Advancements in Spherical Crystallization: Tailoring Drug Particles for Enhanced Properties and Bioavailability

Aditya Sujit Rathod¹, Mrs. Urmila J Patel^2*.

1. A.R.A. college of pharmacy, Nagaon Dhule

2. Sardar Patel Education Campus Vidyanager At Bakrol Anand Gujarat 388315.

Abstract: Spherical crystallization of drugs is the process of obtaining larger particles by agglomeration during crystallization. The principle steps involved in the process of spherical crystallization are flocculation zone, zero growth zone, fast growth zone and constant size zone.  The most common techniques used to obtain such particles are spherical agglomeration and quasi-emulsion solvent diffusion. Ammonia diffusion systems and crystallo- co-agglomeration are extensions of these techniques. By controlling process parameters during crystallization, such as temperature, stirring rate, type and amount of solvents, or excipient selection, it is possible to control the formation of agglomerates and obtain spherical particles of the desired size, porosity, or hardness. Researchers have reported that the particles produced have improved micromeritic, physical, and mechanical properties, which make them suitable for direct compression. In some cases, when additional excipients are incorporated during spherical crystallization, biopharmaceutical parameters including the bioavailability of drugs can also be tailored. Keywords:. Spherical crystallization, Bioavailability

Corresponding Author: Mrs. Urmila J Patel Email ID: urmilapatel.pharmacy@spec.edu.in

Article History Received:        25/10/2023 Revised:          02/11/2023 Accepted:        05/11/2023 Published:       06/11/2023

 

 

 

 

 

 

 

 

 

 

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 [1]. Presently, particle design techniques are widely used in pharmaceutical industries to modify primary properties like particle shape, size, crystal habit, crystal form, density, porosity etc. as well a secondary properties like flow ability , compressibility, compact ability, reduction In air entrapment, etc Spherical crystallization is one of such particle design technique in which crystallization and agglomeration process are carried out simultaneously. Spherical Crystallization process transforms the fine crystal obtain during crystallization into a spherical agglomerates. Agglomerates formed further improves the flowability and compressibility of pharmaceutical ingredient which enables direct tabletting of drug instead of further processing like mixing granulation, seiving, drying etc. There are certain parameters which have to be optimized in order to obtain the maximum amount of spherical crystals [2].

So spherical agglomeration is a multiple unit process in which crystallization, agglomeration, spheronization can be carried out simultaneously in one step [3]. The resultant crystals can be designated as spherical agglomerates. Due to characteristic shape and crystal habit physico-chemical properties (solubility, dissolution rate, bioavailability and stability) and micrometric properties (bulk density, flow property, compactability) of resultant crystals are dramatically improved so that direct tabletting or coating is possible without further processing [4].

Spherical crystallization:

Spherical crystallization is a novel particle engineering technique by which crystallization and agglomeration can be carried out simultaneously in one step to transform crystals directly into compacted spherical form. Crystallization is important phenomenon which is used for both separation and purification in pharmaceutical industries. This process leads to the crystal formation which has chemical stability and convenience in transportation, packing and storage. Most of active pharmaceutical ingredients have different sizes. Active pharmaceutical ingredient particles with less than 10 μm size have the advantage of increased dissolution rate and better bioavailability. Agglomeration is a phenomenon in particles technology which includes smaller crystals adheres to form bigger particles [5]. It is important for both down streaming process e.g. filtration, drying, washing etc. and end use properties e.g. dissolution, product formation and bioavailability.

NEED FOR SPHERICAL CRYSTALLIZATION

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 two techniques commonly used to improve the bioavailability of poorly soluble drugs. The micronization 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 [6].

Objective of the spherical crystallization process:

·         A spherical shape of the final product formed drastically improves the micromeritic property of the drug crystals¹⁴,

·         Improvement in wettability and dissolution rate of some drugs were found by utilization of this process ^6,28.

·         This technique could enable subsequent process such as separation, filtration, drying etc to be carried out more efficiently³³.

·         Furthermore the resultant agglomerated crystals could be easily compounded with other pharmaceutical powders due to spherical shapes. [7]

Advantages of Spherical Crystallization:

·         Physicochemical properties of pharmaceutical crystals are mainly improved for pharmaceutical process i.e. milling, mixing and tabletting by using this technique.

·         The micromeritic properties of the drug crystal shall be drastically improved.

·         Utilization of this process improves wettability and dissolution rate of some drugs.

·         Use of this technique leads to conversion of crystalline forms of a drug into polymorphic form that may have better bioavailability.

·         This technique could enable subsequent processes such as separation, filtration, drying, etc. to be carried out more efficiently.

·         Preparation of microsponges, microspheres and nanospheres, microballoons, nanoparticles and micro pellets as novel particulate drug delivery system is possible by it.

·         It can be used for masking of the bitter taste of drug.[7].

Disadvantages of Spherical Crystallization:

Spherical crystallization method has following disadvantages [7]

·         Selection of suitable solvents is a tedious process.

·         Optimization of processing parameters (temperature, agitation) is difficult.

THE PRINCIPLE STEPS INVOLVED IN THE PROCESS OF SPHERICAL CRYSTALLIZATION: [4]

Bermer and Zuider Wag proposed four steps in the growth of agglomeration.

1. 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 a lens bridge between them. In these zones, loose open flocs of particles are formed by pendular bridges.

 2. Zero Growth Zone: Loose floccules get transferred into tightly packed pellets, during which the entrapped fluid is squeezed out followed by squeezing of the bridging liquid onto the surface of small flocs causing poor space in the pellet of 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.

 3. Fast Growth Zone: The fast growth zone of the agglomerates takes place when sufficient bridging liquid has squeezed out of the surface on the small agglomerates. This formation of large particles 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 deformations and subsequent coalescence. Another reason for the growth of agglomerates size is attributed to growth mechanisms that describe the successive addition of material on already formed nuclei.

4. Constant Size Zone:

In this zone agglomerates cease to grow or even show 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 shatter. 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 particle 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 interfacial tension between the bridging liquid and the continuous liquid phase, contact angle and the ratio of the volumes of the bridging liquid and solid particles.

 

  Flocculation                      Zero Growth                        Fast Growth                  Constant Size

       zone                                     zone                                        zone                                  zone

 

Techniques of Spherical Crystallization:

various methods available for spherical crystallization are:

1.      Spherical Agglomeration Method

2.      Quasi Emulsion Solvent Diffusion Method

3.      Ammonia Diffusion Method

4.      Neutralization Method

5.      Traditional Crystallization Process

6.      Crystal-co-agglomeration Technique

Spherical Agglomeration Method (SA):

This method involves simultaneous crystallization and agglomeration of two or more drugs from a good solvent and bridging liquid by addition of a non-solvent. To obtain fine crystals the solution of the drug and a good solvent is poured into a poor solvent under controlled condition of temperature and speed. The bridging liquid is used for agglomeration of the crystals [11].

Here the good and the poor solvents are freely miscible and interaction (binding force) between the solvents is stronger than drug interaction with the good solvent, which leads to precipitation of crystals immediately [9]. Bridging liquid collects the crystals suspended in the system by forming liquid bridges between the crystals due to capillary negative pressure and interfacial tension between the interface of solid and liquid [10]. SA method proceeds in three steps as shown in Fig.

 

 

Spherical Agglomeration Method

The first step is the selection of the crystallization method to precipitate crystals from solution, i.e., thermal method (temperature decrease or evaporation), physicochemical methods (addition of another solvent, salting out) and chemical reaction. The second step is the choice of the wetting agent that will be immiscible with the solvent of crystallization. Finally, the third step is the hardening of the agglomerates.

The drawback of this system is that it provides low yield, due to co-solvency effect of crystallization solvent. The bridging liquid, the stirring speed and the concentration of solids are the influencing factors for the spherical crystallization [11].

Quasi emulsion solvent diffusion Method:

The drug is dissolved in the good solvent (solvent that readily dissolves the compound to be crystallized), and the solution is dispersed into the poor solvent (an antisolvent generating the required supersaturation), 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. [12]

Quasi emulsion solvent diffusion Method

 

Ammonia Diffusion Method (ADM):

In this technique ammonia-water system is used as the good solvent and bad solvent is selected depending upon the drugs solubility in that solvent. The ammonia-water also acts as a bridging liquid. This technique usually meant for amphoteric drugs which cannot be agglomerated by conventional procedures. The whole process is completed in three stages [13]. First, the drug dissolved in ammonia water is precipitated while the droplets collect the crystals. Simultaneously, ammonia in the agglomerate diffuses to the outer organic solvent. Its ability to act as a bridging liquid weakens and subsequently spherical agglomerates are formed.

Ammonia Diffusion Method

Neutralization Method (NT):

This process involves the formation of fine crystals and their agglomeration. The spherical crystallization of antidiabetic drug tolbutamide was reported by this technique. The drug was dissolved in sodium hydroxide solution. Aqueous solution of Hydroxypropyl methylcellulose and hydrochloric acid was added to neutralize sodium hydroxide solution of tolbutamide, which was then, crystallized out [14]. Besides above mentioned methods there are some other traditional methods for the crystallization which are carried out by controlling the physical and chemical properties and also called as the non-typical spherical crystallization process. These methods include Salting out precipitation, cooling crystallization and crystallization from the melting. [15]

The method consists of dissolving the drug in the good solvent and placing in the cylindrical vessel with constant stirring. During stirring an aqueous polymer solution and one neutral solution was added to neutralize the good solvent, which crystallizes out the drug. The bridging liquid shall be added drop wise at a definite rate. The agglomeration of the crystal form of the drug takes place [14].

Apparatus for spherical crystallization:

Most of the cases spherical crystals are prepared with simple equipment and apparatus viz. Mechanical stirring element, suitable sized container (beaker), thermostat etc, are arranged as shown in the Fig.

   

Apparatus for spherical crystallization

Requirements/ Solvent System:

Typical spherical crystallization employs three solvents: one is the drug dissolution medium i.e. good solvent; another is a medium which partially dissolves the drug and have wetting property i.e. bridging liquid; and the last one is immiscible with the drug substance i.e. bad solvent [20]. Polarity of the solvents and its interactions with hydrophobic phases of the growing crystals has an influence on shape, surface irregularity and roundness of the crystals agglomerates.

 Commonly three types of solvents are used in spherical crystallization

1.Good Solvent

2.Bridging Liquid

3. Poor Solvent

Good Solvent:

The solvent in which the drug is having good solubility is considered as good solvent. It is a perfect solvent for the drug. The selection of good solvent is based on drug solubility and affinity/ miscibility with bridging liquid.

Bridging Liquid:

The agglomerates were formed by agitating the crystals in the liquid suspension in the presence of the bridging liquid. The bridging liquid should be immiscible in the suspending medium but capable of cementing the particle to be agglomerated. The finally divided solid crystals in the liquid suspension initially separated from each other but by adding small amount of bridging liquid which preferentially wets the surface of solids, form the bridges between the solid crystals and finally agglomerate into spherical form [17].

Poor Solvent:

Poor solvent is also called anti solvent or bad solvent. Poor solvent should not be miscible with the solvent system (good solvent and bridging liquid) moreover the affinity between them must be stronger than those between drug and solvent [18, 19]. As this technique is use to improve the solubility of poorly soluble drugs, water acts as most preferable anti solvent. The solvent system and its composition are usually selected by trial and error.

Factors affecting the process of spherical crystallization.

Temperature of the system Temperature has significant influence on the shape, size and texture of the agglomerates .The solubility of drug is affected by the temperature change.

Mode and intensity of agitation The extent of mechanical agitation along with the amount of bridging liquid determines the rate of formation and size of agglomerates. The stirring speed must be optimized. High speed agitation is necessary to disperse the bridging liquid through the system. But in some cases increasing stirring rate, may cause reduction in agglomerate formation due to increased disruptive forces. Higher stirring rates produces agglomerates that are less porous and more resistant to mechanical stress.

 Amount of bridging liquid The spherical agglomeration method has been applied to plenty of drugs,and it has been observed that the properties of spherical agglomerates were very muchsensitive to the amount of bridging liquid.

 Choice of solvent The choice of solvent depends on the solubility profile of drug. A mutually immiscible three solvent system consisting of good solvent, poor or anti-solvent and bridging liquid are necessary. 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 solutions.[21,22]

EVALAUTION OF SPHERICAL CRYSTALS [23, 24]

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.

1.      Flow property

a.      Angle of repose:

 It is determined by following equation

                  Tan ѳ = h/0.5 d

Where   h-height of pile

             d-Diameter of pile

Value

         ≤ 30→free flowing materials

        ≥ 40→poor flowing materials

 

b.      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/V₀)* 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

c.       Hausner’s  ratio:

Calculated from bulk & tapped densities.

                 HR = Tapped density/Bulk density

Value  < 1.25-good flow (20% Carr‘s index).

            > 1.25-poor flow (33% Carr‘s index).

Between 1.25-1.5 –to improve the flow glidant must be added.

2.      DENSITY

Density of spherical crystals is mass per unit volume. Different type of densities such as true density, granular density, apparent bulk density, tapped density can be evaluated.

                     True density = M / Vt.

                     Granular density = M / Vg.

                     Bulk density = M / V b.

                     Tap density = weight of sample in gm/tapped volume of sample in ml.

3.      POROSITY

Porosity affects the compressibility in granules. Porosity is of two types intra granular & intergranular. These are measured with the help of true & granular densities.

                     Intergrannular Porosity = 1 - granular density/ true density

                     Intergrannular Porosity= 1 - bulk density/ granular density

                  Total Porosity= 1 - bulk density/ tapped density

4.      PACKABILITY

Shear cohesive stress, shear indexes & angle of friction are lower than that of single crystals which can be improve packability of agglomerates. Simple packability was assessed by tapping process with kawakita & kuno methods & using parameters a, b & k in equations.

                   N/C=1/(ab) + N/a

                   C=(V₀-Vn)/ Vo, a=(V₀-V∞)/ Vo.

                   ρ f - ρ n = (ρ f - ρ o). exp. (-kn)

          N =Number of tapping.

          C =Difference in volume (degree of volume reduction.)

          a and b = constant for packability and Flowability

          Vo = Initial volume.

          Vn = Final volume after n the tapping.

          V∞ = Powder bed volume at equilibrium.

          ρ f, ρ n, ρ o = Apparent densities at equilibrium, nth tapped and initial state respectively.

5.      COMPRESSION BEHAVIOUR ANALYSIS

a.      Heckel Analysis

b.      Stress Relaxation Test

6.      MECHANICAL STRENGTH

a.      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.

b.      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). At the rate of 10 gm/sec, mercury is introduced from reservoir into the upper chamber 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.

7.      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.

8.      PARTICLE SIZE AND SIZE DISTRIBUTION

Change of crystal habit of pharmaceuticals gives different physicochemical properties. Size & crystal habit of pharmaceuticals changes on recrystallization in spherical crystallization. Using advance technology, Size & volume of particles can be determined by image analyzer. Size of particles & their distributions can be determined by simple sieve analysis. Particle size analysis can be determined by Ro-Tap sieve shaker.

9.      MOISTURE UPTAKE STUDY

The moisture uptake is determined by taking the weighed quantity of drug & spherical crystals & placing them in crucible at accelerated conditions of temperature & humidity i.e., 40}10⁰ C & 75}3% respectively. The weight gain of drug & spherical crystals is measured.

10.  PARTICLE SHAPE / SURFACE TOPOGRAPHY

a.      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.

b.      Electron Scanning Microscopy

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

c.       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.

d.      Fourier Transform Infrared spectrometer (FTIR)

It is much more useful for distinguishing between solvates and anhydrous form then for identifying polymorphs because of the addition of new stretching frequencies resulting from the salvation.

e.       Differential scanning calorimeter (DSC)

DSC measures the heat loss or gain resulting from physical or chemical changes within a sample. If a mixture of drugs and polymer is agglomerated together then change in properties of agglomerates can be studied with DSC.

f.        Thin Layer Chromatography (TLC)

It determines the drug and polymer interaction of spherical agglomerates and also studies the stability of drug in different solvents.

APPLICATIONS OF SPHERICAL CRYSTALLIZATION IN PHARMACEUTICALS

1.      To improve the flowability and compressibility:

2.       For masking bitter taste of drug:

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

4.       Better Bioavailability:

5.      To prepare novel drug delivery systems :

 

 

CONCLUSION:

The spherical crystallization technique is a new inexpensive technique for reducing time and cost by enabling faster operation, less machinery and fewer personnel because it removes most of the steps which are required in granulation technology of tablet manufacturing. It provides advances in tabletting technology by introduction of number of directly compressible excipeints. The spherically agglomerated crystals can be prepared into tablet form or compounded directly into a pharmaceutical system without further processing such as granulation. This technique of particle design of drugs has emerged as one the areas of active research currently of interest in pharmaceutical manufacturing.

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