INTRODUCTION:

Today the tablet is the most popular dosage form of pharmaceuticals. The most economical solution to prepare the tablet is the direct compression of the particles especially for large volume products. The particles to be directly compressed should have very good mechanical properties such as compressibility and flow ability. If the particles can be directly compressible, it requires less equipment and space, lower labor costs, less processing time and lower energy consumption. By this, the manufacturing can be reduced to crystallization, filtration, drying, blending and tabletting. One of the most recent developments to prepare the agglomerates with improved properties is the invention of spherical crystallization in which spherical agglomerates are produced in situ by the agglomeration of the small crystals during crystallization. Spherical crystallization combines several processes into one step, including synthesis, crystallization, separation and agglomeration^29,
25.

Among the advantages of the spherical agglomerates are good physico-chemical properties like compressibility, packability and flow ability that improve mixing, filling and tabletting¹⁷. The compressibility and tablettability of the spherical agglomerates of salicylic acid were improved due to their increased plastic property and reduced adhesive property compared to the original crystals ¹⁸.

The micromeritic properties (size, roundness etc.) of agglomerated crystals and the mechanical properties such as flowability, packability, compactability were dramatically improved, resulting in successful tabletting. In pharmaceutical production improved flowability and compaction reduces the number of formulation components and processing operations. These agglomerates are also desirable for drug delivery since they are comprised of small crystals and contain a large surface area to volume ratio. Once these agglomerates are broken down to their constitutive crystals high dissolution rate as well as bioavailability is retained by these particles.

This review is divided into three main sections. First, a general description of the spherical crystallization and mechanism involved is presented. In the second section, a review of previous research on the influence of process parameters on the spherical crystallization is given. In the third section, previous work on the development of characterization methods for spherical crystal agglomerates is described.

Spherical Crystallization:

General Description and Mechanism:

Spherical crystallization is a process in which spherical agglomerates are produced in situ during crystallization by the agglomeration of the small crystals into a spherical form. Spherical crystallization can be achieved by using four methods:

1. Spherical Agglomeration (SA)

2. Quasi Emulsion Solvent Diffusion (QESD)

3. Ammonia Diffusion system (ADS)

4. Neutralization (NT)

Spherical agglomeration is used for the rapid separation of dispersed solids from liquids for wide range of applications⁵. In the beginning some authors^9,
48, discovered that adding barium sulfate in a mixture of benzene and small amounts of water would cause barium sulfate to form spherical clusters. A deeper study of spherical agglomeration was done in the 1960’s and 1970’s at the Canadian National Research Council ^{9, 14,15,46,48}. Their main interest of study was selective agglomeration of coal, but they also studied several other compounds (silica sand, glass and calcium carbonate). They studied the mechanisms, kinetics of spherical agglomeration, and the effect of process variables on the agglomerates.

Kawashima gave a second boost to spherical crystallization by introducing this technique into pharmaceutical manufacturing in the early 1980’s and inspired research in other fields²⁴. The technique also was exploited in the preparation of food colorants²⁹, and new studies on selective recovery of fine mineral particles were conducted by Sadowski⁴³. Bausch and Leuenberger, have used it for protein crystallization as well¹. Spherical agglomeration provided a significant improvement to the production of pharmaceuticals with bioactive proteins. They agglomerated hydrophilic proteins from organic solvents using water as bridging liquid which wets the particles and causes them to agglomerate spherically. The used spherical agglomeration has been extended to the agglomeration of several other pharmaceutical drugs. For example, acetylsalicylic acid¹⁰, fenbufen³¹, aminophylline²⁴.

In the spherical crystallization process, crystal formation, growth and agglomeration occur simultaneously within the same system. In this method, a third solvent called the bridging liquid is added in a smaller amount to purposely induce and promote the formation of agglomerates¹⁶. Crystals are agglomerated during the crystallization process and large spherical agglomerates are produced. A near saturated solution of the drug in a good solvent is poured into a poor solvent. The poor and good solvents are freely miscible and the “affinity” between the solvents is stronger than the affinity between drug and good solvent, leading to precipitation of crystals immediately. Under agitation, the bridging liquid (the wetting agent) is added, which is immiscible with the poor solvent and preferentially wet the precipitated crystals. As a result of interfacial tension effects and capillary forces, the bridging liquid acts to adhere the crystals to one another and facilitates them to agglomerate²⁵.

Many authors^{9, 18, 21, 27, 47}have discussed the mechanism of spherical agglomeration. Chow and Leung⁶ and Farnand ⁹ suggested that when two immiscible solvents are present and one of the solvents preferentially wets the solid surface, a collision between two wetted particles forms a liquid bridge between the particles. This liquid bridge holds the particles together and further collisions cause formation of larger spherical agglomerates. This behavior is similar to liquid bridge formation in granulation, except the continuous medium is a liquid instead of a gas. Blandin³, developed a phenomenological model based on the experimental observations on the system (salicylic acid-water-chloroform) and on analogy with the granulation process; it is assumed that the agglomeration mechanisms during the growth period are governed by the agglomerate deformability. After a brief period of wetting of the particles by the bridging liquid, the agglomerates grow by coalescence like process until they reach a maximum size and then agglomerates get compacted. Subero⁴⁷ and Muller³⁴ proposed two possible mechanisms based on the relative size of the droplets and the particles and on the physico-chemical properties of the system. In the first case, the average diameter of the droplets is smaller then the small binding liquid droplets coat the solid particles and enable them to agglomerate as irregular flocs. In the second case the average diameter of the droplets is larger than the primary crystals, and the droplets act as collectors and are covered by solid particles, which then penetrate and fill the interior of the droplets.

Generally, for the spherical crystallization, a mixture of miscible or partially miscible liquids is employed as the solvent system^25.Kawashima ²⁰ found that depending on the miscibility of the solvent mixture spherical crystallization may occur via two different mechanisms i.e. quasi emulsion solvent diffusion (QESD) and spherical agglomeration (SA). Kawashima¹⁸ described the spherical crystallization behavior in the miscible region of the three-solvent system in terms of the solubility phase diagram. Spherical agglomeration has got more importance than other methods because it is easy to operate and the selection of the solvents is easier than in the other methods. Quasi emulsion solvent diffusion method has the second importance, below all the methods are explained briefly.

Quasi emulsion solvent diffusion is also known as transient emulsion method. In this method only two solvents are required²⁵ a solvent that readily dissolves the compound to be crystallized (good solvent), and a solvent that acts as an antisolvent generating the required supersaturation (poor solvent). In the ESD method ^44,45 the “affinity” between the drug and the good solvent is stronger than that of good solvent and poor solvent. Because of the increased interfacial tension between the two solvents, the solution is dispersed into the poor solvent producing emulsion (quasi) droplets, even though the pure solvents are miscible. The good solvent diffuses gradually 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. The method is considered 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. Especially hydrophilic/hydrophobic additives are used to improve the diffusion remarkably⁴². In this method the shape and the structure of the agglomerate depend strongly on the good solvent to poor solvent ratio and the temperature difference between the two solvents⁷.

Using QESD method, Kawashima, directly agglomerated the fine crystals of antibacterial drug crystals without using any bridging liquid²⁶. Poorly compressible crystals of acebutolol hydrochloride were agglomerated by the QESD with a two-solvent system to improve the compressibility for direct tabletting ^16,17.

Ueda⁵¹ modified the spherical crystallization technique and developed a new agglomeration system i.e. ammonia diffusion system (ADS) which is applicable to amphoteric drug substances like enoxacin. In this method, ammonia water acts as bridging liquid and collects the fine crystals and transforms them into spherical agglomerates. Puechagut ³⁹and Gohel¹¹ have prepared agglomerated crystals of norfloxacin and ampicillin trihydrate, respectively, by using ADS.

Sano⁴⁵ reported spherical crystallization of anti-diabetic drug tolbutamide (TBM) by neutralization method. The drug was dissolved in a sodium hydroxide solution and in a hydroxypropylmethylcellulose aqueous solution. Hydrochloric acid was added to neutralize the sodium hydroxide solution and to crystallize out tolbutamide. The bridging liquid was added drop wise followed by agglomeration of the tolbutamide crystals.

Influence of Process Parameters:

Important operating parameters in spherical agglomeration are the selection of the solvent system and amount of the bridging liquid, the agitation rate, concentration of the solid, temperature, poor solvent to feed ratio (drowning ratio) and feeding rate.

Spherical crystallization can only be possible through the particular combinations of solvents. The solvent system and composition is usually selected by trial and error. Very limited work has been done on the systematic selection of the solvent system for spherical crystallization. Most articles do not address the reasoning behind their solvent selection; Chow and Leung ⁶ have found some general rules to use as a starting point. There are a few guidelines given in Table 1 to select solvents and to proceed further using different methods.

Table 1: Suggested solvents and agglomeration methods for spherical agglomeration of various types of solids ⁶. SA= Spherical agglomeration, QESD = Quasi emulsion solvent diffusion.

Compound	Continuous phase	Bridging liquid	Method
Soluble in water	Water-immiscible Organic solvent	20% calcium chloride solution	SA
Soluble in organic solvents	Water	Water-immiscible organic solvent	SA
Soluble in water- miscib miscible organic solvents	Saturated aqueous Solution	Organic solvent mixture	QESD
Soluble in water or any organic solvent	Water-immiscible organic solvent	20% calcium chloride solution+ binding agent	SA

Concerning the solvent composition, the first importance goes to the amount of bridging liquid required for the spherical agglomerates formation. Studies have been done to optimize the amount of bridging liquid to be added to the system ^1,3,12. Depending upon the amount of bridging liquid the particles can either form loose flocs or compact pellets. It was found that below the optimum amount of bridging liquid plenty of fine particles were produced whereas above the optimum amount very large agglomerates were formed. In general, increasing amount of the bridging liquid leads to an increase in agglomerate size ^19.Subero⁴⁷ developed the visualization cell to enable the observation of solids capturing by individual droplet. These experiments in the cell were also used to compare the saturation (ratio of the pore volume occupied by the bridging liquid on the total pore volume) of the bridging liquid in the agglomeration process. This could also be used as a first step in the design of the agglomeration process to select the bridging liquid and test different BSR values.

The second process parameter that affects spherical crystallization is the hydrodynamics in the crystallizer. Various studies have reported effects of the agitation speed in the system and it is one of the main parameters determining the average diameter of agglomerated crystals. With increasing agitation speed of the system, the shear force applied increases lead to more consolidated agglomerates. The agglomeration process is less efficient above the optimum stirring rate because with increasing stirring rate the disruptive forces increases ^{4, 49}. Blandin² found that at a higher stirring rate the final agglomerates tend to be less porous and more resistant.

Capes⁵ showed that the final agglomerate size varied directly with the ratio of the interfacial tension to the initial solid particle size. Kawashima ¹⁵ found that the initial solid particle size had a strong influence on the agglomeration process. Very fine particles required less amount of bridging liquid but the agglomerate size distribution was wider with decreasing particle size. Kawashima¹⁹ found the agglomerate size increased with decreasing the size of the initial solid particles in the case of lactose.

Kawashima²⁵, studied the temperature effect for spherical agglomeration of salicylic acid in (water-ethanol-chloroform) system. With increasing temperature the recovery of the crystals decreased because of the increased solubility of the compound. At low temperature the recovery of the crystals increased, where as the constituent crystal size and the solubility of chloroform in the solvent mixture decreased. The bulk density of the agglomerates decreased with increasing crystallization temperature. The large agglomerates produced at higher temperatures were bulky, less spherical and loosely compacted in a container leading to low bulk density. Temperature also affects the crystallization steps such as nucleation, crystallization and agglomeration of crystals. In the kinetic studies, Kawashima and Capes ¹⁴ confirmed that spherical agglomeration follows first order kinetics with respect to increasing number of agglomerates with time.

Characterization Methods:

A wide range of methods has been applied to characterize spherical agglomerates. The physico-mechanical properties of the spherical agglomerates affecting the quality of tablets and capsules have been discussed in the literature. The methods have been developed mainly to characterize the particles for size distribution, morphology and mechanical properties such as compressibility, tensile strength, mechanical strength and elasticity. At first, the method to measure the particle size distribution (PSD) and shape of the spherical agglomerates is important as this influence other properties. The PSD is usually examined with sieve analysis ^{13, 23,
32}. Unfortunately, sieving may be destructive to the spherical agglomerates and can introduce errors into the size distribution measurement if the particles are not strong enough. There are some other sizing techniques such as image analysis by optical microscopy ^{22, 47} or particle size analysis by a photographic counting method using a particle size frequency analyzer⁵¹. Different techniques are also used e.g. Re⁴⁰ used a Malvern master sizer to measure the PSD, Revesz⁴¹ determined the particle size using Laborlux S light microscope and a quantimet 500MC image processing and analysis system and Kumar²⁸used a precalibrated stage micrometer. Nayak³⁵ used Ankersmid CIS-50 particle size analyzer to determine the average particle size.

The morphology and surface topography of the spherical agglomerates has been determined by using optical microscopy^{8, 40} and scanning electron microscopy (SEM)^17,30,33,41. Even though the optical microscope magnification is less compared to electron microscopes, it is advantageous to have an easy sample preparation and the operating is very convenient. The samples can also be collected after the analysis. SEM can provide high resolution and magnification images. SEM images of spherical agglomerates were used to examine the different mechanisms of spherical crystallization⁴⁵. The external and internal morphology of the spherical agglomerates, as well as the cross sections were examined by SEM. Puechagut³⁹ used polarized light microscopy to observe the morphology of the particles.

Porosity and density of spherical agglomerates are important factors in pharmaceutical applications since they directly influence the dissolution rate due to surface area effects. Agglomerate density is determined by comparing the agglomerate true density with its apparent density. The apparent density is determined using particle size and the weight of the sampled agglomerates³². Agglomerate true density can be found by pycnometry¹⁹. Agglomerate bulk density is a loosest packing density of spherical crystals in a specified volume^{16, 25}. Generally, larger spherical agglomerates were found to be less compact and therefore were more porous than small spherical particles.

Mechanical properties such as compressibility, mechanical strength, elastic recovery, pack ability and flow ability of spherical agglomerates are very important for the handling and bioavailability of the particles. Elastic recovery of spherical agglomerates can be evaluated by repeated cycles of compression. From the comparison of stress relaxations and elastic recovery the compressibility of the spherical and single crystals was estimated¹⁷. From the analysis it was found that the spherical agglomerates were more compressible and suitable for dosage than conventional crystals. Several studies were done to reveal the tensile strength (the resistance of the tablet to crushing) of the tablets prepared from spherical agglomerates^{16, 32, 45}. Tensile strength is calculated by using the below equation

F is the compression force required to fracture the tablet, D and L are the diameter and the thickness of the tablet, respectively.

Several authors have studied flow ability, pack ability and compaction of the spherical agglomerates^16,20,36,37. The flow ability is measured by the determination of angle of repose and Carr’s index (CI). Angle of repose was determined by fixed funnel method³⁸. In this method powder flows out of a funnel to form a powder heap, from which the angle of repose can be determined by simple geometrical means.

Carr’s index was calculated from the poured and tapped densities. Tapped density was determined using a tapping machine by tapping the samples into a 2.5 ml measuring cylinder. Low angle of repose and Carr’s index represents higher flow ability.

The pack ability of the particles was investigated by measuring the tapped density. According to Kawakita and Kuno’s equations³⁷pack ability can be estimated from the volume and density of the packed particles as a function of tappings.

Kawakita Eqn:

Kuno Eqn:

Here n is the number of tappings, C is the volume reduction, V₀ andV_nare the initial volume of the powder bed before tapping and after the n^th tapping, respectively. The true density is q_t,, the density of the powder bed at the initial stage is q₀and at the n^th tapping is q_n. The constants a, b, and K represent, packability of the powder under mechanical force (1/a represents compactability and 1/b is cohesivity). The smaller value of parameter ‘a’ indicates higher packability, the larger value of ‘b’ indicates higher packing velocity by tapping and higher K indicates the higher rate of packing.

CONCLUSIONS:

Spherical agglomeration can be achieved by using different techniques under optimized process conditions. Spherical agglomerates are formed by the association of a number of smaller crystals, so these particles are expected to have high dissolution rate and bioavailability. Spherical particles prepared by these techniques are proved to have improved properties like flowability, packability which allows the particle to compress directly into tablet.

ACKNOWLEDGEMENT:

Authors would like to thank DST for funding this project.

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Received on 26.07.2017 Modified on 19.08.2017

Research J. Pharm. and Tech. 2018; 11(1): 412-417.

DOI: 10.5958/0974-360X.2018.00076.8