Understanding the mechanism of dissolution enhancement for poorly water-soluble drugs by solid dispersions containing Eudragit® E PO

Accepted Manuscript Understanding the mechanism of dissolution enhancement for poorly water-soluble ® drugs by solid dispersions containing Eudragit E PO Xia Lin, Lili Su, Na Li, Yang Hu, Gang Tang, Lei Liu, Hongmei Li, Ziyi Yang PII:

S1773-2247(18)30931-6

DOI:

10.1016/j.jddst.2018.10.008

Reference:

JDDST 792

To appear in:

Journal of Drug Delivery Science and Technology

Received Date: 18 August 2018 Revised Date:

5 October 2018

Accepted Date: 8 October 2018

Please cite this article as: X. Lin, L. Su, N. Li, Y. Hu, G. Tang, L. Liu, H. Li, Z. Yang, Understanding the mechanism of dissolution enhancement for poorly water-soluble drugs by solid dispersions containing ® Eudragit E PO, Journal of Drug Delivery Science and Technology (2018), doi: https://doi.org/10.1016/ j.jddst.2018.10.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Understanding the mechanism of dissolution enhancement for poorly water-soluble drugs by

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solid dispersions containing Eudragit® E PO

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Xia Lin, Lili Su, Na Li, Yang Hu, Gang Tang, Lei Liu, Hongmei Li, Ziyi Yang*

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School of Pharmaceutical Science, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China

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8 9 Corresponding author:

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Corresponding author: Ziyi Yang *

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Mailing address: School of Pharmaceutical Science, Jiangnan University, 1800 Lihu Road, Wuxi

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214122, China

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Tel.: +86-(0)510-85197769

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E-mail: [email protected]

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Abstract In this paper, we intended to understand the mechanism of dissolution enhancement for poorly

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water-soluble drugs by amorphous solid dispersions containing EUDRAGIT® E PO (EPO).

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Equilibrium solubility enhancement for three model drugs including ibuprofen, felodipine and

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bifendate were tested in acidic solutions containing different concentrations of EPO. Three model

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drugs were prepared into amorphous solid dispersions by hot melt extrusion with EPO. Results showed

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that EPO can substantially solubilize model drugs in acidic solution to 20 to 300 fold of their

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thermodynamic solubilities. Linear solubilizing relationships between EPO and drugs were achieved

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for all three drugs. It was found that amorphous solid dispersions with drug loadings below solubilizing

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range showed no recrystallization in dissolution tests whereas drug concentration reduction was seen in

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dissolution tests when drug loadings were above the solubilizing range. By combining the results from

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dynamic laser scattering, critical micelle concentration (CMC) and morphology studies, it was

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confirmed that EPO can form micelles in acidic solution, and the CMC value was estimated as 0.99

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µg/ml. In conclusion, the dissolution enhancement for poorly water-soluble drugs by amorphous solid

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dispersions containing EPO was combined contribution from both the physical structure of solid

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dispersions and the solubilizing effect of EPO.

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Keywords: solubilizing effect, micelles, EUDRAGIT® E PO, amorphous solid dispersions, solubility

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enhancement

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ACCEPTED MANUSCRIPT 1. Introduction

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The enhancement of dissolution rate as well as bioavailability of poorly water-soluble active

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pharmaceutical ingredients (API) remained one of the most challenging issues in the pharmaceutical

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industry with increasing production of APIs by the high throughput screening [1]. The preparation of

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amorphous solid dispersions has proved to be effective in improving the dissolution behavior of BCS II

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drugs in many researches [2-4]. Despite the physical instability, the growing quantities of

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commercialized medicines based on solid dispersions approved by FDA further demonstrated that solid

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dispersion was effective and promising in enhancing dissolution rate of poorly water soluble drugs [5,

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6].

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The underpinning mechanism of dissolution enhancement by solid dispersions has been well

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studied in literature [7-9]. Fundamentally, drugs can be evenly dispersed amongst polymeric carriers,

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forming a dispersion where drugs were separated as single molecule within the solid dispersion

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[10,11]. Consequently, the lattice structure of APIs that had to be destroyed during dissolution

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disappeared completely in solid dispersions, and hence the dissolution rate of APIs can be significantly

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enhanced in comparison with the corresponding crystalline APIs [9]. In addition, the applied polymeric

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carriers in solid dispersions may have special physicochemical properties, i.e. hydrophilic, which can

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further improve the dissolution performance [12-14]. The molecularly dispersed structure and the

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assistance from polymeric carriers were considered to be the main reasons that made amorphous solid

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dispersions exhibit considerably enhanced dissolution rate.

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EUDRAGIT® E PO was a cationic copolymer that was composed of dimethylaminoethyl

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methacrylate and neutral methacrylic ester units [15]. It was a pH-dependent soluble polymer which

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only dissolved at the pH below 5 [16]. EUDRAGIT® E PO was naturally amorphous with a glass

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transition temperature of approximately 50 oC, and it was perfectly applicable in hot melt extrusion for

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the preparation of solid dispersions due to being thermoplastic [17-19]. Originally, EUDRAGIT® E PO

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was widely used for taste masking in the pharmaceutical industry [20, 21]. Later, in the field of solid

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dispersions, EUDRAGIT® E PO was reported to be effective in enhancing the dissolution rate of

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poorly water soluble drugs and improving the physical stability of amorphous solid dispersions against

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stressed humidity [22, 23]. In the report where EUDRAGIT® E PO was formulated with curcumin into

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amorphous solid dispersions, it was found that water solubility of curcumin was increased to 3 mg/ml

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that was similar to the solubility in organic solvents, and such solubility enhancement was attributed to

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ACCEPTED MANUSCRIPT the formation of hydrogen bonding between curcumin and EUDRAGIT® E PO [24]. Similarly in

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another report, EUDRAGIT® E PO was formulated with mefenamic acid by cryogenic grinding into

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solid dispersions, and the bioavailability study showed that the AUC value of the solid dispersion was

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7.8 fold higher than that of pure drug. In this research, the increased bioavailability was concluded to

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be the contribution from the molecular interaction between the carboxyl groups from mefenamic acid

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and aminoalkyl groups from EUDRAGIT® E PO in the amorphous solid dispersion [25]. These results

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showed that molecular interaction between EUDRAGIT® EPO and drugs played a significant role in

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enhancing the dissolution rate of poorly water soluble drugs. Previously in our paper, it was reported

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that EUDRAGIT® E PO could solubilize typical BCS II drug, felodipine, increasing its equilibrium

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solubility in 0.1 M HCl by circa over 250 times, and no molecular interaction was observed between

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felodipine and EUDRAGIT® E PO as demonstrated by the FTIR study [23]. The mechanism for such

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solubilizing effect, however, was not revealed in that research, but it indeed proved that in addition to

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the molecular interaction, there may exist other mechanisms that could explain the solubilizing effect.

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EUDRAGIT® E PO has shown the potential of being a useful polymeric carrier candidate for solid

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dispersions to enhance the dissolution rate of poorly water soluble drugs. In addition, it might not be

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common that a new BCS II API could easily form molecular interaction with EUDRAGIT® E PO.

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Consequently, the solubilizing effect of EUDRAGIT® E PO in 0.1 M HCl should be deeply understood

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to better apply this polymer in solid dispersions. In this paper, we intended to understand the

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mechanism of dissolution enhancement for poorly water soluble drugs in EUDRAGIT® E PO based

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solid dispersions. Three typical BCSII drugs including felodipine, ibuprofen and bifendate were

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selected as the model drugs, and were prepared into solid dispersions by hot melt extrusion. The

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equilibrium solubilities of three model drugs in 0.1 M HCl with different concentrations of

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EUDRAGIT® E PO were measured. Comparison between the solubilized equilibrium solubilities and

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the dissolution of drugs from hot melt extrudates was carried out to investigate the role of solubilizing

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effect of EUDRAGIT® E PO in dissolution enhancement. By further using microscopic, fluorescence

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probe and particle sizing approaches, the solubilizing effect of EUDRAGIT® E PO and the dissolution

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mechanism of melt extrudates from solid dispersions containing EUDRAGIT® E PO may be

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understood.

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2. Materials and Methods

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2.1. Materials

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Ibuprofen, felodipine and bifendate were purchased from Hubei Yuancheng Saichuang Technology

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Co., LTD. EUDRAGIT® E PO was donated by Evonik Industries AG. All other chemical reagents

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were of analytical grade.

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2.2. Analytical method High performance liquid chromatography (HPLC) method was developed for the quantification of

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three model drugs.

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HPLC method for ibuprofen was achieved by modifying the USP ibuprofen HPLC method (USP

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39), and the detail of the method in this study was: concentration of ibuprofen was determined by

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Agilent 1260 HPLC (Agilent Technologies Inc., Germany) equipped with a UV detector at 263 nm.

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The column was ZORBAX Eclipse Plus C18 column (5 µm, 4.6×150 mm), and the mobile phase was

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composed of acetonitrile and KH2PO4 buffer solution (2.12 mg/ml, pH 2.5, 45:55, v/v). The validation

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study for ibuprofen HPLC method was described in the Supplementary material.

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HPLC method for felodipine was achieved from the literature [26], and the detail of the method

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was: concentration of felodipine was determined by Agilent 1260 HPLC (Agilent Technologies Inc.,

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Germany) equiped with a UV detector at 238nm. The column was ZORBAX Eclipse Plus C18 column

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(5 µm, 4.6×150 mm), and the mobile phase was composed of methanol, acetonitrile and water

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(50:15:35, v/v/v).

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HPLC method for bifendate was achieved from the China Pharmacopeia 2015 (ChP 2015)

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bifendate HPLC method, and the detail of the method was: concentration of bifendate was determined

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by Agilent 1260 HPLC (Agilent Technologies Inc., Germany) equiped with a UV detector at 278 nm.

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The column was ZORBAX Eclipse Plus C18 column (5 µm, 4.6×150 mm), and the mobile phase was

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composed of methanol and water (56:44, v/v). The validation study for bifendate HPLC method was

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described in the Supplementary material.

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2.3. Determination of equilibrium solubilities of drugs in EUDRAGIT® E PO-0.1 M HCl solutions

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Different amounts of EUDRAGIT® E PO were dissolved in 0.1 M HCl solution to prepare 0.1 M HCl

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solution with EUDRAGIT® E PO concentrations including 5 mg/ml, 15 mg/ml, 25 mg/ml, and 35

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mg/ml (abbreviated as EUDRAGIT® E -HCl). Excessive amount of felodipine, ibuprofen and bifendate

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were dispersed in different EUDRAGIT® E-HCl solutions, and the solutions were maintained at 37 oC

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with continuous magnetic stirring for up to 72 hours. Subsequently, all EUDRAGIT® E-HCl solutions

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were centrifuged at 5000 r/min for 10 min and filtered through 0.22 µm membrane filters. The drug

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in the section of “Analytical method”.

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2.4. Dissolution tests of drugs in EUDRAGIT® E PO-0.1 M HCl solution

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In order to obtain the dissolution rate of pure crystalline drugs with the existence of EUDRAGIT® E

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PO in acidic media, dissolution tests of the three model drugs in the same EUDRAGIT® E-HCl

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solutions were carried out. Paddle method with the speed of 100 r/min at 37 oC was used for the

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dissolution studies of pure drugs, and the volume of media was 900 ml. Excessive amount of each

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model drug was dispersed in different EUDRAGIT® E-HCl solutions, including 5 mg/ml, 15 mg/ml, 25

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mg/ml and 35 mg/ml. 5 ml samples were withdrawn at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h,

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24 h, 48 h, 72 h and filtered through 0.22 µm membrane filters. For all dissolution tests, drug powder

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was screened by 60 mesh sieve before the test, and was directed transferred into the dissolution media.

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Drug concentrations in withdrawn samples were determined using HPLC methods as described in the

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section of “Analytical method”.

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2.5. Hot melt extrusion

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Amorphous solid dispersions of model drugs and EUDRAGIT® E PO were prepared by hot melt

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extrusion method. Prior to extrusion, the model drugs and EUDRAGIT® E PO were passed through a

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60 mesh sieve, respectively. The three model drugs, ibuprofen, felodipine and bifendate, were then

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accurately weighed and mixed with EUDRAGIT® E PO to obtain homogenous physical mixtures,

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respectively. The physical mixtures were extruded using Thermo Fisher Process 11 Twin-Screw

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extruder (Thermo Scientific, Germany). Temperature zones of the extruder were all set at the

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temperatures slightly above the melting points of model drugs (90 oC for ibuprofen, 150 oC for

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felodipine and 180 oC for bifendate) [27-29]. For all sample preparation, the speed of twin screw was

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set at 50 r/min. Extrudates with the drug loading of 4% and 10% (w/w) were prepared for ibuprofen.

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Extrudates with the drug loading of 0.7% and 1.5% (w/w) were prepared for felodipine. Extrudates

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with the drug loading of 1% (w/w) were prepared for bifendate.

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2.6. Dissolution tests of hot melt extrudates

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Dissolution tests of hot melt extrudates containing different model drugs were conducted using paddle

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method. Prior to tests, all the hot melt extrudates were pulverized and passed through a 60 mesh sieve,

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respectively. 2 g of the pulverized hot melt extrudates were accurately weighed and evaluated for the

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dissolution tests. The dissolution tests were performed on a RC806D dissolution tester (Tianda Tianfa

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used as the dissolution media. For all dissolution tests, the pulverized and sieved hot melt extrudates

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were accurately weighted and kept on the folded weighing paper, and these powder samples were

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directly transferred into the dissolution media for the dissolution tests. 5 ml samples were withdrawn at

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5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 1 h, 2 h, 6 h, 10 h, 24 h, 48 h, and 72 h, and were

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substituted with equal volume of fresh dissolution media. The samples were immediately filtered

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through 0.22 µm membrane filters, and were analyzed using HPLC methods as mentioned in the

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section of “Analytical method”.

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2.7. Determination of particle size distribution of EUDRAGIT® E PO solution

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In order to confirm whether or not micelles were formed by EUDRAGIT® E PO in 0.1 M HCl solution,

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dynamic laser scattering was applied to determine the particle size. Basically, EUDRAGIT® E-HCl

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solutions with different concentrations of EUDRAGIT® E PO (1, 2, 5, 15, 25 and 35 mg/ml) were

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tested using NicompTM 380 Particle Sizing System (Santa Barbara, CA, USA) at 25 oC, and the results

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were presented with particle size distribution of the solution. In addition, the particle size distribution

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of each EUDRAGIT® E-HCl solution saturated with the three model drugs at 25 oC was also analyzed.

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2.8. Determination of critical micelle concentration of EUDRAGIT® E PO

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Pyrene-based fluorescent probe method was applied to determine the critical micelle concentration

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(CMC) of EUDRAGIT® E PO [30]. Pyrene was dissolved in acetone to achieve the pyrene solution

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with the concentration of 1×10-5 mol/ml, and the solution was then transferred to 10 volumetric flasks

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(10 ml) with each volumetric flask containing 100 µL pyrene solution, and acetone was evaporated at

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room temperature. EUDRAGIT® E PO was also dissolved in acetone with the concentrations ranging

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from 5×10-3 mg/ml to 10 mg/ml. Subsequently, adequate EUDRAGIT® E PO solution was transferred

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to each volumetric flask that already contained pyrene, and acetone was evaporated at room

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temperature for 8 hours. After evaporation, 0.1 M HCl solution was added into each flask to the

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volume. Finally in each volumetric flask, the concentration of pyrene was 1×10-7 mol/ml, and the

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concentration of EUDRAGIT® E PO was 1 mg/ml, 5×10-1 mg/ml, 1×10-1 mg/ml, 5×10-2 mg/ml, 1×10-2

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mg/ml, 5×10-3 mg/ml, 1×10-3 mg/ml, 5×10-4 mg/ml, 1×10-4 mg/ml and 5×10-5 mg/ml, respectively. All

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solutions were equilibrated for 24 hours at room temperature before test. Solutions were tested using

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fluorescence spectrophotometry. The emission wavelength was set at 390 nm with the slit of 2.5 nm

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and 5 nm. The scanning speed was 240 nm/min with the range from 300 nm to 350 nm. The ratio of

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against the log of concentrations of EUDRAGIT® E PO to achieve the CMC of EUDRAGIT® E PO in

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0.1 M HCl solution.

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2.9. Transmission electron microscopy

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In order to directly observe the micelles formed by EUDRAGIT® E PO, transmission electron

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microscopy (TEM, JEM-2100, JEOL, Japan) was used. The sample was prepared by spreading

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EUDRAGIT® E-HCl solution with the concentration of 2 mg/ml over a copper grid covered with

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carbon film and was dried at room temperature.

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3. Results and discussion

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3.1. Equilibrium solubility enhancement for model drugs by EUDRAGIT® E PO in acidic solution

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The solubilizing effect of EUDRAGIT® E PO in 0.1 M HCl on model drugs was studied in this work.

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Different amounts of EUDRAGIT® E PO were dissolved in 0.1 M HCl to create EUDRAGIT® E-HCl

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solutions with the concentrations of EUDRAGIT® E PO ranging from 5 mg/ml to 35 mg/ml. The

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results of measured equilibrium solubilities of model drugs in different solutions were shown in Table

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S1. It can be seen that in 0.1 M HCl solution, EUDRAGIT® E PO was capable to solubilize all three

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model drugs. For ibuprofen, the equilibrium solubility was increased by almost 45 times when the

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concentration of EUDRAGIT® E PO was 35 mg/ml (close to saturated concentration of EUDRAGIT®

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E PO in 0.1 M HCl). In the same EUDRAGIT® E-HCl solution, compared with the equilibrium

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solubility of each drug, felodipine was solubilized by circa 300 times and bifendate was solubilized by

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almost 12 times. The three model drugs were typical BSCII drugs which had different chemical

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structures and varied in molecular weight and functional chemical groups (Fig. 1). These solubilizing

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results, therefore, may demonstrate that in acidic solution or in simulated gastric media, EUDRAGIT®

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E PO was able to increase the equilibrium solubility of poorly water soluble drugs.

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It was also seen in Table S1 that the solubilized concentrations of model drugs increased with

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increasing concentrations of EUDRAGIT® E PO in EUDRAGIT® E-HCl solutions. Regression

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analysis was carried out to investigate the solubilizing effect as shown in Fig. 2. The measured

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concentrations of the drug in the corresponding EUDRAGIT® E-HCl solution were plotted against the

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concentrations of EUDRAGIT® E PO in EUDRAGIT® E-HCl solutions. It was seen in Fig. 2 that

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linear relationships between the concentration of EUDRAGIT® E PO and the solubilized concentration

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of the drug were confirmed for all three model drugs as proved by the acceptable regression

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coefficients (R>0.99). It should be noted that the concentration of 35 mg/ml for EUDRAGIT® E-HCl

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solution was close to the solubility of EUDRAGIT® E PO in 0.1M HCl. Therefore, these results may

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suggest that within the total concentration range of EUDRAGIT® E-HCl solutions, the solubilizing

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effect of EUDRAGIT® E PO was likely to be linear. In addition, solubility enhancement study by EUDRAGIT® E PO with further pH value

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adjustment was also carried out. Basically, for each equilibrated EUDRAGIT® E-HCl solution with

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saturated drugs, after 72 hour, phosphate buffer solution was added in to adjust the pH value of each

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solution to 6.8. It was observed that with the addition of phosphate buffer, all solutions slightly turned

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into opaque. After 5 to 20 min, however, the slightly opaque solutions all became clear again. By

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measuring the drug concentration, it was found in each pH 6.8 buffered drug solutions, the drug

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concentration was the same as the value before the addition of phosphate buffer. These results may

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demonstrate that formulations that took advantage of the solubilizing effect by EUDRAGIT® E PO

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may not be affected by the change of pH values across the GI tract.

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3.2. Dissolution behavior of model drugs in acidic media with EUDRAGIT® E PO

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The measurement of the equilibrium solubilities of the three model drugs in EUDRAGIT® E-HCl

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solutions demonstrated that EUDRAGIT® E PO was capable to solubilize poorly water soluble drugs in

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acidic media. The time length that was required to reach the equilibrium, however, was not known. In

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addition, when attempting to understand the mechanism of the dissolution enhancement of solid

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dispersions containing EUDRAGIT® E PO, it was necessary to gain the dissolution rate of pure drugs

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with the existence of EUDRAGIT® E PO in acidic media. Therefore the dissolution tests of pure

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crystalline model drugs were conducted in this study. Excessive amount of three drugs were dispersed

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in EUDRAGIT® E-HCl solutions, and samples were withdrawn in predetermined time points up to 72

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hours. Dissolution results of ibuprofen were shown in Fig. 3. Despite the solubilizing effect by

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EUDRAGIT® E PO, it still took 36 hours for all tested ibuprofen samples to reach the concentration

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plateaus as seen in Fig.3. This suggested that the time period could be substantially long for the

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solubilizing effect by EPO to reach the equilibrium. . In addition, it was also seen that the dissolution

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rate of ibuprofen increased with increasing EPO concentrations in EUDRAGIT® E-HCl solutions as

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reflected by the slope of the dissolution curves before the plateau.

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Dissolution tests of felodipine and bifendate in EUDRAGIT® E-HCl solutions also showed

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concentration plateaus after certain time length as seen in Fig. 3. Compared with ibuprofen, the time

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S1). For felodipine, it almost took 12 hours to reach the drug concentration plateaus for all samples,

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and for bifendate, the time length for drug concentration plateau was circa 36 hours. Given the

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generally required in vivo drug release rate or time length for conventional oral preparations, these

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results suggested that the dissolution rate of pure crystalline drug was slow although the drugs could

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eventually be solubilized by EUDRAGIT® E PO. Similarly to ibuprofen, the dissolution rates for both

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drugs also increased with increasing EUDRAGIT® E PO concentrations in EUDRAGIT® E-HCl

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solutions. The solubilized amount of drugs, however, varied significantly amongst the three drugs. For

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instance, with the concentration of EUDRAGIT® E PO at 15 mg/ml, the solubilized concentration of

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ibuprofen could be as high as circa 800 µg/ml, whereas in the same EUDRAGIT® E-HCl solution, the

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solubilized concentrations for felodipine and bifendate were only circa 100 µg/ml and 10 µg/ml. When

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comparing the equilibrated solubilities in pure 0.1 M HCl with the solubilized solubilities of each drug,

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however, it was seen that felodipine was solubilized by the highest level amongst the three drugs. Such

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discrepancy of solubilizing effects between different drugs may be attributed to reasons such as

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interactions between the drug and polymer and the molecular dimension of the drug. Nevertheless,

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EUDRAGIT® E PO exhibited strong ability of solubilizing poorly water soluble drugs.

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3.3. Dissolution studies on amorphous solid dispersions by hot met extrusion

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It has been reported that dissolution rate of poorly water soluble drugs from solid dispersions can be

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significantly increased due to the state of drugs being molecularly dispersed and the hydrophilicity of

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polymeric carriers [7]. Recrystallization during dissolution, however, was found in a few case studies

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regarding solid dispersions whereby a reduction of drug concentration was clearly detected after certain

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time length in dissolution test [23, 31]. This was because that the rapid dissolution of poorly water

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soluble drugs can shortly create super-saturation of drugs in dissolution media, which can strongly

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drive recrystallization for drug molecules, leading to precipitation of dissolved drugs.

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In this study, the above results had already demonstrated that EUDRAGIT® E PO can solubilize

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poorly water soluble drugs in 0.1 M HCl solution, and linear solubilizing relationship were observed

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for all three model drugs. Therefore, it can be hypothesized that if the drug loading of solid dispersions

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was within the solubilized concentration range, no recrystallization should be observed, and hence a

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complete drug release should be achieved. The solubilized concentration range could be calculated

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using the linear regression equation as listed in Fig. 2 for model drugs. Took ibuprofen for example,

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and the linear equation was:

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y = 0.0506x + 0.0457 where x was the concentration of EUDRAGIT® E PO (mg/ml) in EUDRAGIT® E-HCl solution, and y

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was the concentration of ibuprofen (mg/ml) in the same solution. As the volume for EUDRAGIT® E

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PO and the drug was the same in the media, the equation can be used to estimate the amount of drugs

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that can be solubilized by EUDRAGIT® E PO. For instance, given 100 mg EUDRAGIT® E PO, the

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polymers may solubilize approximately 5.10 mg ibuprofen. Therefore, in dissolution, hot melt

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extrudates of ibuprofen and EUDRAGIT® E PO with the drug loading of 4% w/w was just within the

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solubilizing range and drug loading of 10% w/w was significantly beyond the solubilizing range. Drug

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loadings of hot melt extrudates for different model drugs were designed based on this solubilizing

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range. As seen in Fig. 4, ibuprofen hot melt extrudates with the drug loading of 4% w/w showed

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complete drug release within 10 min, whereas progressive reduction of drug concentration was

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observed for 10% w/w hot melt extrudates after 2 hours, indicating the occurrence of drug

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recrystallization in the media. These results may suggest that for solid dispersions composed of

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EUDRAGIT® E PO and poorly water soluble drugs, drug release rate can be significantly increased,

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but the equilibrated drug concentration may be dependent on the solubilized concentration by

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EUDRAGIT® E PO.

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Felodipine hot melt extrudates also showed similar dissolution performance. Felodipine solid

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dispersions prepared by hot melt extrusion were designed with the drug loadings of 0.7% w/w (within

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solubilizing range) and 1.5% w/w (beyond solubilizing range) as calculated by the above mentioned

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method. Results of these two melt extrudates in 0.1 M HCl were shown in Fig. 4. It was seen that

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drug loading just within the solubilizing range, complete drug release was observed within 15min and

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no recrystallization was seen even after 24 hours, whereas extrudates with higher drug loading

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exhibited drug precipitation after 2 hours. The dissolution rate, however, was still fast that over 90% of

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the drug was released within 15min.

the

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For bifendate, the solubilizing value was too small, and therefore solid dispersions with such small

302

drug loading (circa 0.06% w/w) cannot be prepared precisely. Hot melt extrudates with the drug

303

loading of 1% w/w were prepared for the dissolution study to test whether or not recrystallization

304

would occur in the media. It can be seen in Fig. 4 that although complete drug release occurred within

11

ACCEPTED MANUSCRIPT 15 min, reduction of drug concentration was observed after 6 hours of dissolution test. This result again

306

suggested that when drug loading was above the solubilizing range of EUDRAGIT® E PO,

307

recrystallization would occur for amorphous solid dispersions of bifendate. Generally speaking, for

308

conventional oral preparations, drug molecules can hardly stay in the gastrointestinal tract for more

309

than 24 hours. Therefore such drug concentration reduction from the dissolution results may not affect

310

the in vivo therapeutic effect of drugs. Nonetheless, the dissolution studies of the melt extrudates with

311

drug loadings below and beyond the solubilizing range of EUDRAGIT® E PO demonstrated that the

312

EUDRAGIT® E PO concentration was a key factor to maintain the equilibrated drug concentration.

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Hot melt extrudates containing three model drugs for dissolution tests were all confirmed as

314

amorphous solid dispersions by X-Ray and DSC studies (data not shown). Despite the rapid drug

315

release rate, recrystallization still occurred in samples with drug loadings above the solubilizing ratios.

316

This indicated that in the case of EUDRAGIT® E PO based amorphous solid dispersions,

317

transformation of drugs and polymers into molecular dispersion (solid solution) may only increase the

318

dissolution rate, the equilibrated drug concentration, however, was dependent on the solubilizing ability

319

by EUDRAGIT® E PO. For typical poorly water soluble drugs, i.e. the model drugs in this study,

320

recrystallization force (super-saturation level) was extremely high, and hence the equilibrated drug

321

concentration in the media was very low. The complete drug release without recrystallization in the

322

dissolution, therefore, was maintained mainly by the solubilizing effect. The linear solubilizing

323

relationship for all three model drugs may indicate the possibility that EUDRAGIT® E PO might be

324

able to form micelles in 0.1 M HCl, and thus can solubilize poorly water soluble drugs.

325

3.4. Investigation into the formation of micelles by EUDRAGIT® E PO

326

In order to investigate the formation of micelles by EUDRAGIT® E PO, different technologies

327

including dynamic laser scattering, fluorescent probe and microscopy were applied. Theoretically, if

328

micelles could be formed in solution, nanometer scaled particles should be detected by dynamic laser

329

scattering. EUDRAGIT® E-HCl solutions with the concentrations of EUDRAGIT® E PO ranging from

330

1 mg/ml to 35 mg/ml were tested by dynamic laser scattering, and the results were shown in Fig. 5. It

331

can be seen that formed particles were detected in all EUDRAGIT® E-HCl solutions. It should be noted

332

that all the tested EUDRAGIT® E-HCl solutions were naturally clear solutions by naked eyes.

333

Therefore, it was likely that these detected particles might be micelles formed by EUDRAGIT® E PO.

334

In addition, it was found that particle size increased with increasing EUDRAGIT® E PO concentration.

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For instance, with the concentration below 15 mg/ml, the measured mean diameter was circa 10 nm.

336

When the concentration increased to 25 mg/ml and 35 mg/ml, the mean diameter was determined as

337

470 nm and 2000 nm, respectively. The particle size depending on the concentration of EUDRAGIT®

338

E PO may further suggest the formation of micelles, as such phenomenon had been commonly reported

339

in literature regarding surfactants forming micelles [32]. In addition, after saturated with the three model drugs, all the EUDRAGIT® E-HCl solutions were

341

still naturally clear solutions. The EUDRAGIT® E-HCl solutions containing drugs showed similar

342

particle size distribution to the drug-free EUDRAGIT® E-HCl solutions with corresponding

343

EUDRAGIT® E PO concentration (Fig. S2, Fig.S3 and Fig. S4). By increasing the concentration of

344

EUDRAGIT® E from 15 mg/ml to 25 mg/ml, the mean particle size of EUDRAGIT® E-HCl solutions

345

containing drugs also increased from ~10 nm to approximately 500 nm. These results indicated that the

346

drugs might be solubilized into the core of the EUDRAGIT® E PO micelles.

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Pyrene-based fluorescent probe had been widely used for the confirmation of the formation of

348

micelles and the determination of critical micelle concentration (CMC) [33, 34]. Pyrene was strongly

349

hydrophobic with the water solubility of circa 1×10-7 mol/L [35]. When being solubilized into the

350

micelle cores, the polarity of local environment of pyrene would be changed, from being hydrophilic to

351

being hydrophobic, which may lead to different emission spectrum under florescence [36]. It has been

352

reported that the emission spectrum at 337 nm and 334 nm were sensitive to the formation of micelles,

353

and thus these two wavelengths were normally used to determine the CMC of surfactants [35]. A series

354

of EUDRAGIT® E-HCl with the concentrations of EUDRAGIT® E PO ranging from 5 ×10-5 mg/L to 1

355

mg/L were prepared, and pyrene were added into these solutions as mentioned above. The fluorescence

356

spectrum was shown in Fig. 6A. It can be seen that with increased concentration of EUDRAGIT® E PO

357

in solutions, the intensities at 337 nm (I337) and 334 nm (I334) substantially increased, indicating the

358

encapsulation of pyrene into micelles by EUDRAGIT® E PO. By further using the value of I337/I334, the

359

CMC value of EUDRAGIT® E PO can be calculated via the intersection of the regression analysis at

360

the two wavelengths as shown in Fig. 6B. The CMC value of EUDRAGIT® E PO in 0.1 M HCl was

361

estimated as 0.99 µg/ml.

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362

Transmittance electron microscopy was also applied to confirm the existence of micelles by

363

EUDRAGIT® E PO in 0.1 M HCl. EUDRAGIT® E-HCl solution with the concentration of 2 mg/ml

364

was used for the TEM study. As seen in Fig. 7A, small particles with the size of circa 10 nm were

13

ACCEPTED MANUSCRIPT observed in the TEM graph (circled by black solid line). In addition, larger particles with the size over

366

100 nm were also observed (circled by red dash line in Fig. 7A). Such particle size distribution was in

367

agreement with the measured results by dynamic laser scattering as shown in Fig. 7B. Combined with

368

other results, these observed particles were highly likely to be micelles formed by EUDRAGIT® E PO.

369

As the concentration was significantly higher than the estimated CMC value of EUDRAGIT® E PO,

370

formed micelles showed increased particle size. The obtained results so far clearly showed the evidence

371

that EUDRAGIT® E PO could exhibit self-assemble behavior in acidic media and could be formed into

372

micelles to solubilize poorly water soluble drugs. In addition, with increasing concentration of

373

EUDRAGIT® E PO in acidic media, the particle size of micelles started to become larger, indicating

374

that complex structure of micelles may be formed. This was possibly because of further aggregation of

375

EUDRAGIT® E PO molecules at higher concentrations. The actual structure or the arrangement of

376

EUDRAGIT® E PO molecules within the micelles, however, was not yet clearly understood, and

377

should be further investigated in the future.

378

3.5. Mechanism of dissolution enhancement for poorly water soluble drugs by amorphous solid

379

dispersions containing Eudragit® E PO

380

In this paper, we investigated the solubilizing effect of EUDRAGIT® E PO on poorly water soluble

381

drugs in 0.1 M HCl solution, and tried to understand the dissolution mechanism of amorphous solid

382

dispersions containing EUDRAGIT® E PO. The results showed that EUDRAGIT® E PO can

383

significantly increase the equilibrium solubilities of ibuprofen, felodipine and bifendate in acidic

384

solutions, and the solubilizing effect was in a linear relationship with the concentrations of

385

EUDRAGIT® E PO. By further studies using dynamic laser scattering, fluorescent probe and TEM, it

386

was confirmed that micelles were formed in 0.1 M HCl solution, and the CMC value of EUDRAGIT®

387

E PO in the solution was estimated as 0.99 µg/ml. Consequently, the solubilizing effect of

388

EUDRAGIT® E PO could be understood that due to the formation of micelles, poorly water soluble

389

drugs may be encapsulated into the core the micelles. These results were consistent with the previous

390

research reported by Yoshida, et. al., in which tacrolimus-Eudragit® E solid dispersion could form nano

391

particles with particle size ranging from 10 nm to 369.8 nm [37]. The study by Yoshida, et. al. showed

392

that nanometer level structures existed. In this paper, it was confirmed that micelles were evidently

393

formed in 0.1 M HCl solution by EUDRAGIT® E PO.

AC C

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ACCEPTED MANUSCRIPT In the chemical structure of EUDRAGIT® E PO, it contained a tertiary amine group which would

395

be ionized in acidic media, making the molecule amphipathic as previously reported in the literature

396

[38]. Therefore it was likely that once the concentration of the amphipathic molecules was beyond a

397

certain value (the CMC value), self-assemble of the molecules would occur and hence micelles could

398

be formed, solubilizing poorly water soluble drugs. It should be noted that the solubilizing ability on

399

the model drugs were significantly different. For instance, the equilibrium solubility of felodipine was

400

increased by over 300 times, whereas in the same solution the equilibrium solubility of bifendate was

401

only increased by 12 times. This may be attributed to the reason that the properties of drugs, i.e.

402

polarity, hydrophobicity and molecule size, can affect the interactions with EUDRAGIT® E PO in

403

acidic solutions, hence resulting in different solubilizing effect on different drugs.

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The confirmation of the formation of micelles by EUDRAGIT® E PO in acidic solutions may

405

further assist the understanding on the mechanism of dissolution of solid dispersions containing

406

EUDRAGIT® E PO. Dissolution results of hot melt extrudates composed of EUDRAGIT® E PO and

407

model drugs showed that when extrudates with drug loadings beyond the solubilizing range,

408

concentration reduction in drug release profile could be seen for all samples. In addition, the

409

equilibrated drug concentrations at the end of the dissolution tests were calculated to be similar to the

410

values by the solubilizing relationship. These results demonstrated that the steady state of drug release

411

was substantially dependent on the solubilizing effect of EUDRAGIT® E PO. Comparing the drug

412

release rate between hot melt extrudates and pure drugs (in EUDRAGIT® E-HCl solutions), it can be

413

seen that drugs released significantly faster from solid dispersions than from intact drug crystals. Based

414

on these results, we proposed the dissolution mechanism of amorphous solid dispersions containing

415

EUDRAGIT® E PO as illustrated in Fig. 8. Original solid dispersions containing EUDRAGIT® E PO

416

were physically amorphous molecular dispersions in which drugs were dispersed in single molecule

417

amongst polymeric chains. During dissolution, due to the physical structure of solid dispersions, drug

418

molecules can rapidly dissolve in the media (0.1 M HCl). Meanwhile, micelles of EUDRAGIT® E PO

419

started to form as the concentration of the polymer was much higher than the CMC value of

420

EUDRAGIT® E PO. Subsequently, depending on the concentration of drug molecules in the media,

421

complete drug release or recrystallization would occur. If the drug concentration was within the

422

solubilizing range, drug molecules would totally be encapsulated in the micelles. In contrast, the

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ACCEPTED MANUSCRIPT 423

amount of drug molecules that were beyond the solubilizing range would precipitate after the initial

424

dissolution, leading to the observed concentration reduction of drugs. For amorphous solid dispersions containing EUDRAGIT® E PO, the transformation of drugs and

426

the polymer into solid solution may only increase the dissolution rate. The equilibrated drug

427

concentration, however, was dependent on the ratio of the drug to EUDRAGIT® E PO. In summary,

428

the mechanism of dissolution enhancement by amorphous solid dispersions containing EUDRAGIT® E

429

PO could be concluded as the combined contribution from both the physical structure of amorphous

430

solid dispersions and the solubilizing effect of EUDRAGIT® E PO. Results from this study manifested

431

that EUDRAGIT® E PO was useful for the preparation of amorphous solid dispersions. When

432

developing such formulations, however, it was necessary to test the equilibrated drug concentration in

433

the media containing EUDRAGIT® E PO to achieve a complete drug release profile. Additionally,

434

while applying other polymeric carriers for solid dispersions, it was suggested that drug to polymer

435

ratio should be screened not only from manufacturing process viewpoints, but also from the concern of

436

drug release performance.

437

4. Conclusion

438

In this paper, the mechanism of dissolution enhancement by amorphous solid dispersions containing

439

EUDRAGIT® E PO was investigated. It was found that EUDRAGIT® E PO can solubilize typical

440

poorly water soluble drugs in acidic solutions, and equilibrium solubilities of ibuprofen, felodipine and

441

bifendate could be increased by tens to hundreds folds. Such solubilizing effect was attributed to the

442

fact that EUDRAGIT® E PO could form micelles in 0.1 M HCl solution as confirmed by dynamic laser

443

scattering, fluorescent probe and TEM studies. The CMC value of EUDRAGIT® E PO in 0.1 M HCl

444

was estimated as 0.99 µg/ml using pyrene-based fluorescent probe. By comparing the dissolution

445

results of hot melt extruded amorphous solid dispersions and the calculated solubilizing range of

446

EUDRAGIT® E PO to different drugs, it was showed that the equilibrated drug concentration in

447

dissolution was very close the solubilized drug concentration. Amorphous solid dispersions with drug

448

loadings beyond the solubilizing range presented drug recrystallization for all samples. In conclusion,

449

the dissolution enhancement for poorly water soluble drugs by EUDRAGIT® E PO based amorphous

450

solid dispersions in acidic media was contributed by both the physical structure of amorphous solid

451

dispersions and the solubilizing effect of EUDRAGIT® E PO.

452

Conflict of interest

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The authors report no conflict of interest.

454

Acknowledgements

455

The authors would like to thank Dr Sheng Qi at University of East Anglia for the previous discussion. This work was supported by the National Natural Science Foundation of China [grant numbers

457

81603059]; the “Jiangsu Shuangchuang” Program, and the Top-notch Academic Programs Project of

458

Jiangsu Higher Education Institutions [grant numbers PPZY2015B146].

459

Supplementary material

460

The validation of HPLC method for ibuprofen and bifendate, the first 8 hours dissolution profiles of

461

three model drugs in EUDRAGIT® E-HCl solutions with different EUDRAGIT® E PO concentrations

462

at 37 oC (Fig. S1), the particle size distribution of each EUDRAGIT® E-HCl solution saturated with the

463

three model drugs (Fig. S2, Fig. S3 and Fig. S4), and the equilibrium solubilities of three model drugs

464

in each EUDRAGIT® E-HCl solutions (Table S1) were included in the Supplementary material.

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Comparative

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bulk instability of hot melt extruded amorphous solid dispersions, Pharm. Res. 32 (2015)

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1210-1228. [19]

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D.Q.M. Craig, Characterisation of solid dispersions of

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Y.D. Yan, J.S. Woo, J.H. Kang, C.S. Yong and

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J. Li, I.W. Lee, G.H. Shin, X. Chen and

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K. Higashi, K. Yamamoto, M.K. Pandey, K.H. Mroue, K. Moribe, K. Yamamoto and

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564

Polym. J. 45 (2009) 1918-1923.

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S.P. Moulik, Pyrene absorption can be a convenient method

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571

R.V. Alasino, S.F. Ausar, I.D. Bianco, L.F. Castagna, M. Contigiani and D.M. Beltramo Amphipathic and membrane-destabilizing properties of the cationic acrylate polymer

575

Eudragit® E100, Macromol. Biosci. 5 (2005) 207-213.

577

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574

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ACCEPTED MANUSCRIPT Figure captions

579

Fig. 1. The chemical structures of ibuprofen, felodipine and bifendate.

580

Fig. 2. Plot of the concentrations of EUDRAGIT® E PO in EUDRAGIT® E-HCl solutions against the

581

solubilized drug concentrations.

582

Fig. 3. Dissolution profiles of model drugs in EUDRAGIT® E-HCl solutions with different

583

EUDRAGIT® E PO concentrations

584

(mean±SD, n=6).

585

Fig. 4. Dissolution profiles of drug-EUDRAGIT® E PO hot melt extrudates with different drug

586

loadings in 0.1 M HCl at 37 oC: ibuprofen-EUDRAGIT® E PO hot melt extrudates with drug loading of

587

4% (w/w) and 10% (w/w), felodipine-EUDRAGIT® E PO hot melt extrudates with drug loading of 0.7%

588

(w/w) and 1.5% (w/w), bifendate-EUDRAGIT® E PO hot melt extrudate with drug loading of 1%

589

(w/w). The dissolution profiles of first 2-hour dissolution test were scaled up and inserted in the right

590

of corresponding profiles (mean±SD, n=6).

591

Fig. 5.

592

concentrations (1 mg/ml, 2 mg/ml, 5 mg/ml, 15 mg/ml, 25 mg/ml and 35 mg/ml) by dynamic laser

593

scattering.

594

Fig. 6. Results of the determination of CMC for EUDRAGIT® E PO in 0.1 M HCl by pyrene-based

595

fluorescence probe approach: A, fluorescence spectrum; B, plot of the intensity ratio (I337/I334) of the

596

pyrene excitation spectra vs. log concentration of EUDRAGIT® E PO.

597

Fig. 7. TEM graph of EUDRAGIT® E-HCl solution with the EUDRAGIT® E PO concentration of 2

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mg/ml (A); particle size distribution of the same solution measured by dynamic laser scattering and

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presented in “NICOMP Distribution” (B).

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Fig. 8. Proposed mechanism of drug release from amorphous solid dispersions containing

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EUDRAGIT® E PO.

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(0 mg/ml, 5 mg/ml, 15 mg/ml, 25 mg/ml and 35 mg/ml) at 37 oC

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EP

TE D

Particle size distribution of EUDRAGIT® E-HCl solutions with different EUDRAGIT® E PO

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Fig. 1. The chemical structures of ibuprofen, felodipine and bifendate.

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Fig. 2. Plot of the concentrations of EUDRAGIT® E PO in EUDRAGIT® E-HCl solutions against the solubilized drug concentrations.

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Fig. 3. Dissolution profiles of model drugs in EUDRAGIT® E-HCl solutions with different

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(mean±SD, n=6).

(0 mg/ml, 5 mg/ml, 15 mg/ml, 25 mg/ml and 35 mg/ml) at 37 oC

TE D

EUDRAGIT® E PO concentrations

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Fig. 4. Dissolution profiles of drug-EUDRAGIT® E PO hot melt extrudates with different drug loadings in 0.1 M HCl at 37 oC: ibuprofen-EUDRAGIT® E PO hot melt extrudates with drug loading of 4% (w/w) and 10% (w/w), felodipine-EUDRAGIT® E PO hot melt extrudates with drug loading of 0.7% (w/w) and 1.5% (w/w), bifendate-EUDRAGIT® E PO hot melt extrudate with drug loading of 1% (w/w). The dissolution profiles of first 2-hour dissolution test were scaled up and inserted in the right of corresponding profiles (mean±SD, n=6).

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Particle size distribution of EUDRAGIT® E-HCl solutions with different EUDRAGIT® E PO

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Fig. 5.

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concentrations (1 mg/ml, 2 mg/ml, 5 mg/ml, 15 mg/ml, 25 mg/ml and 35 mg/ml) by dynamic laser

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scattering.

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Fig. 6. Results of the determination of CMC for EUDRAGIT® E PO in 0.1 M HCl by pyrene-based fluorescence probe approach: A, fluorescence spectrum; B, plot of the intensity ratio (I337/I334) of the

AC C

pyrene excitation spectra vs. log concentration of EUDRAGIT® E PO.

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Fig. 7. TEM graph of EUDRAGIT® E-HCl solution with the EUDRAGIT® E PO concentration of 2 mg/ml (A); particle size distribution of the same solution measured by dynamic laser scattering and

AC C

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presented in “NICOMP Distribution” (B).

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Fig. 8. Proposed mechanism of drug release from amorphous solid dispersions containing

AC C

EP

TE D

M AN U

EUDRAGIT® E PO.

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