ORIGINAL ARTICLE Year : 2010  Volume : 1  Issue : 2  Page : 180189 Formulation of furosemide solid dispersion with micro crystalline cellulose for achieve rapid dissolution Rajanikant C Patel^{1}, Rajesh A Keraliya^{1}, Madhabhai M Patel^{1}, Natvarlal M Patel^{2}, ^{1} Kalol Institute of Pharmacy, Kalol, Gujarat, India ^{2} Shri B.M. Shah College of Pharmaceutical Education and Research, Modasa, Gujarat, India Correspondence Address: Furosemide, a weekly acidic, loop diuretic drug indicated for treatment of edema and hypertension having high permeability through stomach. It is practically insoluble in gastric fluid (0.006 mg/ mL) and having highly permeability through stomach but due to its solubility limitation it can«SQ»t enter into systemic circulation. It was logically decided to design experiment, so as to achieve the set objectives. Attempt was made to prepare solid dispersion of furosemide with Poly ethylene glycol (PEG) 6000 containing microcrystalline cellulose (MCC) as adsorbent which would dissolve completely in less than 30 minutes (target selected by considering minimum gastric empting time). Microcrystalline cellulose converted sticky dispersion in to free flow powder hence increase surface area which responsible for dissolution improvement. Factorial design was applied to optimize formulation. Amount of poly ethylene glycol 6000 and microcrystalline cellulose were selected as an Independent variable while angle of repose and T_{100%} were selected as dependent variable. Attempts for dissolution rate of furosemide improve bioavailability and consequently dose reduction would possible.
Introduction Recently more than 40% NCEs (new chemical entities) developed in Pharmaceutical Industry are practically insoluble in water. Formulation of poorly soluble compounds for oral delivery now presents one of the interesting challenges to formulation scientists in the pharmaceutical industry. In the case of poorly watersoluble drugs, dissolution is the ratelimiting step in the process of drug absorption. Potential bioavailability problems are prevalent with extremely hydrophobic drugs (aqueous solubility less than 0.1 mg/ ml at 37°), due to erratic or incomplete absorption from GIT [1] . In the Present Investigation, drug which is practically insoluble in gastric fluid and having high permeability through stomach was selected. The rational for selecting such type is "Drug which having highly permeability through stomach but due to its solubility limitation in gastric fluid it can't enter in to systemic circulation. Gastric empting time is ranging form 30 min to 2 hrs after this time drugs go in to small intestine where it is soluble but can't permeate through its membrane due to its permeation limitation." To improve dissolution of such drug is challenging and rational furosemide is one of them. Furosemide is a weekly acidic, nonsteroidal anti inflammatory drug having high permeability through stomach but due to its solubility limitation it can't enter in to systemic circulation and gastric empting time is ranging from 30 min to 2 hr, after this time furosemide goes in to small intestine where it is solubilise but can't permeate through its membrane. To improve dissolution of such drug is challenging and rational. In present investigation, dissolution of fu rosemide improves by preparing floating granules. Furosemide, a weekly acidic, loop diuretic drug indicated for treatment of edema and hypertension having high permeability through stomach because it remain 99.8% unionize in stomach (pKa of Furosemide 3.9, pH of gastric fluid  1.2). Various research article published for dissolution rate enhancement of poorly water soluble drug using solid dispersion [3] and few articles published for enhancement of dissolution rate of furosemide [4],[5] . In present investigation dissolution rate of furosemide improved by novel approach by incorporating adsorbent. Furosemide is practically insoluble in stomach medium (0.006 mg/mL) and having highly permeability through stomach but due to its solubility limitation it can't enter in to systemic circulation. Gastric empting time is ranging from 30 min  2 hrs [2] after this time it goes in to small intestine where it is soluble but can't permeate through its membrane due to its permeation limitation (furosemide having pH depended solubility and permeability). In present work, 40 mg furosemide was taken. Solubility depends on amount of solute, amount of solvent, temperature, stirring speed, time and other factors. Due to low dose of drug it can be dissolves within gastric empting time if solubility enhancing excipients incorporate. Materials and Methods Materials Furosemide Gifted by Torrent Research centre, Ahmedabad and Poly ethylene glycol (PEG) 6000, and Micro crystalline cellulose purchased from S. D. Fine chemicals, Mumbai. Empty Hard gelatine capsules gifted from Astron Research Ltd., Ahmedabad. All other chemicals and reagents used are of analytical grade. Method Solid dispersion prepare by fusion method. PEG 6000 melted in porcelain dish. 40 mg Drug was dispersed in molted PEG 6000 then immediately Micro Crystalline Cellulose as adsorbent was added in porcelain dish (Microcrystalline cellulose having an excellent adsorbent property which converted sticky dispersions in to free flow powder with improved surface area which assisted in dissolution enhancement). Amount of PEG 6000 and adsorbent added as shown in following [Table 1]. 2factor, 3level central composite design and optimization process for floating granules of furosemide was employed. Amount of PEG 6000 (A) and amount of adsorbent (B) were selected as the independent variables whereas angle of repose and T100% (time require to dissolve 100% drug) were selected as dependent variables (Response).{Table 1} In Vitro Dissolution Dissolution of prepared formulations (equivalent to 40 mg of furosemide) was performed in 900 ml 0.1 N HCl (pH 1.2) in USP typeII Dissolution apparatus at 50 RPM., Dissolution medium was kept at 37 ± 0.5°C. 5 ml sample were collected at different time interval and filtered through a whatman filter paper (0.45 μm). The same amount of fresh dissolution medium was added to maintain sink condition. The absorbance was measured at 220.5 nm (λmax of drug of furosemide in 0.1 N HCl) using UVvisible spectrophotometer. The concentration of furosemide was calculated by using standard curve equation. Data Analysis The response surface methodology is a collection of mathematical and statistical techniques used for modeling and analysis of problems in which a response of interest is influenced by several variable and the objectives is to optimize this response. The run or formulation, which are designed based on factorial design were evaluated for the response. The response values are subjected to multiple regression. Analysis to find out the relationship between the factor used and the response value obtained. The response values subjected for this analysis were Angle of repose and T100%. The multiple regression analysis was done using DESIGN EXPERT 7.1.6 (STATEASE), Minneapolis, USA demo version software, which specially meant for this optimization process. Analysis of data was carried out using ANOVA and the individual parameter was evaluated with Ftest. Using the regression coefficient of factor, the polynomial equation for the each response was generated [6] . Formulations Optimization by Factorial Design The computation for optimized formulation was carried using software, DESIGN EXPERT 7.1.6 (STATEASE). The response variable considered for optimization were Angle of repose and T100%. The optimized formulation was obtained by applying constraints (goals) on dependent (response) and independent variables (factors). Constraints for responses and factors are shown in [Table 2].{Table 2} By utilizing DESIGN EXPERT 7.1.6 (STATEASE) demo version software, one solution for optimized formulation. The optimized formulation is prepared and evaluated for angle of repose and T100% . Observe response value of the optimized formulation was compared with predicted value. Results and Discussion In Vitro Dissolution Dissolution comparison of Batch F1F9 shown in [Figure 1]. In batch F1, F2 and F3 same amount of PEG 6000 (80 mg) present with differ amount of Adsorbent (150 mg, 200 mg and 250 mg present in F1, F2 and F3 respectively). 165 minutes, 150 minutes and 135 minutes required to dissolve 100% drug in batch F1, F2 and F3 respectively. It was indicated as the amount of adsorbent increase, T100% decrease proportionally that was due to MCC is adsorbent that convert sticky furosemidePEG 6000 solid dispersion in to free flow powder hence surface area was increase which improve dissolution. Similar to F1, F2 and F3, amount of adsorbent was in increasing order in F4, F5, F6 and F7, F8, F9. In the comparison of Batch F3, F6 and F9 (same amount of adsorbent with differ amount of PEG 6000. 80 mg, 120 mg and 160 mg PEG 6000 present in Batch F3, F6 and F9 respectively), order of T100% was F3 < F6 < F9. It indicated as the amount of PEG 6000 increase T100% decrease that was due to PEG 6000 is high molecular weight, hydrophilic polymer which disperse drug at molecular level and convert crystalline furosemide into amorphous form.{Figure 1} Data Analysis A 3 2 Factorial design was adopted, using the amount of PEG 6000 (A) and amount of microcrystalline cellulose (B) as independent variables. The response (Y) values subjected for this analysis are angle of repose and T100%. The responses (Angle of repose and T100% were recorded and analysis of data was carried out using ANOVA in (STATEASE). The individual parameter was evaluated using Ftest and a polynomial equation for each response was generated using MLRA. The design and response summary data are represented in [Table 3].{Table 3} Response 1:Angle of repose [INLINE:1] Where Y is the response, bo is the intercept, A and B are the independent factors, b 1 and b 2 are coefficients of independent factors. The coefficients with second order terms (b 11 and b 22 ) indicate the quadratic nature and b 12 is the interaction term (combining effect of independent factors). Polynomial Equation in Terms of Coded Factors [INLINE:2] It was arbitrarily decided to obtain the values of the angle of repose less than 30 minutes from the formulated products. The results for dependent variable (angle of repose) of the batches are shown in [Table 3]. A coefficient with a positive sign shows a synergistic effect whereas a coefficient with a negative sign shows an antagonistic effect. In Equation (2), A Coefficient of Independent factor A with a positive sign (+3.83 A) indicates as the amount of PEG 6000 increase, angle of repose increase [Table 3] whereas a coefficient of Independent factor B with a negative sign (7.67 B) indicate as the amount of adsorbent increase, angle of repose decrease [Table 3] The coefficients with second order terms (b 11 and b22) indicate the quadratic nature in which a negative sign indicate (0.17 A 2 ) as the amount of PEG 6000 added in more amount, angle of repose had to be decrease but here it was increase that may be due to higher amount of PEG 6000 retard powder flow [Table 3] whereas a coefficient with a positive sign (+0.33 B 2 ) indicate as higher amount of adsorbent added, angle of repose had to be increase but here it was decrease that may be due to higher amount of adsorbent make free flow powder [Table 3]. Above results were never possible in presence of individual Independent factors hence, one cannot draw conclusions by considering the mathematical signs (positive or negative) of the coefficient of Independent factors (b1 and b2 ) and coefficient of the quadratic term (b11 and b22 ) on the value of angle of repose so combining effect of both of Independent factors was require to predict and achieving targeted value of angle of repose. Negative sign of the interaction term ( 0.50) indicated as the both PEG 6000 and adsorbent increase, angle of repose decrease [Table 3]. The magnitude of b2 (7.67) is greater than b1 (3.83) which indicated the greater influence of Adsorbent comparatively PEG 6000 on angle of repose. The relationship between the dependent and independent variables was further elucidated using contour plots. Here, arbitrarily predecided to obtain the values of the angle of repose less than 30 minutes from the formulated products. In contour plot only formulation F9 showed angle of repose near to desired angle of repose [Figure 2], Indicated by light blue colour). The final selection of the optimized batch would be done after considering the other requirements of the dosage form, i.e., T 100% .{Figure 2} Response 2: T 100% Polynomial Equation in Terms of Coded Factors: [INLINE:3] It was logically decided to obtain the values of the T 100% , was 30 minutes from the formulated products. The results for dependent variables floating time of the batches are shown in [Table 3]. In Equation (3), A Coefficient of Independent factor A with a negative sign (50 A) indicates as the amount of PEG 6000 increase, T 100% decrease [Table 3] similarly a coefficient of Independent factor B with a negative sign (17.5 B) indicate as the amount of adsorbent increase, angle of repose decrease [Table 3]. The coefficients with second order terms (b11 and b22) indicate the quadratic nature in which a negative sign indicate (5.00 A2) as the amount of PEG 6000 added in more amount, T 100% decrease [Table 3] whereas a coefficient with a positive sign (+2.50 B2) indicate as higher amount of adsorbent added, T 100% had to be increase but here it was decrease that may be due to higher amount of adsorbent increase surface area that assist in dissolution [Table 3]. Above results were never possible in presence of individual Independent factors hence, one cannot draw conclusions by considering the mathematical signs (positive or negative) of the coefficient of Independent factors (b1 and b2) and coefficient of the quadratic term (b11 and b22) on the value of angle of repose so combining effect of both of Independent factors was require to predict and achieving targeted value of angle of repose. Negative sign of the interaction term ( 3.75) indicated as the both PEG 6000 and adsorbent increase, T 100% decrease [Table 3]. The magnitude of bl (50) is greater than b2 (17.5) which indicated the greater influence of PEG 6000 comparatively Adsorbent on T 100% . The relationship between the dependent and independent variables was further elucidated using contour plots. Here, logically predecided to obtain the values of the T 100% was 30 minutes from the formulated products. In contour plot only formulation F9 showed T 100% , near to desired T 100% , [Figure 3], Indicated by Blue color). Exact amount of PEG 6000 and MCC for achieving desired response was found out from optimization.{Figure 3} Formulations Optimization For the optimization of solid dispersion of furosemide constraints was fixed for all factors and response (Fable 4). Constraints were set according to formulation of solid dispersion using minimum amt of excipients, which would give desired response values. In the present study our aim was T100% achieved in 30 minutes. In optimization [Figure 4] desirability 1.0 indicated optimum formulation was achieved at 249.56 mg of PEG 6000 and 159.83 mg of MCC. Validation of optimization technique done by preparing checkpoint batch and response were evaluated. The responses value observed in checkpoint batch was very near to optimized batch.{Figure 4} Conclusion Logically predetermined target release profile (within 30 minutes) was successfully achieved at 249.56 mg of PEG 6000 and 159.83 mg of MCC. From above research work it was concluded that for improving dissolution of weakly acidic and those drags which are mostly absorb through stomach, solid dispersion approach is gold standard but if problem observed in preparing dispersion, addition of adsorbent convert sticky dispersion in to free flow powder hence it is easy to formulate tablets or capsules. Academician and Researcher may adopt thus method because of its simplicity. References


