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ENCLOSURE-I
6. BRIEF RESUME OF THE INTENDED WORK
6.1 Need for the study
The oral route remains the preferred route of drug administration due to its
convenience, good patient compliance and low medicine production costs. In order
for a drug to be absorbed into the systemic circulation following oral administration,
the drug must be dissolved in the gastric fluids. For hydrophobic drugs, the
dissolution process acts as the rate-controlling step and which determines the rate and
degree of absorption. Thus, one of the major challenges to drug development today is
poor solubility, as an estimated 40% of all newly developed drugs are poorly soluble
or insoluble in water1. In addition, up to 50% of orally administered drug compounds
suffer from formulation problems related to their high lipophilicity2.
Developing novel methods to increase the bioavailability of drugs that
inherently have poor aqueous solubility is a great challenge to solid dosage form
formulators. Mechanical micronization of crystalline drugs and incorporation of
surfactants during the crystallization process are the techniques commonly used to
improve the bioavailability of poorly soluble drugs3,4. The micronization process was
found to alter the flow and compressibility of crystalline powders and cause
formulation problems. Incorporation of surfactants generally led to less significant
increase in aqueous solubility. To overcome this problem, Kawashima et al5,6
developed a spherical agglomeration during crystallization technique that led to
improving the flow and direct compressibility of number of microcrystalline drugs7.
Improvement of solubility, dissolution profile was also achieved in some cases8.
Efavirenz belongs to the class of nonnucleoside reverse transcriptase inhibitors
and is indicated in the treatment of HIV infection. Efavirenz is practically insoluble in
water having lowest solubility of about 0.01 mg/ml indicates class II drugs of BCS
systems (i.e. High permeability and low solubility). These classes of drugs could
potentially exhibit dissolution rate limited absorption.
In the present study an attempt is to make to prepare spherical agglomerates of
efavirenz and study their improvement in micromeritics, direct compressibility,
solubility and dissolution properties.
ENCLOSURE-II
6.2 Review of literature
Chelakara LV et al9 prepared spherical agglomeration of mefenamic acid and
nabumetone prepared by modified Kawashima technique. They developed novel
spherical
agglomeration
procedure
by
incorporating
polymers
during
the
agglomeration process and choosing different agglomerating solvents. The developed
agglomerates were evaluated by X-ray diffraction, differential scanning calorimetry,
and scanning electron microscopy for flow and direct compressibility and finally for
solubility.
Achutha NU et al10 prepared aceclofenac spherical agglomerates by spherical
crystallization technique using a three solvent system comprising acetone:
dichloromethane (DCM): water (bridging liquid, good solvent and bad solvent,
respectively).
Hydroxypropyl
methylcellulose-50
cps
(HPMC)
in
different
concentrations was used as hydrophilic polymer. They studied effect of speed of
rotation and amount of bridging liquid on spherical agglomeration. The agglomerates
were further subjected to various physicochemical evaluations such as practical yield,
drug content, particle size, loss on drying, porosity, IR spectroscopy, differential
scanning calorimetry, X-ray diffraction studies, relative crystallinity, scanning
electron microscopy, micromeritic properties, solubility and dissolution studies. The
agglomerates showed improved micromeritic properties as well as dissolution
behaviour in comparison to conventional drug crystals.
Kazuhiko I et al11 prepared spherical agglomerates of steroid KSR-592, consisting of
fine primary drug crystals suitable for dry powder inhalation (DPI), by the spherical
agglomeration during crystallization technique in liquid with a bridging liquid. It was
found that the particle size of primary crystals increased until the dispersing medium
was saturated with the bridging liquid, whereas the spherical agglomeration of
primary crystals was continued even after the saturation of medium with the bridging
liquid.
Daniel AG et al12 prepared lobenzarit disodium (LBD) spherical agglomerates during
crystallization. Further they validate this method for selecting the best wetting agent
allowing to obtain spherical agglomerates based on the Washburn’s test (capillary rise
of liquids in a granular medium). Crystallization tests were carried out at different
conditions showed that the best results were obtained in the presence of n-hexane that
was effectively found to be a better wetting liquid of the lobenzarit crystals than the
other solvents.
Yadav VB et al13 studied emulsion solvent diffusion (EDS) technique combines
crystallization and agglomeration directly to generate spherical agglomerates with
improved micromeretic properties. They prepared griseofulvin spherical agglomerates
using emulsion solvent diffusion 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 for recrystallization and agglomeration process. The
spherical agglomeration were
characterized in terms of production yield, drug
content, solubility, in vitro release profile, flowability, density, packability, thermal
behavior (differential scanning calorimetry-DSC), X-ray diffraction (XRD), Fourier
transforms infra red spectroscopy (FTIR). 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 XRD also revealed a characteristic
decrease in crystallinity. The dissolution studies demonstrated a marked increase in
the dissolution rate in comparison with pure drug and physical mixture.
Yadav VB et al14 prepared spherical agglomerates of carbamazepine by quesiemulsion solvent diffusion system (QESDS) with ethanol-chloroform-water system.
They evaluate prepared agglomerates for flowability, compressibility, wettability,
packability and solubility. The prepared agglomerates were white, free flowing and
spherical in shape. The yield of agglomerates was 95% and showed 90-95% drug
content. Prepared agglomerates were also improved in compressibility, packability
and solubility.
Yoshiaki K et al15 prepared spherical agglomeration of salicylic acid crystals during
crystallization. The needle like salicylic acid crystals simultaneously form and
agglomerate in a mixture of three partially miscible liquids, such as water, ethanol,
and chloroform, with agitation. The agglomerates can be made directly into tablets
because of their excellent flowability. Spherical crystallization could eliminate the
usual separate agglomeration step after crystallization and may be adaptable to other
pharmaceutical and chemical systems.
Rammohan
GV
et
al16
prepared
celecoxib
spherical
agglomerates
with
polyvinylpyrrolidone (PVP) using acetone, water and chloroform as solvent, nonsolvent and bridging liquid, respectively. The agglomerates were characterized by
differential
scanning
calorimetry
(DSC),
X-ray
diffraction
(XRD),
FTIR
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 possess a good spherical shape with smooth and regular surface.
Koji M et al17 develop cephalosporin antibiotic spherical agglomeration by
neutralization method. Spherical agglomerates were obtained by adding seed crystals
of 0.1 % wt under a high initial super saturation ratio. The compactly packed spherical
agglomerates were composed of a number of rod shape crystals with a uniform length
of 60 μm, and had good filtration property.
Chourasia MK et al18 prepared spherical crystal agglomerates of flurbiprofen via the
spherical crystallization technique using acetone-water-hexane solvent system. They
studied various parameters such as, amount and mode of addition of bridging liquid,
temperature and agitation speed to get maximum amount of spherical crystals. These
were further characterized for micromeritic properties (particle size and shape,
flowability),
packability
(bulk
density),
wettability
(contact
angle)
and
compressibility. The results suggest that spherical agglomerates exhibited improved
flowability, wettability and compaction behaviour.
ENCLOSURE-III
6.3 Objectives of the study
The present work is planned with the following objectives
1. To prepare efavirenz spherical agglomerates using Kawashima technique by
incorporating polymers during the agglomeration process and choosing
different agglomerating solvents.
2. To evaluate various parameters such as, amount and mode of addition of
bridging liquid, temperature, agitation speed.
3. To characterize micromeritic properties (particle size and shape, flowability),
packability (bulk density), wettability (contact angle) and compressibility.
4. To evaluate spherical agglomerates by X-ray diffraction, differential scanning
calorimetry (DSC), and scanning electron microscopy, solubility and
dissolution.
5. 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. The secondary data will be collected by referring various national and
international journals, books, helinet, pubmed, pharmacopeias and websites etc.
ENCLOSURE –V
7.2 Method of collection of data
The data is planned to collect from laboratory experiments which includes,
1. Prepare efavirenz spherical agglomerates using Kawashima technique by
incorporating polymers during the agglomeration process and choosing different
agglomerating solvents.
2. The prepared systems evaluated for amount and mode of addition of bridging
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
LIST OF REFERENCES
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the wettability and dissolution of compacts of griseofulvin. Int J Pharm 2004;
269:443-450.
2. Gursoy RN, Benita S. Self-emulsifying drug delivery systems for improved
oral delivery of lipophilic drug. Biomed Pharmacotherapy 2004;58:173-182.
3. Atkinson RM, Belford C, Tomich EG. Effect of particle size on blood
Griseofulvin levels in man. Nature 1962;193:588-589.
4. Prescott LF, Steel RF, Ferrier WR. The effect of particle size on the absorption
of Phenacetin in man. A correlation between plasma concentration of
phenacetin and effects on the central nervous system. Clin Pharmacol Ther
1970;496-504.
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Kawashima Y, Okumara M, Takenaka H. A novel agglomeration technique to
transform a microcrystalline drug into an agglomerated form during
crystallization. Science 1982;216:1127-1128.
6. Kawashima Y, Okumara M, Takenaka H, Kojwa A. Direct preparation of
spherically agglomerated salicylic acid crystals during crystallization. J Pharm
Sci 1984;73:1535-1538.
7. Gordon MS, Chowhan LT. Manipulation of naproxen particle morphology via
the spherical crystallization technique to achieve a directly compressible raw
material. Drug Dev Ind Pharm 1990;16:1279-1290.
8. Sano A, Kuriki T, Handa T, Takeuchi H, Kawashima Y. Particle design of
Tolbutamide in the presence of soluble polymer or surfactant by the spherical
crystallization technique: improvement of dissolution rate. J Pharm Sci 1987;
76:471-474.
9. Chelakara LV, Sushrut KK, Dhanashri RK. Spherical Agglomeration of
Mefenamic Acid and Nabumetone to Improve Micromeritics and Solubility: A
Technical Note. AAPS PharmSciTech 2006;7(2):1-4.
10. Achutha NU, Srinivas M, Sreenivasa Reddy M, Averineni KR, Pralhad K,
Udupa N . Preparation and in vitro, preclinical and clinical studies of
aceclofenac spherical agglomerates. European Journal of Pharmaceutics and
Biopharmaceutics 2008;70:674-683.
11. Kazuhiko I, Yoshiaki K, Hirofumi T, Hiromitsu Y, Nobuyuki I, Den-ichi M,
Kiyohisa O. Simultaneous particulate design of primary and agglomerated
crystals of steroid by spherical agglomeration in liquid for dry powder
inhalation. Powder Technology 2003;130:290-297.
12. Daniel AG, Beatrice B. Spherical agglomeration during crystallization of an
active pharmaceutical ingredient. Powder Technology 2002;128:188-194.
13. Yadav VB, Yadav AV. Effect of Different Stabilizers and Polymers on
Spherical Agglomerates of Griseofulvine by Emulsion Solvent Diffusion
(ESD) System. International Journal of PharmTech Research 2009;1(2):149150.
14. Yadav VB, Yadav AV. Comparative Tabletting behavior of Carbamazepine
granules with spherical agglomerated crystals prepared by spherical
crystallization technique. International Journal of ChemTech Research 2009;
1(3):476-482.
15. Yoshiaki K, Motonari O, Hideo T. Spherical Crystallization: Direct Spherical
Agglomeration of Salicylic Acid Crystals during Crystallization. Science
1982;216(4550):1127-1128.
16. Rammohan GV, Srinivas M, Madhobhai MP, Girish KJ. Spherical crystals of
Celecoxib to improve solubility, dissolution rate and micromeritic properties.
Acta Pharm 2007;57;173-184.
17. Koji M, Keiichi K, Takashi M, Shigeru M, Kooji K, Hiroshi O. Production of
Spherical Agglomerates of Cephalosporin Antibiotic Crystals. Journal of
Chemical Engineering of Japan 2008;41(11):1017-1023.
18. Chourasia MK, Jain NK, Jain S, Jain SK. Preparation and characterization of
agglomerates of flurbiprofen by spherical crystallization technique. Indian
Journal of Pharmaceutical Science 2003;65(3):287-291.