International Standard Serial Number (ISSN): 2319 …. RP13140018920014.pdfInternational Standard...

International Standard Serial Number (ISSN): 2319-8141 International Journal of Universal Pharmacy and Bio Sciences 2(5): September-October 2013

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 1.89***

ICV 2.40***

Pharmaceutical Sciences REVIEW ARTICLE……!!!

Received: 03-09-2013; Accepted: 10-09-2013

SPHERICAL CRYSTALLIZATION TO IMPROVE PHYSIOCHEMICAL AND MICROMERITIC

PROPERTIES: A REVIEW

Anjali Gupta, Arundhati Bhattacharya and Dr. U.V.S. Sara.

Raj Kumar Goel Institute of Technology, Department of Pharmacy, 5 Km stone, Delhi-Meerut road,

Ghaziabad (U.P.) Pin code-201003.

KEYWORDS:

Bioavailability, Bridging

liquid, Compressibility,

Direct Tableting,

Flowability, Spherical

Agglomeration.

For Correspondence:

Anjali Gupta *

Address:

Raj Kumar Goel Institute of

Technology, Department of

Pharmacy, 5 Km stone,

Delhi-Meerut road,

Ghaziabad (U.P.) Pin code-

201003.

Email:

[email protected]

ABSTRACT

Direct compression is a technique of tablet manufacturing without an

intermediate granulating step. It can only be applied for those drug

having good micromeritic properties i.e. flowability and

compressibility. But for poorly soluble drugs, spherical

crystallization technique was developed by Kawashima and their

coworkers in 1986. It is a novel particle design technique in which

both crystallization and agglomeration carried out simultaneously in

single step. This technique is used for size enlargement of drugs

which is successfully utilized for improvement of physiochemical

and micromeritic of different poorly soluble drugs. Bioavailability

and solubility enhancement of pharmaceutical drug is reported by

spherical crystallization. In this review we will discuss about the

advantage, methods which are applied in spherical crystallization

process. In addition, list of all the drugs on which spherical

crystallization methods have been performed.

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International Standard Serial Number (ISSN): 2319-8141

INTRODUCTION:

Previously, pharmaceutical industry gave more stress on the formation of different type of

formulation which has more advantage into the market. But nowadays, due to cost pressures

companies want to prefer the most effective or cheaper way for formation of dosage form. The solid

oral dosage form represents the preferred class of product and is most important method of

administering drugs for systemic effects. At least 90% of all drugs used to produce systemic effects

are administered by oral route.

Tablets are the most preferred as well as challenging of all pharmaceutical solid oral dosage form to

design and manufacture. The difficulties are involved in achieving full and reliable drug

bioavailability for drugs with poor wetting and slow dissolution.

Direct tableting is a modern method in tablet manufacturing. There are two type of direct

compression[41]

: 1) those where major proportion is active ingredients and 2) those where active

ingredient in a minor component (<10% of compression weight). Manufacturing of such tablets

involves simple mixing and compression of powders which results in number of benefits such as

time, cost and energy saving. Direct tableting as a technique has been successfully applied to

numerous drugs on the industrial scale. So spherical crystallization that could be reduced to

following steps: crystallization, filtration, drying, dry blending and tableting. It require less

equipment and space, lower labour costs, less processing time and lower energy consumption in

direct tableting process. This technique improves the wettability, bioavailability and dissolution rate

of some poorly soluble drug i.e. BCS class II drug e.g. atorvastatin and ibuprofen.

Spherical crystallisation

It is defined as “a novel particle engineering technique by which crystallization and agglomeration

can be carried out simultaneously in one step to transform crystals directly into compacted spherical

form”.

It is a versatile process that enables to control the type and the size of the crystals. This technique of

particle design of drugs has emerged as one of the areas of active research currently of interest in

pharmaceutical manufacturing and recently came into the forefront of interest or gained great

attention and importance due to the fact that crystal habit (form, surface, size and particle size

distribution) can be modified during the crystallization process. In consequence of such

modifications in the crystal habit certain micrometric properties (bulk density, flow property,

compactability) and physicochemical properties like solubility, dissolution rate, bioavailability and

stability) can also be modified[1]

.

Crystallization is important phenomenon which is used for both separation and purification in

pharmaceutical industries. This process leads to the crystal formation which has chemical stability




and convinence in transportation, packing and storage. Most of active pharmaceutical ingredients

have different sizes. Active pharmaceutical ingredient particles with less than 10µm size have the

advantage of increased dissolution rate and better bioavailability. There are different processes for

producing active pharmaceutical ingredient particles with size less than 10µm size. Micronization

involves milling but causes physical and chemical instability, produces powders with wide size

distribution and poor flowability. Another is crystallization, but many disadvantages are linked that

is handling difficulty, tedious and expensive process. This can be avoided by size enlargement

method.

Tablets are the most preferred as well as challenging of all pharmaceutical solid oral dosage form to

design and manufacture. Granulation is intermediate step in which powder is converted into a

material with improved handling properties. But granulation is time consuming and has higher cost

of manufacturing. This step can be avoided if microcrystals are agglomerated directly in

crystallization step.

Tablets are most popular dosage form. It can also be prepare by direct compression method but

powder should have good mechanical properties e.g. compressibility and flowability. And tableting

will reduced to steps like crystallization, filtration, drying, blending and tableting. Direct

compression methods have many advantages:

1. Requires less equipment and space.

2. Lower labour cost.

3. Less processing time.

4. Lower energy consumption.

Agglomeration is a phenomenon in particles technology which includes smaller crystals adheres to

form bigger particles[2]

. It is important for both down streaming process e.g. filtration, drying,

washing etc. and end use properties e.g. dissolution, product formation and bioavailability.

Agglomerates are difficult to wash by mother liquor as impurities were entrapped inside the solid

particles.

Agglomerates are prepared by spherical crystallization method in which spherical agglomerates

produced in situ by agglomeration of small crystals during crystallization. In spherical

crystallization method several process reduced to single step e.g. synthesis, crystallization,

separation and agglomeration. This technique improved physiochemical properties, micromeritics

and mechanical properties and finally results in improved tableting. Agglomerates are desirable for

drug delivery as it is made up of small crystals and have large surface area to volume ratio. These

agglomerates are broken down to their constitutive crystals leads to higher dissolution rate as well as

bioavailability is retained by these particles.




Techniques

There are two different methods used in spherical crystallization[3]

i.e. typical and non typical

methods. Non typical technique is also called as traditional crystallization method which involves

different steps as salting out, cooling and precipitation. The controlling factors are physical and

chemical properties. Typical technique employs three solvents:

a. Good solvent (dissolution medium).

b. Bridging liquid (partially dissolves the drug and have wetting property).

c. Bad solvent (immiscible with the drug substance).

1. Spherical agglomeration

In this method good solvent and poor solvent are freely miscible and interaction between the

solvents is stronger than the drug interaction with good solvent. This leads to the precipitation of

crystals immediately. The role of bridging liquid is to collects the crystals by forming liquid bridges

between the crystals due the capillary negative pressure and interfacial tension between the interface

of solid and liquid. There are three steps involve in this method.

a. Selection of crystallization method to precipitate crystals from solution i.e. thermal,

physiochemical and chemical reaction.

b. Choice of wetting agent that will be immiscible with solvent of crystallization.

c. Hardening of agglomerates.

For example,

Thati and Rasmuson[10]

(2011) perform particle engineering on benzoic acid by spherical

agglomeration. It was investigated the influence of different process condition on drug and also the

influence of bridging has on the product properties.

Kawashima et.al[23]

(2002) prepared spherical agglomerate of steroid KSR- 592 by spherical

crystallization method in liquid and then designing an ideal dry powder inhalation system. The

primary crystals were mechanically stronger than their agglomerates so that the agglomerates were

disintegrated easily into the primary crystals.

Biscans and Gonzalez[25]

(2002) proposed and validated a method for selecting the best wetting

agent which allowed to obtained spherical agglomerates during crystallization. Crystallization tests

carried out at different conditions showed that the best results were obtained in the presence of n-

hexane that was effectively found to be a better wetting liquid of the lobenzarit crystals than the

other solvents.

Mutalik et.al[4]

(2008) prepared and perform in vitro, preclinical and clinical studies of aceclofenac

spherical agglomerates. It was found to have improved in vitro release rate of agglomerates as

compared to pure aceclofenac.




2. Emulsion solvent diffusion

This method is applied for preparation of microspheres. In this the interaction between the drug and

good solvent is stronger than that of the interaction between good solvent and poor solvent. Hence

good solvent drug solution is dispersed in bridging liquid producing quasi emulsion droplets, even if

the solvent are normally miscible. This results in increase in interfacial tension between good

solvent and bridging liquid. As the solubility of the drug in the droplets decreases containing in poor

solvent, good solvent diffuses out of emulsion droplets in the outer phase of poor solvent and

counter diffusion of poor solvent into the droplets cause the crystallization of drug.

For example,

Patil and Bhokare[18]

(2012) prepared and evaluated directly compressible fenofibrate spherical

agglomerates. It was found that spherical agglomerates showed improved micromeritics properties

as well as dissolution behaviour in comparison to pure drug.

Yadav and Yadav[12]

(2009) investigated comparative tableting behaviour of cefuroxime axetil

granules with spherical agglomerated crystals prepared by spherical crystallization technique. It was

found that the prepare agglomerates were of improved compressibility, packability and solubility.

Ranjit Dash et al[14]

(2011) formulated and evaluated spherical crystal of etoricoxib by quasi

emulsion solvent diffusion. The solvent systems used were acetone, water and chloroform as good,

bad and bridging liquid. The spherical agglomerates exhibited excellent dissolution rate and have

good compressibility and packability characteristic.

Nocent et al[34]

(2001) studied various process parameters for salbutamol sulphate such as

solvent/antisolvent ratio and temperature difference between them which had no influence on the

formation of spherical particles, influence of emulsifier concentration and maturation time on the

size of spherical agglomerates.

Zang et al[36]

preformed micronization of silybin by which uniform spherical and rod shaped

particles were obtained. It possessed decreased crystallanity and enhanced dissolution rate as

compared to commercial product.

3. Ammonia diffusion method

It is basically used for amphoteric drugs as they cannot be agglomerated by conventional procedure.

In this method ammonia water system acts as both good solvent and bridging liquid. And poor

solvent is selected depending upon the drug solubility in that solvent. The drug is dissolved in

ammonia water and it precipitated out. The droplets collect the crystals. Ammonia in agglomerates

diffuses to the outer organic solvent. Ammonia water system ability to act as bridging liquid

weakens and subsequently spherical agglomerates are formed.




Mechanism of the ammonia diffusion system method: It involves the three steps

a) Invasion of acetone into ammonia water droplets.

b) Diffusion of ammonia in the agglomerates to the outer solvent.

c) Agglomeration ending.

For example,

Gokhle et al[8]

(2003) prepared dispersible tablets of ampicillin trihydrate from spherical

agglomerates. These agglomerates were formed by ammonia diffusion method using acetone,

ammonia water and dichloromethane as solvent system. The drug release rate was found to be

enhanced as compared to market product.

Ueda et al[15]

(1991) optimized process parameters of enoxacin such as amount of bridging liquid

and agitation time. It leads to agglomerates of improved flowability, packability and enhanced

dissolution rate.

Bhadra et al[26]

(2004) produced agglomerates of mefenamic acid of good flow, compressibility and

more wettability than pure drug. Also prepared tablet from agglomerates of greater mechanical

strength.

Hector et al[29]

(1998) prepared spherical agglomerates of norfloxacin by ammonia diffusion

technique using ammonia water system as good solvent and bridging liquid, dichloromethane

mixture as bad solvent.

4. Neutralization technique

It involves the formation of fine crystals by neutralization and their agglomeration by bridging

liquid. Drug dissolved in alkaline solution and poured in acidic solution containing polymers and

bridging liquid under constant agitation. Drug crystals precipitated out by neutralization of base with

acid. Then the precipitated crystals were simultaneously agglomerated with co-operated polymer

through wetting action of bridging liquid.

For example:

Dixit and Parthasarthi[22]

(2010) prepared spherical agglomerates of ibuprofen by neutralization

method. Solvent used were 1N sodium hydroxide, 0.07M HCl and isopropyl alcohol as a bridging

liquid. Process variables were amount of bridging liquid, stirring time and duration of stirring. It was

found that spherical agglomerates show decreased crystallinity and improved micromeritics

properties. The dissolution rate was also improved.

Sano et al[37]

(1987) also performed particle designing of tolbutamide in the presence of soluble

polymer or surfactant by neutralization method. Solvent used were HCl and sodium hydroxide

solution containing a water soluble polymer or surfactant. The result was that the dissolution rate of

agglomerates was 8 times faster than the conventional form, solubilty and flowability were also

improved.




Various drug on which different methods of spherical crystallization had been performed.

Drug Solvent Method Reference

Acetylsalicylic acid[5]

Ethanol, water,

carbon tetrachloride

Spherical

agglomeration

Istvan Eros et.al 2000

Aminophylline[6]

Ethanol, chloroform,

water

Spherical

agglomeration

Kawashima Y. et.al

1984

Acebutalol[7]

Ethanol, water,

isopropyl acetate

Emulsion solvent

diffusion

Kawashima Y. et.al

1995

Aspirin[9]

Acid buffer,

methanol, chloroform

Spherical

agglomeration

Deshpande et.al 1997

Bucillamine[11]

Ethanol,

dichloromethane,

water

Spherical

agglomeration

Morishima et.al 1994

Clarithromycin[13]

Ethanol, water,

dichloromethane

Emulsion solvent

diffusion

Vayas S.P. etal 2007

Fenbufen[16]

Tetrahydrofuran,

water, isopropyl

acetate

Spherical

agglomeration

Di Martino et.al 1999

Flurbiprofen[17]

Acetone, water,

hexane

Spherical

agglomeration

Jain et.al 2003

Griseofulvin[19]

Acetone,water Solvent change Shingade G.M. et.al

2011

Glipizide[20]

Dichloromethane,

water, chloroform

Spherical

agglomeration

Dinesh et.al 2010

Indomethacin[21]

Methanol, water,

dichloromethane

Emulsion solvent

diffusion

Yadav et.al 2010

Lornoxicam[24]

Formic acid, water,

chloroform

Spherical

agglomeration

Swamy N. et.al 2012

Mebendazole[27]

Acetone, water,

hexane, octanol,

dichloromethane

Spherical

agglomeration

Kumar et.al 2008




Naproxen[28]

Tetrahydrofuran,

water, isopropyl

acetate

Solvent change Kulkarni et.al 2011

Nabumetone[30]

Acetone, water,

dichloromethane

Spherical

agglomeration

Patil et.al 2012

Phenytoin sodium[31]

Ethanol,

dichloromethane,

water

Spherical

agglomeration

Ansari et.al 2010

Propylphenazone[32]

Ethyl alcohol, water,

isopropyl acetate

Emulsion solvent

diffusion

Piera Di Martino et.al

2000

Roxithromycin[33]

Ethanol, water,

chloroform

Spherical

agglomeration

Yadav et.al 2010

Salicylic acid[35]

Ethanol, water,

chloroform

Spherical

agglomeration

Kawashima Y. et.al

1982

Tranilast[38]

Ethanol, acetone,

water, chloroform,

dichloromethane

Spherical

agglomeration

Kawashima Y. et.al

1991

Theophylline[39]

Ethylene diamine,

aqueous sodium

chloride, water

Spherical

agglomeration

Kawashima Y. et.al

1984

Zaltoprofen[40]

Acetone, water,

dichloromethane

Spherical

agglomeration

Krishna H. et.al 2012

Advantages of spherical crystallization[2]

Spherical crystallization technique has been successfully utilized for improving of

flowability and compressibility of drug powder.

This technique could enable subsequent processes such as separation, filtration, drying etc. to

be carried out more efficiently.

By using this technique, physicochemical properties of pharmaceutical crystals are improved

for pharmaceutical process i.e. milling, mixing and tableting because of their excellent

flowability and packability.

This technique may convert crystalline forms of a drug into different polymorphic form

having better bioavailability.

For masking of the bitter taste of drug.

Preparation of microsponge, microspheres and nanospheres, nanoparticles and micropellets

as novel particulate drug delivery system.




Conclusion

The different techniques of spherical crystallization are responsible for shortening of manufacturing

steps involved in tableting which in turns reduces the cost and time of manufacturing of tableting.

Agglomerates produced exhibit excellent physiochemical and micromeritics properties, solubility,

dissolution rate and stability performance when compared with pure drug as well as marketed

formulation. Through this technology, agglomerates can be directly compressed to tablet form of

poorly compressible and poorly water soluble drug with improved bioavailability.

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