Student- KBHSS Trust’s Institute of Pharmacy, Malegaon -423105
Within the crystallisation process, spherical crystallisation is defined as "an agglomeration process that transforms crystals directly into compact spherical forms." An innovative agglomeration method known as spherical crystallisation allows the tiny crystals formed during the crystallisation process to be directly shaped into a spherical form. Methods for spherical crystallization include symmetric agglomeration, ammonia diffusion, and emulsion solvent diffusion. Three different kinds of solvents are used in spherical crystallization: good, bridge, and poor solvents. The four primary stages of spherical crystal formation are flocculation zone, zero growth zone, fast growth, and constant size. The temperature of the system, residence time, agitation type and intensity, and solubility profile are the factors that govern the agglomeration process. A method for designing particles that allows for the simultaneous execution of agglomeration and crystallisation in a single stage is called spherical crystallisation. The size, shape, and flow characteristics of crystalline pharmaceuticals have all been successfully improved by using this approach on powders. Furthermore, spherical crystallisation is used to study medicinal medication solubility enhancement. In this review, we'll talk about the benefits, the technique, and the variables that the spherical crystallisation process can enhance. The possibilities for spherical crystallisation, both now and in the future, are also covered.
Almost 70% of all pharmaceutical products and 50% of oral drug delivery systems products are tablets, making them a common type of pharmaceutical dosing. One spherical method that works well for producing huge quantities of tablets for many different drugs is direct tableting. This technique, which offers major advantages in terms of time, cost, and energy efficiency, entails the simple mixing and compression of powders. A medicine must possess high flowability and other great micromeritic properties in order to be compressed directly. Nevertheless, poor flowability and handling difficulties are associated with crystals shaped like needles or plates. To overcome this problem, Kawashima suggested increasing the size of the particles as they crystallised in 1974. He proposed regulating the agglomeration of crystals to generate agglomerates that are spherically dense and appropriate for direct tableting. The pharmaceutical industry adopted a process called spherical crystallisation to enhance the manufacturing of pharmaceuticals. They employed aqueous calcium chloride solutions to agglomerate the silica sand that had been disseminated in stirred carbon tetrachloride in their model system. Kawashima began using the spherical crystallisation method in 1986 in order to increase the size of medication particles. In the final recrystallization step, this technique made it possible for precipitated crystals to aggregate into spherical particles without the need for binders [1].
Crystals may be immediately squeezed into spheres using this crystallization technique, which combines agglomeration and crystallization into a single phase. Because it may alter crystal behavior (form, surface, size, and particle size) throughout the crystallization process, this approach is crucial to the generation of particles. This is a significant issue in the pharmaceutical sector that consumers are now aware of. Consequently, the following definition of the global crystallization process is given: An innovative approach to particle engineering that merges the processes of agglomeration and crystallisation into one, transforming crystals straight into compact spherical shapes, or an agglomeration method designed to improve the compactability, flowability, and solubility of crystalline drugs by shaping them into small, spherical forms [2]. The main variables affecting spherical crystallisation are temperature, solid concentration, feeding rate, stirring rate, agitation rate, amount of bridging liquid, and initial particle size. These factors affect the final product's strength, form, and distribution of particle sizes in addition to productivity. Several materials have served as model compounds in earlier research on these properties [3]. Among the several techniques for generating microparticles, spherical crystallisation has attracted more interest since it yields microparticles with characteristics appropriate for direct compression. This method can be changed to create spherical pharmaceutical matrices with sustained release that are easy to use and reasonably priced. Acrylic polymers have been used to directly modify the spheroid crystallization method forms drugs like furosemide, ibuprofen, and ketoprofen into spherical crystals that enhance their bioavailability and provide microspheres with continuous release. [4]. A number of phases are involved in the classic medication production process (granulation):
crystallisation, filtering, drying, blending of powdered formulations, granulation, repeat drying, and tableting. This is a laborious and slow process. The process is reduced to crystallisation, filtering, drying, dry mixing, and tableting with spherical crystallisation, on the other hand [5]. Some poorly soluble drugs, such as fenbufen and celecoxib, are also said to be more detectable, bioavailable, and dissolve more quickly when using this technique [6].To improve compressibility, the spherical crystallisation process makes use of a spanning fluid that also serves as a fluid that granulates. This procedure enhances compressibility as well as flowability. Furthermore, Spherical aggregation technique has been used to used to recrystallize a number of drugs in order to alter their release patterns [7, 8].
For compressible, water-soluble, low-dose drugs, spherical crystallisation is the preferred form. Through altering the drug's crystallisation behaviour, this technique improves the bioavailability of dose forms by influencing different morphological, rheological, and technical elements of pharmacological performance. A pharmaceutical powder's crystal habit affects its dissolution, flow, packing, compaction, syringability, and stability during suspension. This approach Boost the rate of drug dissolution, bioavailability, and wettability of poorly soluble medications medicines [9].
A spherical crystal's necessity
It is desirable for low-dose, compressible, water-soluble drugs to crystallise spherically. By altering the drug's crystallisation behaviour, this technique improves dosage form bioavailability by influencing pharmacological performance in morphological, rheological, and technical domains. A pharmaceutical the dissolving, packing, compaction, syringability, suspension stability, and flowability of powder qualities are all influenced by its crystal habit. This approach enhances wettability, bioavailability, and dissolution rates for drugs that are poorly soluble [9].
Benefits of the spherical crystallisation process
Consequences of the spherical crystallisation method
Symmetric crystallisation principle
Pouring the medication into a poor solvent where its solubility is limited after it has been saturated With a suitable solvent in which the medication is soluble . The use of a bridging liquid, which, when added in modest amounts, facilitates the production of spherical agglomerates by moistening the crystal surfaces of the drug crystals and building liquid bridges between them. Ensuring that there is a greater affinity between the poor and good solvents than there is between the medication and the good solvent, resulting in a freely miscible mixture. Selecting a bridging liquid that wets the precipitated crystals preferentially and is immiscible with the poor solvent [11].
Phases in which spherical crystallisation occurs [12]
Agglomeration growth can be broken down into the following key steps:
1. Flocculation Zone:
The liquid is moved away from crystal surfaces by the bridging liquid.
Crystals come closer together when there is agitation. Adsorbed bridging liquid creates lens bridges, which cause open, loose flocks of particles. Particles are drawn to one another by surface tension and liquid bridges. once the agglomerate's vacant areas have all been filled with liquid, the capillary stage is reached.
2. Zero Growth Zone:
Tightly packed pellets replace loose floccules. Bridging liquid is compressed onto the surfaces of small flocks when trapped fluid is forced out, filling the pellet to the brim with bridging liquid. This transition is driven by the slurry's agitation, which results in liquid turbulence and collisions between the stirrer and the pellets.
3. Fast Growth Zone:
Agglomerates expand quickly in this zone as enough bridging liquid is forced off the surfaces of smaller agglomerates. Coalescence is the process by which large particles are created by the random collision of nuclei that have formed correctly. When there is a small excess of surface moisture on the nuclei, it gives them elasticity and facilitates particle deformation and subsequent coalescence, which leads to successful collisions.
4. Constant Size Zone:
Agglomerates in this zone may stop growing or they might even exhibit a little size drop. Within the agglomerates, the frequency of breakage equalises the frequency of coalescence. Breaking, shattering, and attrition processes can all result in size reduction.
Figure 1: There are four phases in the growth of an agglomeration: flocculation, zero, rapid, and steady size zones.
In spherical crystallisation, three different kinds of solvents are typically utilised
1. A good solvent
The medicine shows excellent solubility in the good solvent; this solvent is chosen because it can function as the ideal solvent for the drug. The drug's solubility and miscibility or affinity with the bridging liquid determine which solvent is best.
2. Transitional Liquid
When liquid-suspended crystals with a bridge liquid present are stirred, agglomerates are formed. The particles are bound together by this bridging liquid, which ought to be immiscible with the suspending medium. The liquid suspension's highly separated solid crystals are initially apart. But when a tiny bit of bridging liquid is added and wets the solids' surface, bridges form between the solid crystals and eventually the crystals clump together to form spheres.
3. Subpar Solvent
The solvent system, which consists Poor solvents, also known as anti-solvents or bad solvents, should not come into contact with either the bridging liquid or the good solvent. Moreover, the subpar solvent's interaction with the solvent system needs to be stronger than the solvent's connection with the medication. In this method, water is frequently the favoured anti-solvent, particularly for increasing the solubility of medications that are weakly soluble. Usually, iterative testing and refining are used to choose the solvent system and define its composition.
Techniques for turning spheres into crystals
1. Clustering of spheres (SA) [13,14]
Poor solvents, also known as anti-solvents or bad solvents, should not come into contact with either the bridging liquid or the good solvent.
2. Transient emulsion/quasi-emulsion solvent diffusion (QESD)[15]
The drug's affinity for the good solvent in
emulsion solvent diffusion is higher than the good solvent's affinity for the bad solvent. The medication is mixed with a low-quality solvent after being initially dissolved in a high-quality solvent to create a solution. While pure liquids mix well, these dispersions result in emulsion droplets. The positive solvent finally diffuses into the surrounding negative solvent phase from the emulsion droplets when the medicine crystallizes within them. The negative solvent diffuses into the water droplets concurrently. Even if the procedure is thought to be less complicated than the difference, it will still need the inclusion of materials required to regulate emulsification and enhance the poor solvent's diffusion into the dispersed phase.
Figure 2: Quasi Emulsion solvent diffusion
3. Diffusion technique of ammonia (ADM)[16]
The crystallisation system used in this procedure consisted of a combination of three somewhat immiscible solvents: dichloromethane, ammonia water, and acetone. Ammonia water performed the combined functions of being an effective solvent and a bridging liquid. Even though it was soluble in water, acetone was not a good solvent. NAs a result, the medication did not precipitate an Nammonium salt as a result of the solvent change. Ammonia water was made easier to release in this system by halogenated hydrocarbons, such as dichloromethane, or hydrocarbons that are not soluble in water.
Figure 3: Steps involved in Ammonia Diffusion System (ADS)
4. Procedure for Neutralisation (NT) [17]
Following their development, the process entails gathering tiny crystals. The crystallization of the diabetes medication tolbutamide was demonstrated using this technique. The solution should first be dissolved in sodium hydroxide solution. To stop the addition of sodium
hydroxide and encourage the crystallization of tolbutamide, an aqueous solution containing hydrochloric acid and hydroxypropyl methylcellulose is added.
Figure 4: Process of Neutralization technique
5. Method of Crystal Co-Agglomeration (CCA)
A vessel created especially for spherical crystallisation by Morishima et al. was used for the processing. This vessel has baffles and a motorised propeller inside a covered container that can be filled with different substances. To provide temperature stability, the vessel is submerged in a water bath with a thermostat. For agglomerates to develop properly, controlled agitation is essential.
Figure 5: The Crystal-Co-Agglomeration Technique's (CCA) process
Enhancement Of The Drug's Physicochemical Properties Through Methods of Spherical Crystallisation:
1. The size and form of the particles: Pharmaceuticals' crystal habits are changed via spherical crystallisation, which has a variety of physicochemical effects.
2. Porosity: The volume of the agglomerates rises as the drug ingredients' density falls.
3. Consistency: Changes in the polymorphism of medicinal compounds during the recrystallization process can cause changes in their stability.
4. Suitability for Flow: Agglomerates have increased flowability due to their lower angle of repose compared to single crystals. The agglomerates' spherical shape, which greatly lowers inter-particle friction and static electric charge, is responsible for this improvement.
5. Stowage: Agglomerates are more packable than single crystals because they have lower shear cohesive stress, shear indices, and angles of friction.
6. Density: When it comes to compaction behaviour in particular, aggregating crystals outperform ordinary crystals in terms of strength attributes.
7. Liquidity: The elementary crystal size and crystallinity of agglomerated crystals affect their wettability. A lower contact angle is correlated with increased wettability.
8. Dissolvability: Significant changes in the molecules' internal energy lead to an enhancement in solubility in produced spherical agglomerates.
9. Disintegration: Particle size, solubility, velocity, and surface area of the generated aggregated crystals are ascribed to their higher dissolving rate and bioavailability [18].
Feature Description
Different analytical approaches are used to determine the description of crystals with spheres:
The differential scanning calorimeter, or DSC, measures the spherical crystals' purity, glass transition, dehydration, dissociation, breakdown, phase transfer, and heat capacity [12].
The spherical crystallisation process produces medicinal components with better parameters.
1. Particle Size and Size Distribution:
This method may be used to change the distribution and size of the particles in pharmaceutical components, usually producing bigger, spherical particles. The bridging agent causes the particles to aggregate, which makes it easier to increase the size of the particles. Furthermore, the process's agitation of the solvent solution promotes the development of spherical particles. The following techniques can be applied to ascertain the size and form of particles with spherical crystals:
1. Optical microscopy: for visual inspection and particle shape measurement.
2. Laser diffraction can be used to identify the particle size distribution.
3. Scanning electron microscopy (SEM): for a detailed analysis of particle size and form.
4.The size of suspended particles can be determined by the use of dynamic light scattering (DLS).
2. Mechanical Strength:
Strong tablets or compacts are immediately impacted by spherical crystals' high mechanical strength. Increased intraparticle tensions within spherically agglomerated crystals could be the cause of this strength. The following techniques are used to calculate mechanical strength:
3. Flow Property:
A material's flow property is affected by a number of variables, including surface area, inter-particle forces, particle size, size distribution, and form. Because of their spherical shape and lower static electric charge, spherical crystals are known to have increased flowability due to a significant reduction in inter-particle friction. Among the techniques used to ascertain flow qualities are:
Tan ? = h/0.5d
I = (1-V/Vo) *100
where Vo is the volume before to tapping and v is the volume occupied by a sample of powder following a normal tapping technique. Good flow qualities are indicated by a score below 15%, while poor flowability is indicated by a value above 25%.
Tap density and bulk density are used to determine it.
Hausner ratio = Tapped density / Bulk density Values
Density: Because of the process of size growth, the mass per unit volume of spherical crystals is used to calculate their density.
Density = M/V
Where M na V in mass and volume of powder respectively.
4. Friability Test:
The attrition and sieving procedures are combined into a single operation to test the spherical crystals' friability. A test screen is covered with plastic balls and granules. After that, a test sieve shaker is used to move the sieve in a typical manner, which causes the granules to attrition. Over time, the weight of the powder going through the sieve is tracked. The friability index is determined by calculating the slope of a graph that plots the weight % of the material left on the sieve versus the shaking duration. Agglomerate friability is calculated using the formula below:
Friability(X) = {1-W/Wo}/100
where Wo is the starting weight of the crystalline agglomerates in the filter. W is the weight of the material that, after five minutes, did not pass through the sieve.
5. Moisture Uptake Study:
This study evaluates how well medications and produced spherical crystals absorb moisture, which may have an effect on their stability. During the process, a crucible with accelerated temperature and humidity conditions is filled with a weighed quantity of the medication or spherical crystals. These conditions are usually around 40°C ± 10°C and 75% ± 3%, respectively. The medication or spherical crystals' gradual weight rise over time reveals how likely they are to absorb moisture in these circumstances.
Prospects for the spherical crystallisation process today and in the future
To improve certain properties, a number of pharmacological compounds have been made into spherical crystals. Yadav VA et al. created spherical crystals of carbamazepine in a solvent system by employing the semi-emulsion solvent diffusion technique, water as a negative solvent, ethanol as a positive solvent, and chloroform as a bridging agent. They came to the conclusion that spherical crystals of CBZ showed better behaviour in direct tabletting and increased dosage form bioavailability when coupled with various hydrophilic and hydrophobic polymers [19]. Despite extensive research on spherical crystallisation techniques, there are still issues that call for investigating novel strategies to overcome current constraints. The poor percentage yield of recovery, which frequently results in significant losses of pharmaceutical substances, is one main cause for concern. Furthermore, choosing the right solvent system continues to be difficult and necessitates careful design considerations. The process of creating spherical crystals becomes more complicated when several parameters like temperature, bridging liquid amount, and agitation speed are adjusted. Consequently, there is a critical need to create new approaches that address these problems with existing methods so that spherical crystallisation can be used more effectively for the development of direct tabletting technologies.
Tools for the formation of spherical crystals:
The majority of the time, straightforward tools and apparatus like a thermostat, a beaker or other suitable-sized container, and a mechanical stirring element can be used to create spherical crystals. Typically, these parts are placed as shown in Figure 6.
Figure 6: Device for Spherical Crystallization
A) mixer, B) box, and C) bath are a few of these.
The following variables affect the spherical crystallisation process:
1. Choosing the Best, Worst, and Bridging Liquid:
Spherical crystallisation depends on a number of variables that affect the drug's physicochemical characteristics. The greatest yield of spherical crystals requires the optimisation of several parameters, including temperature, pH, bridging liquid addition rate, solvent system of choice, and stirring rate. The impact of adjusting these processing settings on achieving perfect spherical crystals is covered in the section that follows.
The drug's solubility properties dictate which solvents should be used. Usually, a three-solvent system is employed, which consists of a bridging liquid, a good solvent, and a bad solvent. A solvent is considered good if it dissolves the medicine entirely; a poor solvent leaves the drug partially dissolved. Solubility studies are used to establish the optimum solvent proportions, which can be used to control the physical form of the product. Determining the drug's solubility in a given solution is also aided by its dielectric constant. Drugs with polar properties typically dissolve more readily in polar solvents like alcohol and water.An incomplete SCHEFFE (1958) system can be used to create a ternary phase diagram that shows the composition of the agglomeration region [20]. The solvent system ratio influences agglomeration. The average diameter of the agglomerated crystals increases as well because crystal agglomeration develops when the concentration of the bridging liquid rises. Instead of mixing with weak solvents, the continuous fluid should ideally moisten the rock that has been laid. The bridging liquid creates interfacial tension and capillary forces that drive the crystals to cling together. The polymorphic character of the solid can also be influenced by the solvent selected. Physical characteristics like melting point and dissolving rate are influenced by changes in molecular mobility and organisation that occur during the transition motion that the solid experiences as it dissolves in the solvent.
2. Mode of Bridging Liquid Addition:
The sphericalness of the crystals is greatly influenced by the rate at which the bridging liquid is introduced. The stability of the droplets within the system, namely the mass transfer of the medication from the droplets, affects this addition rate as well [21]. A medication solution is added dropwise, which lengthens the droplets' contact duration in the system but also shortens their residence time after addition. The medication solution droplets may stick to the paddle if they are unstable in the system. Direct administration of the medication solution may be somewhat helpful in certain situations. By bringing the medication into direct touch with the system, this technique lowers the droplets' surface tension. This prevents the drug from adhering to the paddle by causing a quick mass transfer of the drug from the droplets.
3. Tension between surfaces:
Solvents with similar physicochemical characteristics (such as density, viscosity, solubility, and water miscibility) but varying water concentrations were chosen in order to investigate the impacts of the interface between the crystallization solvent and water. The stability of the emulsion system can be increased by weakening its white side. reduces the interfacial energy between organic solvents and water, therefore lowering droplet coalescence and secondary agglomeration. [21]. It is advised to raise the volume % of the dispersed phase up to the organic phase's miscibility limit in the aqueous phase in order to improve the crystallization process' outcomes. The particles take on the characteristics of a gel-like structure when they approach the liquid phase saturation point in the organic phase concentration. As a result, when in use, this substance serves as a wall of crystallization and a propeller. When the mass transfer from the organic phase to the aqueous phase is extremely sluggish, this gel-like structure develops. Droplet coalescence becomes more common as the emulsion's duration extends. Big water droplets that are created when there is an excessive amount of excellent solvent and insufficient solvent encourage coalescence and obstruct the crystallization sculpture. Utilizing the William plate dynamic approach, one may measure the interface between organic solvents and water and observe changes in the interface over time. First, fill the beaker with 70 ml of water that has been saturated with an organic solvent. Next, submerge each plate in the aqueous phase and gradually raise the water's surface by 10 milliliters of organic solvent. The contact angle may be calculated using the following formula by comparing the applied force to the immersion depth and the substrate's perimeter measurements.
? = F/L cos?
Whereas ? = Angle of Contact
Wetted Perimeter = L
F stands for measured force.
4. Pace of Agitation:
Dispersing the bridging liquid throughout the system is the ideal mixing speed. The mixer's movement controls the flow of liquids through the system. There could be some variations in flow or pressure. An impact on the force exerted on the agglomerates, which will ultimately determine their form. As a result, the agitation speed affects the agglomerates' size, sphericity, and strength [22]. Spherical crystals aggregate into bigger groups at lower speeds and smaller groups at higher speeds. The system's rate of crystallisation determines the necessary agitation speed; certain medications require high crystallisation rates, while others require low speeds. Higher agitation speeds also result in a shorter time needed to reach agglomeration [23].
5. Warmth:
Agglomerate size, texture, and shape are all strongly influenced by temperature. Larger agglomerates are initially produced at higher temperatures, but they quickly find equilibrium. On the other hand, at lower temperatures, crystal growth rates start out slowly but pick up speed later on [24].
Benefits of using the spherical crystallisation process to improve the physicochemical properties of medicinal substances:
The ensuing procedures of It is possible to do separation, filtering, and drying more effectively thanks to spherical crystallisation. This method improves a material's capacity to flow, pack, compress, and wettability. Spherical crystallisation enhances the following physicochemical characteristics [25].
An assessment of spherical crystallisation
1. Stability: Modifications in a drug substance's polymorphism throughout the recrystallization process can cause changes in its stability [26]. Small recrystallized crystals aggregated into spherical agglomerates increase stability by decreasing surface area.
2. Wettability: The elementary crystal size and crystallinity of agglomerated crystals determine their wettability. By measuring the water's contact angle with the compressed crystals, it is evaluated. Indicating increased wettability is a decrease in the contact angle [27]. When compared to crystals with lower crystallinity, those with higher crystallinity show less wettability.
3. Solubility: Different habits and structures, surface modifications, substitution of crystal forms, addition of solvents, or clathrate formation are some of the reasons why spherical agglomerates have higher solubility. The reactivity and surface characteristics of drug particles are altered by these modifications [28]. The flask shaker method is used to perform solubility investigations in both the dissolving medium and distilled water. The dissolution media and distilled water are introduced to flasks together with the spherical agglomerated crystals [29].The mixture is shaken in a flask at room temperature for a whole day. Following filtering, the solution is diluted using the proper medium and its contents are examined using the relevant techniques [30].
The following are some uses for spherical crystallisation:
- Improving flowability and compressibility.
- Enhancing bioavailability.
- Reducing production costs [31].
- Enhancing stability and reducing toxicity.
- Masking bitter tastes.
- Further improving bioavailability [32].
CONCLUSION
Drug delivery made smarter by the functionalized polymeric nanoparticle. The polymer's safety and efficacious drug delivery to a particular spot have been investigated in a wide range of variations. A multitude of applications exist for the functionalized polymeric nanoparticle, including gene therapy, cancer treatment, vaginal medication delivery, and brain use. Some of these developments Nanogels, ligand-based polymer nanoparticles, magnetic nanocarriers, etc. can all be used to deliver drugs with precision. Many functionalized polymer nanoparticles have been commercialized, and many more are in various phases of clinical study. When juxtaposed with pure medication, the spherical crystals produced in this work demo.
REFERENCE
Varun S. Dev*, Development Of Spherical Crystallization Of Some Drug To Improve The Flow Property, Int. J. of Pharm. Sci., 2024, Vol 2, Issue 7, 1807-1819. https://doi.org/10.5281/zenodo.12818175
10.5281/zenodo.12818175
