strategy [10]

Posaconazole (PCZ) is newly developed extended-spec-trum triazole with proven efficacy as antifungal treatment

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 146781 16 pageshttpdxdoiorg1011552014146781

2 BioMed Research International

and used to treat invasive infections by candida speciesand aspergillus species in severely immunogenic patientsThe marketed oral suspension Noxafil (40mgmL of PCZconcentration) should be taken with food to maximizesystemic absorption In this paper a new solid oral SDformulation has been developed using HME with improvedbioavailability that can be administered without regard tofood PCZ has a very low aqueous solubility which impairsits dissolution in upper gastric fluid producing problems toprepared systems [11] Overall these characteristics hinder itstherapeutic application by delaying the absorption rate andthereby onset of action or activity [12] Together solubilitypermeability and dissolution rates of a drug are essentialfactors for determining its oral bioavailability The literaturereports generally revealed the fact that drug materials with avery low aqueous solubility will show dissolution rate limitedabsorption and hence poor bioavailability Improvement ofaqueous solubility in such a case is a valuable assignmentto improve therapeutic efficacy [13] PCZ is structurallyanalogous to itraconazole Itraconazole has been extensivelystudied by various researchers comprising its SD formu-lations by hot melt extrusion using Soluplus as primarysolubilising agent However there is no literature on theenhancement of solubility of PCZ by hot melt extrusionmethod reported Subsequently there is a need to deliverPCZ in formulation with increased solubility and improveddissolution profile The development of amorphous SD is aremarkable approach to increase the bioavailability of poorlysoluble APIs by enhancing their rate and extent of dissolution[14]

For the current study we selected polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer Solu-plus (Sol) a novel polymer with amphiphilic properties andexplored its solubilizing potential using HME technologyThe selected excipients PEG400 Lutrol F127 Lutrol F68and TPGS were prescreened first on the basis of extrusiontemperature processing temperature uniformity of extrudesretention time and solubilization Also these excipientscontributed to the permeability of SD formulation acrossmembrane Various researchers reported that these excipientssuccessfully enhance the bioavailability of poorly solubledrugs Soluplus when processed with PCZ alone the mixingand melt formation residence time is very high which causesformation disordered sticky heterogeneous extrudes Butwith addition of selected surfactant the torque decreases andextrudability and melt viscosity increase This improved thedrug distribution uniformity stability and physicochemicalperformance of obtained extrudes Sol offers exceptionalcapabilities for solubilization of BCS class II and class IVdrugs with the extensive possibility of making SD by hotmelt extrusion [15] Combination effect of Sol along withsurfactants such as PEG400 L F127 (LF127) L F68 (LF68)and TPGS was studied in detail in this paper

2 Materials and Methods

21 Materials PCZ was obtained as a generous gift fromABS life science Ltd India Sol LF127 LF68 and TPGS werekindly donated by BASF Corporation Mumbai India (head

office Ludwigshafen Germany) PEG400 of analytical gradewas procured from Sd Fine Chemicals Mumbai India

22 Methods

221 Calculation of Solubility Parameter (120575) Glass TransitionTemperature (119879119892) and Florey-Huggins Parameter (120594) Asan indicator of the drug-polymer miscibility values of 120575

were calculated using the Hoftyzer and vanKrevelen groupcontribution method described by the following equation

1205752= 1205752

119889 + 1205752

119901 + 1205752

ℎ (1)

where

120575119889 =sum119865119889119894

119881 120575119901 =

(sum1198652119901119894)12

119881 120575ℎ = (

sum119864ℎ119894

119881)

12

(2)

Here 119894 is the groups within the molecule 120575 is the totalsolubility parameter 120575119889 is the contribution from dispersionforces 120575119901 is the contribution from polar interactions 120575ℎis the contribution of hydrogen bonding 119865119889119894 is the molarattraction constant due to molar dispersion forces 119865119901119894 is themolar attraction constant due to molar polarization forces119864ℎ119894 is the hydrogen bonding energy and 119881 is the molarvolume The solubility parameters of polymer and surfactantcombinations were calculated using the following equation

12057512 = 1198811015840

11205751 + 1198811015840

21205751205882 (3)

where 1198811015840 is the volume fraction of each compoundMiscibility of the drug with the polymer can be assessed

based on the shift in melting endotherm or 119879119892 of the drug orcan be predicted theoretically using Gordon-Taylor equationbased on the 119879119892 densities and weight fractions of thecomponents Consider

119879119892mix (HME system) = 11988211198791198921 +11987011988221198791198922

1198821

+ 1198701198822

119870 asymp11987911989211205881

11987911989221205882

(4)

where 1198791198921 is the glass transition temperature of drug1198821 and1198822 are the weight fractions of the components and 119870 is theparameter calculated from the true densities (1205881 of drug and1205882 of polymer) and 1198791198922 of the amorphous components [16]The true density measurement of the PCZ and polymers wasdetermined in duplicate using a gas displacement pycnometer(Accupyc 1330 Micromeritics Norcross Georgia)

The Flory-Huggins (FH) interaction parameter (120594) wascalculated using the following equation

1

119879119898mixminus

1

119879119898pure

= minus119877

Δ119867119891

lnΦdrug + (1 minus1

119898)Φpolymer + 120594Φ

2

polymer

(5)

BioMed Research International 3

Table 1 HME process parameters and drug-polymer composition of prepared formulations

Formulationcodes Batch size (gm)

Formulation compositionExtrusion temp (∘C)(speed 50 rpm for all)

Residence time(min)Drug

(gm)Sol(gm)

PEG400(gm)

LF127(gm)

LF68(gm)

TPGS(gm)

PZ1 60 30 29 1 mdash mdash mdash 115 7ndash9PZ2 60 30 29 mdash 1 mdash mdash 114 9ndash11PZ3 60 30 29 mdash mdash 1 mdash 118 10ndash12PZ4 60 30 29 mdash mdash mdash 1 112 8ndash10

where 119879119898 mix is the melting temperature of the drug in thepresence of the polymer 119879119898 pure is the melting temperatureof the drug in the absence of the polymer Δ119867119891 is the heatof fusion of the pure drug 119898 is the ratio of the volume ofthe polymer to PCZ and Φdrug and Φpolymer are the volumefractions of the drug and the polymer respectively [17]

23 Development of SD Using HME Uniformmixing of drugwith the polymer-surfactant in 1 1 1 2 and 1 3 ratios wasexecuted in a mortar-pestle to prepare physical mixtures(PMs) of 60 g each The PMs were then transferred toa turbula mixer and further mixed for 15min to ensurehomogenous mixing Hot melt extrusion was performedby using lab scale single screw extruder fabricated by SBPanchal pvt Ltd (Mumbai India) Thermal parametersand speed of extruder were kept constant throughout theprocess for respective samples The mixture takes about 3ndash5 minutes to form molten mass between walls of the screwand extruder barrel Residence time was about 8ndash15 minutesfor extruded to come out for various samples The hot meltextrudates were collected allowed to cool milled usingmixergrinder and screened through sieve ofmesh number 100Thepowdered SDwere stored in 50 cc amber colored glass bottlesin a desiccator at room temperature and 0 humidity forfurther analysis and characterisation Overall 12 optimizedformulation batches were practically carried out having drugto polymer ratio 1 1 1 2 and 1 3 In current paper preparedSD formulations containing drug to polymer in 1 1 ratiohas been discussed Physicochemical analytical and in vivoperformance of the same is reported as SD (1 1 in ratio) has50 drug loading [18]

24 Physical State Characterization

241 Differential Scanning Calorimetry (DSC) and (M-DSC)Thermal analysis was performed by using PYRIS-1 Differ-ential Scanning Calorimeter (DSC) (Perkin Elmer USA)equipped with a liquid nitrogen attachment to study thedrug and SD crystalline variability DuringM-DSCaccuratelyweighed samples (4-5mg) were placed in sealed aluminumpans and a heat-cool-heat cycle applied involving heatingfrom 40 to 260∘C at 10∘Cmin then rapidly cooling to 40∘Cand then reheating to 260∘C at 10∘Cmin

242 Powder X-Ray Diffractometry (PXRD) X-ray diffrac-tion patterns were recorded using Advance D8 system withCuK120572 radiation instrument (Bruker USA) The recording

spectral range was set at 0ndash60∘ (2120579) using the Cu-target X-raytube and Xe-filled detector

243 FT-IR Spectroscopy Pure PCZ and SDwere analysed byusing a Fourier transform infrared spectrophotometer model4100 (Spectrum GX-FT-IR Perkin Elmer USA)

244 Scanning Electron Microscopy (SEM) The shape andsurface morphology of the crystalline PCZ and PCZ-loadedSD were examined using XL 30 Model JEOL 6800 scanningelectron microscope made in Japan during analysis

245 Raman Spectroscopic Analyses The Raman spectra ofthe SD were recorded with a LabRamHR800 (Horiba JovanYvon) equipped with a 633 nm Ar-Ne laser The laser excita-tion was focused using 50 objectives (Olympus Corporation)and the scattered light was totally transmitted through thenotch filter towards the confocal hole and entrance slit of thespectrograph [19]

246 Atomic Force Microscopy (AFM) CharacterizationJXA-8530F Hyper Probe Electron Probe Microanalyzerinstrument by JEOL was employed for AFM analysesFreshly fractured extrudates on microscopic glass slideswere mounted on the micrometre positioning stage of aDimension Icon AFM with accelerating voltage of 1ndash30 kVProbe current range was kept between 10 pA and 200 pA andback scattered electron images were obtained [20]

247 Molecular Modelling Studies Themonomer unit struc-tures of polymer Sol LF127 LF68 TPGS and PCZ were con-structed by using Gaussian programme in Schrodinger mae-stro software programme USA The energy minimizationdocking and MD-simulation studies of different conforma-tions of drug-polymer were run to understand the structuralinteraction and to identify most stable conformation of drugwith polymer [21 22]

25 HPLC Analyses PCZ and SD contents were determinedusing a Binary HPLC pump and 2998UV Array detector(Agilent Corporation Milford Massachusetts)The formula-tion codes are given as PZ1 PZ2 PZ3 and PZ4 (see Table 1 fordetailes) Mobile phase composed of methanol-water (75 25vv) at 10mL minminus1 flow rate was used The injectionvolume was 20120583L and detection was at 262 nm for PCZ andSD [23 24]


26 In Vitro Dissolution Studies Quantity equivalent to100mg of PCZ was weighed from powdered SD filled insidethe hard gelatine capsule that was used for the dissolutionstudies The PCZ SD and marketed suspension Noxafilwere investigated for their dissolution behavior Dissolutionstudies were performed as per USFDA reported method inthe 900mL with 03 SLS medium (sodium lauryl sulphate)at 37plusmn02

∘C using a paddle USP type II apparatus (ElectrolabDBK Mumbai India) at speed of 25 rpm PCZ released fromthe SD and Noxafil was characterised by UV absorbancemeasurement at a wavelength of 262 nm [25]

27 In Vivo Pharmacokinetics after Oral Administration

271 Animals and Dosing Protocol A single dose bioavail-ability study was designed in Wistar rats under fastingconditionsThe animal experimentswere implemented by theguidelines of the Committee for the Purpose of Control andSupervision of Experimental Animals (CPCSEA) India Theexperimental protocol was approved by Institutional AnimalEthics Committee (IAEC) of Institute of Chemical Technol-ogy (Protocol number ICTIAEC2013P02) Healthy maleWistar rats (weighing 170ndash200 g) (procured from HaffkineInstitute Mumbai India) were used for the study The ani-mals were randomly divided into four groups (119899 = 6) namelypure PCZ Noxafil PZ1-SD and PZ2-SD All rats receivedoral doses of 10mgkg including PCZ pure marketed Noxafilsuspension and PCZ SD powder The formulations weredispersed in pure water and then immediately administeredto the rats by oral gavage according to the concentrationof PCZ in the formulations Six animals were used foreach formulation Blood samples (sim05mL) were drawn byretroorbital venous plexus puncture at 15 and 30min and 1 24 6 8 12 24 36 48 and 72 h following oral administrationafter dose Aliquots of 05mL of blood were withdrawnin micro centrifuge tube previously containing acid-citrate-dextrose (ACD) buffer (02mL) as an anticoagulant Theplasma blood samples were centrifuged under refrigerationat 7000 rpm for 10min and stored at minus20∘C until furtheranalyzed by HPLC The animal study was carried out inaccordance with the Code of Ethics of the World MedicalAssociation (Declaration of Helsinki)

272 HPLC Quantification of PCZ in Plasma Samples HPLCmethod was developed for the analysis of PCZ in plasma ofrats a species used for safety evaluation The HPLC analysisinvolved protein precipitation with methanol followed byseparation on column and quantitation by UV absorbance at262 nm The method was sensitive with a limit of quantifi-cation of 025 120583gmL in rat plasma Calibration curves wereused for the conversion of the PCZPCZ chromatographicarea to the concentration of PCZ Calibrator and qualitycontrol samples were prepared by adding appropriate vol-umes of standard PCZ solution in acetonitrile to drug freeplasma Calibration curves ranged from 64 to 366120583gmL(1199032 = 0997) Briefly an aliquot (100120583L) of plasma samplewasmixedwith 50120583L of IS solution (Itraconazole 100 120583gmL) and50120583L of drug solution After vortexing for 30 sec a protein

precipitating agent methanol (500120583L) was added and vor-texed for 1min The mixture was centrifuged (Eltek TC 4100D 232 centrifuge) at 7000 rpm for 15min The supernatantwas filtered through 022120583m syringe driven membrane filterunit and 50120583L of the filtrate was injected onto the HPLCsystem The mobile phase consisted of 009M ammoniumphosphate monobasic acetonitrile-triethylamine (55 45 vv)and was delivered at 1mLmin

273 Pharmacokinetic Data Analysis The pharmacokineticanalysis of plasma concentration-time data was analyzed byone compartmental model using Kinetica software (ThermoScientific) Required pharmacokinetics parameters such astotal area under the curve AUC(0minus72) half-life (11990512) peakplasma concentration (119862max) and time to reach the maxi-mum plasma concentration (119879max) were determined

28 Contact Angle Evaluation Studies The contact anglemeasurement was performed using G10 Contact angle meter(Kruss Germany) to evaluate the wetting property of pre-pared system compared to pure hydrophobic drug PCZ Asolid disc with flat surface (100mg) was prepared of purePCZ and the optimized SD PZ1 PZ2 PZ3 and PZ4 Adrop of distilled water was dropped on the disc surface andcontact angle was measured immediately and after 60 sec ofequilibriumThree samples were measured from each batch

29 Stability of Prepared SD Prepared SD were kept insidethe closed glass vials under controlled temperature envi-ronment inside stability chamber (Thermo Lab India) withrelative humidity of 35 60 and 75 RH and temperature37∘C 40∘C and 60∘C for stability studies Samples wereremoved after 1 3 and 6 months evaluated for dissolutionrate study and compared with those SD tested immediatelyafter preparation [26] The assay of the drug and SD wasevaluated using HPLC at 120582 = 262 nm

3 Results and Discussion

31 Mathematical Calculations If Δ120575 is less than 7MPa12both components are miscible When Δ120575 value wasge10MPa12 incompatibility and phase separation betweendrug and polymer occurs The calculated solubilityparameters are presented in Table 2 The calculateddifferences between 120575 (ie Δ120575) values of PCZ and Sol-surfactant blend were found to be in the range 267ndash45MPa12 being less than 7MPa12 indicating likelymiscibility The results suggest that Δ120575 values are usefulparameters in predicting miscibility and polymer selectionfor HME process [27] Incomplete miscibility or reducedsolubility can result in the formation of concentrated drugspheres that may lead to recrystallization after productionand during stability [28] From the results obtainedtheoretically by Gordon-Taylor analysis is found to bein similar range of experimental 119879119892 (temperature usedfor HME process) as shown in Table 3 From the resultscalculated value of FH interaction factor (120594) is not ge05Mwhich signifies higher favorable extent of drug-polymer


Table 2 Solubility parameter calculation for drug polymer compatibility

Drug and polymers 120575hi 120575di 120575pi 120575 Δ120575MPa12 (not ge7) Drug-polymer compatibilityPCZ 904 311 1593 1857 (a) mdash mdashSol + PEG400 (1943 + 960)2 1451 (b) (a minus b) = 406 MiscibleSol + LF127 (1943 + 1120)2 1531 (c) (a minus c) = 326 MiscibleSol + LF68 (1943 + 1237)2 159 (d) (a minus d) = 267 MiscibleSol + TPGS (1943 + 871)2 1407 (e) (a minus e) = 45 Miscible

Table 3 Shows the Gordon-Taylor equation calculated 119879119892mix of SD systems

Formulation codes 1198821 1198791198921 1198821 lowast1198791198921 1199082 1198791198922 1198822 lowast 1198791198922 1205881 1205882 1198791198921 lowast 1205881 1198791198922 lowast 1205882 1199081 + 1198961199082 119879119892mix

PZ1 05 17634 8817 2 115 230 13 086 22113 989 4971 12116PZ2 05 17634 8817 2 114 228 13 086 22113 9804 5011 12022PZ4 05 17634 8817 2 118 236 13 086 22113 10148 4858 12400PZ4 05 17634 8817 2 112 224 13 086 22113 9632 5091 11831

interactions at micro level [29] Adhesive interactionbetween drug and polymer favoured by the reduction in the119879119892 of SD systems which implicate the miscibility of drug andpolymer is shown in Table 4

32 Solid State Characterization

321 Thermal Investigation Using DSC MDSC and XRDSolid-state extruded SD was analysed using DSC andMDSCDSC was used to determine the PCZ state in the extruded SDand to identify possible drug-polymer interactions Figure 1depicts the thermograms of pure PCZ which clearly showendothermic sharp peak at 17634∘C DSC thermographsof PM show characteristic peak of crystalline PCZ Thethermograms of the hot melt extrudates SD showed differentthermal behaviour for PCZ As shown in Figure 1 thedrug melting endotherms disappeared completely in case ofSD The absence of PCZ endotherms suggests either drugsolubilization due to the presence of used excipients orbeing present in an amorphous state Thus it was concludedthat PCZ converted to its amorphous form during hot meltprocessing approach MDSC studies were performed to rec-ognize the stable nature of amorphous SDof PCZprepared byHME Compared to the sharp melting peak of pure PCZ theendothermic peaks in SD broadened during the first heatingcycle and then disappeared in the second heating cycle Thisis caused by gradual dissolution of the crystalline drug in themolten polymers and complete conversion to the amorphousstate during the DSC heating process MDSC shows therespective 119879119892 of SD prepared approximately in similar rangeof temperature which signifies the amorphous drug nature inSD Figure 2 The prepared SD formulations were found to bestable in amorphous state after 6 months The physical stateof PCZ was further investigated by employing X-ray powderdiffraction

XRD of PCZ consist of sharp multiple peaks indicatingthe crystalline nature of the drug with specific crystallinityIn the XRD of PCZ peak intensities are observed at 10231322 1382 1524 1611 1834 1927 2162 2214 2355 23642492 2612 2742 3086 3213 3511 and 4623 Characteristic

peaks intensities of PCZ are observed at 8100 7500 55005300 and 4300 In the case of SD (about 2 gm) whenexposed to X-ray beam it shows disappearance ofmost of thecrystalline endothermic peak and characteristic intensities ofPCZ This indicates complete transformation of crystallinePCZ into amorphous form during HME process From theXRD studies of both fresh and aged SD systems amorphousnature of PCZ after HME was confirmed The observed fewintensity peaks in the diffractograms are attributed to theSD excipients such as PEG400 LF127 LF68 and TPGS asshown in Figure 3 The diffractograms indicate that PCZ isin amorphous state (or molecularly dispersed) in the SDThe XRD results are in good agreement with those of DSCthermograms

322 FTIR Possible interactions between drug and polymerin SD were investigated by FTIR FTIR spectra of PCZ andSD were examined FTIR spectrums are properly labeledand shown in Figure 4 IR of pure PCZ characteristic hassharp peaks of alkene stretching (=CndashH and CH2) vibrationat 385704 cmminus1 and 327412 cmminus1 Alkane stretchingobserved (ndashCH3 ndashCH2 and ndashCH) vibration at 304189295659 and 287019 cmminus1 and also exhibited C=O stretchat 176236 cmminus1 due to saturated ketone and C=OndashNHstretching at 1637 cmminus1 A selective stretching vibration at155535 cmminus1 and 1617 cmminus1 for secondary and tertiary aminewas also observed For functional groups like CndashO stretchand ndashCndashF stretch they showed vibrations at 105424 cmminus1and 100808 cmminus1 respectively Most of the peaks that areobserved in the spectral region 765ndash791 cmminus1 600ndash700 cmminus1and 820ndash980 cmminus1 are due to stretching (bending =CndashHand =CH2) ndashCH deformation and ndashCH bending The IRspectra of PZ1 showed characteristic peaks at 291325 cmminus1173102 cmminus1 153535 cmminus1 137146 cmminus1 108340 cmminus184198 cmminus1 71678 cmminus1 60486 cmminus1 and 57072 cmminus1The IR spectra of PZ2 and PZ3 showed characteristic peaksat 338548 cmminus1 160219 cmminus1 138467 cmminus1 107846 cmminus171402 cmminus1 34008 cmminus1 173175 cmminus1 15959 cmminus1138473 cmminus1 111072 cmminus1 84116 cmminus1 and 71349 cmminus1


Table4Florey

Hug

gins

interactionparameter

(120594)o

fSD

Ratio

1119879mix

1119879pu

reLH

S119877ΔHf119877ΔHfΦdrug119898

11198981minus 1119898ΦPo

lymer

1minus1119898lowast

ΦPo

lymer

log(Φdrug)

lnΦdrug

+1minus

1119898lowastΦPo

lymerΦ2P

olym

er119877ΔHf(lnΦdrug

+1minus

1119898lowastΦPo

lymer)

119877ΔHflowastΦ

2Polym

er120594

Left

120594

PZ1

0008695652

0005670863

0003025

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

000302minus0025

PZ2

000877193

0005670863

0003101

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

00031minus0026

PZ3

0008474576

0005670863

0002804

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

00028minus0023

PZ4

0008928571

0005670863

0003258

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

000326minus0027


40 60 80 100 120 140 160 180 200 220 240 2601171

19

20

21

22

23

24

25

26

1856

Hea

t flow

endo

(mW

)

PZ4 (6M)PZ3 (6M)

PZ2 (6M)PZ1 (6M)

PZ4

PZ3

PZ2

PZ1

PCZ pure

Temperature (∘C)

Hea

t flow

endo

(mW

)

PCZ pur

19

20

21

22

23

24

25

26

1856

Area = 345071mJ

40 60 80 100 120 140 160 180 200 220 240 2601171

Temperature (∘C)

Hea

t flow

endo

(mW

)

19

20

21

22

23

24

25

26

1856

40 60 80 100 120 140 160 180 200 220 240 2601171

Temperature (∘C)

PZ4 (PM)PZ3 (PM)PZ2 (PM)

PZ1 (PM)

ΔH = 690142 Jg

Peak = 17634∘C

Figure 1 DSC pattern of SD (fresh) SD (6 months) PM and PCZ

The IR spectra of PZ4 showed characteristic peaks at303334 cmminus1 288420 cmminus1 228209 cmminus1 222009 cmminus1173023 cmminus1 146258 cmminus1 113304 cmminus1 97411 cmminus183827 cmminus1 71615 cmminus1 67684 cmminus1 and 57158 cmminus1The IR spectra of SD signify the presence of drug and nochange in its functional properties The addition of polymerand surfactant during HME process would not affectPCZ molecule stretching vibrations Interaction betweenthe polymer and drug in SD mixtures formed moleculardispersions with slight shifting of specific intensitiescompared to pure PCZ IR spectrum The carbonyl group ismore favourable for hydrogen bonding and intermolecularinteractions than the nitrogen atom because of sterichindrance For SD the ndashOH stretching bands broadened andthe intensity of the bands decreased to minimal indicating

19

20

21

22

23

24

25

26

27

28 PZ1PZ2

PZ3PZ4

Hea

t flow

endo

(mW

)

40 80 100 120 140 160 180 200 220 240 260 280 300

Temperature (∘C)

205∘C

220∘C

250∘C258∘C

Figure 2 MDSC pattern of SD (6 months)

15000

14000

13000

12000

11000

10000

9000

8000

7000

6000

5000

4000

3000

2000

1000

0

Lin

(cou

nts)

PZ4 (6M)PZ3 (6M)PZ2 (6M)PZ1 (6M)PZ4PZ3PZ2PZ1

5 10 20 30 40 50

2-120579-scale

Figure 3 XRD pattern of pure PCZ SD (fresh) and SD (6months)

specific degree of interaction between the proton donatinggroups of PCZ and the proton accepting groups in the Sol

323 SEM SEM micrograph of pure PCZ consists of largecrystalline formof drug agglomerates with ordered shape andsize Figure 5(a) SEM of SD showed intrinsic miscibility ofdrug and polymer interface at micro level However in SDsystems presence of relatively rough surface also suggests thathydrophilic polymer and surfactant were spread uniformlyon the surface of the drug as shown in Figures 5(b) 5(c)5(d) and 5(e) The PCZ SD appeared to be agglomeratedwith rough surface owing to the miscibility of drug intopolymer


1500

1300

1100

900

700

500

300

100

minus100

minus300

16722

minus52834000 3000 2000 1500 1000 500400

385704356510

327412

304189

295659

281413

287019

264009204560

200857

176236

163795161745

141995132638

127152

123010118540

114747105424

100808

9405787331

82551

83442

59213

52734

51364

42060

41225

48422

T(

)

(a)

52850

46

42

38

34

30

26

22

1753440 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 450

T(

)

291325

235262

173102

164468

161415

155535

148585

144507

133462

137146 119755

123960

108349102338

97280

8419871678

6048657072

51430

(b)

40000 3000 2000 1500 1000 500 400

T(

)

153

131197531

minus1minus3minus5

minus67

338548 160219138467

107846

71402

(c)

4000 3000 2000 1500 1000 500400

T(

)

(cmminus1)

315302826242220181614121086420

minus2minus44

340080

173175

159890

138473

111072

8411678956

71349 60848

(d)

Figure 4 Continued


807

40154 3000 2000 1500 1000 500 2315

T(

)

70

60

50

40

30

20

10

0minus75

(cmminus1)

390973380684

369447360630

349662

303334288420

228209222009173023 124983

113504

97411

83827

71615 57158

67684

74695

146258

(e)

Figure 4 Infrared spectroscopic diagrams of pure PCZ and SD systems

(a) (b)

(c) (d)

(e)

Figure 5 SEM images with surface morphology of pure PCZ (a) PZ1 (b) PZ2 (c) PZ3 (d) and PZ4 (e)


(a)

(b) continued

Inte

nsity

coun

ts

13800

13600

13400

13200

13000

12800

12600

12400

12200

12000

11800

11600

11400

11200

11000

1050 1100 1150 1200 1250 1300

b

a

c

d

X range (10120583m)

Z range (5610nm)PZ1

10

minus120 minus08 minus04 0000 04 08 120 160 200 280240

()

Height (m)

184E + 9

20

10

0

minus10

minus20

minus5 0 5minus5

0

5

08

06

04

02

184E + 9

X range (10120583m)

Yra

nge

(10120583

m)

PZ2

minus200 minus120 minus04 04 120 200

Height (m)

minus5

0

5

10

12

14

08

06

04

02

minus5 0 5

minus04

04

minus08

0

Step height 1055E + 9Z-correction factor 1707E minus 7

784E + 8


minus116E + 9

197E+

Wavelength (cmminus1)

()

Z range (1733120583m)

Yra

nge

(10120583

m)

Figure 6 Continued


minus5

0

X range (10120583m)

PZ3

5

10

12

14

08

06

04

02


Height (m)

Yra

nge

(10120583

m)

minus025

025

05

minus05

0

minus5 0 5

minus5

0

PZ45

02

024

028

032

036

016

012

008

004


Height (m)

Yra

nge

(10120583

m)

X range (10120583m)minus5 0 5

100

200

minus100

0

(b)


minus571E + 8

197E


minus1E + 8

123E + 9(

)(

)

Z range (1388120583m)

Z range (3867nm)

Figure 6 (a) Raman spectra of a (PZ1) b (PZ2) c (PZ3) and d (PZ4) SD (b) Raman images of PZ1 PZ2 PZ3 and PZ4 SD

324 Raman Analyses With Raman spectroscopy a laserphoton is scattered by sample molecule and loses (or gains)energy during the process The intensity of spectral featuresin solution is directly proportional to the concentration ofthe particular species as shown in Figure 6(a) Raman spec-troscopy and its imaging technique are useful tools to evaluatecrystal and amorphous states including discrimination ofcrystalline drug in SD as shown in Figure 6(b) It confirms thepresence of drug in amorphous form in SD and its uniformdistribution [30] Images of the amorphous regions in SD aredescribed by the width at half maximum around 1150 and1300 cmminus1 (green area was thought to be due to amorphousdrug)

325 AFM Analyses Fractured fresh extrudate with smoothsurfaces are used for microscopic investigations using AFMFracture surfaces were generated at determined fracturepoints on the outer surfaces of the extrudates All extrudateshad the form of transparent cylindrical rods 2 and 35 cmlong and of 1 cm width were selected and placed on a sheetof paper The freshly fractured extrudates were mountedon an optical glass slide by use of a 2-component epoxyresin which hardened within sim5min Before the hardening

reaction had been completed the extrudate orientation wascorrected to get the fracture surface as horizontal as possibleThis step is mandatory to enable nondestructive imagingand automated sample changing within AFM operations[31] Freshly fractured extrudates on microscopic glass slideswere mounted on the micrometre positioning stage of aDimension Icon AFM Between 10 and 25 regions per samplewere programmed to be automatically characterized usingthe software routine ldquoprogrammed moverdquo in tapping modeHeight phase and amplitude images were collected simul-taneously using etched silicon cantilevers with a nominalspring constant of 119896 = 40minus100Nm (JEOLAFMProbes)Thetypical free vibration amplitude was in the range of119860 = 10 to50 nm the images were recorded with set-point amplitudescorresponding to 60ndash70 of the free amplitude Image areasof 10 times 10mm were recorded at a resolution of 1024 times

1024 pixels All data were batch-processed using ScanningProbe Image Processor (SPIP 511) Height data were plane-corrected by applying a 3rd order polynomial fit [32] Molec-ular fracture roughness data is also displayed in Figure 7 3Dsurface AFM imaging analysis of SD formulations helps tounderstand the drug-polymer surface morphology as well asinteractionThe roughness parameters reflect the variation

12 BioMed Research InternationalY

(120583m

)

X (120583m)

Z(m

m)

5000minus50

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ1

(a)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ2

100minus100

(b)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ3

500

minus500

(c)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ4

400

minus400

(d)

Figure 7 AFMmicroscopic image of (a) PZ1 (b) PZ2 (c) PZ3 and (d) PZ4

with respect to the topographymean height It indicates fromtheAFManalysis that there is high level of surface interactionand amorphosization of drug inside polymermatrix observedin extrudes

33 Molecular Dynamic Simulation Studies After energyminimization of drug and polymer strong hydrogen bondinginteractions were identified The stable conformation withlowest energy values was optimised and MD simulationdynamics was started MD-simulation studies revealed thestrong drug-polymer interactions The effect of PEG400LF127 LF68 andTPGS on the interaction between PCZ alongwith Sol was found to be favorable The stable conformationsobtained after molecular dynamic simulation showed differ-ent geometric arrangement of the molecules The most stablewas found to be Figure 8(a) with lowest energy and highestbonding interaction between drug and polymer [33 34]

34 In Vitro Dissolution Studies Higher apparent drug sol-ubility and improved dissolution profiles are attributed tothe amorphous nature of PCZ in SD system where PCZ ismolecularly dispersed in the polymer matrix Lattice energy

of SD system is due to short range intermolecular interactionin amorphous system When drug in SD dissolves thenchange in lattice energy is not destructed by the drug itselfso the dissolution rate improved Dissolution profiles ofvarious SD are as shown in Figures 9(a) and 9(b) Thedissolution of the SD with different formulations like PZ1 =10026 PZ2 = 9726 PZ3 = 8445 and PZ4 = 10025at the end of 11987910 minutes was approximately 4599- 4461-3874- and 4598-fold higher than pure PCZ respectivelyThe dissolution of the SD in water (PZ1 = 7125 PZ2 =6125 PZ3 = 5233 and PZ4 = 6755 at 11987960 minutes) wasapproximately 8005- 6882- 5879- and 7589-fold than purePCZ The marketed suspension Noxafil dissolution studiesare also carried out which are found to be inferior in termsof dissolution as compared to prepared SD Dissolution rateof the drug in Sol-surfactant systems is governed by solubi-lization of the polymer to create a hydrotropic environmentfor the insoluble drug It was observed that of the Sol-surfactant SD dissolved rapidly The high dissolution rate ofPCZ from the Sol-PEG400 Sol-LF127 Sol-LF68 and Sol-TPGS dispersion is believed to be due to the drug-polymermolecular intermixing at micro level The aqueous solubility


C

Lp

LpLp

C

H

HLp

Lp

H

C

OLp

CC

C

HH

H

F

F

NN

NN

N

NN

N

O

O

O

OO

OO

O

O

Lp

Lp

Lp

Lp

Lp

Lp

Lp LpLp

Lp

LpLp

Lp

LpC

C

C

C

C

C C

C

C

C

C

C

C

CC

C

C

C

C

CC

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

CC

C C

C

C

C

H

HH

H

HH

H

HH

H

H

H H

HH HHH

H

H

H

H

HH

H

H

H

H H H

HH

H

HH

H

H

HH

H

HH H

HHH

HH

H

H

H

H

H

H

H

H

H

HH

H

H

HH

H

HH

H

H

C

HH

O Lp

C

NC

H

C C H

H

H

Lp

(a)

LpLp

H

H

OLp

H

H C

C

H

HH

H HH

C

HO

OH

H

H

H

H

C H

H

H

O

H

LpO

H

H

HCH

H

Lp

Lp

O

O

O

O

O

O

O

O

C

C

CC

CC

CCC

C

N

N

NN

N N

N

CC

CC C

C

C

C C

CC

C C

C

C C

C

CC

C

C

CC

C

C

C

HH

H H

HH

HH

H

HH

H

HH H

F HH

HH

H

H

H

HH

H

H

H

H

H H

H

HH

HH

HH

H

HH

HH H HH

HH

H

HHH

C

CC

C

C

C

CC

C

C

Lp

Lp

H

H

HH

C

H

OLp

C

Lp

CC

Lp

C H

C

HLp

Lp

LpLp

LpLp

LpLp

LpN

LpLp

H

H H

F

HC H

CH

LpH

HC

O

OLp

Lp

C

H

LpH

C

H H

HCNHH C

C

C

H

(b)

Lp

H

HC

H

H

H

Lp

H

H

HH

HC H

O

C

N

Lp

O

O

O

H

HH

H

CC

CC

C

H

H H H HH H H

H

H

HHHH

HH

HHHHH

H

H

HH H

H

HHH

H

HH H

H

H

H

H

HHHHHH

H

H H HHH

HH

H

HH

H H H

HH

H

H

H

H H

HH

C

CC

C

CC

C

CC

CC

CC

C C

C

C

C

C

C

C

C

CC

C

CCCCC

C

C

CCCC

CLp

C

CC

C

C

C

C

CC

CC

C

CC

C

CC

C

N

N

NN N

N

OO

OOO

O

O

O

O

O

Lp

Lp

Lp

Lp

Lp Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

LpLpLp

FF

H

H

N

H

H

H

H

H

H

HH

N OH

H

(c)

Lp H

HC

HH

HC

HLp

Lp

C

H

Lp

H

Lp

H

Lp

H

Lp

C

H

CH

H

H

H

H

H

HH

H

H

Lp

C

C

C

C

C

H

CCC

H

H

CH

C

H

H

HH

HH

H

H H H

HH

HH

H

H

HHH

H

H

H

H

HH

H

HHH

H H HH

H

H

HH

HHHHHH

HH

HHH

HHH

HHH

H

HH

HH

HH

HHH

H

H

H

H H

H

HH

HHHH

HH

HH

H

H

HH

HH

H

H

H H

H HHH

H H

HH

H

HH

H

HH

H

HH

H

H

C

CC

CC

C CC

CC

C C

CCC

C

CC

C

CC

C

CC

CCC

C

C

C

C

CCC

C CC

CC

C

C

C

C

CC

CC

CCC

C

C

CC

CCCC

C C

C

C

CCC

C

C

C

CC

CC

CC

CC

C

NN

N

NN

N

NN

N

OO

O

O O

O

OO

OO

O

OO

O

O

O

OO

LpLp

LpLpLp

Lp

Lp LpLp

Lp

LpLp

Lp

Lp

F

FLp

H

CH

H

HLpH

H

LpLp

Lp

(d)

Figure 8 MD simulation stable conformations of PCZ-Sol-PEG400 (a) PCZ-Sol-LF127 (b) PCZ-Sol-LF68 (c) and PCZ-Sol-TPGS (d)

and dissolution rate of prepared SD were also significantlyenhanced In comparison to pure PCZ the dissolution rate ofphysical mixtures was slightly increased probably because thehydrophilic polymer can wet the surface of drug particles andact to solubilize them The dissolution of SD was enhancedwith total release occurring within 10minThis clearly showsthat a remarkable improvement in dissolution performancewas achieved by HME From the dissolution profiles it isevident that HME processing can be employed for the manu-facture of PCZ immediate release SD by processing polymer-surfactant combination The preferred dissolution patternscan be achieved through the drug loading percentage and theextrusion process The extrusion appeared to be an effectiveapproach for the development of diffusion controlled SD ofPCZ [35]

35 In Vivo Pharmacokinetic Study Figure 10 shows themeanplasma concentration-time curves of PCZ after admin-istration by oral gavage of crystalline PCZ PCZ suspension(Noxafil) PZ1 and PZ4 SD powder to rats The pharmacoki-netic parameters are listed in Table 5 The PCZSolPEG400(PZ1) and PCZSolTPGS (PZ4) SD had enhanced bioavail-ability This was increased compared with the PCZ suspen-sion although they all improved the bioavailability comparedwith pure crystalline PCZ Also the 119879max of PZ1 and PZ4 SD

was prior than that of PCZ suspension This happened dueto passive transport of PCZ across the membrane in presenceof Sol This was also correlated with the dissolution profileresults which claims that the dissolution rate of PZ SD wasfaster than that of PCZ suspension When passing throughthe GI tract the amorphous PCZ in SDwas quickly dissolvedand absorbed into blood circulation PCZprimarily circulatesas the parent compound in plasma The 119879max of PZ1 and PZ4SD was reached earlier at 1 h with plasma PCZ concentra-tion of 31797 ngmL and 26536 ngmL respectively whichindicates bioavailability enhancement FromTable 5 it can beseen that there was a significant difference between PZ1 SDand crystalline PCZ with the former having 116 times higherAUC(0ndash72) than PCZ and 177 times higher 119862max than PCZrespectively The corresponding results for PCZ suspensionwere having 49 times higher AUC(0ndash72) than PCZ and 62times higher 119862max than PCZ respectively The significantenhancement in the bioavailability of PCZ was achieved bythe PCZSol SD prepared by the HME process Also it isreported that the food intake improves the bioavailabilityof PCZ Supersaturation had a marked effect in which ahigh energy drug and used surfactants act as precipitationinhibitorswhich are induced by the gastrointestinal pHgradi-ent Hence this may result in supersaturated concentrationsand an increased flux across the membrane It was also


100

80

60

40

20

0

Dru

g re

leas

e (

)

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(a)

Dru

g re

leas

e (

)

80

70

60

50

40

30

20

10

0

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(b)

Figure 9 (a) In vitro release of SD systems in medium of 03 SLS (mean plusmn SD (119899 = 3)) (b) in vitro release of SD systems in distilled water(mean plusmn SD (119899 = 3))

Table 5 In vivo pharmacokinetic parameters of the PCZ Noxafil PZ1 and PZ4 tested

Parameters PCZ crystalline Noxafil PZ1 SD PZ4 SD119862max (ngmL) 2742 plusmn 1126 13474 plusmn 4724 31797 plusmn 1458 26536 plusmn 2235119879max (h) 6 plusmn 122 5 plusmn 131 1 plusmn 125 1 plusmn 137AUC(0ndash72) (ng hmL) 88035 plusmn 12435 470728 plusmn 24514 1015964 plusmn 102456 835428 plusmn 7866911990512 (h) 1824 plusmn 234 2558 plusmn 375 2512 plusmn 166 2587 plusmn 244

350

300

250

200

150

100

50

00 10 20 30 40 50 60 70PC

Z pl

asm

a con

cent

ratio

n (n

gm

L)

Time (h)

PCZ pureNoxafil

PZ1PZ4

Figure 10 In vivo plasma drug concentration-time curve of PCZNoxafil PZ1 SD and PZ4 SD

proved by the in vitro dissolution study that the SD showedimproved dissolution which allows further solubilizationby endogenous substances like biliary fluids Apparentlythis phenomenon plays an important role in the absorptionof PCZ in SD Compared with the PCZ suspension thehigher degree of supersaturation obtained with amorphousPCZ in the SD showed a significant enhancement in oralabsorption The Soluplus and added surfactants also act asstabilizer for supersaturation upon drug release by inhibitingprecipitation These factors all increase the oral absorptionand consequently the bioavailability of PCZ to several

folds as compared to PCZ suspension and crystalline PCZAmorphous PCZ SD prepared using HME was found to beeffective therapy with beneficial improvement in therapeuticactivity of PCZ [36ndash38]

36 Statistical Analysis All the results were expressed asmean plusmn standard deviation (SD) Statistical analysis wasperformed with Sigma Stat (Version 203) using one-wayANOVA test with 119875 lt 005 which was considered asstatistically significant difference

37 Contact Angle Calculation The contact angle is the angleformed by the solidliquid interface and the liquidvaporinterface measured from the side of the liquid Contact anglealso is a term used to describe a process where a drop ofliquid is in contact with a solid surface and exhibits its angletowards the surface By analyzing the contact angle we canrelate the valueswith the ratio and solubility andwettability ofthe drugs Disc made from pure PCZ showed higher contactangle after 60 sec of equilibrium whereas SD system showedvery less contact angle after equilibrium time This effectattributed to presence of hydrophilic polymer matrix andsoluble state of drug inside the system Low contact anglevalue indicates highly improved wetting property of PCZ inSD system as shown in Table 6

38 Stability on Storage SD is thermodynamicallymetastablesystem that favours the conversion of amorphous form tothe crystalline form under storage To evaluate the physical


Table 6 Contact angle measurement of pure PCZ and SD formula-tions

Formulation codes (SD) Contact angle (120579)119905 = 0 sec 119905 = 60 sec

PZ1 25 plusmn 02 11 plusmn 02PZ2 33 plusmn 04 16 plusmn 05PZ3 32 plusmn 03 14 plusmn 04PZ4 28 plusmn 05 12 plusmn 02Pure PCZ 93 plusmn 08 86 plusmn 06

state of the drug the systems were characterized by XRDand DSC after storage for 6 months The systems were stableduring a 6-month period In the case of SD no substantialrecrystallization was observed by DSC or XRD over the 6months storage suggesting that PCZ is more stable in thisformulation

4 Conclusions

In the current study it was clearly demonstrated that PCZimmediate release SD formulation can be effectively pro-duced by processing viaHMEwith dissolution rate solubilityand bioavailability enhancement Novel polymer-surfactantcombinations were optimised and stable SD systems weredeveloped successfully Utilization of Soluplus along withsuitable surfactants offers excellent possibilities to developstable amorphous SD Selective use of surfactants withlow concentrations improves process workability increasesmelt viscosity with torque reduction reduces 119879119892 of blendaugments quality of extrudes and reduces residence timeof extrusion The study revealed the importance of suit-able carrier and processing technique selections are criticalparameters during HME AFM analyses revealed micro-scopic surface interaction between drug and polymer MDsimulation studies revealed possible molecular interactionbetween drug-polymer Furthermore this PCZ-incorporatedSD gave higher dissolution compared to the commercialproduct and pure PCZ powder In vivo bioavailability of hotmelt extruded PCZ SD formulations showed several foldenhancements as compared to that of Noxafil suspension andpure PCZ This improved therapeutically active formulationwhich helps to cure opportunistic invasive infections moreeffectively

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors are thankful to UGC (SAP) for providing theresearch fellowship and Institute of Chemical TechnologyELITE status (Mumbai India) for providing all facilities andguidance The authors are thankful to SAIF department atIndian Institute of Technology Mumbai for Raman spec-troscopic experimental help and analyses The authors are

thankful to Mr Madhav Seervi (PhD Fellow) from Pharma-cology Department Institute of Chemical Technology forhelp in animal studies

References

[1] S Guns V Mathot J A Martens and G van den MooterldquoUpscaling of the hot-melt extrusion process comparisonbetween laboratory scale and pilot scale production of solid dis-persionswithmiconazole andKollicoat IRrdquoEuropean Journal ofPharmaceutics and Biopharmaceutics vol 81 no 3 pp 674ndash6822012

[2] R Fule T Meer P Amin D Dhamecha and S GhadlingeldquoPreparation and characterisation of lornoxicam solid disper-sion systems using hot melt extrusion techniquerdquo Journal ofPharmaceutical Investigation vol 44 no 1 pp 41ndash49 2014

[3] K Zhang H Yu Q Luo et al ldquoIncreased dissolution and oralabsorption of itraconazoleSoluplus extrudate compared withitraconazole nanosuspensionrdquo European Journal of Pharmaceu-tics and Biopharmaceutics vol 85 pp 1285ndash1292 2013

[4] J Djuris I Nikolakakis S Ibric Z Djuric and K KachrimanisldquoPreparation of carbamazepine-soluplus solid dispersions byhot-melt extrusion and prediction of drug-polymer miscibilityby thermodynamicmodel fittingrdquo European Journal of Pharma-ceutics and Biopharmaceutics vol 84 no 1 pp 228ndash237 2013

[5] R Fule TMeer A Sav and P Amin ldquoArtemether-Soluplus hot-melt extrudate solid dispersion systems for solubility and disso-lution rate enhancement with amorphous state characteristicsrdquoJournal of Pharmaceutics vol 1 pp 1ndash15 2013

[6] C Vo C Park and B Lee ldquoCurrent trends and future per-spectives of solid dispersions containing poorly water-solubledrugsrdquo European Journal of Pharmaceutics and Biopharmaceu-tics vol 85 pp 799ndash813 2013

[7] I Tho B Liepold J Rosenberg M Maegerlein M Brandland G Fricker ldquoFormation of nanomicro-dispersions withimproved dissolution properties upon dispersion of ritonavirmelt extrudate in aqueousmediardquo European Journal of Pharma-ceutical Sciences vol 40 no 1 pp 25ndash32 2010

[8] M Zhang H Li B Lang et al ldquoFormulation and deliveryof improved amorphous fenofibrate solid dispersions preparedby thin film freezingrdquo European Journal of Pharmaceutics andBiopharmaceutics vol 82 no 3 pp 534ndash544 2012

[9] R Fule TMeer A Sav and P Amin ldquoSolubility and dissolutionrate enhancement of lumefantrine using hot melt extrusiontechnology with physicochemical characterisationrdquo Journal ofPharmaceutical Investigation vol 43 no 4 pp 305ndash321 2013

[10] A L Sarode H Sandhu N Shah W Malick and H ZialdquoHot melt extrusion (HME) for amorphous solid dispersionsPredictive tools for processing and impact of drug-polymerinteractions on supersaturationrdquo European Journal of Pharma-ceutical Sciences vol 48 no 3 pp 371ndash384 2013

[11] D S Schiller and H B Fung ldquoPosaconazole an extended-spectrum triazole antifungal agentrdquo Clinical Therapeutics vol29 no 9 pp 1862ndash1886 2007

[12] G Krishna L Ma M Martinho R A Preston and E OrsquomaraldquoA new solid oral tablet formulation of posaconazole a random-ized clinical trial to investigate rising single- and multiple-dosepharmacokinetics and safety in healthy volunteersrdquo Journal ofAntimicrobial Chemotherapy vol 67 no 11 Article ID dks268pp 2725ndash2730 2012

[13] T Vasconcelos B Sarmento and P Costa ldquoSolid dispersionsas strategy to improve oral bioavailability of poor water soluble


drugsrdquo Drug Discovery Today vol 12 no 23-24 pp 1068ndash10752007

[14] IMKalogeras ldquoAnovel approach for analyzing glass-transitiontemperature vs composition patterns application to pharma-ceutical compound + polymer systemsrdquo European Journal ofPharmaceutical Sciences vol 42 no 5 pp 470ndash483 2011

[15] H Konno and L S Taylor ldquoInfluence of different polymerson the crystallization tendency of molecularly dispersed amor-phous felodipinerdquo Journal of Pharmaceutical Sciences vol 95no 12 pp 2692ndash2705 2006

[16] D J Greenhalgh A C Williams P Timmins and P YorkldquoSolubility parameters as predictors of miscibility in soliddispersionsrdquo Journal of Pharmaceutical Sciences vol 88 no 11pp 1182ndash1190 1999

[17] R Dukeck P Sieger and P Karmwar ldquoInvestigation andcorrelation of physical stability dissolution behaviour andinteraction parameter of amorphous solid dispersions of telmis-artan a drug development perspectiverdquo European Journal ofPharmaceutical Sciences vol 49 no 4 pp 723ndash731 2013

[18] P J Marsac S L Shamblin and L S Taylor ldquoTheoretical andpractical approaches for prediction of drug-polymer miscibilityand solubilityrdquo Pharmaceutical Research vol 23 no 10 pp2417ndash2426 2006

[19] G P Andrews O Abu-Diak F Kusmanto P Hornsby ZHui and D S Jones ldquoPhysicochemical characterization anddrug-release properties of celecoxib hot-melt extruded glasssolutionsrdquo Journal of Pharmacy and Pharmacology vol 62 no11 pp 1580ndash1590 2010

[20] E Widjaja P Kanaujia G Lau et al ldquoDetection of tracecrystallinity in an amorphous system using Raman microscopyand chemometric analysisrdquo European Journal of PharmaceuticalSciences vol 42 no 1-2 pp 45ndash54 2011

[21] E Reitz C Vervaet R H H Neubert andMThommes ldquoSolidcrystal suspensions containing griseofulvinmdashpreparation andbioavailability testingrdquo European Journal of Pharmaceutics andBiopharmaceutics vol 83 no 2 pp 193ndash202 2013

[22] M Maniruzzaman D J Morgan A P Mendham J Pang MJ Snowden and D Douroumis ldquoDrug-polymer intermolecularinteractions in hot-melt extruded solid dispersionsrdquo Interna-tional Journal of Pharmaceutics vol 443 no 1-2 pp 199ndash2082013

[23] MMachackovaa J Tokarsky and P Capkova ldquoA simple molec-ular modeling method for the characterization of polymericdrug carriersrdquo European Journal of Pharmaceutical Sciences vol48 no 1-2 pp 316ndash322 2013

[24] P Zhou X Xie D P Knight X Zong F Deng and W YaoldquoEffects of pH and calcium ions on the conformational transi-tions in silk fibroin using 2D Raman correlation spectroscopyand 13C solid-state NMRrdquo Biochemistry vol 43 no 35 pp11302ndash11311 2004

[25] C V Garcia G R Costa and A S L Mendez ldquoStability-indicating HPLCmethod for posaconazole bulk assayrdquo ScientiaPharmaceutica vol 80 no 2 pp 317ndash327 2012

[26] H Kim P Likhari P Kumari C Lin and A A Nomeir ldquoHigh-performance liquid chromatographic analysis of the anti-fungalagent SCH 56592 in dog serumrdquo Journal of Chromatography BBiomedical Sciences and Applications vol 738 no 1 pp 93ndash982000

[27] J Breitenbach ldquoMelt extrusion from process to drug deliverytechnologyrdquo European Journal of Pharmaceutics and Biophar-maceutics vol 54 no 2 pp 107ndash117 2002

[28] I Weuts D Kempen A Decorte et al ldquoPhase behaviouranalysis of solid dispersions of loperamide and two structurallyrelated compounds with the polymers PVP-K30 and PVP-VA64rdquo European Journal of Pharmaceutical Sciences vol 22 no5 pp 375ndash385 2004

[29] E Karavas E Georgarakis M P Sigalas K Avgoustakis and DBikiaris ldquoInvestigation of the release mechanism of a sparinglywater-soluble drug from solid dispersions in hydrophilic carri-ers based on physical state of drug particle size distribution anddrug-polymer interactionsrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 66 no 3 pp 334ndash347 2007

[30] C Leuner and J Dressman ldquoImproving drug solubility fororal delivery using solid dispersionsrdquo European Journal ofPharmaceutics and Biopharmaceutics vol 50 no 1 pp 47ndash602000

[31] L Saerens L Dierickx B Lenain C Vervaet J P Remonand T D Beer ldquoRaman spectroscopy for the in-line polymer-drug quantification and solid state characterization during apharmaceutical hot-melt extrusion processrdquo European Journalof Pharmaceutics and Biopharmaceutics vol 77 no 1 pp 158ndash163 2011

[32] M E Lauer M Siam J Tardio S Page J H Kindt and OGrassmann ldquoRapid assessment of homogeneity and stabilityof amorphous solid dispersions by atomic force microscopymdashfrom Bench to Batchrdquo Pharmaceutical Research vol 30 no 8pp 2010ndash2022 2013

[33] A Almeida L Saerens T de Beer J P Remon and C VervaetldquoUpscaling and in-line process monitoring via spectroscopictechniques of ethylene vinyl acetate hot-melt extruded formu-lationsrdquo International Journal of Pharmaceutics vol 439 no 1-2pp 223ndash229 2012

[34] N Zajc A Obreza M Bele and S Srcic ldquoPhysical propertiesand dissolution behaviour of nifedipinemannitol solid disper-sions prepared by hot melt methodrdquo International Journal ofPharmaceutics vol 291 no 1-2 pp 51ndash58 2005

[35] F Jijun Z Lili G Tingting T Xing and H Haibing ldquoStablenimodipine tablets with high bioavailability containingNM-SDprepared by hot-melt extrusionrdquo Powder Technology vol 204no 2-3 pp 214ndash221 2010

[36] G Krishna A Moton M Lei M M Medlock and J McLeodldquoPharmacokinetics and 694 absorption of posaconazole oralsuspension under various gastric conditions in healthy 695volunteersrdquoAntimicrobial Agents andChemotherapy vol 53 no3 pp 958ndash966 2009

[37] R Courtney S Pai M Laughlin J Lim and V BatraldquoPharmacokinetics safety and tolerability of oral posaconazoleadministered in single and multiple doses in healthy adultsrdquoAntimicrobial Agents andChemotherapy vol 47 no 9 pp 2788ndash2795 2003

[38] E S Dodds Ashley J B Varkey G Krishna et al ldquoPharma-cokinetics of posaconazole administered orally or by naso-gastric tube in healthy volunteersrdquo Antimicrobial Agents andChemotherapy vol 53 no 7 pp 2960ndash2964 2009

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of


StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of



Advances in Pharmacological Sciences

Tropical MedicineJournal of


Medicinal ChemistryInternational Journal of


AddictionJournal of



BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Autoimmune Diseases


Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of


Pharmaceutics


MEDIATORSINFLAMMATION

of


and used to treat invasive infections by candida speciesand aspergillus species in severely immunogenic patientsThe marketed oral suspension Noxafil (40mgmL of PCZconcentration) should be taken with food to maximizesystemic absorption In this paper a new solid oral SDformulation has been developed using HME with improvedbioavailability that can be administered without regard tofood PCZ has a very low aqueous solubility which impairsits dissolution in upper gastric fluid producing problems toprepared systems [11] Overall these characteristics hinder itstherapeutic application by delaying the absorption rate andthereby onset of action or activity [12] Together solubilitypermeability and dissolution rates of a drug are essentialfactors for determining its oral bioavailability The literaturereports generally revealed the fact that drug materials with avery low aqueous solubility will show dissolution rate limitedabsorption and hence poor bioavailability Improvement ofaqueous solubility in such a case is a valuable assignmentto improve therapeutic efficacy [13] PCZ is structurallyanalogous to itraconazole Itraconazole has been extensivelystudied by various researchers comprising its SD formu-lations by hot melt extrusion using Soluplus as primarysolubilising agent However there is no literature on theenhancement of solubility of PCZ by hot melt extrusionmethod reported Subsequently there is a need to deliverPCZ in formulation with increased solubility and improveddissolution profile The development of amorphous SD is aremarkable approach to increase the bioavailability of poorlysoluble APIs by enhancing their rate and extent of dissolution[14]

For the current study we selected polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer Solu-plus (Sol) a novel polymer with amphiphilic properties andexplored its solubilizing potential using HME technologyThe selected excipients PEG400 Lutrol F127 Lutrol F68and TPGS were prescreened first on the basis of extrusiontemperature processing temperature uniformity of extrudesretention time and solubilization Also these excipientscontributed to the permeability of SD formulation acrossmembrane Various researchers reported that these excipientssuccessfully enhance the bioavailability of poorly solubledrugs Soluplus when processed with PCZ alone the mixingand melt formation residence time is very high which causesformation disordered sticky heterogeneous extrudes Butwith addition of selected surfactant the torque decreases andextrudability and melt viscosity increase This improved thedrug distribution uniformity stability and physicochemicalperformance of obtained extrudes Sol offers exceptionalcapabilities for solubilization of BCS class II and class IVdrugs with the extensive possibility of making SD by hotmelt extrusion [15] Combination effect of Sol along withsurfactants such as PEG400 L F127 (LF127) L F68 (LF68)and TPGS was studied in detail in this paper

2 Materials and Methods

21 Materials PCZ was obtained as a generous gift fromABS life science Ltd India Sol LF127 LF68 and TPGS werekindly donated by BASF Corporation Mumbai India (head

office Ludwigshafen Germany) PEG400 of analytical gradewas procured from Sd Fine Chemicals Mumbai India

22 Methods

221 Calculation of Solubility Parameter (120575) Glass TransitionTemperature (119879119892) and Florey-Huggins Parameter (120594) Asan indicator of the drug-polymer miscibility values of 120575

were calculated using the Hoftyzer and vanKrevelen groupcontribution method described by the following equation

1205752= 1205752

119889 + 1205752

119901 + 1205752

ℎ (1)

where

120575119889 =sum119865119889119894

119881 120575119901 =

(sum1198652119901119894)12

119881 120575ℎ = (

sum119864ℎ119894

119881)

12

(2)

Here 119894 is the groups within the molecule 120575 is the totalsolubility parameter 120575119889 is the contribution from dispersionforces 120575119901 is the contribution from polar interactions 120575ℎis the contribution of hydrogen bonding 119865119889119894 is the molarattraction constant due to molar dispersion forces 119865119901119894 is themolar attraction constant due to molar polarization forces119864ℎ119894 is the hydrogen bonding energy and 119881 is the molarvolume The solubility parameters of polymer and surfactantcombinations were calculated using the following equation

12057512 = 1198811015840

11205751 + 1198811015840

21205751205882 (3)

where 1198811015840 is the volume fraction of each compoundMiscibility of the drug with the polymer can be assessed

based on the shift in melting endotherm or 119879119892 of the drug orcan be predicted theoretically using Gordon-Taylor equationbased on the 119879119892 densities and weight fractions of thecomponents Consider

119879119892mix (HME system) = 11988211198791198921 +11987011988221198791198922

1198821

+ 1198701198822

119870 asymp11987911989211205881

11987911989221205882

(4)

where 1198791198921 is the glass transition temperature of drug1198821 and1198822 are the weight fractions of the components and 119870 is theparameter calculated from the true densities (1205881 of drug and1205882 of polymer) and 1198791198922 of the amorphous components [16]The true density measurement of the PCZ and polymers wasdetermined in duplicate using a gas displacement pycnometer(Accupyc 1330 Micromeritics Norcross Georgia)

The Flory-Huggins (FH) interaction parameter (120594) wascalculated using the following equation

1

119879119898mixminus

1

119879119898pure

= minus119877

Δ119867119891

lnΦdrug + (1 minus1

119898)Φpolymer + 120594Φ

2

polymer

(5)






(gm)Sol(gm)

PEG400(gm)

LF127(gm)

LF68(gm)

TPGS(gm)































PZ1 05 17634 8817 2 115 230 13 086 22113 989 4971 12116PZ2 05 17634 8817 2 114 228 13 086 22113 9804 5011 12022PZ4 05 17634 8817 2 118 236 13 086 22113 10148 4858 12400PZ4 05 17634 8817 2 112 224 13 086 22113 9632 5091 11831








Table4Florey

Hug

gins


(120594)o

fSD

Ratio

1119879mix

1119879pu

reLH


11198981minus 1119898ΦPo

lymer

1minus1119898lowast

ΦPo

lymer

log(Φdrug)

lnΦdrug

+1minus

1119898lowastΦPo

lymerΦ2P

olym


+1minus

1119898lowastΦPo

lymer)

119877ΔHflowastΦ

2Polym

er120594

Left

120594

PZ1

0008695652

0005670863

0003025

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

000302minus0025

PZ2

000877193

0005670863

0003101

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

00031minus0026

PZ3

0008474576

0005670863

0002804

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

00028minus0023

PZ4

0008928571

0005670863

0003258

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

000326minus0027


40 60 80 100 120 140 160 180 200 220 240 2601171

19

20

21

22

23

24

25

26

1856

Hea

t flow

endo

(mW

)

PZ4 (6M)PZ3 (6M)

PZ2 (6M)PZ1 (6M)

PZ4

PZ3

PZ2

PZ1

PCZ pure

Temperature (∘C)

Hea

t flow

endo

(mW

)

PCZ pur

19

20

21

22

23

24

25

26

1856

Area = 345071mJ

40 60 80 100 120 140 160 180 200 220 240 2601171

Temperature (∘C)

Hea

t flow

endo

(mW

)

19

20

21

22

23

24

25

26

1856

40 60 80 100 120 140 160 180 200 220 240 2601171

Temperature (∘C)


PZ1 (PM)

ΔH = 690142 Jg

Peak = 17634∘C



19

20

21

22

23

24

25

26

27

28 PZ1PZ2

PZ3PZ4

Hea

t flow

endo

(mW

)

40 80 100 120 140 160 180 200 220 240 260 280 300

Temperature (∘C)

205∘C

220∘C

250∘C258∘C


15000

14000

13000

12000

11000

10000

9000

8000

7000

6000

5000

4000

3000

2000

1000

0

Lin

(cou

nts)


5 10 20 30 40 50

2-120579-scale





1500

1300

1100

900

700

500

300

100

minus100

minus300

16722

minus52834000 3000 2000 1500 1000 500400

385704356510

327412

304189

295659

281413

287019

264009204560

200857

176236

163795161745

141995132638

127152

123010118540

114747105424

100808

9405787331

82551

83442

59213

52734

51364

42060

41225

48422

T(

)

(a)

52850

46

42

38

34

30

26

22

1753440 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 450

T(

)

291325

235262

173102

164468

161415

155535

148585

144507

133462

137146 119755

123960

108349102338

97280

8419871678

6048657072

51430

(b)

40000 3000 2000 1500 1000 500 400

T(

)

153

131197531

minus1minus3minus5

minus67

338548 160219138467

107846

71402

(c)

4000 3000 2000 1500 1000 500400

T(

)

(cmminus1)

315302826242220181614121086420

minus2minus44

340080

173175

159890

138473

111072

8411678956

71349 60848

(d)

Figure 4 Continued


807

40154 3000 2000 1500 1000 500 2315

T(

)

70

60

50

40

30

20

10

0minus75

(cmminus1)

390973380684

369447360630

349662

303334288420

228209222009173023 124983

113504

97411

83827

71615 57158

67684

74695

146258

(e)


(a) (b)

(c) (d)

(e)



(a)

(b) continued

Inte

nsity

coun

ts

13800

13600

13400

13200

13000

12800

12600

12400

12200

12000

11800

11600

11400

11200

11000

1050 1100 1150 1200 1250 1300

b

a

c

d

X range (10120583m)

Z range (5610nm)PZ1

10


()

Height (m)

184E + 9

20

10

0

minus10

minus20

minus5 0 5minus5

0

5

08

06

04

02

184E + 9

X range (10120583m)

Yra

nge

(10120583

m)

PZ2


Height (m)

minus5

0

5

10

12

14

08

06

04

02

minus5 0 5

minus04

04

minus08

0


784E + 8


minus116E + 9

197E+


()

Z range (1733120583m)

Yra

nge

(10120583

m)

Figure 6 Continued


minus5

0

X range (10120583m)

PZ3

5

10

12

14

08

06

04

02


Height (m)

Yra

nge

(10120583

m)

minus025

025

05

minus05

0

minus5 0 5

minus5

0

PZ45

02

024

028

032

036

016

012

008

004


Height (m)

Yra

nge

(10120583

m)


100

200

minus100

0

(b)


minus571E + 8

197E


minus1E + 8

123E + 9(

)(

)

Z range (1388120583m)

Z range (3867nm)







(120583m

)

X (120583m)

Z(m

m)

5000minus50

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ1

(a)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ2

100minus100

(b)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ3

500

minus500

(c)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ4

400

minus400

(d)







C

Lp

LpLp

C

H

HLp

Lp

H

C

OLp

CC

C

HH

H

F

F

NN

NN

N

NN

N

O

O

O

OO

OO

O

O

Lp

Lp

Lp

Lp

Lp

Lp

Lp LpLp

Lp

LpLp

Lp

LpC

C

C

C

C

C C

C

C

C

C

C

C

CC

C

C

C

C

CC

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

CC

C C

C

C

C

H

HH

H

HH

H

HH

H

H

H H

HH HHH

H

H

H

H

HH

H

H

H

H H H

HH

H

HH

H

H

HH

H

HH H

HHH

HH

H

H

H

H

H

H

H

H

H

HH

H

H

HH

H

HH

H

H

C

HH

O Lp

C

NC

H

C C H

H

H

Lp

(a)

LpLp

H

H

OLp

H

H C

C

H

HH

H HH

C

HO

OH

H

H

H

H

C H

H

H

O

H

LpO

H

H

HCH

H

Lp

Lp

O

O

O

O

O

O

O

O

C

C

CC

CC

CCC

C

N

N

NN

N N

N

CC

CC C

C

C

C C

CC

C C

C

C C

C

CC

C

C

CC

C

C

C

HH

H H

HH

HH

H

HH

H

HH H

F HH

HH

H

H

H

HH

H

H

H

H

H H

H

HH

HH

HH

H

HH

HH H HH

HH

H

HHH

C

CC

C

C

C

CC

C

C

Lp

Lp

H

H

HH

C

H

OLp

C

Lp

CC

Lp

C H

C

HLp

Lp

LpLp

LpLp

LpLp

LpN

LpLp

H

H H

F

HC H

CH

LpH

HC

O

OLp

Lp

C

H

LpH

C

H H

HCNHH C

C

C

H

(b)

Lp

H

HC

H

H

H

Lp

H

H

HH

HC H

O

C

N

Lp

O

O

O

H

HH

H

CC

CC

C

H

H H H HH H H

H

H

HHHH

HH

HHHHH

H

H

HH H

H

HHH

H

HH H

H

H

H

H

HHHHHH

H

H H HHH

HH

H

HH

H H H

HH

H

H

H

H H

HH

C

CC

C

CC

C

CC

CC

CC

C C

C

C

C

C

C

C

C

CC

C

CCCCC

C

C

CCCC

CLp

C

CC

C

C

C

C

CC

CC

C

CC

C

CC

C

N

N

NN N

N

OO

OOO

O

O

O

O

O

Lp

Lp

Lp

Lp

Lp Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

LpLpLp

FF

H

H

N

H

H

H

H

H

H

HH

N OH

H

(c)

Lp H

HC

HH

HC

HLp

Lp

C

H

Lp

H

Lp

H

Lp

H

Lp

C

H

CH

H

H

H

H

H

HH

H

H

Lp

C

C

C

C

C

H

CCC

H

H

CH

C

H

H

HH

HH

H

H H H

HH

HH

H

H

HHH

H

H

H

H

HH

H

HHH

H H HH

H

H

HH

HHHHHH

HH

HHH

HHH

HHH

H

HH

HH

HH

HHH

H

H

H

H H

H

HH

HHHH

HH

HH

H

H

HH

HH

H

H

H H

H HHH

H H

HH

H

HH

H

HH

H

HH

H

H

C

CC

CC

C CC

CC

C C

CCC

C

CC

C

CC

C

CC

CCC

C

C

C

C

CCC

C CC

CC

C

C

C

C

CC

CC

CCC

C

C

CC

CCCC

C C

C

C

CCC

C

C

C

CC

CC

CC

CC

C

NN

N

NN

N

NN

N

OO

O

O O

O

OO

OO

O

OO

O

O

O

OO

LpLp

LpLpLp

Lp

Lp LpLp

Lp

LpLp

Lp

Lp

F

FLp

H

CH

H

HLpH

H

LpLp

Lp

(d)






100

80

60

40

20

0

Dru

g re

leas

e (

)

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(a)

Dru

g re

leas

e (

)

80

70

60

50

40

30

20

10

0

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(b)




350

300

250

200

150

100

50

00 10 20 30 40 50 60 70PC

Z pl

asm

a con

cent

ratio

n (n

gm

L)

Time (h)

PCZ pureNoxafil

PZ1PZ4












4 Conclusions




Acknowledgments



References













































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of






(gm)Sol(gm)

PEG400(gm)

LF127(gm)

LF68(gm)

TPGS(gm)































PZ1 05 17634 8817 2 115 230 13 086 22113 989 4971 12116PZ2 05 17634 8817 2 114 228 13 086 22113 9804 5011 12022PZ4 05 17634 8817 2 118 236 13 086 22113 10148 4858 12400PZ4 05 17634 8817 2 112 224 13 086 22113 9632 5091 11831








Table4Florey

Hug

gins


(120594)o

fSD

Ratio

1119879mix

1119879pu

reLH


11198981minus 1119898ΦPo

lymer

1minus1119898lowast

ΦPo

lymer

log(Φdrug)

lnΦdrug

+1minus

1119898lowastΦPo

lymerΦ2P

olym


+1minus

1119898lowastΦPo

lymer)

119877ΔHflowastΦ

2Polym

er120594

Left

120594

PZ1

0008695652

0005670863

0003025

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

000302minus0025

PZ2

000877193

0005670863

0003101

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

00031minus0026

PZ3

0008474576

0005670863

0002804

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

00028minus0023

PZ4

0008928571

0005670863

0003258

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

000326minus0027


40 60 80 100 120 140 160 180 200 220 240 2601171

19

20

21

22

23

24

25

26

1856

Hea

t flow

endo

(mW

)

PZ4 (6M)PZ3 (6M)

PZ2 (6M)PZ1 (6M)

PZ4

PZ3

PZ2

PZ1

PCZ pure

Temperature (∘C)

Hea

t flow

endo

(mW

)

PCZ pur

19

20

21

22

23

24

25

26

1856

Area = 345071mJ

40 60 80 100 120 140 160 180 200 220 240 2601171

Temperature (∘C)

Hea

t flow

endo

(mW

)

19

20

21

22

23

24

25

26

1856

40 60 80 100 120 140 160 180 200 220 240 2601171

Temperature (∘C)


PZ1 (PM)

ΔH = 690142 Jg

Peak = 17634∘C



19

20

21

22

23

24

25

26

27

28 PZ1PZ2

PZ3PZ4

Hea

t flow

endo

(mW

)

40 80 100 120 140 160 180 200 220 240 260 280 300

Temperature (∘C)

205∘C

220∘C

250∘C258∘C


15000

14000

13000

12000

11000

10000

9000

8000

7000

6000

5000

4000

3000

2000

1000

0

Lin

(cou

nts)


5 10 20 30 40 50

2-120579-scale





1500

1300

1100

900

700

500

300

100

minus100

minus300

16722

minus52834000 3000 2000 1500 1000 500400

385704356510

327412

304189

295659

281413

287019

264009204560

200857

176236

163795161745

141995132638

127152

123010118540

114747105424

100808

9405787331

82551

83442

59213

52734

51364

42060

41225

48422

T(

)

(a)

52850

46

42

38

34

30

26

22

1753440 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 450

T(

)

291325

235262

173102

164468

161415

155535

148585

144507

133462

137146 119755

123960

108349102338

97280

8419871678

6048657072

51430

(b)

40000 3000 2000 1500 1000 500 400

T(

)

153

131197531

minus1minus3minus5

minus67

338548 160219138467

107846

71402

(c)

4000 3000 2000 1500 1000 500400

T(

)

(cmminus1)

315302826242220181614121086420

minus2minus44

340080

173175

159890

138473

111072

8411678956

71349 60848

(d)

Figure 4 Continued


807

40154 3000 2000 1500 1000 500 2315

T(

)

70

60

50

40

30

20

10

0minus75

(cmminus1)

390973380684

369447360630

349662

303334288420

228209222009173023 124983

113504

97411

83827

71615 57158

67684

74695

146258

(e)


(a) (b)

(c) (d)

(e)



(a)

(b) continued

Inte

nsity

coun

ts

13800

13600

13400

13200

13000

12800

12600

12400

12200

12000

11800

11600

11400

11200

11000

1050 1100 1150 1200 1250 1300

b

a

c

d

X range (10120583m)

Z range (5610nm)PZ1

10


()

Height (m)

184E + 9

20

10

0

minus10

minus20

minus5 0 5minus5

0

5

08

06

04

02

184E + 9

X range (10120583m)

Yra

nge

(10120583

m)

PZ2


Height (m)

minus5

0

5

10

12

14

08

06

04

02

minus5 0 5

minus04

04

minus08

0


784E + 8


minus116E + 9

197E+


()

Z range (1733120583m)

Yra

nge

(10120583

m)

Figure 6 Continued


minus5

0

X range (10120583m)

PZ3

5

10

12

14

08

06

04

02


Height (m)

Yra

nge

(10120583

m)

minus025

025

05

minus05

0

minus5 0 5

minus5

0

PZ45

02

024

028

032

036

016

012

008

004


Height (m)

Yra

nge

(10120583

m)


100

200

minus100

0

(b)


minus571E + 8

197E


minus1E + 8

123E + 9(

)(

)

Z range (1388120583m)

Z range (3867nm)







(120583m

)

X (120583m)

Z(m

m)

5000minus50

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ1

(a)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ2

100minus100

(b)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ3

500

minus500

(c)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ4

400

minus400

(d)







C

Lp

LpLp

C

H

HLp

Lp

H

C

OLp

CC

C

HH

H

F

F

NN

NN

N

NN

N

O

O

O

OO

OO

O

O

Lp

Lp

Lp

Lp

Lp

Lp

Lp LpLp

Lp

LpLp

Lp

LpC

C

C

C

C

C C

C

C

C

C

C

C

CC

C

C

C

C

CC

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

CC

C C

C

C

C

H

HH

H

HH

H

HH

H

H

H H

HH HHH

H

H

H

H

HH

H

H

H

H H H

HH

H

HH

H

H

HH

H

HH H

HHH

HH

H

H

H

H

H

H

H

H

H

HH

H

H

HH

H

HH

H

H

C

HH

O Lp

C

NC

H

C C H

H

H

Lp

(a)

LpLp

H

H

OLp

H

H C

C

H

HH

H HH

C

HO

OH

H

H

H

H

C H

H

H

O

H

LpO

H

H

HCH

H

Lp

Lp

O

O

O

O

O

O

O

O

C

C

CC

CC

CCC

C

N

N

NN

N N

N

CC

CC C

C

C

C C

CC

C C

C

C C

C

CC

C

C

CC

C

C

C

HH

H H

HH

HH

H

HH

H

HH H

F HH

HH

H

H

H

HH

H

H

H

H

H H

H

HH

HH

HH

H

HH

HH H HH

HH

H

HHH

C

CC

C

C

C

CC

C

C

Lp

Lp

H

H

HH

C

H

OLp

C

Lp

CC

Lp

C H

C

HLp

Lp

LpLp

LpLp

LpLp

LpN

LpLp

H

H H

F

HC H

CH

LpH

HC

O

OLp

Lp

C

H

LpH

C

H H

HCNHH C

C

C

H

(b)

Lp

H

HC

H

H

H

Lp

H

H

HH

HC H

O

C

N

Lp

O

O

O

H

HH

H

CC

CC

C

H

H H H HH H H

H

H

HHHH

HH

HHHHH

H

H

HH H

H

HHH

H

HH H

H

H

H

H

HHHHHH

H

H H HHH

HH

H

HH

H H H

HH

H

H

H

H H

HH

C

CC

C

CC

C

CC

CC

CC

C C

C

C

C

C

C

C

C

CC

C

CCCCC

C

C

CCCC

CLp

C

CC

C

C

C

C

CC

CC

C

CC

C

CC

C

N

N

NN N

N

OO

OOO

O

O

O

O

O

Lp

Lp

Lp

Lp

Lp Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

LpLpLp

FF

H

H

N

H

H

H

H

H

H

HH

N OH

H

(c)

Lp H

HC

HH

HC

HLp

Lp

C

H

Lp

H

Lp

H

Lp

H

Lp

C

H

CH

H

H

H

H

H

HH

H

H

Lp

C

C

C

C

C

H

CCC

H

H

CH

C

H

H

HH

HH

H

H H H

HH

HH

H

H

HHH

H

H

H

H

HH

H

HHH

H H HH

H

H

HH

HHHHHH

HH

HHH

HHH

HHH

H

HH

HH

HH

HHH

H

H

H

H H

H

HH

HHHH

HH

HH

H

H

HH

HH

H

H

H H

H HHH

H H

HH

H

HH

H

HH

H

HH

H

H

C

CC

CC

C CC

CC

C C

CCC

C

CC

C

CC

C

CC

CCC

C

C

C

C

CCC

C CC

CC

C

C

C

C

CC

CC

CCC

C

C

CC

CCCC

C C

C

C

CCC

C

C

C

CC

CC

CC

CC

C

NN

N

NN

N

NN

N

OO

O

O O

O

OO

OO

O

OO

O

O

O

OO

LpLp

LpLpLp

Lp

Lp LpLp

Lp

LpLp

Lp

Lp

F

FLp

H

CH

H

HLpH

H

LpLp

Lp

(d)






100

80

60

40

20

0

Dru

g re

leas

e (

)

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(a)

Dru

g re

leas

e (

)

80

70

60

50

40

30

20

10

0

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(b)




350

300

250

200

150

100

50

00 10 20 30 40 50 60 70PC

Z pl

asm

a con

cent

ratio

n (n

gm

L)

Time (h)

PCZ pureNoxafil

PZ1PZ4












4 Conclusions




Acknowledgments



References













































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


















PZ1 05 17634 8817 2 115 230 13 086 22113 989 4971 12116PZ2 05 17634 8817 2 114 228 13 086 22113 9804 5011 12022PZ4 05 17634 8817 2 118 236 13 086 22113 10148 4858 12400PZ4 05 17634 8817 2 112 224 13 086 22113 9632 5091 11831








Table4Florey

Hug

gins


(120594)o

fSD

Ratio

1119879mix

1119879pu

reLH


11198981minus 1119898ΦPo

lymer

1minus1119898lowast

ΦPo

lymer

log(Φdrug)

lnΦdrug

+1minus

1119898lowastΦPo

lymerΦ2P

olym


+1minus

1119898lowastΦPo

lymer)

119877ΔHflowastΦ

2Polym

er120594

Left

120594

PZ1

0008695652

0005670863

0003025

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

000302minus0025

PZ2

000877193

0005670863

0003101

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

00031minus0026

PZ3

0008474576

0005670863

0002804

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

00028minus0023

PZ4

0008928571

0005670863

0003258

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

000326minus0027


40 60 80 100 120 140 160 180 200 220 240 2601171

19

20

21

22

23

24

25

26

1856

Hea

t flow

endo

(mW

)

PZ4 (6M)PZ3 (6M)

PZ2 (6M)PZ1 (6M)

PZ4

PZ3

PZ2

PZ1

PCZ pure

Temperature (∘C)

Hea

t flow

endo

(mW

)

PCZ pur

19

20

21

22

23

24

25

26

1856

Area = 345071mJ

40 60 80 100 120 140 160 180 200 220 240 2601171

Temperature (∘C)

Hea

t flow

endo

(mW

)

19

20

21

22

23

24

25

26

1856

40 60 80 100 120 140 160 180 200 220 240 2601171

Temperature (∘C)


PZ1 (PM)

ΔH = 690142 Jg

Peak = 17634∘C



19

20

21

22

23

24

25

26

27

28 PZ1PZ2

PZ3PZ4

Hea

t flow

endo

(mW

)

40 80 100 120 140 160 180 200 220 240 260 280 300

Temperature (∘C)

205∘C

220∘C

250∘C258∘C


15000

14000

13000

12000

11000

10000

9000

8000

7000

6000

5000

4000

3000

2000

1000

0

Lin

(cou

nts)


5 10 20 30 40 50

2-120579-scale





1500

1300

1100

900

700

500

300

100

minus100

minus300

16722

minus52834000 3000 2000 1500 1000 500400

385704356510

327412

304189

295659

281413

287019

264009204560

200857

176236

163795161745

141995132638

127152

123010118540

114747105424

100808

9405787331

82551

83442

59213

52734

51364

42060

41225

48422

T(

)

(a)

52850

46

42

38

34

30

26

22

1753440 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 450

T(

)

291325

235262

173102

164468

161415

155535

148585

144507

133462

137146 119755

123960

108349102338

97280

8419871678

6048657072

51430

(b)

40000 3000 2000 1500 1000 500 400

T(

)

153

131197531

minus1minus3minus5

minus67

338548 160219138467

107846

71402

(c)

4000 3000 2000 1500 1000 500400

T(

)

(cmminus1)

315302826242220181614121086420

minus2minus44

340080

173175

159890

138473

111072

8411678956

71349 60848

(d)

Figure 4 Continued


807

40154 3000 2000 1500 1000 500 2315

T(

)

70

60

50

40

30

20

10

0minus75

(cmminus1)

390973380684

369447360630

349662

303334288420

228209222009173023 124983

113504

97411

83827

71615 57158

67684

74695

146258

(e)


(a) (b)

(c) (d)

(e)



(a)

(b) continued

Inte

nsity

coun

ts

13800

13600

13400

13200

13000

12800

12600

12400

12200

12000

11800

11600

11400

11200

11000

1050 1100 1150 1200 1250 1300

b

a

c

d

X range (10120583m)

Z range (5610nm)PZ1

10


()

Height (m)

184E + 9

20

10

0

minus10

minus20

minus5 0 5minus5

0

5

08

06

04

02

184E + 9

X range (10120583m)

Yra

nge

(10120583

m)

PZ2


Height (m)

minus5

0

5

10

12

14

08

06

04

02

minus5 0 5

minus04

04

minus08

0


784E + 8


minus116E + 9

197E+


()

Z range (1733120583m)

Yra

nge

(10120583

m)

Figure 6 Continued


minus5

0

X range (10120583m)

PZ3

5

10

12

14

08

06

04

02


Height (m)

Yra

nge

(10120583

m)

minus025

025

05

minus05

0

minus5 0 5

minus5

0

PZ45

02

024

028

032

036

016

012

008

004


Height (m)

Yra

nge

(10120583

m)


100

200

minus100

0

(b)


minus571E + 8

197E


minus1E + 8

123E + 9(

)(

)

Z range (1388120583m)

Z range (3867nm)







(120583m

)

X (120583m)

Z(m

m)

5000minus50

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ1

(a)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ2

100minus100

(b)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ3

500

minus500

(c)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ4

400

minus400

(d)







C

Lp

LpLp

C

H

HLp

Lp

H

C

OLp

CC

C

HH

H

F

F

NN

NN

N

NN

N

O

O

O

OO

OO

O

O

Lp

Lp

Lp

Lp

Lp

Lp

Lp LpLp

Lp

LpLp

Lp

LpC

C

C

C

C

C C

C

C

C

C

C

C

CC

C

C

C

C

CC

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

CC

C C

C

C

C

H

HH

H

HH

H

HH

H

H

H H

HH HHH

H

H

H

H

HH

H

H

H

H H H

HH

H

HH

H

H

HH

H

HH H

HHH

HH

H

H

H

H

H

H

H

H

H

HH

H

H

HH

H

HH

H

H

C

HH

O Lp

C

NC

H

C C H

H

H

Lp

(a)

LpLp

H

H

OLp

H

H C

C

H

HH

H HH

C

HO

OH

H

H

H

H

C H

H

H

O

H

LpO

H

H

HCH

H

Lp

Lp

O

O

O

O

O

O

O

O

C

C

CC

CC

CCC

C

N

N

NN

N N

N

CC

CC C

C

C

C C

CC

C C

C

C C

C

CC

C

C

CC

C

C

C

HH

H H

HH

HH

H

HH

H

HH H

F HH

HH

H

H

H

HH

H

H

H

H

H H

H

HH

HH

HH

H

HH

HH H HH

HH

H

HHH

C

CC

C

C

C

CC

C

C

Lp

Lp

H

H

HH

C

H

OLp

C

Lp

CC

Lp

C H

C

HLp

Lp

LpLp

LpLp

LpLp

LpN

LpLp

H

H H

F

HC H

CH

LpH

HC

O

OLp

Lp

C

H

LpH

C

H H

HCNHH C

C

C

H

(b)

Lp

H

HC

H

H

H

Lp

H

H

HH

HC H

O

C

N

Lp

O

O

O

H

HH

H

CC

CC

C

H

H H H HH H H

H

H

HHHH

HH

HHHHH

H

H

HH H

H

HHH

H

HH H

H

H

H

H

HHHHHH

H

H H HHH

HH

H

HH

H H H

HH

H

H

H

H H

HH

C

CC

C

CC

C

CC

CC

CC

C C

C

C

C

C

C

C

C

CC

C

CCCCC

C

C

CCCC

CLp

C

CC

C

C

C

C

CC

CC

C

CC

C

CC

C

N

N

NN N

N

OO

OOO

O

O

O

O

O

Lp

Lp

Lp

Lp

Lp Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

LpLpLp

FF

H

H

N

H

H

H

H

H

H

HH

N OH

H

(c)

Lp H

HC

HH

HC

HLp

Lp

C

H

Lp

H

Lp

H

Lp

H

Lp

C

H

CH

H

H

H

H

H

HH

H

H

Lp

C

C

C

C

C

H

CCC

H

H

CH

C

H

H

HH

HH

H

H H H

HH

HH

H

H

HHH

H

H

H

H

HH

H

HHH

H H HH

H

H

HH

HHHHHH

HH

HHH

HHH

HHH

H

HH

HH

HH

HHH

H

H

H

H H

H

HH

HHHH

HH

HH

H

H

HH

HH

H

H

H H

H HHH

H H

HH

H

HH

H

HH

H

HH

H

H

C

CC

CC

C CC

CC

C C

CCC

C

CC

C

CC

C

CC

CCC

C

C

C

C

CCC

C CC

CC

C

C

C

C

CC

CC

CCC

C

C

CC

CCCC

C C

C

C

CCC

C

C

C

CC

CC

CC

CC

C

NN

N

NN

N

NN

N

OO

O

O O

O

OO

OO

O

OO

O

O

O

OO

LpLp

LpLpLp

Lp

Lp LpLp

Lp

LpLp

Lp

Lp

F

FLp

H

CH

H

HLpH

H

LpLp

Lp

(d)






100

80

60

40

20

0

Dru

g re

leas

e (

)

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(a)

Dru

g re

leas

e (

)

80

70

60

50

40

30

20

10

0

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(b)




350

300

250

200

150

100

50

00 10 20 30 40 50 60 70PC

Z pl

asm

a con

cent

ratio

n (n

gm

L)

Time (h)

PCZ pureNoxafil

PZ1PZ4












4 Conclusions




Acknowledgments



References













































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


Table4Florey

Hug

gins


(120594)o

fSD

Ratio

1119879mix

1119879pu

reLH


11198981minus 1119898ΦPo

lymer

1minus1119898lowast

ΦPo

lymer

log(Φdrug)

lnΦdrug

+1minus

1119898lowastΦPo

lymerΦ2P

olym


+1minus

1119898lowastΦPo

lymer)

119877ΔHflowastΦ

2Polym

er120594

Left

120594

PZ1

0008695652

0005670863

0003025

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

000302minus0025

PZ2

000877193

0005670863

0003101

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

00031minus0026

PZ3

0008474576

0005670863

0002804

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

00028minus0023

PZ4

0008928571

0005670863

0003258

8314

69014minus01204

683

05

205

05

105

minus030103

019897000

41

minus002396958

minus01204

68311

000326minus0027


40 60 80 100 120 140 160 180 200 220 240 2601171

19

20

21

22

23

24

25

26

1856

Hea

t flow

endo

(mW

)

PZ4 (6M)PZ3 (6M)

PZ2 (6M)PZ1 (6M)

PZ4

PZ3

PZ2

PZ1

PCZ pure

Temperature (∘C)

Hea

t flow

endo

(mW

)

PCZ pur

19

20

21

22

23

24

25

26

1856

Area = 345071mJ

40 60 80 100 120 140 160 180 200 220 240 2601171

Temperature (∘C)

Hea

t flow

endo

(mW

)

19

20

21

22

23

24

25

26

1856

40 60 80 100 120 140 160 180 200 220 240 2601171

Temperature (∘C)


PZ1 (PM)

ΔH = 690142 Jg

Peak = 17634∘C



19

20

21

22

23

24

25

26

27

28 PZ1PZ2

PZ3PZ4

Hea

t flow

endo

(mW

)

40 80 100 120 140 160 180 200 220 240 260 280 300

Temperature (∘C)

205∘C

220∘C

250∘C258∘C


15000

14000

13000

12000

11000

10000

9000

8000

7000

6000

5000

4000

3000

2000

1000

0

Lin

(cou

nts)


5 10 20 30 40 50

2-120579-scale





1500

1300

1100

900

700

500

300

100

minus100

minus300

16722

minus52834000 3000 2000 1500 1000 500400

385704356510

327412

304189

295659

281413

287019

264009204560

200857

176236

163795161745

141995132638

127152

123010118540

114747105424

100808

9405787331

82551

83442

59213

52734

51364

42060

41225

48422

T(

)

(a)

52850

46

42

38

34

30

26

22

1753440 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 450

T(

)

291325

235262

173102

164468

161415

155535

148585

144507

133462

137146 119755

123960

108349102338

97280

8419871678

6048657072

51430

(b)

40000 3000 2000 1500 1000 500 400

T(

)

153

131197531

minus1minus3minus5

minus67

338548 160219138467

107846

71402

(c)

4000 3000 2000 1500 1000 500400

T(

)

(cmminus1)

315302826242220181614121086420

minus2minus44

340080

173175

159890

138473

111072

8411678956

71349 60848

(d)

Figure 4 Continued


807

40154 3000 2000 1500 1000 500 2315

T(

)

70

60

50

40

30

20

10

0minus75

(cmminus1)

390973380684

369447360630

349662

303334288420

228209222009173023 124983

113504

97411

83827

71615 57158

67684

74695

146258

(e)


(a) (b)

(c) (d)

(e)



(a)

(b) continued

Inte

nsity

coun

ts

13800

13600

13400

13200

13000

12800

12600

12400

12200

12000

11800

11600

11400

11200

11000

1050 1100 1150 1200 1250 1300

b

a

c

d

X range (10120583m)

Z range (5610nm)PZ1

10


()

Height (m)

184E + 9

20

10

0

minus10

minus20

minus5 0 5minus5

0

5

08

06

04

02

184E + 9

X range (10120583m)

Yra

nge

(10120583

m)

PZ2


Height (m)

minus5

0

5

10

12

14

08

06

04

02

minus5 0 5

minus04

04

minus08

0


784E + 8


minus116E + 9

197E+


()

Z range (1733120583m)

Yra

nge

(10120583

m)

Figure 6 Continued


minus5

0

X range (10120583m)

PZ3

5

10

12

14

08

06

04

02


Height (m)

Yra

nge

(10120583

m)

minus025

025

05

minus05

0

minus5 0 5

minus5

0

PZ45

02

024

028

032

036

016

012

008

004


Height (m)

Yra

nge

(10120583

m)


100

200

minus100

0

(b)


minus571E + 8

197E


minus1E + 8

123E + 9(

)(

)

Z range (1388120583m)

Z range (3867nm)







(120583m

)

X (120583m)

Z(m

m)

5000minus50

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ1

(a)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ2

100minus100

(b)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ3

500

minus500

(c)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ4

400

minus400

(d)







C

Lp

LpLp

C

H

HLp

Lp

H

C

OLp

CC

C

HH

H

F

F

NN

NN

N

NN

N

O

O

O

OO

OO

O

O

Lp

Lp

Lp

Lp

Lp

Lp

Lp LpLp

Lp

LpLp

Lp

LpC

C

C

C

C

C C

C

C

C

C

C

C

CC

C

C

C

C

CC

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

CC

C C

C

C

C

H

HH

H

HH

H

HH

H

H

H H

HH HHH

H

H

H

H

HH

H

H

H

H H H

HH

H

HH

H

H

HH

H

HH H

HHH

HH

H

H

H

H

H

H

H

H

H

HH

H

H

HH

H

HH

H

H

C

HH

O Lp

C

NC

H

C C H

H

H

Lp

(a)

LpLp

H

H

OLp

H

H C

C

H

HH

H HH

C

HO

OH

H

H

H

H

C H

H

H

O

H

LpO

H

H

HCH

H

Lp

Lp

O

O

O

O

O

O

O

O

C

C

CC

CC

CCC

C

N

N

NN

N N

N

CC

CC C

C

C

C C

CC

C C

C

C C

C

CC

C

C

CC

C

C

C

HH

H H

HH

HH

H

HH

H

HH H

F HH

HH

H

H

H

HH

H

H

H

H

H H

H

HH

HH

HH

H

HH

HH H HH

HH

H

HHH

C

CC

C

C

C

CC

C

C

Lp

Lp

H

H

HH

C

H

OLp

C

Lp

CC

Lp

C H

C

HLp

Lp

LpLp

LpLp

LpLp

LpN

LpLp

H

H H

F

HC H

CH

LpH

HC

O

OLp

Lp

C

H

LpH

C

H H

HCNHH C

C

C

H

(b)

Lp

H

HC

H

H

H

Lp

H

H

HH

HC H

O

C

N

Lp

O

O

O

H

HH

H

CC

CC

C

H

H H H HH H H

H

H

HHHH

HH

HHHHH

H

H

HH H

H

HHH

H

HH H

H

H

H

H

HHHHHH

H

H H HHH

HH

H

HH

H H H

HH

H

H

H

H H

HH

C

CC

C

CC

C

CC

CC

CC

C C

C

C

C

C

C

C

C

CC

C

CCCCC

C

C

CCCC

CLp

C

CC

C

C

C

C

CC

CC

C

CC

C

CC

C

N

N

NN N

N

OO

OOO

O

O

O

O

O

Lp

Lp

Lp

Lp

Lp Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

LpLpLp

FF

H

H

N

H

H

H

H

H

H

HH

N OH

H

(c)

Lp H

HC

HH

HC

HLp

Lp

C

H

Lp

H

Lp

H

Lp

H

Lp

C

H

CH

H

H

H

H

H

HH

H

H

Lp

C

C

C

C

C

H

CCC

H

H

CH

C

H

H

HH

HH

H

H H H

HH

HH

H

H

HHH

H

H

H

H

HH

H

HHH

H H HH

H

H

HH

HHHHHH

HH

HHH

HHH

HHH

H

HH

HH

HH

HHH

H

H

H

H H

H

HH

HHHH

HH

HH

H

H

HH

HH

H

H

H H

H HHH

H H

HH

H

HH

H

HH

H

HH

H

H

C

CC

CC

C CC

CC

C C

CCC

C

CC

C

CC

C

CC

CCC

C

C

C

C

CCC

C CC

CC

C

C

C

C

CC

CC

CCC

C

C

CC

CCCC

C C

C

C

CCC

C

C

C

CC

CC

CC

CC

C

NN

N

NN

N

NN

N

OO

O

O O

O

OO

OO

O

OO

O

O

O

OO

LpLp

LpLpLp

Lp

Lp LpLp

Lp

LpLp

Lp

Lp

F

FLp

H

CH

H

HLpH

H

LpLp

Lp

(d)






100

80

60

40

20

0

Dru

g re

leas

e (

)

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(a)

Dru

g re

leas

e (

)

80

70

60

50

40

30

20

10

0

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(b)




350

300

250

200

150

100

50

00 10 20 30 40 50 60 70PC

Z pl

asm

a con

cent

ratio

n (n

gm

L)

Time (h)

PCZ pureNoxafil

PZ1PZ4












4 Conclusions




Acknowledgments



References













































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


40 60 80 100 120 140 160 180 200 220 240 2601171

19

20

21

22

23

24

25

26

1856

Hea

t flow

endo

(mW

)

PZ4 (6M)PZ3 (6M)

PZ2 (6M)PZ1 (6M)

PZ4

PZ3

PZ2

PZ1

PCZ pure

Temperature (∘C)

Hea

t flow

endo

(mW

)

PCZ pur

19

20

21

22

23

24

25

26

1856

Area = 345071mJ

40 60 80 100 120 140 160 180 200 220 240 2601171

Temperature (∘C)

Hea

t flow

endo

(mW

)

19

20

21

22

23

24

25

26

1856

40 60 80 100 120 140 160 180 200 220 240 2601171

Temperature (∘C)


PZ1 (PM)

ΔH = 690142 Jg

Peak = 17634∘C



19

20

21

22

23

24

25

26

27

28 PZ1PZ2

PZ3PZ4

Hea

t flow

endo

(mW

)

40 80 100 120 140 160 180 200 220 240 260 280 300

Temperature (∘C)

205∘C

220∘C

250∘C258∘C


15000

14000

13000

12000

11000

10000

9000

8000

7000

6000

5000

4000

3000

2000

1000

0

Lin

(cou

nts)


5 10 20 30 40 50

2-120579-scale





1500

1300

1100

900

700

500

300

100

minus100

minus300

16722

minus52834000 3000 2000 1500 1000 500400

385704356510

327412

304189

295659

281413

287019

264009204560

200857

176236

163795161745

141995132638

127152

123010118540

114747105424

100808

9405787331

82551

83442

59213

52734

51364

42060

41225

48422

T(

)

(a)

52850

46

42

38

34

30

26

22

1753440 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 450

T(

)

291325

235262

173102

164468

161415

155535

148585

144507

133462

137146 119755

123960

108349102338

97280

8419871678

6048657072

51430

(b)

40000 3000 2000 1500 1000 500 400

T(

)

153

131197531

minus1minus3minus5

minus67

338548 160219138467

107846

71402

(c)

4000 3000 2000 1500 1000 500400

T(

)

(cmminus1)

315302826242220181614121086420

minus2minus44

340080

173175

159890

138473

111072

8411678956

71349 60848

(d)

Figure 4 Continued


807

40154 3000 2000 1500 1000 500 2315

T(

)

70

60

50

40

30

20

10

0minus75

(cmminus1)

390973380684

369447360630

349662

303334288420

228209222009173023 124983

113504

97411

83827

71615 57158

67684

74695

146258

(e)


(a) (b)

(c) (d)

(e)



(a)

(b) continued

Inte

nsity

coun

ts

13800

13600

13400

13200

13000

12800

12600

12400

12200

12000

11800

11600

11400

11200

11000

1050 1100 1150 1200 1250 1300

b

a

c

d

X range (10120583m)

Z range (5610nm)PZ1

10


()

Height (m)

184E + 9

20

10

0

minus10

minus20

minus5 0 5minus5

0

5

08

06

04

02

184E + 9

X range (10120583m)

Yra

nge

(10120583

m)

PZ2


Height (m)

minus5

0

5

10

12

14

08

06

04

02

minus5 0 5

minus04

04

minus08

0


784E + 8


minus116E + 9

197E+


()

Z range (1733120583m)

Yra

nge

(10120583

m)

Figure 6 Continued


minus5

0

X range (10120583m)

PZ3

5

10

12

14

08

06

04

02


Height (m)

Yra

nge

(10120583

m)

minus025

025

05

minus05

0

minus5 0 5

minus5

0

PZ45

02

024

028

032

036

016

012

008

004


Height (m)

Yra

nge

(10120583

m)


100

200

minus100

0

(b)


minus571E + 8

197E


minus1E + 8

123E + 9(

)(

)

Z range (1388120583m)

Z range (3867nm)







(120583m

)

X (120583m)

Z(m

m)

5000minus50

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ1

(a)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ2

100minus100

(b)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ3

500

minus500

(c)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ4

400

minus400

(d)







C

Lp

LpLp

C

H

HLp

Lp

H

C

OLp

CC

C

HH

H

F

F

NN

NN

N

NN

N

O

O

O

OO

OO

O

O

Lp

Lp

Lp

Lp

Lp

Lp

Lp LpLp

Lp

LpLp

Lp

LpC

C

C

C

C

C C

C

C

C

C

C

C

CC

C

C

C

C

CC

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

CC

C C

C

C

C

H

HH

H

HH

H

HH

H

H

H H

HH HHH

H

H

H

H

HH

H

H

H

H H H

HH

H

HH

H

H

HH

H

HH H

HHH

HH

H

H

H

H

H

H

H

H

H

HH

H

H

HH

H

HH

H

H

C

HH

O Lp

C

NC

H

C C H

H

H

Lp

(a)

LpLp

H

H

OLp

H

H C

C

H

HH

H HH

C

HO

OH

H

H

H

H

C H

H

H

O

H

LpO

H

H

HCH

H

Lp

Lp

O

O

O

O

O

O

O

O

C

C

CC

CC

CCC

C

N

N

NN

N N

N

CC

CC C

C

C

C C

CC

C C

C

C C

C

CC

C

C

CC

C

C

C

HH

H H

HH

HH

H

HH

H

HH H

F HH

HH

H

H

H

HH

H

H

H

H

H H

H

HH

HH

HH

H

HH

HH H HH

HH

H

HHH

C

CC

C

C

C

CC

C

C

Lp

Lp

H

H

HH

C

H

OLp

C

Lp

CC

Lp

C H

C

HLp

Lp

LpLp

LpLp

LpLp

LpN

LpLp

H

H H

F

HC H

CH

LpH

HC

O

OLp

Lp

C

H

LpH

C

H H

HCNHH C

C

C

H

(b)

Lp

H

HC

H

H

H

Lp

H

H

HH

HC H

O

C

N

Lp

O

O

O

H

HH

H

CC

CC

C

H

H H H HH H H

H

H

HHHH

HH

HHHHH

H

H

HH H

H

HHH

H

HH H

H

H

H

H

HHHHHH

H

H H HHH

HH

H

HH

H H H

HH

H

H

H

H H

HH

C

CC

C

CC

C

CC

CC

CC

C C

C

C

C

C

C

C

C

CC

C

CCCCC

C

C

CCCC

CLp

C

CC

C

C

C

C

CC

CC

C

CC

C

CC

C

N

N

NN N

N

OO

OOO

O

O

O

O

O

Lp

Lp

Lp

Lp

Lp Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

LpLpLp

FF

H

H

N

H

H

H

H

H

H

HH

N OH

H

(c)

Lp H

HC

HH

HC

HLp

Lp

C

H

Lp

H

Lp

H

Lp

H

Lp

C

H

CH

H

H

H

H

H

HH

H

H

Lp

C

C

C

C

C

H

CCC

H

H

CH

C

H

H

HH

HH

H

H H H

HH

HH

H

H

HHH

H

H

H

H

HH

H

HHH

H H HH

H

H

HH

HHHHHH

HH

HHH

HHH

HHH

H

HH

HH

HH

HHH

H

H

H

H H

H

HH

HHHH

HH

HH

H

H

HH

HH

H

H

H H

H HHH

H H

HH

H

HH

H

HH

H

HH

H

H

C

CC

CC

C CC

CC

C C

CCC

C

CC

C

CC

C

CC

CCC

C

C

C

C

CCC

C CC

CC

C

C

C

C

CC

CC

CCC

C

C

CC

CCCC

C C

C

C

CCC

C

C

C

CC

CC

CC

CC

C

NN

N

NN

N

NN

N

OO

O

O O

O

OO

OO

O

OO

O

O

O

OO

LpLp

LpLpLp

Lp

Lp LpLp

Lp

LpLp

Lp

Lp

F

FLp

H

CH

H

HLpH

H

LpLp

Lp

(d)






100

80

60

40

20

0

Dru

g re

leas

e (

)

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(a)

Dru

g re

leas

e (

)

80

70

60

50

40

30

20

10

0

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(b)




350

300

250

200

150

100

50

00 10 20 30 40 50 60 70PC

Z pl

asm

a con

cent

ratio

n (n

gm

L)

Time (h)

PCZ pureNoxafil

PZ1PZ4












4 Conclusions




Acknowledgments



References













































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


1500

1300

1100

900

700

500

300

100

minus100

minus300

16722

minus52834000 3000 2000 1500 1000 500400

385704356510

327412

304189

295659

281413

287019

264009204560

200857

176236

163795161745

141995132638

127152

123010118540

114747105424

100808

9405787331

82551

83442

59213

52734

51364

42060

41225

48422

T(

)

(a)

52850

46

42

38

34

30

26

22

1753440 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 450

T(

)

291325

235262

173102

164468

161415

155535

148585

144507

133462

137146 119755

123960

108349102338

97280

8419871678

6048657072

51430

(b)

40000 3000 2000 1500 1000 500 400

T(

)

153

131197531

minus1minus3minus5

minus67

338548 160219138467

107846

71402

(c)

4000 3000 2000 1500 1000 500400

T(

)

(cmminus1)

315302826242220181614121086420

minus2minus44

340080

173175

159890

138473

111072

8411678956

71349 60848

(d)

Figure 4 Continued


807

40154 3000 2000 1500 1000 500 2315

T(

)

70

60

50

40

30

20

10

0minus75

(cmminus1)

390973380684

369447360630

349662

303334288420

228209222009173023 124983

113504

97411

83827

71615 57158

67684

74695

146258

(e)


(a) (b)

(c) (d)

(e)



(a)

(b) continued

Inte

nsity

coun

ts

13800

13600

13400

13200

13000

12800

12600

12400

12200

12000

11800

11600

11400

11200

11000

1050 1100 1150 1200 1250 1300

b

a

c

d

X range (10120583m)

Z range (5610nm)PZ1

10


()

Height (m)

184E + 9

20

10

0

minus10

minus20

minus5 0 5minus5

0

5

08

06

04

02

184E + 9

X range (10120583m)

Yra

nge

(10120583

m)

PZ2


Height (m)

minus5

0

5

10

12

14

08

06

04

02

minus5 0 5

minus04

04

minus08

0


784E + 8


minus116E + 9

197E+


()

Z range (1733120583m)

Yra

nge

(10120583

m)

Figure 6 Continued


minus5

0

X range (10120583m)

PZ3

5

10

12

14

08

06

04

02


Height (m)

Yra

nge

(10120583

m)

minus025

025

05

minus05

0

minus5 0 5

minus5

0

PZ45

02

024

028

032

036

016

012

008

004


Height (m)

Yra

nge

(10120583

m)


100

200

minus100

0

(b)


minus571E + 8

197E


minus1E + 8

123E + 9(

)(

)

Z range (1388120583m)

Z range (3867nm)







(120583m

)

X (120583m)

Z(m

m)

5000minus50

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ1

(a)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ2

100minus100

(b)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ3

500

minus500

(c)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ4

400

minus400

(d)







C

Lp

LpLp

C

H

HLp

Lp

H

C

OLp

CC

C

HH

H

F

F

NN

NN

N

NN

N

O

O

O

OO

OO

O

O

Lp

Lp

Lp

Lp

Lp

Lp

Lp LpLp

Lp

LpLp

Lp

LpC

C

C

C

C

C C

C

C

C

C

C

C

CC

C

C

C

C

CC

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

CC

C C

C

C

C

H

HH

H

HH

H

HH

H

H

H H

HH HHH

H

H

H

H

HH

H

H

H

H H H

HH

H

HH

H

H

HH

H

HH H

HHH

HH

H

H

H

H

H

H

H

H

H

HH

H

H

HH

H

HH

H

H

C

HH

O Lp

C

NC

H

C C H

H

H

Lp

(a)

LpLp

H

H

OLp

H

H C

C

H

HH

H HH

C

HO

OH

H

H

H

H

C H

H

H

O

H

LpO

H

H

HCH

H

Lp

Lp

O

O

O

O

O

O

O

O

C

C

CC

CC

CCC

C

N

N

NN

N N

N

CC

CC C

C

C

C C

CC

C C

C

C C

C

CC

C

C

CC

C

C

C

HH

H H

HH

HH

H

HH

H

HH H

F HH

HH

H

H

H

HH

H

H

H

H

H H

H

HH

HH

HH

H

HH

HH H HH

HH

H

HHH

C

CC

C

C

C

CC

C

C

Lp

Lp

H

H

HH

C

H

OLp

C

Lp

CC

Lp

C H

C

HLp

Lp

LpLp

LpLp

LpLp

LpN

LpLp

H

H H

F

HC H

CH

LpH

HC

O

OLp

Lp

C

H

LpH

C

H H

HCNHH C

C

C

H

(b)

Lp

H

HC

H

H

H

Lp

H

H

HH

HC H

O

C

N

Lp

O

O

O

H

HH

H

CC

CC

C

H

H H H HH H H

H

H

HHHH

HH

HHHHH

H

H

HH H

H

HHH

H

HH H

H

H

H

H

HHHHHH

H

H H HHH

HH

H

HH

H H H

HH

H

H

H

H H

HH

C

CC

C

CC

C

CC

CC

CC

C C

C

C

C

C

C

C

C

CC

C

CCCCC

C

C

CCCC

CLp

C

CC

C

C

C

C

CC

CC

C

CC

C

CC

C

N

N

NN N

N

OO

OOO

O

O

O

O

O

Lp

Lp

Lp

Lp

Lp Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

LpLpLp

FF

H

H

N

H

H

H

H

H

H

HH

N OH

H

(c)

Lp H

HC

HH

HC

HLp

Lp

C

H

Lp

H

Lp

H

Lp

H

Lp

C

H

CH

H

H

H

H

H

HH

H

H

Lp

C

C

C

C

C

H

CCC

H

H

CH

C

H

H

HH

HH

H

H H H

HH

HH

H

H

HHH

H

H

H

H

HH

H

HHH

H H HH

H

H

HH

HHHHHH

HH

HHH

HHH

HHH

H

HH

HH

HH

HHH

H

H

H

H H

H

HH

HHHH

HH

HH

H

H

HH

HH

H

H

H H

H HHH

H H

HH

H

HH

H

HH

H

HH

H

H

C

CC

CC

C CC

CC

C C

CCC

C

CC

C

CC

C

CC

CCC

C

C

C

C

CCC

C CC

CC

C

C

C

C

CC

CC

CCC

C

C

CC

CCCC

C C

C

C

CCC

C

C

C

CC

CC

CC

CC

C

NN

N

NN

N

NN

N

OO

O

O O

O

OO

OO

O

OO

O

O

O

OO

LpLp

LpLpLp

Lp

Lp LpLp

Lp

LpLp

Lp

Lp

F

FLp

H

CH

H

HLpH

H

LpLp

Lp

(d)






100

80

60

40

20

0

Dru

g re

leas

e (

)

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(a)

Dru

g re

leas

e (

)

80

70

60

50

40

30

20

10

0

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(b)




350

300

250

200

150

100

50

00 10 20 30 40 50 60 70PC

Z pl

asm

a con

cent

ratio

n (n

gm

L)

Time (h)

PCZ pureNoxafil

PZ1PZ4












4 Conclusions




Acknowledgments



References













































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


807

40154 3000 2000 1500 1000 500 2315

T(

)

70

60

50

40

30

20

10

0minus75

(cmminus1)

390973380684

369447360630

349662

303334288420

228209222009173023 124983

113504

97411

83827

71615 57158

67684

74695

146258

(e)


(a) (b)

(c) (d)

(e)



(a)

(b) continued

Inte

nsity

coun

ts

13800

13600

13400

13200

13000

12800

12600

12400

12200

12000

11800

11600

11400

11200

11000

1050 1100 1150 1200 1250 1300

b

a

c

d

X range (10120583m)

Z range (5610nm)PZ1

10


()

Height (m)

184E + 9

20

10

0

minus10

minus20

minus5 0 5minus5

0

5

08

06

04

02

184E + 9

X range (10120583m)

Yra

nge

(10120583

m)

PZ2


Height (m)

minus5

0

5

10

12

14

08

06

04

02

minus5 0 5

minus04

04

minus08

0


784E + 8


minus116E + 9

197E+


()

Z range (1733120583m)

Yra

nge

(10120583

m)

Figure 6 Continued


minus5

0

X range (10120583m)

PZ3

5

10

12

14

08

06

04

02


Height (m)

Yra

nge

(10120583

m)

minus025

025

05

minus05

0

minus5 0 5

minus5

0

PZ45

02

024

028

032

036

016

012

008

004


Height (m)

Yra

nge

(10120583

m)


100

200

minus100

0

(b)


minus571E + 8

197E


minus1E + 8

123E + 9(

)(

)

Z range (1388120583m)

Z range (3867nm)







(120583m

)

X (120583m)

Z(m

m)

5000minus50

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ1

(a)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ2

100minus100

(b)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ3

500

minus500

(c)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ4

400

minus400

(d)







C

Lp

LpLp

C

H

HLp

Lp

H

C

OLp

CC

C

HH

H

F

F

NN

NN

N

NN

N

O

O

O

OO

OO

O

O

Lp

Lp

Lp

Lp

Lp

Lp

Lp LpLp

Lp

LpLp

Lp

LpC

C

C

C

C

C C

C

C

C

C

C

C

CC

C

C

C

C

CC

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

CC

C C

C

C

C

H

HH

H

HH

H

HH

H

H

H H

HH HHH

H

H

H

H

HH

H

H

H

H H H

HH

H

HH

H

H

HH

H

HH H

HHH

HH

H

H

H

H

H

H

H

H

H

HH

H

H

HH

H

HH

H

H

C

HH

O Lp

C

NC

H

C C H

H

H

Lp

(a)

LpLp

H

H

OLp

H

H C

C

H

HH

H HH

C

HO

OH

H

H

H

H

C H

H

H

O

H

LpO

H

H

HCH

H

Lp

Lp

O

O

O

O

O

O

O

O

C

C

CC

CC

CCC

C

N

N

NN

N N

N

CC

CC C

C

C

C C

CC

C C

C

C C

C

CC

C

C

CC

C

C

C

HH

H H

HH

HH

H

HH

H

HH H

F HH

HH

H

H

H

HH

H

H

H

H

H H

H

HH

HH

HH

H

HH

HH H HH

HH

H

HHH

C

CC

C

C

C

CC

C

C

Lp

Lp

H

H

HH

C

H

OLp

C

Lp

CC

Lp

C H

C

HLp

Lp

LpLp

LpLp

LpLp

LpN

LpLp

H

H H

F

HC H

CH

LpH

HC

O

OLp

Lp

C

H

LpH

C

H H

HCNHH C

C

C

H

(b)

Lp

H

HC

H

H

H

Lp

H

H

HH

HC H

O

C

N

Lp

O

O

O

H

HH

H

CC

CC

C

H

H H H HH H H

H

H

HHHH

HH

HHHHH

H

H

HH H

H

HHH

H

HH H

H

H

H

H

HHHHHH

H

H H HHH

HH

H

HH

H H H

HH

H

H

H

H H

HH

C

CC

C

CC

C

CC

CC

CC

C C

C

C

C

C

C

C

C

CC

C

CCCCC

C

C

CCCC

CLp

C

CC

C

C

C

C

CC

CC

C

CC

C

CC

C

N

N

NN N

N

OO

OOO

O

O

O

O

O

Lp

Lp

Lp

Lp

Lp Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

LpLpLp

FF

H

H

N

H

H

H

H

H

H

HH

N OH

H

(c)

Lp H

HC

HH

HC

HLp

Lp

C

H

Lp

H

Lp

H

Lp

H

Lp

C

H

CH

H

H

H

H

H

HH

H

H

Lp

C

C

C

C

C

H

CCC

H

H

CH

C

H

H

HH

HH

H

H H H

HH

HH

H

H

HHH

H

H

H

H

HH

H

HHH

H H HH

H

H

HH

HHHHHH

HH

HHH

HHH

HHH

H

HH

HH

HH

HHH

H

H

H

H H

H

HH

HHHH

HH

HH

H

H

HH

HH

H

H

H H

H HHH

H H

HH

H

HH

H

HH

H

HH

H

H

C

CC

CC

C CC

CC

C C

CCC

C

CC

C

CC

C

CC

CCC

C

C

C

C

CCC

C CC

CC

C

C

C

C

CC

CC

CCC

C

C

CC

CCCC

C C

C

C

CCC

C

C

C

CC

CC

CC

CC

C

NN

N

NN

N

NN

N

OO

O

O O

O

OO

OO

O

OO

O

O

O

OO

LpLp

LpLpLp

Lp

Lp LpLp

Lp

LpLp

Lp

Lp

F

FLp

H

CH

H

HLpH

H

LpLp

Lp

(d)






100

80

60

40

20

0

Dru

g re

leas

e (

)

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(a)

Dru

g re

leas

e (

)

80

70

60

50

40

30

20

10

0

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(b)




350

300

250

200

150

100

50

00 10 20 30 40 50 60 70PC

Z pl

asm

a con

cent

ratio

n (n

gm

L)

Time (h)

PCZ pureNoxafil

PZ1PZ4












4 Conclusions




Acknowledgments



References













































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


(a)

(b) continued

Inte

nsity

coun

ts

13800

13600

13400

13200

13000

12800

12600

12400

12200

12000

11800

11600

11400

11200

11000

1050 1100 1150 1200 1250 1300

b

a

c

d

X range (10120583m)

Z range (5610nm)PZ1

10


()

Height (m)

184E + 9

20

10

0

minus10

minus20

minus5 0 5minus5

0

5

08

06

04

02

184E + 9

X range (10120583m)

Yra

nge

(10120583

m)

PZ2


Height (m)

minus5

0

5

10

12

14

08

06

04

02

minus5 0 5

minus04

04

minus08

0


784E + 8


minus116E + 9

197E+


()

Z range (1733120583m)

Yra

nge

(10120583

m)

Figure 6 Continued


minus5

0

X range (10120583m)

PZ3

5

10

12

14

08

06

04

02


Height (m)

Yra

nge

(10120583

m)

minus025

025

05

minus05

0

minus5 0 5

minus5

0

PZ45

02

024

028

032

036

016

012

008

004


Height (m)

Yra

nge

(10120583

m)


100

200

minus100

0

(b)


minus571E + 8

197E


minus1E + 8

123E + 9(

)(

)

Z range (1388120583m)

Z range (3867nm)







(120583m

)

X (120583m)

Z(m

m)

5000minus50

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ1

(a)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ2

100minus100

(b)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ3

500

minus500

(c)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ4

400

minus400

(d)







C

Lp

LpLp

C

H

HLp

Lp

H

C

OLp

CC

C

HH

H

F

F

NN

NN

N

NN

N

O

O

O

OO

OO

O

O

Lp

Lp

Lp

Lp

Lp

Lp

Lp LpLp

Lp

LpLp

Lp

LpC

C

C

C

C

C C

C

C

C

C

C

C

CC

C

C

C

C

CC

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

CC

C C

C

C

C

H

HH

H

HH

H

HH

H

H

H H

HH HHH

H

H

H

H

HH

H

H

H

H H H

HH

H

HH

H

H

HH

H

HH H

HHH

HH

H

H

H

H

H

H

H

H

H

HH

H

H

HH

H

HH

H

H

C

HH

O Lp

C

NC

H

C C H

H

H

Lp

(a)

LpLp

H

H

OLp

H

H C

C

H

HH

H HH

C

HO

OH

H

H

H

H

C H

H

H

O

H

LpO

H

H

HCH

H

Lp

Lp

O

O

O

O

O

O

O

O

C

C

CC

CC

CCC

C

N

N

NN

N N

N

CC

CC C

C

C

C C

CC

C C

C

C C

C

CC

C

C

CC

C

C

C

HH

H H

HH

HH

H

HH

H

HH H

F HH

HH

H

H

H

HH

H

H

H

H

H H

H

HH

HH

HH

H

HH

HH H HH

HH

H

HHH

C

CC

C

C

C

CC

C

C

Lp

Lp

H

H

HH

C

H

OLp

C

Lp

CC

Lp

C H

C

HLp

Lp

LpLp

LpLp

LpLp

LpN

LpLp

H

H H

F

HC H

CH

LpH

HC

O

OLp

Lp

C

H

LpH

C

H H

HCNHH C

C

C

H

(b)

Lp

H

HC

H

H

H

Lp

H

H

HH

HC H

O

C

N

Lp

O

O

O

H

HH

H

CC

CC

C

H

H H H HH H H

H

H

HHHH

HH

HHHHH

H

H

HH H

H

HHH

H

HH H

H

H

H

H

HHHHHH

H

H H HHH

HH

H

HH

H H H

HH

H

H

H

H H

HH

C

CC

C

CC

C

CC

CC

CC

C C

C

C

C

C

C

C

C

CC

C

CCCCC

C

C

CCCC

CLp

C

CC

C

C

C

C

CC

CC

C

CC

C

CC

C

N

N

NN N

N

OO

OOO

O

O

O

O

O

Lp

Lp

Lp

Lp

Lp Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

LpLpLp

FF

H

H

N

H

H

H

H

H

H

HH

N OH

H

(c)

Lp H

HC

HH

HC

HLp

Lp

C

H

Lp

H

Lp

H

Lp

H

Lp

C

H

CH

H

H

H

H

H

HH

H

H

Lp

C

C

C

C

C

H

CCC

H

H

CH

C

H

H

HH

HH

H

H H H

HH

HH

H

H

HHH

H

H

H

H

HH

H

HHH

H H HH

H

H

HH

HHHHHH

HH

HHH

HHH

HHH

H

HH

HH

HH

HHH

H

H

H

H H

H

HH

HHHH

HH

HH

H

H

HH

HH

H

H

H H

H HHH

H H

HH

H

HH

H

HH

H

HH

H

H

C

CC

CC

C CC

CC

C C

CCC

C

CC

C

CC

C

CC

CCC

C

C

C

C

CCC

C CC

CC

C

C

C

C

CC

CC

CCC

C

C

CC

CCCC

C C

C

C

CCC

C

C

C

CC

CC

CC

CC

C

NN

N

NN

N

NN

N

OO

O

O O

O

OO

OO

O

OO

O

O

O

OO

LpLp

LpLpLp

Lp

Lp LpLp

Lp

LpLp

Lp

Lp

F

FLp

H

CH

H

HLpH

H

LpLp

Lp

(d)






100

80

60

40

20

0

Dru

g re

leas

e (

)

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(a)

Dru

g re

leas

e (

)

80

70

60

50

40

30

20

10

0

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(b)




350

300

250

200

150

100

50

00 10 20 30 40 50 60 70PC

Z pl

asm

a con

cent

ratio

n (n

gm

L)

Time (h)

PCZ pureNoxafil

PZ1PZ4












4 Conclusions




Acknowledgments



References













































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


minus5

0

X range (10120583m)

PZ3

5

10

12

14

08

06

04

02


Height (m)

Yra

nge

(10120583

m)

minus025

025

05

minus05

0

minus5 0 5

minus5

0

PZ45

02

024

028

032

036

016

012

008

004


Height (m)

Yra

nge

(10120583

m)


100

200

minus100

0

(b)


minus571E + 8

197E


minus1E + 8

123E + 9(

)(

)

Z range (1388120583m)

Z range (3867nm)







(120583m

)

X (120583m)

Z(m

m)

5000minus50

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ1

(a)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ2

100minus100

(b)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ3

500

minus500

(c)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ4

400

minus400

(d)







C

Lp

LpLp

C

H

HLp

Lp

H

C

OLp

CC

C

HH

H

F

F

NN

NN

N

NN

N

O

O

O

OO

OO

O

O

Lp

Lp

Lp

Lp

Lp

Lp

Lp LpLp

Lp

LpLp

Lp

LpC

C

C

C

C

C C

C

C

C

C

C

C

CC

C

C

C

C

CC

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

CC

C C

C

C

C

H

HH

H

HH

H

HH

H

H

H H

HH HHH

H

H

H

H

HH

H

H

H

H H H

HH

H

HH

H

H

HH

H

HH H

HHH

HH

H

H

H

H

H

H

H

H

H

HH

H

H

HH

H

HH

H

H

C

HH

O Lp

C

NC

H

C C H

H

H

Lp

(a)

LpLp

H

H

OLp

H

H C

C

H

HH

H HH

C

HO

OH

H

H

H

H

C H

H

H

O

H

LpO

H

H

HCH

H

Lp

Lp

O

O

O

O

O

O

O

O

C

C

CC

CC

CCC

C

N

N

NN

N N

N

CC

CC C

C

C

C C

CC

C C

C

C C

C

CC

C

C

CC

C

C

C

HH

H H

HH

HH

H

HH

H

HH H

F HH

HH

H

H

H

HH

H

H

H

H

H H

H

HH

HH

HH

H

HH

HH H HH

HH

H

HHH

C

CC

C

C

C

CC

C

C

Lp

Lp

H

H

HH

C

H

OLp

C

Lp

CC

Lp

C H

C

HLp

Lp

LpLp

LpLp

LpLp

LpN

LpLp

H

H H

F

HC H

CH

LpH

HC

O

OLp

Lp

C

H

LpH

C

H H

HCNHH C

C

C

H

(b)

Lp

H

HC

H

H

H

Lp

H

H

HH

HC H

O

C

N

Lp

O

O

O

H

HH

H

CC

CC

C

H

H H H HH H H

H

H

HHHH

HH

HHHHH

H

H

HH H

H

HHH

H

HH H

H

H

H

H

HHHHHH

H

H H HHH

HH

H

HH

H H H

HH

H

H

H

H H

HH

C

CC

C

CC

C

CC

CC

CC

C C

C

C

C

C

C

C

C

CC

C

CCCCC

C

C

CCCC

CLp

C

CC

C

C

C

C

CC

CC

C

CC

C

CC

C

N

N

NN N

N

OO

OOO

O

O

O

O

O

Lp

Lp

Lp

Lp

Lp Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

LpLpLp

FF

H

H

N

H

H

H

H

H

H

HH

N OH

H

(c)

Lp H

HC

HH

HC

HLp

Lp

C

H

Lp

H

Lp

H

Lp

H

Lp

C

H

CH

H

H

H

H

H

HH

H

H

Lp

C

C

C

C

C

H

CCC

H

H

CH

C

H

H

HH

HH

H

H H H

HH

HH

H

H

HHH

H

H

H

H

HH

H

HHH

H H HH

H

H

HH

HHHHHH

HH

HHH

HHH

HHH

H

HH

HH

HH

HHH

H

H

H

H H

H

HH

HHHH

HH

HH

H

H

HH

HH

H

H

H H

H HHH

H H

HH

H

HH

H

HH

H

HH

H

H

C

CC

CC

C CC

CC

C C

CCC

C

CC

C

CC

C

CC

CCC

C

C

C

C

CCC

C CC

CC

C

C

C

C

CC

CC

CCC

C

C

CC

CCCC

C C

C

C

CCC

C

C

C

CC

CC

CC

CC

C

NN

N

NN

N

NN

N

OO

O

O O

O

OO

OO

O

OO

O

O

O

OO

LpLp

LpLpLp

Lp

Lp LpLp

Lp

LpLp

Lp

Lp

F

FLp

H

CH

H

HLpH

H

LpLp

Lp

(d)






100

80

60

40

20

0

Dru

g re

leas

e (

)

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(a)

Dru

g re

leas

e (

)

80

70

60

50

40

30

20

10

0

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(b)




350

300

250

200

150

100

50

00 10 20 30 40 50 60 70PC

Z pl

asm

a con

cent

ratio

n (n

gm

L)

Time (h)

PCZ pureNoxafil

PZ1PZ4












4 Conclusions




Acknowledgments



References













































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


(120583m

)

X (120583m)

Z(m

m)

5000minus50

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ1

(a)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

20

20

40

40

PZ2

100minus100

(b)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ3

500

minus500

(c)

Y(120583

m)

X (120583m)

Z(n

m)

minus40

minus40

minus20

minus20

00

00

00

20

20

40

40

PZ4

400

minus400

(d)







C

Lp

LpLp

C

H

HLp

Lp

H

C

OLp

CC

C

HH

H

F

F

NN

NN

N

NN

N

O

O

O

OO

OO

O

O

Lp

Lp

Lp

Lp

Lp

Lp

Lp LpLp

Lp

LpLp

Lp

LpC

C

C

C

C

C C

C

C

C

C

C

C

CC

C

C

C

C

CC

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

CC

C C

C

C

C

H

HH

H

HH

H

HH

H

H

H H

HH HHH

H

H

H

H

HH

H

H

H

H H H

HH

H

HH

H

H

HH

H

HH H

HHH

HH

H

H

H

H

H

H

H

H

H

HH

H

H

HH

H

HH

H

H

C

HH

O Lp

C

NC

H

C C H

H

H

Lp

(a)

LpLp

H

H

OLp

H

H C

C

H

HH

H HH

C

HO

OH

H

H

H

H

C H

H

H

O

H

LpO

H

H

HCH

H

Lp

Lp

O

O

O

O

O

O

O

O

C

C

CC

CC

CCC

C

N

N

NN

N N

N

CC

CC C

C

C

C C

CC

C C

C

C C

C

CC

C

C

CC

C

C

C

HH

H H

HH

HH

H

HH

H

HH H

F HH

HH

H

H

H

HH

H

H

H

H

H H

H

HH

HH

HH

H

HH

HH H HH

HH

H

HHH

C

CC

C

C

C

CC

C

C

Lp

Lp

H

H

HH

C

H

OLp

C

Lp

CC

Lp

C H

C

HLp

Lp

LpLp

LpLp

LpLp

LpN

LpLp

H

H H

F

HC H

CH

LpH

HC

O

OLp

Lp

C

H

LpH

C

H H

HCNHH C

C

C

H

(b)

Lp

H

HC

H

H

H

Lp

H

H

HH

HC H

O

C

N

Lp

O

O

O

H

HH

H

CC

CC

C

H

H H H HH H H

H

H

HHHH

HH

HHHHH

H

H

HH H

H

HHH

H

HH H

H

H

H

H

HHHHHH

H

H H HHH

HH

H

HH

H H H

HH

H

H

H

H H

HH

C

CC

C

CC

C

CC

CC

CC

C C

C

C

C

C

C

C

C

CC

C

CCCCC

C

C

CCCC

CLp

C

CC

C

C

C

C

CC

CC

C

CC

C

CC

C

N

N

NN N

N

OO

OOO

O

O

O

O

O

Lp

Lp

Lp

Lp

Lp Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

LpLpLp

FF

H

H

N

H

H

H

H

H

H

HH

N OH

H

(c)

Lp H

HC

HH

HC

HLp

Lp

C

H

Lp

H

Lp

H

Lp

H

Lp

C

H

CH

H

H

H

H

H

HH

H

H

Lp

C

C

C

C

C

H

CCC

H

H

CH

C

H

H

HH

HH

H

H H H

HH

HH

H

H

HHH

H

H

H

H

HH

H

HHH

H H HH

H

H

HH

HHHHHH

HH

HHH

HHH

HHH

H

HH

HH

HH

HHH

H

H

H

H H

H

HH

HHHH

HH

HH

H

H

HH

HH

H

H

H H

H HHH

H H

HH

H

HH

H

HH

H

HH

H

H

C

CC

CC

C CC

CC

C C

CCC

C

CC

C

CC

C

CC

CCC

C

C

C

C

CCC

C CC

CC

C

C

C

C

CC

CC

CCC

C

C

CC

CCCC

C C

C

C

CCC

C

C

C

CC

CC

CC

CC

C

NN

N

NN

N

NN

N

OO

O

O O

O

OO

OO

O

OO

O

O

O

OO

LpLp

LpLpLp

Lp

Lp LpLp

Lp

LpLp

Lp

Lp

F

FLp

H

CH

H

HLpH

H

LpLp

Lp

(d)






100

80

60

40

20

0

Dru

g re

leas

e (

)

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(a)

Dru

g re

leas

e (

)

80

70

60

50

40

30

20

10

0

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(b)




350

300

250

200

150

100

50

00 10 20 30 40 50 60 70PC

Z pl

asm

a con

cent

ratio

n (n

gm

L)

Time (h)

PCZ pureNoxafil

PZ1PZ4












4 Conclusions




Acknowledgments



References













































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


C

Lp

LpLp

C

H

HLp

Lp

H

C

OLp

CC

C

HH

H

F

F

NN

NN

N

NN

N

O

O

O

OO

OO

O

O

Lp

Lp

Lp

Lp

Lp

Lp

Lp LpLp

Lp

LpLp

Lp

LpC

C

C

C

C

C C

C

C

C

C

C

C

CC

C

C

C

C

CC

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

CC

C C

C

C

C

H

HH

H

HH

H

HH

H

H

H H

HH HHH

H

H

H

H

HH

H

H

H

H H H

HH

H

HH

H

H

HH

H

HH H

HHH

HH

H

H

H

H

H

H

H

H

H

HH

H

H

HH

H

HH

H

H

C

HH

O Lp

C

NC

H

C C H

H

H

Lp

(a)

LpLp

H

H

OLp

H

H C

C

H

HH

H HH

C

HO

OH

H

H

H

H

C H

H

H

O

H

LpO

H

H

HCH

H

Lp

Lp

O

O

O

O

O

O

O

O

C

C

CC

CC

CCC

C

N

N

NN

N N

N

CC

CC C

C

C

C C

CC

C C

C

C C

C

CC

C

C

CC

C

C

C

HH

H H

HH

HH

H

HH

H

HH H

F HH

HH

H

H

H

HH

H

H

H

H

H H

H

HH

HH

HH

H

HH

HH H HH

HH

H

HHH

C

CC

C

C

C

CC

C

C

Lp

Lp

H

H

HH

C

H

OLp

C

Lp

CC

Lp

C H

C

HLp

Lp

LpLp

LpLp

LpLp

LpN

LpLp

H

H H

F

HC H

CH

LpH

HC

O

OLp

Lp

C

H

LpH

C

H H

HCNHH C

C

C

H

(b)

Lp

H

HC

H

H

H

Lp

H

H

HH

HC H

O

C

N

Lp

O

O

O

H

HH

H

CC

CC

C

H

H H H HH H H

H

H

HHHH

HH

HHHHH

H

H

HH H

H

HHH

H

HH H

H

H

H

H

HHHHHH

H

H H HHH

HH

H

HH

H H H

HH

H

H

H

H H

HH

C

CC

C

CC

C

CC

CC

CC

C C

C

C

C

C

C

C

C

CC

C

CCCCC

C

C

CCCC

CLp

C

CC

C

C

C

C

CC

CC

C

CC

C

CC

C

N

N

NN N

N

OO

OOO

O

O

O

O

O

Lp

Lp

Lp

Lp

Lp Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

Lp

LpLp

Lp

Lp

LpLpLp

FF

H

H

N

H

H

H

H

H

H

HH

N OH

H

(c)

Lp H

HC

HH

HC

HLp

Lp

C

H

Lp

H

Lp

H

Lp

H

Lp

C

H

CH

H

H

H

H

H

HH

H

H

Lp

C

C

C

C

C

H

CCC

H

H

CH

C

H

H

HH

HH

H

H H H

HH

HH

H

H

HHH

H

H

H

H

HH

H

HHH

H H HH

H

H

HH

HHHHHH

HH

HHH

HHH

HHH

H

HH

HH

HH

HHH

H

H

H

H H

H

HH

HHHH

HH

HH

H

H

HH

HH

H

H

H H

H HHH

H H

HH

H

HH

H

HH

H

HH

H

H

C

CC

CC

C CC

CC

C C

CCC

C

CC

C

CC

C

CC

CCC

C

C

C

C

CCC

C CC

CC

C

C

C

C

CC

CC

CCC

C

C

CC

CCCC

C C

C

C

CCC

C

C

C

CC

CC

CC

CC

C

NN

N

NN

N

NN

N

OO

O

O O

O

OO

OO

O

OO

O

O

O

OO

LpLp

LpLpLp

Lp

Lp LpLp

Lp

LpLp

Lp

Lp

F

FLp

H

CH

H

HLpH

H

LpLp

Lp

(d)






100

80

60

40

20

0

Dru

g re

leas

e (

)

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(a)

Dru

g re

leas

e (

)

80

70

60

50

40

30

20

10

0

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(b)




350

300

250

200

150

100

50

00 10 20 30 40 50 60 70PC

Z pl

asm

a con

cent

ratio

n (n

gm

L)

Time (h)

PCZ pureNoxafil

PZ1PZ4












4 Conclusions




Acknowledgments



References













































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


100

80

60

40

20

0

Dru

g re

leas

e (

)

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(a)

Dru

g re

leas

e (

)

80

70

60

50

40

30

20

10

0

Time (min)

Pure PCZPZ1PZ2

PZ3PZ4Noxafil

0 10 20 30 40 50 60

(b)




350

300

250

200

150

100

50

00 10 20 30 40 50 60 70PC

Z pl

asm

a con

cent

ratio

n (n

gm

L)

Time (h)

PCZ pureNoxafil

PZ1PZ4












4 Conclusions




Acknowledgments



References













































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of






4 Conclusions




Acknowledgments



References













































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of
































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of

Research Article Hot Melt Extruded Amorphous Solid...

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