A Review on Solid Dispersions: Preparation, Classification, Evaluation, Characterization and Recent Advancement.

In contemporary pharmaceutical research, one of the most persistent and critical challenges is the poor aqueous solubility of drug molecules. A significant proportion of newly developed chemical entities fall under Biopharmaceutics Classification System (BCS) Class II and Class IV, which are characterized by low solubility, with Class IV compounds additionally exhibiting low permeability. Poor aqueous solubility directly limits the dissolution of drugs in biological fluids, thereby restricting their absorption in the gastrointestinal tract. As a result, the oral bioavailability of such drugs is significantly compromised, leading to suboptimal therapeutic outcomes ^[1,2]   

The dissolution rate is a key determinant of drug absorption, particularly for orally administered formulations. Drugs with low aqueous solubility typically exhibit a slow dissolution rate, which delays their onset of action and may prevent the attainment of adequate plasma drug concentrations required for therapeutic efficacy. Consequently, higher doses are often required to achieve the desired pharmacological effect. However, increasing the dose may elevate the risk of adverse effects and toxicity, especially in drugs with a narrow therapeutic index. Furthermore, variability in dissolution and absorption can lead to inconsistent pharmacokinetic profiles, making it difficult to predict clinical responses^{[3, 4]}

Various conventional techniques have been explored to address solubility-related challenges. These include particle size reduction (e.g., micronization), salt formation, and the use of surfactants. Particle size reduction enhances the surface area available for dissolution, thereby improving the dissolution rate. Salt formation can increase the solubility of ionizable drugs; however, its applicability is limited to compounds capable of forming stable salts. Surfactants improve the wettability and dispersibility of hydrophobic drugs, facilitating better interaction with aqueous media^.[5,6]

To overcome these limitations, advanced formulation strategies such as solid dispersion have been extensively investigated. In this approach, the drug is dispersed within a hydrophilic carrier matrix, which enhances wettability, reduces particle size to a molecular level, and often converts the drug into an amorphous form. These modifications collectively improve the dissolution rate and bioavailability of poorly soluble drugs. Therefore, solid dispersion has emerged as a promising and effective technique for addressing solubility-related challenges in modern drug delivery systems ^[7,8]

Solid Dispersion

Solid dispersion is a formulation technique in which one or more active pharmaceutical ingredients (APIs) are evenly distributed within an inert carrier or matrix in the solid state. This approach is mainly used to improve the aqueous solubility, dissolution rate, and oral bioavailability of drugs that have poor water solubility. Depending on how the drug interacts with the carrier and the method used to prepare the system, the drug may exist in an amorphous state, either molecularly dispersed or as very fine particles within the carrier matrix^.[9-11]

Categorization of the Solid Dispersion

It can be categorized using two methods:

On the basis of carrier and molecular arrangement

Figure 1: solid dispersion   classification ^[11]

Categorization of Solid Dispersion based on Carrier:

Solid dispersion can be divided into four generations according on the carrier that is utilized.

Solid Dispersion of the First Generation

Crystalline carriers like urea and sugars were used to create the first generation of solid dispersions. However, the slow drug release caused by the crystalline form of the carrier materials was this generation's main drawback . ^[12-14]

Solid Dispersion of the Second Generation

This approach to preparing solid dispersions relies on amorphous rather than crystalline carriers, which are generally polymeric. Common synthetic polymers include polyethylene glycol (PEG), povidone, and polymethacrylates, while natural or semi-synthetic options encompass hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and starch-based derivatives such as cyclodextrins. ^[19-17].

Third Generation Solid Dispersion

Recent research has demonstrated that increasing solubility is possible when the carrier possesses surface activity or self-emulsifying qualities, leading to the emergence of third-generation solid dispersion. It has been demonstrated that using surfactants as carriers, such as inulin, Poloxamer 118, and Poloxamer 407, can produce high polymorphism purity and improved in vivo bioavailability.^.[18,19]

Solid Dispersion Solid of Fourth Generation

Solid dispersions of this generation are referred to as Controlled Release Solid Dispersions (CRSDs). Both water-soluble and water-insoluble carriers are utilized in this system. CRSDs' primary goals are to increase the medication's solubility and enable regulated, extended drug release. While poorly soluble or insoluble carriers slow down the drug's release from the matrix and preserve a long-lasting action, water-soluble carriers aid in quick drug release. ^[20-22,]

Molecular arrangement-based classification of solid dispersion

On the basis of molecular arrangement

Figure 2: classification on based of molecular arrangement^[22]

The following kind of solid dispersions can be distinguished: -

1. Eutectics Systems.

In this method, the two components are fused by melting and then swiftly solidified to create a homogeneous solid blend. The materials are fully miscible in the molten phase but show minimal solubility with each other in solid form. From a thermodynamic perspective, the resulting product is a physical blend of two crystalline phases. Consequently, the system involves compounds that mix completely when liquid but only marginally when solid. ^[23,24].

2. Glass Solution & Suspensions:

Glass solution and glass suspension are amorphous solid systems used to improve the solubility of poorly soluble drugs. In a glass solution, the drug is completely dissolved in the polymer and forms a single uniform phase, which gives fast dissolution and better bioavailability. In a glass suspension, the drug is not fully dissolved but present as small particles in the polymer, forming a two-phase system that shows comparatively slower dissolution but better stability. ^[23,25]

3.  Solid Solution: 

Solid solutions can be classified as either continuous or discontinuous based on the degree of miscibility between the two components. In these systems, the drug and carrier crystallize together to form a single, homogeneous phase. This uniform structure ensures that the drug is dispersed at the molecular level within the solid matrix, which significantly enhances its dissolution rate compared to eutectic mixtures.. ^[23,29].

1. 1. Continuous solid solutions:

The components of this type of solution are completely miscible in any ratio, indicating that the interactions between the two substances are stronger than the interactions within each individual component. The pharmaceutical industry does not engage with such solid dispersions.. ^[27,28].

1. 2. Discontinuous solid solutions:

Each component in discontinuous solid solutions shows a restricted degree of solubility in the other.^.[29].

1. 3. Substitutional solid solutions:

This kind of solution only happens when there is less than a 15% size difference between solute molecules and solvent particles.^[29].

1. 4. Interstitial solid solutions:

In this kind, the solute particles fit into the spaces created by the crystal lattice of the solvent. The diameter of the solute molecule must not exceed 0.59 times that of the solvent molecule..  ^[29].

4. Amorphous Precipitation in the Crystalline Matrix -  

Unlike in a eutectic system, where both the drug and carrier crystallize together, the drug can precipitate within the crystalline carrier in an amorphous form. The elevated energy of the drug in its amorphous state typically leads to significantly faster dissolution rate.^[14]

Mechanism of Solid Dispersion :

Increasing the solubility and rate of dissolution of medications that are poorly soluble in water is the main mechanism of solid dispersion.. In solid dispersions, the api  is molecularly dispersed within a hydrophilic carrier, often in an amorphous state, which prevents recrystallization and improves dissolution. The carrier increases the wettability of the drug and may act as a solubilizer, promoting better interaction with the dissolution medium. Additionally, reducing the particle size to a near-molecular level increases the surface area available for dissolution, which further accelerates the release of the drug^{. [17,30]}

Materials Used as Carriers ^(28,29)

1. Polymer carrier
   • PEG4000, PEG 6000, (Increase solubility due to hydrophilic nature, prevent aggregation.)
   • PVP (Forms amorphous dispersion & increase stability)
   • HPMC, MC (A good film former that enhance drug dissolution)
   • Eudragit E100, Eudragit L100 ,  Eudragit RL, Eudragit RS,
2. Surfactant Polymers
   • Poloxamer 118, Tween 80, Tween 60, SLS ,Pluronic F68
3. Sugar

Mannitol, Lactose, dextrose ,  Sorbitol , xytol, maltose,

METHODS

Fusion Method :  The drug and carrier are thoroughly mixed together using a mortar and pestle to ensure even distribution. To achieve a uniform solid dispersion, the mixture is gently heated to or slightly above the melting point of all components, allowing them to fuse completely. As it cools slowly, it solidifies into a hard mass, which is then crushed into smaller pieces and passed through a sieve to get fine, uniform particles. For instance, researchers have successfully sused this fusion or melt method to prepare a solid dispersion of albendazole and urea.^30]

Solvent Evaporation Method : In the solvent evaporation method, the drug and carrier are first dissolved together in a suitable organic solvent, like ethanol or acetone, until everything is completely solubilized. The solution is then allowed to evaporate slowly—often under reduced pressure or gentle heating—to remove the solvent entirely. The remaining solid residue is ground into a fine powder, sieved to achieve uniform particle size, and dried thoroughly to eliminate any traces of moisture. For example, a solid dispersion of furosemide with Eudragits has been effectively prepared using this technique.^.[31-34]

Super Critical Fluid Method : The supercritical fluid method is an advanced technique used to prepare solid dispersions to improve the solubility and bioavailability of poorly water-soluble drugs. In this method, a supercritical fluid, most commonly supercritical carbon dioxide (CO?), is used as a solvent or antisolvent. The drug and polymer are first dissolved in an organic solvent and then introduced into a chamber containing supercritical CO?. The supercritical fluid rapidly removes the solvent, causing the drug and polymer to precipitate together and form fine particles. This rapid precipitation often results in the formation of an amorphous solid dispersion, which enhances the dissolution rate and stability of the drug. The method is advantageous because it operates at relatively low temperatures, produces particles with small and uniform size, and leaves minimal residual solvent. However, the technique requires expensive high-pressure equipment and some drugs show limited solubility in supercritical CO^?.[35-36]

Kneading Method : In this kneading or moistening technique, the carrier is first moistened with a small amount of water (or another solvent) to create a thick paste. The drug powder is then evenly incorporated into the paste and kneaded rigorously for a specific period, usually 30-60 minutes, to ensure uniform distribution. Once kneading is complete, the wet mass is dried in an oven or at room temperature, and if necessary, it's passed through a sieve to obtain fine particles of the solid dispersion^.[37,38]

Co-Grinding Method :  The drug and carrier are first physically mixed and blended for a set time at a controlled speed. This blend is then loaded into a vibration ball mill chamber with steel balls for thorough pulverization. Once milling is done, the resulting powder is collected and kept in a screw-capped glass vial at room temperature until use. For instance, a solid dispersion of chlordiazepoxide and mannitol has been successfully prepared this way.^.[39,31]

Freeze-Drying Method: In this method, the drug and carrier are first dissolved in a common solvent, and the solution is rapidly frozen by immersing it in liquid nitrogen. The frozen mass is then dried using lyophilization (freeze-drying). This technique is considered effective for incorporating drug molecules into a stabilizing matrix, but it is not widely used for preparing solid dispersions because it is expensive. The main advantages of freeze-drying are that the drug is exposed to very low thermal stress during the process, and the chances of phase separation are greatly reduced^.[39-40]

Gel Entrapped Method

The carrier, which tends to swell, is first dissolved in an appropriate organic solvent to create a clear, transparent gel. Next, the drug is incorporated into this gel through sonication for a few minutes. The organic solvent is then removed by evaporation under vacuum. Finally, the resulting solid dispersions are pulverized using a glass mortar and passed through a sieve to reduce particle size^.[42,43]

Marketed Product  ^[17]

Table no. 1

Evaluation And Characterization of Solid Dispersion .

5.   Bulk density

Bulk density, also known as apparent density, untapped density, poured density, or loose bulk density, is measured using a bulk density apparatus. The apparent bulk density is determined by carefully transferring the powder mixer into a graduated cylinder without disturbing its natural packing. The bulk volume and mass of the powder are then recorded. Bulk density is calculated by dividing the mass of the powder by its bulk volume

bulk density (ρb

where M

5. Tapped Density

Tapped density is the density of a powder measured after it has been mechanically tapped or compacted. During tapping, the powder particles rearrange and occupy less space by reducing the void spaces between them. It is calculated by dividing the weight of the powder by its tapped volume. Tapped density helps in understanding the packing ability and compressibility of the powder, and it is commonly used along with bulk density to evaluate flow properties.^[45]

5. Carr's Index %: -

It is sign of the compressibility of powder. It is expressed in %. It  is calculated  using data of bulk and tapped density^.[46

5. Hausner ratio

Hausner ratio indirectly evaluates powder flow properties by comparing how much a powder settles under tapping. It is computed as tapped density divided by bulk density.[46]

5. Drug content: -

Drug content analysis is carried out by diluting the formulations in the proper concentration after dissolving them in an acceptable solvent. Finally drug content is measured by using a suitable analytical method^.47]

5. In-vitro drug release study: -

The United States Pharmacopoeia (USP) type II paddle dissolution equipment is used to assess drug release from tablets. Five milliliters of the dissolution media are removed and replaced with an equivalent volume of new medium at prearranged intervals. The gathered samples are filtered, appropriately diluted, and subjected to a suitable analytical technique. Drug concentration are determined with the help of a standard calibration curve ^[48,].

5. Differential Scanning Calorimetry (DSC) –

This test checks if the drug is crystalline (less soluble) or amorphous (more soluble) by heating it. If a sharp peak is seen in the graph, the drug is still crystalline. If no peak is seen, the drug has become amorphous, which is good for solubility.   If a drug melts at fixed temperature but no peak appears in the solid dispersion, it means it has changed to an amorphous form, improving solubility^.  this method are used to provide the information about melting point, glass transition temperature and energy changed during phase transition comprising melting process and crystallization.  ^[49,50]

5. X-Ray Diffraction (XRD) –

This method checks the drug remains crystalline or turns amorphous. Sharp peaks in the graph appear the drug is still crystalline. No sharp peaks (just broad humps) appear the drug has become amorphous and will dissolve faster.  If the drug powder shows sharp peaks but the solid dispersion does not, it confirms amorphization.[^50]

5. Fourier Transform Infrared Spectroscopy (FTIR) –

FTIR technique is used to identify carrier &drug compatibility and intermolecular interaction because it dectect the physical and chemical rxn  between carrier sand drug . FTIR is used in solid dispersion  to see  the drug and carrier chemically react or just mix. If the drug’s chemical bonds change, new peaks will appear, indicating interaction. If the peaks remain the same, it means the drug is only physically mixed^{. [51,52]}

5. Dissolution Calorimetry :

It evaluates the heat change that occurs during the dissolution process, which is influenced by the crystallinity of the sample. Typically, crystalline substances dissolve with absorption of heat (endothermic),  amorphous materials release heat during dissolution (exothermic).^[53]

5. Scanning Electron Microscopy (SEM)

Scanning Electron Microscopy (SEM) analysis of solid dispersions shows distinct morphological changes, where pure crystalline drugs exhibit defined crystal habits, while dispersions display amorphous, fused particles indicative of molecular dispersion in carriers^.[54]

Recent Advancement of solid dispersion formulation.

Integration of Continuous Manufacturing Of Solid Dispersion

Continuous manufacturing (CM) is an advanced pharmaceutical production system of  in which raw materials are continuously introduced into the process and the finished product is obtained without interruption. Unlike traditional batch manufacturing, where each step such as mixing, granulation, drying, and compression is carried out separately, continuous manufacturing integrates multiple unit operations into a single streamlined process. This integrated approach improves efficiency, product consistency, and overall process control^.[54]

In the preparation of amorphous solid dispersions (ASDs), continuous manufacturing plays a significant role in maintaining uniform drug distribution within the polymer matrix. The properties of ASDs, such as amorphous state formation, drug–polymer miscibility, and physical stability, are highly sensitive to processing conditions. Continuous systems allow precise control over critical parameters such as temperature, screw speed, feed rate, pressure, and residence time. As a result, the risk of drug recrystallization and content variability is reduced and this whole process is controlled by process analytical technology [pat]. In amorphous solid dispersions, technologies like hot-melt extrusion (HME) , kinetisol technology and spray drying are adapted for continuous processing. meloxicam amorphous solid dispersion is created by holt melt extrusion method of continuous system without using solvent. felodipine amorphous solid dispersion is also created with the help of holt melt extrusion techinique. ritonavir is formed with help of the of kinetisol  method. ^[55-60]

Role of pat technology in continiouos  manufacturing system

Process Analytical Technology (PAT), introduced by the U.S. Food and Drug Administration, represents a major advancement in amorphous solid dispersion (ASD) manufacturing. It supports the shift from batch to continuous production by enabling real-time monitoring and control of processing parameters.

In ASD manufacturing, PAT tools monitor Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs) to ensure consistent product quality. Raman spectroscopy is used for confirming the amorphous state and drug–polymer miscibility, while Near-Infrared (NIR) spectroscopy helps control moisture content to prevent recrystallization. During Hot Melt Extrusion, in-line UV–Visible spectroscopy allows rapid monitoring of drug uniformity. The integration of PAT with continuous manufacturing improves process understanding, reduces production time, and supports real-time release testing. Therefore, PAT-assisted continuous manufacturing is considered an important recent advancement in solid dispersion technology^.[61]

Advanced methods are used for preparation solid dispersion under the continuous system.

Holt melt extrusion

Hot melt extrusion is a method used to prepare solid dispersions by melting and mixing the drug with a polymer carrier. In this process, the drug and polymer are fed into an extruder, where heat and mechanical shear are applied to melt and mix them thoroughly. The molten mixture is then pushed through a die to form a uniform product, which is cooled and solidified.

This method does not require the use of solvents, making it safer and more environmentally friendly. It provides uniform drug distribution and can improve solubility and bioavailability. However, it is not suitable for heat-sensitive drugs, as high temperatures may cause drug degradation. HME can also reduce manufacturing steps when combined with in-line monitoring tools such as Process Analytical Technology (PAT), which helps track critical parameters like temperature, torque, and drug distribution.^[64-66]

Sparay drying

Spray drying is a commonly used solvent-based technique for preparing amorphous solid dispersions (ASDs). In this method, the drug and polymer are dissolved together in a suitable  solvent to form a homogeneous solution. This solution is then sprayed through a nozzle into a drying chamber, where it is converted into fine droplets. As these droplets come in contact with hot drying air, the solvent evaporates very quickly, and solid particles are formed. Because of the rapid solvent removal, the drug becomes trapped within the polymer matrix in an amorphous state^.[67] The fas drying process reduces te chance of drug crystallization and helps maintain a uniform molecular dispersion. Spray drying can produce particles in the micro-size, which increases the surface area and improves the dissolution rate of poorly water-soluble drugs. It also allows good control over particle size, morphology, and residual solvent content^.[67] This technique is particularly suitable for thermolabile drugs because the exposure time to heat is very short, even though warm air is used during drying. Additionally, different polymers can be selected to enhance physical stability and maintain supersaturation after dissolution^.[68] Recent advancements in spray drying include the development of closed-loop systems for efficient solvent recovery, continuous spray drying for large-scale manufacturing, and improved nozzle designs for better particle uniformity. Due to these improvements, spray drying remains one of the most important and scalable methods for manufacturing solid dispersions. ^[69,70]

Marketed product is formed by spray dring process[14]

Table no .2

Electrospraying  technology

Electrospraying is a technique used to prepare solid dispersions in which a drug and polymer solution is subjected to a high electric voltage, producing fine charged droplets that quickly dry to form solid particles. The drug becomes uniformly dispersed in the polymer, usually in an amorphous form, which enhances solubility and dissolution rate due to the small particle size and large surface area. However, this method requires specialized equipment, often involves the use of organic solvents, and can be difficult to scale up for industrial production.^[71-74]

Precipitation method

Co-precipitation is an effective method for preparing solid dispersions of poorly water-soluble drugs, especially those that have low solubility in commonly used organic solvents and high melting points, making them unsuitable for melting or conventional solvent techniques.In this approach, both the drug and the carrier are first completely dissolved in a suitable organic solvent. This solution is then added to an anti-solvent, which leads to the simultaneous precipitation of the drug and the carrier. The formed suspension is filtered and washed to remove any remaining solvent. After filtration and drying, the obtained product is known as microprecipitated bulk powder (MPD), which represents a solid dispersion of the drug within the carrier matrix^.[75,76]

Polymers used in the co-precipitation method generally show pH-dependent solubility. Common examples include polymethylacrylate, polymethylmethacrylate, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinyl phthalate, and cellulose acetate phthalate. Strong organic solvents such as dimethylacetamide, dimethylformamide, and N-methyl pyrrolidone are often selected because of their high dissolving capacity, particularly for polymers with high molecular weight.A major advantage of the co-precipitation technique is that it does not require high processing temperatures, which minimizes the risk of heat-induced degradation of the drug or the carrier. The method can also utilize less volatile organic solvents, which can be effectively removed from the final product. Additionally, co-precipitation is suitable for large-scale manufacturing.^[77,78]

Another Advanced Method are Used in Preparation of Solid Dispision.

Kinetisol Technique

It is an advanced manufacturing technique originally developed in the plastics industry and later adapted for pharmaceutical applications to improve the solubility of poorly water-soluble active pharmaceutical ingredients (APIs). It is a fusion-based method that uses intense frictional and shear forces to quickly convert a drug–polymer mixture into a molten state.During this rapid melting process, the API and excipient carrier are mixed uniformly at the molecular level, resulting in the formation of a single-phase amorphous solid dispersion (ASD). Commonly used polymers in this process include Carbopol, Eudragit, HPMC, HPMCAS, copovidone, PVA, PVP, and Soluplus®.^[79,80]

In this technique, the powdered drug–polymer blend is first placed into a processing chamber, which is then tightly sealed. Processing conditions are set in advance through a computer-controlled system. Inside the chamber, rotating blades generate heat through shear and friction. This heat melts the powder trapped between the blades and the chamber wall, forming a uniform molten mass.The molten material is immediately expelled into a cooling (quenching) zone, where it solidifies into an amorphous flat disk. These solidified disks are then milled into granules of the required particle size. Finally, the granules are either compressed into tablets or filled into capsules to produce the finished dosage form.^[81]

Suba^tm Technology

SUBA technology is designed to improve the oral bioavailability of poorly water-soluble active pharmaceutical ingredients. This technology was originally developed by Mayne Pharma USA.The primary aim of SUBA technology is to enhance the absorption of drugs after oral administration. It helps increase bioavailability, reduce the required dose, and minimize differences in drug response between and within patients. In addition, it allows for a more predictable clinical effect based on the administered dose and ensures that effective therapeutic drug levels are achieved in the bloodstream. The novel SUBA^tm process produces amorphous Itraconazole dispersed in a polymer matrix instead of a conventional crystalline form, marketed as TOLSURA® in the US.^[82]

 This method applies spray-drying with an enteric polymer to enhance the solubility of the active ingredient in the gastrointestinal tract, thereby achieving improved or “super” bioavailability compared to conventional formulations. In this process, the API is spray-dried with a novel amorphous pH-dependent enteric polymer hydroxypropyl methylcellulose phthalate (HPMC phthalate).[83] Unlike traditional itraconazole formulations, TOLSURA does not dissolve in the acidic conditions of the stomach. Instead, it becomes soluble at the higher pH of the small intestine, which enhances drug absorption and overall bioavailabilityTop of FormBottom of Form

Adoption of  3d Printing Technology 

3D-printed dosage forms have received significant attention after the approval of the first 3D-printed oral medicine SPRITAM tablet(levetiracetam) developed by Aprecia Pharmaceuticals. This approval marked an important milestone in pharmaceutical manufacturing. Three-dimensional printing (3D printing or 3DP) has brought a major change in the development of personalized dosage forms, allowing medicines to be designed according to individual patient needs.3D printing is an advanced manufacturing technique that converts digital 3D computer models into real physical products using an additive process (layer-by-layer fabrication^).[82,]

The most commonly used techniques for preparing amorphous solid dispersions (ASDs) include direct powder extrusion, selective laser sintering (SLS), 3D inkjet printing, and fused deposition modeling (FDM). These technologies are especially suitable for ASD preparation because their processing conditions naturally support the formation of amorphous systems. In particular, SLS and FDM are widely used and well-established methods for producing ASDs. During processing—often involving thermal or laser-assisted fusion—the drug is dispersed within the polymer matrix in an amorphous state, which can enhance dissolution performance while maintaining structural integrity^.[82,85]

Selective Laser Sintering

Selective Laser Sintering (SLS) is a 3D printing technique that uses a laser to join small powder particles and form a solid object. In this method, a thin layer of powder is first spread evenly on a platform using a roller. Then, a laser beam moves in a pre-designed pattern (based on the final product design) and heats the powder. The temperature is kept slightly below the full melting point, so the particles fuse together and form a solid layer.After one layer is completed, the powder bed moves down by one layer thickness. A new layer of powder is spread on top, and the laser again fuses the particles. This process is repeated layer by layer until the complete 3D object is formed.The unused loose powder around the object acts as support during printing. Once printing is finished, the object is allowed to cool inside the printer. Finally, the solid product is removed from the loose powder manually or by sieving. This method does  not  require any solvent^.[86,87]

Fused Deposition Modelling

Fused Deposition Modeling (FDM), is one of the most commonly used 3D printing techniques. In this method, drug-loaded thermoplastic filaments are first prepared. These filaments are placed inside the printer. The printer heats the filament to a specific temperature until it melts. The melted material is then pushed out through a small nozzle. The printhead moves in a fixed pattern and deposits the melted material layer by layer on the printing platform. After the first layer is formed, the platform moves slightly downward to make space for the next layer. The new layer is placed on top of the previous one. As the material cools, it becomes solid and sticks to the layer below. This process continues until the final 3D object is formed. The temperature of the printhead can be controlled, so different polymers and polymer mixtures can be used.[^88]  the filaments used in FDM are usually prepared by a method called Hot Melt Extrusion . In this process, the drug is mixed with a polymer and other excipients. The mixture is placed inside a heated barrel that contains a rotating screw. The screw moves the material forward while heat and pressure melt and mix it properly. The melted mixture is then pushed out through a small opening. After coming out, it is cooled and becomes hard, forming a solid filament.This filament is later used as the feed material in the FDM printer^.[89]  .

Direct Powder Extrusion

Recently, an improved version of FDM was developed that removes the separate Hot Melt Extrusion (HME) step. This new method is called Direct Powder Extrusion (DPE).In DPE, powder or pellets containing the drug and polymer are directly fed into the printer. A single screw inside the printer pushes the material forward. Heat and pressure melt the mixture, and it is forced out through a nozzle to print the object layer by layer. In this method, extrusion and 3D printing happen at the same time in one step. Because of the heat and mixing during the process, the crystalline form of the drug can change into an amorphous form, which may help improve drug solubility and performance^.[82]

Ternary solid dispersion

ATSD is an advanced solid dispersion system in which the active pharmaceutical ingredient (API) is uniformly dispersed in two different excipients in the solid state. This strategy is specifically designed to address major challenges associated with poorly water-soluble drugs, such as low dissolution rate, limited bioavailability, and physical instability. In conventional amorphous solid dispersions (ASDs), drugs may recrystallize during storage which significantly reduces their solubility and therapeutic performance. ATSD provides a more robust and stable alternative to overcome these limitations.In this system, a third functional component such as a polymer, surfactant, or another compatible excipient is incorporated in the formulation. This component enhances drug solubility and long-term stability by forming strong intermolecular interactions with the drug molecules. These interactions help maintain the drug in an amorphous or stabilized state, reduce molecular mobility, and prevent recrystallization. As a result, ATSD significantly improves dissolution behaviour, enhances stability, and ensures better and more consistent pharmaceutical performance^.[90,91]

Component of Ternary Solid Dispersion And Classification.

1.Drug+ Polymer +Surfactant

In ternary solid dispersions (TSDs), a poorly water-soluble drug is dispersed in a polymer matrix along with a suitable surfactant. The surfactant may be cationic, anionic, or non-ionic. It helps improve the interaction between the drug and the polymer, ensures better dispersion of the drug in the system, and enhances adsorption. In some cases, the surfactant works together with the polymer in a synergistic manner to further improve the drug’s solubility, stability, and overall performance. Sometimes, the surfactant forms a thin layer around the drug particles, which helps increase dissolution when the formulation comes into contact with the dissolution medium. Commonly used surfactants in the preparation of TSDs include TPGS, Poloxamer 407, and Tween80^.[92]

Table no.3 TSD system  with added surfactant^.[90]

2. DRUG+POLYMER +POLYMER

In this system, poorly water-soluble drugs are dispersed in two different polymers. Adding more than one polymer changes the physicochemical properties of the formulation and improves the performance of the amorphous solid dispersion. This leads to better stability, improved wettability. Hydrophilic polymers such as HPMC and polyvinylpyrrolidone (PVP) are commonly used in ternary solid dispersions (TSDs). These systems usually contain a combination of drug and polymers to enhance solubility and overall drug performance^.[93]

Table no.4 TSD system  with added polymers.

However, some studies have shown that adding a third polymer to the drug–polymer system can further improve the stability of the formulation. The stability of this system depends on the chemical nature and structure of the drug and the polymers. In this approach, a third polymer is added as a bridging polymer to the binary solid dispersion (drug + polymer). This third polymer can form hydrogen bonds or other strong intermolecular interactions with both the drug and the first polymer. These interactions help to stabilize the amorphous form and reduce the chance of recrystallization.For example, a solid dispersion of griseofulvin with PVP was found to be unstable because they were not enough non-covalent interactions between the drug and the polymer to maintain stability. however, by adding the third polymer PHPMA, which can form hydrogen bonding with the griseofulvin and PVP, a more thermodynamically stable system of ternary solid dispersion was formed.[^96,99]

3. Drug +Polymer +Excipient         

In this system, polymers and excipients are incorporated to assist in the formulation of poorly water-soluble drugs. These additives perform several functions, such as acting as alkalizing agents, processing aids, or stabilizers. In ternary solid dispersion (TSD) systems, excipients are also used to overcome the limitations of hydrophilic polymers at specific pH conditions.

Table no.5 Tsd with added excipient.