INTRODUCTION:

Drug effectiveness is significantly influenced by solubility. It is important to take into account a drug's fundamental property of water solubility. Particularly for medications with low solubility, the pharmacokinetic profile is crucial. Drugs with limited solubility will have less active drug molecules in the systemic circulation when taken orally, which also reduces the medicine's bioavailability¹.

Solubilityis defined as the maximum content of a given drugwhich gets dissolved in a particular solvent at various parameters of pH, temperature and pressure. Dissolution of drug is a dynamic feature that is closely associated with the rate of bioavailability as compared to solubility of drug when taken in a saturated form².

Biopharmaceutical Classification System (BCS):

In order to categorize medicinal compounds according to their water solubility and membrane permeability, BCS was created in mid of 1990s³. Due to low solubility of Class IV and Class II experiences solubility obstruction, with dissolution acting to be a rate-controlling parameter in the absorption of drug⁴.

Figure 1: BCS Classification System

A variety of methods, including solid dispersion, spray drying, complexation with cyclodextrin, polymeric micelles, nanocrystals, etc., have been used to increase solubility. Undoubtedly, one of the most often used methods for improving the dissolution and solubility of non aqueous medicines is solid dispersion⁵.

What is Solid dispersion?

The term "solid dispersions" was initially used by Sekiguchi and Obi in 1961 after employing eutectic mixes to increase solubility. Chiou and Riegelmann defined solid dispersion to be a dispersion including production of combinations of eutectic nature pharmaceuticals with water soluble carriers"⁶. For producing amorphous particles, drug particle size reduction, and increased wettability all contribute to the solid dispersion approach's high level of interest in improving the bioavailability of extremely hydrophobic medicines.

A mixture of solid components that must have at least two separate elements, frequently a non aqueous drug and aqueous inert matrix or carrier and a hydrophobic medicine must be included in solid dispersions⁷. The matrix might be crystalline or amorphous. Amorphous or Crystalline particles of drug are used to disseminate it at the molecular level⁸. In order to make quick disintegration oral tablets, increase the pace at which hydrophobic drugs dissolve, hide the flavour of the drug component, and create sustained release microspheres, solid dispersion is employed⁹.

Types of solid dispersion¹⁰:

Solid dispersions can be classified by following ways:

1. Based on the carrier utilized

2. Based on solid state structure

Figure 2: Classification of solid dispersion based on the carrier utilized

Figure 3: Classification of solid dispersion based on solid state structure

Mechanism of drug release from solid dispersions^1-14:

When compared to pure medication, the dissolving rate is multiplied by many during the preparation of solid dispersions. To shed light on the mechanism underlying the augmentation of solid dispersions' dissolution, a number of ideas and theories have been proposed. However, these two seem to hold the most promise:

· Carrier-controlled release

· Drug-controlled release

Due to the hydrophilic character of the carrier, concentrated carrier layers or gel layers result from the dispersion of solid dispersions in water. The diffusion of the carrier becomes the rate-limiting step if the drug is dissolved in this layer and creates an extremely viscous barrier to prevent drug diffusion through it. If the medication is not dissolved in the aforementioned concentrated layer, it will directly come into contact with the liquid phase and be dissolved based on the particle size, solubility, and other characteristics of the drug.

Carriers used in solid dispersion:^15-18

A crucial factor in the formation of solid dispersion is the carriers. They may be water-swellable, hydrophilic, or hydrophobic. They can be utilized as release enhancers or retardants depending on their features. The nature of the carriers also affects how well medication molecules dissolve. The following are the requirements for choosing a carrier:

· It should be affordable, pharmacologically inert, and non-toxic.

· Carrier needs to be aqueous and dissolvable in a variety of solvents.

· Carrier ought to be heat-resistant.

· Compatible chemically with drug.

Table 1: carriers used in solid dispersions

Synthetic Hydrophilic carrier	Natural hydrophilic carrier	Semi-synthetic hydrophilic carrier
Mannitol	Aeglemarmelos Gum53	Chito-oligosaccharide
Polyethylene glycol (PEG) 4000	Alginate	Ethyl cellulose, hydroxypropyl methylcellulose
Polyethylene glycol 6000	Arginine	Hydroxypropyl methylcellulose (HPMC E5 LV)
Polyvinylpolypyrrolidone (PVPP)	Caffeine	Hydroxypropyl methylcellulose (HPMC E5 LV)
Polyvinylpyrrolidone (PVP)	Chitosan
Copovidone, PVP K-30, PVP K-17, PVP K-12	Soybean seeds
Sodium Acetate	Sodium alginate

Methods of solid dispersion preparation⁶:

For the preparation of solid dispersions, a number of technologies have been developed, including:

Figure 4: Method of preparation of solid dispersions

Melt Agglomeration Process:

Solid Dispersion has been created using this method, where the binder serves as a carrier. Using a high shear mixer, either drug dispersion in melted binder can be sprayed over the heated excipient, otherwise drug, binder binder, and excipient are brought to a temperature slightly over the binder's melting point. Because temperature can be more easily controlled and more binder may be added to the agglomerates, rotary processor works well as a substitute piece of machinery for melt agglomeration^19-20.

Electrospinning Method:

Solid solution/dispersion technology and nanotechnology are combined in the electrospinning technique used in the polymer sector. In this method, a liquid stream of drug/polymer solutions is subjected to a voltage of between 5 and 30kV. When electrical forces are greater than the surface tension of the drug/polymer solution at the air-liquid interface, submicron-sized fibres are produced. While the solvent evaporates, the produced fibres can be collected on a spinning mandrel or a screen to make a nonwoven fabric. Due to its simplicity and low cost, this method offers enormous potential for creating nanofibers and regulating the release of medicines. In the future, solid dispersions may also be created using this method²¹.

Spray-Drying:

The most popular method for preparing solid dispersion is spray drying. In this procedure, the solvent is removed from the medication and carrier by dissolving them or suspending them in a stream of hot air. The huge surface area of droplets provides, solvents quickly evaporate after that, and within a relatively short time, resulting in formation of solid dispersion, that is quick enough for separating phase. After the material has dried by air, the product is separated²².

Kneading Method:

Water is added to a mixture of medication and polymer, which was vigorously mixed for 30 minutes using a mortar of glass. After that the paste is allowed to dry for twenty-four hours in a vacuum. The dry powder is put through a saw sieve no. 60 and kept in desiccators until further inspection²³.

Solvent evaporation method:

This method's main objective is to simultaneously dissolve the medication and carrier in a single solvent, which is then removed by evaporation. It can be difficult to find a universal solvent that is effective for both the drug and the carrier, and it may take some time to thoroughly remove the solvent from the finished product.The solvent can be eliminated using a variety of techniques, such as heating the combination, vacuum drying, low-temperature, slow-evaporation of the solvent, rotary evaporators, freeze drying, and spray drying. Because of their high melting points, many medicines and polymers that could not be used for melting may be used for solvent evaporation²⁴.

Supercritical fluid method:

A substance over its critical pressure and temperature is referred to as supercritical fluid. The critical point is the greatest pressure and temperature at which a substance can coexist in equilibrium as a liquid and a vapour. In this method, supercritical fluid is employed to create solid dispersions of insoluble materials/polymers with medicine, increasing the drug's ability to dissolve. It is superior to standard techniques (spray drying, hot melt, etc.). Supercritical fluid like carbon dioxide is primarily employed in this process, causing very rapid solid mixture precipitation, leaving no time for separating the medication from the polymer in order to prepare solid dispersion.With a greater surface area for smooth flow and minimal remaining organic solvent, it generates very stable tiny particles²⁵.

Lyophilization:

It involves the movement of mass and heat away from and towards the product. As an alternate to solvent evaporation, the drug and carrier are mixed in a solvent system, refrigerated, and then sublimation occurs in a molecular mixing process²⁶.

Fusion/melting method:

This process involves completely melting the physical mixture of carrier and drug, following a quick molten mixture cooling. After that, the resulting solid dispersion is crushed and sieved. While cooling, supersaturation is created, but because the carrier matrix solidifies, the dispersed medication is trapped inside of it. The fusion method, which benefits thermolabile pharmaceuticals by lowering process temperature, is used when the medication is suspended in a molten carrier. High melt viscosity, which causes only partial miscibility between the medication and carrier, is a drawback of this approach²⁷.

Hot melt extrusion method:

Extruder is used in this procedure to thoroughly mix the components. The barrel, hopper, heating jacket, kneading screw, and die make up the extruder. The carrier and drug are physically combined in the hopper before being fed through the screw and extruded from the die. This process creates a product that is simple to handle since any shape can be utilized^28-29.

Direct Capsule Filling Method:

Grinding-related changes in the crystallinity of the medication are prevented by directly filling solid dispersion’s liquid melt inside hard gelatin capsules. When this molten dispersion cools to ambient temperature, it solidifies inside the capsule, minimizing risk of operator interaction in a dust-free environment and the risk of contamination. This method produced superior content uniformity and fill weight than the powder-fill method³⁰.

Advantages of Solid dispersion³¹

The solid dispersions method offers the following benefits for pharmaceuticals.

· The solid dispersion approach can improve the bioavailability and solubility of medications that have poor solubility in water.

· It is simpler in creating and are more practical.

· It causes a drug's extent and rate of absorption to rise, which causes a rapid rate of disintegration.

· The conversion of a drug's liquid form into its solid form.

· Molecular weight, structure, particle porosity, and wettability can all be controlled, which helps improve the bioavailability of medications that aren't very water soluble.

· Rapidly disintegrating oral pills are simple to make using solid dispersion.

· It increases the permeability of the medication and cover up its unpleasant taste.

Limitations of Solid dispersions³²

Solid dispersion's application in the drug formulation phase is constrained by a number of limitations, including the following:

· Demanding and expensive preparation methods

· Reproducible physicochemical qualities

· Difficulty incorporating dosage forms into formulations

· It is difficult to scale-up the preparation technique

Characterization of solid dispersions:

Various techniques have been employed for the characterization of solid dispersions³³. Like:

Figure 5: Characterization techniques of solid dispersions

Differential Scanning Calorimetry (DSC):

The basic method of DSC techniques involves measuring heat transfer by comparing a sample of test material to a reference sample. Throughout the measurement a constant rate of heating or cooling is maintained. DSC is used to identify polymeric materials based on properties like melting point, glass transition, and crystallisation³⁴. The investigation of phase transitions has a significant impact on the pharmaceutical industry. Understanding phase transitions is required for characterization of amorphous and crystalline nature of solid dispersions. The most commonly used technique for characterising the various phase transitions has been differential scanning calorimetry (DSC). Because different transformations can occur concurrently all through heating, several thermal techniques have been developed as an alternative to conventional DSC. Modulated DSC (MDSC) and temperature-modulated DSC are two calorimetric techniques (TMDSC)³⁵.

X – Ray Diffraction:

X-ray diffraction is a widely utilized technique for the characterization of crystalline structure of inorganic compounds. The resultant diffraction pattern are then compared with reference patterns to identify the crystal structure³⁶. X-ray diffraction is still being used for amorphous powders and crystalline materials in pharmaceutical industry for characterization of drug, polymorphism of drug and pseudopolymorphism³⁷. This approach is beneficial in determining the intermolecular interactions between and polymer of amorphous solid dispersions. Moreover, it can be utilised to spot structural patterns that can be used to forecast macroscopic actions in amorphous pharmaceuticals³⁸.

Transmission Electron Microscopy (TEM):

Transmission electron microscopy helps in providing high spatial resolution imaging and has lately gained popularity as an analytical tool for the investigation of amorphous solid dispersions. Unfortunately, TEM is a potentially damaging technology, particularly for organic compounds. To prevent the sample from being considerably altered during analysis, the number of electrons that are received by the sample (the electron dosage) must be managed³⁹.

Nuclear Magnetic Resonance (NMR):

Solid-state NMR is becoming more popular as a high-resolution, versatile spectroscopic tool for characterising drug substances and products⁴⁰. NMR is a quick method with a straightforward sample preparation procedure that is helpful in determining the solubility of drug in pharmaceutical formulations. However, the inclusion of other components has no bearing on the measurement of physico-chemical properties, and it may even reveal important details about how molecules behave in settings that are more like those found in in vitro and possibly in vivo research⁴¹.

Infrared Spectroscopy:

Since the IR spectrum offers a multitude of structural information, it is a widely used research method for figuring out the structure of organic substances. Recently, FTIR spectroscopy has grown rapidly, in part due to its lower cost, simplicity of usage, and speed of results⁴².

Table 2: Research Work Related to solid dispersions till date

Author (Year)	Carrier	Drug	Outcome	Ref.
Li J et al. (2022)	Eudragit® RL PO	Azithromycin	Amorphous solid azithromycin dispersions were developed to solve the problems of bitterness and limited solubility.	43
Wang H et al. (2022)	Soluplus®	Glycyrrhetinic acid	The formation of glycyrrhetinic acid-salt solid dispersion and the amide bond considerably improved the drug's solubility	44
Alwossabi AM et al. (2022)	Modified and unmodified gum of Ziziphus spina-christi	Loratadine, glimperide and furosemide	All the solid dispersion exhibited improvement in solubility with a varying degree in different pH.	45
Fouad SA et al. (2021)	Polyethylene glycol (PEG) 4000,PEG 8000, Polyvinylpyrrolidone (PVP) K25 and PVP K90	Diacerein	The relative bioavailability of solid dispersion in comparison to the standard drug was 229.52% in healthy adults and 262.02% in elderly patients, respectively.	46
Li Y et al. (2021)	PVP	Ellagic acid	The solubility of ellagic acid in water was considerably enhanced by solid dispersions.	47
Giri BR et al. (2021)	Soluplus®	Telmisartan	In vivo pharmacokinetic testing using rats with Telmisartan powder, the formulation's AUC (area under the drug concentration-time curve) and maximum blood concentration (Cmax) rose to 5.37 and 6.61 times, respectively, in contrast to the powder.	48
Wilson RV et al. (2020)	Cellulose derivatives	Enzalutamide	There was good agreement between the in vivo results and the in vitro diffusion cell tests.	49
Kim SJ et al. (2019)	Polyethylene glycols (PEGs) 4000, PEG 6000, PEG 20000	Ticagrelor	The relative bioavailability and peak plasma levels of the medicine in formulation were higher than in pure medication (Cmax).	50
Huang BB et al. (2019)	PVP K30	Emamectin benzoate	Formation of solid dispersions resulted in significant improvement in the dissolution and solubility of drug, especially the water solubility.	51
Skolakova T et al. (2019)	Polyvinylpyrrolidone	Tadalafil	All the solid dispersions were able to enhance the initial release of drug.	52
Raj AL et al. (2018)	PEG 6000	Nebivolol	There was 42-fold increase in solubility led to a noticeable improvement in the drug's release rate.	53
Song H et al. (2018)	Mannitol	Pravastatin	Solid dispersion helped in improving the disintegration as well as the dissolution of given drug.	54
Kaur S et al. (2017)	Lipoid E80S and Sodium deoxycholate	Exemestane	Prepared formulations showed better solubility and dissolution rates than pure medicines.	55
AdeliE et al. (2017)	Polyvinyl alcohol	Azithromycin	Studies on in vitro drug release revealed that the solid dispersion's rate of drug dissolution was faster than that of the intact drug.	56
Volkova TV et al. (2017)	Polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) and hydroxypropy-lmethylcellulose(HPMC)	Leflunomide (LEF)	The medication's crystallinity was decreased by solid dispersion, which also had a solubilizing impact on the substance. This accelerated the pace of dissolution.	57
Pinho LAG et al. (2017)	Plasdone and PVP	Theobromine (TB)	The rate at which the medication dissolved increased polymer dependently.	58
Albadarin AB et al. (2017)	HPMCP-HP-50 and Soluplus®	Itraconazole	Results were 10 times better than with pure medicine, according to studies on the end point of drug dissolution.	59
Santos KM et al. (2017)	PEG 6000 and PVPK 30	β-lapachone	The dissolving profile of solid -lapachone dispersions produced with PVP and PEG showed improvements.	60
Park JH et al. (2017)	sorbitan-monooleate 80 (Span 80) and polysorbate 80 (Tween 80)	Revaprazan	Each preparation significantly improved in terms of solubility, dissolution, and plasma concentration.	61

CONCLUSION:

It can be difficult to improve a drug's bioavailability when it is poorly soluble. Because the medicine has poor water solubility, it has dissolution issues that impair in vivo absorption and, in turn, bioavailability. As a result, the drug is unsuitable for oral intake, necessitating the need for solubility augmentation for such a therapeutic candidate. The most straightforward and effective method for improving a drug's aqueous solubility is solid dispersion. Further research in solid dispersion and its various aspects can prove to be significant in overcoming the different problems associated with drug delivery.

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Received on 11.04.2023 Revised on 17.05.2024

Accepted on 11.12.2024 Published on 10.04.2025

Available online from April 12, 2025

Research J. Pharmacy and Technology. 2025;18(4):1872-1878.

DOI: 10.52711/0974-360X.2025.00267

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.