13 - Chapter 3

Review
of
Literature
Improvements of Processing Parameters of APIs Raval MK – PhD Thesis 2012
3. REVIEW OF LITERATURE
Sr. Page
Topic
No. No.
3.1 METHODS USED FOR PROPERTY 55
IMPROVEMENT OF APIs
3.1.1 Co-crystallization 55
3.1.2 Pelletization 60
3.1.3 Crystallo-co-agglomeration (CCA) 63
3.1.4 Co-grinding and amorphization 68
3.1.5 Response surface methodology 74
3.2 BIBLIOGRAPHY 76
Department of Pharmaceutical Sciences, Saurashtra University, Rajkot 54

3.1 METHODS USED FOR PROPERTY IMPROVEMENT

OF APIs
3.1.1 CO-CRYSTALLIZATION
Masuda et al.(1) prepared cocrystals or amorphous complex of acyclovir to
improve its dissolution rate and transdermal absorption by using various
pharmaceutical excipients and by applying solution-crystallization as well as
liquid-assisted cogrinding. Acyclovir formed novel cocrystals with tartaric acid
(ACV–TA) and was amorphized with citric acid (ACV–CA). The initial
dissolution rate of the ACV–TA cocrystals was faster than that of anhydrous
acyclovir. In vitro skin permeation of ACV–CA amorphous from polyethylene
glycol (PEG) ointment was remarkably higher than the crystalline acyclovir.
Grossjohann et al.(2) prepared cocrystal of dibenzyl sulfoxide (DBSO) and

benzamide (BA) (1:1), to examine the improvement in solubility and
dissolution in comparison to its pure components and to a physical mixture.
For the cocrystal, the solubility of both components was decreased in
comparison to pure components.
Barot et al.(3) prepared directly compressible form of Metformin HCl using

antisolvent technique (water-acetone system) in presence of various
concentrations of polyvinyl pyrrolidone (PVP K30) ranging from 0 to 2% w/v. A
32 full factorial design (FFD) was employed for optimization of the processing
parameters like percentage PVP K30 in solution (X1) and crystallization time
(X2) as the independent variables and percentage yield (Y1), carr’s index (Y2)
and tensile strength of compacts (Y3) were selected as dependent variables.
Metformin HCl particles crystallized in the presence of 2% w/v PVP K30 with
crystallization time of four hours (CryMet), showed improvement in flow
property, compressibility as well as compactibility as compared to untreated
Metformin HCl (XMet).
Tsutsumi et al.(4) studied salts and cocrystals of miconazole with maleate,

hemifumarate, and hemisuccinate to improve the physicochemical properties
of miconazole. Crystal structure analysis showed that maleate was a salt

formed by proton transfer from the acid to the imidazole group of miconazole.
Hemifumarate and hemisuccinate were determined to be cocrystals formed by
hydrogen bonding between the acids and the base in their crystal lattices. The
formation of salts and cocrystals improved the dissolution rate of miconazole.
Stability tests indicated that maleate and hemifumarate were unstable at 80◦C
and generated a specific degraded product, i.e., a michael adduct, between
miconazole and the acids. Hemisuccinate had a superior intrinsic dissolution
rate and stability, and was thus considered a promising crystal form of
miconazole.
Aakeröy et al.(5) screened a range of pyrazoles, pyridines, and pyrimidines

derivatives for co-crystal formation of diclofenac using solvent assisted
grinding and infrared spectroscopy with an overall success rate of 50%. Three
new diclofenac co-crystals were (diclofenac) · (2-aminopyrimidine),
(diclofenac)·(2-amino-4,6-dimethylpyrimidine), and (diclofenac)·(2-amino-4-
chloro-6-methylpyrimidine) were reported using various characterization
techniques.
Rehder et al.(6) investigated cocrystal formation rates for piracetam during dry
milling and liquid-assisted milling using citric acid and tartaric acid as co-
formers. It was shown that liquid-assisted milling led to faster cocrystal
formation than dry grinding due to higher transformation rate in presence of
liquid. The cocrystal formation rate did not depend on the applied polymorphic
form of the piracetam and no polymorphic cocrystals were obtained.
Cheney et al.(7) prepared cocrystals of meloxicam with aspirin as coformer to

improve physicochemical and pharmacokinetic properties. The resulting
cocrystal exhibited superior kinetic solubility and possessed the potential to
significantly decrease the time required to reach the human therapeutic
concentration compared with meloxicam.
Barot et al.(8) developed directly compressible Metformin HCl by the spray-

drying technique in the presence of polyvinyl pyrrolidone (PVP K30), in
various concentrations ranging from 0–3% (m / V ) by employing spray-drying

technique. The resulting free flowing powder of Metformin HCl crystals

showed excellent packability and compressibility compared to pure drug
without any chemical modifications. Tablets made from the spray-dried drug
(90%, m/m) were evaluated for crushing strength, friability and disintegration
time and the results were found satisfactory.
Luis et al.(9) employed supercritical fluid with enhanced atomization (SEA)

process to produce cocrystals of six different active pharmaceutical
ingredients (APIs): Indomethacin, theophylline, caffeine, sulfamethazine,
aspirin and carbamazepine. Cocrystals using the FDA-approved sweetener
saccharin (SAC) as a cocrystal former were produced from ethanol solutions
using supercritical CO2 as the atomization enhancing fluid.
Oktabec et al.(10) prepared cocrystals of ibandronate monosodium salt with

eleven gluco- and/or galacto pyranoside derivatives to improve intestinal
absorption. A new entity of ibandronate monosodium salt with phenyl-βD-
galactopyranoside gave negative results in absorption compared to pure
ibandronate.
Jung et al.(11) evaluated the in-vitro dissolution and in-vivo bioavailability of

indomethacine – saccharine (IND–SAC) cocrystals in comparison with IND in
a physical mixture and the marketed product Indomee® using cooling batch
crystallization technique without seeding. In-vitro dissolution rate of the
cocrystals was higher than that of IND and similar to that of Indomee® at pH
7.4 and pH 1.2. The in-vivo bioavailability of the cocrystals in dogs was
significantly higher than that of IND.
Padrela et al.(12) prepared cocrystal of indomethacin using saccharin as a

conformer in 1:1 molar ratio using super critical fluid technique. They studied
the effect of processing parameters like solvents (CSS technique), anti-
solvents (SAS technique) and atomization enhancer (AAS technique) on
cocrystal formation. There no sign of cocrystal formation in CSS technique,
where as other two techniques produced cocrystals. Particulate IND-SAC

cocrystals with different morphologies and sizes (nano-to-micron) were

produced using supercritical fluid techniques.
Gagniere et al.(13) prepared co-crystals of carbamazepine (CBZ). The stable

solid form was obtained at the end of the operation. Finally some preliminary
results indicated that the nucleation of co-crystals might be favored by the
presence of CBZ crystals. Epitaxial relationships between CBZ/NCT co-
crystals and CBZ crystals were suspected.
Kumar et al.(14) recrystallized mebendazole in presence of polyvinyl

pyrrolidone and sodium lauryl sulfate by applying anti-solvent technique using
N, N,- dimethyl formamide and N, N-dimethyl acetamide as a good solvent
and water as an anti-solvent. The shape of crystals was changed from needle
to plate in presence of additive. They found that sodium lauryl sulfate had
positive effect where polyvinyl pyrrolidone gave negative impact on dissolution
profile of crystals of drug.
Maghsoodi et al.(15) studied influence of different concentrations of

hydroxypropylcellulose (HPC) on crystallization of naproxen from acetone-
water. HPC exhibited an obvious improvement in their packing, flow, and
mechanical properties compared to naproxen recrystallized in the absence of
the polymer (control particles). The agglomerates produced in the presence of
0.25% HPC displayed superior flow, spherical shape and smooth surface
characteristics compared to other samples. The tensile strength of tablets in
presence of 1% HPC was increased to a greater extent.
Basavoju et al.(16) prepared cocrystals of indomethacin using saccharine as a

co-former using slow evaporation technique from a series of solvents to
improve solubility and dissolution rate. The dissolution rate of IND-SAC
cocrystal system was considerably faster than that of the stable
indomethacine gamma-form.
Childs and Hardcastle,(17) characterized two polymorphs of a

Chlorzoxazone:2, 4-dihydroxybenzoic acid cocrystal and one form of a

Chlorzoxazone:4-hydroxybenzoic acid cocrystal. The crystal structure of

Chlorzoxazone:2,4-dihydroxybenzoic acid (form 1) was reported and
analyzed, revealed an uncommon carbonyl–carbonyl interaction and a
destabilizing C–H - - - - Cl–C interaction.
Nokhodchi et al.(18) prepared carbamazepine (CBZ) crystals from pure

ethanol solutions containing various additives (PEG 4000, PVP K30 or Tween
80). The presence of additives affected the morphology and size of
carbamazepine crystals. Only the samples crystallized in the presence of PVP
K30 showed an improvement in dissolution rate and tensile strength.
Trask et al.(19) produced theophylline cocrystals with oxalic, malonic, maleic

and glutaric acids. The theophylline cocrystals were subjected to relative
humidity challenges to assess their stability in relation to crystalline
theophylline anhydrate and the equivalent caffeine cocrystals. None of the
cocrystals was converted into a hydrated cocrystal upon storage at high
relative humidity.
Raghavan et al.(20) crystallized hydrocortisone acetate (HA) in presence of

hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), polyvinyl
pyrrolidone (PVP) and polyethylene glycol (PEG 400). Habit modification of
drug from polar prismatic morphology to a wing-shaped morphology was
observed when HPMC was used as the additive. The effect of PVP and PEG
400 on the morphology of HA was less pronounced compared to the cellulose
polymers. He found that the habit modification of HA by HPMC was due to
different extents of adsorption on different faces of the crystal.
Ford et al.(21-22) crystallized paracetamol in presence of polyvinyl pyrrolidone

(PVP). The higher molecular weights of PVP were more effective additives
than lower molecular weight PVP. Paracetamol particles obtained in the
presence of 0.5% w/v of PVP K10 or PVP K50 had near spherical structure
and consisted of numerous rod-shaped microcrystals which had
agglomerated together whereas particles obtained in the presence of PVP
2000 consisted of fewer microcrystals. By increasing the molecular weight

and/or the concentration of PVP in the crystallization medium, the amount of

PVP incorporated into the paracetamol particles increased.
It has been reported that PVP can interact with paracetamol in their
aqueous solution and that they can bind together via formation of hydrogen
bonding.(23, 27, 28) It has been also demonstrated that PVP is a strong crystal
growth inhibitor for paracetamol by adsorption on to the surfaces of
paracetamol crystals.(23, 26)
Uekama et al.(25) found that hydroxypropyl β-cyclodextrin was more
effective than PVP in inhibiting the crystal growth and enhancing the
dissolution of nifedipine. A combination of eudragit RS and cellulose acetate
phthalate showed to alter the habit and sustained the release of an iron
chelator besides improving the flowability.(24)
3.1.2 PELLETIZATION
Singh and Chaudhary,(29) developed the hollow floating microspheres of
ranitidine hydrochloride with prolonged stomach retention time using solvent
evaporation method. The polymer used was eudragit RLPO (dissolved in a
mixture of dichloromethane and ethanol). Hollow microspheres could prolong
drug release time (approximately 24 h) and float over stimulate gastric fluid for
more than 12 h.
Vaghani et al.(30) prepared 5-fluorouracil loaded microspheres of Eudragit

(RS 100, RL 100 and RSPO) and ethylcellulose using O/O solvent
evaporation technique using (methanol + acetone)/liquid paraffin system. The
prepared microspheres were characterized for their micromeritic properties. It
was concluded that various eudragit and ethyl cellulose are promising
controlled release carriers for 5-FU.
Gangadhar et al.(31) applied emulsion solvent technique with acetone-liquid

paraffin system to prepare microspheres of indomethacin. Egg albumin, ethyl
cellulose and eudragit L100 were used as polymers for sustained release.
The prepared microspheres were free flowing and spherical in shape. The

release of Indomethacin was influenced by the drug to polymer ratio and

particle size & was found to be both diffusion and dissolution controlled.
Patel et al.(32) prepared sustained release microspheres of quetiapine

fumarate using ethyl cellulose as the polymer and utilizing emulsion solvent
evaporation and extraction technique. DCM: acetonitrile (7:3) and aqueous
solution of PVA was the solvent system used. A 3 2 full factorial design was
applied to investigate the influence of drug: polymer ratio and average particle
size on release characteristics. The drug release from ethyl cellulose
microspheres was diffusion controlled. Excellent sphericity and smoothness of
microspheres were achieved using this technique.
Bhagwat et al.(33) applied non-aqueous emulsification solvent evaporation

method to prepare microspheres of Isosorbide dinitrate using acrycoat S 100
in different ratios with drug. An impact of different factors such as stirring rate,
concentration of acrycoat S 100 as matrix polymer on the characteristics of
the microspheres were investigated. The prepared microspheres were
spherical in shape with smooth surface with enhanced flow characteristics.
Nagda et al.(34) prepared bioadhesive microspheres of aceclofenac by double

emulsion solvent evaporation method (o/w/o type) employing polycarbophil as
bioadhesive polymer with the help of liquid paraffin as a dispersing medium.
The prepared microspheres were free flowing and spherical in shape. The
sustained release microspheres followed Higuchi model.
Nokhodchi and Maghsoodi,(35) prepared directly compressible agglomerates

of naproxen containing disintegrant by spherical crystallization technique.
Acetone–water containing hydroxypropyl cellulose (HPC) and croscarmellose
sodium (Ac–Di–Sol) was used as the crystallization system. The particles
showed good flow and packing properties. The improved compaction
properties of the agglomerated crystals were due to their fragmentation
occurred during compression. The dissolution rate of naproxen from tablets
made of naproxen–(Ac–Di -Sol) agglomerates was enhanced significantly.

Dashora et al.(36) prepared microparticals of nimesulide by modified solvent

evaporation method with acetone – liquid paraffin system using different
variables such as polymer: drug ratios, agitation speeds and stirring time. The
highest entrapment efficiency, size uniformity, free flowability, and
compressibility index of microparticals were found with 1:6 (polymer: drug
ratio). All formulations followed first order release kinetic and diffusion
controlled drug release (Higuchi model).
Muthusamy et al.(37) prepared sustained release system for lansoprazole to

increase its residence time in the stomach without contact with the mucosa
through the preparation of floating micropellets by emulsion solvent diffusion
technique using HPMC, MC and chitosan as a carrier. All floating micro pellet
formulations showed good flow properties (expect formulation contain HPMC
as coating material) and packability. Drug loaded micropellets were found to
float on simulated gastric fluid and simulated intestinal fluid for more than 12
h.
Kawashima et al.(38) prepared spherically agglomerated crystals of ascorbic

acid with improved compactibility for direct tableting using emulsion solvent
diffusion (ESD) technique. The micromeritic properties, such as flowability and
packability of the spherically agglomerated crystals were preferably improved
for direct tableting. Under static compression, the acceptable compact (tablet)
with a sufficient strength was produced successfully without capping, although
the capping occurred with the original unagglomerated crystals.
Kachrimanis et al.(39) studied the effects of eudragit (eudragit S100, L100,

RS, and RL) on the formation of spherical agglomeration of ibuprofen
microcrystals using solvent change (ethanol-water) technique. Crystal yield
was greatly reduced in the presence of water-insoluble polymers. Sphericity,
surface roughness and intra-particle porosity of agglomerates was increased
in the presence of polymer owing to changes in habit and growth rate of the
microcrystals into spherical agglomerates.

Gohel and Amin,(40) applied aqueous sodium alginate solution - liquid paraffin
system using CaCl2 as a cross linking agent to prepare sustained release
microspheres of diclofenac sodium. A 32 full factorial design was used to
investigate the joint influence of variables. The drug was released by diffusion
of anomalous type.
Kawashima et al.(41) used novel quasi-emulsion solvent diffusion method to

prepare the controlled-release microspheres of ibuprofen with acrylic
polymers using ethanol (good) and water (poor) as a solvent system. The
flowability, the packability, and the compressibility of the resultant
microspheres were much improved compared with the raw crystals of the
drug.
3.1.3 CRYSTALLO-CO-AGGLOMERATES (CCA)

Raval et al.(42) studied influence of various polymers/excipients on formation
of directly compressible crystallo-co-agglomerates (CCA) of poorly
compressible drug, secnidazole using acetone-petroleum ether system. Talc,
HPMC E50 LV, eudragit RS100, PVP K30, PEG 400 and lactose
monohydrate were used in the formation of CCA. The CCA showed excellent
flow, sphericity, packability, compatibility and crushing strength. Dissolution
profile of CCA was improved.
Dixit et al.(43) prepared spherical crystals of piroxicam using neutralization

method and found improved micromeritic properties, dissolution with decrease
in crystallinity in case of agglomerates.
Sarfaraz et al.(44) prepared agglomerates of aceclofenac with disintegrant with

improved solubility, flow and compression characteristics using a three
solvent system comprising of acetone: DCM: water. Acetone-water containing
PEG 6000, HPC, sodium starch glycolate (SSG), crospovidone (CP) and
croscarmellose sodium (CCS) in different concentrations. CCA showed good
flow and packing properties. The dissolution rate of aceclofenac from the

agglomerates could be controlled by the amount of included disintegrant,

being enhanced as the latter was increased.
Patil and Sahoo,(45) prepared spherical agglomerates of glibenclamide with

additives (PEG 6000, PVP, β cyclodextrin, eudragit RS100, low acyl gellan
gum and xanthan gum) using methanol, chloroform and water system.
Particle size, flowability, compactibility and packability of plane and
agglomerates with additives except with polyvinyl pyrrolidone were preferably
improved for direct tabletting compared with raw crystals of glibenclamide.
The improvement due to large, spherical shape and enhanced fragmentation
during compaction which was well due to increased tensile strength and less
elastic recovery of its compact. Significant improvement in solubility and
dissolution rate of agglomerates in presence of additives (except PVP) was
observed over the raw crystals of glibenclamide.
Maghsoodi and Barghi,(46) carried out crystallization of ibuprofen using the

quasi emulsion solvent diffusion method in presence of surfactant (SLS and
tween 80). Ibuprofen particles agglomerated in spherical shape with improved
micromeritic properties as well as tableting behavior than untreated drug
crystals. The agglomerates obtained in presence of SLS exhibited enhanced
dissolution rate while the agglomerates made in the presence of Tween 80
had no significant impact on dissolution rate of ibuprofen in comparison to
untreated sample.
Jadhav et al.(47) prepared agglomerates of bromhexine hydrochloride (BXH)

with adequate sphericity and strength required for efficient tableting in the
particles. They found the trend of strength reduction with a decrease in the
size of agglomerates, irrespective of drug loading which was directly
proportional to tensile strength of particles. Interparticulate bridges formed by
BXH and agglomerate size affected their mechanical, compressional and drug
release properties.
Bhattacharyya et al.(48) prepared CCA of nimesulide for direct compression.

The improvement of compressibility and other processing parameters were

obtained. The tablets were prepared by direct compression of nimesulide

agglomerates using PEG 6000 and EC in different ratios (50, 100 and 200
mg). The difference in drug release patterns for the various percentages of
PEG and EC.
Kumar et al.(49) prepared spherical crystals of mebendazole to improve

micromeritic properties. Mebendazole exhibits poor flow and compressibility
due to its needle shaped crystal habit and electrostatic charge. Spherical
agglomeration was carried out in the presence of different bridging liquids
(hexane, octanol, toluene, DCM) and polymers (PEG, cross-povidone, starch,
cross carmellose sodium, HPMC, HPC, EC, eudragit S100, eudragit, RLPO,
eudragit, RD100, eudragit E), by employing different crystallization conditions
such as variation of polymer type, polymer concentration, and rate of stirring.
The final parameters were optimized to obtain crystals with an aspect ratio in
the range of 1–2 compared to a value of 12 for untreated MBZ. Spherical
crystals exhibited good flow properties, high bulk density and improved
compressibility. Agglomerates prepared from eudragit S100 and HPC
indicated better compressibility of spherical crystals.
Chavda and Maheshwari,(50) developed crystallo-co-agglomerates (CCA) of

ketoprofen to obtain directly compressible spherical agglomerates with
improved flowability and compressibility. Dichloromethane-water system
containing PEG 6000, PVA and HPMC K100 M was used as the
crystallization system. Ketoprofen was crystallized from DCM and
agglomerated with talc. Remarkable improvement in micromeritic properties
and compactibility enabled direct compression without any defect.
Nokhodchi et al.(51) prepared spherical crystal of carbamazepine by the

quasi-emulsion mechanism using ethanol – water: ethyl acetate system. The
particles were evaluated in terms of flow properties, particle size analysis,
compression and dissolution behaviors. Spherical grains obtained were made
of small crystals of a drug with adequate properties for direct compression
and better dissolution rate characteristics to untreated crystals.

Jadhav et al.(52) prepared crystallo-co-agglomeration (CCA) to design directly

compressible and deformable agglomerates of talc containing the low-dose
drug bromhexine hydrochloride (BXH). Dichloromethane: water was used as a
solvent system using talc and tween 80. HPMC( 50 cps) 4% wt/wt was used
to impart the desired mechanical strength and PEG 6000 5% wt/wt was used
to impart the desired sphericity to the agglomerates. The yield and drug
entrapment were above 94% wt/wt. CCA were found with good crushing
strength, friability, compressibility and compactibility. Drug release was
sustained from prepared CCA.
Muatlik et al.(53) prepared aceclofenac agglomerates to improve solubility,

dissolution rate, micromeritic properties and bioavailability. Polymers like PVP
K30, PVP K90 and sodium alginate were used to prepare spherical
agglomerates of drug. The agglomerates prepared with PVP K90 exhibited
improved solubility, dissolution rate and micromeritic properties compared to
those prepared with other polymers and pure drug.
Gupta et al.(54) prepared celecoxib spherical agglomerates with PVP using

acetone, water and chloroform as solvent system. The crystals exhibited
significantly improved micromeritic properties loading and dissolution. The
solubility and in vitro drug release rates increased with an increase in PVP
concentration (from 2.5 to 10%).
Maghsoodi et al.(55) prepared agglomerated crystals of lactose for direct

tabletting by spherical crystallization technique. The agglomerates were
prepared by non-solvent technique using water and ethanol as solvent and
non-solvent respectively. The excellent flowability and packability revealed in
Kawakita and Kuno’s constants were attributed to the increase in particle size
and spherical shape resulted in successful direct tableting without capping.
Tayade and Vavia,(56) prepared agglomerates of Ibuprofen-carrageenan by

thermal gelation in liquid media. The in vitro release profile could be altered
significantly by changing various processing parameters to give a sustained
release of drug from the agglomerates.

Pawar et al.(57) formulated directly compressible agglomerates of ibuprofen

with talc by a novel CCA technique using DCM-water as the crystallization
system. The hydrophobicity of talk governed drug release rate up to 13 h with
zero order release kinetic.
Uusi-Penttila and Rasmuson,(58) studied agglomeration behavior of

paracetamol in acetone– toluene– water systems to experimentally determine
how the solvent composition influenced the agglomeration tendency of
paracetamol. Paracetamol crystals agglomerated in organic systems than in
aqueous systems.
Joshi et al.(59) employed granulation as well as spherical crystallization

techniques for preparing directly compressible granules of rifampicin and
Ibuprofen. Pre-gelatinized starch and 2% PVP in isopropyl alcohol (as binder)
were applied in granulation, whereas spherical agglomerates were prepared
by using water as a good solvent and hexane, toluene, benzene and
chloroform were used as bridging liquids. Various parameters like
concentration and mode of addition of bridging liquid, RPM, temperature were
observed. Directly compressible tablets satisfied all the quality control
parameters.
Umprayn et al.(60) prepared spherical agglomerates of ibuprofen using

chloroform: ethanol: water system by adding various concentrations of aerosil
and tween 80 in the binding solvent. They obtained small and round
agglomerates of IPs in which drug microcrystals were rearranged on the
surface. In presence of additives (mainly 1.2% tween 80), highest drug
release obtained. These pellets had a good flow property, compressibility,
flow rate, and angle of repose and they could be compressed into a tablet,
encapsulated by suitable polymer or pulverized to obtain micronized crystals.
Jbilou et al.(61) prepared agglomerates of Ibuprofen by phase separation

method using ethanol and water. Spherical agglomerates showed
improvement in compression and dissolution properties.

Ribardiere et al.(62) prepared ketoprofen agglomerates by the spherical

crystallization technique with two-solvent system (acetone / demineralized
water) using ethyl cellulose, cross-linked PVP and cross-linked CMC, all at a
concentration of 1%. However, no spherical beads could be obtained with the
water-soluble compounds tested (PVP and eudragit L100-55), eudragit RSI00
and colloidal silica. An optimization of the formulation with ethyl cellulose
yielded a controlled release form with 1% of the polymer, whereas the
addition of very low concentrations increased the drug release.
Akbuga,(63) prepared furosemide microspheres by employing spherical

crystallization technique using eudragit L100, eudragit S100, eudragit RL100
and eudragit RS100. The spherical microspheres were obtained with the
average diameters about 250-280 µm and the drug contents in the
microspheres were 75-80%. Type of eudragit affected the release pattern of
drug from particles where eudragit RS100 gave most retarding effect.
Staniforth et al.(64) Optimized tableting behavior of excipients using

alternative crystallization conditions in order to design a directly compressible
mannitol and obtained a highly porous surfaced mannitol by using a special
crystallization medium.
3.1.4 CO-GRINDING AND AMORPHIZATION

Varshosaz et al.(65) improved the dissolution rate of simvastatin using
spherical crystallization method. They found minor reduction in peak intensity
and two fold increments in the dissolution profile and enhanced solubility of
drug.
Elkhodairy et al.(66) improved solubilization by amorphization of etodolac

(ETD) with chitosan (CHT). Binary systems of varying drug polymer ratios
were prepared using different techniques namely physical mixing, cogrinding
and kneading. The results showed loss of drug crystallinity with improved drug
dissolution in the following order kneading> co-grinding> physical mixing >
pure drug.

Patil et al.(67) formulated solid dispersion (SD) of Metformin HCl using HPMC
K100M as the carrier by solvent evaporation and co-grinding method. The
influence of drug polymer ratio on drug release was studied by dissolution
tests. Release data were examined kinetically. Solid dispersion with 1:4 and
1:5 ratio of Metformin HCl: HPMC obtained by solvent evaporation and co-
grinding, respectively were selected as the best candidates suitable for
prolonged-release oral dosage form of Metformin HCl.
Chandrashekar et al.(68) developed four different polymorphs (Form I, Form

II, Form III and Form IV) of Chlorzoxazone in different solvents. The prepared
polymorphs were characterized by using Optical Microscopy, DSC, XRD and
IR spectroscopic methods. The study proved that the Form I, Form II shown
higher solubility than Form III, Form IV and pure Chlorzoxazone.
Balani et al.(69) prepared amorphous salbutamol sulphate using excipients

like -lactose monohydrate (LAC), adipic acid (AA), magnesium stearate
(MgSt), or polyvinyl pyrrolidone (PVP). Co-milling with crystalline excipients,
LAC, AA, and MgSt proved effective in reducing the amorphization of SS.
During co-milling, both SS and LAC turned predominantly amorphous after 45
min but transformed back to a highly crystalline state after 60 min. Co-milled
and physical mixtures of SS and all the carriers were stored under normal and
elevated humidity conditions. Subsequent changes in crystallinity and
morphology of co-milled SS: LAC was very low as compared to significant
changes in milled SS and physical mixture.
Lin et al.(70) studied effect of β-CD and HP-β-CD on amorphization of

loratadine (LOR) in 1:1 molar ratio using ball mill. The formation of inclusion
complex for LOR/β-CD or LOR/HP-β-CD was significantly correlated with the
reduction in LOR crystallinity. The apparent zero-order kinetics for the
reduction in crystallinity of LOR in the presence of β-CD or HP-β-CD was
obtained by increasing the grinding time.

Wang et al.(71) improved solubility and dissolution of ibuprofen using

cogrinding with β-cyclodextrin (β-CD). The results revealed a progressive drug
amorphization during grinding, and X-ray diffraction peak intensities of the co-
ground complex was decreased by grinding. The product transformed into a
non-crystalline solid 30 min after co-grinding. The solubility of co-ground
complex was more than ten times higher than that of intact drug. The
amorphous state of the co-ground complex was the main responsible factor
for the enhanced dissolution efficiency of drug.
Jie and Rohani,(72) prepared cocrystals of sulfamethazine (STH) using

theophylline (TP) as cocrystal formers. Neat cogrinding, solvent-drop
cogrinding and slow evaporation were applied to synthesize the
sulfamethazine–theophylline co-crystal (here after STH–TP co-crystal) which
improved the solubility compared to pure form.
Gao,(73) improved dissolution kinetic by preparing cocrystal of novel adefovir

dipivoxil–saccharin using a novel solution crystallization approach. The
cocrystal had a pH-independent dissolution profile and showed a two-fold
increase in the dissolution efficiency in water and phosphate buffer (pH 6.8)
compared with adefovir dipivoxil. The cocrystals were very much stable at
higher temperature.
Farahani et al.(74) improved dissolution by cogrinding of glicazide with carriers

such as PVP K30, crospovidone and avicel pH-101. The fastest dissolution
rates were observed from co-ground formulations with the drug to carrier ratio
of 1:5. Reduction in crystallinity as well as particle size was observed through
various characterizations.
Vadher et al.(75) prepared and characterized aceclofenac co-ground with

neusilin US2 for its dissolution enhancement by amorphization. Co-grinding of
aceclofenac with neusilin US2 in a ratio of 1:5 was carried out by ball milling
for 20 h. In vitro dissolution rate of aceclofenac from co-ground mixture was
significantly higher compared to pure aceclofenac. The accelerated stability

study of co-ground mixture was carried out at 40 °C / 75% RH for 4 weeks,

which showed no reversion from amorphous to crystalline form.
Garg and Singh,(76) studied effects of different classes of hydrophilic carriers

(PVPs, Plasdone K25 and S-630, cellulosic polymers like HPMC and HPC
and sodium alginate) on the solid state and dissolution rate of Raloxifene
hydrochloride (R-HCl). Only co-grinding with PVPs was more effective in the
reduction of particle size than the milling of drug alone. Significant
enhancement in dissolution rate and extent was observed with co-ground
mixtures of drug and PVPs.
Corti et al.(77) prepared equimolar Metformin HCl (MH): triacetyl – β-

cyclodextrin (TCD) solid compounds by different techniques, i.e., physical
mixing, kneading, co-grinding, sealed-heating and spray-drying in order to
investigate the physical–chemical properties of the final products. Thus, the
MH–TCD products obtained by spray drying and co-grinding were selected as
the best candidates for the future development of a suitable prolonged-
release oral dosage form of Metformin HCl.
Dressman et al.(78) amorphized four drugs (EMD 57033, albendazole,

danazol and felodipine) by ball milling with various excipients like lactose
monohydrate, corn starch, PVP, HPMC and SLS. Solid state characterization
was verified for the maintenance of crystalline state of the active substances
after milling. In vitro dissolution of the co-ground mixtures was much faster
than corresponding physical mixtures for all four compounds, especially EMD
57033. Co-grinding with lactose monohydrate resulted in faster dissolution
with unstable supersaturation for EMD 57033. Co-grinding the same drug with
PVP or HPMC produced a more sustained supersaturation. SLS accelerated
the dissolution of EMD 50733 but inhibited supersaturation.
Jalali et al.(79) prepared carbamazepine solid dispersions by cogrinding

technique using an insoluble but highly hydrophilic crospovidone and soluble
HPMC as the carriers. The decreased crystallinity together with a reduced

particle size enhanced deaggregation, dissolution and increased wettability of

the drug.
Wen et al.(80) studied effect of PVP on etching pattern of the acetaminophen

(010) face, solubility enhancement (in concentration higher than 1 mg/ml) as
well as improved intrinsic dissolution rate (IDR) of acetaminophen crystals.
Dissolution on the (010) face had been affected by the adsorbed PVP through
vander waals interactions rather than hydrogen bonding interactions.
Mallick S,(81) prepared physically stable amorphous phase of ibuprofen by

solid state milling with kaolin. Ibuprofen was milled with kaolin in different
ratios. Characterization of ground mixture revealed complete amorphization
on ball milling with kaolin at 1:2 ratios as well as reduction of C=O peak of
carboxylic acid and formation of carboxylate peaks which indicated an
interaction of ibuprofen and kaolin on milling. After 10 weeks of storage at 40
°C and 75% RH no changes were seen in FT-IR, XRD and SEM which
indicated absence of re-crystallization.
Bogner et al.(82) amorphized four drugs (ketoprofen, indomethacin, naproxen,

and progesterone) by milling with neusilin US2 by ball milling. Ball milling the
drugs alone for 48 h resulted in no amorphization. Characterization tools
showed that all the four drugs on ball milling with neusilin were physically
stable during storage after amorphization.
Nair et al.(83) studied the influence of polyethylene glycol and povidone on the
crystalline modification and subsequently the solubility of carbamazepine in
solid dispersion. Carbamazepine was present in an amorphous form within
the povidone dispersions. In contrast, they found PEG dispersions where the
drug was present in crystalline state. Both the polymeric dispersions showed
an improved dissolution profile for carbamazepine.
Watanabe et al.(84) stabilized amorphous indomethacin (IM) by co-grinding in

a ternary mixture. Amorphization of indomethacin was substantially enhanced
by grinding with SiO2, talc and Mg(OH)2–SiO2 mixture. The rates of

amorphization were in order of Mg(OH)2–SiO2 mixture > talc > SiO2.

Amorphous state stability of IM with the carrier was examined under the
condition of 30 °C and 11% RH. The binary mixture as a carrier was superior
due to mechanically induced strong acidic sites of the carrier.
Mura et al.(85) ground glisentide in presence of PVP for dissolution

improvement by amorphization. Significant increases in dissolution properties
was obtained by co-grinding with PVP, which also reduced time and
frequency of grinding necessary for obtaining complete drug amorphization.
Gohel and Patel,(86) used co-grinding to improve the dissolution

characteristics of nimesulide. A 32 factorial design was adopted using the
concentration of tween 80 and SLS as independent variables. Improved drug
dissolution was obtained when the drug was mixed first with aqueous
surfactant solution and later blended with adjuvant such as lactose and
microcrystalline cellulose. SLS was more effective in increasing the drug
dissolution compared with tween 80. The improved drug dissolution might be
attributed to improved wetting and micellization due to presence of surfactants
or hydrophilic adjuvant.
Liao and Mamoru,(87) enhanced in mechano-chemical dehydration and

amorphization of Ca(OH)2, Mg(OH)2 and Al(OH)3 (gibbsite) by grinding with
SiO2. The rates of those mechano-chemical reactions were in the order of
Al(OH)3 > Ca(OH)2 > Mg(OH)2. They found decomposition of hydroxide and
the incipient formation of metal silicates were stimulated by each other. The
further investigation for gibbsite was also done in the same manner.
Otsuka and Kaneniwa,(88) investigated the effect of grinding on the

crystallinity and hygroscopicity of cephalothin sodium. The X-ray diffraction
peaks of all samples decreased after grinding, but the diffraction profiles had
no halo pattern. However, the crystallinity increased to 50% after grinding for
3-10 h. The chemical stability and Hygroscopicity of drug in the solid state
were closely related to the crystallinity.

3.1.5 RESPONSE SURFACE METHODOLOGY

Raval et al.(89) prepared sustained release microspheres of nimesulide by
emulsion solvent evaporation method using eudragit RS100 and RL100 as
polymer combination. A 32 full factorial experiment was designed to study the
effect of polymer combination on the percent cumulative drug release in first
hour, time to achieve 60% drug release and time to achieve 90% drug
release.
Raval et al.(90) formulated matrix type transdermal patch of ondansetron

hydrochloride using solvent evaporation technique. HPMC E50LV and
eudragit RS100 were used as polymers using glycerin as plasticizer to obtain
controlled release of drug. Various physicochemical parameters were studied
and desirability function was applied to all the batches. The batch with
maximum overall desirability value was selected as optimized batch.
Kotadiya et al.(91) formulated and evaluated microspheres of terbutaline

sulphate by water-in oil-in-water (w/o/w) double emulsion solvent diffusion
method using ethyl cellulose. A 32 full factorial design was applied to
investigate the joint influence of two variables: the drug content and polymer
content on the encapsulation efficiency, time for 50% drug dissolution and
time for 70% drug dissolution.
Martinello et al.(92) applied experimental design methodology (DOE) for the

development and optimization of tablet formulations containing high amounts
of paracetamol (more than 70%) and manufactured by direct compression
using different proportions of Methocel (HPMC), Kollidon VA 64 (PVP+PEG),
Flowlac (lactose), Kollidon CL 30, PEG 4000, Aerosil (Colloidal Silicon
dioxide) and magnesium stearate. Optimization plots were constructed,
mainly for friability. The physical-chemical data found from the optimized
formulation were very close to those from the regression analysis,
demonstrating that the mixture project is a great tool for the research and
development of new formulations.

Mashru et al.(93) optimized fast dissolving film of salbutamol sulphate. The

film was prepared using a solvent evaporation technique using independent
variables like polyvinyl alcohol as a polymer, glycerol as a plasticizer and
mannitol as filler. A 33 full factorial design was utilized to optimize the effect of
independent variables on the mechanical properties, and % drug release of
film. Furthermore, the desirability function was employed in order to determine
the best batch out of all 27 batches of the factorial design.
Paradkar et al.(94) prepared spherical crystals of celecoxib using acetone:

dichloromethane (DCM): water system with the help of 3 2 full factorial design.
The effect of amount of bridging liquid and speed of agitation was studied.
The effect of variables on micromeritic, mechanical, compressional and
dissolution behavior was evaluated by response surface methodology.

3.2 BIBLIOGRAPHY
1. Masuda T, Yoshihashi Y, Yonemochi E, Fujii K, Uekusa H, Terada K.
(2012). Cocrystallization and amorphization induced by drug-excipient
interaction improves the physical properties of Acyclovir. Int J Pharm,
422, 160-169.
2. Grossjohann C, Eccles KS, Maguire AR, Lawrence SE, Tajber L, Corrigan
OI, Healy AM. (2012). Characterization, solubility and intrinsic dissolution
behavior of Benzamide: dibenzyl sulfoxide cocrystal. Int J Pharm, 422,
24-32.
3. Barot BS, Parejiya PB, Patel TM, Parikh RK, Gohel MC. (2011).
Compactibility improvement of Metformin hydrochloride by crystallization
technique. Adv Powder Technol, Electronic version.
doi:10.1016/j.apt.2011.11.002
4. Tsutsumi S, Iida M, Tada N, Kojima T, Ikeda Y, Moriwaki T, Higashi K,
Moribe K, Yamamoto K. (2011). Characterization and evaluation of
miconazole salts and cocrystals for improved physicochemical properties.
Int J Pharm, 421, 230-236.
5. Aakeroy CB, Grommet AB, Desper J. (2011). Co-Crystal Screening of
Diclofenac. Pharmaceutics, 3, 601-614.
6. Rehder S, Klukkert M, Löbmann KM, Strachan CJ, Sakmann A, Gordon
K, Rades T, Leopold CS. (2011). Investigation of the formation process
of two piracetam cocrystals during grinding. Pharmaceutics, 3, 706-722.
7. Cheney ML, Weyna DR, Shan N, Hanna M, Wojtas L, Zaworotko MJ.
(2011). Coformer selection in pharmaceutical cocrystal development: A
case study of a Meloxicam Aspirin cocrystal that exhibits enhanced
solubility and pharmacokinetics. J Pharm Sci, 100, 2172-2181.
8. Barot BS, Parejiya PB, Patel TM, Parikh RK, Gohel MC. (2010).
Development of directly compressible Metformin hydrochloride by the
spray-drying technique. Acta Pharm, 60,165–175.
9. Luis P, Miguel AR, Velaga SP, Fernandez AC, Matos HA, Azevedo HG.
(2010). Screening for pharmaceutical cocrystals using the supercritical
fluid enhanced atomization process. J Supercrit Fluids, 53, 156–164.

10. Oktabec Z, Kos J, Mandelova Z, Havelkova L, Pekarek T, Rezacova A,

Placek L, Tkadlecova M, Havlicek J, Dohnal J, Jampílek J. (2010).
Preparation and properties of new co-crystals of Ibandronate with gluco-
or galactopyranoside derivatives. Molecules, 15, 8973-8987.
11. Jung MS, Kim JS, Kim MS, Alhalaweh A, Cho W, Hwang SJ, Velaga SP.
(2010). Bioavailability of Indomethacin – saccharine cocrystals. J Pharm
Pharmacol, 62, 1560-1568.
12. Padrela L, Rodrigues MA, Velaga SP, Matos HA, De Azevedo EG.
(2009). Formation of Indomethacin-saccharin cocrystals using
supercritical fluid technology. Eur J Pharm Sci, 12, 38, 9-17.
13. Gagniere E, Mangin D, Puel F, Bebon C, Klein JP, Olivier Garcia ME.
(2009). Cocrystal formation in solution: In situ solute concentration
monitoring of the two components and kinetic pathways. Cryst Growth
Des, 9, 3376–3383.
14. Kumar S, Chawla G, Bansal AK. (2008). Spherical crystallization of
Mebendazole to Improve processability. Pharm Dev Technol, 13, 559–
568.
15. Maghsoodi M, Taghizadeh O, Martin GP, Nokhodchi A. (2008). Particle
design of Naproxen-disintegrant agglomerates for direct compression by
a crystallo-co-agglomeration technique. Int J Pharm, 351, 45–54.
16. Basavoju S, Boström D, Velaga SP. (2008). Indomethacin-saccharin
cocrystal: design, synthesis and preliminary pharmaceutical
characterization. Pharm Res, 25, 530-541.
17. Childs SL, Hardcastle KI. (2007). Cocrystals of Chlorzoxazone with
carboxylic acids. Cryst Eng Commun, 9, 364-367.
18. Nokhodchi A, Maghsoodi M, Hassanzadeh D. (2007). An improvement of
physicomechanical properties of Carbamazepine crystals. Iranian J
Pharm Res, 6, 83-93.
19. Trask AV, Motherwell WDS, Jones W. (2004). Solvent-drop grinding:
green polymorph control of cocrystallization. Chem Commun, 7, 890-891.
20. Raghavan SL, Trividic A, Davis AF, Hadgraft J. (2001). Crystallization of
Hydrocortisone acetate: influence of polymers. Int J Pharm, 212, 213–
221.

21. Ford JL, Garekani HA, Rubinstein MH, Rajabi-siahboomi AR. (2000).
Highly compressible Paracetamol-I: crystallization and characterization.
Int J Pharm, 208, 87-99.
22. Ford JL, Garekani HA, Rubinstein MH, Rajabi-siahboomi AR. (2000).
Highly compressible Paracetamol-II: crystallization and characterization.
Int J Pharm, 208, 101-110.
23. Garekani HA. (1996). Characterization and compaction properties of
manipulated Paracetamol crystals. [PhD Thesis], School of Pharmacy,
Liverpool John Moores University, UK, 158–187.
24. Venkataram S, Khohlokwane M. (1996). Microencapsulation of an iron
chelator for sustained release and crystal habit modification. J
Microencapsule, 13, 519-525.
25. Uekama K, Ikegami K, Wang Z, Horiuchi Y, Hirayama F. (1992). Inhibitory
effect of 2-hydroxypropyl-β-cyclodextrin on crystal-growth of Nifedipine
during storage: superior dissolution and oral bioavailability compared with
polyvinylpyrrolidone k-30. J Pharm Pharmacol, 44, 73–78.
26. Ziller KH, Rupprecht H. (1988). Control of crystal growth in drug
suspension: (1) design of a control unit and application to acetaminophen
suspensions. Drug Dev Ind Pharm, 14, 2314–2370.
27. Horn D, Ditter W. (1982). Chromatographic study of interactions between
polyvinylpyrrolidone and drugs. J Pharm Sci, 71, 1021–1026.
28. Sekikawa H, Ito K, Arita T, Hori R, Nakano M. (1979). Effect of
macromolecular additives and urea on the intestinal absorption of
acetaminophen in rats. Chem Pharm Bull, 27, 1106–1111.
29. Singh V, Chaudhary A. (2011). Preparation of eudragit E100
microspheres by modified solvent evaporation method. Acta Poloniae
Pharmaceutica - Drug Research, 68, 975-980.
30. Vaghani SS, Jivani NP, Vasanti S, Satish CS, Patel MM. (2010).
Preparation and characterization of 5-FU loaded microspheres of eudragit
and ethylcellulose. Acta Pharma Sci, 52, 391-399.
31. Gangadhar CB, Sunder SR, Varma VM, Sleeva RM, Sai KM. (2010).
Formulation and evaluation of Indomethacin microspheres using natural
and synthetic polymers as controlled release dosage forms. Int J Drug
Disc, 2, 8-16.

32. Patel J, Dhingani A, Dabhi M, Patel N, Raval M, Sheth N. (2010). Design

and development of sustained release microspheres of Quetiapine
Fumarate using 32 full factorial design. J Pharm Res, 3, 2871-2875.
33. Bhagwat DA, Bhutkar MA, Todkar SS, Gattani YS. (2009). Formulation
and evaluation of controlled release microspheres of Isosorbide dinitrate.
Int J PharmTech Res, 1, 125-128.
34. Nagda C, Chotai N, Patel S, Patel U, Ahir K, Nagda D. (2009). Design
and characterization of bioadhesive microspheres prepared by double
emulsion solvent evaporation method. Acta Pharma Sci, 51, 261- 270.
35. Nokhodchi A, Maghsoodi M. (2008). Preparation of spherical crystal
agglomerates of Naproxen containing disintegrant for direct tablet making
by spherical crystallization technique. AAPS PharmSciTech, 9, 54-59.
36. Dashora K, Saraf S, Saraf SL. (2007). Effect of processing variables and
in-vitro study of micro particulate system of Nimesulide. Brazilian J Pharm
Sci, 43, 555-562.
37. Muthusamy K, Govindarazan G, Ravi TK. (2005). Preparation and
evaluation of Lansoprazole floating micropellets. Ind J Pharm Sci, 67, 75–
79.
38. Kawashima Y, Imai M, Takeuchi H, Yamamoto H, Kamiya K, Hino T.
(2003). Improved flowability and compactibility of spherically
agglomerated crystals of Ascorbic acid for direct tableting designed by
spherical crystallization process. Powder Technol, 130, 283-289.
39. Kachrimanis K, Nikolakakis L, Malamataris S. (2000) Spherical crystal
agglomeration of Ibuprofen by the solvent-change technique in presence
of methacrylic polymers. J Pharm Sci, 89, 250-259.
40. Gohel MC, Amin AF. (1998). Formulation optimization of controlled
release Diclofenac sodium microspheres using factorial design. J
Controlled Release, 51, 115–122.
41. Kawashima Y, Niwa T, Handa T, Takeuchi H, Iwamoto T, Itoh K. (1989).
Preparation of controlled-release microspheres of Ibuprofen with acrylic
polymers by a novel quasi-emulsion solvent diffusion method. J Pharm
Sci, 78, 68–72.
42. Raval MK, Sorathiya KR, Chauhan NP, Patel JM, Parikh RK, Sheth NR.
(2012). Influence of polymers/excipients on development of agglomerated

crystals of Secnidazole by crystallo-co-agglomeration technique to

improve processability. Drug Dev Ind Pharm, Electronic version, 2nd
March, doi: 10.3109/03639045.2012.662508.
43. Dixit M, Kulkarni PK, Selvam RP, Kini AG, Shivakumar HG. (2011).
Preparation and characterization of spherical agglomerates of Piroxicam
by neutralization method. Am J Drug Disc Dev, 1, 188-199.
44. Sarfaraz M, Khan AK, Doddayya H, Reddy SR, Udupi RH. (2011).
Particle design of Aceclofenac-disintegrant agglomerates for direct
compression by crystallo-co-agglomeration technique. Asian J Pharm
Technol, 1, 40-48.
45. Patil SV, Sahoo SK. (2011). Improvement in compressibility, flowability
and drug release of Glibenclamide by spherical crystallization with
additives. Dig J Nanomater Bios, 6, 1463-1477.
46. Maghsoodi M, Barghi L. (2011). Design of agglomerated crystals of
Ibuprofen during crystallization: influence of surfactant. Iranian J Basic
Med Sci, 14, 57-66.
47. Jadhav N, Pawar A, Paradkar A. (2010). Effect of drug content and
agglomerate size on tabletability and drug release characteristics of
Bromhexine hydrochloride talc agglomerates prepared by crystallo-co-
agglomeration. Acta Pharm, 60, 25-38.
48. Bhattacharyya SP, Bhattacharyya I, Patro N. (2010). Standardization and
optimization of micromeritic properties of nimesulide for processing into a
tablet dosage form by crystallo-co-agglomeration technology. Asian J
Pharm, 4, 24-27.
49. Kumar S, Chawla G, Bansal AK. (2008). Role of additives like polymers
and surfactants in the crystallization of Mebendazole. Yakugaku Zasshi,
128, 281-289.
50. Chavda V, Maheshwari RK. (2008). Tailoring of Ketoprofen particle
morphology via novel crystallo-co-agglomeration technique to obtain a
directly compressible material. Asian J Pharm, 2, 61-67.
51. Nokhodchi A, Maghsoodi M, Hassanzadeh D, Barzegar-Jalali M. (2007).
Preparation of agglomerated crystals for improving flowability and
compactibility of poorly flowable and compactable drugs and excipients.
Powder Technol, 175, 73–81.

52. Jadhav NR, Pawar AP, Paradkar AR. (2007). Design and evaluation of
deformable talc agglomerates prepared by crystallo-co-agglomeration
technique for generating heterogeneous matrix. AAPS PharmSciTech, 8,
E61-E67.
53. Muatlik S, Usha AN, Reddy MS, Ranjith AK, Pandey S. (2007). Improved
bioavailability of Aceclofenac from spherical agglomerates: development,
in vitro and preclinical studies. Pak J Pharm Sci, 20, 218-226.
54. Gupta VR, Mutalik S, Patel MM, Jani GK. (2007). Spherical crystals of
Celecoxib to improve solubility, dissolution rate and micromeritic
properties. Acta Pharm, 57, 173–184.
55. Maghsoodi M, Nokhodchi A, Barzegar-Jalali M, Poramjad B. (2006).
Preparation of agglomerated crystals of lactose for direct tabletting by the
spherical crystallization technique. J Pharm Sci, winter, 1-8.
56. Tayade PT, Vavia PR. (2005). Sustained release agglomerates of
Ibuprofen using natural polymer and thermal gelation technique. Ind J
Pharm Sci, 67, 697-702.
57. Pawar AP, Paradkar AR, Kadam SS, Mahadik KR. (2004). Agglomeration
of ibuprofen with talc by novel crystallo-co-agglomeration technique.
AAPS PharmSciTech, 55, 1-6.
58. Uusi-Penttilä MS, Rasmuson AC. (2003). Experimental study for
agglomeration behavior of Paracetamol in acetone–toluene–water
systems. Chemical Eng Res Des, 81, 489–495.
59. Joshi A, Shah SP, Misra AP. (2003). Preparation and evaluation of
directly compressible forms of Rifampicin and Ibuprofen. Ind J Pharm Sci,
65, 232-238.
60. Umprayn K, Luengtummuen A, Kitiyadisai C, Pornpiputsakul T. (2001).
Modification of crystal habit of Ibuprofen using the phase partition
technique: effect of aerosil and tween 80 in binding solvent. Drug Dev Ind
Pharm, 27, 1047–1056.
61. Jbilou M, Ettabia A, Guyot-Hermann A, Guyot JC. (1999). Ibuprofen
agglomerates preparation by phase separation. Drug Dev Ind Pharm, 25,
297–305.

62. Ribardière A, Tchoreloff P, Couarraze G, Puisieux F. (1996). Modification

of ketoprofen bead structure produced by the spherical crystallization
technique with a two-solvent system. Int J Pharm, 144, 195-207.
63. Akbuga J. (1991). Furosemide-loaded ethyl cellulose microspheres
prepared by spherical crystallization technique: morphology and release
characterization. Int J Pharm, 76, 193-198.
64. Staniforth JN, Rees JE, Kayes JB, Priest RC, Cotterill NJ. (1981). The
design of a direct compression tablet excipient. Drug Dev Ind Pharm, 7,
179–190.
65. Varshosaz J, Tavakoli N, Salamat FA. (2011). Enhanced dissolution rate
of Simvastatin using spherical crystallization technique. Pharm Dev
Technol, 16, 529-535.
66. Elkhodairy A, Barakat S, Alanazi K. (2011). Solubilization and
amorphization of non steroidal anti-inflammatory drug with low molecular
weight chitosan for a new guar-based colon delivery formulation. Letters
in Drug Design and Discovery, 8, 292-301.
67. Patil SA, Kuchekar BS, Chabukswar AR, Jagdale SC. (2010). Formulation
and evaluation of extended-release solid dispersion of Metformin
hydrochloride. J Young Pharm, 2, 121–129.
68. Chandrashekar T, Padma B, Srinivas K, Kumar KP. (2010). Preparation
and characterization of polymorphs of Chlorzoxazone. Int J Biopharm, 1,
20-25.
69. Balani PN, Wai NG, Tan BH, Chan SY. (2010). Influence of excipients in
co-milling on mitigating milling-induced amorphization or structural
disorder of crystalline pharmaceutical actives. J Pharm Sci, 99, 2462-
2474.
70. Lin SY, Cheng H, Ming TS. (2010). Curve-fitting FTIR studies of
loratadine/hydroxypropyl-β-cyclodextrin inclusion complex induced by co-
grinding process. J Pharm Biomed Anal, 53, 799–803.
71. Wang Q, Li S, Che X, Fan X, Li C. (2010). Dissolution improvement and
stabilization of ibuprofen by co-grinding in a β-cyclodextrin ground
complex. Asian J Pharm Sci, 5, 188-193.
72. Jie Lu, Rohani S. (2010). Synthesis and preliminary characterization of
Sulfamethazine-theophylline co-crystal. J Pharm Sci, 99, 4042 – 4047.

73. Gao Y. (2010). Pharmaceutical cocrystals. Chem Prog, 22, 829–836.

74. Farahani A, Valizadeh H, Mohammadi G. (2010). Co-grinding as an
approach to enhance dissolution rate of a poorly water-soluble drug
(Gliclazide). Powder Technol, 197, 150-158.
75. Vadher AM, Parikh JR, Parikh RH, Solanki AB. (2009). Preparation and
characterization of co-grinded mixtures of aceclofenac and neusilin US2
for dissolution enhancement of aceclofenac. AAPS PharmSciTech, 10,
606-614.
76. Garg A, Singh S. (2009). Solid state interaction of raloxifane HCl with
different hydrophilic carriers during co-grinding and its effect on
dissolution rate. Drug Dev Ind Pharm, 35, 455–470.
77. Corti G, Cirri M, Maestrelli F, Mennini N, Mura P. (2008). Sustained
release matrix tablets of Metformin hydrochloride in combination with
triacetyl-beta-cyclodextrin. Eur J Pharm Biopharm, 68, 303-309.
78. Dressman JB, Kunath K, Vogt M. (2008). Dissolution improvement of four
poorly soluble water soluble drugs by cogrinding with commonly used
excipients. Eur J Pharm Biopharm, 68, 330-337.
79. Jalali M, Valizadeh H, Dastmalchi S, Reza M, Jalali AB, Adibkia K,
Mohammadi G. (2007). Enhancing dissolution rate of carbamazepine via
cogrinding with crospovidone and hydroxypropyl methylcellulose. Iranian
J Pharm Res, 6, 159-165.
80. Wen H, Morris KR, Park K. (2005). Study on the interactions between
polyvinylpyrrolidone and acetaminophen crystals: partial dissolution
pattern change. J Pharm Sci, 94, 2166-2174.
81. Mallick S. (2004). Effect of solvent and polymer additives on
crystallization. Indian J Pharm Sci, 66, 142-147.
82. Bogner RH, Vanwert A, Gupta MK. (2003). Formation of physically stable
amorphous drugs by milling with neusilin. J Pharm Sci, 92, 536-551.
83. Nair R, Gonen S, Hoag SW. (2002). Influence of polyethylene glycol and
povidone on the polymorphic transformation and solubility of
carbamazepine. Int J Pharm, 240, 11–22.
84. Watanabe T, Ohno I, Wakiyama N, Kusai A, Senna M. (2002).
Stabilization of amorphous Indomethacin by co-grinding in a ternary
mixture. Int J Pharm, 241, 103-111.

85. Mura P, Cirri M, Faucci MT, Ginès-Dorado JM, Bettinetti GP. (2002).
Investigation of effect of grinding and cogrinding on physicochemical
properties of glisentide. J Pharm Biomed Anal, 30, 227-237.
86. Gohel MC, Patel LD. (2000). Improvement of Nimesulide dissolution by a
co-grinding method using surfactants. Pharm Pharmacol Commun, 6,
433–440.
87. Liao J, Mamoru S. (1993). Mechano-chemical dehydration and
amorphization of hydroxides of Ca, Mg and Al on grinding with and
without SiO2. Solid State Ionics, 66, 313-319.
88. Otsuka M, Kaneniwa N. (1990). Effect of grinding on the crystallinity and
chemical stability in the solid state of cephalothin sodium. Int J Pharm, 62,
66-73.
89. Raval MK, Bagda AA, Patel JM, Paun JS, Chaudhari KR, Sheth NR.
(2010). Preparation and evaluation of sustained release nimesulide
microspheres using response surface methodology. J Pharm Res, 3 581-
586.
90. Raval MK, Chaudrari K, Shah B, Patel JD, Sheth NR, Parikh RK. (2010).
Formulation and evaluation of matrix type transdermal drug delivery
system containing ondansetron hydrochloride. Inventi Rapid:
NDDS, Article ID- " Inventi:ndds/69/10 ".
91. Kotadiya R, Patel V, Patel H, Salaniya B. (2009). Evaluation of terbutaline
sulphate encapsulated ethyl cellulose microspheres: a factorial approach.
Int J PharmTech Res, 1, 1271-1278.
92. Martinello T, Kaneko TM, Velasco R, Santos E, Taqueda, Consiglieri VO.
(2006). Optimization of poorly compactable drug tablets manufactured by
direct compression using the mixture experimental design. Int J Pharm,
322, 87–95.
93. Mashru RC, Sutariya VB, Sankalia MG, Parikh PP. (2005). Development
and evaluation of fast-dissolving film of salbutamol sulphate. Drug Dev
Ind Pharm, 31, 25–34.
94. Paradkar AR, Pawar AP, Chordiya JK, Patil VB, Ketkar AR. (2002).
Spherical crystallization of celecoxib. Drug Dev Ind Pharm, 28, 1213-
1220.

13 - Chapter 3

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

13 - Chapter 3

Uploaded by

Copyright:

Available Formats

Review

3.1 METHODS USED FOR PROPERTY 55

3.1.3 Crystallo-co-agglomeration (CCA) 63

3.1.4 Co-grinding and amorphization 68

3.1.5 Response surface methodology 74

Department of Pharmaceutical Sciences, Saurashtra University, Rajkot 54

3.1 METHODS USED FOR PROPERTY IMPROVEMENT

Grossjohann et al.(2) prepared cocrystal of dibenzyl sulfoxide (DBSO) and

Barot et al.(3) prepared directly compressible form of Metformin HCl using

Tsutsumi et al.(4) studied salts and cocrystals of miconazole with maleate,

Department of Pharmaceutical Sciences, Saurashtra University, Rajkot 55

Aakeröy et al.(5) screened a range of pyrazoles, pyridines, and pyrimidines

Cheney et al.(7) prepared cocrystals of meloxicam with aspirin as coformer to

Barot et al.(8) developed directly compressible Metformin HCl by the spray-

Department of Pharmaceutical Sciences, Saurashtra University, Rajkot 56

technique. The resulting free flowing powder of Metformin HCl crystals

Luis et al.(9) employed supercritical fluid with enhanced atomization (SEA)

Oktabec et al.(10) prepared cocrystals of ibandronate monosodium salt with

Jung et al.(11) evaluated the in-vitro dissolution and in-vivo bioavailability of

Padrela et al.(12) prepared cocrystal of indomethacin using saccharin as a

Department of Pharmaceutical Sciences, Saurashtra University, Rajkot 57

cocrystals with different morphologies and sizes (nano-to-micron) were

Gagniere et al.(13) prepared co-crystals of carbamazepine (CBZ). The stable

Kumar et al.(14) recrystallized mebendazole in presence of polyvinyl

Maghsoodi et al.(15) studied influence of different concentrations of

Basavoju et al.(16) prepared cocrystals of indomethacin using saccharine as a

Childs and Hardcastle,(17) characterized two polymorphs of a

Department of Pharmaceutical Sciences, Saurashtra University, Rajkot 58

Chlorzoxazone:4-hydroxybenzoic acid cocrystal. The crystal structure of

Nokhodchi et al.(18) prepared carbamazepine (CBZ) crystals from pure

Trask et al.(19) produced theophylline cocrystals with oxalic, malonic, maleic

Raghavan et al.(20) crystallized hydrocortisone acetate (HA) in presence of

Ford et al.(21-22) crystallized paracetamol in presence of polyvinyl pyrrolidone

Department of Pharmaceutical Sciences, Saurashtra University, Rajkot 59

and/or the concentration of PVP in the crystallization medium, the amount of

Vaghani et al.(30) prepared 5-fluorouracil loaded microspheres of Eudragit

Gangadhar et al.(31) applied emulsion solvent technique with acetone-liquid

Department of Pharmaceutical Sciences, Saurashtra University, Rajkot 60

release of Indomethacin was influenced by the drug to polymer ratio and

Patel et al.(32) prepared sustained release microspheres of quetiapine

Bhagwat et al.(33) applied non-aqueous emulsification solvent evaporation

Nagda et al.(34) prepared bioadhesive microspheres of aceclofenac by double

Nokhodchi and Maghsoodi,(35) prepared directly compressible agglomerates

Department of Pharmaceutical Sciences, Saurashtra University, Rajkot 61

Dashora et al.(36) prepared microparticals of nimesulide by modified solvent

Muthusamy et al.(37) prepared sustained release system for lansoprazole to

Kawashima et al.(38) prepared spherically agglomerated crystals of ascorbic

Kachrimanis et al.(39) studied the effects of eudragit (eudragit S100, L100,

Department of Pharmaceutical Sciences, Saurashtra University, Rajkot 62

Kawashima et al.(41) used novel quasi-emulsion solvent diffusion method to

3.1.3 CRYSTALLO-CO-AGGLOMERATES (CCA)

Dixit et al.(43) prepared spherical crystals of piroxicam using neutralization

Sarfaraz et al.(44) prepared agglomerates of aceclofenac with disintegrant with

Department of Pharmaceutical Sciences, Saurashtra University, Rajkot 63

agglomerates could be controlled by the amount of included disintegrant,

Patil and Sahoo,(45) prepared spherical agglomerates of glibenclamide with

Maghsoodi and Barghi,(46) carried out crystallization of ibuprofen using the

Jadhav et al.(47) prepared agglomerates of bromhexine hydrochloride (BXH)

Bhattacharyya et al.(48) prepared CCA of nimesulide for direct compression.

Department of Pharmaceutical Sciences, Saurashtra University, Rajkot 64

obtained. The tablets were prepared by direct compression of nimesulide

Kumar et al.(49) prepared spherical crystals of mebendazole to improve

Chavda and Maheshwari,(50) developed crystallo-co-agglomerates (CCA) of