“DEVELOPMENT AND IN-VITRO CHARACTERIZATION OF SOLID DISPERSIONS OF PIOGLITAZONE HCL”
M. Pharm. Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Bangalore
Karnataka
By
Mr.J.ABDUL RASOOL, B.Pharm.
Under the Guidance of
Mr. SATHEESH KUMAR. N
Senior Lecturer
DEPARTMENT OF PHARMACEUTICS
EAST WEST COLLEGE OF PHARMACY
BANGALORE–560091
2011-2013
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1 / Name of candidate and address (In Block Letters) / Mr.J.ABDUL RASOOL# 7/104 BABA ENTERPRISES, R.S.RANGAPURAM
BETAMCHERLA, KURNOOL DIST,
ANDHRA PRADESH
PIN-518598
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: / (29/10/2011)
5 / Title of the topic:
“DEVELOPMENT AND IN-VITRO CHARACTERIZATION OF SOLID DISPERSIONS OF PIOGLITAZONE HCL”.
6 / Brief Resume of this intended work:
6.1 Need for the study Enclosure-I
6.2 Review of Literature Enclosure-II
6.3 Objectives of study Enclosure-III
7 / 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
9 / Signature of the candidate / (J.ABDUL RASOOL)
10 / Remarks of the Guide / The proposed research work is recommended for registration and approval
11 / Name and designation of (in block letters)
11.1 Guide
11.2 Signature / Mr. SATHEESH KUMAR. N
SENIOR LECTURER,
DEPT. OF PHARMACEUTICS,
EAST WEST COLLEGE OF PHARMACY,
BANGALORE-560 091.
11.3 Co-Guide (if any)
11.4 Signature / ………………
………………
11.5 Head of Department
11.6 Signature /
Dr. VENKATARAJU. M.P
PROFESSOR & HOD,
DEPARTMENT OF PHARMACEUTICS,
EAST WEST COLLEGE OF PHARMACY.
12 / 12.1 Remarks of the Chairman / Principal
12.2 Signature / Prof. K. A. SRIDHAR
PRINCIPAL,
EAST WEST COLLEGE OF PHARMACY,
BANGALORE-560 091
ENCLOSURE-I
6) Brief resume of the intended work:
6.1) Need for the study:
Oral bioavailability of drugs depends on its dissolution rate, therefore major problems associated with these drugs are, its low aqueous solubility, which results in poor bioavailability after oral administration1. Solubility of drug candidates may be altered by modifying the crystal form or by changing solvent properties and conditions. It may also be altered by altering the chemical composition, as seen with salt formation, co-crystals and solid complexes. Another means of improving “apparent” solubility is by converting the crystalline drug into an amorphous state. An amorphous phase has higher free energy, enthalpy and entropy than the crystalline counterpart, and thus finds application in improving oral bioavailability for biological classification (BCS) class II or class IV compounds2.
Various techniques have been used in attempt to improve the solubility and dissolution rates of poorly water soluble drugs, which include solid dispersion, microinization, lipid based formulations, melt granulation, direct compaction, solvent evaporation, co-precipitation, adsorption, ordered mixing, liqui-solid compacts, solvent deposition, inclusion complexation and steam aided granulation. In these techniques carrier is important in improving the solubility and dissolution rate3.
Pioglitazone Hcl a member of Thiazolidinedione group with the chemical name ([5-[[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione hydrochloride), mol.wt 392.90, mol. formula C19H20N2O3S. HCL5, a widely prescribed anti-diabetic drug belongs to class II under BCS and exhibit low and variable oral bioavailability due to its poor aqueous solubility. Its oral absorption is dissolution rate limited and it requires enhancement in the solubility and dissolution rate for increasing its oral bioavailability4. The antidiabetic activity of the drug depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism6.
The present study is an attempt to overcome the poor aqueous solubility of Pioglitazone an antidiabetic drug, by using various techniques such as solvent evaporation/ spray drying / melt/ kneading or any appropriate suitable method with various hydrophilic/ synthetic or any suitable drug carriers. The prepared solid dispersions will be subjected to physicochemical characterization and in-vitro studies.
ENCLOSURE-II
6.2) Review of literature:
Literature review for understanding the study was done by referring to various national and international journals, published articles in various official standard books and referred to various websites.
Mishra.SR et al., have prepared the Pioglitazone hydrochloride solid dispersion by solvent evaporation method using PEG 6000 as a carrier. The solubility of Pioglitazone Hcl showed linear increase with increasing the concentrations of PEG 6000 up to 1:3 ratios of drug and polymer. They have performed all the pre-formulation, post formulation parameters and accelerated stability studies according to ICH guidelines for a period of 12 weeks. FTIR results showed that there was no drug carrier interaction. The improved dissolution characteristics of solid dispersions may be attributed due to the increase in drug wet-ability, conversion to amorphous form and solubilization of drug due to hydrophilic carrier. Thus SDs of Pioglitazone in PEG 6000 showed enhanced solubility and dissolution rate compared to pure drug1.
Suchetha DB have prepared ternary solid dispersion of Fenofibrate by using Poloxamer 188 and TPGS through melt, spray drying and solvent evaporation methods. The prepared SDs were characterized by DSC, XRPD, SEM analytical techniques. DSC and XRPD studies revealed that the degree of crystallinity is considerably reduced and the drug is present in an amorphous form. Further FTIR studies showed van-der-wall interaction between drug and polymer, it was found improved dissolution of SDs when compared with pure drug and marketed product Lipicard tablet. Thus SDs of Fenofibrate in PXM 188 and TPGS showed enhanced solubility and dissolution rate compared to pure drug and marketed product7.
Squillante E, Sethia S, have prepared solid dispersion of carbamazepine in PVP K30 with or without Gelucire 44/14 by conventional solvent evaporation and supercritical fluid processing methods. They have characterized the physicochemical characteristics of SDs by using DSC and XRD. The changes obtained in the FTIR spectra between physical mixture and SDs is due to the conversion of crystalline form of drug to stable amorphous form. Dissolution studies revealed the improved dissolution characteristics for SDs when compared with physical mixture and pure drug. Thus SDs of PVP K30 with or without amphiphilic carrier has given higher intrinsic dissolution rates8.
Anand Kumar M et al., have prepared solid dispersion of ibuprofen tablets with cyclodextrins as a carrier by co-evaporation technique. They have carried out in-vitro dissolution study of ibuprofen, to demonstrate the effect of cyclodexterins in physical mixture and solid dispersions. Analytical techniques like FTIR and DSC were carried out to characterize the drug in the physical mixtures and solid dispersions. The optimized formulation indicated that there was no interaction between drug and excepients. They have reported that dissolution studies of solid dispersion and marketed product showed greater improvement in drug release, when compared to that of the pure drug. They have formulated ibuprofen solid dispersion as tablet, which showed far better release than the marketed product. Hence ibuprofen solid dispersion tablet was considered as a fast release tablet for pain management9.
Arora SC et al., have prepared solid dispersion of cefpodoxime proxetil by solvent evaporation method with an aim to increase the solubility and dissolution rate with urea. The dispersion granules were characterized by FTIR, DSC and XRD analysis. The analytical studies had revealed that there were no interactions in the solid state between drug and urea. They have reported the dissolution rate of drug in SDs showed greater release rate than physical mixtures and pure drug. They had finally concluded the dissolution rate of prepared SDs increase with increase in urea up to 1:5 ratios of drug and urea10.
Shivalingam MR et al., have prepared solid dispersion of glipizide with HPMC and CCS by solvent evaporation method. They have carried out in-vitro dissolution study of glipizide, its physical mixture and solid dispersion to demonstrate the effect with HPMC and CCS. The FTIR results showed there was no interaction between drug and polymers. The results obtained from dissolution rate studies revealed that increase in polymer concentration increases the drug release from solid dispersions, when compared with the pure drug release11.
Ranjan MS et al., have investigated on Pioglitazone solid dispersion with β- cyclodextrin by kneading technique. They have concluded that the solid dispersion prepared by kneading method showed higher dissolution rate, when compared with other formulations and pure drug. The results of FTIR analysis indicated that there was no interaction occurred in the solid dispersion of drug and polymer. Hence they concluded that kneading technique is suitable for the development of solid dispersion of Pioglitazone with β-cyclodextrin12.
Koshy MK et al., have prepared and characterized the domperidone solid dispersion with β-cyclodextrin-HPC complexes by kneading technique. The physicochemical characteristics of prepared solid dispersions were characterized by FTIR, DSC, SEM analytical techniques. It was found that domperidone was uniformly distributed in the mixture of both carriers with no change in the crystal structure of domperidone through SEM. The FTIR and DSC had revealed that there was no interaction between drug and carriers. They concluded that the dissolution rate of domperidone inclusion complex is increased by increasing the carrier, when compared with the physical mixture and pure drug13.
Guyot M. et al., have prepared and characterized norfloxacin solid dispersion with PEG 6000 and cyclodextrin by melting and inclusion techniques. The physicochemical characteristics of prepared solid dispersions were characterized by XRD, IR and DSC. The analytical techniques had revealed that there were differences between norfloxacin/cyclodextrin complexes and their corresponding physical mixtures, which were not seen with the PEG 6000 solid dispersions. They concluded that the dissolution rate of the prepared solid dispersions were showed faster dissolution rate than norfloxacin itself14.
Van Den Mooter G et al., have developed ternary solid dispersions of itraconazole with PEG 6000/Polyvidone-vinyl acetate 64 blends by spray drying technique. The solubility and release of the ternary solid dispersions was lower than the release of the binary solid dispersions, where as dissolution rate of the ternary solid dispersions was improved than the binary solid dispersions. The physicochemical characteristics of developed solid dispersions were characterized by XRPD, MTDSC and GC-MS techniques. The analytical techniques had revealed that there was no interaction between drug and carriers. They had concluded that the dissolution of itraconazole from a PEG 6000/PVPVA 64 matrix is composition dependent15.
ENCLOSURE-III
6.3) Objective of the study:
The present study is planned with the following objectives:
· To convert crystalline form of drug to amorphous form by using various solid dispersion methods with different polymers ratio.
· To investigate the physicochemical characterization of developed solid dispersion particles by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-Ray diffraction (XRPD), FTIR.
· To estimate the drug content in solid dispersions.
· To study the in- vitro drug release studies.
ENCLOSURE-IV
7) Materials and Methods:
Materials:
Drug: Pioglitazone hydrochloride
Polymers: PEG4000, PEG6000, kollicoat IR, Eudragit RS, Gelucire 44/14, β-cyclodexterins and lutrolF127, Calixarenes or any other appropriate polymers, which will be used for the preparation of solid dispersion formulations during the course of study.
Methods: Pioglitazone solid dispersions will be prepared by hot -melting/ spray drying/ fusion method/ kneading/ solvent evaporation method or any other appropriate method.
7.1) Source of data:
Data is collected from:
1 Textbooks and reference books.
2 Research publications.
3 International and Indian journals.
4 Presentations like pharmaceutical poster presentation.
5 Science Direct & other internet facilities.
6 RGUHS Library.
ENCLOSURE-V
7.2) Method of collection of data:
1. Morphological characters.
Ø Using scanning electron microscope (SEM).
2. Thermal analysis.
Ø Using differential scanning calorimeter (DSC).
3. X-ray diffraction.
Ø Using X-ray diffractometer. (XRD)
4. Compatibility studies with excepients
Ø Fourier Transformer infrared Spectroscopy
5. In vitro drug release studies.
Ø USP dissolution test apparatus
ENCLOSURE-VI
8) List of references:
1. Mishra SR, Elliah P, Jena PK, Nayak BS, Mishra G. An approach for enhancement of dissolution rate of Pioglitazone HCL by solid dispersion technique using PEG 6000. Int J Pharm Sci Res 2011;2(10):2681-85.
2. Qiu Yihong, Chen Yisheng. Solubility of pharmaceutical solids; Amorphous and crystalline solids. Zhang G.Z. Pharmaceutical theory and practice developing solid oral dosage forms 1st ed. U K: Elsevier Inc.2009. p.11,46.
3. Saharan VA, Kukkar V, Kataria M, Gera M, Choudhury PK. Dissolution enhancement of drugs. Int J Health Res 2009;2(2):107-24.
4. Chowdary KP, Rao KSP. Formulation development of Pioglitazone tablets employing β- Cyclodextrin-Poloxamer 407-PVP K30: A factorial study. Scholar’s Res library Der Pharma Lettre 2011;3(6):24-30.
5. www.manusaktteva.in/ details/1/84/view/pioglitazone+hcl.html
6. www.dshs.state.tx.us/mhprograms/efc/Pioglitazone.doc.
7. Suchetha DB, Ternary solid dispersions of Fenofibrate with Poloxamer 188 and TPGS for enhancement of solubility and bioavailability. Int J Res Pharm Biomed Sci 2011;2(2):583-95.
8. Squillante E, Sethia S. Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods. Int J Pharm 2004; 272:1-10.
9. Anand Kumar M, Dr.Lakshmi PK, Prasad VSG. Development and evaluation of solid dispersion formulated ibuprofen tablets using cyclodextrins as carrier. Int J Pharm Res Dev 2012;3(11):93-101.
10. Arora SC et al., Development, characterization and solubility study of solid dispersion of cefpodoxime proxetil by solvent evaporation method. Int J of Chem Tech Res 2010;2(2):1156-62.
11. Shivalingam M.R. et al., Formulation and evaluation of solid dispersion of glipizide for dissolution rate enhancement. Int J Pharm Res Dev 2011;3(1):231-39.