STUDY THE EFFECTS OF POLYMERS / EXCIPIENTS USED IN SOLID ORAL CONTROLLED DRUG DELIVERY SYSTEMS.

DISSERTATION PROTOCOL

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA.

BY

K.NIKHILA,

M.PHARM, PART-I,

DEPARTMENT OF PHARMACEUTICS,

T.JOHN COLLEGE OF PHARMACY,

GOTTIGERE, BANGALORE-83.

UNDER THE GUIDANCE OF

Mrs. BHARATI ARALI,

ASSISTANT PROFESSOR,

DEPARTMENT OF PHARMACEUTICS,

T.JOHN COLLEGE OF PHARMACY,

GOTTIGERE, BANNERGHATTA ROAD,

BANGALORE-83.

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE,KARNATAKA.

ANNEXURER-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / NAME OF THE CANDIDATE
AND ADDRESS (IN BLOCK LETTERS) / K.NIKHILA
T.JOHN COLLEGE OF PHARMACY,
GOTTIGERE,
BANNERGHATTA ROAD,
BANGALORE-83,
KARNATAKA.
2. /

NAME OF THE INSTITUTION

/ T.JOHN COLLEGE OF PHARMACY,
GOTTIGERE,
BANNERGHATTA ROAD,
BANGALORE-83,
KARNATAKA.
3. /

COURSE OF STUDY AND SUBJECT

/ MASTER OF PHARMACY IN PHARMACEUTICS
4. / DATE OF ADMISSION OF COURSE / 15thNov 2010.
5. /

TITLE OF TOPIC

/ STUDY THE EFFECTS OF POLYMERS/EXCIPIENTS USED INORAL SOLID CONTROLLED DRUGDELIVERY SYSTEMS.
6. / SIGNATURE OF THE CANDIDATE / (K.Nikhila)
7. / REMARKS OF THE GUIDE / RECOMMENDED FOR THE DISSERTATION WORK.
8. / Name & Designation of
(in block letters)
8.1 GUIDE
8.2 SIGNATURE / Mrs. BHARATI ARALI.
DEPARTMENT OF PHARMACEUTICS
T.JOHN COLLEGE OF PHARMACY
GOTTIGERE, BANGALORE-83.
(Bharati Arali)
8.3 HEAD OF THE
DEPARTMENT
8.4 SIGNATURE / SANDHYA KV, M.Pharm, Ph.D.
DEPARTMENT OF PHARMACEUTICS
T.JOHN COLLEGE OF PHARMACY
GOTTIGERE, BANGALORE-83.
(Sandhya KV, M.Pharm, Ph.D)
9. / 9.1 REMARKS OF
PRINCIPAL
9.2 SIGNATURE. / FORWARDED AND RECOMMENDED FOR FAVOURABLE CONSIDERATION.
(Dr.Vineeth Chandy)
10.
11.
12. / BRIEF RESUME OF THE INTENDED WORK:
10.1 NEED FOR THE STUDY:
Traditionally, excipients were included in drug formulations as inert vehicles that provided the necessary weight, consistency and volume for the correct administration of the active ingredient. In modern pharmaceutical dosage forms these excipients are also used to fulfillthe multifunctional roles in the oral solid dosage forms such as improvement of the stability,release and bioavailability of the active ingredient,enhancement of patient acceptability and performance of technological functions that ensure ease of manufacture.1
The purpose of this research is to study the effects of polymers/excipientson oral solid dosage forms when used at different concentrations of different polymers/excipients,mixing shear rates and mixing times on the tablet with the help of different evaluating parameters like drug dissolution, drugrelease, bioavailability of drug and its stability from oral solid controlled drug delivery systems.
These may influence the physicochemical properties of granules/powder and tablets. The polymers/excipients improve pre compression parameters like bulk density, tapped density, Carr’s index, Hausner’s ratio, angle of repose and post compression parameters like hardness, friability, tablet ejection forces,mechanical strength of tablet,hydrophobicity,tablet weight,disintegration time,dissolution time and release rate of oral solid controlled drug delivery system.
In excipients particularlylubricants must be added to prevent the adhesion to and then damaging of the tablet press. Too much lubricant, however, will cause the powder to form globules and to resist proper cohesion. Hence this would fail to provide full bioavailabilityof the drug.
The objective isto investigate the correct percentage oflubricant to add without offsetting theunique tablet properties and to determinewhether the efficiency of a lubricant changes when used indifferent concentrations. Because different concentrations used may affect the bioavailability it is necessary to find out the appropriate concentration which does not hinder the effectiveness of the drug or lessening of the bioavailability.
For modified release solid dosage forms, consideration should be given as to whether the excipient is critical or not critical to drug release.
1.Nonrelease-controlling excipient:
Three levels of changes for nonrelease-controlling excipient are,
1. Level 1 changes are those that are unlikely to have any detectable impact on formulation quality and performance.
2. Level 2 changes are those that could have a significant impact on formulation quality and performance.
3. Level 3 changes are those that are likely to have a detectable impact on formulation quality and performance.
2.Release-controlling excipient:
The changes for the release-controlling excipient are categorized into three levels similar to the nonrelease-controlling excipients,
1. Level 1 changes are those that are unlikely to have any detectable impact on formulation quality and performance.
2. Level 2 changes are those that could have a significant impact on formulation quality and performance. Test documentation for a level 2 change would vary depending on whether the product could be considered to have a narrow therapeutic range.
3. Level 3 changes are those that are likely to have any detectable impact on formulation quality and performance affecting all therapeutic ranges of the drug.
10.2 REVIEW OF LITERATURE :
Uzunovic A,Vranic E.Evaluated the effects of two different concentrations of Magnesium Stearate on dissolution properties of ranitidine hydrochloride coated tablet formulations labeled to contain 150 mg. The uniformity content was also checked. During the drug formulation development, several samples were designed for choice of the formulation. For this study, two formulations containing 0.77 and 1.1% of Magnesium Stearate added in the manufacture of cores were chosen. Fraction of ranitidine hydrochloride released in dissolution medium was calculated from calibration curves. The obtained values indicate differences in drug release from analyzed ranitidine hydrochloride formulations and could cause differences in therapeutic response. 2
Sheskey PJ, Robb RT, Moore RD.The effects of the lubricant Magnesium Stearate at different concentrations, mixing shear rates, and mixing times on the tablet properties and drug dissolution from controlled release matrix tablets containing hydroxypropyl methylcellulose 2208,USP, (METHOCEL* K4M Premium) . The impact of Magnesium Stearate on the mechanical strength of tablets appeared to be dependent on the bonding mechanism of the components of the powder mix. Drug release was impacted to the greatest extent by the solubility of the drug an excipient/filler but was only slightly affected by the level of Magnesium Stearate and duration of mixing.3
Mollan MJ, Celik M.The influence of the amount of lubricant on compression behavior of the matrix. The relationship between increase in polymer/lubricant concentration is known. Even at a level of 0.5 %of the lubricant can influence both the compression ability and drug dissolution rate of matrix.4
Rizk S, Guyot JC, Duru C, GaudyD .The effect of Magnesium Stearate on the properties of a direct compression formulation. Assess the effects of the lubricants on powder flowability, tablet ejection forces, tablet hardness, dissolution and coated tablet film adhesion. Starch 1500® (partially pregelatinized corn starch), used as a flow aid and disintegrant, is an example of a plastically deforming excipient which may exhibit sensitivity to high lubricant levels. Microcrystalline cellulose, another plastically deforming excipient, were also included.5
Dietrich P, Bauer-Brandl A, Schubert R. The strongest negative influence on adhesion strength is exerted by the amount of lubricant in the central layer, as expected where as the compression forces for complex layer tablets exerted a positive on layer adhesion.6
Doug Nelson, Rebecca Wu, Kate Wymbs. In order to allow the powder to flow through the tablet press without building up a static charge, glidant must be added and regulated in proper amounts to ensure that the hydrophobicity of the powder does not cause an undesirablylong dissolution rate. Lubricant(Magnesium Stearate) must be added to prevent the adhesion to and then the damaging of the Rotary Tablet Press.7
Raymond C Rowe, Paul J Sheskey, Marian E Quinn. Concentrations between 2% and 5% w/wof Hypromellose may be used as a binder in either wet- or dry-granulation processes. High-viscosity grades may be used to retard the release of drugs from a matrix at levels of 10–80% w/w in tablets and capsules.8
Hiremath SN, Jithendra Patil, Nagarjuna R, Sway PV.The influence of the proportion of the polymer and several co-excipients like lactose, microcrystalline cellulose, and dibasic calcium phosphate on the release rate of the drug from the tablets was studied. The two co-excipients, lactose and microcrystalline cellulose enhanced the release rate of diltiazem hydrochloride, while dibasic calcium phosphate exhibited a much slower release of drug from the prepared matrices.9
CharlesE.Carraher, Jr.Polymers are used as additives in order to modify properties, assist in processing, and introduce new properties to a material. Titanium dioxide is used as a white pigment, China clay as extender, a fungicide, defoaming agent etc.10
10.3 OBJECTIVES OF THE STUDY:
The present study is planned to develop the solidcontrolled drug delivery system using different polymers/lubricants and determine their effects. The work will be scheduled as:
To develop the suitable polymers and lubricants used in the tablet formulation.
To evaluate all the excipients for compatibility studies by different thermo gravimetric analytical methods like X-ray diffraction, DSC and FTIR.
To compress the formulation according to compatibility study.
To evaluate pre compression parameters like bulk density, tapped density, Carr’s index, Hausner’s ratio, angle of repose and post compression parameters like hardness, friability, tablet ejection forces, mechanical strength of tablet, hydrophobicity, tablet weight, disintegration time, dissolution time and release rate of oral solid controlled drug delivery system.
Optimization of concentrations of the polymers and lubricants to be used and mixing time and mixing pattern in controlled relese drug delivery systems.
Assessment of formulations for in-vitro drug release studies.
Best formulation will be subjected for acceleration stability studies as per ICH guidelines.
MATERIALS AND METHODS:
Materials:
Polymers: Different grades of Hydroxy Propyl Methyl cellulose like
HPMC K4M, HPMC K100M, HPMC E50LV etc.Methocel, Carbopol, Eudragit S,Ethyl Cellulose, Starch, Urea, Polyesters, Polystyrenes, Poly acrylic acid, Guar Gum, Xanthum Gum, Cellulose acetate etc.
Lubricants: Lactose, Dicalcium phosphate dihydrate, Magnesium Stearate,
Poly ethylene glycol, Calcium Stearate, Starch, talc,
microcrystallinecellulose,and Calcium Silicate as a porous carrier.
Binders: Lactose, Dicalcium phosphate dihydrate, Starch paste, Sucrose,
Corn paste, Micro crystalline cellulose, Povidone (PVP), HPMC etc.
Disintegrants: Starch and Modified starches, Sodium carboxy methyl cellulose,
Sodium starch glycolate, PVP, Guar Gum, Xanthium Gum,
Cross Carmellose etc.
Glidants: Talc, Dried starch, MCC, colloidal silica, SLS etc.
Anti-adherents: Magnesium Stearate, Talc etc.
Drug: Paracetamol, Aspirin, Diclofenac sodium.
Methods:
The following methods can be used for the formulation of controlled drug delivery system.
  1. Wet granulation method.
  2. Dry granulation method.
3.Direct compression method.
11.1. Source of Data
  1. Library & E-library of T.Johncollege of pharmacy.
  2. Internet:- Google search Engine, Science direct, Indian journal of pharmaceutical science.
11.2. Method Of Collection Of Data
1. Data of physiochemical properties of the drug will be collected through literature search such as Solubility in various solvents, pH of the drug solution and compatibility of the drug with various polymers.
2. Amount of drug released and estimate using the suitable analytical method.
3. Evaluation of dissolution time &stability studies.
11.3. Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please mention briefly.
-NO-
11.4. Has ethical clearance been obtained from your institution in case of11.3?
- NOT APPLICABLE-
LIST OF REFERENCE:
  1. Hamman JH,Tarirai C.Functional excipients. Chemistry Today 2006; 24:57-62.
  2. Uzunovic A, Vranic E. Effect of MagnesiumStearate concentration on dissolution properties of ranitidine hydrochloride coated tablets.Bosnian Journal of Basic MedicalSciences 2007;7(3):279-283.
  3. Sheskey PJ, Robb RT, Moore RD. Effects of lubricant level, method ofmixing, and duration of mixing on a controlled-release matrix tabletcontaining hydroxypropyl methylcellulose, Drug DevelopmentAnd Industrial Pharmacy.
  4. Mollan MJ, Celik M. The effects of lubrication on the compaction andpost-compaction properties of directly compressible maltodextrins.International Journal of Pharmaceutics 1996;144(1):1-9.
  5. Rizk S, Guyot JC, Duru C. Influence of lubricant properties on compression behaviour and drug dissolution rate of scleroglucan hydrophilic matrix.InternationalJournal of Pharmaceutics1995; 126(1-2):57-63.
  6. Dietrich P, Bauer-Brandl A, Schubert R. Influence of tableting forces andlubricant concentration on the adhesion strength in complex layer tablets.Drug Development AndIndustrial Pharmacy2000; 26(7):745-754.
  7. Doug Nelson, Rebecca Wu, Kate Wymbs. “Effect of Magnesium Stearate on tablet properties.”
  8. Raymond C Rowe, Paul J Sheskey, Marian E Quinn. Hand book of pharmaceutical exciepients.6th edition.Washington, USA; RPS publisher; 2009.
  9. Hiremath SN, Jithendra Patil, Nagarjuna R, Sway PV. Studies on influence of co-excipients on release rate of diltiazem from carbopol controlled release tablets.Indian Journal of Pharmaceutical Education and Research2009; 43(4):360-364.
  10. Charles E.Carraher,Jr. Seymour/Carraher’s Polymer Chemistry;6thedition.MarcelDekker; 2005.