There is increasing awareness of seasonal variation in blood pressure (BP). In the present analysis, we investigated seasonal variation in the antihypertensive treatment effect of the irbesartan/hydrochlorothiazide combination in patients with stage 2 and 3 hypertension. The study participants were hypertensive patients enrolled in a 12-week therapeutic study. Antihypertensive treatment was initiated with irbesartan/hydrochlorothiazide 150/12.5 mg/day, with possible uptitration to 300/12.5 mg/day and 300/25 mg/day at 4 and 8 weeks of follow-up, respectively. The month of treatment commencement was classified as spring/summer (May to August) and autumn/winter (September to December). Of the 501 enrolled patients, 313 and 188 commenced antihypertensive treatment in spring/summer and autumn/winter, respectively. The mean changes in systolic/diastolic BP at 8 and 12 weeks of follow-up were greater in patients who commenced treatment in autumn/winter (-32.3/-16.5 and -34.2/-16.7 mmHg, respectively) than those who commenced treatment in spring/summer (-28.4/-13.9 and -27.1/-12.8 mmHg, respectively), with a between-season difference of 3.9 (95% confidence interval [CI], 1.4-6.4, P = 0.002)/2.6 (95% CI, 0.9-4.2, P = 0.002) mmHg and 7.0 (95% CI, 4.7-9.3, P < 0.0001)/3.9 (95% CI, 2.4-5.4, P < 0.0001) mmHg, respectively. Further subgroup analyses according to several baseline characteristics showed a greater between-season difference in the changes in systolic BP in patients aged ≥55 years than in those <55 years (n = 255, 12.6 mmHg vs. n = 246, 6.9 mmHg, P = 0.02), especially in patients who did not use antihypertensive medication at baseline (n = 94, 15.4 mmHg vs. n = 132, 5.4 mmHg, P = 0.006). In conclusion, there is indeed seasonality in the antihypertensive treatment effect, with a greater BP reduction in patients who commenced treatment in cold than warm seasons.

The interindividual heterogeneity in response to the antihypertensive effect of irbesartan has received considerable attention because of gene polymorphism. In this study, we investigated the new combinational influences of AGTR1 and ABCB1 gene polymorphism on the therapeutic effect of irbesartan among Chinese hypertensive patients. A total of 353 samples including 168 normal people and 185 hypertensive patients were adopted, and genotypes comprise ABCB1 (CC, CT, and TT) and AGTR1 (AA and AC) in this study. The results of multiple linear regression models showed that no statistically significant differences were observed in blood pressure change following irbesartan administration in each genotype from either ABCB1 (CC, CT, and TT) or AGTR1 (AA and AC). However, spline smoothing analysis demonstrated that the blood pressure therapeutic responses of irbesartan presented a noticeable difference among different ABCB1 genotypes when irbesartan doses reached over 300 ng/mL. Eventually, we assumed that the different drug responses of irbesartan among various AGTR1 genotypes were due to the diversity of the irbesartan-conjugated protein, which is responsible for crossing-coupled intracellular G-protein-coupled receptors (GPCRs).

Hydrochlorothiazide (HCTZ)/losartan potassium (LOS-K) was used as a model drug to prepare compound tablets through the investigation of the compression and mechanical properties of mixed powders to determine the formulation and preparation factors, followed by D-optimal mixture experimental design to optimize the final parameters. The type and amount of lactose monohydrate (SuperTab®14SD, 19.53-26.91%), microcrystalline cellulose (MCC PH102, 32.86-43.31%), pre-gelatinized starch (Starch-1500, 10.96-15.91%), and magnesium stearate (0.7%) were determined according to the compressive work, stress relaxation curves, and Py value. Then, the compression mechanism of the mixed powder was investigated by the Kawakita equation, Shapiro equation, and Heckel analysis, and the mixed powder was classified as a Class-II powder. The compaction pressure (150-300 MPa) and tableting speed (1200-2400 Tab/h) were recommended. A D-optimal mixture experimental design was utilized to select the optimal formulation (No 1, 26.027% lactose monohydrate, 32.811% MCC PH102, and 15.462% pregelatinized starch) according to the drug dissolution rate, using Hyzaar® tablets as a control. Following oral administration in beagle dogs, there were no significant differences in bioavailability between the No. 1 tablet and the Hyzaar® tablet in HCTZ, losartan carboxylic acid (E-3174), and LOS-K (F < F0.05). Thus, formulation and preparation factors were determined according to the combination of the compression and mechanical properties of the mixed powder and quality of tablets, which was demonstrated to be a feasible method in direct powder compression.

Blutaparon portulacoides is a Brazilian plant species that is widely used in folk medicine. The present study investigated the role of an aqueous extract of B. portulacoides against hypertension in spontaneously hypertensive rats. The aqueous extract of B. portulacoides was obtained from the whole plant. Its chemical profile was analyzed by ultraperformance liquid chromatography-tandem mass spectrometry. The acute toxicity of the aqueous extract of B. portulacoides was evaluated in female Wistar rats. Male 6-month-old spontaneously hypertensive rats then received the aqueous extract of B. portulacoides (30, 100, and 300 mg/kg), hydrochlorothiazide (25 mg/kg), or vehicle once daily for 28 days. On days 1, 14, and 28, the diuretic effects of the aqueous extract of B. portulacoides were evaluated. The role of prostaglandins and the nitric oxide-cyclic guanosine monophosphate-potassium channel pathway in the diuretic activity of the aqueous extract of B. portulacoides was also investigated. At the end of the treatment, hepatic and renal biochemical markers, serum nitrotyrosine, malondialdehyde, nitrite, and aldosterone levels, and angiotensin-converting enzyme activity were measured. The electrocardiographic profile, blood pressure, and renal vascular reactivity were also assessed. The heart, kidneys, and liver were collected to determine relative organ weight, histopathology, and cardiac morphometry. Caffeic acid, ferulic acid, and several flavonoids were identified in the aqueous extract of B. portulacoides. No signs of toxicity were observed. Prolonged treatment with the aqueous extract of B. portulacoides (300 mg/kg) induced significant diuretic activity by activating the nitric oxide-cyclic guanosine monophosphate-potassium channel pathway. These effects reduced blood pressure and oxidative stress and prevented renal vascular dysfunction and left ventricular hypertrophy that was induced by hypertension. Overall, the present data suggest that the aqueous extract of B. portulacoides has important diuretic and cardioprotective effects by activation of the nitric oxide-cyclic guanosine monophosphate-potassium channel pathway.

Treatment inertia is a recognised barrier to blood pressure control, and simpler, more effective treatment strategies are needed. We hypothesised that a hypertension management strategy starting with a single pill containing ultra-low-dose quadruple combination therapy would be more effective than a strategy of starting with monotherapy.

In this paper, hydrochlorothiazide (HCT) and losartan potassium (LSP) in tablets are simultaneously determined with UV-Vis spectrophotometry and chemometrics without separation. The spectra of standard and sample solutions were recorded in the wavelength from 220 to 300 nm at 1.0 nm intervals. The concentrations of HCT and LSP in the sample solutions were computed with the Kalman filter algorithm written on the Microsoft Excel 2016 and Visual Basic for Applications (VBA) platform. The method validation was determined via the accuracy and repeatability of measurements when analyzing HCT and LSP in the Splozarsin Plus tablet and comparing the mean values of their contents in the sample with those analyzed with HPLC. The proposed method is simple with a low cost compared with the standard HPLC method.

The aim of this study was the optimization of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in terms of physicochemical and biopharmaceutical properties, to develop effective and stable aqueous liquid formulations of hydrochlorothiazide, suitable for paediatric therapy, overcoming its low-solubility and poor-stability problems. Based on solubility studies, Precirol® ATO5 and Transcutol® HP were used as solid and liquid lipids, respectively. The effect of different surfactants, also in different combinations and at different amounts, on particle size, homogeneity and surface-charge of nanoparticles was carefully investigated. The best formulations were selected for drug loading, and evaluated also for entrapment efficiency and release behaviour. For both SLN and NLC series, the use of Gelucire® 44/14 as surfactant rather than PluronicF68 or Tween® 80 yielded a marked particle size reduction (95-75 nm compared to around 600-400 nm), and an improvement in entrapment efficiency and drug release rate. NLC showed a better performance than SLN, reaching about 90% entrapped drug (vs. 80%) and more than 90% drug released after 300 min (vs. about 65%). All selected formulations showed good physical stability during 6-month storage at 4 °C, but a higher loss of encapsulated drug was found for SLNs (15%) than for NLCs (<5%). Moreover, all selected formulations revealed the absence of any cytotoxic effect, as assessed by a cell-viability test on Caco-2 cells and are able to pass the intestinal epithelium as suggested by Caco-2 uptake experiments.

Background: Angiotensin II receptor blockers (ARBs) are widely used for the management of hypertension in Japan; however, comparative efficacy data within the ARB drug class remain limited. Methods and Results: This systematic literature review identified randomized controlled trials (RCT) indexed in PubMed and Ichushi in Japanese patients with hypertension receiving ARB monotherapy (azilsartan, candesartan cilexetil, irbesartan, losartan potassium, olmesartan medoxomil, telmisartan, valsartan) in at least 1 arm. Of 763 RCTs identified, 77 met the eligibility criteria; of which, 37 reported mean change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline in the office setting and were used to construct the network. A fixed-effects model (FEM) showed the effect of each drug vs. the reference, azilsartan. Using the FEM, the mean (95% credible interval) change from baseline in SBP/DBP for candesartan cilexetil, irbesartan, losartan potassium, olmesartan medoxomil, telmisartan, and valsartan was 3.8 (2.9-4.8)/2.6 (2.0-3.1), 4.8 (2.0-7.5)/3.7 (1.8-5.6), 3.0 (0.8-5.1)/1.9 (0.5-3.3), 3.2 (1.2-5.1)/2.7 (1.3-4.1), 3.2 (0.8-5.6)/2.0 (0.3-3.6), and 3.1 (1.1-5.1)/2.4 (1.1-3.8) mmHg, respectively. Conclusions: The results of this meta-analysis provide evidence that azilsartan has a more favorable efficacy profile than the other ARBs in reducing SBP and DBP.

Angiotensin-receptor blockers are often considered insufficiently efficacious in reducing blood pressure. However, newer angiotensin-receptor blockers may be more effective than the older ones. A network meta-analysis was performed to compare the efficacy of various angiotensin-receptor blockers in reducing office and ambulatory blood pressure in hypertensive patients. Relevant literature was searched from English and Chinese databases for randomized controlled trials involving angiotensin-receptor blockers in hypertension. Efficacy variables included systolic and diastolic blood pressure either in the office or on ambulatory blood pressure monitoring. Absolute blood pressure reductions at 6-12 weeks of treatment and their credible intervals were reported. A total of 34 publications provided adequate data for analysis (n = 14 859). In 28 studies on office systolic blood pressure (n = 12 731), against the common comparator valsartan 80 mg, the differences in systolic blood pressure were in favor of azilsartan medoxomil (20-80 mg), irbesartan (300 mg), olmesartan (20-40 mg), telmisartan (80 mg), and valsartan (160-320 mg), but not candesartan (8-16 mg), losartan (50-100 mg), irbesartan (150 mg), olmesartan (10 mg), and telmisartan (40 mg). The ranking plot shows that azilsartan medoxomil 80 mg had a possibility of 99% being the best in the class. Similar results were observed for office diastolic blood pressure and from 13 studies for 24-hour ambulatory systolic and diastolic blood pressure. In conclusion, angiotensin-receptor blockers had different blood pressure lowering efficacy. The newest angiotensin-receptor blocker azilsartan medoxomil at the dose of 80 mg seemed to be most efficacious in reducing both systolic and diastolic blood pressure in the office and on ambulatory measurement.

Background. Asphodelus tenuifolius Cav. (Asphodelaceae) is widely used in Pakistan traditional medicine as a hypotensive and diuretic agent. Despite the cardioprotective effects described for A. tenuifolius, the mechanisms involved in its probable hypotensive and diuretic effects have never been evaluated. Firstly, different extracts from A. tenuifolius seeds were obtained, and their antioxidant profiles and chemical constituents by LC-DAD-were determined, including molecular networking by the GNPS platform. Then, to evaluate changes in blood pressure, different groups of anesthetized normotensive rats were intravenously treated with the crude extract (AT-Cr, 1-50 mg/kg), aqueous (AS-AT, 1-25 mg/kg), n-butanol (BS-AT, 1-50 mg/kg), and dichloromethane fraction (DS-AT, 1-80 mg/kg). The diuretic effects of AT-Cr, AS-AT, BS-AT, and DS-AT at 100, 200, and 300 mg/kg, p.o. doses, were also evaluated in comparison with hydrochlorothiazide (HCTZ, 10 mg/kg, p.o). The urinary volume, sodium, potassium, and pH were estimated in the sample collected for 6 h from saline-loaded rats. Using pharmacological antagonists or inhibitors, we determine the involvement of acetylcholine, prostaglandins, and nitric oxide in A. tenuifolius-induced hypotensive and diuresis action. In addition, the activities of angiotensin-converting enzyme, erythrocyte carbonic anhydrase, and renal Na+/K+/ATPase were evaluated in vitro. Acute treatment with crude extract and fractions of A. tenuifolius exhibited significant hypotensive and diuretic potential in normotensive rats. However, AS-AT produced the most potent and significant dose-dependent hypotension and diuretic effects in normotensive rats. Previous treatment with atropine significantly reduced the hypotensive and diuretic action of AS-AT, but pretreatment with indomethacin or L-NAME did not affect these effects. Moreover, the 7-day treatment with AS-AT did not reduce activities of serum angiotensin-converting enzyme, erythrocyte carbonic anhydrase, and renal Na+/K+/ATPase. AS-AT showed four major compound node clusters, which included sugars, alkaloids, nucleoside, amino acid, and glycosylated flavonoids. This research supports and extends the traditional use of A. tenuifolius as a hypotensive and diuretic agent. The results showed that AS-AT from A. tenuifolius could present compounds responsible for hypotensive and diuretic activities through the activation of muscarinic receptors.

In a 12-week, randomized, controlled trial, we investigated whether home blood pressure monitoring (HBPM) would improve treatment adherence and blood pressure control in stage 2 and 3 hypertension. Eligible patients (18-75 years of age and 160-199/100-119 mmHg of clinic systolic/diastolic blood pressure after a 1-week wash-out) were randomized in a 1:4 ratio to an experimental group (with HBPM) and a control group (without HBPM). All patients started antihypertensive treatment with the irbesartan 150 mg/hydrochlorothiazide 12.5 mg/day combination, with the possible addition of irbesartan 150 mg/day and uptitration to irbesartan 300 mg/hydrochlorothiazide 25 mg/day at 4 and 8 weeks of follow-up, respectively. The primary endpoint was the clinic blood pressure control (systolic/diastolic, nondiabetes <140/90 mmHg and diabetes <130/80 mmHg) rate at 12 weeks of follow-up. The randomized patients in the HBPM (n = 96) and control groups (n = 405) had similar characteristics at baseline and similar use of higher dosages of irbesartan/hydrochlorothiazide (300 mg/12.5-25 mg) at 4 (9.4% vs. 12.2%, P = 0.45) and 8 weeks of follow-up (27.1% vs. 35.5%, P = 0.13). During follow-up, both the cumulative treatment discontinuation rate (1.0% vs. 12.6%, P = 0.0008) and the less optimal treatment adherence rate (<90% of prescribed medication, 1.0% vs. 9.9%, P = 0.005) were significantly lower in the HBPM group than in the control group. The proportion of patients who achieved the goal of clinic blood pressure control at 12 weeks of follow-up was significantly higher in the HBPM group than in the control group (66.7% vs. 55.1%, P = 0.04). In conclusion, HBPM improved treatment adherence and blood pressure control in patients with hypertension, despite similar antihypertensive treatment intensities.

Depending on each institution's laboratory test, mean serum calcium levels range between 8.8 and 10.8 mg/dL and hypercalcemia is defined as two standard deviations above the mean. According to recent epidemiological studies, 90% of cases of hypercalcemia are due to hyperparathyroidism or malignancy. Milk Alkali syndrome (MAS) also known as Calcium Alkali syndrome (CAS) is the third biggest cause of hypercalcemia, but its incidence seems to be higher than previously thought. Here we present a case of Calcium Alkali Thiazide syndrome (CATS) in a 57-year-old female who was on calcium and vitamin D supplements (after parathyroidectomy) while also taking thiazide diuretic for hypertension. She was brought to the ED with nausea, vomiting, confusion, difficulty walking along with numbness in extremities. She had parathyroidectomy three weeks ago. During history taking, patient reported intake of calcium carbonate 1 g three times daily, calcitriol 0.5 mcg twice daily, cholecalciferol (vitamin D3) 10,000 units once daily, chlorthalidone 25 mg once daily and irbesartan 300 mg once daily. At admission, her calcium level was 23 mg/dL, ionized calcium 12.03 mg/dL, pH was 7.59 and HCO3 was 33. She was in renal failure with creatinine of 1.9 mg/dL (baseline 0.8 mg/dL). Her parathyroid hormone (PTH) level was 0. A diagnosis of CATS was made. She was treated with intravenous fluids and furosemide and discharged home on hospital day 5 after her calcium and creatinine levels normalized. A triad of hypercalcemia, acute kidney injury and metabolic alkalosis comprises MAS. Traditional MAS was caused by "Sippy diet" (containing milk and alkali) used for the treatment of peptic ulcer disease. Over the decades, the same triad of symptoms occurred in patients using excess calcium and vitamin D, hence changing the name to CAS. A subset of patients at risk for CAS also use thiazide diuretics for hypertension, making them more vulnerable to hypercalcemia and acute kidney injury. In such subset of patients, it is preferable to use the term CATS rather than MAS or CAS.

A Simple, Specific, Precise, Accurate, Linear, Rugged, Robust High Performance Liquid Chromatographic method of analysis for simultaneous determination of assay of Amlodipine, Valsartan and Hydrochlorothiazide drugs in the pharmaceuticals tablet formulations using Pioglitazone as a common internal standard was developed and validated. The assay was accomplished using a mixture of acetonitrile & methanol in the volume ratio of 20:80 v/v (mobile phase B) and Ammonium acetate buffer (Mobile phase A) in gradient flow as mobile phase on an Hibar RP-18e, 250 × 4.6 mm, 5µ as chromatographic column at a flow rate of 1.300 mLmin-1, injection volume 10 µL and at a wavelength 235 nm with UV detector. Linearity of the analytical method was evaluated at a concentration range of 2.5-45.3 µg/ml for Amlodipine, 32.0-720.1 µg/ml for valsartan and 5.0-112.6 µg/ml for Hydrochlorothiazide respectively with Correlation coefficient (r) value more than 0.9997. The limit of detection (LOD) for Amlodipine, Valsartan and Hydrochlorothiazide was found to be 1.1 µg/ml, 8.0 µg/ml & 1.0 µg/ml respectively. Specificity, Method Precision, System Precision, Ruggedness, Robustness, Recovery, Stability of analytical solution, Filter paper selection study, Stress testing (Force Degradation) at various conditions were performed as per the ICH (Q2) recommendations. The chromatographic method may also be applied for simultaneous estimation of analytes in plasma and urine.

The prevalence of emerging contaminants of concern in water regimes is very common these days. High anthropogenic intervention is leading to occurrence of various types of microcontaminants of concern in drinking water systems. Their removal using conventional form of treatment systems employed in water treatment plants is not widely researched upon. Their fate in the conventional as well as advanced water treatment system needs to be focused upon for efficient and safe water disposal. Some compounds may leave the system unchanged or some might transform into much more toxic byproduct. Moreover, understanding level of occurrence of these emerging contaminants in source water bodies is also quintessential for assessing their fate in treatment plant itself as well as in the final treated water. Here in this study, the occurrence and removal of various classes of emerging contaminants were investigated in a moving bed biofilm reactor (MBBR)-based advanced drinking water treatment plant (ADWTP) alongside one conventional drinking water treatment plant, both of which use River Yamuna as the source of water. Non-target analysis utilizing high-performance liquid chromatography combined with time of flight (HPLC-QToF) identified more than 300 compounds. Pharmaceuticals accounted for a major fraction (58%) of the identified compounds, followed by plasticizers and insecticides. Nine parent compound and their transformation products were additionally identified using solid-phase extraction followed by analysis using gas chromatography mass spectrometry and HPLC-QToF. The degradation pathway of the parent compounds in MBBR-based ADWTP was also analyzed in depth. The efficiency of each unit process of MBBR-based drinking water treatment plant was studied in terms of removal of few emerging contaminants. Pharmaceutical compound like diclofenac supposedly was persistent, even, toward the end of the treatment train. Semi-quantitative analysis revealed ineffective removal of pyridine, hydrochlorothiazide, and diethyl phthalate in the outlet of ADWTP. ADWTP was able to remove a few emerging contaminants, but a few were recalcitrant. Likewise, it was established that although some parent compounds were degraded, much more toxic transformation products were formed and were prevalent at the end of the treatment.

Acetazolamide (molecular mass (MM), 222) belongs to the class of sulfonamides (R-SO2-NH2) and is one of the strongest pharmacological inhibitors of carbonic anhydrase activity. Acetazolamide is excreted unchanged in the urine. Here, we report on the development, validation and biomedical application of a stable-isotope dilution GC-MS method for the reliable quantitative determination of acetazolamide in human urine. The method is based on evaporation to dryness of 50 μL urine aliquots, base-catalyzed derivatization of acetazolamide (d0-AZM) and its internal standard [acetylo-2H3]acetazolamide (d3-AZM) in 30 vol% pentafluorobenzyl (PFB) bromide in acetonitrile (60 min, 30 °C), reconstitution in toluene (200 μL) and injection of 1-μL aliquots. The negative-ion chemical ionization (NICI) mass spectra (methane) of the PFB derivatives contained several intense ions including [M]‒ at m/z 581 for d0-AZM and m/z 584 for d3-AZM, suggesting derivatization of their sulfonamide groups to form N,N-dipentafluorobenzyl derivatives (R-SO2-N(PFB)2), i.e., d0-AZM-(PFB)2 and d3-AZM-(PFB)2, respectively. Quantification was performed by selected-ion monitoring of m/z 581 and 83 for d0-AZM-(PFB)2 and m/z 584 and 86 for d3-AZM-(PFB)2. The limits of detection and quantitation of the method were determined to be 300 fmol (67 pg) and 1 μM of acetazolamide, respectively. Intra- and inter-assay precision and accuracy for acetazolamide in human urine samples in pharmacologically relevant concentration ranges were determined to be 0.3%-4.2% and 95.3%-109%, respectively. The method was applied to measure urinary acetazolamide excretion after ingestion of a 250 mg acetazolamide-containing tablet (Acemit®) by a healthy volunteer. Among other tested sulfonamide drugs, methazolamide (MM, 236) was also found to form a N,N-dipentafluorobenzyl derivative, whereas dorzolamide (MM, 324) was hardly detectable. No GC-MS peaks were obtained from the PFB bromide derivatization of hydrochlorothiazide (MM, 298), xipamide (MM, 355), indapamide and metholazone (MM, 366 each) or brinzolamide (MM, 384). We demonstrate for the first time that sulfonamide drugs can be derivatized with PFB bromide and quantitated by GC-MS. Sulfonamides with MM larger than 236 are likely to be derivatized by PFB bromide but to lack thermal stability.

Irbesartan, a long acting selective angiotensin-1 receptor inhibitor, in Marfan syndrome might reduce aortic dilatation, which is associated with dissection and rupture. We aimed to determine the effects of irbesartan on the rate of aortic dilatation in children and adults with Marfan syndrome.

The objectives of this study were to evaluate the impact of formulation variables on the drying of nanocrystalline suspensions either via bead layering or spray granulation and develop mini-tablets from the dried nanocrystalline powders. Irbesartan (crystalline Form B), a poorly soluble drug substance was chosen as a model compound. An optimized irbesartan nanocrystalline suspension with a mean particle size of 300 nm was utilized for the downstream processing. Irbesartan nanocrystalline suspension was dried either by layering onto the microcrystalline cellulose beads (i.e. 200 or 500 µm) or by granulation (mannitol or microcrystalline cellulose as substrates) at two different drug loadings (i.e. 10% or 30% w/w). Smaller size beads layered with nanocrystals resulted in faster dissolution profiles compared to larger size beads at both the studied drug loadings (i.e. 10 and 30% w/w). Mannitol granules containing irbesartan nanocrystals resulted in faster dissolution profiles compared to microcrystalline cellulose granules. Microcrystalline cellulose beads and mannitol granules containing irbesartan nanocrystals (i.e. 30% w/w drug loading) were further compressed into mini-tablets. Mini-tablets retained fast drug dissolution characteristics of the dried powders. The results from this study indicated that the spray granulation is a superior drying approach compared to bead layering for drying of irbesartan nanocrystalline suspension and mini-tablet development.