INTRODUCTION:

Solubility is defined as the essential ability of any solute to be dissolved in any solution at different parameters such as Temperature, Pressure and pH¹. It performs a significant part in the drug efficacy & potency. One critical element that must be carefully taken into account is the drug’s solubility².

The characteristic feature of a chemical compound is its ability to dissolve in a solvent, regardless of the state of the solvent (solid, liquid or gas), thereby giving rise to an equivalent solution. Basically, the whole process of solubility depends upon the amount of pressure, temperature, pH and solvent i.e., used in the process³. According to U.S. Pharmacopoeia, Solubility is the mL of solvent required to break down 1 gm of solute¹. It has been evaluated that, about 30-50% of medicaments have poor solubility and dissolution rate, that effects the absorption of drugs from GIT⁴. The solubility of a drug directly affects the bioavailability and pharmacokinetics². There are several challenges faced in the pharmaceutical industries. Two of the most important issues faced are the rise in drug solubility and the quantity of drug in the circulation. Furthermore, these issues have an impact on the therapeutic index of the drug⁵. The dissolution rate, permeability, sensitivity and first-pass metabolism of a drug are the factors that influences its bioavailability⁶. The drug discovery and development process can be significantly enhanced through the utilization of pharmaceutical formulations^7,8. One of the modern and most used method in the field of pharmaceutical formulation is photopolymerization⁹. Utilizing the dispersion of a solid in a carrier is a sophisticated technique to enhance the release of drugs that have limited solubility in water¹⁰.

Orally administered drugs do not undergo complete absorption into the systemic circulation. This can result in gastrointestinal mucosal toxicity, that may lead to inappropriate bioavailability¹¹. According to BCS, a significant number of drugs exhibit insolubility properties in water¹².

Solubility and dissolution; these are the core concepts of physical as well as chemical science, that includes their biopharmaceutical and pharmacokinetic consideration¹³. For medications to have the desired effect, it is imperative that they be developed with improved solubility and bioavailability¹⁴. Solubility of a drug compound may affect their absorption, permeability and potency⁶. The drug discovery process is greatly impacted by the need to enhance the aqueous solubility of pharmaceutical formulations, making it a challenging characteristic¹. A variety of methods have been developed. Currently, several physiochemical modifications are being studied to improve the aqueous solubility characteristics of a drug^14,15.

When a drug is introduced into the body through the IV route, its bioavailability is 100%. However, when the drug is administered orally, the bioavailability decreases due to incomplete or reduced absorption¹⁶.

The bioavailability of therapeutic agent refers to the amount of the dosage form and the duration it takes for the agent to be circulated within our body, before exerting its effect at the intended site of action¹⁷. Drugs are generally dissolved in different solutions using variety of techniques to increase solubility, which directly influences its therapeutic effectiveness ^3,17. A drug’s solubility can be influenced by a number of variables, including polarity, pressure, molecular size, temperature, particle size, solvent type and polymorphs ^18,19.

Some possible reasons for poor absorption of drugs may be aqueous solubility less than 100mg/ml, Poor dissolution, High molecular weight or High crystal energy¹⁸. The data from drug detection reveals that around 70% of drugs demonstrates low solubility. Therefore, various solubility enhancement techniques are being developed⁶. Slow dissolution rate and poor water solubility of drugs shows less bioavailability in the systemic circulation, poor stability and poor permeation through the bio-membranes²⁰. The pharmacology of any drug is heavily dependent on the dissolution process in poorly soluble drugs. To compensate the effects of first pass metabolism and drug excretion, higher doses are administered to ensure the desired level of effectiveness.²¹

Hence, there are three major approaches to increase the amount of drug in the systemic circulation:

1) Biological approach: In this approach, the route of administration can be interchanged.

2) Pharmacokinetic approach: In this approach, the pharmacokinetics of drug is changed forcefully by modifying its chemical structure. For example, Potassium salt of ibuprofen, HCl salt of propranolol.

3) Pharmaceutical approach: In this approach, chemical structure can’t be changed. But, modifying the process of manufacturing and sometimes changing the physiochemical properties of drugs can enhance the rate of bioavailability.²⁰

BCS has highlighted that, the pharmacology of a drug is heavily influenced by two critical factors- aqueous solubility and membrane permeability. Thus, various technologies have been introduced to enhance the physical properties of drugs.^22,23

IMPORTANCE OF SOLUBILITY:

The oral administration of drugs is widely considered as appropriate and commonly utilized route of drug delivery. Consequently, numerous pharmaceutical companies produce oral drug products, that are compatible with this mode of administration. However, a major challenge is achieving adequate bioavailability. Similarly, in the case of parenteral formulations, solubility plays a crucial role in determining the drug’s effectiveness. Drugs with low solubility in aqueous solutions often requires higher doses to achieve the desired therapeutic plasma levels.²⁴

The limited solubility in water poses a significant challenge during the development process. Many drugs with varying pH levels exhibit less aqueous solubility. Poorly soluble drugs result in minimal absorption. Therefore, solubility plays an important role in facilitating improved drug absorption within the body and promoting a more substantial therapeutic response^5,24. A wide range of methods have been documented and made accessible. The selection of these techniques is dependent on various factors, including its properties, the type of excipients employed, and characteristics of the dose.^14,24

Table 01: Solubility description according to United States Pharmacopoeia

Sl. No	Terms	Relative Amounts of Solvents to Dissolve 1 Part of Solute	Example
01	Very Soluble	Less than 1	Metoprolol
02	Freely Soluble	From 1-10	Ipratropium Bromide
03	Soluble	From 10-30	Cyclophosphamide
04	Sparingly Soluble	From 30-100	Ramipril
05	Slightly Soluble	From 100-1000	Fludropine
06	Very Slightly Soluble	From 1000-10000	Busulphon Flocainide
07	Insoluble	More than 10,000	Lidocaine Melphon

Basic Need for Solubility Enhancement:

The therapeutic efficacy of the medication relies heavily on its capacity to dissolve, especially since it is a drug with poor solubility. Dissolution serves as the rate-limiting step and plays a vital role in determining the desired pharmacological effect. In order to attain the desired therapeutic plasma concentration, it is crucial for a drug to possess hydrophilic properties. Most drugs have weak acidic or weak basic characteristics, which leads to limited solubility in water. Highly water-soluble drugs effectively mitigate the challenges encountered during the development and preparation of NCEs⁵.

In present scenario of pharmaceutical industry, there are more than 8% of drugs shows high solubility and permeability, due to which; toxicity increases in the body. In-vivo absorption of drugs plays an important role in clinical trials phase²⁵. During the last 5 decades, there are more than 40% NCEs formed are classified into insoluble or hydrophobic drug; which leads to gastrointestinal mucosal toxicity. In the gastrointestinal tract (GIT), the acidic environment causes the degradation of a significant number of drugs. To prevent this degradation, drugs must possess the quality of being soluble in water¹⁴. In the pursuit of improving the solubility of drugs, it is important to keep in mind the ultimate goal of enhancing bioavailability and minimizing any adverse effects¹⁰.

In order to eliminate the frequent challenges in the process of development, formulation design and novel chemical entities screening investigation; here are the properties of an active pharmaceutical product, i.e., chemical composition, physical nature, and pharmacokinetic behaviour used to influence solubility of drug substance³. The conversion of a drug into a water-soluble form is of utmost importance²⁶.

To ensure an effective pharmacological response, achieving the desired concentration of orally administered drugs in the circulatory system is crucial, and solubility is a key factor in this process. The FDA has utilized the Biopharmaceutical Classification System (BCS) to issue guidance, with the aim of enhancing the efficiency of drug product development ²⁷.

Factors Affecting Solubility of Drug

Fig 01: Factors affecting solubility of a drug compound

· Some factors depending upon the aqueous solubility of drugs are:

1. Particle size:

Solubility is affected by the size of its particles. As the size of the particles decreases, the surface area increases, which allows a greater interaction with the solvent.

-The solubility property of drug is inversely proportional to the size of the particle.

2. Temperature:

The relationship between temperature and solubility is such that, an increase in temperature causes solubility to increase due to the absorption of energy. On the other hand, decreasing temperature also reduces its solubility property.

3. Pressure:

Changes in pressure do not influence the solubility of solids and liquid part. However, in the case of gaseous solutes, increasing pressure result in solubility enhancement.

4. Nature of solute and solvent:

The concentration and temperature at which solute and solvent are mixed play a crucial role in determining their interaction. For instance, dissolving 1gm of lead chloride in 100gm of water at room temperature is possible, whereas 200gm of zinc chloride can be dissolved in 100gm of water with the same concentration. This dissimilarity is attributed to the distinct nature of the solute.

5. Molecular size:

Solubility of a substance is also affected by the molecular size and weight. As the size and weight increase, the solubility decreases due to the difficulty in the surrounding solvent molecules adequately accommodating larger molecules.

-In case of organic compounds, more the carbon branching; more will be the solubility.

6. Polarity:

The solubility can be affected by the polarity of both the solute and the solvent. Generally, polar solutes are dissolved by polar solvents and vice-versa (like dissolves like).

Polarity scale is used to measure the polarity of compounds.

7. Polymorphism:

A substance that can crystallize in multiple crystalline forms at once is said to possess polymorphism. Due to its ability to take on multiple forms or shapes, the substance's melting point varies. Therefore, polymorphs exhibit different solubility levels depending on their melting points.

· Some factors that may affect the Rate of Dissolution are:

1. Size of solute particles

2. Amount of solute present in solution

3. Temperature

4. Stirring

5. pH etc.^13,18,28,29

BCS CLASSIFICATION:

The biopharmaceutical classification system [BCS] is known as the highly advanced implementable methodology to differentiate drug substances on the basis of enteric permeability, water solubility and dissolution. During 1995, a scientist named Amidon et al and their team conducted several investigations to compare the in vivo bioavailability with the in vitro drug dissolution, terming it a theoretical approach. Consequently, this technique is moreover employed in the initial stages of medication development for novel categories and in the identification of NCEs, as well as in the pharmaceutical domain³⁰.

The FDA officially established the Biopharmaceutics Classification System (BCS) in August 2000. This system organizes pharmaceutical active ingredients into four distinct classes; on their basis of solubility and permeability. The primary purpose of this classification is to address the challenges posed by drugs that have limited solubility in water³¹. To address the difficulties linked with class II BCS drugs, numerous techniques have been developed in recent decades. These approaches involve the use of co-solvents, emulsion formation, micellization, pharmaceutical salt formation, prodrug design, soft gel technology, particle size reduction, and solid dispersion. The primary objective of these methods is to improve the solubilising capacity of hydrophobic drug compounds³².

Determining the rate and extent of absorption involves considering three important factors: solubility, permeability, and dissolution rate³³. Nevertheless, some of the techniques and strategies employed to enhance solubility exhibit limitations. For instance, solid dispersion fails to achieve the desired solubility characteristics due to challenges in manufacturing, stability, and scale-up. Similarly, micronization does not gain significant traction as it does not alter the saturation solubility of drugs and necessitates frequent high-dose administration. Sometimes complexation is also not suitable for large dose drugs due to its exclusive and difficult methods for preparation, scale-up manufacturing process and stability issues, also difficulty in incorporating into formulation of dosage form. Nanosuspension is a process that involves particle size reduction, leading to the transformation of polymorph with higher energy into crystalline form with lower energy. This form may or may not exhibit therapeutic activity³².

· BCS Guidance’s Purpose:

It has two purposes, which are as follows:

1. To expand the BCS’s regulatory application and suggest approach for categorizing medicine.

2. To explain when, considering BCS’s methodology, for in vivo bioequivalence as well as bioavailability investigation may be demanded ³⁴.

Fig 02: Biopharmaceutical Classification System

According to BCS – Biopharmaceutical classification system

1. Class I- Drugs falling under Class I exhibit high dissolution and absorption rates, leading to rapid bioavailability and bioequivalence. Therefore, there is no need for bioavailability and bioequivalence studies for these products.

2. Class II- Drugs having high absorption rate but low disintegration rate, resulting in short bioavailability. Only at high doses, dissolution process occurs; indicating the need for improvement.

3. Class III- Drugs have low permeation rates but high absorption rates, making it challenging to develop controlled-release formulations. These drugs are known for their low bioavailability and require enhanced permeability.

4. Class IV- Drugs exhibit weak bioavailability due to factors such as permeability, dissolution rate, and stomach emptying time, which delay the rate of drug absorption.

Due to the high dissolution and absorption rates of Class I drugs, bioavailability and bioequivalence studies are rendered unnecessary as rapid bioavailability and bioequivalence are attained. However, Class-II drugs have high absorption rates but low disintegration rates, resulting in short bioavailability, indicating the need for improvement. Class III drugs have low permeation rates and high absorption rates, making it challenging to develop controlled-release formulations, leading to low bioavailability. Finally, Class IV drugs exhibit weak bioavailability due to factors such as permeability, dissolution rate, and stomach emptying time, which delay the rate of drug absorption. ^30–34

Advanced Techniques For Solubility Enhancement:

The formulation of NCEs encounters a major challenge due to their inadequate solubility in water, which can have a substantial impact on drug absorption. For drugs to be absorbed, they should be in solution form at the absorption site. However, numerous drugs exhibit limited solubility in water, underscoring the need to enhance their solubility to enhance their bioavailability.³⁵

The improvement of the water solubility of drugs that have poor solubility has been accomplished through the use of various conventional methods and techniques over many years.³⁶ When substances have limited solubility in aqueous media, formulation strategies become necessary during the initial stages of drug discovery. This is vital for selecting lead substances and developing commercial drug products ³⁷. When aiming to increase solubility, techniques can be categorized into two groups: physical modifications and chemical changes to the medicinal ingredient.³⁴

Fig 03: Various techniques used to enhance the solubility of a drug

Table 02: Physical Modifications

S. No

Techniques

Description

Merits

Demerits

References

Particle Size Reduction

- The drug's ability to dissolve is improved, when the size of the particles decreases since it increases the surface area.

- It is generally done by two processes-

(i) Micronization

(ii) Nanosuspension

(i)Efficient, reproducible and economic process

(ii) Increases surface-volume ratio.

(iii) Reduced drug degradation.

(i) Particle agglomeration may occur.

(ii) Thermal pressure might arise.

18, 35, 36, 38–43

Modification of Crystal Habit

(i) Polymorphs

(ii) Pseudo Polymorphs

- Polymorphs, have identical chemical composition, but can assume different polymorphic forms.

- A drug's amorphous form is thought to be more appropriate than its crystalline form.

(i) Improvement in purity of drugs

(ii) Controlled properties.

(iii) Enhanced reactivity.

(i) Complexity and high cost

(ii) Scale up challenges

(iii) Limited applicability

(iv) Unintended

Consequences

18, 31, 35, 44, 45

Complexation

The utilization of cyclodextrins (CDs) to form complexes with drugs is a common practice aimed at enhancing their water solubility and permeability.

(i) Recognized as a safe excipient.

(ii) Strengthen the stability and increase shelf-life.

(i) Requirement of a substantial amount of CDs.

(ii) The lipophilic membranes may act as a barrier.

18, 40, 44, 45

Drug Dispersion in a Carrier

- Here, a hydrophobic drug is distributed among one or more hydrophilic carriers.

- Consequently, the surface area is increased, resulting in improved drug solubility and a faster dissolution rate

(i) Optimal dissolution rate can be attained.

(ii) Increased stability and protection for the drug.

(i) Expensive preparation method

(ii) Difficult to remove complete solvent.

35, 36, 39, 46

Cryogenic Techniques

The drug is formulated into an amorphous nanostructure with a high degree of porosity at low temperatures using cryogenic techniques.

- Works at -150 degree celsius

(i) Stabilization of amorphous form

(ii) Controlled crystallinity.

(iii) Improved solubility and bioavailability.

(i) Potential for instability

(ii) Time consuming for processing.

(iii) Product uniformity is low.

Solubilization by Surfactants

Surfactants are substances that efficiently reduce interfacial tension and encourage the lipophilic dissolution.

- By reducing the surface tension, drug solubility can be improved

(i) Ease of formulation

(ii) Dose reduction

(iii) Increased solubility and bioavailability.

(i) Phase separation

(ii) Foaming and dispersibility issues.

18, 47

Table 03: Chemical Modifications

Sl. No.

Techniques

Description

Merits

Demerits

References

Nanotechnology

Nanotechnology is the practice of utilizing materials and structures at a nano scale level. Here, Nanonisation takes place, which involves milling.

(i) Exellent blood stability

(ii) Cost-effective

(iii) Suitable for different mode of administration.

(i) May lead to flocculation

(ii) Agglomeration may occur.

48–51

Hydrotropy

Introduction of highly concentrated alkali metal salt derived from various organic acids.

-Similar to surfactant

(i) Ease of formulation.

(ii) No organic solvent is required

(i) Taste and palatability issues

(ii) pH dependency.

39,44,48

Co-Solvency

The principle of co-solvency revolves around lowering the interfacial tension of solute with the aqueous solution.

-This entire procedure is sometimes referred as solvent mixing or blending.

(i) Increased solubility and stability.

(ii) Rapid onset of action

(iii) Cost- effective

(iv) Reduced variability.

(i) Mostly drugs react with the excipients.

(ii) The insoluble material possess a lesser degree of stability than its crystalline state.

41,52-54

Co-Crystallisation

When two substances are combined, a co-crystal is formed at ambient conditions.

-The pharmaceutical properties of API are not affected, but it improves the physical properties.

(i) Reduce dependency on solvent

(ii) Enhanced physical property.

(iii) Taste masking.

(i) Complexity of design

(ii) Scale up challenges and limited applicability.

50,55

Salt Formation

The conversion of acidic and basic drugs into their respective salt forms is a highly effective and commonly used method.

- In the production of parenteral, the salt formation technique is reliable.

(i) Increased aqueous dissolution

(ii) Crystallinity control

(iii) Taste masking

(iv) Stability improvement

(i) pH sensitivity.

(ii) Compatibility issues.

iii)Cost-effective

(iv) Limited applicability.

(v) Regulatory consideration.

35,40,50,55

Use of Novel Solubilizers

-The utilization of solubilizing materials, including conventional solubilizer.

For example; Polysorbates.

(i) Introduces innovative excipients.

(ii) Enhanced stability.

(iii) Potential for patentability

(i) May induce toxicity.

(ii) Regulatory approval issues.

(iii) Patient acceptance issues.

18,38,56,57

Table 04: Other Modifications

Sl No.

Techniques

Description

Merits

Demerits

References

PH Adjustment

-Water solubility-deficient drugs may exhibit dissolution in water, when the pH is modified.

-It requires the specification of the buffer's capacity and the pH's tolerance.

(i) Ease of formulation

(ii) Easy process acceleration

(iii) Minimal chemical usage.

(i) Diluting can give rise to precipitation.

(ii) Tolerance and toxicity can arise, affecting systemic environment.

31, 35, 43, 45

By using Pro-drug

A prodrug is a drug molecule that is chemically bonded to an inactive moiety, aiming to improve the physiochemical properties associated with the original drug.

(i) Targeted drug delivery

(ii) Reduced side effects

(iii) Optimization of drug doses.

(i) Complex design

(ii) Enzyme saturation.

(iii) Metabolism variability.

33, 36

Hot-Melt Method

HME is a process that utilizes pressure to shape a material, called extrude, by shoving it through a orifice. -It requires specific conditions, including temperature, pressure, blending and feed rate.

(i) Control release

(ii) Combination of multiple API is possible.

(iii) Efficient technique.

(iv) Thermally stable.

(i) Not suitable for all compounds

(ii) Residual solvent concerns

(iii) High equipment cost

(iv)Process complexity.

18, 35, 40, 43, 50

Sono-crystallisation

By applying ultrasound energy, the nucleation of crystallization can be modified through a process that involves both compression and expansion.

-It is a common process to produce different crystals.

i)Rapid crystallisation

(ii) Reduced energy consumption

(iii) Reduced agglomeration

(iv)Enhances dissolution rate

(i) Specialised equipment needed

(ii) Temperature sensitivity

(iii) Cavitation effect may occur

(iv)Scale up challenges.

33, 43

Liposomes

Resembling bubbles, liposomes are spherical structures composed of materials found in cell membranes

- Both hydrophilic and hydrophobic medications can be incorporated into them.

(i) Site specific targeting

(ii) Improved absorption.

(iii) Protection from degradation.

(iv)Minimal systemic toxicity.

(i) Complex formulation.

(ii) Storage challenges.

(iii) Inter-patient variability.

(iv)Expensive method.

36, 45, 57

Liqui-solid Method

Adsorption as well as absorption occur when a drug dissolved in a liquid medium is added to a carrier.

-The desirable flow characteristic is achieved by utilising a coating material with adsorptive properties.

(i) Enhances the ability to dissolve

(ii) Encapsulate both hydrophilic & hydrophobic drugs.

(iii) Essential for the formulation of oily or liquid drug.

(i) Recipients should exhibit superior adsorption

(ii) Using higher dose of insoluble drugs is not applicable.

18, 31, 35, 50, 51

Spray drying Technique

It is a technique that converts a liquid feed into a dried product by spraying it into a hot drying medium.

-Utilizing a spray dryer enables the evaporation of solvents from both product and polymer solution.

(i) Improves solubility

(ii) Continuous process

(iii) Low operating cost.

(iv)Rapid drying process.

(i) Low yield for small batches

(ii) Highly sensitive at high temperature

18, 43, 47

Freeze drying Technique

Its principle involves direct transition of a solid substance into a gaseous state, without the need for a liquid phase.

- It includes freezing

(-60 to -80 degree Celsius)

(i) Suitable process for encapsulation

(ii) Operates at low temperature.

(iii) Stable products under oxidation

(i) Extended processing time

(ii) Elevated energy usage. (iii) Expensive

28, 47, 50

CONCLUSION:

In conclusion, the review paper on advanced techniques in solubility enhancement of poorly water-soluble drugs underscores the pivotal role of innovative strategies in overcoming pharmaceutical challenges. The comprehensive exploration of various methodologies, including nanotechnology, cyclodextrin complexation, and lipid-based formulation, reveals a rich landscape of possibilities for improving drug solubility and bioavailability. This synthesis of cutting-edge research not only depends our understanding of these techniques but also highlights their potential to revolutionize drug delivery systems.

REFERENCE:

1. Kumari L, Choudhari Y, Patel P, Gupta G Das, Singh D, Rosenholm JM, et al. Advancement in Solubilization Approaches: A Step towards Bioavailability Enhancement of Poorly Soluble Drugs. Life. MDPI. 2023;13.

2. Ainurofiq A, Putro DS, Ramadhani DA, Putra GM, Do Espirito Santo LDC. A review on solubility enhancement methods for poorly water-soluble drugs. Vol. 10, Journal of Reports in Pharmaceutical Sciences. 2021: 137–47.

3. Belsarkar AS, Patil RN, Parekar PB, Sul KT, More A V. International Journal of Current Science Research and Review A Brief Review on Solubility Enhancement Techniques with Drug and Polymer. Available from: www.ijcsrr.org

4. Pawar SR, Barhate SD. Solubility enhancement (Solid Dispersions) novel boon to increase bioavailability. Journal of Drug Delivery and Therapeutics. 2019; 9(2): 583–90.

5. Vimalson DC, Parimalakrishnan S, Jeganathan NS, Anbazhagan S. Techniques to Enhance Solubility of Hydrophobic Drugs: An Overview. Asian Journal of Pharmaceutics. 10,

6. Bhalani D V., Nutan B, Kumar A, Singh Chandel AK. Bioavailability Enhancement Techniques for Poorly Aqueous Soluble Drugs and Therapeutics. Biomedicines. MDPI. 2022; 10.

7. Tan J, Liu J, Ran L. A review of pharmaceutical nano-cocrystals: A novel strategy to improve the chemical and physical properties for poorly soluble drugs. Crystals. MDPI AG. 2021; 11.

8. Solanki SS, Soni LK, Maheshwari RK. Study on Mixed Solvency Concept in Formulation Development of Aqueous Injection of Poorly Water Soluble Drug. J Pharm (Cairo). 2013; 2013: 1–8.

9. Tomal W, Ortyl J. Water-soluble photoinitiators in biomedical applications. Polymers. MDPI AG. 2020;12.

10. Tiwari R, Tiwari G, Srivastava B, Rai AK. Solid Dispersions: An Overview To Modify Bioavailability Of Poorly Water Soluble Drugs. International Journal of PharmTech Research. 1

11. Kumar A, Sahoo SK, Padhee K, Pal P, Kochar S, Satapathy A, et al. Pharmacie Globale International Journal of Comprehensive Pharmacy Review On Solubility Enhancement Techniques For Hydrophobic Drugs. Pharmacie Globale (IJCP). 2011. Available from: www.pharmacie-globale.info

12. Kushare SS, Gattani SG. Microwave-generated bionanocomposites. Journal of Pharmacy and Pharmacology. 2013; 65(1): 79–93.

13. Mahapatra APK, Patil V, Patil R. Solubility Enhancement of Poorly soluble Drugs by using Novel Techniques : A Comprehensive Review. Int J Pharmtech Res. 2020; 13(2): 80–93.

14. Kumar A, Sahoo SK, Padhee K, Pal P, Kochar S, Satapathy A, et al. Pharmacie Globale International Journal of Comprehensive Pharmacy Review On Solubility Enhancement Techniques For Hydrophobic DRUGS. Pharmacie Globale (IJCP). 2011. Available from: www.pharmacie-globale.info

15. Budiman A, Rusdin A, Aulifa DL. Current Techniques of Water Solubility Improvement for Antioxidant Compounds and Their Correlation with Its Activity: Molecular Pharmaceutics. Antioxidants. MDPI. 2023; 12

16. Gupta R, Jain V, Nagar JC, Ansari A, Sharma K, Sarkar A, et al. Bioavailability Enhancement Techniques for Poorly Soluble Drugs: A Review. Asian Journal of Pharmaceutical Research and Development. 2020; 8(2): 75–8.

17. Chouhan M, Rathor S, Garg V, Sharma A, Singh P, Chandra J, et al. Enhancement Of Solubility And Dissolution Characteristics Of Etoricoxib By Solid Dispersion Technique Using Different Grade Of Peg Carrier Using. Journal of Pharmaceutical Negative Results. 14.

18. Yadav K, Sachan AKr, Kumar S, Dubey A. Techniques For Increasing Solubility: A Review Of Conventional And New Strategies. Asian Journal of Pharmaceutical Research and Development. 2022; 10(2): 144–53.

19. Thorat YS, Gonjari ID, Hosmani AH. Solubility Enhancement Techniques: A Review On Conventional and Novel Approaches. IJPSR [Internet]. 2011; 2(10). Available from: www.ijpsr.com

20. Nanotechnology A promising Drug Delivery for Poorly Water Soluble Drugs. 2010

21. Gupta S, Sawarkar S, Ravikumar P. Solubility Enhancement of Poorly Water Soluble Protease Inhibitor. Int J Pharm Sci Res [Internet]. 2016; 7(1): 252–8.

22. van der Merwe J, Steenekamp J, Steyn D, Hamman J. The role of functional excipients in solid oral dosage forms to overcome poor drug dissolution and bioavailability. Pharmaceutics. MDPI AG. 2020; 12

23. Kim DH, Kim YW, Tin YY, Soe MTP, Ko BH, Park SJ, et al. Recent technologies for amorphization of poorly water-soluble drugs. Pharmaceutics. MDPI. 2021; 13

24. Savjani KT, Gajjar AK, Savjani JK. Drug Solubility: Importance and Enhancement Techniques. ISRN Pharm. 2012; 2012: 1–10.

25. Jain P, Goel A, Sharma S, Parmar M. International Journal Of Pharma Professional’s Research Solubility Enhancement Techniques With Special Emphasis On Hydrotrophy [Internet]. 2010; 1. Available from: www.ijppronline.com

26. Lee MK. Liposomes for enhanced bioavailability of water-insoluble drugs: In vivo evidence and recent approaches. Pharmaceutics. MDPI AG. 2020; 12

27. Rupvate SR, Gangurde SA, Adavadkar PR, Ukhade SS, Lale SS. Solid self-emulsifying pellets: Solubility enhancement for oral delivery of poorly soluble BCS Class II drug. Journal of Drug Delivery and Therapeutics. 2022; 12(4-S): 171–6.

28. 2022-Solubility Enhancement Techniques of Anti-Microbial Agents of BCS Class II and IV Drugs.

29. Jagtap S, Magdum C, Jadge D, Jagtap R. Solubility Enhancement Technique: A Review.

30. Samineni R, Chimakurthy J, Konidala S. Emerging Role of Biopharmaceutical Classification and Biopharmaceutical Drug Disposition System in Dosage form Development: A Systematic Review. Vol. 19, Turkish Journal of Pharmaceutical Sciences. Turkish Pharmacists Association. 2022. 706–13.

31. Khatri H, Hussain S, Tyagi S, Sadique Hussain M. Solubility Enhancement Techniques: An Overview. Certified Journal│ Hussain et al World Journal of Pharmaceutical Research [Internet]. 2022;11. Available from: www.wjpr.net

32. Rupvate SR, Gangurde SA, Adavadkar PR, Ukhade SS, Lale SS. Solid self-emulsifying pellets: Solubility enhancement for oral delivery of poorly soluble BCS Class II drug. Journal of Drug Delivery and Therapeutics. 2022; 12(4-S): 171–6.

33. Mahapatra APK, Patil V, Patil R. Solubility Enhancement of Poorly soluble Drugs by using Novel Techniques : A Comprehensive Review. Int J Pharmtech Res. 2020; 13(2): 80–93.

34. S. Belsarkar A, N. Patil R, B. Parekar P, T. Sul K, V. More A. A Brief Review on Solubility Enhancement Techniques with Drug and Polymer. International Journal of Current Science Research and Review [Internet]. 2022; 5(12). Available from: https://ijcsrr.org/single-view/?id=8271&pid=8124

35. Arun Kumar MS, Rajesh M, Subramanian L. Solubility enhancement techniques: A comprehensive review. World Journal of Biology Pharmacy and Health Sciences. 2023; 13(3): 414–149.

36. Kumari L, Choudhari Y, Patel P, Gupta G Das, Singh D, Rosenholm JM, et al. Advancement in Solubilization Approaches: A Step towards Bioavailability Enhancement of Poorly Soluble Drugs. Life. MDPI. 2023; 13.

37. Cb G, Al B, Ab G. A Concise Review on Methods of Solubility Enhancement. Review Article Int J Pharm Sci [Internet]. 2020 Available from: https://ipharmsciencia.edwiserinternational.com/home.php

38. Alik Kumar L, Pattnaik G, Satapathy BS, Patro CS, Naik S, Dash AK, et al. Solubility Enhancement Techniques: Updates and Prospectives. Journal of Pharmaceutical Negative Results. 2022; 13

39. Ainurofiq A, Putro DS, Ramadhani DA, Putra GM, Do Espirito Santo LDC. A review on solubility enhancement methods for poorly water-soluble drugs. Vol. 10, Journal of Reports in Pharmaceutical Sciences. Wolters Kluwer Medknow Publications. 2021: 137–47.

40. Bhalani D V., Nutan B, Kumar A, Singh Chandel AK. Bioavailability Enhancement Techniques for Poorly Aqueous Soluble Drugs and Therapeutics. Biomedicines. MDPI; 2022;10

41. Jain P, Goel A, Sharma S, Parmar M. International Journal Of Pharma Professional’s Research Solubility Enhancement Techniques With Special Emphasis On Hydrotrophy [Internet]. 2010; 1. Available from: www.ijppronline.com

42. Kumar A, Sahoo SK, Padhee K, Pal P, Kochar S, Satapathy A, et al. Pharmacie Globale International Journal Of Comprehensive Pharmacy Review On Solubility Enhancement Techniques For Hydrophobic DRUGS [Internet]. Pharmacie Globale (IJCP). 2011. Available from: www.pharmacie-globale.info

43. Solubility Enhancement Techniques of Anti-Microbial Agents of BCS Class II and IV Drugs. 2022

44. Aishwarya M, Karande A, Amol M, Deshmukh S. Ms. Aishwarya Audumbar Karande et al, Review on Inclusion Complexation: A Technique to Enhance the Solubility of Poorly Water Soluble Drug Review on Inclusion Complexation: A Technique to Enhance the Solubility of Poorly Water Soluble Drug [Internet]. Vol. 2, IJRPAS. Available from: https://idealpublication.in/ijrpas/

45. Hussein M, An /, Ahmed IK. An Overview of Technique for Solubility of Poorly Water Soluble Drugs. 2022; 20: 8027–38. Available from: www.neuroquantology.com

46. Tran P, Pyo YC, Kim DH, Lee SE, Kim JK, Park JS. Overview of the manufacturing methods of solid dispersion technology for improving the solubility of poorly water-soluble drugs and application to anticancer drugs. Pharmaceutics. MDPI AG; 2019; 11.

47. R GN, M SM, R VS, M GN. Review: Solubility Enhancement by Advance Techniques-Lyophilization, Spray Drying And Rotary Evaporator Method. Gade et al World Journal of Pharmaceutical Research [Internet]. 2020; 9: 1127. Available from: www.wjpr.net

48. Vimalson DC, Parimalakrishnan S, Jeganathan NS, Anbazhagan S. Techniques to Enhance Solubility of Hydrophobic Drugs: An Overview. Asian Journal of Pharmaceutics.

49. Jadhav SP, Singh SK, Chawra HS. Review on Nanosuspension as a Novel Method for Solubility and Bioavailability Enhancement of Poorly Soluble Drugs. Advances in Pharmacology and Pharmacy. 2023; 11(2): 117–30.

50. Pawar SR, Barhate SD. Solubility enhancement (Solid Dispersions) novel boon to increase bioavailability. Journal of Drug Delivery and Therapeutics. 2019; 9(2): 583–90.

51. Jagtap S, Magdum C, Jadge D, Jagtap R. Solubility Enhancement Technique: A Review. Journal of Pharmaceutical Sciences and Research. 2018; 10(9): 2205-2211.

52. Devhare LD, Kore PK. A Recent Review on Bioavailability and Solubility Enhancement of Poorly Soluble Drugs by Physical and Chemical Modifications [Internet]. Available from: https://ssrn.com/abstract=4455504

53. Kumar P, Singh C. A Study on Solubility Enhancement Methods for Poorly Water Soluble Drugs. Am J Pharmacol Sci. 2013; 1(4): 67–73.

54. Gupta S, Sawarkar S, Ravikumar P. Solubility Enhancement Of Poorly Water Soluble Protease Inhibitor. Int J Pharm Sci Res [Internet]. 2016; 7(1): 252–8. Available from: http://dx.doi.org/10.13040/IJPSR.0975-8232.7

55. Budiman A, Rusdin A, Aulifa DL. Current Techniques of Water Solubility Improvement for Antioxidant Compounds and Their Correlation with Its Activity: Molecular Pharmaceutics. Antioxidants. MDPI; 2023; 12.

56. Kesarwani P, Rastogi S, Bhalla V, Arora V. Solubility Enhancement Of Poorly Water Soluble Drugs: A Review. Int J Pharm Sci Res [Internet]. 2014; 5(8): 3123. Available from: http://dx.doi.org/10.13040/IJPSR.0975-8232.5

57. Kesharwani SS, Jain V, Dey S, Sharma S, Mallya P, Kumar VA. An overview of advanced formulation and nanotechnology-based approaches for solubility and bioavailability enhancement of silymarin. Vol. 60, Journal of Drug Delivery Science and Technology. Editions de Sante. 2020.

Received on 14.02.2024 Revised on 15.08.2024

Accepted on 19.11.2024 Published on 02.08.2025

Available online from August 08, 2025

Research J. Pharmacy and Technology. 2025;18(8):3987-3994.

DOI: 10.52711/0974-360X.2025.00573

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