DSpace at VNU: Development of a Sustained Release Solid Dispersion Using Swellable Polymer by Melting Method

Pharm Res DOI 10.1007/s11095-015-1767-2 RESEARCH PAPER Development of a Sustained Release Solid Dispersion Using Swellable Polymer by Melting Method Tuong Ngoc-Gia Nguyen & Phuong Ha-Lien Tran 1,2 & Toi Van Vo & Wei Duan & Thao Truong-Dinh Tran 1,3 Received: 19 February 2015 / Accepted: August 2015 # Springer Science+Business Media New York 2015 ABSTRACT Purpose This study is to design a sustained release solid dispersion using swellable polymer by melting method Methods Polyethylene glycol 6000 (PEG 6000) and hydroxypropyl methylcellulose 4000 (HPMC 4000) were used in solid dispersion for not only enhancing drug dissolution rate but also sustaining drug release HPMC 4000 is a common swellable polymer in matrix sustained release dosage form, but could not be used in preparation of solid dispersion by melting method However, the current study utilized the swelling capability of HPMC 4000 accompanied by the common carrier PEG 6000 in solid dispersion to accomplish the goal Results While PEG 6000 acted as a releasing stimulant carrier and provided an environment to facilitate the swelling of HPMC 4000, this swellable polymer could act as a ratecontrolling agent This greatly assisted the dissolution enhancement by changing the crystalline structure of drug to more amorphous form and creating a molecular interaction Conclusions These results suggested that this useful technique can be applied in designing a sustained release solid dispersion with many advantages Tuong Ngoc-Gia Nguyen and Phuong Ha-Lien Tran contributed equally to this work * Phuong Ha-Lien Tran phuong.tran1@deakin.edu.au * Thao Truong-Dinh Tran ttdthao@hcmiu.edu.vn Pharmaceutical Engineering Laboratory, Biomedical Engineering Department, International University, Vietnam National University, Ho Chi Minh City, Vietnam School of Medicine, Deakin University, Waurn Ponds, VIC, Australia Institute for Frontier Materials, Deakin University, Waurn Ponds, VIC, Australia KEY WORDS poorly water-soluble drug solid dispersion sustained release swellable polymer ABBREVIATIONS FTIR HPMC 4000 PEG 6000 PM PXRD SD SR Fourier transform infrared spectroscopy Hydroxypropyl methylcellulose 4000 Polyethylene glycol 6000 Physical mixture Powder X-ray diffraction Solid dispersion Sustained release INTRODUCTION Oral route is preferable in drug administration because of its convenience, patient compliance and production costs Poor bioavailability and low dissolution rate of drug due to poor absorption, rapid metabolism, and rapid systemic elimination are challenging issues for scientists Improving the water solubility of drugs is one of the current strategies in the pharmaceutical industry to overcome those issues (1) Sustained-release (SR) dosage forms were investigated to improve patient compliance through reduced multiple dosing regimens Moreover, these dosage forms could provide patients with reduced high total dose, a uniform and prolonged therapeutic effect in systemic circulation, and minimized side effects (2) In general, the most important issue of SR dosage forms is the work dealing with poorly water-soluble drugs because the limited property usually leads to its low bioavailability The incorporation of poorly water-soluble drugs into SR carriers using solid dispersion (SD) technique can solve the above issues by enhancement of dissolution rate, solubility, oral absorption of water insoluble drugs as well as sustaining drug release with appropriate polymers (3) Nguyen et al Advantages of polymers such as hydroxypropyl methycellulose and polyethylene oxide are hydrophilic and swellable properties which can be utilized in increasing dissolution rate (4–11) and modulating drug release profiles (12–16) The application of these two polymer properties in one system could facilitate the design of a dual function drug delivery system by preparation of SD for dissolution enhancement and compression of matrix tablets for sustained release (3,17) Regarding conventional SDs, there are still some disadvantages to deal with the preparation methods With respect to the solvent method, negative effects on the environment, residual of toxic solvent and high cost of production due to the extra facility for removal of solvents are shortcomings (9) On the other hand, for melting method, swellable polymers are usually not used as carriers of SD preparation mostly due to its high viscosity and undetermined melting point To overcome those drawbacks, in the current study we would explore the use of these polymers in SD with melting method by swelling hydroxypropyl methycellulose in polyethylene glycol 6000 to take a full advantage of for both increasing the drug solubility and sustained release of the system: (1) as a carrier in SD for enhanced dissolution of poorly watersoluble drugs and (2) as a polymer for a SR dosage form by compression of SD powder to form a matrix tablet MATERIALS AND METHODS Materials Sodium hydroxide (NaOH) was purchased from Guanghua Sci-Tech Company (China) Hydroxypropyl methyl cellulose (HPMC 4000) was provided by from Dow Chemical Company (USA) Polyethylene glycol (PEG 6000) was purchased from Sino-Japan chemical (Taiwan) Isradipine was purchased from Shanghai Richem International Company (China) Methanol (MeOH) and Acetonitrile was purchased from Fisher Scientific International, Inc (US) Hydrochloric acid (HCl) and Sodium chloride (NaCl) were purchased from Xilong Chemical Industry Incorporated Company (China) Monopotassium phosphate (KH2PO4) was purchased from Wako Pure Chemical Industries (Japan) Aerosil® 200 was obtained from Jebsen & Jessen Chemicals Holding Pte Ltd (Singapore) Mannitol (Pearlitol®) was purchased from Roquette Pharma Company, France Magnesium stearate was purchased from Nitika Pharmaceutical Specialities Pvt Ltd (India) Methods Preparation of Sustained Release Solid Dispersion PEG 6000 was melted at 160°C until a molten liquid appeared This temperature was maintained until addition of Aerosil® 200 HPMC 4000 was added into the beaker of melted PEG and stirred by a glass agitator for for the completed swelling Then, isradipine was dispersed in the molten mixture and stirred by a glass agitator for to obtain a transparent solution Next, Aerosil® 200 as a moisture absorbance co-efficient was applied to absorb the molten mixture The amount of Aerosil® 200 was selected based on the wetting state of SD as percentage of carriers changed The mixture was then sieved with a 0.5 mm sieve The obtained SDs were kept in a dry place, and protected from light until further use The detailed formulations were illustrated in Table I Preparation of Sustained Release Solid Dispersion Tablet The procedure was repeated as the one in section BPreparation of Sustained Release Solid Dispersion^ with the ratio 1:4:4 for isradipine, PEG 6000, and HPMC 4000, respectively However, a residual amount of HPMC 4000 was divided into parts Part was added after isradipine was dispersed in the molten mixture thoroughly Part was added into the blend with Aerosil® 200 to absorb water The mixture was sieved with a 0.5 mm sieve Mannitol was added into the mixture with an appropriate ratio to perform tablets adequately at a total weight of 150 mg (Table I) Magnesium stearate as a lubricant was added at the end (1% total mass of tablet) Single punch-press machine (TDP 1.5, China) with mm-diameter flat punch was used to prepare tablets with a hardness of around 35–40 N Dissolution Studies Dissolution test machine (DT70 Pharmatest, Germany) was used for the dissolution studies These SDs were conducted at 37±0.5°C on an USP specification dissolution test type II apparatus (Paddle apparatus) The apparatus was set up at 50 rpm of rotation speed For in vitro dissolution test, buffer pH 1.2 (900 ml) and buffer pH 6.8 (900 ml) were used as dissolution media ml of sample was collected at 10, 20, 30, 60, 90, and 120 and dissolution media were compensated by adding ml of the corresponding fresh buffer 100 μl sample solutions were diluted with 900 μl MeOH for HPLC test To evaluate sustained drug release capability, based on the previous research submitted by Ching, A.L et al (18), each of 750 ml of pH 1.2 was added into dissolution vessel for h and then 250 ml of 0.2 M sodium phosphate solution (reheated to 37°C) was added to the medium for adjusting to pH 6.8 M HCl solution (or M NaOH solution) was used for minor adjustment of the pH of dissolution media ml of sample was collected at 1, 2, 6, 10, 14, 18, and 24 h Swellable polymer by melting method Table I Formulation Compositions of SD Powder (from F1 to F5) and Sustained Release Solid Dispersion Tablet (F6, F7, F8) Formulation IS (mg) PEG 6000 (mg) HPMC 4000 (mg) Aerosil (mg) Mannitol (mg) Magnesium stearate (mg) Ratio Total (mg) Comments F1 10 – 10 – – 1:2 25 SD granule F2 20 – 15 – – 1:4 40 SD granule F3 F4 5 10 20 10 10 15 – – – – 1:2:1 1:4:2 30 50 SD granule SD granule F5 F6 5 20 20 20 20 15 15 – 88.5 – 1.5 1:4:4 1:4:4 60 150 SD granule Tablet F7 20 30 15 78.5 1.5 1:4:6 150 Tablet F8 20 40 15 68.5 1.5 1:4:8 150 Tablet HPLC Analysis The quantification of isradipine was performed using an Ultimate 3000 HPLC Thermoscientific Inc., USA The mobile phase consisted of methanol: water: acetonitrile mixture ratio was 7:3:5 with a flow rate of ml/min and the running time was around The UV/VIS detector was set to a wavelength of 325 nm 20 μL of sample was injected to the HPLC system Characterization by Powder X-ray Diffraction (PXRD) In this study, pure isradipine, PEG 6000, HPMC 4000, physical mixture (PM), and SD samples were analyzed by PXRD Diffraction patterns were recorded using a Powder X-ray diffractometer (BRUKER’ D8 Advance Series PXRD, Germany) using Ni-filtered, CuKα (λ=1.54060 Å) radiation at 40 kV and 40 mA Samples were held on quartz frame Drug sample was scanned in a 2θ range from to 50° with a receiving slit 0.1 mm Characterization by Fourier Transform Infrared Spectroscopy (FTIR) The physicochemical properties of pure isradipine, PEG 6000, HPMC 4000, PM, and SD samples were characterized by using Spectrotometer (Bruker’s Vertex 79 series FT-IR, Germany) KBr were prepared by mixing mg of samples with 200 mg KBr The wavelength was from 500 to 4000 cm−1 and the resolution was cm−1 RESULTS AND DISCUSSION Dissolution Studies of SDs The aim of this study was to investigate a new method not only to increase dissolution rate but also to sustain drug release by coordinating a poorly water-soluble drug with a swellable polymer in PEG 6000-based SD When pure isradipine was sprinkled in water, the powder floated on the surface of the medium and prevented surface powder from contacting with the medium, resulting in poor solubility and low dissolution rate As expected, the presence of PEG 6000 increased drug dissolution directly proportional to PEG 6000 concentration in the formulation The interfacial tension between hydrophobic drug and dissolution medium was reduced by PEG 6000 due to hydrophilic property of the polymer, leading to more area surface and greater wetting (19) Thus, the higher PEG 6000 proportion, the higher drug dissolution rate Figure illustrates dissolution profiles of isradipine from SDs at different ratios without HPMC 4000 as a function of time in gastric fluid (pH 1.2) and intestinal fluid (pH 6.8) SDs of the formulations at 1:2 and 1:4 ratio got the moderate percentage drug release after h in both medium Specifically, at pH 1.2 drug released from F1 and F2 was reached at 42.7 and 53.8%, respectively; whereas, at pH 6.8 it increased to 44.8 and 60.5% for F1 and F2, respectively Generally, there is an insignificant difference between the drug releases in both dissolution media regardless of isradipine pKa due to the formation of SDs whose dissolution rates mainly depend on drug crystal changes or drug-polymer interactions figure shows the effect of HPMC 4000 at different ratios on dissolution profiles of isradipine to determine a suitable HPMC proportion for a sustained release system The presence of adequate HPMC 4000 in the formulation could increase dissolution rate of SD up to two folds compared to the formulation without HPMC 4000 Sufficient HPMC 4000 proportion introduced to the formulation could be observed through a yellow colored transparent blend The release rate of SD at 1:2:1 ratio (F3) was increased to 80.8 and 81.7% at pH 1.2 and pH 6.8, respectively This result was impressive as compared to the corresponding SD without HPMC 4000 Similarly, while SD at 1:4 ratio without HPMC 4000 (F2) reached the highest percentage drug release at 53.8 and 60.5% at pH 1.2 and pH 6.8, respectively, dissolution rate of the formulation at 1:4:2 ratio (F4) in the presence of HPMC 4000, increased strongly to 87.5 and 85.1% at pH 1.2 and pH 6.8, respectively Significantly, drug released from the formulation at 1:4:4 ratio (F5) was achieved at approximately 100 120 80 100 % Drug release % Drug release Nguyen et al 60 40 80 60 40 1:2 1:4 20 (a) 20 0 20 40 60 80 100 1:2:1 1:4:2 1:4:4 (a) 120 20 40 Time (min) 100 80 100 120 120 80 100 % Drug release % Drug release 60 Time (min) 60 40 1:2 1:4 20 (b) 60 1:2:1 1:4:2 1:4:4 40 (b) 0 80 20 40 60 80 100 120 Time (min) 20 20 40 60 80 100 120 Time (min) Fig Dissolution profiles of isradipine from SDs of F1 and F2, at different ratio without HPMC 4000, as a function of time in gastric fluid (pH 1.2) (a) and intestinal fluid (pH 6.8) (b) Fig Dissolution profiles of isradipine from SDs of F3, F4 and F5, based on different ratios with HPMC 4000, as a function of time in in gastric fluid (pH 1.2) (a) and intestinal fluid (pH 6.8) (b) 100% in the first 10 Drug dissolution rate was increased with the increase of HPMC 4000 concentration This tendency may occur due to the change in drug crystals or molecular interactions, which will be discussed in the sections below For these reasons, F5 with the ratio 1:4:4 was chosen to be the best fit model in SD formulations increasing HPMC content as polymer chain uncoil slowed (21) Chain entanglement increased the tortuousness of matrix tablet with the increasing concentration of higher levels of HPMC (22,23) Additionally, low porosity produced by high hardness also controlled dissolution rate because it inhibited liquid across the surface of matrix tablet system (24) The sustained release profile was achieved at the 1:4:8 ratio while a little rapid release was observed at the ratios of 1:4:4 and 1:4:6 in tablet dosage forms Specifically, there was a strong burst release after h from F6 tablets, increasing from 59.4 to 86.2% in the range of 2–6 h (Fig 3) However, a significant sustained release was observed as compared to the SD powder (F5) due to the presence of matrix tablets during the dissolution test The drug release was then increased slowly following a constant rate during the next 18 h Meanwhile, dissolution rate of SD from F7 tablets (1:4:6 ratio for IS: PEG: HPMC) exploded from to 10 h, resulting in a twofold growth of drug release from 44.3 to 88.3% which then became stable Therefore, the increase in HPMC 4000 concentration could improve drug dissolution as well as control the percentage of drug release However, the Dissolution Studies of Sustained Drug Delivery System For a sustained release HPMC matrix tablet, the polymer has to go through hydration process to form an outer gel layer on the tablet surface This process occurs gradually when tablets contact with the medium, leading to HPMC chain relaxation, followed by the occurrence of erosion of the matrix Matrix swelling, erosion and diffusion of drug are attributed to factors which controlled the drug release rate and mechanism (20) The preliminary studies obviously identified the relationship between HPMC 4000 ratio and the release behavior of SDs from the hydrophilic matrix system The percentage of HPMC 4000 substantially affected the dissolution rate, resulting in the reduction of dissolution rate with the Swellable polymer by melting method 120 Physicochemical Characterization % Drug release 100 80 60 40 1:4:4 1:4:6 1:4:8 20 0 10 15 20 25 Time (hours) Fig Dissolution profiles of isradipine from SR-SDs of F6, F7, and F8 in 24 h premature burst release may lead to a fast decrease of drug concentration in effective life time Therefore, the concentration of HPMC 4000 would be increased to avoid the risk of burst release F8 tablets (1:4:8 ratio) showed their ability in sustaining drug delivery system through the capability of retaining the shape of matrix tablets up to 10 h while this period of the same performance in other SDs was h Furthermore, drug was gradually released from F8 during 24 h Gel layer formation around the matrix tablet can control drug release rate regardless of the effect of drug solubility Higher HPMC 4000 concentration in formulation formed gel layer quicker and stronger, leading to increased resistance of drug to diffusion and erosion (23) Furthermore, the barrier of HPMC 4000 is less efficient in diminishing drug release rate On the other hand, the translocation of water insoluble drug particles through the gel layer can disrupt the gel layer structure (25), resulting in a burst release in dissolution The formulation at 1:4:8 ratio (F8) provided sufficient amount of HPMC 4000 to develop a rapid formed and strong gel layer around the matrix tablet to sustain drug release and prevent burst release during dissolution or hydration The empirical observations and experimental results indicated that HPMC was a useful swellable polymer with high applicability for both increased dissolution rate and sustained drug delivery system Melting method has some advantages including short time process, solvent-free, lower cost, and prevention of toxicity in the environment Therefore, the preparation in the current study is very convenient for further research and manufacturing Besides, time – controlled release can be regulated by applying appropriate polymer carriers concentration to optimize therapeutically efficiency with better patient compliance figure 4a displays X-ray diffractograms of pure isradipine, PEG 6000, PM, SDs at ratio of 1:2 (F1) and 1:4 (F2) to investigate the effect of different ratio between drug and PEG 6000 without HPMC 4000 on the physical state of SDs The diffractogram of isradipine showed numerous peaks, indicating its high crystallinity in nature The change from crystalline state to amorphous state was identified by the disappearance of instinctive peaks or great diminution in number of characteristic peaks In case of F1, although most of peaks disappeared, peaks at 9.4, 9.8, 11.4, 11.8, 12.2, 13.9, 16.9, 17.6, 19.1, 20.5, 23.3, 25.5, 26.7, and 28.4 2θ still remained Therefore, SD was partially transformed into its amorphous form In SD at 1:4 ratio (F2), the absence of peak at 9.4, 9.8, 11.4, 11.8, 12.2 2θ compared to F1 demonstrated that the amorphous state of SD was improved with the increase of hydrophilic carrier PEG 6000 concentration A new peak was noted at the position of 10.6 2θ The result suggested an interaction between isradipine and PEG 6000 The effect of HPMC 4000 concentration on the physical state of SDs was indicated in Fig 4b HPMC 4000 altered structure of SD formulations into more amorphous form SD with 1:2:1 ratio (F3) still kept some main peaks from pure isradipine such as 11.8, 13.9, 16.9, 17.6, 19.1, 20.5, 22.2, and 23.3 2θ However, some peaks at 9.4, 9.8, 11.4, 11.8, and 12.2 2θ were disappeared, leading to more amorphous form in SD formulation Some peaks at 9.4, 9.8, 25.5, 26.7, and 28.4 were reduced in intensity compared to F1 (1:2 ratio), suggesting that HPMC 4000 helped transformation easier from crystalline to amorphous form In case of F4 (1:4:2 ratio), there was the disappearance of some peaks at 11.8, 13.9, 17.6, 20.5 2θ compared to F3 (1:2:1 ratio) Meanwhile, F5 (1:4:4 ratio) just showed three main peaks of pure isradipine: 6.9, 19.1, 23.3 2θ While PEG 6000 provided one characteristic peak at 21.3 2θ in both F3 (1:2:1 ratio) and F4 (1:4:2 ratio), this peak didn’t appear in F5, F7, F8 (1:4:4, 1:4:6, 1:4:8 ratio) It was suggested that the amount of HPMC 4000 in F5 was sufficient to change SD to its amorphous form The appearance of the new peak at 10.6 2θ in both three SDs with a gradually decrease in intensity confirmed a reaction between isradipine and PEG 6000 The descending in intensity of this peak might be caused by the increased HPMC 4000 concentration in the formulation, which facilitated the dispersion of drug in carrier The excessive amount of HPMC 4000 changed the structural behavior of the drug into amorphous state, resulting in the increasing of dissolution rate Research submitted by Ramasahayam at el showed the isradipine spectra with well-defined functional groups (26) A sharp peak at 3345 cm−1 was aliphatic amine stretching (N-H group) Three characteristic bands of carboxylic acid groups was presented at 1700 cm1 (C=O carboxylic acid stretching), 1366, 1309 cm−1 (C – O carboxylic acid stretching), and Nguyen et al (a) (a) PEG 6000 Pure Isradipine PEG 6000 PM Pure Isradipine 1:2 PM 1:2 1:4 1:4 10 20 30 40 50 Position (2-Theta) 4000 (b) 3000 2000 1000 Wavelenth (cm-1) (b) 1:2 1:2 1:4 1:2:1 1:4 1:2:1 1:4:2 1:4:4 1:4:6 1:4:2 1:4:4 1:4:8 1:4:6 10 20 30 40 50 1:4:8 Fig (a) PXRD patterns of isradipine, PEG 6000, PM and SDs of F1 and F2 in different ratios (b) PXRD patterns of isradipine, PEG 6000, HPMC 4000, PM and SDs of F3, F4 and F5 in different ratios 1001 cm−1 (O – H carboxylic acid out of plane bending) The alkane group assigned peaks at 2943 cm−1 as C – H alkane stretching and 1488 cm−1 as CH3 alkane in the plane bending Moreover, peak at 1488 cm−1 might identify C=C aromatic 4000 3000 2000 Wavelenth (cm-1) 1000 Swellable polymer by melting method ƒFig (a) FTIR spectra of isradipine, PEG 6000, PM and SDs of F1 and F2 in different ratios (b) FTIR spectra of isradipine, PEG 6000, HPMC 4000, PM and SDs of F3, F4, and F5 in different ratios ring stretching (26,27) C-N amine stretching was located at 1219, 1120, 1108, 1018 cm−1; whereas, C-H aromatic out of plane bending was appeared at 868, 757, 742, 620 cm−1 Figure 5a shows the FTIR spectrum of pure isradipine, PEG 6000, and SDs of 1:2 ratio (F1) and 1:4 ratio (F2) without the presence of HPMC 4000 The spectrum of F1 showed that the entirely main function groups of pure isradipine were remained In F2 (1:4 ratio), there was two small peaks at 3345 and 2885 cm−1, indicating the existence of isradipine and PEG 6000 in formulation Different from F1, the peak at 1704 cm−1 of F2 was divided into two small peaks, resulting the formation of hydrogen bonding between carbonyl C=O group of isradipine and O-H group of PEG 6000 There was only one carbonyl peak shifted downwards, inferring that only one of C=O groups of isradipine was hydrogen bonded; whereas, the other was non-hydrogen bond or very weakly hydrogen bond (28,29) It could explain why F2 was dissolved better than F1 FTIR spectra in Fig 5b illustrated the effect of presence of HPMC 4000 at different ratios on dissolution profile of isradipine In case of F3 (1:2:1 ratio), some characteristic peaks of pure isradipine were still maintained Similar to F2, the two carbonyl groups of isradipine in F3 were observed, indicating the intramolecular hydrogen bonding in the structure Thus, F3 with the presence of HPMC 4000 in formulation gave better drug dissolution SDs at ratio 1:4:2 (F4) and 1:4:4, 1:4:6, 1:4:8 (F5, F7, F8) showed that the only one carbonyl group was observed at these SDs at around 1696 cm−1 This peak was overlapped by two carbonyl groups, indicating that no hydrogen bonding occurred However, there was no amine group (N-H) at 3345 cm−1, attributing to the intramolecular hydrogen bonding with anion between aliphatic secondary amine NH of isradipine and OH group of PEG 6000 (28,29) This might be explained that NH stretching frequency was quite high (3345 cm−1) as compared to other compounds, leading to the fact that the hydrogen bonding was stronger than other counterparts (29) The result also explained why the more HPMC 4000 the more increased drug dissolution Furthermore, the IR spectra of F4 and F5 were similar, suggesting that the increase of HPMC 4000 concentration did not change the chemical behaviors of relative formulations Nevertheless, F5 had significantly higher drug dissolution might be due to the more amorphous state CONCLUSION This study investigated a SR system based on the combination of a hydrophilic carrier and a swellable polymer in SD melting method The presence of the swellable polymer not only increased dissolution rate but also sustained drug release from the matrix tablet The interesting point herein is that although melting method is a promising method in solid dispersion preparation with some advantages such as short time process, solvent-free, lower-cost, and prevention of toxicity, etc., a swellable polymer was usually not applied as hydrophilic carrier even This study indicated that the sustained release function could be designed in a SD formulation in addition to the role of enhancing drug dissolution of poorly water-soluble drugs by a selection of an appropriate polymer type and concentration Hence, the dual function SD could bring patients optimized therapeutic efficiency and compliance and pharmaceutical industry a potential product with convenient manufacture FTIR and PXRD results elucidated the ability of SD system in enhanced dissolution rate and sustained drug release by structural behaviors changes from crystalline to amorphous form and intermolecular hydrogen bond ACKNOWLEDGMENTS AND DISCLOSURES This research is supported by Vietnam National University – Ho Chi Minh City We also thank to International University for their continued, generous and invaluable support to our studies as well as greatly boost the efficiency of our research activities REFERENCES Vasconcelos T, Sarmento B, Costa P Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs Drug Discov Today 2007;12:1068–75 De Haanand P, Lerk C Oral controlled release dosage forms A review Pharmaceutisch Weekblad 1984;6:57–67 Tran PHL, Tran TTD, Park JB, Lee B-J Controlled release systems containing solid dispersions: strategies and mechanisms Pharm Res 2011;28:2353–78 Tran TT-D, Tran PH-L, Nguyen MNU, Tran KTM, Pham MN, Tran PC, et al Amorphous isradipine nanosuspension by the sonoprecipitation method Int J Pharm 2014;474:146–50 Riekes MK, Kuminek G, Rauber GS, de Campos CEM, Bortoluzzi AJ, Stulzer HK HPMC as a potential enhancer of nimodipine biopharmaceutical properties via ball-milled solid dispersions Carbohydr Polym 2014;99:474–82 Ohara T, Kitamura S, Kitagawa T, Terada K Dissolution mechanism of poorly water-soluble drug from extended release solid dispersion system with ethylcellulose and hydroxypropylmethylcellulose Int J Pharm 2005;302:95–102 Konno H, Handa T, Alonzo DE, Taylor LS Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine Eur J Pharm Biopharm 2008;70:493–9 Won D-H, Kim M-S, Lee S, Park J-S, Hwang S-J Improved physicochemical characteristics of felodipine solid dispersion particles by supercritical anti-solvent precipitation process Int J Pharm 2005;301:199–208 Nguyen et al Tran TT-D, Tran PH-L, Khanh TN, Van TV, Lee B-J Solubilization of poorly water-soluble drugs using solid dispersions Recent Pat Drug Deliv Formulation 2013;7:122–33 10 Yang M, Wang P, Huang C-Y, Ku MS, Liu H, Gogos C Solid dispersion of acetaminophen and poly(ethylene oxide) prepared by hot-melt mixing Int J Pharm 2010;395:53–61 11 Ozeki T, Yuasa H, Kanaya Y Control of medicine release from solid dispersion composed of the poly(ethylene oxide)-carboxyvinylpolymer interpolymer complex by varying molecular weight of poly(ethylene oxide) J Control Release 1999;58:87–95 12 Siepmannand J, Peppas NA Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC) Adv Drug Deliv Rev 2012;64(Supplement):163–74 13 Devjak Novak S, Šporar E, Baumgartner S, Vrečer F Characterization of physicochemical properties of hydroxypropyl methylcellulose (HPMC) type 2208 and their influence on prolonged drug release from matrix tablets J Pharm Biomed Anal 2012;66:136–43 14 Nochos A, Douroumis D, Bouropoulos N In vitro release of bovine serum albumin from alginate/HPMC hydrogel beads Carbohydr Polym 2008;74:451–7 15 Tranand TT-D, Tran PH-L Investigation of polyethylene oxide – based prolonged release solid dispersion containing isradipine J Drug Deliv Sci Technol 2013;23:269–74 16 Tran PH-L, Tran TT-D, Piao ZZ, Van Vo T, Park JB, Lim J, et al Physical properties and in vivo bioavailability in human volunteers of isradipine using controlled release matrix tablet containing selfemulsifying solid dispersion Int J Pharm 2013;450:79–86 17 Nguyen TN-G, Tran PH-L, Tran TV, Vo TV, Tran TT-D Development of a modified – solid dispersion in an uncommon approach of melting method facilitating properties of a swellable polymer to enhance drug dissolution Int J Pharm 2015;484:228–34 18 Ching AL, Liew CV, Chan LW, Heng PWS Modifying matrix micro-environmental pH to achieve sustained drug release from highly laminating alginate matrices Eur J Pharm Sci 2008;33:361–70 19 Leunerand C, Dressman J Improving drug solubility for oral delivery using SDs Eur J Pharm Biopharm 2000;50:47–60 20 Ghori MU, Ginting G, Smith AM, Conway BR Simultaneous quantification of drug release and erosion from hypromellose hydrophilic matrices Int J Pharm 2014;465:405–12 21 Li CL, Martini LG, Ford JL, Roberts M The use of hypromellose in oral drug delivery J Pharm Pharmacol 2005;57:533–46 22 Chaibva FA, Khamanga SM, Walker RB Swelling, erosion and drug release characteristics of salbutamol sulfate from hydroxypropyl methylcellulose-based matrix tablets Drug Dev Ind Pharm 2010;36:1497–510 23 Mitchell K, Ford J, Armstrong D, Elliott P, Rostron C, Hogan J The influence of concentration on the release of drugs from gels and matrices containing Methocel® Int J Pharm 1993;100:155–63 24 Reza MS, Quadir MA, Haider SS Comparative evaluation of plastic, hydrophobic and hydrophilic polymers as matrices for controlledrelease drug delivery J Pharm Pharm Sci 2003;6:282–91 25 Bettini R, Catellani P, Santi P, Massimo G, Peppas N, Colombo P Translocation of drug particles in HPMC matrix gel layer: effect of drug solubility and influence on release rate J Control Release 2001;70:383–91 26 Coates J Interpretation of infrared spectra, a practical approach Encycl Anal Chem 2000 27 Ramasahayam B, Eedara BB, Kandadi P, Jukanti R, Bandari S Development of isradipine loaded self-nano emulsifying powders for improved oral delivery: in vitro and in vivo evaluation Drug Dev Ind Pharm 2014 1–11 28 Ju J, Park M, Suk J.-M, Lah MS, Jeong K.-S An anion receptor with NH and OH groups for hydrogen bonds Chem Commun 2008 3546–3548 29 Tang X, Pikal M, Taylor L A spectroscopic investigation of hydrogen bond patterns in crystalline and amorphous phases in dihydropyridine calcium channel blockers Pharm Res 2002;19: 477–83  ... was added into the mixture with an appropriate ratio to perform tablets adequately at a total weight of 150 mg (Table I) Magnesium stearate as a lubricant was added at the end (1% total mass of. .. solubility and influence on release rate J Control Release 2001;70:383–91 26 Coates J Interpretation of infrared spectra, a practical approach Encycl Anal Chem 2000 27 Ramasahayam B, Eedara BB, Kandadi... liquid across the surface of matrix tablet system (24) The sustained release profile was achieved at the 1:4:8 ratio while a little rapid release was observed at the ratios of 1:4:4 and 1:4:6 in tablet