الفهرس 
GENERAL INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Flutamide is a non-steroidal anti-androgenic drug used in the
treatment of prostate cancer. Unfortunately, flutamide has low and variable
oral bioavailability which is mainly due to its poor dissolution and presystemic
disposition. Flutamide is administered three times daily which may
cause a variety of side-effects including diarrhea, tiredness, impotence, breast
fullness and liver malfunction. Enhancing the dissolution rate of flutamide
can thus increase the bioavailability of the drug by making more of the drug
available for absorption rapidly and simultaneously. This will provide greater
chance for the drug to escape the pre-systemic metabolism. The benefit
becomes even greater if the formed rapidly dissolved drug is used to develop
a controlled release dosage form, thus decrease the frequency of the drug
administration and therefore reduce the incidence of adverse effects.
Accordingly, the objective of this work was to enhance the dissolution
rate of flutamide and to formulate controlled release granules. This was
achieved by developing a validated analytical method for quantification of
flutamide, preparation of flutamide-sucralose co-crystals and flutamide
crystals using controlled precipitation technique. These systems were
evaluated using the infrared spectroscopy, differential scanning calorimetry
and powder X-ray diffraction to investigate the possibility of interaction
between the drug and polymer and/or to monitor any physical change in the
drug crystals. The system providing the greatest enhancement in drug
dissolution rate was used to prepare controlled release granules. The
proceeding sections will provide a summary of these investigations.
Abstract 2
Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt.
Development of validated analytical method for quantification of
flutamide:
Flutamide quantification was carried out using UV spectrophotometric
analysis. The developed UV method employed a Jasco UVspectrophotometer
and included the construction of a calibration curve of
flutamide in ethanol and in 0.1N HCl (pH 1.2). Flutamide calibration curve in
ethanol was constructed by recording the absorbances of serial dilutions of
ethanolic stock solution of the drug at λmax of 295nm. Calibration curve in
0.1N HCl (pH 1.2) was constructed by preparing ethanolic stock solution of
the drug which is then diluted using 0.1N HCl, the absorbances of the
resultant serial dilutions was recorded at λmax of 306 nm.
Enhancement of the dissolution rate of flutamide by co-crystallization
technique using sucralose as a co-crystal co-former
Flutamide and sucralose co-crystals were prepared using acetone
assisted co-grinding method. The drug was mixed with the sugar at the molar
ratios of 1:1, 1:2 and 1:3 before wet co-grinding process. The drug and the
sugar were treated with acetone in the same manner and employed in the
study as positive controls. The co-crystallization products were characterized
using Fourier transform infrared spectroscopy (FTIR), differential scanning
calorimetry (DSC) and X-ray powder diffraction (XRPD). The FTIR spectra
show the characteristic absorption bands of the drug and the sugar. These
characteristic absorption peaks not changed significantly after separate
precipitation of the drug and the sugar from their solution in acetone. Wet cogrinding
of the drug with the sugar resulted in alterations in the spectrum of
the drug and the sugar. These alterations were evident in the peaks
corresponding to NH-stretching and bending vibrations, those resulting from
Abstract 3
Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt.
NO2 symmetric and asymmetric stretching vibrations as well as the peak
corresponding to C-N torsion. There was also a change in the spectrum of
sucralose especially in the peaks corresponding to the C-O stretching
vibration. The alterations in the absorption bands of the drug and the sugar
after wet co-grinding process depend on the molar ratio of the drug to the
sugar.
Thermal analysis of the drug and the sugar produced thermograms
showing the main endothermic peak of the drug and the sugar which confirms
their crystalline nature. Wet grinding of the drug resulted in shifting in both
the main endothermic peak and the degradation peaks of the drug which
indicated the formation of new crystalline species of the drug. Wet grinding
of the sugar resulted in a crystalline powder with similar melting point but the
melting transition had lower enthalpy. The main endothermic peak of the
drug in case of the co-ground formulations of flutamide with sucralose was
changed depending on the molar ratio of the drug to sucralose. The X-ray
diffraction patterns of the drug and the sugar showed their definite diffraction
peaks indicating their crystalline nature. The diffraction pattern of the drug as
well as the sugar was changed with respect to the position and intensity of
certain diffraction peaks. Wet co-grinding of flutamide with sucralose
produced crystalline material having different X-ray diffraction pattern
depending on the relative proportions of the drug to sucralose which showed
that 1:2 (drug to sugar) is the optimum molar ratio for co-crystal formation.
Dissolution studies were performed to evaluate the effect of cocrystal
formation on the dissolution rate of the drug. The dissolution studies
revealed that the unprocessed flutamide exhibited slow dissolution and the
dissolution rate wasn’t enhanced after wet grinding process (positive control).
Development of co-crystals of drug with sucralose significantly enhanced the
Abstract 4
Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt.
dissolution rate of the drug compared with the unprocessed drug or the
positive control. This enhancement depends on the drug to sugar molar ratio
with 1:2 molar ratio being the optimum.
Enhancement of the dissolution rate of flutamide by controlled
precipitation technique
Drug crystals was prepared by the precipitation of the drug with the
addition of de-solvent in the presence of polyvinylpyrrolidone (PVP 40T) or
hydroxylpropyl methyl cellulose (HPMC E5) as hydrophilic polymers. Each
polymer was used in two different quantities (50 and 100 mg). In vitro drug
release was performed to evaluate the effect of each polymer on the
dissolution of the drug. The in vitro drug release data showed that the
controlled precipitation technique significantly enhance the dissolution of the
drug crystals prepared utilizing both polymers with both quantities. It also
revealed that drug crystal formulation prepared using 50 mg of HPMC E5, as
hydrophilic polymer, showed the fastest dissolution rate. This optimum
formulation was selected for physical characterization.
Unprocessed drug, pure polymer and the optimum formulation were
subjected to solid state characterization which was conducted using DSC,
XRPD and FTIR spectroscopy. The thermogram of unprocessed drug showed
two endothermic peaks, the first was attributed to the melting transition of the
drug and the second was a drug decomposition peak. The pure polymer
thermogram showed two broad endothermic peaks which revealed the
amorphous nature of the polymer. With respect to the prepared formulation,
the main endothermic and decomposition peaks of the drug were shifted to
higher temperature with further broadening which indicate the formation of
new crystalline species. In order to confirm the results of DSC, XRPD was
Abstract 5
Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt.
conducted and the diffraction pattern of the unprocessed drug revealed its
crystalline nature. The diffractogram of HPMC E5 indicated the amorphous
nature of the polymer and confirmed the DSC results. Controlled precipitation
of flutamide in presence of the polymer resulted in the formation of a new
crystalline structure which was evidenced by the appearance of new peaks in
its diffractogram.