1. INTRODUCTION:

Although oral medication delivery has the biggest active surface area of any drug delivery mechanism for the administration of various medicines, it is the most convenient and favored method for administering pharmaceuticals¹.

The leading drug delivery method in pharmaceuticals has gained immense popularity owing to its advantageous features, such as a well-established administration process, ease for patients, convenience, cost-effectiveness, and non-intrusiveness. Presently, a significant challenge in introducing new medications orally lies in achieving adequate drug absorption, consistent bioavailability, and a favorable pharmacokinetic profile in humans². The therapeutic effectiveness of a medicine relies heavily on its bioavailability, which ultimately depends on how well the drug molecules are absorbed and soluble. Solubility is the greatest amount of solute that can dissolve in a given volume of solvent. It is the solute concentration in a saturated solution at a particular temperature, to put it quantitatively³. Simply put, solubility refers to how substances naturally combine to form a consistent mix. The substance getting dissolved is the solute, while the liquid doing the dissolving is the solvent, and together they create a solution. This aspect is crucial in getting the right drug concentration in the body for it to work effectively⁴. Surprisingly, many approved drugs and potential ones in development struggle with being soluble in water, which can impact their effectiveness. In fact, a significant portion of new drug failures can be traced back to these issues with how they interact with water⁷. The oral administration of many current drugs as well as the delivery of novel pharmaceuticals may be impacted by solubility concerns⁵. Therefore, a medication that struggles to dissolve in water often faces challenges in being absorbed due to its slow dissolution rate⁶. Similarly, a medication with limited ability to pass through membranes may experience absorption issues due to its slow permeation rate when drugs have a limited solubility in water, taking them orally can provide challenges. Thus, in order to increase the effectiveness of these drugs, it is necessary to improve their solubility utilizing a variety of methods⁷.

2. The Biopharmaceutical Classification System (BCS):

The medications are arranged in accordance with the biopharmaceutical classification system (BCS), which is predicated on the solubility, permeability, and dissolution of dosage forms that facilitate oral drug absorption². BCS was initially developed by Amidon et al. in 1995. The Biopharmaceutical Pharmacological substances are classified into four categories by the BCS based on their solubility and permeability⁸.

Class I: High Solubility, High Permeability Compounds:

The uptake of those substances is efficient, often surpassing the rate at which they are eliminated from the body. Example: Propanol

Class II: Low-Solubility, High-Permeability Compounds:

The effectiveness of these items to be absorbed by the body is hindered by how quickly they dissolve. There exists a connection between how well they dissolve outside the body and how much can be absorbed inside the body, affecting elimination. Examples: Danazol,

Class III: High Solubility, Low Permeability Compounds:

The phase at which these medications are determined by their permeability through the gut barrier. It doesn't matter whether a medication is released from the mode of delivery because absorption is confined by the permeation rate. Examples: Cimetidine, Acyclovir, Neomycin B, Captopril.

Class IV: Low-Solubility, Low Permeability Compounds:

These substances are soluble and possess a restricted capacity for absorption. through permeability The entire bioavailability is determined by a number of factors, such as the rate of dissolution, intestinal permeability, gastric emptying, and others. substances are challenging to administer and achieve the necessary bioavailability. Examples: Hydrochlorothiazide, Taxol.

BCS Class Boundaries:

§ Solubility: A potent compound is classified as significantly soluble if the maximum dosage can dissolve within 250 milliliters water with a pH between 1 and 7.5

§ Permeability: A material is considered extremely permeable if, upon examination in humans, it's found that 90% of the administered amount is absorbed, either through mass equilibrium assessment or at contrast to an iv dosage⁹.

§ Dissolution: When a pharmaceutical product has ingredients in it, it is considered to dissolve quickly if eighty-five percent of the prescribed dosage dissolves in thirty minutes or less. Either USP apparatus I or II is used to evaluate this procedure in a buffer solution with a maximum capacity of 900 ml¹⁰.

3. Drug Dispersion in Carriers Solid Dispersions:

The study of distributing one or more active components within an inactive matrix throughout the solid phase to promote longer drug release, a faster rate of dissolution, Drug development has focused on improving drug release from ointment and suppository bases, changing the properties of solid compounds, and increasing solubility and stability. Improving the bioavailability of drugs that are not very soluble in water still presents a big obstacle. Making solid dispersions, where an amorphous drugs within a polymer matrix has demonstrated to significantly increase solubility and consequently bioavailability, is one intriguing approach. In 1961, Sekiguchi and Obi presented a useful technique called "Solid Dispersion," which successfully addressed a number of issues related to improving the bioavailability of medications that are poorly soluble in water¹¹.

4. Techniques for Solid Dispersions¹²:

Various methods of preparation solid dispersions are summarized as follows:

4.1 Solvent Evaporation Method

4.1.1 Solvent Evaporation Method

4.1.2 Spray Drying Method

4.1.3 Freeze Drying (Lyophilization Techniques)

4.1.4 Supercritical Fluid Technology

4.1.5 Co-precipitation

4.1.6 Electrospinning

4.2 Melting method:

4.2.1 Melting Method/Fusion Method

4.2.2 Hot-melt Extrusion

4.2.3 Melt Agglomeration Method

4.4 Melting Solvent Method

4.5 Dropping Method

4.1 Solvent Evaporation Method:

4.1.1 Solvent Evaporation Method:

The approach known as solvent evaporation stands as a widely adopted technique within the pharmaceutical sphere, particularly for enhancing the solubility of drugs that struggle to dissolve in water. Initially designed for substances sensitive to heat, this method involves dissolving Both the medication and its carrier in an organic solution. A specialized apparatus, the rotary evaporator, is employed to remove the solvent. Subsequently, the resulting solid is processed through grinding, sieving, and drying. Successful execution relies on the complete drugs and appropriate carrier dissolving in the solvent to produce solid or amorphous dispersions solutions. Originating in 1965, Tachibana and Nakamura pioneered this technique, utilizing β-carotene (the drug) and PVP (the carrier) dissolved in chloroform. Upon complete evaporation of the solvent, a solid mass formed, later sifted and dried. Notably, this method offers the advantage of preserving both the drug and carrier integrity by operating at lower evaporation temperatures, thereby preventing their decomposition.¹²

4.1.2 Spray Drying Method:

Spray-drying ranks among the top three widely employed methods for eliminating solvents in the creation of solid dispersions. The droplets' large surface area speeds up the evaporation of the solvent, resulting in the formation of solid dispersion within seconds. This quick process might prevent phase separation from occurring¹³.

4.1.3 Freeze drying (Lyophilization Techniques):

An alternative method that differs from solvent evaporation is lyophilization. To make a lyophilized molecular dispersion when the medication and carrier have been dissolved in a solvent, liquid nitrogen is used to freeze the mixture¹⁴. This technique is commonly employed for products sensitive to temperature changes, which may destabilize in water-based solutions but maintain stability when dry, enabling extended storage durations.^14.

4.1.4 Supercritical Fluid Technology (SCF):

Utilizing SCF methodologies allows for the creation of solid dispersion drug formulations without solvents, effectively boosting the solubility of compounds with low solubility. These techniques involve harnessing a supercritical fluid a condition in which materials, over certain critical temperature and pressure limits, exist as a single fluid phase. The process entails finely dispersing a hydrophobic drug within a hydrophilic carrier. Among SCFs, carbon dioxide reigns as the most prevalent choice due to its chemical inertness, non-toxic nature, and non-flammable properties.¹⁵

4.1.5 Co-precipitation:

This technique begins by dissolving the carrier in a solvent, resulting in a mixture¹⁶. The medication is then stirred into the mixture while being mixed. ensuring a uniform mix. Water is then slowly introduced into this blend, causing precipitation. Lastly, the resulting precipitate undergoes filtration and drying.¹⁶

4.1.6 Electrospinning:

The process of electrospinning blends elements of SD technology with nanotechnology. It involves generating solid fibers by dispensing a millimeter-scale polymeric fluid flow or melt via a nozzle. This technique offers simplicity and cost-effectiveness as its key advantages. It proves adept at crafting nanofibers and managing the controlled release of biomedical substances¹⁷.

4.2 Melting Method:

4.2.1 Melting Method/ Fusion Method:

The so-called "fusion method" was invented in 1961 by Sekiguchi and Obi¹⁸. A drugs and a hydrophilic carrier are heated in this procedure until the drug and carrier liquefy Just above their point of eutectic¹⁸. The resulting molten mixture is swirled and quickly cooled in a bath of ice. The solid block is then crushed and sieved. This approach is appreciated for being simple and economical^19.

4.2.2 Hot-melt Extrusion:

When a drug is not readily soluble in water, hot-melt extrusion is often employed to improve the drug's solubility and oral absorption. This process creates an amorphous solid dispersion without the use of solvents, eliminating any leftover solvents in the formulation. It involves combining a melting method with an extruder, melting a uniform blend mixture of plasticizer, polymer, and drugs, and then forcing it through the apparatus. It is possible to control the final product shapes at the extruder's exit without having to grind them²⁰.

4.2.3 Melt Agglomeration Method:

Melt Agglomeration through fusion involves a binding agent serving as a transporter. In this approach, the drug, binding agent, and additional additives are raised to a temperature surpassing the binding agent's melting point. As an alternative, the drug can be dispersed and sprayed onto the heated binding agent²¹.

4.2.4 Kneading Method:

This approach involves dispersing the carrier in water to create a paste. Afterward, the drug is introduced and mixed rigorously. The resulting mixture is dried and, if needed, sieved for the final formulation²².

4.2.5 Melting Solvent Method:

The Goldberg et al. pioneered research on the technique of solvent-induced melting. In their investigation, they devised an SD to enhance griseofulvin dissolution. They used methanol as the solvent and succinic acid as the carrier in their method²³. This novel approach combines aspects of the solvent evaporation and melting processes. The drug initially dissolves in a compatible solvent, later integrating into the carrier's molten state. Subsequently, the combined mixture undergoes evaporation until dryness. This method finds significant utility, especially for medications characterized by a notably high melting point.²⁴

4.2.6 Dropping Method:

Bulau and Ulrich (1977) devised the dropping technique to speed up the crystallization of various substances. This innovative technique creates spherical particles by transforming melted solid mixtures⁴. The process involves dropping a melted drug-carrier blend in solid dispersion onto a cooling plate, allowing it to solidify into rounded particles. Unlike methods involving organic solvents, this approach avoids the issues related to solvent evaporation.²⁵

Applications²⁶:

1. To achieve an even spread of a limited quantity of drug.

2. To make the unpredictable medication stable.

3. To give doses of solid material that comprise up to 10% liquid or gas components.

4. To combine a fast-release main dose with a sustained-release dosage form.

5. To provide a prolonged release schedule for soluble medications employing insoluble or weakly soluble carriers.

6. Minimizing the early breakdown of medications such as morphine and progesterone is a goal.

7. Different structures within a system can transform into various types of compounds like solid solutions, eutectics, or molecularly combined entities.

8. Enhance exposure (bioavailability, quicker onset, lower dose)

9. Diminish unpredictability (Reduced Fed/Fasted impact).

BCS (Biopharmaceutics Classification System) class 2 drugs along with their properties²⁷:

§ Ibuprofen:

Drugs of the BCS class 2 have high permeability and poor solubility. One nonsteroidal anti-inflammatory medication (NSAID) with low water solubility is ibuprofen.

§ Ketoconazole:

This antifungal agent has high permeability and poor solubility, placing it in BCS class 2.

§ Indomethacin:

Another NSAID, indomethacin, exhibits high permeability and poor solubility, making it a class 2 drug.

§ Simvastatin:

A widely used cholesterol-lowering medication, simvastatin has low solubility and high permeability.

§ Captopril:

This angiotensin-converting enzyme (ACE) inhibitor has poor water solubility and high permeability, classifying it as a BCS class 2 drug.

§ Candesartan:

Candesartan is an angiotensin II receptor blocker (ARB) with low solubility and high permeability

§ Loratadine:

A common antihistamine, loratadine falls into BCS class 2 due to its high permeability and poor solubility.

§ Atenolol:

This beta-blocker is characterized by high permeability and poor solubility, placing it in BCS class 2.

§ Celecoxib:

Celecoxib is a selective COX-2 inhibitor with high permeability and poor solubility.

§ Glyburide:

An oral antidiabetic medication, glyburide is classified as a BCS class 2 drug due to its high permeability and poor solubility.

Advantages²⁸:

1. Solid dispersions Enhancing bioavailability for poorly water-soluble drugs involves improving their dissolution without relying on similar substances.

2. When it comes to improving solubility, solid dispersions are superior to other methods of reducing particle size because they reduce the size to a limit of about 2–5 microns.

3. Decrease pre-systemic metabolism; this could be brought on by the carrier inhibiting the drug's biotransformation enzyme.

4. The drug can be changed from its liquid to solid state.

5. Solid dispersions can be used to alleviate the drawbacks of solid powder, such as smaller particle sizes that exhibit poor mechanical qualities (such as strong adhesion and poor flow properties).

6. Extended-release dosage forms can be crafted in the form of solid dispersions.

Disadvantages²⁹:

1. Crystallinity changes and the rate of disintegration may be slowed down by aging.

2. The presence of moisture and high temperatures can cause solid dispersions to degrade. Moisture affects the drug's crystallinity, therefore stability problems can be challenging.31–34 Certain polymers utilized in solid dispersion possess hygroscopic properties, meaning they have the potential to absorb moisture and cause crystal formation.

3. Drugs can occasionally be converted from their metastable to stable form. As a result, solubility and dissolution rate could drop.

4. Understanding the relationship between a drug's structure and its release from a solid dispersion is also challenging.

5. Difficulty comprehending solid dispersions' physical structure.

6. The remaining problem

5. CONCLUSION:

The domain of oral drug delivery stands as the foremost choice in pharmaceuticals, offering convenience and accessibility to patients. However, the challenge lies in ensuring optimal drug absorption, consistent bioavailability, and favorable pharmacokinetics in humans. Bioavailability, largely dependent on drug solubility and absorption, determines therapeutic efficacy. The struggle with water solubility hampers the effectiveness of numerous approved and potential medications, affecting their absorption and dissolution rates, especially for those with low aqueous solubility. delineating four classes that impact absorption. Among the methods to improve solubility are physical changes, chemical alterations, lipid-based systems, and nanotechnology-based approaches. Solid dispersion technology, introduced in 1961, emerges as a promising solution to augment solubility and bioavailability, dispersing drugs in an inert matrix to improve dissolution rates and sustained release. Additionally, melting methods like fusion, hot-melt extrusion, melt agglomeration, and kneading present feasible alternatives to enhance drug solubility. Notable BCS class 2 drugs like ibuprofen, ketoconazole, and indomethacin exhibit high permeability but low solubility, presenting challenges in oral delivery. Solid dispersions offer advantages such as improved drug dissolution and reduced pre-systemic metabolism. However, drawbacks like potential crystallization, aging-related changes, and stability concerns arise due to moisture and temperature variations. Despite limitations, solid dispersions find applications in stabilizing drugs, achieving sustained release, and enhancing exposure while minimizing variability. Understanding their physical structure and addressing residual solvent issues remain critical challenges in their application. In conclusion, solid dispersion technology provides a promising pathway to mitigate challenges related to drug solubility, enhancing bioavailability and dissolution rates. Despite certain limitations and challenges, the potential applications of solid dispersions in drug formulation and delivery underscore their significance in pharmaceutical development and improving therapeutic outcomes.

6. ACKNOWLEDGMENT:

We are thankfull to principal and management of Ali Allana College of Pharmacy Akkalkuwa for providing all necessary facilities during this study.

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Received on 05.03.2024 Modified on 15.05.2024

Res. J. Pharma. Dosage Forms and Tech.2024; 16(3):215-220.

DOI: 10.52711/0975-4377.2024.00034