Effect of API-Polymer Miscibility and Interaction on the Stabilization of

Oct 12, 2017 - Ingredient (API) with polymer carriers in solid dispersion system based on ... interaction between API and polymer on the stabilization...
0 downloads 0 Views 3MB Size
Subscriber access provided by Umea University Library

Article

Effect of API-polymer miscibility and interaction on the stabilization of amorphous solid dispersion: A molecular simulation study Yani Yin, Parijat Kanaujia, Pui Shan Chow, and Reginald B. H. Tan Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.7b03187 • Publication Date (Web): 12 Oct 2017 Downloaded from http://pubs.acs.org on October 17, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Industrial & Engineering Chemistry Research is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Industrial & Engineering Chemistry Research

Effect of API-polymer miscibility and interaction on the stabilization of amorphous solid dispersion: A molecular simulation study Yin 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, Jurong Island, Singapore 627833 ‡

Department of Chemical & Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117576 * Corresponding author. Tel: (65) 6796 3852. Email: [email protected]

Abstract In this study, molecular dynamics simulation technique were employed to predict miscibility and interaction of Active Pharmaceutical Ingredient (API) with polymer carriers in solid dispersion system based on Hansen solubility parameter and hydrogen bond formation respectively. Several APIs with and without hydrogen bonding tendency were studied. The Hansen solubility parameters of APIs and polymers calculated by molecular dynamic simulation were similar to reported values in the literature. Our simulation results were able to determine the interactions between APIs and various polymers (ionic and non-ionic) and also predict the hydrogen bond interaction energy and hydrogen bond lifetime. The simulation results were verified by preparing solid dispersions using hot melt extrusion. As predicted by our simulation, clear and colorless extrudates were obtained for ibuprofen/PVP-VA 64, ibuprofen/Eudragit EPO, and fenofibrate/PVP-VA 64, which confirmed the miscibility between APIs (ibuprofen, fenofibrate) and polymers. Stability studies confirmed the amorphous stabilization of ibuprofen/PVP-VA64 and ibuprofen/Eudragit EPO solid dispersions. However, recrystallization of fenofibrate was observed from fenofibrate/PVP-VA 64 due to the lack of molecular interactions between fenofibrate and PVP-VA 64 as predicted in our simulation. This suggests that miscibility alone cannot be used to predict the stability of amorphous dispersion but molecular interactions have to be considered. The simulation method used in this study could be a useful tool for the selection of polymer excipients to form stable amorphous solid dispersions with enhanced performance.

1 ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 28

1. Introduction Solid dispersions 1 of drugs in water-soluble polymeric carriers have been used as a means for improving dissolution rate, and hence possibly bioavailability, for a range of hydrophobic drugs.2 However, the structure and solid state of drug in the carrier, and mechanism for the enhancement of the dissolution rate and stabilization of amorphous phase by the carrier are not yet fully understood. Therefore, the development and commercialization of solid dispersions have been hampered by the lack of performance predictability. There are a few methods to prepare solid dispersion, such as, solvent evaporation 3, spray drying4, electrostatic spinning 5, and hot melt extrusion 6. However, formation of stable solid dispersion requires the presence of intermolecular interactions7 between drug and the polymeric carrier in order to avoid phase separation or recrystallization during storage. The effect of drugpolymer interaction on the stabilization of amorphous solid dispersions has been well understood. 1a, 8 Chauhan and coworkers 9 investigated molecular interactions between Curcumin and various type of polymers using Fourier transform infrared spectroscopy (FTIR) and Raman for successful formulation of amorphous solid dispersion. A polymer to be chosen as excipient in a solid dispersion must show affinity for the API via hydrogen bonding or weak van der Waals interactions

1a, 10

. It is reported that hydrophobic polymers show higher affinity for hydrophobic

APIs 1a. Nevertheless, published literature comparing the use of ionic and non-ionic polymers on the stability and the dissolution enhancement of interacting and non-interacting drugs is unavailable. Several experimental methods have been used to study the miscibility of amorphous drug and polymer system, including glass transition temperature (Tg) measurement by Differential Scanning Calorimetry (DSC), Raman mapping, computational analysis of X-Ray Diffraction 2 ACS Paragon Plus Environment

Page 3 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Industrial & Engineering Chemistry Research

data, solid state Nuclear Magnetic Resonance spectroscopy, and Atomic Force Microscopy. API-polymer miscibility in solid dispersions can also be determined by molecular simulation

11

12

.

Maniruzzaman et al.12b used quantum mechanical simulation to predict API-polymer interactions. They also predicted API/polymer miscibility by determining the Hansen solubility parameters for both drugs and polymers. Larson and coworker

1a

performed all-atom MD

simulation of aqueous solutions of hydroxypropyl methylcellulose (HPMC) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) excipients interacting with a poorly soluble API, phenytoin.

This work aims to understand the effect of miscibility and interaction between API and polymer on the stabilization and the dissolution enhancement of amorphous solid dispersions. The polymers were selected from both groups of ionic polymer (Eudragit-EPO) and non-ionic polymers (PVP-VA64). Various APIs were chosen with some having H-bond forming tendency with the carriers (ibuprofen and clonazepam) and some without H-bond forming tendency with the carriers (fenofibrate and alprazolam). Molecular dynamics (MD) simulation technique was employed to predict the miscibility of drugs in polymer carriers based on Hansen solubility parameter and to determine the preferable site of interaction between drugs and polymers. Based on the simulation results, a few drug/polymer combinations were selected for experimental observation. Hot melt extrusion was performed for the combination of API/polymer in order to verify the simulation results. The physical mixtures and solid dispersions were characterized by X-ray diffraction, Fourier transform infrared spectroscopy (FTIR), and Differential scanning calorimetry (DSC).

2. Computational Method 3 ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 28

2.1. Molecular modeling Molecular dynamics (MD) simulations were carried out using the Accelrys Materials Studio (Version 7.0)13 for APIs (clonazepam, ibuprofen, fenofibrate, and alprazolam), and polymers (PVP-VA64, HPMC, and Eudragit EPO). The crystal structures of APIs were obtained from Cambridge Structural Database, Ver. 5.26. The lattice parameters are reported in Table 1. The crystal structures were extended to 2x3x3, 2x3x3, 3x3x3, 3x2x2 unit cells for clonazepam, ibuprofen, fenofibrate, and alprazolam, respectively. Energy minimization was performed for all systems. COMPASS14 (condensed-phase optimized molecular potentials for the atomistic simulation studies) force field was used to model the atomic interactions for all API molecules. COMPASS force field model gives densities of 1.38, 1.29, 1.39, and 1.10 g/cm3 for pure clonazepam, fenofibrate, alprazolam, and ibuprofen, respectively. These values are in good agreement with the reported clonazepam, fenofibrate, alprazolam, and ibuprofen densities of 1.50, 1.18, 1.37, and 1.03 g/cm3 respectively. The integration timestep used was 1 fs. Ewald summation was used to enable the long range interactions. A cutoff radius of 6.0 Å was used for both non-bonded and electrostatic interactions. Simulation in the NPT (constant number of particle, constant pressure, and constant temperature) ensemble was first conducted at 298 K for 2 ns to obtain an equilibrium density for each system. The production run was then performed by simulation in NVT (isothermal) ensemble for 500 ps. Equilibration was determined by observing the change in the thermodynamic properties (energies, temperatures, and densities) as a function of time. A system was concluded to have reached equilibration condition if these properties showed sufficiently small variations over time. The required time to reach equilibration for all systems was less than 100 ps. The Nose/Hoover15 thermostat and Berendsen barostat16 were used to control the temperature and pressure, respectively. The Hansen solubility parameter was 4 ACS Paragon Plus Environment

Page 5 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Industrial & Engineering Chemistry Research

calculated by choosing five different data sets of trajectories (at timestep range of 0.5-0.75 ns, 1.5-1.75 ns, 1.75-2 ns, 2.3-2.4ns, and 2.4-2.5 ns) from the equilibrated system. Hansen solubility parameter was calculated for each data set and then averaged to obtain the average solubility parameter for all APIs studied. Table 1. Lattice parameters for different APIs APIs Clonazepam Ibuprofen Fenofibrate Alprazolam

Lattice type Lattice parameter (a x b x c) Triclinic 12.33x10.15x12.39 Monoclinic 14.667x7.886x10.73 Triclinic 8.1605x8.2664x14.511 Monoclinic 7.361x13.844x28.929

α

β

γ

108.96 90 93.951 90

103.92 99.362 105.664 92.82

86.17 90 96.002 90

2.2. Solubility Parameter As defined by Hildebrand and Scott17, the solubility parameter, δt, is the square root of the cohesive energy density (CED)18. CED is defined as the cohesive energy (Ecoh) per unit of molar volume (Vm), which is the difference of total energy to intramolecular energy of a system 13. δ =

 

=

(∆  ) 

(1)

where Hv is heat of vaporization, R is the Gas constant and T is temperature. Pharmaceutical solid dispersions are highly complex mixture of small organic molecules dispersed in polymers. Hansen (1969) further refined the Hildebrand model to predict the miscibility of APIs mixed with polymer in a solid dispersion system. He described the total cohesive energy as the resultant contribution of dispersion forces, permanent dipole-dipole interactions and hydrogen bonds

19

. Van Krevelen and Hoftyer (1976) calculated the Hansen

solubility parameter (δt) from nonpolar atomic (dispersion) interactions (δd), dipole-dipole 5 ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 28

molecular interactions (δp) and hydrogen bonding (electron interchange) molecular interactions (δh) of various functional groups present on the drug molecule 19 using eq 2. δ =  +  + 

(2)

The difference of the solubility parameters (∆δt) of two materials is known as the interaction parameter and widely used as a tool to predict miscibility of two solids in melted condition. Compounds with ∆δt value 10 MPa0.5 are most likely to be immiscible 20.

2.3. Interactions of APIs and polymers It has been reported that solid dispersions with strong drug-polymer interactions and less hygroscopic polymer are unlikely to phase separate during storage1b, 21. Therefore, to predict the stability of solid dispersion, molecular simulations were performed to observe the interactions between drugs and polymers. The monomeric structure of HPMC, PVP-VA64, and EudragitEPO and two to four monomeric structures of APIs were constructed and MD simulations were performed in NPT ensemble for 500 ps at 298 K. Energy minimization was then performed for all API-polymer systems to access the non-bonded interaction between API and polymer, such as, hydrogen bonds.

3. Materials and Experimental Procedure 3.1. Materials Ibuprofen was purchased from Hubei Biocause Heilen Pharmaceutical Co. Ltd. Fenofibrate was purchased from Syngenta Huddersfield, UK. Eudragit EPO was purchased from Evonik

6 ACS Paragon Plus Environment

Page 7 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Industrial & Engineering Chemistry Research

Industries AG, Darmstadt, Germany. PVP-VA64 was purchased from BASF Ludwigshafen, Germany. 3.2. Hot Melt Extrusion About 50g of physical mixtures, containing 10wt% of ibuprofen (IBU) and 90wt% of PVPVA64 (PVP64) or Eudragit EPO (EPO) were prepared and mixed for 15 min using an Alphie Powder Mixer. Hot melt extrusion of the physical mixtures was conducted on a laboratory-scale twin-screw extruder (Prism EuroLab 16; Thermo Scientific, Karlsruhe, Germany). The melt extruder was preheated to 120°C and 90°C for IBU/PVP64 and IBU/EPO, respectively. The rotation speed of the screw was fixed at 200 rpm. Physical blend was manually fed into the extruder, and the solid dispersions of ibuprofen were collected on a conveyor belt, air cooled and stored in screw-capped glass bottles at room temperature under low humidity of 25% RH. Several melt extrusion experiments at drug loading of 20wt% and 30wt% were also prepared for IBU/PVP64 and IBU/EPO, but the solid dispersions were very sticky and difficult to handle and characterize. Therefore, only 10wt% of IBU drug loading was analyzed in this work. The physical mixtures of 10wt% of fenofibrate (FF) and 90wt% of PVP64 was also prepared for melt extrusion. The melt extruder was preheated to 110°C and FF/PVP64 physical mixture was manually fed to extruder and processed similary as discussed 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 a stainless steel vessel using a 2.5 cm diameter stainless steel ball. The powdered solid dispersions were stored in a desiccator cabinet (25% RH).

7 ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 28

3.4. Powder X-Ray Diffraction Analysis(PXRD) PXRD measurements were performed with a X-ray powder diffractometer (D8 Advance, Bruker AXS GmbH, Germany) with a Cu Kα radiation over an angle range of 5° ≤ 2θ < 40°. The measurements were operated with step width of 0.02° and scan rate 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 with a FTIR Spectrophotometer (Digilab Excalibur Series FTS 3000) using KBr pellet method. All samples were scanned at a resolution of 4 cm-1 in the range of 4004000 cm-1 and 64 scans were acquired per spectrum. 3.6. Differential scanning calorimetry (DSC) DSC measurements of pure ibuprofen, physical mixtures and extruded samples were performed on Mettler-Toledo DSC 3 (Switzerland). Aluminum pans containing 4-5 mg samples were first heated from 30 °C to 180 °C at a scanning rate of 10 °C/min in a nitrogen atmosphere, then cooled to -40 °C at a scanning rate of 20 °C/min, and reheated again from -40 °C to 180 °C at a scanning rate of 10 °C/min. 3.7. Dissolution Studies Approximately 0.5 g of sample or 50 mg equivalent of API was added to 500 ml of simulated gastric fluid (pH 1.2 + 0.1% of Tween 80) as the dissolution medium in a dissolution Tester (Agilent 708-DS) at 37°C and a stirring speed of 100 rpm. Samples were withdrawn at specific time intervals and filtered through 0.45µm syringe filter. API concentration in the filtrate was measured using HPLC (Agilent HPLC 1100) equipped with a Zorbax Eclipse plus C18 column, 8 ACS Paragon Plus Environment

Page 9 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Industrial & Engineering Chemistry Research

and a mixture of 70% ACN and 30% water containing 0.1%v/v Phosphoric acid as the mobile phase. A flow rate of 1.5 mL/min and a UV absorbance wavelength of 254 nm were employed.

4. Results and Discussions 4.1. Hansen Solubility Parameters Table 2 shows the solubility parameters of APIs and polymers obtained from simulation. In general, the solubility parameters obtained from simulation are comparable to those published in the literature. As mentioned earlier, if the difference in solubility parameters of two compounds is less than 7.0 MPa1/2, they are likely to be miscible. On the other hand, if the difference is more than 10 MPa1/2, they are likely to be immiscible22. As seen in Table 3, except for clonazepam/ EPO and fenofibrate/HPMC, all the API polymer pairs studied are likely to be miscible since the differences 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, there are limited available data for different group contributions. Moreover, it does not take into account the effect of polymer chain conformation, including branching between monomer units and molecular weight. Thus in some cases the calculated solubility parameters may provide unreliable predictions of API/polymer miscibility12b. In addition, Hansen solubility parameters do not provide any information about the interaction between drug and polymer. As discussed earlier, the existence of drug-polymer interactions is important to aid in the stabilization of solid dispersion. A lack of interaction between polymer and API in solid dispersion may result in recrystallization of API during storage and precipitation of dissolved API during the dissolution testing. Therefore, in this work we used MD simulation

9 ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 28

to predict the possible hydrogen bond formation and interaction between different functional groups of drug and polymer. Table 2. Solubility parameter of different APIs and polymers obtained from MD simulation APIs or Polymers

Number of unit cell/Number of monomers

Hansen Solubility Parameter

Solubility Parameters from literature

1/2

1/2

(MPa )

(MPa )

Clonazepam

2x3x3

26.21 ± 0.08

-

Ibuprofen

2x3x3

23.48 ± 0.04

21.8 12b

Fenofibrate

3x3x3

22.12 ± 0.06

-

Alprazolam

3x2x2

25.11 ± 0.07

-

PVP64 (nonionic)

21 monomers

21.69 ± 0.16

22.94 2a

HPMC (nonionic)

21 monomers

29.89 ± 0.17

28.65 23

EPO (ionic)

21 monomers

18.15 ± 0.10

20.55 2a

Table 3. Solubility parameters difference of all pairs of API and Polymer API/Polymer

Hansen Solubility parameters difference

API/Polymer

1/2

Clonazepam/PVP64 Clonazepam/HPMC Clonazepam/EPO IBU/PVP64 IBU/HPMC IBU/EPO

Hansen Solubility parameters difference 1/2

(MPa ) 4.53 3.67 8.07 1.79 6.41 5.33

Fenofibrate/PVP64 Fenofibrate/HPMC Fenofibrate/EPO Alprazolam/PVP64 Alprazolam/HPMC Alprazolam/EPO

(MPa ) 0.43 7.77 3.97 3.42 4.78 6.96

10 ACS Paragon Plus Environment

Page 11 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Industrial & Engineering Chemistry Research

4.2. Hydrogen Bond Formation The specific hydrogen–bond (H-bond) criteria of 0.34 nm/120° (a maximum H···O distance 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 dashed lines and the total H-bond energies are presented in Table 4. The average lifetime of H-bond formed between APIs and polymers is also presented. The hydrogen bond lifetime was averaged from the last 300 ps of simulation time. Hydrogen bonds were found for IBU/PVP64, IBU/EPO, IBU/HPMC, FF/HPMC, Alprazolam/HPMC, Clonazepam/PVP64, Clonazepam/EPO, and Clonazepam/HPMC. Among all the APIs studied, ibuprofen shows the strongest H-bond interaction with the polymers considered. The strongest H-bond interaction energy was found for the pair of IBU/EPO, followed by the pair of IBU/PVP64. Both pairs also show long lifetime of H-bond compared to others. Long lifetime of H-bond is also found for FF/HPMC, Clonazepam/PVP64, and Clonazepam/HPMC pairs, however, H-bond interaction energy is weak for these drug/polymer combinations. No hydrogen bond interaction was found for FF/PVP64, FF/EPO, alprazolam/PVP64 and alprazolam/ EPO. Even though Hansen solubility results predict the four pairs to be miscible, the lack of H-bond interaction suggests that stable solid dispersions are unlikely to be obtained for these drug-polymer pairs. From these observations, our simulation suggests that stable solid dispersions are likely to be obtained for IBU/PVP64 and IBU/EPO due to the strong interaction and long lifetime of H-bond observed between drug and polymer. Table 4: Hydrogen bond energy between drug and polymer APIPolymer

Conformation and Interaction

Total HBond Interaction Energy per monomer

Average H-bond lifetime (ps)

11 ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

IbuprofenPVP64

Page 12 of 28

(kcal/mol) -10.27

16.68

22.84

10.65

-6.660

4.34

OHibu…O=CPVP-VA64 IbuprofenEPO

OHibu…NCEPO , OHibu…OCEPO

ibuprofenHPMC

OHibu…OCHPMC , 12 ACS Paragon Plus Environment

Page 13 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Industrial & Engineering Chemistry Research

COibu…HOHPMC, OHibu…OHHPMC FenofibrateHPMC

3.931

9.77

0.950

3.95

-1.704

6.29

C-ClFeno…HOHPMC, C=OFeno…HOHPMC AlprazolamHPMC

C-NAlpra…HOHPMC Clonazepam - PVP64

N-HClona…O=CPVPVA64

13 ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Clonazepam - EPO

Page 14 of 28

-2.327

2

1.145

7.60

N-HClona…O=CEPO Clonazepam -HPMC

C=OClona…HOHPMC, C-ClClona…HOHPMC ,N=OClona…HOHPMC, NHClona…OCHPMC, NHClona…OHHPMC

4.3. Hot Melt Extrusion Based on the simulation results, IBU/PVP64 and IBU/EPO may produce stable solid dispersions (SD). Therefore, these two pairs were selected for experimental verification by performing hot melt extrusion. FF/PVP64 was also selected as a negative control since our simulation predicted the pair to form unstable SD. The extrudates obtained for all combinations were clear and colorless which confirmed the miscibility of the APIs with PVP64 and with

14 ACS Paragon Plus Environment

Page 15 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Industrial & Engineering Chemistry Research

Eudragit EPO, as predicted from the simulation. Due to the tackiness of EPO, the extrudates were first kept in a refrigerator before being milled. 4.4. DSC Analysis The thermal characteristic of the solid dispersions were then investigated using DSC. Physical mixtures (PM) containing 10 wt% of API and 90 wt% of polymers were also prepared for comparison. As shown in Fig. 1a, two broad overlapping melting peaks at temperatures intermediate between those of the individual components can be seen in the thermograms of the PMs of IBU. For the case of PM of FF/PVP64 (Fig. 1b), only one broad melting peak was observed due to the close proximity of the melting points of FF and PVP64. In contrast, no melting peak was obtained for the SD up to 120oC, which is higher than the melting points of the pure APIs. Instead, single glass transition was observed (shown in Table 5) between the Tg of pure components for SDs of IBU/PVP64, IBU/EPO and FF/PVP64 respectively. This indicates miscible amorphous nature of IBU and FF present in the SDs. Table 5: Glass transition temperatures for pure and solid dispersions systems Systems IBU FF EPO PVP64 IBU/PVP64 SD IBU/EPO SD FF/PVP64 SD

Tg (°°C) -4525 -19.33 48.57 105.5 84.89 31.74 85.43

15 ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

IBU/PVP64 SD Relative Heat Flow (Endo Up)

IBU/EPO SD

PVP64 EPO IBU/ PVP64 PM IBU/ EPO PM

IBU 0

20

40

60 Temperature (°°C)

80

100

120

(a)

FF/PVP64 SD

Relative Heat Flow (Endo Up)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 28

PVP64

FF/PVP64 PM

FF 0

20

40

60 80 Temperature (°°C)

100

120

(b) Figure 1: DSC thermograms for: (a) Pure IBU, PVP64, EPO, IBU/PVP64 PM and SD, IBU/EPO PM and SD, (b) Pure FF, PVP64, FF/PVP64 PM and SD

4.5. Powder Characterization

16 ACS Paragon Plus Environment

Page 17 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Industrial & Engineering Chemistry Research

Fig. 2 shows the presence of the characteristic diffraction peaks of crystalline ibuprofen in the freshly prepared PMs of IBU/PVP64 and IBU/EPO. The crystalline characteristic peaks were also detected for one day old sample of IBU/PVP64 PM. However, the intensities were lower compared to those of the fresh sample. The interaction between ibuprofen and the polymers might have caused the ibuprofen crystalline peaks to diminish. On the other hand, the PXRD of one day old IBU/EPO PM showed no major characteristic peaks of crystalline ibuprofen although characteristic crystalline peaks of ibuprofen could still be identified at 6.1°, 21.7° with very low intensities. This indicates that strong interaction between ibuprofen and Eudragit EPO has occurred in its physical mixture. The PXRD patterns for both IBU/PVP64 and IBU/EPO SDs show the characteristic of amorphous halo, indicating the amorphous nature of ibuprofen present in the SDs. Similar amorphous halo was also observed for FF/PVP64 SD. All SDs were then stored at two different conditions in order to analyze the stability of the SDs: at room temperature and low humidity of 25% RH (closed vial), and at 40°C and high humidity of 75% RH (open vial). The SDs were analyzed every one to two weeks by polarized microscopy and PXRD. IBU/PVP64 and IBU/EPO SDs remained amorphous for 23 weeks at room temperature and low humidity. However, very small amount of crystals was detected by polarized microscopy (not shown) in FF/PVP64 SD after 14 weeks of storage at room temperature and low humidity, indicating the unstable nature of the solid dispersion. PXRD was unable to detect the characteristic crystalline peaks of FF in the sample, due to the small amount of crystals in the SD. At 40oC/75%RH and open vial condition, the recrystallization of FF from FF/PVP64 SD occurred after just five weeks of storage as evident from the prominent characteristic peaks observed in the PXRD pattern (Fig. 3 a). IBU/PVP64 SD, on the other hand, remained

17 ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

amorphous after five weeks of storage under the same condition (Fig. 3b). IBU/PVP64

Fresh PM One day PM SD Pure IBU

5

10

15

20

25

30

35

Fresh PM One Day PM SD Pure IBU

Relative Intensity (a.u.)

IBU/EPO

Relative Intensity (a.u.)

5

40

10

15

2θ θ

20

25

30

35

40

2θ θ

(a)

(b)

FF/PVP64

PM SD Pure FF

Relative Intensity (a.u.)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 28

5

10

15

20

2θ θ

25

30

35

40

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

18 ACS Paragon Plus Environment

FF/PVP64 SD

IBU/PVP64 SD

Pure FF

Pure IBU Relative Intensity (a.u.)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Industrial & Engineering Chemistry Research

Relative Intensity (a.u.)

Page 19 of 28

5

15

2θ θ 25

35

5

15

(a)

2θ θ 25

35

(b)

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

The interaction of APIs (IBU and FF) and polymers was investigated by FTIR spectroscopy. Fig. 4a shows the FTIR spectra of pure ibuprofen, PVP64, IBU/PVP64 physical mixture and solid dispersion. The FTIR spectrum of pure ibuprofen 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 1734 cm-1 and vinyl pyrrolidone group at 1654 cm-1. The FTIR spectrum of the physical mixture gave broad carbonyl absorption bands corresponding to vinyl acetate group at 1730 cm-1 and vinyl pyrrolidone group at 1652 cm-1. The carbonyl absorption peak of ibuprofen at 1720 cm-1 was not seen in both physical mixture and solid dispersion. The FTIR spectrum of solid dispersion showed the absorption band at 1666 cm1

which was shifted to a higher wavenumber compared to 1654 cm-1 of PVP64. This shift

indicates a formation of H-bond 26 between the C=O of the carbonyl group in PVP64 with the OH group of ibuprofen. This reinforces our simulation results that showed H-bond formation between IBU and PVP64.

19 ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 28

In the FTIR spectrum of IBU/EPO physical mixture (Fig. 4b), stretching vibration due to carboxyl group was found at 1726 cm-1, similar to that of pure Eudragit-EPO. The carbonyl absorption peak of ibuprofen at 1720 cm-1 was not seen in both physical mixture and solid dispersion. The FTIR spectrum of solid dispersion showed a broad absorption band at 1726 cm-1. The carbonyl absorption peak of ibuprofen overlapped with the carbonyl group peak of Eudragit EPO polymer, therefore broad absorption band was found in the solid dispersion. This indicates hydrogen bond formation 27 between IBU and EPO. In a similar finding, Doreth et al.28 reported amorphization of ibuprofen and naproxen with Eudragit EPO in water. The FTIR spectrum of solid dispersion showed peaks with low intensity due to amorphization of ibuprofen. The FTIR spectra of fenofibrate with PVP64 are shown in Fig. 4c. The carbonyl stretching vibration bands at 1652 cm-1 and 1734 cm-1 of pure fenofibrate are found in the FTIR spectra of physical mixture and solid dispersion. This indicates a lack of interaction between fenofibrate and the polymer, which also agrees with the simulation results. The lack of interactions and the low glass transition temperature of fenofibrate (-19.33°C) may cause recrystallization to occur and therefore results in an unstable solid dispersion. It was reported that APIs with low glass transition temperature have higher mobility at room temperature which may results in recrystallization.29 This observation agrees with the PXRD analysis (Fig. 3a) that shows the appearance of crystal in fenofibrate solid dispersion sample stored for 5 weeks at 40°C/75%RH in open vial.

20 ACS Paragon Plus Environment

Page 21 of 28

SD

% Transmittance

PM PVP64

IBU

2000

1800

1600 1400 Wavenumber (cm-1) (a)

1200

1000

1800

1600 1400 Wavenumber (cm-1)

1200

1000

SD PM

% Transmittance

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Industrial & Engineering Chemistry Research

EPO IBU

2000

(b)

21 ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

SD PM % Transmittance

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 28

PVP64 FF

2000

1800

1600

1400

1200

1000

Wavenumber (cm-1) (c) Figure 4: FTIR Spectra for (a) pure IBU, PVP64 and IBU/PVP64 PM and SD; (b) pure IBU, EPO, and IBU/EPO PM and SD; (c) pure FF, PVP64 and FF/PVP64 PM and SD.

Fig. 5 shows the dissolution profiles of IBU/PVP64 and IBU/EPO SDs compared with their corresponding PMs and pure ibuprofen. It is observed that both IBU/PVP64 and IBU/EPO SDs exhibit faster initial dissolution rates compared to their corresponding PMs and pure IBU. 86% of IBU has been released from IBU/PVP64 SD within the first 15 min while IBU/EPO experienced burst release of 85 % within the first five min. This indicates that the dissolution rate is significantly improved by the amorphous nature of the ibuprofen in the SDs. Owing to the strong interaction between IBU and the polymers, recrystallization of IBU was prevented and the drug concentration remained at the plateau value after the initial quick/burst release period. This is in contrast to the dissolution behavior of FF/PVP64 SD as shown in Fig. 6. Although FF/PVP64 SD also exhibits quick release of 74% within the first 15 min, the concentration of FF gradual decreased to around 30% after two hours. This characteristic parachute pattern is associated with solid dispersions with no API-polymer interaction 30. Due to the lack of 22 ACS Paragon Plus Environment

Page 23 of 28

interaction, the carrier polymer is not able to inhibit recrystallization of the FF from the amorphous form, thus the concentration of FF gradually decreased.

120

100

100

80

80

60

Release (%)

120

Release (%)

IBU/PVP64 PM IBU/PVP64 SD

40

Pure IBU

20

60

IBU/EPO PM IBU/EPO SD

40

Pure IBU 20

0 0

20

40

60 t (min)

80

100

0

120

0

20

(a)

40

60 80 t (min)

100

120

(b)

Figure 5: Dissolution profiles of (a)IBU/PVP64 and (b) IBU/EPO SDs compared with PMs and pure IBU. 80

FF/PVP64 PM FF/PVP64 SD Pure FF

70 60 Release (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Industrial & Engineering Chemistry Research

50 40 30 20 10 0 0

20

40

60 80 t (min)

100

120

Figure 6: Dissolution profiles of FF/PVP64 SD and PM.

4.6. Miscibility and Molecular Interaction Simulation approach has shown that Hansen solubility parameter is able to predict drugpolymer miscibility. However, miscible system may not be an indication that the system has

23 ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 28

drug-polymer molecular interaction, which is required for successful formulation of stable amorphous solid dispersion. Drug and polymer may be dispersed evenly and produce a miscible system, but no molecular interaction may be found between the two species. One example of miscible system but no molecular interaction observed in our study was FF/PVP64 solid dispersion. In addition, experimental approach has also shown similar observation, in which DSC data showed the miscibility of FF/PVP64, and FTIR showed the lack of interaction between FF and PVP64.

5. Conclusion Molecular dynamics (MD) simulation was performed to obtain the solubility parameters of various drug and polymer combinations. The solubility parameters obtained from our simulation agreed well with those available in the literature. The solubility parameters obtained from simulation suggested that the 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 hydrogen bond analysis revealed that only IBU/PVP64 and IBU/EPO are able to form strong enough hydrogen bonds to sustain a stable solid dispersion. Weak or no hydrogen bond interaction was found for the rest of the drug/polymer combinations. Experimental observations have confirmed the miscibility of IBU and FF in PVP64 and IBU in EPO. Experimental data has also confirmed the stability of IBU/PVP64 and IBU/EPO solid dispersions. The solid dispersions of ibuprofen in PVP64 and EPO showed fast release rates and higher % release compared to pure ibuprofen and physical mixtures of IBU and polymers. On the other hand, experimental results also verified the lack of interaction between fenofibrate and PVP64 and hence poor stability of the FF/PVP64 SD, as evident from the 24 ACS Paragon Plus Environment

Page 25 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Industrial & Engineering Chemistry Research

recrystallization of FF from the SD during storage and the characteristic parachute dissolution behavior of the SD. The findings reported suggest that molecular dynamic simulation can be used as a predictive tool to select excipients for the formulation of stable solid dispersion.

References 1. (a) Jha, P. K.; Larson, R. G., Assessing the Efficiency of Polymeric Excipients by Atomistic Molecular Dynamics Simulations. Molecular Pharmaceutics 2014, 11 (5), 1676-1686; (b) Rumondor, A. C. F.; Taylor, L. S., Effect of Polymer Hygroscopicity on the Phase Behavior of Amorphous Solid Dispersions in the Presence of Moisture. Molecular Pharmaceutics 2010, 7 (2), 477-490. 2. (a) Craig, D. Q. M., The mechanisms of drug release from solid dispersions in water-soluble polymers. International Journal of Pharmaceutics 2002, 231 (2), 131-144; (b) Sareen, S.; Mathew, G.; Joseph, L., Improvement in solubility of poor water-soluble drugs by solid dispersion. International Journal of Pharmaceutical Investigation 2012, 2 (1), 12-17; (c) Li, W.; Buckton, G., Using DVS-NIR to assess the water sorption behaviour and stability of a griseofulvin/PVP K30 solid dispersion. International Journal Of Pharmaceutics 2015, 495 (2), 999-1004. 3. (a) Douroumis, D.; Bouropoulos, N.; Fahr, A., Physicochemical characterization of solid dispersions of three antiepileptic drugs prepared 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 Polyethylene Glycols. Drug Development and Industrial Pharmacy 1996, 22 (9-10), 909-916. 4. Chronakis, I. S.; Öste Triantafyllou, A.; Öste, R., Solid-state characteristics and redispersible properties of powders formed by spray-drying and freeze-drying cereal dispersions of varying (1→3,1→ 4)-β-glucan content. Journal of Cereal Science 2004, 40 (2), 183-193. 5. Verreck, G.; Chun, I.; Peeters, J.; Rosenblatt, J.; Brewster, M. E., Preparation and characterization of nanofibers containing amorphous drug dispersions generated by electrostatic spinning. Pharm Res 2003, 20 (5), 810-7. 6. (a) Kanaujia, P.; Lau, G.; Ng, W. K.; Widjaja, E.; Hanefeld, A.; Fischbach, M.; Maio, M.; Tan, R. B., Nanoparticle formation and growth during in vitro dissolution of ketoconazole solid dispersion. Journal of Pharmaceutical Sciences 2011, 100 (7), 2876-2885; (b) Sarode, A. L.; Sandhu, H.; Shah, N.; Malick, W.; Zia, H., Hot melt extrusion (HME) for amorphous solid dispersions: Predictive tools for processing and impact of drug–polymer interactions on supersaturation. European Journal of Pharmaceutical Sciences 2013, 48 (3), 371-384; (c) Sarode, A. L.; Sandhu, H.; Shah, N.; Malick, W.; Zia, H., Hot Melt Extrusion for Amorphous Solid Dispersions: Temperature and Moisture Activated Drug– Polymer Interactions for Enhanced Stability. Molecular Pharmaceutics 2013, 10 (10), 3665-3675. 7. (a) Prasad, D.; Chauhan, H.; Atef, E., Role of Molecular Interactions for Synergistic Precipitation Inhibition of Poorly Soluble Drug in Supersaturated Drug–Polymer–Polymer Ternary Solution. Molecular 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 Indomethacin Precipitation in Solution and Amorphous Solid Crystallization Based on Molecular Interaction. Pharmaceutical Research 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 by thermodynamic model fitting. European Journal of Pharmaceutics and Biopharmaceutics 2013, 84 (1), 228-237; (b) Punčochová, K.; Heng, J. Y. Y.; Beránek, J.; Štěpánek, F., Investigation of drug–polymer interaction in solid dispersions by vapour sorption methods. International Journal of Pharmaceutics 2014, 469 (1), 159-167; (c) Maniruzzaman, M.; Morgan, D. J.; Mendham, A. P.; Pang, J.; 25 ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 28

Snowden, M. J.; Douroumis, D., Drug–polymer intermolecular interactions in hot-melt extruded solid dispersions. International Journal of Pharmaceutics 2013, 443 (1–2), 199-208; (d) Huang, Y.; Dai, W.G., Fundamental aspects of solid dispersion technology for poorly soluble drugs. Acta Pharmaceutica Sinica B 2014, 4 (1), 18-25. 9. Meng, F.; Trivino, A.; Prasad, D.; Chauhan, H., Investigation and correlation of drug polymer miscibility and molecular interactions by various approaches for the preparation of amorphous solid dispersions. European Journal of Pharmaceutical Sciences 2015, 71 (Supplement C), 12-24. 10. Ilevbare, G. A.; Liu, H.; Edgar, K. J.; Taylor, L. S., Maintaining supersaturation in aqueous drug solutions: impact of different polymers on induction times. Crystal Growth & Design 2012, 13 (2), 740751. 11. Meng, F.; Dave, V.; Chauhan, H., Qualitative and quantitative methods to determine miscibility in amorphous drug–polymer systems. European Journal of Pharmaceutical Sciences 2015, 77 (Supplement C), 106-111. 12. (a) Choi, P.; Kavassalis, T. A.; Rudin, A., Estimation of Hansen Solubility Parameters for (Hydroxyethyl) and (Hydroxypropyl) cellulose through Molecular Simulation. Industrial & Engineering Chemistry Research 1994, 33 (12), 3154-3159; (b) Maniruzzaman, M.; Pang, J.; Morgan, D. J.; Douroumis, D., Molecular modeling as a predictive tool for the development of solid dispersions. Mol Pharm 2015, 12 (4), 1040-9; (c) Kavassalis, T. A.; Choi, P.; Rudin, A., The Calculation of 3D Solubility Parameters Using Molecular Models. Molecular Simulation 1993, 11 (2-4), 229-241; (d) Simperler, A.; Kornherr, A.; Chopra, R.; Bonnet, P. A.; Jones, W.; Motherwell, W. D. S.; Zifferer, G., Glass Transition Temperature of Glucose, Sucrose, and Trehalose:  An Experimental and in Silico Study. The Journal of Physical Chemistry B 2006, 110 (39), 19678-19684. 13. Materials Studio Modeling, 7.0; Accelrys Software Inc. : San Diego, CA. 14. Sun, H., COMPASS: An ab Initio Force-Field Optimized for Condensed-Phase ApplicationsOverview with Details on Alkane and Benzene Compounds. The Journal of Physical Chemistry 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 an external bath. The Journal of Chemical Physics 1984, 81 (8), 3684-3690. 17. Huggins, M. L., The Solubility of Nonelectrolytes. By Joel H. Hildebrand and Robert S. Scott. The Journal of Physical Chemistry 1951, 55 (4), 619-620. 18. Wong, Y.; Chen, Z. J.; Tan, T. T. Y.; Lee, J.-M., Hildebrand Solubility Parameters of Amidium Ionic Liquids. Industrial & Engineering Chemistry Research 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, USA, 2007; p 544. 20. Greenhalgh, D. J.; Williams, A. C.; Timmins, P.; York, P., Solubility parameters as predictors of miscibility in solid dispersions. Journal Of Pharmaceutical Sciences 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 stability and dissolution of fenofibrate and ketoconazole solid dispersions using PXRD, 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 of indomethacin and polymers to assess their suitability for hot-melt extrusion processs as a means to manufacture solid dispersion/solution. J Pharm Sci 2005, 94 (11), 246374. 23. Ghosh, I.; Snyder, J.; Vippagunta, R.; Alvine, M.; Vakil, R.; Tong, W. Q.; Vippagunta, S., Comparison of HPMC based polymers performance as carriers for manufacture of solid dispersions using the melt extruder. Int J Pharm 2011, 419 (1-2), 12-9. 24. (a) Dirama, T. E.; Carri, G. A.; Sokolov, A. P., Coupling between lysozyme and glycerol dynamics: Microscopic insights from molecular-dynamics simulations. The Journal of Chemical Physics 26 ACS Paragon Plus Environment

Page 27 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Industrial & Engineering Chemistry Research

2005, 122 (24), 244910; (b) Busselez, R.; Lefort, R.; Ji, Q.; Affouard, F.; Morineau, D., Molecular dynamics simulation of nanoconfined glycerol. Physical Chemistry Chemical Physics 2009, 11 (47), 11127-11133. 25. Dudognon, E.; Danède, F.; Descamps, M.; Correia, N. T., Evidence for a New Crystalline Phase of Racemic Ibuprofen. Pharmaceutical Research 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 of felodipine from nanodispersions with polyvinylpyrrolidone. Eur J Pharm Biopharm 2006, 63 (2), 103-14. 27. Stott, P. W.; Williams, A. C.; Barry, B. W., Transdermal delivery from eutectic systems: enhanced permeation of a model drug, ibuprofen. Journal of Controlled Release 1998, 50 (1–3), 297-308. 28. Doreth, M.; Löbmann, K.; Grohganz, H.; Holm, R.; Lopez de Diego, H.; Rades, T.; Priemel, P. A., Glass solution formation in water - In situ amorphization of naproxen and ibuprofen with Eudragit® E PO. Journal of Drug Delivery Science and Technology 2016, 34, 32-40. 29. Kanaujia, P.; Poovizhi, P.; Ng, W. K.; Tan, R. B. H., Amorphous formulations for dissolution and bioavailability enhancement of poorly soluble APIs. Powder Technology 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. Journal of Excipients and Food Chemicals 2013, 4 (3), 70-94.

27 ACS Paragon Plus Environment

Industrial & Engineering Chemistry Research

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 28

For Table of Content only

28 ACS Paragon Plus Environment