RESEARCH ARTICLE. Influence of Roller Compaction Parameters on Properties of Granules and Quality Characteristics of Finished Product

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1 ISSN Journal of Global Pharma Technology Available Online at RESEARCH ARTICLE Influence of Roller Compaction Parameters on Properties of Granules and Quality Characteristics of Finished Product Olga Yuryeva, Yuriy Naida, Oksana Tryhubchak, Svitlana Gureyeva, Yuliya Kondratova, Andrew Goy R&D Department, JSC Farmak, Ukraine. *Corresponding Author: Olga Yuryeva Abstract Roller compaction widely used in pharmaceutical industry as alternative to wet granulation. This technology acknowledged as more cost-effective and productive, improves granules properties, which in turn will enhance table ting process. Objective Powder mixtures for products with immediate release: Glucose monohydrate 75 g granulated powder, Sodium picosulfate 7.5 mg tablets and Amlodipine/Valsartan 5/160 mg coated tablets. Methods In this research the analysis of influence roller compaction parameters on flow ability, bulk density and particle size distribution of granules was performed. Tablets, compressed from these granules tested for analytical properties (assay, dissolution, impurities) and technological properties (disintegration, friability, hardness). Results For Glucose monohydrate 75 g optimum compaction parameters are primed: hydraulic pressure 50 bar and 1,25 mm screen size, with roller speed 11,5 rpm and roller gap 2,0 mm. The research of Sodium picosulfate 7.5 mg allowed determining the optimum compaction parameters: 50 bar hydraulic pressure, 0,8 mm screen size, 2.5 mm roller gap, roller speed 11 rpm, mill speed 80 rpm. For Amlodipine/Valsartan 5/160 mg optimal values of properties are indicated by regression analyses. Conclusion As the result, influence of roller compaction parameters on quality characteristics of finished product and perspective of this technology for solid dosage forms manufacturing confirmed. Keywords: Roller compaction, Parameters, Powder, Solid dosage forms. Introduction Today almost 75% of all pharmaceutical products are solid dosage forms [1]. Most often this is tablets, capsules or granules. Three technologies - wet granulation, dry granulation and direct compression are being used in solid dosage forms manufacturing [2]. Wet granulation is mainly used for solid dosage forms manufacturing, but during past few years process optimization, time and cost effectiveness are the main goals for many companies, so they switching to dry granulation and direct compression. Most properties of active pharmaceutical ingredients (particle size, flow ability, bulk density) aren t suitable for direct compression and dry granulation applying provides powders and granules, which fulfil these requirements. [3]. In the pharmaceutical industry there are two types of dry granulation: briquetting and compacting. [4]. Roller compaction has several advantages over briquetting [5]. Due to the forced feeding powder gradually passes through the compaction zone, after deaeration, unlike briquetting leads to less variability of agglomerates and granules properties. Roller compaction is widely used in the pharmaceutical industry as alternative to wet granulation. This technology acknowledged as more cost-effective and productive (liquid addition and drying are excluded). The main goal of roller compaction is to improve flow ability of powder, avoid granulation moisture induced degradation, , JGPT. All Rights Reserved 90

2 improve product stability, prevent segregation, reduce of bulk density, which minimizes storage volume and thus increases the efficiency of transport and reduce the potential danger to the environment, reduces the cost of the production process [6]. Roller compaction technology consists of pre-mixing the active pharmaceutical ingredient and excipients, then pre-mix passes between two counter-rotating rolls under high pressure and form a ribbon. Then ribbons are milled to uniform size granules and after mixing with lubricants, pass to tableting/ encapsulation/ packaging. An important task during R&D phase there is to establish the optimum compaction parameters and their interrelation with quality characteristics, to further obtain product with required quality properties. Therefore, it is necessary to determine the optimal linear roller speed, adjust the flow of powder mass so as to obtain granules with desired optimal reproducible parameters [7]. In addition during determining optimum compaction parameters it is important to consider the physical and mechanical properties of the masses. Thus, researchers [8-10] described experiments that show as increasing compaction force reduces porosity, increases the density and mechanical strength of granules, which reduces the surface area of the granule. Conversely, reducing of compaction force results to get granules with better compressibility and deformations during compaction. Thus it can increase the strength of tablets. The aim of the research was to show how compaction parameters (roller gap, hydraulic pressure, roller speed) affect in properties of powder mixtures (flow ability, bulk density, particle size distribution, angle of repose, Carr index) and the quality of the finished products (dissolution, disintegration, friability, hardness). Material and Methods Materials for Research Objects of study were powder mixtures for products with immediate release: Glucose monohydrate 75 g granulated powder, Sodium picosulfate 7.5 mg tablets and Amlodipine/Valsartan 5/160 mg coated tablets. The first two active pharmaceutical ingredients are highly water-soluble. The feature of the last tablets is that it s a combined drug of amlodipine besylate, which is highly soluble substance, valsartan is characterized poor solubility. Powders for compaction were obtained according to formulations of product manufacturer. Ribbon Production Powders were compressed into a ribbon using an Alexanderwerk WP120 (Alexanderwerk, Germany) roller compactor. During studies variables were hydraulic pressure, roller gap and screen size. Roller speed in each experiment was set to keep highest possible throughput. Research Methods In this research the analysis of roller compaction parameters influence on flow ability, bulk density, tapped density, angle of repose, Carr index and particle size distribution of granules was performed. Tablets, compressed from these granules, were tested for technological properties (disintegration, friability, hardness) and analytical properties according to pharmacopoeia [11]. Technological Properties Bulk density was calculated by determining the volume that holds set weight of powder. Tapped density was calculated by determining the volume that holds set weight of powder after 1250 taps on tapped density tester ERWEKA SVM 202 (ERWEKA GmbH, Germany). The Carr index is calculated by the equation (1): Carr index is an indication of the compressibility of a powder. The resulting index from 12 to 15 is considered to be an indication of good compressibility, fair to passable, poor, very poor, more 40 extremely poor. Flow ability was tested by granulate flow tester ERWEKA , JGPT. All Rights Reserved 91

3 GT (ERWEKA GmbH, Germany). This is the speed of rash powder through a funnel with opening diameter of 10 mm. This device also allows measuring the angle of repose by a laser. The obtained results are the average for 3 measurements. Particle size distribution was estimated by analytical sieving on vibratory sieve shaker RETSCH AS 200 (Retsch GmbH, Germany), using ISO sieves of principal sizes and by laser diffraction on particle analyzer Master size r 3000 (Malvern, UK), using automated dry powder dispersion unit (Aero S). Microscopic examination of granules was performed by using an optical microscope OLYMPUS BX-51 with 100x, 200x and 500x magnifications. Tablets hardness was tested on ERWEKA TBH-525 WTO (ERWEKA GmbH, Germany), which determines the pressure attached to break tablets. The results are the average of 10 measurements. Tablets friability was calculated as loss in weight after 100 rotations of the drum at a speed of 25 rpm. Device used for friability determination ERWEKA TAR 200 (ERWEKA GmbH, Germany). Disintegration test was performed in purified water by using the device for determining the disintegration ERWEKA ZT 33. Noted time when no particulate tablets will remain in the basket. Analytical Properties Glucose monohydrate 75 g granulated powder assay was analyzed by refractometry method. Dissolution in water was tested according to instruction for medical use: g of powder dissolved in 250 ml of purified water and time until complete dissolving was recorded. Sodium picosulfate 7.5 mg tablets assay in tablets was analyzed by using liquid chromatography. Quality test of the tablets consisted of determining 5 impurities, unspecific impurity and total amount of impurities that were determined by liquid chromatography. Amlodipine/Valsartan 5/160 mg tablets dissolution profile analysis was performed by liquid chromatography in buffer solutions of ph 1.2, ph 4.5, ph 6.8, using a device with paddle. Dissolution of the tablets was analyzed by liquid chromatography in phosphate buffer ph 6.8, using a device with paddle. Assay of amlodipine and valsartan in tablets and amount of impurities was analyzed by using liquid chromatography. Design of Experiment During the work symmetrical composition rotatable uniform plan of second order was used. The construction of the matrix was made by including the experimental tests, under which factors are studied on the top «+α» and bottom «-α» star points. The model of the second order for two factors is showed equation (2): y=boxo+b1x1+b2x2+b12x1x2+b11x1 2 +b22x2 2 The relationship between the studied factors and the properties of granules and final product are described by regression equation. After checking of the statistical significance of coefficients, considering the Student test (p = 0.1), it was checked the adequacy of models using F-test (F0,1;6;1 = 58,204). The regression equation proves adequate if Fexp. < F0,1;6;1. It describes the mutual influence factors. The nature of impact of studied factors was determined by values and signs of regression coefficients [12]. Results Glucose Monohydrate 75 g of Granulated Powder Powder before compaction has the following characteristics: bulk density 0.59 g/ml, tapped density 0.75 g/ml, Carr index 21.0 %, flow ability 4.3 g/s, angle of repose Poor compressibility/flow ability caused problems in the machine performance during prepackaging and low dosage uniformity in sachets. Therefore, to improve properties of powder held compaction at a pressure range from 50 N to 125 N and changing of the screen size (1.0 mm, 1.25 mm and 1.6 mm) at a constant distance between the rollers of 2.0 mm. The rollers speed exposed based on the technical properties of compactor for maximum throughput. Compaction parameters are listed in Table 1. Parallel to the research we studied indicators of granules that obtained by wet granulation: bulk density was around 0.7 g/ml, solubility - about 4 minutes , JGPT. All Rights Reserved 92

4 Table 1: Compaction parameters of glucose monohydrate 75 g granulated powder S. No. Hydraulic pressure, Screen size, Roller gap, mm Roller speed, rpm bar mm ,0 2, ,0 2, ,0 2, ,0 2, ,25 2,0 11, ,25 2, ,25 2, ,25 2,0 9, ,6 2,0 11, ,6 2, ,6 2,0 9, ,6 2,0 9,0 Those data show an increase of bulk density and a significant increase of tapped density after compaction in all investigated series against the original mixture. The impact of hydraulic pressure on properties is relatively minor. Figure 1: Granules parameters against hydraulic pressure for each screen size If we have used a sieve size 1 mm, screen holes blocked by mixture. It causes performance degradation of equipment and deterioration of the finished product. Increasing the size of the screen of 1.0 mm to 1.2 mm, while maintaining other parameters improves the flow ability of the granulate. Further increase of screen size from 1.2 mm to 1.6 mm causes small decrease in flow ability and a significant increase in time of dissolution of the drug. Figure 2: Particle size distribution graph , JGPT. All Rights Reserved 93

5 Figure 3: Dissolution time against hydraulic pressure for each screen size Increasing the screen size results in increased particle size. Effect of hydraulic pressure on particle size distribution observed only when using 1 mm screen. Increasing the compacting pressure increases the dissolution time of 40%. Consequently, since the aim is to achieve optimal flow ability performance with minimal dissolution time, optimum compaction parameters are: hydraulic pressure 50 bar and 1,25 mm screen size, with roller speed 11,5 rpm and roller gap 2,0 mm (batch #5). With these parameters throughput of the equipment is 32 kg/h. This drug roller compaction technology can be an alternative to wet granulation. According to refractive index analysis result the assay of glucose in finished product is g. This confirms the compliance of the requirements 75g ± 5%. Sodium Pico Sulfate 7.5 Mg Tablets The powder before compaction has the following characteristics: bulk density 0,49 g/ml, tapped density 0,78 g/ml, Carr index 38,01 %, flow ability 0,7 g/s, angle of repose 41,9. Poor compressibility/flowability of the powder do not ensure obtaining tablets by direct compression. Therefore, to improve properties of powder, held compaction at a pressure range from 25 N to 100 N, roller gap range 1,5-3,5 mm and changing the screen size (0.8 mm and 1.25 mm) The rollers speed exposed, based on the technical properties of compactor for maximum throughput. Compaction parameters and results of product properties analysis are listed in Table 2. Properties of Sodium picosulfate tablets, that made by wet granulation technology are: hardness 75 N, friability 0, 08%, disintegration 4 minutes. Table 2: Compaction parameters and results of product properties analysis after roller compaction and table ting of sodium Pico sulfate 7.5 mg tablets S. No. Hydraulic pressure, bar Screen size, mm Roller gap, mm Roller speed, rpm Mill speed, rpm Bulk density, g/ml Those data show a significant increase of bulk density and density after compaction in all investigated series against the original mixture. Carr index is definite evidence of improved compressibility mass after compaction. There is a clear relationship of these parameters improve with increasing hydraulic pressure. Reducing the screen size Tapped density, g/ml Carr index, % from 1, 25 mm to 0,8 mm, while maintaining other parameters compacting accompanied by minor compressibility/flow ability improvement. Using a 1,25 mm screen the flow ability and angle of repose of granulates are better, but worse uniformity of dosage during tableting. Therefore, we recommend using a 0,8 mm screen , JGPT. All Rights Reserved 94 Flow ability, g/s Angle of repose, Hardness, N Friability, % Desintegration, min ,25 1,5 14,5 80 0,700 0,930 24,73 5,7 40,2 59,0 0,17 1, ,25 1,5 12,0 60 0,748 1,039 28,01 8,0 40,7 62,0 0,11 2, ,25 1,5 13,0 80 0,755 0,971 22,25 7,7 42,1 65,5 0,06 2, ,25 2,5 10,0 60 0,717 0,915 21,64 3,7 41,4 63,0 0,12 2, ,25 2,5 7,0 60 0,722 0,944 23,52 5,6 41,6 70,5 0,05 2, ,25 2,5 13,0 80 0,742 0,951 21,98 6,9 40,8 75,0 0,07 2, ,25 2,5 7,0 60 0,745 0,931 19,98 8,1 40,3 78,0 0,06 3, ,25 3,5 9,0 80 0,715 0,929 23,04 5,1 42,0 77,5 0,03 2, ,25 3,5 9,0 80 0,728 0,922 21,04 6,1 39,9 79,0 0,02 3, ,25 3,5 7,5 80 0,723 0,933 22,51 6,5 41,1 81,0 0,08 3, ,25 3,5 6,8 80 0,737 0,939 21,51 7,0 40,5 60,0 0,05 3, ,8 1,5 14,0 80 0,705 0,943 25,24 1,7 41,8 58,0 0,10 2, ,8 1,5 12,0 80 0,736 0,995 26,03 2,5 40,4 64,0 0,07 3, ,8 2,5 11,0 80 0,684 0,975 29,85 5,5 40,5 75,5 0,01 3, ,8 2,5 8,5 80 0,719 0,953 24,55 5,9 39,4 79,0 0,01 3, ,8 3,5 8,0 80 0,689 0,935 26,31 1,6 38,6 80,5 0,02 3, ,8 3,5 4,5 80 0,701 0,916 23,47 1,6 37,9 86,0 0,01 3,41

6 Hardness of Sodium picosulfate 7,5 mg tablets is directly proportional increases with increasing hydraulic pressure (Fig. 4). Hardness increase of the finished product is observed with increasing of roller gap. Using the 0,8 mm diameter sieve the highest hardness was achieved. Figure 4: Dependence of hardness and hydraulic pressure, sieve diameter and the distance between the rollers of Sodium pico sulfate 7,5 mg tablets. Also, mechanical strength of tablets is characterized by friability. For Sodium picosulfate 7.5 mg tablets loss in weight dependent on compaction parameters (Fig. 5). Figure 5: Chart ratio friability, hydraulic pressure, screen size and roller gap for Sodium picosulfate 7,5 mg tablets Fig. 5 shows reducing friability obtained by high hydraulic pressure, increase roller gap and using a 0,8 mm screen size. Dependencies of disintegration time against compaction parameters shown in Figure 6. Figure 6: Graph of dependence of disintegration time against hydraulic pressure, screen size and roller gap for Sodium pico sulfate 7, 5 mg tablets , JGPT. All Rights Reserved 95

7 Disintegration time of tablets is reduced at hydraulic pressure of 25 bar. Lower results were noticed at roller gap 1, 5 mm, as well. Using a 1, 25 mm screen size we had minimal disintegration time. The research allowed determining the optimum compaction parameters (batch # 14): 50 bar hydraulic pressure, 0, 8 mm screen size, 2.5 mm roller gap, roller speed 11 rpm, mill speed 80 rpm. Established throughput of the equipment-35 kg/h, product losses are 1, 8%. Therefore, roller compaction technology allows receiving Sodium picosulfate 7, 5 mg tablets, which meets quality requirements. It is recommended entry roller compaction technology as an alternative wet granulation technology. Batch # 14 was analyzed in terms of dissolution, impurities and assay. Dissolution test approves 101.2% of active pharmaceutical ingredient release from tablets after 30 minutes. Among the impurities content of impurity D defined as 0.1%, non-specific impurities % and the total amount of impurities - 0, 21%. Impurities A, B, C and E are below detection limit. Assay of sodium picosulfate equal 7, 32 mg for the average weight of the tablets. The analysis confirmed that selected compaction parameters allow receiving finished product which requirement the manufacturer quality. Amlodipine/Valsartan 5/160 mg, tablets For detailed study the influence of roller compaction parameters on quality of the finished product Amlodipine/Valsartan 5/160 mg, the effect of compacting pressure and the distance between the rollers on 5 levels was studied. Investigated quantitative factors are listed in Table 3. Table 3: The list of quantitative factors and their levels which were studied during development Amlodipine/Valsartan 5/160 mg tablets Factor Interval Lower star point «-α» Lower level «-» Main level «0» Upper level «+» Upper star point «+α» х1 hydraulic pressure, 25 18, ,25 bar х2 roller gap, mm 1,0 1,086 1,5 2,5 3,5 1,914 Design of experiment matrix and results of the study of Amlodipine/Valsartan 5/160 mg granules and tablets are showed in Table 4 Table 4: Symmetric matrix of composite rotatable uniform plan of the second order and results of research Amlodipine/Valsartan 5/160 mg granules and tablets S. No. х1 х2 у1 у2 у3 у4 у5 у6 у7 у ,571 0,715 20,14 5,3 40,8 120,20 0, ,490 0,648 24, ,1 87,40 0, ,575 0,814 29,36 5, ,90 0, ,500 0,676 26,04 3,1 39,4 101,56 0, α 0 0,571 0,717 20,36 4,6 42,9 87,10 0, α 0 0,486 0,666 27,03 1,3 41,9 106,30 0, α 0,525 0,689 23,80 3,6 40,7 97,44 0, α 0,543 0,714 23,95 4,9 39,4 99,60 0, ,525 0,700 25,00 4,2 41,6 100,50 0, ,534 0,728 24,37 3,9 41,0 98,50 0,04 35 Notices: у1 bulk density, g/ml; у2 tapped density, g/ml; у3 Carr index, %; у4 - flow ability, g/s; у5 angle of repose, ; у6 - hardness, N; у7 - friability, %; у8 - disintegration, s According to the experimental design matrix (tab. 4) 10 series were prepared. The relationship between the studied factors and bulk density of the granules (у1) is described by regression equation (3) (Fexp. = 0,95): density of 0,53 g/ml and statistically depends on the levels of quantitative factors. With increasing hydraulic pressure the figure improves significantly, while increasing the roller gap deteriorates bulk density of granules. y1=0,530+0,035x1-0,005x2 In the investigated factors study on the main level there is an average granules bulk The relationship between the studied factors and tapped density of the granules (у2) can be represented by the following mathematical model (Fexp. = 1,79), equation (4): , JGPT. All Rights Reserved 96

8 y2 = 0,714+0,035x1-0,020x2 The tapped density of granules in the centre of the experiment is at g/ml. Increasing the hydraulic pressure leads to a significant improvement of this indicator, and increased the roller gap is accompanied by deterioration tapped density. One of the criterions for determining the compressibility of granules was Carr index (у3). All batches were characterized as poor compressibility displayed by granules regression equation (5) of Carr index Amlodipine/Valsartan 5/160 mg (Fexp. =22, 12): y3=24, 70-1, 29x1-1,39x2 In the study investigated factors on the main level observed poor granules compressibility. The investigated compaction parameters clearly improved compressibility. To predict the behaviour of granules flow ability was determined (у4). The regression equation (6) describing the figure has the following expression (Fexp. =1,69): y4=4,1+1,3x1-0,4x2-0,5x1 2 Hydraulic pressure has the biggest impact on this indicator. Adding x1 factor on the upper level significantly improves flow ability to 5.4 g/s and further increasing to the level of upper star point associated with lower flow ability to 3.1 g/s. Compaction with the roller gap in the range of 1.5 mm to 3.5 mm results in flow ability of granules at (4,5-3,7) g/s. The impact of the studied compaction parameters on angle of repose (у5) described by regression equation (7) (Fexp. =4,91): y5=41,3+0,5x1+0,3x2-1,0x2 2 During the studies of investigated quantitative factors on the main level angle of repose at 41.3 was obtained. Increase the roller gap to mm leads to a decrease of the angle of repose. Learning factor х2 on the main level slightly increased this index. Increasing hydraulic pressure to 75 bar characterizes angle of repose to 41.8 degrees. The relationship between the studied factors and hardness of tablets (у6) described by regression equation (8) (Fexp. = 46,20): y6=99,56+1,00x1+7,62x1x2 It should be mentioned that this index of Amlodipine / Valsartan 5/160 mg tablets of each batch is conformed pharmacopoeia requirements. During the study of investigated factors on the main level the observed hardness of tablets N. There is considerable interaction between the factors that leads to a significant increase in tablets hardness. Increasing the hydraulic pressure to 25 bar increases the hardness of tablets in 1 N. One of the key variables that influence the choice of compaction parameters was friability. In all batches this index is conformed pharmacopoeia requirements, but there were substantial variations. The impact of the studied compaction parameters on friability of tablets (у7) is described by regression (Fexp.=35,26), equation (9): y7=0,04+0,04x1-0,03x2+0,03x1 2 +0,03x2 2 All batches of tablets comprised studied quantitative factors on the main level, characterized by 0, 04% loss in weight during friability test. Friability of Amlodipine/Valsartan 5/160 mg tablets doubles with increasing hydraulic pressure and further increase of pressure leads to a finished product with 0,10% friability. During the study of this factor х2 at the upper level there is the lowest loss in weight at 0.01%, and the choice of this factor at star point accompanied by an increase in this indicator. The tablet Amlodipine/Valsartan 5/160 mg of each batches disintegrates in less than 1 minute. The relationship between the studied factors and disintegration (у8) is described by the following equation (10) regression (Fexp.=2,60): y8=33+7x1-3x2 During the studies of investigated quantitative factors on the main level disintegration of tablets within 33 seconds was defined. Compacting at higher pressure causes extension disintegration time of 7 seconds. Increase the roller gap characterized , JGPT. All Rights Reserved 97

9 by a disintegration time reduction. Additionally conducted microscopic examination of batches obtained at different compaction pressures. Among the mass of powder that were exposed to the pressure of 75 bar batch #3 was selected, 25 bar batch #2, 50 bar batch #9. The result of the microscopic analysis of granules is shown in Figure Figure7: Photos of granules 1) batch #3 at 100x magnification; 2) batch #2 at 100x magnification; 3) batch #9 at 100x magnification; 4) batch #3 at 200x magnification; 5)-batch #2 at 200x magnification; 6)- batch #9 at 200x magnification; 7)-batch #3 at 500x magnification; 8)-batch #2 at 500x magnification; 9) batch #9 at 500x magnification Microscopic study allowed to determine the predominant particle size of 0.15 μm for each series at a magnification of 100x, 0.06 μm - at 200x magnification and 30 μm - at 500x magnification. For granules at a pressure of 50 bar occurs most uniform distribution of particles (Fig. 7.3, 7.6, 7.9) and the largest number of particles with a size of 30 μm (Fig. 7.9), which is most suitable for tableting process. Additional research conducted particle size distribution by laser diffraction series obtained at different hydraulic pressures. Among the mass of powder that were exposed to the pressure of 75 bar select batch #3, 25 bar - batch #2, 50 bar - batch #9. The results are shown in Figure , JGPT. All Rights Reserved 98

10 The study shows an increase in the average particle size D50 with increasing compaction pressure. The next step is analysis of regression equations of the second order is necessary to determine whether the extreme Figure 8: Cumulative size distributions and if it is and find its coordinates. Therefore, on the basis of the models build lines of equal access in the coordinate system х1х2 (Fig. 9). x 2 0, ,49 2, ,04 0,68 0, ,75 0,1 y y 1 0,5 y 2 y 6 0,57 0,55 y 3 y 7 4,0 5,0 0, x 1 y 4 y 8 Figure 9: Lines of equal access to the coordinate system х1х2 Considering the results of allocation lines of equal access, optimal values of properties indicated in the center of the experiment (х1=0, х2=0). By the dissolution analysis 90% of amlodipine and 85% of valsartan was released during 30 minutes and with stand the permitted limit - not less than 75%. Amount of impurities found in Amlodipine/Valsartan 5/160 mg tablets are 0.14% of amlodipine impurity D, 0,02% of , JGPT. All Rights Reserved 99

11 valsartan impurity B, any other impurities are absent, and the total amount of impurities are 0.17%, which conform requirements and are no more than 0.5%, 0.2% 0.2%, 2.0% respectively. For estimation of tablets quality analytical properties of Amlodipine/Valsartan 5/160 mg tablets with optimal compaction parameters were tested. According to chromatographic determination of assay 4.99 mg amlodipine and valsartan mg were defined in one tablet. Research indicates compliance with current requirements to finished product. Figure10. Dissolution profile of API Amlodipine/Valsartan 5/160 mg tablets Dissolution profile of active pharmaceutical ingredients (amlodipine besylate and valsartan) are confirmed the optimum roller compaction parameters. Discussion Researchers Robles E.E., Ved P.M., Vora N. et al. developed the method for modeling of the roller compaction process for laboratory tests. Modeling evaluated using microcrystalline cellulose as material models, ribbon solids and tensile strength as key ribbon properties. When the densities of solids of actual and modeled ribbons are identical, similar behavior occurs during pressing and equivalent mechanical properties (resistance to crushing). Consequently, modeling and real ribbons lead to an equivalent granulation. It is possible to predict the impact of critical parameters: feed rate, pressure and diameter -on ribbon properties using a portion of the required material on rolls equipment. Improved methods for material transfer and efficiency will give the opportunity to obtain a solid dosage forms on early stages of drug development [13]. Therefore, the object for process modeling we have selected is glucose monohydrate, which is the finished product - granular powder , JGPT. All Rights Reserved 100

12 Process parameters for a drug candidate, excipient or formulation mix should be determined at laboratory-bench scale. These parameters would be translated directly to large-scale process equipment, thus saving time and materials during early product development. Results were proved by the example of model compounds lactose monohydrate using laboratory bench and production scale [14]. Studies show that roller compaction parameters affect quality characteristics of finished product. Optimization of process parameters such as compression force, roll speed, roll gap, screw speed, milling speed, and milling screen orifice size are essential and critical in roller compaction [15]. The main parameter is the hydraulic pressure. Experimental results show that increasing hydraulic pressure increases tablet hardness reduces friability and extends dissolution time for immediate release tablets. Similar results have been confirmed by other authors [6]. The influence of hydraulic pressure on the powder mixture characteristics and tablets properties of immediate release formulations containing poorly soluble active pharmaceutical ingredients show as the hydraulic pressure significantly affects tablets dissolution, even when the hardness of tablets is the same [13]. Quality of the finished product can be predicted by technological properties of granules. Thus, with higher hydraulic pressure we obtain granulate with a higher bulk density, tapped density, reduced Carr index, improved flow ability and angle of repose. This indicates improved performance of granules. As a result, an indicator improves the properties of tablets and tableting process. The same dynamics of product properties observed for granulated powder as the finished product. For example other tablets are also demonstrated the impact of compaction pressure on the particle size distribution of granulate, its bulk density and tapped density, Carr index as well as the hardness of the tablets, their structure and appearance [16]. The influence of the screen size on properties of the granules and tablets were experimentally shown. Increasing the screen size while maintaining other parameters can increase particle size and improve the flow ability of granulate. This clearly affects the quality of the finished product. When using smallest screen size the highest hardness, reduced friability and extend disintegration time was observed. Limiting parameter for compacting was the screw speed, with its maximum of 81 rpm, so it set depending on the product and conditions of roller compaction. The article presents data that increasing roller gap occurs is increased hardness, reduced friability and extend disintegration time of tablets. Roller speed always set lower while increasing hydraulic pressure and keeping other compaction parameters constant. Therefore, inverse dependence influence of roller speed and parameters of the finished product was observed. So you can think about the interdependence compaction parameters that affect the properties of the finished product. Used mathematical planning and obtaining regression equations are determined the product properties in any relationship between hydraulic pressure and screen size in the test range. Figure of lines of equal access clearly shows the changes of the studied granules and tablets parameters. This allows to choose the optimal ratio of investigated factors while taking into account all product properties. Such studies can be used for other drugs. Conclusion Dry granulation method using roller compaction has a number of significant advantages over the briquetting using tablet press and it can be an alternative wet granulation. Roller compaction process parameters show a significant effect on the properties of the granules and as a result - the quality characteristics of the finished product , JGPT. All Rights Reserved 101

13 Thus, in the examples Glucose monohydrate, 75 grams granulated powder, Sodium picosulfate 7.5 mg tablets Amlodipine/Valsartan 5/160 mg tablets were demonstrated the impact of compaction parameters (hydraulic pressure, screen size, roller gap and roller speed) for quality characteristics of the finished product. Influence of roller compaction parameters on quality characteristics of finished product and perspective of this technology for solid References 1. A Friedrich, (2016) Dry Agglomeration Technology (Using BEPEX Roller Compaction Technology, New Jersey: Hosokawa Micron Powder Systems). 2. Ch Pallavi, KD Gowtham (2013) Direct Compression An Overview, International Journal of Research in Pharmaceutical and Biomedical Sciences, 4, OV Tryhubchak, ТА Groshovyj, OО Yuryeva (2016) the use of compaction in the manufacture of tablets, Current issues in pharmacy and medicine: science and practice, 2, R Ayasha, LK Sukhbir, C Abhishek, P Gauri, KS Run (2011) Overview on roll compaction/dry granulation process, Pharmacology online, 3, ME Aulton (2002) Pharmaceutiks, The Science of Dosage Form Design, 2 (Edinburgh) , S Dhumal, PA Kulkarni, VS Kashikar, J Baweja, M Thottasseri (2013) A Review: Roller Compaction for Tablet Dosage Form Development, Research and Reviews, Journal of Pharmacy and Pharmaceutical Sciences, 2, RF Mansa, RH Bridson, RW Greenwood, H Barker, JPK Seville (2008) Using Intelligent Software to Predict the Effect of Formulation and Processing Parameters on Roller Compaction, Powder Technol, 181, F Freitag, P Kleinebudde (2003) How Do Roll Compaction affect the tableting behaviour of inorganic materials? Comparison of four magnesium carbonates, European Journal of Pharmaceutical Sciences, 19, dosage forms, which confirmed manufacturing. Acknowledgements We would like to thank to the executives and employees of JSC "Farmak" for the opportunity and support in research. We acknowledge for using the roller compactor Alex and erwerk WP120 from Alex and erwerk GmbH, Germany. 9. LAL Soares, GG Ortega, PR Petrovick, PC Schmidt (2005) Dry granulation and Compression of Spray-Dryed Plant Extracts, AAPS Phar Sci Tech, 6, E359-E TP Souza, JL Gomez-Amoza, R Martinez- Pacheco, PR Petrovick (2006) Compression Behaviour of Formulations from Phyllanthusniuri spray dried extract, Pharmazie, 61 (3), European Pharmacopoeia 9th Edition (EDQM, Strasbourg: Council of Europe, 2016). 12. ТА Groshovyj, VP Marceniuk, LI Kucherenko, LV Vronska, SM Gureyeva (2008) Mathematical planning of experiment in scientific research in pharmacy (Ternopil: Ukrmedknyha). 13. EE Robles, PM Ved, N Vora, TY Kim, D Cartwright, JA Williamson, N Kanikkannan, P Skultety (2014) Effect of roller compaction pressure on the blend and tablet properties of a formulation containing a poorly soluble drug, Xcelience, 3, GW Gereg, ML Cappola, Roller (2002) Compaction Feasibility for New Drug Candidates. Laboratory to Production Scale, Pharmaceutical Technology. Tableting & Granulation, S Pimple, A Joshi, M Digge, A Swami (2015) Roller Compaction Design and Critical Parameters in Drug Formulation and Development: Review, International Journal of PharmTech Research, 7, V Mohylyuk (2015) Roller compactors in the design and manufacture of solid dosage forms, Pharmaceutical industry, 3, , JGPT. All Rights Reserved 102