Download process development and optimization for moisture activated dry

“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