Download ENCLOSURE- I 6.1. BRIEF RESUME OF INTENDED WORK NEED

ENCLOSURE- I
6.1. BRIEF RESUME OF INTENDED WORK
NEED FOR THE STUDY
Poor aqueous solubility of drugs is a major limiting factor with many new drugs
in their successful launch in market in spite of their potential pharmacokinetic activity.
Poor solubility (less than 10 %) of a drug, leads to poor dissolution in the gastro intestinal
tract (GIT) hence, incomplete and erratic absorption ultimately limits its clinical utility.
Further, poorly soluble drugs are generally administered at much higher doses than the
actual dose in order to achieve necessary drug plasma levels leading to increased adverse
reaction & cost of therapy and often yields erratic pharmacological response and hence
poor patient compliance. About 40% of drugs being in the pipeline of pharmaceutical
companies are poorly soluble, which emphasizes the need of a technique to overcome
such problems1.
Poorly water soluble drugs are associated with slow drug dissolution followed by
slow absorption leading eventually to inadequate and variable bioavailability. Thus a
greater understanding of dissolution and absorption behaviors of drugs with low aqueous
solubility is required to successfully formulate them into bioavailable drug products2.
Solubility, one of the key parameter in BCS, as well as dissolution rate is the most
essential factors controlling the rate and extent of drug absorption.
A number of approaches are practiced to improve the aqueous solubility of poorly
soluble drugs viz., solid dispersion3, spherical agglomeration4, complexation5, pH
adjustment6 etc. Among the methods spherical agglomeration is a versatile process that
enables to control the size and type of crystals.
The spherical agglomeration technique has been used as an efficient particle
preparation technique7,8. Initially, spherical agglomeration technique was used to improve
powder flowability and compressibility9,10. Then, polymers were introduced in this
system to modify their release11,12. Currently, this technique is used more frequently for
the solid dispersion preparation of water insoluble drugs in order to improve their
solubility, dissolution rate and simplify the manufacturing process.
Ritonavir, a widely prescribed antiretroviral protease inhibitor drug belong 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 solubility and dissolution rate for increasing its oral bioavailability. The
solubility of ritonavir in 0.1 N HCl is 400 µg/ml, the IDR value is only 0.03±0.001
mg/cm2-min. Compounds with IDR<0.1 mg/min/cm2 usually exhibit dissolution ratelimited absorption. These classes of drugs could potentially exhibit dissolution rate
limited absorption and their dissolution rates may be improved through spherically
agglomerated solid dispersions.
In the present study an attempt was made to evaluate solubility, dissolution rate
and micromeritic properties of a model drug Ritonavir by preparing spherically
agglomerated solid dispersions using hydrophilic polymers.
ENCLOSURE- II
6.2 REVIEW OF LITERATURE
Amit T et al13 prepared spherical agglomeration of poorly water soluble drug,
carvedilol to improve micromeritic properties and dissolution rate in presence of Inutec
SP1. The prepared spherical agglomerates were evaluated for its percentage yield, drug
content, morphology, thermal behavior, micromeritic properties and in vitro drug
release. Differential scanning calorimetric and powder X-ray diffraction studies confirm
that formulation process altered the crystalline nature of carvedilol. In vitro drug release
studies indicated that the spherical agglomerates CI-1 showed significant increase
(P<0.05) in dissolution rate than pure carvedilol alone.
Sujani S et al14 prepared spherical agglomerates of meloxicam by simple
agglomeration technique using a three solvent system. Agglomerates were prepared by
agitating the crystals in a liquid suspension and adding a bridging liquid, which wets the
crystal surface causing binding. The addition of bridging liquid promotes the formation
of liquid bridges between drug crystals. Spherical agglomerates of three different
polymers (PVP, poloxamer and cross povidone) and physical mixtures were prepared
dried at room temperature. Particle size, saturation solubility, drug content, FTIR studies
and dissolution characteristics were also investigated.
Mudit dixit et al15
prepared
spherical
agglomerates of ketoprofen by
neutralization method. Crystallization medium used for spherical agglomerates of
ketoprofen consisted of 1 M Sodium hydroxide; 0.25 M hydrochloric acid; chloroform
(bridging liquid) in the ratio of 20:55:25, respectively. Spherical agglomerates were
characterized by differential scanning calorimetry, Infrared spectroscopy, X-ray
diffractometry and scanning electron microscopy. Micromeritic and dissolution
behaviour studies were also carried out. Process variables such as amount of bridging
liquid, stirring time and duration of stirring were optimized. Dissolution profile of the
spherical agglomerates was compared with pure sample and recrystallized sample.
Spherical agglomerates exhibited decreased crystallinity and improved micromeritic
properties. The dissolution of the spherical agglomerates was improved compared with
pure sample. The dissolution profiles of ketoprofen tablets prepared using spherical
agglomerates exhibit greater dissolution behaviour than tablets prepared by powder raw
material
Varshosaz J et al16 prepared simvastatin spherical crystals by emulsion solvent
diffusion method. The study was to determine the effect of processing temperature and
stirring rate on micromeretic properties of prepared crystals. Particle size analysis,
dissolution rate profiles, packability, hydrophobicity, and flow properties of spherical
crystals were studied. The particle size of spherical aggregates was about 37 μm and the
dissolution efficiency of simvastatin up to 60 min increased to about 2 fold in phosphate
buffer solution containing 0.5% sodium dodecyl sulfate (pH 7) using the rotating paddle
method. Spherical crystallization is an effective to improve the dissolution rate of
simvastatin but its flow should be facilitated by some free flow excipients.
Gupta MM et al17 revived that spherical crystallization is the novel agglomerated
technique that can directly transform the fine crystals produced in the crystallization
process into a spherical shape. It is the particle engineering technique by which
crystallization and agglomeration can be carried out simultaneously in one step to
transform crystals directly into compacted spherical form. This technique gained interest
due to the fact that crystal habit can be modified during crystallization process which
would result in better micrometric properties like particle size those can enhance the
flowability of the powder drug and prepared spherical crystals can be compress directly
without performing granulation, drying and so many steps those are require in wet
granulation and in dry granulation process of tablet manufacturing.
Yadav VB et al18 tried spherical crystallization of an antifungal drug griseofulvin
by emulsion solvent diffusion technique to generate spherical agglomerates with
improved micromeretic properties. They used technique in which distilled water as an
external phase and the internal phase consisted of dichloromethane which acts as good
solvent as well as bridging liquid. The spherical agglomeration was carried out in the
presence of different polymers viz., hydroxyl propyl cellulose (HPC), Eudragit-RLPO
and stabilizers beta cyclodextrin, poloxomer-F68 and polyethylene glycol. The pure
griseofulvin and the prepared agglomerates were characterized in terms of production
yield, drug content, solubility, in vitro release profile, flowability, density, packability,
thermal behaviour. The optimized spherical agglomerates exhibited excellent
physicochemical and micromeritic properties, solubility, dissolution rate, flowability and
packability when compared with pure drug as well as the physical mixture of drug with
excipients. The considerable improvement in the dissolution rate of griseofulvin from
optimized crystal formulation was attributed to the wetting effect of polymers, decreased
drug crystallinity, altered surface morphology and micronization.
Yadav BV et al19 prepare and characterize the recrystallized agglomerates of
water insoluble non steroidal antiinflammatory drug, indomethacin (IM) with
hydrophilic polymers like polyvinyl pyrrolidone (PVP), hydroxyl ethyl cellulose (HEC)
and hydroxyl propyl methyl cellulose (HPMC) by using emulsion solvent diffusion
(ESD) technique for enhancing the solubility, dissolution rate, flowability, wettability
and packability. The solubility and dissolution studies demonstrated a marked increase
in solubility and dissolution rate of recrystallized agglomerates as compared to the pure
indomethacin. The prepared spherical crystals with used polymers exhibited excellent
physicochemical properties like flowability, packability, and wettability compared with
the pure raw crystals of indomethacin.
Ram Mohan G et al20 prepared celecoxib spherical agglomerates with
polyvinylpyrrolidone (PVP) using acetone, water and chloroform as solvent, non solvent
and bridging liquid, respectively. The agglomerates were characterized by differential
scanning calorimetry (DSC), X-ray diffraction (XRD), IR spectroscopic studies and
scanning electron microscopy (SEM). The IR spectroscopy and DSC results indicated
the absence of any interactions between drug and additives. XRD studies showed a
decrease in crystallinity in agglomerates. The crystals exhibited significantly improved
micromeritic properties compared to pure drug. The aqueous solubility and dissolution
rate of the drug from crystals was significantly (p < 0.05) increased (nearly two times).
The SEM studies showed that the crystal posseses a good spherical shape with smooth
and regular surface spherical crystals of celecoxib to improve solubility, dissolution rate
and micromeritic properties
ENCLOSURE – III
6.3 OBJECTIVE OF THE STUDY
The present work is planned with the following objectives
1. To prepare ritonavir spherical agglomerates using emulsion solvent diffusion
/neutralization technique by incorporating hydrophilic polymers during the
agglomeration process and choosing different agglomerating solvents.
2. To characterize micromeritic properties (particle size and shape, flowability),
packability (bulk density), wettability (contact angle) and compressibility.
3. To evaluate spherical agglomerates by X-ray diffraction, differential scanning
calorimetry (DSC), scanning electron microscopy, solubility and dissolution.
4. Statistical interpretation of the data.
ENCLOSURE – IV
7. MATERIALS AND METHODS
7.1 Source of data
The primary data will be collected by performing various tests and investigations
in the laboratory and websites etc. The secondary data will be collected by referring
various national and international jouranls, books, helinet, pumbed, and pharmacopoeia.
ENCLOSURE – V
7.2 METHOD OF COLLECTION OF DATA
The data is planned to collect from laboratory experiments which includes,
1. Emulsion solvent diffusion /neutralization technique was used to prepare spherical
agglomerates by incorporating hydrophilic polymers
during the process and
choosing different agglomerating solvents.
2.
The prepared systems evaluated for amount and mode of addition of binding liquid,
temperature, agitation speed, micromeritic properties ( particle size and shape,
flowability), packability(bulk density), wettability(contact angle) and compressibility
and solubility.
3.
Instruments like USP dissolution test apparatus, UV spectrophotometer, over head
stirrer, scanning electron microscope, FTIR spectrophotometer, differential scanning
colorimeter, XRD, will be used to collect the above data.
ENCLOSURE VI
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