E!ect of API-Polymer Miscibility and Interaction on the Stabilizationof Amorphous Solid Dispersion: A Molecular Simulation StudyYin Yani,*,† Parijat Kanaujia,† Pui Shan Chow,† and Reginald B. H. Tan†,‡

†Institute of Chemical & Engineering Sciences, A*STAR (Agency for Science, Technology and Research), 1 Pesek Road, JurongIsland 627833, Singapore‡Department of Chemical & Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, 117576 Singapore

ABSTRACT: In this study, a molecular dynamics simulation technique wasemployed to predict miscibility and interaction of Active PharmaceuticalIngredient (API) with polymer carriers in solid dispersion system based onHansen solubility parameter and hydrogen bond formation, respectively. SeveralAPIs with and without hydrogen bonding tendency were studied. The Hansensolubility parameters of APIs and polymers calculated by molecular dynamicsimulation were similar to reported values in the literature. Our simulation resultswere able to determine the interactions between APIs and various polymers(ionic and nonionic) and also predict the hydrogen bond interaction energy andhydrogen bond lifetime. The simulation results were veri!ed by preparing soliddispersions using hot melt extrusion. As predicted by our simulation, clear andcolorless extrudates were obtained for ibuprofen/PVP-VA 64, ibuprofen/EudragitEPO, and feno!brate/PVP-VA 64, which con!rmed the miscibility between APIs(ibuprofen, feno!brate) and polymers. Stability studies con!rmed the amorphousstabilization of ibuprofen/PVP-VA64 and ibuprofen/Eudragit EPO solid dispersions. However, recrystallization of feno!bratewas observed from feno!brate/PVP-VA 64 due to the lack of molecular interactions between feno!brate and PVP-VA 64 aspredicted in our simulation. This suggests that miscibility alone cannot be used to predict the stability of amorphous dispersionbut molecular interactions have to be considered. The simulation method used in this study could be a useful tool for theselection of polymer excipients to form stable amorphous solid dispersions with enhanced performance.

1. INTRODUCTIONSolid dispersions1 of drugs in water-soluble polymeric carriershave been used as a means for improving the dissolution rate,and hence possibly bioavailability, for a range of hydrophobicdrugs.2 However, the structure and solid state of drug in thecarrier, and mechanism for the enhancement of the dissolutionrate and stabilization of amorphous phase by the carrier are notyet fully understood. Therefore, the development andcommercialization of solid dispersions have been hamperedby the lack of performance predictability.There are a few methods to prepare solid dispersion, such as,

solvent evaporation,3 spray drying,4 electrostatic spinning,5 andhot melt extrusion.6 However, formation of stable soliddispersion requires the presence of intermolecular interactions7

between the drug and the polymeric carrier in order to avoidphase separation or recrystallization during storage. The e"ectof drug!polymer interaction on the stabilization of amorphoussolid dispersions has been well understood.1a,8 Chauhan andco-workers9 investigated molecular interactions betweenCurcumin and various type of polymers using Fouriertransform infrared spectroscopy (FTIR) and Raman forsuccessful formulation of amorphous solid dispersion. Apolymer to be chosen as excipient in a solid dispersion mustshow a#nity for the API via hydrogen bonding or weak van derWaals interactions.1a,10 It is reported that hydrophobic

polymers show higher a#nity for hydrophobic APIs.1a

Nevertheless, published literature comparing the use of ionicand nonionic polymers on the stability and the dissolutionenhancement of interacting and noninteracting drugs isunavailable.Several experimental methods have been used to study the

miscibility of amorphous drug and polymer system, includingglass transition temperature (Tg) measurement by Di"erentialScanning Calorimetry (DSC), Raman mapping, computationalanalysis of X-ray Di"raction data, solid state Nuclear MagneticResonance spectroscopy, and Atomic Force Microscopy.11 API-polymer miscibility in solid dispersions can also be determinedby molecular simulation.12 Maniruzzaman et al.12b usedquantum mechanical simulation to predict API-polymerinteractions. They also predicted API/polymer miscibility bydetermining the Hansen solubility parameters for both drugsand polymers. Larson and co-worker1a performed all-atom MDsimulation of aqueous solutions of hydroxypropyl methylcellu-lose (HPMC) and hydroxypropyl methylcellulose acetate

Received: August 1, 2017Revised: October 2, 2017Accepted: October 12, 2017Published: October 12, 2017

Article

pubs.acs.org/IECR

© XXXX American Chemical Society A DOI: 10.1021/acs.iecr.7b03187Ind. Eng. Chem. Res. XXXX, XXX, XXX!XXX

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succinate (HPMCAS) excipients interacting with a poorlysoluble API, phenytoin.This work aims to understand the e"ect of miscibility and

interaction between API and polymer on the stabilization andthe dissolution enhancement of amorphous solid dispersions.The polymers were selected from both groups of ionic polymer(Eudragit-EPO) and nonionic polymers (PVP-VA64). VariousAPIs were chosen with some having an H-bond formingtendency with the carriers (ibuprofen and clonazepam) andsome without H-bond forming tendency with the carriers(feno!brate and alprazolam). Molecular dynamics (MD)simulation technique was employed to predict the miscibilityof drugs in polymer carriers based on Hansen solubilityparameter and to determine the preferable site of interactionbetween drugs and polymers. On the basis of the simulationresults, a few drug/polymer combinations were selected forexperimental observation. Hot melt extrusion was performedfor the combination of API/polymer in order to verify thesimulation results. The physical mixtures and solid dispersionswere characterized by X-ray di"raction, Fourier transforminfrared spectroscopy (FTIR), and Di"erential scanningcalorimetry (DSC).

2. COMPUTATIONAL METHOD2.1. Molecular Modeling. Molecular dynamics (MD)

simulations were carried out using the Accelrys MaterialsStudio (Version 7.0)13 for APIs (clonazepam, ibuprofen,feno!brate, and alprazolam), and polymers (PVP-VA64,HPMC, and Eudragit EPO). The crystal structures of APIswere obtained from Cambridge Structural Database, Ver. 5.26.The lattice parameters are reported in Table 1. The crystalstructures were extended to 2 ! 3 ! 3, 2 ! 3 ! 3, 3 ! 3 ! 3,and 3 ! 2 ! 2 unit cells for clonazepam, ibuprofen, feno!brate,and alprazolam, respectively. Energy minimization wasperformed for all systems. COMPASS14 (condensed-phaseoptimized molecular potentials for the atomistic simulationstudies) force !eld was used to model the atomic interactionsfor all API molecules. COMPASS force !eld model givesdensities of 1.38, 1.29, 1.39, and 1.10 g/cm3 for pureclonazepam, feno!brate, alprazolam, and ibuprofen, respec-tively. These values are in good agreement with the reportedclonazepam, feno!brate, alprazolam, and ibuprofen densities of1.50, 1.18, 1.37, and 1.03 g/cm3 respectively. The integrationtime step used was 1 fs. Ewald summation was used to enablethe long-range interactions. A cuto" radius of 6.0 Å was usedfor both nonbonded and electrostatic interactions. Simulationin the NPT (constant number of particle, constant pressure,and constant temperature) ensemble was !rst conducted at 298K for 2 ns to obtain an equilibrium density for each system. Theproduction run was then performed by simulation in NVT(isothermal) ensemble for 500 ps. Equilibration wasdetermined by observing the change in the thermodynamicproperties (energies, temperatures, and densities) as a functionof time. A system was concluded to have reached equilibrationcondition if these properties showed su#ciently small variations

over time. The required time to reach equilibration for allsystems was less than 100 ps. The Nose/Hoover15 thermostatand Berendsen barostat16 were used to control the temperatureand pressure, respectively. The Hansen solubility parameter wascalculated by choosing !ve di"erent data sets of trajectories (attime step range of 0.5!0.75 ns, 1.5!1.75 ns, 1.75!2 ns, 2.3!2.4 ns, and 2.4!2.5 ns) from the equilibrated system. Hansensolubility parameter was calculated for each data set and thenaveraged to obtain the average solubility parameter for all APIsstudied.

2.2. Solubility Parameter. As de!ned by Hildebrand andScott,17 the solubility parameter, !t, is the square root of thecohesive energy density (CED).18 CED is de!ned as thecohesive energy (Ecoh) per unit of molar volume (Vm), which isthe di"erence of total energy to intramolecular energy of asystem.13

! = = ! "EV

H RTV

( )t2 coh

m

v

m (1)

where Hv is heat of vaporization, R is the Gas constant, and T istemperature.Pharmaceutical solid dispersions are highly complex mixture

of small organic molecules dispersed in polymers. Hansen(1969) further re!ned the Hildebrand model to predict themiscibility of APIs mixed with polymer in a solid dispersionsystem. He described the total cohesive energy as the resultantcontribution of dispersion forces, permanent dipole!dipoleinteractions, and hydrogen bonds.19 Van Krevelen and Hoftyer(1976) calculated the Hansen solubility parameter (!t) fromnonpolar atomic (dispersion) interactions (!d), dipole!dipolemolecular interactions (!p) and hydrogen bonding (electroninterchange) molecular interactions (!h) of various functionalgroups present on the drug molecule19 using eq 2.

! ! ! != + +t2

d2

p2

h2

(2)

The di"erence of the solubility parameters (!!t) of twomaterials is known as the interaction parameter and is widelyused as a tool to predict miscibility of two solids in meltedcondition. Compounds with !!t value <7.0 MPa0.5 are likely tobe miscible and compounds with !!t value >10 MPa0.5 aremost likely to be immiscible.20

2.3. Interactions of APIs and Polymers. It has beenreported that solid dispersions with strong drug!polymerinteractions and less hygroscopic polymer are unlikely to phaseseparate during storage.1b,21 Therefore, to predict the stabilityof solid dispersion, molecular simulations were performed toobserve the interactions between drugs and polymers. Themonomeric structure of HPMC, PVP-VA64, and Eudragit-EPOand two to four monomeric structures of APIs wereconstructed, and MD simulations were performed in NPTensemble for 500 ps at 298 K. Energy minimization was thenperformed for all API-polymer systems to access the non-bonded interaction between API and polymer, such as,hydrogen bonds.

Table 1. Lattice Parameters for Di!erent APIs

APIs lattice type lattice parameter (a ! b ! c) " # $

clonazepam triclinic 12.33 ! 10.15 ! 12.39 108.96 103.92 86.17ibuprofen monoclinic 14.667 ! 7.886 ! 10.73 90 99.362 90feno!brate triclinic 8.1605 ! 8.2664 ! 14.511 93.951 105.664 96.002alprazolam monoclinic 7.361 ! 13.844 ! 28.929 90 92.82 90

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3. MATERIALS AND EXPERIMENTAL PROCEDURE3.1. Materials. Ibuprofen was purchased from Hubei

Biocause Heilen Pharmaceutical Co. Ltd. Feno!brate waspurchased from Syngenta Hudders!eld, U.K. Eudragit EPO waspurchased from Evonik Industries AG, Darmstadt, Germany.PVP-VA64 was purchased from BASF Ludwigshafen, Germany.3.2. Hot Melt Extrusion. About 50 g of physical mixtures,

containing 10 wt % of ibuprofen (IBU) and 90 wt % of PVP-VA64 (PVP64) or Eudragit EPO (EPO) were prepared andmixed for 15 min using an Alphie Powder Mixer. Hot meltextrusion of the physical mixtures was conducted on alaboratory-scale twin-screw extruder (Prism EuroLab 16;Thermo Scienti!c, Karlsruhe, Germany). The melt extruderwas preheated to 120 and 90 °C for IBU/PVP64 and IBU/EPO, respectively. The rotation speed of the screw was !xed at200 rpm. Physical blend was manually fed into the extruder,and the solid dispersions of ibuprofen were collected on aconveyor belt, air cooled, and stored in screw-capped glassbottles at room temperature under low humidity of 25% RH.Several melt extrusion experiments at drug loading of 20 and 30wt % were also prepared for IBU/PVP64 and IBU/EPO, butthe solid dispersions were very sticky and di#cult to handle andcharacterize. Therefore, only 10 wt % of IBU drug loading wasanalyzed in this work.The physical mixtures of 10 wt % of feno!brate (FF) and 90

wt % of PVP64 was also prepared for melt extrusion. The meltextruder was preheated to 110 °C and FF/PVP64 physicalmixture was manually fed to extruder and processed similary asdiscussed above.3.3. Milling of Extrudates. The extrudates were milled in a

Retsch Mill MM 301 for 2 min at a frequency of 20 Hz in astainless steel vessel using a 2.5 cm diameter stainless steel ball.The powdered solid dispersions were stored in a desiccatorcabinet (25% RH).3.4. Powder X-ray Di!raction Analysis(PXRD). PXRD

measurements were performed with a X-ray powder di"rac-tometer (D8 Advance, Bruker AXS GmbH, Germany) with aCu K" radiation over an angle range of 5° " 2% < 40°. Themeasurements were operated with step width of 0.02° and scanrate of 1°/min.3.5. Fourier Transform Infrared Spectroscopy (FTIR).

FTIR analysis was performed to analyze the interaction

between APIs and polymers. The spectra were obtained witha FTIR Spectrophotometer (Digilab Excalibur Series FTS3000) using KBr pellet method. All samples were scanned at aresolution of 4 cm!1 in the range of 400!4000 cm!1, and 64scans were acquired per spectrum.

3.6. Di!erential Scanning Calorimetry (DSC). DSCmeasurements of pure ibuprofen, physical mixtures, andextruded samples were performed on Mettler-Toledo DSC 3(Switzerland). Aluminum pans containing 4!5 mg sampleswere !rst heated from 30 to 180 °C at a scanning rate of 10°C/min in a nitrogen atmosphere, then cooled to !40 °C at ascanning rate of 20 °C/min, and reheated again from !40 to180 °C at a scanning rate of 10 °C/min.

3.7. Dissolution Studies. Approximately 0.5 g of sample or50 mg equivalent of API was added to 500 mL of simulatedgastric $uid (pH 1.2 + 0.1% of Tween 80) as the dissolutionmedium in a dissolution Tester (Agilent 708-DS) at 37 °C anda stirring speed of 100 rpm. Samples were withdrawn at speci!ctime intervals and !ltered through 0.45 &m syringe !lter. APIconcentration in the !ltrate was measured using HPLC(Agilent HPLC 1100) equipped with a Zorbax Eclipse plusC18 column, and a mixture of 70% ACN and 30% watercontaining 0.1%v/v phosphoric acid as the mobile phase. A $owrate of 1.5 mL/min and a UV absorbance wavelength of 254nm were employed.

4. RESULTS AND DISCUSSIONS4.1. Hansen Solubility Parameters. Table 2 shows the

solubility parameters of APIs and polymers obtained fromsimulation. In general, the solubility parameters obtained fromsimulation are comparable to those published in the literature.As mentioned earlier, if the di"erence in solubility parametersof two compounds is less than 7.0 MPa1/2, then they are likelyto be miscible. On the other hand, if the di"erence is more than10 MPa1/2, they are likely to be immiscible.22 As seen in Table3, except for clonazepam/EPO and feno!brate/HPMC, all theAPI polymer pairs studied are likely to be miscible since thedi"erences in the solubility parameters are all below 7.0 MPa1/2.Even though Hansen solubility parameter is known to be a

reliable approach to predict the drug-polymer miscibility, thereare limited available data for di"erent group contributions.Moreover, it does not take into account the e"ect of polymer

Table 2. Solubility Parameter of Di!erent APIs and Polymers Obtained from MD Simulation

APIs or polymers number of unit cell/number of monomers Hansen solubility parameter (MPa1/2) solubility parameters from literature (MPa1/2)

clonazepam 2 ! 3 ! 3 26.21 ± 0.08ibuprofen 2 ! 3 ! 3 23.48 ± 0.04 21.812b

feno!brate 3 ! 3 ! 3 22.12 ± 0.06alprazolam 3 ! 2 ! 2 25.11 ± 0.07PVP64 (nonionic) 21 monomers 21.69 ± 0.16 22.942a

HPMC (nonionic) 21 monomers 29.89 ± 0.17 28.6523

EPO (ionic) 21 monomers 18.15 ± 0.10 20.552a

Table 3. Solubility Parameters Di!erence of All Pairs of API and Polymer

API/polymer Hansen solubility parameters di"erence (MPa1/2) API/polymer Hansen solubilityparameters di"erence (MPa1/2)clonazepam/PVP64 4.53 feno!brate/PVP64 0.43clonazepam/HPMC 3.67 feno!brate/HPMC 7.77clonazepam/EPO 8.07 feno!brate/EPO 3.97IBU/PVP64 1.79 alprazolam/PVP64 3.42IBU/HPMC 6.41 alprazolam/HPMC 4.78IBU/EPO 5.33 alprazolam/EPO 6.96

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Table 4. Hydrogen Bond Energy between Drug and Polymer

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chain conformation, including branching between monomerunits and molecular weight. Thus, in some cases the calculatedsolubility parameters may provide unreliable predictions ofAPI/polymer miscibility.12b In addition, Hansen solubilityparameters do not provide any information about theinteraction between drug and polymer. As discussed earlier,the existence of drug-polymer interactions is important to aid inthe stabilization of solid dispersion. A lack of interactionbetween polymer and API in solid dispersion may result in

recrystallization of API during storage and precipitation ofdissolved API during the dissolution testing. Therefore, in thiswork we used MD simulation to predict the possible hydrogenbond formation and interaction between di"erent functionalgroups of drug and polymer.

4.2. Hydrogen Bond Formation. The speci!c hydrogen!bond (H-bond) criteria of 0.34 nm/120° (a maximum H···Odistance of 0.34 nm and a minimum O!H···O angle of 120°)24

was used in this study. All possible H bonds are shown in

Table 4. continued

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dashed lines and the total H-bond energies are presented inTable 4. The average lifetime of H-bond formed between APIsand polymers is also presented. The hydrogen bond lifetimewas averaged from the last 300 ps of simulation time. Hydrogenbonds were found for IBU/PVP64, IBU/EPO, IBU/HPMC,FF/HPMC, Alprazolam/HPMC, clonazepam/PVP64, clonaze-pam/EPO, and clonazepam/HPMC. Among all the APIsstudied, ibuprofen shows the strongest H-bond interaction withthe polymers considered. The strongest H-bond interactionenergy was found for the pair of IBU/EPO, followed by the pairof IBU/PVP64. Both pairs also show long lifetime of H-bondcompared to others. Long lifetime of H-bond is also found forFF/HPMC, clonazepam/PVP64, and Clonazepam/HPMCpairs, however, H-bond interaction energy is weak for thesedrug/polymer combinations. No hydrogen bond interactionwas found for FF/PVP64, FF/EPO, alprazolam/PVP64 andalprazolam/EPO. Even though Hansen solubility results predictthe four pairs to be miscible, the lack of H-bond interactionsuggests that stable solid dispersions are unlikely to be obtainedfor these drug!polymer pairs. From these observations, oursimulation suggests that stable solid dispersions are likely to beobtained for IBU/PVP64 and IBU/EPO due to the stronginteraction and long lifetime of H-bond observed between drugand polymer.4.3. Hot Melt Extrusion. On the basis of the simulation

results, IBU/PVP64 and IBU/EPO may produce stable soliddispersions (SD). Therefore, these two pairs were selected forexperimental veri!cation by performing hot melt extrusion. FF/PVP64 was also selected as a negative control since oursimulation predicted the pair to form unstable SD. Theextrudates obtained for all combinations were clear andcolorless which con!rmed the miscibility of the APIs withPVP64 and with Eudragit EPO, as predicted from thesimulation. Due to the tackiness of EPO, the extrudates were!rst kept in a refrigerator before being milled.4.4. DSC Analysis. The thermal characteristic of the solid

dispersions were then investigated using DSC. Physicalmixtures (PM) containing 10 wt % of API and 90 wt % ofpolymers were also prepared for comparison. As shown inFigure 1a, two broad overlapping melting peaks at temperaturesintermediate between those of the individual components canbe seen in the thermograms of the PMs of IBU. For the case ofPM of FF/PVP64 (Figure 1b), only one broad melting peakwas observed due to the close proximity of the melting pointsof FF and PVP64. In contrast, no melting peak was obtained forthe SD up to 120 °C, which is higher than the melting points ofthe pure APIs. Instead, single glass transition was observed(shown in Table 5) between the Tg of pure components forSDs of IBU/PVP64, IBU/EPO, and FF/PVP64, respectively.This indicates miscible amorphous nature of IBU and FFpresent in the SDs.4.5. Powder Characterization. Figure 2 shows the

presence of the characteristic di"raction peaks of crystallineibuprofen in the freshly prepared PMs of IBU/PVP64 andIBU/EPO. The crystalline characteristic peaks were alsodetected for 1 day old sample of IBU/PVP64 PM. However,the intensities were lower compared to those of the freshsample. The interaction between ibuprofen and the polymersmight have caused the ibuprofen crystalline peaks to diminish.However, the PXRD of 1 day old IBU/EPO PM showed nomajor characteristic peaks of crystalline ibuprofen althoughcharacteristic crystalline peaks of ibuprofen could still beidenti!ed at 6.1°, 21.7° with very low intensities. This indicates

that strong interaction between ibuprofen and Eudragit EPOhas occurred in its physical mixture. The PXRD patterns forboth IBU/PVP64 and IBU/EPO SDs show the characteristic ofamorphous halo, indicating the amorphous nature of ibuprofenpresent in the SDs. Similar amorphous halo was also observedfor FF/PVP64 SD. All SDs were then stored at two di"erentconditions in order to analyze the stability of the SDs: at roomtemperature and low humidity of 25% RH (closed vial), and at40 °C and high humidity of 75% RH (open vial). The SDs wereanalyzed every one to 2 weeks by polarized microscopy andPXRD. IBU/PVP64 and IBU/EPO SDs remained amorphousfor 23 weeks at room temperature and low humidity. However,very small amount of crystals was detected by polarizedmicroscopy (not shown) in FF/PVP64 SD after 14 weeks ofstorage at room temperature and low humidity, indicating theunstable nature of the solid dispersion. PXRD was unable to

Figure 1. DSC thermograms for the following: (a) pure IBU, PVP64,EPO, IBU/PVP64 PM and SD, IBU/EPO PM and SD, and (b) pureFF, PVP64, FF/PVP64 PM and SD.

Table 5. Glass Transition Temperatures for Pure and SolidDispersions Systems

systems Tg (°C)

IBU !4525

FF !19.33EPO 48.57PVP64 105.5IBU/PVP64 SD 84.89IBU/EPO SD 31.74FF/PVP64 SD 85.43

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detect the characteristic crystalline peaks of FF in the sample,due to the small amount of crystals in the SD. At 40 °C/75%RH and open vial condition, the recrystallization of FF fromFF/PVP64 SD occurred after just 5 weeks of storage as evidentfrom the prominent characteristic peaks observed in the PXRDpattern (Figure 3 a). IBU/PVP64 SD, however, remainedamorphous after 5 weeks of storage under the same condition(Figure 3b).The interaction of APIs (IBU and FF) and polymers was

investigated by FTIR spectroscopy. Figure 4a shows the FTIRspectra of pure ibuprofen, PVP64, IBU/PVP64 physicalmixture, and solid dispersion. The FTIR spectrum of pureibuprofen showed a carbonyl absorption peak at 1720 cm!1,whereas the FTIR spectrum of PVP64 showed broad carbonyl

absorption bands corresponding to vinyl acetate group at 1734cm!1 and vinylpyrrolidone group at 1654 cm!1. The FTIRspectrum of the physical mixture gave broad carbonylabsorption bands corresponding to vinyl acetate group at1730 cm!1 and vinylpyrrolidone group at 1652 cm!1. Thecarbonyl absorption peak of ibuprofen at 1720 cm!1 was notseen in both physical mixture and solid dispersion. The FTIRspectrum of solid dispersion showed the absorption band at1666 cm!1 which was shifted to a higher wavenumbercompared to 1654 cm!1 of PVP64. This shift indicates aformation of H-bond26 between the C!O of the carbonylgroup in PVP64 with the O!H group of ibuprofen. Thisreinforces our simulation results that showed H-bondformation between IBU and PVP64.

Figure 2. X-ray di"raction patterns of (a) pure IBU, IBU/PVP64 physical mixture and SD, (b) pure IBU, IBU/EPO PM and SD, and (c) pure FF,FF/PVP64 PM and SD.

Figure 3. X-ray di"raction patterns of (a) FF/PVP64 SD and (b) IBU/PVP64 SD after 5 weeks storage in open vial at 40 °C/75%RH.

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In the FTIR spectrum of IBU/EPO physical mixture (Figure4b), stretching vibration due to carboxyl group was found at1726 cm!1, similar to that of pure Eudragit-EPO. The carbonylabsorption peak of ibuprofen at 1720 cm!1 was not seen inboth physical mixture and solid dispersion. The FTIR spectrumof solid dispersion showed a broad absorption band at 1726cm!1. The carbonyl absorption peak of ibuprofen overlappedwith the carbonyl group peak of Eudragit EPO polymer,therefore the broad absorption band was found in the soliddispersion. This indicates hydrogen bond formation27 betweenIBU and EPO. In a similar !nding, Doreth et al.28 reportedamorphization of ibuprofen and naproxen with Eudragit EPOin water. The FTIR spectrum of solid dispersion showed peakswith low intensity due to amorphization of ibuprofen.The FTIR spectra of feno!brate with PVP64 are shown in

Figure 4c. The carbonyl stretching vibration bands at 1652 and1734 cm!1 of pure feno!brate are found in the FTIR spectra ofphysical mixture and solid dispersion. This indicates a lack ofinteraction between feno!brate and the polymer, which alsoagrees with the simulation results. The lack of interactions andthe low glass transition temperature of feno!brate (!19.33 °C)may cause recrystallization to occur and therefore results in anunstable solid dispersion. It was reported that APIs with lowglass transition temperature have higher mobility at roomtemperature which may results in recrystallization.29 Thisobservation agrees with the PXRD analysis (Figure 3a) thatshows the appearance of crystal in feno!brate solid dispersionsample stored for 5 weeks at 40 °C/75%RH in open vial.Figure 5 shows the dissolution pro!les of IBU/PVP64 and

IBU/EPO SDs compared with their corresponding PMs andpure ibuprofen. It is observed that both IBU/PVP64 and IBU/EPO SDs exhibit faster initial dissolution rates compared totheir corresponding PMs and pure IBU. 86% of IBU has beenreleased from IBU/PVP64 SD within the !rst 15 min whileIBU/EPO experienced burst release of 85% within the !rst !vemin. This indicates that the dissolution rate is signi!cantlyimproved by the amorphous nature of the ibuprofen in the SDs.Owing to the strong interaction between IBU and thepolymers, recrystallization of IBU was prevented, and thedrug concentration remained at the plateau value after theinitial quick/burst release period. This is in contrast to thedissolution behavior of FF/PVP64 SD as shown in Figure 6.Although FF/PVP64 SD also exhibits quick release of 74%within the !rst 15 min, the concentration of FF gradualdecreased to around 30% after 2 h. This characteristicparachute pattern is associated with solid dispersions with noAPI!polymer interaction.30 Due to the lack of interaction, the

Figure 4. FTIR spectra for (a) pure IBU, PVP64 and IBU/PVP64 PMand SD; (b) pure IBU, EPO, and IBU/EPO PM and SD; and (c) pureFF, PVP64, and FF/PVP64 PM and SD.

Figure 5. Dissolution pro!les of (a) IBU/PVP64 and (b) IBU/EPO SDs compared with PMs and pure IBU.

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carrier polymer is not able to inhibit recrystallization of the FFfrom the amorphous form, thus the concentration of FFgradually decreased.4.6. Miscibility and Molecular Interaction. A simulation

approach has shown that the Hansen solubility parameter isable to predict drug!polymer miscibility. However, themiscible system may not be an indication that the system hasa drug!polymer molecular interaction, which is required forsuccessful formulation of stable amorphous solid dispersion.Drug and polymer may be dispersed evenly and produce amiscible system, but no molecular interaction may be foundbetween the two species. One example of a miscible systemwith no molecular interaction observed in our study was FF/PVP64 solid dispersion. In addition, the experimental approachhas also shown a similar observation, in which DSC datashowed the miscibility of FF/PVP64, and FTIR showed thelack of interaction between FF and PVP64.

5. CONCLUSIONSMolecular dynamics (MD) simulation was performed to obtainthe solubility parameters of various drug and polymercombinations. The solubility parameters obtained from oursimulation agreed well with those available in the literature. Thesolubility parameters obtained from simulation suggested thatthe combinations of IBU/PVP64, IBU/EPO, IBU/HPMC,clonazepam/PVP64, clonazepam/HPMC, FF/PVP64, FF/EPO, alprazolam/PVP64, alprazolam/EPO, and alprazolam/HPMC are likely to be miscible. However, further hydrogenbond analysis revealed that only IBU/PVP64 and IBU/EPO areable to form strong enough hydrogen bonds to sustain a stablesolid dispersion. Weak or no hydrogen bond interaction wasfound for the rest of the drug/polymer combinations.Experimental observations have con!rmed the miscibility of

IBU and FF in PVP64 and IBU in EPO. Experimental data havealso con!rmed the stability of IBU/PVP64 and IBU/EPO soliddispersions. The solid dispersions of ibuprofen in PVP64 andEPO showed fast release rates and higher % release comparedto pure ibuprofen and physical mixtures of IBU and polymers.However, experimental results also veri!ed the lack ofinteraction between feno!brate and PVP64 and hence poorstability of the FF/PVP64 SD, as evident from therecrystallization of FF from the SD during storage and thecharacteristic parachute dissolution behavior of the SD. The!ndings reported suggest that molecular dynamic simulationcan be used as a predictive tool to select excipients for theformulation of stable solid dispersion.

! AUTHOR INFORMATIONCorresponding Author*Tel: (65) 6796 3852. E-mail: yin_yani@ices.a-star.edu.sg(Y.Y.).ORCIDYin Yani: 0000-0001-7602-084XPui Shan Chow: 0000-0002-5100-2677NotesThe authors declare no competing !nancial interest.

! REFERENCES(1) (a) Jha, P. K.; Larson, R. G. Assessing the Efficiency of PolymericExcipients by Atomistic Molecular Dynamics Simulations. Mol.Pharmaceutics 2014, 11 (5), 1676!1686. (b) Rumondor, A. C. F.;Taylor, L. S. Effect of Polymer Hygroscopicity on the Phase Behaviorof Amorphous Solid Dispersions in the Presence of Moisture. Mol.Pharmaceutics 2010, 7 (2), 477!490.(2) (a) Craig, D. Q. M. The mechanisms of drug release from soliddispersions in water-soluble polymers. Int. J. Pharm. 2002, 231 (2),131!144. (b) Sareen, S.; Mathew, G.; Joseph, L. Improvement insolubility of poor water-soluble drugs by solid dispersion. InternationalJournal of Pharmaceutical Investigation 2012, 2 (1), 12!17. (c) Li, W.;Buckton, G. Using DVS-NIR to assess the water sorption behaviourand stability of a griseofulvin/PVP K30 solid dispersion. Int. J. Pharm.2015, 495 (2), 999!1004.(3) (a) Douroumis, D.; Bouropoulos, N.; Fahr, A. Physicochemicalcharacterization of solid dispersions of three antiepileptic drugsprepared by solvent evaporation method. J. Pharm. Pharmacol. 2007,59 (5), 645!53. (b) Mura, P.; Manderioli, A.; Bramanti, G.; Ceccarelli,L. Properties of Solid Dispersions of Naproxen in Various Poly-ethylene Glycols. Drug Dev. Ind. Pharm. 1996, 22 (9!10), 909!916.(4) Chronakis, I. S.; O" ste Triantafyllou, A.; O" ste, R. Solid-statecharacteristics and redispersible properties of powders formed byspray-drying and freeze-drying cereal dispersions of varying (1!3,1!4)-#-glucan content. J. Cereal Sci. 2004, 40 (2), 183!193.(5) Verreck, G.; Chun, I.; Peeters, J.; Rosenblatt, J.; Brewster, M. E.Preparation and characterization of nanofibers containing amorphousdrug dispersions generated by electrostatic spinning. Pharm. Res. 2003,20 (5), 810!817.(6) (a) Kanaujia, P.; Lau, G.; Ng, W. K.; Widjaja, E.; Hanefeld, A.;Fischbach, M.; Maio, M.; Tan, R. B. Nanoparticle formation andgrowth during in vitro dissolution of ketoconazole solid dispersion. J.Pharm. Sci. 2011, 100 (7), 2876!2885. (b) Sarode, A. L.; Sandhu, H.;Shah, N.; Malick, W.; Zia, H. Hot melt extrusion (HME) foramorphous solid dispersions: Predictive tools for processing andimpact of drug!polymer interactions on supersaturation. Eur. J.Pharm. Sci. 2013, 48 (3), 371!384. (c) Sarode, A. L.; Sandhu, H.;Shah, N.; Malick, W.; Zia, H. Hot Melt Extrusion for Amorphous SolidDispersions: Temperature and Moisture Activated Drug!PolymerInteractions for Enhanced Stability. Mol. Pharmaceutics 2013, 10 (10),3665!3675.(7) (a) Prasad, D.; Chauhan, H.; Atef, E. Role of MolecularInteractions for Synergistic Precipitation Inhibition of Poorly SolubleDrug in Supersaturated Drug!Polymer!Polymer Ternary Solution.Mol. Pharmaceutics 2016, 13 (3), 756!765. (b) Chauhan, H.;Kuldipkumar, A.; Barder, T.; Medek, A.; Gu, C.-H.; Atef, E.Correlation of Inhibitory Effects of Polymers on IndomethacinPrecipitation in Solution and Amorphous Solid Crystallization Basedon Molecular Interaction. Pharm. Res. 2014, 31 (2), 500!515.(8) (a) Djuris, J.; Nikolakakis, I.; Ibric, S.; Djuric, Z.; Kachrimanis, K.Preparation of carbamazepine!Soluplus® solid dispersions by hot-melt extrusion, and prediction of drug!polymer miscibility bythermodynamic model fitting. Eur. J. Pharm. Biopharm. 2013, 84(1), 228!237. (b) Punc #ochova $, K.; Heng, J. Y. Y.; Bera $nek, J.;S#te #pa $nek, F. Investigation of drug!polymer interaction in soliddispersions by vapour sorption methods. Int. J. Pharm. 2014, 469 (1),159!167. (c) Maniruzzaman, M.; Morgan, D. J.; Mendham, A. P.;

Figure 6. Dissolution pro!les of FF/PVP64 SD and PM.

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DOI: 10.1021/acs.iecr.7b03187Ind. Eng. Chem. Res. XXXX, XXX, XXX!XXX

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Pang, J.; Snowden, M. J.; Douroumis, D. Drug!polymer intermo-lecular interactions in hot-melt extruded solid dispersions. Int. J.Pharm. 2013, 443 (1!2), 199!208. (d) Huang, Y.; Dai, W.-G.Fundamental aspects of solid dispersion technology for poorly solubledrugs. Acta Pharm. Sin. B 2014, 4 (1), 18!25.(9) Meng, F.; Trivino, A.; Prasad, D.; Chauhan, H. Investigation andcorrelation of drug polymer miscibility and molecular interactions byvarious approaches for the preparation of amorphous solid dispersions.Eur. J. Pharm. Sci. 2015, 71 (SC), 12!24.(10) Ilevbare, G. A.; Liu, H.; Edgar, K. J.; Taylor, L. S. Maintainingsupersaturation in aqueous drug solutions: impact of differentpolymers on induction times. Cryst. Growth Des. 2013, 13 (2), 740!751.(11) Meng, F.; Dave, V.; Chauhan, H. Qualitative and quantitativemethods to determine miscibility in amorphous drug!polymersystems. Eur. J. Pharm. Sci. 2015, 77 (SC), 106!111.(12) (a) Choi, P.; Kavassalis, T. A.; Rudin, A. Estimation of HansenSolubility Parameters for (Hydroxyethyl) and (Hydroxypropyl)cellulose through Molecular Simulation. Ind. Eng. Chem. Res. 1994,33 (12), 3154!3159. (b) Maniruzzaman, M.; Pang, J.; Morgan, D. J.;Douroumis, D. Molecular modeling as a predictive tool for thedevelopment of solid dispersions. Mol. Pharmaceutics 2015, 12 (4),1040!9. (c) Kavassalis, T. A.; Choi, P.; Rudin, A. The Calculation of3D Solubility Parameters Using Molecular Models. Mol. Simul. 1993,11 (2!4), 229!241. (d) Simperler, A.; Kornherr, A.; Chopra, R.;Bonnet, P. A.; Jones, W.; Motherwell, W. D. S.; Zifferer, G. GlassTransition Temperature of Glucose, Sucrose, and Trehalose: AnExperimental and in Silico Study. J. Phys. Chem. B 2006, 110 (39),19678!19684.(13) Materials Studio Modeling, 7.0; Accelrys Software Inc.: SanDiego, CA.(14) Sun, H. COMPASS: An ab Initio Force-Field Optimized forCondensed-Phase Applications-Overview with Details on Alkane andBenzene Compounds. J. Phys. Chem. B 1998, 102 (38), 7338!7364.(15) Frenkel, D.; Smit, B. Understanding Molecular Simulation, 2nd ed.;Academic Press: San Deigo, CA, 2002.(16) Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F.;DiNola, A.; Haak, J. R. Molecular dynamics with coupling to anexternal bath. J. Chem. Phys. 1984, 81 (8), 3684!3690.(17) Huggins, M. L. The Solubility of Nonelectrolytes. By Joel H.Hildebrand and Robert S. Scott. J. Phys. Chem. 1951, 55 (4), 619!620.(18) Wong, Y.; Chen, Z. J.; Tan, T. T. Y.; Lee, J.-M. HildebrandSolubility Parameters of Amidium Ionic Liquids. Ind. Eng. Chem. Res.2015, 54 (48), 12150!12155.(19) Hansen, C. M. Hansen Solubility Parameters: A User’s Handbook,2nd ed.; CRC Press/Taylor Francis Group: Boca Raton, FL, 2007; p544.(20) Greenhalgh, D. J.; Williams, A. C.; Timmins, P.; York, P.Solubility parameters as predictors of miscibility in solid dispersions. J.Pharm. Sci. 1999, 88 (11), 1182!1190.(21) Kanaujia, P.; Lau, G.; Ng, W. K.; Widjaja, E.; Schreyer, M.;Hanefeld, A.; Fischbach, M.; Saal, C.; Maio, M.; Tan, R. B.Investigating the effect of moisture protection on solid-state stabilityand dissolution of fenofibrate and ketoconazole solid dispersions usingPXRD, HSDSC and Raman microscopy. Drug Dev. Ind. Pharm. 2011,37 (9), 1026!35.(22) Chokshi, R. J.; Sandhu, H. K.; Iyer, R. M.; Shah, N. H.; Malick,A. W.; Zia, H. Characterization of physico-mechanical properties ofindomethacin and polymers to assess their suitability for hot-meltextrusion processs as a means to manufacture solid dispersion/solution. J. Pharm. Sci. 2005, 94 (11), 2463!74.(23) Ghosh, I.; Snyder, J.; Vippagunta, R.; Alvine, M.; Vakil, R.;Tong, W. Q.; Vippagunta, S. Comparison of HPMC based polymersperformance as carriers for manufacture of solid dispersions using themelt extruder. Int. J. Pharm. 2011, 419 (1!2), 12!9.(24) (a) Dirama, T. E.; Carri, G. A.; Sokolov, A. P. Coupling betweenlysozyme and glycerol dynamics: Microscopic insights from molecular-dynamics simulations. J. Chem. Phys. 2005, 122 (24), 244910.(b) Busselez, R.; Lefort, R.; Ji, Q.; Affouard, F.; Morineau, D.

Molecular dynamics simulation of nanoconfined glycerol. Phys. Chem.Chem. Phys. 2009, 11 (47), 11127!11133.(25) Dudognon, E.; Dane %de, F.; Descamps, M.; Correia, N. T.Evidence for a New Crystalline Phase of Racemic Ibuprofen. Pharm.Res. 2008, 25 (12), 2853!2858.(26) (a) Pignatello, R.; Spadaro, D.; Vandelli, M.; Forni, F.; Puglisi,G. Characterization of the mechanism of interaction in ibuprofen-Eudragit RL100 coevaporates. Drug Dev. Ind. Pharm. 2004, 30 (3),277!288. (b) Karavas, E.; Ktistis, G.; Xenakis, A.; Georgarakis, E.Effect of hydrogen bonding interactions on the release mechanism offelodipine from nanodispersions with polyvinylpyrrolidone. Eur. J.Pharm. Biopharm. 2006, 63 (2), 103!14.(27) Stott, P. W.; Williams, A. C.; Barry, B. W. Transdermal deliveryfrom eutectic systems: enhanced permeation of a model drug,ibuprofen. J. Controlled Release 1998, 50 (1!3), 297!308.(28) Doreth, M.; Lo"bmann, K.; Grohganz, H.; Holm, R.; Lopez deDiego, H.; Rades, T.; Priemel, P. A. Glass solution formation in water -In situ amorphization of naproxen and ibuprofen with Eudragit® EPO. J. Drug Delivery Sci. Technol. 2016, 34, 32!40.(29) Kanaujia, P.; Poovizhi, P.; Ng, W. K.; Tan, R. B. H. Amorphousformulations for dissolution and bioavailability enhancement of poorlysoluble APIs. Powder Technol. 2015, 285, 2!15.(30) Surikutchi, B. T.; Patil, S. P.; Shete, G.; Patel, S.; Bansal, A. K.Drug-excipient behavior in polymeric amorphous solid dispersions. J.Excipients Food Chem. 2013, 4 (3), 70!94.

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DOI: 10.1021/acs.iecr.7b03187Ind. Eng. Chem. Res. XXXX, XXX, XXX!XXX

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