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“PROCESS DEVELOPMENT AND OPTIMIZATION FOR MOISTURE ACTIVATED DRY GRANULATION METHOD OF METFORMIN TABLETS” M. Pharm. Dissertation Protocol Submitted to Rajiv Gandhi University of Health Sciences, Bangalore Karnataka By Mr.G.JAYANTH KUMAR REDDY B.Pharm. Under the Guidance of Mr. MIKKILINENI RAVIKANTH Assistant Professor DEPARTMENT OF PHARMACEUTICS EAST WEST COLLEGE OF PHARMACY BANGALORE – 56 2010-2012 1 ANNEXURE II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION 1 G.JAYANTH KUMAR REDDY, Name of candidate and address s/o G.MUNIGOPAL REDDY, (In Block Letters) D.NO-16-3-807, 2nd STREET, NEAR RAMALAYAM, HARINADHAPURAM, NELLORE, ANDHRA PRADESH. 2 Name of the Institute EAST WEST COLLEGE OF PHARMACY, BANGALORE -560 091. 3 Course of study and subject: M.PHARM, PHARMACEUTICS. 4 Date of admission of course: 30-07-2010 5 Title of the topic: “PROCESS DEVELOPMENT AND OPTIMIZATION FOR MOISTURE ACTIVATED DRY GRANULATION METHOD OF METFORMIN TABLETS” 6 7 Brief Resume of this intended work: 6.1 Need for the study 6.2 Review of Literature 6.3 Objectives of study Enclosure-I Enclosure-II Enclosure-III Materials and Methods: 7.1 Source of data Enclosure-IV 7.2 Method of collection of data (Including sampling procedure, if any) Enclosure-V 7.3 Does the study require any investigation or interventions to be conducted on patients of humans or animals? If so, please describe briefly. ---------NO---------7.4 Has ethical clearance been obtained from your institution in case of 7.3? -------NOT APPLICABLE------ 8 List of References Enclosure-VI 2 9 Signature of the candidate (G.JAYANTH KUMAR REDDY) The proposed research work is recommended for 10 Remarks of the Guide 11 Name and designation of MIKKILINENI RAVIKANTH (in block letters) DEPT. OF PHARMACEUTICS, 11.1 Guide ASSISTANT.PROFESSOR EAST WEST COLLEGE OF PHARMACY, BANGALORE-560 091. 11.2 Signature registration and approval 11.3 Co-Guide (if any) ----------- 11.4 Signature ----------- 11.5 Head of Department Dr. JAGADEESH.G.HIREMATH, PROFESSOR& HOD, DEPT. OF PHARMACEUTICS, EAST WEST COLLEGE OF PHARMACY, BANGALORE-560 091. 11.6 Signature 12 12.1 Remarks of the Chairman/Principal 12.2 Name Prof. K.A. SRIDHAR, PRINCIPAL, EAST WEST COLLEGE OF PHARMACY, BANGALORE - 560 091. 12.3 Signature 3 ENCLOSURE-I Brief resume of intended work: 6.1) Need for study: Granulation is one of the most important unit operations in the production of pharmaceutical oral dosage forms. Granulation is the process in which primary powder particles are made to adhere to form larger, multi particle aggregates called granules. After granulation process the granules will either be packed (when used as a dosage form - powder), or they may be mixed with other excipients prior to tablet compaction or capsule filling.Granulation is used mainly to improve flow, compressibility of powders, and to prevent segregation of the blend componentsimprove content uniformity, and eliminate excessive amounts of fine particles. Particle size of the granulate is mainly affected by the quantity and feeding rate of granulating liquid.1Pharmaceutical granules typically have a size range between 0.2 and 4.0 mm, depending on their subsequent use.2 Granulation method can be broadly classified into two types: Wet granulation and Dry granulation. Wet granulation technique is receiving great significance, because direct compression method is not most suitable technique for many active substances that are in high dosages or in fine powder form. The moisture content of drugs, excipients combined with the drugs to manufacture a final dosage form (i.e. compressed tablets), and/or processing manipulations involving moisture may have a significant impact on wide range of chemical and physical properties of the finished product. But wet granulation technique also has drawback such as it is not suitable for moisture sensitive active substances. So to overcome the problems associated with it, MoistureActivated Dry Granulation(MADG) was developed in response to the difficulties experienced with wet granulation, in terms of end point, drying, and milling.3 Other granulating techniques that are widely used in the pharmaceutical Industries are Pneumatic Dry Granulation (PDG) 1, Freeze granulation Technology1, Foamed Binder Technologies (FBT) 1, Melt Granulation Technology1, 4 Thermal Adhesion Granulation Process (TAGP)1, Steam Granulation1, Granulex Technology1, Moisture Activated Dry Granulation (MADG) 4-6. Among all granulating techniques, MADG technology is widely used in granulation of moisture sensitive active pharmaceutical ingredients. The present study will be carried out with the Metformin as ideal drug candidate for the preparation of granules by innovative MADG technology & optimization of water content, concentration of granulating binder and moisture absorbents along with other excipients. Metformin an anti-diabetic drug, used as oral medication that lowers blood glucose level to normal level for treating type 2 diabetes. Insulin is a hormone produced by the pancreas that controls glucose levels in the blood by reducing the amount of glucose produced by the liver and uptake of glucose from the blood to muscle, fat and other tissues. These actions lower the level of glucose in the blood.7 Moisture content of drugs, excipients combined to manufacture a final dosage form and processing manipulations involving moisture may have a significant impact on a wide range of chemical and physical properties of the finished product.8 Moisture activated dry granulation techniqueused to decrease the moisture content in the granulation and reduce the drying time. Moisture activated dry granulation technique is more advantageous because it takes less time for preparation of granules and the fines produced during granulation are less which results in more drug content in tablets. 5 6.2) Review of literature: Raikar AM and Schwartz JB have modified the moist granulation technique to develop thecontrolled-release dosage forms of acetaminophen.The moist granulation technique (MGT), which involves agglomeration and moisture absorption, has only been applied to immediate-release dosage forms. Their results indicate that MGT appears to be applicable in developing a controlled-release formulation. They added small amount of granulating fluid (water) to a powder blend to activate a dry binder (such as polyvinylpyrrolidone [PVP] at 2% and 3.6%) and to facilitate agglomeration. Then,they added a moisture-absorbing material (microcrystalline cellulose [MCC]) to absorb any excess moisture. By the addition of MCC, they avoided the drying step. They have prepared acetaminophen controlled release tablets using Hydroxypropylcellulose (HPC) as the controlled-release agent and lactose fastflo and Dicalcium phosphate as the diluents.And they have also compared the MGT with conventional wet granulation (WG) and direct compression (DC) processing methods. Finally they concluded that MGT can be applicable in developing a controlled-release formulation.9 Christensen LH, Johansen and Schaefer Thave examinedthe applicability of a 25 liter high shear mixer for moisture-activated dry granulation. Microcrystalline cellulose, potato starch or a mixture of 50% w/w of each was used as moisture absorbing material. The effects of water content, wet massing time, moisture absorbing material and dry mixing time on the size distribution, and the compressibility of the granulations were investigated. Tablets were compressed on a single punch press from all the granulations and on a rotary press from a few of the granulations. The results of the physical properties of the tablets revealed that the tablets primarily affected by the water content, the moisture absorbing material, and the compression force. Tablets with low mass variation, high crushing strength, low friability, and short disintegration time were achieved with both tablet presses by using a mixture of microcrystalline cellulose and potato starch as moisture absorbing material.10 Raikar AM and Schwartz JB have performed the evaluation &comparison of a moist granulation technique to conventional methods. They have prepared acetaminophen tablets using polyvinylpyrrolidone as binder and 6 microcrystalline cellulose as moisture-absorbing material. Water was used as the granulating fluid. They compared MGT with direct compression, wet granulation methods which were accomplished by sieve analysis (particle size) and density measurements. They found that moist granulation provided an increase in particle size compared to direct compression; these results were compared to those from the traditional wet granulation after drying and screening. Finally they concluded that the moist granulation technique appears to be potential for the development of controlled-release formulations.11 Mohsen AB, Al-Suwayeh AS and El-Helw MAhave prepared the sustained-release theophylline (TPH) tablets by applying the moisture-activated dry granulation method. The interaction between the excipients sodium alginate and calcium gluconate was the base forthe formation of a cross-linked matrix that may regulate TPH release from the formulated tablets. The prepared granules showed good physical characteristics concerning the flow properties and compressibility, with the angles of repose in the range 29–31, and the compressibility indices ranged between 15% and 25%. The granules had low friability values (3.0%–4.2%), depending on sodium alginate and calcium gluconate ratios. The resulting tablets showed good physical properties, with a lower rate of drug release compared with the commercial TPH tablets.They found that the release of TPH from the prepared tablets was not markedly affected by either the concentration of added dry binder (carbopol934) or the tablet hardness, indicating that the rate-determining step in drug release was the diffusion through the produced calcium alginate matrix. Tablets formulated with equal ratios of sodium alginate and calcium gluconate that showed good physical properties and slow TPH release were chosen for bioavailability studies in beagle dogs, and results were compared with the commercial TPH tablets. The in-vivo data showed a comparable plasma concentration profile for both tablet formulations, with prolonged appearance of drug in the plasma in detectable amounts for upto 24 h.12 Debra SH hadcompared the processes of low shear, high shear, and fluid bed granulation during low dose tablet development.Three processing methods were compared to develop a low dose (0.1%) immediate release tablet. They used similar formulations to evaluate low shear, high shear, and fluid bed granulation methods. For each granulation process, they dissolved or suspended in the granulating fluid and sprayed into the granulator with water and methanol as granulating fluids. The low shear granulation was performed in a Patterson‐Kelley 7 V‐Blender with I‐bar. The high shear granulation was performed in a GRAL (top entry impeller) andDiosna (bottom mounted impeller). Fluid bed granulation was also performed using top‐spray. Acceptable content uniformity was obtained using each technology. In conclusion, they found that the type of granulator and granulating solvent affected the granulation particle size distribution and bulk/tap densities. However, the addition of extra granular microcrystalline cellulose minimized the effect of variable granulation properties and allowed similar tablets to be produced from each granulation process.13 Raikar AM and Schwartz JB have studied the effects of formulation factors on the moist granulation technique for controlled-release tablets. Controlled-release tablets were prepared by the moist granulation technique, with Acetaminophen as the model drug, and the polymer hydroxypropylcellulose as the controlled-release agent. The effects of varying drug, binder (polyvinylpyrrolidone, PVP), polymer, and micro crystalline cellulose levels on granule properties and tablet dissolution were studied. They performed dissolution testing in distilled water using the USP paddle method. In all cases, the granules flowed and compressed well. The granule properties were evaluated by calculating the mean particle size for all batches from sieve analysis data. In conclusion, the results showedthat MGT can be applied to control drug release, and polymer content of 44.6% or more.14 Chih MC, Dhananjaya A , Michael RI and Jeffrey LC have performed the comparison of moisture-activated dry granulation process with two conventional granulation methods i.e. wet granulation and dry granulation with a roller compactor, as well with a direct compression formulation method for cohesive and fluffy sematilide hydrochloride tablets. They found that the granules produced by MADG with excellent flow ability which were equivalent in a number of ways to those produced by either conventional wet granulation or dry granulation methods and which were much better than the powder blend from the direct compression formulation. It is proved that the tablets prepared using the MADG method has better content uniformity than those made using material from wet and dry granulation processes. Other tablet properties, such as weight variation, friability and dissolution, were similar among the tablets produced by the four processes.15 Christensen JT had examined the effect of moisture on the stability of solid dosage forms prepared with aspirin as a model drug candidate. Usually aspirin is not prepared by wet granulation. Even though the water wasdriven 8 off in a wet granulation, there is still sufficient moisture stress in the process to induce excessive decomposition on subsequent storage. In other instances, the results of the moisture sensitivity of a drug may be used to apply a hard shell capsule approach. This presumed that the drug substance is not particularly hygroscopic, sinceotherwise, the capsule shell will provide an unwanted source of moisture.16 9 ENCLOSURE-III 6.3) Objectives of the study: The present study is planned with the following objectives: Standardization and development of Metformin granules by moisture activated dry granulation (MADG) technique with suitable binders and suitable excipients. To evaluate the prepared granules for pre-compressional parameters such as Angle of repose, Bulk density, Tapped density, Compressibility index, drug solubility, particle size distribution, drug content and content uniformity. The developed formulation will be subjected for post compression parameters such as Hardness, Friability, weight variation, drug content, thickness. To carry out In-vitro drug release studies using suitable buffer. To investigate the physicochemical characterization of developed tablets. 10 ENCLOSURE-IV 7) Materials and Methods: Materials: Drug: Metformin Fillers: lactose monohydrate/ mannitol, microcrystalline cellulose/ starch or any other suitable filler. Binders: polyvinylpyrrolidone (PVPs) such as PVP K-12/ copovidone/ maltodextrins/ cellulose derivatives or any suitable binders. Moisture absorbents: Avicel PH101, PH102, and PH200/ Aeroperl 300/ coarse grade of crospovidone/ regular silicone dioxide or any suitable moisture absorbants. Method: Preparation ofgranules containing metformin along with other excipients is carried out by using the moisture activated dry granulation technique and then formulated into tablets. 7.1) Source of data: Data is collected from: 1 Internet 2 Presentations 3 Research publications. 4 International and Indian journals. 5 Textbooks and reference books. 6 RGUHS Library. 11 ENCLOSURE-V 7.2) Method of collection of data: Formulation of the metformin tablets using moisture activated dry granulation technique. Evaluations of pre-compression and post-compression parameters for developed formulations are as follows. Precompression parameters Angle of repose Bulk density Tapped density Compressibility index Drug solubility Particle size distribution Drug content Content uniformity Post compression parameters Weight variation Hardness Thickness Friability Disintegration To investigate the physicochemical characterization of developed metformin tablets. To carry out In- vitro drug release studies. Estimation of drug content in the developed formulation. Fitting the data to various kinetic equations and to find the release parameters. 12 ENCLOSURE-VI List of References: 1. Himanshu KS, Basuri T, Thakkar JH, Patel CA. Recent advances in granulation technology. Int J Pharm sci Rev Res 2010;5(3):008. 2. Aulton M. Pharmaceutics: The Science of Dosage Form Design. Edinburgh: Churchill Livingstone, 2000;15–32. 3. Ullah I et al., Moisture-Activated Dry Granulation. Pharm Tech Eur. 2011;23(3):1–3. 4. Optimization of Binder Level in Moisture Activated Dry Granulation(MADG) Using Absorbent Starch to Distribute Moisture. 2011;May 19: 2:26. Available from www.vectorcorporation.com/news/papers.asp 5. Ullah I, Wang J, Chang SY, Wiley G J, Jain N B, Kiang S. Moisture-Activated Dry Granulation-Part I: A Guide to Excipient and Equipment Selection and Formulation Development. Pharm Tech 2009;33(11):62-70. 6. Ullah I, Wang J, Chang SY, Wiley G J, Jain N B, Kiang S. Moisture-Activated Dry Granulation Part II: The Effects of Formulation Ingredients and Manufacturing-Process Variables on Granulation Quality Attributes, Pharm Tech 2009;33(12):42-51. 7. Indian pharmacopeia;2007(2):729 8. Shoung Y, Hungting Y. United State Patent Application: Process for the preparation of direct tableting formulation and aids. 20030017198;2003;23(1). 9. Raikar AM , Schwartz JB. Use of a Moist Granulation Technique (MGT) to Develop Controlled-Release Dosage Forms of Acetaminophen. Drug Dev Ind Pharm 2001; 27(4): 337- 43. Available from http://informahealthcare.com/doi/abs/10.1081/DDC-100103733. 10. Christensen LH, Johansen HE, Schaefer T. Moisture-Activated dry Granulation in a high Shear Mixer. Drug Dev Ind Pharm 2009;20(14):2195-213. Available from http://informahealthcare.com/doi/abs/10.3109/03639049409050233. 11. Raikar AM, Schwartz JB. Evaluation andcomparison of a moist granulation technique to conventional methods. Drug Dev Ind Pharm 2000;26(8):885-89. Available from 13 http://informahealthcare.com/doi/abs/10.1081/DDC-100101313. 12. Mohsen AB, Saleh AAS, Abdel-Rehim MEH. Excipient-Excipient Interaction in the Design of Sustained-Release Theophylline Tablets: In Vitro and In Vivo Evaluation. Drug Dev Ind Pharm 2001;27(6):499-506. Available from http://informahealthcare.com/doi/abs/10.1081/DDC-100105174. 13. Debra SH. Comparison of Low Shear, High Shear, and Fluid Bed Granulation During Low Dose Tablet Process Development. Drug Dev Ind Pharm 2004;30(3):259-66. Available from http://informahealthcare.com/doi/abs/10.1081/DDC-120030419. 14. Raikar AM, Schwartz JB. The Effects of Formulation Factors on the Moist Granulation Technique for Controlled-Release Tablets. Drug Dev Ind Pharm 2001;27(9):893-8. Available from http://informahealthcare.com/doi/abs/10.1081/DDC-100107669. 15. Chih MC, Dhananjaya A , Michael RI, Jeffrey LC. Comparison of Moisture-Activated Dry Granulation Profess with Conventional Granulation Methods for Sematilide Hydrochloride Tablets. Drug Dev Ind Pharm 1990;16(3):379-94. Available from http://informahealthcare.com/doi/abs/10.3109/0363904900911. 16. Carstensen JT. Effect of Moisture on the Stability of Solid Dosage Forms. Drug Dev Ind Pharm 1998;14(14):1927-69 Available from http://informahealthcare.com/doi/abs/10.3109/0363904880915. 14