Improvement of Physico Chemical Properties of Bcs Class Iv Drugs by Spherical Crystallization

IMPROVEMENT OF PHYSICO CHEMICAL PROPERTIES OF BCS CLASS IV DRUGS BY SPHERICAL CRYSTALLIZATION.

DISSERTATION PROTOCOL

SUBMITTED TO THE

RAJIVGANDHI UNIVERSITY OF HEALTH SCIENCE

BANGLORE, KARNATAKA.

BY

SUMIT MISHRA

DEPARTMENT OF PHARMACEUTICS

UNDER THE GUIDANCE OF

MR. VAZIR ASHFAQ AHMED

ASST. PROFESSOR

DEPARTMENT OF PHARMACEUTICS

M.M.U COLLEGE OF PHARMACY

RAMNAGARAM-571511.

KARNATAKA

RAJIV GANDHI UNIVESITY OF HEALTH SCIENCES,

KARNATAKA, BANGALORE

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / NAME OF THE CANDIDATE
AND ADDRESS (IN BLOCK LETTERS) / SUMIT MISHRA
S/O Dr. S.K MISHRA
MO_BALLIPURA MAU NATH BHANJAN-275101
UTTAR PRADESH
2. / NAME OF THE INSTITUTION / M.M.U COLLEGE OF PHARMACY
K.K DODDI, RAMADEVERA BETTA ROADRAMANAGARAM-571511
KARNATAKA
3. /

COURSE OF STUDY AND SUBJECT

/ M. PHARM
PHARMACEUTICS.
4. / DATE OF ADMISSION OF COURSE / 30-06-2009
5. /

TITLE OF TOPIC

/ IMPROVEMENT OF PHYSICO CHEMICAL PROPERTIES OF BCS CLASS IV DRUGS BY SPHERICAL CRYSTALLIZATION
6. / BRIEF RESUME OF THE
INTENDED WORK
6.1 Need for the study
6.2 Review of the literature
6.3 Objectives of the study / ENCLOSURE-I
ENCLOSURE-II
ENCLOSURE-III
7. /

MATERIALS AND METHODS

7.1 Source of data
7.2 Method of collection of data
7.3 Does study require any Investigations or interventions to be conducted on patients or Other human or animal? If so, Please describe briefly.
7.4 Has ethical clearance been obtained from your institution in case of 7.3 / ENCLOSURE-IV
ENCLOSURE-V
ENCLOSURE-VI
ENCLOSURE-VI
8. / LIST OF REFERENCES / ENCLOSURE-VII
9. / SIGNATURE OF CANDIDATE
10. / REMARKS OF GUIDE / FORWARDED FOR APPROVAL
NAME AND DESIGNATION OF
11.1 Guide
11.2 Signature
11.3 Co guide (if any)
11.4 Signature
11.5 Head of department
11.6 Signature / MR. VAZIR ASHFAQ AHMED
ASST. PROFESSOR
M.M.U COLLEGE OF PHARMACY
K.K DODDI, RAMADEVERA BETTA ROADRAMANAGARAM-571511
KARNATAKA
Not applicable
Not applicable
VAZIR ASHFAQ AHAMED
ASST.PROFESSOR
DEPARTMENT OF PHARMACEUTICS,
M.M.U COLLEGE OF PHARMACY
K.K DODDI, RAMADEVERA BETTA ROADRAMANAGARAM-571511
KARNATAKA
12. / 12.1 Remarks of the
Chairman and principal
12.2 Signature / SUBMITTED FOR APPROVAL
6. / BRIEF RESUME OF THE INTENDED WORK
ENCLOSURE-I

6.1 Need for the study

Cefpodoxime proxetil is an orally absorbed broad spectrum third generation cephalosporin antibacterial. It is a prodrug, de-esterified inin vivo to its active metabolite, cefpodoxime. After single and multiple (12-hourly) administration of cefpodoxime proxetil in the therapeutic dose range of 100 to 400mg of cefpodoxime equivalents, average peak plasma concentrations of cefpodoxime range from 1.0 to 4.5 mg/L and occur between 1.9 and 3.1 hours after administration. The half-life of cefpodoxime ranges from 1.9 to 2.8 hours. The absolute bioavailability of cefpodoxime proxetil tablets is 50%, and absorption is enhanced by concomitant administration of food. The bactericidal activity of cefpodoxime results from its inhibition of cell wall synthesis.
The present aim of the work is to study the effect of polymer on the solubility and dissolution rate of Cefpodoxime proxetil(CDP) prepared by emulsion solvent diffusion (ESD) technique.This technique involves three test solvents: first, substance dissolution medium-good solvent (acetone); second, partial dissolution medium for the substance-bridging liquid(dichloromethane), and third, immiscible with the substance-poor solvent (distilled water). The pure CDPand the prepared agglomerates were characterized in terms of production yield, drug content, solubility,in vitro release profile, flowability, density, wettability, as well as by thin layer chromatography (TLC),to checkthe chemical interaction between polymers and pure drug we will go for Fourier transforms infra red spectroscopy (FTIR) and stability test.
ENCLOSURE II
6.2Review of literature
1. The emulsion solvent diffusion technique was used to produced agglomerates that exhibited significantly faster dissolution rates than the unmodified cefuroxime axetil crystals. The improvedsolubility and dissolution are attributable to the modification of cefuroxime axetil within theagglomerates due to specific interaction between the drug and the polymers, as well as increased wettability,flowability and a reduction in particle size were achieved,the ESD technique can be considered a suitable method for formulating CFUpreparations with better physicochemical properties.1
2. Indomethacin drug was used as a model drug for the coating of agglomerates with a permeable film (Eudragit NE). The agglomeration of the crystals increased the flowability of the bulk crystals. The coating further improved the flowability, and also the uniformity of the mass of the filled capsules. The coating film also influenced the wetting of the samples. The coating decreased the surface free energy and therefore reduced the adhesion forces between both the dry and the wet particles. The modification of the flow properties and the even capsule filling can be explained by this phenomenon. Since coating film does not dissolve in the artificial gastric juice, the dissolution test was performed only in the artificial intestinal juice. The dissolution of indomethacin from the coated sample was changed significantly. Accordingly, coating of the crystals can be performed in order to protect the mucosa of the gastrointestinal tract or to promote the preparation of solid dosage form.2
3. The effects of Eudragitt nature on the formation and spherical agglomeration
of ibuprofen microcrystals have been examined when solvent change (ethanolwater)
technique is applied. Four methacrylic polymers (Eudragitt S100, L100, RS, and
RL), with different solubility and solubilizing ability, were used. The extrapolated
points of maximum temperature deviation rate in crystallization liquid that reflect the
maximum crystallization rate and the corresponding water addition were determined,
as well as crystal yielding and incorporation of drug and polymer in the agglomerates.
The physic mechanical properties of the agglomerates, such as size, sphericity, surface
roughness and porosity, as well as flow and packing or compression behavior during
tableting, were evaluated for different drug/polymer ratios. It was found that crystal
yield is greatly reduced in the presence of water-insoluble polymers and that formation
of the microcrystals and incorporation of drug and polymer are affected by the polymer
nature. Crystal formation changes are attributed to alterations in the metastable zone,
whereas the changes in drug and polymer incorporation and crystal yield are caused by
changes in the polymers’ solubility and micellization. The size of agglomerates depends
on the polymer nature and its interactions with the ibuprofen microcrystals formed.
Sphericity, surface roughness, and intraparticle porosity of agglomerates increase, in
general, with the presence of polymer owing to changes in habit and growth rate of the
microcrystals and to their coating before binding into spherical agglomerates. The
particle density or intraparticle porosity and size changes determine flow or packing
behavior and densification of agglomerates at low compression.3
4. Celecoxib agglomerates obtained by the solventchange method exhibited decreased drug crystallinityand satisfactory micromeritic, mechanical, andcompressional properties. Response surface methodologywas found to be a useful tool to study the
effect of variables. The amount of bridging liquidand speed of agitation significantly affect themicromeritic and compressional properties of theagglomerates. The compacts of the agglomerateshave shown in vitro drug release performancecomparable with the marketed capsule formulation.Therefore, this technique can be exploited to obtainagglomerates of celecoxib for tabletting.4
5. Spherical propyphenazone crystals were produced by an agglomeration technique using a three solvents system. After selecting the best propyphenazone solvent (ethyl alcohol), non-solvent (demineralized water) and bridging liquid (isopropyl acetate), several of their ratios were tested by a Sheffe´ ternary diagram. Micromeritic properties of agglomerates such as flowability, were improved and their compression behavior was investigated and compared to that of raw crystals. By compression and densification studies, along with tablet SEM analysis, we have been able to explain the compression mechanism of propyphenazone spherical crystals and have shown that their better tablet:ability can be due to the small size of individual particles in the agglomerates5 .
6. Furosemide-loaded ethyl cellulose microspheres were prepared by a spherical crystallization technique. The average diameters were about 330-335 pm and the drug contents in the microspheres were 65-84%. The size and formation of microspheres can be controlled by the rate of agitation. Furthermore, as the concentration of ethyl cellulose increased, the release rate of furosemide decreased. The results are examined kinetically and the mechanism is discussed. Dissolution data indicated that the release followed the Higuchi matrix model. These results show that furosemide-loaded ethyl cellulose microspheres could be prepared providing a controlled release property.6
7. Novel emulsion solvent diffusion methods in water or oil were developed to prepare the peptide (TRH and elcatonin)-loaded PLGA nanospheres, via the coprecipitation of drug and polymer in the emulsion droplets induced by the diffusion of solvent. The PLGA nanospheres prepared by the emulsion solvent diffusion method in water were unimodally dispersed particles with an average diameter of about 250 nm, whereas those prepared by the emulsion solvent diffusion method in oil and the phase separation method exhibited bimodal distribution with average diameter of about 700 and 800 nm, respectively. The content and recovery of the peptide and nanospheres prepared by the emulsion solvent diffusion method in oil were superior to those of nanospheres prepared using other methods. The drug release properties from nanospheres depended strongly on their preparation processes. The nanospheres prepared by the emulsion solvent diffusion method in oil, released the drug continuously over 14 days, the rate of which was determined by the diffusion of drug in the rigid matrix structure of the nanosphere. The drug release behavior of nanospheres prepared by the phase separation method exhibited a triphasic release pattern with an initial burst and an induction period followed by the diffusion of drug through the walls of the reservoir type nanospheres, which were produced via the phase separation of polymer deposited around the emulsion droplets of the drug.7
8. Agglomerates. crystals of carbamazepine with different hydrophilic and hydrophobic polymers prepared by quasi solvent emulsion technique showed an improvement in the solubility,dissolution rate, packability wettability,flowability and strengths compare with raw carbamazepine crystals and granules.PEG was found to be better polymer in dissolution enhancement .8
9. Zidovudin-ethylcellulose microsphere were prepared by water-in-oil-in –oil double emulsion solvent diffusion technique .spherical free flowing microspheres having an entrapment efficiency of 32-45% wereobtained. The effect of polymer drug ratio, surfactant concentration for secondary emulsion process, volume of processing medium and stirring speed of secondary emulsification process was evaluated with respect to entrapment efficiency and in vitro drug release behaviour.Infrared spectroscopy and
differentialscanning colorimetric analysis confirmed the absence of any drug polymer interaction. The in vitro release profiles from microsphere of different polymer drug ratio were applied on variouskinetic models. The best fit with highest correlation co-efficient was observed in Higuchi model indicating diffusion controlled priciple.9
10. From this reseach we obtain directly compressible agglomerates of ibuprofen-paracetamol containing a desired ratio of drugs using a crystallo-co-agglomeration technique. Crystallo-co-agglomeration is an extension of the spherical crystallization technique, which enables simultaneous crystallization and agglomeration of 2 or more drugs or crystallization of a drug and its simultaneous agglomeration with another drug or excipient. Dichloromethane (DCM)- water system containing polyethylene glycol (PEG) 6000, polyvinyl pyrollidone, and ethylcellulose was used as the crystallization system. DCM acted as a good solvent for ibuprofen and bridging liquid for agglomeration. The process was performed at pH 5, considering the low solubility of ibuprofen and the stability of paracetamol. Loss of paracetamol was reduced by maintaining a low process temperature and by the addition of dextrose as a solubility suppressant. Ethylcellulose imparted mechanical strength to the agglomerates as well as compacts. The agglomerates containing PEG have better compressibility but drug release in the initial stages was affected owing to asperity melting, yielding harder compacts. The agglomeration and properties of agglomerates were influenced by the nature of polymer.10
11. Erythromycin, a lipophlic macrolide antibiotic which is destructed in gastric acid was successfully converted into enteric recrystallized agglomerates by novel emulsion
Solvent diffusion method. The prepared enteric recrystallized agglomerates show significantimprovement in flowability and packability as compared to the raw crystals of erythromycin. The prepared tablets form these enteric recrystallized agglomerates show the release pattern as per the pharmacopoeial specifications.11
12. Cefpodoxime proxetil is an orally administered, extended-spectrum, semi-synthetic
antibiotic of the cephalosporin class. Protein binding of cefpodoxime ranges from 22% to 33% in serum and from 21% to 29% in plasma. Over the recommended dosing range (100–400 mg), approximately 29–33% of the administered cefpodoxime dose was
excreted unchanged in the urine in 12 hours. There is minimal metabolism of cefpodoxime invivo. Cefpodoxime proxetil is contraindicated in patients with a known allergy to cefpodoxime or to the cephalosporin group of antibiotics.12
ENCLOSURE-III
6.3 Objectives of the study
1. To investigate the method for enhancement of solubility of cefpodoxime proxetil
2. To study the various physiochemical properties of prepared agglomerates
3.To prepare and evaluate cefpodoxime proxetil tablet and comparison with marketed product
MATERIALS AND METHODS:
Materials:
Drug : cefpodoxime proxetil
Polymer: Cellulose acetate phthalate, Eudragit, Methocel, Hydropropyl cellulose
Additives: direct compression lactose, talc, magnesium stearate etc.
Equipments: Rotatory punch machine, Hot air oven, Mortar and pastel, Sieve, Dissolution apparatus, Disintegration apparatus, UV 1700 Series, etc.
Methods:
Enhancement of solubility by emulsion solvent diffusion technique of cefpodoxime proxetil, evalution of the prepared tablets of cefpodoxime proxetil.
ENCLOSURE-IV
7.1. Source of Data
a.Library: M.M.U College of Pharmacy
b.E- Library Rajiv Gandhi University Of health science
ENCLOSURE-V
7.2. Method of Collection of Data
Data on drugs will be collected through literature survey and from physiochemical database. Extensive preformulation trials would provide the basis of selection the excipients and system for final formulation development.
1. Preformulation studies
a)Drug excipient compatibility studies
b)Pharmaceutical evaluation :

• Bulk density
• Tapped density
• True density
• Porosity
• Angle of repose
• Haunser ratio
• Carr’s index

2. Preparation of tablets:

• Wet granulation method / suitable method
• Evaluation parameters: weight variation, hardness, friability, disintegration, dissolution etc. (as per Indian Pharmacopoeia).

3.Comparative dissolution studies of marketed formulation:
ENCLOSURE-VI
7.3. Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please mention briefly.
-NO-
7.4. Has ethical clearance been obtained from your institution in case of 7.3?
-NOT APPLICABLE-
ENCLOSURE-VII
LIST OF REFERENCES
1.VB Yadav and AV Yadav “Polymeric Recrystallized Agglomerates of Cefuroxime Axetil Prepared by Emulsion Solvent DiffusionTechnique" Tropical. J .Pharm. Research, August 2009;vol no.4:361-369 .
2.Ja´nos Bajdik et al. “Surface Treatment of Indomethacin Agglomerates with Eudragit” Drug Dev. Ind. Pharm2004Vol. 30, No. 4, 381–3.
3.Kyriakos kachrimanis et al. “Spherical Crystal Agglomeration of Ibuprofen by the Solvent-Change Technique in Presence of Methacrylic Polymers”: J.Pharm Sci, Feb 2000 VOL. VOL. 89, NO. 2, 250-258
4.A. R. Paradkar et al. “Spherical Crystallization of Celecoxib” Drug Dev.Ind. Pharm 2002 Vol. 28, No. 10, 1213– 1220.
5.Piera Di Martino et al, “Improved compression properties of propyphenazone spherical crystals”: Int. J.Pharm 197 (2000) 95–106.
6.Julide Akbuga, “Furosemide-loaded ethyl cellulose microspheresprepared by spherical crystallization technique:Morphology and release characteristics”Int. J. Pharm,[1991 ]176 , 193-198.
7.Yoshiaki Kawashima, “Properties of a peptide containing DL lactide:glycolide copolymer nanospheres prepared by novel emulsion solvent diffusion methods”: Euro. J. Pharm and Biopharm, (1998) 45,41–48.
8.Adhikrao v yadav, venkat b yadav , “preparation and evaluation of poly meric corbamazepine spherical crystals by emulsion solvent diffusion technique”:Asia J.Pharm, January-march 2009,18-25.
9.M.k das and K rama rao ,”microencapsulation of zidovudine by double emulsion solvent diffusion technique using ethylcellulose”,IndJ.Pharm Sci, march-april 2007,244-250.
10.Atmaram P.pawar et al ,”crystallo-co-agglomeration, A novel technique to obtain ibuprofen paracetamol agglomerates”,aaps pharm sci tech ,2004,5[3] , 44.
11.A.V. Yadav1, V. B. Yadav , Erythromycin enteric recrystallized agglomerates for Directly Compressible Tablets, Int.J. PharmTech Research”2009,vol.1,no 4,1109-1114.
12.Website:-