Mesoporous silica based macromolecules for dissolution enhancement of Irbesartan drug using pre-adjusted pH method

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Mesoporous silica based macromolecules for dissolution enhancementof Irbesartan drug using pre-adjusted pH method

Mai Khanfar a, Mohammad M. Fares b,⇑, Mu’taz Sheikh Salem a,⇑, Amjad M. Qandil c,d

a Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordanb Department of Chemical Sciences, Faculty of Science and Arts, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordanc Department of Medicinal Chemistry & Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordand Pharmaceutical Sciences Department, College of Pharmacy King Saud Bin Abdulaziz University for Health Sciences, Riyadh, 11426, Saudi Arabia

a r t i c l e i n f o

Article history:Received 25 November 2012Received in revised form 24 January 2013Accepted 6 February 2013Available online 15 February 2013

Keywords:IrbesartanSilica-based microcapsulesDissolution enhancementPre-adjusted pH methodSolid dispersion

a b s t r a c t

Dissolution enhancement of poorly water-soluble Irbesartan drug through formation of Irbesartan-silicabased microcapsules has been investigated. The microcapsules were fully characterized using FTIR, DSC,XRD and SEM techniques. Pre-adjusted pH method has been utilized to form efficient Irbesartan–silicabased microcapsules capable to enhance dissolution rate of Irbesartan drug at the challenging pH 5.5value. The formed Irbesartan–silica based microcapsules showed large dissolution increase as Neusilinfeed ratio and as pre-adjusted pH were increased. The maximum dissolution enhancement was achievedvia salt formation at pre-adjusted pH 7.4 and 1:3 ratio of Irbesartan-silica based microcapsules. The suc-cessful dissolution enhancement was owed to destruction of the crystallinity of the drug accompaniedwith Irbesartan-silica based salt formation at elevated pH pre-adjustment leading to apparent drugdissolution.

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1. Introduction

Poorly water-soluble drugs are becoming the major concernand the challenging issue for many oral drug implementationsdue to its direct relationship with therapeutic effectiveness andcure. Their poor solubility and hence poor bioavailability have di-verted many researchers to overcome this obstacle via theenhancement of dissolution rate [1–4]. The continuous need to findnew methods and technique that could enhance the poorly water-soluble drugs is in continual persistence due to unceasing emergeof new potential drugs that suffer from water solubility problems,and hence poor bioavailability in human tissues. Therefore, manytechniques and methods appeared in the literature that play dom-inant role in the improvement of drug dissolution such as; micron-ization [5,6], solubilization [7], naturally occurring polysaccharides[8], salt formation [9], reduction of drug’s particle size [10], mi-cron-sized crystalline particles [11], or the solid dispersion tech-nique [12,13].

On the other hand, stable mesoporous silica materials used inpharmaceutical formulations gains increasing attention due to itstunable porosity, high surface area, non-toxicity, and good biocom-patibility, which adapt it to be used in drug delivery and/or disso-lution enhancement processes [14,15]. Adsorption of drugs on

silica-based materials first described in the early 1970’s wasre-acknowledged by the formation of synthetic grades like poroussilicon dioxide (Sylysia�), polypropylene foam powder (Accurel�),porous calcium silicate (Florite�), and magnesium aluminumsilicate (Neusilin�) [16–19]. Neusilin US2 have high specificsurface area (�300 m2/g), high porosity, anti-caking and flowenhancing properties. It consists of amorphous microporousmagnesium aluminum silicates with an empirical formula ofAl2O3�MgO�1.7SiO2�xH2O. It has a silanol group on its surface,which makes it a potential proton donor or acceptor [20]. Mean-while, Irbesartan drug is a strong and long effective non-peptidetetrazole derivative and an angiotensin II type 1 receptor (AT1)antagonist considered as class II drug according to biopharmaceu-tical classification system, and used alone or with other antihyper-tensive agents to treat high blood pressure [21–23]. Such potentialdrug suffers from poor water solubility and hence bioavailability.Therefore, in this research, mesoporous silica-based Neusilin–Irbe-sartan microcapsules were evaluated to enhance the dissolution ofthe poorly water-soluble Irbesartan drug. Different spectroscopicmeans was used to elucidate the guest–host microcapsules suchas FTIR, DSC, XRD and SEM techniques. The formation of the micro-capsules were subjected to different mixing techniques (i.e. phys-ical mixing and solid dispersion) to enhance the dissolution atthe challenging solution pH = 5.5 value. In addition, pre-adjustedpH method was also tested and verified to promptly enhance thedissolution of the poorly water-soluble Irbesartan drug.

1387-1811/$ - see front matter � 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.micromeso.2013.02.007

⇑ Corresponding authors.E-mail addresses: [email protected] (M.M. Fares), [email protected] (M.S. Salem).

Microporous and Mesoporous Materials 173 (2013) 22–28

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2. Experimental

2.1. Materials

Irbesartan drug was kindly supplied by Dar El-Dawa Pharma-ceuticals, Jordan, and Neusilin US2 was also gifted by Fuji ChemicalIndustry Co., Japan. Mono- and di-basic phosphate buffer was usedfor the adjustment of different pH values. Deionized and doubledistillated water was used in all experiments. All other reagentswere of analytical grade and used as supplied without furtherpurification.

2.2. Spectroscopic and thermal techniques

FTIR: Shimadzu IRAffinity-1 FTIR spectrophotometer for func-tional groups were recorded in the range of 4000–400 cm–1 usingKBr pellets. Differential Scanning calorimeter (DSC) model: Netzch,204 F1 Phoenix DSC equipped with intra-cooler, Indium standardwas used to calibrate the DSC temperature and enthalpy scale.The system was purged with nitrogen gas at a flow rate 70 ml/min., and heated from 30–275 �C using a heating rate of 10 �C/min. X-ray diffraction (XRD): Rigaku Goniometer Ultima IV(185 mm) X-ray powder diffractometer with cobalt radiation, at avoltage of 40 kV and a current of 20 MA. The scanning rate was1 �/min over a diffraction angle of (2h) and range of 3–70� with0.02 step change. Scanning Electron Microscope (SEM): The filmsamples were mounted on the specimen stabs and coated withgold ion by sputtering method with (DSM 950 (ZEISS) model)(USA), Polaron (E6100) model. Micrographs were of Polaroid films.

2.3. Sample preparation and dissolution studies

For the solid dispersion samples, 150 mg of Irbesartan was putinto a stoppered 100 ml round bottom flask. A small quantity ofmethanol just enough to solubilize Irbesartan was added, and aweighed quantity of Neusilin US2 was dispersed with shaking intodrug solution. Three respective Irbesartan–Neusilin ratios was pre-pared as follows; 1:0.5, 1:1, and 1:3 (w/w), then methanol solventwas slowly evaporated under vacuum using a rotary evaporator(Heidolph 4000 efficient) of speed of rotation equals 40 rpm at

60 �C. Collected samples were dried at 70 �C for 72 h. The dissolu-tion process was performed using USP XXIV type II dissolutionapparatus (Dissolution tester RC-8DS). The dissolution mediumused was 900 ml phosphate buffer maintained at 37 �C ± 0.5. Thepaddle speed was 100 rpm and 5.0 ml sample was collected peri-odically and replaced with equal quantity of dissolution medium.The samples were then filtered with 0.45 lm pore size membranefilter. Consequently, filtered solutions were suitably diluted andanalyzed by UV spectrophotometer (Beckman DU-62 spectropho-tometer) at 230 nm. Schematic representation of solid dispersionof Irbesartan and Neusilin US2 is available in Scheme 1. For thephysically mixed samples three different Irbesartan–Neusilin ra-tios were mixed 1:0.5, 1:1 and 1:3 ratios respectively in a closedglass tube using vortex.

2.4. Microcapsules formation using pre-adjusted pH method

Specific amount of Irbesartan was weighed and put into a stop-pered 100 ml round bottom flask. Minimum amount of methanolwas added enough to solubilize Irbesartan and a weighed quantityof Neusilin US2 was dispersed in the solution. The solution wasthoroughly mixed and the pH of the solid dispersion solutionwas adjusted to pH = 1.2. The solution was left under continuoushomogenous shaking using magnetic stirrer for 30 min. After timecompletion, the solvent was slowly evaporated and the pre-ad-justed pH 1.2 microcapsules were collected. The same procedurerepeated using different pre-adjusted pH values namely 4.2, 5.5,7.4, and different Irbesartan–Neusilin ratios. Dissolution studiesusing the different pre-adjusted pH microcapsules were carriedout at the challenging pH 5.5 for which the drug shows the mini-mum drug dissolution (Section 3.2.3).

3. Results and discussion

3.1. Characterization of Irbesartan–Neusilin microcapsules

3.1.1. Fourier transform infrared (FTIR)The FTIR spectra of Neusilin US2 and solid dispersed Irbesartan–

Neusilin microspheres (1:1) illustrated in Fig. 1 and Table 1. Appar-ently, the OH stretching band of silanol group of Neusilin US2 in

Scheme 1. Solid dispersion and dissolution enhancement of Irbesartan and Neusilin US2.

M. Khanfar et al. / Microporous and Mesoporous Materials 173 (2013) 22–28 23


the Irbesartan–Neusilin microcapsules have been reduced byaround 14 cm�1 as a result of H-bonding interactions. This was fur-ther confirmed by the reduction of Al–O and Al–O–Si band stretch-ings [24] in the Neusilin-drug microcapsules. The NH stretching ofIrbesartan was broad but much less intensed than OH stretching ofNeusilin and overlapped with OH stretching, and hence no conclu-sive remarks could be deduced. The carbonyl group in Irbesartanlocated at 1733 cm�1 was reduced to 1726 cm�1 in the Irbesar-tan–Neusilin microspheres indicating stronger electrostatic inter-actions between Irbesartan and Neusilin macromolecules.Furthermore, the bending bands in Neusilin US2 (i.e. O–Al–O, Al–O–Si, and O–Si–O bands) did not show any significant shift, whichindicates insignificant contribution of molecular interactions.

3.1.2. Differential scanning calorimetry (DSC)The ability to destroy the drug’s crystalline structure into amor-

phous structure is a characteristic feature in the dissolutionenhancement of poorly water-soluble drugs. Different methodshave been employed to increase the amorphization of crystallinedrugs such as; melt quenching [25], spray drying [26], melt adsorp-tion [27], and co-grinding [28]. The amorphization process de-scribes the tendency of Neusilin US2 macromolecule to separatepacked and crystalline drug macromolecules from each other, in-crease the free volume between the macromolecules, which allowwater penetration, lead to better oriented drug-solvent interac-tions, better drug’s hydration, and eventually better drug dissolu-tion. Neusilin US2 high surface area and especially the silanolgroups could form strong H-bonding with tetrazole groups of Irbe-sartan leading to destruction of crystalline regions [19,29], whichresulted with enhanced drug solubility. Fig. 2 illustrates the melt-ing endotherm characteristics, derived from DSC thermogram, ofNeusilin US2, Irbesartan drug, and Irbesartan–Neusilin microcap-sules. Apparently, the melting enthalpy of Irbesartan has been con-siderably lowered in Irbesartan–Neusilin microcapsules (Table 2).This could be explained by the destruction of crystalline regionsof Irbesartan drug as a result of the interaction with Neusilin US2macromolecules. Such interaction would lead to weaker drug-druginteractions, stronger drug-excipient interactions, hence lowermelting enthalpy of the drug obtained.

The %crystallinity change of the solid dispersed samples de-duced from DSC thermogram was measured using the followingrelation [30];

%Crystallinity change ¼ 100� ðDHm;SD=ðDHm;Irbesaratan �WÞÞ ð1Þ

where DHm,SD and DHm,Irbesaratan were the melting enthalpy (in J/g)of solid dispersed samples and pure Irbesaratn drug, respectively,and W was the weight fraction of Irbesatan in the solid dispersionsamples. Table 2 illutrates thermal properties of solid dispersedNeusilin–Irbesartan microparticles. Clearly, the %crystallinity ofIrbesartan drug was decreased down to 30.7% in the SD (1:3) sam-ple due to the interaction with Neusilin US2 macromolecules, whichled to the destruction of crystalline regions, and hence better disso-lution would be obtained.

Fig. 1. FTIR spectra of Neusilin macromolecules and Irbesartan–Neusilin US2 microcapsules (1:1 ratio).

Table 1FTIR characteristic bands of Neusilin US2, Irbesartan, and solid dispersed Irbesartan–Neusilin US2 microcapsules (1:1 ratio).

Polymer cm�1 A Bands

Neusilin US2 3453 0.90 O–H str. (Silanol group)1023 0.97 Al–O–Si str.874 0.42 Al–O str.683 0.66 O–Al–O550 0.59 Al–O–Si450 0.87 O–Si–O

Irbesartan 3438 0.09 NH str.1733 1.25 C@O str.1622 0.70 Aromatic C@N str.

Irbesartan–Neusilin microcapsules 3439 0.63 O–H str. (Silanol group)1017 0.82 Al–O–Si str.866 0.40 Al–O str.683 0.52 O–Al–O550 0.45 Al–O–Si450 0.60 O–Si–O1726 0.56 C@O str.1622 0.41 Aromatic C@N str.

24 M. Khanfar et al. / Microporous and Mesoporous Materials 173 (2013) 22–28


3.1.3. X-ray diffraction (XRD)Fig. 3 domonstrated the X-ray diffraction pattern of Neusilin

US2, Irbesartan drug, solid dispersion and physical mixing of Irbe-sartan–Neusilin microcapsules. The diffraction pattern of Neusilinshow complete amorphous structure whereas, Irbesartan showthat the drug exist in crystalline form. This was revealed by thepresence of several sharp intensity peaks at diffraction angles(2h) at 4.75�, 12.49�, 19.45�, 23.18� that corresponds to crystallineregions of Irbesartan drug. However, in the physical mixing micro-capsules lower intensities of the diffraction peaks observed andmuch lower intensity peaks were observed in the solid dispersionmicrocapsules. The reduction in intensity suggests reduction incrystalline regions of drug as a result of amorphization of thedrug’s molecules upon salt formation with Neusilin macromole-cules. Such results came in accordance with DSC results mentionedabove.

3.1.4. Scanning electron microscope (SEM)Fig. 4 demonstrated the morphologic changes of Irbesartan

drug, Irbesartan–Neusilin microparticles and Neusilin US2 macro-molecules, respectively using SEM images. Apparently, large crys-talline rectangular roddy-like structures of Irbesartan drug with5–20 lm length and 2–4 lm width were observed (Fig. 4A). Onthe contrary, Neusilin US2 macromolecules show mesoporousand amorphous microspheres with 30–50 lm diameters as seenin Fig. 4E. Fig. 4B provides evidence on the adsorption of the drug’scrystalline rods on the surface of Neusilin US2 macromolecules.This adsorption occurred via the H-bonding interactions of Neusi-lin silanol groups with secondary and tertiary amines in the tetra-zole groups of Irbesartan drug. Furthermore, the increase of

Neusilin content in the Irbesartan–Neusilin microparticles resultswith more adsorption and coverage of Neusilin macromoleculeswith the crystalline rods of the drug (Fig. 4C). This could lead todestruction of the drug’s crystallinity as depicted in Fig. 2, andhence enhance the dissolution of the drug. Fig. 4D shows the 1:3Irbesartan–Neusilin microparticles. It could be seen that almostno crystalline rods of the drug observed but rather more scattereddrug molecules adsorbed on the surface of the Neusilin micro-spheres. Eventually, such results emphasizes on the role of Neusi-lin in the destruction of drug’s crystalline regions and theenhancement of the drug solubility and came in accordance withthe DSC and XRD results.

3.2. Dissolution enhancement parameters

3.2.1. Effect of solution pHThe bioavailability of the drug in human tissues depends on the

rate of absorption. In addition, the rate of absorption depends onrate of dissolution, which is pH dependent. Therefore, the studyof the dissolution of the drug at simultaneous pH increase aqueoussolutions (i.e. GI tract) became extremely important. Fig. 5 illus-trates the change of dissolution of Irbesartan drug versus time atdifferent pH values. Obviously, within the first 60 min the Irbesar-tan release reached �81% at both pH 1.2 and pH 7.4. The pKa ofIrbesartan determined to be 4.7 [31,32] indicating that at pH 1.2,nitrogen atoms could be protonated forming positive chargegroups (i.e. @N�? @NH+–), whereas at pH 7.4 the tetrazole groupcould be deprotonated forming negative charge groups (i.e.�NH�? �N��). In either case, the ionization of Irbesartan drugleads to formation of similar charge groups that tend to repel each

Fig. 2. DSC thermograms of Neusilin US2, Irbesartan, and Irbesartan–Neusilin microcapsules.

Table 2Thermal properties of Irbesartan and solid dispersion Irbesartan–Neusilin microcapsules derived from DSC thermograms.

Sample Composition DH (J/g) Tm (�C) %Crystallinity

Irbesartan (%) Neusilin (%)

Irbesartan 100 0 125.1 187.7 –SD (1:0.5) 67 33 52.8 184.1 63.3SD (1:1) 50 50 19.7 184.6 31.5SD (1:3) 25 75 9.6 183.8 30.7



other, decrease structure consistency, allow water penetration andhence increase the drug dissolution in the aqueous medium. Onthe other hand, at pH 5.5 almost no ionized form of the drug and

dominant hydrophobic moieties effect resulted with very low dis-solution rate (i.e. %Irbesartan release �8%). The U-shaped curve ofIrbesartan dissolution profile, depicted in Fig. 6, showed poorly

Fig. 3. X-ray diffraction pattern (XRD) of Neusilin US2, Irbesartan drug, solid dispersion and physically mixed Irbesartan–Neusilin (1:1 ratio) microcapsules.

Fig. 4. SEM images of (A) Irbesartan drug, (B) Solid dispersion Irbesartan–Neusilin microparticles (1:0.5 ratio), (C) Solid dispersion Irbesartan–Neusilin microparticles (1:1ratio), (D) Solid dispersion Irbesartan–Neusilin microparticles (1:3 ratio), and (E) Neusilin US2.



water-soluble drug behavior at pH 5.5, which was the challengingissue for our desire to enhance the dissolution at this significant pHfor drug absorption and bioavailability. Therefore, the next dissolu-tion profiles (i.e. Figs. 7 and 8) of the drug were accomplished at pH5.5 value.

3.2.2. Effect of mixing techniqueThe mixing type technique of the polymeric vehicle with the

model drug play significant role in the drug release and solubility.Therefore, two mixing techniques namely; solid dispersion andphysical mixing of Irbesartan with Neusilin were performed. Thesolid dispersion technique found to be a better technique than

physically mixed technique due to micro- and nano-structuredincorporations of the drug into the polymeric system. Such nano-structured incorporations adapt the drug for better and controlledrelease, and as a result enhance its solubility. This could also en-hance the drug’s absorption and bioavailability. Fig. 7 illustratesthe release profiles of the solid dispersion and the physically mixedIrbesartan–Neusilin microcapsules at pH 5.5. It could be clearlyseen that the solid dispersion samples showed 100% increase thanthe physically mixed samples. In addition, as the content of Neusi-lin US2 increased, the drug dissolution enhanced. This could be ex-plained by the amorphous microspheric granules of Neusilin US2macromolecules that had high specific surface area (i.e. �300m2/g) [33,34] capable to adsorb higher amount of Irbesartanmolecules on its surface in a well-oriented and accumulated forms.

3.2.3. Pre-adjusted pH methodThe pre-adjusted pH method meant to establish good interac-

tion between Irbesartan and Neusilin US2 prior to dissolution testsat pH 5.5. The presence of silanol groups in Neusilin US2 host mac-romolecules play dominant role in formation of microcapsuleswith Irbesartan guest molecules. Ong et al. [35] demonstrated that19% of silanol groups on fused silica surfaces exhibit a pKa of 4.5,while 81% exhibit pKa = 8.5, and this confirm that the silanolgroups function as Bronsted acid or as Bronsted base. Furthermore,the similar pKa values for Irbesartan and Neusilin US2 demonstrateamphoteric behavior of both guest and host macromolecules lead-ing to good interaction and salt formation as reported by Watana-ble et al. [36]. Such good interaction persists and steadily increasesas pre-adjusted pH increase due to the formation of larger fractionsof positive and negative charges on either Irbesartan or Neusilinmolecules. This would lead to higher amount of salt formation,higher amount of crystallinity destruction of Irbesartan drug andhence larger dissolution of the drug at elevated pH pre-adjustment.Fig. 8 shows the dissolution profiles of Irbesartan drug release atpH 5.5 using pre-adjusted pH method of Irbesartan–Neusilinmicrocapsules different ratios. Very low drug release at pre-ad-justed pH 1.2 microcapsules was observed. This indicated poorinteraction of Irbesartan and Neusilin macromolecules due tohighly repulsive forces between protonated nitrogen atoms of Irbe-sartan and silanol groups. Such poor interaction reduced the solu-bility of Irbesartan and hence poorer drug release was obtained (i.e.drug release = 22.8%). On the other hand, gradual increase of pre-adjusted pH microcapsules led to better and enhanced drug re-lease. This could be explained by gradual mutual appearance ofBronsted acid or Bronsted base guest/host macromolecules leadingto enhanced Irbesartan–Neusilin interaction and better drug re-

Fig. 5. The dissolution profiles of 150 mg Irbesartan drug at different pH values.

Fig. 6. Change of drug release (in %) with solution pH after the passage of 60 min.

Fig. 7. The dissolution profiles of 150 mg Irbesartan drug at pH 5.5 using soliddispersion (SD) or physically mixed (PM) techniques of Irbesartan–Neusilindifferent ratios.

Fig. 8. The dissolution profiles of Irbesartan drug release at pH 5.5 using pre-adjusted pH method of Irbesartan–Neusilin microcapsules different ratios.



lease. Eventually, the increase of Irbesartan–Neusilin ratio from 1:1to 1:3 using pre-adjusted pH 7.4 microcapsules increased the drugrelease from 71.9% to 92.5%. This distinguished drug release at 1:3ratio confirm higher amount of silanol groups acting as Bronstedacid that protonated Irbesartan drug, leading to continuous amor-phization of crystalline regions, and hence larger amount of saltformation of Irbesartan–Neusilin microcapsules that guaranteesmaximum drug dissolution enhancement as been depicted byFig. 4.

4. Conclusions

The dissolution of poorly water-soluble Irbesartan drug wasgreatly enhanced using Irbesartan-silica based microcapsules atthe challenging pH 5.5 value. Characterization techniques such asFTIR, DSC, XRD and SEM elucidate destruction of crystalline regionsof the drug and salt formation of Irbesartan–Neusilin microcap-sules. Dissolution of the drug was largely increased as pre-adjustedpH increased and as the Neusilin US2 feed ratio increased in themicroparticles. The maximum drug release of 92.5% was achievedusing pre-adjusted pH 7.4 and Irbesartan–Neusilin microcapsules(1:3 ratio). This had adapted the Irbesartan–Neusilin microcap-sules to successfully release the drug and enhance its dissolutionat the proper time and position.

Acknowledgment

Authors wish to acknowledge Jordan University of Science &Technology for support and facilities.

References

[1] V.K. Nagabandi, T. Ramarao, K.N. Jayaveera, IJPBS 1 (3) (2011) 89–102.[2] G. Chawla, A.K. Bansal, Eur. J. Pharm. Sci. 32 (2007) 45–57.[3] E. Watanabe, M. Takahashi, M. Hayashi, Eur. J. Pharm. Biopharm. 58 (2004)

659–665.[4] N. Rasenack, H. Hartenhauer, B.W. Müller, Int. J. Pharm. 254 (2003) 137–145.[5] Ganesh.P. Sanganwar, Ram.B. Gupta, Int. J. Pharm. 360 (1–2) (2008) 213–218.[6] M. Vogt, K. Kunath, J.B. Dressman, Eur. J. Pharm. Biopharm. 68 (2) (2008) 283–

288.

[7] T. Loftsson, D. Hreinsdóttir, M. Másson, Int. J. Pharm. 302 (1–2) (2005) 18–28.[8] M.M. Fares, M.S. Salem, M. Khanfar, Int. J. Pharm. 410 (2011) 206–211.[9] A.T.M. Serajuddin, Adv. Drug Delivery Rev. 59 (7) (2007) 603–616.

[10] J. Jinno, N. Kamada, M. Miyake, K. Yamada, T. Mukai, M. Odomi, H. Toguchi,G.G. Liversidge, K. Higaki, T. Kimura, J. Controlled Release 111 (1–2) (2006) 56–64.

[11] Z.L. Zhang, Y. Le, J.X. Wang, J.F. Chen, Drug Dev. Ind. Pharm. 37 (11) (2011)1357–1364.

[12] M.S. Nagarsenker, R.N. Meshram, G. Ramprakash, J. Pharm. Pharmacol. 52(2000) 949–956.

[13] G.P. Sanganwar, R.B. Gupta, Int. J. Pharm. 360 (2008) 213–218.[14] M. Vallet-Regí, L. Ruiz-González, I. Izquierdo-Barba, J.M. Gonzalez-Callbet, J.

Mater. Chem. 16 (2006) 26–31.[15] Shou-Cang Shen, Wai Kiong Ng, Leonard Chia, Jun Hu, Reginald B.H. Tan, Int. J.

Pharm. 410 (2011) 188–195.[16] D.C. Monkhouse, J.L. Lach, J. Pharm. Sci. 61 (9) (1972) 1430–1435.[17] T. Uchino, N. Yasuno, Y. Yanagihara, H. Suzuki, Pharmazie 62 (8) (2007) 599–

603.[18] S. Sharma, Sher, S. Badve, A. Pawar, AAPS Pharm. Sci. Tech. 6 (4) (2005) E618–

E625.[19] M.K. Gupta, A. Vanwert, R.H. Bogner, J. Pharm. Sci. 92 (2003) 536.[20] http://www.fujihealthscience.com/Fuji_Email_Blast_Neusilin_JAN21.pdf.[21] L.X. Yu, G.L. Amidon, J.L. Polli, H. Zhao, M.U. Mehta, D.P. Conner, V.P. Shah, L.J.

Lesko, M.L. Chen, V.H.L. Lee, A.S. Hussain, Pharm. Res. 19 (2002) 921–925.[22] http://www.drugs.com/mtm/irbesartan.html.[23] R.J. Boghra, P.C. Kothawade, V.S. Belgamwar, P.P. Nerkar, A.R. Tekade, S.J.

Surana, Chem. Pharm. Bull. 59 (4) (2011) 438–441.[24] S. Jakobsson, Spectrsc. Tech. 56 (6) (2002) 797–799.[25] T. Watanabe, N. Wakiyama, F. Usui, M. Ikeda, T. Isobe, M. Senna, Int. J. Pharm.

226 (2001) 81–91.[26] E. Yonemochi, S. Kitahara, S. Maeda, S. Yamamura, T. Oguchi, K. Yamamoto,

Eur. J. Pharm. Sci. 7 (1999) 331–338.[27] M. Kinoshita, K. Baba, A. Nagayasu, K. Yamabe, T. Shimooka, Y. Takeichi, M.

Azuma, H. Houchi, K. Minakuchi, J. Pharm. Sci. 91 (2002) 362–370.[28] H. Sekizaki, K. Danjo, H. Eguchi, Y. Yonezawa, H. Sunada, A. Otsuka, Chem.

Pharm. Bull. 43 (1995) 988–993.[29] D. Bahl, R.H. Bogner, Pharm. Res. 23 (10) (2006) 2317–2325.[30] C.F. Rawlinson, A.C. Williams, P. Timmins, I. Grimsey, J. Pharm. 336 (2007) 42–

48.[31] E. Cagigal, L. Gonzalez, R.M. Alonso, et al., J. Pharm. Biomed. Anal. 26 (2001)

477–486.[32] S.R. El-Shaboury, S.A. Hussein, N.A. Mohamed, M.M. El-Sutohy, J. Pharm. Anal.

2 (1) (2012) 12–18.[33] A. Krupa, A. Krupa, D. Majda, R. Jachowicz, W. Mozgawa, Thermochim. Acta

509 (2010) 12–17.[34] I.S. Chuang, G.E. Maciel, J. Phys. Chem. Part B 101 (1997) 3052–3064.[35] S.W. Ong, X.L. Zhao, K.B. Eisenthal, Chem. Phys. Lett. 191 (1992) 327.[36] T. Watanabe, S. Hasegawa, N. Wakiyama, F. Usui, A. Kusai, J. Solid State Chem.

164 (2002) 27–33.


Mesoporous silica based macromolecules for dissolution enhancement of Irbesartan drug using pre-adjusted pH method

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