1. INTRODUCTION:

Particles, the elements of matter are important phenomenon that defines the properties of the substances around us. A particle’s physicochemical property represents the physicochemical properties of the materials. So to change the properties of the compounds one should think about manipulating the properties of the particles. By taking this into consideration the particle engineering has step its foot in pharmaceutical industry for solid state property optimization. Particle engineering is a technique that allows the customization the pharmaceutical API and excipients to obtain desired properties. Particle engineering technique involves the various techniques to obtain the desired particle size, shape, particle size distribution and other morphological characters¹. With rise in the new pharmaceutical API and excipients the problem of their poor solubility is also an increasing problem. The poor dissolution and solubility of the particles can lead to their poor bioavailability especially through the oral route^2,3,4.

The pharmaceutical industry Continually seek making drug substances of the right quality and the properties of the materials determine the product performance. Pharmaceutical products can exhibit different polymorphic forms, these forms have different physicochemical properties and no one form exhibit all the desired properties. The aim of particle engineering in this case is to obtain the stable polymorphic form having desired properties to improve product and formulation performance⁵. The crystalline drugs are stable in nature but they exhibit poor solubility. One of the way to improve solubility of these drugs is to convert them into their amorphous form. But this process is not as easy as it looks, the reason is amorphous forms are having less stability and they tend to turn back into their crystalline form. Role of particle engineering in this case is to formulate drug substances into amorphous forms which having more stability^6,7. Besides solubility and polymorphism the particle size plays an important role in drug delivery, as smaller particles provide more surface area and improve dissolution. Various micronization techniques like ball milling, high pressure homogenization, and micro crystallization can be used for the size reduction purpose⁸. For the thermolabile products jet mills are preferable for the size reduction purpose ⁹. The use of supercritical fluid technology can also be used to formulate products of desired physicochemical properties¹⁰.

The pulmonary drug delivery system is gaining attention as it provides great relief in lung and respiratory diseases like COPD and asthma. The pulmonary drug delivery delivers drug through inhalation directly into lungs it has more bioavailability than the oral route¹¹. Pulmonary delivery can also bypass the first pass metabolism and hence reduce drug dose. The pulmonary delivery has advantage over intradermal and intramuscular drug delivery as it is a non-invasive technique and has more acceptance in pediatrics. Particle engineering technologies can be used to formulate drug products suitable for pulmonary drug delivery and to enhance of lessen the uptake of drug by alveoli, which include micronization techniques, spray drying and supercritical fluid technologies¹¹. Not only improvement of physicochemical properties of drug molecules but also for the organoleptic properties of particle, particle engineering has wide applications in the pharmaceutical field. Let’s see about different methods for the particle engineering¹¹.

2. Micronization:

2.1. Milling Techniques:

Milling is the traditional method for the powder micronization¹². The most of currently marketed inhalation products such as Dry Powder Inhalers, Multi Dose Inhalers and suspension nebulizers consist of micronized drug in either agglomerated or blended form ¹¹. Micronized particles are produced by batch crystallisation and followed by filtering, drying, crystallisation and micronization. The particle size reduction can be done by various mechanisms like Attrition, Impact, Shear, Pressure or Friction. Various milling techniques can be used for the micronization process such as Ball Milling, Vibration Milling and Fluid Energy Mill (Jet Mill). Size reduction can be done on both wet and dry materials, but dry milling is commonly preferred as is more convenient. A fluid energy jet mill uses the energy of the fluid (high pressure air) to achieve ultra-fine grinding of pharmaceutical powders¹³. This process is a dry grinding process and produces particles of micro size with less size distribution, contamination free and being suitable for heat sensitive products are its main advantages^8,11,12. In Jet milling process the mechanism for micronization is attrition and inter-particle collision¹². The media used for milling is high velocity air which passes through nozzles. The gas passed through nozzles carry coarse particle to be size reduced with it. When gas comes the jet mill the particles get suspended in the mill with the turbulent air flow. In jet milling process, the starting material undergoes many impact events before a substantial quantity of the required particle size fraction is achieved and separated from the larger particles by inertial impaction¹¹. This event ensures the required size of particle for formulation of desired dosage form. The coarse suspended particles collide on each other and undergo impact and attrition and results in formation of fine particles. The fine particles take a spherical and elliptical path along with air flow and removed outside the mill which remain behind coarse particles which further undergo attrition and size reduction⁹. From jet milling process we get either round or tabular particles whose sphericity is close to 1. The size obtained by the jet mill is in range of 1 – 20µm^12,13,14.

Fig. 1 Fluidised Jet mill

The problem with the Micronization technique is that the size reduced particles produce electrostatic charges¹¹. The second problem is it generates the amorphous particle surface. In extreme cases the whole powder bed can become amorphous in nature. As amorphous forms are being unstable it may undergo recrystallization forming solid bridges between particles and again formation of coarse particles¹¹. The material is also prone to chemical decomposition and water sorption. All these physical and chemical changes are highly undesirable, and can adversely affect the in vitro and in vivo performance of the formulations¹¹. For decreasing the amorphous content in powders produced by milling, jet milling can be carried out at elevated humidity to enhance in situ crystallization. The milled products are mostly crystalline with particle size distributions similar to those produced by the conventional milling process. The system entails control of the relative humidity (e.g., 30–70%) of the milling chamber by humidifying the feed gas (e.g., by superheated steam to minimize condensation) used for milling the powder¹⁵. Media milling is mostly having its applications in processing of biopharmaceuticals. It involves using a liquid as a medium during milling and was first recommended by Adjei et al. using non-CFC propellants for the preparation of peptide suspensions for pressurized metered dose inhaler¹². Media milling is mostly being used for the size reduction of proteins and biomolecules. It is a low temperature process and it helps reducing the milling steps¹². Wet milling is a technique of size reduction to nanoparticles. Fine-ball mills are popular because of their simplicity and scalability. Since the particles are produced in water, amorphous regions in the particles may undergo recrystallization. Thus, the wet-milled powder is anticipated to be crystalline and more stable to moisture than powders produced by dry milling¹⁵. A ball mill is another famous mill for size reduction to fine particles. A pharmaceutical ball mill is a cylindrical crushing device which bring out size reduction by mechanism of attrition or impact. The mill crush pharmaceutical powders in a hollow rotating cylinder rotating around horizontal axis. The device is partially filled with the material to be ground plus the grinding medium usually ceramic balls, flint pebbles or stainless steel balls. Back in 1995, Liversidge and Cundy reported that ball milling could be used for preparing nanoparticulate formulation of a poorly water soluble drug, danazol, which showed enhanced bioavailability in beagle dogs when compared to that of aqueous suspension of conventional danazol particles ^[8]. Ball mill produce amorphous powder of drug when milling is done with the polymeric compounds. With higher Gibbs free energy than crystalline form amorphous form improves dissolution of drug⁸.

3. High Pressure Homogenization:

High pressure homogenization is a mechanical process which is used to reduce size of poorly soluble compounds. Jet steam homogenizers and micro fluidizers can be used as a medium for size reduction. When frontal collision of two fluid streams under high pressure up to 1,700 bar takes place there are particle collision, shear forces and cavitation forces are created which results in the process of size reduction¹⁵. For stabilizing the nanoparticles there’s a need of surfactants, which stabilize the particles to desired size¹⁵. In piston gap homogenisation cavitation forces are created in a high pressure homogenizer. A suspension mixture of drug and surfactant is passed through high pressure homogenizer with a pressure of 1500 bar repeatedly for 3- 20 times. Due to the small gap, the high streaming velocity of the suspension and the increased dynamic fluid pressure (according to Bernoulli’s law) are compensated by the reduction in the static pressure on the fluid below the boiling point of water at room temperature¹⁵. Water stars boiling at room temperature during this process resulting in formation of small bubbles, which collapse as soon as fluid leaves homogenization gap. This process cause shearing of particles due to produced cavitation induced shock waves. Homogenization processes are available in a wide range ranging from few hundred to a few thousand liter per hour. High pressure homogenization overcomes drawbacks of conventional size reduction techniques such as polymorphism, amorphization and contamination due to high mechanical energy associated with conventional milling process⁸. High pressure homogenization is convenient for both aqueous and non-aqueous fluid media. High pressure homogenization is used to improve solubility of poorly water soluble drugs such as spironolactone, budesonide and omeprazole by effective size reduction to the nano-size range⁸. It is used in both oral dosage form formulation and parenteral dosage forms. This process is widely used in parenteral dosage form as there is no risk of contamination and microbial incorporation⁸.

Fig. 2 High Pressure Homogenizer

4. Spray Drying:

Spray drying is a simple technique and is used extensively for production of dry powder formulation. Spray drying is easy for operation and for scale up, it has an ability to produce composite materials. Using this technology we can manipulate different powder and particle characteristics like particle size, density, morphology and level of residual solvent and a wide range of powders can be obtained mainly from very fine particles for the inhalation to the directly compressible large particles^20,21,22. Materials previously thought not suitable for spray drying, such as temperature and mechanical shear-sensitive compounds, have been successfully processed with appropriate formulation and process design²³. Spray-dried drug particles can produce higher respirable fractions than micronized particles, and this has been ascribed to their spherical shape resulting in less drug–carrier contact area and in turn less drug–carrier adhesive forces. Moreover, spray-dried particles may have more homogenous particle size distribution (PSD)²². Spray drying process consist of mainly four steps:1) Atomization of feed solution into a spray. 2) Spray-air contact involving flow and mixing. 3) Drying of sprayed droplets at elevated temperature and 4) Separation of dried product from the air¹¹. In spray drying a feed solution containing drug is atomized into droplets that dry rapidly due to their high surface area and contact with drying gas¹². The drying time for droplets depends on the process conditions such as flow rate, pump rate, aspiration rate and heat. This drying time can range from less than 100 min to a few seconds ¹². The droplets experience lower temperature due to evaporation cooling than the air temperature¹⁵. In spray drying though thermal degradation can be avoided but degradation during atomization may be a problem during processing biopharmaceuticals which can be avoided by using suitable excipients. Spray drying has relatively low cyclone collection efficiency for particles below 2μm. The typical yield from a spray dryer is between 20% and 50%¹².

For feed atomizers, selection can be made from rotary atomizer, pressure nozzle or two fluid nozzle while air/product flow inside the drying chamber can be co-current, counter-current or mixed flow type. More recently, four-fluid nozzles with in-line mixing have been developed for production of composite particles¹¹. With two fluid nozzle particles up to 4-6 µm can be obtained while by using a centrifugal nozzle particle of size 1-8µm can be obtained. The rate of particle formation is a key parameter that dictates the minimum required size of the drying chamber and hence the scale of equipment required to produce a desired particle size at the target production rate. Bench-scale spray dryers typically produce particles in the 1–15μm particle size range, while large multi-storey, single-pass dryers can produce particles up to 100μm in diameter or greater if configured to produce particle agglomerates²³. By adjusting parameters like feed rate, air flow, atomization pressure feed properties and drying temperature we can optimize particulate product characteristics. Smaller droplets can be prepared by using plain jet air blast atomizers while large droplets can be prepared from the larger nozzle orifice, smaller atomization airflow and higher feed concentration. Common excipients such as lactose and polysorbate 20 (Tween 20) can also be added to the feed solution to yield particles with rougher surfaces^11,12. Morphology of the powder depend on the powder composition. By removing volatile solvents from mother liquor following crystallization step spray drying process has been utilized to isolate small molecules active ingredients. One of the advantage of using spray drying is obtaining large porous particles (LPP). LPPs are particles with mass density significantly less than 1 g cm–3, such that a low (respirable) aerodynamic diameter (Dae) can be achieved but with the particles having a mean geometric diameter (Dg or De) greater than 10μm, or even as high as 20μm. LPPs can be prepared by a standard, one-step pharmaceutical spray-drying process using ‘generally recognized as safe’ (GRAS) excipients ²².

A. Solution or suspension to be dried in,

B. Atomization gas in,

1) Drying gas in

2) Heating of drying gas

3) Spraying of solution or suspension

4) Drying chamber

5) Part between drying chamber and cyclone separator

6) Cyclone separator

7) Drying gas is taken away

8) Collection vessel of product

Fig.3 Spray Dryer

5. Spray Freeze Drying:

In spray freeze drying technique aqueous drug solution is atomized via a two fluid or an ultrasonic nozzle into cryogenic liquid usually liquid nitrogen, oxygen, argon or halocarbon refrigerant such as fluorocarbon or CFC (chlorofluorocarbon)^11,12. Depending on position of the nozzle spraying process can be performed beneath or above the cryogenic liquid. As cryogenic solution tend to evaporation the level of the cryogenic liquid falls, so while performing lengthy atomization processes there is need of continuous addition of the cryogenic liquid. Upon contact with the cryogenic medium, the liquid droplets solidify rapidly (in milliseconds time scale) because of the high heat-transfer rate and result in spherical porous particles¹⁵. Atomization into the nitrogen vapour above the liquid gas leads to gradual agglomeration and solidification of the solution droplets that pass through the vapour phase and then settle to the surface of the cryogenic liquid. As a result, broad particle size distributions and non-micronized dry powders may result¹⁵. It has been established that these droplets may begin to freeze during the time of flight through the cold vapour phase and then completely freeze upon contact with cryogenic liquid¹². Once the spraying process is completed, the whole content can be lyophilized, as with conventional freeze-drying¹¹. The drying of particles is done by stream of dry cold air in an insulated stainless steel. Spray freeze-dried particles can be engineered to the desired respiratory size range below 5µm or even down to nano-scale¹¹. The mass flow ratio of atomized nitrogen to liquid feed is the most significant operating parameter which has impact on particle size and particles with smaller particle size can be obtained by increasing mass flow ratio and addition of excipients can lead to increased particle size¹². To limit the time of exposure to the air–liquid interface during atomization. Two techniques have been developed and they include:

· Spray freezing into liquid

· Spray freezing with compressed CO2

5.1. Spray freezing into liquid (SFL):

SFL is a novel particle engineering technique which was initially developed for particle engineering poorly water soluble or insoluble drugs by atomizing a feed liquid containing a poorly water soluble drug and solubility enhancing excipients below the surface of a cryogenic liquid to produce rapidly frozen particles that are subsequently dried. The ultra-rapid freezing prevents phase separation of the drug and excipient and also prevents crystalline growth in frozen water. These two factors could result in nonhomogeneous powder aggregates consisting of crystalline drug domains. Ultra-rapid freezing rates produce a porous micronized flowable powder with a high surface area. This technique has successfully been adapted for proteins. The liquid solution of protein is sprayed directly into the liquid nitrogen through an insulated nozzle, rather than into cold vapour as compared to SFD^12,24,25.

5.2. Spray-freezing with compressed CO2:

In this process, aqueous solution of the biopharmaceutical and excipients is simultaneously atomized and frozen by dispersing supercritical CO2 in it. The solution containing the biopharmaceutical is mixed with compressed CO2 in a static mixer to form droplets of a CO2-saturated aqueous solution dispersed in CO2. Joule–Thomson expansion cooling brings about the rapid freezing of the droplets when injected into the spray tower through a nozzle. Once the spraying process is completed, the frozen particles are lyophilized to obtain dried particles. The main goal of this method is to obtain stable, porous or hollow protein particles with a narrow size distribution suitable for inhalation ^{[10, 12]}. Claimed advantages of this process are: the minimal decomposition of thermally labile drugs, the absence of a high pressure vessel, and the small size of produced particles (below 3µm in diameter)¹⁰.

Fig.4. Spray Freeze Drying

6. Applications of Particle Engineering in Pharmaceuticals:

6.1. Improved Solubility:

Solubility is an important criteria in case of liquid formulation. Solubility is also first step towards absorption of drugs through the oral route. Drug candidates with less solubility can be a great challenge for a formulation scientist. BCS class II and IV drugs are having less solubility and it is necessary to improve drug’s solubility to enhance and improve drug’s efficacy ⁴. Improving solubility of drug without compromising with the stability is a great challenge in the pharmaceutical field. For the success of any drug molecule, lipophilicity and hydrophilicity are two most important phenomenon. From Noyes‐Whitney equation, possibilities for improving drug dissolution are to increase the surface area of drug available for dissolution by decreasing the particle size of the solid compound and/or by optimizing the wetting characteristics of the compound surface²⁹. So various methods of improving solubility are developed which include particle size reduction, complexation, salt formation, use of surfactants and wetting agents, cosolvancy and hydrotrophy. Use of various particle engineering techniques is also being used for the formation of water soluble and improved solubility compounds. Use of size reduction is most common method for the improved solubility. Micronization techniques are mostly used for the solubility improvement of the BCS class II drugs. Micronization refers to conversion of coarse particles to fine particles of range 2-5µm and with a very little faction of particles lie below 1µm⁸. Micronization techniques helps to increase the surface area of particle resulting in improved dissolution. Conventional size reduction techniques bring about size reduction by milling, grinding and crushing. The mills like ball mill are used to reduce particle size which uses the mechanism of impact and attrition. A fluid energy jet mill uses high pressure air for size reduction, the particle undergo a fluidised state due to high pressure air and undergo collision and impact. Fluid energy jet mill is used for generation of ultrafine particles and is suitable for the size reduction of heat sensitive compounds and biopharmaceuticals as it produces less heat while size reduction than other conventional techniques. The major problem with the jet mills or any milling technique is processing of the crystalline compounds. While processing the crystalline material the broken surfaces may become amorphous in nature which reduce the stability of the compounds. In extreme cases whole powder bed may turn into the less stable amorphous form ^11,12. Micronization techniques also leads to dust formation and generation of electrostatic charges resulting in poor flow properties. In spite of disadvantages micronization techniques are widely used to improve solubility. E.g. In a study conducted by Jinno et al., the in vitro dissolution rate of a poorly soluble drug cilostazol was improved by milling and a moderate enhancement of bioavailability was observed in absorption from cilostazol suspension produced by jet milling⁸.

One of the trending method of improving solubility is by crystal engineering. Crystal engineering has been described as the ‘exploitation of non-covalent interactions between molecular or ionic components for the rational design of solid-state structures that might exhibit interesting electrical, magnetic, and optical properties¹². One of the way to improve solubility by crystal engineering is by formation of co-crystals of these molecules with water soluble molecules⁴. The solubility of the co-crystals is based on the strength of intermolecular interactions between crystal lattice and solvation of co-crystal compound. The solubilization of a cocrystal in dissolution medium involves two main steps: (1) Release of the solute molecules from the crystal lattice of the cocrystal and (2) The solvation of the released molecules⁴. Various factors like ionization of parent compound, pH of aqueous medium, effect of solubilizing agent, dissolution of co-crystal and crystal habit affect the dissolution and the solubility of the co-crystals. Several other techniques like use of supercritical CO2, freeze drying and spray drying are also being used for the formulation of more soluble compounds by increasing surface area⁴.

6.2. Pulmonary Drug Delivery System:

Increase in air pollution levels, smoking and increased severe respiratory infections led to increased use of pulmonary drug delivery system for local and systemic actions. Pulmonary drug delivery system is gaining much more attention as it provides fast and effective route of administration over oral dosage forms. Pulmonary drug delivery is used to treat local and systemic lung diseases and airway diseases. Drugs which are unable to administer orally due to first pass metabolism can be easily administered through inhalation therapy without undergoing any metabolism. Drugs previously having stability issues in the gastric juices or less solubility can also be administered through pulmonary drug delivery for greater local and systemic action. It gained advantage over intravenous and intramuscular delivery systems as it is a non-invasive technique. Inhalation therapy is currently available for diseases such as chronic obstructive pulmonary disease (COPD), asthma and various lung infections. There are many inhalation products for the treatment of osteoporosis, diabetes and erectile dysfunction for the systemic therapy¹¹. Systemic delivery of biopharmaceuticals by inhalation is currently attracting considerable attention because a number of these molecules are more efficiently absorbed from the lungs compared to oral, nasal or transdermal routes¹². The inhalation route offers an enormous absorptive surface area in the range 35–140 m2, thin (0.2 μm) and highly vascularized epithelium, which leads to high bioavailability¹².

The size of particle plays important role in pulmonary drug delivery as the phagocytosis by the alveolar macrophages is size dependent. The macrophages are involved in the clearance of the drug molecules from the lungs. This process of phagocytosis can be either an advantage or a disadvantage depending upon condition is being treated. The uptake through the alveolar macrophages is desired if the target of therapy is to target the lung pathogens that use macrophages as a carrier for infection. In modulating the immune and inflammatory responses in lung diseases like asthma, COPD or cancer uptake through the macrophages is of a great advantage. The uptake through the macrophages can be undesired if the target of the therapy is to enhance residence time of inhalation particles or to obtain the sustained drug delivery³². The particles with spherical hard and non-porous particles with size in range of 100-200 nm and 1-6 µm having high positive or negative charge can enhance the uptake through macrophages. Drugs with high lipophilicity can also be taken up by macrophages more preferably. While the particles of size greater than 6 µm and less than 1µm are less taken up by the macrophages. Similarly elongated, tod and filament shaped particles, particles with neutral charges and soft and porous particles are less taken up by the macrophages³². Spray drying is a favourable technique for particle engineering having an aerodynamic particle size in the range of 3±2μm. This size range is important for optimum drug deposition in the lungs²⁴. The micronization process generates fine solid particle which can be taken up by macrophages for the systemic action. Similarly various techniques like sono crystallization, precipitation technology, supercritical fluid technology, high pressure homogenization can also be used for formulation of particle that can be easily absorbed from the lungs and having aerodynamic properties ¹⁵. Among the inhalation products available for such diseases, the combination of salmeterol xinafoate (SX, LABA) and fluticasone propionate (FP, ICS) (Seretide/Advair, GlaxoSmithKline, UK) has achieved widespread acceptance among physicians and patients and is listed in the top ten best-selling pharmaceutical products of recent years. This combination therapy shows greater efficacy compared to monotherapy treatments with the individual components, and reduced mortality rates in COPD beyond that achieved by single therapies²⁸.

6.3. Improved stability:

Powders obtained from drying of functional fruit and vegetable concentrates are used in the food and drug industry to impart colour, flavour or nutritional value to a wide range of products ³⁵. During storage retention of its properties is a key element. While preserving these compounds special care for the stability should be taken to retain its properties. Carotenoids, the lipophilic pigments found in many fruits and vegetables (e.g. red pepper, carrot, and mango) are prominent examples for such functional key components due to their function as coloring ingredient in food and beverage formulations. Due to their sensitivity towards oxidation, carotenoids require a protective environment in order to avoid rapid losses during storage ³⁵. Spray drying is an effective method for the stabilization of these products from oxidation. But the problem with the spray drying is when lipophilic compounds are spray dried it forms a thin walls of spray dried particles which may result in oxygen escape. The spray dried compounds may also degrade in ambient temperature. This problem can be resolved with the fluidized bed processing. Powders which are produced through spray granulation or agglomeration often exhibit superior quality such as flowability, wettability and water dispensability compared to spray dried powders. Additionally, FB processes have the potential to achieve superior product quality in terms of oxidation stability as results of encapsulation of oxidation sensitive lipids and aromas compared to SD powders. The formulation of the amorphous drugs gained attention when the problem of poor solubility of the crystalline structure arrived. The amorphous powders are more soluble than the crystals but the problem with the amorphous powder is that they tend to turn into their metastable forms and this concerns about the stability of the amorphous forms. The instability of the amorphous form is thermodynamically driven by difference between free energies of amorphous and crystal forms, the propensity for transformation from the former to the latter is strongly linked to kinetic factors such as nucleation probability and molecular mobility in the amorphous state⁶. This change in the form of the state may lead to the decreased solubility of the compound. The amorphous state can be preserved and stabilized by admixing it with a polymer. The polymer helps in inhibiting the initial nucleation of the crystal lattice or reduce the molecular mobility and slow down the nucleation process^6,36. The ability of the polymer to retard crystallization is known to depend on the polymer’s strength of interaction with the drug, its concentration, and its molecular weight ³⁶. The amount of polymer added should be of proper quantity though there’s no specific rule for the quantity of polymer added to specific quantity of drug. But if less quantity of polymer is added there will be large gaps between polymer molecules and in the gaps the nucleation may start and result in crystallization. While on other hand if large quantity of polymer is added there will be increase in the dosage form of drug that is being administered. The improved stability of vegetable and fruit concentrate and the stability of the amorphous forms leads to easy processing of the pharmaceuticals and also decreases need of using preservatives. Previously unstable amorphous forms can be stabilized with the use of particle engineering today³⁶.

6.4. Improved Processability:

The two fundamental properties of powder that impact the tablet formulation are the compressibility and flowability. The majority of the formulations contains 10 – 80% of the active pharmaceutical ingredient depending on the dose. The flow property and the compressibility of the powder influence the final product. The particle engineering strategy to enhance the tablet manufacturing by direct compression can eliminate the need of use of the excipients to enhance the flow of powder throughout the process and to enhance compression ³⁸. The production of the directly compressible powders not only saves time but also is cost effective. By manufacturing directly compressible powders the cost and time required to make granules is reduced. Direct compression is also convenient in case of materials which are unstable in moisture or that are thermo labile. The crystallization of the poorly compressible compounds can significantly improve the compressibility of the powder. By using crystal engineering approach such as polymorphism, co-crystallization, salt formation and hydrate formation the compression properties of the pharmaceutical materials. The polymorphism involves the formation of the greater bonding area by increasing crystal plasticity through introduction of the flat slip planes. In co-crystallization the bonding area can be increased by the incorporating the flat slip planes. The increased bonding areas extensively lead to increase in bond formation between particles and thus results in improved direct compressibility. The salt formation and hydrates also use the same mechanism to improve the compressibility. The hydrates also include the formation of the 3D hydrogen bonding network which enhance bonding strength by increased lattice energy. The particle engineering techniques like surface coating can also be used for the improved compressibility. The powders having particle size greater than 10µm are highly cohesive and oppose the flow under gravity. The reduced flow of powders may lead to improper filling of dies and may lead to the formation of brittle tablets. The API having less flow characteristics may led to improper dosing of the drug in the dosage form. The micronized powders also tend to the electrostatic charges and oppose to the flow properties. The powders micronized by the conventional micronization techniques have less flow properties. The powders obtained by the spray drying are or highly porous and fluffy in nature and have poor flow properties. The micro crystallization and in situ micronization can be advanced ways to reduce cohesiveness of the particles. The powders obtained by the in situ micronization have greater surface area and has great flowability. The flowability and dispersibility of the in situ micronized powder were improved effectively and used in pulmonary drug delivery^2,12.

6.5. Colour Polymorphism:

Most of the organic molecules have more than one crystal form and this property is known as polymorphism. Polymorphs are having same chemical composition but they differ in the crystal structure. This structural difference results in different physicochemical properties of the same substances. Polymorphs may have different melting point, solubilities, dissolution rates and crystal shapes⁴⁴. With change in crystal structure there is a change in colour also. Colour polymorphism is defined as a molecule that is presents polymorphs with different colour is known as colour polymorphism This means that one of the physical properties that varies with the different crystallographic structures of the same compound is, indeed, the colour⁶⁵. This explains compounds having same chemical composition with or without substituents may be present different solid state colours. Colour polymorphism is a rare phenomenon but still is has potential application in pigment, technology and pharmaceutical industry. The difference in the colour of the compound is caused by the dissimilar electron distribution within chromophore of constituent molecules which affect the electronic levels and consequently, the photons frequencies the materials are able to absorb when exposed to light. The colour change induced by conformational polymorphism is exhibited by the π electron delocalization in two conformations where extension of delocalization is different. The length of the π delocalized system can be reduced with the conformational change. The reduced length of π delocalized system leads to the increase in the energy difference between excited and ground state electron to a decrease of wavelength associated with the electronic absorption associated with the colour change. The phenomenon of this colour polymorphism can be applied in pigment industry and the pharmaceutical industry. By changing the crystal structure we can change colour of the compounds, this can be used to get acceptable colours of the compounds which have the less acceptable colours. Particle engineering can help to get acceptable colour compounds by using conformational colour polymorphism¹².

6.6. Taste masking:

The organoleptic properties are important factor governing actability of the drug formulation especially in case of paediatric formulations. Most of pharmaceutical drugs are of bitter taste and it becomes very important to mask the bitter taste to increase the patient compliance. The sense of taste is mediated by the taste buds, which is a group of taste receptors cells (50-100 cells), bundled together in cluster and gives sensation of taste through central nervous system⁴⁶. Following table explains the position of each taste buds on the tongue. Various techniques can be used to mask the bitter taste of the compounds. The one of the popular method for taste masking is to use a masking agent. The masking agent may include sugars, flavours sweeteners and lipoproteins. The taste masking can be done by various techniques like reduction of drug solubility in saliva, creating barrier between taste receptor and drug and by adding flavours and sweeteners. Addition of sweeteners and flavours is a common method but it loses its advantage when comes to highly bitter drugs. Next method to mask taste is to use ion exchange resin complexes. Ion exchange resins exchange their labile ions for present in the solution which they are in contact with. Microencapsulation of the drug avoids contact of the API with the tongue receptors as it is coated with the polymer film⁴⁷. The novel approach for the taste masking is by formation of co-crystals. Co-crystals are composed of two or more components that are solid at room temperature. Co-crystallization is a crystal engineering strategy to enhance the properties of the API. When co-crystallization of an API is done by using a co-crystal former which is one of effective artificial sweeteners fit for human use such as saccharin, aspartame, acesulfame and sucralose, they are called sweet co-crystals⁴⁸. The API prepared with the co-crystallization with sweeteners are shown to have improved properties over its original form as it show improved solubility, bioavailability and increased patient compliance. The co-crystallisation can be done by solid state co-crystallization or solvent mediated co-crystallization. In former method solid-state co-crystallization, is usually used when the first one fails. It depends on mechanical treatment or grinding of both the API and the co-former leading to formation of amorphous phase, vapour diffusion and eutectic melting which increases the molecular mobility of co-formers and enhances the rate of reaction. While in second method which is mainly depends on the phase solubility diagram of both the API and the co-former is used for commercial scale due to availability of the solvents and equipment of crystallization although the outcome of this method isn't usually predictable. Co-crystallization not only improves patient acceptance but also improves drug properties and this is the reason why co-crystallization is being used widely in pharmaceutical industries for taste masking⁴⁸.

CONCLUSION AND OUTCOMES:

This review covers the particle engineering basics and various methods used for the particle engineering of the pharmaceutical products. Particle engineering can be done by use of various techniques like Micronization, Spray drying, high pressure homogenization, Supercritical fluid technology and freeze drying. The use of particle engineering is in obtaining optimum particle size and particle size distribution and getting particles of desired size. The other aspects of the particle engineering involves the morphological changes of the drug substances. The particle engineering involves improvement of physicochemical properties such as solubility, stability, improved bioavailability and formulation of novel drug delivery systems such as pulmonary drug delivery system. With the fusion of various techniques the new techniques can born and particle properties can be customized. For example spray drying and freezing techniques are combined to get a new technique Spray freeze drying, which can be used to get particles of spherical shape and improved solubility particles. This article inspires to try combined techniques for the manufacturing of customized particles. One can think of making a single excipient which has a good flow property, solubility, great compressibility, without anxious taste or odour and with improved stability. The main outcome of this article is the idea of making custom drug and excipient particles which can be easily processed, has all desired properties and can be administered with the routes of administration which previously was a challenge to administer.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

REFERENCES:

1. Tanhaei, M. Mohammadi, H. Hamishehkar, et al., Electrospraying as a novel method of particle engineering for drug delivery vehicles, Journal of Controlled Release (2020), https://doi.org/10.1016/j.jconrel.2020.10.059

2. Vandana KR, Raju YP, Chowdary VH, Sushma M, Kumar NV. An overview on in situ micronization technique–An emerging novel concept in advanced drug delivery. Saudi Pharmaceutical Journal. 2014 Sep 1;22(4):283-9.

3. Blagden N, de Matas M, Gavan PT, York P. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Advanced Drug Delivery Reviews. 2007 Jul 30;59(7):617-30.

4. Sathisaran I, Dalvi SV. Engineering cocrystals of poorly water-soluble drugs to enhance dissolution in aqueous medium. Pharmaceutics. 2018 Sep;10(3):108.

5. Kim S, Wei C, Kiang S. Crystallization process development of an active pharmaceutical ingredient and particle engineering via the use of ultrasonics and temperature cycling. Organic Process Research & Development. 2003 Nov 21;7(6):997-1001.

6. Edueng K, Mahlin D, Larsson P, Bergström CA. Mechanism-based selection of stabilization strategy for amorphous formulations: Insights into crystallization pathways. Journal of Controlled Release. 2017 Jun 28;256:193-202.

7. Laitinen R, Löbmann K, Strachan CJ, Grohganz H, Rades T. Emerging trends in the stabilization of amorphous drugs. International Journal of Pharmaceutics. 2013 Aug 30;453(1):65-79.

8. Khadka P, Ro J, Kim H, Kim I, Kim JT, Kim H, Cho JM, Yun G, Lee J. Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability. Asian Journal of Pharmaceutical Sciences. 2014 Dec 1;9(6):304-16.

9. Midoux N, Hošek P, Pailleres L, Authelin JR. Micronization of pharmaceutical substances in a spiral jet mill. Powder Technology. 1999 Sep 1;104(2):113-20.

10. Pasquali I, Bettini R, Giordano F. Solid-state chemistry and particle engineering with supercritical fluids in pharmaceutics. European Journal of Pharmaceutical Sciences. 2006 Mar 1;27(4):299-310.

11. Albert H. L. Chow,1,4 Henry H. Y. Tong,2 Pratibhash Chattopadhyay,3 and Boris Y. Shekunov3, Particle Engineering for Pulmonary Drug Delivery, Pharmaceutical Research, Vol. 24, No. 3, March 2007 (# 2007) DOI: 10.1007/s11095-006-9174-3

12. Shoyele SA, Cawthorne S. Particle engineering techniques for inhaled biopharmaceuticals. Advanced Drug Delivery Reviews. 2006 Oct 31;58(9-10):1009-29.

13. Giry K, Péan JM, Giraud L, Marsas S, Rolland H, Wüthrich P. Drug/lactose co-micronization by jet milling to improve aerosolization properties of a powder for inhalation. International Journal of Pharmaceutics. 2006 Sep 14;321(1-2):162-6.

14. Kougoulos E, Smales I, Verrier HM. Towards integrated drug substance and drug product design for an active pharmaceutical ingredient using particle engineering. AAPS Pharmscitech. 2011 Mar;12(1):287-94.

15. El-Gendy N, Bailey MM, Berkland C. Particle engineering technologies for pulmonary drug delivery. InControlled pulmonary drug delivery 2011 (pp. 283-312). Springer, New York, NY.

16. Herpin MJ, Smyth HD. Super-heated aqueous particle engineering (SHAPE): A novel method for the micronization of poorly water soluble drugs. Journal of Pharmaceutical Investigation. 2018 Jan;48(1):135-42.

17. Moura C, Neves F, Costa E. Impact of jet-milling and wet-polishing size reduction technologies on inhalation API particle properties. Powder Technology. 2016 Sep 1;298:90-8.

18. Brunaugh A, Smyth HD. Process optimization and particle engineering of micronized drug powders via milling. Drug Delivery and Translational Research. 2018 Dec 15;8(6):1740-50.

19. Fukunaka T, Sawaguchi K, Golman B, Shinohara K. Effect of particle shape of active pharmaceutical ingredients prepared by fluidized-bed jet-milling on cohesiveness. Journal of Pharmaceutical Sciences. 2005 May 1;94(5):1004-12.

20. Silva AS, Tavares MT, Aguiar-Ricardo A. Sustainable strategies for nano-in-micro particle engineering for pulmonary delivery. Journal of Nanoparticle Research. 2014 Nov;16(11):1-7.

21. Vehring R. Pharmaceutical particle engineering via spray drying. Pharmaceutical Research. 2008 May;25(5):999-1022.

22. Kaialy W, Nokhodchi A. Particle engineering for improved pulmonary drug delivery through dry powder inhalers. Pulmonary drug delivery: advances and challenges. Eds. Nokhodchi, A., Martin, GP. 2015 May 29:171-98.

23. Kumar RS, Sai TM. Particle Engineering Techniques: A Boon in Enhancing Dissolution Rate of Poorly Water Soluble Drugs. Journal of Drug Delivery and Therapeutics. 2019 Dec 18;9(4-A):897-900.

24. Hu J. A nanoparticle engineering process: Spray-freezing into liquid to enhance the dissolution of poorly water soluble drugs. The University of Texas at Austin; 2003.

25. Rogers TL, Nelsen AC, Sarkari M, Young TJ, Johnston KP, Williams RO. Enhanced aqueous dissolution of a poorly water soluble drug by novel particle engineering technology: Spray-freezing into liquid with atmospheric freeze-drying. Pharmaceutical Research. 2003 Mar; 20(3): 485-93.

26. Patel RP, Patel MP, Suthar AM. Spray drying technology: an overview. Indian Journal of Science and Technology. 2009 Oct 1;2(10):44-7.

27. Arpagaus C. Pharmaceutical particle engineering via nano spray drying—process parameters and application examples on the laboratory-scale. Int. J. Med. Nano Res. 2018;5(1):026.

28. Khandouzi F, Daman Z, Gilani K. Optimized particle engineering of fluticasone propionate and salmeterol xinafoate by spray drying technique for dry powder inhalation. Advanced Powder Technology. 2017 Feb 1;28(2):534-42.

29. Deelip Derle*1, Jatin Patel1, Devendra Yeole1, Amit Patel1, Ashok Pingle1, Particle Engineering Techniques To Enhance Dissolution Of Poorly Water Soluble Drugs, International Journal Of Current Pharmaceutical Research Vol 2, Issue 1, 2010

30. Sapra M, Ugrani S, Mayya YS, Venkataraman C. Estimation of critical supersaturation solubility ratio for predicting diameters of dry particles prepared by air-jet atomization of solutions. Journal of Colloid and Interface Science. 2017 Aug 15;500:172-81.

31. Bohr A, P Boetker J, Rades T, Rantanen J, Yang M. Application of spray-drying and electrospraying/electospinning for poorly watersoluble drugs: A particle engineering approach. Current Pharmaceutical Design. 2014 Jan 1;20(3):325-48.

32. Patel B, Gupta N, Ahsan F. Particle engineering to enhance or lessen particle uptake by alveolar macrophages and to influence the therapeutic outcome. European Journal of Pharmaceutics and Biopharmaceutics. 2015 Jan 1;89:163-74.

33. Shoyele SA, Sivadas N, Cryan SA. The effects of excipients and particle engineering on the biophysical stability and aerosol performance of parathyroid hormone (1-34) prepared as a dry powder for inhalation. AAPS Pharmscitech. 2011 Mar;12(1):304-11.

34. Lorraine M. Nolan, Jianhe Li, Lidia Tajber, Owen I. Corrigan, Anne Marie Healy∗,Particle engineering of materials for oral inhalation by dry powder inhalers. II—Sodium cromoglicate, International Journal of Pharmaceutics 405 (2011) 36–46 doi:10.1016/j.ijpharm.2010.11.040

35. Björnmalm M, Yan Y, Caruso F. Engineering and evaluating drug delivery particles in microfluidic devices. Journal of Controlled Release. 2014 Sep 28;190:139-49.

36. Sahoo A, Suryanarayanan R, Siegel RA. Stabilization of Amorphous Drugs by Polymers: The Role of Overlap Concentration (C*). Molecular Pharmaceutics. 2020 Sep 25;17(11):4401-6.

37. Klara Haas, Thomas Dohnal, Patricia Andreu, Egon Zehetner, Anke Kiesslich, Marcus Volkert, Peter Fryer, Henry Jaeger, Particle engineering for improved stability and handling properties of carrot concentrate powders using fluidized bed granulation and agglomeration, Powder Technology 370 (2020) 104–115 https://doi.org/10.1016/j.powtec.2020.04.065

38. Chattoraj S, Sun CC. Crystal and particle engineering strategies for improving powder compression and flow properties to enable continuous tablet manufacturing by direct compression. Journal of Pharmaceutical Sciences. 2018 Apr 1;107(4):968-74.

39. R Williams D. Particle engineering in pharmaceutical solids processing: surface energy considerations. Current Pharmaceutical Design. 2015 Jun 1;21(19):2677-94.

40. Marwaha M, Sandhu D, Marwaha RK. Coprocessing of excipients: a review on excipient development for improved tabletting performance. International Journal of Applied Pharmaceutics. 2010 Apr;2(3):41-7.

41. Perumalla SR, Sun CC. Enabling tablet product development of 5-fluorocytosine through integrated crystal and particle engineering. Journal of Pharmaceutical Sciences. 2014 Apr 1;103(4):1126-32.

42. Solomon S, Ziaee A, Giraudeau L, O'Reilly E, Walker G, Albadarin AB. Particle engineering of excipients: A mechanistic investigation into the compaction properties of lignin and [co]-spray dried lignin. International Journal of Pharmaceutics. 2019 May 30;563:237-48.

43. Martyn David Ticehursta And Ivan Marzianob, Integration Of Active Pharmaceutical Ingredient Solid Form Selection And Particle Engineering Into Drug Product Design. Journal Of Pharmacy And Pharmacology, Doi: 10.1111/Jphp.12375 (2014)

44. He X, Griesser UJ, Stowell JG, Borchardt TB, Byrn SR. Conformational color polymorphism and control of crystallization of 5‐methyl‐2‐[(4‐methyl‐2‐nitrophenyl) amino]‐3‐thiophenecarbonitrile. Journal of Pharmaceutical Sciences. 2001 Mar;90(3):371-88.

45. Nogueira BA, Castiglioni C, Fausto R. Color polymorphism in organic crystals. Communications Chemistry. 2020 Mar 17;3(1):1-2.

46. Sharma Deepak, Kumar Dinesh, Singh Mankaran, Singh Gurmeet, Rathore Mahendra Singh, Taste Masking Technologies: A Novel Approach For The Improvement Of Organoleptic Property Of Pharmaceutical Active Substance, In International Research Journal Of Pharmacy. April 2012

47. Dhakate CS, Upadhye KP, Dixit GR, Bakhale SS, Umate RM. Taste masking by co-crystallization: A review. World J Pharm Res. 2017 May 18.

48. Savjani JK. Co‐crystallization: An approach to improve the performance characteristics of active pharmaceutical ingredients. Asian Journal of Pharmaceutics (AJP): Free full text articles from Asian J Pharm. 2015 Jul 15;9(3):147-51.

49. Wadhwa J, Puri S. Taste masking: A novel approach for bitter and obnoxious drugs. International Journal of Biopharmaceutical & Toxicological Research. 2011;1(1):47-60.

50. Madene A, Jacquot M, Scher J, Desobry S. Flavour encapsulation and controlled release–a review. International Journal of Food Science & Technology. 2006 Jan;41(1):1-21.

51. Suphla Gupta, Saima Khan, Malik Muzafar, Manoj Kushwaha, Arvind Kumar Yadav, Ajai Prakash Gupta, Encapsulation: Entrapping Essential Oil/Flavors/ Aromas In Food, Encapsulations. Http://Dx.Doi.Org/10.1016/B978-0-12-804307-3.00006-5

52. Abdou EM. Sweet co-crystals for pediatric drugs formulation. Acta Scientific Pharmaceutical Sciences. 2018;2:01.

53. Antonio Tabernero, Eva M. Martín del Valle∗, Miguel A. Galán, Supercritical fluids for pharmaceutical particle engineering: Methods, basic fundamentals and modelling, Chemical Engineering and Processing 60 (2012) 9– 25 http://dx.doi.org/10.1016/j.cep.2012.06.004

54. Dennehy RD. Particle engineering using power ultrasound1. Organic Process Research & Development. 2003 Nov 21;7(6):1002-6.

55. Kougoulos E, Marziano I, Miller PR. Lactose particle engineering: Influence of ultrasound and anti-solvent on crystal habit and particle size. Journal of Crystal Growth. 2010 Nov 15;312(23):3509-20.

56. Rojas PE, Sala S, Elizondo E, Veciana J, Ventosa N. Particle engineering with CO 2-Expanded Solvents: The DELOS platform. InAdvances in Organic Crystal Chemistry 2015 (pp. 73-93). Springer, Tokyo.

57. Sowa M, Klapwijk AR, Ostendorf M, Beckmann W. Particle engineering of an active pharmaceutical ingredient for improved micromeritic properties. Chemical Engineering & Technology. 2017 Jul;40(7):1282-92.

58. Vinjamuri BP, Haware RV, Stagner WC. Inhalable ipratropium bromide particle engineering with multicriteria optimization. Aaps Pharmscitech. 2017 Aug;18(6):1925-35.

59. Stefan Bötschi, Ashwin Kumar Rajagopalan, Igor Rombaut Manfred Morari, Marco Mazzotti. From needle-like toward equant particles: A controlled crystal shape engineering pathway, Computers and Chemical Engineering 131 (2019) 106581 https://doi.org/10.1016/j.compchemeng.2019.106581

60. Yang Y, Nie D, Liu Y, Yu M, Gan Y. Advances in particle shape engineering for improved drug delivery. Drug Discovery Today. 2019 Feb 1;24(2):575-83.

61. Pallai-Varsányi E, Tóth J, Gyenis J. Drying of suspensions and solutions on inert particle surface in mechanically spouted bed dryer. China Particuology. 2007 Oct 1;5(5):337-44.

62. Majerik V, Horváth G, Charbit G, Badens E, Szokonya L, Bosc N, Teillaud E. Novel particle engineering techniques in drug delivery: Review of coformulations using supercritical fluids and liquefied gases. Hungarian Journal of Industry and Chemistry. 2004 Sep 1;32(1).

63. Pawar N, Saha A, Nandan N, Parambil JV. Solution cocrystallization: A scalable approach for cocrystal production. Crystals. 2021 Mar;11(3):303.

64. Ronald G. Iacocca, Christopher L. Burcham, Lori R. Hilden, Particle Engineering: A Strategy For Establishing Drug Substance Physical Property Specifications During Small Molecule Development, Journal Of Pharmaceutical Sciences, Vol. 99, No. 1, January 2010

65. Joshi R, Raje S, Akram W, Garud N. Particle engineering of fenofibrate for advanced drug delivery system. Future Journal of Pharmaceutical Sciences. 2019 Dec;5(1):1-1.

66. Li Z, Lin X, Shen L, Hong Y, Feng Y. Composite particles based on particle engineering for direct compaction. International Journal of Pharmaceutics. 2017 Mar 15;519(1-2):272-86.

67. Lobo JM, Schiavone H, Palakodaty S, York P, Clark A, Tzannis ST. SCF-engineered powders for delivery of budesonide from passive DPI devices. Journal of Pharmaceutical Sciences. 2005 Oct 1;94(10):2276-88.

68. Majerik V, Horváth G, Charbit G, Badens E, Szokonya L, Bosc N, Teillaud E. Novel particle engineering techniques in drug delivery: Review of coformulations using supercritical fluids and liquefied gases. Hungarian Journal of Industry and Chemistry. 2004 Sep 1;32(1).

69. Wan F, Maltesen MJ, Bjerregaard S, Foged C, Rantanen J, Yang M. Particle engineering technologies for improving the delivery of peptide and protein drugs. Journal of Drug Delivery Science and Technology. 2013 Jan 1;23(4):355-63.

70. Ógáin ON, Li J, Tajber L, Corrigan OI, Healy AM. Particle engineering of materials for oral inhalation by dry powder inhalers. I—Particles of sugar excipients (trehalose and raffinose) for protein delivery. International Journal of Pharmaceutics. 2011 Feb 28;405(1-2):23-35.

71. Rathod S, Mali S, Shinde N, Aloorkar N. Cosmeceuticals and Beauty Care Products: Current trends with future prospects. Research Journal of Topical and Cosmetic Sciences. 2020;11(1):45-51.

72. Kale N, Rathod S, More S, Shinde N. Phyto-Pharmacological Profile of Wrightia tinctoria. Asian Journal of Research in Pharmaceutical Sciences. 2021 Nov 26;11(4):301-8.

73. Sanket Rathod, Ketaki Shinde, Namdeo Shinde, Nagesh Aloorkar. Cosmeceuticals and Nanotechnology in Beauty Care Products. Research Journal of Topical and Cosmetic Sciences. 2021; 12(2):93-1.

74. B.A. Bhairav, J.K. Bachhav, R.B. Saudagar. Review on Solubility Enhancement Techniques. Asian J. Pharm. Res. 2016; 6(3): 147-152.

75. Rutuja S. Shah, Rutuja R. Shah, Manoj M. Nitalikar, Chandrakant S. Magdum. Microspheres by Spray Drying: An Approach to Enhance Solubility of Bicalutamide. Asian J. Pharm. Res. 2017; 7(3): 183-188.

Received on 28.12.2021 Modified on 05.02.2022

Asian J. Pharm. Res. 2022; 12(4):349-358.

DOI: 10.52711/2231-5691.2022.00055