A review on spherical crystallization: A novel technique in the field of particle engineering

In the production of tablets, the direct compression method is mostly used. In comparison to the traditional wet granulation approach, this cannot be used with sensitive pharmaceuticals and also has a lot more processing limitations. Spherical agglomeration is a novel method for creating pharmaceutical dosage forms that are immediately compressible, the process of spherical agglomeration, which improves the powder's qualities such as particle size, shape, flow characteristics, solubility, and bioavailability of pharmaceutical medicinal ingredients, includes transforming tiny crystals into a spherical shape. The spherical crystallization was improved for use with hydrophilic polymers in order to improve the dissolution properties of pharmaceuticals that are poorly water-soluble. The flow characteristics, particle size analysis, compression, and dissolution behaviour of the spherical agglomerates were also improved. Wet spherical agglomeration (WSA) and the quasiemulsion solvent diffusion method (QESD) are the two most used methods for crystallizing spheres. Additionally, these approaches have two additions: the ammonia diffusion system (ADS) and crystallo-coagglomeration (CCA).The neutralization technique is another method used in this procedure. Any of the aforementioned methods can be employed simultaneously for both crystallization and agglomeration. The crystal physical characteristics, including their shape, polymorphism detection using x-ray powder diffraction (XRD), and thermodynamic characteristics using differential scanning calorimetry (DSC), were examined.


Introduction
Tablets are a relatively common dosage form, making up 70% of all pharmaceutical preparations and at least 50% of all oral drug delivery systems.Direct tableting of pharmaceutical ingredients is a spherical technique for making tablets that has been successfully used to make many medications on a large scale.Simple mixing and compression of powders are used in the manufacture of tablets, which has a variety of advantages in terms of time, money, and energy savings.However, a medication needs to have high micromeritic qualities, such as flowability, in order to be compressed directly.However, crystals with needle or plated shapes have very poor flowability and are challenging to work with.In order to achieve the size enlargement of particles during the crystallization step, Kawashima proposed this method in 1974.He suggested managing crystal agglomeration with regulated features.By demonstrating that spherically dense agglomerates could be generated and were suited for direct tableting, he introduced this process into the pharmaceutical production industry and described it as spherical crystallization.They employed silica sand as their model system, distributed in stirred carbon tetrachloride, and subsequently agglomerated with aqueous calcium chloride solutions.Kawashima employed the spherical crystallization technique to increase the size of drug particles over a period of several years beginning in 1986.By using this technique, the precipitated crystals were agglomerated into spherical particles without the use of binders during the final step of synthesis (recrystallization) [1].This kind of crystallization allows crystals to be formed directly into compacted spheres by combining crystallization and agglomeration in one step.
Because crystal habit (form, surface, and size as well as particle size distribution) can be altered during the crystallization process, this technique for designing drug particles has recently gained significant attention and importance.It is one of the active research areas currently of interest in pharmaceutical manufacturing.Hence spherical crystallization process can be defined as: A revolutionary particle engineering method that unites agglomeration and crystallization in a single process to convert crystals directly into compacted spherical form OR An agglomeration procedure for increasing the flowability, solubility, and compactability of crystalline pharmaceuticals by converting them directly into compact spherical forms [2].
The key factors that affect spherical crystallization include the solvents and their composition, the amount of bridging liquid, the agitation rate, the initial particle size, the feeding rate, the stirring rate, the temperature, and the concentration of the solid, among others.These factors affect the productivity as well as the product's strength, shape, and particle size distribution.Earlier research on the effects of the aforementioned characteristics used other materials as model compounds [3].
The spherical crystallization technique, one of many methods for creating microparticles, has drawn increased attention since it creates microparticles with the necessary qualities that can be used as a directly compressible material.To create spherical matrices of pharmaceuticals with sustained release, the spherical crystallization approach can be changed into an easy and less expensive procedure.In order to create microspheres with longer release and increased bioavailability, the spherical crystals of several medicines, including furosemide, ibuprofen and ketoprofen were directly changed during spherical crystallization using acrylic polymers [4].

Figure 1
Scanning electron microraph of spherical agglomerates [5] The traditional drug manufacturing procedure (granulation) involves the following steps: Crystallization; filtration; drying; blending of formulated powders; granulation; drying; tableting.This is a slow and time-consuming process, whereas in spherical crystallization the process could be reduced to: Crystallization, filtration, drying, dry blending, and tableting [6].
Additionally, several weakly soluble medications, such as celecoxib and fenbufen, are said to have improved detectability, bioavailability, and dissolving rates as a result of this method [7].
The spherical crystallization method also uses a bridging liquid that acts as a granulating fluid to give compressibility [8].
So, the process of spherical crystallization aids in achieving superior flowability and compressibility.In order to alter their release patterns, several medications have also been recrystallized using the spherical agglomeration approach [9]

Need for spherical crystallization
It is the approach of choice for low-dose medications that are water soluble and compressible.This procedure alters the drug's crystallization behaviour, which has an impact on a number of morphological, rheological, and technological elements of pharmacological behaviour and, consequently, dosage form bioavailability.A medicinal powder's flowability, packing, compaction, syringability, suspension stability, and dissolving properties can all be affected by the crystal habit of the powder.Some poorly soluble medications benefit from this method's improved wettability, bioavailability, and dissolving rate [10].

Advantages of spherical crystallization process
 In comparison to other size enlargement methods, this is the simplest. There are fewer unit operations required. The need for manpower is limited because there are fewer operations. Economic  Proper GMP considerations  It has been traditionally used for improving flow, compressibility, solubility, and bioavailability. This technique could enable subsequent processes such as separation, filtration, drying, etc. to be carried out more efficiently. By using this technique, the physicochemical properties of pharmaceutical crystals are improved for pharmaceutical processing, i.e., milling, mixing, and tableting, because of their excellent flowability and packability. This technique may convert crystalline forms of a drug into a different polymorphic form with better bioavailability. For masking the bitter taste of the drug. The preparation of microsponge, microspheres, and nanospheres, as well as nanoparticles and micropellets as novel particulate drug delivery systems [11].

Disadvantages of spherical crystallization process
 The selection of a solvent is a tedious process. It is challenging to maintain process parameters (stirring rate, temperature, and agitation) [11].

Principle of spherical crystallization
 This process involves pouring the saturated solution of the drug in a good solvent (in which the drug is soluble) into a poor solvent (in which the drug is slightly soluble). A third solvent, called the "bridging liquid," is added in small amounts to promote the formation of agglomerates.Bridging liquid wets the crystal surface, causing binding, and promotes the formation of liquid bridges between drug crystals, allowing spherical agglomerates to form. Poor and good solvents should be freely miscible, and the affinity between the solvents must be stronger than the affinity between the drug and the good solvent. The bridging liquid should not be miscible with the poor solvent and should preferentially wet the precipitated crystals [12].

The spherical crystallization process's steps include:
Four steps were suggested by Bermer and Zuider for the growth of an agglomeration.

Flocculation Zone
In this zone, the bridging liquid displaces the liquid from the surface of the crystals, which are brought into 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, and this stage of the agglomeration process, where the ratio of liquid to void volume is low and air is the continuous phase, is known as the pendular state.The mutual attraction of particles is brought about by the 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 liquid.An intermediate state known as the funicular state exists between the pendular and capillary stages.The cohesive strength of agglomerate is attributed to the bonding forces exerted by the pendular bridges and capillary suction pressure [13].

Zero Growth Zone
Loose floccules get transferred into tightly packed pellets, during which the entrapped fluid is squeezed out followed by the squeezing of the bridging liquid onto the surface of small flocs, causing a poor 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, which causes liquid turbulence and pellet-pellet and pellet-stirrer collisions [13].

Fast Growth Zone
The fast growth zone of the agglomerates takes place when sufficient bridging liquid has been squeezed out of the surface of the small agglomerates.This formation of large particles following random collisions of well-formed nuclei is known as coalescence.Only if the nucleus has a slight excess of surface moisture does a collision occur.This gives the nucleus plasticity and promotes particle deformation and subsequent coalescence.Another reason for the growth of agglomerates' size is attributed to growth mechanisms that describe the successive addition of material onto already formed nuclei [13].

Constant Size Zone
In this zone, agglomerates cease to grow or even show a 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, and shattering.The rate-determining step in agglomeration growth occurs in zero growth zones when bridging liquid is squeezed out of the pores as the initial floccules are transformed into small agglomerates.The rate-determining step is the collision of particles 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 the interfacial tension between the bridging liquid and the continuous liquid phase, the contact angle, and the ratio of the volumes of the bridging liquid and solid particles [13].

Techniques of spherical crystallization
Spherical crystals can be obtained by two different techniques:  The typical spherical crystallization technique  The non-typical spherical crystallization technique.
The non-typical spherical crystallization technique can also be considered the traditional crystallization process (salting out, cooling, precipitation, etc.).This process is carried out by controlling the physical and chemical factors [14].
In typical spherical crystallization, three different solvents are used.A good solvent for dissolving the medication, a bridging liquid for partial dissolution and wetting properties, and a bad solvent for being immiscible with the drug ingredient [15]. 5. Types

Wet spherical agglomeration or solvent change
Here, the good and bad solvents are easily miscible and their interaction (binding force) is stronger than that of the drug with the good solvent, causing crystals to precipitate right away.Due to capillary negative pressure and the tension at the liquid-solid interface, bridging liquid gathers the suspended crystals in the system by creating liquid bridges between the crystals.The WSA approach has three steps.Here, the good and bad solvents are easily miscible and their interaction (binding force) is stronger than that of the drug with the good solvent, causing crystals to precipitate right away.Due to capillary negative pressure and the tension at the liquid-solid interface, bridging liquid gathers the suspended crystals in the system by creating liquid bridges between the crystals.The three steps of the WSA approach are depicted in Fig.
The first is choosing the crystallization technique, such as thermal (temperature drop or evaporation), physicochemical (addition of another solvent, salting out), or chemical reaction.The second stage is selecting a wetting agent that will not mix with the crystallization solvent.The third and final process involves hardening the agglomerates.
Drawback of this system is that it produces the low yield, due to co-solvency effect of crystallization solvent.The bridging liquid, the stirring speed and the concentration of solids are the other factors which need to be taken care of [16].
Figure 3 steps involved in spherical agglomeration [16] Chow et al postulated some general guide lines for the spherical agglomeration of drugs.
 A salt solution of high concentration without common ions can be employed as the bridge liquid for molecules that are water soluble, while a water-immiscible organic solvent is utilised as the external medium. Water is used as the exterior phase and an organic solvent that is not miscible with water is used as the bridging liquid for molecules that are soluble in one or more organic solvents. A saturated aqueous solution of the molecule can act as the exterior phase and an organic solvent mixture as the bridging solvent for compounds that are only soluble in water-miscible organic solvents. A water-immiscible organic solvent can serve as the exterior phase and a 20% calcium chloride solution as the bridging liquid for substances that are insoluble in water or any organic solvents.Additionally, since the powders are insufficiently soluble in the bridging liquids to allow binding by recrystallization and fusion, a binding agent like PVP or PEG is needed for agglomeration [17].
When using this procedure, the medication and the good solvent interact more strongly than the good solvent and the poor solvent.Therefore, even though the solvents are generally miscible, a good solvent drug solution is distributed in a bridging liquid, resulting in quasi-emulsion droplets.This causes the interfacial tension between the bridging liquid and the excellent solvent to increase.Drug crystallization results from the counter-diffusion of the poor solvent into the droplets when the drug's solubility in droplets containing poor solvent declines.Good solvent diffuses out of the emulsion droplets in the poor solvent's outer phase.The remaining excellent solvent in the droplets serves as a connecting liquid to aggregate the crystals that are produced.Then, spherical crystal agglomerates are formed if the process parameters are set accordingly.
Finding an appropriate addition to maintain the system's emulsification and enhance the diffusion of the poor solute into the dispersed phase can be challenging, which is a drawback of this approach [18].
A water-soluble medication, salbutamol sulphate, can be crystallized into spheres using the QESD method.For the purpose of producing spherical particles with a size range of 80-500 mm, the type of solvent, antisolvent, and emulsifier to be used, as well as the concentration of emulsifier to be used, are determined.Further research is done on the solvent/antisolvent ratio and the temperature difference (DT) between the two.It was found that the DT value has no effect on the production of spherical particles when salbutamol sulphate is included.This behaviour might be explained by a sizable salbutamol sulphate metastable zone in water.Lastly, the effect of maturation time and emulsifier concentration on the size of spherical particles is studied.The findings indicate that in order to regulate the size of the recovered particles, these two parameters must be fixed [19].

Neutralization method
In this process, tiny crystals are formed and then aggregated.This method was used to create spherical crystals of the anti-diabetic medication tolbutamide.A NaOH solution was used to dissolve the medication.Tolbutamide was precipitated out by adding aqueous solutions of HPMC and HCl to the tolbutamide NaOH solution to neutralize it.After adding the bridging liquid drop wise at a rate of 10 ml/min, the tolbutamide crystals clumped together.
According to Sano et al., tolbutamide agglomerates prepared by neutralization technique have a higher specific surface area, greater wettability, and a faster dissolution rate than agglomerates prepared by emulsion solvent diffusion and solvent change method.The agglomerates prepared by the neutralization method were instantly permeated with water, showing strikingly greater wettability.The reason for the superior wettability of agglomerated crystals and tablets reported is due to the fact that, at the time of agglomeration, hydrophilic polymer (HPMC) in the crystallization solvent adheres firmly to the agglomerated crystals [20].

Ammonia Diffusion System (ADS)
This technique is usually meant for amphoteric drugs, which cannot be agglomerated by conventional procedures [21].
The good solvent in this case is an ammonia-water mixture, and the bad solvent is chosen based on how soluble the medication is.The ammonia-water mixture serves as a bridging liquid as well [22,23].

Figure 5 Ammonia diffusion system[24]
Three stages make up the entire procedure.The medication is first precipitated when the droplets gather the crystals after it has been dissolved in ammonia water.Ammonia in the agglomeration simultaneously diffuses to the surrounding organic solvent.Spherical agglomerates are created as a result of the liquid's diminished capacity to serve as a bridging liquid.By using this technique, the agglomerated crystals of numerous amphoteric medicines have been created.
Drawback of this method is that it is only meant for amphoteric drugs which cannot be agglomerated by conventional methods [24].

Crystallo-co-agglomeration
Kadam and colleagues developed crystallo-co-agglomeration in an effort to get beyond the restrictions of spherical crystallization procedures, which were limited to size enlargements of single high-dose medications exclusively.A drug is crystallized and agglomerated with an excipient or with another drug in this version of the spherical crystallization techniques mentioned above.Similar to spherical agglomeration, this approach solubilizes the drug with a good solvent, crystallizes it with a poor solvent, and forms liquid bridges during agglomeration with a bridging liquid that is immiscible with the poor solvent.
The drawback of this method is that choosing a solvent solution for the crystal-co-agglomeration technique is quite difficult due to the differences in the physicochemical properties of the drug molecules and the excipients [25].
Figure 6 Crytsallo-co-agglomeration process for preparation of spherical crystals [26] 6 Solvent selection Spherical agglomeration is more significant than the other methods due to its simplicity of usage and the ease with which the solvents can be chosen.The quasi-emulsion method trails behind other techniques.
Guidelines for choosing solvents and moving on with various techniques For the spherical agglomeration of various types of solids, the suggested solvents and agglomeration techniques (Chow and Leung, 1996) The terms SA and QESD stand for spherical agglomeration and quasi-emulsion solvent diffusion [17].7 Factors affecting the agglomeration process

Role of solvents
The solvent's characteristics as well as the quantity and make-up of the bridging liquid have an impact on how spherical the agglomerates are.The general rule in a normal SA process indicates that as the amount of bridging liquid increases, so does the size of the agglomeration. 14The size of the agglomerates do not appear to vary with additional additions of bridging liquid, according to observation, after a certain volume has been supplied to the system [27].

Role of temperature
A crucial part of the agglomeration process is the attainment of the ideal temperature.The crystals did not agglomerate and had high fine content at temperatures greater than room temperature.Agglomerates formed at lower temperatures were bigger than those formed at ambient temperature, which plainly affects their solubility and mechanical strength [28].

Role of agitation
It is obvious that the particle size of the agglomerates is greatly influenced by agitation.The shape and size of the product will change if the rate and length of agitation are altered.Agglomerates are sheared by increased agitation rates, which leave behind smaller, finer agglomerates or none at all.Lower rates of agitation will result in spheres with irregular sizes, defeating the purpose of the approach.For the manufacture of satisfying products, the agitation speed must be optimized [29].

Role of additives
Polymers like polyethylene glycol, polyvinyl pyrrolidone, and hydroxypropyl methyl cellulose slow down the nucleation process.These polymers stop crystals from spontaneously aggregating, giving spherical agglomerates plenty of time to develop.The polymers' altered crystal habits cause them to interfere with sphericity and particle size [30].

Duration of residence of agglomerates in crystallization medium
It has been observed that larger agglomerates are generated as the time that agglomerates spend in the crystallization media increases [30].

Physico chemical characterization of spherical agglomerates:
The following criteria must be used to assess the spherical crystals since they have a substantial impact on the design and production of medicinal dosage forms:

Particle size and size distribution
Particle size and distribution can be determined using a straightforward sieve analysis.The Ro-Tap sieve shaker, however, makes it possible to use particle size analysis.An image analyzer is employed in spherical technology to calculate the particle's size and volume [31].

Particle shape/surface topography
Following methods are used:

Optical microscopy
By viewing the crystals under an optical microscope, spherical crystal forms can be investigated.A variety of magnifications, including 10X, 45X, 60X, and others, are used to make the observations [32].

Electron scanning microscopy
Scanning electron microscopy is used to analyse the surface topography and crystal type (polymorphism and crystal habit) of the spherical crystals [32].

X-ray powder diffraction
This is an important technique for establishing batch-to-batch reproducibility of a crystalline form.Technique is used to determine the crystal form in agglomerates.An amorphous form does not produce a pattern.The X-rays scattered in a reproducible pattern of peak intensities at a distinct angle (2θ) relative to the incident beam.Each diffraction pattern is characteristic of a specific crystalline lattice for a compound [32].

Fourier Transform Infrared spectrometer (FTIR)
Due to the inclusion of new stretching frequencies brought on by the salvation, it is significantly more helpful for recognising solvates and anhydrous forms than polymorphs [32].

Differential scanning calorimeter (DSC)
DSC calculates the heat gain or loss brought on by alterations in a sample's physical or chemical composition.DSC can be used to analyse changes in the characteristics of agglomerates made from a combination of medicines and polymers [32].

Thin layer chromatography (TLC)
It establishes the relationship between the drug and polymer in spherical agglomerates and investigates the stability of the drug in various solvents [32].

Residual solvent determination by gas chromatography
By using gas chromatography, the agglomerates are examined for solvent residue that might have remained trapped during the agglomeration process [33].

In vitro dissolution studies
Studies are carried out by adding medium to the spherical crystals in the capsule shell to confirm the better disintegration.Dissolution investigations will show that agglomerates have an advantage over pure drugs [34].

Stability studies
To verify that the agglomerates will remain stable during the shelf life of the final dosage form that will be commercialized, stability tests should be carried out in accordance with ICH criteria [34].

Drug loss in supernatant liquid
In particular for the CCA approach, the liquid supernatant is analysed for the medication that is lost after the whole procedure has been completed.If there is a substantial quantity of drug loss, there may not be enough excipient available to deposit the medicine [35].

Micromeritic properties
Particle size distribution, roundness, angle of repose, Carr's index, Hausner's ratio, compactibility, and packability are examples of micromeritic qualities.Densities are physical traits that depend on the dimensions, morphology, and spherical crystals that are produced as the end result [36].

Practical yield
By crushing and dissolving a specified amount of the generated agglomerates in an appropriate solvent, and then analysing the results using an ultraviolet spectrophotometer, the practical yield of the agglomerates can be ascertained.based on a straightforward mathematical operation [35]; Practical yield (%) = Weight of product Weight of feed × 100

Friability of agglomerates
Each batch of plastic balls and agglomerates has a sample placed on a sieve, which is then shaken for a predetermined amount of time.The mean geometric diameter is determined for each time period.
Percentage friability index (FI) as a function of time can be calculated at each time using the following equation FI= [(dg)t /(dg)0] × 100 Here, (dg)t = mean geometric diameter after time t (dg)0 = mean geometric diameter at initial time [36].

Compression properties
The preparation of the tablet often makes use of this feature.Compaction is another name for this action.When the porosity shifts, Plastic behaviour: compact powder deforms under compression and is tapped into close packing.
Unexpected expansion under stress is known as dilatant behaviour, and some substances show more porosity when compressed than powder and packed closely [37].

Strength analysis
The mechanical toughness of single agglomerates was assessed by compression in materials on a testing apparatus.The agglomerate was positioned as shown in Figure 2, and a steady movement of the upper plane towards the lower plane at a speed of 0.5 mm/min was used to apply a load that gradually increased.The powder bed was compacted after 100 to 150 mg of agglomerates (8.2 mm in diameter) was added to the steel cup.

Heckel analysis
The subsequent In order to analyze and evaluate the compatibility of agglomerated crystals, Heckel's equation was applied.
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.

Applications of spherical crystallization in pharmaceuticals 9.1 To improve the flowability and compressibility
Agglomerates have been shown to possess qualities that make them appropriate for direct compression tableting.Crystals can be produced through sublimation, solvent evaporation, vapour diffusion, thermal processing, crystallization from melt precipitation by a change in pH, growth in the presence of additives, or grinding.Thus, the innovative agglomeration technology that, during the crystallization process, converts the crystals themselves directly into a compacted spherical form has been desired.Making advantage of Spherical crystallization appears to be a successful alternate method for producing direct compression-ready particles.Numerous medications exhibit unfavourableflowability and compressibility as a result of various crystal habits.So these problems can be solved by converting them into agglomerated crystals by changing the crystal habit and spheronization so as to increase the flowability and compressibility [39].

To mask the bitter taste of drug
To cover up the medication's unpleasant taste, microcapsules are created.Since spherical material may be uniformly coated with a relatively small amount of polymer, they are appropriate for coating grains.To cover up the bitter taste, the following medications were made into microcapsules [39].

To increase the solubility and dissolution rate of poorly soluble drug
Some medications with limited water solubility and a slow dissolution profile have been said to respond well to spherical crystallization, according to research [39].

Microparticles by spherical crystallization
For sustained drug release, spherical crystallization using acrylic polymers was used to create a variety of drug microparticles.The traditional approach of generating microspheres, which involves co-precipitating drugs and polymers to create functional drug delivery systems based on the characteristics of the polymer, is less beneficial than spherical crystallization.As a simple and less expensive process, the spherical crystallization technique can be modified to create spherical matrices of prolonged release drugs as an alternative to traditional methods.It offers many benefits, such as the avoidance of harmful organic solvents and additives and the avoidance of raising the system's temperature as in the phase separation method.Additionally, the produced matrix spheres can be directly compressed, skipping the tiresome and drawn-out granulation process [40].

Conclusion
Spherical crystallization has emerged as a significant technology in recent years that not only streamlines the stages necessary in direct compression of tablets but also offers improved flowability over the initial pure amorphous medication.The spherical crystal, which is a cheap technique, The solvent change method, the quasi-emulsion solvent, the ammonia diffusion system, and the neutralisation method are all used in the formation of spherical crystals.This method takes less time than wet granulation since it crystallises, aggregates, and spheronizes in one process.Spherical crystals have a higher solubility in aqueous solvents, increasing the bioavailability of poorly soluble medications, particularly Biopharmaceutical Classification System class II medications, where the bioavailability is dissolution rate limited and the in vivo performance is improved when compared to that of the pure medication as well as the marketed formulation, in addition to exhibiting no preclinical toxicity.However, it is necessary to monitor the organic solvent residues for compliance with legal requirements after the production of agglomerates.Techniques for spherical crystallization can be used successfully as an alternative.Creating microparticles involves Appropriate polymers can be used to get a sustained release of API from the microparticles or compacts of them.By using a spherical crystallization technique instead of the laborious and time-consuming traditional method, sustained-release API microparticles can be created.This approach offers the potential to produce directly compressed tablets of poorly compressible and water-soluble pharmaceuticals with higher bioavailability if the production scale can be increased.

Table 2
Summarizes the different techniques and solvents used in preparing spherical agglomeration of drugs