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  • Acta Poloniae Pharmaceutica Drug Research, Vol. 69 No. 2 pp. 299308, 2012 ISSN 0001-6837Polish Pharmaceutical Society

    Carvedilol (CAR), an antihypertensive agent,is used in the treatment of hypertension, congestiveheart failure, cardiac arrhythmias and angina pec-toris (1). It is a nonselective -adrenergic blockerwith selective -adrenergic blocking (2). However,drug bioavailability is very limited (2530%),since it is practically insoluble in water and its dis-solution is rate limiting for its absorption from gas-tro-intestinal tract. Also CAR is poorly flowableand compressible drug (3, 4). One of the approach-es to enhance the dissolution rate is the use of soliddispersions. At present, the solvent method andmelting method are widely used in the preparationof solid dispersions (5, 6). In general, subsequentgrinding, sieving, mixing and granulation are nec-essary to produce different desired formulations.The spherical agglomeration technique has beenused as an efficient particle preparation technique(7, 8). Initially, spherical agglomeration techniquewas used to improve powder flowability and com-pressibility (9, 10). Then, polymers were intro-duced in this system to modify their release(1113). Currently, this technique is used more fre-quently for the solid dispersion preparation of

    water-insoluble drugs in order to improve their sol-ubility, dissolution rate and simplify the manufac-turing process. Spherical agglomeration is carriedout by following methods: 1) Solvent change sys-tem, 2) Quasi-emulsion solvent diffusion system(QESD), 3) Ammonia diffusion system, 4)Neutralization technique. Out of these techniques,the QESD is most commonly used. This methodemploys three solvents: 1) Good solvent solventthat dissolves API, 2) Poor solvent solvent inwhich API is insoluble, 3) Bridging liquid sol-vent that dissolves API and is immiscible with poorsolvent while miscible with good solvent. Whenbridging liquid plus good solvent containing APIare poured into the poor solvent under agitation,quasi-emulsion droplets of bridging liquid or goodsolvent form in the poor solvent and induce crys-tallization of the drug followed by agglomeration.

    In the present study, to overcome the problemsrelated to solubility, dissolution rate, flowability andcompressibility, the spherically agglomerated soliddispersions of CAR were prepared by QESD byusing a hydrophilic polymer polyvinylpyrrolidoneK30 (PVP K30).

    AN IMPROVEMENT IN PHYSICOCHEMICAL PROPERTIES OF CARVEDILOL THROUGH SPHERICALLY AGGLOMERATED

    SOLID DISPERSIONS WITH PVP K30

    AMIT TAPAS1*, PRAVIN KAWTIKWAR2 and DINESH SAKARKAR1

    1Sudhakarrao Naik Institute of Pharmacy, Pusad-445204, Dist. Yavatmal, Maharashtra, India2Shri Sureshdada Jain Institute of Pharmaceutical Education and Research, Jamner-424206, Dist. Jalgaon,

    Maharashtra, India

    Abstract: Spherically agglomerated solid dispersions of carvedilol (CAR) were prepared with polyvinyl-pyrrolidone (PVP) using acetone, water and dichloromethane as solvent, non-solvent and bridging liquid,respectively. The prepared agglomerates were evaluated for its percentage yield, drug content, morphology,thermal behavior, micromeritic properties, aqueous solubility and in vitro drug release. Differential scanningcalorimetric and powder X-ray diffraction studies confirm that formulation process altered the crystalline natureof carvedilol. The recrystallized agglomerates exhibited significant increase (p < 0.05) in micromeritic proper-ties than untreated carvedilol. Solubility and in vitro drug release studies indicated that the spherical agglomer-ates showed significant increase (p < 0.05) in solubility and dissolution rate than pure carvedilol alone.

    Keywords: carvedilol, spherically agglomerated solid dispersion, solubility, micromeritic properties, dissolu-tion rate

    299

    * Corresponding author: phone/fax: +91-7233-245308; e-mail: [email protected]

  • 300 AMIT TAPAS et al.

    EXPERIMENTAL

    MaterialsCarvedilol was supplied by Dr. Reddys

    Laboratory, Hyderabad, India as a gift sample. PVPK30 was supplied by Lupin Research Park, Pune,India. All other chemicals used were of analyticalgrade.

    Preparation of spherically agglomerated solid dis-persion

    A solution of CAR (1 g) in acetone (12 mL)and dichloromethane (2 mL) was added dropwise toa solution of hydrophilic polymer (PVP K30,1.59% w/v) in distilled water (100 mL) containingAerosil 200 Pharma (0.1 g). The mixture was stirredcontinuously using a mechanical stirrer (RemiMotors, India) at 1000 rpm at room temperature for0.5 h to obtain spherical agglomerates. The agglom-erates were separated by filtration using Whatmanfilter paper no. 42 and placed in a thin layer in anoven at 60OC for 1 h. Composition of agglomeratesis given in Table 1.

    Percentage yield and drug content studyThe yield of spherical agglomerates was deter-

    mined by comparing the whole weight of theagglomerates formed against the combined weightof the polymer and drug:

    The drug content study of agglomerates wasdetermined by dissolving 100 mg of crystals in 3 mLof methanol and diluting further with distilled water(100 mL) followed by measuring the absorbance ofappropriately diluted solution spectrophotometrical-ly (PharmaSpec UV-1700, UV-Vis spectrophotome-ter, Shimadzu) at 286 nm.

    Fourier transform infrared spectroscopy (FTIR)The FTIR spectra of powder CAR, and its

    agglomerates were recorded on an FTIR spec-trophotometer (JASCO, FTIR V-430 Plus).

    Differential scanning calorimetry (DSC)DSC analysis was performed using a DSC 823

    calorimeter (Mettler Toledo model) operated bySTARe software. Samples of CAR and its agglom-erates were sealed in an aluminium crucible andheated at the rate of 10OC/min up to 300OC under anitrogen flow (40 mL/min).

    Powder X-ray diffraction studiesPowder X-ray diffraction patterns (XRD) of

    CAR and its spherical agglomerates were monitoredwith an x-ray diffractometer (Philips AnalyticalXRD) using copper as x-ray target, a voltage of 40KV, a current of 25 mA and with 2.28970 wave-length. The samples were analyzed over 2 range of10.0199.99O with scanning step size of 0.02O (2)and scan step time of 0.8 s.

    Scanning electron microscopyThe surface morphology of the agglomerates

    was accessed by SEM. The crystals were spluttercoated with gold before scanning.

    Micromeritic propertiesThe size of agglomerates was determined by

    microscopic method using stage and eyepiecemicrometers. The shape of the agglomerates wasobserved under an optical microscope (60 magnifi-cation) attached to a computer. Flowability ofuntreated carvedilol and agglomerates was assessedby determination of angle of repose, Carrs index(CI) and Hausners ratio (HR) (14). Angle of reposewas determined by fixed funnel method (15). Themean of three determinations was reported. The CI

    Weight of agglomerates obtainedPercentage yield = 100

    Total weight of drug and polymer used

    Table 1. Composition of spherical agglomerates.

    Ingredients/Parameters CP-1 CP-2 CP-3 CP-4 CP-5 CP-6

    Carvedilol (g) 1.0 1.0 1.0 1.0 1.0 1.0

    Acetone (mL) 12.0 12.0 12.0 12.0 12.0 12.0

    DCM (mL) 2.0 2.0 2.0 2.0 2.0 2.0

    Water (mL) 100 100 100 100 100 100

    PVP K30 (%w/v) 1.5 3.0 4.5 6.0 7.5 9.0

    Aerosil 200 Pharma (g) 0.1 0.1 0.1 0.1 0.1 0.1

    Stirring speed (rpm) 1000 1000 1000 1000 1000 1000

  • An improvement in physicochemical properties of carvedilol... 301

    and HR were calculated from the loose and tappeddensities. Tapped density was determined by tap-ping the samples into a 10 mL measuring cylinder.The CI and HR was calculated according to the fol-lowing equation:

    Tapped density Bulk densityCI = 100

    Tapped density

    Tapped densityHR = Bulk density

    Solubility studiesA quantity of crystals (about 100 mg) was

    shaken with 10 mL of distilled water in stopperedconical flask in incubator shaker for 24 h at roomtemperature. The solution was then passed through aWhatman filter paper (no. 42) and amount of drugdissolved was analyzed spectrophotometrically.

    Dissolution rate studiesThe dissolution rate studies of carvedilol alone

    and its spherical agglomerates were performed intriplicate in a dissolution apparatus (Electrolab,India) using the paddle method (USP Type II).Dissolution studies were carried out using 900 mLof 0.1 M HCl (pH 1.2) at 37 0.5OC at 50 rpmaccording to US FDA guidelines (16, 17).Carvedilol (12.5 mg) or its equivalent amount ofspherical agglomerates were added to 900 mL of 0.1M HCl (pH 1.2). Samples (5 mL) were withdrawn attime intervals of 10, 20, 30, and 60 min. The volumeof dissolution medium was adjusted to 900 mL byreplacing each 5 mL aliquot withdrawn with 5 mLof fresh 0.1 M HCl (pH 1.2). The solution wasimmediately filtered, suitably diluted and the con-centrations of carvedilol in the samples were deter-mined spectrophotometrically at 286 nm. Theresults obtained from the dissolution studies werestatistically validated using ANOVA.

    Dissolution efficiency studiesThe dissolution efficiency (DE) of the batches

    was calculated by the method mentioned by Khan(18). It is defined as the area under the dissolutioncurve between time points t1 and t2 expressed as apercentage of the curve at maximum dissolution,y100, over the same time period or the area underthe dissolution curve up to a certain time, t, (meas-ured using trapezoidal rule) expressed as a percent-age of the area of the rectangle described by 100%dissolution in the same time. DE60 values were cal-culated from dissolution data and used to evaluatethe dissolution rate (19).

    Stability studiesThe agglomerates were charged for the accel-

    erated stability studies in accordance with ICHguidelines (40 2OC and 75 5% RH for a periodof six months). The initial drug co