DSpace at VNU: An investigation of effects of modification processes on physical properties and mechanism of drug release for sustaining drug release from modified rice

DSpace at VNU: An investigation of effects of modification processes on physical properties and mechanism of drug releas...

Ờ Å ỊÙ× Ư Ờ An investigation of effects of modification processes on physical properties and mechanism of drug release for sustaining drug release from modified rice Vuong Duy Ngo, Thinh Duc Luu, Toi Van Vo, Van-Thanh Tran, Wei Duan, Phuong Ha-Lien Tran, Thao Truong-Dinh Tran PII: DOI: Reference: S0928-4931(16)30412-X doi: 10.1016/j.msec.2016.04.098 MSC 6478 To appear in: Materials Science & Engineering C Received date: Revised date: Accepted date: 28 December 2015 15 April 2016 29 April 2016 Please cite this article as: Vuong Duy Ngo, Thinh Duc Luu, Toi Van Vo, Van-Thanh Tran, Wei Duan, Phuong Ha-Lien Tran, Thao Truong-Dinh Tran, An investigation of effects of modification processes on physical properties and mechanism of drug release for sustaining drug release from modified rice, Materials Science & Engineering C (2016), doi: 10.1016/j.msec.2016.04.098 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 ACCEPTED MANUSCRIPT An investigation of effects of modification processes on physical properties and mechanism of drug release for sustaining drug release from modified rice IP T Vuong Duy Ngo1, Thinh Duc Luu1, Toi Van Vo1, Van-Thanh Tran3, Wei Duan2, Phuong HaLien Tran2,* and Thao Truong-Dinh Tran1,* SC R Pharmaceutical Engineering Laboratory, Biomedical Engineering Department, International University, Vietnam National University – Ho Chi Minh City, Vietnam School of Medicine, Deakin University, Pigdons Road, Waurn Ponds, Victoria, Australia Faculty of pharmacy, University of medicine and pharmacy, Ho Chi Minh City AC CE P TE D MA NU *Correspondence to: Thao Truong-Dinh Tran (ttdthao@hcmiu.edu.vn) Phuong Ha-Lien Tran (phuong.tran1@deakin.edu.au) ACCEPTED MANUSCRIPT Abstract The aim of this study was to investigate the effect of modification processes on T physical properties and explain the mechanism of sustained drug release from modified rice IP (MR) Various types of Vietnamese rice were introduced in the study as the matrices of SC R sustained release dosage form Rice was thermally modified in water for a determined temperature at different times with a simple process Then tablets containing MR and isradipine, the model drug, were prepared to investigate the capability of sustained drug NU release Scanning electron microscopy (SEM) was used to determine different morphologies MA between MR formulations Flow property of MR was analyzed by Hausner ratio and Carr’s indices The dissolution rate and swelling/erosion behaviors of tablets were evaluated at pH 1.2 and pH 6.8 at 37 ± 0.5°C The matrix tablet containing MR showed a sustained release as TE D compared to the control The SEM analyses and swelling/erosion studies indicated that the morphology as well as swelling/erosion rate of MR were modulated by modification time, CE P drying method and incubation It was found that the modification process was crucial because it could highly affect the granule morphologies and hence, leading to the change of AC flowability and swelling/erosion capacity for sustained release of drug Keywords: modified rice, flow property, sustained release, morphology, incubation ACCEPTED MANUSCRIPT Introduction Hydrophilic polymer matrices have been widely used in formulations of sustained T release (SR) systems to achieve slow release of drug over an extended period of time [1-4] IP due to low cost, ease of manufacture and relative independence of the physicochemical SC R and physiological conditions of the gastrointestinal tract [5, 6] Generally, the hydrophilic polymer hydrates when it exposes to dissolution medium to form the gel layer as the barrier controlling drug release Hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose NU (HPC), hydroxyethyl cellulose (HEC), xanthan gum, sodium alginate, poly (ethylene used as hydrophilic matrices [7-11] MA oxide) and crosslinked homopolymers and copolymers of acrylic acid are commonly D Rice has been widely used in food industry and direct food use [12] Despite TE promising characteristics of a safe material with starch component adding up to almost 90% of milled rice [13], its application in pharmaceutical industry is still limited Recently, starch CE P has been considered as a promising biomaterial in pharmaceutical industry due to the unique physicochemical and functional characteristics [14-16] Native starches have been well AC explored as binders and disintegrants in solid dosage forms; however, the utilization is restricted due to poor flowability Meanwhile, modified starches have been investigated for applications of sustained release agents as hydrophilic matrices [17-21] in drug delivery systems Starch-based biodegradable polymers used in preparation of microspheres or hydrogels have been studied for drug delivery [22, 23] Starch like rice starch could be modified by chemical, physical or enzymatic methods to have distinctive properties Mechanism of drug release from modified rice matrices would be a result of the passage of drug molecules controlled by the matrix structure and gel layer formation The granular structure and swelling ability in cold water of native starches have been investigated by physical modifications such as extrusion, drum-drying and a controlled ACCEPTED MANUSCRIPT pregelatinization-spray-drying [17] However, few studies have investigated thermal modification on physical properties and changes of drug release mechanism from modified T rice in details so far The study introduced various types of Vietnamese rice as possible IP carriers for sustained release of drug in a simple process with common apparatuses The SC R potential rice was selected for further use in investigation of effects of modifying time, incubation method, and drying method on the flow property, granule morphology, swelling and erosion capacity of modified rice-based tablets Hence, dissolution profiles of tablets, NU analysis of flowability, SEM images as well as swelling and erosion studies were carried out MA in the study TE D Materials and Methods 2.1 Materials CE P Various types of Vietnamese rice which were harvested and packed in the same year (2014) were introduced in the study: Nep Bac (NB) from Xuan Hong company (Viet Nam), AC Nep Thom (NT) from Gentraco Corporation (Viet Nam), Vua Lieu (VL) from ITA Fragrant Rice Research & Export Corporation (Viet Nam), Hoa Vang (HV) from Ngoc Hoan company (Viet Nam) Rice packages were stored at room temperature (25 °C) for study Microcrystalline cellulose (Avicel® PH 102) was purchased from Brenntag Group (Germany) Magnesium stearate (MgS) was purchased from Nitika Pharmaceutical Specialities Pvt Ltd (India) Hydrochloric acid (HCl) and Sodium chloride (NaCl) were purchased from Xilong Chemical Industry Incorporated Company (China) Hydroxypropyl methyl cellulose 4000 (HPMC) was provided by Dow Chemical Company (USA) Polyethylene glycol (PEG) was purchased from Sino-Japan chemical (Taiwan) Methanol (MeOH) was purchased from Fisher Scientific International, Inc (US) Monopotassium ACCEPTED MANUSCRIPT phosphate (KH2PO4) was purchased from Wako Pure Chemical Industries (Japan) Aerosil® 200 was from Jebsen & Jessen Chemicals Holding Pte Ltd (Singapore) Mannitol (Pearlitol®) T was purchased from Roquette Pharma Company, France SC R IP 2.2 Methods 2.2.1 Modification of rice Four varieties of glutinous rice were milled and sieved by 500 μm sieve Then, 15 g of NU each type of glutinous rice was dispersed in 150 mL of distilled water and incubated at 90 °C for h The swelling rice was then heated in an oven at 120 °C with different times The MA mucilage was dried in the oven at 60 °C or freeze-dried at –52 °C The modified rice (MR) was finally passed through 500 μm sieve The detailed conditions for MR were described in D the Table CE P TE Table Method of rice-based tablet formulations Incubation time (h) Type of rice Drying method Code 120 NT Oven at 60 °C NT h F2 120 NB Oven at 60 °C NB h F3 120 HV Oven at 60 °C HV h F4 120 VL Oven at 60 °C VL h F5 120 10 NT Oven at 60 °C NT 10 h F6 120 12 NT Oven at 60 °C NT 12 h NT Freeze-drying at - 52 °C NT h freezedrying F1 F7 AC Modifying time (h) Formulation Modified Temperature (oC) 120 ACCEPTED MANUSCRIPT 120 10 NT F9 120 12 NT Freeze-drying at - 52 °C F10 120 NT Oven at 60 °C NT 10 h freezedrying NT 12 h freezedrying NT h without incubation SC R 2.2.2 Preparation of prolonged release tablet IP T F8 Freeze-drying at - 52 °C Solid dispersion of isradipine was prepared by melting method Briefly, mixture of NU polymer (PEG:HPMC=1:1) and drug at the ratio 8:1 was melted at 160 oC Drug was dispersed in the melted polymer Aerosil® 200 was used as a sorbent of solid dispersion MA (Aerosil® 200: solid dispersion = 1:3) The resultant mixture was passed through a 500 μm sieve and thoroughly mixed with MR and mannitol Finally, MgS was blended with the above D mixture which was then compressed into tablets of diameter 8mm using a single punch-press TE machine (TDP 1.5, China) Hardness of the tablets was controlled at 30 ± N Each 150 mg mg MgS CE P tablet contained 60 mg solid dispersion of isradipine, 20 mg MR, 68.5 mg mannitol and 1.5 2.2.3 Dissolution studies AC The tablets were introduced to an in vitro dissolution test at 37 ± 0.5 °C using type II apparatus dissolution tester (DT70 Pharmatest, Germany) at 50 rpm To evaluate capability of sustained drug release, each dissolution vessel contained 750 ml of 0.1N hydrochloric acid (pH 1.2) for h and then the pH of the medium was adjusted to pH 6.8 by adding 250 mL of 0.2 M sodium phosphate solution, preheated to 37 °C (2 M hydrochloric acid or M sodium hydroxide was used for minor pH adjustment) [24] 1ml of sample was collected from the media at 1, 2, 6, 10, 14, 18, and 24 h 100 µl sample solutions were diluted for HPLC test 2.2.4 High performance liquid chromatography (HPLC) analysis ACCEPTED MANUSCRIPT The quantification of isradipine was performed using Ultimate 3000 HPMC Thermoscientific Inc., USA The mobile phase contained Methanol: Water: Acetonitrile T mixture at the ratio 46 %, 20 % and 34 %, respectively with a flow rate of 1.00 ml/min and IP the running time was The UV/VIS detector was set at a wavelength of 325 nm 20 µL SC R of sample was injected to HPLC system 2.2.5 Flow property test The Carr’s compressibility index and the Hausner ratio were calculated to provide a NU measure of the flow properties and compressibility of MR powders However, firstly bulk MA and tap densities of MRs were determined before and after 1250 taps, respectively, using the tap density tester (SVM, ERWEKA GmbH, Germany) (1) bulk density (tapped density−bulk density) CE P Carr index = tapped density TE Hausner ratio = D The Hausner ratio and Carr’s index was determined as follows: tapped density X 100 (2) AC 2.2.6 Scanning Electron Microscopy (SEM) Samples were stuck onto conductive carbon adhesive tape The morphology was then examined under the scanning electron microscope (Hitachi’s S-4800 FE-SEM, Japan) 2.2.7 Swelling and erosion studies The rate of MR swelling was determined by equilibrium weight gain method [25] Tablets were accurately weighed (W0) and put in sinkers to conduct the swelling test using the USP II apparatus (50 rpm, 37 °C, and a 900 mL dissolution medium of buffer pH 1.2 and buffer pH 6.8) with a dissolution tester (DT70 Pharmatest, Germany) Sinkers of tablets were carefully removed from the media after 1, and h and the tablets were lightly blotted with ACCEPTED MANUSCRIPT tissue paper to remove excess surface water and then reweighed (Wt) The percent water uptake or swelling rate due to absorbed liquid was estimated at each time point using Eq (3): Matrix swelling (%) = (Wt−W0)/W0 x 100 (3) IP T Wt: weight at time t (1 h, h, h) SC R W0: initial weight Matrix erosion study was performed by a method of Roy and Rohera [26] After the swelling study, the wet samples were then dried in an oven until the samples were completely MA erosion at time t was estimated from Eq (4) NU dried and finally weighed until a constant weight was achieved (Wd) The percentage matrix Matrix erosion (%) = (W0−Wd)/W0 x 100 D W0: initial weight (4) CE P TE Wd: weight after drying Results and discussion 3.1 Dissolution studies AC 3.1.1 Effect of types of rice The drug release behaviors depend on type of the matrix, capability of swelling, diffusion and erosion process [27] Hydrophilic polymers are commonly used to control release of drug due to their capability of swelling in the presence of water and forming a gellike substance To compare effect of types of rice on dissolution rates, the samples (NT, NB, VL, HV) were prepared under the following conditions: incubating at 90 ºC for h, heating at 120 ºC for h, and then drying in an oven (F1, F2, F3, F4) The NT tablets showed more sustained release rates than NB, VL and HV tablets (Figure 1) Specifically, after h the drug dissolution release of NT, NB and VL tablets were 24.6 %, 26.45 % and 28.4 %, respectively, while the dissolution rate of HV tablets was 35.3 % After h, the dissolution ACCEPTED MANUSCRIPT rate of NT, NB and VL tablets was increased to about 30 % of drug released but the difference between these formulations was not significant; whereas, the dissolution profile of T HV tablets was still at the highest which was 50.0 % drug released After h, while the drug IP dissolution release of NB and VL tablets was enhanced to over 74.0 % similar to that of HV SC R tablets, the dissolution rate of NT tablet was at the lowest of 56.0 % drug released The release patterns of these tablets with the lowest dissolution rate of NT were also occured until 18 h, indicating that NT would be a potential rice to prolong the release of drug Physical NU modification of rice would lead to changes of granular structures and conversion of native MA rice into cold water-soluble rice or small-crystallite rice [28] Mechanism of drug release from such gel-forming matrices would elucidate those different release patterns Hence, NT TE D was selected for further studies CE P 120 80 60 AC Drug release (%) 100 40 NB h oven drying NT h oven drying VL h oven drying HV h oven drying 20 0 10 15 Time ( Hours ) 20 25 ACCEPTED MANUSCRIPT 120 T IP 80 60 SC R Drug Release (%) 100 40 NT h freeze drying NT h oven drying NT 12 h freeze drying NT 12 h oven drying NU 20 0 10 15 20 25 MA Time ( Hours ) Figure Effects of freeze-drying and oven drying on dissolution rate of tablets of NT TE D incubated at 90 ºC for h and heated at 120 ºC (n=3) CE P 3.1.3 Effect of incubation method To investigate the role of incubation for MR, the NT sample in water was directly heated at 120 ºC for h and dried in the oven This MR was compared with the sample which AC was prepared in the same condition except for the additional incubation step before heating the rice (F10 compared to F1) Figure shows the effect of incubation method in the modification process on the dissolution rate of tablets For incubation method, there was a sustained release after h, increasing from 28.6 % to 49.3 % in the range of time points from to h Then drug release was increased slowly at a constant rate during the next 18 h Meanwhile, from h to h, dissolution rate of the method without incubation was significantly enhanced, which was twofold enhancement from 38.6 % to 84.2 % These results proved that the incubation method is one of the most important steps in modification process for sustaining drug release 13 ACCEPTED MANUSCRIPT 120 IP SC R 80 60 40 NU Drug release (%) T 100 20 NT h incubated h/ 90 0C dried 60 0C NT h without incubated dried 60 0C MA 10 15 20 25 Time ( Hours ) dried in the oven (n=3) TE D Figure Effects of incubation method on dissolution rate of tablets of NT at 120 ºC and CE P 3.2 Flow properties and morphology of MR Bulk and tapped density of different formulations were measured Table shows the AC Hausner ratio and Carr index, parameters for the measurement of flow properties of powders If Carr index (CI) or Hausner ratio (HR) of a material is lower than that of another one, it indicates better flow properties A CI 1.60 is considered ‘very poor’ flow Meanwhile, other values express the scales as follows: intermediate scales for CI between 11–15 or HR between 1.12–1.18 is considered ‘good’ flow, CI between 16–20 or HR between 1.19–1.25 is considered ‘fair’ flow, CI between 21–25 or HR between 1.26–1.34 is considered passable flow, CI between 26–31 or HR between 1.35–1.45 is considered ‘poor’ flow, and CI between 32–37 or HR between 1.46–1.59 is considered ‘very poor’ flow [29] It was found that flow of F1, F2, F4, F5 and F10 were rated as “good”; whereas, F3, F6, F7, F8 and F9 were cohesive and ranged 14 ACCEPTED MANUSCRIPT from “passable flow” to “poor flow” Although the incubation method including the modifying process could retard the dissolution rate of drug, there was an insignificant change T of flow properties (F1 compared to F10) Also, the flow properties depended on the types of IP rice, for instance, F3 (HV) was passable while F1 (NT), F2 (NB) and F4 (VL) had good flow SC R Moreover, the increase of modifying time could reduce the flowability of MR, in which the increase of modifying time from h to 10 h still ensured a good flowability, while 12 h of the modifying time resulted in fair flowability More importantly, the oven-dried samples showed NU that drying using the oven was more suitable than freeze-drying method to have good powder Carr index (%) Comment 1.16 13.79 Good flow 1.13 11.50 Good flow F3 1.30 23.08 Passable flow F4 1.14 12.28 Good flow F5 1.13 11.50 Good flow F6 1.26 20.63 Fair flow F7 1.39 28.06 Poor flow F8 1.40 28.57 Poor flow F9 1.41 29.08 Poor flow F10 1.13 11.50 Good flow F1 AC F2 Hausner ratio CE P Formulation TE D Table Physical properties of MRs MA flowability 15 ACCEPTED MANUSCRIPT Furthermore, SEM micrographs of NT rice granules before and after modification T were used to explain the flowability of rice granules (Figure 6) Native NT rice showed a IP specific angular shape and rather uneven surface (Figure 6A) When comparing the two SC R methods, images of the MR from the oven drying method show cubic form (Figure 6B, Figure 6C and Figure 6F) Meanwhile, in the freeze-drying method, MR had large adhesive plaque form and numerous foam-like shapes were observed on surface of the samples NU (Figure 6D and Figure 6E) These results demonstrated that the good flowability of the MA samples dried in the oven was the consequence of preferable shape of the samples The comparison between images of the samples under oven drying time of h (Figure 6B and D Figure 6F) and 12h (Figure 6C) indicated that the longer modifying time, the more TE indentations on surface of the particles, leading to the worse flow properties of the samples Overall, these results suggested that modifying time and drying method generated the CE P morphology of granules which mainly contributed to the flowability of MR facilitating the AC tablet compression process 16 CE P TE D MA NU SC R IP T ACCEPTED MANUSCRIPT AC Figure SEM pictures with magnifications of 2000 of native NT rice (A); F1 (B); F6 (C); F7 (D); F9 (E); F10 ( F) 3.3 Swelling and erosion analyses Figure 7A shows effects of types of rice on swelling and erosion during dissolution process Tablets from NT rice with 8h of modifying time had the highest swelling rate, which could be related to its lower erosion compared to tablets of NB, VL and HV In details, at the time point of 1h, the swelling rate of NB, VL and HV tablets around 21.2-23.4 % while the swelling rate of NT tablets was 26.5 % At the time point of h, the swelling rate of tablets from NT, NB, VL and HV increased to 26.2-31.6 % However, after h, while the swelling rate of NB, VL and HV tablets were approximately 35 %, the swelling rate of NT tablets was significantly increased to 52.4 % In addition, Figure 7B shows the results of erosion studies 17 ACCEPTED MANUSCRIPT HV tablets got the highest erosion rate, while NT-modified tablets had the lowest erosion rate These results could be explained by the formation of a gel layer around the tablet under T swelling Therefore, various types of rice would have distinct capability of swelling and IP erosion by modification The highest rate of swelling and the lowest erosion rate of NT could SC R be attributed to the capability of this rice in prolonging drug release 60 NU A 50 MA Swelling (%) 40 30 D 20 CE P TE 10 NB h oven drying NT h oven drying VL h oven drying HV h oven drying Time ( Hours ) AC 18 B 16 14 Erosion (%) 12 10 NB h oven drying NT h oven drying VL h oven drying HV h oven drying 0 Time ( Hours ) Figure Effects of types of rice on swelling (A) and erosion (B) behaviors of tablets of NT incubated at 90 ºC for h, heated at 120 ºC for h and dried in the oven (n=3) 18 ACCEPTED MANUSCRIPT The modifying time was also investigated its effects on the swelling and erosion of MR After exposing in dissolution media for h, NT tablets which were modified for h, 10 T h and 12 h had a swelling rate at around 23.7-26.5 % (Figure 8A) However, after h, the IP swelling rate of NT sample with h of modifying time was significantly enhanced from 31.6 SC R % to 52.4 %, while the swelling rate of NT modified for 12 h suddenly declined from 28.7 % to 15.4 % This phenomenon was due to the faster erosion of NT with modification for 12 h (Figure 8B) On the other hand, the lowest erosion rate of NT was observed with 8h NU modification The increase of modifying time hence could decrease the swelling rate and MA increase the erosion, which led to the reduction in drug release Furthermore, these results were also explained by the fact that the increase of time in modification could increase D numerous depressions on the granule surface (Figure 6B and Figure 6C) which caused NT AC CE P TE modified for 12 h prone to erosion 19 ACCEPTED MANUSCRIPT 60 A T 50 IP SC R Swelling (%) 40 30 20 NU NT h oven drying NT 10 h oven drying NT 12 h oven drying 10 MA D Time ( Hours ) B CE P 10 AC Erosion (%) 15 TE 20 NT h oven drying NT 10 h oven drying NT 12 h oven drying 0 Time ( Hours ) Figure Effects of modifying time on swelling (A) and erosion (B) behaviors of tablets of NT incubated at 90 ºC for h, heated at 120 ºC and dried in the oven (n=3) In addition to modifying time, effects of drying method were also investigated through swelling and erosion studies Figure 9A shows that there were negligible differences between the swelling rate of NT h oven drying and NT h freeze-drying, while the 20 ACCEPTED MANUSCRIPT swelling rate between NT 12 h oven drying and NT 12 h freeze-drying had significant differences Specifically, from h to h, the swelling rate of NT h freeze drying and NT T h oven drying increased remarkably from 33.4 % to 56.5 % and 31.6 % to 52.4 %, IP respectively The swelling rate of NT 12 h freeze-drying slowly increased from 29.4 % to SC R 36.5 % (from h – h) However, the swelling rate of NT 12 h oven drying suddenly decreased from 28.7 % to 15.4 % Figure 9B illustrates the erosion rate of NT h, 12 h under oven drying method and NT h, 12 h under freeze-drying method There was insignificant NU difference in tablet erosion of MRs which were modified at h Meanwhile, the erosion rate MA between NT 12 h oven drying and NT 12 h freeze-drying had significant differences For instance, at the time point of h the erosion rate of NT h oven drying and NT h freeze- D drying were around 4.8-5.8 %; whereas, the erosion rate of NT 12 h using oven drying and TE NT 12 h freeze-drying were 8.1 % and 6.1 %, respectively After h, the erosion of NT h oven drying and NT h freeze-drying increased to 10.8 % and 11.7 %, correlatively CE P Nevertheless, the erosion rate of NT 12 h oven drying was 18.8 % different from 14 % of NT 12 h freeze-drying Therefore, as comparing the swelling and erosion rate between two AC drying methods with the modification time of 8h, there was not much significant difference On the other hand, when increasing the modification time to 12 h, the oven drying method strongly affected the swelling and erosion Oven drying caused lower swelling rate, leading to higher erosion of NT tablets Therefore, freeze-drying method had a minor effect on reduction of swelling rate as well as increment of erosion compared with oven drying, in general Effects of the swelling and erosion on morphology of the samples were discovered through SEM images in the previous section (Figure 6B, Figure 6C, Figure 6D and Figure 6E) The presence of numerous foams at the surface of the samples that resulted from freezedrying method could facilitate water absorption for swelling even when increasing modification time to 12 h 21 ACCEPTED MANUSCRIPT 70 A 60 IP 40 30 SC R Swelling (%) T NT h freeze drying NT h oven drying NT 12 h freeze drying NT 12 h oven drying 50 20 NU 10 0 7 MA Time ( Hours ) 25 D B TE NT h freeze drying NT h oven drying NT 12 h freeze drying NT 12 h oven drying CE P 15 10 AC Erosion (%) 20 0 Time ( Hours ) Figure Effects of drying method on swelling (A) and erosion (B) behaviors of tablets of NT incubated at 90 ºC for h and heated at 120 ºC (n=3) Finally, effects of the incubation method on swelling and erosion were investigated The swelling rate of NT h - incubation tablets which was incubated h before modification was 26.5 % at the time point of h and increased steadily over time (Figure 10A) From h 22 ACCEPTED MANUSCRIPT to h, the swelling rate of NT h - incubation tablets increased considerably from 31.6 % to 52.4 % On the other hand, at the time point of h, the swelling rate of NT h without T incubation was 21.8 % and decreased slowly from time to time Hence, the incubation could IP enhance the swelling of modified rice Additionally, Figure 10B indicates the erosion rate of SC R NT 8h-incubation lower than that of NT h without incubation Therefore, the incubated rice before modification not only could enhance the swelling but also decrease the erosion rate of MR These results could be explained thoroughly by morphology of the samples caused by NU modification processes Numerous depressions on the granule surface were observed with the MA samples under incubation as comparing to the surface of samples without incubation (Figure 6C and Figure 6F), resulting in the improvement of water absorption of MR for favorable D swelling However, the increase of modification time could lead to extensive depressions on AC CE P TE the granule surface which facilitated the MR erosion 23 ACCEPTED MANUSCRIPT 60 A IP T 50 SC R Swelling (%) 40 30 NU 20 10 MA NT h incubated h / 90 0C dried 60 0C NT h without incubated dried 60 0C 0 20 16 Erosion (%) AC 14 CE P B 18 TE D Time ( Hours ) 12 10 NT h incubated h / 90 0C dried 60 0C NT h without incubated dried 60 0C 0 Time ( Hours ) Figure 10 Effects of incubation method on swelling (A) and erosion (B) behaviors of tablets of NT at 120 ºC and dried in the oven (n=3) 24 ACCEPTED MANUSCRIPT Conclusions This study provides a potential approach to modify property of rice for prolonging the T release of drug by increasing the swelling rate Importantly, the study demonstrated that the IP modification process covering factors of time, drying method, incubation affected SC R morphology and flowability of MRs, leading to the direct influence of swelling and erosion of MR tablets on the controlled drug release Specifically, the higher modifying time the NU higher the drug release rate due to increment of erosion Freeze-drying method could decrease the erosion as well as increase the swelling rate Nevertheless, the poor flowability MA of the MR was observed with freeze-drying method as compared with the oven drying method The study also indicated the promising application of Vietnamese rice to the D pharmaceutical industry as a sustained release agent, providing that the materials are CE P Acknowledgements TE introduced into the modifying process with consideration of those important parameters This research is funded by International University, Vietnam National University – Ho Chi Minh City under grant number T2014-01-BME We also thank to Vietnam National AC University – Ho Chi Minh City for equipment support to our research activities Conflict of Interest The authors confirm that this article content has no conflicts of interest References [1] P van Aerde, J.P Remon, International Journal of Pharmaceutics 45 (1988) 145-152 [2] J.D Sarkar B, Agarwal A, Panwar A S, Asian Journal of Biomedical and Pharmaceutical Sciences (2011) 08-10 [3] T.K Giri, K Kumar, A Alexander, Ajazuddin, H Badwaik, D.K Tripathi, Bulletin of Faculty of 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swelling/erosion capacity for drug sustained release Freeze-drying could decrease the erosion as well as increase the swelling rate AC    27 ...ACCEPTED MANUSCRIPT An investigation of effects of modification processes on physical properties and mechanism of drug release for sustaining drug release from modified rice IP T Vuong Duy Ngo1,... potential rice to prolong the release of drug Physical NU modification of rice would lead to changes of granular structures and conversion of native MA rice into cold water-soluble rice or small-crystallite... ACCEPTED MANUSCRIPT pregelatinization-spray-drying [17] However, few studies have investigated thermal modification on physical properties and changes of drug release mechanism from modified T rice