STUDY ON EFFECT OF PROCESSING PARAMETERS

ON PHASE INVERSION OF SIBUTRAMINE HCl

SYNOPSIS FOR

M. PHARM. DISSERTATION

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA

BY

PATEL DHIMANTKUMAR NAVNITBHAI

I M. PHARM.

Department of Pharmaceutics

Dayananda Sagar College of Pharmacy

2008

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / Name of the candidate and address (in block letters) / PATEL DHIMANTKUMAR NAVNITBHAI
I M. PHARM.,
DEPARTMENT OF PHARMACEUTICS,
DAYANANDA SAGAR COLLEGE OF PHARMACY,
KUMARASWAMY LAYOUT,
BANGALORE-560078.
PERMANENT ADDRESS,
UBHARAN AT&POST,
MALPUR TA,
SABARKANTHA DISTRICT,
GUJARAT-383335.
2. / Name of the institute / Dayananda Sagar College of Pharmacy, Shavige Malleswara Hills,
Kumaraswamy Layout,
Bangalore-560078,
Karnataka.
3. / Course of study and subject / Master of Pharmacy in Pharmaceutics
4. / Date of admission to course / 25th Feb 2008
5. / Title of the project:
Study on effect of processing parameters on phase inversion of Sibutramine HCl.
6. / Brief resume of the intended work:
6.1 Need of the study:
Many pharmaceutical solid exhibit polymorphism and lead to different chemical and physical properties which include packing, thermodynamic, spectroscopy, kinetic and mechanical properties. It may affect drug’s processability and drug product quality/performance such as stability, dissolution and bioavailability. Therefore, it is essential to understand various polymorphic forms of a given drug and their physicochemical properties. Pharmaceutical solids can be in contact with water during processing steps like lyophilization, wet granulation, aqueous film coating and spray drying and also be exposed to water during storage in an atmosphere containing water vapor. Water molecules may be present as an integral part of the crystal structure so that when the water is removed the crystal collapses into an amorphous form or into different crystalline form. Monohydrated sibutramine hydrochloride is a widely used active ingredient for the treatment of obesity. There is need to study the effect of various processes on phase inversions of the monohydrate form to anhydrate form as it may affect the stability, dissolution and bioavailabililty of the drug.
6.2 Review of literature

1. Ibuprofen was recrystallized1 from several solvents by two different methods to obtain four samples characterized by different crystal habits as sample A, E ,T and M. Samples were analyzed by SEM analysis with respect to crystal habit, mean particle diameter and elongation ratio. Micromeritic properties, densification behavior and compression ability were analyzed for all the samples. Sample M showed a higher densification tendency and increase in powder bed porosity which permits particle – particle interactions of greater extension during subsequent stages of compaction. This allowed high tablatability and compressability.

2. Norbert Rasenock and Bernd W Muller2 have studied the tableting behavior of drug due to changes in crystal habit. Common analgesic drugs ibuprofen and acetaminophen were selected and prepared. Their tableting behavior was characterized to find the crystal form that is suitable for direct compression with only a low amount of excepeints. Tableting behavior was evaluated by a comparative factors based on typical parts of the punch, force/displacement profile and properties of the resulting compact.
3. The influence of 1. Proccessing induced decrease in drug crystallinity3. 2. phase transformations during dissolution on the the performance of tablet formulations. The crystallinity of anhydrate drug was lower than that of the unprocessed drug, leading to lower dissolution rate. Tablet formulations prepared from granules exhibited high hardness, lower disintegration time and slower dissolution than those containing the milled drug. Phase transformations during processing and during dissolution influenced the observed dissolution rates.
4. Chacterization of the various polymorph4 of tolbutamide was carried out by DSC, XRD, FTIR, optical microscopy and dissolution studies. Two solvents, acetonitrile and octanol were used to prepare polymorph A and O respectively. Tablets of both A and O were produced by compression pressure of 2500 pounds and 5000 pounds using corn starch and talc and exposed to 40%, 75% and 95% RH conditions. The authors report that DSC and XRD studies did not show any significant drug excepient interaction. Dissolution studies showed a significantly lower drug release rate from form O tablets compressed at 5000 pounds and exposed to 95% RH. Pressure and humidity had no significant effect on the dissolution profiles of the form A tablets. Therefore it was concluded that form A was the choice for further formulation development.
5. A novel crystallo-co-agglomeration method5 was developed for ketoprofen to obtaine directly compressable spherical agglomerates with improved flowability and compressibility. Dichloromethane water system containing PEG-6000, PVP, and HPMC-100 centipoises have been used as a crystallization system. The crystallized ketoprofen was agglomerated with talc. The agglomerate evaluated for micromeratic properties moisture content, compressibility, pack ability and drug release properties. It was characterized by DSC,XRD, SEM ,FTIR. The authors have reported remarkable improvement in micromeritic properties and compactibility, which enable direct compaction. DSE, XRD, SEM, FTIR result showed no change in crystalline forms of ketoprofen.
6. Guillermo Torrado et.al.,6 has studied the physicochemical changes and in dissolution behaviors of various recrytallized forms of acetylsalicylic acid SCM, DSE, XRD, FTIR were applied to evaluate the sample. The XRD analysis showed reduction in the drug crystal size induced by recrystallization method and this reduction in the crystalline size was responsible for faster dissolution rate of the recrystallized sample compared to non-recrystallized form.
7. A patent claims, synthesis7 of a novel monohydrate crystalline forms of rabeprazole sodium by crystallization from ethyl ether. The crystalline hydrate form γ has been characterized by XRD, H-NMR, DSC. The patent claimed that recrystalline form is more stable compared to the other two forms of rabeprazole α and β.
8. V.Tantishaiyakal et.al.,8 have studied the crystalline structure of piroxicam when dispersed in PVP K-17PF and PVP K-90 by solvent method. Dissolution study indicated a significant increase in dissolution of piroxicam when dispersed in PVP. Dissolution was maximum with the amorphous solid dispersions containing drug PVP K-17 1:5 and 1:6. Which showed a 40-fold increase in dissolution with in 5 min as compared with pure drug.
9. The effect of HPMC on solubility and dissolution of Carbazepam9 (CB2) form III has been investigated in 50% w/w CB2 form III in HPMC solid dispersion and physical mixture. The products were characterized by DSC, XRD and FT IR. Solubility and dissolution studies were carried out in different simulated GI fluids. Both solubility and dissolution studies revealed that HPMC had a profound effect of enhanced solubility and dissolution of CB2 form III in both physical and solid dispersions. It was opined that HPMC prevents formation of CB2 dihydrate and thereby improves the solubility and dissolution
10. A study has been conducted on six oxytetracycline HCl10 powders which were collected randomly and compared. Comparative physicochemical raw materials analysis showed no major difference with respect to DSC, IR, powder dissolution and particle size. But samples could be divided into two groups based on XRD. The two polymorphic forms exhibited different dissolution properties in water and 0.1N HCl. The powders containing form A were less soluble than that containing form B on dissolution.
6.3 Objective of the study:
1. Preparation of anhydrate form of sibutramine HCl.
2. Characterization of anhydrate and monohydrate forms using FTIR, DSC and XRD techniques.
3. Study on effect of potential processing parameters like wet granulation, lyophilization, drying, storage, humidity etc.
7. / Materials and methods
7.1 Source of data:
I. Review of Literature from
a. Books:
- Official Pharmacopeias
- Handbook of Excipients
- Textbook of Pharmacology by R. S. Satoskar
- Control and Novel Drug Delivery by N. K. Jain
-  Remington, The Science and Practice of Pharmacy, 21st edition, Volume I & II
b. Journals & articles :
- Advanced Drug Delivery Reviews.
- International Journal of Pharmaceutical Sciences.
- Journal of Controlled Release.
- International Journal of Pharmaceutics.
- Journal of Pharmaceutical Sciences.
- European Journal of Pharmaceutics and Biopharmaceutics.
-  AAPS Pharm Sci Tech.(American Association of Pharmaceutical
Scientists)
- PNAS (Proceedings of the National Academy of sciences of the united
States of America)
- Circulation – Basic science reports.
- European Journal of Pharmaceutical Science
- Journal of Control Release
- European Journal of Medicinal Chemistry
c. Internet Browsing.
- www.sciencedirect.com
- www.google.com
7.2 Method of collection of the data (including sampling procedure, if any):
Data pertaining to the drug will be collected from standard book, journal and databases like medline, science direct etc.
7.3. Does the require any investigation or interventions to be conducted or patients or other humans or animals? If so please describe briefly:
No
7.4. Has ethical clearance been obtained from your institute in case of 7.3
Not applicable
8. / List of references:
1. Piesa Di Maltono, Moila Beccelica, Ltiennl Joim’s, Giovanni F, Palnieri, Anne Gayot of Sante Martelli. Influence of Crystal habit on the compression mechanism of Ibuprofen. J.of Crystal Growth. 2002; 243(2): 345-55.
2. Norbert Rasenock and Bernd W Muller. Crystal habit and tableting behavior. Int J Pharm. 2002; 244(1-2,5): 45-57.
3. Smita Debnali and Raj Suryanarayana. Influence of processing induced phase transformation on dissolution of Theophylline tablet. AAPS Pharm Sci Tech. 2004; 5(1): 08.
4. P Chakravathy, K.S Alexander, A T Riga, K Chattergee. Crystal forms of tolbutamide from acetonitrile and 1-octanol. Effect of solvent humidity and compression pressure. Int J Pharm. 2005; 288(2): 335-48.
5. Vikash Chandra, Rajesh Kumar Maheshwari.Tailoring of Ketoprofen particle morphology via novel crystallo co-agglomeration technique to obtain a directly compressible material. Asian J Pharm. 2008; 2(1): 61-67.
6. Guillermo Torrado, Susana Fraile, Susana Torrado, Santiago Torrado. Process induced crystalline size and dissolution changes elucidated by a variety of analytical methods. Int J Pharm. 1998; 166(1): 55-63.
7. European patent. EP 1935891 A1.
8. V. Tantishaiyakal, N. Kaewnopparat, S. Ingkatawolnwong. Purification and solid dispersion of piroxicam in polyvinyl pyrrolidine. Int J Pharm. 1999; 181(2): 143-51.
9. SB Bhise, M Raj Kumar. Effect of HPMC on solubility and dissolution of carbazepam form-III in simulated gastrointestinal fluids. Asian J Pharm. 2008; 2(1): 38-42.
10. Libenberg W, DE Villiers M.M, Wurster D.E, Swanepoel E, Dekker T.h, Lotter A.P. The effect of polymorphism on powder compaction and dissolution properties of chemically equivalent oxytetracycline HCl powder. Drug Dev Ind Pharm. 1999; 25(9): 1027-33.
9. / Signature of the candidate /

PATEL DHIMANTKUMAR NAVNITBHAI

10. / Remarks of the guide:
11. / Name and Designation (in block letters)
11.1. Guide
11.2. Signature / Smt. BRAHMANI PRIYADARSHINI S. R, ASSOCIATE PROFESSOR,
Department of Pharmaceutics,
Dayananda Sagar College of Pharmacy,
Kumaraswamy Layout,
Bangalore-560078.
11.3. Co-guide if any / Not applicable
11.4. Signature
11.5. Head of the department
11.6. Signature / Dr. ARSHIA SHARIFF
HEAD,
Department of Pharmaceutics,
Dayananda Sagar College of Pharmacy,
Kumaraswamy Layout,
Bangalore-560078.
12. / 12.1. Remarks of the principal
12.2 Signature / Dr. V. Murugan,
Principal,
Dayananda Sagar College of Pharmacy,
Kumaraswamy Layout,
Bangalore-560078