introduction & literature review -...

Introduction

& Literature Review

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:



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



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).



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



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.



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



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.



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



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.



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].



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



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



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).



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)




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.


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



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)



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.

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)



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.


Microballoones. Method and solvent system Research findings

Riboflavin-containing microballoons for

floating controlled drug delivery system:


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

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)



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)




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.


Nanoparticles/Nanocrystals. Method and solvent system Research findings

Indomethacin (IMC) nanocrystals


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).


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)




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



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.


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


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



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):


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)



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.


Micronization of silybin


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.



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)



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)




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


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


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


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


Solvent system: acetone-water-hexane

Spherical agglomerates exhibited improved flowability,

wettability and compaction behavior.(88)




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


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)




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


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


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


Solvent system: Water-Aqueous solution of

phosphoric acid Citric acid.

Free flowing, porous directly compressible

agglomerated crystals formed.(109)

Tranilast agglomerates


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)

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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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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.



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.



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.

Growth.237–239.

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–

74.

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.



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.



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.

introduction & literature review -...

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