Soluplus®, Eudragit®, HPMC-AS foams and solid dispersions for enhancement of Carvedilol dissolution rate prepared by a supercritical CO2 process

Accepted Manuscript ® ® Soluplus , Eudragit , HPMC-AS foams and solid dispersions for enhancement of Carvedilol dissolution rate prepared by a supercritical CO2 process Stoja Milovanovic, Jelena Djuris, Aleksandra Dapčević, Djordje Medarevic, Svetlana Ibric, Irena Zizovic PII:

S0142-9418(18)31989-5

DOI:

https://doi.org/10.1016/j.polymertesting.2019.03.001

Reference:

POTE 5813

To appear in:

Polymer Testing

Received Date: 23 October 2018 Revised Date:

4 February 2019

Accepted Date: 1 March 2019

Please cite this article as: S. Milovanovic, J. Djuris, A. Dapčević, D. Medarevic, S. Ibric, I. Zizovic, ® ® Soluplus , Eudragit , HPMC-AS foams and solid dispersions for enhancement of Carvedilol dissolution rate prepared by a supercritical CO2 process, Polymer Testing (2019), doi: https://doi.org/10.1016/ j.polymertesting.2019.03.001. 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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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT Soluplus®, Eudragit®, HPMC-AS foams and solid dispersions for enhancement of Carvedilol dissolution rate prepared by a supercritical CO2 process

Zizovic3

University of Belgrade, Faculty of Technology and Metallurgy, Karnegijeva 4, 11120 Belgrade, Serbia 2

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University of Belgrade, Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia

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Stoja Milovanovic1∗, Jelena Djuris2, Aleksandra Dapčević1, Djordje Medarevic2, Svetlana Ibric2, Irena

Wroclaw University of Science and Technology, Faculty of Chemistry, Wybrzeze Wyspianskiego 27, 50-370

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Wroclaw, Poland

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Stoja Milovanovic ([email protected]) ORCID 0000-0003-0701-1995 Jelena Djuris ([email protected]) ORCID 0000-0002-1833-6704

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Aleksandra Dapčević ([email protected]) ORCID 0000-0001-7650-7156 Djordje Medarevic ([email protected]) ORCID 0000-0003-4516-2575 Svetlana Ibric ([email protected]) ORCID 0000-0003-1101-6174 Irena Zizovic ([email protected]) ORCID 0000-0003-3945-7051

∗

Corresponding author. Tel.: +381 11 3303 795. E-mail address: [email protected] (S. Milovanovic)

ACCEPTED MANUSCRIPT 1

Abstract

2 The present work is aimed towards designing advanced materials by means of sustainable

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processes. In that sense, the utilization of supercritical CO2 (scCO2) for processing of pharmaceutical

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polymers (Soluplus®, Eudragit®, and hydroxypropyl methylcellulose acetate succinate), alone and

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with an addition of cardiovascular drug Carvedilol, was explored. Employed single-step static scCO2

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process (pressure of 30 MPa and temperature of 100 °C for 2 h) enabled fabrication of solvent-free

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polymeric foams and Carvedilol solid dispersions with controlled microstructure and average pore

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diameter of 101–257 µm suitable for application in the pharmaceutical industry. ScCO2 did not

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remain in the foams after processing or affected the polymer composition, while Carvedilol formed

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hydrogen bonds with the polymers. Carvedilol was molecularly dispersed in the fabricated solid

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dispersions and its transition from the crystalline to amorphous form was complete. Korsmeyer-

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Peppas model was successfully used for the mathematical description of Carvedilol dissolution from

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solid dispersions. The dissolution rate of Carvedilol in acidic medium was significantly enhanced by

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its dispersion in tested polymers using the proposed high-pressure method.

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Key words: Carvedilol; Eudragit®; Soluplus®; HPMC-AS; supercritical CO2; solid dispersion.

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Abbreviations scCO2 HPMC-AS

supercritical carbon dioxide hydroxypropyl methylcellulose acetate succinate

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1. Introduction

19 Processing of polymers in the pharmaceutical industry usually includes methods such as

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solvent casting, spray drying, and extrusion which imply the utilization of large amounts of organic

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solvents and high temperatures. Exposure of polymers and drugs to high temperatures and shear stress

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during extrusion can restrict their processing and influence their stability during the production and

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storage [1-3], while the use of organic solvents may have an impact on end-product toxicity as well as

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on the environment [4,5]. These issues may be overcome by employing supercritical CO2 (scCO2) for

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polymer processing. The CO2 is non-flammable, chemically inert, and easily available [2,6-8]. In the

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supercritical state, it has gas-like and liquid-like properties and can act as a solvent and/or plasticizer

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for a number of amorphous and semi-crystalline polymers [4,6-15]. Also, easy separation of CO2 from

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the polymer matrix at the end of the process allows fabrication of solvent-free products without

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employing expensive solvent removal processes [4,6,9-11]. Due to advantageous properties of scCO2

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and compliance with the Green Chemistry rules, the scCO2 technology has been successfully utilized

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in the preparation of polymeric foams with potential application in the drug delivery and tissue

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engineering [7,8,15]. Formation of polymeric foams using scCO2 occurs when the pressure in the

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polymer-scCO2 system is suddenly decreased, allowing for the CO2 to escape from the polymer

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causing the nucleation and bubbles growth within the polymer matrix [5-8,15]. Polymeric foams have

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attracted wide interests in both academic research and industry due to their excellent properties such

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as controlled structure, lightweight, controlled release of drugs, applicability in cells adhesion,

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proliferation, growth etc. [7,9,15]. Consequently, the optimization of the scCO2 foaming process may

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open a wide range of opportunities for designing novel multi-functional materials and products [8].

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Polymers chosen for this study are amorphous and pharmaceutical grade Soluplus®,

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Eudragit®, and hydroxypropyl methylcellulose acetate succinate (HPMC-AS), commonly used for the

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preparation and/or coating of solid dosage forms such as capsules and tablets [1,5]. Although, there

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are several reports on the scCO2-assisted melt extrusion of these polymers [5,9,16,17], there is only

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one report in the available literature on a single-step scCO2 processing focused on Soluplus® only

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[18]. Soluplus®, Eudragit®, and HPMC-AS are able to act as carriers of poorly soluble drugs and to 3

ACCEPTED MANUSCRIPT form drug solid dispersions [1,5,18] which can increase drug dissolution rate and provide drug

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controlled release. Many reports describe different methods for the preparation of drug solid

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dispersions with these polymers [1,5,19,20,21], but the information on the preparation of Soluplus®,

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Eudragit®, and HPMC-AS microcellular foams containing cardiovascular drugs using scCO2 static

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method is not available. Carvedilol is a cardiovascular drug that has a wide medical application

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(treatment of hypertension, ischemic heart diseases, post-myocardial infarction, and mild-to-severe

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congestive heart failures) but low bioavailability (25–35%) due to its low solubility [22-25]. An

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increase in its solubility would have a considerable contribution to its application, especially in the

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chronic therapy. This consequently prompted the research on different methods for Carvedilol

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incorporation in polymers, focused on overall effects on the drug dissolution rate [1,20,21,23-25]. A

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few reports in available literature on Carvedilol solid dispersions, with polymers of interests for this

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study, include only those with Soluplus® and Eudragit® produced by electrospinning [21], solvent

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evaporation [1],

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nanoprecipitation method [20].

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spray-drying [1], freeze-drying

[1],

scCO2-assisted extrusion

[5], and

The aim of this study was the evaluation of the single-step scCO2 static process impact on

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pharmaceutical polymers Soluplus®, Eudragit®, and HPMC-AS, alone and with an addition of the

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poorly soluble drug Carvedilol. Ultimately, solvent-free polymeric foams and Carvedilol solid

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dispersions, that can find application in the pharmaceutical industry, were obtained. To the best of our

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knowledge, this is the first report on the effect of scCO2 on processing of Soluplus®, Eudragit®, and

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HPMC-AS regarding their morphology and composition of obtained foams, with and without

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Carvedilol. Furthermore, there are no previous reports on the Carvedilol-HPMC-AS solid dispersions.

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Effects of both, the scCO2 treatment and presence of the drug, on the polymers were assessed by

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FESEM, FTIR, TGA, and XRD methods. The Carvedilol dissolution rate from the obtained solid

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dispersions in acidic medium was determined and described by the Korsmeyer-Peppas model.

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2. Materials and Methods

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2.1. Materials Materials used in the presented study were: drug Carvedilol ((±)-1-(Carbazol-4-yloxy)-3-[[2-

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(o-methoxyphenoxy) ethyl] amino]-2-propanol, Ph. Eur. 9.0) kindly provided by Hemofarm (Vrsac,

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Serbia) and polymers: polyvinyl caprolactam-poly acetate-polyethylene glycol graft co-polymer

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(Soluplus®, BASF, Ludwigshafen, Germany), poly-N-dimethylaminoethyl methacrylate-co-methyl

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methacrylate-co-butyl methacrylate (Eudragit®, Evonik, Darmstadt, Germany) and hydroxypropyl

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methylcellulose acetate succinate MF (HPMC-AS, kindly provided by Hemofarm, Vrsac, Serbia).

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Information about the properties of the polymers and drug provided by the manufacturers is listed in

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Table 1. Carbon dioxide (purity 99%) was supplied by Messer-Tehnogas (Belgrade, Serbia).

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Table 1 Properties of Carvedilol and selected polymers Tg (°C)

ρ (kg/m3)

Structure

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406.5

Soluplus®

90000-140000

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70

1200

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Carvedilol

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Eudragit®

150000

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1104-1133

HPMC-AS

18000

120

1270-1300

Tg- glass transition temperature

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2.2. Methods

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2.2.1.

Tests on scCO2 interaction with polymers Interaction of scCO2 with polymers (Soluplus®, Eudragit® and HPMC-AS) was monitored in a

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high pressure unit equipped with a view cell (Eurotechnica GmbH, Bargteheide, Germany) (Fig. 1).

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Polymers (~0.5 g), in a cylindrical shaped glass recipient (d~12 mm, h~13 mm), were placed inside

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the cell (volume of 25 mL). After heating to 100 °C, provided by an electrical heating jacket located

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around the cell, CO2 was introduced using a high pressure pump for liquids (Milton Roy, Pont-Saint-

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Pierre, France). After the pressure of 30 MPa had been reached in the system, the cell was closed and

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kept in a static mode for 2 h [26]. Decompression of the cell followed at the rate of 1.5 MPa/min.

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Fig. 1. Schematic presentation of high pressure unit with view cell

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(1- CO2 tank, 2- cryostat, 3- pump, 4- LED light, 5- view cell, 6- CCD camera)

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The volume change of the polymers exposed to scCO2 was monitored by recording the two-

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dimensional projection of the rotationally symmetric sample with time by using a CCD monochrome

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camera and the IC Capture 2.1 software [10]. The change of the samples' dimension due to scCO2

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interaction with polymers was determined by the image processing program ImageJ. Volume change

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(∆V/V) was calculated using Eq. 1:

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∆V / V =

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where V0 is the volume of polymer at the beginning of the process, Vt is the volume of polymer at any

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time t during the experiment, L0 and Lt are the heights of polymer at the beginning of the process and

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at the time t, respectively.

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L  Vt − V0 ⋅ 100 % =  t − 1 ⋅ 100 % V0  L0 

(1)

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2.2.2.

Preparation of polymer-drug formulation An amount of about 2 grams of polymer-drug mixture (polymer to drug mass ratio 1:0.3 [4])

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was mixed in a mortar using pestle for 2 minutes and placed in a mesh-covered glass vial (d~23 mm,

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h~66 mm). The vial with the mixture was placed in a high pressure vessel (volume of 280 mL) of a

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high pressure unit presented in Fig. 2 (Eurotechnica GmbH, Bargteheide, Germany). Uniform heating

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of the sample was provided by an electrical heating jacket located around the vessel. After the

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temperature of 100 °C had been reached, the pressure was elevated to 30 MPa [26]. The system was

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kept at the desired conditions for 2 h after which decompression of the system commenced at the rate

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of 1.5 MPa/min. For comparison reasons, the polymers without Carvedilol were also exposed to

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scCO2 under the same conditions as polymer-Carvedilol mixtures, in this equipment.

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Fig. 2. Schematic presentation of high pressure unit

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(1- CO2 tank, 2- cryostat, 3- pump, 4- high pressure vessel)

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2.3. Characterization

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2.3.1.

Chemico-physical and morphological characterizations

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Density of the polymer and polymer-Carvedilol samples (ρSample) after the scCO2-assisted

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process was determined by using a Mettler analytical balance (AE100) with a density kit and

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calculated using Eq. 2 [11,13]:

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ρ Sample =

ρ H O ⋅ w1 2

w1 + w2 − w3

(2)

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ACCEPTED MANUSCRIPT where w1 is the mass of sample, w2 is the mass of pycnometer filled with water, w3 is the mass of

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pycnometer containing both water and the sample. Density of water (ρH20) at 29.5 ± 0.5 °C was 995.5

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± 0.1 kg/m3.

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Porosity of the samples (ε) was calculated using the Eq. 3 [9,11] where ρPolymer is the density of

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polymer before scCO2 treatment given in

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Table 1.

  

ε = 1 −

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ρ Sample   ⋅ 100% ρ Polymer 

(3)

The relative density of the foam, Rρ, was defined as the ratio of the density of foamed sample

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relative to that of the polymer [7]:

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Rρ =

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The volume expansion ratio (Rv) of the foamed samples can be defined as the reciprocal of Rρ

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[7]:

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Rv =

1 Rρ

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ρ Sample ρ Polymer

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(5)

Field emission scanning electron microscopy analysis (FESEM, Mira3, Tescan, Brno-

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Kohoutovice, Czech Republic) was performed for the non-treated polymers, polymers treated with

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scCO2, and polymer-drug formulations treated with scCO2. The samples were cut and their cross

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section was coated with a thin layer of Au/Pd (85/15) using a sputter coater (Polaron SC502, Fisons

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Instruments, Ipswich, UK) prior to the analysis. Image analysis software ImageJ was used to estimate

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the pore size of all samples. For each sample, 2–4 images were used.

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The thermal stability of samples was studied through thermogravimetric analysis (TGA)

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performed with on a TA Instruments SDT Q600 analyzer (TA Instruments, New Castle, Delaware,

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USA) under a nitrogen flow rate of 100 cm3/min, at a heating rate of 20 °C/min, at temperatures

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ranging from room temperature to 250 °C.

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Fourier transform infrared (FTIR) spectra of the obtained samples was recorded using an

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ATR-FTIR spectrometer Nicolet iS10 (Thermo Fisher Scientific Inc., Madison, WI, USA) in mid-IR 8

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region (500 cm-1 - 4000 cm-1). To evaluate the potential interactions of scCO2 and drug with

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polymers, FTIR spectra of the non-treated polymers and Carvedilol were also recorded. The pure Carvedilol as well as Carvedilol solid dispersions obtained by scCO2 process were

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examined on an Ital Structure APD 2000 X-ray powder diffractometer using Cu Kα radiation (λ =

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1.5418 Å) and step-scan mode (2θ range was from 3 to 50 °2θ, step width 0.02 °2θ, time per step 1 s)

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in order to distinguish the crystalline and amorphous nature of samples and determine if the drug was

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dissolved in polymers. For comparison, physical mixtures of polymers with Carvedilol (ratio 1:0.3)

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were also examined.

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2.3.2.

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Dissolution studies were carried out in 0.1N HCl (900 mL) of pH 1.2 at 37 ºC ± 0.5 ºC using

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USP dissolution apparatus type II (Erweka DT 600, Hausenstamm, Germany). Solid dispersions, each

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containing 12.5 mg of Carvedilol (corresponding to its therapeutic dose), were gently placed in the

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vessels. Paddle rotation was 50 rpm. Aliquots of dissolution medium were withdrawn for the total

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period of 3 hours. Carvedilol content was determined by using UV spectrophotometer (Evolution 300,

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Thermo Fisher Scientific, Loughborough, USA) at 285 nm. The following dissolution parameters

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were determined: Q10 (%) and Q180 (%), which are the amount of Carvedilol (in %) released after 10

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and 180 minutes of the dissolution test; t50 (min) which is the time (in minutes) required for the

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dissolution of 50% of Carvedilol; %DE30, %DE60 and %DE90, which are percentages of dissolution

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efficiencies (DE) after 30, 60 and 90 minutes, respectively. Determination of DE parameters has been

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demonstrated as a valuable tool for comparison of dissolution profiles [27].

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In order to simulate the dissolution kinetic of Carvedilol from solid dispersions, the

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Korsmeyer–Peppas model was used [28]:

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Mt = k ⋅ tn M∞

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where: Mt is the amount of dissolved Carvedilol in any time t, M∞ is the amount of dissolved

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Carvedilol at infinite time, k is the release rate constant and n is the release exponent [28]. Release

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exponent n provides information on the drug release mechanisms involved while kinetic constant k

(6)

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includes structural and geometric characteristics of the solid dispersion. It was previously shown that

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Eq. (6) adequately described the release of drugs from slabs, spheres, cylinders, and discs regardless

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of the release mechanism, for short time approximation of complex exact relationships, and therefore

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its use is confined for the description of the first 60% of the release curve [28].

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3. Results and Discussion

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3.1. Effect of scCO2 on polymer swelling kinetic

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Interaction of the Soluplus®, Eudragit® and HPMC-AS with scCO2 was recorded for the first

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time. Some representative images of the polymers before, during, and after the exposure to scCO2 at

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the constant pressure and temperature are shown in Fig. 3. Under the atmospheric conditions,

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Soluplus® and HPMC-AS have a form of white powder, while Eudragit® has a form of a light yellow

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transparent pellet. Immediately after the system was pressurized to 30 MPa (Fig. 3, 0 min), a decrease

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in apparent volume of the samples was observed indicating that the plasticization process started i.e.

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the movement of polymer segments and chains that leads to transition of the polymer into a liquid-like

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state which is denser than a loosely packed powder or pellet sample [14]. Under the selected

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conditions of 30 MPa and 100 °C, Soluplus® and Eudragit® samples completely plasticized after 10

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min and 20 min of the treatment, respectively, becoming transparent liquefied polymer melts. Fast

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plasticization of the polymers after exposure to scCO2 was also reported by Fanovich and Jaeger [29]

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and Tai et al. [14] for polycaprolactone and poly(lactic-co-glycolic acid), respectively. Fig. 3 also

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shows that, although it was plasticized after 2 h of the scCO2 treatment, the HPMC-AS sample

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retained a solid-like form.

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Fig. 3. Images of polymers from the view cell: a) Soluplus®, b) Eudragit®, and c) HPMC-AS

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Optical experiments in the high pressure view cell allowed quantification of polymers’

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volume change during their interaction with the scCO2 (Fig. 4). In all three cases, a substantial volume

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change was recorded for the first 30 min of the polymer exposure to scCO2. As can be seen, the

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volume was close to the final value for Eudragit® and HPMC-AS after 30 min of the exposure to

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scCO2 while for the Soluplus® it took about 1 h. Obaidat et al. [18] also showed that the sorption of

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CO2 into Soluplus® matrix reaches equilibrium after about 75 min at 9.1 MPa and 35 °C. Therefore,

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these findings justified selected processing time of 2 h as an appropriate for reaching the equilibrium

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in the system of the proposed scCO2 process for all tested polymers.

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Volumes of the Soluplus® and Eudragit® samples increased for 52% and 17% after 2 h,

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respectively compared to the volumes at the beginning of the process (30 MPa, 100 °C, 0 min) while

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the volume of the HPMC-AS sample decreased for 12% (Fig. 4). Volume of the polymer changes due

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to the increase of the CO2 concentration within the polymer matrix. CO2 molecules fill void fractions

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between the polymer chains and induce an increase of segmental and chain mobility [30]. As a

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consequence, the plasticizing effect of CO2 on the polymer becomes stronger allowing easier diffusion

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of the CO2 [6,29]. Solubility and diffusivity of CO2 depend on the polymer (its molecular weight, Tg,

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chemical composition, structure etc.) as well as on the operating conditions of the process employed 11

ACCEPTED MANUSCRIPT [6,8,14,29,30]. HPMC-AS has larger number of carbonyl groups than Eudragit® and Soluplus® which

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indicates the potential for higher CO2 solubility in HPMC-AS [6]. At the same time, its high Tg

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(120 °C, Table 1) could be the reason for low CO2 diffusivity and subsequent smaller volume change

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compared to Eudragit® and Soluplus® (Tg=70 °C, Table 1). Guo and Kumar [31] reported that CO2

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had higher solubility, but lower diffusivity in the polymer with higher Tg (158 °C) compared to the

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same polymer with lower Tg (78 °C). Decreased CO2 diffusivity in a polymer could be also a

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consequence of the dominant effect of the hydrostatic pressure [11,30]. Strong effect of hydrostatic

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pressure that decreases the free volume of the polymer could be, therefore, considered as the main

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reason for the volume decrease of the HPMC-AS sample. To the best of our knowledge there are no

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reports in the available literature on volume changes for Soluplus®, Eudragit® and HPMC-AS during

237

an exposure to scCO2. Fanovich and Jaeger [29] reported the increase of polycaprolactone (Tg= -60

238

ºC) volume for 9% after 20 min of the scCO2 process at 18 MPa and 35 °C. Milovanovic et al. [10]

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reported the increase of poly(lactic acid) (Tg~160 °C) volume for 7% after 24 h of the scCO2 process

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at 10 MPa and 40 °C.

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Fig. 4. Volume change of tested polymers during exposure to scCO2 at 30 MPa and 100 °C

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Volumes of the Soluplus®, Eudragit® and HPMC-AS samples, after the system decompression

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(Fig. 3, Atmospheric conditions- end), increased approximately 2.9, 2.4 and 2.3 times, respectively, 12

ACCEPTED MANUSCRIPT 246

compared to their volume at the beginning of the process (30 MPa, 100 °C, 0 min). An increase of the

247

polymer’s volume during the depressurization of the system occurs due to the escape of CO2 from the

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plasticized polymer. Once the significant amount of the CO2 escapes, the temperature in system

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decreases causing the anti-plasticization thus “freezing” polymer structure [6].

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Based on the results presented in the previous section, the processing time of 2 h was

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indicated as sufficient for scCO2 diffusion and dissolution into the polymers’ matrix at 30 MPa and

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100 °C (Fig. 4). Therefore, the same conditions were employed for the treatment of physical mixtures

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of Soluplus®, Eudragit® and HPMC-AS with Carvedilol. In that manner Carvedilol solid dispersions

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were obtained. Since the high pressure vessel of the larger volume was used, approximately 4 times

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larger mass of samples, compared to the experiments in the view cell, was processed. In order to

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compare results, the pure polymer foams were fabricated in the same manner as well. Similar to our

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study, Potter et al. [4] produced the solid dispersion of indomethacin and Soluplus® at 15 MPa and

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70 ºC with the exposure time of 2 h. Gong et al. [12] fabricated the solid dispersion of indomethacin

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and HPMC at 17.2 MPa and 130 °C for 3 h.

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3.3. Chemico-physical and morphological characterizations

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Fig. 5 shows the morphology of the cross-section of the samples as assessed by means of

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FESEM analysis. The reported images evidence stable solid foams produced in the proposed scCO2

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process. Foams exhibit open interconnected cell structure with spherical shapes and thin cell walls

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that are prone to rupture. Although Carvedilol has a typical crystalline morphology [23,32], the

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morphology of the obtained foams with Carvedilol is without visible crystals which could be an

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indication that the drug has been adsorbed and dispersed in the polymers at the molecular level [24].

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Fig. 5. FESEM images of the polymer foams and Carvedilol solid dispersions

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The pore size distribution of all samples is shown in Fig. 6. It can be seen it is affected by

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both the type of the polymer and the presence of the Carvedilol. Soluplus® and Eudragit® foams have

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a broad pore size distribution in the range of 75 to 560 µm, while the pore size distribution of HPMC-

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AS foams is more uniform (ranging from 90 to 340 µm). Eudragit® foams produced by Nikitine at al.

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[9] by the CO2-asisted extrusion at 5.8-13 MPa and 110-130 ºC have a much broader pore size

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distribution which is in the range of 200–1200 µm. The pore size distribution of a foam is influenced

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by the specific interactions of scCO2 with polymer which depend on the polymer chemical

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composition and its molecular weight, as well as on the operating conditions of the scCO2 process

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(pressure, temperature, time, and decompression rate) [8,14,29]. Polymers with higher molecular

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weight like Soluplus® and Eudragit® have long chains that entangle to lock CO2 in subsequently

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allow easier escape of CO2 from the polymer [14]. Also, lower solubility of CO2 in a polymer, which

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presents the energy barrier to nucleation and reduces nucleation sites, is responsible for larger cell size

288

[7]. Foam pore size distribution is also affected by Tg of the polymer. When Tg of the polymer is

289

lower than the process temperature, it will lead to formation of pores with larger diameter. But when

290

Tg of the polymer is above the process temperature, it will lead to formation of pores with smaller

291

diameter [33]. The presence of Carvedilol led to a decrease in the pore size distribution in Eudragit®

292

and HPMC-AS matrix (pore size distribution decreased to 63-410 µm and 45-175 µm, respectively).

293

The solid dispersion with HPMC-AS again had a more uniform pore size distribution compared to

294

Soluplus® and Eudragit®. Recently reported solid dispersion of Indomethacin with Soluplus®

295

produced by static scCO2 process at 9.7 MPa and 100 °C after 15 min [19] had significantly wider

296

pore size distribution (from 200 to 1000 µm) than ones produced in this study.

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a)

b)

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Fig. 6. Pore size distribution in foams and Carvedilol solid dispersions of:

298

a) Soluplus®, b) Eudragit®, and c) HPMC-AS

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297

299

The average pore diameter (davg), foam density (ρFoam), porosity (ε), relative density of the

301

foam (Rρ), and volume expansion ratio (Rv) of the samples are given in Table 2. It can be seen that

302

presence of Carvedilol induced the growth of Soluplus® pores (davg increased for 41%) while in

303

Eudragit® and HPMC-AS solid dispersions Carvedilol inhibited the pore growth (davg decreased for

304

10% and 47%, respectively) confirming Carvedilol’s role as an additional plasticizer [5].

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Density of the obtained pure foams ranges from 454 to 557 kg/m3, while the foams with

306

Carvedilol have density in the range of 326–667 kg/m3 (Table 2). When Verreck et al. [14] processed

307

Eudragit® by the CO2-asisted extrusion (up to 12.5 MPa and up to 180 ºC), they obtained sample with

308

density of 1167 kg/m3 which is significantly higher than density of the foams obtained in process

309

proposed by this study. Density of Soluplus®, Eudragit® and HPMC-AS foams obtained in this study

310

lower than 700 kg/m3 is indicating their potential applicability in the development of floating drug

311

delivery systems [34]. Namely, to remain in the stomach for a prolonged period of time the floating

312

drug formulation must have a density lower than 1000 kg/m³ [34]. By the longer retention in the

313

stomach, drug formulations can release the drug for the longer time, thus increasing the drug

314

absorption and subsequently bioavailability which is especially significant in a chronic therapy

315

[34,35].

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ACCEPTED MANUSCRIPT 316 Table 2 Properties of the pure foams and solid dispersions obtained by the scCO2 process davg (µm)

ρFoam (kg/m3)

ε (%)

Rρ

184±69

557±136

53.5±11.3

0.47±0.11

2.24±0.53

Soluplus with Carvedilol

257±107

326±39

72.8±3.2

0.27±0.03

3.71±0.44

Eudragit®

213±87

472±43

57.8±3.8

Eudragit® with Carvedilol

193±70

667±44

40.3±3.9

HPMC-AS

191±49

454±91

64.7±7.1

HPMC-AS with Carvedilol

101±24

400±28

68.9±2.2

Soluplus®

0.42±0.04

2.39±0.22

0.60±0.04

1.68±0.11

0.35±0.07

2.92±0.65

0.31±0.02

3.22±0.23

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®

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317

318

Fucuda et al. [35] produced Eudragit®-Chlorpheniramine maleate floating tablets (by hot-melt

320

extrusion at 90–100 ºC) that had the density in the range of 756–1062 kg/m3. Nakamichi et al. [36]

321

produced HPMC-AS-Nicardipine hydrochloride solid dispersion (by the extrusion at 100–130 °C)

322

with the pore diameter larger than 350 µm and porosity of 5% for the gastric floating dosage forms.

323

Their solid dispersion expressed considerable buoyancy achieving a long intra-gastric retention. The

324

single-step scCO2 process applied in this study for Soluplus®, Eudragit® and HPMC-AS processing

325

enabled the preparation of polymeric foams with smaller pore diameters, more uniform pore size

326

distribution, and/or smaller density compared to the processes reported in the literature

327

[9,16,19,35,36]. By using scCO2 for polymer foaming, the addition of auxiliary substances is avoided

328

and there are no harmful residues that have to be eliminated from the final product prior to its

329

application. The final polymer foam is clean and suitable to be used as a pharmaceutical product.

331

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319

Thermal stability of the samples was evaluated through TGA and the results are presented in

332

Fig. 7. Thermal analysis was carried out on pure foams and solid dispersions in order to ascertain if

333

the addition of Carvedilol during the processing of the polymer matrices had any lingering effect on

334

their thermal properties. TGA curves of the pure polymers correspond to ones reported in literature

335

[18,37,38]. The initial weight loss, of approximately 0.5 to 3.5% up to 100 °C, regarding adsorbed

336

water [18,19] point out to the samples hygroscopic nature.

17

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337 338

Fig. 7. TGA curves of pure polymers and solid dispersions

339

18

ACCEPTED MANUSCRIPT 340

TGA analysis data show increased thermal stability of Carvedilol solid dispersions compared

341

to the pure foams at operating temperature of interest (i.e. 100 °C). Also, data show that degradation

342

of the samples will happen at temperatures above 200 °C which are significantly above the process

343

temperature.

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344 The obtained samples were analyzed by FTIR spectrometry in order to check for polymers

346

possible degradation and/or interaction with CO2 and selected drug under the processing conditions.

347

FTIR spectra of untreated Soluplus® (Fig. 8a) showed peaks characteristic to Soluplus® reported in the

348

literature. Peaks attributed to O-H stretching can be seen at 3450 cm-1, aromatic C-H stretching at

349

2923 cm-1, C=O stretching corresponding to vinyl acetate at 1732 cm-1, C=O stretching corresponding

350

to vinyl caprolactam carbonyl at 1630 cm-1, and C-O-C stretching at 1476 cm-1 [1,4,18,21].

351 352 353 354

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Fig. 8. FTIR spectra of: a) untreated Soluplus®, b) Soluplus® treated with scCO2, and c) Soluplus®-Carvedilol solid dispersion

355

Fig. 8b shows that FTIR spectra for Soluplus® did not change after its treatment with scCO2.

356

Potter and coworkers [4] reported the appearance of a band at 2338 cm−1 in Soluplus® spectra after the

357

scCO2 process. They attributed this pick (CO2 υ3 antisymmetric stretching) to the reaction of two

358

carbonyls of Soluplus® with CO2 and to CO2 that remained in the polymer. Since this peak was not

19

ACCEPTED MANUSCRIPT 359

recorded in the spectra of our Soluplus® foam, we can assume that CO2 did not remain in the polymer

360

post-processing due to a slower decompression rate that we had employed (1.5 MPa/min compared to

361

30 MPa/min that Potter et al. [4] employed), which allowed for all CO2 to diffuse out of the Soluplus®

362

sample during the foam formation. Carvedilol has two common polymorphic crystalline forms (form I and form II) that have

364

different FTIR spectra [5]. Carvedilol form I has two strong bands at ~3250 cm−1 and 3450 cm−1 while

365

Carvedilol form II has one strong band at ~3340 cm−1 [5]. FTIR spectra of Carvedilol (Fig. S1) shows

366

that the one used in this study has form II due to characteristic peak at 3343 cm-1 that corresponds to

367

the N-H stretching vibration of the secondary amine [1,21,24,25,32]. Peaks at 2995 cm-1 and 2925 cm-

368

1

369

[1,21,24,25,32]. These peaks cannot be seen in the FTIR spectra of Soluplus®-Carvedilol solid

370

dispersion (Fig. 8c). Presence of Carvedilol in this solid dispersion is confirmed by peaks at 1505 cm-1

371

corresponding to C–C aromatic stretching [1,21,24,25] and 1099 cm-1 corresponding to C-O

372

stretching [1]. Absence of Carvedilol characteristic peaks in FTIR spectra of solid dispersion could be

373

related to its entrapment into the polymer cavity during inclusion complexation and/or to an

374

interaction between the N-H group of Carvedilol and the C=O group of Soluplus® [1,4,21,25].

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correspond to C-H aliphatic stretching, and peak at 1589 cm-1 corresponds to N-H bending

Characteristic peaks of untreated Eudragit® (Fig. 9a), attributed to dimethylamino groups can

376

be seen at 2820 cm-1 and 2770 cm-1 [37,39,40]. Also, the characteristic carbonyl vibration of ester

377

group is recorded at 1722 cm-1 [39,41]. Exposure of Eudragit® to scCO2 did not result in polymers’

378

composition change which is supported by Fig. 9b. FTIR spectra of Eudragit®-Carvedilol solid

379

dispersion (Fig. 9c) shows peaks characteristic to Carvedilol at 3343 cm-1, 2995 cm-1, 2925 cm-1, 1589

380

cm-1, and 1504 cm-1 [1,21,24,25,32]. Also, characteristic Carvedilol peaks that correspond to C–C

381

aromatic stretching, O-H bending, and C-O stretching can be seen at 1401cm-1, 1251 cm-1, and at

382

1021 cm-1, respectively [1,21,24,25]. Interaction of Eudragit®-Carvedilol is evident in the significantly

383

lowered intensity of Eudragit® bands at 2820 cm-1 and 2770 cm-1 of dimethylamino group. This

384

indicates a decrease of non-protonated amine at the expense of its ionic form. Corresponding to these

385

results, carboxylate absorption bands appearing at 1606 cm-1 increased in favor of asymmetric

386

stretching vibrations of carbonyl group at 1722 cm-1 [40].

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387

Fig. 9. FTIR spectra of: a) untreated Eudragit®, b) Eudragit® treated with scCO2, and

389

c) Eudragit®-Carvedilol solid dispersion

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390

FTIR spectra of untreated HPMC-AS (Fig. 10a) has a peak at 3468 cm-1 attributed to

392

stretching of OH group [39,41]. Characteristic carboxylic acid C=O peak can be seen at 1735 cm-1

393

(carbonyl group stretching) [39,41]. Fig. 10b shows spectra of HPMC-AS treated with scCO2 which is

394

the same as the spectra of untreated HPMC-AS. FTIR spectra of the HPMC-AS solid dispersion with

395

Carvedilol (Fig. 10c) has peaks characteristic for Carvedilol at 1589 cm-1 and 1504 cm-1, as well as

396

peak corresponding to aromatic secondary C–N vibrations 1251 cm-1 [1,21,24,25]. The absence of

397

Carvedilols’ peak at 3343 cm-1 and decrease in the HPMC-AS peak intensity at 1735 cm-1 can be

398

attributed to a possible interaction between the N-H group of Carvedilol and the C=O group of

399

HPMC-AS [1,4,21] as well as Carvedilol entrapment into the carrier cavity during inclusion

400

complexation [25].

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391

21

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402

Fig. 10. FTIR spectra of: a) untreated HPMC-AS, b) HPMC-AS treated with scCO2, and

404

c) HPMC-AS-Carvedilol solid dispersion

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405

Compared with the untreated polymers, FTIR spectra of polymers after scCO2 treatment at

407

30 MPa and 100 °C did not show a changed or new peaks. This suggests that there was no CO2

408

residue in the foams, no chemical changes in the polymers, or detectable polymer decomposition

409

during the scCO2-assisted foaming under the selected conditions. These findings indicate proposed

410

scCO2 process as appropriate for fabrication of pure Soluplus®, Eudragit®, and HPMC-AS foams.

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406

As proved by the change in polymer FTIR spectra, all tested polymers created the solid

412

dispersion with Carvedilol. These spectra change is attributed to hydrogen bonding between drug and

413

polymers which is desirable considering the stability of drugs in solid dispersions [42]. These findings

414

contribute to pharmaceutical development strategies oriented towards selection of polymers and

415

processes for production of solid drug formulations with suitable physical and chemical

416

characteristics.

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417 418

Being a well‐established method to characterize and distinguish crystalline and amorphous

419

materials [5], state of the drug in obtained solid dispersions was further investigated by XRD analysis.

420

The XRD patterns of pure drug Carvedilol, as well as its solid dispersions with Soluplus®, Eudragit®,

22

ACCEPTED MANUSCRIPT HPMC-AS are shown in Fig. 11. The chemical formula of polymorph used for X-ray analysis is

422

C24H26N2O4 [43]. It crystalizes in P21/c space group with following unit cell parameters:

423

a=15.5414(14) Å, b=15.2050(12) Å, c=9.1174(8) Å, β=100.730(7)°. Regarding the microcrystalline

424

nature of Carvedilol, the sharp intense peaks are visible on its diffractogram (Fig. 11a) showing main

425

reflections at 5.26, 11.08, 12.39, 14.28, 16.91, 17.86, 22.83, 25.87 and 28.81° of 2θ, which correspond

426

to d-values of 16.79, 7.98, 7.14, 6.20, 5.24, 4.96, 3.73, 3.44 and 3.10 Å, respectively. The similar

427

patterns were previously recorded [5,23,25,32].

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428 429

Fig. 11. X-ray patterns of: a) untreated Carvedilol, b) Soluplus®-Carvedilol,

430

c) Eudragit®-Carvedilol, and d) HPMC-AS-Carvedilol solid dispersion

431

23

ACCEPTED MANUSCRIPT Diffractograms of Carvedilol solid dispersions were compared with Carvedilol physical

433

mixtures (Fig. S2). Although Carvedilol preserved its form II polymorphic structure in the physical

434

mixtures (Fig.S2), it is transformed to fully amorphous form during scCO2 process (Fig. 11b,c,d).

435

There was no sharp peak of crystalline Carvedilol in the diffractograms of the solid dispersions in

436

contrast to the physical mixture of the polymer matrix and the crystalline drug. The absence of clearly

437

distinctive peaks of the drug in solid dispersions proved that the Carvedilol was dispersed in the

438

amorphous or molecular form in all three polymers. Since the pure drug shows the most intensive

439

reflection at 16.91° 2θ while the broad peaks found in diffractograms of solid dispersions are between

440

15 and 25° 2θ, it is clear that the transition of Carvedilol from crystalline to amorphous form was

441

complete. Although the solid dispersion of Eudragit® with Carvedilol shows the highest intensity of

442

the mentioned broad peak, this is still too low to cause any doubt if the Carvedilol transformed to fully

443

amorphous form or not.

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444 445

3.4. Dissolution studies

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446

Dissolution of a poorly water-soluble drug is the rate-limiting step in the oral absorption

448

process and an important parameter related to the drug bioavailability [1]. Therefore, the improvement

449

in drug dissolution is crucial for the development of poorly soluble drug formulation. It has been

450

recognized that the drug dissolution rate could be increased through the preparation of foamed drug-

451

polymer formulations as well as by the production of polymer-drug solid dispersions by the

452

supercritical fluid technology [1,12,23,24,42]. In that sense, dissolution rates of the untreated poorly

453

soluble drug Carvedilol and Carvedilol solid dispersions prepared by the scCO2 process were

454

compared in acidic media which simulates stomach environment (Fig. 12). Increase in Carvedilol

455

dissolution can be seen for all three solid dispersions prepared by the proposed process. Generally, the

456

solid dispersion formulations improve the solubility and dissolution rate of poorly water-soluble drugs

457

by reduction of the drug particle size, increase in surface area, by a change of the drug crystalline state

458

(preferably into amorphous), and/or by enhancement of the drug wettability [19,42].

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459 24

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460

Fig. 12. Dissolution profiles of untreated Carvedilol and Carvedilol from solid dispersions

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461 462

Dissolution parameters, represented as the percentage of the drug released after 10 min (Q10)

464

or 180 min (Q180), as well as the time required for the release of 50% of the drug (t50), were calculated

465

and presented in Table 3. In addition, the percentage dissolution efficiency (%DE) after 30, 60 and

466

90 min (%DE30, %DE60 and %DE90, respectively) was calculated from the area under each dissolution

467

curve at the certain time (t) [23]. Untreated Carvedilol showed poor dissolution with Q10 of only

468

18.3%. The overall amount of the drug dissolved after 180 min was 44.3%, while %DE30 and %DE90

469

were 20.2 and 31.2, respectively. Such a slow dissolution rate and poor solubility of Carvedilol in

470

acidic media were previously reported [21,23].

472

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463

Table 3 Dissolution parameters of Carvedilol Sample

Q10 (%)

Q180 (%)

t50 (min)

%DE30

%DE60

%DE90

18.32

44.26

> 180

20.19

27.25

31.23

Soluplus -Carvedilol

41.39

97.27

12

51.37

71.57

79.29

Eudragit®-Carvedilol

58.70

90.57

6

56.8

67.02

71.51

HPMC-AS-Carvedilol

16.10

65.04

88

19.68

29.48

35.82

Carvedilol ®

473

25

ACCEPTED MANUSCRIPT Tested solid dispersions showed significant differences in Carvedilol dissolution parameters

475

depending on the polymer used (Table 3). The solid dispersion prepared with Eudragit® demonstrated

476

the fastest onset of Carvedilol release with 58.7% of the drug being released after 10 min while solid

477

dispersion prepared with Soluplus® had the highest overall dissolution efficiency (Fig. 12). While the

478

time required for the release of 50% of Carvedilol from Eudragit® was 6 min, Lyons et al. [17]

479

reported t50 of 30-55 min for Carvedilol dissolution from Eudragit®-Polyethylene oxide produced by

480

scCO2-assisted extrusion. Carvedilol dissolution from HPMC-AS solid dispersion showed to be the

481

lowest. The reason for overall lower drug dissolution can be found in polymer morphology and

482

solubility in release media. Unlike Soluplus® and Eudragit® which have good solubility in acidic

483

media, the solubility of HPMC-AS in acidic media is poor [9,19,39] Also, HPMC-AS solid dispersion

484

has smaller pore size than other two solid dispersions (Table 2) which may be the cause of the

485

resistance to solvent diffusion. For a description of the drug dissolution mechanism, Korsmeyer-

486

Peppas model can be used [12]. Correlation coefficients of Carvedilol dissolution according to the

487

Korsmeyer-Peppas model, limited to the description of the first 60% of the release, are presented in

488

Table 4. Korsmeyer-Peppas model can be used for the mathematical description of Carvedilol

489

dissolution from solid dispersions of Soluplus®, Eudragit® and HPMC-AS considering that coefficient

490

of correlation (R2) is higher than 0.95 [44].

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474

EP

491 492

Table 4 Correlation coefficients according to Korsmeyer-Peppas model used for description of the

493

dissolution mechanism of Carvedilol from solid dispersions of a cylindrical shape Eudragit®

HPMC-AS

k (min )

0.034

0.299

0.046

n

1.081

0.289

0.541

R2

0.999

0.998

0.964

AC C

Soluplus®

-n

494 495

The highest value of release rate constant (k) is for Eudragit® solid dispersion indicating less

496

restricted and the fastest Carvedilol release compared to other two solid dispersions. A value of n=1

497

which corresponds to the Carvedilol release from Soluplus® solid dispersion means that the drug

498

release is independent of time, regardless of the geometry and thus reflects zero-order release [28]. It 26

ACCEPTED MANUSCRIPT indicates an acceleration of the drug release by swelling or dissolution of the polymer matrix due to

500

the relaxation of the polymer chain [43]. Diffusion exponent n=0.54 of HPMC-AS-Carvedilol solid

501

dispersion falls within the range that corresponds to anomalous drug release or non-Fickian diffusion

502

release [28]. This means that Carvedilol release from the HPMC-AS solid dispersion is contributed to

503

the combination of dissolution and diffusion [41,44]. Gong et al. [12] showed the good fit of

504

Korsmeyer-Peppas model for the description of Indomethacin dissolution rate from solid dispersion

505

with HPMC also reporting n value of 0.54. A value of n=0.29 which corresponds to the Carvedilol

506

release from Eudragit® solid dispersion corresponds to the drug release from the polydisperse spheres

507

[28].

SC

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499

The physical and chemical structure of the pharmaceutical formulations can be finely tuned

509

by the appropriate polymer and drug selection and by the optimization of the scCO2 process operating

510

parameters. As a direct consequence, polymeric foams will be able to fulfill the desired performance

511

for specific applications. Given that Soluplus®, Eudragit® and HPMC-AS are pH-sensitive [41], their

512

foams can be used for the production of drug solid dispersions for pH-dependent site-specific release.

513

Among tested polymers and solid dispersions, the one with Soluplus® stands out fulfilling the demand

514

of the United States Pharmacopeia who states that Carvedilol immediate-release tablets should release

515

80% of the drug within the 30 minutes of the dissolution test in the simulated gastric fluid media [45].

516

518 519

4. Conclusion

AC C

517

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508

Tested single-step static scCO2 process (30 MPa and 100 °C for 2 h) was proven to be suitable

520

for the production of Soluplus®, Eudragit® and HPMC-AS macrocellular foams with the average pore

521

size in the range 184–213 µm and the porosity in the range 54–65%. The CO2 did not affect the

522

composition of tested polymers, nor did it remain in the foams post-processing. Obtained polymeric

523

foams could be used for the development of floating drug delivery systems considering their purity

524

and density lower than 700 kg/m3.

525

Cardiovascular drug Carvedilol created solid dispersions with polymers during the scCO2

526

process due to the formation of hydrogen bonds and Carvedilol transition from the crystalline to an 27

ACCEPTED MANUSCRIPT 527

amorphous form. Obtained solid dispersions increased the Carvedilol dissolution rate. Thus, the use of

528

Soluplus®, Eudragit® and HPMC-AS as carriers of Carvedilol, together with the proposed method of

529

preparation of solvent-free formulations, represent a promising approach in the enhancement of the

530

solubility of poorly soluble drug and improvement of its biopharmaceutical performance.

532

RI PT

531 Acknowledgments

Financial support of this work from the Ministry of Education, Science and Technological

534

Development of the Republic of Serbia (Projects III 45017, TR 34007, III 45007) is gratefully

535

acknowledged.

SC

533

536 Data availability

538

The raw/processed data required to reproduce these findings cannot be shared at this time due to legal

539

reasons.

540

The raw/processed data required to reproduce these findings cannot be shared at this time as the data

541

also forms part of an ongoing study.

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542 543

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544

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537

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Soluplus®, Eudragit®, HPMC-AS were processed by a single-step static scCO2 process

•

Foams with density ~500 kg/m3 and average pore diameter ~200 µm were obtained

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CO2 did not remain in foams after processing, nor it affected polymers’ composition

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Crystalline Carvedilol converted to amorphous form and formed solid dispersions

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Solid dispersions increased Carvedilol dissolution rate up to 2.5-times

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