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Preformulation is a branch of pharmaceutical sciences that utilizes biopharmaceutical principles in the determination of physicochemical properties of a drug substance. The goal of preformulation studies are to choose the correct form of the drug sudstance, evaluate its physical properties and generate a thorough understanding of the material's stability under various conditions, leading to the optimal drug delivery system. The preformulation study focuses on the physicochemical parameters that could effect the development of efficacious dosage form. A thorough understanding of these properties may ultimately provide a rationale for formulation design. Also it will help in minimizing problems in later stages of drug development, reducing drug development costs and decreasing product's time to market.
The compatibility of the drug and formulation is an important prerequisite for formulation. Therefore, in preformulation study, compatability evaluation was carried out using infra-red spectraThe objective of preformulation testing is to generate information useful to the formulation in developing stable and bioavailable dosage forms.The use of preformulation parameters maximizes the chances in formulating an acceptable, safe, efficacious and stable product.
Preformulation encompasses following tests :
Fourier transforms Infrared spectroscopy study
The FT-IR spectrum of pure drug, physical mixture, Formlation was analysed for compatibility study using Shimadzu Forier Transform Spectophotometer.Aceclofenac was dried in hot air oven at 50áµ’C for 2 hours. The sample were prepared by mixed it thoroughly with potassium bromide. This physical mixture was compressed under pressure of 10 Ton/nm2 and converted in a circular disc. This disc was then placed in the scanning slot of Fourier Transform Infra-red (FT_IR) of aceclofenac. Compared the spectrum with reference spectrum given in IP 2007.
X-Ray Diffraction Study
Diffraction pattern of powdered sample were recorded with an X-ray diffractometer (Philips X-ray generator, Holland). X-ray diffraction was performed at room temperature (30áµ’C) with a diffractometer. The target was carried out by using Copper (λ=1.54) with the Nickel filter, under a voltage of 40 kv, with a current of 30 mAáµ’. The time constant was maintained as 10 min/second with scanning rate of 2áµ’/min measured from 10-35Í¦ at full scale of 200.
Nuclear Magnetic Resonance Study (NMR)
The NMR spectrum was recorded for sample solution in D2O. The sample was dissolved by heating.
Isolation of gum from Tamarind Seed
The crushed seeds of Tamarindus indica were soaked in water for 24 h, boiled for 1 h, and kept aside for 2 h for the release of gum into water. The soaked seeds were taken and squeezed in a muslin bag to remove marc from filtrate. Then, to the filtrate, equal quantity of absolute ethyl alcohol was added to precipitate the gum. The gum was separated by filtration. The marc was not discarded but it was sent for multiple extraction with decreasing quantity of extracting solvent¸ i.e., water with the increase of number of extractions. The isolation was continued until the material was free of gum. The separated gum was continued until the material was free of gum. The separated gum was dried in hot air oven at temperature 40áµ’C. The dried gum was powdered and stored in airtight containers at room temperature.
Preparation of Standard curve for Aceclofenac ;
50 mg of aceclofenac was first dissolved in 3 ml of methanol and made up to 100 ml with buffer solution pH 7.4. 1 ml of this solution contain 50 mg of aceclofenac, 20 ml of this solution was taken and made up to 100ml with buffer. This solution treated as stock solution. 1 ml of the solution contain 50 mg of aceclofenac. From this stock solution dilution 2 mg/ml, 4 mg/ml, 6mg/ml, 8mg/ml, 10 mg/ml.
Preparation of dilution media :
pH 7.4 Phosphate Buffer :
50 ml of the 0.2M Potassium dihydrogen phosphate was taken in the 200 ml volumetric flask; to it 39.6 ml of 0.2N NaOH was added. The volume was made upto mark using distilled water.
0.1 N Hydrochloric acid :
Solution of 0.1 N Hydrochloric acid was prepared by diluting 8.5 ml of Hydrochloric acid to 1000 ml with water.
Preparation of Sustained Release matrix tablet :
Sustained Release matrix tablet of Aceclofenac were prepared by using different drug:polymer ratios as 1:1, 1:1.25, 1:3, 1:3.5, 1:4 for various batches F1 to F5 were prepared by using Guar Gum as the polymer and the batches F6 to F10 were formulated by using Tamarind gum as the matrix forming polymer. Microcrystalline cellulose were used as the fillers to maintain the tablet weight. All ingredients were passed through sieve no. 20, weighed and bleneded.
Table No. 1 Formulation of Sustained release matrix Tablet with Guar gum
Formulation of Sustained release matrix Tablet with Tamarind gum
Table No. 2
The powders were subjected to the various characteristics studies, such as angle of Repose, compressibility index, Bulk density, tapped density, Hauner's ratio etc as follows
Evaluation of Blends
The ideal characteristics of a tablet that make it a popular and acceptable dosage form are compactness, physical stability, rapid production capability, chemical stability and efficacy. In general , above characteristics of tablet are dictated by the quality of the bled from which it is made. Many formulation and process variables involved in the blending step can affect the characteristics of final blend produced. Therefore, various methods to measure certain blend characteristics have been developed to monitor blending suitability for tableting. The main characteristics required to be monitored in blending are flow properties and compressibility.
Micromeretic Property :
Physical mixture of drug with different excipiaents were prepared by mixing in a dried mortar for 5 min. Angle of repose (θ), Compressibility index (C.I.), Bulk density, Tapped density, etc were calculated as follows.
Angle of Repose:
The angle of repose is used as an indirect measure of quantifying powder flowability. The angle of repose of granules was determined by the funnel method. The accurately weighed granules were 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 granules. The granules were allowed to flow through the funnel freely onto the surface. The diameter of the powder cone was measured and angle of repose was calculated using the following equation,
tan θ = h/r
Where, θ = angle of repose
h = height of the powder cone
r = radius of the powder cone
Table No : 3 Angle of repose as an indication of powder flow properties.
Angle of repose
Type of flow
Bulk density is indicative of the packing of particles and as such is greatly influenced by the size of granules. Both loose bulk density (LBD) and tapped bulk density (TBD) were determined. A quantity of 2 g of powder from each formula, previously lightly shaken to break any agglomerates formed, was introduced into a 10 mL measuring cylinder. After the initial volume was observed, the cylinder was allowed to fall under its own weight onto a hard surface from the height of 2.5 cm at 2 second intervals. The tapping was continued until no further change in volume was noted. LBD and TBD were calculated using the following formulas,
LBD = W/V0
TBD = W/Vt
Where, W = weight of the powder
V0 = volume of packing
Vt = tapped volume of the packing
Compressibility index is a measure of flow rate of powder and measure of relative importance of inter particulate interactions. The compressibility index of the granules was determined by Carr's compressibility index.
Carr's compressibility index (%) = [(TBD - LBD) - 100]/TBD
Table No. 4 Relationship between % Compressibility and Flowability
Hausner's ratio is indicative of flow property. It is derived property from bulk and tapped density. Lower the Hausner's ratio is indicating better flow whereas higher ratio indicates poor flow of granules Hausner's ratio is calculated by the following formula,
Hausner's ratio = TBD/LBD
The powder were compressed by a direct compression technique with the help of tablet compression machine 8mm shallow concave die and punch set ( Cad mach Machinery Co. India). The prepared tablets of each formulation were subjected for the evaluation of physical properties, drug content and in-vitro drug release study, swelling behavior, stability test.
Evaluation of Sustained release matrix tablet:
All prepared SR matrix tablets were evaluated for weight variation as per USP XXIV monograph. Twenty tablets of each batch were used to evaluate weight variation .
Friability was determined by subjecting a sample of twenty preweighed matrix tablets to abrasion in automated USP friabilator ( Roche Friability test apparatus, model EF-2, Electro lab, Mumbai ). It was operated 25 rpm for 4 min. The percentage friability was calculated by using formula-
F = 100 ( 1- W0/W )
Where F = percentage friabiity
Wo = Initial weights of 20 tablets
W = weight after friability testing
Hardness of ten tablets of each formulation was determined Monsanto hardness tester in triplicate for all formulation as peer USP XXIV monograph.
Thickness was measured by vernier caliper as per USP XXIV monograph. The readings were carried out in triplicate and average value was noted.
Drug content :
The tablets were powdered, and 50 mg equivalent weight of Aceclofenac in tablet powder was accurately weight and transferred in to a 100 ml volumetric flask. Initially, 10 ml of pH 7.4 phosphate buffer was added and shaken for 10 min. then the volume was made up to 100m ml with phosphate buffer pH 7.4. Subsequently, the solution in volumetric flask was filtered, and 1 ml of filtrate was diluted and analyzed at 276 nm using UV-visible spectrophotometer.
Swelling behavior of Sustained release matrix tablet ;
A known weight of tablet was placed in Petridish containing pH 7.4 phosphate buffer and allowed to swell. A required period of time tablet was withdrawn blotted with filter paper. Then their change in weight was measured until attainment of equilibrium.
Swelling ratio was then calculated using the following formula:
SR = W g - W o/ W o
Where SR = Swelling Ratio
Wo = Initial weight of tablet
Wg = final weight of tablet
The weight of tablet was noted after every hour.
In- vitro drug release study :
In vitro drug release study was determined by using USP - XXIV Dissolution apparatus. Dissolution medium was 900 ml of 0.1N HCl for 0 to 2 hrs. After each 2 hrs 5 ml of sample was withdrawn and was replaced by equal volume of fresh dissolution medium of same pH. The collected sample was analyzed UV- visible spectrophotometrically measured at 275 nm and cumulative percent drug release was calculated.
Drug release kinetics:
In order to investigate the kinetic release study of matrix tablet, the data of in vitro drug release were fitted different models like zero order, first order, higuchi, korsmeyer peppa's model. The n value was employed selecting most appropriate kinetic model.
From the formulated SR matrix tablet formulation Guar gum and Tamarind gum which shows appropriate study for selected stability study. The stability study was carried out according to USP FDA stability guidelines and ICH guidelines short term stability testing carried at low, high, medium temperature. Sampling was carried out 15, 30 and 60 days. The samples was analyzed by physical absorbance and drug content was evaluated at regularly interval of time.