The Study On Solubility Of Several NSAIDs & Preparation And Characteristics Evaluation Of Their Sustained Release Systems

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widelyused therapeutic agents,primarily for the treatment of fever,pain and inflammation,especially arthritis.With the recent advent of high throughput screening of newNSAIDs,the number of poorly soluble drug candidates (e.g.Valdecoxib andRofecoxib) has risen sharply and the formulation of such drugs for either oral ortopical and injectable delivery now presents one of the most frequent and greatestchallenges to formulation scientists in the pharmaceutical industries.Solubility and itsenhancement of poorly soluble drug are of continuously growing interest to thepharmaceutical industry while formulating poorly soluble drugs.Therefore,weperformed extensive investigations on their solubility behaviors in the presence ofeffective cosolvents,hydrophilic polymers and surfactants in order to select anappropriate medium to enhance their solubility,and obtained a lot of solubility data,such a database is useful in developing oral and injectable formulations containingrofecoxib or valdecoxib.Preliminary investigations indicated both ethanol and SLS are respectively aneffective cosolvent and surfactant for the solubilization of valdecoxib.The aqueoussolubility of valdecoxib could be enhanced significantly by using ethanol as acosolvent at various concentrations as well as by increasing the temperature of thedissolution media.The solubility of valdecoxib increased with increasing massfraction of ethanol up to 80%,but solubility decreased in pure ethanol at all thetemperature.Experimental solubility data of valdecoxib were correlated with thosecalculated by a log-linear equation.Calculated Gibbs free energy values were allnegative for all the ethanol + water mixtures at (25,30,and 35)℃,indicating thespontaneous nature of valdecoxib solubilization.In the case of SLS + water mixtures, the solubility of valdecoxib linearly increased with increasing mass fraction of SLS inwater at all the temperatures.The solubility of valdecoxib increased with increasing mass fraction of glycerol,propylene glycol,and PEG 400 at (25,30,and 35)℃.For PEG 400 + water mixtures,the solubility of valdecoxib was higher when compared to the glycerol + water andpropylene glycol + water mixtures.The solubilization power of glycerol,propyleneglycol,and PEG 400 at (25,30,and 35)℃was 1.1,1.5,and 1.8,2.6,2.8,and 2.9,and3.0,3.5,and 3.9,respectively.For PEG 4000,PEG 6000,PEG 8000 and PEG 10000,the aqueous solubility ofvaldecoxib could be enhanced by the addition of an increasing mass fraction of all ofthe PEGs tested as well as by increasing the temperature of the dissolution media.Themolecular weight of the PEGs tested played an important role in valdecoxibsolubilization in the aqueous medium.Among the PEGs studied,PEG 4000 exhibiteda higher solubilization potential than the others.Calculated Gibbs free energy valueswere all negative for all of the PEG +water mixtures at (25,30,and 35)℃,indicatingthe spontaneous nature of valdecoxib solubilization.In the case of PEG 4000 + watermixtures,the⊿ G_tr^o values decreased to a greater extent than those for the othercarriers (PEG 6000,PEG 8000,and PEG 10000) + water mixtures,indicating that thereaction conditions were more favorable in PEG 4000 + water mixtures than in othercarrier + water mixtures.The solubilization of rofecoxib in aqueous solution using mannitol,PVP K30,urea,PEG 4000,and PEG 6000 were investigated at (25,30,and 35)℃.The aqueoussolubility of rofecoxib could be enhanced by the addition of increasing mass fractionof all of the hydrophilic carriers tested except mannitol as well as by increasing thetemperature of the dissolution medium.Among the hydrophilic carriers studied,ureaexhibited a higher solubilization potential than the other carriers.Calculated Gibbsfree energy values were all negative for all of the hydrophilic carriers + watermixtures,indicating the spontaneous nature of rofecoxib solubilization.In the case ofurea + water mixtures,the values decreased to a greater extent than those for the other carriers (mannitol,PVP K30,PEG 4000,and PEG 6000) + water mixtures,indicatingthat the reaction conditions were more favorable in urea + water mixtures than inother carriers + water mixtures.The solubility of rofecoxib increased with increasing mass fraction of cosolvents(glycerol,propylene glycol,and ethanol) and surfactants(Span 20,Tween 80,and SLS)at (25,30,and 35)℃.For ethanol + water mixtures,the solubility of rofecoxib washigher when compared to the glycerol + water and propylene glycol + water mixtures.The solubilization power of glycerol,propylene glycol,and ethanol at (25,30,and 35)℃was 0.81,0.87,and 0.88;2.2,2.3,and 2.4;and 3.4,3.6,and 3.8,respectively.Incase of surfactants,SLS exhibited higher solubilizing efficiency at (25,30,and 35)℃than Span 20 and Tween 80.Solubility and dissolution rate of drugs in water are important properties thatinfluence the release,transport,and rate of absorption in the gastrointestinal tract.SDsprovide the possibility of reducing the particle size of such drugs by nearly amolecular level,and transform the drugs from the crystalline to the (partial)amorphous state and/or to locally increase the saturation solubility.It is useful indeveloping oral and topical formulations containing rofecoxib or valdecoxib.The SDs of valdecoxib with PEG 4000 were prepared at 1:1,1:2,1:5,and 1:10(valdecoxib:PEG 4000) ratio by melting method.The SDs of valdecoxib with PEG4000 exhibited enhanced dissolution rate of valdecoxib,and the rate increased withincreasing concentration of PEG 4000 in SDs.Mean dissolution time (MDT) ofvaldecoxib decreased significantly after preparation of SDs and physical mixture withPEG 4000.The FTIR spectroscopic studies showed the stability of valdecoxib andabsence of well-defined valdecoxib-PEG 4000 interaction.The DSC and XRD studiesindicated the amorphous state of valdecoxib in SDs of valdecoxib with PEG 4000.The SEM pictures showed the formation of effective SDs of valdecoxib with PEG4000,since well-defined changes in the surface nature of valdecoxib,SDs,andphysical mixture were observed.The dissolution rate of rofecoxib was enhanced rapidly by its SDs with urea andincreased with increasing concentrations of urea in SDs.The mean dissolution time (MDT) of rofecoxib decreased after preparation of SDs and physical mixtures withurea.FTIR spectroscopic studies showed the stability of rofecoxib and the absence ofa well-defined rofecoxib-urea interaction.DSC and XRD studies confirmed theamorphous state of rofecoxib in SDs of rofecoxib with urea.SEM pictures showed theformation of effective SDs of rofecoxib with urea since well-defined changes in thesurface nature of rofecoxib,SDs,and physical mixture were observed.The dissolution rate of rofecoxib from its solid dispersions by PEG 4000increased with an increasing amount of PEG 4000.The MDT of rofecoxib decreasedsignificantly after preparing its solid dispersions with PEG 4000.The FTIRspectroscopic studies showed the stability of rofecoxib and absence of well-definedrofecoxib-PEG 4000 interaction.The DSC and XRD studies indicated the amorphousstate of rofecoxib in solid dispersions of rofecoxib with PEG 4000.SEM picturesshowed the formation of effective solid dispersions of rofecoxib with PEG 4000 sincewell-defined change in the surface nature of rofecoxib and solid dispersions wereobserved.Solid dispersions formulation with highest drug dissolution rate (rofecoxib:PEG 4000 1:10 ratio) was used for the preparation of solid dispersion-based rofecoxibtablets by the direct compression method.Solid dispersion-based rofecoxib tabletsobtained by direct compression,with a hardness of 8.1 Kp exhibited rapid drugdissolution and produced quick anti-inflammatory activity when compared toconventional tablets containing pure rofecoxib at the same drug dosage.Thisindicated that the improved dissolution rate and quick anti-inflammatory activity ofrofecoxib can be obtained from its solid dispersion-based oral tablets.There is a continuously growing interest of the pharmaceutical industry for drugdelivery in sustained or controlled release dosage forms.Controlled drug deliverysystems offer numerous advantages compared to conventional dosage forms.Of thedifferent dosage forms reported,micro-and nano-particles occupy unique position indrug delivery technology due to their attractive properties.The mean particle size and encapsulation efficiency of cross-linked chitosanmicrospheres was between 3.8 to 4.2μm and 96.3 to 98.7%,respectively.Spray-driedchitosan microspheres were spherical in shape with smooth surface.The surface morphology of spray-dried chitosan microspheres was affected by the crystallinity ofthe loaded drug and cross-linking agent.The release data of the spray-dried chitosanmicrospheres were treated with Zero-order,First-order,Higuchi,Korsmeyer,andKopcha kinetic models and best fit was observed with Higuchi model,indicating therelease of drug from spray-dried chitosan microspheres followed Fick's law ofdiffusion.The mean particle size of drug-loaded spray-dried SPS microparticles wasbetween 10.3 to 13.1μm.The mean particle size increased slightly with increase inthe concentration of SPS.The % yield of spray-dried SPS microparticles did not varymuch among the various formulations and it was between 65.2 to 70.1%.The drugloading efficiency of spray-dried SPS microparticles decreased slightly with anincreasing concentration of SPS.The loading efficiencies are 77.4,72.3,and 68.5 %,respectively.The cumulative amount of drug release from the spray-dried SPSmicroparticles decreased with an increase in the concentration of SPS and in the drugloading.The dissolution data were treated with Higuchi equation and it was found thatrelease of the drug from spray-dried SPS microparticles followed Fick's law ofdiffusion since good correlation coefficient (R²) was observed with the Higuchi plots.