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ENCLOSURE-I 6. BRIEF RESUME OF THE INTENDED WORK 6.1 Need for the study The oral route remains the preferred route of drug administration due to its convenience, good patient compliance and low medicine production costs. In order for a drug to be absorbed into the systemic circulation following oral administration, the drug must be dissolved in the gastric fluids. For hydrophobic drugs, the dissolution process acts as the rate-controlling step and which determines the rate and degree of absorption. Thus, one of the major challenges to drug development today is poor solubility, as an estimated 40% of all newly developed drugs are poorly soluble or insoluble in water1. In addition, up to 50% of orally administered drug compounds suffer from formulation problems related to their high lipophilicity2. Developing novel methods to increase the bioavailability of drugs that inherently have poor aqueous solubility is a great challenge to solid dosage form formulators. Mechanical micronization of crystalline drugs and incorporation of surfactants during the crystallization process are the techniques commonly used to improve the bioavailability of poorly soluble drugs3,4. The micronization process was found to alter the flow and compressibility of crystalline powders and cause formulation problems. Incorporation of surfactants generally led to less significant increase in aqueous solubility. To overcome this problem, Kawashima et al5,6 developed a spherical agglomeration during crystallization technique that led to improving the flow and direct compressibility of number of microcrystalline drugs7. Improvement of solubility, dissolution profile was also achieved in some cases8. Efavirenz belongs to the class of nonnucleoside reverse transcriptase inhibitors and is indicated in the treatment of HIV infection. Efavirenz is practically insoluble in water having lowest solubility of about 0.01 mg/ml indicates class II drugs of BCS systems (i.e. High permeability and low solubility). These classes of drugs could potentially exhibit dissolution rate limited absorption. In the present study an attempt is to make to prepare spherical agglomerates of efavirenz and study their improvement in micromeritics, direct compressibility, solubility and dissolution properties. ENCLOSURE-II 6.2 Review of literature Chelakara LV et al9 prepared spherical agglomeration of mefenamic acid and nabumetone prepared by modified Kawashima technique. They developed novel spherical agglomeration procedure by incorporating polymers during the agglomeration process and choosing different agglomerating solvents. The developed agglomerates were evaluated by X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy for flow and direct compressibility and finally for solubility. Achutha NU et al10 prepared aceclofenac spherical agglomerates by spherical crystallization technique using a three solvent system comprising acetone: dichloromethane (DCM): water (bridging liquid, good solvent and bad solvent, respectively). Hydroxypropyl methylcellulose-50 cps (HPMC) in different concentrations was used as hydrophilic polymer. They studied effect of speed of rotation and amount of bridging liquid on spherical agglomeration. The agglomerates were further subjected to various physicochemical evaluations such as practical yield, drug content, particle size, loss on drying, porosity, IR spectroscopy, differential scanning calorimetry, X-ray diffraction studies, relative crystallinity, scanning electron microscopy, micromeritic properties, solubility and dissolution studies. The agglomerates showed improved micromeritic properties as well as dissolution behaviour in comparison to conventional drug crystals. Kazuhiko I et al11 prepared spherical agglomerates of steroid KSR-592, consisting of fine primary drug crystals suitable for dry powder inhalation (DPI), by the spherical agglomeration during crystallization technique in liquid with a bridging liquid. It was found that the particle size of primary crystals increased until the dispersing medium was saturated with the bridging liquid, whereas the spherical agglomeration of primary crystals was continued even after the saturation of medium with the bridging liquid. Daniel AG et al12 prepared lobenzarit disodium (LBD) spherical agglomerates during crystallization. Further they validate this method for selecting the best wetting agent allowing to obtain spherical agglomerates based on the Washburn’s test (capillary rise of liquids in a granular medium). Crystallization tests were carried out at different conditions showed that the best results were obtained in the presence of n-hexane that was effectively found to be a better wetting liquid of the lobenzarit crystals than the other solvents. Yadav VB et al13 studied emulsion solvent diffusion (EDS) technique combines crystallization and agglomeration directly to generate spherical agglomerates with improved micromeretic properties. They prepared griseofulvin spherical agglomerates using emulsion solvent diffusion 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 for recrystallization and agglomeration process. The spherical agglomeration were characterized in terms of production yield, drug content, solubility, in vitro release profile, flowability, density, packability, thermal behavior (differential scanning calorimetry-DSC), X-ray diffraction (XRD), Fourier transforms infra red spectroscopy (FTIR). 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 XRD also revealed a characteristic decrease in crystallinity. The dissolution studies demonstrated a marked increase in the dissolution rate in comparison with pure drug and physical mixture. Yadav VB et al14 prepared spherical agglomerates of carbamazepine by quesiemulsion solvent diffusion system (QESDS) with ethanol-chloroform-water system. They evaluate prepared agglomerates for flowability, compressibility, wettability, packability and solubility. The prepared agglomerates were white, free flowing and spherical in shape. The yield of agglomerates was 95% and showed 90-95% drug content. Prepared agglomerates were also improved in compressibility, packability and solubility. Yoshiaki K et al15 prepared spherical agglomeration of salicylic acid crystals during crystallization. The needle like salicylic acid crystals simultaneously form and agglomerate in a mixture of three partially miscible liquids, such as water, ethanol, and chloroform, with agitation. The agglomerates can be made directly into tablets because of their excellent flowability. Spherical crystallization could eliminate the usual separate agglomeration step after crystallization and may be adaptable to other pharmaceutical and chemical systems. Rammohan GV et al16 prepared celecoxib spherical agglomerates with polyvinylpyrrolidone (PVP) using acetone, water and chloroform as solvent, nonsolvent and bridging liquid, respectively. The agglomerates were characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), FTIR 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 possess a good spherical shape with smooth and regular surface. Koji M et al17 develop cephalosporin antibiotic spherical agglomeration by neutralization method. Spherical agglomerates were obtained by adding seed crystals of 0.1 % wt under a high initial super saturation ratio. The compactly packed spherical agglomerates were composed of a number of rod shape crystals with a uniform length of 60 μm, and had good filtration property. Chourasia MK et al18 prepared spherical crystal agglomerates of flurbiprofen via the spherical crystallization technique using acetone-water-hexane solvent system. They studied various parameters such as, amount and mode of addition of bridging liquid, temperature and agitation speed to get maximum amount of spherical crystals. These were further characterized for micromeritic properties (particle size and shape, flowability), packability (bulk density), wettability (contact angle) and compressibility. The results suggest that spherical agglomerates exhibited improved flowability, wettability and compaction behaviour. ENCLOSURE-III 6.3 Objectives of the study The present work is planned with the following objectives 1. To prepare efavirenz spherical agglomerates using Kawashima technique by incorporating polymers during the agglomeration process and choosing different agglomerating solvents. 2. To evaluate various parameters such as, amount and mode of addition of bridging liquid, temperature, agitation speed. 3. To characterize micromeritic properties (particle size and shape, flowability), packability (bulk density), wettability (contact angle) and compressibility. 4. To evaluate spherical agglomerates by X-ray diffraction, differential scanning calorimetry (DSC), and scanning electron microscopy, solubility and dissolution. 5. 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. The secondary data will be collected by referring various national and international journals, books, helinet, pubmed, pharmacopeias and websites etc. ENCLOSURE –V 7.2 Method of collection of data The data is planned to collect from laboratory experiments which includes, 1. Prepare efavirenz spherical agglomerates using Kawashima technique by incorporating polymers during the agglomeration process and choosing different agglomerating solvents. 2. The prepared systems evaluated for amount and mode of addition of bridging 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 LIST OF REFERENCES 1. Naseem A, Olliff CJ, Martini LG, Lloyd AW. Effects of plasma irradiation on the wettability and dissolution of compacts of griseofulvin. Int J Pharm 2004; 269:443-450. 2. Gursoy RN, Benita S. Self-emulsifying drug delivery systems for improved oral delivery of lipophilic drug. Biomed Pharmacotherapy 2004;58:173-182. 3. Atkinson RM, Belford C, Tomich EG. Effect of particle size on blood Griseofulvin levels in man. Nature 1962;193:588-589. 4. Prescott LF, Steel RF, Ferrier WR. The effect of particle size on the absorption of Phenacetin in man. A correlation between plasma concentration of phenacetin and effects on the central nervous system. Clin Pharmacol Ther 1970;496-504. 5. Kawashima Y, Okumara M, Takenaka H. A novel agglomeration technique to transform a microcrystalline drug into an agglomerated form during crystallization. Science 1982;216:1127-1128. 6. Kawashima Y, Okumara M, Takenaka H, Kojwa A. Direct preparation of spherically agglomerated salicylic acid crystals during crystallization. J Pharm Sci 1984;73:1535-1538. 7. Gordon MS, Chowhan LT. Manipulation of naproxen particle morphology via the spherical crystallization technique to achieve a directly compressible raw material. Drug Dev Ind Pharm 1990;16:1279-1290. 8. Sano A, Kuriki T, Handa T, Takeuchi H, Kawashima Y. Particle design of Tolbutamide in the presence of soluble polymer or surfactant by the spherical crystallization technique: improvement of dissolution rate. J Pharm Sci 1987; 76:471-474. 9. Chelakara LV, Sushrut KK, Dhanashri RK. Spherical Agglomeration of Mefenamic Acid and Nabumetone to Improve Micromeritics and Solubility: A Technical Note. AAPS PharmSciTech 2006;7(2):1-4. 10. Achutha NU, Srinivas M, Sreenivasa Reddy M, Averineni KR, Pralhad K, Udupa N . Preparation and in vitro, preclinical and clinical studies of aceclofenac spherical agglomerates. European Journal of Pharmaceutics and Biopharmaceutics 2008;70:674-683. 11. Kazuhiko I, Yoshiaki K, Hirofumi T, Hiromitsu Y, Nobuyuki I, Den-ichi M, Kiyohisa O. Simultaneous particulate design of primary and agglomerated crystals of steroid by spherical agglomeration in liquid for dry powder inhalation. Powder Technology 2003;130:290-297. 12. Daniel AG, Beatrice B. Spherical agglomeration during crystallization of an active pharmaceutical ingredient. Powder Technology 2002;128:188-194. 13. Yadav VB, Yadav AV. Effect of Different Stabilizers and Polymers on Spherical Agglomerates of Griseofulvine by Emulsion Solvent Diffusion (ESD) System. International Journal of PharmTech Research 2009;1(2):149150. 14. Yadav VB, Yadav AV. Comparative Tabletting behavior of Carbamazepine granules with spherical agglomerated crystals prepared by spherical crystallization technique. International Journal of ChemTech Research 2009; 1(3):476-482. 15. Yoshiaki K, Motonari O, Hideo T. Spherical Crystallization: Direct Spherical Agglomeration of Salicylic Acid Crystals during Crystallization. Science 1982;216(4550):1127-1128. 16. Rammohan GV, Srinivas M, Madhobhai MP, Girish KJ. Spherical crystals of Celecoxib to improve solubility, dissolution rate and micromeritic properties. Acta Pharm 2007;57;173-184. 17. Koji M, Keiichi K, Takashi M, Shigeru M, Kooji K, Hiroshi O. Production of Spherical Agglomerates of Cephalosporin Antibiotic Crystals. Journal of Chemical Engineering of Japan 2008;41(11):1017-1023. 18. Chourasia MK, Jain NK, Jain S, Jain SK. Preparation and characterization of agglomerates of flurbiprofen by spherical crystallization technique. Indian Journal of Pharmaceutical Science 2003;65(3):287-291.