Indo American Journal of Pharmaceutical Research, 2015
ISSN NO: 2231-6876
FORMULATION & EVALUATION OF FAST DISSOLVING TABLET MONTELUKAST SODIUM BY USING QbD APPROACH Omprakash G. Bhusnure*, Ashwini V. Nandgave, Sachin B. Gholve, Sanjay S. Thonte, Chanderkant A. Shinde, Nitin Shinde Channabasweshwar Pharmacy College, Maharashtra, India- 413512. ARTICLE INFO Article history Received 05/03/2015 Available online 31/03/2015
Keywords 2
3 Full Factorial Design, DOE, Fast Dissolving Tablets (Fdt’s), Superdisintegrants, Variables, Direct Compression.
ABSTRACT The focus of the current investigations was to apply quality by design (QbD) approach to the development of fast dissolving tablets. Critical material and process parameters are linked to the critical quality attributes of the product. Variability is reduced by product and process understanding which translates into quality improvement, risk reduction and productivity enhancement. The development of Montelukast sodium fast dissolving tablet was proposed in the current study through a QbD paradigm for a better patient compliance and product quality. Montelukast sodium is a leukotriene receptor antagonist used in treatment of asthma & its bioavailability is 63%. It is usually administered orally. It has extensive first-pass metabolism & show a very poor dissolution rate. Montelukast sodium is widely used as an antiasthmatic drug, It has low bioavailability due to first pass metabolism. Fast dissolving tablets of Montelukast sodium was developed, optimized and characterized by statically designed by using 32 factorial design in which three variables namely concentration of Gum Guar, CCS(Croscarmellose sodium) & MCC(Microcrystalline cellulose) were at two levels. The main interactive influences were tested using statistical model. The response surface plots were generated by software for analyzing effect of the independent variables on the response. All the batches were prepared by direct compression. The tablets were evaluated for Precompression parameters e.g. Angle of repose, Bulk density, Tapped density, Carr‟s compressibility index and Hauser‟s ratio and post compression parameters like drug content uniformity, hardness, wetting time, friability, Thickness, Disintegration time & In vitro dissolution. Before the formulation of the tablets IR Spectroscopic studies 2
were also performed to check the compatibility with the excipients. The 3 full factorial design revealed that the amount of superdisintegrant significantly affect the dependent variables disintegration time. the negative value indicates that the increase in concentration of that particular excipients retards the disintegration time. The same value i.e. -0.75 for the two factor interactions (Gum Guar & CSS) & three factor interactions (Gum guar, CSS & MCC) indicates that the disintegration caused due to both superdisintegrants Gum guar & CSS is unaffected by the use of MCC. Increase in concentration of particular excipient retards disintegration time. All these interpretations and implications of disintegrates characteristics over release profile were supported statistically.
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Please cite this article in press as Dr. Bhusnure O.G et al. Formulation & Evaluation of Fast Dissolving Tablet Montelukast Sodium By Using QbD Approach. Indo American Journal of Pharm Research.2015:5(03).
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Corresponding author Dr. Bhusnure O.G M. Pharm, Ph.D. Professor and Head Department Head Of Quality Assurance, Channabasweshwar Pharmacy College (Degree), Kava Road, Latur-413512, Dist. Latur. (MS) +91-2382-641008 (O), +91-2382-240008(O)+91-2382-243855,+91 9765360611
[email protected]
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Copy right © 2015 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. INTRODUCTION Quality by design (QbD) is an intelligent approach to built quality in products and process. This can be achieved by constructive planning and the previous data available. Although it is based on risks, but it has its fruits that it minimizes the end product tastings and increases the chances of regulatory acceptance. QbD was first proposed by a well known researcher Joseph Moses Juran. Later it has been accepted by ICH, US-FDA and other regulatory bodies. The principles of QbD is best explained by ICH Q8, ICH Q9 & ICH Q10, which gives the guidelines on Science & Risk-based assessment, product‟s life cycle and its approach, and the various method designs. The traditional quality by testing (QbT) approach tests product quality by checking it against the approved regulatory specifications at the end of manufacturing stream at great effort and cost. There is a great deal of unpredictability in scaling up a product from research and development to production scale, and reasons for failure are generally not understood. QbD is a major shift from the traditional approach of QbT in ensuring quality control of products across the manufacturing stream. QbD principles promote innovation and continuous improvement of the product. Knowledge-based commercial manufacturing ensures enough regulatory flexibility for setting specifications and post-approval changes. Product and process are designed using innovative risk-based techniques to meet predefined quality objectives thereby satisfying the most critical patient needs and regulatory requirements at low cost [1-3]. Formal Experimental Design or DOE is defined as “a structured analysis wherein inputs are changed and differences or variations in outputs are measured to determine the magnitude of the effect of each of the inputs or combination of inputs.” Factorial designs allow for the simultaneous study of the effects that several factors like concentration of super disintegrants and diluents concentration may have on the physical characteristics of the tablets. There are several advantages to statistically designed experiments, and when compared with other test methods, the results are striking. One chief reason is that it is strongly favoured by regulatory agencies because it justifies the choice of ranges and finds a robust (optimum) region. In addition, it gives the researcher the ability to study interactions between factors. In contrast, merely studying one factor at a time does not allow the researcher to study interactions and is not scalable to production. It provides a more economical use of resources, especially when many factors exist and provides a greater chance of finding optimum conditions. Finally, predictions can be made about future experiments Fast dissolving drug delivery systems (FDDDS) are a new generation of formulations which combine the advantages of both liquid and conventional tablet formulations and at the same time, offer added advantages over both the traditional dosage forms2. United States Food and drug administration (FDA) defined fast dissolving tablet (FDT) as “a solid dosage form containing medicinal substance or active ingredient which disintegrate rapidly usually within a matter of seconds when placed up on the tongue” 1. Fast dissolving tablets are the solid dosage form, which disintegrates rapidly in the oral cavity without the need of water. Oral fast dissolving films are useful for the geriatric and paediatric patients and also for the patients suffering from emesis, diarrhea, allergic attacks, cough, mental disorder, bedridden patients etc 2. The advantages of fast dissolving films are the administration to pediatric and geriatric patient population where the difficulty of swallowing larger oral dosage forms is eliminated. It could find a better application for patient compliance especially in children. Hence there is need to formulate fast dissolving delivery to control these severe conditions3. Fast dissolving drug delivery is rapidly gaining acceptance as an important new drug delivery technology. Not all fast dissolving technologies actually dissolve; some use different disintegration mechanisms such as high levels of disintegrates and/or effervescent agents that cause the dosage form to disintegrate rapidly in the patient‟s mouth within a minute and can be gulped easily without the need of water. Thus, it offers increased patient compliance and convenience 4. Fast dissolving tablets are those when put on tongue disintegrate instantaneously releasing the drug, which dissolve or disperses in the saliva. The faster the drug into solution quicker the absorption and fast on-set of clinical effect. Some drugs are absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach. In such cases, bioavailability of drug is significantly greater than those observed from conventional tablets dosage form. The advantage of mouth dissolving dosage forms are increasingly being recognized in both, industry and academics 5. Among the different routes of administration, the oral route of administration continues to be most preferred route due to various advantages including ease of administration, avoidance of pain, versatility and most importantly patient compliance. One such relatively new dosage form is the oral strip, a thin film that is prepared using hydrophilic polymers that rapidly dissolves on the tongue or buccal cavity. Recently, fast dissolving drug delivery system have started gaining popularity and acceptance as new drug delivery systems, because they are easy to administer and lead to better compliance. Such delivery system either dissolves or disintegrates in mouth rapidly, without requiring any water to aid in swallowing 6. They also impart unique product differentiation, thus enabling use as line extensions for existing commercial products. This novel drug delivery system can also be beneficial for meeting the current needs of the industry are improved solubility/stability, biological half life and bioavailability enhancement of drugs. 7,8 In the development of pharmaceutical dosages form with appropriate characteristics an important issue is to design an optimized pharmaceutical formulation in a short time of periods with minimum trials. For that now a day‟s response surface methodology (RSM) gaining attention to identify and quantify the effect of different formulation variables on the important characteristics. The aim of this study was to develop, optimize and characterize fast disintegrating tablets by statically designed by using 32 factorial design in which three variables namely concentration of Gum Guar, CCS (Croscarmellose sodium) & MCC(Microcrystalline cellulose) were at two levels.. The main interactive influences were tested using statistical model. The response surface plots were generated by software for analyzing effect of the independent variables on the response. The effect of formulation variables on the product characteristics can be predicted and precisely interpret by using a 2-level factorial design and generated quadratic mathematical equation.
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MATERIALS AND METHODS: Pure drug sample of Montelukast sodium was kindly gifited by Reserch-Lab Fine chem. Industries, Mumbai. Table No 1: Materials used with source & use. Sr. No. Material Uses 1 Montelukast sodium API 2 Gum guar Disintigrante 3 CCS Disintegrant 4 MCC Diluent 5 Mg. streate Lubricant 6 Talc Glident 7 Perpermint Flavor 8 Sodium saccharine Sweetening 9 Mannitol Diluent Method: Fast dissolving tablets of Montelukast Sodium formula (Shown in Table-1).9
Source Research-Lab Fine chem. Industries, Mumbai. Research-Lab Fine chem. Industries, Mumbai Research-Lab Fine chem. Industries, Mumbai. Research-Lab Fine chem. Industries, Mumbai Research-Lab Fine chem. Industries, Mumbai. Research-Lab Fine chem. Industries, Mumbai. Research-Lab Fine chem. Industries, Mumbai Research-Lab Fine chem. Industries, Mumbai Research-Lab Fine chem. Industries, Mumbai were prepared by direct compression method according to the
Table No. 1 :- Formulations from F1 to F8. Ingredients
Quantity in mg F1 F2 F3 F4 F5 F6 F7 F8 Montelukast sodium 5 5 5 5 5 5 5 5 Gum guar 4 8 4 8 4 8 4 8 CCS 5.5 5.5 10.5 10.5 5.5 5.5 10.5 10.5 MCC 65.5 65.5 65.5 65.5 70.5 70.5 70.5 70.5 Mg. Stearate 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Talc 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Peppermint 1 1 1 1 1 1 1 1 Sodium Saccharine 2 2 2 2 2 2 2 2 Mannitol 14 10 9 5 9 5 4 0 All the ingredients were passed through 60 # sieve separately, Magnesium stearate & Talc through 40 #. Then the ingredients were weighed and mixed in geometrical order and tablets were compressed with 8 mm sizes flat round punch to get tablet using Rimek Compression Machine. EVALUATION PARAMETERS: Precompressional Parameters Study Angle of repose:Angle of repose is defined as the maximum angle possible between the surface of pile of powder and horizontal plane. The angle of repose was determined by the funnel method. The accurately weighed powder was taken in a funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just touched the apex of the heap of the powder. The powder was allowed to flow through the funnel freely onto the surface. The diameter of the powder cone was measured. The angle of repose was calculated by substituting the values of the base radius „R‟ and pile height „H‟ in the following equation (Aulton, 2003). Tan= H / R ---------Equation I
Bulk density (ρo) = M/Vo --------Equation II M = mass of powder taken Where,Vo = Apparent unstirred volume
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Bulk density:The sample equivalent to 25g was accurately weighed and filled in a 100 ml graduated cylinder and the powder was leveled and the unsettled volume, Vo was noted. The bulk density was calculated by the formula (Lachman et al, 1991)
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Where, H = Pile height and R = Radius of Pile Therefore; = tan –1 H / R
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Tapped density:The tapped density was determined by mechanically tapping the measuring cylinder and the volume was noted (Lachman et al, 1991) Where, ρt = tapped density Tapped density (ρt) = M / Vt --------Equation III M = weight of granules Vt = tapped volume of granules in cm3 Compressibility index:The bulk volume and tapped volume was measured and compressibility index was calculated using the formula (Aulton, 2003). Compressibility index =100 (Vo-Vf)/Vo --------Equation IV Where,Vo = Bulk volume Vf = Tapped volume Hausner’s ratio:Tapped volume and bulk volume were measured and the hausner‟s ratio was calculated using the formula Hausner’s ratio = Vo/Vf --------Equation V Where, Vo = Bulk volume Vf = Tapped volume Pre-compression parameter study: The tablet blends were evaluated for their bulk density, tapped density, carr‟s index and flow properties. (Table No 2). Table No. 2:- Pre-compression parameter study. Formulation code F1 F2 F3 F4 F5 F6 F7 F8
Angle of repose 19.29±1.18 23.29±0.89 17.22±0.49 12.41±0.51 19.39±0.85 19.64±0.89 14.03±1.56 22.29±0.51
Bulk density (wt/ml) 0.90±0.02 0.96±0.02 0.93±0.03 0.98±0.02 0.93±0.03 0.90±0.01 0.92±0.02 0.93±0.01
Taped density (wt/ml) 1.04±0.01 1.08±0.02 1.11±0.03 1.06±0.04 1.11±0.03 1.04±0.01 1.06±0.02 1.13±0.01
Hausner ratio 1.14±0.04 1.13±0.06 1.17±0.07 0.083±0.06 1.17±0.04 1.14±0.04 1.15±0.04 1.13±0.01
Compressibiliy index (%) 12.68±0.23 11.51±0.23 15.12±0.46 7.80±0.58 15.12±0.46 12.68±0.23 13.78±0.64 13.78±0.64
Post compression parameter study Average weight and weight variation: For weight variation test IP procedure was followed. Twenty tablets were taken and their weight was determined individually and collectively using single pan electronic balance (AR 0640, Ohaus Corp. USA). The average weight of the tablets was determined from collective weight. From the individual tablets weight, the range and percentage standard deviation was calculated. Not more than 2 tablets should deviate from the average weight of tablets and the maximum percentage of deviation allowed. In direct compression of tablet, uniform weight of tablets represents appropriate powder flow and uniform die filling. Official values for uniformity of weight are enlisted in table no.3.
Maximum percentage of deviation allowed 10 7.5 5
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Average weight of tablets (mg) 80 or less 80 - 250 More than 250
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Table No 3: Standard values for uniformity of weight.
Hardness:
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Hardness exhibits tensile strength of tablet. The force needed to fracture the tablet by diametral compression is referred as crushing strength of tablet. Hardness is a deformation property of a solid. The hardness of the six tablets from each formulation batch was determined using Monsanto hardness tester. Friability: Friability test indicates physical strength of compressed tablets. During handling tablets are subjected to stresses from collisions and tablets sliding towards one another and other solid surfaces, which can result in the removal of small fragments and particles from tablet surface. The result will be progressive reduction in tablet weight and a change in its appearance. Test for tablet Friability was carried out according to I.P 2007, according to which friability below 1% passes the test. Tablets from each formulation were tested for friability using Roche Friabilator (Rolex Scientific Engineers Limited). Twenty tablets were weighed initially and transferred to the Friabilator. The instrument was operated at 25 rpm for 4 minutes. The tablets were reweighed and percentage loss was calculated using formula:
Drug content uniformity: For the content uniformity test, twenty tablets were weighed and pulverized to a fine powder. A quantity of powder equivalent to 2 mg of granisetron hydrochloride was extracted into distilled water and liquid was filtered (0.22 µm membrane filter disc). The drug content was determined by measuring the absorbance at 301.5 nm (using Shimadzu, Pharmaspec 1700, Japan) after appropriate dilution with distilled water. The drug content was determined using standard calibration curve. The mean percent drug content was calculated as an average of three determinations. Wetting time and Water absorption ratio (R): A tissue paper folded twice was placed in a petridish containing 6ml of water in which amaranth dye was dissolved. A tablet was placed carefully on the surface of tissue paper in the petridish. The time required for red colored solution to reach the upper surface of the tablet and to completely wet it was noted as the wetting time. For measuring water absorption ratio the weight of the tablet before keeping in the petri- dish was noted (Wb). The wetted tablet from the petridish was taken and reweighed (W a) Water absorption ratio (R) was then determined according to following equation:
In vitro disintegration time: Disintegration of FDT was generally occurring due to water uptake by superdisintegrant via capillary action, which results in swelling of superdisintegrants and tablet get disintegrated. It was also reported that increased compaction force may increase or decrease disintegration time. In the present study disintegration test was carried out on six tablets using the apparatus specified in USP (Electrolab disintegration apparatus USP). The distilled water at 37 0C ± 20C was used as a disintegration media and time in second taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured in seconds. In vitro dissolution study: In vitro dissolution of the tablets (n=3) was determined using USP- Type-II dissolution test apparatus rotating at 50 rpm in 900 ml phosphate buffer of ph 6.8 as medium at 37.0 ºC + 0.5 ºC. Aliquots (5ml) were withdrawn at intervals of 5 min for 30 minutes. The amount of montelukast sodium in solution was determined spectrophotometricaly at 344 nm. Sink conditions was maintained throughout the study.
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Post compression parameter study: The prepared tablet were evaluated for weight variation, hardness, friability, disintegration time, wetting time, water absorption ratio, drug content studies. In weight variation test 20 tablets were selected at a random and average weight was calculated. The post compression parameters were shown in table no. 4.
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Stability study: The fast disintegrating tablets were packed in aluminium foil and stored under the following environmental conditions for a period as prescribed by ICH guidelines for accelerated studies i.e. 40 ± 10C and RH 75% ± 5%. The tablets were withdrawn at end of 30, 60 and 90 days and evaluated for parameters including disintegration time, wetting time, percent drug release, dissolution study and test for dispersibility etc.
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Table No 4:- Post compression parameter study. Formulation code F1 F2 F3 F4 F5 F6 F7 F8 The values represents mean ± SD, n = 3
Hardness (kg/cm2)
Friability (%)
Weight variation (mg)
Thickness (mm)
2.5 ±0.12 3.1±0.12 2.9±0.15 3.0±0.11 2.7±0.09 2.5±0.13 2.8±0.11 3.2±0.12
0.39±0.06 0.43±0.09 0.36±0.05 0.38±0.08 0.42±0.03 0.44±0.04 0.38±0.08 0.36± 0.05
0.097±0.03 100.1±0.06 100.3±0.02 0.09±40.09 102. ±10.05 0.09±90.09 100.0±0.03 101.1±0.05
3.20±0.03 3.00±0.04 3.20±0.03 3.25±0.01 3.30±0.02 3.35±0.02 3.00±0.04 3.25±0.05
RESULT AND DISCUSSIONS Hardness: The hardness of the tablets prepared was determined by Monsanto Hardness tester and found to be within the range of 2.5 kg/cm2 to 3.2 kg/cm2. Friability test: The friability was found in all designed formulations in the range 0.36% to 0.44% to be well within the approved range (
