1. INTRODUCTION:

One of the most studied and discussed field but still having several unresolved issues in formulation science is solubility. Therefore the study of dissolution enhancement techniques has retained its standing as one of the more vibrant fields among the researchers. Solubility and dissolution are two of the inevitable parameters that affect the science dealing with the biopharmaceutical and pharmacokinetic considerations in medicinal therapy. Promising lead compounds are being successfully put out through synthetic production for almost all pharmacological classes, but they tend to have bulkier molecular structures. The outcome being the lead molecules entering the developmental phases of drug discovery fail because of biopharmaceutical properties which are not optimal. Major impact on pharmacokinetic attributes was observed due to properties such as rate and degree of absorption, delivery frequency, amount of drug required to attain lowest effective concentration and to prevent side effects.

Conventional as well as most commonly used practices to improve the water solubility and thereby the bioavailability of BCS Class II drugs entail applying principles like pH alteration, co-solvency, microemulsion formation, self-emulsification, micelle formation, liposome and emulsification. Each has its own advantages and disadvantages; thus, its choice is a crucial decision-making stage in the course of formulation.

1.1 Use of surface active agents:

A common and thoroughly studied technique in order to solubilise BCS class 2 drugs are by solubilizing them by reducing the tension formed in the interface of solute and solvent. Thus the utilization of amphiphilic surfactants can bring about the improved solubility through an overall reduced surface tension, improved wetting, and micellar solubilization.

Example: The use of surfactants like Triton™ X100, Triton™ X114, Brij™ 35, Sodium dodecyl sulphate, Triton™ X 405 to improve the aqueous solubility of 1,1 bis (p-chloro- phenyl) -2,2,2 trichloroethane (DDT), and 1,2,3 trichloro benzene (TCB), were found to be successful. Both DDT and TCB showed profound increase in solubility at and above critical micellar concentration (CMC). Whereas DDT showed enhanced solubility in presence of Triton™ X 405 and BRIJ™ 35 even at a concentration below CMC.^(I)

1.2 pH adjustments:

Modification of ionization behaviour is one of the easiest, effective and commonly used principle that can alter the water solubility of ionizable compounds, which can be attained by adjusting the micro environmental pH. From study of Henderson- Hasselbalch equation it is understood that pH of media and the drug’s pKa have a drastic effect on the ionization property of the compound.

Example: An experimental drug Thiazolobenzimidazole (TBI) used for the treatment of AIDS in normal conditions cannot be administered as an injectable solution due to its inability to be dissolved in aqueous media (11µg/mL), but it’s injectability has been made possible by lowering the pH at 3.55 pKa. The compound has a single ionizable functional group which attains maximum solubility at pH 2 (0.4mg/ml). This is further enhanced to a magnitude of 3^rd order by complexation using beta cyclodextrin.^(II)

1.3 Salt formation:

An effective strategy used to enhance solubility in parenteral, liquid formulation as well as solid dosage form is the use of salt formation on water insoluble candidate (weak bases and acids). The use of this method for improving solubility goes back several decades.

Example: Parenteral administration of α‐(2‐piperidyl)‐3,6‐bis(trifluoromethyl)‐9‐phenanthrene methanol (a molecule synthesized for the treatment of malaria) was made feasible by judicious choice of its salt form, which greatly affected the solubility of the compound. Wherein the lactate salt was shown to have solubility 200 times more than that of its hydrochloride salt.^(III)

1.4 Co-solvents:

Solubilization of lipophilic drugs can be achieved through the use of mixture of miscible solvents to obtain a co solvent system. Organic solvents commonly used for the same are polyethylene glycol 400 (PEG 400), ethanol, propylene glycol, and glycerine, which are aqueous soluble. The aqueous insoluble ones comprise of long-chain triglycerides (i.e. arachis oil, corn oil, soybean oil, sesame oil, olea europaea, peppermint oil, hydrogenated vegetable oil and hydrogenated soybean oil), medium-chain triglycerides (Miglyol™ 812), beeswax, d-α- tocopherol (vitamin E) and oleic acid.

Example: Co solvent principle was applied in the formulation of Procardia (Nifedipine) which is an anti-anginal drug developed by Pfizer. It is in the form of soft gelatine capsules containing glycerine, peppermint oil, PEG 400 and sodium saccharin.^(IV)

1.5 Particle size reduction:

One of the best and simple procedures for attaining a better solubility and bioavailability is by comminution. In this method size of particle is reduced to sub-micron levels by micronization or nanonization. This allows for a rise in the surface area and thereby the saturation solubility which help to increase the solubility and bioavailability.

Example: In vitro dissolution studies of three suspensions of cilostazol with varying particle size prepared by three different mechanisms were done. The suspension with the smaller particle size had ensured an increased solubility and bioavailability on oral administration^(V)

1.5.1 Co-grinding/co-micronization:

An effective method to improve apparent solubility of a lipophilic drug while maintaining the drug crystallinity is by co grinding. Here the poorly soluble drugs are ground together with polymers, like hydroxy propyl methyl cellulose (HPMC), that are soluble even in small amounts of water

Example: Furosemide’s dissolution rate showed marked improvement on co grinding with crospovidone at a ratio of 1:2 using a ceramic ball mill.^(VI)

1.5.2 Solution enhanced dispersion by the supercritical fluids (SEDS):

Coaxial nozzle helps in dispersion of compressed fluid CO₂with drug in organic solvent solution,both of which flows through a minute orifice into the particle forming chamber .High velocity impact of the solutions allow for the easier break up due to which strong frictional forces are formed on the surface causing the other solution to form droplets.

Example: In vitro release studies disclosed that there was an enhanced solubility for curcumin when SEDS principle was applied. Curcumin solubility was improved by fabricating a silk fibroin based delivery system in supercritical CO₂ (20 MPa pressure) and curcumin: silk fibroin ratio of (1:2). A controllable particle size of < 100 nm and a narrow size distribution were observed using scanning electron microscopy.^(VII)

1.5.3 Spray freezing into liquid (SFL):

Solution, suspension or emulsion containing drug and other excipients can be atomized directly into a compressed gas or cryogenic liquids. These frozen particles are then lyophilized to receive a micronized, dry, and free flowing powder.

Example: 100% dissolution was obtained in 5 minutes in case of micronized SFL powder of Danazol, prepared along with PVA, PVP k15 and poloxamer 407.^(VIII)

1.5.4 Evaporative precipitation into aqueous solution (EPAS):

Separation of phase rapidly leads to nucleation and growth which is the basic principle involved in the process of preparing nanoparticles and microparticle of lipophilic drugs by EPAS.

Example: Carbamazepine, a drug which is practically insoluble in aqueous media has been enveloped with hydrophilic stabilizers using evaporative precipitation into aqueous solution (EPAS) technique to enhance the rate of dissolution. This enhancement is primarily due to the minute particle size, improved wetting due to the hydrophilic coating , and low crystallinity as a result of EPAS.^(IX)

1.5.5 Ultra-rapid freezing:

Nanostructured drug dosages with large surfaces can be created using an innovative technology undertaken in presence of low temperatures known as ultra-rapid freezing. Solvent system and process conditions can be varied in order to obtain desired morphology. A drug is dissolved in aqueous polymer solution and frozen onto a cryogenic substrate whose thermal conductivity (k) is in the range of 10 and 20 W.m^-1 K^-1. The frozen particles are collected and removal of the solvent is done to ensure a porous and agglomerated particles.

Example: Ultra - rapid freezing of Repaglinide/excipient solution was done on a cryogenic substrate, this was collected and a dry powder was obtained after lyophilization. The composition was also incorporated with surface active agents, including sodium dodecyl sulphate, and alkalizers such as diethanolamine (DEA) and tromethamine (TRIS) .The product obtained was observed to be fast dissolving, physically and chemically stable.^(X)

1.6 Kneading technique:

This is a technique used for preparation of inclusion complexes, by impregnating cyclodextrin with water, and by incorporating the drug to the paste formed. The mixture is dried and sieved. These have shown marked improvement in solubility and bioavailability.

Example: Glipizide, Rofecoxib, Piroxicam and Carvedilol inclusion complexes incorporating β-cyclodextrin (β-CD) were formed using kneading technique. They showed enhanced solubility and bioavailability ^(XI)

1.7 Co-precipitation:

A solution of β-CD is prepared to which required drug is added. Constant magnetic agitation is provided in the system along with other process parameters which are also maintained. Vacuum clarification is done to isolate the formed precipitate and is then dried at room temperature to avoid loss of structure.

Example: Co-precipitation aids formation of curcumin and β-Cyclodextrin complex (which was confirmed by FT-IR) with 74% efficiency and solubility increase of upto 31-fold when compared to pure drug.^(XII)

1.8 Neutralization:

An alkaline solution of drug is prepared to which β-CD is added to properly dissolve the drug. The solution is subjected to agitation and neutralized with HCl until equivalence point is reached. Straightaway there will be formation of a white precipitate, which ensures the creation of inclusion complex. Which is further sifted and dehydrated.

Example: Naproxen – beta cyclodextrin solid complexes in molar ratio 1:1 were formed by freeze drying and neutralization method. Its formation can be confirmed using X-ray diffractometry, IR spectroscopy and differential scanning calorimetry (DSC) etc. Naproxen inclusion complex showed much rapid dissolution rate than that of naproxen alone. ^(XIII)

1.9 Spray-drying method:

Stoichiometric amount of β-cyclodextrin is dissolved in water, which is sonicated (or by other suitable methods) along with drug dissolved in suitable solvent, to receive a solution that is clear. Which is then fed into spray drier to obtain spray dried inclusion complexes.

Example: It was experimentally proven that the spray dried amorphous inclusion complexes of drugs like acetaminophen, indomethacin, piroxicam and warfarin with β-cyclodextrin showed improved dissolution rates than that of their pure drugs and physical mixtures of drug and carrier^(XIV)

1.10 Solid dispersions:

Solid dispersion is prepared by melting and solvent evaporation methods by which hydrophobic drug is dispersed in an inert hydrophilic polymer. Lately, new techniques have been brought up for solid dispersion preparation. Some of the common techniques used are:

· Melting

· Hot melt extrusion

· Solvent evaporation

· Melting solvent

· Super critical fluid technology

· Spray drying

The amorphous state of solid dispersion is the characteristic property which allows for the superior dissolution rate and bioavailability of the drug.

Example: A highly lipophilic molecule like curcumin showed complete release within 30 min when presented in the form of spray dried solid dispersion with PVP. It is a drastic improvement in comparison to the pure form of the drug and also the physical mixture which showed release within only 90 min.^(XV)

2. Nanoparticles:

The application Nanoscience and nanotechnology in medicine is raking in a lot of attention in modern times, it sees the use of nanocarriers loaded with API to form nano delivery systems in the size range of up to 1000 nm. API selected can be framed into large number of varying forms including nanocrystals, micelles, nano dispersions, nano emulsions, nano sized liposomes, etc., using the technology available.

Advantages:

· Nano particles compared to other available forms of drug generally improves the solubility and dissolution rate of the drugs which are insoluble in aqueous media due to the increased surface area to volume ratio that is attainable on its formulation. Thereby they can enhance the absorption and bioavailability of BCS class II drugs.

· Nanodrug formulations have the ability to improve chemical stability and release profile of certain drugs.

· Targeted drug delivery and longer circulation time in the system can be achieved through nanoparticles by modifying their surface functionalities.

· Simple and Rapid method

· Profitable

· Colloidal dispersion prepared will be of narrow size dispersion

· Scale up is easy

· Substantial reproducibility

· Preparation of nanospheres and nanocapsules

2.1 Mechanism:

Top-down and bottom-up methods are the widely accepted fabrication techniques for nanoparticle preparation (shown in Figure 1.)

Figure 1: Methods used in preparation of nanoparticles

· The top-down method just as the name suggests is a mechanism of sizing down the large drug solid crystals into their nanometre scale by using the principle of shear, attrition, friction, pressure or any of their combination. Studies have shown that these methods with the aid of specific stabilizers will ensure a process which is highly reproducible and particles obtained is usually in the range of 2-100 nm.

· On the other hand bottom up methods focuses on building up the particle to its anticipated size. These methods have the ability to produce particles of size less than that of top-down methods.

2.2 Flash nanoprecipitation (FNP):

Among the aforementioned methods is flash nanoprecipitation, which is a unique, efficient, easy to scale up, reproducible bottom up method. It is a method for formation of nanoparticles with help of unique composition with stabilizers under rapid mixing, which aids in attaining the desired size and surface properties. This review will further detail about FNP, its principle, instrumentation, aspects involved in preparation of drug nanoparticles and its application on BCS class 2 formulations.

2.2.1 Principle of flash nano precipitation:

As mentioned before the FNP process is for preparing tailor made drug nanoparticles by bottom up method, especially for lipophilic drugs. Just like the conventional crystallization process, FNP also includes an initial nucleation stage, which is followed by the growth of the newly formed nucleation seeds growth by capturing the dissolved molecules. Basically the FNP process takes place in a confined chamber where two or more miscible liquids are mixed by rapid impingement. The basic steps are mentioned below.

· Supersaturated condition is created when drug solution and antisolvent are flash mixed.

· This will trigger the nucleation stage of solute (drug)

· Coagulation and condensation will aid in the growth of the particle.

· Stabilizers in the form of lipids, polymers, or/and surfactants are usually added which encapsulate the water insoluble core and ensures its stability. This is attained by the formation of a layer of hydrophilic substance enclosing the nano particle which prevents additional growth of the nanoparticle. Thus the stabilizers perform a vital role in controlling the size of the particle formed.^(XVI)

2.2.2 Major parameters affecting (FNP):

Many of the essential features of drug nanoparticles, including particle size, polydispersity, zeta potential, morphology, purity, and stability are mainly influenced by the magnitude of solute super saturation, frequency and uniformity in the mixing system. The characteristics of the nanoparticles formed are also widely affected by the properties of active ingredient, solvent media, antisolvent, stabilizers, and temperature etc. which are expressed in detail below and also summarised in a fishbone diagram (Figure 2.).

2.2.2.1 Drug:

FNP process is for triggering formation of large number hydrophobic drug nanoparticles. Two major steps before final nanoparticle is obtained are nucleation and growth of the drug molecule. For this to happen the drug molecule property should be such that it does not dissolve in the aqueous solution easily.

Generally it is seen that drugs having high log P values, showed better stability among the formed nanoparticles. This is clearly understood in the formation of nanoparticle of highly hydrophobic drugs like cyclosporine A, doxorubicin, itraconazole, curcumin, Beta carotene etc. Prodrugs having more hydrophobicity than their parent molecule have also seen success in improving nanoparticle stability. Other properties of drug that also affect the stability include ionization and crystallinity.

As already mentioned the degree of solute supersaturation plays a vital role in several critical attributes that are expected in the nanoparticle. Hence the concentration of drug in solvent remains to be a vital process parameter in FNP process for nanoparticles. Higher drug concentrations create higher supersaturation and nucleation rates, which in turn result in smaller particle size. At the same time a higher concentration can lead to larger number of nuclei which tends to increase the viscosity and reduce diffusion and also cause particle aggregation In order to obtain nanoparticles in the desired size range, with appropriate nucleation rates and growth kinetics, an optimal drug concentration must therefore be established.^(XVI)

2.2.2.2 Effect of solvent and anti - solvent

Generally solvents used in FNP are organic solvents which are a mixture of dimethyl sulfoxide, dimethyl formamide, ethanol, acetone etc. which are highly polar ( have high dipole moments) and are freely miscible and compatible with the antisolvent. Widely accepted and used anti solvents are water or aqueous buffer solution, its selection criteria is founded on both the drug’s high supersaturation condition of drug needed to enable nucleation and growth of nanoparticles under controlled mixing conditions.

· Solvent/antisolvent ratio is responsible for enforcing varying levels of supersaturation which are responsible of nanoparticle nucleation and growth. High volume ratio improves the drug solubility hence reduces the supersaturation and the limits the triggering of nucleation. Whereas low volume ration solvent/ antisolvent induces a high supersaturation condition which triggers a higher nucleation rates for drug nanoparticles

· Mixing rates of antisolvent and solvent which is related to the τ_mixplays a vital role in the nucleation and growth of solute.^(XVI)

2.2.2.3 Stabilizers:

As discussed earlier stabilizers influences the size and also the long term stability of the nanoparticles prepared through flash nano precipitation. Most stabilizers used are in form of lipids, polymer and/or surfactants. They encapsulate or protect the nanoparticles from further growth and aggregation, through which desired particle size and stability can be achieved. It reduces particle size significantly through its ability to reduce interfacial energy at solid liquid interfaces. Limited Ostwald ripening , crystal form transformation and nanoparticle agglomeration leads to the improved stability of the nanoparticle.

FNP formulation has seen the usage of the following stabilizers

Polymers:

· nonionic polymer, example: Hydroxy methyl cellulose, Hydroxy propyl cellulose etc

· ionized polymer, example: Sodium carboxy methyl cellulose, Chitosan etc

· linear chain polymer, example: Poly vinyl pyrrolidone, poly ethylene glycol etc.

· hydrophobic group polymer, example: Poly(lactic-co-glycolic acid), Poly lactic acid etc.

· amphiphilic group copolymer, example: poloxamer etc.

Surface active agents:

· ionized type example: Sodium dodecyl sulphate, Sodium cholic acid etc

· nonionic type example: Tween, Span etc

Effect of stabilizers:

1. Adsorption kinetics is influenced by the attraction on the drug’s surface by various stabilizers

2. Electrostatic repulsion, steric stabilization properties of the stabilizer have a key role in maintaining stability of the nanoparticle.

3. Water solubility and molecular structure of the stabilizer often affects the particle size and nanoparticle stabilization. ^(XVI)

2.2.2.4 Temperature:

Temperature has a significant role in FNP since it has a significant influence on the particle size and its distribution by altering solubility supersaturation, nucleation rate, and process kinetics. Decrease in temperature showed significant reduction particle size, this is due to reduced equilibrium solubility and increased supersaturation which in turn increases the nucleation rate. The reduced temperature will also lead to deceleration of coagulation and reduces the Ostwald ripening. Hence researchers tend to use temperature such as 4 °C and in ice-bath conditions to formulate drug nano particles which are even smaller and having narrow particle size distribution. ^(XVI)

2.2.3 Instrumentation:

There are multiple devices used for mixing which were developed for producing nanoparticles of lipophilic drugs in an efficient, reproducible, and controllable manner via FNP. They are listed below:

1. Confined impinging jets mixer (CIJM) developed by Johnson and Prud׳homme

2. Multi-inlet vortex mixer (MIVM) by Liu and Prud׳homme.

3. Micro fluidic mixer system

4. This review will discuss in detail about confined impinging jet mixer.

Confined Impinging Jet Mixer (CIJM):

Confined impinging jets are one of the mixing devices that are extensively in use for the preparation of FNP based drug nano formulations. As represented in Figure 3. the CIJM is composed of two opposing liner jets and syringe pumps for sample injection into common a mixing chamber. The opposing entry of solvent and antisolvent from the liner jets at high velocity, leads to the collision of the fluid streams which limits the segregation between the liquid streams that take part in the mixing. Researches time and time again have used this instrument for preparing drug nanoparticles which are further seen in Table1. This was commonly used in preparation of drug polymeric micelle products, nanoparticles of polymeric origin as well as solid lipid nanoparticles. The CIJM is highly efficient in its mixing and also leads to small and highly uniform product, which helps in increased supersaturation and nucleation speed, which in turn are the basis for nanoparticles having high drug encapsulating efficiency (DEE) and drug loading capacity (DLC).^(XVI)

Figure 3: Mechanism of CIJM

Table 1: Application, QTPP, CMA, CPP of CIJM for Flash Nanoprecipitation.¹⁶

API (log P)

Solvent (S)

Flow Rate (S/W flow ratio)

Dilution ratio

Stabilizer

API/Stabilizer mean ratio

Mean size

Zeta (mV)

PDI

Stability

β-Carotene (15.232)

THF

30 mL/min (1:1)

72ml/min

(1:1)

1:9

1:4

PEG-PLA

PEG-PCL;PEG-PS

1:1

2:1-2:9

70-130

n/a

Curcumin(2.517)

Acetone/DMF/THF

Acetone

n/a (1:1)

30ml/min (1:1)

1:9

PEG-PLA

PEG-PLA;

PVP

1:1

70-150

<100

-0.715

0.11

0.05-0.2

n/a

5day

Doxorubicin (1.27)

Acetone or THF

40 to 120 mL/min (1:1–1:8)

n/a

P(MePEGCA-co-HDCA)

1:20–1:5

80 –300

–20 to

-50

n/a

Paclitaxel(4.73)

Paclitaxel prodrug (18.36)

THF

72 ml/min (1:1)

1:9

PEG-PLGA

1:1

122

n/a

90min

8day

Florfenicol (2.84)

Acetone

40,80 or120ml/min (1:1)

2:1

PCL

PLGA

1:12-

5:6

1:12-

5:6

230-300

70-105

-32 to

-40

-15 to

-25

<0.1

<0.2

n/a

Melatonin

(1.34)

Acetone

5to 120ml/min (1:1)

2:1

PCL

0.18-6

250-400

-17

Menthol

(3.216)

Acetone/ACN/THF

5to 120ml/min (1:1)

0.24-2

PCL

0.76-2

200-500

-20 to

-45

0.05-0.3

n/a

Cyclosporin

(3.0)

Ethanol

120ml/min (1:1

40to 120ml/min (1:3)

1:5

4:5

Soyalecithin;

lactose

Lecithin;dextrose monohydrate

10:

1.025

0.7:

1.8

180-700

260

n/a

Clofazimine(7.66)

Acetone/THF

12ml/min (1:1)

1:4

HPMCAS

Lecithin

n/a

170

-28.7

-52.3

0.24

0.16

n/a

https://creativecommons.org/licenses/by-nc-nd/4.0/

2.2.4 Applications:

Nanoprecipitation is well established in the medical, pharmaceutical, agriculture, food and cosmetics industries. Agriculture field has seen a rise in need of controlled release systems which play decisive role in lowering environmental and health problems that comes along with the usage of pesticides. But still the most possibly investigated applications are in the medical field, since the practice of using simple and versatile drug nanoparticles and nano systems in pre-clinical and clinical trials garner special attention in the pharmaceutical industry.

As already discussed above CIJM can be widely used in industry in preparation of nanoparticles. Some of its application in pharmaceutical as well as other industries are listed below:

· Synthesis of cobalt ferrite nanoparticles.^(XVII)

· CIJM was used for FNP of nanoparticles of rhabdophane-structured lanthanum orthophosphate.^(XVIII)

· A superior fast charging–discharging nano-LiFePO₄/C was synthesised from nano-FePO₄with the help of CIJM. ^(XIX)

· Preparation of inhalable cyclosporine A powders by confined liquid impinging jet precipitation.^(XX)

· Production of colloidal Zein particles using flash nano precipitation.^(XXI)

· Preparation of nanometric particles of hydrophobic curcumin from an oil in water emulsion.^(XXII)

· Route of Production of metal nanocatalysts supported by polymeric nanospheres by flash nano precipitation.^(XXIII)

3. CONCLUSION:

As reviewed above FNP with the help of CIJM has proved itself to be a promising technique for the preparation of nanoparticles. FNP by this device is an easy, quick and reproducible method with ability to prepare nano formulations of small and controlled sizes and size distribution. These devices are versatile in optimizing its conditions to tailor the nanoparticles to the manufacturer’s desire. As discussed earlier the keys to ultrafine particles are increased supersaturation and rapid speed at which nucleation occurs. Likewise the characteristics of drug, solvent, anti-solvent, stabilizer and temperature will also play role in the formation and obtaining the desired characteristics of the nanoparticles.

4. ACKNOWLEDGEMENT:

The authors acknowledge the support by the management of Krupanidhi College of Pharmacy, Dr. Amit Kumar Das, Principal, Krupanidhi College of Pharmacy, and Dr.Khalid Imran, Head, Krupanidhi Research Incubation Centre.

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Received on 05.12.2019 Modified on 08.02.2020

Research J. Pharm. and Tech. 2020; 13(11):5583-5590.

DOI: 10.5958/0974-360X.2020.00974.9