Formulation and dissolution kinetics study of hydrophilic matrix tablets with tramadol hydrochloride and different co-processed dry binders

    Formulation and dissolution kinetics study of hydrophilic matrix tablets with tramadol hydrochloride and different co-processed dry binders Alena Komersov´a, V´aclav Lochaˇr, Kateˇrina Mysl´ıkov´a, Jitka Muˇz´ıkov´a, Martin Bartoˇs PII: DOI: Reference:

S0928-0987(16)30291-3 doi: 10.1016/j.ejps.2016.08.002 PHASCI 3646

To appear in: Received date: Revised date: Accepted date:

8 January 2016 7 July 2016 2 August 2016

Please cite this article as: Komersov´a, Alena, Lochaˇr, V´ aclav, Mysl´ıkov´a, Kateˇrina, Muˇz´ıkov´ a, Jitka, Bartoˇs, Martin, Formulation and dissolution kinetics study of hydrophilic matrix tablets with tramadol hydrochloride and different co-processed dry binders, (2016), doi: 10.1016/j.ejps.2016.08.002

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ACCEPTED MANUSCRIPT Formulation and dissolution kinetics study of hydrophilic matrix tablets with tramadol hydrochloride and different co-processed dry binders

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Alena Komersováa, Václav Lochařa*, Kateřina Myslíkováa, Jitka Mužíkováb, Martin Bartošc

Department of Physical Chemistry, Faculty of Chemical Technology, University

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Department

of

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of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic

Pharmaceutical

Technology,

Charles

University

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Prague,

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Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 500 05 Hradec Králové, Czech

Department of Analytical Chemistry, Faculty of Chemical Technology, University

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Republic

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of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic

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Corresponding author at: Department of Physical Chemistry, Faculty of Chemical

Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic Fax: +420 466 037 068 E-mail address: [email protected]

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ABSTRACT

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The aim of this study is to present the possibility of using of co-processed dry binders for

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formulation of matrix tablets with drug controlled release. Hydrophilic matrix tablets with

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tramadol hydrochlorid, hypromellose and different co-processed dry binders were prepared by direct compression method. Hypromelloses MethocelTM K4M Premium CR or MethocelTM K100M Premium CR were used as controlled release agents and Prosolv® SMCC 90 or

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DisintequikTM MCC 25 were used as co-processed dry binders. Homogeneity of the tablets was evaluated using scanning electron microscopy and energy dispersive X-ray

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microanalysis. The release of tramadol hydrochlorid from prepared formulations was studied by dissolution test method. The dissolution profiles obtained were evaluated by non-linear

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regression analysis, release rate constants and other kinetic parameters were determined. It

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was found that matrix tablets based on Prosolv® SMCC 90 and MethocelTM Premium CR

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cannot control the tramadol release effectively for more than 12 hours and tablets containing

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DisintequikTM MCC 25 and MethocelTM Premium CR more than 8 hours.

Keywords: Tramadol hydrochloride, hypromellose, co-processed dry binders, matrix tablets, dissolution kinetics

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1.

Introduction

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Matrix tablets represent a type of tablets with prolonged release. They are formed by a

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homogeneous mixture of the active ingredient and excipients (including retarding component)

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in the whole tablet volume. According to the type of retarding component used, matrix tablets are classified as insoluble polymeric, hydrophilic gel, lipophilic and mixed (Colombo et al., 1996; Nochhodchi et al., 2012; Pundir et al., 2013).

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The simplest method of matrix tablet production is direct compression. The direct compression requires excipients which fulfill the function of fillers and binders

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simultaneously. Such requirements are satisfied by the so-called dry binders (Carlin, 2008). As no substance alone possesses completely ideal properties for tableting in terms of

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flowability and compressibility especially, co-processed dry binders are gradually beginning

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to win recognition. These materials combine more excipients with the same or different

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functions for tableting (Gupta et al., 2006; Nachaegari and Bansal, 2004; Gohel and Jogani, 2005). If the functions of the ingredients are different, it gives rise to multifunctional

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substances which significantly reduce the process of tablet production due to elimination of mixing steps with the individual auxiliary substances, which are already contained in the coprocessed excipient. The examples of co-processed dry binders are also Prosolv® SMCC 90 and DisintequikTM MCC 25. Prosolv® SMCC 90 is silicified microcrystalline cellulose containing 98% of microcrystalline cellulose and 2% of colloidal silicon dioxide. This coprocessed dry binder exhibits excellent flowability, compressibility and also lower lubricant sensitivity (Sherwood and Becker, 1998; Moreton, 2006; Allen, 1996). DisintequikTM MCC 25 contains 75% of α-lactose monohydrate and 25% of microcrystalline cellulose (MCC) (Kerry 2015, Product brochure). A combination of lactose and MCC is advantageous and very frequently used. MCC, which is deformed plastically, provides above all good binding

ACCEPTED MANUSCRIPT properties. Lactose as a fragile material acts as a filler and decreases the sensitivity of the tableting material to the added lubricants (Gar and Rubinstein, 1991).

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This study investigates the using of co-processed dry binders Prosolv® SMCC 90 and

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DisintequikTM MCC 25 for preparation of hydrophilic matrix tablets with controlled release of

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tramadol hydrochloride.

Hydrophilic matrix tablets contain a water soluble polymer which quickly hydrates in contact with the dissolution medium and forms a gelatinous layer and consequential water

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penetration allow the controlled drug release (Colombo et al., 1996; Nochhodchi et al., 2012).

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Once the original protective gel layer is formed, it controls the further penetration of water into the tablet and release of drug (Colorcon 2014, Product brochure). It is clear that drug release from a water soluble polymer system is controlled by a process of drug diffusion

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through the gel layer as well as erosion of the swollen gel layer (Colombo et al., 1996). The mechanism of drug release from matrix tablets is also influenced by the solubility of the drug.

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Release of highly water soluble drug from a hydrophilic matrix system is controlled mainly by diffusion through the swollen gel layer (Bettini et al., 2001). Tablet geometry is also an

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important factor affecting drug release kinetics from diffusion-controlled systems and it has been studied in detail by Siepmann et al. (Siepmann et al., 2000). The effect of the tablet surface/tablet volume ratio on the drug release from hydrophilic matrices containing hypromellose was studied by (Reynolds et al. , 1998). This work is focused on the study of the viscosity grade effect of hypromellose (HPMC) in combination with different co-processed dry binders on the drug release mechanism of a water soluble drug from a hydrophilic system.

ACCEPTED MANUSCRIPT 2. Materials and methods 2. 1. Materials

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Tramadol hydrochloride (TH, European Pharmacopoeia Reference Standard, Sigma Aldrich Chemie GmbH, Germany) was chosen as the model water soluble drug.

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Hypromelloses MethocelTM K4M Premium CR or MethocelTM K100M Premium CR (both from Colorcon GmbH, Germany) were used as controlled release agents forming a

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hydrophilic matrix system and Prosolv® SMCC 90 (JRS PHARMA, GmbH & Co. KG, Germany) or DisintequikTM MCC 25 (Kerry, USA) were used as co-processed dry binders.

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Magnesium stearate (Acros Organics, USA) was used as lubricant. For the preparation of dissolution media and standard solution of tramadol hydrochloride,

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redistilled water and chemicals of analytical grade (Lach - Ner s.r.o., Neratovice, Czech

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Republic) were used. Acetonitrile and trifluoracetic acid (both for HPLC, ≥ 99.9%, Sigma

hydrochloride.

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Aldrich Chemie GmbH, Germany) were used for HPLC determination of tramadol

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2. 2. Methods

2. 2. 1. Preparation of tableting materials The composition of the formulations studied is described in Table 1. The tableting materials were prepared by mixing in mixing cube KB 15S (Erweka GmbH, Germany). The components

were mixed step by step, first the appropriate type of Methocel

DisintequikTM MCC 25 or Prosolv® SMCC 90

with

for a period of 5 minutes, subsequently

tramadol was added for another 5 minutes of mixing. Magnesium stearate was added to all tableting materials at the end for a period of mixing of 2.5 minutes. The mixtures without the active ingredient were prepared in the same manner, omitting the mixing step with tramadol.

ACCEPTED MANUSCRIPT The cube rotated with a speed of 17 rev/min. The amount of prepared mixtures was always 30 g.

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2. 2. 2. Preparation of tablets

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Tablets were prepared by direct compression using material testing equipment T1-FRO

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50 TH.A1K Zwick/Roell (Zwick GmbH&Co, Germany) by means of a special die with a lower and an upper punch. The rate of compaction was 40 mm/min, pre-load was 2 N, and the

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rate of pre-load 2 mm/s. The tablets were of cylindrical shape without facets of a diameter of 13 mm and weight of 0.5 ± 0.0010 g. Compression forces were adjusted in such a way that the

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tablet strength ranged between 0.8 – 0.9 MPa, so for the tableting materials with Prosolv® SMCC 90 a compression force of 4.5 kN and for the tableting materials with DisintequikTM

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MCC 25 a compression force of 6 kN were employed. For the dissolution, 6 tablets with the

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active ingredient and 1 tablet without the active ingredient as the blind sample (69% of Prosolv® SMCC 90 or DisintequikTM MCC 25, 30% of MethocelTM K4M (or K100M)

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Premium CR and 1% of magnesium stearate) were compressed. In the same way, tablets for the photographic observation were prepared.

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2.2 3. Scanning electron microscopy (SEM), energy dispersive X-ray microanalysis (EDX) The compact scanning electron microscope VEGA3 SBU (Tescan, Brno, Czech Republic) integrated with the energy dispersive X-ray microanalysis system Quantax (Bruker Nano XFlash® Detector 410-M, software Quantax Esprit 1.9, Bruker Nano GmbH, Berlin, Germany) was used to investigate the structure and homogeneity of the prepared tablets. The acceleration voltage of 20 kV, backscattered electron BSE) detector and low vacuum mode (10 Pa, N2) were applied. Prior to being cut, the unmodified external surface of a tablet was analyzed. The tablet was then split in half transversely using a sharp knife and then cut into several thin slices. Folloving this, the cut surface of the tablet was analyzed.

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2.2.4. In vitro dissolution studies

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The release of TH from prepared drug formulations was studied by the dissolution test

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method according to the European Pharmacopoeia 8th (European Pharmacopoeia, 2013) using

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rotating basket apparatus (Sotax AT 7 Smart, Allschwil, Switzerland). Dissolution test was performed in two different dissolution media: 1) acidic medium pH 1.2 - HCl with the

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addition of NaCl (250 mL of 0.2 M NaCl was mixed with 425 mL of 0.2 M HCl and the solution was diluted to 1000.0 mL with redistilled water); 2) phosphate buffer pH 6.8 (29 mL

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of 1 M sodium dihydrogen phosphate and 50 mL of 0.5 M disodium hydrogen phosphate were mixed and made up with redistilled water to 1000.0 mL).

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Six tablets containing 100 mg of TH and one blank tablet were placed to the baskets

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and immersed in the dissolution medium (900 mL). All tests were carried out for 24 hours at a stirring rate of 125 rpm. Temperature was maintained at 37 ± 0.5°C. At predetermined times,

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3 mL of the dissolution medium was automatically withdrawn and same volume of fresh tempered medium was replaced. Consecutive samples were filtered and the TH concentration

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was determined using HPLC with spectrophotometric detection (271 nm). Each experiment was performed once (with six tablets) and the mean values of the released amount of TH with their standard deviations were calculated.

2.2.5. Determination of TH using HPLC High-performance liquid chromatography analyses were performed in accordance with European Pharmacopoeia 8th (European Pharmacopoeia, 2013). Ecom HPLC system (Ecom Prague, Czech Republic) consisting of system controller, high pressure pump Beta, degasser, injector and UV VIS detector Safir was used. Chromatographic data were analyzed and stored

ACCEPTED MANUSCRIPT using chromatography software Data Apex Clarity. The column used for separation of the dissolution products was 250 × 4.6 mm C18 column (Kromsil 60 Silica 7 μm, Ecom Prague,

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Czech Republic). The mobile phase was prepared from trifluoracetic acid and water (2 mL

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CF3COOH + 998 mL H2O) and mixed with acetonitrile (70:30, v/v). A wavelength of 271 nm

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and an isocratic method was applied with a flow rate of 1 mL/min and column temperature of 37˚C.

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2.2.6. Photographic observation

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In situ photographic observation of the TH tablets during dissolution testing was carried out using the paddle method (Sotax AT 7 Smart, Allschwil, Switzerland). Photographs

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were taken at intervals (1, 6, 12, 18 hr) using a Panasonic Lumix DMC- FZ18 digital camera.

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2.2.7. Mathematical and statistical evaluation of the experimental data In order to describe and quantitatively evaluate TH release from hydrophilic matrix

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tablets containing co-processed dry binders Prosolv® SMCC 90 or DisintequikTM MCC 25, the obtained dissolution profiles were fitted to the first-order kinetic model, Higuchi, Korsmeyer-Peppas and Weibull model. All mathematical equations were applied in nonlinearized form. Because an increase of TH concentration in the dissolution medium was observed, the first order kinetic model (Costa and Sousa Lobo, 2001; Dash et al., 2010; Libo and Reza, 1996) was used in form

ACCEPTED MANUSCRIPT where At(l) is the released amount of drug in time t, A∞ represents the maximum releasable amount of drug in infinite time (it should be equal to the absolute amount of drug

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incorporated in solid drug formulation at time t = 0) and k1 is the first order release rate

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constant in units of time-1. By a derivative of Eq. (1), the drug release rate can be obtained

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(Laidler et al., 2003).

Higuchi diffusion model (Higuchi, 1963), describing drug release as a diffusion

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process based on the Fickʼs law, was used in a general form

valid for the first 60% of the total drug released. In Eq. (2), KH is the Higuchi dissolution

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constant and At(l) is the amount of drug released in time t, A∞ represents the maximum

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releasable amount of drug in infinite time. In order to examine the mechanism of TH release,

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Peppas, 1985)

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the dissolution profiles were fitted to Korsmeyer-Peppas model (Korsmeyer et al., 1983;

where

is the amount of drug released in time t, A∞ represents the maximum releasable

amount of drug,

is a constant incorporating structural and geometric characteristics of the

dosage form and n is the release exponent indicating of the drug release mechanism. The release exponent and interpretation of the diffusion release mechanism is discussed in (Costa and Sousa Lobo, 2001; Dash et al., 2010; Korsmeyer et al., 1983). The Weibull model adapted to the disssolution process (Costa and Sousa Lobo, 2001) was expressed by the equation

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is the amount of drug released in time t, A∞ is the maximum releasable amount of

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where

(4)

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drug, λ represents the reciprocal value of time scale of the process, the location parameter Ti represents the lag time before the onset of the dissolution (in most case is zero) and b describes the shape of the dissolution curve progression.

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By a derivative of Eq. (1) and by second-order approximation of the first derivative

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(Mortimer, 2005), the time dependence of the release rate was obtained. All experimental data were mathematically processed and statistically evaluated by

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means of the computer programmes Graph Pad Prism and Origin 9 Pro. Coefficient of

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determination (R2) and residual sum of squares (RSS) were used for comparison of the kinetic models. Statistical significance was tested using Student’s t test for unpaired samples, at a

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significance level of P<0.05.

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3. Results and discussion

3. 1. Evaluation of tablets homogeneity using by of SEM and EDX 3.1.1. SEM observation Representative SEM images of the surface of tablets without the active ingredient are given in Fig. 1. Significant rods and grains of MethocelTM Premium CR (K4M or K100M) between which the pulp of Prosolv® SMCC 90 or DisintequikTM MCC 25 can be observed. Particles of magnesium stearate are not visually identifiable. Similar SEM images of the cut surface of the tablet (Fig. 1) like the external tablet surfaces were observed. It is clear, that the structure of tablets containing co-processed dry binder Prosolv® SMCC 90 is not different from tablets

ACCEPTED MANUSCRIPT containing DisintequikTM MCC 25. Significant differences between tablets with active ingredient (Fig. 2) and without active ingredient (Fig. 1) were found. In the mass of the

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tablets, Tramadol hydrochloride transforms what were probably originally spherical clusters

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into oval structures as a result of compression. Inside these structures is not just tramadol,

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other components of the tablet may to a certain extent be present. Using a BSE detector, clusters containing an increased amount of tramadol are clearly visible and distinguishable from other parts of the tablet because chlorine from tramadol hydrochloride increases the

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average atomic number and therefore the brightness of the area of the sample (Fig. 2). Based

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on EDX analysis (see 3.1.2.), it was proved that this is indeed an area with increased content

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of tramadol (Fig. 2).

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3.1. 2. EDX analysis

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Using EDX allows the evaluation of the tablet homogeneity by the determination of chemical composition of different parts of the sample. The local composition at selected points as well as the distribution of element in the sample area (mapping mode) was investigated.

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Individual components of investigated tablets contain in their molecules carbon, hydrogen and oxygen. These elements was not evaluated using EDX. Futhermore, the molecule of tramadol hydrochloride contains nitrogen (4.7% per molecule, resp. 0.9% per tablet) and chlorine (11.8% per molecule, resp. 2.4% per tablet), magnesium stearate contains magnesium (4.1% per molecule, resp. 0.03% per tablet) and co-processed dry binder Prosolv® SMCC 90 contains silicon (0.9% per molecule, resp. 0.5% per tablet). A signal for nitrogen was found as non-evaluable due to the interference of strong signals of carbon and oxygen. The magnesium and silicon signal is very weak (at the detection limit) and reliably it can be identified only by the local analysis of selected areas with increased concentrations of both elements (particles of magnesium stearate and Prosolv® SMCC 90, resp.). The signal of

ACCEPTED MANUSCRIPT chlorine is disturbed, probably by the sublimation of chlorine from the surface of crystals under conditions of analysis (irradiation by the beam of accelerated electrons in vacuum).

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This is reflected by the gradual reducing of the brightness of corresponding parts of the image

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when viewing with a BSE detector. In both kinds of tablets (Prosolv® SMCC 90 or

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DisintequikTM MCC 25), the content of chlorine in the selected areas on cut surface of the tablet ranged between 7 and 9% (in tramadol clusters) and at other places between 2 and 3%. Mapping of the chemical composition of the surface and cut surface of the tablet confirmed

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the existence of tramadol hydrochlorid clusters which are often quite sharply separated from

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the surrounding tablet matrix (Fig. 2). These clusters are the most frequently smaller than 0.1 mm but occasionally clusters larger than 0.5 mm were found. The highest identified contents of magnesium were between 0.4 and 0.6%. Using

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mapping mode, isolated particles of 10 μm and smaller were found. From this it can be assumed that the particles of magnesium stearate are very fine and are relatively uniformly

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distributed in the tablet matrix.

The highest contents of silicon were between 0.1 and 0.2% which is less than its

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average content in tablets. Moving to the detection limit of the method, precision of the determination is decreased. This result could also indicate that the molecules crystals of silicon dioxide are coated in Prosolv® SMCC 90 by thin layer of molecules of MethocelTM Premium CR which shield the electron beam.

3. 2. Evaluation of drug release from hydrophilic matrix tablets In order to study the release mechanism, the time dependence of released amount of TH was measured in two dissolution media (pH of 1.2 and 6.8) with regard to changing pH of gastrointestinal tract. Dissolution profiles of F1-F4 formulations fitted to the first order kinetic model (Eq. (1)) and Weibull model (Eq. (4)) are given in Fig. 3. It is apparent, that all

ACCEPTED MANUSCRIPT studied hydrophilic formulations follow the first order kinetic model and Weibull model with high values of R2 in both dissolution media (Table 2A and 2B). As can be seen from (Eq. (4))

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and (Eq. (1)), when the shape parameter b in (Eq. (4)) is equal to one, the Weibull empiric

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model corresponds to the first order kinetic model and the parameter λ in (Eq. (4))

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corresponds to the first order release rate constant k1. The values of b about 1 were found for F1 and F2 formulation in acidic dissolution medium (Table 2A and 2B). This result confirms the fact that the dissolution process of F1 and F2 formulation in acidic medium can be

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considered for the first order kinetics. But this comparison is only theoretical because the

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Weibull model is an empiric equation without kinetic fundamentals and the dependence of drug release rate on At(l) cannot be expressed.

From Fig. 3 it is also clear, that the cumulative amount of TH released in 24 h limits to

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100% regardless of the matrix type and pH of the dissolution medium. Regression analysis of the dissolution profiles proved, that the amount of drug which will be released in infinite time

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(A∞) is in a range from 95 to 104% including standard deviation. These results confirmed, that all initial dose of the active substance in the solid drug form is released into the dissolution

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medium.

The higher curve slope of F3 and F4 profiles in comparison with F1 and F2 formulations is apparent in Fig. 3, which proves the higher drug release rate for the formulations containing co-processed dry binder DisintequikTM MCC 25. The higher release rate of TH from these formulations was found in both dissolution media. Disintequik™ MCC 25 contains 75% of α-lactose monohydrate and 25% of microcrystalline cellulose (MCC). The addition of lactose increases the hydrophilic character of the tablets and fast penetration of the dissolution fluid into the matrix allows faster release of good soluble active substance TH in comparison with matrix tablets containing pure silicified MCC. The values of rate constants (Table 2A,B) confirm that the addition of lactose has a stronger effect on the drug release than

ACCEPTED MANUSCRIPT the viscosity grade of Methocel. The higher release rate of TH from F3 and F4 formulations is apparent also in Fig. 4 and Fig. 5, where the numerical (second-order approximation of the

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first derivative) and analytical derivative (Rate Law) of the dissolution profile are given.

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Generally, the derivative of a function is the rate of change of the dependent variable (in this

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case change of the realeased amount of drug) with respect to the independent variable (in this case time). From this follows that derivative of the dissolution profile at any given point corresponds to the rate of drug release. It is apparent, that for all studied formulations the

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curves of analytical derivative overlap the curves of numerical derivative. The release rate

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decreases with time and in time of about 12 hours (F3 and F4) and of about 8 hours (F1 and F2), respectively, is equal to zero. This fact shows that formulations F3 and F4 allow to control the tramadol release effectively maximally for 12 hours and formulations F1 and F2

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maximally for 8 hours.

The release rate of TH from studied matrix tablets was also affected by the viscosity

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grade of the MethocelTM Premium CR used. MethocelTM Premium CR is a water soluble polymer (propylene glycol ether of methylcellulose) widely used as the controlled release

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agent in hydrophilic matrix systems and the viscosity of its solutions is stable over a wide range of pH due to nonionic character of the molecules (Colorcon, 2014. Product brochure). In the present study, MethocelTM K100M and K4M were studied as hydrophilic matrixing agents. On contact with aqueous media, MethocelTM K100M Premium CR forms stronger viscous gel than MethocelTM K4M Premium CR, which can be used for prolongation of highly water soluble drug (TH) release. Based on the results of regression analysis (Table 2A and 2B), the higher values of release rate constant were found for formulations with Methocel of lower viscosity grade (F1 and F3). The lower viscosity of gel layer of MethocelTM K4M Premium CR allows higher

ACCEPTED MANUSCRIPT mobility of water molecules in the matrix leading to faster release of water soluble TH from tablet matrix.

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Swelling of F2 and F4 formulations is shown in Fig. 6 (side view) and disintegration

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of F3 tablet is shown in Fig. 7 (top view). Increasing tablets height with time (Fig. 6)

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corresponds to the swelling process and decreasing tablets diameter (Fig. 7) represents disintegration. Swelling is the first part of the tablet matrix degradation. Concurent processes of swelling and disintegration lead to gel sphere formation and TH release rate decreases.

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To evaluate the transport mechanism of TH from matrix tablets containing co-

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processed dry binder Prosolv® SMCC 90 or DisintequikTM MCC 25, obtained dissolution profiles were also fitted to Korsmeyer-Peppas (Eq. (3), Fig. 8) and Higuchi model (Eq. (2)). Results of regression analysis are given in Table 3A and 3B. From values of the release

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exponent n (0.59 < n < 0.69 for F1 and F2, 0.57 < n < 0.61 for F3 and F4), it follows that all formulations show anomalous transport - superposition of case-II transport and diffusion-

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controlled drug release mechanism. All studied formulations are based on swellable HPMC matrix, wherein the diffusion coefficients of water and incorporated drugs are strongly

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concentration dependent, therefore the application of Korsmeyer-Peppas equation cannot give exact information about drug release mechanism (Siepmann and Peppas, 2001). For a more detailed description of the release mechanism, some mechanistic theory involving the fact mentioned above had to be used.

4. Conclusion Hydrophilic matrix tablets containing co-processed dry binders Prosolv® SMCC 90 or DisintequikTM MCC 25, MethocelTM Premium CR as release retardant and tramadol hydrochlorid as active substance were formulated using the direct compression method. Based on non-linear regression analysis of the dissolution profiles, the release kinetics of tramadol

ACCEPTED MANUSCRIPT hydrochloride was evaluated. A higher drug release rate was found for the formulations containing co-processed dry binder DisintequikTM MCC 25 in comparison with the tablets

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containing Prosolv® SMCC. Futhermore, it was found that the drug release rate is influenced

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but it does not depend on pH of the dissolution media.

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by the viscosity grade of the MethocelTM Premium CR (K4M - higher release rate of TH) used

Studied hydrophilic matrix tablets based on Prosolv® SMCC 90 and MethocelTM Premium CR cannot control the tramadol release effectively for more than 12 hours and tablets containing

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DisintequikTM MCC 25 and MethocelTM Premium CR for more than 8 hours.

This study demonstrates the possibility of using of co-processed dry binders for

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Acknowledgement

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formulation of matrix tablets with drug controlled release.

This work was supported by the grant SG_2015005 of The Ministry of Education, Youth and Sports of The Czech Republic and by the firms Colorcon GmbH, JRS PHARMA, GmbH

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& Co. KG and Kerry, which supplied the samples of the excipients.

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Gupta, P., Nachaegari, S.K., Bansal, A.K., 2006, Improved Excipient Functionality by Coprocessing. In: Excipient Development for Pharmaceutical, Biotechnology and Drug Delivery Systems, Katdare, A., Chaubal, M. V. (eds). Informa Healthcare, Inc., USA, pp. 109-126.

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Higuchi T., 1963, Mechanism of sustained-action medication. Theoretical analysis of rate

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of release of solid drugs dispersed in solid matrices. J. Pharm. Sci. 52, 1145-1149.

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Kerry 2015, DisintequikTM MCC 25. Product brochure [online].

Available at: http://www.sheffieldbioscience.com/disintequik MCC25/

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Korsmeyer, R.W., Gurny, R., Doelker, E.M., Buri, P., Peppas, N.A., 1983, Mechanism of

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solute release from porous hydrophilic polymers. Int. J. Pharm. 15, 25-35.

Laidler, K.J., Meiser, J.H., Sanctuary, B.C., 2003, Chemical Kinetics I., The Basic Ideas.

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In: Physical Chemistry, Stratton, R., Dinovo, K., (eds.) 4th ed. New York, Boston,

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Houghton Mifflin Company, pp. 363-364.

Libo, Y., Reza, F., 1996, Kinetic Modeling on drug release from controlled drug delivery

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system. J Pharm Sci 85: 170-173.

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Mortimer, R.G., 2005, Mathematical Functions and Differential Calculus, In: Mathematics for Physical Chemistry, Hayhurst J. (Ed.), 3rd ed. Elsevier Academic Press, Burlington, USA, pp. 89-113.

ACCEPTED MANUSCRIPT Nachaegari, S.K., Bansal, A.K., 2004, Coprocessed Excipients for Solid Dosage Forms.

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Pharm. Technol 28 (1), 52-64.

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Nochhodchi, A., Raja, S., Patel, P., Asare-Addo, K., 2012, The Role of Oral Controlled

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Release matrix Tablets in Drug Delivery Systems. Bioimpacts 2 (4), 175-187.

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Pharm. Acta Helv. 60, 110-111.

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Peppas, N.A., 1985, Analysis of Fickian and non-Fickian drug release from polymers.

Pundir, S., Badola, A., Sharma, D., 2013, Sustained release matrix technology and recent advance in matrix drug delivery system: A review. Int. J. Drug Res. Tech. 3(1),

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Reynolds, T.D., Gehrke, S.H., Hussain, A.S., Shenouda, L.S., 1998, Polymer Erosion and Drug Release Characterization of Hydroxypropyl Methylcellulose Matrices. J.

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Pharm. Sci. 87, 1115-1123.

Siepmann, J., Peppas N. A., 2001, Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv. Drug Dev. Rev. 48, 139-157.

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release profiles. Int. J. Pharm. 201, 151-164.

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Figure 1 Representative SEM images of F1 (right column) and F4 (left column) formulations without active ingredient. Images of tablet surface (top), images of tablet cut (bottom), width 1 mm.

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Figure 2 Representative SEM images of F1cut (bottom) and F4 surface (top) formulations with TH. Chorine EDX mapping (right column), width 1 mm.

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Figure 3 Dissolution profiles of F1-F4 formulations fitted by the first order kinetic model (full line) and Weibull model (dashed line). Symbols of empty circles correspond to acidic dissolution medium, full squares correspond to pH 6.8.

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Figure 4 Numerical and analytical derivative of F1 and F2 dissolution profile. Symbols of empty squares represent analytical and full squares numerical derivative.

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Figure 5 Numerical and analytical derivative of F3 and F4 dissolution profile. Symbols of empty squares represent analytical and full squares numerical derivative.

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Figure 6 In situ photographic observation (side view) of F2 (left column) and F4 (right column) formulations during the dissolution test (1, 6, 12 h) in acidic medium (pH 1.2).

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Figure 7 In situ photographic observation (top view) of F3 formulation during the dissolution test (top-1, 6 h, bottom-12, 18 h) in medium pH of 6.8.

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Figure 8 Dissolution profiles fitted by Korsmeyer-Peppas model. Symbols: empty square (F1), full square (F2), empty circle (F3) and full circle (F4).

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Table 2A Kinetic parameters of TH release in acidic dissolution medium (pH 1.2) – the first order and Weibull model.

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k1 is the first order release rate constant, A∞ is the maximum releasable amount of drug in infinite time, λ is the reciprocal value of time scale of the process, Ti is the location parameter and b is the shape parameter, RSS is residual sum of squares, SD is the standard deviation and R2 is the coefficient of determination, values represent mean ± SD (N=6)

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Table 2B Kinetic parameters of TH release in the dissolution medium of pH 6.8 – the first order and Weibull model.

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k1 is the first order release rate constant, A∞ is the maximum releasable amount of drug in infinite time, λ is the reciprocal value of time scale of the process, Ti is the location parameter and b is the shape parameter, RSS is residual sum of squares, SD is the standard deviation and R2 is the coefficient of determination, values represent mean ± SD (N=6)

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Table 3A Kinetic parameters of TH release in acidic dissolution medium (pH 1.2) Korsmeyer-Peppas and Higuchi model.

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a is the structural and geometric characteristics of the dosage form, n is the release rate exponent, KH is the Higuchi dissolution constant, RSS is residual sum of squares, SD is the standard deviation, R2 is the coefficient of determination, values represent mean ± SD (N=6) Table 3B Kinetic parameters of TH release in the dissolution medium of pH 6.8 - KorsmeyerPeppas and Higuchi model.

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a is the structural and geometric characteristics of the dosage form, n is the release rate exponent, KH is the Higuchi dissolution constant, RSS is residual sum of squares, SD is the standard deviation, R2 is the coefficient of determination, values represent mean ± SD (N=6)

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F1

F2

Prosolv® SMCC 90

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49

MethocelTM K4M Premium CR

20

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Table 1

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Tramadol hydrochloride

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30

MethocelTM K100M Premium CR 1

49

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Magnesium stearate

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DisintequikTM MCC 25

F3

30

1

1

1

20

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F4

0.424 3± 0.008 0 0.361 2± 0.011 3

F1

F2

F3

F4

Table 2B

95.1 ± 0.95

0.991 1

1591.0 1

0.976 8

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Formulatio n

98.1 ± 0.50

312.71

0.995 0

0.223 7± 0.005 9

106. 0± 1.32

0.174 0± 0.005 7 0.404 2± 0.007 0 0.323 1± 0.012 4

R2

0.994 5

0.9 6± 0.0 2

292.0 8

0.995 2

99.9 ± 0.47

0.8 5± 0.0 2

311.2 5

0.995 6

97.8 ± 1.09

0.8 0± 0.0 3

953.8 1

0.985 9

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Table 2A

104. 4± 0.88

0.994 5

± SD

Weibull A∞ ± b ± RSS SD SD (%) 101. 1.0 327.2 6± 2± 5 0.94 0.0 3

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0.180 6± 0.004 1

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k1 ± SD (h-1) 0.221 6± 0.004 9

First-order A∞ ± RSS SD (%) 101. 330.23 2± 0.76

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Formulatio n

First-order A∞ ± RSS SD (%) 103. 413.3 0± 0.84 4

99.4 ± 1.16 98.4 ± 0.42 97.0 ± 0.59

626.4 7

788.5 7

771.8 7

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0.993 1

0.988 2

0.992 0

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± SD

0.2135 ± 0.0069 0.152 6± 0.006 4 0.392 1± 0.005 7 0.3354 ± 0.006 9

Weibull A∞ ± b ± RSS SD SD (%) 105. 0.9 333.6 4± 1± 9 1.18 0.0 2 109. 0.7 153.0 5± 9± 1 1.65 0.0 2 100. 0.8 389.8 4± 5± 0 0.40 0.0 1 0.8 343.4 99.8 3 ± 6 0.0 ± 0.59 2

R2

0.994 3

0.997 0

0.996 0

0.995 2

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F3 F4

22.284 ± 0.299 19.839 ± 0.352 36.987 ± 0.420 32.680 ± 0.754

26.96 0.9943 44.66 0.9926 87.05 0.9834 315.03 0.9496

F3 F4

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Table 3B

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23.925 ± 0.847 23.159 ± 0.272 35.914 ± 0.353 33.292 ± 0.406

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0.662 ± 0.034 0.593 ± 0.010 0.608 ± 0.015 0.580 ± 0.016

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Korsmeyer-Peppas n ± SD a ± SD RSS

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Table 3A

Formulation

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Higuchi KH ± SD RSS 25.715 ± 0.489 23.936 ± 0.525 38.093 ± 0.386 34.158 ± 0.537

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F2

0.671 ± 0.013 0.689 ± 0.015 0.572 ± 0.018 0.579 ± 0.030

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Korsmeyer-Peppas n ± SD a ± SD RSS

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Formulation

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216.23 0.9609 26.39 0.9951 108.76 0.9857 91.20 0.9849

263.13 0.9613 401.47 0.9501 149.02 0.9850 401.10 0.9619

Higuchi KH ± SD RSS 27.393 ± 0.650 25.429 ± 0.305 37.565 ± 0.401 34.803 ± 0.357

R2

R2

464.96 0.9413 135.94 0.9825 289.18 0.9787 177.57 0.9831

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Graphical abstract