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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BANGALORE, KARNATAKA ANNEXURE – II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION 1. NAME OF THE CANDIDATE NAYAZ AHMED S/O PSA Bashu Saheb, AND ADDRESS: Door no: 216,144(new).Elahi Manzil, 2nd Cross Road, Behind Rajasthan Oil Mill, Reddy Layout, Bowrilalpet, Robertsonpet, Kolar Gold Field, Karnataka.563122. Email: [email protected] 2. NAME OF THE INSTITUTE: Krupanidhi College of Pharmacy, Chikka Bellandur, Carmelaram Post, Varthur Hobli, Bangalore – 560035. 3. COURSE OF THE STUDY & Master of Pharmacy SUBJECT: (Pharmaceutics) 4. DATE OF ADMISSION TO July 6th 2010 THE COURSE: 5. TITLE OF THE TOPIC: SOLUBILITY ENHANCED CIPROFLOXACIN FORMULATION AND ITS EVALUATION OF SELENO-QUIANAZOLONE AND EVALU 6. BRIEF STUDY OF THE INTENDED WORK: 6.1 Need of Study: A number of new active compounds show a very low solubility in biological media due to lipophilic nature. The most pharmaceutical industries are facing a major challenge to increase the solubility by using different formulation technique to reach an acceptable bioavailability. The ability of surfactants to enhance the solubility of poorly water-soluble compounds in an aqueous solution is widely known and used in many aspects of drug formulation development. Surfactants are used as wetting agents to improve tablet dissolution and are commonly used in the media for dissolution testing to maintain sink conditions for the drug1. Ciprofloxacin is the most potent first generation fluoroquinolone active against a broad range of bacteria, the most susceptible ones are the aerobic gram negative bacilli2. The Minimal Inhibitory Concentration against these bacteria is usually < 0.1µ mL-1. it has oral efficacy and good tolerability. It is used in urinary tract infections, gonorrhea, chancroid , bacterial gastroenteritis, typhoid, respiratory infections etc. It is rapidly absorbed orally, but food delays absorbtion and first pass metabolism occurs. It has an oral bioavailability of 60-80% and elimination half life of 3-5 hours. It has an high penetrability but low aqueous levels due to its very low aqueous solubility and poor dissolution can cause formulation problems and limit its therapeutic application by delaying the rate of absorption and the onset of action2. The solubility of the ciprofloxacin can be enhanced by using surfactants. The enhancement of aqueous solubility by surfactants occurs as a result of the dual nature of the surfactant molecule. Surfactants typically contain discrete hydrophobic and hydrophilic regions, which allow them to orient at polar–non polar interfaces, such as water/air interfaces. Once the interface is saturated, the surfactants selfassociate to form micelles and other aggregates, whereby their hydrophobic regions are minimized and shielded from aqueous contact by their hydrophilic regions. This creates a discrete hydrophobic environment suitable for solubilisation of many hydrophobic compounds1. Objective of the study : The primary goal of this investigation would be to formulate and evaluate poorly water soluble drug ciprofloxacin for enhancing its solubility by using surfactants in the formulation. The individual objectives to be achieved include: 1) Enhancement of solubility. 2) Enhancement of absorption. 3) Improvement of stability. Review of Literature: Modi A, Tayade P studied comparative solubility enhancement profile of valdecoxib with different solubilization approaches . This method is commonly known as micellar solubilization since they form micelles, which are association aggregates of surfactant molecule. Different types of surfactants viz. cationic, anionic and Non-ionic were studied for improvement of solubility of valdecoxib. A number of non-ionic surfactants were studied since non-ionic surfactants are more tolerable and compatible with biological system than ionic surfactants. All surfactants exhibit significant improvement of aqueous solubility of Valdecoxib. The solubility of drug increased with increasing surfactant concentration linearly3. Yadav VB, Yadav AV studied enhancement of solubility and dissolution rate of BCS class ll pharmaceuticals by using Nonaquious Granulation Technique. Liquisolid and Compaction granulation technique has been proved to be a imperative development to increase the solubility, dissolution rate and other physicochemical characteristics of fenofibrate (FF), griseofulvin (GF) and Lemotrazine(LT)which are very slightly water soluble using PEG-400 as hydrophilic binder, silca as absorbent/coating material, microcrystalline cellulose and sodium starch glycolate as excipients in granulation technique4. Bandela JJ, Anupama CH presented Advanced PEGylation for the development of raloxifene hydrochloride, BCS class II drug by using solvent evaporation technique and it was found that the PEG conjugates of raloxifene HCl are useful to enhance the dissolution rate of raloxifene HCl, a poorly water-soluble drug5. Sharma D, Soni M, Kumar S, GD Gupta studied various methods to enhance the solubility of BCS class ll drug and conclusion was Solid dispersions are one of the most attractive processes to improve drug’s poor water solubility. Various solubility enhancers like water-soluble carriers, co solvents, surfactants and superdisintegrants via solid dispersion approach (fusion method and solvent evaporation method) aids in solubility enhancement. These significantly help to improve the bioavailability and bioequivalence6. Chaudhari P, Sharma P, Barhate N, Kulkarni P, Mistry C studied the Solubility enhancement of hydrophobic drugs using synergistically interacting cyclodextrins and cosolvent and suggested that the increase in valdecoxib solubility was due to synergistic effect in the presence of CDs and PEG-400, as well as increase in CD complexation efficiency. Addition of PEG-400, poloxamer-188 and CDs increased the solubility of the model drug from 0.01 mg/ml in distilled water. However, addition of poloxamer- 188 made the system more complex and hampered the synergistic effect at higher concentrations. The study describes the increase in solubility produced by cosolvents as well as the increase in solubility produced at all CD concentrations. Thus it provides the dynamics of the combined cosolvent–CD technique in solubilisation of non-polar drugs7. Ahire BR, Rane BR, Bakliwal SR, Pawar SP studied Solubility Enhancement of Poorly Water Soluble Drug by Solid Dispersion Techniques and found the Formulation Kneading method 1:2 (KM 1:2) showed an exceptional increase in solubility of Nevirapine as compared to other Formulations. It was observed that an increase in solubility of about 1.7 and 1.8 fold with (KM 1:2) as compared to the drug alone in distilled water and pH 6.8. Solubility studies clearly indicated Kneading method of preparing solid dispersions is the method which enhances the solubility greatly as compared to physical mixing and Solvent evaporation because of synergistic effect of trituration and solubilization of used solvent leading to improvement in solubility8. Nagabhushanam MV studied formulation studies on cyclodextrin complexes of meloxicam and found that Among the two cyclodextrins, that is-Cyclodextrin (-CD) and HP--Cyclodextrin (HP--CD), CD complexes were found to be more suitable for tablet formulation by both direct compression and wet granulation methods. Thus, cyclodextrin complexation employing kneading method is recommended as an effective and efficient technique for enhancing the dissolution rate, dissolution efficiency of meloxicam9. Varanda F et al studied Solubility of Antibiotics in Different Solvents. Hydrochloride Forms of Tetracycline, Moxifloxacin, and Ciprofloxacin The solubilities of tetracycline hydrochloride, moxifloxacin hydrochloride, and ciprofloxacin hydrochloride were measured in several solvents, such as water, ethanol, 2-propanol, and acetone, in the temperature range of 293.15-323.15 K for ciprofloxacin.HCl and moxifloxacin.HCl and 288.15-310.15 K for tetracycline. All the antibiotics have the same solubility order; that is, they are more soluble in water than in ethanol, and more soluble in ethanol than in 2-propanol and acetone10. Dash S, Nath LK, Bhise S, Bhuyan N studied Aqueous solubility of ciprofloxacin in the presence of metal cations and result was The solubility of ciprofloxacin in 0.05M H2SO4 at 37.0 ± 0.2°C was 46.65 mgml-1 (0.12M). Except for magnesium sulphate, all the cations investigated progressively increased the aqueous solubility of ciprofloxacin. Ferrous ion had the greatest increase. It was followed by ferric, calcium and aluminium ions. Potassium and sodium ions had very slight increase in ciprofloxacin solubility. As the amount of magnesium sulphate increased, the aqueous solubility of ciprofloxacin increased slightly initially but then decreased progressively11. Kumar S, Prabha SK, Sathish K, Satyanarayan K, Kumar RH studied solubility enhancement of a drug by liquisolid technique. In this Liquisolid technique gives a design to enhance the absorption as well as dissolution rate their by it may enhance the bio availability of a poorly soluble, insoluble or lipophilic drug and to formulate them into immediate release or else sustain release by selection of suitable solvent and carrier. In this technique drug is dissolved in a non volatile solvent and their by this liquid medicament is converted to non adherent, dry looking and free flowing by using suitable carrier and coating material. Because of the presence of drug in the state of solubilised or moleculary dispersed state, so solubility of insoluble drug is enhanced12. Deshmukh DB, Gaikwad PD, Bankar VH, Pawar SP studied Dissolution Enhancement of Poorly Water Soluble Diacerein by Solid Dispersion Technique in presence of PVP K-30 and HPMC classified as AL type. The study shows that the dissolution rate of Diacerein can be enhanced to a great extent by solid dispersion technique using solvent evaporation method due to wetting and solubilisation phenomenon13. Viral S, Dhiren P, Mane S, Umesh U studied Solubility and Dissolution Rate Enhancement of Licofelone by Using Modified Guar Gum The results of present investigation indicated that co-grinding mixture of licofelone with modified guar gum could be useful in developing an oral dosage form with increased solubility and hence improved dissolution and oral bioavailability of poorly water soluble drug14. Kamalakkannan V, Puratchikody A, Masilamani K, Senthilnathan B Studied solubility enhancement of poorly soluble drugs by solid dispersion technique and concluded that Solid dispersions can increase dissolution rate of drugs with poor water-solubility but stability of these systems needs consideration and the carriers need to be selected for drugs on a case by case basis. Solvent systems consisting of mixtures of solvents can be used to optimize concentration in solution processing parameters influence the type of glass amorphous system formed15. Ahmed MA, Rhgigh AM, Shakeel F Studied effect of surfactants on the crystal properties and dissolution behaviour of aspirin The effect of surfactant concentration on melting point, true density, bulk density, crystal porosity and solubility of aspirin crystals were examined. The dissolution profiles of tablets prepared with different concentration of SLS were significantly different from control aspirin tablets. The best drug release (97 %) was obtained in 120 min with 0.1 M concentration of SLS. Overall SLS was found to be the best surfactant for the preparation of aspirin tablets16. Seedher N ,Agarwal P Studied various solvent systems for solubility enhancement of enrofloxacin and found that aqueous solubility of enrofloxacin could be increased up to 26 times. Co-solvents alone produced only small increase in solubility. However, the combined effect of co-solvents and buffer was synergistic and a large increase in solubility could be attained. Ionic surfactants were found to be much better solubilizing agents than non-ionic surfactant. Amongst ionic surfactants, solubility was found to be very high in anionic surfactant, sodium dodecylsulphate as compared to the cationic surfactant, cetyltrimethylammonium bromide17. 7. Materials & Methods: 7.1 Source of Data: Data will be obtained from the literature search and experimental work, which includes preformulation studies, formulation, product evaluation, optimization and subjecting the formulation to accelerated stability studies. Data on drugs will be collected from drug information centre, physicochemical data base and literature search. 7.2 Method of Collection of Data (including sampling procedure, if any): The physicochemical properties, of the drug will be collected from drug information center, various standard Books, journals, websites and other sources like research literature bases data such as Medline, Science Direct etc. The experimental data will be collected from study of the drug; its formulation, through investigation of the process and product variables in the laboratory of Krupanidhi College of Pharmacy, Bangalore-35. The steps involved in the methodology are: 1. Selection of the excipients and surfactant 2. Pre-formulation studies 3. Conducting phase solubility studies to determine the solubility. 4. Formulation by wet granulation technique 5. Evaluation of the formulation e.g. weight variation, friability etc 6. In vitro drug release studies 7. Stability studies under ICH guide lines. 7.3 Does the study require any investigations or interventions to be conducted on patients or other human or animals? If so please describe briefly: N/A 7.4 Has the Ethical Clearance been obtained from your Institution in case of 7.3? N/A 8. LIST OF REFERENCES: 1. Liu R. Water insoluble drug formulation. 2nd ed. Boca raton: CRC Press Taylor and Francis Group; 2008. p.271. 2. Tripathi KD. Essentials of medical pharmacology. 6th ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2008.p. 688-90. 3. Modi A, Tayade P. A comparative solubility enhancement profile of valdecoxib with different solubilization approaches. Ind J Pharm Sci 2010 Nov 30;69:274-8. 4. Yadav VB, Yadav AV. Enhancement of solubility and dissolution rate of BCS class ll pharmaceuticals by using non-aqueous granulation technique. liquisolid and compaction granulation. Int J Pharm Res Dev 2008 Feb;1(12):1-12. 5. Bandela JJ, Anupama CH. Advanced pegylation for the development of raloxifene hydrochloride, BCS class II drug. J Young Pharm 2009;1:295300. 6 . Sharma D, Soni M, Kumar S, GD Gupta. Various methods to enhance the solubility of BCS class ll drug. Res J Pharm Technol 2009 AprJun;2(2).220-4. 7 . Chaudhari P, Sharma P, Barhate N, Kulkarni P, Mistry C. Solubility enhancement of hydrophobic drugs using synergistically interacting cyclodextrins and cosolvent. Curr Sci 2007 jun 10;92(11):1586-91. 8 . Ahire BR, Rane BR, Bakliwal SR, Pawar SP. Solubility enhancement of poorly water soluble drug by solid dispersion techniques. International Journal of PharmTech Research 2010July-Sept;2(3); 2007-15. 9 . Nagabhushanam MV. Formulation studies on cyclodextrin complexes of meloxicam. Int J Pharm Technol 2010 Mar;2(1); 89-102. 10. Varanda F, Maria JPM, Ana IC, Dohrn R, Makrydaki FA, Voutsas E et al. Solubility of antibiotics in different solvents hydrochloride forms of tetracycline ,moxifloxacin, and ciprofloxacin. Ind Eng Chem Res 2006; 45(18):6368-74. 11. Dash S, Nath LK, Bhise S, Bhuyan N. Aqueous solubility of ciprofloxacin in the presence of metal cations. Trop J Pharm Res 2005; 4(1): 349-54. 12. Kumar S, Prabha SK, Sathish K, Satyanarayan K, Kumar RH. Solubility enhancement of a drug by liquisolid technique. Int J Pharm Bio Sci 2010 sep-jul;1(3):1-5. 13. Deshmukh DB, Gaikwad PD, Bankar VH, Pawar SP. Dissolution enhancement of poorly water soluble diacerein by solid dispersion technique. J Pharm Sci Res 2010; 2 (11): 734-9. 14. Viral S, Dhiren P, Mane S, Umesh U. Solubility and dissolution rate enhancement of licofelone by using modified guar gum. Int J Pharm Technol Res 2010 Jul-Sep;2(3):1847-54. 15. Kamalakkannan V, Puratchikody A, Masilamani K, Senthilnathan B. Solubility enhancement of poorly soluble drugs by solid dispersion technique. J Pharm Res 2010; 3(9):2314-21. 16. Ahmed MA, Rhgigh AM, Shakeel F. Effect of surfactants on the crystal properties and dissolution behavior of aspirin. Asian Journal of Research in Chemistry 2009 Jul-Sep;2(2):202-6. 17. Seedher N ,Agarwal P. Various solvent systems for solubility enhancement of enrofloxacin. Indian J Pharm Sci 2009 Jan–Feb; 71(1): 82–87. 9. Signature of the candidate: (NAYAZ AHMED) (((Rajesh 10. Remarks of the Guide: Pharmacokinetic profile of drug has direct bearing on clinical performance. Formulation strategy to alter it, is important breakthrough in improving clinical efficacy. This work is an effort in this direction for a widely used molecule. The protocol may be approved. 11. Name & Designation (in BLOCK LETTERS) 11.1 Guide Prof. Dr.R.S THAKUR PROFESSOR AND HEAD Department of Pharmaceutics Krupanidhi College of Pharmacy Bangalore – 560035 11.2 Signature of guide 11.3 Head of the Department Prof. Dr.R.S THAKUR PROFESSOR AND HEAD Department of Pharmaceutics Krupanidhi College of Pharmacy Bangalore – 560035. 11.4 Signature of HOD: 12. 12.1 Remarks of the Principal: The program and the that Mr. Rajesh 12.2 Signature of the Principal Prof. Dr. N. PREMKUMAR Principal Krupanidhi College of Pharmacy, Chikka Bellandur, Carmelaram Post, Varthur Hobli, Bangalore – 560035.