International Journal of Innovative Pharmaceutical ...Mahammad Rafi. Shaik Department of Pharmaceutics, MAK College of Pharmacy, Hyderabad, INDIA Email: [email protected]

REVIEW ARTICLE Mahammad et.al / IJIPSR / 3 (2), 2015, 97-110

Department of Pharmaceutics ISSN (online) 2347-2154

Available online: www.ijipsr.com February Issue 97

SPHERICAL CRYSTALLIZATION – A NOVEL PARTICLE

DESIGN TECHNIQUE FOR SOLUBILITY ENHANCEMENT

1Mahammad Rafi. Shaik*,

2Hajira Abdul Jabbar,

3Kafia Firdouse,

4Renuka,

5T. Rajitha,

6R. Krishna prasad

Department of Pharmaceutics, MAK College of Pharmacy, Chilkoor (V), Moinabad, Greater

Hyderabad, INDIA

Corresponding Author

Mahammad Rafi. Shaik

Department of Pharmaceutics,

MAK College of Pharmacy, Hyderabad, INDIA

Email: [email protected]

Phone: +919700983502

International Journal of Innovative

Pharmaceutical Sciences and Research www.ijipsr.com

Abstract

Direct compression of powders is simple and easy way of making tablets. In direct compression of drugs Good

compressibility and flowability plays a major role. There are several techniques available to impart required

compressibility to drugs. Spherical crystallization methods are very useful methods in which the drug crystals are

modified using different solvents to directly compressible spherical agglomerates, which cost effective and time

saving. Spherical crystallization is a fast developing technique of particle design in which crystallization and

agglomeration can be achieved simultaneously in one step. Spherical crystallization is “An agglomeration process

that changes crystals directly into compact spherical forms during the crystallization process” It is the novel

agglomeration technique that can transform directly as fine crystals produced in the crystallization process into a

spherical shape. Spherical agglomeration, emulsion solvent diffusion and ammonia diffusion method are general

methods in Spherical crystallization. In this spherical crystallization poor solvent, good solvents and bridging

liquid are used. The principle steps involved in the process of spherical crystallization are zero growth zone,

flocculation zone, constant size zone and fast growth zone. Factor controlling the process of agglomeration are

intensity of agitation, solubility profile mode, residence time and temperature of the system. This crystal habit

(form, surface, size and particle size distribution) can be modified during the process of crystallization. The

modifications of such consequences in certain micrometric properties, physicochemical properties (solubility,

dissolution rate, bioavailability and stability) and crystal habit are also modified. Spherical crystallization have

applications in pharmaceuticals like improvement of flowability and compressibility of poor compressible of

drugs, masking bitter taste of drugs and improve the solubility and dissolution rate of poor solublility drugs.

Characterization of spherical crystals determine by optical microscopy, Fourier Transform Infrared spectrometer

(FTIR), Differential scanning calorimeter (DSC).

Keywords: Spherical crystallization, flowability, compactability and agglomeration.

mailto:[email protected]




INTRODUCTION

Tablet is very specific dosage form, accounting for 50% of all oral drug delivery system and 70%

of all pharmaceutical preparation produced. [1] Today the most popular dosage form as Tablets in

all pharmaceutical preparations produced. From the manufacturing point of view tablets can be

produced at much higher rate than any other dosage form. Tablet is the most stable readily

portable and consumed dosage form. [2]. The most popular dosage form (Tablets) of all

pharmaceutical preparations for oral route administration because of easy administration, least

content variations and great accuracy. Along with these advantages, manufacturing of tablets is

most efficient and easy process. flowability and compressibility of materials are important factors

which influences the success of tablets. Direct compressibility is one of the best, economical and

simple techniques for manufacturing of tablets. This facilitates formulation without the moisture,

heat and involves small number of formulating steps. But, the method depends on, the particle

size, flowability, the particle size distribution, bulk density and compressibility of the crystalline

drug substances. Most of the drugs like NSAIDs shows poor flowability and compressibility and

were not suitable for direct compression. For enhancing the flow properties and compressibility of

such drugs several methods have been introduced. Recently pharmaceutical companies are using

modified crystalline techniques for reducing the formulation cost as well as increasing the

production process. Spherical agglomeration is one of the efficient techniques among those. [3].

In 1986, kawashima 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.”[4] Spherical crystallization is a particle design technique, by which

crystallization and agglomeration can be carried out simultaneously in one step and which has

been successfully utilized for improvement of flowability and compactability of crystalline drugs.

[5] Presently, particle design techniques are widely used in pharmaceutical industries to modify

primary properties like particle shape, size, crystal habit, crystal form, density, porosity etc. as

well a secondary properties like flow ability, compressibility, compact ability, reduction in air

entrapment, etc Spherical crystallization process transforms the fine crystal obtain during

crystallization into a spherical agglomerates. Agglomerates formed further improves the

flowability and compressibility of pharmaceutical ingredient which enables direct tabletting of

drug instead of further processing like mixing, granulation, sieving, drying etc. There are certain




parameters which have to be optimized in order to obtain the maximum amount of spherical

crystals. [6]

METHODS OF SPHERICAL CRYSTALLIZATION:-

Quasi emulsion solvent diffusion (QESD):-

It was first mentioned in 1989. This technique was usually applied for the preparation of

microspheres. [7] The drug dissolved in the good solvent (solvent that easily dissolves the

compound to be crystallized), and the solution is dispersed into the poor solvent (an antisolvent

generating the required super saturation), producing emulsion (quasi) droplets, even though the

pure solvents are miscible. The good solvent gradually diffuses out of the emulsion droplets into

the surrounding poor solvent phase, and the poor solvent diffuses into the droplets by which the

drug crystallizes inside the droplets due to the interfacial tension between the two solvents. The

crystallization of the drug occurs by the counter diffusion of the good solvent and poor solvent.

The method is said to be simpler than the SA method, but it can be difficult to find a suitable

additive to keep the system emulsified and to improve the diffusion of the poor solute into the

dispersed phase. At increasing stirring rate the agglomeration was reduced in case of lactose

because of increasing disruptive forces. [8] Higher stirring rate produces agglomerates that are

less porous and more resistant to mechanical stress, and the porosity decreases when the solid

increases. [9] The choice of bridging liquid has an influence on the rate of agglomeration and on

the strength of the agglomerates. In this process, the emulsion is stabilized by the selection of the

suitable polymer which is required for the proper crystallization. In the droplets, the process of

solidification proceeds inwards and the liquid are not maintained on the surface and the

agglomerate formed without coalescence.

Steps involved in QESD method:-

Drug + good solvent

Into poor solvent

Formation of emulsion

(With agitation)

Good solvent which acts as a bridging liquid diffuses out into the poor solvent phase

Formation of spherical agglomerates

Polymeric solution

Stabilized spherical crystal




Spherical agglomeration:

In spherical agglomeration involve implications of three different solvents. One liquid acts as a

perfect solvent for the drug moiety, second liquid is categorized as antisolvent/poor solvent for

the chemical moiety and third liquid significantly used as bridging liquid should be added in

smaller quantity for promoting the formation of agglomerates. A nearly saturated solution of drug

in good solvent is poured in to the poor solvent, provided that the poor and the good solvents are

freely miscible and affinity between good and poor solvent is stronger than the affinity between

the drug and the good solvent, this leads to the formation of crystals immediately. Further third

solvent called bridging liquid is added in smaller amount to promote the formation of

agglomerates. Under continuous agitation, the bridging liquid is added. The bridging liquid

should not be miscible with the poor solvent and must wet the precipitated crystals. As a result of

interfacial tension effects and capillary forces, the bridging liquid act to adhere the crystals to one

another to form agglomerates. The spherical agglomeration has been applied to several drugs and

it has been found that the product properties are quite sensitive to the amount of bridging liquid.

Relatively less amount of optimum bridging liquid produces plenty of fine crystals and vice versa.

Also the choice of bridging liquid, the starring speed and concentration of solute are of

importance. Higher stirring rate produces agglomerates that are less porous and are more resistant

to mechanical stress, porosity decreases as the concentration of the solid increases.

Ammonium diffusion (AD) method:

In this method, the mixture of three partially immiscible solvent i.e. acetone, ammonia water,

dichloromethane was used as a crystallization system. In this system ammonia water acts as a

bridging liquid as well as good solvent, acetone was the water miscible but a poor solvent, thus

drug precipitated by solvent change without forming ammonium salt. Water immiscible solvent

such as hydrocarbons or halogenated hydrocarbons. [10]

E.g. dichloromethane induced liberation of ammonia water.

This technique usually meant for the amphoteric drugs which cannot be agglomerated by

conventional procedures [11] the whole process is completed in three steps. [12] First the drug

dissolved in ammonia water is precipitated while the droplets collect the crystals. Simultaneously,

ammonia in the agglomerate diffuses to the outer organic solvent. Its ability to act as a bridging

liquid weakens and subsequently spherical agglomerates are formed.




Steps involved in ammonia diffusion method:

Drug + ammonia water

Added to

Acetone

Dichloromethane added drop wise

Spherical agglomerates

Neutralization technique (NT):

This technique involves the formation of fine crystals by neutralization and consequently their

agglomeration by a bridging liquid. Spherical crystallization of tolbutamide and phenytoin was

reported by this technique. [13] 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, which was then, crystallized out. [14]

Steps involved in neutralization technique (NT):

Drug + good solvent

Added in

Neutralizing solution

Crystallization

Adding bridging liquid

Drop wise


Traditional crystallization process:

Spherical agglomerates shall be produced in these methods by controlling the physical and

chemical properties and can be called as non typical spherical crystallization processes. [15]

These are salting out precipitation, cooling crystallization, crystallization under melting. Heat

some solvent to boiling. Place the solid to be recrystallized in an Erlenmeyer flask. Pour a small

amount of the hot solvent into the flask containing the solid. Swirl the flask to dissolve the solid.

Place the flask on the steam bath to keep the solution warm. If the solid is still not dissolved in

solution, set it on the bench top. Do not disturb it. After a while, crystals should appear in the

flask. Simultaneously bridging liquid was added drop wise at a definite rate, followed by

crystallization of the crystal form of the drug takes place.




Solvent change method (SC):

Solvent change method involves simultaneous crystallization and agglomeration of two or more

drugs from a good solvent and bridging liquid by addition of a non-solvent. To obtain fine

crystals the solution of the drug and a good solvent is poured into a poor solvent under controlled

condition of temperature and speed. The bridging liquid is used for agglomeration of the crystals.

The poor solvent has miscibility with good solvent but has low solubility with solvent mixture, so

that, during agitation of the solvent system the crystals are formed. The drawback of this system

is that it provides low yield, due to co-solvency effect of crystallization solvent. The bridging

liquid, the stirring speed and the concentration of the solids are the influencing factors for the

spherical crystallization [16]. Lesser amount of bridging liquid will yield fine particles where as

larger amount of bridging liquid will produce coarse particles. [17] By increasing stirring rate the

agglomeration get reduced because of increasing disruptive forces. [18] Higher stirring rate

produces agglomerates that are less porous and more resistant to mechanical stress. The porosity

decreases when the concentration of the solid increases. [19] The viscosity of the continuous

phase has an effect on the size distribution of the agglomerates. The choice of bridging liquid has

an influence on the rate of agglomeration and also on the strength of the agglomerates.

Steps involved in solvent change method:

Good solvent + drug

In bad solvent

Formation of crystals with addition of bridging liquid (drop wise) and continuous agitation

Precipitated crystals and aggregation with the bridging liquid


Enlarged spherical agglomerates

Crystallo-co-agglomeration(CCA):

Crystallo-co-agglomeration was invented by kadam and coworkers as an attempt to overcome the

limitations of spherical crystallization techniques, which were restricted to size enlargements of

single high-dose drugs only. Similar to spherical agglomeration, a good solvent is used in this

method to solubilize the drug, the poor solvent to form liquid bridges during the agglomeration

process. CCA is complex process and is influenced by many formulation and process variables.




Techniques there are two different methods used in spherical crystallization, 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).

Spherical agglomeration is a novel agglomeration technique involving agglomerate formation

based on addition of bridging solvent. In typical spherical agglomeration method the drug

dissolved in a good solvent is poured in a poor solvent under controlled condition of agitation

with the addition of bridging solvent which wets the crystal surface to form agglomerate. The

bridging liquid should be immiscible in the suspending medium but capable of cementing the

particles to be agglomerated [20].

Table 1: Different techniques and solvents used in preparing spherical agglomeration of

Drug

Solvent system Drug Good solvent Bad

solvent

Bridging liquid Technique NSAIDS

Aceclofenac [21] Acetone Water Dichloromethane SA Aspirin [22] Acid buffer Methanol Chloroform SA

Acetylsalicyclic acid [23] Ethanol Water Carbon

tetrachloride

SA Celocoxib [24] Acetone Water Chloroform SA Fenbufen [25] THF Water Isopropyl acetate SA

Flubiprofen [26] Acetone Water Hexane SA Ibuprofen [27] Ethanol Water Ethanol SA

Ibuprofen-Paracetamol

[28]

Dichlorometha

ne

Water Dichloromethane CCA Ibuprofen-Talc [29] Dichlorometha

ne

Water Dichloromethane CCA Indomethacin [30] Dimethyl

formamide

Water Chloroform SA

Indomethacin Mepirizole

[31]

Ethyl acetate Water Ethyl acetate CCA Ketoprofen [32] Isopropyl

acetate

Water Choroform SA Ketoprofen-Talc [33] Dichlorometha

ne

Water Dichloromethane CCA Mefenamic acid [34] Ammonia-

water

Acetone Ammonia-water ADM Naproxane [35] Acetone-

ethanol

Water Chloroform SA Nabumetone [36] Ethanol Water Cyclohexane SA

Piroxicam [37] NaOH HCl Chloroform NT Propylphenazone [38] Ethyl alcohol Water Isopropyl acetate SA




Drug Solvent system Technique

Good solvent Bad solvent Bridging liquid

Antibiotics

Ampicillin Tri

ydrate(ATH) [39]

Ammonia water Acetone Dichloromethane ADM

Cefuroxime Axetil [40] Acetone Water Dichloromethane ESD

Enoxacin [41] Ammonia-water Acetone Ammonia-water ADM

Norfloxacin [42] Ammonia-water Acetone Ammonia-water ADM

Roxythromycin [43] Methanol Water Choroform SA Antihelminthic

Mebandazole [44] Acetone Water Hexane SA

Antiallergic

Tranilast [45] Acetone Water Dichloromethane SA

Antihypertensive

Felodipine [46] Acetone Water Dichloromethane ESD

Antiepileptic

Carbamazepine [47] Ethanol Water Chloroform ESD

Antifungal

Gresiofulvin [48] Dichloromethane Water Dichloromethane ESD

Bronchodialator

Aminophylline [49] Ethanol Water Chloroform SA

Theophylline [50] Ethylene diamine Sod. Chloride Water SA

ß-adrenergic blocker

Acebutalol HCl [51] Ethanol Water Isopropyl acetate ESD

Antidiabetic

Glibenclamide [52] Dichloromethane Water Chloroform SA

Tolbutamine [53] Ethanol Water Isopropyl acetate ESD,NT

Others

Ascorbic acid [54] Water Ethyl Acetate Ethyl Acetate SA,ESD

Aspartic acid [55] Methanol Water - SA

Benzoic acid [56] Ethanol Water Chloroform SA

Bromohexin HCl [57] Dichloromethane Water Dichloromethane CCA

DCP (`Dibasic

calcium Phosphate)

[58]

Citric acid Water Phosphoric acid SA

Valsartan [59] Acetone Water Choroform SA




SA = Spherical Agglomeration, ESDS = Quasi-Emulsion Solvent Diffusion System, ADS =

Ammonia Diffusion System, NT = Neutralization Technique, CCA = Crystal-co-agglomeration

technique.

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Documents

International Journal of Innovative Pharmaceutical ...Mahammad Rafi. Shaik Department of Pharmaceutics, MAK College of Pharmacy, Hyderabad, INDIA Email: [email protected]