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ENCLOSURE- I 6.1. BRIEF RESUME OF INTENDED WORK NEED FOR THE STUDY Poor aqueous solubility of drugs is a major limiting factor with many new drugs in their successful launch in market in spite of their potential pharmacokinetic activity. Poor solubility (less than 10 %) of a drug, leads to poor dissolution in the gastro intestinal tract (GIT) hence, incomplete and erratic absorption ultimately limits its clinical utility. Further, poorly soluble drugs are generally administered at much higher doses than the actual dose in order to achieve necessary drug plasma levels leading to increased adverse reaction & cost of therapy and often yields erratic pharmacological response and hence poor patient compliance. About 40% of drugs being in the pipeline of pharmaceutical companies are poorly soluble, which emphasizes the need of a technique to overcome such problems1. Poorly water soluble drugs are associated with slow drug dissolution followed by slow absorption leading eventually to inadequate and variable bioavailability. Thus a greater understanding of dissolution and absorption behaviors of drugs with low aqueous solubility is required to successfully formulate them into bioavailable drug products2. Solubility, one of the key parameter in BCS, as well as dissolution rate is the most essential factors controlling the rate and extent of drug absorption. A number of approaches are practiced to improve the aqueous solubility of poorly soluble drugs viz., solid dispersion3, spherical agglomeration4, complexation5, pH adjustment6 etc. Among the methods spherical agglomeration is a versatile process that enables to control the size and type of crystals. The spherical agglomeration technique has been used as an efficient particle preparation technique7,8. Initially, spherical agglomeration technique was used to improve powder flowability and compressibility9,10. Then, polymers were introduced in this system to modify their release11,12. Currently, this technique is used more frequently for the solid dispersion preparation of water insoluble drugs in order to improve their solubility, dissolution rate and simplify the manufacturing process. Ritonavir, a widely prescribed antiretroviral protease inhibitor drug belong to Class II under BCS and exhibit low and variable oral bioavailability due to its poor aqueous solubility. Its oral absorption is dissolution rate limited and it requires enhancement in solubility and dissolution rate for increasing its oral bioavailability. The solubility of ritonavir in 0.1 N HCl is 400 µg/ml, the IDR value is only 0.03±0.001 mg/cm2-min. Compounds with IDR<0.1 mg/min/cm2 usually exhibit dissolution ratelimited absorption. These classes of drugs could potentially exhibit dissolution rate limited absorption and their dissolution rates may be improved through spherically agglomerated solid dispersions. In the present study an attempt was made to evaluate solubility, dissolution rate and micromeritic properties of a model drug Ritonavir by preparing spherically agglomerated solid dispersions using hydrophilic polymers. ENCLOSURE- II 6.2 REVIEW OF LITERATURE Amit T et al13 prepared spherical agglomeration of poorly water soluble drug, carvedilol to improve micromeritic properties and dissolution rate in presence of Inutec SP1. The prepared spherical agglomerates were evaluated for its percentage yield, drug content, morphology, thermal behavior, micromeritic properties and in vitro drug release. Differential scanning calorimetric and powder X-ray diffraction studies confirm that formulation process altered the crystalline nature of carvedilol. In vitro drug release studies indicated that the spherical agglomerates CI-1 showed significant increase (P<0.05) in dissolution rate than pure carvedilol alone. Sujani S et al14 prepared spherical agglomerates of meloxicam by simple agglomeration technique using a three solvent system. Agglomerates were prepared by agitating the crystals in a liquid suspension and adding a bridging liquid, which wets the crystal surface causing binding. The addition of bridging liquid promotes the formation of liquid bridges between drug crystals. Spherical agglomerates of three different polymers (PVP, poloxamer and cross povidone) and physical mixtures were prepared dried at room temperature. Particle size, saturation solubility, drug content, FTIR studies and dissolution characteristics were also investigated. Mudit dixit et al15 prepared spherical agglomerates of ketoprofen by neutralization method. Crystallization medium used for spherical agglomerates of ketoprofen consisted of 1 M Sodium hydroxide; 0.25 M hydrochloric acid; chloroform (bridging liquid) in the ratio of 20:55:25, respectively. Spherical agglomerates were characterized by differential scanning calorimetry, Infrared spectroscopy, X-ray diffractometry and scanning electron microscopy. Micromeritic and dissolution behaviour studies were also carried out. Process variables such as amount of bridging liquid, stirring time and duration of stirring were optimized. Dissolution profile of the spherical agglomerates was compared with pure sample and recrystallized sample. Spherical agglomerates exhibited decreased crystallinity and improved micromeritic properties. The dissolution of the spherical agglomerates was improved compared with pure sample. The dissolution profiles of ketoprofen tablets prepared using spherical agglomerates exhibit greater dissolution behaviour than tablets prepared by powder raw material Varshosaz J et al16 prepared simvastatin spherical crystals by emulsion solvent diffusion method. The study was to determine the effect of processing temperature and stirring rate on micromeretic properties of prepared crystals. Particle size analysis, dissolution rate profiles, packability, hydrophobicity, and flow properties of spherical crystals were studied. The particle size of spherical aggregates was about 37 μm and the dissolution efficiency of simvastatin up to 60 min increased to about 2 fold in phosphate buffer solution containing 0.5% sodium dodecyl sulfate (pH 7) using the rotating paddle method. Spherical crystallization is an effective to improve the dissolution rate of simvastatin but its flow should be facilitated by some free flow excipients. Gupta MM et al17 revived that spherical crystallization is the novel agglomerated technique that can directly transform the fine crystals produced in the crystallization process into a spherical shape. It is the particle engineering technique by which crystallization and agglomeration can be carried out simultaneously in one step to transform crystals directly into compacted spherical form. This technique gained interest due to the fact that crystal habit can be modified during crystallization process which would result in better micrometric properties like particle size those can enhance the flowability of the powder drug and prepared spherical crystals can be compress directly without performing granulation, drying and so many steps those are require in wet granulation and in dry granulation process of tablet manufacturing. Yadav VB et al18 tried spherical crystallization of an antifungal drug griseofulvin by emulsion solvent diffusion technique to generate spherical agglomerates with improved micromeretic properties. They used technique in which distilled water as an external phase and the internal phase consisted of dichloromethane which acts as good solvent as well as bridging liquid. The spherical agglomeration was carried out in the presence of different polymers viz., hydroxyl propyl cellulose (HPC), Eudragit-RLPO and stabilizers beta cyclodextrin, poloxomer-F68 and polyethylene glycol. The pure griseofulvin and the prepared agglomerates were characterized in terms of production yield, drug content, solubility, in vitro release profile, flowability, density, packability, thermal behaviour. The optimized spherical agglomerates exhibited excellent physicochemical and micromeritic properties, solubility, dissolution rate, flowability and packability when compared with pure drug as well as the physical mixture of drug with excipients. The considerable improvement in the dissolution rate of griseofulvin from optimized crystal formulation was attributed to the wetting effect of polymers, decreased drug crystallinity, altered surface morphology and micronization. Yadav BV et al19 prepare and characterize the recrystallized agglomerates of water insoluble non steroidal antiinflammatory drug, indomethacin (IM) with hydrophilic polymers like polyvinyl pyrrolidone (PVP), hydroxyl ethyl cellulose (HEC) and hydroxyl propyl methyl cellulose (HPMC) by using emulsion solvent diffusion (ESD) technique for enhancing the solubility, dissolution rate, flowability, wettability and packability. The solubility and dissolution studies demonstrated a marked increase in solubility and dissolution rate of recrystallized agglomerates as compared to the pure indomethacin. The prepared spherical crystals with used polymers exhibited excellent physicochemical properties like flowability, packability, and wettability compared with the pure raw crystals of indomethacin. Ram Mohan G et al20 prepared celecoxib spherical agglomerates with polyvinylpyrrolidone (PVP) using acetone, water and chloroform as solvent, non solvent and bridging liquid, respectively. The agglomerates were characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), IR spectroscopic studies and scanning electron microscopy (SEM). The IR spectroscopy and DSC results indicated the absence of any interactions between drug and additives. XRD studies showed a decrease in crystallinity in agglomerates. The crystals exhibited significantly improved micromeritic properties compared to pure drug. The aqueous solubility and dissolution rate of the drug from crystals was significantly (p < 0.05) increased (nearly two times). The SEM studies showed that the crystal posseses a good spherical shape with smooth and regular surface spherical crystals of celecoxib to improve solubility, dissolution rate and micromeritic properties ENCLOSURE – III 6.3 OBJECTIVE OF THE STUDY The present work is planned with the following objectives 1. To prepare ritonavir spherical agglomerates using emulsion solvent diffusion /neutralization technique by incorporating hydrophilic polymers during the agglomeration process and choosing different agglomerating solvents. 2. To characterize micromeritic properties (particle size and shape, flowability), packability (bulk density), wettability (contact angle) and compressibility. 3. To evaluate spherical agglomerates by X-ray diffraction, differential scanning calorimetry (DSC), scanning electron microscopy, solubility and dissolution. 4. Statistical interpretation of the data. ENCLOSURE – IV 7. MATERIALS AND METHODS 7.1 Source of data The primary data will be collected by performing various tests and investigations in the laboratory and websites etc. The secondary data will be collected by referring various national and international jouranls, books, helinet, pumbed, and pharmacopoeia. ENCLOSURE – V 7.2 METHOD OF COLLECTION OF DATA The data is planned to collect from laboratory experiments which includes, 1. Emulsion solvent diffusion /neutralization technique was used to prepare spherical agglomerates by incorporating hydrophilic polymers during the process and choosing different agglomerating solvents. 2. The prepared systems evaluated for amount and mode of addition of binding liquid, temperature, agitation speed, micromeritic properties ( particle size and shape, flowability), packability(bulk density), wettability(contact angle) and compressibility and solubility. 3. Instruments like USP dissolution test apparatus, UV spectrophotometer, over head stirrer, scanning electron microscope, FTIR spectrophotometer, differential scanning colorimeter, XRD, will be used to collect the above data. ENCLOSURE VI REFERENCES 1. Speiser PP. Poorly soluble drugs, a challenge in drug delivery. In: Muller RH, Benita S, Bohm B Eds. Emulsions and nano suspensions for the formulation of poorly soluble drugs. Medpharm Scientific Publishers, Stuttgart, 1998, 15-28. 2. Chaudhari PD et al. Current trends in solid dispersions technology. Pharma InfoTech 2006. 3. Habib MJ. Pharmaceutical Solid Dispersion Technology. CRC PR Lic 2000:3-95. 4. Viswanathan CL, Kulkarni SK, Kolwankar DR. Spherical Agglomeration of Mefenamic Acid and Nabumetone to Improve Micromeritics and Solubility: A Technical Note. AAPS Pharm SciTech 2006; 7(2): Article 48. 5. Derle DV, Bele M, Kasliwal N. In vitro and in vivo evaluation of mefenamic acid and its complexes with β-Cyclodextrin and HP-β-Cyclodextrin. Asian J Pharma 2008; 2:30-34. 6. Levy G. Effect of dosage form on drug absorption. A frequent variable in clinical pharmacology. Arch Int Pharmacodyn Ther 1964; 152: 59-68. 7. Gupta VR, Mutalik S, Patel MM, Jani GK. Spherical crystals of celecoxib to improve solubility, dissolution rate and micromeritic properties. Acta Pharm 2007; 57:173184. 8. Usha AN, Mutalik S, Reddy MS, Ranjith AK, Kushtagi P, Udupa N. Preparation and in vitro preclinical and clinical studies of aceclofenac spherical agglomerates. Eur J Pharm Biopharm 2008; 70:674-683. 9. Yadav AV, Yadav VB. Designing of pharmaceuticals to improve physicochemical properties by spherical crystallization technique J Pharm Res 2008; 1:105-112. 10. Kawashima Y, Cui F, Takeuchi H, Niwa T, Hino T, Kiuchi K. Improvements in flowability and compressibility of pharmaceutical crystals for direct tabletting by spherical crystallization with a two-solvent system. Powder Techno 1994b; 78:151157. 11. Bodmeier R, Paeratakul R. Spherical agglomerates of water insoluble drugs. J Pharm Sci 1989; 78:964-967. 12. Tapas AR, Kawtikwar PS, Sakarkar DM. Enhanced dissolution rate of felodipine using spherical agglomeration with Inutec SP1 by quasi emulsion solvent diffusion method. Res Pharm Sci 2009; 4:77-84. 13. Amit T, Pravin K, Dinesh S. An improvement of micromeritic properties and dissolution behaviors of carvedilol spherical agglomerates crystallized in presence of inutec sp1. Turk J Pharm Sci 2012; 9(1):101-112. 14. Sujani S, Hari Babu R, Ravindra Reddy K. Preparation of meloxicam spherical agglomerates to improve dissolution rate. Asian J Pharm Res 2012; 2 (1):32-36. 15. Mudit D, Kulkarni PK, Shahnawaz A, Ashwini G. Preparation and characterization of spherical agglomerates of ketoprofen by neutralization method. Int J Pharm Bio Sci 2010; 1(4):395-406. 16. Varshosaz J, Naser T, Salamat FA. Effect of temperature and stirring rate on flow and compactability properties of simvastatin spherical crystals. Int J Pharma Pharma Sci 2011; 3(3):175-179. 17. Gupta MM, Srivastava B, Monika S, Vinita A. spherical crystallization: A tool of particle engineering for making drug powder suitable for direct compression. Int J Pharm Res Dev.2010; 1(12):1-10. 18. Yadav VB, Yadav AV. Effect of Different Stabilizers and Polymers on Spherical Agglomerates of Gresiofulvine by Emulsion Solvent Diffusion (ESD) System. Int J Pharm Tech Res. 2009;1(2):149-150. 19. Yadav VB, Yadav AV. recrystallized agglomerates of indomethacin by emulsion solvent diffusion (esd) technique. Int J Pharm Bio Sci 2010; 1(10):1-13. 20. Venkadari RMG, Srinivas M, Madhobhai, Girish K. Solubility, dissolution rate and micromeritic properties. 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