Accepted Manuscript

Mesoporous Silica based Macromolecules for Dissolution Enhancement of Ir‐

besartan Drug using Pre-adjusted pH method

Mai Khanfar, Mohammad M. Fares, Mu’taz Sheikh Salem, Amjad M. Qandil

PII: S1387-1811(13)00073-5

DOI: http://dx.doi.org/10.1016/j.micromeso.2013.02.007

Reference: MICMAT 5917

To appear in: Microporous and Mesoporous Materials

Received Date: 25 November 2012

Revised Date: 24 January 2013

Accepted Date: 6 February 2013

Please cite this article as: M. Khanfar, M.M. Fares, M.S. Salem, A.M. Qandil, Mesoporous Silica based

Macromolecules for Dissolution Enhancement of Irbesartan Drug using Pre-adjusted pH method, Microporous and

Mesoporous Materials (2013), doi: http://dx.doi.org/10.1016/j.micromeso.2013.02.007

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1

Mesoporous Silica based Macromolecules for Dissolution Enhancement 2 of Irbesartan Drug using Pre-adjusted pH method 3

Mai Khanfar1, Mohammad M. Fares2,*, Mu’taz Sheikh Salem1,*, Amjad M. Qandil3 4

5 1Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of 6

Science and Technology, P.O. Box 3030,Irbid 22110, JORDAN 7 8

2Department of Chemical Sciences, Faculty of Science & Arts, Jordan University of 9 Science and Technology, P.O. Box 3030, Irbid 22110, JORDAN 10

11 3Department of Medicinal Chemistry, Faculty of Pharmacy, Jordan University of Science 12

and Technology, P.O. Box 3030, Irbid 22110, JORDAN 13 14

*Correspondence: salem@just.edu.jo (M. S. Salem), fares@just.edu.jo (M. M. Fares) 15 16

ABSTRACT 17

Dissolution enhancement of poorly water-soluble Irbesartan drug through formation of 18

Irbesartan-silica based microcapsules has been investigated. The microcapsules were 19

fully characterized using FTIR, DSC, XRD and SEM techniques. Pre-adjusted pH 20

method has been utilized to form efficient Irbesartan-silica based microcapsules capable 21

to enhance dissolution rate of Irbesartan drug at the challenging pH5.5 value. The formed 22

Irbesartan-silica based microcapsules showed large dissolution increase as Neusilin feed 23

ratio and as pre-adjusted pH were increased. The maximum dissolution enhancement was 24

achieved via salt formation at pre-adjusted pH7.4 and 1:3 ratio of Irbesartan-silica based 25

microcapsules. The successful dissolution enhancement was owed to destruction of the 26

crystallinity of the drug accompanied with Irbesartan-silica based salt formation at 27

elevated pH pre-adjustment leading to apparent drug dissolution. 28

29

Keywords: Irbesartan, silica-based microcapsules, dissolution enhancement, pre-adjusted 30 pH method, solid dispersion 31 32

33

34

35

36

1. INTRODUCTION 37

Poorly water-soluble drugs are becoming the major concern and the challenging issue for 38

many oral drug implementations due to its direct relationship with therapeutic 39

effectiveness and cure. Their poor solubility and hence poor bioavailability have diverted 40

many researchers to overcome this obstacle via the enhancement of dissolution rate 41

[1−4]. The continuous need to find new methods and technique that could enhance the 42

poorly water-soluble drugs is in continual persistence due to unceasing emerge of new 43

potential drugs that suffer from water solubility problems, and hence poor bioavailability 44

in human tissues. Therefore, many techniques and methods appeared in the literature that 45

play dominant role in the improvement of drug dissolution such as; micronization [5, 6], 46

solubilization [7], naturally occurring polysaccharides [8], salt formation [9], reduction of 47

drug’s particle size [10], micron-sized crystalline particles [11], or the solid dispersion 48

technique [12, 13]. 49

On the other hand, stable mesoporous silica materials used in pharmaceutical 50

formulations gains increasing attention due to its tunable porosity, high surface area, non-51

toxicity, and good biocompatibility, which adapt it to be used in drug delivery and/or 52

dissolution enhancement processes [14, 15]. Adsorption of drugs on silica-based 53

materials first described in the early 1970's was re-acknowledged by the formation of 54

synthetic grades like porous silicon dioxide (Sylysia®), polypropylene foam powder 55

(Accurel®), porous calcium silicate (Florite®), and magnesium aluminum silicate 56

(Neusilin®) [16-19]. Neusilin US2 have high specific surface area (~ 300 m2/g), high 57

porosity, anti-caking and flow enhancing properties. It consists of amorphous 58

microporous magnesium aluminum silicates with an empirical formula of 59

Al2O3·MgO·1.7SiO2·xH2O. It has a silanol group on its surface, which makes it a 60

potential proton donor or acceptor [20]. Meanwhile, Irbesartan drug is a strong and long 61

effective non-peptide tetrazole derivative and an angiotensin II type 1 receptor (AT1) 62

antagonist considered as class II drug according to biopharmaceutical classification 63

system, and used alone or with other antihypertensive agents to treat high blood pressure 64

[21-23]. Such potential drug suffers from poor water solubility and hence bioavailability. 65

Therefore, in this research, mesoporous silica-based Neusilin-Irbesartan microcapsules 66

were evaluated to enhance the dissolution of the poorly water-soluble Irbesartan drug. 67

Different spectroscopic means was used to elucidate the guest-host microcapsules such as 68

FTIR, DSC, XRD and SEM techniques. The formation of the microcapsules were 69

subjected to different mixing techniques (i.e. physical mixing and solid dispersion) to 70

enhance the dissolution at the challenging solution pH=5.5 value. In addition, pre-71

adjusted pH method was also tested and verified to promptly enhance the dissolution of 72

the poorly water-soluble Irbesartan drug. 73

2. EXPERIMENTAL 74

2.1. Materials. Irbesartan drug was kindly supplied by Dar El-Dawa Pharmaceuticals, 75

Jordan, and Neusilin US2 was also gifted by Fuji Chemical Industry Co., Japan. Mono- 76

and di-basic phosphate buffer was used for the adjustment of different pH values. 77

Deionized and double distillated water was used in all experiments. All other reagents 78

were of analytical grade and used as supplied without further purification. 79

80

2.2. Spectroscopic and thermal techniques. FTIR: Shimadzu IRAffinity-1 FTIR 81

spectrophotometer for functional groups were recorded in the range of 4000−400 cm−1 82

using KBr pellets. Differential Scanning calorimeter (DSC) model: Netzch, 204 F1 83

Phoenix DSC equipped with intra-cooler, Indium standard was used to calibrate the DSC 84

temperature and enthalpy scale. The system was purged with nitrogen gas at a flow rate 85

70 ml/min., and heated from 30-275 °C using a heating rate of 10 °C /min. X-ray 86

diffraction (XRD): Rigaku Goniometer Ultima IV (185mm) X-ray powder diffractometer with 87

cobalt radiation, at a voltage of 40 KV and a current of 20 MA. The scanning rate was 1°/min 88

over a diffraction angle of (2θ) and range of 3°-70° with 0.02 step change. Scanning Electron 89

Microscope (SEM): The film samples were mounted on the specimen stabs and coated 90

with gold ion by sputtering method with (DSM 950 (ZEISS) model) (USA), Polaron 91

(E6100) model. Micrographs were of Polaroid films. 92

93

2.3. Sample preparation and Dissolution Studies. For the solid dispersion samples, 150 94

mg of Irbesartan was put into a stoppered 100 ml round bottom flask. A small quantity of 95

methanol just enough to solubilize Irbesartan was added, and a weighed quantity of 96

Neusilin US2 was dispersed with shaking into drug solution. Three respective Irbesartan-97

Neusilin ratios was prepared as follows; 1:0.5, 1:1, and 1:3 (w/w), then methanol solvent 98

was slowly evaporated under vacuum using a rotary evaporator (Heidolph 4000 efficient) 99

of speed of rotation equals 40 rpm at 60 °C. Collected samples were dried at 70 °C for 72 100

hrs. The dissolution process was performed using USP XXIV type II dissolution 101

apparatus (Dissolution tester RC-8DS). The dissolution medium used was 900 ml 102

phosphate buffer maintained at 37 °C ± 0.5. The paddle speed was 100 rpm and 5.0 ml 103

sample was collected periodically and replaced with equal quantity of dissolution 104

medium. The samples were then filtered with 0.45 µm pore size membrane filter. 105

Consequently, filtered solutions were suitably diluted and analyzed by UV 106

spectrophotometer (Beckman DU-62 spectrophotometer) at 230 nm. Schematic 107

representation of solid dispersion of Irbesartan and Neusilin US2 is available in Scheme 108

1. For the physically mixed samples three different Irbesartan-Neusilin ratios were mixed 109

1:0.5, 1:1 and 1:3 ratios respectively in a closed glass tube using vortex. 110

111

2.4. Microcapsules formation using pre-adjusted pH method. Specific amount of 112

Irbesartan was weighed and put into a stoppered 100 ml round bottom flask. Minimum 113

amount of methanol was added enough to solubilize Irbesartan and a weighed quantity of 114

Neusilin US2 was dispersed in the solution. The solution was thoroughly mixed and the 115

pH of the solid dispersion solution was adjusted to pH=1.2. The solution was left under 116

continuous homogenous shaking using magnetic stirrer for 30 minutes. After time 117

completion, the solvent was slowly evaporated and the pre-adjusted pH1.2 microcapsules 118

were collected. The same procedure repeated using different pre-adjusted pH values 119

namely 4.2, 5.5, 7.4, and different Irbesartan-Neusilin ratios. Dissolution studies using 120

the different pre-adjusted pH microcapsules were carried out at the challenging pH5.5 for 121

which the drug shows the minimum drug dissolution (section 3.2.3.). 122

123

124

Scheme 1. Solid dispersion and dissolution enhancement of Irbesartan and Neusilin US2 125

126

3. RESULTS & DISCUSSION 127

3.1. Characterization of Irbesartan-Neusilin microcapsules 128

3.1.1. Fourier transform infrared (FTIR). The FTIR spectra of Neusilin US2 and solid 129

dispersed Irbesartan-Neusilin microspheres (1:1) illustrated in Figure 1 and Table 1. 130

Apparently, the OH stretching band of silanol group of Neusilin US2 in the Irbesartan-131

Neusilin microcapsules have been reduced by around 14 cm-1 as a result of H-bonding 132

interactions. This was further confirmed by the reduction of Al-O and Al-O-Si band 133

stretchings [24] in the Neusilin-drug microcapsules. The NH stretching of Irbesartan was 134

broad but much less intensed than OH stretching of Neusilin and overlapped with OH 135

stretching, and hence no conclusive remarks could be deduced. The carbonyl group in 136

Irbesartan located at 1733 cm-1 was reduced to 1726 cm-1 in the Irbesartan-Neusilin 137

microspheres indicating stronger electrostatic interactions between Irbesartan and 138

Neusilin macromolecules. Furthermore, the bending bands in Neusilin US2 (i.e. O-Al-O, 139

Al-O-Si, and O-Si-O bands) did not show any significant shift, which indicates 140

insignificant contribution of molecular interactions. 141

142

143

Figure 1. FTIR spectra of Neusilin macromolecules and Irbesartan-Neusilin US2 144 microcapsules (1:1 ratio). 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162

Table 1. FTIR characteristic bands of Neusilin US2, Irbesartan, and solid dispersed 163 Irbesartan-Neusilin US2 microcapsules (1:1 ratio). 164

Bands A cm−1 Polymer

Neusilin US2

O-H str. (Silanol group) Al-O-Si str. Al-O str. O-Al-O Al-O-Si O-Si-O

0.90 0.97 0.42 0.66 0.59 0.87

3453 1023 874 683 550 450

NH str. C=O str. Aromatic C=N str.

0.09 1.25 0.70

3438 1733 1622

Irbesartan

O-H str. (Silanol group) Al-O-Si str. Al-O str. O-Al-O Al-O-Si O-Si-O C=O str. Aromatic C=N str.

0.63 0.82 0.40 0.52 0.45 0.60 0.56 0.41

3439 1017 866 683 550 450 1726 1622

Irbesartan-Neusilin microcapsules

165

3.1.2. Differential scanning calorimetry (DSC). The ability to destroy the drug’s 166

crystalline structure into amorphous structure is a characteristic feature in the dissolution 167

enhancement of poorly water-soluble drugs. Different methods have been employed to 168

increase the amorphization of crystalline drugs such as; melt quenching [25], spray 169

drying [26], melt adsorption [27], and co-grinding [28]. The amorphization process 170

describes the tendency of Neusilin US2 macromolecule to separate packed and crystalline 171

drug macromolecules from each other, increase the free volume between the 172

macromolecules, which allow water penetration, lead to better oriented drug-solvent 173

interactions, better drug’s hydration, and eventually better drug dissolution. Neusilin US2 174

high surface area and especially the silanol groups could form strong H-bonding with 175

tetrazole groups of Irbesartan leading to destruction of crystalline regions [19, 29], which 176

resulted with enhanced drug solubility. Figure 2 illustrate the melting endotherm 177

characteristics, derived from DSC thermogram, of Neusilin US2, Irbesartan drug, and 178

Irbesartan-Neusilin microcapsules. Apparently, the melting enthalpy of Irbesartan has 179

been considerably lowered in Irbesartan-Neusilin microcapsules (Table 2). This could be 180

explained by the destruction of crystalline regions of Irbesartan drug as a result of the 181

interaction with Neusilin US2 macromolecules. Such interaction would lead to weaker 182

drug-drug interactions, stronger drug-excipient interactions, hence lower melting 183

enthalpy of the drug obtained. 184

185

Figure 2. DSC thermograms of Neusilin US2, Irbesartan, and Irbesartan-Neusilin 186 microcapsules 187 188 The %crystallinity change of the solid dispersed samples deduced from DSC thermogram 189

was measured using the following relation [30]; 190

191

%Crystallinity Change =100x (ΔHm,SD/(ΔHm, Irbesaratan x W)) (1) 192

193

Where ΔHm,SD and ΔHm,Irbesaratan were the melting enthalpy (in J/g) of solid dispersed 194

samples and pure Irbesaratn drug, respectively, and W was the weight fraction of 195

Irbesatan in the solid dispersion samples. Table 2 illutrates thermal properties of solid 196

dispersed Neusilin-Irbesartan microparticles. Clearly, the %crystallinity of Irbesartan 197

drug was decreased down to 30.7% in the SD (1:3) sample due to the interaction with 198

Neusilin US2 macromolecules, which led to the destruction of crystalline regions, and 199

hence better dissolution would be obtained. 200

201 202 203

Table 2. Thermal properties of Irbesartan and solid dispersion Irbesartan-Neusilin 204 microcapsules derived from DSC thermograms. 205

Sample Composition Irbesartan(%) Neusilin(%)

ΔH (J/g)

Tm (°C) %Crystallinity

Irbesartan SD (1:0.5)

100 0 67 33

125.1 52.8

187.7 184.1

--- 63.3

SD (1:1) 50 50 19.7 184.6 31.5 SD (1:3) 25 75 9.6 183.8 30.7

206

3.1.3. X-Ray Diffraction (XRD). Figure 3 domonstrated the X-ray diffraction pattern of 207

Neusilin US2, Irbesartan drug, solid dispersion and physical mixing of Irbesartan-208

Neusilin microcapsules. The diffraction pattern of Neusilin show complete amorphous 209

structure whereas, Irbesartan show that the drug exist in crystalline form. This was 210

revealed by the presence of several sharp intensity peaks at diffraction angles (2θ) at 211

4.75°, 12.49°, 19.45°, 23.18° that corresponds to crystalline regions of Irbesartan drug. 212

However, in the physical mixing microcapsules lower intensities of the diffraction peaks 213

observed and much lower intensity peaks were observed in the solid dispersion 214

microcapsules. The reduction in intensity suggests reduction in crystalline regions of drug 215

as a result of amorphization of the drug’s molecules upon salt formation with Neusilin 216

macromolecules. Such results came in accordance with DSC results mentioned above. 217

218 Figure 3. X-ray diffraction pattern (XRD) of Neusilin US2, Irbesartan drug, solid 219 dispersion and physically mixed Irbesartan-Neusilin (1:1 ratio) microcapsules. 220 221 222

3.1.4. Scanning electron microscope (SEM). Figure 4 demonstrated the morphologic 223

changes of Irbesartan drug, Irbesartan-Neusilin microparticles and Neusilin US2 224

macromolecules, respectively using SEM images. Apparently, large crystalline 225

rectangular roddy-like structures of Irbesartan drug with 5-20 μm length and 2-4 μm 226

width were observed (Figure 4A). On the contrary, Neusilin US2 macromolecules show 227

mesoporous and amorphous microspheres with 30-50 μm diameters as seen in Figure 4E. 228

Figure 4B provides evidence on the adsorption of the drug’s crystalline rods on the 229

surface of Neusilin US2 macromolecules. This adsorption occurred via the H-bonding 230

interactions of Neusilin silanol groups with secondary and tertiary amines in the tetrazole 231

groups of Irbesartan drug. Furthermore, the increase of Neusilin content in the Irbesartan-232

Neusilin microparticles results with more adsorption and coverage of Neusilin 233

macromolecules with the crystalline rods of the drug (Figure 4C). This could lead to 234

destruction of the drug’s crystallinity as depicted in Figure 2, and hence enhance the 235

dissolution of the drug. Figure 4D show the 1:3 Irbesartan-Neusilin microparticles. It 236

could be seen that almost no crystalline rods of the drug observed but rather more 237

scattered drug molecules adsorbed on the surface of the Neusilin microspheres. 238

Eventually, such results emphasizes on the role of Neusilin in the destruction of drug’s 239

crystalline regions and the enhancement of the drug solubility and came in accordance 240

with the DSC and XRD results. 241

242

243

244

245

246

247

248

249

Figure 4. SEM images of (A) Irbesartan drug, (B) Solid dispersion Irbesartan-Neusilin microparticles (1:0.5 ratio), (C) Solid dispersion 250 Irbesartan-Neusilin microparticles (1:1 ratio), (D) Solid dispersion Irbesartan-Neusilin microparticles (1:3 ratio), and (E) Neusilin US2 251

3.2. Dissolution Enhancement Parameters 252

3.2.1. Effect of solution pH. The bioavailability of the drug in human tissues depends on the rate 253

of absorption. In addition, the rate of absorption depends on rate of dissolution, which is pH 254

dependent. Therefore, the study of the dissolution of the drug at simultaneous pH increase 255

aqueous solutions (i.e. GI tract) became extremely important. Figure 5 illustrates the change of 256

dissolution of Irbesartan drug versus time at different pH values. Obviously, within the first 60 257

minutes the Irbesartan release reached ∼81% at both pH1.2 and pH7.4. The pKa of Irbesartan 258

determined to be 4.7 [31, 32] indicating that at pH1.2, nitrogen atoms could be protonated 259

forming positive charge groups (i.e. =N− � =NH+−), whereas at pH7.4 the tetrazole group could 260

be deprotonated forming negative charge groups (i.e. −NH− � −N−−). In either case, the 261

ionization of Irbesartan drug leads to formation of similar charge groups that tend to repel each 262

other, decrease structure consistency, allow water penetration and hence increase the drug 263

dissolution in the aqueous medium. On the other hand, at pH5.5 almost no ionized form of the 264

drug and dominant hydrophobic moieties effect resulted with very low dissolution rate (i.e. 265

%Irbesartan release ∼8%). The U-shaped curve of Irbesartan dissolution profile, depicted in 266

Figure 6, showed poorly water-soluble drug behavior at pH5.5, which was the challenging issue 267

for our desire to enhance the dissolution at this significant pH for drug absorption and 268

bioavailability. Therefore, the next dissolution profiles (i.e. Figures 7 and 8) of the drug were 269

accomplished at pH5.5 value. 270

271

Figure 5. The dissolution profiles of 150 mg Irbesartan drug at different pH values. 272

273

274

275

Figure 6. Change of drug release (in %) with solution pH after the passage of 60 minutes. 276

277

278

279

3.2.2. Effect of mixing technique. The mixing type technique of the polymeric vehicle with the 280

model drug play significant role in the drug release and solubility. Therefore, two mixing 281

techniques namely; solid dispersion and physical mixing of Irbesartan with Neusilin were 282

performed. The solid dispersion technique found to be a better technique than physically mixed 283

technique due to micro- and nano-structured incorporations of the drug into the polymeric 284

system. Such nano-structured incorporations adapt the drug for better and controlled release, and 285

as a result enhance its solubility. This could also enhance the drug’s absorption and 286

bioavailability. Figure 7 illustrates the release profiles of the solid dispersion and the physically 287

mixed Irbesartan-Neusilin microcapsules at pH5.5. It could be clearly seen that the solid 288

dispersion samples showed 100% increase than the physically mixed samples. In addition, as the 289

content of Neusilin US2 increased, the drug dissolution enhanced. This could be explained by the 290

amorphous microspheric granules of Neusilin US2 macromolecules that had high specific surface 291

area (i.e. ∼300 m2/g) [34] capable to adsorb higher amount of Irbesartan molecules on its surface 292

in a well-oriented and accumulated forms. 293

294

Figure 7. The dissolution profiles of 150 mg Irbesartan drug at pH5.5 using solid dispersion (SD) 295 or physically mixed (PM) techniques of Irbesartan-Neusilin different ratios. 296 297

298

299

3.2.3. Pre-adjusted pH method. The pre-adjusted pH method meant to establish good interaction 300

between Irbesartan and Neusilin US2 prior to dissolution tests at pH5.5. The presence of silanol 301

groups in Neusilin US2 host macromolecules play dominant role in formation of microcapsules 302

with Irbesartan guest molecules. Ong et al.[35] demonstrated that 19% of silanol groups on fused 303

silica surfaces exhibit a pKa of 4.5, while 81% exhibit pKa=8.5, and this confirm that the silanol 304

groups function as Bronsted acid or as Bronsted base. Furthermore, the similar pKa values for 305

Irbesartan and Neusilin US2 demonstrate amphoteric behavior of both guest and host 306

macromolecules leading to good interaction and salt formation as reported by Watanable et al. 307

[36]. Such good interaction persists and steadily increases as pre-adjusted pH increase due to the 308

formation of larger fractions of positive and negative charges on either Irbesartan or Neusilin 309

molecules. This would lead to higher amount of salt formation, higher amount of crystallinity 310

destruction of Irbesartan drug and hence larger dissolution of the drug at elevated pH pre-311

adjustment. Figure 8 show the dissolution profiles of Irbesartan drug release at pH5.5 using pre-312

adjusted pH method of Irbesartan-Neusilin microcapsules different ratios. Very low drug release 313

at pre-adjusted pH1.2 microcapsules was observed. This indicated poor interaction of Irbesartan 314

and Neusilin macromolecules due to highly repulsive forces between protonated nitrogen atoms 315

of Irbesartan and silanol groups. Such poor interaction reduced the solubility of Irbesartan and 316

hence poorer drug release was obtained (i.e. drug release =22.8%). On the other hand, gradual 317

increase of pre-adjusted pH microcapsules led to better and enhanced drug release. This could be 318

explained by gradual mutual appearance of Bronsted acid or Bronsted base guest/host 319

macromolecules leading to enhanced Irbesartan-Neusilin interaction and better drug release. 320

Eventually, the increase of Irbesartan-Neusilin ratio from 1:1 to 1:3 using pre-adjusted pH7.4 321

microcapsules increased the drug release from 71.9 to 92.5%. This distinguished drug release at 322

1:3 ratio confirm higher amount of silanol groups acting as Bronsted acid that protonated 323

Irbesartan drug, leading to continuous amorphization of crystalline regions, and hence larger 324

amount of salt formation of Irbesartan-Neusilin microcapsules that guarantees maximum drug 325

dissolution enhancement as been depicted by Figure 4. 326

327

328

Figure 8. The dissolution profiles of Irbesartan drug release at pH5.5 using pre-adjusted pH 329 method of Irbesartan-Neusilin microcapsules different ratios. 330 331

332

4. CONCLUSIONS 333

The dissolution of poorly water-soluble Irbesartan drug was greatly enhanced using Irbesartan-334

silica based microcapsules at the challenging pH5.5 value. Characterization techniques such as 335

FTIR, DSC, XRD and SEM elucidate destruction of crystalline regions of the drug and salt 336

formation of Irbesartan-Neusilin microcapsules. Dissolution of the drug was largely increased as 337

pre-adjusted pH increased and as the Neusilin US2 feed ratio increased in the microparticles. The 338

maximum drug release of 92.5% was achieved using pre-adjusted pH7.4 and Irbesartan-Neusilin 339

microcapsules (1:3 ratio). This had adapted the Irbesartan-Neusilin microcapsules to successfully 340

release the drug and enhance its dissolution at the proper time and position. 341

342

5. ACKNOWLEDGMENT 343

Authors wish to acknowledge Jordan University of Science & Technology for support and 344

facilities. 345

346

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27–33. 396

HIGHLIGHTS 397

• Dissolution enhancement of poorly water-soluble Irbesartan via silica microcapsules 398

investigated. 399

• The microparticles were fully characterized using FTIR, DSC, XRD and SEM 400

techniques. 401

• Pre-adjusted pH method was established to enhance dissolution at challenging pH5.5. 402

• The maximum dissolution using microcapsules and pre-adjusted pH method at pH7.4 was 403

92.5%. 404

405

406