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Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 1
1. Introduction:
The quality and efficiency of a solid pharmaceutical dosage form is influenced by
primary micrometric properties (shape, size of crystals etc) and macrometric properties
(bulk density, Flowability.) of active or inactive medical substances especially when the
large amounts of water insoluble drug with poor rheological properties are formulated.
The formulation and manufacturing of solid oral dosage forms particularly tablet, the
most convenient pharmaceutical dosage forms that are widely used in the
chemotherapeutic field should comprise only a few manufacturing steps (1).The
material used for the production of tablet should be in physical form that flow smoothly
and uniformly, directly compressible and physically stable so as to achieve rapid
production capability of tablet formulation. Therefore one of the most important
changes in the manufacturing of tablet in the last decade is the large-scale introduction
of direct compression of tablets (direct tabletting method). The main tabletting method
involved first making granules and then compressing them into tablets by way of
indirect (granule) tabletting, but the need in recent year for process validation, GMP
and automation of production process has focused renewed attention on direct tabletting
method, which involved few steps.
Direct tabletting in pharmaceuticals has been successfully industrialized by formulation
with higher amount of fillers. However, it is desirable to reduce amount of filler so as to
reduce the size of dosage form in order to decrease production cost. To achieve this
goal, the macromeritic properties like Flowability, packability, compressibility of the
drug must be improved without pharmaceutical aids or with their minimum quantities
like fillers and binders.
The direct tabletting technique has been extensively investigated and successfully
industrialized for some drugs because of requirements of fewer machines and operation
steps. Present progress in direct tabetting was accomplished by the addition of large
amount of fillers to the drug powder to improve various micromeritic properties. Direct
tabletting necessitates an active ingredient powder that excels in flowability,
bindiability and mechanical strength. There are currently limited pharmaceutical tablets
on commercial production that can be made by direct tabletting and hence development
of active pharmaceutical ingredient crystals that can be directly tabletted has been
waited. Most powders cannot be compressed directly into tablet because of the lack of
the proper characteristics of binding or bonding together into a compact entity. For
these reasons, particle design is done to improve the properties of particle to impart a
new function to preparation and to guarantee more stable and reliable powder
processing. Thus the efficiency of the tablet manufacturing can be improved by using
directly compressible materials instead of having wet granulation and drying steps (2).
Direct compression is the modern and the most efficient process used in tablet
manufacturing. The materials used for the direct compression should have free flowing
property, able to form stable compacts at low punch forces and free from sticking
behavior with die and punches. Many processing steps (granulation, drying) are
eliminated in direct compression. However the use of this technique is quite simple and
depends on the following properties
1. The flowability of the drug crystals.
2. The particle size and the particle size distribution of the materials.
3. The bulk density of the powder.
4. The compressibility of the powder.
Some drug crystals exhibit such properties, but many materials have very poor
flowability and compressibility for tablet making. The possible solution for such
materials includes:
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 2
Granulation: The different granulation techniques were used to improve the different
physicochemical properties of drug substances.
By using direct compressible excipients: The use of direct tablet making with good
excipients bypass all the granulation technique. Theses types of excipients give good
flow and promote direct compression.
Spherical crystallization method: It includes the direct tabetting with spherical
agglomerates of recrystallized drug substances with good flowability and
compressibility properties (3).
1.1. Granulation:
The ideal physical form of the material for tabletting is agglomerated sphere so as to
minimize contact surface between them and with wall of the machine part. The
production of uniform tablet dosage units depends on several granular properties. The
partial benefits associated with spherical granulation are an improvement of powder
flow, uniform particle size and particle size distribution, reduction in punch face
adherence, and reduction in capping tendency. Granulation is the generic method for
particle size enlargement that refers to the accumulation of small particle to form larger
aggregates. It is frequently used process in tablet manufacturing. By using granulation
method particle size enlargement with better flowability and homogeneity of tablet
mass is obtained. Granulations also prevent segregation and minimize dust, a
compression characteristic of drug is improved and finally appearance of the tablet
improved. But the granulation step in tablet manufacturing is time and energy intensive
and exposes the formulation to water or solvent and heat. Various granulation methods
that are widely used in pharmaceutical industries, includes:
1.1.1. Dry granulation (slugging): Dry granulation can be accomplished with the use of special processing equipment
known as roller compactor or chilsonator. Dry granulation procedure is slugging
technique in which slug or large tablet are compressed using heavy-duty tablet
compaction equipment and subsequently grounded to the desired granules. This process
was used for materials that ordinarily will not be compressed using the more
conventional wet granulation technique. These types of granules prepared by a
prolonged milling operation, which allows excess energy input to be utilized in
agglomerating the intrinsically cohesive particle produced during the grinding
operation. Tablet produced by this mechanism show comparatively high strengths,
however the granules produced comparatively weaker mechanical properties.
1.1.2. Wet granulation method:
It employ granulating agent and find widest application in pharmaceutical industry. In
this process liquid is added to a powder in a vessel equipped with any type of agitation
that will produce agglomeration or granules. The general disadvantage of wet
granulation is its cost because of the space, time and equipment. The process is also
labor intensive and involve number of steps.
1.1.3. Fluidized Bed Granulation:
It has many advantages over conventional wet massing. All granulation process are
performed in one unit, saving labor cost, transfer losses and time. Another advantage of
the process is that automation of process can be achieved once the conditions affecting
the granulation have been optimized. The equipment used in the process is expensive
and optimization of process parameters affecting granulation needs extensive
development work not only during initial development work but also during scale up
from development to production scale. This long and very product specific
development has proved to be a serious problem with fluidized bed granulation in
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 3
pharmaceutical industry. There are numerous parameters should be optimized which is
related to apparatus, process and product which affect the quality of final granules.
1.1.4. Melt granulation:
A melt granulation technique is a process by which pharmaceutical powders can be
efficiently agglomerated by using molten polymers or additives at relatively low
temperature. This technique was mostly used to prepare fast release melt granules by
utilizing water-soluble polymers and surfactants, such as PEG and poloxamers. The
technique is also used for the preparation of sustained released dosage forms by using
lipophilic polymers, such as glycerol monostearate. In recent years, the interest in melt
granulation has increased due to the advantage of this technique over traditional wet
granulation, that is, elimination of water or organic solvents from the melt granulation
process. This negates any risk originating from residual solvents; moreover, in melt
granulation the drying step is not necessary, thus the process is less consuming in terms
of time and energy as compared to wet granulation .The apparatus of choice for melt
granulation are the high shear mixers, where the product temperature is raised above
the melting point of the binder either by using a heating jacket or via the heat of friction
generated by the impeller blades, when the impeller speed is high enough. The main
disadvantage of the technique include it requires high energy input, the technique
cannot be applied to heat-sensitive materials, lower-melting-point binder creates risks
situations where melting or softening of the binder occurs during handling and storage
of the agglomerates and higher-melting-point binders require high melting temperatures
and can contribute to instability problems especially for heat-labile materials.
1.2. Tablet manufacturing by using directly compressible excipients:
By using directly compressible excipients it is possible to prepare directly compressible
tablets but if the drug and the good excipients are having different crystal habit it may
greatly affect the flow properties of the final powder blend fed to die cavity. For poor
compressible drug substances large quantity of directly compressible excipients are
required to prepared tablets.
1.3. Spherical crystallization:
The crystal morphology of many drug substances causes them to have extremely poor
flow characteristics, thereby eliminating the possibility of a direct compression process
for formulations with high levels of drug. Crystal morphology can also significantly
impact materials compression characteristics and many formulations with a high
percentage of drug substance do not lend themselves to direct compression due to a
poor compressibility.
In 1986, Kawashima, Y., et al. used the spherical crystallization technique for size
enlargement of the drug in the field of pharmacy. Spherical crystallization was defined
by Kawashima as “An agglomeration process that transforms crystals directly in to a
compact spherical forms during the crystallization process.” It also enables co-
precipitation of drug and encapsulating polymer in the form of spherical particle (4).
This technique involves selective formation of agglomerates of crystals held together
by liquid bridges. Spherical crystallization technique has been successfully utilized for
improvement of flowability and compressibility of crystalline drug preparations of
microsponges and microspheres and masking of the bitter taste (5). It is the simple
process and is inexpensive enough for scaling up to a commercial level. This reduces
time and cost by involving faster operation, less machinery and fewer personnel with
great advances in tabletting technology. By using this technology, physicochemical
properties of pharmaceutical crystals are dramatically improved for pharmaceutical
process such as milling, mixing and tabletting because of their excellent flowability and
packability (6).
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 4
There are many active pharmaceutical agents in pharmaceutical industry with
unfavorable flowability and compressibility properties due to irregular crystal habit.
Poor compressibility of a specific crystal habit of drug can be attributed to the presence
of crystal faces that gives poor adhesion to each other and absences of the faces that are
required for optimal adhesion. The close co-operation of chemists and pharmaceutical
technologists can lead to progress in this field. The spherically agglomerated crystals
can be prepared in tablet form or compounded directly into a pharmaceutical system
without further processing such as granulation. In addition, this technique may enable
conversion of crystalline form of a dug to a different polymorphic form and thus attain
better bioavailability. The spherical crystallization or particle spherical agglomeration
method employs three solvents i.e. good solvent, bridging liquid and poor solvent.
1.3.1. Role of bridging liquid in the spherical crystallization technique:
The spherical crystallization technique involves the selective formation of
agglomerated crystals held together by liquid bridges. The agglomerates are formed by
agitating the crystals in the liquid suspension in the presence of the bridging liquid. The
bridging liquid should be immiscible in the suspending medium but capable of
cementing the particle to be agglomerated. Thus the nature of bridging liquid and
surface properties of crystals play important role in agglomeration process.
1.3.2. Theory of spherical crystallization:
Finely divided solids in liquid suspension can be agglomerated and separated by the
addition of small amount of bridging liquid, which preferentially wets the surface of
solids. Thus surface properties of the crystals and nature of the bridging liquid play an
important role in the agglomeration process. The behavior of suspension of fine
particles that are formed during crystallization process to which small amount of
bridging liquid added, is controlled by three main factors,
1. Free energy relationships at the liquid-liquid-solid interface
2. The amount of second liquid (bridging liquid) used in relation to the amount of
solids
3. The type and intensity of mixing employed.
From a thermodynamic stand point, the driving force from the wetting by the bridging
liquid and subsequent agglomeration of hydrophilic/hydrophobic particle results in the
reduction of the total surface free energy in the system.
1.3.3. The principle steps involved in the process of spherical crystallization
Bose and Heerens have studied the change in agglomerate size with time using light
scattering technique (7). Bermer and Zuider Wag proposed four steps in the growth of
agglomeration as shown in figure: 1.1 (8).
a) Flocculation Zone
b) Zero Growth Zone
c) Fast Growth Zone
d) Constant Size Zone
a) Flocculation Zone:
In this zone, the bridging liquid displaces the liquid from the surface of the crystals &
these crystals are brought in close proximity by agitation; the adsorbed bridging liquid
links the particles by forming a lens bridge between them. In these zones, loose open
flocs of particles are formed by pendular bridges. In any wet agglomeration process it is
the liquid phase in the system that initially generates the cohesive forces between
particles. The liquid fill parts of the void space in the randomly packed material to form
discrete lens like ring at the contacts & coordination points between particles forming
the agglomerates. The stage of agglomeration process where the ratio of liquid to void
volume is low & air is the continuous phase is known as pendular state. Mutual
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 5
attraction of particles is brought about by surface tension of the liquid & the liquid
bridges. The capillary stage is reached when all the void space within the agglomerates
is completely filled with the liquid. An immediate state known as funicular state exists
between pendular & capillary stage. In funicular state as in pendular state, liquid
bridges containing pores filled with liquid are present, however, the liquid forms the
continuous phase & the pocket of air dispersed throughout the agglomerates. The
cohesive strength of the agglomerate is attributed to the bounding forces exerted by the
pendular bridges & capillary suction pressure. In the droplet state the liquid envelops
the agglomerates.
b) Zero Growth Zone:
Loose flocs get transferred into tightly packed pellets, during which the entrapped fluid
is squeezed out followed by squeezing of the bridging liquid onto the surface of small
flocs causing poor space in the pellet completely filled with the bridging liquid. The
driving force for the transformation is provided by the agitation of the slurry causing
liquid turbulence, pellet-pellet & pellet-stirrer collision.
c) Fast Growth Zone:
The fast growth zone of the agglomerates takes place when sufficient bridging liquid
has squeezed out of the surface of the small agglomerates. This formation of large
particles following random collision of well-formed nucleus is known as coalescence.
Successful collision occurs only if the nucleus has slight excess surface moisture. This
imparts plasticity on the nucleus and enhances particle deformations and subsequent
coalescence. Another reason for the growth of agglomerates size is attributed to growth
mechanisms that describe the successive addition of material on already formed nuclei.
d) Constant Size Zone:
In this zone agglomerates cease to grow or even show slight decrease in size. Here the
frequency of coalescence is balanced by the breakage frequency of agglomeration. The
size reduction may be due to attrition, breakage & shatter. The rate determining step in
agglomeration growth occurs in zero growth zones when bridging liquid is squeezed
out of the pores as the initial flocs are transformed into small agglomerates. Another
view process that the rate determining step is the collision of particle with the bridging
liquid droplets prior to the formation of liquid bridges. The rate is governed by the rate
of agitation. The strength of the agglomerates is determined by interfacial tension
between the bridging liquid & the continuous liquid phase, contact angle & the ratio of
the volumes of the bridging liquid & solid particles.
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 6
Figure: 1.1. Steps involved in the mechanism of spherical crystallization.
(A) Pendular state: Initail step after immediate addition of bridging liquid.
(B) Funicular state: In this step the bridging liquid forms the conform bridges in
between the recrystallized particles.
(C) Capillary state: In this step the formed bridges coalescence together to form
recrystallized agglomerates.
(D) Droplet state: In this step the bridging liquid comes out to the surface by capillary
action and ready for big agglomerates formation depending upon the stirring rate and
other process variables.
1.3.4. Factors controlling the process of recrystallization and agglomeration
A) Solubility profile:
The selection of solvent is dictated by solubility characteristic of drug. A mutually
immiscible three solvent system consisting of a poor solvent (suspending liquid), good
solvent and bridging liquid are necessary. Physical form of product i.e. whether micro-
agglomerate or irregular macro-agglomerates or a paste of drug substance can be
controlled by selection of proper solvent proportions. The proportion of solvent to be
used is determined by carrying out solubility studies and constructing triangular phase
or Scheffe ternary diagram to define the region of mutual immiscibility.
B) Mode and intensity of agitation:
High speed agitation is necessary to disperse the bridging liquid throughout the system.
The product of high speed shaker blender is usually in the form of irregular
agglomerates. When tanks are used as a reaction vessel, more irregular but less
spherical agglomerates were obtained. An inclined pan and drum agglomerator
facilitated the size enlargement process. Any change in agitation pattern or fluid flow
would be reflected as change in force acting on agglomerate, which ultimately affects
the shape of agglomerate. Mechanical agitation is the prime variable affecting the
process and is necessary to bring the particles into proximity so that the force
responsible for agglomeration may become operative. The extent of mechanical
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 7
agitation in conjugation with the amount of bridging liquid determines the rate of
formation of agglomerate and their final size. [9].
C) Temperature of the system:
The average size of agglomerate was smallest at the crystallization temperature 10oC.
At higher temperature, the larger agglomerates were produced initially and the
equilibrium attained more rapidly than at lower temperature. At lower temperature, it
was characteristic that the growth rate of crystals was slow at the initial stage but
become faster at the later stage. At low temperature, the initial numbers of crystals
produced were greater than a high temperature, the number of nuclei increased with
decreased crystallization temperature.
D) Residence time: The time for which agglomerates remain suspended in reaction mixture affect their size
shape and strength. Optimum residence time for the agglomeration of recrystallized
crystals was required. Below the optimized residence time the incomplete
agglomeration occurs due to incomplete diffusion of good solvent and bridging liquid
from the formed droplets in the dispersion medium. At longer residence time the
formed agglomerates were break down and the size of the agglomerated particles
decreases. This might be due to the solubilization of the agglomerates by the bridging
liquid that diffuses out from them.
1.3.5. Operating variables in spherical crystallization technique: The operating variable includes:
a) Agitator speed.
b) Drug concentration.
c) pH and temperature of the system
d) Type and amount of bridging liquid
e) Type, amount and method of dispersion.
f) Way of addition of bridging liquid.
g) Quantity of solvent system used.
h) Type of stirrer used.
1.3.6. Methods of spherical crystallization: Spherical crystallization is a solvent exchange crystallization method in which crystal
agglomeration is purposely induced through the addition of third solvent known as
bridging liquid. Crystal agglomeration, which is usually avoided during normal
processing, is performed in a controlled fashion during spherical crystallization to bring
about improved flow and compaction properties of the material. These properties are
highly advantageous for pharmaceutical production. The main requirement in spherical
crystallization system is that, it should require a small amount of bridging liquid. The
proportion of bridging liquid in the given system can be determined by plotting a
ternary or solubility diagram of the bridging liquid in the given system.
Following are the methods to prepare the spherical crystals.
1) Spherical Agglomeration method (SA).
2) Quasi-Emulsion Solvent Diffusion method (QESD).
3) Ammonia diffusion system (ADS).
4) Neutralization Technique (NT).
5) Traditional crystallization process.
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 8
1) Spherical Agglomeration method (SA):-
A) Solvent Change technique by using liquid as poor solvent.
Figure: 1.2. Mechanism of recrystallized agglomerates formation by spherical
agglomeration technique.
The process involves the formation of fine crystals and their agglomeration.
Crystallization generally achieved by the change of solvent system or salting out. The
solution of material in good solvent is poured in a poor solvent, so as to favor formation
of fine crystals. The agglomerates are formed by agitating the crystals in a liquid
suspension and adding the bridging liquid, which preferentially wets the surface
crystals to cause binding (figure: 1.2). The agglomerates may be spherical if the amount
of bridging liquid and the rate of agitation are controlled. Crystallization of Salicylic
acid was carried out by solvent change method using ethanol as good solvent and water
as poor solvent. The crystals were agglomerated using chloroform as bridging liquid
[10].Martino, D. et al. produced spherical propyphenazone crystals by an
agglomeration technique using a three solvent system. After selecting the best
propyphenazone solvent (ethyl alcohol), non solvent (deminerlized water) and bridging
liquid (isopropyl acetate) [11].
A) Solvent Change technique by CO2 gas as poor solvent/supercritical
Antisolvent (SAS) process:
Recently, processes of formulation and preparation of recrystallized agglomerates with
different polymers were based on the use of supercritical fluids as solvents or
antisolvents for poorly water soluble active pharmaceutical ingredients (APIs) have
been introduced as a viable means of controlling particle formation to improve
physicochemical properties in solid state. Supercritical CO2 (SC-CO2) is the most
widely used supercritical fluid because of its mild critical conditions (Tc = 31.10C, Pc =
7.38 MPa), non-toxicity, on-flammability and low price. The pharmaceutical
applications of supercritical fluid technology using carbon dioxide enable to modify the
solid state properties of APIs, such as characteristics of particles (size, shape, surface,
crystal structure and morphology), crystallinity and polymorphism affecting their
dissolution rate and bioavailability. Many researchers have employed supercritical fluid
techniques for micronization and for recrystallization of various APIs . In addition, the
modification of solid state characteristics, such as crystal habit, crystallinity and
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 9
polymorphism, has been successfully achieved through the recrystallization of drug
particles using various SAS processes.
(A, Drug solution in good solvent; B, Peristaltic pump; C, Spraying gun for drug
solution;D,Chamber with saturated CO2 gas.)
Figure: 1.3.Polymeric recrystallized agglomerates formation by using supercritical
Antisolvent (SAS) process.
2) Quasi-Emulsion Solvent Diffusion Method (QESD)
Figure: 1.4. Mechanism of recrystallized agglomerates formation by Quasi-
emulsion solvent diffusion method.
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 10
Figure: 1.5. Mechanism of recrystallized agglomerates formation by Quasi-
emulsion solvent diffusion method with stabilizers.
By this method, spherical crystallization can be carried out using a mixed system of two
or three partially miscible solvents, i.e. bridging liquid-poor solvent system or good
solvent-bridging liquid-poor solvent system. When bridging liquid (or plus good
solvent) solution of drug is poured in to poor solvent (dispersion medium) under
agitation, quasi emulsion droplets of bridging liquid or good solvent forms the emulsion
droplet in to the dispersing medium and induce the crystallization of drug followed by
agglomeration(figure:1.3). Antirheumatic drug like bucillamine was crystallized as
agglomerates by emulsion solvent diffusion method using Hydroxypropyl
methylcellulose for coating (figure: 1.4). Uniformly coated directly compressible
crystal agglomerates were obtained. When the aqueous solution of drug was poured in
the dispersing phase, finally dispersed aqueous droplets were instantly formed,
resulting in w/o emulsion. The outer surface of droplet was immediately covered with a
thin shell of precipitated drug crystals. Further, crystallization occurred in droplet and
transformed it into spherical agglomerate [12].
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 11
3) Ammonia Diffusion System (ADS)
Figure: 1.6. Mechanism of recrystallized agglomerates formation by ammonia
diffusion system.
1. Invasion of acetone into ammonia water droplets.
2. Diffusion of ammonia from the agglomerates to the outer solvent.
3. Agglomeration ending.
Mechanism of the ammonia diffusion system:
It is the novel method for spherical crystallization of amphoteric drug substance. It is
assumed that acetones in the solvent enters into droplets of ammonia water which are
librated from the acetone ammonia water dichloromethane system, and consequently
Enoxacin dissolved in ammonia water is precipitated while the droplets collect the
crystals (I).Simultaneously a part of the ammonia contained in the agglomerates
diffuses to the outer organic solvent phase and its ability, as a bridging liquid become
weaker (II),thereby formation of Enoxacin spherical agglomerates takes place (III).This
technique is termed as ammonia diffusion system(ADS) and is useful in agglomeration
of drugs which are soluble only in an acid or in alkaline solution(figure:1.5).
The spherical crystallization of Enoxacin, an antibacterial agent was carried out which
is slightly soluble in water but soluble in acidic and alkaline solution. A mixture of
three partially immiscible solvent i.e. acetone, ammonia water, dichloromethane was
used as a crystallization system. In this system ammonia water acted as bridging liquid
as well as good solvent for Enoxacin, Acetone was the water miscible but a poor
solvent, thus Enoxacin got precipitated by solvent change without forming ammonium
salt. Water immiscible solvent such as hydrocarbons or halogenated hydrocarbons e.g.
dichloromethane induced liberation of ammonia water [13].
Agglomerated crystals of Norfloxacin were prepared by spherical crystallization
technique using the ammonia diffusion method. This techniques make it possible to
agglomerate amphoteric drug like Norfloxacin, which cannot be agglomerated by
conventional procedures. When the ammonia water solution of Norfolxacin was poured
in to the acetone, dichloromethane mixture under agitation, a small amount of ammonia
was liberated in the system. The ammonia-water solution played role both as good
solvent for Norfloxacin and as bridging liquid, allowing the crystals collection to take
place in one step [14].
4) Neutralization Method (NT):
Drug crystals
Invasion of
acetone
Ammonia water
Diffusion of
Ammonia
Spherical agglomerates
I
II
III
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 12
This process involves the formation of fine crystals and their agglomeration. The
spherical crystallization of antidiabetic drug tolbutamide was reported by this
technique. The drug was dissolved in sodium hydroxide solution. Aqueous solution of
Hydroxypropyl methylcellulose and hydrochloric acid was added to neutralize sodium
hydroxide solution of tolbutamide and the tolbutamide was crystallized out. The
bridging liquid was added drop wise at a rate of 10ml/min followed by agglomeration
of the tolbutamide crystals.
The agglomerates of tolbutamide prepared by neutralization technique were found to
have more specific surface area, more wettability and hence better dissolution rate as
compared to the agglomerates prepared by emulsion solvent diffusion method and
solvent change method. The agglomerates prepared by the neutralization method were
instantaneously permeated with water showing strikingly greater wettability. The
reason for this superior wettability of agglomerated crystals and tablet is due to fact
that, at the time of agglomeration process, hydrophilic Hydroxypropyl methylcellulose
in the crystallization solvent adheres firmly to the agglomerated crystals [15].
5) Traditional crystallization process: These methods also can be used to produce spherical crystal agglomerates, which are
carried out by controlling the physical and chemical properties and can be called the
non-typical spherical crystallization process. These are
Salting out precipitation.
Cooling crystallization.
Crystallization from the melting.
1.3.7. Characteristics of recrystallized agglomerated crystals:
A) Flowability: Flowability of the agglomerates is much improved as the agglomerate exhibits lower
angle of repose than that of single crystals. This improvement in the flowability of
agglomerates could be attributed to the significant reduction in inter-particle friction,
due to their spherical shape and a lower static electric charge [16].
B) Packability: Improved packability has been reported for agglomerates prepared by spherical
crystallization. The angle of friction, shear cohesive stress and shear indexes are lower
than that of single crystals, which can improve the packability of the agglomerates.
Kawashima, Y., et al. prepared spherical agglomerates using two solvent systems and
compared with those of original powder of the drug. It was found that the packability of
agglomerates was improved compared with those of the original crystals and that the
agglomerated crystals were adaptable to direct tabletting [17].
C) Compaction behaviors of Agglomerated Crystals: Good compactibility and compressibility are essential properties of directly
compressible crystals. The compaction behaviors of agglomerated crystals and single
crystals have been studied by plotting the relative volume against the compression
pressure. Spherical agglomerates possess superior strength characteristics in
comparison to conventional crystals. It is suggested that the surface are freshly
prepared by fracture during compression of agglomerates, which enhances the plastic
inter particle bonding, resulting in a lower compression force required for compressing
the agglomerates under plastic deformation compared to that of single crystals.
Morishima et al. investigated tabletting properties of bucillamine agglomerates
prepared by spherical crystallization techniques. Compaction of agglomerates and
conventional crystals was carried out by using compaction test apparatus, equipped
with flat-faced punches. The improved compactibility of agglomerates was attributed to
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 13
their structural characteristics. Agglomerates were built up with extremely small
crystals. This characteristic structure was responsible for large relative volume change
during the early stage of the compaction process due to their fragmentation. The
specific surface area of agglomerates increased greatly during compression, while no
change in specific surface area was observed with conventional crystals [18].
D) Mechanical strength of resultant tablets: The tablets compressed with the agglomerated crystals exhibit higher tensile strength
than that of compressed original crystals. Kawashima et al. prepared the spherical
agglomerated crystals of Acebutalol hydrochloride by the spherical crystallization
technique with a two solvent system. The preparation of tablet and the measurement of
tensile strength were carried out. The powder sample was compressed with a flat faced
punch under different compression pressures applying different compression speeds.
The tensile strength of tablets prepared from agglomerated crystals was always higher
than the tablets prepared from single crystal at the same compression pressure. This
was due to plastic deformation of the agglomerated crystals resulting in greater
permanent particle contact and stronger bond force than in case of the original crystals.
It has been established that the production of fresh surface by fracturing during the
compression process is necessary to expose to air to bind the particles strongly for
tabletting. If fractured surface is exposed to air for a long time after breaking, no
improvement in inter particle bond occurs because of the reduction in free energy of the
surface when absorbed with air [19].
E) Wettability:
Wettability of agglomerated crystals by water is investigated by measuring the contact
angle of water to the compressed crystals. The wettability depends on the crystallinity
and elementary crystal size of the agglomerated crystals. As the contact angle decreases
the wettability increases. Crystals with low crystallinity are more wettable than crystals
with higher crystallinity.
F) Dissolution Rate and Bioavailability:
The dissolution rate and hence bioavailability of agglomerated crystal depends on
crystalline form, particle size, particle density and specific surface area of the
agglomerated crystals. It has been elucidated that the dissolution of agglomerates
increases as apparent specific surface area increases. Tabletting compacts partially
breaks the agglomerated crystals and thus the average particle size is reduced. But
compression also increases the particle density, which may adversely affect dissolution.
Specific surface area of crystals is found to depend on the method used for spherical
crystallization. The formed recrystallized agglomerate by using spherical crystallization
technique shows changes in crystalline form due to recrystallization and hence there
may be changes in solubility, dissolution rate and their in vivo performance (BA).
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 14
1.4. Literature review:
Applications of spherical crystallization technique:
The potential and achievements of the spherical crystallization techniques in
pharmaceutical fields were described as follows.
The spherical crystallization technique can be modified to a simple and less expensive
process to prepare spherical matrices of prolonged release particulate drug delivery
system. The advantages of this technique include the avoidance of harmful organic
solvent and additives such as isobutylene used in the process of microencapsulation
phase separation. This process does not require elevation of temperature of the system
as in phase separation method and finally resultant matrix spheres obtained are directly
compressible.
1) Microspheres:
The quasi-emulsion solvent diffusion method of spherical crystallization technique has
been accepted as a useful technique for particle design of pharmaceuticals. It could
provide remarkable advantages over conventional microsphere preparation methods. In
this process, drug and polymers are co precipitated to form functional drug devices
according to the polymer properties. Microspheres prepared with slightly and very
slightly soluble drugs such as Salicylic acid, Naproxen, Piroxicam, Indomethacin and
Methylprednisolon indicated controlled release properties.
Table: 1.1 Application of spherical crystallization for preparation of microspheres.
Method and solvent system Research findings
Sustained-release nitrendipine microspheres
having solid dispersion structure
Method: Quasi-emulsion solvent diffusion
method.
Internal phase :
Nitrendipine was dissolved with HP-55, EuRS,
EC , Aerosil, triethyl citrate in a mixed organic
solution containing ethanol, acetone and
dichloromethane.
External phase:
Distilled water containing 0.08% of SDS.
Improvement in micromeritic properties.
The release rate of nitrendipine from the microspheres
could be modulated as desired by adjusting the
formulations of the microspheres and preparation
conditions.The markedly improved bioavailability of
nitrendipine indicating the effectively method for
designing sustained-release microspheres with water-
insoluble drugs.HP-55 could be used as a desired
enteric agent to prepare solid dispersions in the
pharmaceutical field to enhance the solubility and
dissolution rate of the drug.(20)
Sustained-release nitrendipine microspheres
with Eudragit RS and Aerosil
Method:QESD
Internal phase : Nitrendipine,Eud RS,Acetone,
Dichloromethane,Aerosil
External phase:
Distilled water containing 0.02–0.15% of SDS.
Desired micromeritic properties.The release profiles of
the microspheres were modulated with adjusting the
ratio of the retarding agent to the dispersing carrier.
The relatively high recovery and incorporation
efficiency of microspheres showed an advantage over
the other conventional method of preparing
microspheres.(21)
pH-dependent gradient-release microsphere
system for nitrendipine
Method: Quasi-emulsion solvent diffusion
method.
Internal phase : pH-dependent polymers like Acrylic resins
Eudragit E-100,HPMC phthalate,HPMC acetate
succinate, With acetone/ ethanol as good
solvent, and dichloromethane as bridging liquid,
External phase:
Distilled water containing 0.08% of SDS
The drug dissolution behavior of the system under the
simulated gastrointestinal pH conditions revealed the
gradient-release characteristics.The dissolution
profiles and content of the systems stored at 40 0C
75% RH were unchanged during a 3-month period of
accelerating storage conditions.
The results of the bioavailability testing in six healthy
dogs suggested that the pH-dependent gradient-release
delivery system could improve efficiently the uptake
of the poorly water-soluble drug and prolong the Tmax
value in vivo.(22)
Captopril Microsphere
Method:ESDS
Solvent system: Dichloromethane-Alcohol-0.1N
HCl Eudragit RL100, Eudragit RS100 and Ethyl
cellulose.
Increase in the concentration of polymer decreases the
release the release rate significantly.
The most retardant effect was obtained using Eudragit
RS100.Increase in stirring rate increases the drug
release rate.(23)
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 15
Method and solvent system Research findings
Ibuprofen Microsphere
Method: Solvent change method
Solvent system: ethanol-water, Eudragit S100.
Flow, packing behavior were improved and
densification of agglomerates at low compression.(24)
Furosemide Microsphere
Method: SA
Solvent system: Eudragit L100, EudragitS100,
EudragitRL100 and EudragitRS100.
The most retardant effect was obtained by using
EudragitRS easily changed release pattern of
Furosemide.
Dissolution data showed that the release followed
Higuchi matrix model kinetics.(25)
2) Microsphere for masking bitter taste of drug:
Preparation of microcapsules to mask the bitter test of the drug. They are suitable for
coating granules, since spherical material can be uniformly coated with a relatively
small amount of polymer. Microcapsules of Enoxacin, Ampicillin trihydrate were
prepared by masking of bitter taste.
Table: 1.2 Application of spherical crystallization for taste masking of bitter drugs. Method and solvent system Research findings
Roxithromycin-polymeric microspheres
for taste masking
Method: Emulsion solvent diffusion
method
Internal phase : ethanol, acetone (good
solvent) and dichloromethane (bridging
liquid) with roxithromycin, polymer-
Eudragit and silica
External phase:
Distilled water containing 1% of PVA.
The bitter taste of roxithromycin was masked by the
microspheres produced with Eud S100.
The DSC graphs and XRD showed that the drug was in an
amorphous state in the microspheres.
The microspheres masking the bitter taste of the drug could
be incorporated into a suitable dosage form for oral
administration in the future.
The opposite electric groups between drug and polymer can
take better effects on taste-masking with the interaction, but
must be considered the chemical stability on the interaction
between them.(26)
3) Formation of complexes:
This technique was also applicable for the formation of complexes of two compounds,
which are beneficial over utilization of single.
Table: 1.3 Application of spherical crystallization for complex formation.
Method and solvent system Research findings
spherical crystals of Aminophylline
(theophylline and ethylenediamine)
Solvent system:
organic solvent-ethanol-water.
The resultant agglomerates were identical with the
theophylline-ethylenediamine complex by IR, XRPD, and
DSC analysis. Ethylenediamine content in the agglomerated
crystals could be controlled by changing the amount of
ethylenediamine added in the crystallization solvent. (27)
Indomethacin and Epirizole
Solvent system:
Ethanol-water-chloroform, ethyl acetate-
water, or ethylacetate-aquious sodium
chloride.
The rate of release of Indomethacin from complex was three
times more rapid than that from the physical mixture in the
disintegration test solution. These agglomerated crystals can
be compounded directly into pharmaceutical system without
further processing such as granulation. Reduction in the
gastric and intestinal ulcerogenicity of Indomethacin when
co-administered with Epirizole. Concomitant administration
of Indomethacin and Eepirazole reduces the adverse effects
of such fluctuation in concentration. (28)
4) Crystallo-co-agglomeration (CCA):
Crystallo-co-agglomeration (CCA), a technique first described by Kadam and their
coworkers. It is a modification of a spherical crystallization technique in which a drug
is crystallized and agglomerated with excipients or with another drug, which may or
may not be crystallized in the system.CCA has been designed to overcome the
limitations of spherical crystallization to obtain directly compressible agglomerates of
low-dose and poorly compressible drugs and combination of drugs. In the application
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 16
of CCA to obtain directly compressible agglomerates, excipients to be incorporated in
the agglomerates should have affinity toward the bridging liquid. Talc, due to its
hydrophobicity, undergoes preferential wetting with bridging liquid and is a suitable
excipients for incorporation in the CCA.
Table: 1.4 Application of spherical crystallization for preparation of crystallo-co-
agglomerates. Name of agglomerates with Solvent system and
additives
Research findings
Ibuprofen-Paracetamol Agglomerates:
Dichloromethane (DCM) - water system containing
polyethylene glycol (PEG) 6000, PVP, and ethyl
cellulose was used as the crystallization system.
Ethylcellulose imparted mechanical strength to the
agglomerates as well as compacts. The
agglomerates containing PEG have better
compressibility.(29)
Ibuprofen-Talc Agglomerates: Dichloromethane (DCM)-water as the
crystallization system with talc as additive.
Higher proportion of talc in formulation showed
zero order kinetics and drug release was extended
up to 13 hours.(30)
Bromhexine HCl- Deformable Talc
Agglomerates.
Dichloromethane (DCM)-water as the
crystallization system. Talc as diluent, Tween as
dispersing agent, HPMC to impart the desired
mechanical strength and PEG-6000 used to impart
the desired sphericity to the agglomerates.
Crushing strength and friability showed good
handling qualities of agglomerates. Heckel plot
studies showed excellent compressibility and
compactibility of agglomerates.
Agglomerates are spherical, deformable, and
directly compressible agglomerates, generating a
heterogeneous matrix system and providing
sustained drug release.(31)
Naproxen-disintegrant agglomerates
Acetone–water containing hydroxypropylcellulose
(HPC) and sodium starch glycolate as super
disintegrants were used as the crystallization
medium.
Flowability, compactibility and dissolution rate
were improved profoundly resulting in successful
direct tableting without need to additional process
of physical blending of agglomerates and
disintegrants.Disintegrants used in both intra and
extra granularly during agglomeration of naproxen
shows faster release rate than in tablets dosage
form.(32)
5) Microencapsulation:
Microcapsules composed of a core substance (active component) and a polymer shell
(protective component or excipients) are generally defined as spherical particles in the
size range of about 50–2000 µm. Microencapsulation is a very useful technique for
protecting the active components from environmental stimuli. Therefore, there have
been intensive studies on the production of polymer microcapsules in the fields of
pharmaceutics and cosmetics.
Table: 1.5 Application of spherical crystallization for preparation of
microencapsules. Method and solvent system Research findings
Ibuprofen Microcapsules
Method: Emulsion solvent diffusion technique
Internal phase: Ibuprofen and Eudragit RS 100
polymer were dissolved in ethanol.
External phase: distilled water and emulsifying
agent, sucrose fatty acid ester F-70 (0.025% m/v).
The formulation variables, ibuprofen percentage,
Eudragit RS 100 content and the volume of ethanol
used influences the microencapsulation efficiency,
micromeritic and in vitro drug release characteristics
of the prepared microspheres..(33)
Reservoir-Type Microcapsules for lysozyme
protein
Method: Solvent exchange method
Solvent system:PLGA solution in Ethyl acetate
(PLGA-EA) and aqueous solution 0.5% PVA
solution.
This method could encapsulate protein drugs with
high efficiency under an optimized condition and was
mild enough to preserve the integrity of the
encapsulated lysozyme during the process.
In vitro release studies showed that the microcapsules
could release proteins in a controllable manner. It is a
mild and simple microencapsulation method that
could encapsulate lysozyme, maintaining its
functional integrity.(34)
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 17
6) Microsponges:
Advances in preparing microparticles have caused a renewal of interest in delivering of
drugs to the colon. While the monolithic forms such as tablets provide uniform transit
time through gastrointestinal tract, the particulate pharmaceutical forms such as
microsponges show several advantages such as uniform distribution at the target region
and smaller risk of dose dumping. Microsponges are porous, polymeric microspheres
that are used mostly for topical and recently for oral administration. Microsponges are
designed to deliver a pharmaceutical active ingredient efficiently at the minimum dose
and also to enhance stability, reduce side effects and modify drug release.
Table: 1.6 Application of spherical crystallization for preparation of microsponges. Method and solvent system Research findings
Ketoprofen microsponges
Method: Quasi-emulsion solvent
diffusion method.
Internal phase: ketoprofen, ethyl alcohol,
polymer- Eudragit RS 100 and
triethylcitrate (TEC)
External phase: DW with polyvinyl
alcohol (PVA)
The effects of different mixing speeds, drug-polymer ratios,
solvent-polymer ratios on the physical characteristics of the
microsponges as well as the in vitro release rate of the drug
from the microsponges were investigated.
All the factors studied had an influence on the physical
characteristics of the microsponges. In vitro dissolution
results showed that the release rate of ketoprofen was
modified in all formulations.(35)
Benzoyl peroxide(BPO) microsponges
Method: ESDM
Internal phase: Benzoyl peroxide,
Dichloromethane and polymer
External phase: DW containing 5.6 g of
5% (w/v) PVA
The morphology and particle size of microsponges were
affected by drug: polymer ratio, stirring rate and the amount
of emulsifier used.
Increase in the ratio of drug: polymer resulted in a reduction
in the release rate of BPO from the microsponges.(36)
Benzoyl peroxide (BPO) microsponge
for topical delivery for the treatment
of acne and athletes foot.
Method: ESDM
Internal phase: Benzoyl peroxide,
Dichloromethane and polymer –Ethyl
cellulose
External phase: DW containing PVA as
emulsifying agent.
The microsponges were spherical in shape and contained
pores which were resulted from the diffusion of solvent from
the surface of the microparticles and thus the particles were
designated as microsponges.
Drug: polymer ratio, stirring rate, volume of dispersed phase
influenced the particle size and drug release behavior of the
formed microsponges.
Increase in the ratio of drug: polymer resulted in a reduction
in the release rate of BPO from a microsponge which was
attributed to a decreased internal porosity of the
microsponges.(37)
Colon specific Flurbiprofen
microsponges
Method: Quasi-emulsion solvent
diffusion method.
Internal phase: FLB, Eudragit RS 100 in
ethyl alcohol.
External phase: DW containing PVA as
emulsifying agent.
These are spherical in shape and showed high porosity
values. Mechanically strong tablets prepared for colon
specific drug delivery was obtained owing to the plastic
deformation of sponge-like structure of microsponges.(38)
Direct tabletting microsponges of
ketoprofen.
Method: QESDM
Internal phase: Ketoprofen, Ethyl
alcohol, Eudragit RS 100
External phase: distilled water
containing PVA as emulsifying agent.
Results indicated that microsponge compressibility was
much improved over the physical mixture of the drug and
polymer and owing to the plastic deformation of sponge-like
structure, microsponges produce mechanically strong
tablets.(39)
Ibuprofen Microsponges
Method: Emulsion solvent diffusion
method.
The resultant microsponges had a higher porosity and
tortuosities.Microsponges compressibility was much
improved over the physical mixture of drug and polymer
owing to plastic deformation of their sponge like structure.
The more porous microsponges produced stronger tablet.(40)
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 18
7) Microballoones (MB):
A multiple-unit floating system that can be distributed widely throughout the
gastrointestinal tract, providing the possibility of achieving a longer-lasting and more
reliable release of drugs. Kawashima et al. developed a multiple-unit intragastric
floating system involving hollow microspheres (microballoons) with excellent buoyant
properties. This gastrointestinal transit-controlled preparation is designed to float on
gastric juice with a specific density of less than one. This property results in delayed
transit through the stomach, which could be applicable for a drug absorbed mainly at the
proximal small intestine. Optimum preparation temperature with respect to microballoon
cavity formation and factors influencing the buoyancy properties of microballoons were
examined. Different drugs, which exhibited distinct water solubility, were tested in
terms of entrapment within microballoons. The efficiency of drug entrapment into
microballoons and the buoyancy properties of the microballoons were also investigated.
Hollow microspheres were prepared by the emulsion solvent diffusion method using
enteric acrylic polymers with drug in a mixture of dichloromethane and ethanol. It was
found that preparation temperature determined the formation of cavity inside the
microsphere and the surface smoothness, determining the floatability and the drug
release rate of the microballoon.
Table: 1.7 Application of spherical crystallization for preparation of
Microballoones. Method and solvent system Research findings
Riboflavin-containing microballoons for
floating controlled drug delivery system:
Method: Emulsion solvent diffusion
method
Internal phase: Riboflavin, polymers and
monostearin in a mixture of
dichloromethane and ethanol.
External phase: Aqueous solution of
polyvinyl alcohol (0.75 w/v%.
They are able to float in the stomach sufficiently in the fed
condition. This phenomenon could prolong the gastric
residence time and delay drug arrival at the absorption site;
consequently, the sustained pharmacological action could
be provided.MB enabled increased absorption rate of drug
as the floating MB in the stomach gradually sank and
arrived at the absorption site.MB multiple unit floating
systems should be possibly beneficial with respect to
sustained pharmacological action.(41)
Hollow microballoons of Aspirin,
Salicylic acid,Ethoxybenzamide,
Indomethacin,Riboflavin
Method: Emulsion solvent diffusion
method
Internal phase:
Drug, polymers and monostearin were
dissolved or dispersed in a mixture of
dichloromethane and ethanol
External phase:
Aqueous solution of polyvinyl alcohol (0.75
w/v%
In the case of aspirin, salicylic acid and ethoxybenzamide,
the drug release profiles of microballoons proved linear
relationships by Higuchi plotting.
However, indomethacin and riboflavin release profiles did
not follow the Higuchi equation.
When the loading amount of riboflavin was higher than the
solubility in the mixture of dichloromethane and ethanol,
the drug release profiles of the microballoons displayed an
initial burst release.
The insoluble riboflavin in the mixture of dichloromethane
and ethanol adsorbed on to the microballoon surface in the
crystal state.
Such riboflavin crystals were released preferentially at the
initial stage of the release test, which was attributable to
the initial burst.
In addition, by incorporating a polymer such as
Hydroxypropylmethylcellulose within the shell of
microballoons, the release rate of riboflavin from the
microballoons could be controlled while maintaining high
buoyancy.(42)
Hallow microbaloons of Tranilast or
Ibuprofen
The drugs incorporated in the solidified shell of the
polymer were found to be partially or completely
amorphous. The flowability and packability of the resultant
microballoons were much improved compared with the
raw crystals of the drug.(43)
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 19
8) Nanospheres:
Polymeric nanospheres have been used to deliver medicines because of their advantages
such as high stability, easily uptaken into the cells by endocytosis, and targeting ability to
specific tissues or organs by adsorption or binding with ligand at the surface of the
particles. In particular, biodegradable nanospheres are available for delivering drugs and
degraded after passing required specific site. Among them poly (lactide) (PLA) and poly
(d,l-lactideco-glycolide) (PLGA) have been approved by the FDA for certain human
clinical uses. The degradation time of PLGA can be altered from days to years by varying
the molecular weight, the lactic acid to glycolic acid ratio in copolymer, or the structure of
nanospheres.
Table: 1.8 Application of spherical crystallization for preparation of Nanospheres. Method and solvent system Research findings
Surface-modified PLGA nanospheres with
chitosan (CS). for pulmonary delivery of
peptide
Method: Emulsion solvent diffusion method
PLGA microparticles
Internal phase:The PLGA, pyren, acetone
External phase:1% PVA in water
surface-modified PLGA nanospheres
Internal phase: The PLGA, elcatonin,, acetone,
methanol, Span 80
External phase: n-hexane (40 ml)–Triester F-
810 (60 ml) mixture containing 1.2% w/w
HGCR as emulsifier.
Retention of nanospheres adhered to the bronchial
mucus and lung tissue and sustained drug release at the
adherence site.
In addition, CS and CS on the surface of the nanospheres
enhanced the absorption of drug.
The absorption-enhancing effect may have been caused
by opening the intercellular tight junctions.
CS-modified PLGA nanosphere is useful for improving
peptide delivery via a pulmonary route due to prolonged
mucoadhesion for sustained drug release at the
absorption site and the absorption-enhancing action of
the surface modifier chitosan.(44)
Lipidic nanospheres (LN):
Method; Emulsification-diffusion method
Internal phase:
Lipid in water saturated water-miscible
organic solvents
External phase:
solvent-saturated aqueous solution containing
5% (w/v) of stabilizer (dispersion medium).
Reduce the particle size by increasing the process
temperature, the stirring rate, the amount of stabilizer,
and by lowering the amount of lipid.
Poly (vinyl alcohol) (PVAL) was able to preserve the
physical stability of the dispersion for long periods after
preparation.
This effect was attributed to the ability of PVAL chains
to form a strongly attached layer on the nanoparticle
surface with an excellent repulsion effect.(45)
PLGA nanospheres for Pulmonary delivery
of insulin to prolong hypoglycemic effect
Method: Modified emulsion solvent diffusion
method
Internal phase:
PLGA ,insulin in acetone and 0.01 M
hydrochloric acid
External phase:
Mixture of aqueous PVA solution and 0.01 M
sodium hydroxide solution.
The nebulized PLGA nanospheres were administered via
a spacer by using a constant volume respirator into the
trachea of the fasted guinea pig for 20 min.
After the administration of 3.9 I.U. /kg insulin with the
PLGA nanospheres, the blood glucose level was
reduced significantly and the hypoglycemia was
prolonged over 48 h, compared to the nebulized aqueous
solution of insulin as a reference (6 h).
This result could be attributed to the sustained releasing
of insulin from the nanospheres deposited widely on to
the whole of lung.(46)
PLGA nanosphere platform with chitosan
(CS) for gene delivery:
Method: Emulsion solvent diffusion (ESD)
method.
Internal phase:
The PLGA (100 mg) and pDNA complex
solution in acetone
External phase:
Chitosan (0.05%, w/v)-PVA (1%, w/v) mixed
solution was used as dispersing phase.
By coating the PLGA nanospheres with CS, the loading
efficiency of nucleic acid in the modified nanospheres
increased significantly.
The release profile of nucleic acid from PLGA
nanospheres exhibited sustained release after initial
burst.
The PLGA nanospheres coated with chitosan reduced
the initial burst of nucleic acid release and prolonged the
drugs releasing at later stage.
Chitosan coated PLGA nanosphere platform was
established to encapsulate satisfactorily wide variety of
nucleic acid for an acceptable gene deliverysystem.(47)
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 20
Method and solvent system Research findings
Cyclosporin A (CyA) loaded PLA-PEG
micro- and nanoparticles.
Method: Emulsion-solvent evaporation
method.
Internal phase:
CyA dissolved in dichloromethane
With PLA-PEG microparticles
External phase:
0.3% (w/v) Polyvinyl alcohol (PVA) aqueous
solution.
In vitro release experiments revealed that PLA-PEG
particles provided a more adequate control of CyA
release than conventional PLA micro- and
nanoparticles.
Physico-chemical characterization of the systems during
the release studies showed that the developed PLA and
PLA-PEG micro- and nanoparticles were not degraded,
which suggest a diffusion-mediated release mechanism.
Furthermore, hypothesized that the hydrophilic outer
shell of PEG provides a stationary layer for the diffusion
of CyA.(48)
9) Nanoparticles/Nanocrystals:
The technology of particle size reduction to the nano-scale usually results in a
significant increase in drug solubility and dissolution rate with subsequent improvement
of drug bioavailability for fine drug powders, the effect of surface area is more
pronounced and the dissolution velocity is highly enhanced. In addition, the saturation
solubility of the drug can be highly increased by converting the drug particles to the
nano-scale. Nanoparticle precipitation by the anti-solvent method is a direct and simple
procedure for the preparation of drug nanocrystals.
However, it is usually difficult to control the particle size in the submicron region and
the addition of surfactant as stabilizer is necessary to avoid the formation of
microparticles.The hazards of organic solvent residuals emerged the use of supercritical
fluid-based technologies as new preparation methods of drug nanocrystals. The
commonly known processes are supercritical anti-solvent precipitation and rapid
expansion of supercritical solutions.
Table: 1.9 Application of spherical crystallization for preparation of
Nanoparticles/Nanocrystals. Method and solvent system Research findings
Indomethacin (IMC) nanocrystals
Method: Emulsion solvent diffusion method
Internal phase: Ethanolic drug solution
External phase: aqueous Beta Cyclodextrin
solution.
The prepared IMC nanocrystals showed a uniform
particle size distribution with an average diameter in
the range of 300–500 nm.
Compared to the commercial drug powder, fast and
complete dissolution of IMC was achieved as a result
of particle size reduction to the nano-order and
polymorphic change to a meta-stable form.(49)
Cystatin PLGA nanoparticles (NP).
Method: Emulsion solvent diffusion method
Internal phase:
Ethyl acetate/ dichloromethane
and acetone (1:1) with Cystatin and PLGA
External phase:
aqueous solution of PVA (5%, w/v)
A trehalose and a mixture of sugars was used as
cryoprotectant and bovine serum albumin (2%,
w/v), as lyoprotectant alone or in combination
with sugars.
The protein activity was preserved more in the case
when protectants were in direct contact with cystatin,
protecting it during the whole NP-formation.
Furthermore, NP-entrapped cystatin is more stable
than a solution of free cystatin, and that the stability is
increased by the selection of optimal PLGA
derivatives.(50)
Amorphous cefuroxime axetil (CFA)
nanoparticles
Method:Anti-solvent method
Cefuroxime axetil solution poured into the anti-
solvent under magnetic stirring and the
precipitation was formed immediately upon
mixing.
The CFA nanoparticles produced via the controlled
nanoprecipitation are amorphous with a narrow PSD.
The dissolution of nanosized CFA is significantly
enhanced compare with the spray-dried CFA. In
conclusion, the controlled nanoprecipitation method
offers a direct process to obtain drug nanoparticles of
controllable size, amenable for continuous and
consistent production.(51)
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 21
Method and solvent system Research findings
Oridonin(ORI)-PLA nanoparticles(NP)
Method:
Modified spontaneous emulsion solvent diffusion
Internal phase:
ORI and PLA co-dissolved in the mixture of
acetone and ethanol
External phase:
Aqueous phase containing Poloxamer 188
The release of ORI from the PLA nanoparticles was
in a biphasic way, which could be expressed well by
the Higuchi equation. When these formulations of
nanoparticles injected, ORI could obtain prolonged
circulation time and accumulate in liver, spleen and
lung. The results of research provided a towardly new
thought and method for the effective delivery of
ORI.(52)
PLGA nanoparticles (NP) for mini-depot
tablets preparation by direct compression.
Method: Modified spontaneous emulsion solvent
diffusion
Internal phase:PLGA was dissolved in the
mixture of acetone or acetonitrile and alcohol
External phase: PVA solution (4%, w/w) in DW.
Prepared the mini tablets by using PLGA
nanoparticles and drug substance. PLGA
nanoparticles seemed to provide long-acting matrix
tablets by direct compression with drug, and the drug
release rate could be controlled simply by choosing
polymer species, mixing ratio and surface area of
tablets, and may be useful for implantable depot
use.(53)
Cyclosporine A(CyA) pH-sensitive
nanoparticles
Method:QESD
Internal phase:CyA and the pH-sensitive polymer
were co-dissolved in ethanol.
External phase: Aqueous solution of Poloxamer
188
The pH-sensitive polymers: Eudragit (L100-55,
L100, S100 and E100.)
In vitro release experiments revealed that the
nanoparticles exhibited perfect pH-dependant release
profiles. The relative bioavailability of CyA was
markedly increased, with these results; the potential
of pH-sensitive nanoparticles for the oral delivery of
CyA was confirmed.(54)
PLA and PLGA nanopartieles
Method:
Binary organic solvent diffusion
Internal phase: PLA or PLGA was dissolved in
binary Organic solvent consisting of acetone and
ethanol.
External phase: Aqueous PVA solution.
Binary organic solvent has an important role in
improving the yields and size of nanoparticles. The
yields of nanoparticles increase with the increase of
ethanol in the acetone solution and attain the
maximum at the cloud point of ethanol, while the size
of nanoparticles decreases with the increase of
ethanol in the acetone solution and attains the
minimum at the cloud point of ethanol.(56)
solid lipid nanoparticles
Method: Solvent emulsification–diffusion
technique
Internal phase: Solvent(Benzyl alcohol or butyl
lactate)-saturated aqueous solution containing
GM to it add solvent-saturated aqueous solution
containing emulsifier
External phase: water.
The method produce solid lipid nanospheres with the
emulsification–diffusion process using benzyl alcohol
or butyl lactate. The use of these solvents should be
useful to prepare drug-loaded nanospheres as carrier
systems.
A relatively high lipid load could be obtained
increasing the temperature process. Furthermore, the
GMS nanospheres are attractive for different
applications because of their submicron-sized
structure, narrow size distribution and their
biodegradability.(55)
Cyclosporine(CyA)PLA-PEG micro-and
nanoparticles:
Method: Emulsion-solvent evaporation method
Internal phase: CyA dissolved in DCM
containing nanoparticles or microparticles of
PLA or PLA-PEG.
External phase: 0.3% (w/v) PVA aqueous
solution.
PLA-PEG particulate carriers with different particle
sizes can be designed as new CyA carriers, showing
promising characteristics as compared with
conventional PLA micro- and nanoparticles.CyA-
loaded PLA-PEG micro- and nanoparticles provide
new opportunities to improve present marketed CyA
formulations, to improve CyA-based therapies in the
areas of CyA biomedical application.(57)
10) Microparticles:
The techniques of obtaining microcrystals or submicron size particles or even
amorphous particles with a controlled particle size distribution and polymorphic purity
using solvent change precipitation. The use of stabilizing agents improves the drug
dissolution rates. These approaches are advantageous against the traditional milling
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 22
techniques. Jet-milling, milling in a pearl-ball mill or high-pressure homogenizations
frequently produce agglomerates due to the high energetic surfaces creating materials
with poor wettability properties.Microcrystallization by precipitation permits
homogeneous systems of small and non-cohesive particles of different poor water
soluble drugs with enhanced dissolution properties to be obtained.
Table: 1.10 Application of spherical crystallization for preparation of
Microparticles. Method and solvent system Research findings
Microparticles of β-lapachone
Method:
Solvent change precipitation
Internal phase:
β-lapachone ethanolic solution
External phase:
Aqueous phase with low viscosity HPMC
β-lapachone microparticles are crystalline with a
narrow particle size distribution, small mean particle
size and an enhanced drug dissolution rate. Compared
to other technological approaches to increase β-
lapachone solubility as Cyclodextrin inclusion
complex, the amount of drug in the preparation is
much higher (≈90%) and as a consequence the
Solvent change technique is more suitable in
developing oral solid dosage forms.(58)
In situ forming microparticle (ISM) system of
leuprolide
Method:
Solvent change precipitation
Internal phase:
PLGA and leuprolide acetate in a solvent mixture
of methylene chloride and methanol.
External phase:
0.25% w/w PVA aqueous solution.
ISM prepared with PLGA combinations showed a
decreasing initial release with increasing low-
molecular-weight PLGA content. A slower solvent
diffusion from the low-molecular-weight PLGA
solution droplets into the release medium led to a less
porous structure of the resulting microparticles, thus
explaining the lower initial release.PLGA with free
carboxylic acid end groups led to a lower drug release
compared to PLGA with esterified end groups.
Six-month controlled release leuprolide ISM could be
obtained by blending poly (lactides) (PLA) with
different molecular weights.(59)
11) Beads formation:
When preliminary granulation is necessary, the spherical crystallization technique
appears to be an efficient alternative for obtaining particles destined for direct tableting
in the form of beads, since crystallization and agglomeration are carried out in a single
step without any filler. The principal aim of bead formation was to improve mechanical
properties of the solid drugs such as flowability, packability or compressiablity.The
different results have pointed out the importance of the particle texture, since a
modification of the internal microstructure, crystal size or organization can change the
mechanical properties.
Table: 1.11 Application of spherical crystallization for Beads formation. Method and solvent system Research findings
Ketoprofen Beads
Method: Emulsion solvent diffusion
technique(two-solvent system)
Internal phase: Ketoprofen dissolved in
acetone
External phase: demineralized water
(50 ml) containing an emulsifier.
Polymers:
Ethylcellulose cross-linked PVP and
cross-linked CMC, PVP and Eudragit
and colloidal silica.
Formulations with the methacrylic acid derivatives were found
to be incompatible with the operating conditions, in terms of
temperatures changes, stirring or residence time.
Optimization of the formulation with ethylcellulose yielded a
controlled release form with 1% of the polymer, whereas the
addition of very low concentrations increased the drug release.
Ethylcellulose acts as a surface agent, modifying the surface
properties of the beads and so improving the wettability of the
drug.
At large concentrations, this effect is masked by the creation
of a diffusional barrier.(60)
12) Dry powder inhalations (DPIs):
Dry powder inhalations (DPIs) of steroids have been used clinically for the delivery of
the drugs into the bronchi or alveoli for the treatment of asthma. In order to prepare a
DPI formulation, it is required that the aerodynamic diameter of the active components
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 23
should be 0.5–7 mm so as to allow their deposition on the proper area of the lung tissue.
However, the cohesion between the drug particles or the adhesion of the drug particle to
carrier lactose often results in insufficient dispersion of the drug particles at emission,
thus leading to decreased amount of drug delivered to the respiratory tract. Particle
engineer for the DPI formulation of steroid found that aerosolization of the drug was
difficult due to its strong cohesive and adhesive properties. To overcome these
undesirable properties, improved the dispersion properties of this drug by forming
crystal agglomerates consisting of fine crystals suitable for DPI which easily disintegrate
into primary crystals by collision with the carrier lactose in the air stream by a newly
designed inhalation device.
Table: 1.12 Application of spherical crystallization for preparation of Dry powder
inhalations (DPIs). Method and solvent system Research findings
Ideal dry powder inhalation(DPI)
system of steroid KSR-592:
Method: Solvent change method Internal phase: KSR-592 in acetone
External phase: water
Bridging liquid: Ethyl acetate
The primary crystals in the agglomerates produced by the
bridging liquid in agitated aqueous medium grew until the
dispersing medium was saturated with the bridging liquid as
well as growing the agglomerates.
The growth rates of primary crystals and agglomerates
increased with an increase in the temperature and/or a
reduction in the agitation speed of the system.
The growth of primary crystals in the spherical
agglomerates was explained by a crystallization and fusion
mechanism.
The primary crystals were mechanically stronger than their
agglomerates so that the agglomerates were disintegrated
easily into the primary crystals, which retained their original
size, under the shear force generated on being mixed with
carrier particles for DPI.(61)
Agglomerated dry powder inhalation
formulation of steroid KSR-592( β-form
crystal):
Method: Solvent change method
Internal phase: KSR-592 crystals (α- form)
hexane containing 5% ethanol
External phase: cooled water with ethyl
acetate as bridging liquid.
The DPI formulation with these agglomerates exhibited
ideal fluidity and provided a larger fine particle fraction
than the formulation with agglomerates consisting of a-form
(plate-like) crystals.
The air-flow rate of inhalation had no effect on the
disintegration properties of these agglomerates, suggesting a
reliable inhalation performance in vivo.(62)
Insulin PLGA nanospheres for
Pulmonary delivery
Method: Modified emulsion solvent
diffusion method
Internal phase: PLGA and insulin in the
mixture of acetone and 0.01 M
hydrochloric acid
External phase: Mixture of aqueous PVA
solution and 0.01 M sodium hydroxide
solution.
Eighty five percent of the drug was released from the
nanospheres at the initial burst, followed by prolonged
releasing of the remaining drug for a few hours.
The aqueous dispersions of PLGA nanospheres
administered pulmonarily to the guinea pig via nebulization
reduced significantly the blood glucose level over 48 h,
compared to the nebulized aqueous solution of insulin as a
reference.This result could be attributed to the deposition of
nanospheres widely spread through the whole lung and the
sustained release of insulin from the deposited
nanospheres.(63)
Microsized spherical aggregates of
ultrafine ciprofloxacin(CPF)
Method: Neutralization technique
Internal phase:0.1N HCl
External phase:NaOH solution and
Isopropyl alcohol (IPA) as antisolvent
Drying method: Spray drying
CPF dry powder can form uniform spherical particles with
diameter of 3–4 μm and exhibited great improved aerosol
performance.
Spherical aggregates with ultrafine primary CPF particles
can be obtained and exhibited great improved aerosol
performance with fine particle fraction (FPF) up to
60%.(64)
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 24
13) Micronization by spherical crystallization:
For biopharmaceutical class II drugs, the bio-absorption process is rate-limited by
dissolution in gastrointestinal fluids. According to the Noyes–Whitney equation, the
dissolution rate of poorly water-soluble drugs could be increased by reducing the
particle size to the micro- or nano-scale thus increasing the interfacial surface area
The conventional approaches to produce untrafine drug particles can be divided into
top-down and bottom-up techniques.
In the case of top-down techniques which include jet-milling, pear/ball milling and
high-pressure homogenizing, the bulk drugs are comminuted into micro or nano-sized
range by the use of mechanical force. However, these techniques need high energy
input and exhibit some disadvantages in practice such as contamination of drugs,
variation of crystal structures, uncontrolled particle morphology, and broad particle size
distribution. In the last decade, bottom-up techniques that rely on dissolving the drug in
a solvent and precipitating it by the addition of a non-solvent, like supercritical fluid
(SCF) technique and liquid precipitation, have been widely investigated to obtain
ultrafine drug particles.
Emulsion solvent diffusion (ESD) method, proposed by Kawashima and their co-
workers developed the spherical crystallization technique which is an effective way
to prepare drug-loaded polymeric micro/nanoparticles for masking taste, controlled
release, drug targeting etc. In the usual applications of ESD method, drug and polymer
are dissolved in a suitable solvent with or without a bridging liquid. The solution is then
added into an aqueous medium (as a poor solution) under stirring and
the emulsion droplets are immediately formed in the external poor solution. As the ESD
proceeds, the solvent diffuses out of the droplets and water diffuses into the droplets.
Therefore, the drug and polymer are co-precipitated, leading to the solidification of
emulsion droplets.
Table: 1.13 Application of spherical crystallization for micronization.
Method and solvent system Research findings
Micronization of silybin
Method: Emulsion solvent diffusion
method
Internal phase: Acetone
External phase: Deionized water
containing 0.01–0.10 wt% SDS
The particle size and morphology could be controlled by
temperature and SDS concentration.
With the increase of temperature from 15 to 30 ◦C, the
morphology of the prepared silybin particles gradually
transformed from rod-shaped to spherical while the mean
particle size increased from 0.89 to 2.48µm. Moreover, the
mean particle size decreased
and the PSD became narrower with the increase of SDS
concentration. Compared to the commercial silybin powder, the
as-prepared silybin particles possessed decreased crystallinity
and showed very
similar chemical composition. More importantly, the
dissolution of the spherical and rod-shaped silybin particles was
markedly improved when compared to the commercial silybin
powder. Therefore, ESD method offers a potentially feasible
way to prepare
micronized drug particles with controlled size and
morphology.(65)
14) Improvement of drug substances physicochemical properties:
Due to different crystal habit many drugs show inconvenient flowability and
compressibility. These problems can be solved by converting them into recrystallized
agglomerated crystals by changing the crystal habit and spheronization so as to increase
the flowability, compressibility and other tablettability properties.
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 25
Table: 1.13 Application of spherical crystallization for improvement of
physicochemical properties of drug substances. Name of method and solvent system Research findings
Propyphenazone agglomerates
Method:SA (Solvent change method)
Solvent system
ethyl alcohol- isopropyl acetate-
demineralized water
The improvement in flowability contributes to making the filling
of the die easier and more precise and thus gives more
reproducible results.
Increase in tabletability and compatibility properties,
helps to obtain a material for direct compression.
The prepared agglomerated crystals were small, favorable to
compression.(66)
Aceclofenac agglomerates
Method:SA (Solvent change method)
Solvent system: chitosan in 1% glacial
acetic acid-Water or sodium citrate
solution.
Aceclofenac-chitosan crystals enhance its aqueous solubility and
dissolution rate.
The prepared crystals also exhibited exceptional stability and
better in vivo performance in comparison with pure drug.(67)
Acebutolol hydrochloride spherical
crystals
Method:QESDS
Solvent system: ethanol - water -
isopropyl acetate
The behavior of spherical crystallization via a quasi-emulsion
produced by pouring the good solvent solution of the drug into the
poor solvent and determined the diffusion rates of good solvent
or/and bridging liquid from the emulsion droplet into the
dispersing medium (= poor solvent).
The agitation speed of the system is the main parameter
determining the average diameter of agglomerated crystals.(68)
Benzoic acid spherical agglomerates
Method:SA (Solvent change
method)/QESDS
Solvent system: ethanol – Chloroform-
water.
Prepared spherical agglomerates appear in the larger size
fractions.
The agglomerate size increases with increasing initial solute
concentration and increasing agitation rate up to a certain level,
but there is no significant influence found on the mechanical
properties. A higher fraction of spherical agglomerates is obtained
when the bridging liquid is initially mixed into the feed solution,
instead of being added to the agitated solution afterwards.(69)
Acetylsalicylic acid spherical
agglomerates
Method: solvent-change technique
Solvent system:ethanol - carbon
tetrachloride–water mixture
The growth of particle size and the spherical form of the
agglomerates resulted in formation of products with good bulk
density, flow, compactibility and cohesivity properties.
The crystal agglomerates were developed for direct capsule-filling
and tablet-making.(70)
Ibuprofen spherical agglomerates
Method: solvent-change technique
Solvent system: (ethanol–water)
method
With Eudragit S100 as polymer
Particle size decreases while sphericity, surface roughness and
intraparticle porosity increase with polymer presence, probably
due to changes in habit and growth rate of ibuprofen
microcrystals, as well as to a coating developed before their
binding into spherical agglomerates.
Flow or packing behavior and densification of agglomerates at
low compression are determined by the sphericity changes.(71)
Aceclofenac spherical agglomerates
Method: QESDS
Solvent system: Acetone:
dichloromethane (DCM): water
HPMC as polymer
The dissolution rate of prepared tablets of prepared agglomerates
was better than that of marketed tablet and pure drug.
The optimized agglomerates and tablet formulations were found
to be stable for 6 months under accelerated conditions.
The results of preclinical studies revealed that the agglomerates
provided improved pharmacodynamic and pharmacokinetic
profiles of drug besides being nontoxic. The results of
pharmacokinetic studies of optimized tablet in human subjects
indicated improved pharmacokinetic parameters of drug in
comparison with that of marketed tablet.(72)
Ascorbic acid spherical
agglomerates
Method: spherical agglomeration (SA)
Solvent system: purified water (good
Solvent) - ethyl acetate (poor solvent)
The micromeritic properties like flowability and packability of the
spherically agglomerated crystals were preferably improved for
direct tableting.The improved compaction properties of the
agglomerated crystals were due to their fragmentation and plastic
deformation occurred significantly during compression.The
spherically agglomerated crystals were tableted directly without
capping.(73)
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 26
Name of method and solvent system Research findings
Aspartic acid spherical agglomerates
Method: salting-out
Solvent system: Water–Alcohol
Improve flowability, compressiability of the prepared
agglomerated crystals.(74)
Bucillamine spherical agglomerates
Method: Emulsion solvent diffusion method.
Solvent system: Ethanol: dichloromethane:
water HPMC
The excellent compatibility of agglomerates was
attributed to the fragmentation property and a greater
degree of plastic deformation under compression.
Spherical agglomerates possessed superior strength
characteristics to conventional crystals.(75)
Gliclazide (GL) spherical agglomerates
Method: solvent change method
Solvent system: Acetone-Water HPMC or Brij
35 as stabilizing agents
Higher dissolution rate compared to untreated sample.
Changing the concentration of drug and stabilizing agent
changed the size of crystals. However, dissolution
efficiency was more affected by drug concentration and
stabilizing agent type.(76)
Naproxen agglomerated crystals
Method: Solvent change method.
Solvent system: Acetone–water containing
HPC and disintegrant croscarmellose
sodium (Ac–Di–Sol)
Formation of products with 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 because of including the disintegrant in to
the particles. This was attributed to an increase in
the surface area of the practically water insoluble drug
when exposed to the dissolution medium.(77)
Mebendazole agglomerates crystals
Method: solvent change method with bridging
liquid
Solvent system: N, N-Dimethylformamide
(DMF)- water-bridging solvent
(hexane,octanol, or toluene)
Polymers (HPMC or Eudragit S100
These agglomerates crystals of Mebendazole exhibited
good flow properties, high bulk density and improved
compressibility.
These agglomerates also showed improved dissolution
compared to Mebendazole, however the crystals from
Eudragit had a poor drug release because of its pH
dependent release property, which failed to release in
acidic medium. Such a technique can successfully be
employed to generate ready-to-formulate API, thus
saving on time and effort at the formulator’s end.(78)
Mebendazole recrystallized agglomerates
Method: solvent change method without
bridging liquid Solvent system; N, N-Dimethylformamide
(DMF) - water with PVP and SLS.
The presence of additives like PVP and SLS shows the
impact on crystallization and leading to modified
performance.SLS improves the excellent dissolution
while PVP gives negative impact on dissolution
process.(79)
Mefenamic Acid and Nabumetone
agglomerates
Method: solvent change method with bridging
liquid
Solvent system:
Mefenamic Acid:Dimethylformamide (DMF)-
DW-Chloroform
Nabumetone: HPMC Ethanol-DW-
cyclohexane/n-hexane
Lecithin
Incorporation of polymer HPMC during agglomeration
significantly enhanced the dissolution rate of mefenamic
acid while incorporation of solubilizing agent lecithin
improved the solubility of nabumetone.
Thus, spherical agglomeration is an important technique
for improving direct compressibility of pharmaceutical
powders and is especially useful when the drug dosage is
high.(80)
Paracetamol recrystallized agglomerates
Method: Salting out method
Solvent system: Ethanol-Water With PVP
It was found that PVP is an effective additive
during crystallization of paracetamol and significantly
influenced the crystallization process and changed the
crystal habit.
These effects were attributed to adsorption of PVP onto
the surfaces of growing crystals. It was found that the
higher molecular weights of PVP (PVP 10 000 and PVP
50 000) were more effective additives than lower
molecular weight PVP (PVP 2000).(81)
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 27
Name of method and solvent system Research findings
Acebutolol HCl spherical agglomerates
Method: Emulsion solvent diffusion method.
Solvent system: Water-isopropyl acetate seed
crystals
(rug powder)
spherically agglomerated crystals prepared
by the spherical crystallization technique with a
two-solvent system exhibit improved flowability and
packability for direct tabletting.
The main factor in the improvement of these
micromeritic properties was a significant reduction in
interparticle friction, due to their spherical shape, and a
lower static electricity charge. Compressibility of the
agglomerates was much improved, due to the increased
interparticle bonding of agglomerates fractured during
compression.(82)
Celecoxib spherical agglomerates
Method: Solvent change method
Solvent system: Acetone-Water with PVP-
chloroform
Spherical agglomerates of celecoxib prepared with PVP
exhibited improved micromeritic properties in addition to
improving the solubility and dissolution rate.This
technique may be applicable for producing oral solid
dosage forms of celecoxib with improved dissolution rate
and oral bioavailability.(83)
Gliclazide Microcrystal’s
Method: solvent change method
Solvent system: Acetone-Water with
solubilizing agent
Micrystallization of GL in aceton resulted in cube or
diamond shape crystals whereas the untreated crystals
were rod like or columnar.
Using ultrahomogenizer and stabilizing agents produced
microcrystals, with higher dissolution rate, compared to
untreated sample.
Changing the concentration of drug and stabilizing agent
changed the size of crystals.
Dissolution efficiency was more affected by drug
concentration and stabilizing agent type.(84)
Acetaminophen spheres
Method: Cross-linking technique
Solvent system: Drug with carrageenan
aqueous solution- Aqueous solutions of cross-
linking agent.
The physical properties and the drug release from spheres
varied according to the amount of drug entrapped into the
spheres, level of polymer in the dispersion and the cross-
linking agent used.
The level of polymer in the dispersion was critical in
controlling the drug release.
Its ability to undergo gelation enables a gel matrix to be
formed and consequently control the drug release.(85)
Carbamazepine spherical agglomerates
Method: Solvent change method
Solvent system: Ethanol-water with isopropyl
acetate
Improved micromeritics of CBZ for direct tableting.
The micromeritic properties of the agglomerated crystals
like flowability, packability and compactibility were
dramatically improved.
The compression of treated carbamazepine samples
resulted in successful direct tableting without
capping.(86)
Fenbufen spherical agglomerates
Method: Solvent change method
Solvent system: Tetrahydrofuran- isopropyl
acetate- deminralized water
Improvement in dissolution capacity, probably due to
better wettability in presence of bridging liquid (isopropyl
acetate).(87)
Flurbiprofen spherical agglomerates
Method: Solvent change method
Solvent system: acetone-water-hexane
Spherical agglomerates exhibited improved flowability,
wettability and compaction behavior.(88)
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 28
Name of method and solvent system Research findings
Tolbutamide agglomerated crystals.
Method: solvent change method (SC),
Neutralization method(NT),
Quasi-emulsion solvent diffusion
method(QESD)
The Tolbutamide dissolution rate from the physical mixtures
and tablets increased the order of bulk ≤ QESD<SC<NT in
direct proportion to an increase in the specific surface area
of the agglomerated crystals.
In vivo studies in beagle dogs the physical mixture and
tablet of agglomerated crystals show significantly higher
value than those of bulk in area under the curve of plasma
concentration (AUC-8hr),Cmax,especially high value were
obtained with the NT physical mixture and tablet.(89)
Salicylic acid agglomerated crystals
Method: Solvent change method
Solvent system: Ethanol-water-chloroform
The crystallinity of the agglomerated Salicylic acid
decreased when the amount of ethanol in the solvent mixture
was decreased.
The wettability of agglomerated crystals increased when the
amount of ethanol in the solvent mixture was decreased and
this enhances the dissolution rate of the crystals. The
remarkable improvement in the flow and packing of the
agglomerated crystals enabled the direct compression of the
crystals.(90)
Mefenamic acid spherical crystals
The spherical crystals demonstrated good flowability and
compressibility and had more wettability than the drug
powder.
The tablets prepared from the spherical crystals had greater
mechanical strength and lower flowability than tablet made
from Mefenamic acid powder.(91)
Chlorpromazine HCl gelled microcapsules
Improve flowability, packability and compressibility of
prepared microcapsules.
By filling the microcapsules in hard gelatin capsules or
tabletting than, their drug release rates became retarded
compared with the physical mixture treated in same way
having the same formulation as the microcapsules.(92)
Agglomerated crystals of Acebutalol HCl The tensile strength of the tablet of agglomerated crystals
was greater than that of the original crystals.(93)
Roxythromycin spherical agglomerates
Method:Solvent change method
Solvent system: Methanol-Chloroform-Water.
Improved flowability, packability,
Wettability in comparison to conventional drug crystals.(94)
Aminophylline spherical agglomerates
Method:
Solvent system: Chloroform-Ethanol-Water
The resultant Aminophylline agglomerates were free
flowing and directly compressible due to their spherical
shape. (95).
Naproxen spherical agglomerates
Method:
Solvent system: Acetone-Water-Bridging
liquid(Hexinol, octanol,Toluene)
Improved the intrinsic compressibility and flow
characteristic of agglomerates, which is directly
compressible.(96)
Aspirin spherical agglomerates
Method:
Solvent system: Acid buffer-Methanol-
Chloroform
Significantly improved flow property, compressibility and
stability.(97)
Ampicillin trihydrate agglomerates
Method: ADS
Solvent system: Ammonia water-Acetone-
Dichloromethane.
Improved micromeritic properties, compressibility, and
compaction property. Tablet prepared from agglomerates
showed comparable drug release with that of obtained from
marketed product.(98)
Salicylic acid spherical agglomerates
Method:
Solvent system: Water-Ethanol-Chloroform.
Agglomerates are having excellent flow ability used directly
for the compression of tablet. (99)
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 29
Name of method and solvent system Research findings
Aspartic acid spherical agglomerates
Method:
Solvent system: Water (solvent)-Methanol
(salting out agent).
Agglomerates showed very good flowability and faster
rearrangement. (100)
Norfloxacin Agglomerates
Method: ADS
Solvent system: Ammonia water-Acetone-
Dichloromethane.
Improved micrometric and micrometrics properties.
(101)
Ibuprofen spherical agglomerates
Method:
Solvent system: Water-Ethanol
Increased compressibility, dissolution rate. (102)
Acetyl salicylic acid agglomerates
Method:
Solvent system: Ethanol-Water-carbon
tetrachloride.
Agglomerates are having excellent flow properties and
favorable compact ability, cohesiveness and tablet
ability value(103)
Ascorbic acid spherical crystasls
Method: SA and QESDS
Solvent system: Purified water-Ethyl acetate-
Methanol.
Improved the micrimeratic and compaction properties
of the original Ascorbic acid crystals. (104)
Enoxacin spherical crystasls
Method: ADS
Solvent system: Ammonia water-Acetone-
Dichloromethane
Improved flowability, packability without much delay
in their dissolution rate.(105)
Bucillamine spherical crystasls
Method: SA and QESDS
Solvent system: Ethanol-Dichloromethane-water.
Agglomerates show excellent compatibility,
Packability.(106)
Ibuprofen microsphere
Method: QESDS
Solvent system: Ethanol-Water with sucrose fatty
acid ester.
Improved Flowability, packability
Compressibility of the resultant microspheres. (107)
Tolbutamide agglomerates
Method: Neutralization technique
Solvent system: NaoH solution-Aqueous
solution with polymer or surfactant-1M HCl.
Increased dissolution rate, flowability, and solubility of
agglomerated crystals.(108)
Dibasic calcium phosphate agglomerates
Method: Solvent change method
Solvent system: Water-Aqueous solution of
phosphoric acid Citric acid.
Free flowing, porous directly compressible
agglomerated crystals formed.(109)
Tranilast agglomerates
Method: Solvent change method
Solvent system: Ethanol/Acetone-Water-
Chloroform/Dichloromethane.
Improved in vitro availability as well as micromeratic
properties such as flowability, packability.(110)
Acebutalol HCl agglomerates
Method: QESDS
Solvent system:Water-Ethanol-Isopropyl acetate
Agitation speed is a main factor for controlling
diameter. Improved flowability, compressibility of
prepared agglomerated crystals.(111)
1.5. References:
1. Chouracia MK, Jain A, Valdya S and Jain SK (2004) Utilization of spherical
crystallization for preparation of directly compressible materials. Indian
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2. Kawashima Y, Imai M, Takeuchi H, Yamamoto H and Kamiya K (2002)
Development of agglomerated crystals of Ascorbic acid by the spherical
crystallization techniques. KONA. 20(3); 251-61.
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 30
3. Szabo RP, Goczo H, PintyeHodi K, Kasajr P, Eros I, HasznosNezdei M and
Farkas B (2001) Development of spherical crystals of an Aspartic acid salt for
direct tablet making. Powder Technology.114; 118-24.
4. Goczo H, Szabo RP, HasznosNezdei M and Farkas B et al (2000) Development
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making.Chem.Pharm.Bull. 48(12); 1877-81.
5. Kawashima Y, Yang L, Nito M and Takenaka H (1982) Direct agglomeration of
sodium theophylline crystals produced by salting out in the
liquid.Chem.Pharm.Bull.30 (5);1837-43.
6. Kawashima Y, Cui F, Takeuchi H, Hino T, Niwa T and Kiuchi K (1995)
Parameters determining the agglomeration behavior and the micrometric
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crystallization technique with miscible solvent system.Int.J.Pharm.119;139-147.
7. Bermer GG and Zuiderweg FG (1992) Proceedings of international symposium
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8. Bose AJ and Herens JJ (1982) Light backscattering technique to measure solid
particle size and concentration in suspension.Chem.Eng.Commum. 16; 301-11.
9. Paradkar A R, Pawar A P, Mahadik KR and Kadam SS (1994) Spherical
crystallization: A novel particle design technique. Indian Drug.31 (6); 229-33.
10. Kawashima Y, Okumura M and Takenaka H (1982) Spherical crystallization:
direct spherical agglomeration of Salicylic acid crystals during crystallization.
Science. 216(4); 1127-28.
11. Martino DP, Cristofaro DP, Barthememy C and Joiris E (2000) Improved
compression properties of Propyphenazone spherical crystals. Int. J. Pharm.
197; 95-100.
12. Morshima K and Kawashima Y (1993) Micrometric characteristic and
agglomeration mechanism I the spherical crystallization of Bucilllamine by the
spherical agglomeration and the emulsion solvent diffusion method. Powder
Technology. 76; 57-61.
13. Kawashima Y, Takeuchi H and Hino T (1990) Particle design of Enoxacin by
spherical crystallization technique I, principal of ammonia diffusion system
(ADS). Chem.Pharm.Bull.38; 2537-2540.
14. Pucchagut HG, Bianchotti J and Chiale CA (1998) Preparation of Norfloxacine
spherical agglomerates by ammonia diffusion system. J. Pharm. Sci. 87; 519-23.
15. Sano A, Kuriki T, Kawashima Y, Takeuchi H, Hino T and Niwa T (1992)
Particle design of Tolbutamide by the spherical crystallization technique IV,
Improved of dissolution and bioavailability of direct compression tablets
prepared using Tolbutamide agglomerated crystals.Chem.Pharm.Bull.40;3030-
3035.
16. Deshpande MC, Mahadik KR, Pawar AP and Paradkar AR (1997) Evaluation of
spherical crystallization as particle size enlargement technique for
Aspirin.Ind.J.Pharm.Sci.59 (1); 32-34.
17. Kawashima Y, Takeuchi H, Hino T, Niwa T and Kiuchi K (1994) Improvement
in flowability and compressibility of pharmaceutical crystals for direct tabletting
by spherical crystallization with a two solvent system. Powder Technology. 78;
151-157.
18. Morshima K, Kawashima Y, Takeuchi H, Niwa T and Hino T (1994) Tabletting
properties of Bucillamine agglomerates prepared by the spherical crystallization
technique.Int.J.Pharm.105;11-18.
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 31
19. Kawashima Y, Cui F, Takeuchi H, Hino T, Niwa T and Kiuchi K (1995)
Improved static compression behavior of tablettabilities of spherically
agglomerated crystals produced by the spherical crystallization technique with
two solvent system.Pharm.Res.12;1040-44.
20. Cui F, Yang M, Jiang Y, Cun D, Lin W, Fan Y, Kawashima Y (2003) Design of
sustained-release nitrendipine microspheres having solid dispersion structure by
quasi-emulsion solvent diffusion method. J.Control.Rel. 91; 375–384.
21. Yang M, Cui F, You B, Fan Y, Wang L, Yue P, Yang H (2003) Preparation of
sustained-release nitrendipine microspheres with Eudragit RS and Aerosil using
quasi-emulsion solvent diffusion method. Int. J.Pharm. 259; 103–113.
22. Yang M, Cui F, You B, You J, Wang L, Zhang L, Kawashima Y (2004) A
novel pH-dependent gradient-release delivery system for nitrendipine I.
Manufacturing, evaluation in vitro and bioavailability in healthy dogs. J.
Control. Rel. 98; 219– 229.
23. Jayaswal SB, Reddy TSR, Kumar MV and Gupta VK (1993) Preparation and
evaluation of Captopril microspheres by spherical crystallization. Indian Drug.
32(9); 454-457.
24. Kachirmanis K, Ktistis G and Malamatris S (1998) Crystallization conditions
and physico-chemical properties of Ibuprofen-Eudragit S-100 spherical crystal
agglomerates prepared by solvent change technique. Int.J.Pharm. 173; 61-74.
25. Julide A (1989) Preparation and evaluation of controlled release Furosemide
microspheres by spherical crystallization. Int.J.Pharm. 53; 99-100.
26. Gao Y, Cui F, Guan Y, Yang L, Wang Y, Zhang L (2006) Preparation of
roxithromycin-polymeric microspheres by the emulsion solvent diffusion
method for taste masking. International Journal of Pharmaceutics. 318; 62–69.
27. Kawashima Y, Aoki S, Takenaka H and Miyake Y (1984) Preparation of
spherically agglomerated crystals of Aminophylline. J.Pharm.Sci.73 (10); 1407-
10.
28. Kawashima Y, Lin SY, Ogawa M, Tanda T and Takenaka H (1985)
Preparations of agglomerated crystals of polymorphic mixtures and a new
complex of Indomethacin-Epirazol by spherical crystallization technique. J.
Pharm. Sci. 74(11); 1152-56.
29. Pawar AP, Paradkar AR, Kadam SS, and Mahadik KR (2004) Crystallo-co-
agglomeration: A Novel Technique to Obtain Ibuprofen-Paracetamol
Agglomerates. AAPS PharmSciTech. 5 (3); Article 44.
30. Pawar A, Paradkar A, Kadam S, and Mahadik K (2004) Agglomeration of
Ibuprofen with Talc by Novel Crystallo-Co-Agglomeration Technique. AAPS
PharmSciTech. 5 (4); Article 55.
31. Jadhav N, Pawar A and Paradkar A (2007) Design and Evaluation of
Deformable Talc Agglomerates Prepared by Crystallo-Co-Agglomeration
Technique for Generating Heterogeneous Matrix. AAPS PharmSciTech. 8 (3);
Article 59.
32. 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.
33. Perumal D (2001) Microencapsulation of ibuprofen and Eudragit® RS 100 by
the emulsion solvent diffusion technique. Int. J. Pharm. 218; 1–11.
34. Yeo Y and Park K (2004) Characterization of Reservoir-Type Microcapsules
Made By the Solvent Exchange Method. AAPS PharmSciTech. 5 (4); Article
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Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 32
35. Comogclu T, Gonul N, Baykara T (2003) Preparation and in vitro evaluation of
modified release ketoprofen microsponges. IL Farmaco. 58; 101-/106.
36. Nokhodchi A, Jelvehgari M, Siahi MR, Mozafari MR (2007) Factors affecting
the morphology of benzoyl peroxide microsponges. Micron. 38; 834–840.
37. Jelvehgari M, Siahi-Shadbad MR, Azarmi S, Martin GP, Nokhodchi A(2006)
The microsponge delivery system of benzoyl peroxide: Preparation,
characterization and release studies., Int. J. Pharma. 308; 124–132.
38. Orlu M, Cevher E, Araman A (2006) Design and evaluation of colon specific
drug delivery system containing flurbiprofen microsponges. Int. J. Pharm. 318;
103–117.
39. Comoglu T, Gonul N, Baykara T (2002) The effects of pressure and direct
compression on tabletting of microsponges. Int. J. Pharm. 242; 191–195.
40. Kawashima Y, Takeuchi H, Hino T, Niwa T and Ito Y (1992) Controlled of the
prolonged drug release and compression properties of Ibuprofen microsponges
with the acrylic polymers, Eudragit RS, by changing their intraparticle porosity.
Chem.Pherm.Bull.40 (1); 196-201.
41. Sato Y, Kawashima Y, Takeuchi H, Yamamoto H (2003) In vivo evaluation of
riboflavin-containing microballoons for floating controlled drug delivery system
in healthy human volunteers. J.Control.Rel. 93; 39– 47.
42. Sato Y, Kawashima Y, Takeuchi H, Yamamoto H (2004) In vitro evaluation of
floating and drug releasing behaviors of hollow microspheres (microballoons)
prepared by the emulsion solvent diffusion method. Eur. J.Pharm. and
Biopharm. 57; 235–243.
43. Kawashima Y, Takeuchi H, Hino T, Niwa T and Itoh Y (1992) Hollow
microspheres for use as floating controlled drug delivery system in the
stomach.J.Pharm.Sci.81 (2); 135-39.
44. Yamamoto H, Kuno Y, Sugimoto S, Takeuchi H, Kawashima Y(2005)
Surface-modified PLGA nanosphere with chitosan improved pulmonary
delivery of calcitonin by mucoadhesion and opening of the intercellular tight
junctions. J. Control. Rel. 102; 373–381.
45. Quintanar-Guerrero D, Tamayo-Esquivel D, Ganem-Quintanar A, Allemanna E,
Doelker E (2005) Adaptation and optimization of the emulsification-diffusion
technique to prepare lipidic nanospheres. Eur. J. Pharm. Sci. 26; 211–218.
46. Kawashima Y, Yamamoto H, Takeuchi H, Fujioka S, Hino T (1999)
Pulmonary delivery of insulin with nebulized DL-lactide / glycolide copolymer
(PLGA) nanospheres to prolong hypoglycemic effect. J. Control. Rel. 62; 279–
287.
47. Tahara K, Sakai T, Yamamoto H, Takeuchi H, Kawashima Y (2008)
Establishing chitosan coated PLGA nanosphere platform loaded with wide
variety of nucleic acid by complexation with cationic compound for gene
delivery. Int.J. Pharm. 354(1-2);210-216.
48. Gref R, Quellec P, Sanchez A, Calvo P, Dellacherie E, Alonso MJ (2001)
Development and characterization of CyA-loaded poly(lactic acid)-
poly(ethylene glycol)PEG micro- and nanoparticles. Comparison with
conventional PLA particulate carriers. Eur. J.Pharm. and Biopharm. 51; 111-
118.
49. Makhlof A, Miyazaki Y, Tozuka Y, Takeuchi H (2008) Cyclodextrins as
stabilizers for the preparation of drug nanocrystals by the emulsion solvent
diffusion method. Int. J.Pharm. 357; 280–285.
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Direct tabletting and BA improvements of MA by spherical crystallization tech. 33
50. Cegnar M, Kos J, Kristl J (2004) Cystatin incorporated in poly (lactide-co-
glycolide) nanoparticles: development and fundamental studies on preservation
of its activity. Eur. J. Pharm. Sci. 22; 357–364.
51. Zhang JY, Shen ZG, Zhong J, Hu TT, Chen JF, Mac ZQ, Yun J(2006)
Preparation of amorphous cefuroxime axetil nanoparticles by controlled
nanoprecipitation method without surfactants. Int. J.Pharm. 323; 153–160.
52. Xing J, Zhang D, Tan T (2007) Studies on the oridonin-loaded poly (d, l-lactic
acid) nanoparticles in vitro and in vivo. Int. J. Bio. Macromolecul. 40; 153–158.
53. Murakami H, Kobayashi M, Takeuchi H, Kawashima Y (2000) Utilization of
poly (DL-lactide-co-glycolide) nanoparticles for preparation of mini-depot
tablets by direct compression. J.Control. Rel. 67; 29–36.
54. Dai J, Nagai T, Wang X, Zhang T, Meng M, Zhang Q (2004) pH-sensitive
nanoparticles for improving the oral bioavailability of cyclosporine A. Int. J.
Pharm. 280; 229–240.
55. Trotta M, Debernardi F, Caputo O (2003) Preparation of solid lipid
nanoparticles by a solvent emulsification–diffusion technique. Int. J. Pharm.
257; 153–160.
56. Xin-yu J, Chun-shan Z, Ke-wen T (2003) Preparation of PLA and PLGA
nanoparticles by binary organic solvent diffusion method. J. Cent. South Univ.
Technol.10; No. 3.
57. Gref R, Quellec P, Sanchez A, Calvo P, Dellacherie E, Alonso MJ(2001)
Development and characterization of CyA-loaded poly(lactic acid)-
poly(ethylene glycol)PEG micro- and nanoparticles. Comparison with
conventional PLA particulate carriers. Eur. J. Pharm. and Biopharm. 51; 111-
118.
58. Marcılio SS. Filho C, Martınez-Pacheco R, Landın M (2008) Dissolution rate
enhancement of the novel antitumoral b-lapachone by solvent change
precipitation of microparticles. Eur. J. Pharm. and Biopharm. 69; 871–877.
59. Luan X, Bodmeier R (2006) Influence of the poly (lactide-co-glycolide) type
on the leuprolide release from in situ forming microparticle systems. J. Control.
Rel. 110; 266–272.
60. Tchoreloff RP, 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.
61. Ikegami K, Kawashima Y, Takeuchi H, Yamamoto H, Isshiki N, Momose D,
Ouchi K (2002) Primary crystal growth during spherical agglomeration in
liquid: designing an ideal dry powder inhalation system. Powder Technology.
126; 266– 274.
62. Ikegami K, Kawashima Y, Takeuchi H, Yamamoto H, Mimura K, Momose D,
Ouchi K (2003) A new agglomerated KSR-592 b-form crystal system for dry
powder inhalation formulation to improve inhalation performance in vitro and
in vivo. J.Control Rel. 88; 23–33.
63. Kawashima Y, Yamamoto H, Takeuchi H, Fujioka S, Hino T(1999)
Pulmonary delivery of insulin with nebulized DL-lactide / glycolide copolymer
(PLGA) nanospheres to prolong hypoglycemic effect. J. Control. Rel. 62; 279–
287.
64. Hong Zhao, Yuan Le , Haoying Liu , Tingting Hu , Zhigang Shen , Jimmy Yun
, Jian-Feng Chen (2009) Preparation of microsized spherical aggregates of
ultrafine ciprofloxacin particles for dry powder inhalation (DPI).Powder
Technology. 194; 81–86.
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 34
65. Zhang ZB, Shen ZG, Wang JX, Zhang HX, Zhao H, Chen JF, Yun J (2009)
Micronization of silybin by the emulsion solvent diffusion method. Int. J.
Pharm. 376; 116–122.
66. Martino PD, Cristofaro RD, Barthelemy C, Joiris E, Filippo GP, Sante M(2000)
Improved compression properties of propyphenazone spherical crystals. Int. J.
Pharm. 197; 95–106.
67. Mutalik S, Anjua P, Manoja K, Ushaa AN (2008) Enhancement of dissolution
rate and bioavailability of aceclofenac: A chitosan-based solvent change
approach. Int. J.Pharm. 350; 279–290.
68. Kawashima Y, Cui F ,Takeuchi H, Niwa T, Hino T, Kiuchi K(1995)
Parameters determining the agglomeration behaviour and the micromeritic
properties of spherically agglomerated crystals prepared by the spherical
crystallization technique with miscible solvent systems. Int. J. Pharma. 119;
139-147.
69. Katta J, Rasmuson AC (2008) Spherical crystallization of benzoic acid. Int. J.
Pharma. 348; 61–69.
70. SzaboRevesz P, Hasznos-Nezdei M, Farkas B, Goczo H, Pintye-Hodi K, Eros I
(2002) Crystal growth of drug materials by spherical crystallization. J. Cry.
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71. Kachrimanis K, Ktistis G, Malamataris S (1998) Crystallisation conditions and
physicomechanical properties of ibuprofen–Eudragit S100 spherical crystal
agglomerates prepared by the solvent-change technique. Int. J. Pharm. 173; 61–
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72. Usha AN, Mutalik S, Reddy MS, Ranjith AK, Kushtagi P, Udupa N(2008)
Preparation and, in vitro, preclinical and clinical studies of aceclofenac
spherical agglomerates. Eur. J. Pharm. and Biopharm.70(2);674-683.
73. 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 Technology, 130; 283– 289.
74. SzaboRevesz P, Goczo H, PintyeHodi K, Kasajr P, Eros I, Hasznos-Nezdei M,
Farkas B (2001) Development of spherical crystal agglomerates of an aspartic
acid salt for direct tablet making. Powder Technology. 114; 118–124.
75. Morishima K, Kawashima Y, Takeuchi H, Niwa T, Hino T(1994) Tabletting
properties of bucillamine agglomerates prepared by the spherical crystallization
technique. Int. J. Pharm. 105; 11-18.
76. Varshosaz J, Talari R, Mostafavi SA, Nokhodchi A (2008) Dissolution
enhancement of gliclazide using in situ micronization by solvent change
method. Powder Technology. 187(3);222-230.
77. Nokhodchi A and Maghsoodi M (2008) Preparation of Spherical Crystal
Agglomerates of Naproxen Containing Disintegrant for Direct Tablet Making
by Spherical Crystallization Technique. AAPS PharmSciTech. Vol 9; No. 1.
78. Kumar S, Chawla G, Bansal AK (2008) Spherical Crystallization of
Mebendazole to Improve Processability. Pharm. Dev. Technol. 1–10.
79. Kumar S, Chawla G, and Bansal AK (2008) Role of Additives like Polymers
and Surfactants in the Crystallization of Mebendazole. Yakugaku Zasshi 128(2);
281 289.
80. Viswanathan CL, Kulkarni SK, and Kolwankar DR (2006) Spherical
Agglomeration of Mefenamic Acid and Nabumetone to Improve Micromeritics
and Solubility: A Technical Note. AAPS PharmSciTech.7 (2); Article 48.
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Direct tabletting and BA improvements of MA by spherical crystallization tech. 35
81. Garekani HA, Ford JL, Rubinstein MH, Rajabi-Siahboomi AR (2000) Highly
compressible paracetamol: I: crystallization and Characterization. Int. J. Pharm.
208; 87–99.
82. Kawashima Y, Cuib F, Takeuchi H, Niwa T, Hino T and Kiuchi K (1994)
Improvements in flowability and compressibility of pharmaceutical crystals for
direct tabletting by spherical crystallization with a two-solvent system. Powder
Techdogy. 78; 151-157.
83. 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.
84. Varshosaz J, Talari R, Mostafavi SA, Nokhodchi A (2008) Dissolution
enhancement of gliclazide using in situ micrcronization by solvent change
method. Powder Technology.
85. Garcia AM, Ghaly ES (1996) Preliminary spherical agglomerates of water
soluble drug using natural polymer and cross-linking technique. J. Control. Rel.
40; 179-186.
86. Nokhodchi A, Maghsoodi M, Hassan-Zadeh D, Barzegar-Jalali M(2007)
Preparation of agglomerated crystals for improving flowability and
compactibility of poorly flowable and compactible drugs and excipients.
Powder Technology. 175; 73–81.
87. Martino PD, Barthelemy C, Piva F, Joiris E and Marthelemy C(1999) Improved
dissolution behavior of Fenbufen by spherical crystallization. Drug
Dev.Ind.Pharm.25 (10); 1073-1081.
88. Chourasia MK, Jain SK, Jain S and Jain NK (2003) Preparation and
characterization of agglomerates of Flurbiprofen by spherical crystallization
technique. Ind.J.Pharm.Sci.287-291.
89. Sano A, Kuriki T, Kawashima Y, Takeuchi H, Hino T and Niwa T (1992)
Particle design of Tolbutamide by the spherical crystallization technique IV,
Improved of dissolution and bioavailability of direct compression tablets
prepared using Tolbutamide agglomerated crystals.Chem.Pharm.Bull.40; 3030-
3035.
90. Kawashima Y, Takenaka H, Okumura M and Kojma K (1984) Direct
preparation of spherically agglomerated Salicylic acid crystals using
crystallization. J.Pharm.Sci.73 (11); 1534-38.
91. Bhadra S, Kumar M, Jain S, Agrawal S and Agrawal GR (2004) Spherical
crystallization of Mefenamic acid. Pharmaceutical Technology. 66-76.
92. Niwa T, Takeuchi H, Hino T, Kawashima Y, Kiuchi K et al (1994) Preparation
of agglomerated crystals for direct tabletting and microencapsulation technique
with a continuous system.Pharm.Res.11;478-484.
93. Kawashima Y, Cui F, Niwa T, Takeuchi H, Kiuchi K, et al (1994) Improved
static compression behavior and tablettabilities of spherically agglomerated
crystals produced by the spherically crystallization technique. Pharm.Res.12;
1040-44.
94. Chouracia M K, Jain SK, Jain S, Jain N and Jain N K (2004) Preparation and
characterization of spherical crystal agglomerates for direct tabletting by the
spherical crystallization technique. Indian Drugs .41(4); 214-20.
95. Kawashima Y, Aoki S and Takenaka H (1982) Spherical agglomeration of
Aminophylline crystals during reaction in liquid by the spherical crystallization.
Chem. Pharm. Bull.30 (5); 1900-1902.
Chapter 1: Introduction and Literature Review
Direct tabletting and BA improvements of MA by spherical crystallization tech. 36
96. Gordon MS and Chowhan ZT (1990) Manipulation of Naproxen particle
morphology via the spherical crystallization technique to achieve a directly
compressible raw material. Drug.Dev.Ind.Pharm.16 (8); 1279-1290.
97. Deshpande MC, Mahadik KR, Pawar AP and Paradkar AR (1997) Evaluation of
spherical crystallization as particle size enlargement technique for
Aspirin.Ind.J.Pharm.Sci.59 (1); 32-34.
98. Gohle MC, Parikh RK, Shen H and Rubey RR (2003) Improvement in
flowability and compressibility of Ampicilline Trihydrate by spherical
crystallization.Ind.J.Pharm.Sci.634-37.
99. Kawashima Y, Okumura M and Takenaka H (1982) Spherical crystallization:
direct spherical agglomeration of Salicylic acid crystals during crystallization.
Science. 216(4); 1127-28.
100. Szabo RP, Goczo H, PintyeHodi K, Kasajr P, Eros I, HasznosNezdei M and
Farkas B (2001) Development of spherical crystals of an Aspartic acid salt for
direct tablet making. Powder Technology.114; 118-24.
101. Hector GP, Jorge B and Carlo A (1998) Preparation of Norfolxacin spherical
agglomerates using the ammonia diffusion system. J. Pharm. Sci. 87(4); 519-23.
102. Jbilou M, Ettabia A, Guyot-Hermann A M and Guyot JS (1990) Ibuprofen
agglomeration prepared by phase separation. Drug. Dev. Ind. Pharm. 25(3);
297-305.
103. Goczo H, Szabo RP, HasznosNezdei M and Farkas B, et al(2000) Development
of spherical crystals of Acetyl salicylic acid for direct tablet
making.Chem.Pharm.Bull. 48(12);1877-81.
104. Kawashima Y, Imai M, Takeuchi H, Yamamoto H and Kamiya K (2002)
Development of agglomerated crystals of Ascorbic acid by the spherical
crystallization techniques. KONA. 20(3); 251-61.
105. Ueda M, Nakamura Y, Makita H, Imasato Y and Kawashima Y (1991) Particle
design of Enoxacin by spherical crystallization technique II, Characteristics of
agglomerated crystals.Chem.Pharm.Bull.39 (5); 1277-1281.
106. Morshima K, Kawashima Y, Takeuchi H, Niwa T and Hino T (1994)
Tabletting properties of Bucillamine agglomerates prepared by the spherical
crystallization technique.Int.J.Pharm.105;11-18.
107. Kawashima Y, Niwa T, Handa T, Takeuchi H, Iwamoto T (1989) Preparation of
controlled release microspheres of Ibuprofen with acrylic polymers by a novel
quasi-emulsion solvent diffusion method. J. Pharm. Sci. 78(1); 68-72.
108. Sano A, Kuriki T, Kawashima Y, Takeuchi H, Handa T (1987) Particle design
of Tolbutamide in presence of soluble polymers or surfactants by spherical
crystallization technique: Improvement of dissolution rate. J. Pharm. Sci. 76(6);
471-474.
109. Takami K, Machimura H, Takado K, Inagaki M and Kawashima Y (1996)
Novel preparation of free flowing spherically agglomerated dibasic calcium
phosphate anhydrous for direct tabletting. Chem.Pharm.Bull.44 (4); 686-870.
110. Kawashima Y, Niwa T, Takeuchi H, Hino T, Itoh Y and Furuyama S (1991)
Characterization of polymorphs of Tranilast anhydrate and Tranilast
monohydrate when crystallization by two solvents changes spherical
crystallization technique. J.Pharm.Sci. 80(5); 472-78.
111. Kawashima Y, Cui F, Takeuchi H, Hino T, Niwa T and Kiuchi K(1995)
Parameters determining the agglomeration behavior and the micrometric
properties of spherically agglomerated crystals prepared by spherical
crystallization technique with miscible solvent system.Int.J.Pharm.119;139-147.