lable at ScienceDirect Journal of Drug Delivery Science and Technology 40 (2017) 83e94 Contents lists avai Journal of Drug Delivery Science and Technology journal homepage: www.elsevier .com/locate/ jddst Evaluation of retrograded starch as excipient for controlled release matrix tablets Ana Cristina Diniz Recife a, Andr�eia Bagliotti Meneguin b, Beatriz Stringhetti Ferreira Cury a, *, Raul Cesar Evangelista a, 1 a Department of Drugs and Pharmaceuticals, School of Pharmaceutical Sciences, S~ao Paulo State University-UNESP, 14800-903, Araraquara, SP, Brazil b Interdisciplinary Laboratory of Advanced Materials, Centro de Ciências da Natureza - CNN, Universidade Federal do Piauí - UFPI, 64049-550, Teresina, PI, Brazil a r t i c l e i n f o Article history: Received 2 January 2017 Received in revised form 30 May 2017 Accepted 5 June 2017 Available online 7 June 2017 Keywords: Retrograded starch Pectin Biodegradable polymers Matrix tablets Dissolution * Corresponding author. E-mail addresses: dinizrecife@yahoo.com.br (A hotmail.com (A.B. Meneguin), curybsf@fcfar.unesp. yahoo.com.br (R.C. Evangelista). 1 in memorian. http://dx.doi.org/10.1016/j.jddst.2017.06.003 1773-2247/© 2017 Elsevier B.V. All rights reserved. a b s t r a c t High amylose starch (HAS) was retrograded by two different methods. The physicochemical properties of the retrograded materials were evaluated and structural changes were highlighted. Micromeritics properties were demonstrated as suitable for the compression process. Hydrophilic matrices were prepared by dry granulation of the retrograded starch. The in vitro release of diclofenac sodium (DS) in media with different pH values (1.2 and 7.4) was evaluated. The release profiles demonstrated the lowering of drug release rates in acid medium, mainly when pectin was associated to the matrix by physical mixture. In enteric medium, increased rates of drug release were observed, so that t80% occurred at approximately 60 min, while for the tablets obtained with HAS, this time was of approximately 120 min. The matrix obtained with pectin (during retrogradation and by physical mixture) enabled a more effective control over the drug release rates, so that t80% of DS was 150 min and 210 min, respectively. © 2017 Elsevier B.V. All rights reserved. 1. Introduction Despite the wide and successful research with alternative routes of drug administration, the oral route remains the preferable choice because of its inherent benefits, such as safety, easy administration, flexibility of formulation, greater patient adherence to the treat- ment and the possibility of releasing drugs both locally and sys- temically [1,2]. Among oral controlled release systems, matrix tablets were noteworthy by presenting efficient manufacturing technology and high reproducibility, which reflects in lower costs of production, mainly when the direct compression of the powders is their way of obtainment [3,4]. Swellable hydrophilic matrices are monolithic systems that do not degrade upon contact with the aqueous medium, undergoing hydration, which leads to the formation of a swollen diffusion layer, controlling the rates of release. The polymer swelling, the solute .C.D. Recife), abagliottim@ br (B.S.F. Cury), raulrasec@ diffusion throughout the matrix, and erosion are also mechanisms involved in the control of drug release [5,6]. Natural polymers play an important role in the design of these systems, since they are materials from renewable and abundant sources, additionally, they are nontoxic and biodegradable. Besides, they can confer or enhance controlled release properties to the systems due to molecular properties of polymers, such as their monomer nature and type/degree of substitution [7e9]. Further- more, in situ drug release can be reached because of the presence of glycoside bonds in the polymer structure that are hydrolytically cleaved by colonic enzymes [10]. Starch, a natural high molecular weight polysaccharide composed by glucose units, has received great attention as a carrier of matrix tablets, since it can be modified by a number of physical, chemical and enzymatic procedures, such as cross-linking [11], pre- gelatinization [12], retrogradation [13], complexation [14] and others, considering that native starch does not present suitable properties to reach desired drug release rates [12,13,15]. The retrogradation process of the starch, which occurs by hy- drothermal treatments, converts the pregelatinized starch (amor- phous) to a more resistant and compacted crystalline form [16,17], known as resistant starch (RS), which can exist in different mailto:dinizrecife@yahoo.com.br mailto:abagliottim@hotmail.com mailto:abagliottim@hotmail.com mailto:curybsf@fcfar.unesp.br mailto:raulrasec@yahoo.com.br mailto:raulrasec@yahoo.com.br http://crossmark.crossref.org/dialog/?doi=10.1016/j.jddst.2017.06.003&domain=pdf www.sciencedirect.com/science/journal/17732247 www.elsevier.com/locate/jddst http://dx.doi.org/10.1016/j.jddst.2017.06.003 http://dx.doi.org/10.1016/j.jddst.2017.06.003 http://dx.doi.org/10.1016/j.jddst.2017.06.003 A.C.D. Recife et al. / Journal of Drug Delivery Science and Technology 40 (2017) 83e9484 subtypes. RS-I is physically inaccessible to digestion by its entrap- ment in the matrix of grains, seeds and legumes, whereas RS-II corresponds to the non-gelatinized starch (native granular starch). RS-III is the retrograded starch and finally RS-IV is the chemically modified starch. However, advantages such as high thermal stability and low water solubility are attributed to the RS- III [13,18]. RS has been considered a promising material for the develop- ment of systems intended for colonic drug delivery, since such starch fraction is not absorbed in the stomach and the small in- testine, but is selectively degraded by the microbiota of the colon [19e21]. In this regard, the colon has been viewed as an important site for drug delivery due to reduced proteolytic activity, longer transit time, and pH values close to neutrality, being effective not only in the treatment of local pathologies, such as ulcerative colitis, Crohn's diseases, colon carcinomas and infections [22], but also in the treatment of systemic pathologies. Besides, the colon repre- sents an important site for oral administration of proteins [23,24]. The brush-border present in the colonic membrane and the high responsiveness of the mucosa make the colon a site with increased chances of drug absorption [25]. Recently, a great number of studies have shown that high amylose starch (HAS) e a hybrid variety of starch composed of amylose and amylopectin (70:30) [26] - is the more suitable ma- terial to obtain high levels of RS because the crystallites formed remain embedded in the amylose matrix and thereby they are protected from rapid exposure to digestive enzymes [16,27]. Pectin (P) is a natural polysaccharide composed mainly by homogalacturonans and rhamnogalacturonans residues, which correspond to linear and smooth fractions, respectively [28]. It has been used as excipient for targeting drugs to the colon, because when in contact with acid medium, it remains as macromolecular aggregates and due to its digestibility by colonic microbiota [29]. In our research group, the impact of the pectin addition onto release properties has been studied in different drug delivery systems, such as cross-linked HAS/P matrices loaded with nimesulide [30], mucoadhesive beads of gellan gum/P intended to the controlled release of ketoprofen [31], blends of cross-linkedHAS/P loaded with DS [11], free films of HAS/P mixtures cross-linked with sodium trimetaphosphate [32], colon-specific films coating based on RS/P [13], and more recently, RS/P free-standing films reinforced with nanocellulose to colon-specific release of methotrexate [33]. Based on promising results, the use of the RS and RS/P blend as an excipient to design hydrophilic matrix tablets was evaluated. Henceforth, HAS was retrograded by two different methods (through constant temperature and thermal cycles), in order to verify its impact on the RS yield and on the performance of tablets as a controlled release system. DS, a nonsteroidal anti- inflammatory drug (NSAID), was used as a model drug. The physi- cochemical (crystallinity, swelling and porosity) and thermal (TG/ DTG) properties of such retrograded materials were evaluated, as well as micromeritic properties (size distribution, density and flow). The performance of the materials as tablet excipient inten- ded to the control of drug release rates throughout gastrointestinal tract (GIT) was evaluated by in vitro tests in media with different pH values (1.2 and 7.4). 2. Materials and methods 2.1. Materials High amylose corn starch (Hylon VII type e 70% amylose, lot:HA9140) was obtained from National Starch & Chemical (New Jersey, USA), sodium hydroxide (lot: 611648) was supplied by Grupo Química (Rio de Janeiro, Brazil), 37% hydrochloric acid (lot: 29957) was provided by Quimis (Diadema, Brazil), diclofenac so- dium was purchased from Henrifarma (S~ao Paulo, Brazil), pectin (type LM-5206CS e DE < 50%, lot: S74431) was provided by CP Kelco (Copenhagen, Denmark), pancreatin (lot: 0903372) was purchased from Vetec (Duque de Caxias, Brazil), 3,5-dinitrosalicylic acid (purity � 98.0%, lot: 125k3664) was provided by Sigma- eAldrich Co. (St. Louis, USA), purified water (Milli Q, Millipore). 2.2. Methods 2.2.1. Retrogradation of high amylose starch (HAS) Aqueous dispersions of HAS at different concentrations (20 or 40%) were autoclaved at 121 �C (15 min) for starch gelatinization. The gelatinized starch (GS) was retrograded according to two different methods in order to assess the impact of the storage time and temperature in the material properties. InM1, the temperature was kept constant (4 �C) for 8 days (isothermal cycle) and in M2 it was employed alternating cycles of temperature (4 �C and 30 �C, 2 days at each temperature) for 16 days [34]. All samples were dried in a forced air circulation oven-drier at room temperature until constant weight. Retrograded samples were labeled as M120, M140, M220 and M240 respective to the method of retrogradation (M1 or M2) and concentration of polymers (20 or 40%). In this sense, the M220 sample was those obtained fromM2method and composed by 20% of polymer. 2.2.2. Enzymatic digestion and resistant starch content In order to eliminate RSI and RSII fractions, a known mass (100 mg) of HAS, M120, M140, M220 andM240 samples were mixed with 2 mL of phosphate buffer (0.1 mol/L; pH 7.1) and kept in water bath (100 �C) by 30 min [35]. After that, cooled samples were incubated in 0.5 mL of a pancreatin enzymatic solution (0.15 g/mL), at 37 �C for different times (20, 60, 120, 150 and 180 min). Ethanol (80%) was added to the samples for stopping the enzymatic activity. The glucose content provided by starch hydrolysis was quanti- fied by the reaction with 3.5-dinitrosalicylic acid (DNS) [36] based on the standard glucose. Both RDS (rapid digestible starch e digested at 20 min) and SDS (slowly digestible starch e digested between 20 and 120 min) were used to calculate RS content, ac- cording to Equation (1) [37]: RS ¼ ðTotal Starch� RDS� SDSÞ Total Starch � 100 (1) 2.2.3. Physicochemical characterization of samples 2.2.3.1. Moisture content. Moisture content of HAS, M120, M140, M220 andM240 samples was assessed gravimetrically on analytical infrared moisture balance (MettlerTM, PL 200/LP 11). A sufficient mass of samples (about 1 g) was uniformly disposed on themetallic pan of the balance and heated by infrared (105 �C) until constant weight was reached. The results were expressed as percentage of water loss in relation to the initial mass [38]. 2.2.3.2. X-ray diffraction (XRD) analysis. Crystallinity patterns of the GS, HAS, M120, M140, M220 and M240 samples were evaluated from their diffractograms recorded on a X-ray diffractometer (Siemens® e Model D5000; Germany), using nickel-filtered Cu Ka radiation (l ¼ 1.5406 Å) (tube operating at 40 kV and 30 mA). The scanning regions were collected from 4 to 70� (2q) in step size of 0.05� (2q). A.C.D. Recife et al. / Journal of Drug Delivery Science and Technology 40 (2017) 83e94 85 2.2.3.3. Thermogravimetric (TG) and derivative thermogravimetric (DTG) analysis. TG/DTG analysis of the GS, HAS, M120, M140, M220 andM240 samples were performed via a TA Instruments (SDT 600) (New Castle, DE, USA) at a heating rate of 10�C/min, from 25 to 600 �C, under nitrogen atmosphere (flow rate of 50 mL/min), in open cylindrical alumina pans containing about 5 mg of sample. 2.2.4. Micromeritic properties 2.2.4.1. Granulometric distribution. The particle size distribution analysis was performed using a set of test sieves (0.297; 0.250; 0.210; 0.177; 0.125 mm) attached to a sieve shaker (Haver & Bocker Model EML Digital Plus, Westfalen, Germany) operated by 20 min. The average particle diameter was calculated according Equation (2) [39]: davg ¼ X ðMO$Fr%Þ 100 (2) where davg is the arithmetic average diameter (mm); MO is the average of passage and retentionmesh opening (mm) and Fr% is the percentage of mass retained on each sieve. 2.2.4.2. Apparent bulk and tapped densities. The apparent bulk (db) and tapped (dt) densities were indirectly determined from the apparent and tapped volumemeasurements, respectively. A known mass (about 10 g) ofHAS,M120,M140,M220,M240 samples and the DS þ M120, DS þ M140, DS þ M220 and DS þ M240 physical mix- tures (PM) were introduced in a 25mL graduated cylinder glass and the bulk volume (Vb) was recorded. After this, to determine the tapped volume (Vt), the samples were submitted to cycles of 1250 taps in an automatic volumeter compactor (Volumeter Tapped, model SVM, ERWEKA, Heusenstamm, Germany) until the differ- ence between two consecutive measurements was lesser than 2%. The values of db and dt were calculated according to Equations (3) and (4): db ¼ m Vb (3) dt ¼ m Vt (4) where db ¼ bulk apparent density (g/mL); dt ¼ tapped apparent density; m ¼ mass (g); Vb ¼ apparent bulk volume (mL) and Vt ¼ apparent tapped volume (mL). 2.2.4.3. Analysis of flow ability. The angle of reposewas determined according to free base cone technique [40]. An accurately mass (20 g) ofHAS,M120,M140,M220,M240 samples and theDSþM120, DS þ M140, DS þ M220 and DS þ M240 physical mixtures (PM) was introduced in a stainless steel funnel (14 mm opening) coupled to a vibrating device. The orifice of the funnel was opened and the powder flowed onto a flat surface. The a angle was calculated by Equation (5): tan a ¼ h r (5) where h ¼ cone height (cm) and r ¼ base radius of cone (cm). 2.2.5. Porosity determination The porosity of the GS, HAS, M120, M140, M220 and M240 samples was evaluated on ASAP 2010 surface area analyzer (Micrometrics®), according to gas adsorption-desorption technique using N2 (T ¼ 77.35 K) as the adsorptive gas. Specific surface area, pore volume and pore size were calculated from isotherms of nitrogen adsorption/desorption by the BrunauereEmetteTeller (BET) method [41] over a relative pressure range of 0.05e0.25 on the adsorption branch. 2.2.6. Liquid uptake ability The determination of liquid uptake ability of samples was car- ried out on an Enslin's device [13,32,42,43]. About 0.05 g of samples were accurately weighed and carefully disposed on the sintered glass filter of funnel. The volume of different media (0.1 N HCl, pH 1.2; 0.1 mol/L phosphate buffer pH 7.4 and 6.8) absorbed by the samples was measured on the graduated pipette of the device at different times for 120 min and expressed as medium absorbed (%) in relation to initial mass of sample. The tests were performed in triplicate. Samples containing DS were also evaluated. 2.2.7. Preparation of tablets Tablets were produced by dry granulation of excipients, in which retrograded samples and control samples were compressed (single punch machine KORSHI AR 400 -Erweka®; 10 mm punch and die set), milled in a mortar and calibrated on a sieve (0.297 mm mesh opening). The granulated excipients (300 mg) were thor- oughly mixed with DS (100 mg) and compressed to producing tablets with a minimal hardness of 30 N. Tablets were labeled ac- cording to 2.2.1 section, however M prefix was replaced by the T prefix, resulting in T120, T140, T220 and T240 samples. For comparative analysis, tablets of retrograded starch/pectin (added RSP suffix) and retrograded starch and pectin physical mixture (added RSP-M suffix) were also evaluated. Retrograded starch/pectin materials were prepared according to procedure previously described by Meneguin et al. (2014). 2.2.8. Physical properties of tablets Forty tablets wereweighed on an analytical balance Owa Labor® and the mean and standard deviation was calculated [44]. Tablets hardness was determined using a durometer Schleuniger Phar- matron® ‒ 6D model (n ¼ 30). Thickness of 30 tablets was measured using an electronic micrometer (Mitutoyo MDC-M293, Tokyo, Japan) immediately after the compression and after 24 h. Friability was determined on Erweka® friabilator (TA 20 model) with 20 tablets accurately weighed and submitted to 100 revolu- tions. After rotations, tablets were carefully cleaned and weighed again. The mass loss during the test was calculated according Equation (6): Friabilityð%Þ ¼ Wi �Wf Wf � 100 (6) Where Wi ¼ initial tablet weight (g) and Wf ¼ final tablet weight (g). 2.2.9. In vitro dissolution study Dissolution tests of tablets were carried out using USP type II dissolution apparatus (paddle) in a Hanson Research (New Hanson SR-8 Plus) dissolution station, according to sink conditions. The systemwas kept at 37 ± 0.5 �C under 50 rpm rotation speed. Buffer solutions with different pH values were used (900 mL per vessel). At first, test was performed at HCl solution (0.1 N, pH 1.2) con- taining 1.5% of polysorbate 80 for 120 min, followed by step at phosphate buffer (0.1 mol/L, pH 7.4) for 240 min. Aliquots (5 mL) were collected at different times with replacement of equal volume medium. The amount of DS released from tablets (100 mg) was determined on a UV-VIS spectrophotometer (l ¼ 296 nm for acid medium and l ¼ 276 nm for phosphate buffer). The t80% (time required to release 80% of drug) was determined. Analysis were performed in triplicate. A.C.D. Recife et al. / Journal of Drug Delivery Science and Technology 40 (2017) 83e9486 2.2.9.1. Analysis of in vitro drug release mechanism. The analysis of mechanisms of drug release process was performed and dissolution data obtained in 2.2.9 section were fitted (SigmaPlot 10.0 software) to mathematical models like Korsmeyer-Peppas and Weibull. Mathematical models were fitted only until 60 and 63.2% of data, respectively. 2.2.10. Statistical analysis When applied, the results were treated by one-way analysis of variance (ANOVA) to assess the significance of the differences be- tween data. TukeyeKramer post-test was used to compare the means of different treatment data (GraphPad Prism 5 software). Results with p < 0.05 were considered statistically significant. 3. Results and discussion 3.1. Enzymatic digestion and resistant starch content The hampered digestibility of RS is due to the packing of amylose double helices, which reduces the access of a-amylase to glycosidic linkages [13,45]. The specific enzymatic digestion of RS in the colon assigns the retrograded samples as a promising material to the development of carriers that aim to target the drug to the colon [46,47]. The results of the resistance against enzymatic digestion of HAS, GS (40% HAS dispersion),M120,M140,M220 andM240 samples are presented in Table 1. It was found that the original RS content present in the HAS was 57.07%, however, the gelatinization process promoted its significant reduction, getting to levels of about 44%, since this process destroys the molecular order of the starch granule, making it more easily digested [48]. The amount of RS in M220 and M240 samples was improved (75.84e76.55%) and greater, in relation to those presented in M120 and M140 samples (72.30e73.85%). This raise in the RS content can be attributed to increased temperature (30 �C) and storage time (16 days) employed in M2, which allowed a higher mobility of poly- meric chains, promoting a more extensive structural rearrange- ment followed by the increasing of crystallinity. Furthermore, temperatures near to Tg (around 6 �C), favor the nucleation of crystals, while higher temperatures (30e40 �C) contribute for their propagation. So, when retrogradation is per- formed by using alternating thermal cycles, the crystallization rate is increased, and more perfect crystallites are built [34,49]. Park [34] also reported an increase of RS yield fromwaxymaize starch by retrogradation alternating thermal cycle against the isothermal cycle. The different polymeric concentrations (20 and 40%) employed may also have influenced on starch retrogradation, since samples prepared with 40% of HAS led to the highest amounts of RS (73.85%e76.55%), in contrast with samples at lowest concentration that yielded about 72.30%e75.84% of RS. There is a great number of chains to interact with each other when the amylose is in highest Table 1 Moisture content (%) of retrograded samples, surface area, volume and size of the pore a LDS: low digestible starch, RS: retrograded starch). Samples RDS (%) LDS (%) RS (%) Moisture conten HAS 18.48 ± 0.012 24.45 ± 0.025 57.07 ± 0.023 12.23 ± 0.321 GS 17.13 ± 0.014 38.07 ± 0.014 44.80 ± 0.003 e M120 10.58 ± 0.003 17.12 ± 0.018 72.30 ± 0.015 7.30 ± 0.100 M140 11.02 ± 0.003 15.12 ± 0.029 73.85 ± 0.026 7.06 ± 0.152 M220 10.40 ± 0.002 13.77 ± 0.013 75.84 ± 0.015 7.13 ± 0.057 M240 10.56 ± 0.015 12.90 ± 0.007 76.55 ± 0.022 7.00 ± 0.100 concentrations, promoting the great crystallization of the structure [50]. 3.2. Physicochemical characterization 3.2.1. Moisture content The moisture content can affect a set of physical and mechanical properties, and therefore contributing to decrease the apparent density of particles, affecting the compressibility, porosity, flow ability and the dissolution of tablets [51]. Furthermore, the mois- ture existent in the drug accelerates its hydrolysis as well as facil- itates the reactions to excipients and adjuvants [52]. According to Table 1, the moisture content of samples is within the limits for starch (from 10 to 14%) [53]. The slightly lower water content of M2 samples can be attributed to the alternated tem- peratures for starch retrogradation (4 �C and 30 �C), and higher time of retrogradation (16 days), which favor the evaporation of water. Moreover, the lower moisture of some materials is frequently associated to a higher structural crystallinity, since less hydroxyl groups will be available for interacting with water mol- ecules [54]. This relation can be confirmed by XRD patterns (3.2.2 section), in which the samples that had lower water content (M2 samples), also showed different crystallinity patterns indicated by the presence of an additional peak at 13� (2q). 3.2.2. X-ray diffraction measurements (XRD) HAS is a semi crystalline polymer and it presents different crystalline structures. The X-ray diffractogram of the HAS sample (HYLON VII) (Fig. 1) exhibited pronounced peaks at 17.02� and 23� (2q), which are characteristic of the B polymorph. The peak at 25� (2q) can be related to the A polymorphs [55]. The occurrence of peak at 19.8� (2q) indicates the occurrence of the V polymorph, suggesting a highly ordered crystalline structure of amylose-lipid complexes into starch granules [11,46,56]. XRD of HAS demon- strated that it consists of a heterogenic mix of B and V structures as previously reported by Shamai [57]. The GS diffractogram evidenced the disappearance of the main characteristic peaks of the HAS, showing a predominantly amor- phous pattern as the gelatinization process promotes the disrup- tion of starch granules, leading to disappearing of crystalline regions [58,59]. In theM120 andM140 diffractograms, peaks about 17�, 19.8� and 23� (2q) were maintained, which are related to the predominance of the B type (~17� and 23� (2q)) and the V type (19.8� (2q)) poly- morphs while the peak at 25� (2q) disappeared. In the XRD patterns of M220 and M240 the same peaks observed for M120 and M140 were preserved, but the peak around 13� (2q) was more intense, which is related to the V crystalline structure [57] and such change is indicative of the resistant starch presence. Cui [27] reported that the V type crystallinity reduces the water uptake of starch granules and make them more resistant to digestive enzymes. nd parameters obtained from enzymatic digestion test (RDS: rapid digestible starch, t (%) Surface area (BET) (m2/g) Pore volume (cm3/g) Pore size (Å) e e e No measurable No measurable No measurable 0.023 0.000246 28.185 0.206 0.000567 28.218 0.030 0.003504 28.345 1.098 0.000764 28.306 Fig. 1. X-ray diffraction patterns of the samples. A.C.D. Recife et al. / Journal of Drug Delivery Science and Technology 40 (2017) 83e94 87 3.2.3. Thermogravimetric (TG) and derivative thermogravimetric (DTG) analysis The TG/DTG curves of M120, M140, M220 and M240 samples displayed in Fig. 2 show a first degradation stage between 40 and 110 �C, which is related to the moisture evaporation during the heating, according to previous studies with other polysaccharides [33]. The second and main stage of degradation (69e75%) occurred between 250 and 350 �C and it was related to the elimination of polyhydroxyl groups, followed by the depolymerization and decomposition of the starch [60]. The GS showed 66% of mass loss and the principal degradation event occurred between 200 �C and 300 �C, while the degradation peak of the samples submitted to retrogradation process shifted to highest values, indicating that the process promoted the increase of thermal stability. Besides, this set of results evidences the lower thermal stability of the GS attributed to the granular structure loss due to the heating in water excess [61]. The preparation method and amylose concentration did not influence the thermal behavior, since no significant differences between the TG/DTG curves of M1 and M2 samples were observed. 3.3. Micromeritic properties 3.3.1. Granulometric distribution It was possible to observe a great similarity among granulo- metric distribution profiles ofM120, M140, M220 andM240 samples (Fig. 3), and the higher size frequency for all samples ranging be- tween 0.210 mm and 0.250 mm (about 26.15%). There was no dif- ference between the values of the mean diameter (about 0.19 mm) (p > 0.05). 3.3.2. Bulk and tapped apparent densities Bulk density and tapped density ofM120, M140, M220 andM240 samples and their physical mixtures (PM) with DS (Table 2) were statistically different (p < 0.05). Retrograded samples containing 20% of polymer showed lower density values than those prepared with 40% of polymer, indicating that the increase of the starch concentration promoted the building of denser particles, which should lead to better flow properties [62]. Furthermore, PM exhibited higher values of both bulk and tapped densities. This density raise can be related to the presence of the drug, which probably led to a higher number of interparticle contacts, making powder more packed and dense [30]. 3.3.3. Analysis of flow ability The values of repose angle of samples (Table 2) were similar (p > 0.05) and ranged between 20� and 30�, indicating their free flowing ability. On the other hand, the high value of repose angle of HAS (39.96�) demonstrated its poor flow. This behavior can be related to the lower moisture percentage of M120, M140, M220 and M240 (7e7.3%) in relation to HAS (12.23%) (Table 1). According to Albero [63], the decrease of flowability can be caused by the in- crease of the adhesion in existent points of contact between granules as a result of the water surface tension. 3.4. Porosity determination Porosity represents the total sum of void spaces in solid mate- rials in the form of pores, cracks and cavities of different sizes and shapes and it can influence important physical-chemical proper- ties, such as adsorptive properties, mechanical strength, dissolution and wettability [64]. According to Table 1, porosity values for GS were not measur- able. This fact can be associated to the starch heating in an aqueous medium that allows structural changes by the disruption of hydrogen bonds, which stabilize the granule internal crystal structure. Thus, an amorphous mass is formed, and therefore, it is not possible to observe the occurrence of pores, possibly because they are located in inaccessible regions for the adsorptive gas [65]. According to the results, it was observed that the surface area, the volume and size of these pores were affected mainly through the retrograded starch obtaining method, since samples prepared according M2 were more porous than those prepared by M1 (Table 1). This behavior can be related to the fact that the method that employed alternating cycles of temperature (M2) was Fig. 2. TG/DTG curves of GS, M120, M140, M220 and M240 samples. A.C.D. Recife et al. / Journal of Drug Delivery Science and Technology 40 (2017) 83e9488 responsible for the construction of more crystalline structures, as already evidenced in the X-rays diffraction analysis (3.2.2 section). Samples obtained with higher concentration of polymers (40%) also showed higher values of surface area in relation to the others (20%). In addition, such data are in agreement with the density data (Table 2), in which 20% samples exhibited lower density than 40% samples. Based on the IUPAC pore size classification, in which micropo- rous materials have pore diameters of less than 2 nm (20 Å), mesoporous materials between 2 nm and 50 nm (20 Å e 500 Å) and Fig. 3. Profile of granulometric distribution of the samples. Table 2 Values of bulk and tapped density and angle of repose. Samples Apparent bulk density (db) (g/mL) Apparent tapped density (dc) (g/mL) Angle of repose (�) M120 0.721 ± 0.011 0.768 ± 0.005 30.92 ± 0.60 M140 0.733 ± 0.006 0.793 ± 0.011 30.58 ± 0.60 M220 0.725 ± 0.022 0.775 ± 0.013 30.35 ± 0.67 M240 0.738 ± 0.002 0.795 ± 0.002 30.69 ± 0.41 PM (DS þ M120) 0.769 ± 0.006 0.813 ± 0.007 29.99 ± 0.42 PM (DS þ M140) 0.788 ± 0.012 0.865 ± 0.019 29.03 ± 0.64 PM (DS þ M220) 0.776 ± 0.008 0.829 ± 0.013 29.74 ± 0.65 PM (DS þ M240) 0.785 ± 0.014 0.864 ± 0.012 29.38 ± 0.67 HAS 0.504 ± 0.003 0.590 ± 0.014 39.96 ± 0.04 A.C.D. Recife et al. / Journal of Drug Delivery Science and Technology 40 (2017) 83e94 89 macroporous materials have a pore diameters greater than 50 nm (500 Å) [66], all samples of this study have predominantly meso- porous structures. 3.5. Liquid uptake ability The drug release rate from swellable matrices is controlled by three sequential events: water absorption, matrix swelling and drug diffusion throughout gel layer, and it can be influenced by ionic strength and/or dissolution medium pH [67,68]. All samples had a pH-responsive behavior (Fig. 4) with lower liquid uptake in acid medium (pH 1.2) than at pH 7.4, which is an inherent behavior of anionic polymers. In acid medium, the hy- drophilicity is lower because the carboxyl groups remain in their protonated form, causing a strong entanglement of the polymeric chains, and thus reducing the water entrance and retention [69]. Fig. 4. Liquid uptake (%) of samples at equilibrium (120 min) in different media. A.C.D. Recife et al. / Journal of Drug Delivery Science and Technology 40 (2017) 83e9490 Otherwise, the increase of pH values promotes the ionization of carboxyl groups and the consequent repulsion of chains with network dilation, which favors the water entrance [70]. M120, M140, M220 and M240 samples had a low water uptake compared to HAS due to changes in the crystallinity as a result of the starch retrogradation by the action of mechanical and thermal energy [71,72]. In fact, the presence of another polymorph, indi- cated by the appearance of a new peak in the DRX studies (3.2.2 section), may have resulted in different chain arrangements, with lower probability of hydroxyl groups interacting with water mol- ecules [54], lowering the water uptake. 3.6. Physical properties of tablets The physical parameters values of the tablets' quality (Table 3) showed low weight variation (0.5e0.75%) on them, demonstrating that suitable flow properties of granules allowed the uniform filling of the die and punch set. All tablets showed hardness greater than 30 N and friability lower than 1.0%, indicating that the tablets have suitable mechan- ical strength and are resistant to breakage during packing, shipping and handling of the product [44]. After 24 h of obtaining the tablets, there was no significant in- crease in thickness (Table 3) (p > 0.05), indicating that the material did not undergo significant elastic recovery after compression. 3.7. In vitro drug release profile There are several factors that can influence the kinetics of the drug release. Among them are drug properties as polymorphic Table 3 Physical properties of the tablets. Samples Thickness T0 (mm) T24h(mm) A T120% 3.990 ± 0.162 4.081 ± 0.154 3 T140% 4.047 ± 0.100 4.053 ± 0.106 4 T220% 3.857 ± 0.150 3.940 ± 0.154 3 T240% 4.002 ± 0.051 4.324 ± 0.063 4 form, crystallinity, particle size, solubility and the amount of drug incorporated into the dosage form. Physical properties of polymers, such as composition, molecular weight, crosslinking density and porosity also are decisive in the control of release rates [73]. When the hydrophilic matrix is in contact with GIT fluids, the surface hydration leads to a liquid uptake and to the formation of a swollen layer, which represents a physical barrier against the drug diffusion and controls the drug release rates [74]. DS, a nonsteroidal benzeneacetic acid derivative, belonging to BSC class II drug, has weak acidic properties (pKa ~4) and pH- dependent solubility, being practically insoluble in hydrochloric acid pH 1.2 (BARTOLOMEI et al., 2006; MERCK INDEX, 2006). DS release profiles from tablets with a different composition are pre- sented in Fig. 5, which demonstrates that drug release rates in acid medium (0.1 N HCl; pH 1.2) were always lower than those shown in phosphate buffer (pH 7.4). This pH-dependent behavior is in agreement with the liquid uptake data, which increased with the change of medium pH of 1.2e7.4. Besides, at acid pH, DS is in the protonated form, and therefore, has lower release rates. In acid medium (0.1 HCl; pH 1.2), the DS release from T120, T140, T220, and T240 started only after 15 min of test, and after 120 min, 42% of drug was released. Unlike, the HAS tablet started the release after 5 min and reached 49.4% after 120 min. Although HAS also gelatinizes and possesses the V polymorph, which is characteristic of a highly ordered crystalline structure, it is believed that the higher control of the release rates from retro- graded samples is a result of the changes in the crystallinity pat- terns. Such modifications are caused by the retrogradation process, as the formation of resistant starch in the shape of small crystallites, for example, that can fill the void spaces of the polymeric network, verage weight (mg) Hardness (N) Friability (%) 98 ± 0.003 36 ± 0.585 0.8487 ± 0.023 03 ± 0.005 38 ± 0.445 0.8833 ± 0.194 99 ± 0.004 34 ± 0.659 0.8436 ± 0.145 01 ± 0.003 37 ± 0.503 0.8124 ± 15.95 Fig. 5. In vitro drug release profiles in hydrochloric acid (0.1 N; pH 1.2) and phosphate buffer (0.1 M; pH 7.4). A.C.D. Recife et al. / Journal of Drug Delivery Science and Technology 40 (2017) 83e94 91 difficulting the entrance of water and subsequent diffusion of drug molecules. Furthermore, these retrograded samples showed infe- rior liquid uptake in relation to the HAS, so polymeric chains should be in a more entangled state with a more viscous gel layer, hampering the diffusion of drug molecules for the dissolution medium. However, a highest delay in the DS release was observed for samples obtained with pectin addition (RSP and RSP-M), as the Table 4 Release coefficients for DS in acid media (pH 1.2) and in phosphate buffer (pH 7.4) fitted with mathematical models. Release models 0.1 N Hydrochloric acid (pH 1.2) SAMPLES T120 T140 T220 T240 HAS RSP RSP-M T120 T140 T220 T240 T120 T140 T220 T240 Weibull k 43.1700 41.6204 42.5241 41.3635 11.1942 271.5325 152.1325 37.4176 51.7832 34.4121 31.5525 35.9721 32.8621 r2 0.9985 0.9999 0.9995 0.9986 0.9699 0.9998 0.9958 0.9996 0.9983 0.97514 0.9823 0.9844 0.9895 b 1.2191 1.1863 1.3353 1.3944 0.2354 0.5095 0.5519 0.8531 0.7215 1.2282 1.6252 1.4163 1.2914 Phosphate Buffer (pH 7.4) Korsmeyer-Peppas k 0.3147 1.7192 0.2580 0.1583 e 0.1500 0.2347 0.1293 0.5041 e e e e r2 0.9990 0.9990 0.9998 0.9996 e 0.9985 0.9972 0.9899 0.9987 e e e e n 1.7051 1.9202 1.8084 1.9811 e 1.4110 1.2300 1.5030 1.7470 e e e e Weibull k e e e e 204.532 e e e e 49.8502 65.380 23.980 19.097 r2 e e e e 0.9974 e e e e 0.9937 0.9994 0.9943 0.9904 b e e e e 0.2770 e e e e 1.2130 1.1340 1.2780 1.2470 A.C.D. Recife et al. / Journal of Drug Delivery Science and Technology 40 (2017) 83e9492 release started only after 30min of test. Moreover, it was verified an important reduction of release rates (~35% from RSP, 30% from RSP- M and 25% from T140RSP-M) after 120 min. This behavior was attributed to the pectin presence, which forms insoluble aggregates in acid medium [75] and allows the building of a swollen layer that controls the release rates [76]. The increase of pH from 1.2 to 7.4 probably caused an expansion of the polymeric network due to the ionization of carboxylate groups, contributing to the drug diffusion and to increase of the release rates [31]. The ionization of DS in increased pH (pka ~4) also contributes to enhance the drug release rates, favoring the disso- lution process. So, the DS release from T120, T140, T220 and T240 samples reached 100% in 60 min, against 87% in 120 min from HAS tablets, fact that was attributed to the formation of a more cohesive gelled matrix [62]. Drug release of RSP and RSP-M was significantly sustained to 240 min. The analysis time for reaching 80% of the drug release (t80%) in 0.1 M phosphate buffer (pH 7.4) shows that RSP-M samples allowed control for a longer time (t80% ¼ 210 min) than RSP (t80%¼ 150 min). This behavioral difference was assigned to conditions of retrogra- dation process for RSP, possibly leading to changes in pectin prop- erties, and therefore, resulting in the viscosity reduction of the gel layer formed during the dissolution process. 3.8. Analysis of in vitro drug release mechanisms Based on the values of adjusted r2 (Table 4), it can be noted that in acid medium all samples fitted better with the Weibull model, wherein for samples obtained by M1 and M2 methods and RSP-M samples a complex mechanism of release (b ¼ 1.186e1.625), involving simultaneously the relaxation of the polymer chains and erosion of the polymer during the release of the drug was observed. However, for HAS tablets in acid and phosphate buffer, the DS release occurred by Fickian diffusion (b ¼ 0.2354; b ¼ 0.2770, respectively), while for the RSP in acid medium the release was reported according to the anomalous Fickian transport (b ¼ 0.5095 to 0.8531), i.e., depending on the processes of diffusion and poly- mer relaxation. In phosphate buffer (pH 7.4), M1, M2 and RSP samples fitted better to the Korsmeyer-Peppas. This change of drug release mechanism was considered consistent as these samples also showed pH-dependent swelling and release behavior. A complex mechanism classified as super case II transport (n ¼ 1.230e1.981) was observed, which implies a high rate of medium permeation through the matrix, enhancing the erosion process of system [77]. For RSP-M, the pH change from 1.2 to 7.4 did not lead to changes in the release mechanism. 4. Conclusions The previously exploited methods for retrogradation of HAS were efficient, as they have provided materials with high RS con- tents, increased resistance to enzymatic digestion and suitable micromeritic properties. However, the structural changes pro- moted by different retrogradation processes did not significantly affect the release properties. Thus, similar DS release profiles exhibited by both RS from M1 and M2 evidenced that M1 repre- sents a simpler and shorter process that should lead to the reduc- tion of production costs. The RS blending with pectin allows the drug release for a longer time, so that different drug release fea- tures can be reached, according to different therapeutic needs, making the applicability of these materials in the development of several controlled drug delivery systems possible. Declaration of conflicts of interest The authors report no declarations of interest. 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Introduction 2. Materials and methods 2.1. Materials 2.2. Methods 2.2.1. Retrogradation of high amylose starch (HAS) 2.2.2. Enzymatic digestion and resistant starch content 2.2.3. Physicochemical characterization of samples 2.2.3.1. Moisture content 2.2.3.2. X-ray diffraction (XRD) analysis 2.2.3.3. Thermogravimetric (TG) and derivative thermogravimetric (DTG) analysis 2.2.4. Micromeritic properties 2.2.4.1. Granulometric distribution 2.2.4.2. Apparent bulk and tapped densities 2.2.4.3. Analysis of flow ability 2.2.5. Porosity determination 2.2.6. Liquid uptake ability 2.2.7. Preparation of tablets 2.2.8. Physical properties of tablets 2.2.9. In vitro dissolution study 2.2.9.1. Analysis of in vitro drug release mechanism 2.2.10. Statistical analysis 3. Results and discussion 3.1. Enzymatic digestion and resistant starch content 3.2. Physicochemical characterization 3.2.1. Moisture content 3.2.2. X-ray diffraction measurements (XRD) 3.2.3. Thermogravimetric (TG) and derivative thermogravimetric (DTG) analysis 3.3. Micromeritic properties 3.3.1. Granulometric distribution 3.3.2. Bulk and tapped apparent densities 3.3.3. Analysis of flow ability 3.4. Porosity determination 3.5. Liquid uptake ability 3.6. Physical properties of tablets 3.7. In vitro drug release profile 3.8. Analysis of in vitro drug release mechanisms 4. Conclusions Declaration of conflicts of interest Acknowledgements References