Iraqi J Pharm Sci, Vol.31( 2 ) 2022 Oroslippery tablets irbesartan and hydrochlorothiazide DOI: https://doi.org/10.31351/vol31iss2pp91-100 91 Preparation and Evaluation of Oroslippery Tablets Contain Irbesartan and Hydrochlorothiazide Combination Yaseen T. Khalaf *, Yasir Q. Almajidi1,**, Naeem M. Shalan*, Israa H. Alani* and Wael A. Abu Dayyih*** *Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Al-Ahliyya Amman University, Jordan. ** Department of Pharmaceutics, Baghdad College of Medical Sciences, Baghdad, Iraq *** Faculty of Pharmacy, Mutah University, Jordan. Abstract Oro slippery tablets (OSTs) is a technique used to improve swallowing of tablets for patients with dysphagia. The aim of this study was to formulate irbesartan, a hypotensive agent and hydrochlorothiazide, a duiretic as Oroslippery tablets (OST) containing 150 mg irbesartan and 25 mg hydrochlorothiazide designed for dysphagia patients. A simple and rapid method of analysis was developed and validated according to the ICH guideline using HPLC with UV detector. Tablets were prepared by direct compression and then coated with the slippery coat of three different concentrations of the slippering substance “xanthan gum’ (2%, 3% and 4%) in Opadry Colorcone® and evaluated according to USP. Slipperiness test was performed using Albino rabbits. Results showed that 2% xanthan gum gave the shortest swallowing time. Also, disintegration time was increased by the coat significantly with the increase of the gum’s concentration in the coat. The release kinetics study of the tested formulations (uncoated versus coated with 2% gum) gave the highest correlation for the "first-order release model" for both drugs in the absence and presence of the slippering agent which indicates that the coating did not interfere with the release kinetics of both drugs. In a conclusion, 2% xanthan gum as slippering agent was the optimum concentration used to promote easy ingestion of this tablet. Keywords: Dysphagia, Hydrochlorothiazide, Irbesartan, Oroslippery tablets (OST), and Slipperiness test, HPLC, ICH guideline. زلقة التي تحتوي على مزيج اربيسارتان وهيدروكلور ثايازايد نوتقييم األقراص الفموية الم تحضير * إسراء حامد العاني ،*شعالن مصطفى نعيم ،1**،ياسر قاسم الماجدي ،*ياسين طه خلف *** أبوديةأحمد وائل و االردن -قسم الصيدالنيات والتقنية، كلية الصيدلة، جامعة عمان االهلية* العراق -قسم الصيدالنيات، كلية بغداد للعلوم الطبية، بغداد ** ا األرد -كلية الصيدلة، جامعة مؤتة *** الخالصة ( المنزلقة تحفيز OSTsاألقراص عامل دمج تحضيرها يتضمن البلع. عسر لمرضى األقراص بلع لتحسين تستخدم تقنية هي ) وهو مدرر والهيدروكلورثايازايدوالذي هو عامل مخفض لضغط الدم االنزالق في مادة الطالء. تهدف هذه الدراسة الى صياغة عقار االربيسارتان لمرضى عسر البلع مصممة ملغم هيدروكلورثايازايد 25لغم اربيسارتان وم 150على شكل أقراص فمويه منزلقة تحتوي على ( باستخدام التحليل السائل عالي ICHالمؤتمر العالمي للتوافقية ) تم تطوير طريقة بسيطة وسريعة للتحليل والتحقق من صحتها وفقًا إلرشادات الكفاءة مع كاشف االشعة فوق البنفسجية. ٪ 3٪ ، 2تم تحضير األقراص عن طريق الضغط المباشر ثم تم تغطيتها بطبقة زلقة من ثالثة تراكيز مختلفة من المادة المنزلقة "صمغ الزانثان" ) الغالف "كولوركون" ثم تقييمها حسب دستور االدوية االمريكي. ٪( في4و ٪ أعطى أقصر وقت للبلع. كما زاد وقت تفكك الطبقة بشكل 2ائج أن صمغ الزانثان أظهرت النتو تم إجراء اختبار االنزالق باستخدام أرانب ألبينو . في الغالف الصمغكبير مع زيادة تركيز ( أعلى ارتباط لـ "نموذج اإلطالق من الدرجة األولى" لكال الزانثان٪ صمغ2أعطت دراسة حركية اإلطالق للصيغ المختبرة )غير المطلية مقابل . وجود عامل االنزالق مما يشير إلى أن الطالء لم يتدخل مع حركية إطالق كال العقارينالعقارين في غياب و هذه االقراص. ٪ صمغ الزانثان كعامل انزالق ، هو التركيز األمثل المستخدم لتعزيز سهولة تناول2 فإن في الختام ، رشادات ، االتحليل السائل عالي الكفاءة ، اختبار االنزالق ، األقراص الفموية المنزلقة ، اربيسارتان ، هيدروكلور ثايازايد، عسر البلع لكلمات المفتاحية:ا المؤتمر العالمي للتوافقية 1Corresponding author E-mail: almajidiyasir@gmail.com Received: 29/9 /2021 Accepted: 5/12 /2021 Iraqi Journal of Pharmaceutical Science https://doi.org/10.31351/vol31iss2pp91-100 Iraqi J Pharm Sci, Vol.31(2) 2022 Oroslippery tablets irbesartan and hydrochlorothiazide 92 Introduction The term “dysphagia” is widely used to describe a symptom that is manifested as subjective perception of swallowing difficulty during the passage of a liquid or a solid bolus from the oral cavity to the stomach or obstruction perception during swallowing (1-3). Oropharyngeal dysphagia is a common type of dysphagia that refers to an oral preparatory, pharyngeal and/or oral swallowing disturbance (4). Various dosage forms are developed to combat dysphagia for which medications are administered into the oral cavity even without requirement for chewing to create a systemic or local effect. Effervescent and lozenges tablets, as well as sublingual (SL), buccal, Orodispersible (ODTs), and the newly developed oroslippery (OS) tablets, are among them (5-8). Dysphagia is a serious problem requires continuous treatments; new formulations will be helpful in controlling the progression of this problem and offer comfort to the patients. Modification of the available dosage forms especially the widely used oral tablets is an ongoing process in pharmaceutical industry. One new modification is by the introduction of a material that induce a slipperiness characteristic to the tablet coat which facilitate easy smooth swallowing of the tablet (9,10) Hypertension (HTN) affects over one billion persons globally, with a systolic BP of higher than the 140 mmHg and/or the diastolic BP lesser than the 90 mmHg. HTN is a serious health issue that is a common risk factor of cardiovascular disease (CVD) and death (11). More than 50% of hypertensive patients have additional cardiovascular risk factors. The most common additional risk factors are diabetes (15%– 20%), lipid disorders (elevated low-density lipoprotein-cholesterol [LDL-C] and triglycerides [30%]), overweight-obesity (40%), hyperuricemia (25%) and metabolic syndrome (40%), as well as unhealthy lifestyle habits (e.g., smoking, high alcohol intake, sedentary lifestyle). The presence of one or more additional cardiovascular risk factors proportionally increases the risk of coronary, cerebrovascular, and renal diseases in hypertensive patients (12). Irbesartan is administered orally and competitively antagonize the angiotensin II receptors that is being used to manage the hypertension and the kidney impairment in hypertensive and diabetic individuals. Among humans’ smooth muscle vascular cells, it shows high affinity to the receptor of AT1, causing a decrease of peak response for angiotensin II (13). Irbesartan is a solid crystalline powder slightly soluble in water with M.Wt. 428.5 and pKa(s) 4.08, 4.29 (14). Hydrochlorothiazide is a diuretic of the thiazide form that has been available for more than 5 decades for clinical use (14). Hydrochlothiazide hydrochloride is a thiazide derivative with Mwt (334.2 g/mol). It is a white crystalline powder, slightly soluble in water and freely soluble in sodium hydroxide solution.(15) Irbesartan is available in a fixed-dose combination formulation with hydrochlorothiazide, to achieve an additive antihypertensiveeffect. Irbesartan/hydrochlorothiaz ide combination preparations are marketed under various brand names. A 25mg of HCT with 300mg IRB can exhibit synergistic antihypertensive efficacy in such a dose-dependent way with excellent tolerability in a variety of patient classes. In individuals who are not managed neither IRB nor HCT alone, the mixture lowers the BP considerably. The combination of these drugs had a beneficial impact. IRB seemed to attenuate hypokalemia, uric acid and the total cholesterol side effects that caused by HCT in many experiments (16). Oroslippery tablets (OSTs) aim to facilitate the swallowing of the tablets by the modification of the coat to offer slippery smooth passage of the tablet especially that of large size through pharynx and esophagus. Very few studies are available and many factors that affect the efficiency of the coat are still in need to be studied. A study of Mahdi and Marie in 2015 described coating of valsartan tablet with kollicoat immediate release (IR) (film former) and xanthan gum(slipperiness inducer) at different coating levels.(10) Opadry Colorcone is a coating mixtute powder introduced by Colorcone. It is one-step film coating system which combines polymer, plasticizer and pigment, as required, in a dry concentrate. Different types of Opadry are available depending on the type of polymer if it produces immediate release, controlled release or enteric coating. (17) Xanthan gum is an extracellular polysaccharide secreted by the microorganism Xanthomonas campestris. Commercially it is manufactured by a fermentation process. The xanthan gum polysaccharide consists of a backbone of β‐(1→4) linked d‐glucose molecules. Every second glucose molecule is substituted at C3 with a trisaccharide side chain consisting of β‐d‐mannose‐(1→4)‐β‐d‐glucuronic acid‐(1→2)‐α‐d‐mannose. It has many uses as food additives, viscosity builder and pharmaceutical uses. (18) The aim of this study is to formulate a combination of Irbesartan and hydrochlothiazide as oroslippery tablets by formulation of this combination as core tablets then coating with https://en.wikipedia.org/wiki/Fixed-dose_combination https://en.wikipedia.org/wiki/Hydrochlorothiazide Iraqi J Pharm Sci, Vol.31(2) 2022 Oroslippery tablets irbesartan and hydrochlorothiazide 93 Opadry colorcone immediate release tablets with different ratios of xanthan gum as slippery agent and evaluation of the tablets. Materials and Methods Materials Irbesartan was purchased from (purity 99.5%, Jiangsu Yew Pharmaceuticals Co. Limited, China) Hydrochlorthiazide (purity 99.6% Provizer Pharma, India), sodium starch glycolate, Avicel (PH102), aspartame, mannitol, peppermint flavor, aerosol (hydrophilic grade), Na stearate, Xanthan gum and Opedry ® Colorcon were all given as gift from Dar Al Dawa pharmaceutical/Jordan. Methanol (Merck) HPLC grade, tetrahydrofuran, sodium acetate (Sigma), acetic acid (Sigma), sodium hydroxide (Sigma). Methods Chromatographic condition High Performance Liquid Chromatography (HPLC) was used as a method of analysis to detect and quantitate IRB and HCT in tablet intended to be prepared. After several trials the chromatographic conditions showed in Table 1 were decided and followed. The elusion was isocratic were the composition and flow rate of mobile phase was constant along the run time. Table 1. Chromatographic conditions used in method development Component Type HPLC Server (LC-Thermo) with by LC Solution Software Detector UV detector. Wavelength 265 nm Mobile Phase methanol-tetrahydrofuran: acetate buffer pH 6.5 (47:10:43) v/v/v. Flow Rate 1ml/min Injection Volume 20 µl Total Run Time 9 min Column Supelcosil C18 (150 mm × 4.6 mm, 5 nm part..size) Column Temp. Room temp (25oC). The method was validated by measuring Linearity, precision, accuracy and recovery for both drugs measured simultaneously. Linearity of IRB was measured by measuring concentrations range (10, 20, 40, 80, 140, 180) μg /ml and of HCT (1, 12, 24, 36, 44, 50) μg/ml. Regression and correlation coefficient was calculated. Inter and intra-day precision of the method were determined by the analysis of 6 samples (calibration conc.) with 3 replicates and calculation of percent coefficient of variation (%CV). While recovery of drugs was calculated by analysis of powder mixture (before compression). Conc. of IRB used were (35, 50, and 65 μg/ml) and for HCT also, (31, 45, and 58 μg/ml) μg/ml) using different degrees of dilution. All tests were performed and evaluated according to the ICH guideline. Formulation of core tablet A standard formula was prepared as in Table 2. One hundred tablets were prepared and evaluated. Then other batches were prepared for coating Table 2. Composition of IRB-HCT combination core tablet Ingredient Amount (mg) /tab. Irbesartan (IRB) 150 mg Hydrochlorothiazide (HCT) 25 mg Sodium starch glycolate 20 mg Avicel (PH102) 150 mg Mannitol 47 mg Aerosil (hydrophilic grade) 4 mg Na stearate 4 mg Total weight 400 mg One hundred (100) tablets - batch of the formula was prepared. All ingredients were weighed, and mixing process was performed manually by wide mouth conical flask. First all materials were sieved through mesh no. 36 to get rid of any particulate materials. Then all constituents except the lubricant were put the flask and rotated manually in one direction for 20 min. After that the lubricant was sieved in 60 mesh size and added to the mixture and mixed for 1-2 min (19). The obtained powder blend was directly compressed into tablets using tablet press (Erweka, single punch compression machine) using oval shape upper punch and die (20). One hundred tablets of the formula were compressed Evaluation of the prepared tablets Uniformity of weight Weight variation of the prepared tablets were performed by weighing, randomly selected, twenty tablets individually from each formula using electrical sensitive balance (Shimadzu, Japan) and the average weight ±SD was calculated (21). Tablet thickness Thickness of tablets was measured using thickness caliper (Mitutoyo® CD-15B, England) for 10 randomly selected tablets. Average thickness in mm ±SD was recorded (22). Iraqi J Pharm Sci, Vol.31(2) 2022 Oroslippery tablets irbesartan and hydrochlorothiazide 94 Hardness and friability The breaking force (hardness) was measured using hardness taster (Dr. Schleuniger Pharmatron 8M, Switzerland). The test was performed in the beginning, during and at the end of the tablet production to ensure a fixed hardness over the production process. Friability of the tablets was determined using (Erweka® TA 100 friability tester, Germany). Twenty tablets were initially weighed (Wt1) and transferred into Friabilator. The Friabilator was operated at 25 rpm for 4 mins. The tablets were weighed again (Wt2). The percentage (%) of friability was then calculated using equation 7: Percentage of friability = 𝑾𝟏−𝑾𝟐 𝑾𝟏 x 100 % Where W1 is weight of 20 tablets before placing in Friabilator and W2 is the weight of 20 tablets after taking out of Friabilator (23). Disintegration time Disintegration time was determined using the disintegration apparatus USP (Electrolab, Bangalore, India) in D.W maintaining the temperature at 37 ± 1°C. Six tablets were used. Each tablet was put in each vessel and time of disintegration was recorded in minutes± SD (24). Assay of APIs in the tablets Twenty tablets were taken randomly from the prepared tablets and crushed to fine powder. A powder weight was taken equivalent to 150 mg IRB and to 25 mg HCT. Mobile phase of the validated method was used to solubilize the drug each time to 50 ml total volume. Solution was filtered through 0.45 µm membrane filter to get clear solution. Suitable dilutions were made to get concentration of IRB 50 µg/ml and 40 µg/ml HCT and each drug content was calculated from its calibration curve(25). Coating process Tablets were coated using Opadry colorcone® to which added the slippering agent in different concentrations and other additives. Table 3 shows the coating formulations. Three liters of each coating formula was prepared. Solid materials were all weighed and put aside. A mixture of solvent system (60:40) water: ethanol (90%) was prepared in 3500 ml hard glass beaker and put under electrical stirrer. 2750 ml solvent system was put first then gradually adding the solid material while starting low speed stirring until the whole quantity is added. The stirring speed was then increased until fixed onto 1000 rpm for 40 min. Then the speed was gradually decreased to avoid air bubbles and stopped. Volume was completed to 3 L and additional 15 min of stirring were added to ensure homogenization. The coating dispersion was freshly prepared before each coating run (17). Due to small number of tablets prepared, the coating pan was loaded with placebo tablets (made of compressed avicel) to make tablets rolling over and the optimization of coating parameters easier (17). The tablets prepared for the animal study were smaller in size (50 mg wt.) in addition to the placebo bulk. The bed was pre-heated to 40oC using dryer and thermometer, the coating pan was loaded with the tablets and switched on. Few tablets were taken after 60, 80 and 100 min for inspection and weighing. The coating process was stopped after 100 mins. where the weight gain was 3 % (average 11-14 mg) (26). Table 3. The experimental design and formulas of the slippering coat. Material Control formula (CF)(%) Coating formula 1 (CF1)(%) Coating formula 2 (CF2)(%) Coating formula 3 (CF3)(%) Opadry 12 12 12 12 Xanthan gum (Slippering agent) 0 2 3 4 Peppermint flavor 0.5 0.5 0.5 0.5 Aspartame (sweetener) 0.1 0.1 0.1 0.1 Total solid concentration 12.6 14.6 15.6 16.6 Evaluation of the coated tablets Weight gain by coat Weight uniformity test was repeated on coated tablets and the average weight gain by coating process was calculated.(27) Thickness of coated tablets Thickness of coated tablets was measured to check the increase in tablet thickness due to coating process. 10 tablets were chosen randomly, and the thickness was measured by (Mitutoyo® CD-15B, England). Average thickness ±SD was recorded and compared with the thickness of the uncoated tablet statistically. (22) Disintegration time Disintegration time was repeated for the coated tablets, average time ±SD was recorded for Iraqi J Pharm Sci, Vol.31(2) 2022 Oroslippery tablets irbesartan and hydrochlorothiazide 95 each formula and compared statistically to the standard uncoated formula. (24) Slipperiness test Four albino rabbits were used in this test. (Ethical approval dec. 6/7 20-21, Al-Ahliyya Amman University). Each one received 3 tablets of the specified concentration of the slippering agents. Rat 1 received tablets coated with Opadry without slippering agent, rat 2 received coated tablets with 2% Slippering agent, Rat 3 received tablets of 3% slippering agent and Rat 4 received tablets of 4% slippering agent. The rabbits were given water to drink immediately prior the test to avoid dry mouth. Then a tablet is put on his tongue and time is recorded as zero time, then the hand is put gently on his throat to sense the swallowing of the tablet. This moment is recorded as time from zero. Three readings were taken for each tablet tested, average ±SD was estimated.(10) Drug release and dissolution The dissolution test conditions were chosen according to the USP monographs and published works of both drugs. USP App II with 0.1 N HCl (900 ml) as a dissolution media, 75 rpm stirring rate and the temperature of 37±0.5 oC were chosen as dissolution conditions. Time points: 5, 10, 15, 20, 30, 45, 60 min. Six (6) tablets were put each in a jar and 5 ml samples were withdrawn and replaced by fresh media to keep sink condition, Samples were taken at time points; 5, 10, 15, 20, 30, 45, and 60 min., filtered through 0.45µm and suitably diluted by mobile phase and analyzed using the validated method developed and data was reported as average conc. ±SD of each reading. Then percent drug dissolved vs time was plotted as the dissolution profile. Dissolution test was performed on the uncoated formula and the coated formulas. (28) Results and Discussion Method development and validation IRB absorbs at 270 nm (29) and HCT has maximum absorption at 238 and 271 nm (30). These values differ slightly according to the method. Here, 265 nm was chosen as suitable λ for best results where a good absorption of both occurs and both peaks appeared in the same chromatogram clearly using the specified mobile phase. HCT was eluted first with RT = 3.0 min, then next IRB with RT= 6.5 min. Figure 1 shows one chromatogram of IRB and HCT and the clear separation of the two APIs. Figure 1. Chromatogram showing peaks of HCT (30 µg/ml) and IRB (80 µg/ml) IRB and HCT showed linearity in the specified concentrations with correlation coefficient equals to 0.999 for both drugs and relative standard deviation (RSD) less than 2.00. Calibration curves are shown in figure 2 (A and B). 4 A B Figure 2. Calibration curves of Irbesartan (A) and Hydrochlorothiazide (B) Inter and intra-day precision results gave the mean value of percent accuracy between 97.7 - 101.1% for both IRB and HCT and the %RSD is below 2%, which means an accepted criterion according to the ICH guideline. Recovery of IRB from the formula was 99.3% with RSD 0.46 and that of HCT was 98.0 with RSD equals to 0.9. Formulation design and powder preparation The master formula was prepared using sodium starch glycolate as disintegrant, avicel and mannitol as bulking agents. The powder mix was Iraqi J Pharm Sci, Vol.31(2) 2022 Oroslippery tablets irbesartan and hydrochlorothiazide 96 prepared, and no segregation of materials was detected. This may be related to close particle size achieved by sieving before mixing process. No clogging or attachment of powder to the flask walls was observed except minor dusting. Physical evaluation of the prepared tablets The obtained tablets were inspected visually. Tablets were good shaped with sharp edges, shiny, smooth with bright white color. No cracks, no capping or peeling were observed. Considering uniformity of weight, the average weight of ten tablets was measured individually according to the specification of the USP (21). Tablets weigh less than 180 mg might have less than ±10 % of weight variation. Tablet’s weight 180-325 mg would accept ±7.5 % while tablets weigh more than 325 mg would accept ± 5 % of its weight variation. No tablet should weigh more or less than double the allowed percent variation. Average theoretical weight of the tablets is 400 mg, and it follows the third category All tablets were in the USP specifications, and this reflects the efficiency of compression process. Results are shown in Table 8. Thickness of tablets are shown in table 8. Coating will add to the tablets and would be measured again to detect how much thickness the coat would add. Hardness and friability Hardness of tablets should be enough to handle coating process and satisfy the properties of immediate release tablets and allow disintegration and dissolution. Friability of tablets should not exceed 1% according to the USP which is like regular tablets. After several trials in compression of the formula, the hardness was kept on 5 Kg and friability was below1%. Results of weight uniformity, hardness, friability and disintegration test are shown in table 5. Disintegration time of the uncoated tablets was 5.6 ± 0.8 min, this result is compatible with the specification of USP of immediate release tablets. Table 5. Results of physical evaluation of the uncoated tablets Test Results (Average ± SD) Weight Uniformity test (mg) N= 20 403±6.2 Hardness (Kg) 5.0 ± 0.1 Friability (%) 0.3 Disintegration time (min) 5.6 ± 0.8 min Assay of active ingredient in the tablets Results of assay of APIs in the prepared tablets are presented in table 6. Percent drug recovery of IRB and HCT was high and close to 100% knowing that the guideline allows 90-110% drug content in the dosage form. Table 6. Results of assay of IRB and HCT in the prepared uncoated tablets Tablets APIs Theoretical Concentration (µg/ml) Average Area measured n=3 Actual Concentration (µg/ml) Percent content (%) Precision (RSD) IRB 50.0 21047.42 48.90±1.2 97.8 0.8 HCT 40.0 37735.6 41.1±0.9 102.75 0.7 Tablet coating The coated tablets with the slippering coat were prepared as described earlier. The 3 batches were re-evaluated physically before performing the slipperiness test. The coated tablets were examined visually. They showed good appearance, uniform white color with no peeling or mottling. Tablets are shown in Figure 3. Weight gain by coating Film coating should not add much weight to the tablets. Weight gain was checked during or before finishing the process. However, re- weighing the tablets after coating and drying was done. Results gave increase in the weight about 3.25%. Thickness was also increased due to the coating process. Results showed increase in thickness about 1.3 % as illustrated in Table 7. Figure 3.The coated tablets and the animal model Iraqi J Pharm Sci, Vol.31(2) 2022 Oroslippery tablets irbesartan and hydrochlorothiazide 97 Disintegration time Disintegration test was repeated for the coated tablets to investigate effect of coat and slippering agent on the physical characteristics of the tablets. Disintegration time was elongated by coating due to extra wetting time needed by the coat. Increasing the percent of xanthan gum resulted in increase in disintegration time as shown in Table 7. Xanthan gum is an extracellular bacterial exopolysaccharide synthesized by Xanthomonas campestris. The unique properties of xanthan gum make it widely used in different applications. It is highly soluble in water, stable over a wide range of temperature, acidic and alkaline conditions (31). Xanthan gum is a stabilizer used in suspensions and cosmetics that helps “binding” materials together. Possibly this “net” formed by the gum within the film resulted in increase in disintegration time of the coated tablets, although all values are still accepted according to the USP. Statistically, disintegration time increased significantly (p<0.05) of all coated formulas compared to the uncoated formulas. And the disintegration time was increased significantly in CF1, CF2 and CF3 compared to CFe (without Xanthan gum). Table 7. Weight gain and disintegration time of the coated formula. Formula code Average weight (mg) Disintegration time (min: sec) Uncoated formula S 402 ± 3.2 1:00 ± 2 Sec CF (0%) e 406.8 ± 2.5 1:10 ± 2 Sec CF1 (2%) 408 ± 3.2 1:30 ± 3 Sec CF2 (3%) 407.2 ±3.1 2:20 ±4 Sec CF3 (4%) 405.5 ±2.3 3:00 ± 3 Sec Slipperiness test Results of slipperiness test are listed in Table 8. The properties that enable the application of xanthan gum in pharmaceutical industries are emulsifying, thickening, stabilizing, film forming and gelling nature (31). Here, xanthan gum is used as “slippering agent”. This characteristic is obtained due to its nature of fast wetting and forming a thin stable layer within the film that have that slippery nature when mixed with saliva. The coated tablet without slippering agent (CF) took the longest time in swallowing and swallowing was difficult and the animal was helped to swallow it. All coated formulas with the slippering agent gave significantly shorter time of swallowing than CF (p<0.05). CF1 gave the shortest slippering time among the three concentrations used (30 ± 1 sec) and it was significantly shorter than CF2 (37 ±2 sec) and CF3 (40±2 sec) (p<0.05). Increasing the concentration of xanthan gum from 2% to 3 and 4 %, did not enhance the slipperiness of the tablets, on the contrast it resulted in elongation of time. Although xanthan gum is described as (non-gelling agent), Other studied described xanthan gum as gel inducing agent (16) but increasing concentration was observed to form “over wet” sticky tablet which in turn faced a slight difficulty in swallowing it. Figure 5 show the performance of the test. In conclusion, 2% xanthan gum with Opadry immediate release coat is the best concentration used to enhance swallowing of this tablet.(10) Table 8. Results of slipperiness test on Rabbit Formula code Percent of slippering agent Slippering time (sec) CF 0% 80±5 CF1 2% 30±1 CF2 3% 37±2 CF3 4% 40±2 Figure 4. Performing slippering test in albino Rabbit Dissolution of IRB and HCT Figures 5 and 6 show the dissolution rate profile of the uncoated formula and CF1 which gave the best result in slipperiness test in animal. Both APIs were released from the uncoated ablets (>75 % in 45 min). When they were coated, the dissolution profile was highly like that of the uncoated (also >75 % in 45 min). Taking the 30 min as a comparative point, non-significant Iraqi J Pharm Sci, Vol.31(2) 2022 Oroslippery tablets irbesartan and hydrochlorothiazide 98 difference (p>0.05) was observed between the release of both APIs from the coated formula CF1 with respect to the coated formula (Table 9). This indicates that the coat didn’t have a negative effect on the drug release. It neither enhanced nor delayed drug release. The only effect was an elongation in the disintegration time which resulted in these slight differences in amount of drug released with time. Mahdi and Maraie, 2015 showed also that 0.3% xanthan gum dis not affect the release of valsartan from OST using different ratios of coating materials (9). Studying the release kinetics of IRB and HCT from the tested formulas (uncoated and CF1) gave the highest correlation (R) of “first order release model” for IRB (uncoated): 0.987, HCT (uncoated): 0.975 and for CF1, IRB 0.979 and HCT 0.982. This indicates that the coat also did not interfere with release kinetics of both APIs and the idea of “Immediate Release tablet dosage forms Figure 5.Dissolution profile of IRB and HCT of uncoated tablets at 0.1 N HCl, 37oC and 75 rpm showing T3. Figure 6.Dissolution profile of IRB and HCT of formula CF1 at 0.1 N HCl, 37oC and 75 rpm showing T30. Table 9. T30 of release of IRB and HCT from the uncoated formula and CF1 T30 (Percent API released in 30 min) Percent API released in 30 min T(30%) t-test result IRB from Uncoated tablet 70 ± 2.0 % IRB from CF1 68 ±3.0 % P> 0.05, non-significant compared to the uncoated HCT from Uncoated tablet 77 ±2.0% HCT CF1 77 ±2.5.0% P> 0.05, non-significant compared to the uncoated Conclusion A successful, simple, valid method of analysis for simultaneous determination of IRB and HCT was developed using HPLC with UV detector. All coated formulas with the slippering agent gave significantly shorter time of swallowing than CF (p<0.05). CF1 gave the shortest slippering time among the three concentrations used (30 ± 1 sec) and it was significantly shorter than CF2 (37 ±2 sec) and CF3 (40±2 sec) (p<0.05). Increasing the concentration of xanthan gum from 2% to 3 and 4 %, did not enhance the slipperiness of the tablets, on the contrast it resulted in the elongation of time. In conclusion, 2% xanthan gum with Opadry immediate release coat is the best concentration used to enhance swallowing of this tablet. Iraqi J Pharm Sci, Vol.31(2) 2022 Oroslippery tablets irbesartan and hydrochlorothiazide 99 Acknowledgment The authors would like to thank Al- Ahliyya Amman University, Amman-Jordan for supporting this work. Thanks are extended to Dar Al Dawa pharmaceuticals in Jordan for their help and support. Authors Contributions All the authors have contributed equally Conflict of Interests Declared none References 1. Khan A, Carmona R, Traube M. Dysphagia in the Elderly. Clin Geriatr Med 2014; 30: 43–53. 2. 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