INTRODUCTION:

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. The various parameters optimized are type, amount and mode of addition of bridging liquid, temperature, and agitation speed to get maximum amount of spherical crystals. These were characterized for micromeritic properties (particle size and shape, flow ability), Packability (bulk density), wettability (contact angle) and compressibility. It was revealed from the studies that spherical agglomerates exhibited improved flowability, wettability, compaction behavior and bioavailability.

The oral route of administration is the most important method of administering drugs for systemic effects.

In this, the solid dosage form, particularly, tablets are the dosage form of choice because of their special Characteristics like unit dosage form with greatest dose precision and least content variability, lower cost, easy administration by a patient and temper proof nature. The formation of solid oral dosage forms and tablets in particular, have undergone rapid changes and development over the last several decades and one of the most revolutionary technologies is that of direct compression. It is economical, facilitates processing without the need for moisture and heat and small number of processing steps are involved The basic requirement for commercial production of tablet is a particulate solid with good flowability, mechanical strength and compressibility. Hence it is necessary to evaluate and manipulate the above said properties. To impart these properties the drugs are subjected to particle design techniques. Spherical crystallization is one of the techniques of particle design. The particle size can be enhanced by the help of wet granulation method, dry granulation method, extrusion spheronization and by spherical crystallization methods. The spherical crystallization is a nonconventional particle- size enlargement technique that involves crystallization and agglomeration using bridging liquid¹.

Steps Involved In Spherical Crystallization¹

Flocculation Zone:

In this zone the bridging liquid displaces the liquid from the surface of the crystals and these crystals are brought in close proximity by agitation, the adsorbed bridging liquid links the particles by forming bridge or lens between them. In this zone, loose open flocs of particles are formed by pendular bridges and this stage of agglomeration process where the ratio of liquid to the void volume is low and air is the continuous phase, is known as the pendular state. Mutual attraction of particles is brought about by surface tension of the liquid and the liquid bridges. The capillary stage is reached when all the void space within the agglomerate is completely filled with the liquid. An intermediate state known as funicular state exists between the pendular and capillary stage. The cohesive strength of agglomerate is attributed to the bonding forces exerted by the pendular bridges and capillary suction pressure.

Zero Growth Zone:

Loose flocs get transferred into tightly packed pellets, during which the entrapped fluid is squeezed out followed by the squeezing of the bridging liquid On to the surface of the small flocs causing pore space in the pellet to be 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 and pellet-stirrer collision.

Fast Growth Zone:

The fast growth zone of the agglomerate takes place when sufficient bridging liquid has squeezed out of the surface of the small agglomerates. This formation of large size particle 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 deformation and subsequent coalescence.

Constant Size Zone:

In this zone agglomerate ceases to grow or even show slight decrease in size. Here the frequency of coalescence is balanced by the breakage frequency of agglomerate. The size reduction may be due to attrition, breakage and shatter. The rate-determining step in agglomeration growth occurs in zero growth zone When bridging liquid is squeezed out of the pores as the initial flocs are transformed into small agglomerates.

Methods of Spherical Crystallization¹

Figure 1

Solvent Change Method (SC):

The solution of the drug in a good solvent is poured in a poor solvent under controlled condition of temperature and speed to obtain fine crystals. These crystals are agglomerated in the presence of bridging liquid. The poor solvent has miscibility with good solvent but low solubility with solvent mixture so during agitation of the solvent system the crystals are formed. The Drawback of this system is that it provides low yield because the drug shows significant solubility in the crystallization solvent due to cosolvency effect. This method is not applicable for water insoluble drugs.

Quasi Emulsion Solvent Diffusion Method (QESD):

It involves the formation of quasi- emulsion of solution of drug in good solvent with a non-solvent. The crystallization of drug occurs by counter diffusion of good solvent and poor solvent. Residual good solvent in droplets acts as a bridging liquid to agglomerate the generated crystals. In this process the emulsion is stabilized by the selection of suitable polymer which is required for proper crystallization. In the droplets, the process of solidification proceeds inwards so the liquid is not maintained on the surface so the agglomerate is formed without coalescence.

Ammonia Diffusion Method (AD):

In this method ammonia water act as a good solvent and bridging solvent, other components of this method are bad solvent and hydrocarbon/halogenated hydrocarbon (acetone). The hydrocarbon is miscible with the system but it reduces the miscibility of ammonia water with bad solvent. The fraction of ammonia water in the system that exists as an immiscible phase, forms droplet. The counter diffusion process across the droplet involves movement of bad solvent into and ammonia out of the droplet. The droplet collects the crystals as a drug in ammonia water precipitates slowly and growth of agglomerates occurs.

Salting Out Method (SO):

This method involves the addition of suitable salt for drug to crystallize out in the presence of bridging liquid.

Factors Controlling the Process of Agglomeration²

1.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), a good solvent and a 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 diagram to define the region of mutual immiscibility by using Ternary diagram.

2.Mode and intensity of agitation:

High speed agitation is necessary to disperse the bridging liquid throughout the system. 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. The extent of mechanical agitation in conjugation with the amount of bridging liquid determines the rate of formation of agglomerate and their final size.

3.Temperature of the system:

Study revealed that the temperature has a significant influence on the shape, size and texture of the agglomerates. The effect of temperature on spherical crystallization is probably due to the effect of temperature on the solubility of drug substance in the ternary system.

4. Residence time:

The time for which agglomerates remain suspended in reaction mixture affect their strength.

Need for Spherical Crystallization³

Developing novel methods to increase the bioavailability of drugs that inherently have poor aqueous solubility is a great challenge to formulate solid dosage form. Mechanical micronization of crystalline drugs and incorporation of surfactants during the crystallization process are the techniques commonly used to improve the bioavailability of poorly soluble drugs. The mirconization process alters the flow and compressibility of crystalline powders and cause formulation problems. Addition of surfactant generally led to less significant increase in aqueous solubility. To overcome this problem Kawashima developed a spherical crystallization technique that led to improving the flow and direct compressibility of number of microcrystalline drugs.

Advantages of Spherical Crystallization¹

· Spherical crystallization technique has been successfully utilized for improving of flowability and compressibility of drug powder.

· This technique could enable subsquent processes such as seperation, flitration, drying etc to be carried out more efficiently.

· By using this technique, physicochemical properties of pharmaceutical crystlas are dramatically improved for pharmaceutical process i.e. milling, mixing and tabletting because of their excellentflowability and packability.

· This technique may enable crystalline forms of a drug to be converted into different polymorphic form having better bioavilablity.

· For masking of the bitter taste of drug.

· Praparation of microsponge, microspheres and nanospheres, microbaloons, Nanoparticles and micro pellets as novel particulate drug delivery system.

Evalaution of Spherical Crystals³

As these spherical agglomerated crystals showing significant effect on the formulation and manufacturing of pharmaceutical dosage forms so it is necessary to evaluate them by using different parameters.

Flow Property:

Flow property of the material depends on the force developed between the particle, particle size, particle size distribution, particle shape, surface texture or roughness and surface area. Flowability of the agglomerates is much improved as the agglomerate exhibits lower angle of repose then that of single crystals. Studies on spherically agglomerated aspirin crystals revealed that, the angle of repose of agglomerated crystals was 31.13 while that of unagglomerated crystals was 47.12.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. Following are the methods used to determine of flow property

Angle of Repose:

This is the common method used for determination of flow property. The angle of repose is the angle between the horizontal and the slop of the heap or cone of solid dropped from some elevation. Values for angle of repose ≤ 30 usually indicate free flowing material and angle ≥ 40 suggested a poor flowing material. The angle of repose can be obtained from equation

Tan θ = h/0.5d

Where h- height of the cone and d- diameter of the cone

Compressibility or Carr Index:

A simple indication of ease with which a material can be induced to flow is given by application of compressibility index

I = (1-V/Vo) *100

Where v = the volume occupied by a sample of powder after being subjected to a standardized tapping procedure and Vo = the volume before tapping. The value below 15% indicates good flow characteristics and value above 25% indicate poor flow ability

Hausner Ratio:

It is calculated from bulk density and tap density.

Hausner ratio = Tapped density / Bulk density

Values less than 1.25 indicate good flow (20% Carr Index) and the value greater then 1.25 indicates poor flow (33% Carr Index).

Density

Density of the spherical crystals is the mass per unit volume.

Density = M/V

Porosity:

Porosity of granules affects the compressibility. Porosities are of two types “intragranular and intergranular and these are measured with the help of true and granular densities.

Intragranular porosity = 1- Granular density /True density.

Intergranular porosity = 1- Bulk density / Granular density

Total Porosity = 1- Bulk density/ True density

Packability:

Improve packability has been reported for agglomerates prepared by spherical crystallization. The angle of friction, shear cohesive stress and shear indexes are lower then that of single crystals, which can improve the packability of the agglomerates. The packability of agglomerates improved compared with those of the original crystals and that the agglomerated crystals are adaptable to direct tabletting. The packability assessed by analysis of the tapping process with the Kawakita(I) and Kuno(II) method and using the parameters a, b,1/b, k in the equation

N/C = 1/ (ab) +N/a..................................................... I

C = (Vo-Vn)/Vo,

a =(Vo-V∞) /Vo.

ρf- ρn= (ρf- ρo) . exp. (-kn)………………………… II

Where, N =Number of tapping

C =Difference in volume (degree of volume reduction.) and a, b are constant.

Compression Behaviour Analysis:

Good compactibility and compressibility are essential properties of directly compressible crystals. The compaction behavior of agglomerated crystals and single crystals is obtained by plotting the relative volume against the compression pressure. Spherical agglomerates possess superior strength characteristics in comparison to conventional crystals. It is suggest 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 forcompressing the agglomerates under plastic deformation compared to that of single crystals. Compaction behaviour of agglomerated crystals were evaluated by using following parameters

Heckel Analysis:

The following Heckel's equation used to analyze the compression process of agglomerated crystals and assessed their comapctibility.

In [1/(1-D)]=KP+A

Where:

D is the relative density of the tablets under compression Pressure

K is the slope of the straight portion of the Heckel Plot

The reciprocal of K is the mean yield is the mean yield pressure (Py).

The following equation gives the intercept obtained by extrapolating the straight portion of the plots

A = 1n [1/(1-D0)]+B

Where:

D0 is the relative density of the powder bed when P=0.

The following equation gives the relative densities corresponding to A and B.

DA = 1-e-A

DB = DA-D0

Stress Relaxation Test:

In this test put specific quantity of spherical agglomerated crystals sample in a die specific diameter the surface of which is coated with magnesium stearate in advance, then used the universal tensile compression tester to compress the samples at a constant speed. After the certain limit of pressure attained, the upper punch held in the same position for 20 min, during which measured time for the reduction amount of the stress applied on the upper punch. The result corrected by subtracting from this measurement the relaxation measured without powder in the die under the same conditions. The following equation finds the relationship between relaxation ratio Y(t) and time t, calculated the parameters As and Bs, and assessed relaxation behavior.

t/Y(t) = 1/AsBs-t/As

Y(t) = (P0-Pt)/P0

Where:

P0 is the maximum compression pressure, and Pt is the pressure at time t.

Mechanical Strength:

Spherical crystals should posses good mechanical strength as that directly reflects the mechanical strength of compact or tablet. It is determine by using the following two methods

Tensile strength:

Tensile strength of spherical crystals is measured by applying maximum load required to crush the spherical crystal. This method is a direct method to measure the tensile strength of spherical crystals

Crushing Strength:

It is measured by using 50ml glass hypodermic syringe. The modification includes the removal of the tip of the syringe barrel and the top end of the plunger. The barrel is then used as hallow support and the guide tube with close fitting tolerances to the Plunger. The hallow plunger with open end served as load cell in which mercury could be added. A window cut into the barrel to facilitate placement of granule on the base platen. The plunger acted as movable plates and set directly on the granules positioned on the lower platen as the rate of loading may affect crushing load (gm). Mercury is introduced from reservoir into the upper chamber at the rate of 10 gm/sec until the single granule crushed; loading time should be <3 minutes. The total weight of the plunger and the mercury required to fracture a granule is the crushing load.

Friability Test:

The friability of the spherical crystals is the combination of the attrition and sieving process in to a single operation. Granules along with the plastic balls placed on a test screen. The sieve is then subjected to the usual motion of a test sieve shaker provided the necessary attrition on the granules. The weight of powder passing through the sieve is recorded as function of time. The friability index is determined from the slop of the plot of % weight of granules remaining on the sieve as a function of time of shaking.

Friability of agglomerates determined by using formula

Friability(X) = {1-W/Wo}/100

Where

Wo = Initial weight of the crystalline agglomerates placed in sieve

W = Weight of the material which does not passed through sieve after 5 min.

Particle Size and Size Distribution:

Size of the particle and their distributions can be determined by simply sieve analysis. Now with the help of Ro-Tap sieve shaker, particle size analysis can be determined. In advance technology image-analyzer is used to determined size and volume of the particle.

Moisture Uptake Study:

The study indicates the behavior of uptake of moisture by drug and the prepared spherical crystals, which affect the stability. The weighted quantity of drug and spherical crystals placed in crucible at accelerated condition of temperature and humidity,40 C ± 10C and 75% ± 3%respectively. The gain in weight of drug and spherical crystals is measured

Particle Shape / Surface Topography:

Following methods are used

· Optical Microscopy:

The shape of the spherical crystals is studied by observing these under a optical microscope. The observations are made under the observation like 10X, 45X, 60X etc.

· Electron Scanning Microscopy:

The surface topography, type of crystals (polymorphism and crystal habit) of the spherical crystals is analyzed by using scanning electron microscopy.

· X-ray Powder Diffraction:

This is an important technique for establishing batch-to-batch reproducibility of a crystalline form. The form of crystal in agglomerates determine by using technique. An amorphous form does not produce a pattern. The X-ray scattered in a reproducible pattern of peak intensities at distinct angle (2θ) relative to the incident beam. Each diffraction pattern is characteristics of a specific crystalline lattice for a compound.

Applications of spherical crystallization in pharmaceuticals²

1.To improve the flow ability and compressibility:

Today the tablet is the most popular dosage form of 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. The formulation of tablet is optimized to achieve goals. The focus today in the business is better drug delivery concepts, but also makes the simple standard formulations as economical as possible to produce. One of the most economical solutions is to find directly compressible formulations and this is especially at interest for large volume products.

2. For masking bitter taste of drug:

Microcapsules are prepared to mask the bitter taste 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 following drugs were prepared for masking of bitter taste. Various drugs of which taste masking has done were listed in table.

3.For increasing solubility and dissolution rate of poorly soluble drug:

Spherical crystallization has been described as a very effective technique in improving the dissolution behavior of some drugs having low water solubility and a slow dissolution profile.

Table 1. List of drugs on various spherical agglomeration technique have been tried for improving physicochemical properties.

Sr. no.	Drug	Method	Property improved
01	Aspirin	SA	Flowability and Compressibility
02	Salicylic acid	SA	Flowability and Compressibility
03	Aspartic acid	SA	Flowability and Compressibility
04	Ibuprofen	QESD	Flowability and Compressibility
05	Ampiciline trihydrate	ADM	Taste masking
06	Norfloxacin	ADM	Flowability and Compressibility

CONCLUSION:

The spherical crystallization technique is a simple and inexpensive for scaling up to a commercial level. It reduces time and cost by enabling faster operation, less machinery and fewer personnel because it eliminates most of the steps which are required in granulation technology of tablet manufacturing. The spherically agglomerated crystals can be prepared into tablet form or compounded directly into a pharmaceutical system without further processing such as granulation.

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