“PROCESS DEVELOPMENT AND OPTIMIZATION FOR MOISTURE ACTIVATED
DRY GRANULATION METHOD FOR SERTRALINE TABLETS”
M. Pharm. Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Bangalore
Karnataka
By
Mr. P.MADHUSUDHAN B.Pharm.
Under the Guidance of
Mr. MANJUNATHA. N,
Assistant Professor.
DEPARTMENT OF PHARMACEUTICAL TECHNOLOGY
EAST WEST COLLEGE OF PHARMACY
BANGALORE – 560 091
2010-2012
1
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1
Name of candidate and address
(In Block Letters)
2
Name of the Institute
P.MADHUSUDHAN,
C/O G.RAMIREDDY,
PANCHEDU(VIL),
BUCHIREDDYPALEM(MD),
NELLORE(DIST),
ANDHRAPRADESH.
EAST WEST COLLEGE OF PHARMACY,
BANGALORE-560 091
3
Course of study and subject:
M.PHARM.
(PHARMACEUTICAL TECHNOLOGY)
4
Date of admission of course:
10-07-2010
5
Title of the topic:
“PROCESS DEVELOPMENT AND OPTIMIZATION FOR MOISTURE
ACTIVATED DRY GRANULATION METHOD FOR SERTRALINE
TABLETS”
6
Brief Resume of this intended work:
6.1 Need for the study
6.2 Review of Literature
6.3 Objectives of study
7
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
(P.MADHUSUDHAN)
10
Remarks of the Guide
The proposed work can be carried out in the laboratory.
Protocol is as per university guidelines.
11
Name and designation of
(in block letters)
11.1 Guide
Mr. MANJUNATHA. N,
ASSISTANT PROFESSOR,
DEPT. OF PHARMACEUTICAL TECHNOLOGY,
EAST WEST COLLEGE OF PHARMACY,
BANGALORE-560 091.
11.2 Signature
11.3 Co-Guide (if any)
Mr. SUBHASH P.G
11.4 Signature
11.5 Head of Department
Dr. VENKATA RAJU M.P,
PROFESSOR & HOD,
DEPT. OF PHARMACEUTICAL TECHNOLOGY,
EAST WEST COLLEGE OF PHARMACY,
BANGALORE-560 091.
11.6 Signature
12
12.1 Remarks of the
Chairman / Principal
12.2 Signature
Prof. K. A. SRIDHAR,
PRINCIPAL,
EAST WEST COLLEGE OF PHARMACY,
BANGALORE-560 091.
3
ENCLOSURE-I
6) Brief resume of the intended work:
6.1) Need for the study:
Granules are prepared agglomerates of smaller particles of powder. They are irregularly shaped but may be
prepared to be spherical. Depending on the usage granules are employed in the size range 0.2-0.4 nm for the
development of pharmaceutical product. Granulation is used mainly to improve flow, compressibility of
powders, and to prevent segregation of the blend components improve content uniformity, and eliminate
excessive amounts of fine particles. Concentration and pouring rate of granulating liquid governs the particle size
of the granules. Granulation method can be broadly classified into two types: Wet granulation (WG) and Dry
granulation (DG).1, 2
Wet granulation technique has inviting greater significance because the direct compression (DC) method not
suitable from active compound which are in high dosage or available in fine powder form. Though the WG
technique is widely used, it suffers from one major drawback i.e. not suitable for moisture sensitive active
compounds. So in order to overcome the limitations associated with WG, moisture activated dry granulation
(MADG) was developed to achieve the benefits in end point, drying, and milling process.3
Different granulating techniques that are widely used in the pharmaceutical Industries are as follows:
Pneumatic Dry Granulation (PDG) 1, Freeze granulation Technology1, Foamed Binder Technologies (FBT) 1,
Melt Granulation Technology1,
Steam Granulation1, Moisture Activated Dry Granulation (MADG)
4-6
,
Granulex® Technology7, Thermal Adhesion Granulation Process (TAGP).1
Currently in pharmaceutical industry, MADG technology is widely employed in granulation of moisture
sensitive active pharmaceutical ingredients. The present study will be carried out with the Sertraline as ideal drug
candidate for the preparation of granules by innovative MADG technology and optimization of water content,
concentration of granulating binder and moisture absorbents along with other excipients.
Sertraline is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class, used in the treatment of
depression. Sertraline is used for a number of conditions including: major depression, obsessive-compulsive
disorder (OCD), posttraumatic stress disorder (PTSD), premenstrual dysphonic disorder (PMDD), panic disorder
4
and social phobia (social anxiety disorder).8 It has also been used for premature ejaculation and vascular
headaches but the evidence is less robust. This active substance is selected with the attributes of slightly soluble
in water, less bioavailability (44 %) and terminal half-life of sertraline is approximately 26 hours.9
5
ENCLOSURE-II
6.2) Review of literature:
Extensive literature review was made for understanding the study and there has been number of reports
concerning the applications of MADG in the formulation of different types of dosage forms like immediate
release /sustain release / controlled release matrix tablets. Literature review made by referring to various national
and international journals , databases such as pharmaceutical technology Europe, inform healthcare and various
other web resources along with general books for pharmaceutical scientists.
Chen CM et al., have performed the comparison of MADG process with two conventional granulation methods
i.e. WG and DG with a roller compactor, as well as with a DC 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 WG or DG and which were
much better than the powder blend from the DC 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.10
Christensen LH et al., have examined the applicability of a 25 liter high shear mixer for MADG. MCC, 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 MCC and potato starch as
moisture absorbing material.11
6
Aniruddha MR et al., have performed the evaluation & comparison of a MGT to conventional methods. They
have prepared acetaminophen tablets using PVP as binder and MCC as moisture-absorbing material. Water was
used as the granulating fluid. They compared of the MGT with DC and WG methods were accomplished by
sieve analysis (particle size) and density measurements. They found that MG provided an increase in particle size
compared to DC, these results were compared to those from the traditional WG after drying and screening.
Finally can concluded that the MGT appears to have potential for the development of CR formulations.12
Debra SH has compared the processes of low shear, high shear, and fluid bed granulation during low dose (0.1%)
immediate release tablet development using three processing methods. 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 (water/methanol) and sprayed into the granulator. For low shear, high shear
and fluid bed granulation, Patterson-Kelley V-Blender, GRAL and Diosna are used as equipment, respectively.
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 distributions and bulk/tap densities.
However, the addition of extra granular MCC minimized the effect of variable granulation properties and
allowed similar tablets to be produced from each granulation process.13
Aniruddha MR et al., have modified the moist granulation technique (MGT) to develop the controlled-release
(CR) dosage forms of acetaminophen. The 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 CR 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.
There by avoided the drying step. They have prepared acetaminophen CR tablets using hydroxypropylcellulose
as the controlled-release agent and lactose fastflo® and dicalcium phosphate as the diluents, and they have also
compared the MGT with conventional WG and direct compression (DC) processing methods. Finally in
conclusion MGT can be applicable in developing a CR formulation.14
7
Aniruddha MR et al., have studied the effects of formulation factors on the MGT for CR tablets. CR tablets were
prepared by the MGT, with acetaminophen and the polymer hydroxypropylcellulose as the controlled-release
agent. The effects of varying drug, binder (PVP), polymer, and MCC 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 showed that MGT can be
applied to control drug release, and at a polymer content of 44.6% or more.15
Mohsen AB et al., have prepared the sustained-release (SR) theophylline (TPH) tablets by applying the MADG.
The interaction between the excipients sodium alginate (SAL) and calcium gluconate (CG) was the base for the
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 SAL: CG ratios. The resulting tablets showed good physical
properties, with a lower rate of drug release compared with the commercial TPH tablets (Quibron®). They found
that the release of TPH from the tablets was not markedly affected by either the concentration of added dry
binder (carbopol 934) or the tablet hardness, indicating that the rate-determining step in drug release was the
diffusion. Tablets formulated with equal ratios of CG and SAL that showed good physical properties and slow
TPH release were chosen for bioavailability studies in beagle dogs, and results were compared with those for
Quibron. The in-vivo data showed a comparable plasma concentration profile for both tablet formulations, with
prolonged appearance of drug in the plasma up to 24 hr.16
Carstensen JT has 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 WG. Even though he driven off water in a WG, 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 shall capsule approach.
This presumes that the drug substance is not particularly hygroscopic, since otherwise, the capsule shell will
provide an unwanted source of moisture.17
8
ENCLOSURE-III
6.3) Objectives of the study:
The present study is planned with the following objectives:
 Standardization and development of sertraline granules by moisture activated dry granulation (MADG)
technique with suitable binders and remaining excipients.
 To evaluate the prepared granules for precompressional parameters such as angle of repose, bulk density,
tapped density, porosity, compressibility index, drug solubility, particle size distribution, drug loading
capacity, and drug content uniformity.
 The developed formulations will be subjected for post compression parameters.
 To carry out in-vitro drug release studies.
 To investigate the physicochemical characterization of developed sertraline tablets.
9
ENCLOSURE-IV
7) Materials and Methods:
Materials:
Drug: sertraline.
Fillers (Agglomeration): lactose monohydrate/ mannitol, microcrystalline cellulose/ starch or any other suitable
appropriate filler.
Binders (Agglomeration): polyvinylpyrrolidones (PVPs) such as PVP K-12/ hydroxypropyl cellulose /
copovidone/ maltodextrins/ sodiumcarboxymethylcellulose (NaCMC)/
hydroxypropyl methylcellulose (HPMC) or any other suitable binders
Moisture absorbents:
.
Microcrystalline cellulose (e.g., Avicel PH101, PH102, and PH200)/ Avicel PH 200
LM/ Aeroperl 300/ coarse grade of crospovidone/ regular silicone dioxide or any
other suitable moisture absorbents.
Method: Development of tablets containing sertraline will be carried out using different polymers with suitable
methods such as MADG by using synthetic/ semi synthetic or natural polymers.
7.1) Source of data:
Data is collected from:
1
Internet.
2
Presentations like pharmaceutical poster presentation.
3
Research publications.
4
International and Indian journals.
5
Textbooks and reference books.
6
RGUHS Libr
10
ENCLOSURE-V
7.2) Method of collection of data:
1. Standardization, selection, process development, optimization of MADG and preparation of sertraline tablets.
2. Evaluation of precompression and post compression parameters for developed formulations are as follows.
Precompression parameters
 Angle of repose

Fixed Funnel Method.
 Bulk density

Measurement in a graduated cylinder.
= Mass of powder
Initial volume
 Tapped density
= Initial volume of powder
Final volume of powder

Electro lab Tap Density Tester USP1 and 2(ETD-1020)
 Porosity
E= 1- True volume
Bulk volume
 Compressibility index (I)
_
= Tapped Bulk Density (Dt) Bulk Density (Db) X 100
Tapped Bulk Density (Dt)
 Drug solubility

Solubility of sertraline in suitable solvent system.
 Particle size distribution

Sieving (Quantitative particle size distribution analysis).
 Drug content uniformity

UV-visible spectrophotometer (shimadzu 1800).
11
Post compression parameters
 Weight variation
 According to USP /IP.
 Hardness

Monsanto/Pfizer hardness tester
 Thickness

Vernier caliper
 Friability

Roche’s Friability Testers (Electrolab EF - 2)
 Disintegration

USP Disintegration tester (Electro lab 2 Station Unit ED - 2L) .
3. To investigate the physicochemical characterization of developed tablets using suitable analytical methods.
4. Estimation of drug content in the developed formulation.
5. To carry out in-vitro drug release studies.

USP dissolution apparatus (Electro lab 8 station (EDT-08lx) Labindia dissolution test apparatus (DS
8000)).
6. Fitting the data to various kinetic equations to find the release parameters.
12
ENCLOSURE-VI
8) List of references:
1. Himanshu K, Tarashankar B, Jalaram H T, Chirag AP. Recent advances in granulation technology. Int J
Pharm Sci Rev Res 2010;5(3):48-54.
2. Ansel C. Pharmaceutical dosage form and drug delivery system ,2000;198-9
3. Ismat U. Moisture-activated dry granulation. Pharm Tech Eur 2011;23(3):1-3.
4. Susan F, Carrie S, Brian J, Shawn E, Ismat U. Optimization of binder level in moisture-activated dry
granulation using absorbent starch to distribute moisture. Available from:
URL:www.vectorcorporation.com/news/papers.asp. 2011;May 19:14:26.
5. Ismat U, Jennifer W, Shih-YC, Gary JW, Nemichand BJ, San K. Moisture activated dry granulation-Part
I: A guide to excipient and equipment selection and formulation development. Pharm Tech
2009;33(11):62-70.
6. Ismat U, Jennifer W, Shih YC, Hang G, San K, Nemichand BJ. 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. Available from: URL: www.vectorcorporation.com/technology/granurex.asp.2011; May 24: 12.30.
8. Available from: URL: http://www.drugs.com/pro/sertraline.html.2011;May21:12.00.
9. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant
trials and its influence on apparent efficacy. N Engl J Med 2008;358(3):252-60.
10. Chen MC, Dhananjaya A, Michael RI, Jeffrey LC. Comparison of moisture-activated dry granulation
processes with conventional granulation methods for sematilide hydrochloride tablets. Drug Dev Ind
Pharm 1990;16(3):379-94. Available from: URL:
http://informahealthcare.com/doi/abs/10.3109/0363904900911.
13
11. 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: URL:
http://informahealthcare.com/doi/abs/10.3109/03639049409050233.
12. Aniruddha MR , Joseph BS. Evaluation and comparison of a moist granulation technique to conventional
methods. Drug Dev Ind Pharm 2000;885-89. Available from: URL:
http://informahealthcare.com/doi/abs/10.1081/DDC-100101313.
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.
Availablefrom:URL:http://informahealthcare.com/doi/abs/10.1081/DDC-120030419.
14. Aniruddha MR, Joseph BS. 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: URL:
http://informahealthcare.com/doi/abs/10.1081/DDC-100103733.
15. Aniruddha MR, Joseph BS. 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:
URL:http://informahealthcare.com/doi/abs/10.1081/DDC-100107669.
16. 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: URL:
http://informahealthcare.com/doi/abs/10.1081/DDC-100105174.
17. Carstensen JT. Effect of moisture on the stability of solid dosage forms. Drug Dev Ind
Pharm1998;14(14):1927-69.Available from:
URL:http://informahealthcare.com/doi/abs/10.3109/0363904880915.
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