There has been a drastic and vast range of complications that is involved in marketing of novel pharmaceutical substances and acknowledges of the therapeutic benefits of controlled drug delivery, greater attention has been focused on development of sustained or controlled release drug delivery systems. Reducing the frequency of dosing or increasing the medication's efficacy by localization at the site of action, lowering the dosage needed, or ensuring consistent drug administration are the main objectives when creating a sustained or controlled delivery system. Although the dependency on the polymer-based matrix formulations have exceeded in recent times and has made Successful fabrication of sustained release products is often challenging in pharmaceutical formulations considering various factors, encompassing  the properties of the drug, the desired release profile, and the specific requirements of the formulation. There are many advantages as well as disadvantages of completely relying on the polymer-based formulation but sintering offers a synergistic effect in preparing a dosage form. In pharmaceuticals, sintering has been used to produce porous drug delivery systems, such as microspheres or scaffolds, and drug-eluting stents. The process can help control the pore size and distribution in these systems, which is important for drug release kinetics. Both sintering and polymers have their own merits and demerits, and the decision frequently depends on the particular needs of the drug and the desired therapeutic outcomes.  Sintering is described as the process of increasing the mechanical strength of the powders or granules by enhancing the association of adjacent particles in a mass of powder, or solidifying or consolidating by the application of heat and pressure at the time of tablet compression1,2,3,4,5. Conventional sintering entails heating the compact at a temperature below the melting point of the solid constituent in a controlled atmosphere under air pressure 6 . There has been Substantial Research and development that has been carried out on the evolution of sintered matrix tablet technology in pharmaceutical production. Where, it has wide range of pros than the cons when compared to polymer dependent matrix tablet technology 3,6. In detail, the considerations of choosing the sintering technique over using polymers are Porous Matrix Structure; Sintering creates a porous matrix structure within the tablet, allowing for controlled drug release. This porous matrix can be advantageous in achieving sustained release profiles without the need for external polymer coatings 2,3 and also Reduced Dependency on Polymers; Certain medications may not be suitable for encapsulating in polymer matrices due to chemical instability or compatibility. Sintering provides an alternate approach that does not rely on polymers, possibly avoiding problems with drug-polymer interactions2.Heat-Sensitive Drug Compatibility Challenges; Certain medications are heat-sensitive, which makes conventional sintering difficult. No Need for Polymer Coating; Sintering may provide a stable matrix that protects the drug from external stimuli and may ultimately lead to an improvement in the stability of the drug. For drugs which are vulnerable to degradation, this may be essential 2,7,8. Easy-to-Make Formulation; Sintered matrix tablets can be produced with a reasonable base composition, often including only a few excipients and drug granules. For some drugs, this simplicity can be useful because it eliminates the need for complex polymer-based 9,10. Enhanced Drug Stability; Sintering might provide a stable matrix that protects the drug from external stimuli and could ultimately make the drug more stable. For drugs that are prone to degradation, this may be essential 3,8. However, modified sintering processes, such as microwave or laser sintering, may allow for the processing of heat-sensitive drugs without compromising their stability and Microwave sintering has been used in the pharmaceutical industry for the production of tablets with controlled porosity and the potential for personalized medicine7,11,12 . Ease of Scale-Up; Sintering is a proven manufacturing technology that can be scaled up for large-scale production. This scalability may be helpful for the commercial manufacture of prolonged release formulations 1,5. Material properties; Sintering allows for high purity, uniformity, and the ability to form complex shapes, making it suitable for manufacturing high-melting-point metals. Polymers, on the other hand, offer low weight, corrosion resistance, and good insulation properties. Manufacturing process; Sintering involves heating materials below their melting point, while polymers are shaped into desired forms using various techniques such as injection moulding, extrusion, or lamination 13. Sintering is a green technology with low material waste and good energy efficiency. Polymers, depending on the type, can be more affordable than sintered materials, and some polymers are biodegradable, contributing to sustainability efforts. Although sintering has not been widely used in the manufacture of pharmaceutical products. Due to some reasons like Prolonged exposure to high temperatures during sintering may cause thermal decomposition of some drug molecules, affecting the stability of pharmaceutical products and another main concern about this technology is Material Waste and Safety Concerns: The sintering process can generate fine powder, posing potential respiratory and explosive hazards, and resulting in higher material waste compared to other manufacturing methods3,7.

IDEAL CHARACTERSTICS OF SINTERING TECHNIQUES IN PHARMACEUTICALS

Particle size and distribution :

A limited range of particle sizes and constant particle size can assist ensure consistent sintering and improve the overall quality of the product. The particle size distribution can impact the packing density of powders as well as the sintered density of the finished product. Research has demonstrated that using bimodal powder mixes enhances powder packing when compared to components printed with Mono sized fine powders 7.

Sintering temperature and time :

The sintering temperature and duration have a considerable influence on pharmaceutical sintering techniques. The sintering temperature impacts the final product's surface shape, microstructure, degradability, and drug release qualities. Thermal sintering is the process where the compressed tablet is open to high heat, which is usually more than the glass transition temperature leading to altering and strengthening the mechanical bonding. Ultimately due to stronger bonding of the matrix it manages sintering temperature and duration and improvises release kinetics and tablet characteristics. Increased sintering temperatures and durations can lead to Abnormal size of the powder and deformation in addition to improving densification and strength 14.

Environment factors:

This plays a significant role in the process of sintering as the temperature alters the bond strength of the tablet also others factors like chemical reactions such as oxidation, reduction, and other undesirable processes which might impact on the quality of the product. The atmospheric changes or the moisture exposure can be prevented also the  chemical reactions can be managed by close monitoring of the end product.

Cooling temperature:

As the temperature is significantly increased for increasing the mechanical strength, after a period of time it should be cooled. The cooling temperature impacts on the microstructure and characteristics of the sintered tablet. The cooling of the process is proportional to minimal cracking and deformation but Efficiency can be increased and sintering time shortened with a faster cooling rate.

Post sintering factor:

Sintering is mainly based on the temperature control and depends on cooling and increasing the temperature. So, the temperature will directly impact density, hardness, microstructure, and tensile characteristics of sintered steel. i.e. In the case of wax matrix tablets 15, sintering at varying temperatures and periods can cause variations in surface qualities , wax matrix structure and drug release profiles. post-sintering processes have increased the tablets hardness and density and sintering the tablets could've caused wax to melt and redistribute throughout the matrix, perhaps changing the nature of the pores. In order to achieve the best drug release kinetics, pharmaceutical sintering operations must carefully control post-sintering treatments.

Binding agent :

A material or substance that, via mechanical, chemical, adhesive, other cohesive methods, holds or attracts other materials together to form a cohesive whole is called a binder or binding agent. It plays a major role in the manufacturing of the tablet in sintering process where it can affect its density, strength, and surface finish. Binders are added to the formulation to enhance the binding capacity and obtain a desired shape of the tablet. They also reduce or minimize the porosity in the sintered tablet leading to increase in longevity and strength of the tablet. Binders, still may increase both the temperature and the amount of time required for sintering in order to get the right final product properties.

Lubricants :

These are included in the powder mixture to lessen friction and enhance the powder's flowability during compaction. They can also aid to lower the amount of force necessary to extract the compacted powder from the mold, extending the life of the equipment. But using lubricants can also cause the sintered product to become more porous, which can be detrimental to its strength and longevity.

FORMULATION

Sintering is one of the most effective methods in prolonging the release of the drug. To stabilize and delay the release of medication, sustained-release (SR) matrix tablets are made by the sintering process. The process entails the fusing of particles or the development of welded links amongst particles of a polymer, which enhances cross-linking between the particles Two approaches are available for achieving sintering: solvent casting and thermal processing. The required characteristics of the tablet, such as its hardness, friability, density, and floating qualities, determine which material is used to make sintered tablets. For example, eudragit S-100 is a commonly used polymer for sintered matrix tablet 8,16,17.

There are prominently 7 techniques:

 Thermal Sintering is defined as the bonding of adjacent particle surfaces in a mass of powder, or in compact, by the application of heat. The thermal sintering method involves exposure of the polymer matrix to the temperature above the glass transition temperature of the polymer offers several properties like Strengthening of mechanical properties, Solid matrix formation during tablet compression, Elimination of shrinkage, no need for additional binders3,17 and the procedure starts by taking sufficient  quantity for a batch of tablets and the powders are mixed thoroughly to ensure complete mixing. Tablets containing drug are compressed to an applied force of 500-kg/cm?2; and compression time of 11 sec using 11 mm round, flat and plain punches and the produced tablets are sintered at varying temperatures like 60, 70 and 80° for over 1.5, 3.0 & 4.5 hours in constant temperature ovens. The temperature of ovens was maintained within a degree Celsius18.

Solvent casting sintering

 This process helps to sinter the tablets by exposing them to acetone vapor, which dissolves the surface of the polymer particles and allows them to fuse together. The tablets are then dried to remove any remaining acetone and stored in a desiccator to prevent moisture-related degradation. The process of sintering tablets using acetone vapor goes as follows; to begin with, the lower part of the desiccator is saturated with acetone and the desiccator environment is maintained. Next, the compressed tablets are placed on the mesh which is present in between the lower and upper chamber of the desiccator and is sealed from the outside so that there is no influx of air inwards. In here,  the acetone vapor enters into the pores of the compressed tablet and dissolve the surface of the polymer particles, causing them to fuse together and sinter.  Later, After the exposure of the acetone vapours (1.5, 3.0 & 4.5 hours). Then, the tablets are removed from the vacuum desiccator and dried fir 24 hours to evaporate the leftover acetone and the tablets are segregated into the batched and followed by thermal treatment at different durations. Then, the tablets are dried at 300°C over fused CaCl2 solution for 22-24 hours to remove any residual acetone. Finally, The sintered tablets are kept in the same desiccator to maintain low humidity environment for more studies 3,7,19.

Selective laser sintering

It is a powder-based three-dimensional printing process that employs the use of lasers to fuse multiple layers of material into a finished item. It is a highly effectual sintering technique. Numerous medication dosage forms, particularly high-dose controlled release pharmaceutical dosage forms, have been engineered using SLS. Due to their intrinsic porosity and loose structure, three-dimensional in nature (3D)-printed tablets made using powder-based printing methods like selective laser sintering (SLS) usually melt and release the medication in a matter of minutes. The development site & the powder canister are first heated to a temperature that's, in a sense, slightly below the dissolving point of the polymer. A very thin layer of powder is applied to the building platform before a re-coating blade is built. Whenever a re-coating blade is originally built, the building platform is coated with just a small amount of powder. Next, the polymer powder fragments are selectively sintered. That is, the particles are fused together by a Co2 laser. This process is repeated whilst scanning his contours in following levels. After applying finishing touches to each layer, lower the construction platform and paint the surface again with the blade. This process was continued until the item had fully developed by the time it was completed. Following the printing process, the components are completely covered with powder that has not yet been sintered. The powder bottle must be allowed to cool until the pieces may be unpacked. It's possible that the cooling process will take up to 12 h to 12 h. After that, the Items that have been SLS printed are ready for use, and this can be achieved by blasting or cleaning with compressed air, depending on whether additional post-cleaning is required 20,21,22.

Spark plasma sintering

It is a kind of sintering process which produces dense and consistent bulk materials from powders. Pulsed direct current (DC) and uniaxial pressure are delivered to the powder within a die. The DC current flows through the powder, generating a plasma discharge between the particles, which results in fast heating and sintering. SPS is frequently done in a vacuum or regulated environment so as to intercept oxidation & maintain purity. Pressure, Temperature and heating rate can be accurately governed during the process, allowing for the production of materials with unique microstructures and characteristics23,24. In summary, SPS offers several advantages over traditional sintering methods, including faster heating rates, the application of pressure, a controlled atmosphere, reduced energy consumption, and increased versatility 25.

Liquid-state sintering

It happens anytime a liquid-state is found in the fine powder complex while sintering, whereas solid-phase sintering takes place when the powder compact gets fully consolidated above the temperature of sintering. Other sintering methods, including transient liquid state sintering and viscous flow sintering, can also be employed in addition to solid state & liquid state sintering.

Viscous flow sintering

It takes place when a volume fraction of a fluid is large enough to allow a viscous flow of grain-liquid combinations to accomplish the whole the densification process of the compact without causing any alterations in grain form while densification. Plastic flow takes over as the main mass-transport mechanism, when sintering is done with pressure, especially occurs during a hot-pressing procedure. Liquid state and solid-phase sintering are combined in transient liquid phase sintering. With this sintering method, Initially a liquid phase appears in the compact, but as the sintering process goes on and the densification takes place in the solid state, the liquid phase evaporates 7,14. The above are some of the majorly followed sintering technique in the formulation of Matrix tablets and also have shown a significant progress in the pharmaceutical industry.

THE SINTERING IN PHARMACEUTICAL COMPACTS

Effect on Microstructures

There are various stages to the structural changes which occurs within a compact during sintering. Some events may occur at the same moment. It is demonstrated in five different stages

Interparticle Bonding

 The movement of molecules during particle contact creates physical bonds and grain boundaries. The earliest bondings occur swiftly.

Neck Growth

 Continuous material transit creates a noticeable "neck" between particles. At this time, the compact's strength has increased significantly.

Pore-Channel Closure

 As the neck grows, certain pore channels close, resulting in isolated pores inside the compact.

Pore Rounding

 As neck development advances, material movement from the bulk to the neck regions smoothens the pore walls. This step enhances the compact's toughness.

Pore Shrinkage

 As sintering continues, the pores in the compact diminish in size and quantity. This allows for additional densification. During this step, materials are transported extensively and voids in the compact are eliminated 2,26,27.

Effect on Dissolution rate

When the disintegration forces are more than the binding forces within the tablet, the tablet disintegrates in water. The disintegration time (or pace at which a tablet breaks down) is determined by the respective strengths of these two forces. The impact of sintering on the disintegration time of acetaminophen and oxytetracycline tablets was investigated by Pilpel and Esczobo. They found that tablets made at a higher temperature had longer disintegration times and higher tensile strengths 28 .Ando et al. additionally verified that ethyl amino benzoate prolonged the disintegration period of tablets upon sintering.4 They explained this increase by pointing to the tablet's improved tensile strength during sintering. Li studied how sintering affected the tensile strength and disintegration time of ibuprofen tablets with a "super-disintegrate," Ac-DI-Sol(An internally cross-linked sodium carboxymethyl cellulose, Ac-Di-Sol is a hydrophilic, thus insoluble polymer that supports quicker medication breakdown and disintegration by having good water absorption and swelling characteristics .After sintering, tablets' tensile strength and disintegration time increased. Sintering mostly affects the dissolving rate of formulations. Eudragit RL100 matrices' drug release characteristics were significantly altered by sintering time. The release rate of rifampicin was shown to be inversely linked to sintering time. This might be attributed to increased sintering, which compacts the bulk and affects medication release . The study found that heat treatment causes polymer chain displacement and redistribution in the tablet matrix structure, resulting in prolonged drug release. The heat treatment caused the polymer to melt and resolidify, resulting in a redistribution of the polymer throughout the matrix as well as probable altering the character of the pores within the matrix 2.

APPLICATIONS

There is a wide range of applications using sintering techniques which are explained in brief below;

3D Printing of Pharmaceuticals

 A powerful laser is used in the 3D printing process known as "selective laser sintering" to fuse powdered material into a solid structure. SLS may be used to the pharmaceutical industry to create customized medication, in which a drug's dose and release profile are adjusted to meet the needs of a specific patient. This is accomplished by building porous structures with precise geometries that regulate the drug's release. Overall, the sintering process, particularly selective laser sintering, offers a lot of potential in the pharmaceutical industry, especially for individualized treatment 11,8.

Tablet manufacturing

 Sintering is a potential technology for pharmaceutical tablet manufacture because it enables the creation of SR matrix tablets with controlled drug release qualities. This approach can be accomplished through physical or chemical means, and it can be utilized to create sintered floating tablets containing certain pharmaceuticals with release-controlling components. There are based on several principles such as thermal ,chemical and using laser. Sintering can be accomplished through both physical (thermal) and chemical (solvent casting) processes. However, extended exposure of some medication compounds to higher temperatures might induce thermal breakdown, therefore cautious attention is essential when using this approach7,29.

Controlled Release formulations

 Sintering helps in improving the dissolution rate of the poorly water-soluble drugs. It makes it possible by decreasing the particle size which increases the surface area of the powdered particle ultimately increasing the dissolution and enhancing the bioavailability of the drug and the therapeutic effect 7,10,30.

Production of the catalyst

 Sintering is a best method used in the manufacturing of catalysts with bigger and stronger particles. It involves heating of the catalyst to a very high temperature  to cause the particles to bond altogether and form a more stable, solid bulk. Sintering is the best method to increase the durability and successful in the production of the catalyst. Sintering is also very well known for its  cost-effectiveness in the production of the catalyst in the  industrial point of view as it shoes enhanced activity of the catalyst 31,32,33.

CHALLENGES

Sintering process involves the high temperature moulding but below the melting point of the drug. Since, it entails temperature there are some challenges that follows such as some of the drugs or excipients are thermolabile in nature which makes it difficult to be compatible and may be a task to ensure stability and integrity of the active constituents 32,47.Thermolabile constituents may undergo degradations on exposure to high temperature and might lose its potency . As we know that the size of the powder should have uniformity for a proper compression 48. So, in some cases sintering may disturb the size of the powder due to variation in the temperature and makes it tougher for producing g a dosage form or indirectly affects the bioavailability of the dosage form. Although, Sintering is considered as most effective manufacturing procedure. Conventional sintering requires sophisticated and expensive and high temperature equipment’s leading to think about in case large scale ups. Sintering is an advantageous technique in making small batches, but it can be difficult to scale up for commercial application 49. Additionally, in case of Selective laser sintering it requires adherence to legal requirements and since it is an advanced technique it has very less regulatory guidelines to be followed also can be a tough part in obtaining the approval for the manufacturing of the tablets 50,51.

SOLUTIONS

 As we know that heating or high temperatures would lead to degradation of thermolabile substances it necessary to overcome this problem to ensure a highly efficient product. So, to overcome this problem researchers have come up with a solution by using 2 step sintering method where in the powder is first pre-sintered at relatively low temperature adjusting the mechanical strength and later is heated at the sintered temperature to ensure that it possess adequate mechanical strength. Another problem is that it has a very limited range of use of drugs. So, to overcome this problem researchers have come up with an idea to  expand the materials by using composite materials and additives3,20,52.?