"Need for the study"
“FORMULATION AND OPTIMIZATION OF ATORVASTATIN CALCIUM SOLID DISPERSIONS” BRIEF RESUME OF INTENDED WORK: 6.1. Need for the study: The successful formulation of poorly water-soluble drugs is one of the major problems for pharmaceutical scientist. Over the years, a variety of solubilization techniques have been studied to improve the dissolution rate. To obtain more rapid and complete absorption such as using surfactant, hydrotropes and cosolvents, preparing coprecipitate, liquisolid compacts fast releasing microparticles interactive mixtures and number of researches had been carried to increase the solubility of poorly soluble drugs.1 Solid dispersion is one of the significant and widely used method for solubility enhancement. Solid Dispersion technology has been successfully used to increase the dissolution rate and bioavailability of poorly water soluble drugs. Recently attempts are being made to incorporate porous materials in solid dispersion to increase the solubility. It has been widely used to improve the dissolution rate, solubility and oral absorption of poorly water- soluble drugs.2 Atorvastatin is a white crystalline powder, molecular formula:(C33H34FN2O5)2 Ca.3H2O, molecular weight:1209.12, bioavalability-12%, and halflife:18-24hrs. it is a selective competitive HMG-COA reductase inhibitor drug that lowers the level of cholesterol in the blood and triglyserides in patients with hypercholestrolemia.3 It belongs to a class of drugs referred to as statins, which includes lovastatin (Mevacor), simvastatin, (Zocor), fluvastatin (Lescol), and pravastatin (Pravachol) and rosuvastatin (Crestor). All statins, including atorvastatin, prevent the production of cholesterol in the liver by blocking HMG- CoA reductase, an enzyme that makes cholesterol. Statins reduce total cholesterol as well as LDL cholesterol in blood. LDL cholesterol is believed to be the "bad" cholesterol that is primarily responsible for the development of coronary artery disease. Reducing LDL cholesterol levels retards progression and may even reverse coronary artery disease. Atorvastatin also raises the concentrations of HDL ("good") cholesterol that protects against coronary artery disease and reduces the concentration of triglycerides in the blood. (High blood concentrations of triglycerides also have been associated with coronary artery disease.) The FDA approved atorvastatin in December 1996. The purpose of the current study is to prepare Atorvastatin calcium solid dispersions by using various techniques and to characterize the solid-state properties of the solid dispersion system of Atorvastatin calcium. 6.2. Objective of the study: The present study is planned with the following objectives: Selection of appropriate carriers for the preparation solid dispersions for Atorvastatin calcium. To develop and characterize Atorvastatin calcium solid dispersion and to investigate the physicochemical characterization of developed solid dispersions. To prepare the amorphous/semi crystalline Atorvastatin calcium by solvent evaporation/solvent deposition/spray drying method/fusion method/ lyophilization technique/kneading method. Screening of different techniques for selection of optimal technique for preparation of solid dispersions. FTIR studies of developed solid dispersions. Thermal studies of developed solid dispersions by differential scanning calorimetry To characterize the crystal structure in the solid dispersion. To improve the solubility and dissolution rate and oral bioavailability. To estimate drug content in solid dispersions. To study the in vitro drug release aspects. To minimize the dose of the drug. To improve therapeutic action of the drug. 6.3. Review of literature: Formulation and evaluation of fenofibrate solid dispersion tablets by incorporation of super disintegrants shown that the incorporation of super disintegrants in solid dispersion tablets containing a high drug load strongly enhance the dissolution rate of the highly lipophilic drug fenofibrate. In addition, the dissolution rate was more increased when the superdisintegrant was incorporated in the drug containing solid dispersions than when it was physically mixed with the solid dispersions. The dissolution rate enhancement strongly depended on the type of superdisintegrants and increased in the order Polyplasdone_ XL-10 < Polyplasdone_ XL_Ac-Di-Sol_ _ Primojel_.4 Formulation and evaluation lansoprazole/PVP solid dispersion prepared by fluid-bed coating technique. The in-vitro dissolution test in pH 7.4 phosphate buffer showed that the dissolution rate was dramatically enhanced even at an LSP/PVP ratio of 1/1.75 or with more PVP. DSC and powder X-ray diffractometry proved the absence of crystallinity in LSP/PVP solid dispersion at a ratio of 1/2 or with more PVP. However, at an LSP/PVP ratio of 1/1, the LSP melting and decomposition peaks could be observed by DSC indicating presence of LSP crystalline in LSP/PVP solid dispersion. The FTIR spectrometry indicated formation of hydrogen bond between LSP and PVP.5 Formulation and evaluation of solid dispersion of Atorvastatin with various carriers were carried out. Preliminary solubility analysis was carried out for the selection of carriers and solid dispersion was prepared with mannitol, PEG 4000 and PVP-K30. These solid dispersions were analysed for the solubility and in-vitro dissolution profile, solid dispersion of drug with PEG 4000 had shown enhanced solubility with improved dissolution rate. Further FTIR, DSC, SEM studies were carried out. Solid dispersion prepared with PEG 4000 showed the presence of amorphous form confirmed by the characterization study .The study also showed that the dissolution rate of Atorvastatin can be enhanced to considerable extent by solid dispersion technique with PEG.6 Formulation and evaluation of Atorvostatin nanosuspensions were carried out to enhance the solubility and dissolution. Nanoparticles were characterized in terms of size and morphological characteristics. Saturation solubility and dissolution characteristics were investigated and compared to the commercial drug. Crystallinity of the drug was also evaluated by performing thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) to denote eventual transformation to amorphous state during the homogenization process. Through this study, it was shown that the crystalline state of the drug is reduced following particle size reduction and the dissolution rates of amorphous atorvastatin calcium nanoparticles were highly increased in comparison with commercial drug by the enhancement of intrinsic dissolution rate and the reduction of particle size, resulting in an increased specific surface area.7 Formulation and evaluation of Atorvastatin calcium using solid dispersions with PEG-4000 Atorvastatin calcium was formulated by physical mixtures and solid dispersions (dropping method) using 1:1, 1:2 and 1:3 ratios of drug and carrier (PEG 4000). The Phase and saturation solubility study, in-vitro dissolution of pure drug, physical mixtures and solid dispersions were carried out. The prepared dispersions showed PEG was found to be effective in increasing the saturation solubility and dissolution rate of atorvastatin calcium than that of pure drug. The dispersion with PEG 4000 (1:3) by dropping method showed faster dissolution rate (85.038%) as compared to other dispersions with PEG 4000 (1:1 and 1:2) whichever prepared by physical mixture and dropping method.8 Formulation and evaluation of the solid dispersion of indomethacin with different types of silica, non-porous (Aerosil 200) or Porous silica (sylysia 350) by using spray drying method. Powder X-ray diffraction analysis showed that indomethacin in solid dispersions particles are in amorphous state irrespective of the type of silica which have been formulated. The dissolution rate of Indomethacin from the solid dispersions with sylysia 350 were showed faster dissolution than aerosil 200.9 Formulation and evaluation of Telmisatan solid dispersions. In this study solid dispersions were prepared using Polyvinyl pyrrolidone (PVP), Polyethylene glycol- 1500 (PEG-1500) and Polyethylene glycol-4000(PEG-4000) to increase its aqueous solubility. Telmisartan solid dispersions were prepared in 1:1, 1:2 and 1:4 ratios of the drug to polymer ratio (by weight) using solvent evaporation method. The formulations were characterized for solubility parameters, drug content studies, drug release studies and drug-polymer interactions by using FTIR spectrum. Formulation containing 1:2 ratio of drug: PEG-4000 showed the best release with a cumulative release of 99.49% as compared to 35.82 % for the pure drug. The interaction studies showed no interaction between the drug and polymer. It was concluded that PEG- 4000 as a carrier can be very well utilized to improve the solubility of poorly soluble drugs.10 MATERIALS AND METHODS: 7.1 Source of Data: The data is obtained from the literature search and previous experimental works sourced from the library such as scientific books and journals, internet, and database. 7.2 MATERIALS: Drug: Atorvastatin calcium. Polymers: Different grades of poly ethylene glycol (PEG)/ PVP/ Gelucire/Eudragit and/ or other appropriate polymers, which will be used for the preparation of formulations during the course of the study. METHOD: Atorvastatin calcium solid dispersion will be prepared by solvent evaporation/solvent deposition/spray drying method/fusion method/lyophilization technique/kneading method. EVALUATION STUDIES: Drug content analysis Dissolution studies Phase solubility studies 7.3 METHOD OF COLLECTION OF DATA: The data which is related to physicochemical, pharmacological details of the drug would be collected from various standard books, journals, patents and other sources like computer database. In laboratory the data will be collected from the preformulation studies like UV, TLC, etc. and carrying out various studies on the formulation as stated in the objective 7.4. Does these studies require any investigation or intervention to be conducted on patients or other humans or animals? If so, please describe briefly. No 7.5. Has ethical clearance been obtained from your institution in case of 7.4? Not Applicable LIST OF REFERENCES: 1. Aremanda, Sindhu P. Improving solubility of poorly water soluble drug indomethacin by incorporating porous material in solid dispersion. The brooklyn center 2010;14:110. 2. Tiwari V, Kinikar J D, Pillai K, Gokulan D P. Preparation and evaluation of fast dissolving tablets of celecoxib. J Pharm Res 2010;04:4-11. 3. Tripathi KD.Essentials of medical pharmacology.6th ed Jaypee Brothers Medical Publications. New delhi :(IND) 2008:460-62. 4. Srinarong P, Faber JH, Visser MR, Hinrichs WLJ, Frijlink HW. Strongly enhanced dissolution rate of fenofibrate solid dispersion tablets by incorporation of super disintegrants. Eur J Pharm Bio Pharm 2009;73:154-61. 5. Yi LU, Wei WU, Xingwang Z, Ningyun S, Baojian WU,Tianzheng G. Physical characterization of lansoprazole/PVP solid dispersion prepared by fluid-bed coating technique. Powder Tech 2008;182:480-85. 6. Bobe KR, Subrahmanya CR, Suresh S, Gaikwad DT, Patil MD, Khade TS, et al., Formulation and evaluation of solid dispersion of atorvastatin with various carriers. Int J Comp Pharm 2011;1(2):1-6. 7. Arunkumar N, Deccaraman M, Rani C, Mohanraj KP, Venkates kumar K. Preparation and characterization of Atorvastatin nanosuspensions for enhanced solubility and dissolution. Int J Pharm Tech Res 2009;1(4):1725-30. 8. Lakshmi Narsaiah V, Kalyan Reddy B, Rajkumar M, Kiran Kumar A, Raju CH, Sanjeeva Kumar A, et al., Improved dissolution rate of atorvastatin calcium using solid dispersions with PEG-4000. J Chem Pharm Res 2010;2(3):304-11. 9. Takeuchi H, Nagira S,Yamamoto H, Kawashima Y. Solid dispersion particles of amorphous indomethacin with fine porous silica particles by using spray drying method. Int J Pharm 2005;293:155-64. 10. Kothawade SN, Kadam NR, Aragade PD, Baheti DG. Formulation and characterization of telmisatan solid dispersions. 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